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Giovanna ZAMBONI

Professore Associato
Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze sede ex-Neuroscienze

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2022 - Automated Detection of Candidate Subjects With Cerebral Microbleeds Using Machine Learning [Articolo su rivista]
Sundaresan, V.; Arthofer, C.; Zamboni, G.; Dineen, R. A.; Rothwell, P. M.; Sotiropoulos, S. N.; Auer, D. P.; Tozer, D. J.; Markus, H. S.; Miller, K. L.; Dragonu, I.; Sprigg, N.; Alfaro-Almagro, F.; Jenkinson, M.; Griffanti, L.

Cerebral microbleeds (CMBs) appear as small, circular, well defined hypointense lesions of a few mm in size on T2*-weighted gradient recalled echo (T2*-GRE) images and appear enhanced on susceptibility weighted images (SWI). Due to their small size, contrast variations and other mimics (e.g., blood vessels), CMBs are highly challenging to detect automatically. In large datasets (e.g., the UK Biobank dataset), exhaustively labelling CMBs manually is difficult and time consuming. Hence it would be useful to preselect candidate CMB subjects in order to focus on those for manual labelling, which is essential for training and testing automated CMB detection tools on these datasets. In this work, we aim to detect CMB candidate subjects from a larger dataset, UK Biobank, using a machine learning-based, computationally light pipeline. For our evaluation, we used 3 different datasets, with different intensity characteristics, acquired with different scanners. They include the UK Biobank dataset and two clinical datasets with different pathological conditions. We developed and evaluated our pipelines on different types of images, consisting of SWI or GRE images. We also used the UK Biobank dataset to compare our approach with alternative CMB preselection methods using non-imaging factors and/or imaging data. Finally, we evaluated the pipeline's generalisability across datasets. Our method provided subject-level detection accuracy > 80% on all the datasets (within-dataset results), and showed good generalisability across datasets, providing a consistent accuracy of over 80%, even when evaluated across different modalities.

2022 - Eliciting Implicit Awareness in Alzheimer’s Disease and Mild Cognitive Impairment: A Task-Based Functional MRI Study [Articolo su rivista]
Tondelli, M.; Benuzzi, F.; Ballotta, D.; Molinari, M. A.; Chiari, A.; Zamboni, G.

Background: Recent models of anosognosia in dementia have suggested the existence of an implicit component of self-awareness about one’s cognitive impairment that may remain preserved and continue to regulate behavioral, affective, and cognitive responses even in people who do not show an explicit awareness of their difficulties. Behavioral studies have used different strategies to demonstrate implicit awareness in patients with anosognosia, but no neuroimaging studies have yet investigated its neural bases. Methods: Patients with amnestic mild cognitive impairment and dementia due to Alzheimer’s disease underwent functional magnetic resonance imaging (fMRI) during the execution of a color-naming task in which they were presented with neutral, negative, and dementia-related words (Dementia-Related Emotional Stroop). Results: Twenty-one patients were recruited: 12 were classified as aware and 9 as unaware according to anosognosia scales (based on clinical judgment and patient-caregiver discrepancy). Behavioral results showed that aware patients took the longest time to process dementia-related words, although differences between word types were not significant, limiting interpretation of behavioral results. Imaging results showed that patients with preserved explicit awareness had a small positive differential activation of the posterior cingulate cortex (PCC) for the dementia-related words condition compared to the negative words, suggesting attribution of emotional valence to both conditions. PCC differential activation was instead negative in unaware patients, i.e., lower for dementia-related words relative to negative-words. In addition, the more negative the differential activation, the lower was the Stroop effect measuring implicit awareness. Conclusion: Posterior cingulate cortex preserved response to dementia-related stimuli may be a marker of preserved implicit self-awareness.

2022 - How long does it take to diagnose young-onset dementia? A comparison with late-onset dementia [Articolo su rivista]
Chiari, A.; Tondelli, M.; Galli, C.; Carbone, C.; Fiondella, L.; Salemme, S.; Vinceti, G.; Bedin, R.; Molinari, M. A.; Zamboni, G.

Introduction: Dementia occurring in young people may be difficult to recognize. We compared the time to diagnosis between young- (YOD, age < 65) and late-onset dementia (LOD). Methods: Time between the onset of symptoms and the diagnosis was measured in YOD and LOD patients consecutively seen in a cognitive neurology clinic. Multivariable regression analyses were performed to identify determinants of time to diagnosis. Results: Mean time to diagnosis in 95 YOD patients was 11.2 months longer than in 73 LOD patients (p = 0.022). The delay was driven by a longer time taken by YOD patients to be seen in the specialist centre, which in turn was related to the presence of language disturbances and coexisting depression. Discussion: Young people take longer than elderly people to receive a dementia diagnosis because they take longer to be referred to dementia specialist centres. More awareness on YOD is needed in primary care and the public.

2022 - Implementation of preventive and predictive BRCA testing in patients with breast, ovarian, pancreatic, and prostate cancer: a position paper of Italian Scientific Societies [Articolo su rivista]
Russo, A.; Incorvaia, L.; Capoluongo, E.; Tagliaferri, P.; Gori, S.; Cortesi, L.; Genuardi, M.; Turchetti, D.; De Giorgi, U.; Di Maio, M.; Barberis, M.; Dessena, M.; Del Re, M.; Lapini, A.; Luchini, C.; Jereczek-Fossa, B. A.; Sapino, A.; Cinieri, S.; Beretta, G.; Bella, M. A.; Bracarda, S.; Colombo, N.; Conteduca, V.; Del Mastro, L.; Galvano, A.; Gristina, V.; Guarneri, V.; La Verde, N.; Lorusso, D.; Marchetti, P.; Normanno, N.; Ottini, L.; Pensabene, M.; Pignata, S.; Procopio, G.; Ricevuto, E.; Silvestris, N.; Tassone, P.; Tucci, M.; Donato, V.; Carrara, S.; Paiella, S.; Gentilini, O.; Gunelli, R.; Nicolis, F.; Buttitta, F.; Colecchia, M.; Fassan, M.; Malapelle, U.; Marchetti, A.; Marchio, C.; Scarpa, A.; Truini, M.; Zamboni, G.; Gion, M.; Trevisiol, C.; Gronchi, A.; Danesi, R.; Di Marco, V.; Carrera, P.; Ghiorzo, P.; Pasini, B.; Varesco, L.; Artibani, W.; Ludovico, G.; Campanella, O.; Vatrano, S.; Tagliafico, E.

2022 - Predictive value of phospho-tau/total-tau ratio in amyloid-negative Mild Cognitive Impairment [Articolo su rivista]
Tondelli, M.; Salemme, S.; Vinceti, G.; Bedin, R.; Trenti, T.; Molinari, M. A.; Chiari, A.; Zamboni, G.

Background: In patients with Mild Cognitive Impairment and normal biomarkers of amyloid-β deposition, prognostication remains challenging. Methods: We aimed at identifying clinical features, patterns of brain atrophy, and risk of subsequent conversion to dementia in a clinical cohort of consecutive patients with Mild Cognitive Impairment and normal CSF amyloid-β1-42 presenting to our Cognitive Neurology Clinic who were followed prospectively over an average of 25 months. We stratified them as Converters/Non-Converters to dementia based on clinical follow-up and compared baseline clinical features, CSF biomarkers, and pattern of atrophy on MRI data between groups. Results: Among 111 eligible patients (mean age 65,61 years; 56,8% were male), 41 patients developed a clinical diagnosis of dementia. Subjects with low baseline p/t-tau had twofold risk of future conversion compared to high p/t-tau ratio subjects (HR = 2.0, p = 0.026). When stratifying converters according to CSF p/t-tau ratio cut off value (0,17), those with values lower than the cut-off had significantly more MRI atrophy at baseline relative to Non-Converters in limbic structures. Conclusion: In Mild Cognitive Impairment patients with negative CSF amyloid biomarker, CSF p/t-tau ratio may be useful to identify those at greater risk of subsequent conversion, possibly because of TDP43-related underlying pathology.

2022 - Pure word deafness: a case report of an atypical manifestation of Alzheimer’s disease [Articolo su rivista]
Salemme, S.; Benuzzi, F.; Fiondella, L.; Carbone, C.; Vinceti, G.; Magarelli, S.; Molinari, M. A.; Malagoli, M.; Zamboni, G.; Chiari, A.

Auditory agnosia refers to the impairments in sound recognition despite intact hearing and written language abilities. When auditory agnosia is specific to spoken language, it can be indicated as pure word deafness (PWD), which is characterized by the isolated difficulty in understanding spoken language, despite preserved reading comprehension, recognition of nonverbal sounds, and production of written and spoken language.

2022 - Selenium Species in Cerebrospinal Fluid and Hippocampal Volume among Individuals with Mild Cognitive Impairment [Articolo su rivista]
Vinceti, Marco; Balboni, Erica; Filippini, Tommaso; Wise, Lauren A; Nocetti, Luca; Eichmüller, Marcel; Zamboni, Giovanna; Chiari, Annalisa; Michalke, Bernhard

2022 - Selenoprotein P Concentrations in the Cerebrospinal Fluid and Serum of Individuals Affected by Amyotrophic Lateral Sclerosis, Mild Cognitive Impairment and Alzheimer’s Dementia [Articolo su rivista]
Urbano, Teresa; Vinceti, Marco; Mandrioli, Jessica; Chiari, Annalisa; Filippini, Tommaso; Bedin, Roberta; Tondelli, Manuela; Simonini, Cecilia; Zamboni, Giovanna; Shimizu, Misaki; Saito, Yoshiro

Selenoprotein P, a selenium-transporter protein, has been hypothesized to play a role in the etiology of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's dementia (AD). However, data in humans are scarce and largely confined to autoptic samples. In this case-control study, we determined selenoprotein P concentrations in both the cerebrospinal fluid (CSF) and the serum of 50 individuals diagnosed with ALS, 30 with AD, 54 with mild cognitive impairment (MCI) and of 30 controls, using sandwich enzyme-linked immunosorbent assay (ELISA) methods. We found a positive and generally linear association between CSF and serum selenoprotein P concentrations in all groups. CSF selenoprotein P and biomarkers of neurodegeneration were positively associated in AD, while for MCI, we found an inverted-U-shaped relation. CSF selenoprotein P concentrations were higher in AD and MCI than in ALS and controls, while in serum, the highest concentrations were found in MCI and ALS. Logistic and cubic spline regression analyses showed an inverse association between CSF selenoprotein P levels and ALS risk, and a positive association for AD risk, while an inverted-U-shaped relation with MCI risk emerged. Conversely, serum selenoprotein P concentrations were positively associated with risk of all conditions but only in their lower range. Overall, these findings indicate some abnormalities of selenoprotein P concentrations in both the central nervous system and blood associated with ALS and neurocognitive disorders, though in different directions. These alterations may reflect either phenomena of etiologic relevance or disease-induced alterations of nutritional and metabolic status.

2022 - The impact of transfer learning on 3D deep learning convolutional neural network segmentation of the hippocampus in mild cognitive impairment and Alzheimer disease subjects [Articolo su rivista]
Balboni, E.; Nocetti, L.; Carbone, C.; Dinsdale, N.; Genovese, M.; Guidi, G.; Malagoli, M.; Chiari, A.; Namburete, A. I. L.; Jenkinson, M.; Zamboni, G.

Research on segmentation of the hippocampus in magnetic resonance images through deep learning convolutional neural networks (CNNs) shows promising results, suggesting that these methods can identify small structural abnormalities of the hippocampus, which are among the earliest and most frequent brain changes associated with Alzheimer disease (AD). However, CNNs typically achieve the highest accuracy on datasets acquired from the same domain as the training dataset. Transfer learning allows domain adaptation through further training on a limited dataset. In this study, we applied transfer learning on a network called spatial warping network segmentation (SWANS), developed and trained in a previous study. We used MR images of patients with clinical diagnoses of mild cognitive impairment (MCI) and AD, segmented by two different raters. By using transfer learning techniques, we developed four new models, using different training methods. Testing was performed using 26% of the original dataset, which was excluded from training as a hold-out test set. In addition, 10% of the overall training dataset was used as a hold-out validation set. Results showed that all the new models achieved better hippocampal segmentation quality than the baseline SWANS model (ps <.001), with high similarity to the manual segmentations (mean dice [best model] = 0.878 ± 0.003). The best model was chosen based on visual assessment and volume percentage error (VPE). The increased precision in estimating hippocampal volumes allows the detection of small hippocampal abnormalities already present in the MCI phase (SD = [3.9 ± 0.6]%), which may be crucial for early diagnosis.

2022 - Why can spontaneous intracranial hypotension cause behavioral changes? A case report and multimodality neuroimaging comparison with frontotemporal dementia [Articolo su rivista]
Carbone, Chiara; Bardi, Elisa; Corni, Maria Giulia; Balboni, Erica; Filippini, Nicola; Fiondella, Luigi; Salemme, Simone; Vinceti, Giulia; Molinari, Maria Angela; Tondelli, Manuela; Chiari, Annalisa; Zamboni, Giovanna

Frontotemporal Brain Sagging Syndrome (FBSS) is a rare condition characterized by the presence of spontaneous intracranial hypotension associated with behavioural disturbances mimicking the behavioural variant of Frontotemporal dementia (bvFTD). It has been suggested that behavioural symptoms are caused by damage to the connectivity of the frontal lobes due to the brain sagging. However, no studies have directly explored brain connectivity in patients with FBSS. Here, we report a new case of FBSS with persistent behavioural disturbances, whom we compared to 20 patients with bvFTD and to 13 cognitively healthy controls using Magnetic Resonance Imaging (MRI). We explored differences related to grey matter (GM) volume with voxel-based morphometry, functional connectivity with seed-based analysis, and white matter (WM) microstructural integrity with tract-based spatial statistics. We found that the FBSS patient, like the controls, had greater GM volume relative to the bvFTD patients. Moreover, the FBSS patient had greater functional connectivity from a left inferior frontal gyrus seed than both the bvFTD patients and healthy controls groups in dorsolateral frontal areas. Like the bvFTD group the FBSS patient had decreased WM integrity relative to the controls, especially in the posterior part of the corpus callosum, and the magnitude of these abnormalities correlated with measures of apathy across the FBSS and bvFTD patients. Our results suggest that behavioural changes associated with SIH are mainly due to altered WM connectivity.

2021 - Anosognosia in Early- and Late-Onset Dementia and Its Association With Neuropsychiatric Symptoms [Articolo su rivista]
Tondelli, M.; Galli, C.; Vinceti, G.; Fiondella, L.; Salemme, S.; Carbone, C.; Molinari, M. A.; Chiari, A.; Zamboni, G.

Background: The symptom anosognosia or unawareness of disease in dementia has mainly been studied in patients with late-onset dementia (LOD, ≥65 years), whereas little is known on whether it is also present in patients with early-onset dementia (EOD, <65 years). We aimed at investigating differences in anosognosia between LOD and EOD, by also studying its association with different clinical variants of EOD and the presence of neuropsychiatric symptoms. Methods: A total of 148 patients, 91 EOD and 57 LOD, were recruited and underwent extended clinical assessment and caregiver interview that included questionnaires aimed at measuring anosognosia and neuropsychiatric symptoms. Differences in anosognosia between EOD and LOD and between subgroups with different clinical variants were investigated, as well as correlation between anosognosia and neuropsychiatric symptoms. A regression analysis was applied to explore the association between anosognosia and development of neuropsychiatric symptoms during disease progression. Results: Median levels of anosognosia were not significantly different between EOD and LOD. Anosognosia increased overtime with disease progression and was higher in frontotemporal dementia patients or, more precisely, in frontotemporal dementia and Alzheimer's disease variants associated with involvement of the frontal lobes. Higher levels of early anosognosia were associated with higher frequency and severity of subsequent neuropsychiatric symptoms, in particular apathy, later in the course of the disease. Conclusion: Anosognosia is a frequent symptom of EOD, occurring in 94.5% of all-cause EOD, and it is associated with higher risk of developing neuropsychiatric symptoms during disease progression. Recognising anosognosia may be helpful for clinicians and families to reduce diagnostic delay and improve disease managment.

2021 - Atrial fibrillation and other risk factors for early-onset dementia: an Italian case-control study [Abstract in Rivista]
Filippini, T; Adani, G; Garuti, C; Malavolti, M; Vinceti, G; Zamboni, G; Tondelli, M; Galli, C; Costa, M; Chiari, A; Vinceti, M

2021 - Comparison of domain adaptation techniques for white matter hyperintensity segmentation in brain MR images [Articolo su rivista]
Sundaresan, V.; Zamboni, G.; Dinsdale, N. K.; Rothwell, P. M.; Griffanti, L.; Jenkinson, M.

Robust automated segmentation of white matter hyperintensities (WMHs) in different datasets (domains) is highly challenging due to differences in acquisition (scanner, sequence), population (WMH amount and location) and limited availability of manual segmentations to train supervised algorithms. In this work we explore various domain adaptation techniques such as transfer learning and domain adversarial learning methods, including domain adversarial neural networks and domain unlearning, to improve the generalisability of our recently proposed triplanar ensemble network, which is our baseline model. We used datasets with variations in intensity profile, lesion characteristics and acquired using different scanners. For the source domain, we considered a dataset consisting of data acquired from 3 different scanners, while the target domain consisted of 2 datasets. We evaluated the domain adaptation techniques on the target domain datasets, and additionally evaluated the performance on the source domain test dataset for the adversarial techniques. For transfer learning, we also studied various training options such as minimal number of unfrozen layers and subjects required for fine-tuning in the target domain. On comparing the performance of different techniques on the target dataset, domain adversarial training of neural network gave the best performance, making the technique promising for robust WMH segmentation.

2021 - Corrigendum to: Splenial white matter integrity is associated with memory impairments in posterior cortical atrophy [Articolo su rivista]
Julie¨tte Overman, Margot; Zamboni, Giovanna; Butler and Samrah Ahmed, Christopher

[This corrects the article DOI: 10.1093/braincomms/fcab060.].

2021 - Cortical diffusivity investigation in posterior cortical atrophy and typical Alzheimer’s disease [Articolo su rivista]
Torso, M.; Ahmed, S.; Butler, C.; Zamboni, G.; Jenkinson, M.; Chance, S.

Objectives: To investigate the global cortical and regional quantitative features of cortical neural architecture in the brains of patients with posterior cortical atrophy (PCA) and typical Alzheimer’s disease (tAD) compared with elderly healthy controls (HC). Methods: A novel diffusion MRI method, that has been shown to correlate with minicolumnar organization changes in the cerebral cortex, was used as a surrogate of neuropathological changes in dementia. A cohort of 15 PCA patients, 23 tAD and 22 healthy elderly controls (HC) were enrolled to investigate the changes in cortical diffusivity among groups. For each subject, 3 T MRI T1-weighted images and diffusion tensor imaging (DTI) scans were analysed to extract novel cortical DTI derived measures (AngleR, PerpPD and ParlPD). Receiver operating characteristics (ROC) curve analysis and the area under the curve (AUC) were used to assess the group discrimination capability of the method. Results: The results showed that the global cortical DTI derived measures were able to detect differences, in both PCA and tAD patients compared to healthy controls. The AngleR was the best measure to discriminate HC from tAD (AUC = 0.922), while PerpPD was the best measure to discriminate HC from PCA (AUC = 0.961). Finally, the best global measure to differentiate the two patient groups was ParlPD (AUC = 0.771). The comparison between PCA and tAD patients revealed a different pattern of damage within the AD spectrum and the regional comparisons identified significant differences in key regions including parietal and temporal lobe cortical areas. The best AUCs were shown by PerpPD right lingual cortex (AUC = 0.856), PerpPD right superior parietal cortex (AUC = 0.842) and ParlPD right lateral occipital cortex (AUC = 0.826). Conclusions: Diagnostic group differences were found, suggesting that the new cortical DTI analysis method may be useful to investigate cortical changes in dementia, providing better characterization of neurodegeneration, and potentially aiding differential diagnosis and prognostic accuracy.

2021 - Determinants of Caregiver Burden in Early-Onset Dementia [Articolo su rivista]
Chiari, Annalisa; Pistoresi, Barbara; Galli, Chiara; Tondelli, Manuela; Vinceti, Giulia; Molinari, Maria Angela; Addabbo, Tindara; Zamboni, Giovanna

Caregivers of patients with early-onset dementia (EOD) experience high levels of burden, which is known to be affected by caregivers’ psychological features as well as by patients’ and caregivers’ demographical and social variables. Although potential clinical, demographical, and social determinants have been separately examined, it is not known how they reciprocally interact. Methods: Ninety- two consecutive patient-caregiver dyads were recruited from the Cognitive Neurology Clinics of Modena, Northern Italy. Caregivers were asked to fill in questionnaires regarding their burden, psychological distress, and family economic status. Data were analyzed with multivariable regression models and then entered in a mediation model. Results: Caregiver burden was positively related to female caregiver sex, spousal relationship to the patient, severity of patient’s behavioral symptoms, diagnostic delay, and financial distress of the family. It was negatively related to disease duration, patient’s education, region of birth, caregiver age, number of caregiver’s days off work, number of offspring, and caregiver perception of patient’s quality of life. While the effect of caregiver age, diagnostic delay, and of proxies of family or social network directly impacted on caregiver’s burden, the effect of patient’s disease duration, being a wife caregiver, financial distress, and number of caregiver’s days off work was entirely mediated by the level of caregiver psychological distress. Conclusions: Both direct actions (such as increasing social networks and shortening diagnostic delay) and indirect actions aimed at reducing psychological distress (such as increasing the number of caregiver’s days off work and financial support) should be planned to reduce caregiver’s burden.

2021 - Integrating large-scale neuroimaging research datasets: Harmonisation of white matter hyperintensity measurements across Whitehall and UK Biobank datasets [Articolo su rivista]
Bordin, V.; Bertani, I.; Mattioli, I.; Sundaresan, V.; McCarthy, P.; Suri, S.; Zsoldos, E.; Filippini, N.; Mahmood, A.; Melazzini, L.; Lagana, M. M.; Zamboni, G.; Singh-Manoux, A.; Kivimaki, M.; Ebmeier, K. P.; Baselli, G.; Jenkinson, M.; Mackay, C. E.; Duff, E. P.; Griffanti, L.

Large scale neuroimaging datasets present the possibility of providing normative distributions for a wide variety of neuroimaging markers, which would vastly improve the clinical utility of these measures. However, a major challenge is our current poor ability to integrate measures across different large-scale datasets, due to inconsistencies in imaging and non-imaging measures across the different protocols and populations. Here we explore the harmonisation of white matter hyperintensity (WMH) measures across two major studies of healthy elderly populations, the Whitehall II imaging sub-study and the UK Biobank. We identify pre-processing strategies that maximise the consistency across datasets and utilise multivariate regression to characterise study sample differences contributing to differences in WMH variations across studies. We also present a parser to harmonise WMH-relevant non-imaging variables across the two datasets. We show that we can provide highly calibrated WMH measures from these datasets with: (1) the inclusion of a number of specific standardised processing steps; and (2) appropriate modelling of sample differences through the alignment of demographic, cognitive and physiological variables. These results open up a wide range of applications for the study of WMHs and other neuroimaging markers across extensive databases of clinical data.

2021 - Splenial white matter integrity is associated with memory impairments in posterior cortical atrophy [Articolo su rivista]
Overman, M. J.; Zamboni, G.; Butler, C.; Ahmed, S.

Posterior cortical atrophy is an atypical form of Alzheimer's disease characterized by visuospatial impairments and predominant tissue loss in the posterior parieto-occipital and temporo-occipital cortex. Whilst episodic memory is traditionally thought to be relatively preserved in posterior cortical atrophy, recent work indicates that memory impairments form a common clinical symptom in the early stages of the disease. Neuroimaging studies suggest that memory dysfunction in posterior cortical atrophy may originate from atrophy and functional hypoconnectivity of parietal cortex. The structural connectivity patterns underpinning these memory impairments, however, have not been investigated. This line of inquiry is of particular interest, as changes in white matter tracts of posterior cortical atrophy patients have been shown to be more extensive than expected based on posterior atrophy of grey matter. In this cross-sectional diffusion tensor imaging MRI study, we examine the relationship between white matter microstructure and verbal episodic memory in posterior cortical atrophy. We assessed episodic memory performance in a group of posterior cortical atrophy patients (n = 14) and a group of matched healthy control participants (n = 19) using the Free and Cued Selective Reminding Test with Immediate Recall. Diffusion tensor imaging measures were obtained for 13 of the posterior cortical atrophy patients and a second control group of 18 healthy adults. Patients and healthy controls demonstrated similar memory encoding performance, indicating that learning of verbal information was preserved in posterior cortical atrophy. However, retrieval of verbal items was significantly impaired in the patient group compared with control participants. As expected, tract-based spatial statistics analyses showed widespread reductions of white matter integrity in posterior cortical regions of patients compared with healthy adults. Correlation analyses indicated that poor verbal retrieval in the patient group was specifically associated with microstructural damage of the splenium of the corpus callosum. Post-hoc tractography analyses in healthy controls demonstrated that this splenial region was connected to thalamic radiations and the retrolenticular part of the internal capsule. These results provide insight into the brain circuits that underlie memory impairments in posterior cortical atrophy. From a cognitive perspective, we propose that the association between splenial integrity and memory dysfunction could arise indirectly via disruption of attentional processes. We discuss implications for the clinical phenotype and development of therapeutic aids for cognitive impairment in posterior cortical atrophy.

2021 - Triplanar ensemble U-Net model for white matter hyperintensities segmentation on MR images [Articolo su rivista]
Sundaresan, V.; Zamboni, G.; Rothwell, P. M.; Jenkinson, M.; Griffanti, L.

White matter hyperintensities (WMHs) have been associated with various cerebrovascular and neurodegenerative diseases. Reliable quantification of WMHs is essential for understanding their clinical impact in normal and pathological populations. Automated segmentation of WMHs is highly challenging due to heterogeneity in WMH characteristics between deep and periventricular white matter, presence of artefacts and differences in the pathology and demographics of populations. In this work, we propose an ensemble triplanar network that combines the predictions from three different planes of brain MR images to provide an accurate WMH segmentation. In the loss functions the network uses anatomical information regarding WMH spatial distribution in loss functions, to improve the efficiency of segmentation and to overcome the contrast variations between deep and periventricular WMHs. We evaluated our method on 5 datasets, of which 3 are part of a publicly available dataset (training data for MICCAI WMH Segmentation Challenge 2017 - MWSC 2017) consisting of subjects from three different cohorts, and we also submitted our method to MWSC 2017 to be evaluated on the unseen test datasets. On evaluating our method separately in deep and periventricular regions, we observed robust and comparable performance in both regions. Our method performed better than most of the existing methods, including FSL BIANCA, and on par with the top ranking deep learning methods of MWSC 2017.

2020 - Detection of Alzheimer's Disease using cortical diffusion tensor imaging [Articolo su rivista]
Torso, M.; Bozzali, M.; Zamboni, G.; Jenkinson, M.; Chance, S. A.

The aim of this research was to test a novel in-vivo brain MRI analysis method that could be used in clinical cohorts to investigate cortical architecture changes in patients with Alzheimer's Disease (AD). Three cohorts of patients with probable AD and healthy volunteers were used to assess the results of the method. The first group was used as the “Discovery” cohort, the second as the “Test” cohort and the last “ATN” (Amyloid, Tau, Neurodegeneration) cohort was used to test the method in an ADNI 3 cohort, comparing to amyloid and Tau PET. The method can detect altered quality of cortical grey matter in AD patients, providing an additional tool to assess AD, distinguishing between these and healthy controls with an accuracy range between good and excellent. These new measurements could be used within the “ATN” framework as an index of cortical microstructure quality and a marker of Neurodegeneration. Further development may aid diagnosis, patient selection, and quantification of the “Neurodegeneration” component in response to therapies in clinical trials.

2020 - Dietary Habits and Risk of Early-Onset Dementia in an Italian Case-Control Study [Articolo su rivista]
Filippini, Tommaso; Adani, Giorgia; Malavolti, Marcella; Garuti, Caterina; Cilloni, Silvia; Vinceti, Giulia; Zamboni, Giovanna; Tondelli, Manuela; Galli, Chiara; Costa, Manuela; Chiari, Annalisa; Vinceti, Marco

Risk of early-onset dementia (EOD) might be modified by environmental factors and lifestyles, including diet. The aim of this study is to evaluate the association between dietary habits and EOD risk. We recruited 54 newly-diagnosed EOD patients in Modena (Northern Italy) and 54 caregivers as controls. We investigated dietary habits through a food frequency questionnaire, assessing both food intake and adherence to dietary patterns, namely the Greek-Mediterranean, the Dietary Approaches to Stop Hypertension (DASH), and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets. We modeled the relation between dietary factors and risk using the restricted cubic spline regression analysis. Cereal intake showed a U-shaped relation with EOD, with risk increasing above 350 g/day. A high intake (>400 g/day) of dairy products was also associated with excess risk. Although overall fish and seafood consumption showed no association with EOD risk, we found a U-shaped relation with preserved/tinned fish, and an inverse relation with other fish. Similarly, vegetables (especially leafy) showed a strong inverse association above 100 g/day, as did citrus and dry fruits. Overall, sweet consumption was not associated with EOD risk, while dry cake and ice-cream showed a positive relation and chocolate products an inverse one. For beverages, we found no relation with EOD risk apart from a U-shaped relation for coffee consumption. Concerning dietary patterns, EOD risk linearly decreased with the increasing adherence to the MIND pattern. On the other hand, an inverse association for the Greek-Mediterranean and DASH diets emerged only at very high adherence levels. To the best of our knowledge, this is the first study that explores the association between dietary factors and EOD risk, and suggests that adherence to the MIND dietary pattern may decrease such risk.

2020 - Environmental Risk Factors for Early-Onset Alzheimer's Dementia and Frontotemporal Dementia: A Case-Control Study in Northern Italy [Articolo su rivista]
Adani, G.; Filippini, T.; Garuti, C.; Malavolti, M.; Vinceti, G.; Zamboni, G.; Tondelli, M.; Galli, C.; Costa, M.; Vinceti, M.; Chiari, A.

Background: Early-onset dementia (EOD) is defined as dementia with symptom onset before 65 years. The role of environmental risk factors in the etiology of EOD is still undefined. We aimed at assessing the role of environmental risk factors in EOD etiology, taking into account its different clinical types. Methods: Using a case-control study, we recruited all EOD cases referred to Modena hospitals from 2016 to 2019, while the referent population was drawn from cases' caregivers. We investigated residential history, occupational and environmental exposures to chemicals and lifestyle behaviors through a self-administered questionnaire. We computed the odds ratios of EOD risk (overall and restricting to the Alzheimer's dementia (AD) or frontotemporal dementia (FTD) diagnoses) and the corresponding 95% confidence intervals using an unconditional logistic regression model. Results: Fifty-eight EOD patients (19 FTD and 32 AD) and 54 controls agreed to participate. Most of the investigated exposures, such as occupational exposure to aluminum, pesticides, dyes, paints or thinners, were associated with an increased odds ratio (OR) for FTD but not for AD. Long-term use of selenium-containing dietary supplements was associated with increased OR for EOD and, particularly, for FTD. For both EOD forms, smoking and playing football showed an increased odds ratio, while cycling was associated with increased risk only in FTD. Overall sports practice appeared to be a protective factor for both types. Conclusions: Our results suggest a role of environmental and behavioral risk factors such as some chemical exposures and professional sports in EOD etiology, in particular with reference to FTD. Overall sports practice may be associated with a reduced EOD risk.

2020 - Environmental and occupational risk factors for early onset dementia in an Italian community [Abstract in Rivista]
Adani, G.; Filippini, T.; Garuti, C.; Malavolti, M.; Vinceti, G.; Zamboni, G.; Tondelli, M.; Galli, C.; Costa, M.; Vinceti, M.; Chiari, A.

Background: Early onset dementia (EOD) is defined as dementia with symptoms onset before 65 years. Little is known about the etiological role of environmental and occupational risk factors. We aimed at assessing the role of these factors in disease etiology.Methods: Using a case-control design, we recruited all EOD cases resident in Modena province from October, 2016 to October, 2019, as well as a referent population drawn from patients’ care-givers. We investigated residential history of study participants, and their occupational and environmental exposures to pesticides, solvents and metals through a self-administered questionnaire. We computed the odds ratios (ORs) of disease risk, and the corresponding 95% confidence intervals (CIs), according to exposure to the investigated risk factors, using an unconditional logistic regression model adjusted for sex, age, and education. Results: Fifty-eight EOD cases and fifty-four controls agreed to participate. Among occupational factors, disease risk was associated with exposure to aluminum (OR 2.6, 95% CI 0.4-15.7), pesticides (OR 2.3, 95% CI 0.7-7.8) particularly from agricultural occupational exposure (OR 3.1, 95% CI 0.7-13.3) and dyes, paints or thinners (OR 1.7, 95% CI 0.6-5.0). Among lifestyles factors, smoking (OR 1.3, 95% CI 0.6-2.9) and playing football (OR 2.2, 95% CI 0.5-9.3) or cycling (OR 2.3, 95% CI 0.4-13.4) were associated with higher EOD risk, although overall sports practice appeared to be protective factor (OR 0.4, 95% CI 0.2-0.9). Risk was also positively associated with history of head trauma (OR 1.2, 95% CI 0.3-4.1) and particularly upper arm trauma (OR 2.2, 95% CI 0.7-7.5), but not overall trauma. No association emerged for exposure to electromagnetic fields. Conclusions:Despite the study limitations, our results appear to support a role of environmental risk factors in EOD etiology, particularly of some chemical exposures and professional sports, while overall sports practice may have a beneficial effect.

2020 - Epidemiology of early onset dementia and its clinical presentations in the province of Modena, Italy [Articolo su rivista]
Chiari, A.; Vinceti, G.; Adani, G.; Tondelli, M.; Galli, C.; Fiondella, L.; Costa, M.; Molinari, M. A.; Filippini, T.; Zamboni, G.; Vinceti, M.

Introduction: Patients with early onset dementia (EOD), defined as dementia with symptom onset at age <65, frequently present with atypical syndromes. However, the epidemiology of different EOD presentations, including variants of Alzheimer's disease (AD) and frontotemporal dementia (FTD), has never been investigated all together in a population-based study. Epidemiologic data of all-cause EOD are also scarce. Methods: We investigated EOD epidemiology by identifying patients with EOD seen in the extended network of dementia services of the Modena province, Northern Italy (≈700,000 inhabitants) from 2006 to 2019. Results: In the population age 30 to 64, incidence was 13.2 per 100,000/year, based on 160 new cases from January 2016 to June 2019, and prevalence 74.3 per 100,000 on June 30, 2019. The most frequent phenotypes were the amnestic variant of AD and behavioral variant of FTD. Discussion: EOD affects a significant number of people. Amnestic AD is the most frequent clinical presentation in this understudied segment of the dementia population.

2019 - Age-dependent association of white matter abnormality with cognition after TIA or minor stroke [Articolo su rivista]
Zamboni, G.; Griffanti, L.; Mazzucco, S.; Pendlebury, S. T.; Rothwell, P. M.

ObjectiveTo investigate if the association between MRI-detectable white matter hyperintensity (WMH) and cognitive status reported in previous studies persists at older ages (>80 years), when some white matter abnormality is almost universally reported in clinical practice.MethodsConsecutive eligible patients from a population-based cohort of all TIA/nondisabling stroke (Oxford Vascular Study) underwent multimodal MRI, including fluid-Attenuated inversion recovery and diffusion-weighted imaging, allowing automated measurement of WMH volume, mean diffusivity (MD), and fractional anisotropy (FA) in normal-Appearing white matter using FSL tools. These measures were related to cognitive status (Montreal Cognitive Assessment) at age ≤80 vs >80 years.ResultsOf 566 patients (mean [range] age 66.7 [20-102] years), 107 were aged >80 years. WMH volumes and MD/FA were strongly associated with cognitive status in patients aged ≤80 years (all p < 0.001 for WMH, MD, and FA) but not in patients aged >80 years (not significant for WMH, MD, and FA), with age interactions for WMH volume (pinteraction = 0.016) and MD (pinteraction = 0.037). Voxel-wise analyses also showed that lower Montreal Cognitive Assessment scores were associated with frontal WMH in patients ≤80 years, but not >80 years.ConclusionMRI markers of white matter damage are strongly related to cognition in patients with TIA/minor stroke at younger ages, but not at age >80 years. Clinicians and patients should not overinterpret the significance of these abnormalities at older ages.

2019 - Attention network dysfunction underlies memory impairment in posterior cortical atrophy [Articolo su rivista]
Veldsman, M.; Zamboni, G.; Butler, C.; Ahmed, S.

Accumulating evidence suggests that memory is impaired in posterior cortical atrophy (PCA), alongside the early and defining visual disorder. The posterior parietal cortex is a key region of pathology in PCA and memory impairment may be the result of dysfunction of parietally dependent network function rather than the medial temporal lobe dependent dysfunction that defines the storage deficits in typical Alzheimer's disease. We assessed episodic memory performance and network function in16 PCA patients and 19 healthy controls who underwent structural and resting-state functional MRI and neuropsychological testing. Memory was assessed using the Free and Cued Selective Reminding Test (FCSRT), a sensitive test of episodic memory storage and retrieval. We examined correlations between memory performance and functional connectivity in the dorsal attention (DAN) and default mode network (DMN). Immediate recall on the FCSRT was relatively preserved in PCA patients. Total recall performance was impaired in patients relative to healthy controls and performance benefitted from retrieval cues. In patients only, disrupted connectivity in the DAN, but not the DMN, was associated with total recall. Memory impairment may arise from disruption to the dorsal attention network, subserved by the dorsal posterior parietal cortex, a key region of pathology in PCA, rather than classic medial temporal lobe memory circuitry.We propose that functional dysconnectivity in attentional circuits underpins memory impairment in PCA.

2019 - Automated lesion segmentation with BIANCA: Impact of population-level features, classification algorithm and locally adaptive thresholding [Articolo su rivista]
Sundaresan, V.; Zamboni, G.; Le Heron, C.; Rothwell, P. M.; Husain, M.; Battaglini, M.; De Stefano, N.; Jenkinson, M.; Griffanti, L.

White matter hyperintensities (WMH) or white matter lesions exhibit high variability in their characteristics both at population- and subject-level, making their detection a challenging task. Population-level factors such as age, vascular risk factors and neurodegenerative diseases affect lesion load and spatial distribution. At the individual level, WMH vary in contrast, amount and distribution in different white matter regions. In this work, we aimed to improve BIANCA, the FSL tool for WMH segmentation, in order to better deal with these sources of variability. We worked on two stages of BIANCA by improving the lesion probability map estimation (classification stage) and making the lesion probability map thresholding stage automated and adaptive to local lesion probabilities. Firstly, in order to take into account the effect of population-level factors, we included population-level lesion probabilities, modelled with respect to a parametric factor (e.g. age), in the classification stage. Secondly, we tested BIANCA performance when using four alternative classifiers commonly used in the literature with respect to K-nearest neighbour algorithm (currently used for lesion probability map estimation in BIANCA). Finally, we propose LOCally Adaptive Threshold Estimation (LOCATE), a supervised method for determining optimal local thresholds to apply to the estimated lesion probability map, as an alternative option to global thresholding (i.e. applying the same threshold to the entire lesion probability map). For these experiments we used data from a neurodegenerative cohort, a vascular cohort and the cohorts available publicly as a part of a segmentation challenge. We observed that including population-level parametric lesion probabilities with respect to age and using alternative machine learning techniques provided negligible improvement. However, LOCATE provided a substantial improvement in the lesion segmentation performance, when compared to the global thresholding. It allowed to detect more deep lesions and provided better segmentation of periventricular lesion boundaries, despite the differences in the lesion spatial distribution and load across datasets. We further validated LOCATE on a cohort of CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients, a genetic form of cerebral small vessel disease, and healthy controls, showing that LOCATE adapts well to wide variations in lesion load and spatial distribution.

2019 - Disseminated leptomeningeal tumour mimicking a subarachnoid haemorrhage [Articolo su rivista]
Teoh, S.; Hofer, M.; Kerr, R.; Warner, N.; Kueker, W.; Rothwell, P. M.; Zamboni, G.

This article describes an unusual presentation of disseminated oligodendroglial-like leptomeningeal tumour. A previously healthy 23-year-old Caucasian woman presented with headache, photophobia and recurrent seizures. Initial investigations were suggestive of subarachnoid haemorrhage. Her symptoms deteriorated rapidly and within weeks she developed complete blindness and diffuse sensory ataxia. The aim of this article is to increase awareness of this rare disease, especially in patients who present with acute, rapidly progressive neurological symptoms with signs of acute or chronic central nervous system bleeding.

2019 - Epidemiology and social impact of early onset dementia in the province of Modena, Northern Italy [Abstract in Atti di Convegno]
Fiondella, Luigi; Galli, C.; Tondelli, M.; Vinceti, G.; Filippini, T.; Garuti, Caterina; Vinceti, M.; Chiari, A.; Zamboni, G.; Molinari, MARIA ANGELA; COSTA (Modena), M.

Aims of the study. Early onset dementia (EOD), defined as onset of dementia <65 years, has a much higher social impact compared to the more common late onset dementia. EOD epidemiologic data in Italy are extremely scarce, and international estimates of prevalence are considerably variable, ranging between 15.1 and 153/100.000 in the age 45-65. We present data from an ongoing study aimed at establishing EOD epidemiology in a Northern Italy community (Modena province, around 700.000 inhabitants). Materials. We retrospectively recruited all patients residing in Modena province referred to the Modena Baggiovara Hospital Neurologic Clinic CDCD (Centro disturbi cognitivi e demenze), by family practitioners and geriatricians of the province. Eligible patients were those affected by EOD from 2012 to January 2019. EOD was diagnosed in patients <65 years presenting with cognitive/behavioral symptoms, following a comprehensive neurological examination by a cognitive neurologist, as well as brain MRI, FDG PET scanning and CSF analyses when appropriate. Methods. We collected clinical data such as age at onset, disease severity at time of diagnosis, time delay from onset to diagnosis, and epidemiologic data including residence and occupational status. Results. We identified 223 patients with an EOD diagnosis from 2012 to January 2019. Of these, 103 are males (46,2%). 97 patients have AD (21 lvPPA, 13 PCA, 2 frontal variant), 47 have FTD (33 bvFTD, 14 svPPA), 6 have leucoencephalopathy. Mean onset age was 58,6 years (SD 5,1). Median time from symptoms onset to diagnosis was 3.1 years (SD 29,83). Mean MMSE score at diagnosis was 22,63/30 (SD 5,2). 24 patients were working at time of diagnosis (10,76%) and had to quit working due to the cognitive impairment. Two patients (0,89%) had young children (<18) at time of diagnosis. Discussion. We provide the first epidemiological data on EOD in Italy. These are consistent with the estimates calculated by transposing European data to the population of Modena province (estimated prevalence=200 patients, detected prevalence=223 patients)1. Our data show a higher percentage of atypical AD phenotypes and FTD in the EOD group compared to late onset disease2. Also, CAA and leucoencephalopaties were over-represented compared to LOD. From a social perspective, EOD has significant impacts on patients and their families: patients are generally forced to leave work, and their children are expected to need psychological support, currently not routinely available. Conclusions. Our population study provides the first data regarding EOD epidemiology and social impact in Italy.

2019 - Erratum: Aβ42/Aβ40 and Aβ42/Aβ38 Ratios Are Associated with Measures of Gait Variability and Activities of Daily Living in Mild Alzheimer's Disease: A Pilot Study (Journal of Alzheimer s Disease (2018) 65:4 (1377-1383) DOI: 10.3233/JAD-180622) [Articolo su rivista]
Koychev, I.; Galna, B.; Zetterberg, H.; Lawson, J.; Zamboni, G.; Ridha, B.; Rowe, J. B.; Thomas, A.; Howard, R.; Malhotra, P.; Ritchie, C.; Lovestone, S.; Rochester, L.

On page 1378, it is stated that one of the main inclusion criteria for the DFP study was age between 55-80 years. This should be: age between 55-85 years.

2019 - Erratum: Gait in Mild Alzheimer's Disease: Feasibility of Multi-Center Measurement in the Clinic and Home with Body-Worn Sensors: A Pilot Study (Journal of Alzheimer's Disease (2018) 63:1 (331-341) DOI: 10.3233/JAD-171116) [Articolo su rivista]
Mc Ardle, R.; Morrisa, R.; Hickey, A.; Del Din, S.; Koychev, I.; Gunn, R. N.; Lawson, J.; Zamboni, G.; Ridha, B.; Sahakian, B. J.; Rowe, J. B.; Thomas, A.; Zetterberg, H.; MacKay, C.; Lovestone, S.; Rochester, L.

On page 333 it says: Participants inclusion criteria were: between 55 and 80 . This should be: Participants inclusion criteria were: between 50 and 85.

2019 - Hippocampal network abnormalities explain amnesia after VGKCC-Ab related autoimmune limbic encephalitis [Articolo su rivista]
Loane, C.; Argyropoulos, G. P. D.; Roca-Fernandez, A.; Lage, C.; Sheerin, F.; Ahmed, S.; Zamboni, G.; Mackay, C.; Irani, S. R.; Butler, C. R.

Objective: Limbic encephalitis associated with antibodies to components of the voltage-gated potassium channel complex (VGKCC-Ab-LE) often leads to hippocampal atrophy and persistent memory impairment. Its long-term impact on regions beyond the hippocampus, and the relationship between brain damage and cognitive outcome, are poorly understood. We investigated the nature of structural and functional brain abnormalities following VGKCC-Ab-LE and its role in residual memory impairment. Method: A cross-sectional group study was conducted. Twenty-four VGKCC-Ab-LE patients (20 male, 4 female; mean (SD) age 63.86 (11.31) years) were recruited post-acutely along with age- and sex-matched healthy controls for neuropsychological assessment, structural MRI and resting-state functional MRI (rs-fMRI). Structural abnormalities were determined using volumetry and voxel-based morphometry; rs-fMRI data were analysed to investigate hippocampal functional connectivity (FC). Associations of memory performance with neuroimaging measures were examined. Results: Patients showed selective memory impairment. Structural analyses revealed focal hippocampal atrophy within the medial temporal lobes, correlative atrophy in the mediodorsal thalamus, and additional volume reduction in the posteromedial cortex. There was no association between regional volumes and memory performance. Instead, patients demonstrated reduced posteromedial cortico-hippocampal and inter-hippocampal FC, which correlated with memory scores (r = 0.553; r = 0.582, respectively). The latter declined as a function of time since the acute illness (r = -0.531). Conclusion: VGKCC-Ab-LE results in persistent isolated memory impairment. Patients have hippocampal atrophy with further reduced mediodorsal thalamic and posteromedial cortical volumes. Crucially, reduced FC of remaining hippocampal tissue correlates more closely with memory function than does regional atrophy.

2019 - Longitudinal brain atrophy rates in transient ischemic attack and minor ischemic stroke patients and cognitive profiles [Articolo su rivista]
Munir, M.; Ursenbach, J.; Reid, M.; Sah, R. G.; Wang, M.; Sitaram, A.; Aftab, A.; Tariq, S.; Zamboni, G.; Griffanti, L.; Smith, E. E.; Frayne, R.; Sajobi, T. T.; Coutts, S. B.; D'Esterre, C. D.; Barber, P. A.

Introduction: Patients with transient ischemic attack (TIA) and minor stroke demonstrate cognitive impairment, and a four-fold risk of late-life dementia. Aim: To study the extent to which the rates of brain volume loss in TIA patients differ from healthy controls and how they are correlated with cognitive impairment. Methods: TIA or minor stroke patients were tested with a neuropsychological battery and underwent T1 weighted volumetric magnetic resonance imaging scans at fixed intervals over a 3 years period. Linear mixed effects regression models were used to compare brain atrophy rates between groups, and to determine the relationship between atrophy rates and cognitive function in TIA and minor stroke patients. Results: Whole brain atrophy rates were calculated for the TIA and minor stroke patients; n = 38 between 24 h and 18 months, and n = 68 participants between 18 and 36 months, and were compared to healthy controls. TIA and minor stroke patients demonstrated a significantly higher whole brain atrophy rate than healthy controls over a 3 years interval (p = 0.043). Diabetes (p = 0.012) independently predicted higher atrophy rate across groups. There was a relationship between higher rates of brain atrophy and processing speed (composite P = 0.047 and digit symbol coding P = 0.02), but there was no relationship with brain atrophy rates and memory or executive composite scores or individual cognitive tests for language (Boston naming, memory recall, verbal fluency or Trails A or B score). Conclusion: TIA and minor stroke patients experience a significantly higher rate of whole brain atrophy. In this cohort of TIA and minor stroke patients changes in brain volume over time precede cognitive decline.

2019 - Modelling the distribution of white matter hyperintensities due to ageing on MRI images using Bayesian inference [Articolo su rivista]
Sundaresan, V.; Griffanti, L.; Kindalova, P.; Alfaro-Almagro, F.; Zamboni, G.; Rothwell, P. M.; Nichols, T. E.; Jenkinson, M.

White matter hyperintensities (WMH), also known as white matter lesions, are localised white matter areas that appear hyperintense on MRI scans. WMH commonly occur in the ageing population, and are often associated with several factors such as cognitive disorders, cardiovascular risk factors, cerebrovascular and neurodegenerative diseases. Despite the fact that some links between lesion location and parametric factors such as age have already been established, the relationship between voxel-wise spatial distribution of lesions and these factors is not yet well understood. Hence, it would be of clinical importance to model the distribution of lesions at the population-level and quantitatively analyse the effect of various factors on the lesion distribution model. In this work we compare various methods, including our proposed method, to generate voxel-wise distributions of WMH within a population with respect to various factors. Our proposed Bayesian spline method models the spatio-temporal distribution of WMH with respect to a parametric factor of interest, in this case age, within a population. Our probabilistic model takes as input the lesion segmentation binary maps of subjects belonging to various age groups and provides a population-level parametric lesion probability map as output. We used a spline representation to ensure a degree of smoothness in space and the dimension associated with the parameter, and formulated our model using a Bayesian framework. We tested our algorithm output on simulated data and compared our results with those obtained using various existing methods with different levels of algorithmic and computational complexity. We then compared the better performing methods on a real dataset, consisting of 1000 subjects of the UK Biobank, divided in two groups based on hypertension diagnosis. Finally, we applied our method on a clinical dataset of patients with vascular disease. On simulated dataset, the results from our algorithm showed a mean square error (MSE) value of , which was lower than the MSE value reported in the literature, with the advantage of being robust and computationally efficient. In the UK Biobank data, we found that the lesion probabilities are higher for the hypertension group compared to the non-hypertension group and further verified this finding using a statistical t-test. Finally, when applying our method on patients with vascular disease, we observed that the overall probability of lesions is significantly higher in later age groups, which is in line with the current literature.

2019 - Occupational risk factors for early onset dementia (EOD) in the Modena population: a case-control study [Abstract in Rivista]
Adani, Giorgia; Filippini, Tommaso; Garuti, Caterina; Vinceti, Giulia; Chiara, Galli; Zamboni, Giovanna; Tondelli, Manuela; Manuela, Costa; Malavolti, Marcella; Vinceti, Marco; Chiari, Annalisa

Introduction Dementia is a clinical condition generally affecting subjects in the elderly. However, it may occur also at younger age, yielding a condition called early-onset dementia (EOD) characterized by an onset before 65 years 1 2. Despite the limited epidemiological data and the paucity of information regarding possible risk fac- tors 3 4, there is a general agreement that clinical presentation and consequences on daily life are different than late-onset demen- tia, due to the occurrence when subjects are still involved within occupational activities as well as familiar responsibilities 5. The aim of this work is to assess the epidemiological, clinical and prognostic role of occupational risk factors in EOD. Materials and methods Using a case-control design, we recruited newly-diagnosed EOD cases from the two Centers of Cognitive Disease of the Neurol- ogy Units of Modena-Baggiovara and Carpi Hospitals, as well as from the community health centers and general practitioners, October 1, 2016 to May 31, 2019. Referent population have been recruited from care-givers of EOD and LOD (late onset demen- tia) subjects. We investigated as possible risk factors of the dis- ease the occupational history, by administering a questionnaire collecting information about personal characteristics, family his- tory of diseases, clinical history and comorbidities, occupation activities, hobbies and other leisure activities, residential history, domestic use of pesticides, and dental care. We computed the odds ratios (ORs) of EOD risk, and the corresponding 95% con- fidence intervals (CIs), according to exposure to the investigated risk factors using an unconditional logistic regression model ad- justing for sex, age, and educational attainment. Results Fifty-six cases and fifty-three controls agreed to participate, with generally higher number of women (60% cases and 55% controls) and people over 65 (60% cases compared to 49% con- trols). About occupational factors, working in the agricultural sector seemed to be only slightly associated with risk of EOD (OR 1.31, 95% CI 0.26-6.59), while an increased risk was found for industrial sector (OR 2.23, 95% CI 0.85-5.88). Occupational exposure to contaminants showed positive association for occupational exposure to selenium (OR 2.23, 95% CI 0.11-46.42), aluminum (OR 2.75, 95% CI 0.42-18.11), pesticides (OR 2.10, 95% CI 0.60-7.36), dyes, paints or thinners (OR 2.07, 95% CI 0.70-6.05), while no association was found for exposure to or use of electric and electronic system or electromagnetic fields. Conclusions Results of this study suggest that some occupational factors, namely use of pesticides, dyes/paints, and metalloids such as alu- minum and selenium, could be associated with increased disease risk. Despite study limitations due to case-control design, includ- ing possible occurrence of selection and recall bias, our findings support the hypothesis of an environmental etiology of EOD.

2019 - Prevalenza ed impatto sociale delle demenze ad esordio precoce (Early onset dementia-EOD) nella provincia di Modena [Abstract in Rivista]
Chiari, A; Galli, C; Tondelli, M; Vinceti, G; Fiondella, L; Molinari, M; Costa, M; Garuti, C; Adani, G; Filippini, T; Zamboni, G

Introduzione. Le demenze in cui l’esordio dei sintomi si verifica prima dei 65 anni (Early Onset Dementia-EOD), hanno caratteristiche cliniche ed impatto socio-sanitario diversi rispetto alle demenze ad esordio tardivo. I dati epidemiologici disponibili sono scarsi, con stime di prevalenza variabili tra 15 e 150/100.000 soggetti appartenenti alla fascia di età 45-64 anni. Non sono attualmente disponibili dati di prevalenza in Italia. Metodi. Abbiamo ricercato i casi di EOD in pazienti residenti in Provincia di Modena, esaminando i pazienti valutati presso i Centri per i Disturbi Cognitive e Demenze (CDCD) della provincia (2 neurologici, 8 geriatrici dislocati in tutto il territorio provinciale) tra il 1/1/2006 e il 31/12/2018. I casi con esordio antecedente al 1/1/2017 sono stati identificati retrospettivamente, mentre i casi con esordio successivo sono stati accertati prospetticamente, mediante invio da parte dei Medici di Medicina Generale e dai Geriatri ai due CDCD neurologici della provincia. La diagnosi di EOD è stata posta da un Neurologo esperto in disturbi cognitivi. Abbiamo incluso nello studio i pazienti con diagnosi di EOD al 31/12/2018. Abbiamo esaminato diagnosi, età di insorgenza, età e gravità dei disturbi cognitivi alla diagnosi. Per un sottogruppo di pazienti abbiamo inoltre raccolto variabili socio-demografiche quali la composizione del nucleo familiare e la condizione occupazionale del paziente e del caregiver principale. Risultati. Abbiamo identificato 248 pazienti con EOD al 31/12/2018, con una prevalenza di 116,5/100.000 soggetti a rischio nella fascia di età 45-64 anni e 71,8/100.000 nella fascia di età 30-64 anni. Il 41% dei pazienti ha ricevuto una diagnosi di malattia di Alzheimer (31% non amnesici), il 26% di demenza fronto-temporale, il 10% di demenza vascolare, il 7% demenza in parkinsonismo. L’età media all’esordio è stata di 58,9 anni (range 39-64), l’età media alla diagnosi è stata di 61,9 (range 40-72) con un significativo ritardo diagnostico. Il MMSE medio alla diagnosi è risultato pari a 22,2/30 (range 10-28). Il 22% dei pazienti svolgeva attività lavorativa alla diagnosi, mentre il 24% è stato costretto a lasciare il lavoro a causa della malattia. Il 3,4% dei pazienti aveva figli minori al momento della diagnosi. I caregivers, aventi età media di 59 anni, per il 70% svolgevano attività lavorativa, sperimentando una perdita media di 2 giornate lavorative al mese a causa della malattia del familiare. Il 7,4% e 20,5% dei pazienti ha usufruito rispettivamente di un centro diurno o struttura protetta, che tuttavia in nessun caso era specificamente dedicata a pazienti con EOD. Conclusioni. I dati raccolti permettono per la prima volta di valutare il numero e le caratteristiche dei pazienti con EOD nella Provincia di Modena. I risultati ottenuti saranno essenziali per organizzare servizi appropriati, dal punto di vista sanitario e socioassistenziale, per pazienti con EOD ed i loro familiari.

2019 - Risk of early onset dementia (EOD) in relation to fruit and vegetable consumption: a case-control study [Abstract in Rivista]
Filippini, Tommaso; Garuti, Caterina; Adani, Giorgia; Vinceti, Giulia; Chiara, Galli; Zamboni, Giovanna; Tondelli, Manuela; Manuela, Costa; Malavolti, Marcella; Vinceti, Marco; Chiari, Annalisa

Introduction Early onset dementia (EOD) is a condition characterized by the onset of severe cognitive impairment before 65 year 1. There is a general agreement that clinical presentation and conse- quences on daily life are different than late-onset dementia, due to the occurrence when subjects are still involved within occupational activities as well as familiar responsibilities 2. Previous studies have raised the possibility that the risk factors may also differ between the two forms, including the role of environmental and life-style determinants such as diet 3. There is some epidemiologic evidence of an association between dietary habits and protective relations to cognitive decline and incident dementia 4 5. The aim of this study is to evaluate, for the first time to our knowledge, the association between diet and EOD risk. Materials and methods Using a case-control design, we recruited newly-diagnosed EOD cases from 2016 to 2019 in Modena province, Northern Italy. We recruited controls from care-givers of dementia patients referring the Neurology Units of Modena-Baggiovara and Carpi Hospi- tals. We investigated dietary habits through a self-administered semi-quantitative food frequency questionnaire, designed and validated to capture eating behaviors in Italy, and specifically developed as part of the European Prospective Investigation into Cancer and Nutrition (EPIC) study for the Northern Italy pop- ulation 6. Participants were asked to respond to 248 questions about 188 different food items, in order to assess frequency and quantity of daily consumption for each food item. We specifically focused on consumption of fruits and vegetables that were categorized into major and sub-group categories as previously reported 7. We computed the odds ratios (ORs) of EOD risk, and the corresponding 95% confidence intervals (CIs), according to increasing tertile of intake using an unconditional logistic regres- sion model and we also modeled the relation using restricted cu- bic splines with three knots (10, 50 and 90%). We implemented a model adjusted for sex, age (years), educational attainment (years), and total energy intake (kcal/day). Results We recruited 56 (men/women: 22/34) and 53 (men/women: 24/29) controls who agreed to participate and returned study ma- terial. Regarding food intake, cases showed a lower intake than controls of vegetables (119 g/day versus 148 g/day), pulses (19 g/day versus 22 g/day), potatoes (15 g/day versus 23 g/day), and dry fruits (2.6 g/day versus 4.0 g/day). Conversely cases showed a higher intake than controls of fresh fruits (256 g/day versus 240 g/day). In the analysis of EOD risk according to increasing tertile we found an inverse association with all vegetables overall considered and also for individual subgroup, particularly leafy vegetables and other vegetables (e.g. eggplant, zucchini or sweet pepper). Also, an inverse association was found for potatoes and slightly for legumes. Conversely, the higher tertile of intake of fresh fruits was associated with no difference in EOD risk, but in the stratified analysis for non-citrus and citrus fruits we found inverse association for the latter. Interestingly, for non-citrus fruits we found inverse association in the second tertile of consumption, and an opposite positive association in the third tertile. Finally, with increasing tertile of dry fruits intake, we found a strong inverse association with EOD risk. Similarly in the spline analysis, the increasing consumption of vegetables, particularly leafy vegetables showed a strong inverse association, as simi- larly also increased pulse intake. Regarding fruit consumption, fresh fruit overall considered showed ambivalent relation, while higher consumption of citrus fruits only, as well as dry fruits, showed a negative association with EOD risk. Conclusions In this study, we found an association of consumption of vegeta- bles and to some extent fruit with EOD risk in an Italian popula- tio

2019 - Selenium and selenium species in the etiology of Alzheimer's dementia: The potential for bias of the case-control study design [Articolo su rivista]
Vinceti, Marco; Michalke, Bernhard; Malagoli, Carlotta; Eichmüller, Marcel; Filippini, Tommaso; Tondelli, Manuela; Bargellini, Annalisa; Vinceti, Giulia; Zamboni, Giovanna; Chiari, Annalisa

Several human studies imply that the trace element selenium and its species may influence the onset of neurological disease, including Alzheimer's dementia (AD). Nevertheless, the literature is conflicting, with reported associations between exposure and risk in opposite direction, possibly due to biases in exposure assessment. After conducting a cohort study that detected an excess AD risk associated with higher levels of inorganic-hexavalent selenium in subjects with mild cognitive impairment (MCI), we investigated the relation between selenium and AD using a case-control study design. We determined cerebrospinal fluid levels of selenium species in 56 MCI participants already included in the cohort study, considered as referents, and in 33 patients with established AD. AD risk was inversely correlated with inorganic selenium species and with the organic form bound to selenoprotein P. Selenium bound to other organo-selenium species was positively correlated with AD risk, suggesting compensatory selenoprotein upregulation following increased oxidative stress. The finding of an increased AD risk associated with inorganic-hexavalent selenium from the cohort study was not replicated. This case-control study yielded entirely different results than those generated by a cohort study with a partially overlapping participant population, suggesting that case-control design does not allow to reliably assess the role of selenium exposure in AD etiology. This inability appears to be due to exposure misclassification, falsely indicating an etiologic role of selenium deficiency likely due to reverse causation, and involving most selenium species. The case-control design may instead lend insights into the pathologic process underlying disease progression.

2018 - APOE genotype and cognition in healthy individuals at risk of Alzheimer's disease: A review [Articolo su rivista]
O'Donoghue, M. C.; Murphy, S. E.; Zamboni, G.; Nobre, A. C.; Mackay, C. E.

APOE-ε4 is best known as a risk factor for Alzheimer's disease (AD). Consequently, there is considerable research interest in understanding whether APOE-ε4 influences cognition in healthy adults. Despite a substantial literature reporting effects of APOE genotype on cognition, findings are inconsistent. In particular, it is challenging to separate whether cognitive deficits in APOE-ε4 carriers reflect the influence of prodromal dementia pathology (“prodromal hypothesis”), or a direct contribution of APOE genotype to individual differences (“phenotype hypothesis”). Variable methodology across studies further complicates the issue. These challenges have limited what can be learnt about the processes underlying cognitive ageing and dementia by studying the influence of APOE genotype on cognition. In this review, we focus on the two compatible neurobiological mechanisms by which APOE genotype may influence cognition in healthy adults (prodromal and phenotype). We summarise the behavioural evidence for the influence of APOE on cognition in non-demented adults and explore key methodological challenges for disentangling the cognitive effects of different neurobiological mechanisms of APOE. Evidence suggests that at least some APOE-ε4 cognitive deficits are due to early AD pathology, whilst sensitive measures of cognition are beginning to reveal subtle cognitive differences between APOE genotypes in mid-adulthood, prior to the onset of the AD prodromal period. We conclude with recommendations for future research to investigate the cognitive consequences of neurobiological processes affected by APOE and maximise the translational potential of this research.

2018 - Association between precuneus volume and autobiographical memory impairment in posterior cortical atrophy: Beyond the visual syndrome [Articolo su rivista]
Ahmed, S.; Irish, M.; Loane, C.; Baker, I.; Husain, M.; Thompson, S.; Blanco-Duque, C.; Mackay, C.; Zamboni, G.; Foxe, D.; Hodges, J. R.; Piguet, O.; Butler, C.

Posterior cortical atrophy is a neurodegenerative syndrome characterised by progressive disruption of visual and perceptual processing, associated with atrophy in the parieto-occipital cortex. Current diagnostic criteria describe relative sparing of episodic memory function, but recent findings suggest that anterograde memory is often impaired. Whether these deficits extend to remote memory has not been addressed. A large body of evidence suggests that the recollection of an autobiographical event from the remote past coincides with the successful retrieval of visual images. We hypothesised that the profound visual processing deficits in posterior cortical atrophy would result in impaired autobiographical memory retrieval. Fourteen posterior cortical atrophy patients, eighteen typical Alzheimer's disease patients and twenty-eight healthy controls completed the Autobiographical Interview. Autobiographical memory in posterior cortical atrophy was characterised by a striking loss of internal, episodic detail relative to controls and to same extent as typical Alzheimer's disease patients, in conjunction with an increase in external details tangential to the memory described. The memory narratives of posterior cortical atrophy patients showed a specific reduction in spatiotemporal and perceptual detail. Voxel-based morphometry analysis revealed atrophy of the parieto-occipital cortices in posterior cortical atrophy but relatively spared hippocampi bilaterally, compared with characteristic atrophy of the medial temporal lobes in typical Alzheimer's disease. Analysis of brain regions showing posterior cortical atrophy-specific atrophy revealed a correlation between perceptual details in autobiographical memory and grey matter density in the right precuneus. This study demonstrates remote memory impairment in posterior cortical atrophy despite relatively preserved medial temporal lobe structures. The results demonstrate, for the first time, profound autobiographical memory impairment in PCA and suggest that this is driven by the well-recognised deficits in higher-order visual processing. The findings are discussed in the context of posterior parietal contributions to imagery and memory, and the clinical implications of autobiographical memory impairment for diagnostic and management protocols in posterior cortical atrophy.

2018 - Aβ42/Aβ40 and Aβ42/Aβ38 Ratios Are Associated with Measures of Gait Variability and Activities of Daily Living in Mild Alzheimer's Disease: A Pilot Study [Articolo su rivista]
Koychev, I.; Galna, B.; Zetterberg, H.; Lawson, J.; Zamboni, G.; Ridha, B. H.; Rowe, J. B.; Thomas, A.; Howard, R.; Malhotra, P.; Ritchie, C.; Lovestone, S.; Rochester, L.

Gait disturbances are some of the earliest changes in dementia and their monitoring presents an opportunity for early diagnosis. The exact relationship between gait and well-established biomarkers of Alzheimer's disease (AD) remains to be clarified. In this study we compared gait-related measures with cerebrospinal fluid (CSF) markers of AD pathology. We recruited seventeen participants with mild AD in a multi-site study and performed gait assessment as well as lumbar punctures to obtain CSF. CSF Aβ42/Aβ40 and Aβ42/Aβ38 correlated positively with measures of variability (step time and step length) in the clinic-based assessments. This was driven by a negative relationship between gait variability and Aβ40 and Aβ38 but not Aβ42.The amyloid ratios and gait variability measures were also associated with more severe functional impairment. We interpret these data as an indication that increasing amyloid production (i.e., increasing Aβ40 and Aβ38) is associated with diminishing cognitive-motor control of gait. These preliminary results suggest that the two amyloid ratios may be a marker of the earliest disturbances in the interplay between cognitive and motor control which characterize dementia.

2018 - Classification and characterization of periventricular and deep white matter hyperintensities on MRI: a study in older adults [Articolo su rivista]
Griffanti, Ludovica; Jenkinson, Mark; Suri, Sana; X, X; Mahmood, Abda; Filippini, Nicola; Sexton, Claire E; Topiwala, Anya; Allan, Charlotte; Kivimäki, Mika; Singh Manoux, Archana; Ebmeier, Klaus P; Mackay, Clare E; Zamboni, Giovanna

White matter hyperintensities (WMH) are frequently divided into periventricular (PWMH) and deep (DWMH), and the two classes have been associated with different cognitive, microstructural, and clinical correlates. However, although this distinction is widely used in visual ratings scales, how to best anatomically define the two classes is still disputed. In fact, the methods used to define PWMH and DWMH vary significantly between studies, making results difficult to compare. The purpose of this study was twofold: first, to compare four current criteria used to define PWMH and DWMH in a cohort of healthy older adults (mean age: 69.58 ± 5.33 years) by quantifying possible differences in terms of estimated volumes; second, to explore associations between the two WMH sub-classes with cognition, tissue microstructure and cardiovascular risk factors, analysing the impact of different criteria on the specific associations. Our results suggest that the classification criterion used for the definition of PWMH and DWMH should not be considered a major obstacle for the comparison of different studies. We observed that higher PWMH load is associated with reduced cognitive function, higher mean arterial pressure and age. Higher DWMH load is associated with higher body mass index. PWMH have lower fractional anisotropy than DWMH, which also have more heterogeneous microstructure. These findings support the hypothesis that PWMH and DWMH are different entities and that their distinction can provide useful information about healthy and pathological aging processes.

2018 - Exploring variability in basal ganglia connectivity with functional MRI in healthy aging [Articolo su rivista]
Griffanti, Ludovica; Stratmann, Philipp; Rolinski, Michal; Filippini, Nicola; Zsoldos, Enikő; Mahmood, Abda; Zamboni, Giovanna; Douaud, Gwenaëlle; Klein, Johannes C; Kivimäki, Mika; Singh-Manoux, Archana; Hu, Michele T; Ebmeier, Klaus P; Mackay, Clare E

Changes in functional connectivity (FC) measured using resting state fMRI within the basal ganglia network (BGN) have been observed in pathologies with altered neurotransmitter systems and conditions involving motor control and dopaminergic processes. However, less is known about non-disease factors affecting FC in the BGN. The aim of this study was to examine associations of FC within the BGN with dopaminergic processes in healthy older adults. We explored the relationship between FC in the BGN and variables related to demographics, impulsive behavior, self-paced tasks, mood, and motor correlates in 486 participants in the Whitehall-II imaging sub-study using both region-of-interest- and voxel-based approaches. Age was the only correlate of FC in the BGN that was consistently significant with both analyses. The observed adverse effect of aging on FC may relate to alterations of the dopaminergic system, but no unique dopamine-related function seemed to have a link with FC beyond those detectable in and linearly correlated with healthy aging.

2018 - Gait in Mild Alzheimer's Disease: Feasibility of Multi-Center Measurement in the Clinic and Home with Body-Worn Sensors: A Pilot Study [Articolo su rivista]
Mc Ardle, R.; Morris, R.; Hickey, A.; Del Din, S.; Koychev, I.; Gunn, R. N.; Lawson, J.; Zamboni, G.; Ridha, B.; Sahakian, B. J.; Rowe, J. B.; Thomas, A.; Zetterberg, H.; Mackay, C.; Lovestone, S.; Rochesteron, L.

Gait is emerging as a potential diagnostic tool for cognitive decline. The 'Deep and Frequent Phenotyping for Experimental Medicine in Dementia Study' (D&FP) is a multicenter feasibility study embedded in the United Kingdom Dementia Platform designed to determine participant acceptability and feasibility of extensive and repeated phenotyping to determine the optimal combination of biomarkers to detect disease progression and identify early risk of Alzheimer's disease (AD). Gait is included as a clinical biomarker. The tools to quantify gait in the clinic and home, and suitability for multi-center application have not been examined. Six centers from the National Institute for Health Research Translational Research Collaboration in Dementia initiative recruited 20 individuals with early onset AD. Participants wore a single wearable (tri-axial accelerometer) and completed both clinic-based and free-living gait assessment. A series of macro (behavioral) and micro (spatiotemporal) characteristics were derived from the resultant data using previously validated algorithms. Results indicate good participant acceptability, and potential for use of body-worn sensors in both the clinic and the home. Recommendations for future studies have been provided. Gait has been demonstrated to be a feasible and suitable measure, and future research should examine its suitability as a biomarker in AD.

2018 - Imaging Aβ and tau in early stage Alzheimer’s disease with [18F]AV45 and [18F]AV1451 [Articolo su rivista]
Firouzian, A.; Whittington, A.; Searle, G. E.; Koychev, I.; Zamboni, G.; Lovestone, S.; Gunn, R. N.

Background: AD is a progressive neurodegenerative disorder that is associated with the accumulation of two different insoluble protein aggregates, Aβ plaques and hyperphosphorylated tau. This study aimed to investigate the optimal acquisition and quantification of [18F]AV45 and [18F]AV1451 to image Aβ and tau, respectively, in subjects with AD. Fifteen subjects with early stage AD underwent a T1-weighted structural MRI and two dynamic PET scans to image Aβ (60 min, [18F]AV45) and tau (120 min, [18F]AV1451). Both dynamic BPND and static SUVR outcome measures were calculated and compared for 12 out of 15 subjects who completed 60 min of the Aβ PET scan and at least 110 min of the tau PET scan. The SRTM and reference Logan graphical analysis were applied to the dynamic data to estimate regional BPND values and SUVR ratios from the static data. Optimal acquisition windows were explored for both the dynamic and static acquisitions. In addition, the spatial correlation between regional Aβ and tau signals was explored. Results: Both the SRTM and graphical analysis methods showed a good fit to the dynamic data for both Aβ and tau dynamic PET scans. Mean regional BPND estimates became stable 30 min p.i. for [18F]AV45 and 80 min p.i. for [18F]AV1451. Time stability analysis of static SUVR data showed that the outcome measure starts to become stable for scan windows of 30–50 min p.i. for [18F]AV45 and 80–100 min p.i. for [18F]AV1451. The results from these time windows correlated well with the results from the full dynamic analysis for both tracers (R2 = 0.74 for [18F]AV45 and R2 = 0.88 for [18F]AV1451). There was a high correlation between amyloid uptake estimate using both dynamic analysis methods in thalamus and tau uptake in thalamus, hippocampus and amygdala. Conclusions: Short static PET scans at appropriate time windows provided SUVR values which were in reasonable agreement with BPND values calculated from dynamic scans using SRTM and reference Logan. These simplified methods may be appropriate for classification and intervention studies, although caution should be employed when considering interventional studies where blood flow and extraction could change. © 2018, The Author(s).

2018 - Lateral parietal contributions to memory impairment in posterior cortical atrophy [Articolo su rivista]
Ahmed, S.; Loane, C.; Bartels, S.; Zamboni, G.; Mackay, C.; Baker, I.; Husain, M.; Thompson, S.; Hornberger, M.; Butler, C.

Objective: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterised by progressive impairment in visuospatial and perceptual function. Recent findings show that memory functioning can also be compromised early in the course of disease. In this study, we investigated the neural basis of memory impairment in PCA, and hypothesised that correlations would be observed with parietal cortex rather than classic medial temporal memory structures. Methods: Eighteen PCA patients, 15 typical Alzheimer's disease (tAD) patients and 21 healthy controls underwent memory testing with the Rey Auditory Verbal Learning Test (RAVLT) word list and MRI. Voxel-based morphometry (VBM) was used to identify regions in the parietal and medial temporal lobes that correlated with memory performance. Results: Compared with controls, PCA patients were impaired at learning, immediate and delayed recall and recognition of the RAVLT. Learning rate and immediate recall was significantly better in PCA compared to tAD, whereas there was no difference in delayed recall. Recognition memory also was not statistically different between patient groups, but PCA patients made significantly more false positive errors than tAD patients. VBM analysis in the PCA patients revealed a significant correlation between total learning and grey matter density in the right supramarginal gyrus, right angular gyrus and left postcentral gyrus. The left post central gyrus also significantly correlated with immediate and delayed recall and with recognition memory. No correlations were detected in the medial temporal lobe. Conclusions: The findings provide novel evidence that early verbal memory impairment is frequently observed in PCA, and is associated with damage to lateral parietal structures. The results have implications for the diagnosis and management of PCA. © 2018 The Authors

2018 - Neural correlates of anosognosia in Alzheimer’s disease and mild cognitive impairment: A multi-method assessment [Articolo su rivista]
Tondelli, M.; Barbarulo, Anna Maria; Vinceti, G.; Vincenzi, Chiara; Chiari, A.; Nichelli, P. F.; Zamboni, G.

Patients with Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI) may present anosognosia for their cognitive deficits. Three different methods have been usually used to measure anosognosia in patients with AD and MCI, but no studies have established if they share similar neuroanatomical correlates. The purpose of this study was to investigate if anosognosia scores obtained with the three most commonly used methods to assess anosognosia relate to focal atrophy in AD and MCI patients, in order to improve understanding of the neural basis of anosognosia in dementia. Anosognosia was evaluated in 27 patients (15 MCI and 12 AD) through clinical rating (Clinical Insight Rating Scale, CIRS), patient-informant discrepancy (Anosognosia Questionnaire Dementia, AQ-D), and performance discrepancy on different cognitive domains (self-appraisal discrepancies, SADs). Voxel-based morphometry correlational analyses were performed on magnetic resonance imaging (MRI) data with each anosognosia score. Increasing anosognosia on any anosognosia measurement (CIRS, AQ-D, SADs) was associated with increasing gray matter atrophy in the medial temporal lobe including the right hippocampus. Our results support a unitary mechanism of anosognosia in AD and MCI, in which medial temporal lobes play a key role, irrespectively of the assessment method used. This is in accordance with models suggesting that anosognosia in AD is primarily caused by a decline in mnemonic processes.

2018 - Outdoor air pollution and risk of conversion from mild cognitive impairment to dementia: a cohort study. [Abstract in Atti di Convegno]
Filippini, T; Chiari, A; Zamboni, G; Tondelli, M; Vinceti, G; Maffeis, G; Cherubini, A; Malagoli, C; Vinceti, M.


2018 - Progress toward standardized diagnosis of vascular cognitive impairment: Guidelines from the Vascular Impairment of Cognition Classification Consensus Study [Articolo su rivista]
Skrobot, O. A.; Black, S. E.; Chen, C.; Decarli, C.; Erkinjuntti, T.; Ford, G. A.; Kalaria, R. N.; O'Brien, J.; Pantoni, L.; Pasquier, F.; Roman, G. C.; Wallin, A.; Sachdev, P.; Skoog, I.; Taragano, F. E.; Kril, J.; Cavalieri, M.; Jellinger, K. A.; Kovacs, G. G.; Engelborghs, S.; Lafosse, C.; Bertolucci, P. H.; Brucki, S.; Caramelli, P.; de Toledo Ferraz Alves, T. C.; Bocti, C.; Fulop, T.; Hogan, D. B.; Hsiung, G. R.; Kirk, A.; Leach, L.; Robillard, A.; Sahlas, D. J.; Guo, Q.; Tian, J.; Hokkanen, L.; Jokinen, H.; Benisty, S.; Deramecourt, V.; Hauw, J.; Lenoir, H.; Tsatali, M.; Tsolaki, M.; Sundar, U.; Coen, R. F.; Korczyn, A. D.; Altieri, M.; Baldereschi, M.; Caltagirone, Calogero; Caravaglios, G.; Di Carlo, A.; Di Piero, V.; Gainotti, G.; Galluzzi, S.; Logroscino, G.; Mecocci, P.; Moretti, D. V.; Padovani, Alessandro; Fukui, T.; Ihara, M.; Mizuno, T.; Kim, S. Y.; Akinyemi, R.; Baiyewu, O.; Ogunniyi, A.; Szczudlik, A.; Bastos-Leite, A. J.; Firmino, H.; Massano, J.; Verdelho, A.; Kruglov, L. S.; Ikram, M. K.; Kandiah, N.; Arana, E.; Barroso-Ribal, J.; Calatayud, T.; Cruz-Jentoft, A. J.; López-Pousa, S.; Martinez-Lage, P.; Mataro, M.; Börjesson-Hanson, A.; Englund, E.; Laukka, E. J.; Qiu, C.; Viitanen, M.; Biessels, G. J.; de Leeuw, F. -E.; den Heijer, T.; Exalto, L. G.; Kappelle, L. J.; Prins, N. D.; Ferdig, RICHARD EUGENE; Schmand, B.; van den Berg, E.; van der Flier, W. M.; Bilgic, B.; Allan, L. M.; Archer, J.; Attems, J.; Bayer, A.; Blackburn, D.; Brayne, C.; Bullock, R.; Connelly, P. J.; Farrant, A.; Fish, M.; Harkness, K.; Ince, P. G.; Langhorne, P.; Mann, J.; Matthews, F. E.; Mayer, P.; Pendlebury, S. T.; Perneczky, R.; Peters, R.; Smithard, D.; Stephan, B. C.; Swartz, J. E.; Todd, S.; Werring, D. J.; Wijayasiri, S. N.; Wilcock, G.; Zamboni, G.; Au, R.; Borson, S.; Bozoki, A.; Browndyke, J. N.; Corrada, M. M.; Crane, P. K.; Diniz, B. S.; Etcher, L.; Fillit, H.; Greenberg, S. M.; Grinberg, L. T.; Hurt, S. W.; Lamar, M.; Mielke, M.; Ott, B. R.; Perry, G.; Powers, W. J.; Ramos-Estebanez, C.; Reed, B.; Roberts, R. O.; Romero, J. R.; Saykin, A. J.; Seshadri, S.; Silbert, L.; Stern, Y.; Zarow, C.; Ben-Shlomo, Y.; Passmore, A. P.; Love, S.; Kehoe, P. G.

INTRODUCTION: Progress in understanding and management of vascular cognitive impairment (VCI) has been hampered by lack of consensus on diagnosis, reflecting the use of multiple different assessment protocols. A large multinational group of clinicians and researchers participated in a two-phase Vascular Impairment of Cognition Classification Consensus Study (VICCCS) to agree on principles (VICCCS-1) and protocols (VICCCS-2) for diagnosis of VCI. We present VICCCS-2. METHODS: We used VICCCS-1 principles and published diagnostic guidelines as points of reference for an online Delphi survey aimed at achieving consensus on clinical diagnosis of VCI. RESULTS: Six survey rounds comprising 65-79 participants agreed guidelines for diagnosis of VICCCS-revised mild and major forms of VCI and endorsed the National Institute of Neurological Disorders-Canadian Stroke Network neuropsychological assessment protocols and recommendations for imaging. DISCUSSION: The VICCCS-2 suggests standardized use of the National Institute of Neurological Disorders-Canadian Stroke Network recommendations on neuropsychological and imaging assessment for diagnosis of VCI so as to promote research collaboration.

2017 - A selenium species in cerebrospinal fluid predicts conversion to Alzheimer's dementia in persons with mild cognitive impairment [Articolo su rivista]
Vinceti, Marco; Chiari, Annalisa; Eichmüller, Marcel; Rothman, Kenneth J; Filippini, Tommaso; Malagoli, Carlotta; Weuve, Jennifer; Tondelli, Manuela; Zamboni, Giovanna; Nichelli, Paolo F; Michalke, Bernhard

Little is known about factors influencing progression from mild cognitive impairment to Alzheimer's dementia. A potential role of environmental chemicals and specifically of selenium, a trace element of nutritional and toxicological relevance, has been suggested. Epidemiologic studies of selenium are lacking, however, with the exception of a recent randomized trial based on an organic selenium form.

2017 - Clinical Correlates, Ethnic Differences, and Prognostic Implications of Perivascular Spaces in Transient Ischemic Attack and Ischemic Stroke [Articolo su rivista]
Lau, Kui Kai; Li, Linxin; Lovelock, Caroline E.; Zamboni, Giovanna; Chan, Tsz Tai; Chiang, Man Fung; Lo, Kin Ting; Küker, Wilhelm; Mak, Henry Ka Fung; Rothwell, Peter M.

Background and Purpose-Perivascular spaces (PVSs) are considered markers of small vessel disease. However, their long-Term prognostic implications in transient ischemic attack/ischemic stroke patients are unknown. Ethnic differences in PVS prevalence are also unknown. Methods-Two independent prospective studies were conducted, 1 comprising predominantly whites with transient ischemic attack/ischemic stroke (OXVASC [Oxford Vascular] study) and 1 comprising predominantly Chinese with ischemic stroke (University of Hong Kong). Clinical and imaging correlates, prognostic implications for stroke and death, and ethnic differences in basal ganglia (BG) and centrum semiovale (CS) PVSs were studied with adjustment for age, sex, vascular risk factors, and scanner strength. Results-Whites with transient ischemic attack/ischemic stroke (n=1028) had a higher prevalence of both BG and CS-PVSs compared with Chinese (n=974; >20 BG-PVSs: 22.4% versus 7.1%; >20 CS-PVSs: 45.8% versus 10.4%; P<0.0001). More than 20 BG or CS-PVSs were both associated with increasing age and white matter hyperintensity, although associations with BG-PVSs were stronger (all P<0.0001). During 6924 patient-years of follow-up, BG-PVSs were also independently associated with an increased risk of recurrent ischemic stroke (adjusted hazard ratio compared with <11 PVSs, 11-20 PVSs: HR, 1.15; 95% confidence interval, 0.78-1.68; >20 PVSs: HR, 1.82; 1.18-2.80; P=0.011) but not intracerebral hemorrhage (P=0.10) or all-cause mortality (P=0.16). CS-PVSs were not associated with recurrent stroke (P=0.57) or mortality (P=0.072). Prognostic associations were similar in both cohorts. Conclusions-Over and above ethnic differences in frequency of PVSs in transient ischemic attack/ischemic stroke patients, BG and CS-PVSs had similar risk factors, but although >20 BG-PVSs were associated with an increased risk of recurrent ischemic stroke, CS-PVSs were not.

2017 - PET tau and amyloid-β burden in mild Alzheimer's disease: Divergent relationship with age, cognition, and cerebrospinal fluid biomarkers [Articolo su rivista]
Koychev, Ivan; Gunn, Roger N.; Firouzian, Azadeh; Lawson, Jennifer; Zamboni, Giovanna; Ridha, Basil; Sahakian, Barbara J.; Rowe, James B.; Thomas, Alan; Rochester, Lynn; Ffytche, Dominic; Howard, Robert; Zetterberg, Henrik; Mackay, Clare; Lovestone, Simon

Background: Combining PET amyloid-β (Aβ) and tau imaging may be critical for tracking disease progression in Alzheimer's disease (AD). Objective:We sought to characterize the relationship betweenAβ and tau ligands as well as with other measures of pathology. Methods: We conducted a multi-center observational study in early AD (MMSE > 20) participants aged 50 to 85 y. The schedule included cognitive assessments (ADAS-Cog) and CSF measurement of A- and tau at baseline and 6 months; PET-CT imaging with Aβ ([18F]AV45) and tau ([18F]AV1451) ligands at baseline. Results: 22 participants took part in the study with 20 completing its 6-month duration and 12 having both tau and amyloid PET. The PET biomarker analysis revealed a strong negative correlation between age and tau in multiple regions. Entorhinal cortex tau and age interacted significantly in terms of cognitive change over 6 months which may have been to older participants deteriorating faster despite lower levels of cortical tau. Cortical Aβ associated with entorhinal cortex tau while CSF tau/Aβ ratio correlated strongly with cortical tau but not Aβ Conclusion: The negative relationship between age and cortical tau whereby younger patients with mild AD had relatively greater tau burden is potentially important. It suggests that younger-age onset AD may be primarily driven by tau pathology while AD developing later may depend on a multitude of pathological mechanisms. These data also suggest that PET-tau performs better than PET-amyloid in predicting the best validated AD diagnostic marker'the CSF total tau/Aβ ratio.

2017 - Selenium levels in patients with mild cognitive impairment and Alzheimer’s disease [Abstract in Atti di Convegno]
Vinceti, M; Chiari, A; Eichmüller, M; Rothman K., J; Filippini, T; Malagoli, C; Weuve, J; Tondelli, M; Zamboni, G; Nichelli P., F; Michalke, B.


2017 - The Vascular Impairment of Cognition Classification Consensus Study [Articolo su rivista]
Skrobot, O. A.; Love, S.; Kehoe, P. G.; O'Brien, J.; Black, S.; Chen, C.; Decarli, C.; Erkinjuntti, T.; Ford, G. A.; Kalaria, R. N.; Pantoni, L.; Pasquier, F.; Roman, G. C.; Wallin, A.; Sachdev, P.; Kril, J.; Skoog, I.; Ben-Shlomo, Y.; Passmore, A. P.; Engelborghs, S.; Lafosse, C.; Bertolucci, P. H.; Brucki, S.; Caramelli, P.; de Toledo Ferraz Alves, T. C.; Bocti, C.; Fulop, T.; Hogan, D. B.; Hsiung, G. R.; Kirk, A.; Leach, L.; Robillard, A.; Sahlas, D. J.; Guo, Q.; Tian, J.; Hokkanen, L.; Jokinen, H.; Benisty, S.; Deramecourt, V.; Hauw, J.; Lenoir, H.; Tsatali, M.; Tsolaki, M.; Sundar, U.; Coen, R. F.; Korczyn, A. D.; Altieri, M.; Baldereschi, M.; Caltagirone, C.; Caravaglios, G.; Di Carlo, A.; DI Piero, V.; Gainotti, G.; Galluzzi, S.; Logroscino, G.; Mecocci, P.; Moretti, D. V.; Padovani, A.; Fukui, T.; Ihara, M.; Mizuno, T.; Kim, S. Y.; Akinyemi, R.; Baiyewu, O.; Ogunniyi, A.; Szczudlik, A.; Bastos-Leite, A. J.; Firmino, H.; Massano, J.; Verdelho, A.; Kruglov, L. S.; Ikram, M. K.; Kandiah, N.; Arana, E.; Barroso-Ribal, J.; Calatayud, T.; Cruz-Jentoft, A. J.; Lopez-Pousa, S.; Martinez-Lage, P.; Mataro, M.; Borjesson-Hanson, A.; Englund, E.; Laukka, E. J.; Qiu, C.; Viitanen, M.; Biessels, G. J.; de Leeuw, F. -E.; den Heijer, T.; Exalto, L. G.; Kappelle, L. J.; Prins, N. D.; Richard, E.; Schmand, B.; van den Berg, E.; van der Flier, W. M.; Bilgic, B.; Allan, L. M.; Archer, J.; Attems, J.; Bayer, A.; Blackburn, D.; Brayne, C.; Bullock, R.; Connelly, P. J.; Farrant, A.; Fish, M.; Harkness, K.; Ince, P. G.; Langhorne, P.; Mann, J.; Matthews, F. E.; Mayer, P.; Pendlebury, S. T.; Perneczky, R.; Peters, R.; Smithard, D.; Stephan, B. C.; Swartz, J. E.; Todd, S.; Werring, D. J.; Wijayasiri, S. N.; Wilcock, G.; Zamboni, G.; Au, R.; Borson, S.; Bozoki, A.; Browndyke, J. N.; Corrada, M. M.; Crane, P. K.; Diniz, B. S.; Etcher, L.; Fillit, H.; Greenberg, S. M.; Grinberg, L. T.; Hurt, S. W.; Lamar, M.; Mielke, M.; Ott, B. R.; Perry, G.; Powers, W. J.; Ramos-Estebanez, C.; Reed, B.; Roberts, R. O.; Romero, J. R.; Saykin, A. J.; Seshadri, S.; Silbert, L.; Stern, Y.; Zarow, C.

Introduction: Numerous diagnostic criteria have tried to tackle the variability in clinical manifestations and problematic diagnosis of vascular cognitive impairment (VCI) but none have been universally accepted. These criteria have not been readily comparable, impacting on clinical diagnosis rates and in turn prevalence estimates, research, and treatment. Methods: The Vascular Impairment of Cognition Classification Consensus Study (VICCCS) involved participants (81% academic researchers) from 27 countries in an online Delphi consensus study. Participants reviewed previously proposed concepts to develop new guidelines. Results: VICCCS had a mean of 122 (98-153) respondents across the study and a 67% threshold to represent consensus. VICCCS redefined VCI including classification of mild and major forms of VCI and subtypes. It proposes new standardized VCI-associated terminology and future research priorities to address gaps in current knowledge. Discussion: VICCCS proposes a consensus-based updated conceptualization of VCI intended to facilitate standardization in research.

2017 - White Matter Imaging Correlates of Early Cognitive Impairment Detected by the Montreal Cognitive Assessment after Transient Ischemic Attack and Minor Stroke [Articolo su rivista]
Zamboni, Giovanna; Griffanti, Ludovica; Jenkinson, Mark; Mazzucco, Sara; Li, Linxin; Küker, Wilhelm; Pendlebury, Sarah T; Rothwell, Peter M.

BACKGROUND AND PURPOSE:  Among screening tools for cognitive impairment in large cohorts, the Montreal Cognitive assessment (MoCA) appears to be more sensitive to early cognitive impairment than the Mini-Mental State Examination (MMSE), particularly after transient ischemic attack (TIA) or minor stroke. We reasoned that if MoCA-detected early cognitive impairment is pathologically significant, then it should be specifically associated with the presence of white matter hyperintensities (WMH) and reduced fractional anisotropy (FA) on MRI. METHODS: Consecutive eligible patients with TIA or minor stroke (Oxford Vascular Study) underwent MRI and cognitive assessment. We correlated MoCA and MMSE scores with WMH and FA, then specifically studied patients with low MoCA and normal MMSE. RESULTS: Among 400 patients, MoCA and MMSE scores were significantly correlated (all p<0.001) with WMH volumes (rMoCA=-0.336, rMMSE=-0.297) and FA (rMoCA=0.409, rMMSE=0.369), and -on voxel-wise analyses- with WMH in frontal white matter and reduced FA in almost all white matter tracts. However, only the MoCA was independently correlated with WMH volumes (r=-0.183, p<0.001), average FA values (r=0.218, p<0.001), and voxel-wise reduced FA in anterior tracts after controlling for the MMSE. In addition, patients with low MoCA but normal MMSE (N=57) had higher WMH volumes (t=3.1,p=0.002), lower average FA (t=-4.0,p<0.001), and lower voxel-wise FA in almost all white matter tracts than those with normal MoCA and MMSE (N=238). CONCLUSIONS: In patients with TIA or minor stroke, early cognitive impairment detected with the MoCA but not with the MMSE was independently associated with white matter damage on MRI, particularly reduced FA.

2016 - BIANCA (Brain Intensity AbNormality Classification Algorithm): A new tool for automated segmentation of white matter hyperintensities [Articolo su rivista]
Griffanti, Ludovica; Zamboni, Giovanna; Khan, Aamira; Li, Linxin; Bonifacio, Guendalina; Sundaresan, Vaanathi; Schulz, Ursula G.; Kuker, Wilhelm; Battaglini, Marco; Rothwell, Peter M.; Jenkinson, Mark

Reliable quantification of white matter hyperintensities of presumed vascular origin (WMHs) is increasingly needed, given the presence of these MRI findings in patients with several neurological and vascular disorders, as well as in elderly healthy subjects. We present BIANCA (Brain Intensity AbNormality Classification Algorithm), a fully automated, supervised method for WMH detection, based on the k-nearest neighbour (k-NN) algorithm. Relative to previous k-NN based segmentation methods, BIANCA offers different options for weighting the spatial information, local spatial intensity averaging, and different options for the choice of the number and location of the training points. BIANCA is multimodal and highly flexible so that the user can adapt the tool to their protocol and specific needs. We optimised and validated BIANCA on two datasets with different MRI protocols and patient populations (a “predominantly neurodegenerative” and a “predominantly vascular” cohort). BIANCA was first optimised on a subset of images for each dataset in terms of overlap and volumetric agreement with a manually segmented WMH mask. The correlation between the volumes extracted with BIANCA (using the optimised set of options), the volumes extracted from the manual masks and visual ratings showed that BIANCA is a valid alternative to manual segmentation. The optimised set of options was then applied to the whole cohorts and the resulting WMH volume estimates showed good correlations with visual ratings and with age. Finally, we performed a reproducibility test, to evaluate the robustness of BIANCA, and compared BIANCA performance against existing methods. Our findings suggest that BIANCA, which will be freely available as part of the FSL package, is a reliable method for automated WMH segmentation in large cross-sectional cohort studies.

2016 - Brain imaging in dementia [Articolo su rivista]
Bonifacio, Guendalina; Zamboni, Giovanna

The introduction of MRI and positron emission tomography (PET) brain imaging has contributed significantly to the understanding of different dementia syndromes. Over the past 20 years these imaging techniques have been increasingly used for clinical characterisation and differential diagnosis, and to provide insight into the effects on functional capacity of the brain, patterns of spatial distribution of different dementia syndromes and their natural history and evolution over time. Brain imaging is also increasingly used in clinical trials, as part of inclusion criteria and/or as a surrogate outcome measure. Here we review all the relatively specific findings that can be identified with different MRI and PET techniques in each of the most frequent dementing disorders.

2016 - Challenges in the reproducibility of clinical studies with resting state fMRI: An example in early Parkinson's disease [Articolo su rivista]
Griffanti, Ludovica; Rolinski, Michal; Szewczyk Krolikowski, Konrad; Menke, Ricarda A.; Filippini, Nicola; Zamboni, Giovanna; Jenkinson, Mark; Hu, Michele T. M.; Mackay, Clare E.

Resting state fMRI (rfMRI) is gaining in popularity, being easy to acquire and with promising clinical applications. However, rfMRI studies, especially those involving clinical groups, still lack reproducibility, largely due to the different analysis settings. This is particularly important for the development of imaging biomarkers. The aim of this work was to evaluate the reproducibility of our recent study regarding the functional connectivity of the basal ganglia network in early Parkinson's disease (PD) (Szewczyk-Krolikowski et al., 2014). In particular, we systematically analysed the influence of two rfMRI analysis steps on the results: the individual cleaning (artefact removal) of fMRI data and the choice of the set of independent components (template) used for dual regression.Our experience suggests that the use of a cleaning approach based on single-subject independent component analysis, which removes non neural-related sources of inter-individual variability, can help to increase the reproducibility of clinical findings. A template generated using an independent set of healthy controls is recommended for studies where the aim is to detect differences from a "healthy" brain, rather than an "average" template, derived from an equal number of patients and controls. While, exploratory analyses (e.g. testing multiple resting state networks) should be used to formulate new hypotheses, careful validation is necessary before promising findings can be translated into useful biomarkers.

2016 - Donepezil Enhances Frontal Functional Connectivity in Alzheimer's Disease: A Pilot Study [Articolo su rivista]
Griffanti, Ludovica; Wilcock, Gordon K.; Voets, Natalie; Bonifacio, Guendalina; Mackay, Clare E.; Jenkinson, Mark; Zamboni, Giovanna

Background: We have previously shown that increased resting-state functional magnetic resonance imaging (fMRI)-based functional connectivity (FC) within the frontal resting-state networks in Alzheimer's disease (AD) patients reflects residual, possibly compensatory, function. This suggests that symptomatic treatments should aim to enhance FC specifically in these networks. Methods: 18 patients with probable AD underwent brain MRI and neuropsychological assessment at baseline and after 12 weeks of treatment with donepezil. We tested if changes in cognitive performance after treatment correlated with changes in FC in resting-state networks known to be altered in AD. Results: We found increases in FC in the orbitofrontal network that correlated with cognitive improvement after treatment. The increased FC was greatest in patients who responded most to treatment. Conclusion: This 'proof of concept' study suggests that changes in network-specific FC might be a biomarker of pharmacological intervention efficacy in AD.

2016 - Functional specialization and network connectivity in brain function [Capitolo/Saggio]
Zamboni, Giovanna

Do mental processes depend from ‘localized’ brain regions or are they ‘global’ resulting from the integrated functioning of the brain as a whole? Brain lesion studies and neuroimaging methods have given evidence of both interpretations, allowing contemporary neuroscience to reach the conclusion that localized regions of the brain do carry out specific cognitive functions but they do so through multiple and complex interactions with many other brain regions forming large-scale networks.

2016 - Tocilizumab-associated multifocal cerebral thrombotic microangiopathy [Articolo su rivista]
Jewell, Paul; Ansorge, Olaf; Kuker, Wilhelm; Irani, Sarosh R.; Zamboni, Giovanna

Tocilizumab is a humanized monoclonal antibody that targets the interleukin-6 receptor (IL-6-R). It is approved for use in moderate to severe refractory rheumatoid arthritis and more recently has been found to be effective in treating neuromyelitis optica.1 Common side effects include raised hepatic transaminases, gastroenteritis, infections, and hypertension. Neurologic side effects have been described in 2 single case reports, which were confounded by the concomitant use of other antirheumatic therapies and lengthy durations between tocilizumab administration and onset of neurologic symptoms.,3 We describe the clinico-histologic analysis of an acute neurologic deterioration 2 weeks after the first infusion of tocilizumab.

2015 - Aberrant functional connectivity within the basal ganglia of patients with Parkinson's disease [Articolo su rivista]
Rolinski, Michal; Griffanti, Ludovica; Szewczyk Krolikowski, Konrad; Menke, Ricarda A. L.; Wilcock, Gordon K.; Filippini, Nicola; Zamboni, Giovanna; Hu, Michele T. M.; Mackay, Clare E.

Resting state functional MRI (rs-fMRI) has been previously shown to be a promising tool for the assessment of early Parkinson's disease (PD). In order to assess whether changes within the basal ganglia network (BGN) are disease specific or relate to neurodegeneration generally, BGN connectivity was assessed in 32 patients with early PD, 19 healthy controls and 31 patients with Alzheimer's disease (AD). Voxel-wise comparisons demonstrated decreased connectivity within the basal ganglia of patients with PD, when compared to patients with AD and healthy controls. No significant changes within the BGN were seen in AD, when compared to healthy controls. Moreover, measures of functional connectivity extracted from regions within the basal ganglia were significantly lower in the PD group. Consistent with previous radiotracer studies, the greatest change when compared to the healthy control group was seen in the posterior putamen of PD subjects. When combined into a single component score, this method differentiated PD from AD and healthy control subjects, with a diagnostic accuracy of 81%. Rs-fMRI can be used to demonstrate the aberrant functional connectivity within the basal ganglia of patients with early PD. These changes are likely to be representative of patho-physiological basal ganglia dysfunction and are not associated with generalised neurodegeneration seen in AD. Further studies are necessary to ascertain whether this method is sensitive enough to detect basal ganglia dysfunction in prodromal PD, and its utility as a potential diagnostic biomarker for premotor and early motoric disease.

2015 - The neural bases for devaluing radical political statements revealed by penetrating traumatic brain injury [Articolo su rivista]
Cristofori, Irene; Viola, Vanda; Chau, Aileen; Zhong, Wanting; Krueger, Frank; Zamboni, Giovanna; Grafman, Jordan

Given the determinant role of ventromedial prefrontal cortex (vmPFC) in valuation, we examined whether vmPFC lesions also modulate how people scale political beliefs. Patients with penetrating traumatic brain injury (pTBI; N1/4102) and healthy controls (HCs; N1/431) were tested on the political belief task, where they rated 75 statements expressing political opinions concerned with welfare, economy, political involvement, civil rights, war and security. Each statement was rated for level of agreement and scaled along three dimensions: radicalism, individualism and conservatism. Voxel-based lesionsymptom mapping (VLSM) analysis showed that diminished scores for the radicalism dimension (i.e. statements were rated as less radical than the norms) were associated with lesions in bilateral vmPFC. After dividing the pTBI patients into three groups, according to lesion location (i.e. vmPFC, dorsolateral prefrontal cortex [dlPFC] and parietal cortex), we found that the vmPFC, but not the dlPFC, group had reduced radicalism scores compared with parietal and HC groups. These findings highlight the crucial role of the vmPFC in appropriately valuing political behaviors and may explain certain inappropriate social judgments observed in patients with vmPFC lesions.

2014 - Aberrant functional connectivity in dissociable hippocampal networks is associated with deficits in memory [Articolo su rivista]
Voets, Natalie L.; Zamboni, Giovanna; Stokes, Mark G.; Carpenter, Katherine; Stacey, Richard; Adcock, Jane E.

In the healthy human brain, evidence for dissociable memory networks along the anterior-posterior axis of the hippocampus suggests that this structuremaynot function as a unitary entity. Failure to consider these functional divisionsmayexplain diverging resultsamong studies of memory adaptation in disease. Using task-based and resting functional MRI, we show that chronic seizures disrupting the anterior medial temporal lobe (MTL) preserve anterior and posterior hippocampal-cortical dissociations, but alter signaling between these and other key brain regions. During performance of a memory encoding task, we found reduced neural activity in human patients with unilateral temporal lobe epilepsy relative to age-matched healthy controls, but no upregulation of fMRI signal in unaffected hippocampal subregions. Instead, patients showed aberrant resting fMRI connectivity within anterior and posterior hippocampal-cortical networks, which was associated with memory decline, distinguishing memory-intact from memory-impaired patients. Our results highlight a critical role for intact hippocampo-cortical functional communication in memory and provide evidence that chronic injuryinduced functional reorganization in the diseased MTL is behavioral inefficient. © 2014 the authors.

2014 - Functional connectivity in the basal ganglia network differentiates PD patients from controls [Articolo su rivista]
Szewczyk Krolikowski, Konrad; Menke, Ricarda A. L.; Rolinski, Michal; Duff, Eugene; Salimi Khorshidi, Gholamreza; Filippini, Nicola; Zamboni, Giovanna; Hu, Michele T. M.; Mackay, Clare E.

Objective: To examine functional connectivity within the basal ganglia network (BGN) in a group of cognitively normal patients with early Parkinson disease (PD) on and off medication compared to age- and sex-matched healthy controls (HC), and to validate the findings in a separate cohort of participants with PD. Methods: Participants were scanned with resting-state fMRI (RS-fMRI) at 3T field strength. Resting-state networks were isolated using independent component analysis. A BGN template was derived from 80 elderly HC participants. BGN maps were compared between 19 patients with PD on and off medication in the discovery group and 19 age- and sex-matched controls to identify a threshold for optimal group separation. The threshold was applied to 13 patients with PD (including 5 drug-naive) in the validation group to establish reproducibility of findings. Results: Participants with PD showed reduced functional connectivity with the BGN in a wide range of areas. Administration of medication significantly improved connectivity. Average BGN connectivity differentiated participants with PD from controls with 100% sensitivity and 89.5% specificity. The connectivity threshold was tested on the validation cohort and achieved 85% accuracy. Conclusions: We demonstrate that resting functional connectivity, measured with MRI using an observer-independent method, is reproducibly reduced in the BGN in cognitively intact patients with PD, and increases upon administration of dopaminergic medication. Our results hold promise for RS-fMRI connectivity as a biomarker in early PD. Classification of evidence: This study provides Class III evidence that average connectivity in the BGN as measured by RS-fMRI distinguishes patients with PD from age- and sex-matched controls. © 2014 American Academy of Neurology.

2014 - Recovery from Emotion Recognition Impairment after Temporal Lobectomy [Articolo su rivista]
Benuzzi, Francesca; Zamboni, Giovanna; Meletti, Stefano; Serafini, Marco; Lui, Fausta; Baraldi, Patrizia; Duzzi, Davide; Rubboli, Guido; Albertotassinari, Carlo; Nichelli, Paolo Frigio

Mesial temporal lobe epilepsy (MTLE) can be associated with emotion recognition impairment that can be particularly severe in patients with early onset seizures (1–3). Whereas, there is growing evidence that memory and language can improve in seizure-free patients after anterior temporal lobectomy (ATL) (4), the effects of surgery on emotional processing are still unknown. We used functional magnetic resonance imaging (fMRI) to investigate short-term reorganization of networks engaged in facial emotion recognition in MTLE patients. Behavioral and fMRI data were collected from six patients before and after ATL. During the fMRI scan, patientswere asked to make a gender decision on fearful and neutral faces. Behavioral data demonstrated that two patients with early onset right MTLE were impaired in fear recognition while fMRI results showed they lacked specific activations for fearful faces. Post-ATL behavioral data showed improved emotion recognition ability, while fMRI demonstrated the recruitment of a functional network for fearful face processing. Our results suggest that ATL elicited brain plasticity mechanisms allowing behavioral and fMRI improvement in emotion recognition.

2014 - Role of depression in predicting time to conversion to mild cognitive impairment [Articolo su rivista]
Dean, Katherine; Oulhaj, Abderrahim; Zamboni, Giovanna; Dejager, Celeste A.; Wilcock, Gordon K.

Objective: To establish whether, in a cohort with normal cognition, severity of depressive symptoms at baseline was related to the time taken for conversion to mild cognitive impairment (MCI) and whether this interacted with other potential risk factors, including APOE ε4 status and demographic and cognitive variables. Methods: In a population-based cohort study, 126 cognitively normal subjects were assessed for depressive symptoms at baseline using the Geriatric Depression Scale (GDS) and were then followed over 20 years with regular cognitive assessments. The interval-censored accelerated failure time model was used to establish whether GDS and other factors, including APOE ε4 status, predicted the median time to development of MCI. Results: Fifty subjects developed MCI. In APOE ε4 noncarriers, the degree of depressive symptoms at baseline predicted the time to development of MCI: An increase in GDS of 1 standard deviation (3.85) was associated with shortening of the median time to conversion to MCI by 25.4% (p = 0.0024, z = -5.6). This relationship remained statistically significant after controlling for cognitive and other confounding variables. The relationship was not significant in APOE ε4 carriers. Conclusion: Depressive symptoms (measured by GDS) predict time to conversion to MCI in cognitively normal people who do not carry the APOE ε4 allele. This may explain conflicting results of previous studies where APOE ε4 status was not taken into account when exploring the relationship between depression and MCI. It may also have a clinical application in helping to identify people at greater risk of developing MCI. © 2014 American Association for Geriatric Psychiatry.

2013 - Brain microstructure reveals early abnormalities more than two years prior to clinical progression from mild cognitive impairment to Alzheimer's disease [Articolo su rivista]
Douaud, Gwenaëlle; Menke, Ricarda A. L.; Gass, Achim; Monsch, Andreas U.; Rao, Anil; Whitcher, Brandon; Zamboni, Giovanna; Matthews, Paul M.; Sollberger, Marc; Smith, Stephen

Diffusion imaging is a promising marker of microstructural damage in neurodegenerative disorders, but interpretation of its relationship with underlying neuropathology can be complex. Here, we examined both volumetric and brain microstructure abnormalities in 13 amnestic patients with mild cognitive impairment (MCI), who progressed to probable Alzheimer's disease (AD) no earlier than 2 years after baseline scanning, inorder to focus on early, and hence more sensitive, imaging markers. We compared them to 22 stable amnestic MCI patients with similar cognitive performance and episodic memory impairment but who did not show progression of symptoms for at least 3 years. Significant group differences were mainly found in the volume and microstructure of the left hippocampus, while white matter group differences were also found in the body of the fornix, left fimbria, and superior longitudinal fasciculus (SLF). Diffusion index abnormalities in the SLF were the sign of a subtle microstructural injury not detected by standard atrophy measures in the corresponding gray matter regions. The microstructural measure obtained in the left hippocampus using diffusion imaging showed the mostsubstantial differences between the two groups and was the best single predictor of future progression to AD. Anoptimal prediction model (91% accuracy, 85% sensitivity, 96% specificity) was obtained by combining MRI measures and CSF protein biomarkers. These results highlight the benefit of using the information of brain microstructural damage, in addition to traditional gray matter volume, to detectearly, subtle abnormalities in MCI prior to clinical progression to probable AD and, in combination with CSF markers, to accurately predict such progression. © 2013 the authors.

2013 - Neuroanatomy of impaired self-awareness in Alzheimer's disease and mild cognitive impairment [Articolo su rivista]
Zamboni, Giovanna; Drazich, Erin; Mcculloch, Ellen; Filippini, Nicola; Mackay, Clare E.; Jenkinson, Mark; Tracey, Irene; Wilcock, Gordon K.

Introduction: Patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) may be unaware of their cognitive impairment. The neuroanatomical mechanisms underlying this symptom, termed anosognosia or impaired self-awareness, are still poorly understood. In the present study we aimed to explore the functional correlates of self-awareness in patients with MCI and AD. Methods: Fifty-one participants (17 healthy elderly, 17 patients with MCI, and 17 patients with AD), each accompanied by a study partner, took part in a functional magnetic resonance imaging (fMRI) study, in which they were presented with questions regarding themselves (Self condition) or their study partner (Other condition). The study partner was asked to complete a paper questionnaire answering the same questions so the responses of participant and study partner could be compared and "discrepancy" scores calculated for each of the 2 conditions (Self and Other). Results: Behavioural results showed that AD patients had significantly higher "Self discrepancy scores" than controls and MCI patients, whereas there were no significant differences between groups for "Other discrepancy scores" Imaging results showed a significant group-by-condition interaction in brain activation in medial prefrontal and anterior temporal regions, with AD patients showing significantly decreased activation in these regions only for the Self condition. There were no significant differences between Self and Other conditions in either control or MCI groups, suggesting that, in these groups, Self- and Other-appraisal share similar neuroanatomical substrates. Conclusions: Decreased functional activation of medial prefrontal and anterior temporal cortices is associated with impaired self-awareness in AD patients. This dysfunction, which is specific for Self- but not for Other-appraisal, may be a contributing factor to anosognosia in AD. © 2012 Elsevier Ltd.

2013 - Resting functional connectivity reveals residual functional activity in Alzheimer's disease [Articolo su rivista]
Zamboni, Giovanna; Wilcock, Gordon K.; Douaud, Gwenaelle; Drazich, Erin; Mcculloch, Ellen; Filippini, Nicola; Tracey, Irene; Brooks, Jonathan C. W.; Smith, Stephen M.; Jenkinson, Mark; Mackay, Clare E.

Background Functional magnetic resonance imaging (fMRI) has great potential for measuring mechanisms of functional changes in Alzheimer's disease (AD) and mild cognitive impairment, but task fMRI studies have produced conflicting results, partly due to failure to account for underlying morphological changes and to variations in patients' ability to perform the tasks. Resting fMRI has potential for assessing brain function independently from a task, but greater understanding of how networks of resting functional connectivity relate to the functioning of the brain is needed. We combined resting fMRI and task fMRI to examine the correspondence between these methods in individuals with cognitive impairment. Methods Eighty elderly (25 control subjects, 25 mild cognitive impairment, 30 AD) underwent a combined multimodal magnetic resonance imaging protocol including task fMRI and resting fMRI. Task fMRI data were acquired during the execution of a memory paradigm designed to account for differences in task performance. Structural and physiological confounds were modeled for both fMRI modalities. Results Successful recognition was associated with increased task fMRI activation in lateral prefrontal regions in AD relative to control subjects; this overlapped with increased resting fMRI functional connectivity in the same regions. Conclusions Our results show that task fMRI and resting fMRI are sensitive markers of residual ability over the known changes in brain morphology and cognition occurring in AD and suggest that resting fMRI has a potential to measure the effect of new treatments. © 2013 Society of Biological Psychiatry.

2013 - Structural and functional bases of visuospatial associative memory in older adults [Articolo su rivista]
Zamboni, Giovanna; de Jager, Celeste A.; Drazich, Erin; Douaud, Gwenaëlle; Jenkinson, Mark; Smith, A. David; Tracey, Irene; Wilcock, Gordon K.

Impaired visuospatial associative memory may be one of the earliest changes predicting cognitive impairment and Alzheimers disease. We explored the relationship between performance on a visuospatial associative memory task (the Placing Test) and brain structure and function in cognitively healthy older adults. First, we performed a voxel-based morphometry correlational analysis on structural magnetic resonance imaging (MRI) data from 144 healthy older adults with their scores on the Placing Test. Second, we carried out a functional MRI study on another group of 28 healthy older adults who performed a similar task during functional MRI. Decreased performance on the Placing Test was associated with increased atrophy in medial-temporal regions. Functional activation of the same regionscontrolling for the effect of atrophyoccurred during successful performance of the same task. The colocalization of structural and functional MRI correspondents of visuospatial associative test performance within medial-temporal regions validates multimodal imaging in describing behaviorally relevant variability in the aging brain and suggests that the Placing Test has the potential for detecting early cognitive changes occurring in preclinical phases of Alzheimer's disease. © 2013 Elsevier Inc.

2012 - "My sister's hand is in my bed": a case of somatoparaphrenia. [Articolo su rivista]
Pugnaghi, Matteo; Molinari, M; Panzetti, Patrizia; Nichelli, Paolo Frigio; Zamboni, Giovanna

Case report of a patient who, after a right thalamic, developed somatoparaphrenia

2012 - Differences in cognitive profile between TIA, stroke and elderly memory research subjects: A comparison of the MMSE and MoCA [Articolo su rivista]
Pendlebury, S. T.; Markwick, A.; De Jager, C. A.; Zamboni, Giovanna; Wilcock, G. K.; Rothwell, P. M.

Background: The Montreal Cognitive Assessment (MoCA) appears more sensitive to mild cognitive impairment (MCI) than the Mini-Mental State Examination (MMSE): over 50% of TIA and stroke patients with an MMSE score of ≥27 ('normal' cognitive function) at ≥6 months after index event, score <26 on the MoCA, a cutoff which has good sensitivity and specificity for MCI in this population. We hypothesized that sensitivity of the MoCA to MCI might in part be due to detection of different patterns of cognitive domain impairment. We therefore compared performance on the MMSE and MoCA in subjects without major cognitive impairment (MMSE score of ≥24) with differing clinical characteristics: a TIA and stroke cohort in which frontal/executive deficits were expected to be prevalent and a memory research cohort. Methods: The MMSE and MoCA were done on consecutive patients with TIA or stroke in a population-based study (Oxford Vascular Study) 6 months or more after the index event and on consecutive subjects enrolled in a memory research cohort (the Oxford Project to Investigate Memory and Ageing). Patients with moderate-to-severe cognitive impairment (MMSE score of <24), dysphasia or inability to use the dominant arm were excluded. Results: Of 207 stroke patients (mean age ± SD: 72 ± 11.5 years, 54% male), 156 TIA patients (mean age 71 ± 12.1 years, 53% male) and 107 memory research subjects (mean age 76 ± 6.6 years, 46% male), stroke patients had the lowest mean ± SD cognitive scores (MMSE score of 27.7 ± 1.84 and MoCA score of 22.9 ± 3.6), whereas TIA (MMSE score of 28.4 ± 1.7 and MoCA score of 24.9 ± 3.3) and memory subject scores (MMSE score of 28.5 ± 1.7 and MoCA score of 25.5 ± 3.0) were more similar. Rates of MoCA score of <26 in subjects with normal MMSE ( ≥27) were lowest in memory subjects, intermediate in TIA and highest after stroke (34 vs. 48 vs. 67%, p < 0.001). The cerebrovascular patients scored lower than the memory subjects on all MoCA frontal/executive subtests with differences being most marked in visuoexecutive function, verbal fluency and sustained attention (all p < 0.0001) and in stroke versus TIA (after adjustment for age and education). Stroke patients performed worse than TIA patients only on MMSE orientation in contrast to 6/10 subtests of the MoCA. Results were similar after restricting analyses to those with an MMSE score of ≥27. Conclusions: The MoCA demonstrated more differences in cognitive profile between TIA, stroke and memory research subjects without major cognitive impairment than the MMSE. The MoCA showed between-group differences even in those with normal MMSE and would thus appear to be a useful brief tool to assess cognition in those with MCI, particularly where the ceiling effect of the MMSE is problematic. Copyright © 2012 S. Karger AG, Basel.

2012 - Profiles of cognitive subtest impairment in the Montreal Cognitive Assessment (MoCA) in a research cohort with normal Mini-Mental State Examination (MMSE) scores [Articolo su rivista]
Markwick, Arwen; Zamboni, Giovanna; De Jager, Celeste A.

The comparative ability of the Montreal Cognitive Assessment (MoCA) and MMSE to detect mild cognitive difficulties was investigated in 107 older adults. The sensitivity of the MoCA to detect cognitive impairment with a cutoff score of <26 was investigated, as compared to the MMSE across all scores, and at a cutoff of 27. Performance on MoCA subtests was compared at these MMSE cutoffs to determine profiles of early cognitive difficulties. The MoCA detected cognitive impairment not detected by the MMSE in a high proportion of participants, and this impairment was evident across various subtests. The MoCA appears to be a sensitive screening test for detection of early cognitive impairment. © 2012 Psychology Press.

2012 - Structural MRI changes detectable up to ten years before clinical Alzheimer's disease [Articolo su rivista]
Tondelli, Manuela; G. K., Wilcock; Nichelli, Paolo Frigio; C. A., De Jager; M., Jenkinson; Zamboni, Giovanna

Structural brain changes have been described in both mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, less is known about whether structural changes are detectable earlier, in the asymptomatic phase. Using voxel-based morphometry (VBM) and shape analyses of magnetic resonance imaging (MRI) data, we investigated structural brain differences between groups of healthy subjects, stratified by subsequent diagnoses of MCI or AD during a 10-year follow-up. Images taken at baseline, at least 4 years before any cognitive symptoms, showed that subjects with future cognitive impairment (preclinical AD and MCI) had reduced brain volume in medial temporal lobes, posterior cingulate/precuneus, and orbitofrontal cortex, compared with matched subjects who remained cognitively healthy for 10 years (HC). For only those subjects later diagnosed as AD, significantly greater atrophy at baseline was detected in the right medial temporal lobe, which was also confirmed by shape analysis of the right hippocampus in these subjects. Our results demonstrate that structural brain changes occur years before clinical cognitive decline in AD and are localized to regions affected by AD neuropathology.

2012 - The Neural Structure of Political Beliefs [Capitolo/Saggio]
Moretti, Laura; Cristofori, Irene; Zamboni, Giovanna; Sirigu, Angela

The purpose of this chapter is to show how political beliefs and political behavior are processed in the brain. We first introduce the concept of politic behavior as formalized in cognitive psychology, then, we show how neuroscience has contributed to uncover the brain mechanisms implicated in political thinking.

2012 - The role of MRI in the early diagnosis of Alzheimer’s disease or other dementias in persons with mild cognitive impairment (MCI) [Articolo su rivista]
Filippini, Graziella; Casazza, Giovanni; Bellatorre, Alessandro Giacco; Lista, Chiara; Duca, Piergiorgio; Beecher, Deirdre; Costantino, Giorgio; Falcone, Chiara; Zamboni, Giovanna; Cavedo, Enrica; Frisoni, Giovanni

This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the accuracy of structural MRI in identifying people with MCI due to AD versus people with MCI due to other dementias or with no dementia. To evaluate how the performance of MRI may vary according to the spectrum of tested patients, the setting, the brain region of interest and the technical characteristics of the imaging test.

2011 - Lack of awareness of symptoms in people with dementia: The structural and functional basis [Articolo su rivista]
Zamboni, Giovanna; Wilcock, G.

Objective To review studies investigating the brain correlates of unawareness of cognitive and behavioural symptoms in people with dementia. Design A detailed search of the literature was conducted to include all the peer-reviewed studies published in English aimed at identifying the structural or functional brain correspondents of unawareness in dementia patients. Their results were interpreted in relation to the methodological differences in terms of type of dementia studied, the protocol adopted to measure lack of awareness, the imaging techniques employed, the experimental designs and statistical analyses performed. Results Eighteen studies undertaken to explore the functional and structural correlates of unawareness of cognitive symptoms in dementia were identified. Although their results showed a disparate range of brain correlates, they were mainly localized in frontal and temporo-parietal regions. Conclusions Although the anatomical correlates of unawareness of disease in dementia have not yet been exhaustively explored, understanding the correlates of unawareness may also contribute to understand the brain correlates of self-awareness and self-reflection. We discuss the current knowledge base and consider potential future directions for research. Copyright © 2010 John Wiley & Sons, Ltd.

2011 - Regional brain atrophy and impaired decision making on the Balloon Analog Risk Task in behavioral variant frontotemporal dementia [Articolo su rivista]
Strenziok, Maren; Pulaski, Sarah; Krueger, Frank; Zamboni, Giovanna; Clawson, Deborah; Grafman, Jordan

Objective:: The goal of this study was 2-fold, first, to compare decision making in behavioral variant frontotemporal dementia (bvFTD) patients and healthy adults using the Balloon Analog Risk Task (BART), and, second, to identify the regions of gray matter atrophy associated with bvFTD patients' BART performance. Background:: Stimulus-reinforcement learning is required to evaluate the results of previously chosen actions to improve future decisions. Although there is a well established literature suggesting altered decision making in FTD patients and data from lesion studies suggest orbitofrontal cortex (OFC) involvement in decision making, there is very little research looking at the brain correlates of decision making in FTD populations specifically. Method:: Twenty-seven bvFTD patients and 19 age-matched and education-matched normal controls completed the BART. Voxel-based morphometry analysis was performed on the magnetic resonance imaging scans of a subset of patients. Results:: Compared with healthy controls, the bvFTD patients did not learn and pumped less to inflate a balloon to receive a reward, indicating altered stimulus-reinforcement learning. The voxel-based morphometry analysis indicated that bvFTD patients' impaired BART performance was related to atrophy in the right lateral OFC. Conclusions: The right lateral OFC is crucial for stimulus-reinforcement learning required for the adjustment of behavior under changing reward contingencies. Copyright © 2011 by Lippincott Williams & Wilkins.

2011 - resting and task-related functional MRI in mild cognitive impairment and Alzheimer's disease [Abstract in Atti di Convegno]
Zamboni, Giovanna; Drazich, Erin; Filippini, Nicola; Mcculloch, Ellen; Tracey, Irene; Wilcock, Gordon


2010 - Anosognosia for behavioral disturbances in frontotemporal dementia and corticobasal syndrome: A voxel-based morphometry study [Articolo su rivista]
Zamboni, Giovanna; Grafman, J.; Krueger, F.; Knutson, K. M.; Huey, E. D.

Background: Patients with syndromes of the frontotemporal dementia spectrum are frequently unaware of their behavioral changes. Methods: Seventy patients with a clinical diagnosis of behavioral variant frontotemporal dementia (bv-FTD, n = 27), aphasic variant frontotemporal dementia (a-FTD, n = 12) and corticobasal syndrome (CBS, n = 31) participated in the study. Anosognosia for behavioral disturbances was measured as discrepancy between caregiver's and patient's ratings on the Frontal Systems Behavior Scale for present and premorbid behavioral symptoms. Voxel-based morphometry analysis of MRI data was performed to explore the association between anosognosia and gray matter loss. Results: Although behavioral symptoms were reported in all the groups, the comparison between present and premorbid anosognosia revealed that bv-FTD patients not only underestimated their present behavioral disturbances compared to their caregivers, but also overestimated their premorbidbehavioral disturbances. Across all groups, the degree of anosognosia for present behavioral impairment correlated with gray matter atrophy in a posterior region of the right superior temporal sulcus (adjacent to the temporoparietal junction). Conclusion: These results confirm the role of the right temporoparietal cortex in the genesis of anosognosia and suggest that, in clinical syndromes of the frontotemporal dementia spectrum, anosognosia is associated with the dysfunction of temporoparietal mechanisms of self versus others knowledge. Copyright © 2010 S. Karger AG, Basel.

2010 - Interest in politics modulates neural activity in the amygdala and ventral striatum [Articolo su rivista]
Gozzi, Marta; Zamboni, Giovanna; Krueger, Frank; Grafman, Jordan

Studies on political participation have found that a person's interest in politics contributes to the likelihood that he or she will be involved in the political process. Here, we looked at whether or not interest in politics affects patterns of brain activity when individuals think about political matters. Using functional magnetic resonance imaging (fMRI), we scanned individuals (either interested or uninterested in politics based on a self-report questionnaire) while they were expressing their agreement or disagreement with political opinions. After scanning, participants were asked to rate each political opinion presented in the scanner for emotional valence and emotional intensity. Behavioral results showed that those political opinions participants agreed with were perceived as more emotionally intense and more positive by individuals interested in politics relative to individuals uninterested in politics. In addition, individuals interested in politics showed greater activation in the amygdala and the ventral striatum (ventral putamen) relative to individuals uninterested in politics when reading political opinions in accordance with their own views. This study shows that having an interest in politics elicits activations in emotion- and reward-related brain areas even when simply agreeing with written political opinions. © 2010 Wiley-Liss, Inc.

2010 - Lower Lateral Orbitofrontal Cortex Density Associated With More Frequent Exposure to Television and Movie Violence in Male Adolescents [Articolo su rivista]
Strenziok, Maren; Krueger, Frank; Pulaski, Sarah J.; Openshaw, Anne E.; Zamboni, Giovanna; van der Meer, Elke; Grafman, Jordan

The relationship between cortical grey matter density and media violence exposure in healthy male adolescents was investigated using voxel-based morphometry and the Childrens' Report of Exposure to Violence. Adolescents with more frequent exposure have lower left lateral orbitofrontal cortex density-a possible risk factor for altered socioemotional functioning.

2010 - The structural and functional neuroanatomy of successful visuospatial learning in normal aging [Abstract in Atti di Convegno]
Zamboni, Giovanna; Drazich, Erin; Jenkinson, Mark; De Jager, Celeste; Smith, A. David; Tracey, Irene; Wilcock, Gordon

studio imaging in pazienti con AD e soggetti sani

2009 - Cognitive and neural foundations of religious belief [Articolo su rivista]
Kapogiannis, Dimitrios; Barbey, Aron K.; Su, Michael; Zamboni, Giovanna; Krueger, Frank; Grafman, Jordan

We propose an integrative cognitive neuroscience framework for understanding the cognitive and neural foundations of religious belief. Our analysis reveals 3 psychological dimensions of religious belief (God's perceived level of involvement, God's perceived emotion, and doctrinal/experiential religious knowledge), which functional MRI localizes within networks processing Theory of Mind regarding intent and emotion, abstract semantics, and imagery. Our results are unique in demonstrating that specific components of religious belief are mediated by well-known brain networks, and support contemporary psychological theories that ground religious belief within evolutionary adaptive cognitive functions.

2009 - Executive dysfunction in frontotemporal dementia and corticobasal syndrome [Articolo su rivista]
Huey, E. D.; Goveia, E. N.; Paviol, S.; Pardini, M.; Krueger, F.; Zamboni, Giovanna; Tierney, M. C.; Wassermann, E. M.; Grafman, J.

OBJECTIVE: To determine the pattern of executive dysfunction in frontotemporal dementia (FTD) and corticobasal syndrome (CBS) and to determine the brain areas associated with executive dysfunction in these illnesses. METHOD: We administered the Delis-Kaplan Executive Function System (D-KEFS), a collection of standardized executive function tests, to 51 patients with behavioral-variant FTD and 50 patients with CBS. We also performed a discriminant analysis on the D-KEFS to determine which executive function tests best distinguished the clinical diagnoses of FTD and CBS. Finally, we used voxel-based morphometry (VBM) to determine regional gray matter volume loss associated with executive dysfunction. RESULTS: Patients with FTD and patients with CBS showed executive dysfunction greater than memory dysfunction. Executive function was better preserved in the patients with CBS than the patients with FTD with the exception of tests that required motor, visuospatial ability, or both. In patients with CBS, dorsal frontal and parietal and temporal-parietal cortex was associated with executive function. In FTD, tests with a language component (Verbal Fluency) were associated with left perisylvian cortex, sorting with the left dorsolateral prefrontal cortex, and reasoning (the Twenty Questions task) with the left anterior frontal cortex. The Twenty Questions test best distinguished the clinical diagnoses of CBS and FTD. CONCLUSIONS: The neuroanatomic findings (especially in frontotemporal dementia [FTD]) agree with the previous literature on this topic. Patients with FTD and patients with corticobasal syndrome (CBS) show disparate performance on higher-order executive functions, especially the Twenty Questions test. It may be difficult to distinguish motor and visuospatial ability from executive function in patients with CBS using tests with significant motor and visuospatial demands such as Trail Making. © 2009 by AAN Enterprises, Inc.

2009 - Individualism, conservatism, and radicalism as criteria for processing political beliefs: a parametric fMRI study [Articolo su rivista]
Zamboni, Giovanna; Gozzi, Marta; Krueger, Frank; Duhamel, Jean René; Sirigu, Angela; Grafman, Jordan

Politics is a manifestation of the uniquely human ability to debate, decide, and reach consensus on decisions affecting large groups over long durations of time. Recent neuroimaging studies on politics have focused on the association between brain regions and specific political behaviors by adopting party or ideological affiliation as a criterion to classify either experimental stimuli or subjects. However, it is unlikely that complex political beliefs (i.e., othe government should protect freedom of speecho) are evaluated only on a liberal-to-conservative criterion. Here we used multidimensional scaling and parametric functional magnetic resonance imaging to identify which criteria/dimensions people use to structure complex political beliefs and which brain regions are concurrently activated. We found that three independent dimensions explained the variability of a set of statements expressing political beliefs and that each dimension was reflected in a distinctive pattern of neural activation: individualism (medial prefrontal cortex and temporoparietal junction), conservatism (dorsolateral prefrontal cortex), and radicalism (ventral striatum and posterior cingulate). The structures we identified are also known to be important in self-other processing, social decision-making in ambivalent situations, and reward prediction. Our results extend current knowledge on the neural correlates of the structure of political beliefs, a fundamental aspect of the human ability to coalesce into social entities.

2009 - The neural bases of key competencies of emotional intelligence [Articolo su rivista]
Krueger, Frank; Barbey, Aron K.; Mccabe, Kevin; Strenziok, Maren; Zamboni, Giovanna; Solomon, Jeffrey; Raymont, Vanessa; Grafman, Jordan

Emotional intelligence (EI) refers to a set of competencies that are essential features of human social life. Although the neural substrates of EI are virtually unknown, it is well established that the prefrontal cortex (PFC) plays a crucial role in human social-emotional behavior. We studied a unique sample of combat veterans from the Vietnam Head Injury Study, which is a prospective, long-term follow-up study of veterans with focal penetrating head injuries. We administered the Mayer-Salovey-Caruso Emotional Intelligence Test as a valid standardized psychometric measure of EI behavior to examine two key competencies of EI: (i) Strategic EI as the competency to understand emotional information and to apply it for the management of the self and of others and (ii) Experiential EI as the competency to perceive emotional information and to apply it for the integration into thinking. The results revealed that key competencies underlying EI depend on distinct neural PFC substrates. First, ventromedial PFC damage diminishes Strategic EI, and therefore, hinders the understanding and managing of emotional information. Second, dorsolateral PFC damage diminishes Experiential EI, and therefore, hinders the perception and integration of emotional information. In conclusion, EI should be viewed as complementary to cognitive intelligence and, when considered together, provide a more complete understanding of human intelligence.

2008 - Apathy and disinhibition in frontotemporal dementia: Insights into their neural correlates. [Articolo su rivista]
Zamboni, Giovanna; E. D., Huey; F., Krueger; Nichelli, Paolo Frigio; J., Grafman

BACKGROUND: Aberrant social behavior is a defining symptom of frontotemporal dementia (FTD) and may eventually occur in all syndromes composing the FTD spectrum. Two main behavioral abnormalities have been described: apathy and disinhibition, but their neuroanatomical correlates remain underspecified. METHODS: Sixty-two patients with a clinical diagnosis of FTD participated in the study. Voxel-based morphometry of MRI data was performed to explore the association between gray matter loss and severity of the two behavioral profiles as measured by the Apathy and Disinhibition subscales of the Frontal Systems Behavior Scale. RESULTS: Compared with a group of controls, the FTD group showed extensive bilateral atrophy predominantly involving frontal and temporal lobes. Within the FTD group, the severity of apathy correlated with atrophy in the right dorsolateral prefrontal cortex. The severity of disinhibition correlated with atrophy in the right nucleus accumbens, right superior temporal sulcus, and right mediotemporal limbic structures. CONCLUSIONS: Prefrontal and temporal regions are differentially associated with apathy and disinhibition. Our results support the view that successful execution of complex social behaviors relies on the integration of social knowledge and executive functions, represented in the prefrontal cortex, and reward attribution and emotional processing, represented in mesolimbic structures.

2008 - Clinica e neuropsicologia del deterioramento cognitivo [Capitolo/Saggio]
Nichelli, Paolo Frigio; Zamboni, Giovanna

non disponibile

2008 - Neural correlates of caregiver burden in cortical basal syndrome and frontotemporal dementia [Articolo su rivista]
Knutson, K. M.; Zamboni, Giovanna; Tierney, M. C.; Grafman, J.

Aims: To determine areas of atrophy in patients that are associated with caregiver burden. Methods: We measured caregiver burden, dementia and neuropsychiatric scores in 22 patients with corticobasal syndrome (CBS) and 25 with frontotemporal dementia (FTD), and in 14 healthy controls. We used voxel-based morphometry to correlate caregiver burden with gray matter loss. Results: Increased dementia and behavioral disturbances contributed to higher burden scores in CBS patients, while behavioral disturbances alone significantly affected burden scores in frontal-variant FTD (FTD-fv) patients. In CBS patients, caregiver burden scores correlated with atrophy in left inferior and middle temporal gyri. Conclusions: Caregivers of FTD-fv patients had significantly higher burden scores than caregivers of CBS patients. Damage to areas important in semantic knowledge appears critical in increased burden for CBS caregivers. Copyright © 2008 S. Karger AG.

2005 - Seeing oneself: a case of autoscopy [Articolo su rivista]
Zamboni, Giovanna; C., Budriesi; Nichelli, Paolo Frigio

Autoscopy is the experience of seeing an image of one's body in external space. We describe the case of a patient who reported longstanding autoscopic hallucinations following post-eclamptic brain damage. The MR scan demonstrated damage involving the occipital cortex and the basal ganglia bilaterally. We hypothesize that the image was the result of aberrant plasticity mechanisms involving cortical areas that play a central role in high-order body or representation of oneself.

2004 - Impaired fear processing in right mesial temporal sclerosis: a fMRI study [Articolo su rivista]
Benuzzi, Francesca; Meletti, Stefano; Zamboni, Giovanna; G., Calandra Buonaura; M., Serafini; Lui, Fausta; Baraldi, Patrizia; G., Rubboli; C. A., Tassinari; Nichelli, Paolo Frigio

Lesion and neuroimaging studies have demonstrated that the mesial temporal lobe is crucial for recognizing emotions from facial expressions. In humans, bilateral amygdala damage is followed by impaired recognition of facial expressions of fear. To evaluate the influence of unilateral mesial temporal lobe damage we examined recognition of facial expressions and functional magnetic resonance (fMRI) brain activation associated with incidental processing of fearful faces in thirteen mesial temporal lobe epilepsy (MTLE) patients (eight with right MTLE, five with left MTLE). We also examined the effect of early versus later damage, comparing subjects with hippocampal-amygdalar sclerosis (MTS) and seizures occurring before five years of age to epilepsy patients with late onset seizures. Fourteen healthy volunteers participated as controls. Neuropsychological testing demonstrated that the ability of right MTLE patients to recognize fearful facial expressions is impaired. Patients with early onset of seizures were the most severely impaired. This deficit was associated with defective activation of a neural network involved in the processing of fearful expressions, which in controls and left MTLE included the left inferior frontal cortex and several occipito-temporal structures of both hemispheres.

2003 - Reorganization of neural circuit for fear recognition after anterior temporal lobectomy (selected for oral presentation). [Relazione in Atti di Convegno]
Benuzzi, Francesca; Meletti, Stefano; Zamboni, Giovanna; G., Calandra Buonaura; M., Serafini; Lui, Fausta; G., Rubboli; C. A., Tassinari; Nichelli, Paolo Frigio

Introduction: Several studies demonstrate the critical role on processing emotional stimuli of mesial temporal lobe structures, which are the common pathologic substrate of Temporal Lobe Epilepsy (TLE). We used fMRI to examine the reorganization of neural circuits underlying fear recognition after anterior temporal lobectomy in a group of TLE patients. Methods: Seven right-handed patients with a history of drug-resistant TLE (three with right and four with left TLE), were evaluated before and six months after lobectomy. Six right-handed healthy volunteers were tested as controls and re-tested after six months. Subjects were asked to make a gender decision task on fearful (F) and neutral faces (N). In a control condition (C) subjects were asked to detect a white square within scrambled faces. EPI data were acquired using a GE Signa HHS77 system at 1.5 Tesla (TR=3380 ms; TE=40 ms) across 16 axial 5 mm slices (64 x 64 matrix) and were analysed using SPM99. Before scanning, patients underwent a neuropsychological evaluation to assess their facial emotion recognition abilities. Results: Controls: A conjunction analysis (F and N) showed increased signal in occipito-temporal regions and mesial temporal lobe structures bilaterally, consistently with the activation of a specific face-selective network. This pattern of responses was similar at re-testing. Fearful expressions evoked activations in the inferior frontal and posterior cortex (fusiform gyrus and temporal lobe) bilaterally; re-test data showed activations reduced in extent and restricted to the left hemisphere. Patients: Preoperative and postoperative data showed regions of increased signal for faces similar to those found in controls. The activation of distinct regions for processing fearful faces was present in five of the seven patients; it was missing only in the two patients with right TLE and early amygdala damage. These two patients also failed in explicit recognition of fearful expressions. After surgery, they improved their performance at neuropsychological testing, and their fMRI data showed activation areas partially resembling the fearful activations found in controls and in left preoperative TLE patients. In the other patients the pattern of responses to fearful faces was not consistent on re-testing. Conclusions: In control subjects the neural network activated by faces (either neutral or fearful) did not vary on re-testing. Neither TLE nor anterior temporal lobectomy affected the response of this network. On the contrary, right early amygdala damage impaired explicit recognition of fearful expressions and it was associated with lack of fMRI activations during incidental processing of fearful faces. Re-test data showed that the selective pattern of activation to fearful expressions varied with the re-presentation of the emotional faces in controls and according to the side and the nature of the preoperative damage in TLE patients. Indeed, anterior temporal lobectomy improved emotional recognition in patients with early right amygdala damage and was associated with activation of a neural network for incidental processing of fearful faces. We suggest that an early discharging right mesial temporal lobe damage can prevent the brain from undergoing functional reorganization. Right anterior lobectomy, removing the discharging tissue, can release brain plasticity mechanisms, leading to recovery of emotion recognition.