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Roberta Ghidoni

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6 papers

1 author row

YNICL Journal 2026 Journal Article

Mapping the multiscale neuroanatomy of GRN-related frontotemporal dementia using mode-based morphometry

Enrico Premi
Giada Bianchetti
Valeria Bracca
Giulia Campana
Elena Gatti
Trang Cao
Alex Fornito
Valentina Cantoni

BACKGROUND: Individuals carrying Progranulin (GRN) mutations show asymmetrical grey matter atrophy, which could be used for early detection in the long asymptomatic phase. To capture these alterations, we employed both conventional Surface-Based Morphometry (SBM) and Mode-Based Morphometry (MBM). While the former provides high-resolution, location-specific estimates of cortical thickness (CT) differences, the latter has recently been introduced as a novel framework that decomposes CT maps into geometric eigenmodes, allowing a multiscale characterization of brain structural variability. Using both approaches enables the detection of complementary aspects of GRN-related neurodegeneration across spatial scales. METHODS: SBM and MBM were applied to CT maps to quantify structural alterations in individuals, 15 presymptomatic and 27 symptomatic, compared to 19 healthy controls (HC). SBM was used to assess vertex-wise CT differences, whereas MBM was used to decompose individual CT maps into geometric eigenmodes and quantify alterations across spatial scales. From both pipelines asymmetry indices (SBM-AI and MBM-AI) were computed. Associations between SBM/MBM-derived measures and domain-specific cognitive performance as well as global disease severity scores were then assessed. RESULTS: MBM-AI), only the MBM-AI revealed a U-shaped trajectory across disease progression, characterized by an early increase in asymmetry followed by a partial re-symmetrisation in later stages. CONCLUSIONS: MBM revealed multiscale cortical alterations in symptomatic GRN mutation carriers, capturing both large-scale hemispheric differences and more localized regional variations in CT that are less apparent with conventional SBM. These findings indicate that GRN-related neurodegeneration involves complex spatial pattern across multiple anatomical scales. Brain asymmetry remains a core hallmark of GRN-related pathology, supporting the use of asymmetry indices (derived from both SBM and MBM) as potential markers of disease progression at the symptomatic stage.

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YNIMG Journal 2019 Journal Article

Spatiotemporal analysis for detection of pre-symptomatic shape changes in neurodegenerative diseases: Initial application to the GENFI cohort

Claire Cury
Stanley Durrleman
David M. Cash
Marco Lorenzi
Jennifer M. Nicholas
Martina Bocchetta
John C. van Swieten
Barbara Borroni

Brain atrophy as measured from structural MR images, is one of the primary imaging biomarkers used to track neurodegenerative disease progression. In diseases such as frontotemporal dementia or Alzheimer's disease, atrophy can be observed in key brain structures years before any clinical symptoms are present. Atrophy is most commonly captured as volume change of key structures and the shape changes of these structures are typically not analysed despite being potentially more sensitive than summary volume statistics over the entire structure. In this paper we propose a spatiotemporal analysis pipeline based on Large Diffeomorphic Deformation Metric Mapping (LDDMM) to detect shape changes from volumetric MRI scans. We applied our framework to a cohort of individuals with genetic variants of frontotemporal dementia and healthy controls from the Genetic FTD Initiative (GENFI) study. Our method, take full advantage of the LDDMM framework, and relies on the creation of a population specific average spatiotemporal trajectory of a relevant brain structure of interest, the thalamus in our case. The residuals from each patient data to the average spatiotemporal trajectory are then clustered and studied to assess when presymptomatic mutation carriers differ from healthy control subjects. We found statistical differences in shape in the anterior region of the thalamus at least five years before the mutation carrier subjects develop any clinical symptoms. This region of the thalamus has been shown to be predominantly connected to the frontal lobe, consistent with the pattern of cortical atrophy seen in the disease.

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YNIMG Journal 2019 Journal Article

The inner fluctuations of the brain in presymptomatic Frontotemporal Dementia: The chronnectome fingerprint

Enrico Premi
Vince D. Calhoun
Matteo Diano
Stefano Gazzina
Maura Cosseddu
Antonella Alberici
Silvana Archetti
Donata Paternicò

Frontotemporal Dementia (FTD) is preceded by a long period of subtle brain changes, occurring in the absence of overt cognitive symptoms, that need to be still fully characterized. Dynamic network analysis based on resting-state magnetic resonance imaging (rs-fMRI) is a potentially powerful tool for the study of preclinical FTD. In the present study, we employed a "chronnectome" approach (recurring, time-varying patterns of connectivity) to evaluate measures of dynamic connectivity in 472 at-risk FTD subjects from the Genetic Frontotemporal dementia research Initiative (GENFI) cohort. We considered 249 subjects with FTD-related pathogenetic mutations and 223 mutation non-carriers (HC). Dynamic connectivity was evaluated using independent component analysis and sliding-time window correlation to rs-fMRI data, and meta-state measures of global brain flexibility were extracted. Results show that presymptomatic FTD exhibits diminished dynamic fluidity, visiting less meta-states, shifting less often across them, and travelling through a narrowed meta-state distance, as compared to HC. Dynamic connectivity changes characterize preclinical FTD, arguing for the desynchronization of the inner fluctuations of the brain. These changes antedate clinical symptoms, and might represent an early signature of FTD to be used as a biomarker in clinical trials.

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YNICL Journal 2019 Journal Article

White matter hyperintensities in progranulin-associated frontotemporal dementia: A longitudinal GENFI study

Carole H. Sudre
Martina Bocchetta
Carolin Heller
Rhian Convery
Mollie Neason
Katrina M. Moore
David M. Cash
Ione O.C. Woollacott

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers - in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load - a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year. In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial.

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YNICL Journal 2017 Journal Article

White matter hyperintensities are seen only in GRN mutation carriers in the GENFI cohort

Carole H. Sudre
Martina Bocchetta
David Cash
David L. Thomas
Ione Woollacott
Katrina M. Dick
John van Swieten
Barbara Borroni

Genetic frontotemporal dementia is most commonly caused by mutations in the progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72) genes. Previous small studies have reported the presence of cerebral white matter hyperintensities (WMH) in genetic FTD but this has not been systematically studied across the different mutations. In this study WMH were assessed in 180 participants from the Genetic FTD Initiative (GENFI) with 3D T1- and T2-weighed magnetic resonance images: 43 symptomatic (7 GRN, 13 MAPT and 23 C9orf72), 61 presymptomatic mutation carriers (25 GRN, 8 MAPT and 28 C9orf72) and 76 mutation negative non-carrier family members. An automatic detection and quantification algorithm was developed for determining load, location and appearance of WMH. Significant differences were seen only in the symptomatic GRN group compared with the other groups with no differences in the MAPT or C9orf72 groups: increased global load of WMH was seen, with WMH located in the frontal and occipital lobes more so than the parietal lobes, and nearer to the ventricles rather than juxtacortical. Although no differences were seen in the presymptomatic group as a whole, in the GRN cohort only there was an association of increased WMH volume with expected years from symptom onset. The appearance of the WMH was also different in the GRN group compared with the other groups, with the lesions in the GRN group being more similar to each other. The presence of WMH in those with progranulin deficiency may be related to the known role of progranulin in neuroinflammation, although other roles are also proposed including an effect on blood-brain barrier permeability and the cerebral vasculature. Future studies will be useful to investigate the longitudinal evolution of WMH and their potential use as a biomarker as well as post-mortem studies investigating the histopathological nature of the lesions.

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YNIMG Journal 2006 Journal Article

Genotype (cystatin C) and EEG phenotype in Alzheimer disease and mild cognitive impairment: A multicentric study

Claudio Babiloni
Luisa Benussi
Giuliano Binetti
Paolo Bosco
Gabriella Busonero
Simona Cesaretti
Gloria Dal Forno
Claudio Del Percio

Previous findings demonstrated that haplotype B of CST3, the gene coding for cystatin C, is a recessive risk factor for late-onset Alzheimer's disease (AD; Finckh, U. , von der Kammer, H. , Velden, J. , Michel, T. , Andresen, B. , Deng, A. , Zhang, J. , Muller-Thomsen, T. , Zuchowski, K. , Menzer, G. , Mann, U. , Papassotiropoulos, A. , Heun, R. , Zurdel, J. , Holst, F. , Benussi, L. , Stoppe, G. , Reiss, J. , Miserez, A. R. , Staehelin, H. B. , Rebeck, G. W. , Hyman, B. T. , Binetti, G. , Hock, C. , Growdon, J. H. , Nitsch, R. M. , 2000. Genetic association of the cystatin C gene with late-onset Alzheimer disease. Arch. Neurol. 57, 1579–1583). In the present multicentric electroencephalographic (EEG) study, we analyzed the effects of CST3 haplotypes on resting cortical rhythmicity in subjects with AD and mild cognitive impairment (MCI) with the hypothesis that sources of resting EEG rhythms are more impaired in carriers of the CST3 B haplotype than non-carriers. We enrolled a population of 84 MCI subjects (42% with the B haplotype) and 65 AD patients (40% with the B haplotype). Resting eyes-closed EEG data were recorded in all subjects. EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10. 5 Hz), alpha 2 (10. 5–13 Hz), beta 1 (13–20 Hz), and beta 2 (20–30 Hz). EEG cortical sources were estimated by low-resolution brain electromagnetic tomography (LORETA). Results showed that the amplitude of alpha 1 (parietal, occipital, temporal areas) and alpha 2 (occipital area) was statistically lower in CST3 B carriers than non-carriers (P < 0. 01). Whereas there was a trend towards statistical significance that amplitude of occipital delta sources was stronger in CST3 B carriers than in non-carriers. This was true for both MCI and AD subjects. The present findings represent the first demonstration of relationships between the AD genetic risk factor CST3 B and global neurophysiological phenotype (i. e. , cortical delta and alpha rhythmicity) in MCI and AD subjects, prompting future genotype–EEG phenotype studies for the early prediction of AD conversion in individual MCI subjects.

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