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Background: The neural correlates of behavioral symptoms in frontotemporal dementia (FTD) are still to be elucidated. Neurotransmitter abnormalities could be correlated to the pathophysiology of negative and positive symptoms in FTD., Objective: To evaluate if the imbalance between inhibitory and excitatory cortical circuits, evaluated with transcranial magnetic stimulation (TMS), correlate with the magnitude of negative and positive symptoms, as measured by Frontal Behavioral Inventory (FBI) scores, in patients with FTD., Methods: Paired-pulse TMS was used to investigate the activity of different intracortical circuits in 186 FTD patients (130 bvFTD, 35 avPPA, 21 svPPA). We applied short interval intracortical inhibition (SICI - GABAAergic transmission), intracortical facilitation (ICF - glutamatergic transmission), long interval intracortical inhibition (LICI - GABABergic transmission), and short latency afferent inhibition (SAI - cholinergic transmission). Linear and stepwise multiple regression analysis were used to determine the contribution of each neurophysiological measures to the total variance of FBI scores., Results: At the stepwise multivariate analysis, we observed a significant negative correlation between FBI-A scores (negative symptoms) and ICF (β = -0.57, p < 0.001, adjusted R2 = 0.32). For FBI-B scores (positive symptoms), we observed a significant positive correlation for SICI (β = 0.84, p < 0.001, adjusted R2 = 0.56). Significant correlations were observed for single items of the FBI-A score with ICF and FBI-B scores with SICI, with a medium-large size effect for several items., Conclusions: The present study shows that the imbalance between inhibitory and excitatory intracortical circuits, evaluated with TMS, correlated with the magnitude of negative and positive symptoms in FTD, respectively.

Objective: Cognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie, brain maintenance). In cross-sectional studies of presymptomatic frontotemporal dementia (FTD), higher education has been related to increased grey matter volume. Here, we examine the effect of education on grey matter loss over time., Methods: Two-hundred twenty-nine subjects at-risk of carrying a pathogenic mutation leading to FTD underwent longitudinal cognitive assessment and T1-weighted MRI at baseline and at 1 year follow-up. The first principal component score of the graph-Laplacian Principal Component Analysis on 112 grey matter region-of-interest volumes was used to summarise the grey matter volume (GMV). The effects of education on cognitive performances and GMV at baseline and on the change between 1 year follow-up and baseline (slope) were tested by Structural Equation Modelling., Results: Highly educated at-risk subjects had better cognition and higher grey matter volume at baseline; moreover, higher educational attainment was associated with slower loss of grey matter over time in mutation carriers., Conclusions: This longitudinal study demonstrates that even in presence of ongoing pathological processes, education may facilitate both brain reserve and brain maintenance in the presymptomatic phase of genetic FTD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Frontotemporal dementia (FTD) is characterized by behavioural and language impairment, accompanied by atrophic changes in fronto-temporo-insular cortices. In the presymptomatic phases of genetic FTD, subtle or no volumetric changes have been reported. Transcranial magnetic stimulation (TMS) represents an approach to explore cortical connectivity, and some TMS measures have been demonstrated to be impaired in Granulin (GRN) mutation carriers. We aimed at exploring cross-sectional changes in cortical thickness (CT) and surface area (SA) in the presymptomatic phases of GRN-related FTD, and their relationship with TMS parameters. Nineteen presymptomatic GRN mutation carriers and seventeen age and sex-matched non-carriers underwent 3T MRI scanning and a paired-pulse TMS protocol. The surface-based pipeline of FreeSurfer was applied in order to obtain cortical volumes (CVs), CT and SA measures. Then, between groups differences and correlation with TMS parameters were assessed. GRN carriers showed increased CT and decreased SA of the right parietal lobe, without significant volume changes. TMS parameters of intracortical inhibition and facilitation, which were significantly impaired in presymptomatic GRN mutation carriers, correlated with reduced SA and CV of the right insula. Our results suggest that splitting CV into its two main components could improve the sensitivity when exploring structural brain changes in presymptomatic or early phases of neurodegenerative conditions. TMS parameters might reflect damage within cortical regions reported to be affected early in the conversion to the symptomatic phase of the disease.

Introduction: Brain iron homeostasis dysregulation has been widely related to neurodegeneration. In particular, human haemochromatosis protein (HFE) is involved in iron metabolism, and HFE H63D polymorphism has been related to the risk of amyotrophic lateral sclerosis and Alzheimer's disease. Recently, iron accumulation in the basal ganglia of frontotemporal lobar degeneration (FTLD) patients has been described., Objective: To explore the relationship between HFE genetic variation and demographic, clinical and imaging characteristics in a large cohort of FTLD patients., Methods: A total of 110 FTLD patients underwent neuropsychological and imaging evaluation and blood sampling for HFE polymorphism determination. HFE H63D polymorphism was considered in the present study. Two imaging approaches were applied to evaluate the effect of HFE genetic variation on brain atrophy, namely voxel-based morphometry and region of interest-based probabilistic approach (SPM8; Wellcome Trust Centre for Neuroimaging)., Results: FTLD patients carrying the D* genotype (H/D or D/D) showed greater atrophy in the basal ganglia, bilaterally, compared to H/H carriers (x, y, z: -22, -4, 0; T = 3.45; cluster size: 33 voxels, x, y, z: 24, 4, -2; T = 3.38; cluster size: 36 voxels). The former group had even more pronounced behavioural symptoms, as defined by the Frontal Behavioural Inventory total scores., Conclusions: Our data suggest that H63D polymorphism could represent a disease-modifying gene in FTLD, fostering iron deposition in the basal ganglia. This suggests a new possible mechanism of FTLD-associated neurodegeneration., (© 2015 S. Karger AG, Basel.)

Background: Late-onset glycogenosis type II (GSD II) is a rare, multisystem disorder mainly affecting limb and respiratory muscles due to acid alpha glucosidase deficiency. Despite evidence at autopsy of glycogen accumulation in the brain, no study exploring brain functions is yet available., Objective: Our objective in this study was to assess brain changes in late-onset GSD II., Methods: Each patient underwent a standardized neuropsychological assessment, regional grey-matter (GM) atrophy, and resting-state functional magnetic resonance imaging (RS-fMRI). Functional connectivity maps of the salience (SN) and default-mode (DMN) networks were considered. A group of age- and gender-matched healthy controls was enrolled for MRI comparisons. P values family-wise error (FWE) cluster level corrected inferior to 0.05 were considered., Results: Nine GSD II patients (age 46.6 ± 8.0; 55% male) were recruited. No significant GM atrophy was found in patients compared with controls (n = 18; age 48.0 ± 9.8,;40% male). Functional connectivity within the SN was selectively reduced in patients, and cingulate gyrus and medial frontal cortex were mainly involved. Accordingly, patients had significant impairment of executive functions (as measured by Wisconsin Card Sorting test), whereas other cognitive domains were within mean normal ranges., Conclusions: Our findings extend the clinical spectrum of GSD II by indicating that brain changes occur in this muscular disorder. Above all, these results should lead to better examinations of therapeutic approaches and perspectives for the affected patients. Further studies evaluating in depth these issues are warranted.

Background: Behavioural variant of frontotemporal dementia (bvFTD) frequently presents complex behavioural changes, that rarely occur in isolation. Targeting behavioural phenotypes instead of single behavioural symptoms may potentially provide a disease model in which to investigate brain substrates of behavioural abnormalities., Objective: To identify behavioural phenotypes and to assess the associated brain correlates in a cohort of patients with bvFTD., Methods: Two hundred and seven consecutive individuals fulfilling clinical criteria for bvFTD were enrolled. Each participant's caregiver completed frontal behavioural inventory on 24 key behavioural disturbances. Confirmatory factor analysis (CFA) models were applied, and behavioural phenotypes identified. For each phenotype, a score was derived based on the "best" CFA model (Bifactor CFA). One hundred two participants underwent SPECT scan. A regression analysis between scores for each factor and regional cerebral blood flow was carried out (P<0.001)., Results: One "general" behavioural phenotype and four factors were identified, that were termed "disinhibited", "apathetic", "aggressive", and "language" phenotypes. The most robust brain correlate was identified for "disinhibited" phenotype, in the region of the anterior cingulated and anterior temporal cortex, bilaterally, and for apathetic phenotype in the left dorsolateral frontal cortex. As expected, language phenotype correlated with greater hypoperfusion in the left frontotemporal lobes. No significant correlation between aggressive phenotype and regional cerebral blood flow was found. Moreover, the "general" behavioural severity was associated with greater damage in the right frontal lobe., Conclusions: Behavioural phenotypes are associated with specific brain damage in bvFTD, involving distinct cerebral networks., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Prediction of survival in frontotemporal lobar degeneration (FTLD) is guesswork. The aim of the present study was to evaluate whether SPECT scan may be useful to predict prognosis of long term survival in FTLD patients. A cohort of 125 patients with FTLD who underwent brain SPECT scan at the time of enrollment and who were further followed up for at least one year were considered. In each subject, volume of interests (VOIs) covering frontotemporal and parietal regions, bilaterally, were drawn. Principal component analysis (PCA) was applied on VOIs, and a Cox regression model was carried out to find out best predictors of survival. A two-pattern PCA solution was chosen, explaining more than 70% of variance, and "frontal" PC1 and "temporal" PC2 components were identified. The frontal PC1 was associated with higher rate of faster progression (HR = 2.06, 95% CI = 1.23-3.44, p = 0.006 for univariate model, and HR = 1.85, 95% CI = 1.04-3.28, p = 0.03 for multivariate model). In particular, right orbitofrontal cortex showed the higher loadings in PC1; the worse the scores of this region the shorter the survival was reported. We suggest that SPECT imaging, beyond a helpful tool in diagnostic assessment, may be an easily and accessible marker of disease outcome in FTLD. Further studies considering structural neuroimaging are warranted.