Mario Torso

Abnormal Functional Brain Connectivity and Personality Traits in Myotonic Dystrophy Type 1

IMPORTANCE Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy observed in adults, is a genetic multisystem disorder affecting several other organs besides skeletal muscle, including the brain. Cognitive and personality abnormalities have been reported; however, no studies have investigated brain functional networks and their relationship with personality traits/disorders in patients with DM1. OBJECTIVE To use resting-state functional magnetic resonance imaging to assess the potential relationship between personality traits/disorders and changes to functional connectivity within the default mode network (DMN) in patients with DM1. DESIGN, SETTING, AND PARTICIPANTS We enrolled 27 patients with genetically confirmed DM1 and 16 matched healthy control individuals. Patients underwent personality assessment using clinical interview and Minnesota Multiphasic Personality Inventory-2 administration; all participants underwent resting-state functional magnetic resonance imaging. Investigations were conducted at the Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Catholic University of Sacred Heart, and Azienda Ospedaliera San Camillo Forlanini. INTERVENTION Resting-state functional magnetic resonance imaging. MAIN OUTCOMES AND MEASURES Measures of personality traits in patients and changes in functional connectivity within the DMN in patients and controls. Changes in functional connectivity and atypical personality traits in patients were correlated. RESULTS We combined results obtained from the Minnesota Multiphasic Personality Inventory-2 and clinical interview to identify a continuum of atypical personality profiles ranging from schizotypal personality traits to paranoid personality disorder within our DM1 patients. We also demonstrated an increase in functional connectivity in the bilateral posterior cingulate and left parietal DMN nodes in DM1 patients compared with controls. Moreover, patients with DM1 showed strong associations between DMN functional connectivity and schizotypal-paranoid traits. CONCLUSIONS AND RELEVANCE Our findings provide novel biological evidence that DM1 is a clinical condition that also involves an alteration of functional connectivity of the brain. We speculate that these functional brain abnormalities, similarly to frank psychiatric disorders, may account for the atypical personality traits observed in patients with DM1.

Longitudinal Changes in Functional Brain Connectivity Predicts Conversion to Alzheimer’s Disease

This longitudinal study investigates the modifications in structure and function occurring to typical Alzheimers disease (AD) brains over a 2-year follow-up, from pre-dementia stages of disease, with the aim of identifying biomarkers of prognostic value. Thirty-one patients with amnestic mild cognitive impairment were recruited and followed-up with clinical, neuropsychological, and MRI assessments. Patients were retrospectively classified as AD Converters or Non-Converters, and the data compared between groups. Cross-sectional MRI data at baseline, assessing volume and functional connectivity abnormalities, confirmed previous findings, showing a more severe pattern of regional grey matter atrophy and default-mode network disconnection in Converters than in Non-Converters. Longitudinally, Converters showed more grey matter atrophy in the frontotemporal areas, accompanied by increased connectivity in the precuneus. Discriminant analysis revealed that functional connectivity of the precuneus within the default mode network at baseline is the parameter able to correctly classify patients in Converters and Non-Converters with high sensitivity, specificity, and accuracy.

Constructional Apraxia as a Distinctive Cognitive and Structural Brain Feature of Pre-Senile Alzheimer's Disease

Constructional apraxia (CA) is often, but not always, observed in patients with Alzheimers disease (AD). CA is usually explained by impairment of either basic perceptual and motor abilities, or executive functions. This study aims to evaluate the structural correlates of CA in AD. Forty-eight patients with AD and 20 healthy age-matched controls underwent a thorough neuropsychological investigation and an MRI scan to collect high-resolution T1-weighted data. Patients were classified as having (ADca) or not having (ADnonca) CA based on performance on the Freehand copying of drawings task. T1-weighted volumes were process according to the voxel based morphometry protocol, to assess the presence of significant differences in local to grey matter volumes in patients compared to controls and in ADca compared to ADnonca. Post-hoc, the mean grey matter volume of clusters that resulted significantly different between groups was regressed against the neuropsychological scores in which the two patient groups performed differently. A pre-senile disease onset was significantly more frequent in patients with CA compared to ADnonca. ADca patients also showed worse performances than patients with ADnonca at some tests requiring the processing of visuo-spatial data and testing working memory. They also showed widespread reductions in grey matter volume, mainly located in areas known to be implicated in object recognition and localization, and in maintenance and re-orienting of spatial attention. These findings suggest that the occurrence of CA in AD is often associated with a peculiar clinical onset (i.e., pre-senile), neuropsychological profile, and distribution of grey matter atrophy.

Different Patterns of Correlation between Grey and White Matter Integrity Account for Behavioral and Psychological Symptoms in Alzheimer's Disease.

Behavioral disorders and psychological symptoms (BPSD) in Alzheimers disease (AD) are known to correlate with grey matter (GM) atrophy and, as shown recently, also with white matter (WM) damage. WM damage and its relationship with GM atrophy are reported in AD, reinforcing the interpretation of the AD pathology in light of a disconnection syndrome. It remains uncertain whether this disconnection might account also for different BPSD observable in AD. Here, we tested the hypothesis of different patterns of association between WM damage of the corpus callosum (CC) and GM atrophy in AD patients exhibiting one of the following BPSD clusters: Mood (i.e., anxiety and depression; ADmood), Frontal (i.e., dishinibition and elation; ADfrontal), and Psychotic (delusions and hallucinations; ADpsychotic) related symptoms, as well as AD patients without BPSD. Overall, this study brings to light the strict relationship between WM alterations in different parts of the CC and GM atrophy in AD patients exhibiting BPSD, supporting the hypothesis that such symptoms are likely to be caused by characteristic patterns of neurodegeneration of WM and GM, rather than being a reactive response to accumulation of cognitive disabilities, and should therefore be regarded as potential markers of diagnostic and prognostic value in AD.

Brain connectivity changes in autosomal recessive Parkinson Disease: a model for the sporadic form

Biallelic genetic mutations in the Park2 and PINK1 genes are frequent causes of autosomal recessive PD. Carriers of single heterozygous mutations may manifest subtle signs of disease, thus providing a unique model of preclinical PD. One emerging hypothesis suggests that non-motor symptom of PD, such as cognitive impairment may be due to a distributed functional disruption of various neuronal circuits. Using resting-state functional MRI (RS-fMRI), we tested the hypothesis that abnormal connectivity within and between brain networks may account for the patients’ cognitive status. Eight homozygous and 12 heterozygous carriers of either PINK1 or Park2 mutation and 22 healthy controls underwent RS-fMRI and cognitive assessment. RS-fMRI data underwent independent component analysis to identify five networks of interest: default-mode network, salience network, executive network, right and left fronto-parietal networks. Functional connectivity within and between each network was assessed and compared between groups. All mutation carriers were cognitively impaired, with the homozygous group reporting a more prominent impairment in visuo-spatial working memory. Changes in functional connectivity were evident within all networks between homozygous carriers and controls. Also heterozygotes reported areas of reduced connectivity when compared to controls within two networks. Additionally, increased inter-network connectivity was observed in both groups of mutation carriers, which correlated with their spatial working memory performance, and could thus be interpreted as compensatory. We conclude that both homozygous and heterozygous carriers exhibit pathophysiological changes unveiled by RS-fMRI, which can account for the presence/severity of cognitive symptoms.

Calretinin interneuron density in the caudate nucleus is lower in autism spectrum disorder.

Autism spectrum disorder is a debilitating condition with possible neurodevelopmental origins but unknown neuroanatomical correlates. Whereas investigators have paid much attention to the cerebral cortex, few studies have detailed the basal ganglia in autism. The caudate nucleus may be involved in the repetitive movements and limbic changes of autism. We used immunohistochemistry for calretinin and neuropeptide Y in 24 age- and gender-matched patients with autism spectrum disorder and control subjects ranging in age from 13 to 69 years. Patients with autism had a 35% lower density of calretinin+ interneurons in the caudate that was driven by loss of small calretinin+ neurons. This was not caused by altered size of the caudate, as its cross-sectional surface areas were similar between diagnostic groups. Controls exhibited an age-dependent increase in the density of medium and large calretinin+ neurons, whereas subjects with autism did not. Diagnostic groups did not differ regarding ionized calcium-binding adapter molecule 1+ immunoreactivity for microglia, suggesting chronic inflammation did not cause the decreased calretinin+ density. There was no statistically significant difference in the density of neuropeptide Y+ neurons between subjects with autism and controls. The decreased calretinin+ density may disrupt the excitation/inhibition balance in the caudate leading to dysfunctional corticostriatal circuits. The description of such changes in autism spectrum disorder may clarify pathomechanisms and thereby help identify targets for drug intervention and novel therapeutic strategies.

Whole brain white matter histogram analysis of diffusion tensor imaging data detects microstructural damage in mild cognitive impairment and alzheimer's disease patients: DTI Histograms for Staging AD

Amnestic mild cognitive impairment (MCI) is a transitional stage between normal aging and Alzheimers disease (AD). However, the clinical conversion from MCI to AD is unpredictable. Hence, identification of noninvasive biomarkers able to detect early changes induced by dementia is a pressing need.

CORTICAL DISARRAY MEASUREMENT USING DIFFUSION MRI CORRELATES WITH BRAAK STAGING AND IMPROVES AMYLOID PET PREDICTION OF AD PROGRESSION

Intercept 4.07 3.09 4.19 3.10 -1.37 3.12 -1.54 3.12 -57.80 30.61 -60.27 30.63 Years of Education 0.12 0.05 0.12 0.05 0.13 0.05 0.13 0.05 0.14 0.05 0.14 0.05 Visit Age -0.05 0.01 -0.98 0.31 -0.93 0.31 -1.06 0.32 -0.90 0.33 2.11 2.95 AB42 (ln) 0.72 0.46 0.69 0.46 0.42 0.44 0.41 0.44 9.00 4.67 9.37 4.67 AB42 (ln)*Visit Age 0.14 0.05 0.14 0.05 0.13 0.05 0.10 0.05 -0.36 0.45 Hippocampal Volume 1.32 0.23 1.36 0.23 11.78 5.65 12.12 5.64 Hippocampal Volume*Visit Age 0.04 0.02 0.04 0.02 -0.54 0.56 AB42 (ln)*Hippocampal Volume -1.59 0.86 -1.64 0.86 AB42 (ln)*Hippocampal Volume*Visit Age 0.09 0.09

NEW DIFFUSION IMAGING MEASUREMENTS OF CELLULAR ORGANISATION IN THE CORTEX IDENTIFY ALZHEIMER'S DISEASE AND PROGRESSIVE MCI

correlations with cognitive measures. The main regression analysis (see Methods section) was repeated twice, replacing p-tau/Ab42 with score on memory alteration test (M@T; Rami et al., 2007) and score on free recall of selective reminding test (Grober & Buschke, 1987), controlling for age, gender and level of education. Results were corrected for whole-brain multiple comparisons using identical methods to the main analysis. Top row left: significant positive correlations between EC and p-tau/Ab42; top row middle: significant negative correlations between EC and M@T scores; top row right: green voxels display regions where EC correlated significantly with both ptau/Ab42 and M@T scores. Bottom row left: significant negative correlation between EC and p-tau/Ab42; bottom row middle: significant positive (red) and significant negative (blue) correlations between EC and scores of free recall; bottom row right: green voxels display regions where EC correlated significantly with both p-tau/Ab42 and free recall scores. Poster Presentations: Wednesday, July 19, 2017 P1349