Giuseppe Magnani

Quantification of tissue damage in AD using diffusion tensor and magnetization transfer MRI

The authors measured mean diffusivity (D̄) and magnetization transfer ratio (MTR) of the brain from 18 patients with AD and 16 healthy control subjects. The peak heights of cortical gray matter (cGM) D̄ (p < 0.001) and MTR (p < 0.001) histograms were lower and average cGM D̄ (p < 0.01) higher in patients with AD than in control subjects. A composite MR score based on brain volume and cGM MTR peak height was correlated with patient cognitive impairment (r = 0.65, p = 0.003). This preliminary study presents a novel approach to quantify AD-related tissue damage in-vivo.

The contribution of voxel-based morphometry in staging patients with mild cognitive impairment

Objective: To assess whether different patterns of regional gray matter loss in patients with mild cognitive impairment (MCI) are associated with different risks of conversion to Alzheimer disease (AD), using MRI and voxel-based morphometry (VBM). Methods: The authors recruited 22 patients with MCI, 22 patients with probable AD, and 20 healthy subjects (HS). T1 volumes from each subject were postprocessed according to an optimized VBM protocol. All patients were clinically followed up (mean [SD] time = 28.7 [5.7] months), and patients with MCI were reclassified into two groups (converters and nonconverters to AD). Results: When comparing patients with AD to HS, widespread areas of reduced gray matter density were found predominantly in temporal, frontal, and parietal lobes and in the insula. Comparing MCI converters and nonconverters with HS, the converters showed more widespread areas of reduced gray matter density than nonconverters, with a pattern of abnormalities similar to that seen in patients with AD. Conversely, when comparing the same groups with patients with AD, MCI nonconverters showed a pattern of gray matter density similar to that of HS. Areas of decreased gray matter density were also found in MCI converters compared with nonconverters. Conclusions: Different patterns of gray matter density distribution in patients with mild cognitive impairment may be associated to different rates of conversion to Alzheimer disease.

Fatigue in multiple sclerosis is associated with abnormal cortical activation to voluntary movement--EEG evidence.

Converging evidence is consistent with the view that fatigue in Multiple Sclerosis is independent from pyramidal tract involvement, suggesting a possible involvement of frontal areas. During voluntary movement, changes of the EEG rhythms can be observed over sensorimotor areas. Event-related desynchronization (ERD) of the 10 and 20 Hz frequency bands occurs during motor planning and execution and is followed after movement termination by event-related synchronization (ERS), expressing cortical idling or inhibition. We evaluated the pattern of cortical activation to voluntary movement in MS patients complaining of fatigue assessed using the Fatigue Severity Scale. Fifteen MS patients complaining of fatigue, 18 MS patients without fatigue, and 14 normal controls were studied. The two patients groups were similar for age, sex, disease duration, and were not disabled (score <1.5 at the Expanded Disability Status Scale). Twenty-nine channel EEG was recorded during about 60 self-paced extensions of the right thumb. The onset latency and amount of the contralateral sensorimotor (C3 electrode) 10 and 18--22 Hz ERD were similar in the three groups. ERD was more widespread anteriorly in the fatigue group compared with normal controls (P < 0.01 over Fz electrode). Postmovement contralateral sensorimotor 18--22 Hz ERS was significantly lower in fatigue MS patients compared with normal subjects (P < 0.005) and with nonfatigue MS patients (P = 0.02). These findings are consistent with a central origin of fatigue in MS and indicate cortical dysfunction even during a simple motor task, resulting in hyperactivity during movement execution and failure of the inhibitory mechanisms intervening after movement termination.

Functional network connectivity in the behavioral variant of frontotemporal dementia.

INTRODUCTION The aim of this study was to investigate, using resting state (RS) functional magnetic resonance imaging (fMRI), the functional connectivity within and among brain networks in patients with the behavioral variant of frontotemporal dementia (bvFTD), compared with healthy controls and patients with probable Alzheimers disease (pAD). METHODS Twelve bvFTD patients were compared with 30 controls and 18 pAD patients. Functional connectivity within the salience, default mode (DMN), executive (EXN), attention/working memory (ATT/WM), and dorsal attentional networks was assessed using independent component analysis. The temporal associations among RS networks (RSNs) were explored using the functional network connectivity toolbox. RESULTS A decreased dorsal salience network (DSN) connectivity, mainly involving the anterior cingulum, was observed in bvFTD versus controls and pAD. BvFTD was also characterized by a decreased ventral salience network connectivity in the basal ganglia, and divergent connectivity effects versus controls in the dorsolateral prefrontal cortex (decreased) and precuneus (enhanced) within the right ATT/WM network. The dorsal attentional network had a decreased connectivity with the DMN and EXN in bvFTD versus controls, and a decreased connectivity with the DSN versus pAD. CONCLUSIONS RSN functional abnormalities occur in bvFTD, involving not only the salience network, but also the DMN and fronto-parietal network associated with ATT and WM modulation. The pattern of functional changes differs from that seen in pAD. The altered interactions among RSN observed in bvFTD and pAD may provide a new venue to explore the functional correlates of cognitive abnormalities in neurodegenerative and psychiatric disorders.

White Matter Damage in Frontotemporal Lobar Degeneration Spectrum

White matter (WM) tract damage was assessed in patients with the behavioral variant frontotemporal dementia (bvFTD) and the 3 primary progressive aphasia (PPA) variants and compared with the corresponding brain atrophy patterns. Thirteen bvFTD and 20 PPA patients were studied. Tract-based spatial statistics and voxel-based morphometry were used. Patients with bvFTD showed widespread diffusion tensor magnetic resonance imaging (DT MRI) abnormalities affecting most of the WM bilaterally. In PPA patients, WM damage was more focal and varied across the 3 syndromes: left frontotemporoparietal in nonfluent, left frontotemporal in semantic, and left frontoparietal in logopenic patients. In each syndrome, DT MRI changes extended beyond the topography of gray matter loss. Left uncinate damage was the best predictor of frontotemporal lobar degeneration diagnosis versus controls. DT MRI measures of the anterior corpus callosum and left superior longitudinal fasciculus differentiated bvFTD from nonfluent cases. The best predictors of semantic PPA compared with both bvFTD and nonfluent cases were diffusivity abnormalities of the left uncinate and inferior longitudinal fasciculus. This study provides insights into the similarities and differences of WM damage in bvFTD and PPA variants. DT MRI metrics hold promise to serve as early markers of WM integrity loss that only at a later stage may be detectable by volumetric measures.

Microglia convert aggregated amyloid- β into neurotoxic forms through the shedding of microvesicles

Alzheimer’s disease (AD) is characterized by extracellular amyloid-β (Aβ) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Aβ species, rather than insoluble fibrils, are the most toxic forms of Aβ. Preventing soluble Aβ formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Aβ species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Aβ forms trafficked to MVs after Aβ internalization into microglia. MV neurotoxicity was neutralized by the Aβ-interacting protein PrP and anti-Aβ antibodies, which prevented binding to neurons of neurotoxic soluble Aβ species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease.

Autosomal Dominant Frontotemporal Lobar Degeneration Due to the C9ORF72 Hexanucleotide Repeat Expansion: Late-Onset Psychotic Clinical Presentation

BACKGROUND A hexanucleotide repeat expansion in the first intron of C9ORF72 has been shown to be responsible for a high number of familial cases of amyotrophic lateral sclerosis or frontotemporal lobar degeneration (FTLD). Atypical presentations have been described, particularly psychosis. METHODS We determined the frequency of the hexanucleotide repeat expansions in a population of 651 FTLD patients and compared the clinical characteristics of carriers and noncarriers. In addition, we genotyped 21 patients with corticobasal syndrome, 31 patients with progressive supranuclear palsy, and 222 control subjects. RESULTS The pathogenic repeat expansion was detected in 39 (6%) patients with FTLD (17 male and 22 female subjects); however, it was not detected in any corticobasal syndrome and progressive supranuclear palsy patients or controls. Twenty-four of 39 carriers had positive family history for dementia and/or amyotrophic lateral sclerosis (61.5%), whereas only 145 of 612 noncarriers had positive family history (23.7%; p<.000001). Clinical phenotypes of carriers included 29 patients with the behavioral variant frontotemporal dementia (bvFTD; 5.2% of all bvFTD cases), 8 with bvFTD/motor neuron disease (32% bvFTD/motor neuron disease cases), 2 with semantic dementia (5.9% of patients with semantic dementia), and none with progressive nonfluent aphasia. The presentation with late-onset psychosis (median age = 63 years) was more frequent in carriers than noncarriers (10/33 vs. 3/37, p = .029), as well as the presence of cognitive impairment at onset (15/33 vs. 5/37; p = .0039). CONCLUSIONS The repeat expansion in C9ORF72 is a common cause of FTLD and often presents with late-onset psychosis or memory impairment.

Electroencephalographic coherence analysis in multiple sclerosis: correlation with clinical, neuropsychological, and MRI findings

OBJECTIVE To explore functional corticocortical connections in multiple sclerosis by means of coherence of the EEG, and to evaluate their correlations with the degree of cognitive impairment and with brain lesion load assessed by MRI. METHODS EEG coherence was studied from 28 patients with clinically definite multiple sclerosis. Ten minutes of resting EEG were recorded with 20 scalp electrodes, with binaural reference. FFT power and coherence were calculated in artifact free epochs of 1 second and compared with values from 22 control subjects of comparable age and sex distribution. Patients also underwent MRI (n=27) and neuropsychological examination (n=21). RESULTS Compared with controls, patients with multiple sclerosis showed increased θ power in the frontotemporal-central regions (p<0.005). θ Band coherence was decreased between homologous areas (p<0.02). α Band coherence was decreased both in the local and long distance connections (p<0.0005). These findings were most striking both in patients with high MRI subcortical lesion load and in patients with cognitive involvement. A significant correlation was found between interhemispheric θ (p=0.02) and α (p=0.017) and anteroposterior α (p=0.013) coherence and subcortical MRI lesion load, but not with exclusively periventricular lesion load. CONCLUSIONS These findings support the hypothesis that cognitive impairment in multiple sclerosis is mostly dependent on involvement of corticocortical connections related to demyelination and/or axonal loss within the white matter immediately underlying the cortex.

Brain network connectivity assessed using graph theory in frontotemporal dementia.

Objective: To investigate whether brain functional network connectivity is disrupted in patients with the behavioral variant of frontotemporal dementia (bvFTD). Methods: Graph theoretical analysis was applied to resting state functional MRI data from 18 patients with probable bvFTD and 50 healthy individuals. Functional connectivity between 90 cortical and subcortical brain regions was estimated using bivariate correlation analysis and thresholded to construct a set of undirected graphs. Correlations between network properties and cognitive variables were tested. Results: Global topologic organization of the functional brain network in bvFTD was significantly disrupted as indicated by reduced mean network degree, clustering coefficient, and global efficiency and increased characteristic path length and assortativity relative to normal subjects. Compared to controls, bvFTD data showed retention of major “hub” regions in the medial parietal, temporal, and occipital lobes, but cortical hubs were not noted in the frontal lobes. Medial and dorsal frontal regions, left caudate nucleus, left insular cortices, and some regions of the temporal, parietal, and occipital lobes showed decreased nodal centrality. BvFTD patients showed the greatest decrease in inter-regional connectivity between the frontal and occipital regions, and the insular cortices and occipital, temporal, subcortical, and frontal regions. In bvFTD, altered global network properties correlated with executive dysfunction. Conclusions: Global and local functional networks are altered in bvFTD, suggesting a loss of efficiency in information exchange between both distant and close brain areas. Altered brain regions are located in structures that are closely associated with neuropathologic changes in bvFTD. Aberrant topology of the functional brain networks in bvFTD appears to underlie cognitive deficits in these patients.

A diffusion tensor MRI study of patients with MCI and AD with a 2-year clinical follow-up

Objective The authors assessed whether brain changes detected by diffusion tensor (DT) MRI can improve the understanding of structural damage in Alzheimers disease (AD) and are associated with different risks of conversion to AD in amnestic mild cognitive impairment (aMCI). Methods Twenty-one aMCI patients, 21 AD patients and 20 healthy subjects underwent conventional and DT MRI at baseline. All subjects were clinically followed up over 2 years; at the end of follow-up, aMCI were grouped into converters to AD (aMCI-C) and non-converters (aMCI-NC). The mean diffusivity (MD) and fractional anisotropy (FA) were obtained from total grey matter (GM) and white matter (WM), and from several GM and WM regions of interest (ROIs). On T1-weighted images, normalised volumes of the whole brain (NBV), GM (NGMV) and WM were measured. Results A significant ‘trend’ of worsening with a trajectory ‘normal/aMCI/AD’ was found for NBV and NGMV, total GM and WM MD, total WM FA, as well as for diffusivity abnormalities in several GM and WM ROIs, mainly located in posterior brain regions. aMCI-C had GM and WM changes similar to those seen in AD, whereas aMCI-NC showed a DT MRI pattern similar to that of healthy subjects. DT MRI metrics that better distinguished aMCI-C from aMCI-NC were MD of total GM and WM, hippocampi, anterior insulae, frontal and parietal WM, occipital GM and WM, and FA of temporal WM. Volumetric variables were not able to distinguish the two aMCI subgroups (aMCI-C and aMCI-NC). Conclusions Subtle brain diffusivity changes occur from the prodromal stages of AD, mainly in posterior brain regions, and spread over the course of the disease to involve the frontal lobe. In aMCI, the severity of microstructural damage within and beyond the medial temporal lobe is associated with an increased short-term risk to develop AD.