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We describe brain structural damage and cognitive profile evolution of an adult patient with 17q21.31 microduplication, a rare condition associated with psychomotor delay, behavioural disturbances and poor social interaction.A.B., 57 years old, male, displayed obsessive and repetitive behaviours, irritability, scarce hygiene and memory loss at disease onset. He had strong familiarity for adult-onset behavioural alterations (his father and sister) and neuropsychiatric conditions (his son). Blood and cerebrospinal fluid (CSF) samples revealed 17q21.31 microduplication, shared also by his son and sister, and raised CSF tau, respectively. He was hospitalized 1 year after disease onset and underwent an MRI scan and a neuropsychological assessment, the latter being repeated 7 months later. To quantitatively investigate patient's grey matter (GM) volume, 16 age- and education-matched male controls were selected and voxel-based morphometry analysis was performed.During hospitalization, his behavioural profile was characterized by anosognosia, impulsivity, apathy and aggressiveness. Cognitive testing revealed main attentive-executive disturbances and difficulties in understanding non-literal language. Compared to controls, A.B. had greater GM atrophy mainly in the right hemisphere, involving amygdala, hippocampus, inferior/superior temporal gyri and temporal pole. He received a diagnosis of early onset dementia. After 7 months, he developed empathy loss, perseverative behaviour, changes in eating habits and worsening in executive-attentive abilities.In A.B., 17q21.31 microduplication caused a neurodegenerative condition with prevalent right temporal damage, raised CSF tau level, behavioural disturbances, memory impairment, attentive-executive and abstract language dysfunctions and fast disease progression, thus reflecting the complex interaction between such genetic substrate and clinical phenotypes.

Background and purpose: This study was undertaken to determine the diagnostic and prognostic value of a panel of serum biomarkers and to correlate their concentrations with several clinical parameters in a large cohort of patients with amyotrophic lateral sclerosis (ALS). Methods: One hundred forty-three consecutive patients with ALS and a control cohort consisting of 70 patients with other neurodegenerative disorders (DEG), 70 patients with ALS mimic disorders (ALSmd), and 45healthy controls (HC) were included. Serum neurofilament light chain (NfL), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), glial fibrillary acidic protein (GFAP), and total tau protein levels were measured using ultrasensitive single molecule array. Results: NfL correlated with disease progression rate (p&nbsp

Introduction Differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) is crucial for an adequate patients' management but might be challenging. We investigated with advanced MRI techniques gray (GM) and white matter (WM) damage in DLB patients compared to those with AD. Methods 24 DLB patients, 26 age- and disease severity-matched AD patients, and 20 age and sex-matched controls performed clinical and neuropsychological assessment, and brain structural and diffusion-tensor MRI. We measured GM atrophy using voxel-based morphometry, WM hyperintensities (WMH) using a local thresholding segmentation technique, and normal-appearing WM (NAWM) damage using tract-based spatial statistic. Results DLB and AD patients exhibited mild-to-moderate-stage dementia. Compared to controls, GM damage was diffuse in AD, while limited to bilateral thalamus and temporal regions in DLB. Compared to DLB, AD patients exhibited GM atrophy in bilateral fronto-temporal and occipital regions. DLB and AD patients showed higher WMH load than controls, with no differences among each other. WMH in DLB were diffuse with relative prevalence in posterior parietal-occipital regions. Compared to controls, both DLB and AD patients showed reduced microstructural integrity of the main supratentorial and infratentorial NAWM tracts. AD patients exhibited greater posterior NAWM damage than DLB. Conclusions DLB showed prominent WM degeneration compared to the limited GM atrophy, while in AD both tissue compartments were severely involved. In DLB, NAWM microstructural degeneration was independent of WMH, thus revealing two possible underlying processes. Different pathophysiological mechanisms are likely to drive GM and WM damage distribution in DLB and AD.

Background Alzheimer's Disease is characterized by a heterogeneous course. Predicting a fast rather than a slow decline over time is crucial to both provide a reliable prognosis and elaborate stricter enrolment criteria in clinical trials. Here we searched for independent predictors of cognitive decline rate to assess the risk of fast disease progression already at baseline. Methods 53 subjects with an "in-vivo biomarker confirmed" diagnosis of Alzheimer's Disease were included. Neuropsychological assessment, plasma neurofilaments (NfL) concentrations and, in a subsample of 23 patients, Brain Magnetic Resonance Imaging were available. Patients were labelled FAST or SLOW depending on the Mini Mental State Test (MMSE) points lost per year (FAST if more than 3 points). We adopted single logistic regression models to search for independent predictors of FAST progression. Results At baseline no differences were found between FAST and SLOW subgroups in demographics, MMSE scores, vascular burden and Medial Temporal Lobe (MTL) atrophy measurements. Higher plasma NfL concentrations and worse scores at Semantic Verbal Fluency (SVF) and Clock Drawing Test (CDT) were independent predictors of FAST decline, after controlling for age, education, sex and baseline disease severity stage. The regression model combining all the predictors correctly classified 80% of patients overall. The risk of FAST decline was 81.2% if all the three predictors were abnormal (i.e., SVF ≤ 21.5; CDT ≤ 5.5; NfL ≥ 22.19). Conclusions An easily applicable algorithm including plasma neurofilament measurement and two neuropsychological tests worldwide adopted in clinical practice (SVF and CDT), may allow the clinicians to reliably stratify AD patients depending on the risk of fast cognitive decline.

Background: Mild cognitive impairment (MCI) is a transitional condition between normal cognition and dementia. [18F]FDG-PET reveals brain hypometabolism patterns reflecting neuronal/synaptic dysfunction, already in the prodromal MCI phase. Activated microglia is part of the pathogenetic processes leading to neurodegeneration. Objective: Using [11C]-(R)-PK11195 and [18F]FDG-PET, we aimed to in vivo investigate the presence of microglial activation, and the relationship with brain glucose metabolism, in single MCI subjects. Methods: Eight MCI subjects underwent both [18F]FDG-PET and [11C]-(R)-PK11195 PET. We used validated quantification methods to obtain brain hypometabolism maps and microglia activation peaks in single subjects. We investigated both the spatial overlap and the relationship between brain glucose hypometabolism and microglia activation, by means of Dice similarity coefficient and using Pearson’s correlation at single subject level. Results: Each MCI showed a specific brain hypometabolism pattern indicative of different possible etiologies, as expected in MCI population (i.e., Alzheimer’s disease-like, frontotemporal dementia-like, hippocampal-type, normal aging type). [11C]-(R)-PK11195 PET analysis revealed a spatial concordance with regional hypometabolism in all subjects with several clusters of significant microglia activation showing an inverse correlation with the regional metabolism. This was proportional to the strength of between-signals correlation coefficient (β = –0.804; p = 0.016). Conclusion: Microglia activation is present in the prodromal MCI phase of different underlying etiologies, showing spatial concordance and inverse correlation with brain glucose metabolism at single-subject level. These findings suggest a possible contribution of activated microglia to neurodegeneration, showing important implications for local immune activity in the early neurodegenerative processes.

Background Corticobasal syndrome (CBS) is the usual clinical presentation of patients with corticobasal degeneration pathology. Nevertheless, there are CBS individuals with postmortem neuropathology typical of Alzheimer's disease (AD). Objective In this study, we aim to detect FDG-PET metabolic signatures at the single-subject level in a CBS sample, also evaluated with cerebrospinal fluid (CSF) markers for AD pathology. Methods 21 patients (68.9±6.4 years; MMSE score = 21.7±6.3) fulfilling current criteria for CBS were enrolled. All underwent a clinical-neuropsychological assessment and an instrumental evaluation for biomarkers of neurodegeneration, amyloid and tau pathology (i.e., FDG-PET imaging and CSF Aβ42 and tau levels) at close intervals. CBS subjects were classified according to the presence or absence of CSF markers of AD pathology (i.e., low Aβ42 and high phosphorylated tau levels). Optimized voxel-based SPM procedures provided FDG-PET metabolic patterns at the single-subject and group levels. Results Eight CBS had an AD-like CSF profile (CBS-AD), while thirteen were negative (CBS-noAD). The two subgroups did not differ in demographic characteristics or global cognitive impairment. FDG-PET SPM t-maps identified different metabolic signatures. Namely, all CBS-AD patients showed the typical AD-like hypometabolic pattern involving posterior cingulate cortex, precuneus and temporo-parietal cortex, whereas CBS-noAD cases showed bilateral hypometabolism in fronto-insular cortex and basal ganglia that is typical of the frontotemporal lobar degeneration spectrum. Discussion These results strongly suggest the inclusion of FDG-PET imaging in the diagnostic algorithm of individuals with CBS clinical phenotype in order to early identify functional metabolic signatures due to different neuropathological substrates, thus improving the diagnostic accuracy.

Given the challenges posed by the clinical diagnosis of atypical Alzheimer’s disease (AD) variants and the limited imaging evidence available in the prodromal phases of atypical AD, we assessed brain hypometabolism patterns at the single-subject level in the AD variants spectrum. Specifically, we tested the accuracy of [18F]FDG-PET brain hypometabolism, as a biomarker of neurodegeneration, in supporting the differential diagnosis of atypical AD variants in individuals with dementia and mild cognitive impairment (MCI). We retrospectively collected N = 67 patients with a diagnosis of typical AD and AD variants according to the IWG-2 criteria (22 typical-AD, 15 frontal variant-AD, 14 logopenic variant-AD and 16 posterior variant-AD). Further, we included N = 11 MCI subjects, who subsequently received a clinical diagnosis of atypical AD dementia at follow-up (21 ± 11 months). We assessed brain hypometabolism patterns at group- and single-subject level, using W-score maps, measuring their accuracy in supporting differential diagnosis. In addition, the regional prevalence of cerebral hypometabolism was computed to identify the most vulnerable core regions. W-score maps pointed at distinct, specific patterns of hypometabolism in typical and atypical AD variants, confirmed by the assessment of core hypometabolism regions, showing that each variant was characterized by specific regional vulnerabilities, namely in occipital, left-sided, or frontal brain regions. ROC curves allowed discrimination among AD variants and also non-AD dementia (i.e., dementia with Lewy bodies and behavioral variant of frontotemporal dementia), with high sensitivity and specificity. Notably, we provide preliminary evidence that, even in AD prodromal phases, these specific [18F]FDG-PET patterns are already detectable and predictive of clinical progression to atypical AD variants at follow-up. The AD variant-specific patterns of brain hypometabolism, highly consistent at single-subject level and already evident in the prodromal stages, represent relevant markers of disease neurodegeneration, with highly supportive diagnostic and prognostic role.

Background and ObjectivesA significant overlap between amyotrophic lateral sclerosis (ALS) and behavioral variant of frontotemporal dementia (bvFTD) has been observed at clinical, genetic, and pathologic levels. Within this continuum of presentations, the presence of mild cognitive or behavioral symptoms in patients with ALS has been consistently reported, although it is unclear whether this is to be considered a distinct phenotype or rather a natural evolution of ALS. Here, we used mathematical modeling of MRI connectomic data to decipher common and divergent neural correlates across the ALS–frontotemporal dementia (FTD) spectrum.MethodsWe included 83 patients with ALS, 35 patients with bvFTD, and 61 healthy controls, who underwent clinical, cognitive, and MRI assessments. Patients with ALS were classified according to the revised Strong criteria into 54 ALS with only motor deficits (ALS-cn), 21 ALS with cognitive or behavioral involvement (ALS-ci/bi), and 8 ALS with bvFTD (ALS-FTD). First, we assessed the functional and structural connectivity patterns across the ALS-FTD spectrum. Second, we investigated whether and where MRI connectivity alterations of patients with ALS with any degree of cognitive impairment (i.e., ALS-ci/bi and ALS-FTD) resembled more the pattern of damage of one (ALS-cn) or the other end (bvFTD) of the spectrum, moving from group-level to single-subject analysis.ResultsAs compared with controls, extensive structural and functional disruption of the frontotemporal and parietal networks characterized bvFTD (bvFTD-like pattern), while a more focal structural damage within the sensorimotor-basal ganglia areas characterized ALS-cn (ALS-cn-like pattern). ALS-ci/bi patients demonstrated an ALS-cn-like pattern of structural damage, diverging from ALS-cn with similar motor impairment for the presence of enhanced functional connectivity within sensorimotor areas and decreased functional connectivity within the bvFTD-like pattern. On the other hand, patients with ALS-FTD resembled both structurally and functionally the bvFTD-like pattern of damage with, in addition, the structural ALS-cn-like damage in the motor areas.DiscussionOur findings suggest a maladaptive role of functional rearrangements in ALS-ci/bi concomitantly with similar structural alterations compared to ALS-cn, supporting the hypothesis that ALS-ci/bi might be considered as a phenotypic variant of ALS, rather than a consequence of disease worsening.

Aberrations of large-scale brain networks are found in the majority of neurodegenerative disorders. The brain connectivity alterations underlying dementia with Lewy bodies (DLB) remain, however, still elusive, with contrasting results possibly due to the pathological and clinical heterogeneity characterizing this disorder. Here, we provide a molecular assessment of brain network alterations, based on cerebral metabolic measurements as proxies of synaptic activity and density, in a large cohort of DLB patients (N = 72). We applied a seed-based interregional correlation analysis approach (p < .01, false discovery rate corrected) to evaluate large-scale resting-state networks' integrity and their interactions. We found both local and long-distance metabolic connectivity alterations, affecting the posterior cortical networks, that is, primary visual and the posterior default mode network, as well as the limbic and attention networks, suggesting a widespread derangement of the brain connectome. Notably, patients with the lowest visual and attention cognitive scores showed the most severe connectivity derangement in regions of the primary visual network. In addition, network-level alterations were differentially associated with the core clinical manifestations, namely, hallucinations with more severe metabolic dysfunction of the attention and visual networks, and rapid eye movement sleep behavior disorder with alterations of connectivity of attention and subcortical networks. These multiple network-level vulnerabilities may modulate the core clinical and cognitive features of DLB and suggest that DLB should be considered as a complex multinetwork disorder.

A novel study about the synthesis of zirconia and calcia-stabilized zirconia powders were carried out by DC thermal plasma starting from cheap precursors as the carbonates. Different operational parameters were investigated to explore the effects of the process conditions, such as the plasma torch power and the gas flow rate on the composition and the morphology of the powders. The products phase changes from a metastable tetragonal to monoclinic/tetragonal mixture. Basically a main tetragonal phase was obtained at low torch power (7 kW) while the amount of monoclinic phase linearly rises with the power, up to 66 wt% at 26 kW of plasma power and high gas flow rate. The gas flow rate also affects the shape and the size of the powder, where high values reduce powder aggregation and enhance the spherical shape. The best results were achieved at 22 kW of plasma power and high gas flow rate, with powders of roundness about 79% and a wide particle size distribution. Adding the calcium carbonate to the zirconium carbonate (corresponding to 8 wt% CaO in the final mixture), the plasma treatment mainly produces a tetragonal phase zirconia, that at 1400 °C in furnace changes in a stable cubic phase. These powders could be made suitable for further industrial applications after proper treatments.

In order to improve the oxidation resistance of Cf/Cs produced by chemical vapour infiltration, a multilayer coating based on silicon carbide and molybdenum disilicide was produced by two-step pack cementation technique. The inner SiC layer with a thickness up to 25 μm was obtained without promoted reaction additives by varying the composition, and thermal treatment conditions. The SiC/SiC-MoSi2 coating was produced with a thickness up to 80 μm by two step pack cementation, considering the effect of the inner layer characteristic. The enhancement of the oxidation resistance, observed in SiC/SiC-MoSi2 coated Cf/Cs by means of thermal analysis in flowing air up to 1500 °C, was due to the formation of SiO2 promoted by the passive oxidation of silicon carbide and molybdenum disilicide.

The Two-Step Sintering (TSS) process is a useful method to obtain sintered materials of high density and to limit the grain growth associated with the final stage of the sintering process. One of the main advantages of this method is the lowering of the sintering temperature. The development of bulk, dense and small grain size in the wurtzite phase of the ZnS ceramic was investigated by using a micron-sized ZnS powder as a precursor material. The microstructure and morphology of the TSS-fabricated ZnS ceramic pellets were observed by Scanning Electron Microscopy (SEM) and compared to those produced by the conventional sintering process. The ZnS ceramic produced using the TSS method at 1100°C showed comparable density and a much finer microstructure (five times smaller grain size) than the ZnS ceramic produced using conventional sintering at 1250°C. It was demonstrated that the TSS process is a pressureless, simple and cost‐effective sintering method, able to deliver high density bulk, wurtzite phase ZnS ceramics with controlled grain size. &nbsp

The pyroelectric performances of non-ferroelectric pyroelectrics like wurtzite- based materials (e.g. AlN, GaN, CdS or ZnO) make them important, although not widely used, compared to the current state-of-the-art ferroelectrics. Their high chemical and thermal stability allows their use at high temperatures in air, whereas ferroelectrics become ineffective when heated beyond their Curie temperature (TC). Wurtzite based materials have a higher thermal conductivity allowing them to react faster to ambient temperature changes, their raw material costs are lower and many of them are eco-friendly. Current pyroelectrics applications are limited to portable systems or tasks needing only μW–mW power. To be commercially viable, we must improve the current low efficiency of pyroelectric systems and intrinsically enhance the pyroelectric properties of modern materials through suitable doping or material engineering. We chose to study hexagonal wurtzite phase of ZnS, among the structurally simplest of pyroelectrics, as a possible energy harvesting material. An easy synthesis method – a co-precipitation technique, was tailored for nanocrystalline wurtzite ZnS production. This method is easy to scale-up and our next step is to build an in-house pilot plant that will produce substantial amounts of wurtzite ZnS nano-powder in an environmentally friendly and cost-effective manner. We further investigated the development of bulk, dense pyroelectric ceramics by the Two-Step Sintering (TSS) fabrication process, using as the precursor material both a micron-sized commercial powder of the ZnS cubic and hexagonal phases mixture, and an in-house produced wurtzite ZnS nanopowder. The TSS was chosen as being a pressureless, simple and cost‐effective sintering method for obtaining high density materials with controlled grain growth operating at a lower temperature than the conventiona process. Electron Microscopy techniques helped us to study the microstructure and morphology of both the precursor nanopowders and the obtained ceramics. Acknowledgement: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 797951.

Brain connectivity measures represent candidate biomarkers of neuronal dysfunction in neurodegenerative diseases. Previous findings suggest that the behavioural variant of frontotemporal dementia (bvFTD) and its variants (i.e., frontal and temporo-limbic) may be related to the vulnerability of distinct functional connectivity networks. In this study, 82 bvFTD patients were included, and two patient groups were identified as frontal and temporo-limbic bvFTD variants. Two advanced multivariate analytical approaches were applied to FDG-PET data, i.e., sparse inverse covariance estimation (SICE) method and seed-based interregional correlation analysis (IRCA). These advanced methods allowed the assessment of (i) the whole-brain metabolic connectivity, without any a priori assumption, and (ii) the main brain resting-state networks of crucial relevance for cognitive and behavioural functions. In the whole bvFTD group, we found dysfunctional connectivity patterns in frontal and limbic regions and in all major brain resting-state networks as compared to healthy controls (HC N = 82). In the two bvFTD variants, SICE and IRCA analyses identified variant-specific reconfigurations of whole-brain connectivity and resting-state networks. Specifically, the frontal bvFTD variant was characterised by metabolic connectivity alterations in orbitofrontal regions and anterior resting-state networks, while the temporo-limbic bvFTD variant was characterised by connectivity alterations in the limbic and salience networks. These results highlight different neural vulnerabilities in the two bvFTD variants, as shown by the dysfunctional connectivity patterns, with relevance for the different neuropsychological profiles. This new evidence provides further insight in the variability of bvFTD and may contribute to a more accurate classification of these patients.

Background Early-onset Alzheimer’s disease (EOAD) is characterized by young age of onset ( Methods We prospectively enrolled 12 EOAD patients, classified according to standard criteria, who underwent standard neurological and neuropsychological evaluation, CSF analysis, brain MRI, and both [18F]-FDG PET and [11C]-(R)-PK11195 PET. Healthy controls databases were used for statistical comparison. [18F]-FDG PET brain metabolism in single subjects and as a group was assessed by an optimized SPM voxel-wise single-subject method. [11C]-PK11195 PET binding potentials were obtained using reference regions selected with an optimized clustering procedure followed by a parametric analysis. We performed a topographic interaction analysis and correlation analysis in AD-signature metabolic dysfunctional regions and regions of microglia activation. A network connectivity analysis was performed using the interaction regions of hypometabolism and [11C]-PK11195 PET BP increases. Results EOAD patients showed a significant and extended microglia activation, as [11C]-PK11195 PET binding potential increases, and hypometabolism in typical AD-signature brain regions, i.e., temporo-parietal cortex, with additional variable frontal and occipital hypometabolism in the EOAD variants. There was a spatial concordance in the interaction areas and significant correlations between the two biological changes. The network analysis showed a disruption of frontal connectivity induced by the metabolic/microglia effects. Conclusion The severe microglia activation characterizing EOAD and contributing to neurodegeneration may be a marker of rapid disease progression. The coupling between brain glucose hypometabolism and local immune response in AD-signature regions supports their biological interaction.

ObjectiveTo investigate the types of errors produced in a picture naming task by patients with neurodegenerative dementia due to different etiologies and their neural correlates.MethodsThe same standardized picture naming test was administered to a consecutive sample of patients (n = 148) who had been studied with [18F] FDG-PET. The errors were analyzed in 3 categories (visual, semantic, and phonologic). The PET data were analyzed using an optimized single-subject procedure, and the statistical parametric mapping multiple regression design was used to explore the correlation between each type of error and brain hypometabolism in the whole group. Metabolic connectivity analyses were run at the group level on 7 left hemisphere cortical areas corresponding to an a priori defined naming network.ResultsSemantic errors were predominant in most patients, independent of clinical diagnosis. In the whole group analysis, visual errors correlated with hypometabolism in the right inferior occipital lobe and in the left middle occipital lobe. Semantic errors correlated with hypometabolism in the left fusiform gyrus, the inferior and middle temporal gyri, and the temporal pole. Phonologic errors were associated with hypometabolism in the left superior and middle temporal gyri. Both positive (occipital–posterior fusiform) and negative (anterior fusiform gyrus and the superior anterior temporal lobe) connectivity changes were associated with semantic errors.ConclusionsNaming errors reflect the dysfunction of separate stages of the naming process and are specific markers for different patterns of brain involvement. These correlations are not limited to primary progressive aphasia but extend to other neurodegenerative dementias.

ObjectiveTo understand whether the clinical phenotype of nonfluent/agrammatic primary progressive aphasia (nfvPPA) could present differences depending on the patient’s native language.MethodsIn this cross-sectional study, we analyzed connected speech samples in monolingual English (nfvPPA-E) and Italian speakers (nfvPPA-I) who were diagnosed with nfvPPA and matched for age, sex, and Mini-Mental State Examination scores. Patients also received a comprehensive neuropsychological battery. All patients and 2 groups of age-matched healthy controls underwent an MRI scan with 3D T1-weighted sequences. Connected speech measures and the other cognitive features were compared between patient groups. MRI variables, in terms of gray matter volume, were compared between each patient group and the corresponding controls.ResultsCompared to nfvPPA-E, nfvPPA-I had fewer years of education and shorter reported disease duration. The 2 groups showed similar regional atrophy compatible with clinical diagnosis. Patients did not differ in nonlanguage domains, comprising executive scores. Connected speech sample analysis showed that nfvPPA-E had significantly more distortions than nfvPPA-I, while nfvPPA-I showed reduced scores in some measures of syntactic complexity. On language measures, Italian speakers performed more poorly on syntactic comprehension.ConclusionsnfvPPA-E showed greater motor speech impairment than nfvPPA-I despite higher level of education and comparable disease severity and atrophy changes. The data also suggest greater grammatical impairment in nfvPPA-I. This study illustrates the need to take into account the possible effect of the individual's spoken language on the phenotype and clinical presentation of primary progressive aphasia variants.

To know whether mild cognitive impairment (MCI) patients will develop Alzheimer's disease (AD) dementia in very short time or remain stable is of crucial importance, also considering new experimental drugs usually tested within very short time frames. Here we combined cerebrospinal fluid (CSF) AD biomarkers and a neurodegeneration marker such as brain FDG-PET to define an objective algorithm, suitable not only to reliably detect MCI converters to AD dementia but also to predict timing of conversion.We included 77 consecutive MCI patients with neurological/neuropsychological assessment, brain 18F-FDG-PET and CSF analysis available at diagnosis and a neuropsychological/neurological evaluation every 6 months for a medium- to a long-term follow-up (at least 2 and up to 8 years). Binomial logistic regression models and Kaplan-Meier survival analyses were performed to determine the best biomarker (or combination of biomarkers) in detecting MCI converters to AD dementia and then, among the converters, those who converted in short time frames.Thirty-five out of 77 MCI patients (45%) converted to AD dementia, with an average conversion time since MCI diagnosis of 26.07 months. CSF p-tau/Aβ42 was the most accurate predictor of conversion from MCI to AD dementia (82.9% sensitivity; 90% specificity). CSF p-tau/Aβ42 and FDG-PET-positive MCIs converted to AD dementia significantly earlier than the CSF-positive-only MCIs (median conversion time, 17.1 vs 31.3 months).CSF p-tau/Aβ42 ratio and brain FDG-PET may predict both occurrence and timing of MCI conversion to full-blown AD dementia. MCI patients with both biomarkers suggestive for AD will likely develop an AD dementia shortly, thus representing the ideal target for any new experimental drug requiring short periods to be tested for.

Visual hallucinations (VH) are a core clinical feature of dementia with Lewy bodies (DLB), but their specific neural substrate remains elusive. We used 18F-FDG-PET to study the neural dysfunctional signature of VH in a group of 38 DLB patients (mean age±SD 72.9 ± 7.5) with available anamnestic records, cognitive and neurological examination and NeuroPsychiatric Inventory assessing VH. We tested the voxel-wise correlation between 18F-FDG-PET hypometabolism and VH NPI scores at the whole-group level, then adopting inter-regional correlation analysis to explore the resting-state networks (RSNs) metabolic connectivity in DLB patients with and without visual hallucinations, as compared to N = 38 age-matched healthy controls (HCs) (mean age±SD 71.5 ± 6.9). At the whole-group level, we found a negative correlation between VH NPI scores and 18F-FDG-PET hypometabolism in the right occipito-temporal cortex (p < .001 uncorrected, p < .05 Family-Wise Error cluster-corrected). Then, splitting the group according to VH presence, we found that DLB non-hallucinators presented a pattern of connectivity seeding from this occipito-temporal cluster and extending to the ventral visual stream. At difference, the DLB hallucinators showed a metabolic connectivity pattern limited to the occipital-dorsal parietal regions. As for RSNs, both the DLB subgroups showed a markedly reduced extent of attention and visual networks compared to HCs, with a variable alteration in the topography. DLB-VH patients showed a more pronounced shrinkage of the primary visual network, which was disconnected from the higher visual hubs, at difference with both HC and DLB non-hallucinators. These findings suggest that an altered brain metabolic connectivity within and beyond visual systems may promote VH in DLB. These results support the most recent neurocognitive models interpreting VH as the result of an inefficient recruitment of the ventral visual stream and of a large-scale multi-network derangement.

Background Cognitive reserve may delay disease onset and mitigate symptoms presentation in neurodegenerative dementias. Although high occupation levels can be associated with higher cognitive reserve in the behavioural variant of frontotemporal dementia (bvFTD), it was never addressed how specific occupation profiles involving social interaction, executive and attention abilities can modulate neural reserve in bvFTD. Materials and methods We retrospectively included thirty-seven bvFTD patients with clinical-neuropsychological and FDG-PET brain metabolic data. We considered occupation levels according to 1) a 5-point scale and 2) the specific cognitive dimensions from the O*Net network database. We used the Principal Component Analysis (PCA) with the O*Net variables most representative of “worker” and “occupation” socio-cognitive skills to merge the best components describing such occupation profiles. We then performed regression analyses with brain metabolism using either 5-level occupation scale or the PCA specific profiles as independent variables, controlling for education and disease severity. Results According to the brain reserve hypothesis, higher occupation levels were associated with a more severe hypometabolism in the dorsolateral prefrontal cortex. In addition, among the identified PCA profiles, social skills were associated with severe hypometabolism in medial and dorsolateral prefrontal regions, and cognitive control in the left fronto-insular cortex. Discussion This study contributes to define the role of specific occupation profiles as proxy of cognitive reserve in bvFTD, providing the first evidence for social interaction and cognitive control skills in life-occupation activities as influencing factors of neural reserve against neurodegeneration in bvFTD. Jobs placing high demand on such abilities seem to act as protective factors in bvFTD.

Co-existence of Alzheimer's disease (AD) in normal pressure hydrocephalus (NPH) is a frequent finding, thus a common pathophysiological basis between AD and NPH has been postulated. We measured CSF amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) concentrations in a sample of 294 patients with different types of dementia and 32 subjects without dementia. We then compared scores on neuropsychological tests of NPH patients with pathological and normal CSF Aβ42 values. Aβ42 levels were significantly lower in NPH than in control patients, with no significant differences between AD and NPH. On the contrary, t-tau and p-tau levels were significantly lower in NPH than in AD, with no differences between NPH and controls. NPH patients with pathological Aβ42 levels did not perform worse than NPH patients with normal Aβ42 levels in any cognitive domains. Our data seem to support the hypothesis of amyloid accumulation in brains of NPH patients. Nevertheless, amyloid does not seem to play a pathogenetic role in the development of cognitive deficits in NPH.

BACKGROUND Alzheimer's disease (AD) and frontotemporal dementia (FTD) are leading causes of cognitive decline. Optical coherence tomography (OCT) allows the measurement of thickness of retinal neuroaxonal layers. While in AD and mild cognitive impairment (MCI), retinal nerve fiber layer (RNFL) thinning is frequently reported, less information is available on ganglion cell layer-inner plexiform layer (GCL-IPL). Data on FTD are lacking. OBJECTIVE To obtain cross-sectional information on RNFL and GCL-IPL thickness among MCI, AD, FTD, and healthy controls (HC), and their correlations with dementia severity. METHODS Peripapillary OCT scans were obtained in 27 MCI, 39 AD, 17 FTD, 49 HC using high-definition Heidelberg Spectral-domain OCT, with RNFL and GCL-IPL thickness measurement. Statistical analysis tested group effects and correlation with gender, disease duration and severity (Mini-Mental State Examination, MMSE). RESULTS RNFL showed a significant group effect [F(4,132) = 3.786, p = 0.006], being reduced versus controls in MCI (p = 0.033), moderate AD (p = 0.025), and FTD (p

Introduction Dementia with Lewy Bodies (DLB) is characterized by a prominent deficit in visuospatial abilities. Visuospatial impairment is also detectable in the course of Alzheimer's dementia (AD). However, visuospatial impairment presents some differences in these two conditions, suggesting pathological involvement of distinct brain circuits. Recent studies applied a new method to score the Mini Mental State Examination (MMSE) pentagon copy subtest, namely the Qualitative Scoring Pentagon Test (QSPT), which is a sensitive measure of visuospatial abilities. Using [18F]fluorodeoxy-glucose positron emission tomography (FDG-PET), we assessed the relationship between in vivo brain metabolic dysfunction and visuospatial deficits, in terms of QSPT total value, in DLB and AD. Materials and methods Sixty Patients were diagnosed as DLB (n = 35) and AD (n = 25) dementia according with the standard research diagnostic criteria. Each patient underwent a FDG-PET scan as support for the final diagnosis. Patients underwent an extended neuropsychological evaluation, including MMSE, language, memory, executive functions and visuospatial abilities tests. The MMSE QSPT scoring was calculated following the methods by Caffarra et al. (2013). Offline voxel-wise correlation analysis between QSPT total scores and FDG-PET brain metabolism was then performed, correcting for MMSE, sex and disease duration. Results Both groups presented reduced visuospatial performances, as assessed by QSPT scores. DLB compared to AD showed a statistically significant difference in QSPT rotation parameter (p = 0.022). In DLB, worse performance at QSPT total score, i.e. more severe visuospatial impairment, correlated with brain occipital hypometabolism (i.e. lateral occipital cortex, calcarine cortex, fusiform and lingual gyri). In AD, worse performance at QSPT total score correlated with brain hypometabolism in the right parietal cortex (i.e. superior and inferior parietal cortex and angular gyrus). Discussion These findings reveal that visuospatial deficits may derive from distinct brain alterations in AD and DLB. We propose that the inabilities to perform correctly the QSPT task is related to altered visuoperceptual process in DLB, and visuospatial process in AD. This is consistent with our results showing hypometabolism in brain system related to visuoperceptual processing, namely the occipital cortex in DLB, and visuospatial processing, namely parietal cortex in AD.

Background: The incoming disease-modifying therapies against Alzheimer’s disease (AD) require reliable diagnostic markers to correctly enroll patients all over the world. CSF AD biomarkers, namely amyloid-β 42 (Aβ42), total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau181), showed good diagnostic accuracy in detecting AD pathology, but their real usefulness in daily clinical practice is still a matter of debate. Therefore, further validation in complex clinical settings, that is patients with different types of dementia, is needed to uphold their future worldwide adoption. Methods: We measured CSF AD biomarkers’ concentrations in a sample of 526 patients with a clinical diagnosis of dementia (277 with AD and 249 with Other Type of Dementia, OTD). Brain FDG-PET was also considered in a subsample of 54 patients with a mismatch between the clinical diagnosis and the CSF findings. Results: A p-tau181/Aβ42 ratio higher than 0.13 showed the best diagnostic performance in differentiating AD from OTD (86% accuracy index, 74% sensitivity, 81% specificity). In cases with a mismatch between clinical diagnosis and CSF findings, brain FDG-PET partially agreed with the p-tau181/Aβ42 ratio, thus determining an increase in CSF accuracy. Conclusions: The p-tau181/Aβ42 ratio alone might reliably detect AD pathology in heterogeneous samples of patients suffering from different types of dementia. It might constitute a simple, cost-effective and reproducible in vivo proxy of AD suitable to be adopted worldwide not only in daily clinical practice but also in future experimental trials, to avoid the enrolment of misdiagnosed AD patients.

Highlights • CBS and PSP patients show heterogeneous language profiles. • Patients with nfvPPA profile show the typical nfvPPA hypometabolic pattern. • Parietal hypometabolism characterizes CBS cases with undefined language deficits. • Frontal hypometabolism characterizes PSP cases with undefined language deficits. • Patients without language deficit show a predominant right hemisphere involvement., Purpose To assess the clinical-metabolic correlates of language impairment in a large sample of patients clinically diagnosed as corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPs). Methods We included 70 patients fulfilling current criteria for CBS (n = 33) or PSPs (n = 37). All subjects underwent clinical-neuropsychological and FDG-PET assessments at the time of diagnosis. The whole patient's cohort was grouped into three subgroups according to the language characteristics, i.e., (a) nfv-PPA; (b) subtle language impairments, LANG-; (c) no language deficits, NOL-. FDG-PET data were analysed using an optimized voxel-based SPM method at the single-subject and group levels in order to evaluate specific hypometabolic patterns and regional dysfunctional FDG-PET commonalities in subgroups. Results 21 patients had a nfvPPA diagnosis (i.e., nfv-PPA/CBS = 12 and nfv-PPA/PSPs = 9), while 20 patients had a subtle language impairment LANG- (i.e., CBS = 12 and PSPs = 8), not fulfilling the criteria for a nfv-PPA diagnosis. The remaining sample (i.e., 9/33 CBS and 20/37 PSPs patients) did not show any language deficit. FDG-PET results in individuals with a nfv-PPA diagnosis were consistent with the typical nfv-PPA pattern of hypometabolism (i.e., left fronto-insular and superior medial frontal cortex involvement), both in CBS and PSPs. The LANG-CBS and LANG-PSPs subjects had different FDG-PET hypometabolic patterns involving, respectively, parietal and frontal regions. As expected, NOL-CBS and NOL-PSPs showed a predominant right hemisphere involvement, with selective functional metabolic signatures typical of the two syndromes. Conclusions Language impairments, fulfilling the nfv-PPA criteria, are associated with both CBS and PSPs clinical presentations early in the disease course. Subtle language deficits may be present in an additional proportion of patients not fulfilling the nfv-PPA criteria. The topography of brain hypometabolism is a major dysfunctional signature of language deficits in CBS and PSPs clinical phenotypes.

Background and Objective: Primary progressive aphasia (PPA) is a clinical syndrome due to different neurodegenerative conditions in which an accurate early diagnosis needs to be supported by a reliable diagnostic tool at the individual level. In this study, we investigated in PPA the FDG-PET brain metabolic patterns at the single-subject level, in order to assess the case-to-case variability and its relationship with clinical-neuropsychological findings. Material and Methods: 55 patients (i.e., 11 semantic variant/sv-PPA, 19 non fluent variant/nfv-PPA, 17 logopenic variant/lv-PPA, 3 slowly progressive anarthria/SPA, and 5 mixed PPA/m-PPA) were included. Clinical-neuropsychological information and FDG-PET data were acquired at baseline. A follow-up of 27.4±12.55 months evaluated the clinical progression. Brain metabolism was analyzed using an optimized and validated voxel-based SPM method at the single-subject level. Results: FDG-PET voxel-wise metabolic assessment revealed specific metabolic signatures characterizing each PPA variant at the individual level, reflecting the underlying neurodegeneration in language networks. Notably, additional dysfunctional patterns predicted clinical progression to specific dementia conditions. In the case of nfv-PPA, a metabolic pattern characterized by involvement of parietal, subcortical and brainstem structures predicted progression to a corticobasal degeneration syndrome or to progressive supranuclear palsy. lv-PPA and sv-PPA cases who progressed to Alzheimer’s disease and frontotemporal dementia at the follow-up presented with extended bilateral patterns at baseline. Discussion: Our results indicate that FDG-PET voxel-wise imaging is a valid biomarker for the early differential diagnosis of PPAs and for the prediction of progression to specific dementia condition. This study supports the use of FDG-PET imaging quantitative assessment in clinical settings for a better characterization of PPA individuals and prognostic definition of possible endo-phenotypes.

BACKGROUND: The diagnosis of probable behavioral variant of fronto-temporal dementia (bvFTD) according to current criteria requires the imaging evidence of frontal and/or anterior temporal atrophy or hypoperfusion/hypometabolism. Different variants of this pattern of brain involvement may, however, be found in individual cases, supporting the presence of heterogeneous phenotypes. OBJECTIVE: We examined in a case-by-case approach the FDG-PET metabolic patterns of patients fulfilling clinical criteria for probable bvFTD, assessing the presence and frequency of specific FDG-PET features. MATERIALS AND METHODS: Fifty two FDG-PET scans of probable bvFTD patients were retrospectively analyzed together with clinical and neuropsychological data. Neuroimaging experts rated the FDG-PET hypometabolism maps obtained at the single-subject level with optimized voxel-based Statistical Parametric Mapping (SPM). The functional metabolic heterogeneity was further tested by hierarchical cluster analysis and principal component analysis (PCA). RESULTS: Both the SPM maps and cluster analysis identified two major variants of cerebral hypometabolism, namely the "frontal" and the "temporo-limbic", which were correlated with different cognitive profiles. Executive and language deficits were the cognitive hallmark in the "frontal" subgroup, while poor encoding and recall on long-term memory tasks was typical of the "temporo-limbic" subgroup. DISCUSSION: SPM single-subject analysis indicates distinct patterns of brain dysfunction in bvFTD, coupled with specific clinical features, suggesting different profiles of neurodegenerative vulnerability. These findings have important implications for the early diagnosis of bvFTD and for the application of the recent international consensus criteria.

Neuropsychiatric symptoms (NPSs) often occur in early-age-of-onset Alzheimer's disease (EOAD) and cluster into sub-syndromes (SSy). The aim of this study was to investigate the association between 18 F-FDG-PET regional and connectivity-based brain metabolic dysfunctions and neuropsychiatric SSy. NPSs were assessed in 27 EOAD using the Neuropsychiatric Inventory and further clustered into four SSy (apathetic, hyperactivity, affective, and psychotic SSy). Eighty-five percent of EOAD showed at least one NPS. Voxel-wise correlations between SSy scores and brain glucose metabolism (assessed with 18 F-FDG positron emission tomography) were studied. Interregional correlation analysis was used to explore metabolic connectivity in the salience (aSN) and default mode networks (DMN) in a larger sample of EOAD (N = 51) and Healthy Controls (N = 57). The apathetic, hyperactivity, and affective SSy were highly prevalent (>60%) as compared to the psychotic SSy (33%). The hyperactivity SSy scores were associated with increase of glucose metabolism in frontal and limbic structures, implicated in behavioral control. A comparable positive correlation with part of the same network was found for the affective SSy scores. On the other hand, the apathetic SSy scores were negatively correlated with metabolism in the bilateral orbitofrontal and dorsolateral frontal cortex known to be involved in motivation and decision-making processes. Consistent with these SSy regional correlations with brain metabolic dysfunction, the connectivity analysis showed increases in the aSN and decreases in the DMN. Behavioral abnormalities in EOAD are associated with specific dysfunctional changes in brain metabolic activity, in particular in the aSN that seems to play a crucial role in NPSs in EOAD. Hum Brain Mapp 37:4234-4247, 2016. © 2016 Wiley Periodicals, Inc.

Objective To determine the added value of multimodal structural magnetic resonance imaging (MRI) to language assessment in the differential diagnosis of primary progressive aphasia (PPA) variants. Methods 59 PPA patients [29 nonfluent (nfvPPA), 15 semantic (svPPA), 15 logopenic (lvPPA)] and 38 healthy controls underwent 3D T1-weighted and diffusion tensor (DT) MRI. PPA patients also performed a comprehensive language assessment. Cortical thickness measures and DT MRI indices of white matter tract integrity were obtained. A random forest analysis identified MRI features associated with each clinical variant. Using ROC curves, the discriminatory power of the language features alone (“language model”) and the added contribution of multimodal MRI variables were assessed (“language + MRI model”). Results The ‘language model’ alone was able to differentiate svPPA from both nfvPPA and lvPPA patients with high accuracy (area under the curve [AUC] = .95 and .99, respectively). When left inferior parietal cortical thickness and DT MRI metrics of the genu of the corpus callosum and left frontal aslant tract were added to the “language model”, the ability to discriminate between nfvPPA and lvPPA cases increased from AUC .82 (“language model” only) to .94 (“language + MRI model”). Conclusions Language measures alone are able to distinguish svPPA from the other two PPA variants with the highest accuracy. Multimodal structural MRI improves the distinction of nfvPPA and lvPPA, which is challenging in the clinical practice.

Background: Mild cognitive impairment (MCI) is a heterogeneous syndrome resulting from Alzheimer's disease (AD) as well as to non-AD and non-neurodegenerative conditions. A subset of patients with amnestic MCI (aMCI) present with an unusually long-lasting course, a slow rate of clinical neuropsychological progression, and evidence of focal involvement of medial temporal lobe structures. In the present study, we explored positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers in a sample of subjects with aMCI with such clinical features in order to provide in vivo evidence to improve disease characterisation in this subgroup.Methods: Thirty consecutive subjects with aMCI who had long-lasting memory impairment (more than 4 years from symptom onset) and a very slow rate of cognitive progression were included. All subjects underwent fluorodeoxyglucose-positron emission tomography (FDG-PET) metabolic imaging. A measure of cerebral amyloid load, by PET and/or CSF, was obtained in 26 of 30 subjects. The mean clinical follow-up was 58.3 ± 10.1 months.Results: No patient progressed to dementia during the follow-up. The typical AD FDG-PET pattern of temporoparietal hypometabolism was not present in any of the subjects. In contrast, a selective medial temporal lobe hypometabolism was present in all subjects, with an extension to frontolimbic regions in some subjects. PET imaging showed absent or low amyloid load in the majority of samples. The values were well below those reported in prodromal AD, and they were slightly elevated in only two subjects, consistent with the CSF β-amyloid (1–42) protein values. Notably, no amyloid load was present in the hippocampal structures.Conclusions: FDG-PET and amyloid-PET together with CSF findings questioned AD pathology as a unique neuropathological substrate in this aMCI subgroup with long-lasting disease course. The possibility of alternative pathological conditions, such as argyrophilic grain disease, primary age-related tauopathy or age-related TDP-43 proteinopathy, known to spread throughout the medial temporal lobe and limbic system structures should be considered in these patients with MCI.

To test a multimodal magnetic resonance (MR) imaging-based approach composed of cortical thickness and white matter (WM) damage metrics to discriminate between variants of primary progressive aphasia (PPA) that are nonfluent and/or agrammatic (NFVPPA) and semantic (SVPPA).This study was approved by the local ethics committees on human studies, and written informed consent from all patients was obtained before their enrollment. T1-weighted and diffusion-tensor (DT) MR images were obtained from 13 NFVPPA patients, 13 SVPPA patients, and 23 healthy control participants. Cortical thickness and DT MR imaging indices from the long-associative and interhemispheric WM tracts were obtained. A random forest (RF) analysis was used to identify the image features associated with each clinical syndrome. Individual patient classification was performed by using receiver operator characteristic curve analysis with cortical thickness, DT MR imaging, and a combination of the two modalities. RESULTS RF analysis showed that the best markers to differentiate the two PPA variants at an individual patient level among cortical thickness and DT MR imaging metrics were diffusivity abnormalities of the left inferior longitudinal and uncinate fasciculi and cortical thickness measures of the left temporal pole and inferior frontal gyrus. A combination of cortical thickness and DT MR imaging measures (the so-called gray-matter-and-WM model) was able to distinguish patients with NFVPPA and SVPPA with the following classification pattern: area under the curve, 0.91; accuracy, 0.89; sensitivity, 0.92; specificity, 0.85. Leave-one-out analysis demonstrated that the gray matter and WM model is more robust than the single MR modality models to distinguish PPA variants (accuracy was 0.86, 0.73, and 0.68 for the gray matter and WM model, the gray matter-only model, and the WM-only model, respectively).A combination of structural and DT MR imaging metrics may provide a quantitative procedure to distinguish NFVPPA and SVPPA patients at an individual patient level. The discrimination accuracies obtained suggest that the gray matter and WM model is potentially relevant for the differential diagnosis of the PPA variants in clinical practice.

Cognitive reserve (CR) prevents cognitive decline and delays neurodegeneration. Recent epidemiological evidence suggests that lifelong bilingualism may act as CR delaying the onset of dementia by ∼4.5 y. Much controversy surrounds the issue of bilingualism and its putative neuroprotective effects. We studied brain metabolism, a direct index of synaptic function and density, and neural connectivity to shed light on the effects of bilingualism in vivo in Alzheimer's dementia (AD). Eighty-five patients with probable AD and matched for disease duration (45 German-Italian bilingual speakers and 40 monolingual speakers) were included. Notably, bilingual individuals were on average 5 y older than their monolingual peers. In agreement with our predictions and with models of CR, cerebral hypometabolism was more severe in the group of bilingual individuals with AD. The metabolic connectivity analyses crucially supported the neuroprotective effect of bilingualism by showing an increased connectivity in the executive control and the default mode networks in the bilingual, compared with the monolingual, AD patients. Furthermore, the degree of lifelong bilingualism (i.e., high, moderate, or low use) was significantly correlated to functional modulations in crucial neural networks, suggesting both neural reserve and compensatory mechanisms. These findings indicate that lifelong bilingualism acts as a powerful CR proxy in dementia and exerts neuroprotective effects against neurodegeneration. Delaying the onset of dementia is a top priority of modern societies, and the present in vivo neurobiological evidence should stimulate social programs and interventions to support bilingual or multilingual education and the maintenance of the second language among senior citizens.

Objectives We have described cerebrospinal fluid (CSF) myeloid microvesicles (MVs) as a marker of microglia activation during neuroinflammation in Alzheimer disease (AD), and characterized their ability to produce toxic amyloid β1–42 (Aβ1–42) oligomers from aggregated or soluble substrate. The aim of this study is to investigate the association of CSF myeloid MVs with neuroimaging, clinical, and paraclinical data in AD and mild cognitive impairment (MCI). Methods We collected CSF from 106 AD patients, 51 MCI patients, and 29 neurologically healthy controls. We examined CSF myeloid MV content and AD markers. A subgroup of 34 AD and 21 MCI patients underwent structural and diffusion tensor MRI. Results Higher levels of myeloid MVs were found in the CSF of AD patients and MCI patients converting within 3 years relative to controls, but also, at a lower level, in MCI patients not converting to AD. CSF myeloid MVs were associated with Tau but not with Aβ1–42 CSF levels. CSF MVs levels correlated with white matter (WM) tract damage in MCI, and with hippocampal atrophy in AD. Interpretation Microglial MVs are neurotoxic and myelinotoxic in the presence of Aβ1–42. CSF myeloid MVs, mirroring microglia activation and MV release, are associated with WM damage in MCI and hippocampal atrophy in AD. This suggests that hippocampal microglia activation, in the presence of Aβ1–42 in excess, produces neurotoxic and oligodendrotoxic oligomers that, through WM tract damage, spread disease to neighboring and connected areas, causing local microglia activation and propagation of disease through the same sequence of events. Ann Neurol 2014;76:813–825