Citations

Abstract Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a complex heterogeneous neurodegenerative disorder for which mechanisms are poorly understood. To explore transcriptional changes underlying FTLD-TDP, we performed RNA-sequencing on 66 genetically unexplained FTLD-TDP patients, 24 FTLD-TDP patients with GRN mutations and 24 control participants. Using principal component analysis, hierarchical clustering, differential expression and coexpression network analyses, we showed that GRN mutation carriers and FTLD-TDP-A patients without a known mutation shared a common transcriptional signature that is independent of GRN loss-of-function. After combining both groups, differential expression as compared to the control group and coexpression analyses revealed alteration of processes related to immune response, synaptic transmission, RNA metabolism, angiogenesis and vesicle-mediated transport. Deconvolution of the data highlighted strong cellular alterations that were similar in FTLD-TDP-A and GRN mutation carriers with NSF as a potentially important player in both groups. We propose several potentially druggable pathways such as the GABAergic, GDNF and sphingolipid pathways. Our findings underline new disease mechanisms and strongly suggest that affected pathways in GRN mutation carriers extend beyond GRN and contribute to genetically unexplained forms of FTLD-TDP-A.

Abstract Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer’s disease based on inferred underlying histopathology. Parkinson’s disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington’s disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned—more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers—we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.

Abstract At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed ‘mild behavioural and/or cognitive impairment in bvFTD’ (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of <10% in healthy controls. Finally, the MBCI-FTD criteria were tested on a cohort of individuals with prodromal Alzheimer’s disease, and the false positive rate of diagnosis was 11–16%. Future research will need to refine the sensitivity and specificity of these criteria, and incorporate emerging biomarker evidence.

A rare APOE variant APOE3 -Jac reduces self-aggregation and promotes healthy brain aging.

Abstract Posterior cortical atrophy is a neurodegenerative syndrome with a heterogeneous clinical presentation due to variable involvement of the left, right, dorsal and ventral parts of the visual system, as well as inconsistent involvement of other cognitive domains and systems. 18F-fluorodeoxyglucose (FDG)-PET is a sensitive marker for regional brain damage or dysfunction, capable of capturing the pattern of neurodegeneration at the single-participant level. We aimed to leverage these inter-individual differences on FDG-PET imaging to better understand the associations of heterogeneity of posterior cortical atrophy. We identified 91 posterior cortical atrophy participants with FDG-PET data and abstracted demographic, neurologic, neuropsychological and Alzheimer’s disease biomarker data. The mean age at reported symptom onset was 59.3 (range: 45–72 years old), with an average disease duration of 4.2 years prior to FDG-PET scan, and a mean education of 15.0 years. Females were more common than males at 1.6:1. After standard preprocessing steps, the FDG-PET scans for the cohort were entered into an unsupervised machine learning algorithm which first creates a high-dimensional space of inter-individual covariance before performing an eigen-decomposition to arrive at a low-dimensional representation. Participant values (‘eigenbrains’ or latent vectors which represent principle axes of inter-individual variation) were then compared to the clinical and biomarker data. Eight eigenbrains explained over 50% of the inter-individual differences in FDG-PET uptake with left (eigenbrain 1) and right (eigenbrain 2) hemispheric lateralization representing 24% of the variance. Furthermore, eigenbrain-loads mapped onto clinical and neuropsychological data (i.e. aphasia, apraxia and global cognition were associated with the left hemispheric eigenbrain 1 and environmental agnosia and apperceptive prosopagnosia were associated with the right hemispheric eigenbrain 2), suggesting that they captured important axes of normal and abnormal brain function. We used NeuroSynth to characterize the eigenbrains through topic-based decoding, which supported the idea that the eigenbrains map onto a diverse set of cognitive functions. These eigenbrains captured important biological and pathophysiologic data (i.e. limbic predominant eigenbrain 4 patterns being associated with older age of onset compared to frontoparietal eigenbrain 7 patterns being associated with younger age of onset), suggesting that approaches that focus on inter-individual differences may be important to better understand the variability observed within a neurodegenerative syndrome like posterior cortical atrophy.

Abstract Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α-synuclein aggregates, but many DLB cases show concurrent Alzheimer’s disease pathology in the form of amyloid-β plaques and tau neurofibrillary tangles. The first objective of this study was to investigate the effect of Alzheimer’s disease co-pathology on functional network changes within the default mode network (DMN) in DLB. Second, we studied how the distribution of tau pathology measured with PET relates to functional connectivity in DLB. Twenty-seven DLB, 26 Alzheimer’s disease and 99 cognitively unimpaired participants (balanced on age and sex to the DLB group) underwent tau-PET with AV-1451 (flortaucipir), amyloid-β-PET with Pittsburgh compound-B (PiB) and resting-state functional MRI scans. The resing-state functional MRI data were used to assess functional connectivity within the posterior DMN. This was then correlated with overall cortical flortaucipir PET and PiB PET standardized uptake value ratio (SUVr). The strength of interregional functional connectivity was assessed using the Schaefer atlas. Tau-PET covariance was measured as the correlation in flortaucipir SUVr between any two regions across participants. The association between region-to-region functional connectivity and tau-PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot- and cold spots) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot and cold spots. A reduction in posterior DMN connectivity correlated with overall higher cortical tau- (r = −0.39, P = 0.04) and amyloid-PET uptake (r = −0.41, P = 0.03) in the DLB group, i.e. patients with DLB who have more concurrent Alzheimer’s disease pathology showed a more severe loss of DMN connectivity. Higher functional connectivity between regions was associated with higher tau covariance in cognitively unimpaired, Alzheimer’s disease and DLB. Furthermore, higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher flortaucipir SUVrs in the target region, whereas higher functional connectivity to the tau cold spot (i.e. sensory-motor cortex) was related to lower flortaucipir SUVr in the target region. Our findings suggest that a higher burden of Alzheimer’s disease co-pathology in patients with DLB is associated with more Alzheimer’s disease-like changes in functional connectivity. Furthermore, we found an association between the brain’s functional network architecture and the distribution of tau pathology that has recently been described in Alzheimer’s disease. We show that this relationship also exists in patients with DLB, indicating that similar mechanisms of connectivity-dependent occurrence of tau pathology might be at work in both diseases.

ABSTRACTBackgroundRapid eye movement (REM) sleep behavior disorder (RBD) occurs occasionally in essential tremor (ET), but polysomnographic REM sleep without atonia (RSWA) analyses have been sparse.ObjectiveTo characterize the amount and distribution of polysomnographic RSWA, the electrophysiologic substrate of RBD, in patients with Parkinson's disease (PD) and ET.MethodsWe analyzed quantitative RSWA in 73 patients: PD (23), ET (23), and age‐sex‐matched controls (27). None had dream‐enactment behavior history or received antidepressants. Phasic, tonic, “any,” and phasic‐burst duration RSWA measures were calculated in the submentalis (SM) and anterior tibialis (AT) muscles. The automated REM atonia index (RAI) was also determined. Statistical analysis was performed by Kruskal‐Wallis rank‐sum and Mann‐Whitney tests.ResultsSM phasic RSWA was significantly greater for PD than ET patients and controls (12.5% ± 12.8% vs. 4.9% ± 6.7%, 3.9% ± 2.6%), as was SM “any” (13.54% ± 14.30% vs. 5.2% ± 7.6%, 4.2% ± 2.6%). RAI was significantly lower in PD than in ET and controls (0.78 ± 0.23 vs. 0.92 ± 0.09 vs. 0.90 ± 0.17, P ≤ 0.005), but no different between ET and controls. AT phasic and “any” RSWA was similar between the 3 groups. ET and control RSWA was similar in all measures. Two ET patients (8.7%) had SM RSWA similar to PD patients.ConclusionsElevated SM RSWA distinguished PD from ET in patients without dream‐enactment symptoms and occurs frequently in PD patients, and in isolated tremor suggests underlying synucleinopathy. Prospective studies will further validate these findings.

AbstractIntroductionThe Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes.MethodsWe screened the major dementia‐associated genes in 302 sporadic and 390 familial (symptomatic or at‐risk) participants enrolled in these studies.ResultsAmong the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule‐associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes.DiscussionOur study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.