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Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

Introduction Longitudinal positron emission tomography (PET) studies of tau accumulation in Alzheimer's disease (AD) have noted reduced increases or frank decreases in tau signal. We investigated how such reductions related to analytical confounds and disease progression markers in atypical AD. Methods We assessed regional and interindividual variation in longitudinal change on 18 F-flortaucipir PET imaging in 24 amyloid beta (Aβ)+ patients with atypical, early-onset amnestic or non-amnestic AD plus 62 Aβ- and 132 Aβ+ Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. Results In atypical AD, 18 F-flortaucipir uptake slowed or declined over time in areas with high baseline signal and older, more impaired individuals. ADNI participants had reduced longitudinal change in early Braak stage regions relative to late-stage areas. Discussion Results suggested radioligand uptake plateaus or declines in advanced neurodegeneration. Further research should investigate whether results generalize to other radioligands and whether they relate to changes of the radioligand binding site structure or accessibility.

ObjectivesTo investigate the impact of Alzheimer's disease (AD) co-pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD).MethodsWe studied 72 LBD patients (Parkinson disease (PD)=2, PD-MCI=25, PD with dementia=10, dementia with Lewy bodies=35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co-pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co-pathology (t-tau/Aβ1-42 >0.3) (LBD+AD, N=19), and those without AD co-pathology (LBD-AD, N=53). We also included a reference group of 25 patients with CSF biomarker-confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBD-AD=14, LBD+AD=7), directly tested the association between antemortem MRI and post-mortem burdens of tau, Aβ, and alpha-synuclein using digital histopathology in five representative neocortical regions.ResultsThe LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions (P&nbsp

Brain aging is a complex process that includes atrophy, vascular injury, and a variety of age-associated neurodegenerative pathologies, together determining an individual’s course of cognitive decline. While Alzheimer's disease and related dementias contribute to the heterogeneity of brain aging, these conditions themselves are also heterogeneous in their clinical presentation, progression, and pattern of neural injury. We reviewed studies that leveraged data-driven approaches to examining heterogeneity in Alzheimer's disease and related dementias, with a principal focus on neuroimaging studies exploring subtypes of regional neurodegeneration patterns. Over the past decade, the steadily increasing wealth of clinical, neuroimaging, and molecular biomarker information collected within large-scale observational cohort studies has allowed for a richer understanding of the variability of disease expression within the aging and Alzheimer's disease and related dementias continuum. Moreover, the availability of these large-scale datasets has supported the development and increasing application of clustering techniques for studying disease heterogeneity in a data-driven manner. In particular, data-driven studies have led to new discoveries of previously unappreciated disease subtypes characterized by distinct neuroimaging patterns of regional neurodegeneration, which are paralleled by heterogeneous profiles of pathological, clinical, and molecular biomarker characteristics. Incorporating these findings into novel frameworks for more differentiated disease stratification holds great promise for improving individualized diagnosis and prognosis of expected clinical progression, and provides opportunities for development of precision medicine approaches for therapeutic intervention. We conclude with an account of the principal challenges associated with data-driven heterogeneity analyses and outline avenues for future developments in the field., This work was supported in part by the Allen H. and Selma W. Berkman Charitable Trust (Accelerating Research on Vascular Dementia) and National Institutes of Health Grant Nos. 1RF1AG054409 (to MH, CD, DW), R01 HL127659-04S1 (to MH), AG057832 (to CM), AG054519 (to CM), AG055005 (to DW, MH, CM), and P30-AG010124 (to DW, MH, CM). MJG is supported by the “Miguel Servet” program [CP19/00031] of the Spanish Instituto de Salud Carlos III (ISCIII-FEDER).

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns. Electronic supplementary material The online version of this article (10.1007/s00401-020-02158-2) contains supplementary material, which is available to authorized users.

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.

Parkinson9s disease (PD) and Alzheimer9s disease (AD) are progressive neurodegenerative disorders that affect millions of people worldwide. In this work, we propose a deep learning approach to classify these diseases based on 3D T1-weighted brain MRI. We analyzed several datasets including the Parkinson9s Progression Markers Initiative (PPMI), an independent dataset from the University of Pennsylvania School of Medicine (UPenn), the Alzheimer9s Disease Neuroimaging Initiative (ADNI), and the Open Access Series of Imaging Studies (OASIS) dataset. PPMI and ADNI were partitioned to train (70%), validate (20%), and test (10%) a 3D convolutional neural network (CNN) for PD and AD classification. The UPenn and OASIS datasets were used as independent test sets to evaluate the model performance during inference. We also implemented a random forest classifier as a baseline model by extracting key radiomics features from the same T1-weighted MRI scans. The proposed 3D CNN model was trained from scratch for the classification tasks. For AD classification, the 3D CNN model achieved an ROC-AUC of 0.878 on the ADNI test set and an average ROC-AUC of 0.789 on the OASIS dataset. For PD classification, the proposed 3D CNN model achieved an ROC-AUC of 0.667 on the PPMI test set and an average ROC-AUC of 0.743 on the UPenn dataset. We also found that model performance was largely maintained when using only 25% of the training dataset. The 3D CNN outperformed the random forest classifier for both the PD and AD tasks. The 3D CNN also generalized better on unseen MRI data from different imaging centers. Our results show that the proposed 3D CNN model was less prone to overfitting for AD than for PD classification. This approach shows promise for screening of PD and AD patients using only T1-weighted brain MRI, which is relatively widely available. This model with additional validation could also be used to help differentiate between challenging cases of AD and PD when they present with similarly subtle motor and non-motor symptoms.

Frontotemporal lobar degeneration proteinopathies with tau inclusions (FTLD-Tau) or TDP-43 inclusions (FTLD-TDP) are associated with clinically similar phenotypes. However, these disparate proteinopathies likely differ in cellular severity and regional distribution of inclusions in white matter (WM) and adjacent grey matter (GM), which have been understudied. We performed a neuropathological study of subcortical WM and adjacent GM in a large autopsy cohort (n = 92; FTLD-Tau = 37, FTLD-TDP = 55) using a validated digital image approach. The antemortem clinical phenotype was behavioral-variant frontotemporal dementia (bvFTD) in 23 patients with FTLD-Tau and 42 with FTLD-TDP, and primary progressive aphasia (PPA) in 14 patients with FTLD-Tau and 13 with FTLD-TDP. We used linear mixed-effects models to: (1) compare WM pathology burden between proteinopathies; (2) investigate the relationship between WM pathology burden and WM degeneration using luxol fast blue (LFB) myelin staining; (3) study regional patterns of pathology burden in clinico-pathological groups. WM pathology burden was greater in FTLD-Tau compared to FTLD-TDP across regions (beta = 4.21, SE = 0.34, p p = 0.002) and FTLD-TDP (beta = 0.40, SE = 0.08, p p

Background. Frontotemporal dementia (FTD) clinical diagnosis is challenged by the variable correspondence between the clinical syndrome and underlying neuropathological changes, the phenotypic overlap with Alzheimer's disease (AD) and the lack of pathophysiologic diagnostic biomarkers. As synapse degeneration is an early event in pathological frontotemporal lobar degeneration (FTLD), a surrogate marker of synapse loss could be used to monitor early pathologic changes. The aim of this study was to evaluate the relationship of antemortem cerebrospinal fluid (CSF) levels of 9 synaptic proteins with postmortem global tau and TDP-43 burden in a neuropathological FTLD cohort. Methods. We included patients with a neuropathological confirmation of FTLD-Tau (n=24, mean age-at-CSF 67 years+/-11), FTLD-TDP (n=25, 66 years+/-9) or AD (n=25, 73 years+/-6) as well as cognitively normal controls (n=35, 69 years+/-7) from the Penn FTD Center and ADRC. A subset of 39 FTLD patients presented without AD comorbidity (neurofibrillary tangle score of B0/B1 according to the NIA-AA classification) and 18 AD patients presented without TDP-43 comorbidity. We quantified the synaptic panel in antemortem CSF by targeted mass spectrometry using isotopically-labeled peptides as internal standards. We used a semi-quantitative measure of tau and TDP-43 inclusions to quantify pathological burden across 16 brain regions. Statistical methods included Spearman rank correlations, one-way analysis of covariance (controlling for sex and age-at-CSF), linear regression (controlling for age-at-death) and receiver-operating characteristic curves. Result. CSF calsyntenin-1 and neurexin-2a were correlated in all patient groups (rs=.55 to .88). In FTLD-TDP, we observed low antemortem CSF levels of calsyntenin-1 and neurexin-2a compared to AD (.72-fold, p=.001, .77-fold, p=.04, respectively) and controls (.80-fold, p=.02, .78-fold, p=.02, respectively), which were inversely associated with post-mortem global TDP-43 burden (regression r2=.36, p=.04 and r2=.35, p=.04, respectively). Neurexin-2a showed 75.0% (95% CI 60-88) accuracy to discriminate FTLD-TDP from controls. Calsyntenin-1 showed 75.1% (95% CI 62-87) accuracy to discriminate FTLD-TDP from AD. None of the synaptic proteins were altered in FTLD-Tau compared to controls (0.79 to 1.12-fold, p>.12) or associated with post-mortem global tau burden (r2=.12, p=.36). Comorbidity had a limited effect on these findings. Conclusion. CSF calsyntenin-1 and neurexin-2a have potential as objective measures of TDP-43-mediated degeneration in FTLD.

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies (4RT), including cortico-basal degeneration and progressive supranuclear palsy (PSP). Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4RTs, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assessed whether connectivity drives 4R-tau spreading patterns by combining resting-state fMRI connectomics with both 2nd generation 18F- PI-2620 tau-PET in 46 patients with clinically diagnosed 4RTs and post-mortem cell-type- specific regional tau assessments from two independent PSP samples (n=97/96). We found that inter-regional connectivity was associated with higher inter-regional correlation of both tau- PET and post-mortem tau levels in 4RTs. In regional cell-type specific post-mortem tau assessments, this association was stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with trans-neuronal tau spread. Using tau-PET we found that patient-level tau patterns can be predicted by the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence for brain connectivity as a key mediator of trans-neuronal tau spreading in 4RTs.

Objective: To measure the correlation between single breath counting (SBC) and forced vital capacity (liters, FVCL) in amyotrophic lateral sclerosis (ALS) patients and to define the utility of SBC ...

Primary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a mediator of neurofibrillary degeneration.

Recent models of Alzheimer's disease progression propose that disease may be transmitted between brain areas either via local diffusion or long-distance transport via white matter fibre pathways. However, it is unclear whether such models are applicable in non-amnestic Alzheimer's disease, which is associated with domain-specific cognitive deficits and relatively spared episodic memory. To date, the anatomical progression of disease in non-amnestic patients remains understudied. We used longitudinal imaging to differentiate earlier atrophy and later disease spread in three non-amnestic variants, including logopenic-variant primary progressive aphasia (n = 25), posterior cortical atrophy (n = 20), and frontal-variant Alzheimer's disease (n = 12), as well as 17 amnestic Alzheimer's disease patients. Patients were compared to 37 matched controls. All patients had autopsy (n = 7) or CSF (n = 67) evidence of Alzheimer's disease pathology. We first assessed atrophy in suspected sites of disease origin, adjusting for age, sex, and severity of cognitive impairment; we then performed exploratory whole-brain analysis to investigate longitudinal disease spread both within and outside these regions. Additionally, we asked whether each phenotype exhibited more rapid change in its associated disease foci than other phenotypes. Finally, we investigated whether atrophy was related to structural brain connectivity. Each non-amnestic phenotype displayed unique patterns of initial atrophy and subsequent neocortical change that correlated with cognitive decline. Longitudinal atrophy included areas both proximal to and distant from sites of initial atrophy, suggesting heterogeneous mechanisms of disease spread. Moreover, regional rates of neocortical change differed by phenotype. Logopenic-variant patients exhibited greater initial atrophy and more rapid longitudinal change in left lateral temporal areas than other groups. Frontal-variant patients had pronounced atrophy in left insula and middle frontal gyrus, combined with more rapid atrophy of left insula than other non-amnestic patients. In the medial temporal lobes, non-amnestic patients had less atrophy at their initial scan than amnestic patients, but longitudinal rate of change did not differ between patient groups. Medial temporal sparing in non-amnestic Alzheimer's disease may thus be due in part to later onset of medial temporal degeneration than in amnestic patients rather than different rates of atrophy over time. Finally, the magnitude of longitudinal atrophy was predicted by structural connectivity, measured in terms of node degree; this result provides indirect support for the role of long-distance fibre pathways in the spread of neurodegenerative disease. 10.1093/brain/awz091_video1 awz091media1 6041544065001.

Objective To measure postmortem burden of frontotemporal lobar degeneration (FTLD) with TDP-43 (FTLD-TDP) or tau (FTLD-Tau) proteinopathy across hemispheres in primary progressive aphasia (PPA) using digital histopathology and to identify clinicopathological correlates of these distinct proteinopathies. Methods In an autopsy cohort of PPA (FTLD-TDP = 13, FTLD-Tau = 14), we analyzed laterality and regional distribution of postmortem pathology, quantified using a validated digital histopathological approach, in available brain tissue from up to 8 cortical regions bilaterally. We related digital pathology to antemortem structural neuroimaging and specific clinical language features. Results Postmortem cortical pathology was left-lateralized in both FTLD-TDP (beta = -0.15, standard error [SE] = 0.05, p = 0.007) and FTLD-Tau (beta = -0.09, SE = 0.04, p = 0.015), but the degree of lateralization decreased with greater overall dementia severity before death (beta = -8.18, SE = 3.22, p = 0.015). Among 5 core pathology regions sampled, we found greatest pathology in left orbitofrontal cortex (OFC) in FTLD-TDP, which was greater than in FTLD-Tau (F = 47.07, df = 1,17, p

Objective: To identify novel CSF biomarkers in GRN-associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS). Methods: Unbiased MS was applied to CSF samples from 19 presymptomatic and 9 symptomatic GRN mutation carriers and 24 noncarriers. Protein abundances were compared between these groups. Proteins were then selected for validation if identified by ≥4 peptides and if fold change was ≤0.5 or ≥2.0. Validation and absolute quantification by parallel reaction monitoring (PRM), a high-resolution targeted MS method, was performed on an international cohort (n = 210) of presymptomatic and symptomatic GRN, C9orf72 and MAPT mutation carriers. Results: Unbiased MS revealed 20 differentially abundant proteins between symptomatic mutation carriers and noncarriers and nine between symptomatic and presymptomatic carriers. Seven of these proteins fulfilled our criteria for validation. PRM analyses revealed that symptomatic GRN mutation carriers had significantly lower levels of neuronal pentraxin receptor (NPTXR), receptortype tyrosine-protein phosphatase N2 (PTPRN2), neurosecretory protein VGF, chromogranin-A (CHGA), and V-set and transmembrane domain-containing protein 2B (VSTM2B) than presymptomatic carriers and noncarriers. Symptomatic C9orf72 mutation carriers had lower levels of NPTXR, PTPRN2, CHGA, and VSTM2B than noncarriers, while symptomatic MAPT mutation carriers had lower levels of NPTXR and CHGA than noncarriers. Interpretation: We identified and validated five novel CSF biomarkers in GRN-associated FTD. Our results show that synaptic, secretory vesicle, and inflammatory proteins are dysregulated in the symptomatic stage and may provide new insights into the pathophysiology of genetic FTD. Further validation is needed to investigate their clinical applicability as diagnostic or monitoring biomarkers.

Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n=174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aβ pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p=0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p=0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (pp=0.03) and hippocampal atrophy (p=0.04) were also associated. In contrast, sex, APOE, psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.

Background Little is known about the heterogeneous etiology of suspected non-Alzheimer’s pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of β-amyloid. Using antemortem MRI and pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal lobe (MTL) measures in β-amyloid-negative subjects. Methods Subjects with antemortem MRI and autopsy data were selected from ADNI (n=63) and the University of Pennsylvania (n=156). Pathological diagnoses and semi-quantitative scores of MTL tau, neuritic plaques, α-synuclein, and TDP-43 pathology and MTL structural MRI measures from antemortem T1-weighted MRI scans were obtained. β-amyloid status (A+/A−) was determined by CERAD score and neurodegeneration status (N+/N−) by hippocampal volume. Results SNAP reflects a heterogeneous group of pathological diagnoses. In ADNI, SNAP (A−N+) had significantly more neuropathological diagnoses than A+N+. In the A− group, tau pathology was associated with hippocampal, entorhinal cortex, and Brodmann area 35 volume/thickness and TDP-43 pathology with hippocampal volume. Conclusion SNAP had a heterogeneous profile with more mixed pathologies than A+N+. Moreover, a role for TDP-43 and tau pathology in driving MTL neurodegeneration in the absence of β-amyloid was supported.

Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that include two main pathologic categories of tau (FTLD-Tau) and TDP-43 (FTLD-TDP) proteinopathies. These distinct proteinopathies are often clinically indistinguishable during life, posing a major obstacle for diagnosis and emerging therapeutic trials tailored to disease-specific mechanisms. Moreover, MRI-derived measures have had limited success to date discriminating between FTLD-Tau or FTLD-TDP. T2*-weighted (T2*w) ex vivo MRI has previously been shown to be sensitive to non-heme iron in healthy intracortical lamination and myelin, and to pathological iron deposits in amyloid-beta plaques and activated microglia in Alzheimer’s disease (AD). However, an integrated, ex vivo MRI and histopathology approach is understudied in FTLD. We apply joint, whole-hemisphere ex vivo MRI at 7T and histopathology to the study autopsy-confirmed FTLD-Tau (n=3) and FTLD-TDP (n=2), relative to an AD disease-control brain with antemortem clinical symptoms of frontotemporal dementia and an age-matched healthy control. We detect distinct laminar patterns of novel iron-laden glial pathology in both FTLD-Tau and FTLD-TDP brains. We find iron-positive ameboid and hypertrophic microglia and astrocytes largely in deeper GM and adjacent WM in FTLD-Tau. In contrast, FTLD-TDP presents prominent superficial cortical layer iron reactivity in astrocytic processes enveloping small blood vessels with limited involvement of adjacent WM, as well as more diffuse distribution of punctate iron-rich dystrophic microglial processes across all GM lamina. This integrated MRI/histopathology approach reveals ex vivo MRI features that are consistent with these pathological observations distinguishing FTLD-Tau and FTLD-TDP, including prominent irregular hypointense signal in deeper cortex in FTLD-Tau whereas FTLD-TDP showed upper cortical layer hypointense bands and diffuse cortical speckling. Moreover, differences in adjacent WM degeneration and iron-rich gliosis on histology between FTLD-Tau and FTLD-TDP were also readily apparent on MRI as hyperintense signal and irregular areas of hypointensity, respectively that were more prominent in FTLD-Tau compared to FTLD-TDP. These unique histopathological and radiographic features were distinct from HC and AD brains, suggesting that iron-sensitive T2*w MRI, adapted to in vivo application at sufficient resolution, may offer an opportunity to improve antemortem diagnosis of FTLD proteinopathies using tissue-validated methods.

ObjectiveAccurate diagnosis and prognosis of frontotemporal lobar degeneration (FTLD) during life is an urgent concern in the context of emerging disease-modifying treatment trials. Few CSF markers have been validated longitudinally in patients with known pathology, and we hypothesized that CSF neurofilament light chain (NfL) would be associated with longitudinal cognitive decline in patients with known FTLD-TAR DNA binding protein ~43kD (TDP) pathology.MethodsThis case-control study evaluated CSF NfL, total tau, phosphorylated tau, and β-amyloid1-42 in patients with known FTLD-tau or FTLD-TDP pathology (n = 50) and healthy controls (n = 65) and an extended cohort of clinically diagnosed patients with likely FTLD-tau or FTLD-TDP (n = 148). Regression analyses related CSF analytes to longitudinal cognitive decline (follow-up ∼1 year), controlling for demographic variables and core AD CSF analytes.ResultsIn FTLD-TDP with known pathology, CSF NfL is significantly elevated compared with controls and significantly associated with longitudinal decline on specific executive and language measures, after controlling for age, disease duration, and core AD CSF analytes. Similar findings are found in the extended cohort, also including clinically identified likely FTLD-TDP. Although CSF NfL is elevated in FTLD-tau compared with controls, the association between NfL and longitudinal cognitive decline is limited to executive measures.ConclusionCSF NfL is associated with longitudinal clinical decline in relevant cognitive domains in patients with FTLD-TDP after controlling for demographic factors and core AD CSF analytes and may also be related to longitudinal decline in executive functioning in FTLD-tau.

Altres ajuts: Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland grant numbers 7330550813, 733050103); Dioraphte Foundation (grant number 1402 1300); the European Joint Programme - Neurodegenerative Disease Research (JPND, PreFrontALS); NIH (grant number AG017586); Wyncote Foundation; Arking Family Fund; Invetissements d'avenir (grant number ANR-11-INBS-0011); Schörling Foundation - Swedish FTD Initiative; Swedish Research Council (2015-02926, 2018-02754, 2019-02248); Swedish Alzheimer's Foundation; Brain Foundation; Demensfonden, Stiftelsen för Gamla Tjänarinnor; Stohnes foundation; Region Stockholm (ALF project). Excessive microglial activation might be a central pathological process in GRN-related frontotemporal dementia (FTD-GRN). We measured soluble triggering receptor expressed on myeloid cells 2 (sTREM2), which is shed from disease-associated microglia following cleavage of TREM2, in cerebrospinal fluid of 34 presymptomatic and 35 symptomatic GRN mutation carriers, 6 presymptomatic and 32 symptomatic C9orf72 mutation carriers and 67 healthy noncarriers by ELISA. Although no group differences in sTREM2 levels were observed (GRN: symptomatic (median 5.2 ng/mL, interquartile range [3.9-9.2]) vs. presymptomatic (4.3 ng/mL [2.6-6.1]) vs. noncarriers (4.2 ng/mL [2.6-5.5]): p = 0.059; C9orf72: symptomatic (4.3 [2.9-7.0]) vs. presymptomatic (3.2 [2.2-4.2]) vs. noncarriers: p = 0.294), high levels were seen in a subset of GRN, but not C9orf72, mutation carriers, which might reflect differential TREM2-related microglial activation. Interestingly, 2 presymptomatic carriers with low sTREM2 levels developed symptoms after 1 year, whereas 2 with high levels became symptomatic after >5 years. While sTREM2 is not a promising diagnostic biomarker for FTD-GRN or FTD-C9orf72, further research might elucidate its potential to monitor microglial activity and predict disease progression.

Highlights • Social and leisure activity may contribute to mitigation of cortical loss in bvFTD. • This relationship was found in regions important for social cognition. • Findings provide new evidence in burgeoning non-AD cognitive reserve literature., Behavioral variant frontotemporal degeneration (bvFTD) is clinically characterized by progressive decline in social and executive domains. Previous work suggests that early lifestyle factors such as education and occupational attainment may relate to structural integrity and moderate the rate of cognitive decline in bvFTD, but the role of other cognitively stimulating activities is understudied. We sought to investigate the effect of such activities on cortical thickness (CT) in bvFTD. bvFTD patients (n = 31) completed a baseline MRI scan, and informants for the patients completed the Lifetime of Experiences Questionnaire (LEQ), which measures specific activities considered to be undertaken primarily within one particular life phase, such as education (young-life), occupation (mid-life), and social/leisure activity (late-life). At baseline, linear models assessed the effect of LEQ scores from each life phase on regional CT. A subset (n = 19) of patients completed longitudinal MRI, and to evaluate the association of LEQ with longitudinal rates of CT decline, we derived individualized slopes of decline using linear mixed effects models and these were related to LEQ scores from each life phase. At baseline, a higher late-life LEQ score was associated with less atrophy in left superior and inferior anterior temporal regions as well as right middle temporal gyrus. Longitudinally, we observed that higher late-life LEQ scores were associated with an attenuated rate of CT loss in insular cortex. Late-life LEQ score was positively associated with both relatively preserved CT early in bvFTD and a slower rate of cortical loss in regions important for social functioning. These findings suggest that social and leisure activities may contribute to a form of resilience against pathologic effects of disease.

Behavioral variant frontotemporal degeneration (bvFTD) is clinically characterized by progressive decline in social and executive domains. Previous work suggests that early lifestyle factors such as education and occupational attainment may relate to structural integrity and moderate the rate of cognitive decline in bvFTD, but the role of other cognitively stimulating activities is understudied. We sought to investigate the effect of such activities on cortical thickness (CT) in bvFTD. bvFTD patients (n=31) completed a baseline MRI scan, and informants for the patients completed the Lifetime of Experiences Questionnaire (LEQ), which measures specific activities considered to be undertaken primarily within one particular life phase, such as education (young-life), occupation (mid-life), and social/leisure activity (late-life). At baseline, linear models assessed the effect of LEQ scores from each life phase on regional CT. A subset (n=19) of patients completed longitudinal MRI, and to evaluate the association of LEQ with longitudinal rates of CT decline, we derived individualized slopes of decline using linear mixed effects models and these were related to LEQ scores from each life phase. At baseline, a higher late-life LEQ score was associated with less atrophy in bilateral superior anterior temporal regions. Longitudinally, we observed that higher late-life LEQ scores were associated with an attenuated rate of CT loss in insular cortex. Late-life LEQ score was positively associated with both relatively preserved CT early in bvFTD and a slower rate of cortical loss in regions important for social functioning. These findings suggest that social and leisure activities may contribute to a form of resilience against pathologic effects of disease.

Amyotrophic lateral sclerosis (ALS) is a multi‐system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine‐learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post‐mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS., Single nucleotide polymorphisms (SNPs) previously identified through genome‐wide association studies as risk factors for amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) further associate in a polygenic manner with risk for cognitive dysfunction in ALS and related disorders.

Contains fulltext : 244253.pdf (Publisher’s version ) (Open Access) BACKGROUND: Brain structure abnormalities throughout the course of Parkinson's disease have yet to be fully elucidated. OBJECTIVE: Using a multicenter approach and harmonized analysis methods, we aimed to shed light on Parkinson's disease stage-specific profiles of pathology, as suggested by in vivo neuroimaging. METHODS: Individual brain MRI and clinical data from 2357 Parkinson's disease patients and 1182 healthy controls were collected from 19 sources. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effects models. Patients grouped according to Hoehn and Yahr stage were compared with age- and sex-matched controls. Within the patient sample, we investigated associations with Montreal Cognitive Assessment score. RESULTS: Overall, patients showed a thinner cortex in 38 of 68 regions compared with controls (d(max) = -0.20, d(min) = -0.09). The bilateral putamen (d(left) = -0.14, d(right) = -0.14) and left amygdala (d = -0.13) were smaller in patients, whereas the left thalamus was larger (d = 0.13). Analysis of staging demonstrated an initial presentation of thinner occipital, parietal, and temporal cortices, extending toward rostrally located cortical regions with increased disease severity. From stage 2 and onward, the bilateral putamen and amygdala were consistently smaller with larger differences denoting each increment. Poorer cognition was associated with widespread cortical thinning and lower volumes of core limbic structures. CONCLUSIONS: Our findings offer robust and novel imaging signatures that are generally incremental across but in certain regions specific to disease stages. Our findings highlight the importance of adequately powered multicenter collaborations. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.

ImportanceAmyotrophic lateral sclerosis (ALS) is a multi-system disorder characterized primarily by motor neuron degeneration, but may be accompanied by cognitive dysfunction. Statistically appropriate criteria for establishing cognitive impairment (CI) in ALS are lacking.ObjectiveDefine thresholds for CI in ALS using quantile regression (QR) that accounts for age and education in a North American (NAmer) cohort.DesignQR of cross-sectional data from a multi-center NAmer cohort of healthy adults was used to model the 5th percentile of cognitive scores on the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). The QR approach was compared to a traditional 2 standard deviation (SD) cut-off approach using the same NAmer cohort (2SD-NAmer) and to existing UK-based normative data derived using the 2SD approach (2SD-UK) to assess the impact of cohort selection and statistical model in identifying CI ALS patients.Participants269 healthy adults from NAmer, recruited by the University of Pennsylvania (PENN; N=82), the University of Miami through the CRiALS study (CRiALS; N=40), and the Canadian ALS Neuroimaging Consortium (CALSNIC; N=147) were included to establish ECAS thresholds for defining CI. We then evaluated the frequency of CI in 182 ALS patients from PENN.Main OutcomesWe defined two new sets of normative thresholds, based on NAmer heathy adult performance, for each ECAS domain score and the composite scores using QR and 2SD statistical approaches. We then applied the 2SD-NAmer and QR-NAmer, as well as the previously established and widely-used 2SD-UK, thresholds to evaluate the frequency of CI in ALS patients.ResultsQR-NAmer models revealed that increased age and reduced educational attainment negatively impact cognitive performance on the ECAS. Based on the QR-NAmer normative cutoffs, the prevalence of CI in the 182 PENN ALS patients was 15.9% for ECAS ALS-Specific and 15.4% for ECAS Total. These estimates are more conservative than estimates ranging from 15.4%-34.6% impaired based on 2SD approaches.Conclusions and RelevanceThis report establishes normative thresholds for using ECAS to identify whether ALS patients in the NAmer population have CI. The choice of statistical method and normative cohort has a substantial impact on defining CI in ALS.Key PointsQuestionHow to define cognitive impairment (CI) in amyotrophic lateral sclerosis (ALS) using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS)?FindingsAge- and education-adjusted quantile regression (QR) yields thresholds for defining CI that differ meaningfully from those derived from parametric methods without age- and education-adjustment. Thresholds also differ between UK and North American cohorts. Applying our North American-based QR norms to an American ALS cohort at a single center identified CI based on ECAS performance in ∼16% patients, compared to 15.4%-34.6% patients using other approaches.MeaningThe choice of statistical method and normative cohort has a substantial impact on defining CI in ALS.

The T allele in rs1768208 located in or near the myelin oligodendrocyte basic protein gene (MOBP) is a risk factor for frontotemporal degeneration pathology. We evaluated the hypothesis that the presence of a T allele in rs1768208 will be associated with rate of cognitive decline in behavioral variant frontotemporal degeneration (bvFTD) related to compromised frontal networks. We studied 81 individuals clinically diagnosed with bvFTD who were genotyped for rs1768208 and coded using a dominant model reflecting the presence (i.e., MOBP +) or absence (MOBP −) of the T risk allele. Linear mixed-effects models assessed the association of genotype on neuropsychological performance over time. Regression analyses examined differences in network structure by MOBP genotype. We found a genotype by time interaction for declining cognitive performance, whereby MOBP + individuals demonstrated faster rates of decline in executive function. The presence of a MOBP risk allele was associated with degradation of white matter network features in the frontal lobe. These findings suggest that individual genetic variation may contribute to heterogeneity in clinical progression.

INTRODUCTION: The ATN framework provides an in vivo diagnosis of Alzheimer’s disease (AD) using cerebrospinal fluid (CSF) biomarkers of pathologic amyloid plaques (A), tangles (T), and neurodegeneration (N). ATN is rarely evaluated in pathologically confirmed patients and its poor sensitivity to suspected non-Alzheimer’s pathophysiologies (SNAP), including frontotemporal lobar degeneration (FTLD), leads to misdiagnoses. We compared accuracy of ATN (ATN(TAU)) using CSF total tau (t-tau) to a modified strategy (ATN(NfL)) using CSF neurofilament light chain (NfL) in an autopsy cohort. METHODS: ATN(TAU) and ATN(NfL) were trained in an independent sample and validated in autopsy-confirmed AD (n = 67) and FTLD (n = 27). RESULTS: ATN(NfL) more accurately identified FTLD as SNAP (sensitivity = 0.93, specificity = 0.94) than ATN(TAU) (sensitivity = 0.44, specificity = 0.97), even in cases with co-occurring AD and FTLD. ATN(NfL) misclassified fewer AD and FTLD as “Normal” (2%) than ATN(TAU) (14%). DISCUSSION: ATN(NfL) is a promising diagnostic strategy that may accurately identify both AD and FTLD, even when pathologies co-occur.

AIMS Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aβ) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing. METHODS Hippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aβ. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing. RESULTS LBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P

ObjectiveWe implemented automated methods to analyze speech and evaluate the hypothesis that cognitive and motor factors impair prosody in partially distinct ways in patients with amyotrophic lateral sclerosis (ALS).MethodsWe recruited 213 participants, including 67 with ALS (44 with motor ALS, 23 with ALS and frontotemporal degeneration [FTD]), 33 healthy controls, and neurodegenerative reference groups with behavioral variant FTD (n = 90) and nonfluent/agrammatic primary progressive aphasia (n = 23). Digitized, semistructured speech samples obtained from picture descriptions were automatically segmented with a Speech Activity Detector; continuous speech segments were pitch-tracked; and duration measures for speech and silent pause segments were extracted. Acoustic measures were calculated, including fundamental frequency (f0) range, mean speech and pause segment durations, total speech duration, and pause rate (pause count per minute of speech). Group comparisons related performance on acoustic measures to clinical scales of cognitive and motor impairments and explored MRI cortical thinning in ALS and ALS-FTD.ResultsThe f0 range was significantly impaired in ALS spectrum disorders and was related to bulbar motor disease, and regression analyses related this to cortical thickness in primary motor cortex and perisylvian regions. Impaired speech and pause duration measures were related to the degree of cognitive impairment in ALS spectrum disorders, and regressions related duration measures to bilateral frontal opercula and left anterior insula.ConclusionAutomated analyses of acoustic speech properties dissociate motor and cognitive components of speech deficits in ALS spectrum disorders.

Neurodegeneration of the locus coeruleus (LC) in age-related neurodegenerative diseases such as Alzheimer's disease (AD) is well documented. However, detailed studies of LC neurodegeneration in the full spectrum of frontotemporal lobar degeneration (FTLD) proteinopathies comparing tauopathies (FTLD-tau) to TDP-43 proteinopathies (FTLD-TDP) are lacking. Here, we tested the hypothesis that there is greater LC neuropathology and neurodegeneration in FTLD-tau compared to FTLD-TDP. We examined 280 patients including FTLD-tau (n = 94), FTLD-TDP (n = 135), and two reference groups: clinical/pathological AD (n = 32) and healthy controls (HC, n = 19). Adjacent sections of pons tissue containing the LC were immunostained for phosphorylated TDP-43 (1D3-p409/410), hyperphosphorylated tau (PHF-1), and tyrosine hydroxylase (TH) to examine neuromelanin-containing noradrenergic neurons. Blinded to clinical and pathologic diagnoses, we semi-quantitatively scored inclusions of tau and TDP-43 both inside LC neuronal somas and in surrounding neuropil. We also digitally measured the percent area occupied of neuromelanin inside of TH-positive LC neurons and in surrounding neuropil to calculate a ratio of extracellular-to-intracellular neuromelanin as an objective composite measure of neurodegeneration. We found that LC tau burden in FTLD-tau was greater than LC TDP-43 burden in FTLD-TDP (z = - 11.38, p 0.0001). Digital measures of LC neurodegeneration in FTLD-tau were comparable to AD (z = - 1.84, p 0.05) but greater than FTLD-TDP (z = - 3.85, p 0.0001) and HC (z = - 4.12, p 0.0001). Both tau burden and neurodegeneration were consistently elevated in the LC across pathologic and clinical subgroups of FTLD-tau compared to FTLD-TDP subgroups. Moreover, LC tau burden positively correlated with neurodegeneration in the total FTLD group (rho = 0.24, p = 0.001), while TDP-43 burden did not correlate with LC neurodegeneration in FTLD-TDP (rho = - 0.01, p = 0.90). These findings suggest that patterns of disease propagation across all tauopathies include prominent LC tau and neurodegeneration that are relatively distinct from the minimal degenerative changes to the LC in FTLD-TDP and HC. Antemortem detection of LC neurodegeneration and/or function could potentially improve antemortem differentiation of underlying FTLD tauopathies from clinically similar FTLD-TDP proteinopathies.

BackgroundBrain structure abnormalities throughout the course of Parkinson’s disease (PD) have yet to be fully elucidated. Inconsistent findings across studies may be partly due to small sample sizes and heterogeneous analysis methods. Using a multicenter approach and harmonized analysis methods, we aimed to overcome these limitations and shed light on disease stage-specific profiles of PD pathology as suggested by in vivo neuroimaging.MethodsIndividual brain MRI and clinical data from 2,367 PD patients and 1,183 healthy controls were collected from 19 sites, deriving from 20 countries. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effect linear models. Patients were grouped according to the Hoehn & Yahr (HY) disease stages and compared to age- and sex-matched controls. Within the PD sample, we investigated associations between Montreal Cognitive Assessment (MoCA) scores and brain morphology.FindingsThe main analysis showed a thinner cortex in 38 of 68 regions in PD patients compared to controls (dmax = −0·25, dmin = −0·13). The bilateral putamen (left: d = −0·16, right: d = −0·16) and left amygdala (d = −0·15) were smaller in patients, while the left thalamus was larger (d = 0·17). HY staging indicated that a thinner cortex initially presents in the occipital, parietal and temporal cortex, and extends towards caudally located brain regions with increased disease severity. From HY stage 2 and onwards the bilateral putamen and amygdala were consistently smaller with larger effects denoting each increment. Finally, we found that poorer cognitive performance was associated with widespread cortical thinning as well as lower volumes of core limbic structures.InterpretationOur findings offer robust and novel imaging signatures that are specific to the disease severity stages and in line with an ongoing neurodegenerative process, highlighting the importance of such multicenter collaborations.FundingNIH Big Data to Knowledge program, ENIGMA World Aging Center, and ENIGMA Sex Differences Initiative, and other international agencies (listed in full in the Acknowledgments).

Objective Nearly all adults >50 years of age have evidence for neurofibrillary tau tangles (NFTs) and a significant proportion of individuals additionally develop amyloid plaques (Aβ) consistent with Alzheimer's disease (AD). In an effort to identify the independent genetic risk factors for NFTs and Aβ, we investigated genotypic frequencies of AD susceptibility loci between autopsy‐confirmed AD and primary age‐related tauopathy (PART), a neuropathological condition defined by characteristic neurofibrillary tau tangles (NFTs) with minimal or absent Aβ. Methods General linear models assessed the odds of AD (N = 1190) relative to PART (N = 376) neuropathologically confirmed cases from two independent series: the Penn Brain Bank (PENN; AD N = 312; PART N = 65) and National Alzheimer's Coordinating Center (NACC; AD N = 878; PART N = 311). We also evaluated the odds of Braak stage NFT burden. Results Three genotypes significantly associated with reduced AD risk relative to PART in the PENN (N = 377) and NACC (N = 1189) cohorts including APOE ε4, APOE ε2, and rs6656401 in the CR1 gene. The genotypes rs6733839 in the BIN1 gene and rs28834970 in the PTK2B gene approached significance in the PENN cohort and were significantly associated with reduced AD risk in the NACC cohort. In a combined cohort analysis (N = 1566), APOE ε4 dosage was highly associated with higher Braak stage of NFT burden in Probable PART and AD, but not Definite PART. Interpretation The presence of genotypic differences between PART and AD suggest that PART can provide a genetic model of NFT risk and potential Aβ resistance to inform disease‐modifying therapies.

ObjectiveTo test the association of antemortem CSF biomarkers with postmortem pathology in Lewy body disorders (LBD).MethodsPatients with autopsy-confirmed LBD (n = 24) and autopsy-confirmed Alzheimer disease (AD) (n = 23) and cognitively normal (n = 36) controls were studied. In LBD, neuropathologic criteria defined Lewy body α-synuclein (SYN) stages with medium/high AD copathology (SYN + AD = 10) and low/no AD copathology (SYN − AD = 14). Ordinal pathology scores for tau, β-amyloid (Aβ), and SYN pathology were averaged across 7 cortical regions to obtain a global cerebral score for each pathology. CSF total tau (t-tau), phosphorylated tau at threonine181, and Aβ1-42 levels were compared between LBD and control groups and correlated with global cerebral pathology scores in LBD with linear regression. Diagnostic accuracy for postmortem categorization of LBD into SYN + AD vs SYN − AD or neocortical vs brainstem/limbic SYN stage was tested with receiver operating curves.ResultsSYN + AD had higher CSF t-tau (mean difference 27.0 ± 8.6 pg/mL) and lower Aβ1-42 (mean difference −84.0 ± 22.9 g/mL) compared to SYN − AD (p < 0.01, both). Increasing global cerebral tau and plaque scores were associated with higher CSF t-tau (R2 = 0.15–0.16, p < 0.05, both) and lower Aβ1-42 (R2 = 0.43–0.49, p < 0.001, both), while increasing cerebral SYN scores were associated with lower CSF Aβ1-42 (R2 = 0.31, p < 0.001) and higher CSF t-tau/Aβ1-42 ratio (R2 = 0.27, p = 0.01). CSF t-tau/Aβ1-42 ratio had 100% specificity and 90% sensitivity for SYN + AD, and CSF Aβ1-42 had 77% specificity and 82% sensitivity for neocortical SYN stage.ConclusionsHigher antemortem CSF t-tau/Aβ1-42 and lower Aβ1-42 levels are predictive of increasing cerebral AD and SYN pathology. These biomarkers may identify patients with LBD vulnerable to cortical SYN pathology who may benefit from both SYN and AD-targeted disease-modifying therapies.

Introduction Mutations in the progranulin (GRN) gene are a major source of inherited frontotemporal degeneration (FTD) spectrum disorders associated with TDP-43 proteinopathy. We use structural MRI to identify regions of baseline differences and longitudinal changes in gray matter (GM) and white matter (WM) in presymptomatic GRN mutation carriers (pGRN+) compared to young controls (yCTL). Methods Cognitively intact first-degree relatives of symptomatic GRN+ FTD patients with identified GRN mutations (pGRN+; N = 11, mean age = 41.4) and matched yCTL (N = 11, mean age = 53.6) were identified. They completed a MRI session with T1-weighted imaging to assess GM density (GMD) and diffusion-weighted imaging (DWI) to assess fractional anisotropy (FA). Participants completed a follow-up session with T1 and DWI imaging (pGRN+ mean interval 2.20 years; yCTL mean interval 3.27 years). Annualized changes of GMD and FA were also compared. Results Relative to yCTL, pGRN+ individuals displayed reduced GMD at baseline in bilateral orbitofrontal, insular, and anterior temporal cortices. pGRN+ also showed greater annualized GMD changes than yCTL at follow-up in right orbitofrontal and left occipital cortices. We also observed reduced FA at baseline in bilateral superior longitudinal fasciculus, left corticospinal tract, and frontal corpus callosum in pGRN+ relative to yCTL, and pGRN+ displayed greater annualized longitudinal FA change in right superior longitudinal fasciculus and frontal corpus callosum. Conclusions Longitudinal MRI provides evidence of progressive GM and WM changes in pGRN+ participants relative to yCTL. Structural MRI illustrates the natural history of presymptomatic GRN carriers, and may provide an endpoint during disease-modifying treatment trials for pGRN+ individuals at risk for FTD., Highlights • Presymptomatic GRN mutation carriers (pGRN+) show decreased gray matter and white matter relative to young controls (yCTL) • pGRN+ show greater longitudinal changes in gray matter and white matter relative to yCTL • Regions with decreased gray matter and white matter in pGRN+ are in regions showing disease in symptomatic GRN+

Author(s): Schonhaut, Daniel R; McMillan, Corey T; Spina, Salvatore; Dickerson, Bradford C; Siderowf, Andrew; Devous, Michael D; Tsai, Richard; Winer, Joseph; Russell, David S; Litvan, Irene; Roberson, Erik D; Seeley, William W; Grinberg, Lea T; Kramer, Joel H; Miller, Bruce L; Pressman, Peter; Nasrallah, Ilya; Baker, Suzanne L; Gomperts, Stephen N; Johnson, Keith A; Grossman, Murray; Jagust, William J; Boxer, Adam L; Rabinovici, Gil D | Abstract: Objective18 F-flortaucipir (formerly 18 F-AV1451 or 18 F-T807) binds to neurofibrillary tangles in Alzheimer disease, but tissue studies assessing binding to tau aggregates in progressive supranuclear palsy (PSP) have yielded mixed results. We compared in vivo 18 F-flortaucipir uptake in patients meeting clinical research criteria for PSP (n = 33) to normal controls (n = 46) and patients meeting criteria for Parkinson disease (PD; n = 26).MethodsParticipants underwent magnetic resonance imaging and positron emission tomography for amyloid-β (11 C-PiB or 18 F-florbetapir) and tau (18 F-flortaucipir). 18 F-flortaucipir standardized uptake value ratios were calculated (t = 80-100 minutes, cerebellum gray matter reference). Voxelwise and region-of-interest group comparisons were performed in template space, with receiver operating characteristic curve analyses to assess single-subject discrimination. Qualitative comparisons with postmortem tau are reported in 1 patient who died 9 months after 18 F-flortaucipir.ResultsClinical PSP patients showed bilaterally elevated 18 F-flortaucipir uptake in globus pallidus, putamen, subthalamic nucleus, midbrain, and dentate nucleus relative to controls and PD patients (voxelwise p l 0.05 family wise error corrected). Globus pallidus binding best distinguished PSP patients from controls and PD (area under the curve [AUC] = 0.872 vs controls, AUC = 0.893 vs PD). PSP clinical severity did not correlate with 18 F-flortaucipir in any region. A patient with clinical PSP and pathological diagnosis of corticobasal degeneration had severe tau pathology in PSP-related brain structures with good correspondence between in vivo 18 F-flortaucipir and postmortem tau neuropathology.Interpretation18 F-flortaucipir uptake was elevated in PSP versus controls and PD patients in a pattern consistent with the expected distribution of tau pathology. Ann Neurol 2017;82:622-634.

Objective: To test the hypotheses that 1) antemortem cerebrospinal fluid tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration and 2) tauopathy patients have higher phosphorylated-tau levels compared to TDP-43 proteinopathy patients while accounting for Alzheimer's disease co-pathology. Methods: Patients had autopsy-confirmed frontotemporal lobar degeneration with tauopathy (n=31), TDP-43 proteinopathy (n=49), or Alzheimer's disease (n=26) with antemortem cerebrospinal fluid. Cerebrospinal fluid tau levels were compared between groups and correlated with digital histology measurement of postmortem tau pathology averaged from three cerebral regions (angular gyrus, mid-frontal cortex, anterior cingulate gyrus). Multivariate linear regression tested the association of ante mortem cerebrospinal fluid tau levels with post mortem tau pathology adjusting for demographics. Results: Multivariate regression found an independent association of ante mortem cerebrospinal fluid phosphorylated tau levels with post mortem cerebral tau pathology in frontotemporal lobar degeneration (Beta=1.3, 95%CI=0.2-2.4, p

Objective:To determine whether logopenic features of phonologic loop dysfunction reflect Alzheimer disease (AD) neuropathology in primary progressive aphasia (PPA).Methods:We performed a retrospective case-control study of 34 patients with PPA with available autopsy tissue. We compared baseline and longitudinal clinical features in patients with primary AD neuropathology to those with primary non-AD pathologies. We analyzed regional neuroanatomic disease burden in pathology-defined groups using postmortem neuropathologic data.Results:A total of 19/34 patients had primary AD pathology and 15/34 had non-AD pathology (13 frontotemporal lobar degeneration, 2 Lewy body disease). A total of 16/19 (84%) patients with AD had a logopenic spectrum phenotype; 5 met published criteria for the logopenic variant (lvPPA), 8 had additional grammatical or semantic deficits (lvPPA+), and 3 had relatively preserved sentence repetition (lvPPA−). Sentence repetition was impaired in 68% of patients with PPA with AD pathology; forward digit span (DF) was impaired in 90%, substantially higher than in non-AD PPA (33%, p < 0.01). Lexical retrieval difficulty was common in all patients with PPA and did not discriminate between groups. Compared to non-AD, PPA with AD pathology had elevated microscopic neurodegenerative pathology in the superior/midtemporal gyrus, angular gyrus, and midfrontal cortex (p < 0.01). Low DF scores correlated with high microscopic pathologic burden in superior/midtemporal and angular gyri (p ≤ 0.03).Conclusions:Phonologic loop dysfunction is a central feature of AD-associated PPA and specifically correlates with temporoparietal neurodegeneration. Quantitative measures of phonologic loop function, combined with modified clinical lvPPA criteria, may help discriminate AD-associated PPA.

Introduction Primary age-related tauopathy (PART) is a neuropathological diagnosis characterized by tau neurofibrillary tangles (NFTs) in the absence of amyloid plaque pathology. Although most individuals over 50 years of age have evidence of NFTs, the clinical and cognitive consequences of PART are not known. Methods We evaluated 226 neuropathologically confirmed PART cases from the National Alzheimer's Coordinating Center database who participated in a total of 846 longitudinal neuropsychological assessments from the Alzheimer's Disease Center program‘s Uniform Data Set. Mixed-effects statistical models tested whether cognitive decline was associated with Braak stage NFT burden. Results Higher stages of NFT burden in PART, with no evidence or minimal evidence of amyloid pathology, were associated with more rapid decline on tasks involving episodic and semantic memory along with tests of processing speed and attention. Discussion We conclude that PART has cognitive consequences that should be considered in the context of emerging tau-targeted therapies in age-associated neurodegenerative diseases.

Objective:To apply network-based statistics to diffusion-weighted imaging tractography data and detect Alzheimer disease vs non-Alzheimer degeneration in the context of corticobasal syndrome.Methods:In a cross-sectional design, pathology was confirmed by autopsy or a pathologically validated CSF total tau-to-β-amyloid ratio (T-tau/Aβ). Using structural MRI data, we identify association areas in fronto-temporo-parietal cortex with reduced gray matter density in corticobasal syndrome (n = 40) relative to age-matched controls (n = 40). Using these fronto-temporo-parietal regions of interest, we construct structural brain networks in clinically similar subgroups of individuals with Alzheimer disease (n = 21) or non-Alzheimer pathology (n = 19) by linking these regions by the number of white matter streamlines identified in a deterministic tractography analysis of diffusion tensor imaging data. We characterize these structural networks using 5 graph-based statistics, and assess their relative utility in classifying underlying pathology with leave-one-out cross-validation using a supervised support vector machine.Results:Gray matter density poorly discriminates between Alzheimer disease and non-Alzheimer pathology subgroups with low sensitivity (57%) and specificity (52%). In contrast, a statistic of local network efficiency demonstrates very good discriminatory power, with 85% sensitivity and 84% specificity.Conclusions:Our results indicate that the underlying pathologic sources of corticobasal syndrome can be classified more accurately using graph theoretical statistics derived from patterns of white matter network organization in association cortex than by regional gray matter density alone. These results highlight the importance of a multimodal neuroimaging approach to diagnostic analyses of corticobasal syndrome.

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients, however factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N=327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort, and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N=90) as well as post mortem motor cortical neuronal loss (N=87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS.

Although the pathogenesis of amyotrophic lateral sclerosis (ALS) is far from being elucidated, a central role is played by the aggregation of TAR DNA binding protein 43 (TDP-43) in the brain and the spinal cord of patients with ALS, as shown by postmortem neuropathologic studies.1,2 Accompanying the great clinical and genetic heterogeneity of this disease, heterogeneous TDP-43 pathology has also been described. Patients with ALS with a C9orf72 repeat expansion, the most common pathogenic genetic risk factor,3 have more extensive pathologic TDP-43 deposition in extramotor brain regions relative to patients with ALS without a C9orf72 repeat expansion.4 While intermediate-length polyglutamine repeat expansions in ataxin 2 ( ATXN2 ) are associated with increased genetic risk for ALS and the morphology of TDP-43 pathologic inclusions in ATXN2 appears to be different from sporadic forms of ALS,5 the levels of phosphorylated and nonphosphorylated TDP-43 have not been previously reported. By investigating the regional deposition levels of TDP-43 (posttranslationally modified or not) in patients with ALS with C9orf72 or ATXN2 repeat expansions compared with cases of sporadic ALS, we may able to uncover insights about pathogenic mechanisms contributing to ALS disease heterogeneity. This is an important topic because it may direct the choice of potential specific therapeutic strategies.

Background The differential diagnosis of progressive supranuclear palsy (PSP) and Lewy body disorders, which include Parkinson disease and dementia with Lewy bodies, is often challenging due to the overlapping symptoms. Purpose To develop a diagnostic tool based on diffusion tensor imaging (DTI) to distinguish between PSP and Lewy body disorders at the individual-subject level. Materials and Methods In this retrospective study, skeletonized DTI metrics were extracted from two independent data sets: the discovery cohort from the Swedish BioFINDER study and the validation cohort from the Penn Frontotemporal Degeneration Center (data collected between 2010 and 2018). Based on previous neuroimaging studies and neuropathologic evidence, a combination of regions hypothesized to be sensitive to pathologic features of PSP were identified (ie, the superior cerebellar peduncle and frontal white matter) and fractional anisotropy (FA) was used to compute an FA score for each individual. Classification performances were assessed by using logistic regression and receiver operating characteristic analysis. Results In the discovery cohort, 16 patients with PSP (mean age ± standard deviation, 73 years ± 5; eight women, eight men), 34 patients with Lewy body disorders (mean age, 71 years ± 6; 14 women, 20 men), and 44 healthy control participants (mean age, 66 years ± 8; 26 women, 18 men) were evaluated. The FA score distinguished between clinical PSP and Lewy body disorders with an area under the curve of 0.97 ± 0.04, a specificity of 91% (31 of 34), and a sensitivity of 94% (15 of 16). In the validation cohort, 34 patients with PSP (69 years ± 7; 22 women, 12 men), 25 patients with Lewy body disorders (70 years ± 7; nine women, 16 men), and 32 healthy control participants (64 years ± 7; 22 women, 10 men) were evaluated. The accuracy of the FA score was confirmed (area under the curve, 0.96 ± 0.04; specificity, 96% [24 of 25]; and sensitivity, 85% [29 of 34]). Conclusion These cross-validated findings lay the foundation for a clinical test to distinguish progressive supranuclear palsy from Lewy body disorders. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Shah in this issue.

Introduction It is unclear how different proteinopathies (tau, transactive response DNA-binding protein 43 [TDP-43], amyloid β [Aβ], and α-synuclein) contribute to atrophy within medial temporal lobe (MTL) subregions in Alzheimer's disease (AD). Methods We utilized antemortem structural magnetic resonance imaging (MRI) data to measure MTL substructures and examined the relative contribution of tau, TDP-43, Aβ, and α-synuclein measured in post-mortem tissue from 92 individuals with intermediate to high AD neuropathology. Receiver-operating characteristic (ROC) curves were analyzed for each subregion in order to discriminate TDP-43-negative and TDP-43-positive patients. Results TDP-43 was strongly associated with anterior MTL regions, whereas tau was relatively more associated with the posterior hippocampus. Among the MTL regions, the anterior hippocampus showed the highest area under the ROC curve (AUC). Discussion We found specific contributions of different pathologies on MTL substructure in this population with AD neuropathology. The anterior hippocampus may be a relevant region to detect concomitant TDP-43 pathology in the MTL of patients with AD.

Two ways to get tangled? Neurodegeneration in Alzheimer's disease dementia is associated with neurofibrillary tangles composed of aggregated tau protein. Darwich et al. describe an additional form of autosomal-dominant dementia with neurofibrillary tangles linked to a hypomorph mutation in valosin-containing protein (VCP). VCP was found to disaggregate pathologic tau, and the hypomorph mutation increased tau accumulation in cells and mice. These findings highlight the role of protein turnover in maintaining neuronal health and suggest that VCP may provide a therapeutic target for Alzheimer's disease. Science , this issue p. eaay8826