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Transneuronal degeneration of retinal ganglion cells was directly demonstrated in a patient who had unilateral removal of the striate cortex forty years prior to necropsy. For comparison, another case is presented showing anterograde transneuronal atrophy forty years after enucleation of one eye. [ABSTRACT FROM AUTHOR]

Objective: Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD). Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD prompted us to screen PGRN in patients with ALS and ALS-FTD.Methods: The PGRN gene was sequenced in 272 cases of sporadic ALS, 40 cases of familial ALS and in 49 patients with ALS-FTD.Results: Missense changes were identified in an ALS-FTD patient (p.S120Y) and in a single case of limb onset sporadic ALS (p.T182M), although the pathogenicity of these variants remains unclear.Conclusion: PGRN mutations are not a common cause of ALS phenotypes. [ABSTRACT FROM AUTHOR]

This paper began as a letter to the editor, commenting on several methodological and conceptual problems with the paper by Rajput et al. [1]. We were asked by the editors to expand the paper to include a more general discussion of the role of the cerebellum in essential tremor (ET). The study of the neuropathological underpinnings of essential tremor (ET) is a relatively new undertaking. The purpose of this paper is three-fold. The first is to comment on methodological problems in a recently-published paper by Rajput et al., the major one being the small sample size of that study, which resulted in a Type II statistical error. Hence, one cannot conclude based on their data that there is no Purkinje cell (PC) loss in ET. Secondly, we comment on conceptual problems with that study, which suggested that PC loss might not be a featured characteristic of ET because it is also found in other disease states. We discuss why this is an erroneous conclusion. Our third purpose is to more broadly discuss the role of the cerebellum in ET, giving consideration to the wealth of clinical and postmortem data that have accumulated over recent years. In this discussion, we make the following points: (1) it is now generally recognized that ET is a disease of cerebellar systems dysfunction, (2) given the nature of the postmortem work, revealing the presence of several types of structural-anatomical changes within the cerebellum and absence of detectable changes in other brain regions, the most empirically-based explanation is that the primary problem in ET is in the cerebellum itself, (3) that the collection of cellular changes in the cerebellum in ET are also present in other cerebellar degenerations should add to rather than detract from the notion that ET is a disease of cerebellar degeneration. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the selective regional vulnerability to neurodegeneration in Huntington's disease (HD) have not been fully defined. To explore the role of astrocytes in this phenomenon, we used single-nucleus and bulk RNAseq, lipidomics, HTT gene CAG repeat-length measurements, and multiplexed immunofluorescence on HD and control post-mortem brains. We identified genes that correlated with CAG repeat length, which were enriched in astrocyte genes, and lipidomic signatures that implicated poly-unsaturated fatty acids in sensitizing neurons to cell death. Because astrocytes play essential roles in lipid metabolism, we explored the heterogeneity of astrocytic states in both protoplasmic and fibrous-like (CD44+) astrocytes. Significantly, one protoplasmic astrocyte state showed high levels of metallothioneins and was correlated with the selective vulnerability of distinct striatal neuronal populations. When modeled in vitro, this state improved the viability of HD-patient-derived spiny projection neurons. Our findings uncover key roles of astrocytic states in protecting against neurodegeneration in HD., (© 2024. The Author(s).)

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyses, we further identify for the first time genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified VIPR1 , RBPJL , and L3MBTL1 as novel subtype specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signalling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.

Frontotemporal dementia (FTD) is an incurable group of early-onset dementias that can be caused by the deposition of hyperphosphorylated tau in patient brains. However, the mechanisms leading to neurodegeneration remain largely unknown. Here, we combined single-cell analyses of FTD patient brains with a stem cell culture and transplantation model of FTD. We identified disease phenotypes in FTD neurons carrying the MAPT-N279K mutation, which were related to oxidative stress, oxidative phosphorylation, and neuroinflammation with an upregulation of the inflammation-associated protein osteopontin (OPN). Human FTD neurons survived less and elicited an increased microglial response after transplantation into the mouse forebrain, which we further characterized by single nucleus RNA sequencing of microdissected grafts. Notably, downregulation of OPN in engrafted FTD neurons resulted in improved engraftment and reduced microglial infiltration, indicating an immune-modulatory role of OPN in patient neurons, which may represent a potential therapeutic target in FTD., Competing Interests: Declaration of interests Z.K.W. serves as PI or co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206), Vigil Neuroscience, Inc. (VGL101-01.002, VGL101-01.201), and ONO-2808-03 projects/grants. He serves as co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for Vigil Neuroscience, Inc. and as a consultant for Eli Lilly & Company and for NovoGlia, Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess for TDP-43 deposits in brains with and without a LRRK2 G2019S mutation., Background: LRRK2 G2019S mutations have been associated with parkinsonism and a wide range of pathological findings. There are no systematic studies examining the frequency and extent of TDP-43 deposits in neuropathological samples from LRRK2 G2019S carriers., Methods: Twelve brains with LRRK2 G2019S mutations were available for study from the New York Brain Bank at Columbia University; 11 of them had samples available for TDP-43 immunostaining. Clinical, demographic, and pathological data are reported for 11 brains with a LRRK2 G2019S mutation and compared to 11 brains without GBA1 or LRRK2 G2019S mutations with a pathologic diagnosis of Parkinson's disease (PD) or diffuse Lewy body disease. They were frequency matched by age, gender, parkinsonism age of onset, and disease duration., Results: TDP-43 aggregates were present in 73% (n = 8) of brains with a LRRK2 mutation and 18% (n = 2) of brains without a LRRK2 mutation (P = 0.03). In one brain with a LRRK2 mutation, TDP-43 proteinopathy was the primary neuropathological change., Conclusions: Extranuclear TDP-43 aggregates are observed with greater frequency in LRRK2 G2019S autopsies compared to PD cases without a LRRK2 G2019S mutation. The association between LRRK2 and TDP-43 should be further explored. © 2023 International Parkinson and Movement Disorder Society., (© 2023 International Parkinson and Movement Disorder Society.)

The complexity of affected brain regions and cell types is a challenge for Huntington's disease (HD) treatment. Here we use single nucleus RNA sequencing to investigate molecular pathology in the cortex and striatum from R6/2 mice and human HD post-mortem tissue. We identify cell type-specific and -agnostic signatures suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) are arrested in intermediate maturation states. OL-lineage regulators OLIG1 and OLIG2 are negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells shows decreased accessibility regulated by OL maturation genes. The data implicates glucose and lipid metabolism in abnormal cell maturation and identify PRKCE and Thiamine Pyrophosphokinase 1 (TPK1) as central genes. Thiamine/biotin treatment of R6/1 HD mice to compensate for TPK1 dysregulation restores OL maturation and rescues neuronal pathology. Our insights into HD OL pathology spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism., (© 2022. The Author(s).)

Objective: Pyramidal signs are common but often under-recognized in multiple system atrophy (MSA). The clinicopathological correlates of pyramidal signs in MSA are not well characterized. The present study aims to understand the role of pyramidal signs in MSA., Methods: We examined 40 autopsy-confirmed MSA cases in New York Brain Bank. The pyramidal signs were quantified by an established rating scale, summarized as the pyramidal score. We assessed whether pyramidal scores are associated with autonomic, parkinsonism, and cerebellar features and survival. We also examined whether the density of glial cytoplasmic inclusions (GCIs) in the motor cortex and its underlying white matter is associated with the pyramidal score., Results: MSA parkinsonian type cases have higher pyramidal scores compared to cerebellar type cases (p = 0.017). MSA cases with high pyramidal scores are more likely to have laryngeal stridor (OR = 4.89, p = 0.022), but less likely to have orthostatic hypotension (OR = 0.11, p = 0.006) and erectile dysfunction (OR = 0.05, p = 0.018). MSA cases with high pyramidal scores do not differ from those with low pyramidal scores in terms of bowel dysfunction, dry eyes and mouth, and survival. Finally, MSA cases with more GCIs in the motor cortex have higher pyramidal scores compared to those with few GCIs (p = 0.017)., Interpretation: Pyramidal signs in MSA are associated with the parkinsonian subtype, laryngeal stridor, and certain autonomic dysfunction., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Blood-based phosphorylated tau (Ptau) 181 and 217 biomarkers are sensitive and specific for Alzheimer's disease. In this racial/ethnically diverse cohort study, participants were classified as biomarker positive (Ptau+) or negative (Ptau-) based on Ptau 181 and 217 concentrations and as cognitively impaired (Sym) or unimpaired (Asym). The four groups, Ptau-/Asym, Ptau+/Asym, Ptau-/Sym, and Ptau+/Sym, differed by age, APOE-4 allele frequency, total tau, neurofilament light chain, and cortical thickness measured by MRI. Our results add to increasing evidence that plasma Ptau 181 and 217 concentrations are valid Alzheimer's disease biomarkers in diverse populations., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Selective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer's disease (AD). Understanding the molecular origins of this selective vulnerability is, therefore, of fundamental importance. Tau protein aggregates have been found in Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD. The role of WFS1 in Tauopathies and its levels in tau pathology-associated neurodegeneration, however, is largely unknown. Here we report that WFS1 deficiency is associated with increased tau pathology and neurodegeneration, whereas overexpression of WFS1 reduces those changes. We also find that WFS1 interacts with tau protein and controls the susceptibility to tau pathology. Furthermore, chronic ER stress and autophagy-lysosome pathway (ALP)-associated genes are enriched in WFS1-high excitatory neurons in human AD at early Braak stages. The protein levels of ER stress and autophagy-lysosome pathway (ALP)-associated proteins are changed in tau transgenic mice with WFS1 deficiency, while overexpression of WFS1 reverses those changes. This work demonstrates a possible role for WFS1 in the regulation of tau pathology and neurodegeneration via chronic ER stress and the downstream ALP. Our findings provide insights into mechanisms that underpin selective neuronal vulnerability, and for developing new therapeutics to protect vulnerable neurons in AD., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Huntington disease is characterized by progressive neurodegeneration, especially of the striatum, and the presence of polyglutamine huntingtin (HTT) inclusions. Although HTT inclusions are most abundant in the neocortex, their neocortical distribution and density in relation to the extent of CAG repeat expansion in the HTT gene and striatal pathologic grade have yet to be formally established. We immunohistochemically studied 65 brains with a pathologic diagnosis of Huntington disease to investigate the cortical distributions and densities of HTT inclusions within the calcarine (BA17), precuneus (BA7), motor (BA4) and prefrontal (BA9) cortices; in 39 of these brains, a p62 immunostain was used for comparison. HTT inclusions predominate in the infragranular cortical layers (layers V-VI) and layer III, however, the densities of HTT inclusions across the human cerebral cortex are not uniform but are instead regionally contingent. The density of HTT and p62 inclusions (intranuclear and extranuclear) in layers V-VI increases caudally to rostrally (BA17 < BA7 < BA4 < BA9) with the median burden of HTT inclusions being 38-fold greater in the prefrontal cortex (BA9) than in the calcarine cortex (BA17). Conversely, intranuclear HTT inclusions prevail in the calcarine cortex irrespective of HTT CAG length. Neocortical HTT inclusion density correlates with CAG repeat expansion, but not with the neuropathologic grade of striatal degeneration (Vonsattel grade) or with the duration of clinical disease since motor onset. Extrapolation of these findings suggest that HTT inclusions are at a regionally-contingent, CAG-dependent, density during the advanced stages of HD. The distribution and density of HTT inclusions in HD therefore does not provide a measure of pathologic disease stage but rather infers the degree of pathogenic HTT expansion., (© 2022. The Author(s).)

Background and Objectives: Age-related cognitive impairment is driven by the complex interplay of neurovascular and neurodegenerative disease. There is a strong relationship between cerebral microbleeds (CMBs), cerebral amyloid angiopathy (CAA), and the cognitive decline observed in conditions such as Alzheimer disease. However, in the early, preclinical phase of cognitive impairment, the extent to which CMBs and underlying CAA affect volumetric changes in the brain related to neurodegenerative disease remains unclear., Methods: We performed cross-sectional analyses from 3 large cohorts: The Northern Manhattan Study (NOMAS), Alzheimer's Disease Neuroimaging Initiative (ADNI), and the Epidemiology of Dementia in Singapore study (EDIS). We conducted a confirmatory analysis of 82 autopsied cases from the Brain Arterial Remodeling Study (BARS). We implemented multivariate regression analyses to study the association between 2 related markers of cerebrovascular disease-MRI-based CMBs and autopsy-based CAA-as independent variables and volumetric markers of neurodegeneration as dependent variables. NOMAS included mostly dementia-free participants age 55 years or older from northern Manhattan. ADNI included participants living in the United States age 55-90 years with a range of cognitive status. EDIS included community-based participants living in Singapore age 60 years and older with a range of cognitive status. BARS included postmortem pathologic samples., Results: We included 2,657 participants with available MRI data and 82 autopsy cases from BARS. In a meta-analysis of NOMAS, ADNI, and EDIS, superficial CMBs were associated with larger gray matter (β = 4.49 ± 1.13, p = 0.04) and white matter (β = 4.72 ± 2.1, p = 0.03) volumes. The association between superficial CMBs and larger white matter volume was more evident in participants with 1 CMB (β = 5.17 ± 2.47, p = 0.04) than in those with ≥2 CMBs (β = 1.97 ± 3.41, p = 0.56). In BARS, CAA was associated with increased cortical thickness (β = 6.5 ± 2.3, p = 0.016) but not with increased brain weight (β = 1.54 ± 1.29, p = 0.26)., Discussion: Superficial CMBs are associated with larger morphometric brain measures, specifically white matter volume. This association is strongest in brains with fewer CMBs, suggesting that the CMB/CAA contribution to neurodegeneration may not relate to tissue loss, at least in early stages of disease., (© 2022 American Academy of Neurology.)

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., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: PLXNA1 encodes for Plexin-A, a transmembrane protein expressed in the developing nervous system. Mutations in this gene have been associated with developmental delay but have not been previously associated with the development of parkinsonism., Objectives: To describe the case of a 38-year-old patient with developmental delay who developed parkinsonism later in life., Methods: Post-mortem exome sequencing was performed with confirmation by Sanger sequencing. Brain autopsy was also performed., Results: Post-mortem exome sequencing on the proband identified a heterozygous predicted nonsense PLXNA1 variant (c.G3361T:p.Glu1121Ter). Pathology demonstrated arhinencephaly with brainstem heterotopia, diffuse Lewy body disease, and frontotemporal lobar dementia-tau., Conclusions: This case of a patient with developmental delay and parkinsonism with PLXNA1 mutation highlights a need for assessing long-term outcomes of individuals with neurodevelopmental disorders, as well as the need for genetic testing in adults. It also suggests that the link between PLXNA1 and α-synuclein should be explored in the future. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Purpose: Up to 25% of patients diagnosed as idiopathic Parkinson's disease (IPD) have an atypical parkinsonian syndrome (APS). We had previously validated an automated image-based algorithm to discriminate between IPD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). While the algorithm was accurate with respect to the final clinical diagnosis after long-term expert follow-up, its relationship to the initial referral diagnosis and to the neuropathological gold standard is not known., Methods: Patients with an uncertain diagnosis of parkinsonism were referred for 18 F-fluorodeoxyglucose (FDG) PET to classify patients as IPD or as APS based on the automated algorithm. Patients were followed by a movement disorder specialist and subsequently underwent neuropathological examination. The image-based classification was compared to the neuropathological diagnosis in 15 patients with parkinsonism., Results: At the time of referral to PET, the clinical impression was only 66.7% accurate. The algorithm correctly identified 80% of the cases as IPD or APS (p = 0.02) and 87.5% of the APS cases as MSA or PSP (p = 0.03). The final clinical diagnosis was 93.3% accurate (p < 0.001), but needed several years of expert follow-up., Conclusion: The image-based classifications agreed well with autopsy and can help to improve diagnostic accuracy during the period of clinical uncertainty., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Blood-based Alzheimer's disease (AD) biomarkers provide opportunities for community studies and across ethnic groups. We investigated blood biomarker concentrations in the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multi-ethnic community study of aging and dementia., Methods: We measured plasma amyloid beta (Aβ)40, Aβ42, total tau (t-tau), phosphorylated tau (p-tau)181, and p-tau217, and neurofilament light chain (NfL) in 113 autopsied participants (29% with high AD neuropathological changes) and in 300 clinically evaluated individuals (42% with clinical AD). Receiver operating characteristics were used to evaluate each biomarker. We also investigated biomarkers as predictors of incident clinical AD., Results: P-tau181, p-tau217, and NfL concentrations were elevated in pathologically and clinically diagnosed AD. Decreased Aβ42/Aβ40 ratio and increased p-tau217 and p-tau181 were associated with subsequent AD diagnosis., Discussion: Blood-based AD biomarker concentrations are associated with pathological and clinical diagnoses and can predict future development of clinical AD, providing evidence that they can be incorporated into multi-ethnic, community-based studies., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Neuropathologic hallmarks of Huntington Disease (HD) include the progressive neurodegeneration of the striatum and the presence of Huntingtin (HTT) aggregates that result from abnormal polyQ expansion of the HTT gene. Whether the pathogenic trinucleotide repeat expansion of the HTT gene causes neurodevelopmental abnormalities has garnered attention in both murine and human studies; however, documentation of discrete malformations in autopsy brains of HD individuals has yet to be described. We retrospectively searched the New York Brain Bank (discovery cohort) and an independent cohort (validation cohort) to determine whether developmental malformations are more frequently detected in HD versus non-HD brains and to document their neuropathologic features. One-hundred and thirty HD and 1600 non-HD whole brains were included in the discovery cohort and 720 HD and 1989 non-HD half brains were assessed in the validation cohort. Cases with developmental malformations were found at 6.4-8.2 times greater frequency in HD than in non-HD brains (discovery cohort: OR 8.68, 95% CI 3.48-21.63, P=4.8 × 10 -5 ; validation cohort: OR 6.50, 95% CI 1.83-23.17, P=0.0050). Periventricular nodular heterotopias (PNH) were the most frequent malformations and contained HTT and p62 aggregates analogous to the cortex, whereas cortical malformations with immature neuronal populations did not harbor such inclusions. HD individuals with malformations had heterozygous HTT CAG expansions between 40 and 52 repeats, were more frequently women, and all were asymmetric and focal, aside from one midline hypothalamic hamartoma. Using two independent brain bank cohorts, this large neuropathologic series demonstrates an increased occurrence of developmental malformations in HD brains. Since pathogenic HTT gene expansion is associated with genomic instability, one possible explanation is that neuronal precursors are more susceptible to somatic mutation of genes involved in cortical migration. Our findings further support emerging evidence that pathogenic trinucleotide repeat expansions of the HTT gene may impact neurodevelopment.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including the pathognomonic lesion of CTE as "an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern," based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5-267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6-1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as "Low CTE" or "High CTE" for use in future clinical, pathological, and molecular studies., (© 2021 American Association of Neuropathologists, Inc.)

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered., Competing Interests: Declaration of Interests S.P.-B., A.B.S., J.A.H., H.R.M., and B.J.T. hold US, EU, and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9 or f72. S.W.S. serves on the scientific advisory council of the Lewy Body Dementia Association and is an editorial board member for the Journal of Parkinson’s Disease. B.J.T. is an editorial board member for JAMA Neurology, JNNP, and Neurobiology of Aging. V.S. is on the journal editorial boards of Amyotrophic Lateral Sclerosis, European Neurology, American Journal of Neurodegenerative Diseases, and Frontiers in Neurology. He has also received compensation for consulting services and speaking activities from AveXis, Cytokinetics, Italfarmaco, and Zambon. J.B.R. is an editor for Brain and has received compensation for consulting services from Asceneuron, Biogen, UCB, Astex, and SV Health. J.E.L. is a member of the scientific advisory board for Cerevel Therapeutics and a consultant and provides expert testimony for Perkins Coie., (Published by Elsevier Inc.)

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., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

In Huntington's disease (HD), the mutant Huntingtin (mHTT) is postulated to mediate template-based aggregation that can propagate across cells. It has been difficult to quantitatively detect such pathological seeding activities in patient biosamples, e.g. cerebrospinal fluids (CSF), and study their correlation with the disease manifestation. Here we developed a cell line expressing a domain-engineered mHTT-exon 1 reporter, which showed remarkably high sensitivity and specificity in detecting mHTT seeding species in HD patient biosamples. We showed that the seeding-competent mHTT species in HD CSF are significantly elevated upon disease onset and with the progression of neuropathological grades. Mechanistically, we showed that mHTT seeding activities in patient CSF could be ameliorated by the overexpression of chaperone DNAJB6 and by antibodies against the polyproline domain of mHTT. Together, our study developed a selective and scalable cell-based tool to investigate mHTT seeding activities in HD CSF, and demonstrated that the CSF mHTT seeding species are significantly associated with certain disease states. This seeding activity can be ameliorated by targeting specific domain or proteostatic pathway of mHTT, providing novel insights into such pathological activities.

The expanded HTT CAG repeat causing Huntington's disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Huntington Disease (HD) is an inherited movement disorder caused by expanded CAG repeats in the Huntingtin gene. We have used single nucleus RNASeq (snRNASeq) to uncover cellular phenotypes that change in the disease, investigating single cell gene expression in cingulate cortex of patients with HD and comparing the gene expression to that of patients with no neurological disease. In this study, we focused on astrocytes, although we found significant gene expression differences in neurons, oligodendrocytes, and microglia as well. In particular, the gene expression profiles of astrocytes in HD showed multiple signatures, varying in phenotype from cells that had markedly upregulated metallothionein and heat shock genes, but had not completely lost the expression of genes associated with normal protoplasmic astrocytes, to astrocytes that had substantially upregulated glial fibrillary acidic protein (GFAP) and had lost expression of many normal protoplasmic astrocyte genes as well as metallothionein genes. When compared to astrocytes in control samples, astrocyte signatures in HD also showed downregulated expression of a number of genes, including several associated with protoplasmic astrocyte function and lipid synthesis. Thus, HD astrocytes appeared in variable transcriptional phenotypes, and could be divided into several different "states", defined by patterns of gene expression. Ultimately, this study begins to fill the knowledge gap of single cell gene expression in HD and provide a more detailed understanding of the variation in changes in gene expression during astrocyte "reactions" to the disease.

Background: The pathological hallmark in MSA is oligodendrocytic glial cytoplasmic inclusions (GCIs) containing α-synuclein, in addition to neuronal loss and astrogliosis especially involving the striatonigral and olivopontocerebellar systems. Rarely, TAR DNA-binding protein of 43 kDa (TDP-43), a component of ubiquitinated inclusions observed mainly in amyotrophic lateral sclerosis and frontotemporal lobar degeneration has been demonstrated in cases of MSA and, more recently, was shown to colocalize with α-synuclein pathology in GCIs in 2 patients., Methods: A 66-year-old woman presented with a syndrome characterized by spasticity, dysautonomia, bulbar dysfunction, and parkinsonism. Symptoms progressed until her death at age 74. Neuropathological evaluation was performed at the New York Brain Bank at Columbia University., Results: On gross examination, there was striking severe volume loss of the left striatum compared to mild involvement of the right striatum. Microscopically, neuronal loss and gliosis of the putamen and globus pallidus were severe on the left side, in contrast to mild involvement on the right side. Immunohistochemistry for α-synuclein revealed widespread GCIs. The sections subjected to TDP-43 antibodies showed a few GCIs with definite nucleocytoplasmic translocation of the labeling within the lenticular nucleus and within the paracentral cortex., Conclusions: This report adds to the evidence that TDP-43 and α-synuclein colocalize in GCIs. Whether this coexistence contributes to the pathogenesis of a subset of MSA patients or is an age-related process is not known. More cases with these peculiar pathological hallmarks might help determine whether TDP-43 contributes to neurodegeneration in a subset of patients with MSA., Competing Interests: Columbia University Parkinson's Brain Bank is funded by the Parkinson's Foundation. The authors report no conflicts of interest., (© 2019 International Parkinson and Movement Disorder Society.)

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Background: Frontotemporal lobar degeneration (FTLD) is the third most common dementing neurodegenerative disease with nearly 80% having no known etiology., Objective: Growing evidence that neurodegeneration can be linked to dysregulated metabolism prompted us to measure a panel of trophic factors, receptors, and molecules that modulate brain metabolic function in FTLD., Methods: Postmortem frontal (Brodmann's area [BA]8/9 and BA24) and temporal (BA38) lobe homogenates were used to measure immunoreactivity to Tau, phosphorylated tau (pTau), ubiquitin, 4-hydroxynonenal (HNE), transforming growth factor-beta 1 (TGF-β1) and its receptor (TGF-β1R), brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3, neurotrophin-4, tropomyosin receptor kinase, and insulin and insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2) and their receptors by direct-binding enzyme-linked immunosorbent assay., Results: FTLD brains had significantly elevated pTau, ubiquitin, TGF-β1, and HNE immunoreactivity relative to control. In addition, BDNF and neurotrophin-4 were respectively reduced in BA8/9 and BA38, while neurotrophin-3 and nerve growth factor were upregulated in BA38, and tropomyosin receptor kinase was elevated in BA24. Lastly, insulin and insulin receptor expressions were elevated in the frontal lobe, IGF-1 was increased in BA24, IGF-1R was upregulated in all three brain regions, and IGF-2 receptor was reduced in BA24 and BA38., Conclusions: Aberrantly increased levels of pTau, ubiquitin, HNE, and TGF-β1, marking neurodegeneration, oxidative stress, and neuroinflammation, overlap with altered expression of insulin/IGF signaling ligand and receptors in frontal and temporal lobe regions targeted by FTLD. Dysregulation of insulin-IGF signaling networks could account for brain hypometabolism and several characteristic neuropathologic features that characterize FTLD but overlap with Alzheimer's disease, Parkinson's disease, and Dementia with Lewy Body Disease.

Objective: To develop, replicate, and validate an MRI-based quantitative measure of both cerebrovascular and neurodegeneration in Alzheimer disease (AD) for clinical and potentially research purposes., Methods: We used data from a cross-sectional and longitudinal community-based study of Medicare-eligible residents in northern Manhattan followed every 18-24 months (n = 1,175, mean age 78 years). White matter hyperintensities, infarcts, hippocampal volumes, and cortical thicknesses were quantified from MRI and combined to generate an MRI measure associated with episodic memory. The combined MRI measure was replicated and validated using autopsy data, clinical diagnoses, and CSF biomarkers and amyloid PET from the Alzheimer's Disease Neuroimaging Initiative., Results: The quantitative MRI measure was developed in a group of community participants (n = 690) and replicated in a similar second group (n = 485). Compared with healthy controls, the quantitative MRI measure was lower in patients with mild cognitive impairment and lower still in those with clinically diagnosed AD. The quantitative MRI measure correlated with neurofibrillary tangles, neuronal loss, atrophy, and infarcts at postmortem in an autopsy subset and was also associated with PET amyloid imaging and CSF levels of total tau, phosphorylated tau, and β-amyloid 42. The MRI measure predicted conversion to MCI and clinical AD among healthy controls., Conclusion: We developed, replicated, and validated an MRI measure of cerebrovascular and neurodegenerative pathologies that are associated with clinical and neuropathologic diagnosis of AD and related to established biomarkers., (© 2018 American Academy of Neurology.)

Huntington's disease (HD) is an inherited neurodegenerative disorder that causes progressive breakdown of striatal neurons. Standard white matter integrity measures like fractional anisotropy and mean diffusivity derived from diffusion tensor imaging were analyzed in prodromal-HD subjects; however, they studied either a whole brain or specific subcortical white matter structures with connections to cortical motor areas. In this work, we propose a novel analysis of a longitudinal cohort of 243 prodromal-HD individuals and 88 healthy controls who underwent two or more diffusion MRI scans as part of the PREDICT-HD study. We separately trace specific white matter fiber tracts connecting the striatum (caudate and putamen) with four cortical regions corresponding to the hand, face, trunk, and leg motor areas. A multi-tensor tractography algorithm with an isotropic volume fraction compartment allows estimating diffusion of fast-moving extra-cellular water in regions containing crossing fibers and provides quantification of a microstructural property related to tissue atrophy. The tissue atrophy rate is separately analyzed in eight cortico-striatal pathways as a function of CAG-repeats (genetic load) by statistically regressing out age effect from our cohort. The results demonstrate a statistically significant increase in isotropic volume fraction (atrophy) bilaterally in hand fiber connections to the putamen with increasing CAG-repeats, which connects the genetic abnormality (CAG-repeats) to an imaging-based microstructural marker of tissue integrity in specific white matter pathways in HD. Isotropic volume fraction measures in eight cortico-striatal pathways are also correlated significantly with total motor scores and diagnostic confidence levels, providing evidence of their relevance to HD clinical presentation., (© 2018 Wiley Periodicals, Inc.)

Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers., Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10 -5 ) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin., Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46-0·63; p=3·54 × 10 -16 ), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30-1·71; p=1·58 × 10 -8 ). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2., Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals., Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency., (Copyright © 2018 Elsevier Ltd. All rights reserved.)