Multi-omic analysis of Huntington's disease reveals a compensatory astrocyte state.

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.

Pathologically based criteria to distinguish essential tremor from controls: analyses of the human cerebellum.

Objective: Essential tremor is among the most prevalent neurological diseases. Diagnosis is based entirely on neurological evaluation. Historically, there were few postmortem brain studies, hindering attempts to develop pathologically based criteria to distinguish essential tremor from control brains.

Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons.

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.

Multi-OMIC analysis of Huntington disease reveals a neuroprotective astrocyte state.

Huntington disease (HD) is an incurable neurodegenerative disease characterized by neuronal loss and astrogliosis. One hallmark of HD is the selective neuronal vulnerability of striatal medium spiny neurons. To date, the underlying mechanisms of this selective vulnerability have not been fully defined.

Patterns of TDP-43 Deposition in Brains with LRRK2 G2019S Mutations.

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.

Histopathology of the cerebellar cortex in essential tremor and other neurodegenerative motor disorders: comparative analysis of 320 brains.

In recent years, numerous morphologic changes have been identified in the essential tremor (ET) cerebellar cortex, distinguishing ET from control brains. These findings have not been fully contextualized within a broader degenerative disease spectrum, thus limiting their interpretability. Building off our prior study and now doubling the sample size, we conducted comparative analyses in a postmortem series of 320 brains on the severity and patterning of cerebellar cortex degenerative changes in ET (n = 100), other neurodegenerative disorders of the cerebellum [spinocerebellar ataxias (SCAs, n = 47, including 13 SCA3 and 34 SCA1, 2, 6, 7, 8, 14); Friedreich's ataxia (FA, n = 13); multiple system atrophy (MSA), n = 29], and other disorders that may involve the cerebellum [Parkinson's disease (PD), n = 62; dystonia, n = 19] versus controls (n = 50).

Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation.

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.

The distribution and density of Huntingtin inclusions across the Huntington disease neocortex: regional correlations with Huntingtin repeat expansion independent of pathologic grade.

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.

Wolframin is a novel regulator of tau pathology and neurodegeneration.

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.

Correlation of plasma and neuroimaging biomarkers in Alzheimer's disease.

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.

Cerebral Microbleeds, Cerebral Amyloid Angiopathy, and Their Relationships to Quantitative Markers of Neurodegeneration.

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.

Neuropathological Findings in a Case of Parkinsonism and Developmental Delay Associated with a Monoallelic Variant in PLXNA1.

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.

Tau Isoform Profile in Essential Tremor Diverges From Other Tauopathies.

Patients with essential tremor (ET) frequently develop concurrent dementia, which is often assumed to represent co-morbid Alzheimer disease (AD). Autopsy studies have identified a spectrum of tau pathologies in ET and tau isoforms have not been examined in ET. We performed immunoblotting using autopsy cerebral cortical tissue from patients with ET (n = 13), progressive supranuclear palsy ([PSP], n = 10), Pick disease ([PiD], n = 2), and AD (n = 7).

Neuropathological correlation supports automated image-based differential diagnosis in parkinsonism.

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.

The Second NINDS/NIBIB Consensus Meeting to Define Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy.

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.

Plasma p-tau181, p-tau217, and other blood-based Alzheimer's disease biomarkers in a multi-ethnic, community study.

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).

Early Selective Vulnerability of the CA2 Hippocampal Subfield in Primary Age-Related Tauopathy.

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).

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

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.

Disease-related Huntingtin seeding activities in cerebrospinal fluids of Huntington's disease patients.

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.

Patterns of CAG repeat instability in the central nervous system and periphery in Huntington's disease and in spinocerebellar ataxia type 1.

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).