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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.

Combination antiretroviral therapy (cART) has extended lifespans of people living with HIV (PWH), increasing both the risk for age-related neuropathologies and the importance of distinguishing effects of HIV and its comorbidities from neurodegenerative disorders. The accumulation of hyperphosphorylated tau (p-tau) in hippocampus is a common degenerative change, with specific patterns of hippocampal subfield vulnerability observed in different disease contexts. Currently, associations between chronic HIV, its comorbidities, and p-tau burden and distribution in the hippocampus are unexplored. We used immunohistochemistry with antibody AT8 to analyze hippocampal p-tau in brain tissues of PWH ( n  = 71) and HIV negative controls ( n  = 25), for whom comprehensive clinical data were available. Using a morphology-based neuroanatomical segmentation protocol, we annotated digital slide images to measure percentage p-tau areas in the hippocampus and its subfields. Factors predicting p-tau burden and distribution were identified in univariate analyses, and those with significance at p  ≤ 0.100 were advanced to multivariable regression. The patient sample had a mean age of 61.5 years. Age predicted overall hippocampal p-tau burden. Subfield p-tau predictors were for Cornu Ammonis (CA)1, age; for CA2 and subiculum, seizure history; for CA3, seizure history and head trauma; and for CA4/dentate, history of hepatitis C virus (HCV) infection. In this autopsy sample, hippocampal p-tau burden and distribution were not predicted by HIV, viral load, or immunologic status, with viral effects limited to associations between HCV and CA4/dentate vulnerability. Hippocampal p-tau pathologies in cART-era PWH appear to reflect age and comorbidities, but not direct effects of HIV infection.

Essential tremor (ET) is among the most common neurological diseases. Postmortem studies have noted a series of pathological changes in the ET cerebellum. Heterotopic Purkinje cells (PCs) are those whose cell body is mis-localized in the molecular layer. In neurodegenerative settings, these are viewed as a marker of the progression of neuronal degeneration. We (1) quantify heterotopias in ET cases vs. controls, (2) compare ET cases to other cerebellar degenerative conditions (spinocerebellar ataxias (SCAs) 1, 2, 3, and 6), (3) compare these SCAs to one another, and (4) assess heterotopia within the context of associated PC loss in each disease. Heterotopic PCs were quantified using a standard LH&E-stained section of the neocerebellum. Counts were normalized to PC layer length (n-heterotopia count). It is also valuable to consider PC counts when assessing heterotopia, as loss of PCs extends both to normally located as well as heterotopic PCs. Therefore, we divided n-heterotopias by PC counts. There were 96 brains (43 ET, 31 SCA [12 SCA1, 7 SCA2, 7 SCA3, 5 SCA6], and 22 controls). The median number of n-heterotopias in ET cases was two times higher than that of the controls (2.6 vs. 1.2, p < 0.05). The median number of n-heterotopias in the various SCAs formed a spectrum, with counts being highest in SCA3 and SCA1. In analyses that factored in PC counts, ET had a median n-heterotopia/Purkinje cell count that was three times higher than the controls (0.35 vs. 0.13, p < 0.01), and SCA1 and SCA2 had counts that were 5.5 and 11 times higher than the controls (respective p < 0.001). The median n-heterotopia/PC count in ET was between that of the controls and the SCAs. Similarly, the median PC count in ET was between that of the controls and the SCAs; the one exception was SCA3, in which the PC population is well known to be preserved. Heterotopia is a disease-associated feature of ET. In comparison, several of the SCAs evidenced even more marked heterotopia, although a spectrum existed across the SCAs. The median n-heterotopia/PC count and median PC in ET was between that of the controls and the SCAs; hence, in this regard, ET could represent an intermediate state or a less advanced state of spinocerebellar atrophy.

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 ( p  < 0.0001), but other features including ARTAG ( p  = 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.

Abstract 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). Total tau in ET samples was similar to that in PSP and PiD but was significantly lower than that in AD. Abnormal tau levels measured using the AT8 phospho-tau specific (S202/T205/S208) monoclonal antibody in ET were similar to those in PSP but were lower than in PiD and AD. In aggregates, tau with 3 microtubule-binding domain repeats (3R) was significantly higher in AD than ET, while tau with 4 repeats (4R) was significantly higher in PSP. Strikingly, the total tau without N-terminal inserts in ET was significantly lower than in PSP, PiD, and AD, but total tau with other N-terminal inserts was not. Monomeric tau with one insert in ET was similar to that in PSP and PiD was lower than in AD. Thus, ET brains exhibit an expression profile of tau protein isoforms that diverges from that of other tauopathies.

Microglia are implicated in Alzheimer’s Disease (AD) pathogenesis. In a middle-aged cohort enriched for neuroinflammation, we asked whether microgliosis was related to neocortical amyloid beta (A β ) deposition and neuronal phosphorylated tau (p-tau), and whether microgliosis predicted cognition. Frontal lobe tissue from 191 individuals autopsied with detectable (HIV-D) and undetectable (HIV-U) HIV infection, and 63 age-matched controls were examined. Immunohistochemistry (IHC) was used to evaluate A β plaques and neuronal p-tau, and quantitate microgliosis with markers Iba1, CD163, and CD68 in large regions of cortex. Glia in the A β plaque microenvironment were quantitated by immunofluorescence (IF). The relationship of microgliosis to cognition was evaluated. No relationship between A β or p-tau accumulation and overall severity of microgliosis was discerned. Individuals with uncontrolled HIV had the greatest microgliosis, but fewer A β plaques; they also had higher prevalence of APOE ε 4 alleles, but died earlier than other groups. HIV group status was the only variable predicting microgliosis over large frontal regions. In contrast, in the A β plaque microenvironment, APOE ε 4 status and sex were dominant predictors of glial infiltrates, with smaller contributions of HIV status. Cognition correlated with large-scale microgliosis in HIV-D, but not HIV-U, individuals. In this autopsy cohort, over large regions of cortex, HIV status predicts microgliosis, whereas in the A β plaque microenvironment, traditional risk factors of AD (APOE ε 4 and sex) are stronger determinants. While microgliosis does not predict neurodegenerative protein deposition, it does predict cognition in HIV-D. Increased neuroinflammation does not initiate amyloid deposition in a younger group with enhanced genetic risk. However, once A β deposits are established, APOE ε 4 predicts increased plaque-associated inflammation.

Variants in GBA are associated with Lewy Body (LB) pathology. We investigated whether variants in other lysosomal storage disorder (LSD) genes also contribute to disease pathogenesis. We performed a genetic analysis of four LSD genes including GBA, HEXA, SMPD1, and MCOLN1 in 231 brain autopsies. Brain autopsies included neuropathologically defined LBD without Alzheimer Disease (AD) changes (n = 59), AD without significant LB pathology (n = 71), Alzheimer disease and lewy body variant (ADLBV) (n = 68), and control brains without LB or AD neuropathology (n = 33). Sequencing of HEXA, SMPD1, MCOLN1 and GBA followed by 'gene wise' genetic association analysis was performed. To determine the functional effect, a biochemical analysis of GBA in a subset of brains was also performed. GCase activity was measured in a subset of brain samples (n = 64) that included LBD brains, with or without GBA mutations, and control brains. A lipidomic analysis was also performed in brain autopsies (n = 67) which included LBD (n = 34), ADLBV (n = 3), AD (n = 4), PD (n = 9) and control brains (n = 17), comparing GBA mutation carriers to non-carriers. In a 'gene-wise' analysis, variants in GBA, SMPD1 and MCOLN1 were significantly associated with LB pathology (p range: 0.03-4.14 x10(-5)). Overall, the mean levels of GCase activity were significantly lower in GBA mutation carriers compared to non-carriers (p<0.001). A significant increase and accumulation of several species for the lipid classes, ceramides and sphingolipids, was observed in LBD brains carrying GBA mutations compared to controls (p range: p<0.05-p<0.01). Our study indicates that variants in GBA, SMPD1 and MCOLN1 are associated with LB pathology. Biochemical data comparing GBA mutation carrier to non-carriers support these findings, which have important implications for biomarker development and therapeutic strategies.

Early onset and late onset essential tremor (ET) cases differ in several respects. Whether they differ with respect to cerebellar pathologic changes remains to be determined. We quantified a broad range of postmortem features (Purkinje cell (PC) counts, PC axonal torpedoes and associated axonal changes, heterotopic PCs, and hairy basket ratings) in 30 ET cases with age of tremor onset <50 years, 30 ET cases with age of tremor onset ≥50 years, and 30 controls (total n  = 90). We also used two alternative age of onset cut-points (<40 vs. ≥40 years, and <60 vs. ≥60 years) to define early onset vs. late onset ET. We found that ET cases with tremor onset <50 years and tremor onset ≥50 years had similar PC counts (8.78 ± 1.70 vs. 8.86 ± 1.24, p  = 0.839), PC axonal torpedo counts (17.87 ± 18.27 [median =13.00] vs. 12.90 ± 10.60 [median =9.0], p  = 0.486) and associated axonal pathology (all p values >0.05), heterotopic PC counts (9.90 ± 11.55 [median =6.00] vs. 5.40 ± 5.10 [median =3.50], p  = 0.092), and hairy basket ratings (1.95 ± 0.62 [median =2.00] vs. 2.05 ± 0.92 [median =2.00], p  = 0.314). When using the age of onset cut-points of 40 or 60 years, results were similar. Early onset and late onset ET cases share similar cerebellar postmortem features. These data do not support the notion that these age-of-onset related forms of ET represent distinct clinical-pathological entities.

A review of the brain banking literature reveals a primary focus either on the factors that influence the decision to become a future donor or on the brain tissue processing that takes place after the individual has died (i.e., the front-end or back-end processes). What has not been sufficiently detailed, however, is the complex and involved process that takes place after this decision to become a future donor is made yet before post-mortem processing occurs (i.e., the large middle-ground). This generally represents a period of many years during which the brain bank is actively engaged with donors to ensure that valuable clinical information is prospectively collected and that their donation is eventually completed. For the past 15 years, the Essential Tremor Centralized Brain Repository has been actively involved in brain banking, and our experience has provided us valuable insights that may be useful for researchers interested in establishing their own brain banking efforts. In this piece, we fill a gap in the literature by detailing the processes of enrolling participants, creating individualized brain donation plans, collecting clinical information and regularly following-up with donors to update that information, and efficiently coordinating the brain harvest when death finally arrives.