As lifespans increase in people with HIV (PWH), there is concern that age-related neurodegenerative disorders may contribute to cognitive decline. We asked whether brain accumulation of Alzheimer's ...disease (AD)-associated proteins amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) predicted cognitive performance in middle-aged PWH.
In a prospectively followed, cognitively-characterized autopsy sample of 135 PWH, we used immunohistochemistry to assess Aβ plaques and neuronal p-tau in medial temporal and lateral frontal lobes. These pathologies were tested for associations with cognitive performance in seven domains: motor, speed of information processing, working memory, memory encoding, memory retrieval, verbal fluency, and abstraction/executive function. Univariate and multivariate analyses accounting for HIV-associated variables, reading level, and comorbidities were conducted. Longitudinal trajectories of memory functions were evaluated in 60 individuals with a median follow-up of 6.0 years.
In this population with mean age 51.4 ± 0.9 years, 58% displayed neuronal p-tau and 29% Aβ plaques. Neuronal p-tau, but not Aβ, predicted worse memory encoding and retrieval, but not other cognitive functions. With an ordinal hierarchy of neuronal p-tau locations (entorhinal, hippocampal, neocortical), decreased memory performance correlated with neocortical distribution. Memory function trajectories could not be distinguished between individuals with and without neuronal p-tau, and over 80% of the sample showed no change over time.
In this middle-aged sample, neuronal p-tau accumulation contributes to memory deficits, but is not associated with accelerated decline in function over time. In the absence of AD-like deterioration, other etiologies for neuronal p-tau in cognitively impaired PWH must be considered.
Lipids are key regulators of brain function and have been increasingly implicated in neurodegenerative disorders including Alzheimer disease (AD). Here, a systems-based approach was employed to ...determine the lipidome of brain tissues affected by AD. Specifically, we used liquid chromatography-mass spectrometry to profile extracts from the prefrontal cortex, entorhinal cortex, and cerebellum of late-onset AD (LOAD) patients, as well as the forebrain of three transgenic familial AD (FAD) mouse models. Although the cerebellum lacked major alterations in lipid composition, we found an elevation of a signaling pool of diacylglycerol as well as sphingolipids in the prefrontal cortex of AD patients. Furthermore, the diseased entorhinal cortex showed specific enrichment of lysobisphosphatidic acid, sphingomyelin, the ganglioside GM3, and cholesterol esters, all of which suggest common pathogenic mechanisms associated with endolysosomal storage disorders. Importantly, a significant increase in cholesterol esters and GM3 was recapitulated in the transgenic FAD models, suggesting that these mice are relevant tools to study aberrant lipid metabolism of endolysosomal dysfunction associated with AD. Finally, genetic ablation of phospholipase D2, which rescues the synaptic and behavioral deficits of an FAD mouse model, fully normalizes GM3 levels. These data thus unmask a cross-talk between the metabolism of phosphatidic acid, the product of phospholipase D2, and gangliosides, and point to a central role of ganglioside anomalies in AD pathogenesis. Overall, our study highlights the hypothesis generating potential of lipidomics and identifies novel region-specific lipid anomalies potentially linked to AD pathogenesis.
Background: Lipid dyshomeostasis has been linked to Alzheimer disease (AD).
Results: Lipidomic analyses of brain tissue from AD patients reveal region-specific changes in multiple bioactive lipids, some of which are phenocopied in AD mouse models.
Conclusion: Lipid anomalies observed in AD may be linked to pathogenesis, including endolysosomal dysfunction.
Significance: This study highlights the hypothesis-generating potential of lipidomics and its applicability to other diseases.
Abnormal deposition of the antimicrobial peptide amyloid beta (Aβ) is a characteristic of Alzheimer's disease. The objective of this study was to elucidate risk factors for brain Aβ in a cohort ...enriched for HIV and other neurotropic pathogens.
Cross-sectional cohort study.
We examined autopsy brains of 257 donors with a mean age of 52.8 years; 62% were men; and 194 were HIV+ and 63 HIV-. Hyperphosphorylated tau (p-tau) and Aβ were identified in frontal and temporal regions by immunohistochemistry. APOE genotyping was performed. Clinical and neuropathological predictors for Aβ were identified in univariate analyses, and then tested in multivariate regressions.
Cortical Aβ was identified in 32% of the sample, and active brain infection in 27%. Increased odds of Aβ were seen with increasing age and having an APOE ε4 allele; for the overall sample, HIV+ status was protective and brain infection was not a predictor. Within the HIV+ population, predictors for Aβ were duration of HIV disease and APOE alleles, but not age. When HIV disease duration and other HIV parameters were introduced into models for the entire sample, HIV disease duration was equivalent to age as a predictor of Aβ.
We hypothesize that dual aspects of immune suppression and stimulation in HIV, and beneficial survivor effects in older HIV+ individuals, account for HIV+ status decreasing, and HIV duration increasing, odds of Aβ. Importantly, with HIV, disease duration replaces age as an independent risk for Aβ, suggesting HIV-associated accelerated brain senescence.
Essential tremor (ET) is one of the most common movement disorders and the prototypical disorder for abnormal rhythmic movements. However, the pathophysiology of tremor generation in ET remains ...unclear. Here, we used autoptic cerebral tissue from patients with ET, clinical data, and mouse models to report that synaptic pruning deficits of climbing fiber (CF)-to-Purkinje cell (PC) synapses, which are related to glutamate receptor delta 2 (GluRδ2) protein insufficiency, cause excessive cerebellar oscillations and might be responsible for tremor. The CF-PC synaptic pruning deficits were correlated with the reduction in GluRδ2 expression in the postmortem ET cerebellum. Mice with GluRδ2 insufficiency and CF-PC synaptic pruning deficits develop ET-like tremor that can be suppressed with viral rescue of GluRδ2 protein. Step-by-step optogenetic or pharmacological inhibition of neuronal firing, axonal activity, or synaptic vesicle release confirmed that the activity of the excessive CF-to-PC synapses is required for tremor generation. In vivo electrophysiology in mice showed that excessive cerebellar oscillatory activity is CF dependent and necessary for tremor and optogenetic-driven PC synchronization was sufficient to generate tremor in wild-type animals. Human validation by cerebellar electroencephalography confirmed that excessive cerebellar oscillations also exist in patients with ET. Our findings identify a pathophysiologic contribution to tremor at molecular (GluRδ2), structural (CF-to-PC synapses), physiological (cerebellar oscillations), and behavioral levels (kinetic tremor) that might have clinical applications for treating ET.
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.
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.
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.
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.
In familial and sporadic multiple system atrophy (MSA) patients, deficiency of coenzyme Q10 (CoQ10) has been associated with mutations in COQ2, which encodes the second enzyme in the CoQ10 ...biosynthetic pathway. Cerebellar ataxia is the most common presentation of CoQ10 deficiency, suggesting that the cerebellum might be selectively vulnerable to low levels of CoQ10. To investigate whether CoQ10 deficiency represents a common feature in the brains of MSA patients independent of the presence of COQ2 mutations, we studied CoQ10 levels in postmortem brains of 12 MSA, 9 Parkinson disease (PD), 9 essential tremor (ET) patients, and 12 controls. We also assessed mitochondrial respiratory chain enzyme activities, oxidative stress, mitochondrial mass, and levels of enzymes involved in CoQ biosynthesis. Our studies revealed CoQ10 deficiency in MSA cerebellum, which was associated with impaired CoQ biosynthesis and increased oxidative stress in the absence of COQ2 mutations. The levels of CoQ10 in the cerebella of ET and PD patients were comparable or higher than in controls. These findings suggest that CoQ10 deficiency may contribute to the pathogenesis of MSA. Because no disease modifying therapies are currently available, increasing CoQ10 levels by supplementation or upregulation of its biosynthesis may represent a novel treatment strategy for MSA patients.
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