RESUMO
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.
Assuntos
Infecções por HIV , Hepatite C , Tauopatias , Humanos , Pessoa de Meia-Idade , Infecções por HIV/complicações , Infecções por HIV/patologia , Imageamento por Ressonância Magnética/métodos , Hipocampo/patologia , Tauopatias/patologia , Convulsões/patologia , Hepatite C/patologiaRESUMO
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-ß (Aß) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aß 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.
Assuntos
Proteínas de Homeodomínio/genética , Tauopatias/genética , Tauopatias/patologia , Proteínas Supressoras de Tumor/genética , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Animais , Estudos de Coortes , Drosophila , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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.
Assuntos
Coristoma/patologia , Tremor Essencial/patologia , Células de Purkinje/patologia , Ataxias Espinocerebelares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autopsia , Diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ataxias Espinocerebelares/classificaçãoRESUMO
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.
Assuntos
Encéfalo/fisiologia , Bancos de Tecidos , Doadores de Tecidos , Funerárias , Humanos , Obtenção de Tecidos e ÓrgãosRESUMO
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.
Assuntos
Cerebelo/patologia , Tremor Essencial/patologia , Idade de Início , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Estudos ProspectivosRESUMO
Familial and sporadic essential tremor (ET) cases differ in several respects. Whether they differ with respect to cerebellar pathologic changes has yet to be studied. We quantified a broad range of postmortem features (Purkinje cell (PC) counts, PC axonal torpedoes, a host of associated axonal changes, heterotopic PCs, and hairy basket ratings) in 60 ET cases and 30 controls. Familial ET was defined using both liberal criteria (n = 27) and conservative criteria (n = 20). When compared with controls, ET cases had lower PC counts, more torpedoes, more heterotopic PCs, a higher hairy basket rating, an increase in PC axonal collaterals, an increase in PC thickened axonal profiles, and an increase in PC axonal branching. Familial and sporadic ET had similar postmortem changes, with few exceptions, regardless of the definition criteria. The PC counts were marginally lower in familial than sporadic ET (respective p values = 0.059 [using liberal criteria] and 0.047 [using conservative criteria]). The PC thickened axonal profile count was marginally lower in familial ET than sporadic ET (respective p values = 0.037 [using liberal criteria] and 0.17 [using conservative criteria]), and the PC axonal branching count was marginally lower in familial than sporadic ET (respective p values = 0.045 [using liberal criteria] and 0.079 [using conservative criteria]). After correction for multiple comparisons, however, there were no significant differences. Overall, familial and sporadic ET cases share very similar cerebellar postmortem features. These data indicate that pathological changes in the cerebellum are a part of the pathophysiological cascade of events in both forms of ET.
Assuntos
Cerebelo/patologia , Tremor Essencial/patologia , Idoso de 80 Anos ou mais , Cerebelo/metabolismo , Tremor Essencial/genética , Tremor Essencial/metabolismo , Feminino , Humanos , Imuno-Histoquímica , MasculinoRESUMO
The diagnostic hallmarks of hippocampal sclerosis (HS) are severe volume loss of the hippocampus, severe neuronal loss, and reactive gliosis involving primarily two especially vulnerable fields, CA1 and the subiculum. Occasionally, HS may be the only neuropathological change detected in older individuals with dementia and is known as pure HS. In the majority of cases, HS occurs in the setting of other degenerative changes, usually Alzheimer's disease (AD). In these cases, it is classified as combined HS. Although a clinical profile for HS has been identified, its similarities with AD make the diagnosis during life quite challenging; thus, the diagnosis is often made postmortem. The pathogenesis of HS is not completely understood, but the strong association with transactive response DNA-binding protein 43 (TDP-43), in approximately 90%, and the recent discovery of genetic risk factors are important contributions to a better understanding of the disease process.
Assuntos
Hipocampo/patologia , Esclerose/patologia , Resistência a Medicamentos , Humanos , Testes Neuropsicológicos , Fatores de Risco , Esclerose/tratamento farmacológico , Esclerose/psicologiaRESUMO
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 D(2), 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 D(2), 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.
Assuntos
Doença de Alzheimer/metabolismo , Química Encefálica , Cerebelo/metabolismo , Metabolismo dos Lipídeos , Lipídeos , Doença de Alzheimer/genética , Animais , Cerebelo/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos TransgênicosRESUMO
OBJECTIVES: 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 (Aß) and hyperphosphorylated tau (p-tau) predicted cognitive performance in middle-aged PWH. METHODS: In a prospectively followed, cognitively-characterized autopsy sample of 135 PWH, we used immunohistochemistry to assess Aß 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 6.0âyears. RESULTS: In this population with mean age 51.4 ± 0.9âyears, 58% displayed neuronal p-tau and 29% Aß plaques. Neuronal p-tau, but not Aß, 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. CONCLUSION: 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.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Infecções por HIV , Pessoa de Meia-Idade , Humanos , Proteínas tau , Infecções por HIV/complicações , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Transtornos da Memória , Memória de Curto Prazo , Tomografia por Emissão de PósitronsRESUMO
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[Formula: see text]) 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[Formula: see text] plaques and neuronal p-tau, and quantitate microgliosis with markers Iba1, CD163, and CD68 in large regions of cortex. Glia in the A[Formula: see text] plaque microenvironment were quantitated by immunofluorescence (IF). The relationship of microgliosis to cognition was evaluated. No relationship between A[Formula: see text] or p-tau accumulation and overall severity of microgliosis was discerned. Individuals with uncontrolled HIV had the greatest microgliosis, but fewer A[Formula: see text] plaques; they also had higher prevalence of APOE [Formula: see text]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[Formula: see text] plaque microenvironment, APOE [Formula: see text]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[Formula: see text] plaque microenvironment, traditional risk factors of AD (APOE [Formula: see text]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[Formula: see text] deposits are established, APOE [Formula: see text]4 predicts increased plaque-associated inflammation.
Assuntos
Doença de Alzheimer , Infecções por HIV , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/metabolismo , Cognição , Lobo Frontal/metabolismo , Infecções por HIV/complicações , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Humanos , Microglia/patologia , Pessoa de Meia-Idade , Placa Amiloide/patologia , Proteínas tau/metabolismoRESUMO
OBJECTIVE: Abnormal deposition of the antimicrobial peptide amyloid beta (Aß) is a characteristic of Alzheimer's disease. The objective of this study was to elucidate risk factors for brain Aß in a cohort enriched for HIV and other neurotropic pathogens. DESIGN: Cross-sectional cohort study. METHODS: We examined autopsy brains of 257 donors with a mean age of 52.8âyears; 62% were men; and 194 were HIV+ and 63 HIV-. Hyperphosphorylated tau (p-tau) and Aß were identified in frontal and temporal regions by immunohistochemistry. APOE genotyping was performed. Clinical and neuropathological predictors for Aß were identified in univariate analyses, and then tested in multivariate regressions. RESULTS: Cortical Aß was identified in 32% of the sample, and active brain infection in 27%. Increased odds of Aß 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 Aß 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 Aß. CONCLUSION: 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 Aß. Importantly, with HIV, disease duration replaces age as an independent risk for Aß, suggesting HIV-associated accelerated brain senescence.
Assuntos
Doença de Alzheimer , Infecções por HIV , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4 , Encéfalo/metabolismo , Estudos Transversais , Feminino , Infecções por HIV/complicações , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Encéfalo/metabolismo , Tremor Essencial/metabolismo , Tauopatias/metabolismo , Proteínas tau/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Humanos , Pessoa de Meia-Idade , Paralisia Supranuclear Progressiva/metabolismoRESUMO
Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aß) 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 Aß 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.
Assuntos
Encéfalo/patologia , Transtornos Cerebrovasculares/epidemiologia , Disfunção Cognitiva/epidemiologia , Emaranhados Neurofibrilares/patologia , Tauopatias/epidemiologia , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Autopsia , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Disfunção Cognitiva/psicologia , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placa Amiloide/patologia , Estudos Retrospectivos , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/psicologia , Proteínas tau/genéticaRESUMO
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.
Assuntos
Líquido Cefalorraquidiano/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Proteína Huntingtina/metabolismo , Doença de Huntington/patologia , Chaperonas Moleculares/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Agregação Patológica de Proteínas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Linhagem Celular , Éxons/genética , Feminino , Genes Reporter/genética , Proteínas de Choque Térmico HSP40/genética , Humanos , Proteína Huntingtina/líquido cefalorraquidiano , Proteína Huntingtina/genética , Doença de Huntington/líquido cefalorraquidiano , Doença de Huntington/genética , Microscopia Intravital , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares/genética , Mutação , Proteínas do Tecido Nervoso/genética , Agregação Patológica de Proteínas/líquido cefalorraquidiano , Agregação Patológica de Proteínas/genética , Domínios Proteicos/genética , Engenharia de Proteínas , Dobramento de ProteínaRESUMO
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.
Assuntos
Cerebelo/metabolismo , Tremor/metabolismo , Tremor/patologia , Animais , Humanos , Camundongos , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Receptores de Glutamato/metabolismo , Sinapses/metabolismo , Sinapses/patologiaRESUMO
BACKGROUND: In traditional models of essential tremor, the inferior olivary nucleus was posited to play a central role as the pacemaker for the tremor. However, recent data call this disease model into question. CASE PRESENTATION: Our patient had progressive, long-standing, familial essential tremor. Upper limb tremor began at age 10 and worsened over time. It continued to worsen during the nine-year period he was enrolled in our brain donation program (age 85 - 94 years), during which time the tremor moved from the moderate to severe range on examination. On postmortem examination at age 94, there were degenerative changes in the cerebellar cortex, as have been described in the essential tremor literature. Additionally, there was marked degeneration of the inferior olivary nucleus, which was presumed to be of more recent onset. Such degeneration has not been previously described in essential tremor postmortems. Despite the presence of this degeneration, the patient's tremor not only persisted but it continued to worsen during the final decade of his life. CONCLUSIONS: Although the pathophysiology of essential tremor is not completely understood, evidence such as this suggests that the inferior olivary nucleus does not play a critical role in the generation of tremor in these patients.
RESUMO
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.
Assuntos
Ataxia/metabolismo , Cerebelo/metabolismo , Doenças Mitocondriais/metabolismo , Atrofia de Múltiplos Sistemas/metabolismo , Debilidade Muscular/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/deficiência , Idoso , Idoso de 80 Anos ou mais , Ataxia/complicações , Ataxia/patologia , Estudos de Casos e Controles , Cerebelo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/complicações , Doenças Mitocondriais/patologia , Atrofia de Múltiplos Sistemas/complicações , Atrofia de Múltiplos Sistemas/patologia , Debilidade Muscular/complicações , Debilidade Muscular/patologia , Estresse Oxidativo/fisiologia , Ubiquinona/metabolismoRESUMO
Glucose metabolism is reduced in the brains of patients with Huntington disease (HD). The mechanisms underlying this deficit, its link to the pathology of the disease, and the vulnerability of the striatum in HD remain unknown. Abnormalities in some of the key mitochondrial enzymes involved in glucose metabolism, including the pyruvate dehydrogenase complex (PDHC) and the tricarboxylic acid (TCA) cycle, may contribute to these deficits. Here, activities for these enzymes and select protein levels were measured in human postmortem cortex and in striatum and cortex of an HD mouse model (Q175); mRNA levels encoding for these enzymes were also measured in the Q175 mouse cortex. The activities of PDHC and nearly all of the TCA cycle enzymes were dramatically lower (-50% to 90%) in humans than in mice. The activity of succinate dehydrogenase increased with HD in human (35%) and mouse (23%) cortex. No other changes were detected in the human HD cortex or mouse striatum. In Q175 cortex, there were increased activities of PDHC (+12%) and aconitase (+32%). Increased mRNA levels for succinyl thiokinase (+88%) and isocitrate dehydrogenase (+64%) suggested an upregulation of the TCA cycle. These patterns of change differ from those reported in other diseases, which may offer unique metabolic therapeutic opportunities for HD patients.
Assuntos
Córtex Cerebral/enzimologia , Ciclo do Ácido Cítrico/fisiologia , Corpo Estriado/enzimologia , Doença de Huntington , Complexo Cetoglutarato Desidrogenase/metabolismo , Aciltransferases/genética , Aciltransferases/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Di-Hidrolipoamida Desidrogenase/genética , Di-Hidrolipoamida Desidrogenase/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Doença de Huntington/enzimologia , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Complexo Cetoglutarato Desidrogenase/genética , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Mutação/genética , Mudanças Depois da Morte , Complexo Piruvato Desidrogenase/genética , Complexo Piruvato Desidrogenase/metabolismo , Estudos RetrospectivosRESUMO
BACKGROUND: Cerebral deposition of phospho-tau in Alzheimer's disease (AD) occurs with varying patterns within hippocampus. Lamina-specific tau changes in AD may reflect trans-synaptic propagation of phospho-tau along neuroanatomical pathways. OBJECTIVE: To study patterns of tau deposition within inner (IML) and outer (OML) molecular layers of dentate gyrus and their clinical and neuropathological correlates. METHODS: 98 consecutive autopsied brains from the Columbia University Brain Bank were stained for phospho-tau using AT-8. Staining density was rated as High versus Low within IML and OML. Four patterns were observed among the 98 brains: High IML&OML, n = 44; High OML Only (n = 35); High IML Only (n = 5); and Low IML&OML (n = 14). Demographic, clinical, and neuropathological characteristics of these four groups were compared. RESULTS: High IML&OML subjects, versus High OML Only, were more likely to fulfill CERAD criteria for Definite AD (93% versus 66%, p < 0.01) and to have higher median Braak stage (6 versus 5, p < 0.01) and earlier mean age of onset (65.9 versus 73.7 y, p = 0.02), with similar symptom duration. Using logistic regression, the association between High IML&OML and AD remained significant after adjustment for demographics but not symptom duration. In the 70 subjects with Definite AD, High IML&OML was associated with younger age of onset (mean difference 3.7 years, 95%CI -6.7 to -0.7, p < 0.01), after adjustment for demographics and symptom duration. CONCLUSIONS: Phospho-tau pathology, when prominent within both IML and OML, is associated with CERAD diagnosis of Definite AD and earlier age of onset in AD. Laminar patterns of tau deposition reflect regional involvements during disease course.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Giro Denteado/metabolismo , Giro Denteado/patologia , Proteínas tau/metabolismo , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Huntington Disease (HD) is a neurodegenerative disorder resulting from the expansion of polyglutamine stretch in the huntingtin protein (Htt). Mutant HTT (mHtt) leads to progressive impairment of several molecular pathways that have been linked to disease pathogenesis. Defects in the production of a number of neurotrophic factors have been described as important determinants contributing to the development of HD. We have previously demonstrated that production of transforming growth factor-ß1 (TGF-ß1) is also deregulated in HD. Peripheral levels of TGF-ß1 were markedly reduced early in the disease and returned to normal levels with disease severity. However, the cause and the biochemical origin of such abnormalities are still unclear. RESULTS: We report here that the abnormal production of peripheral TGF-ß1 depends on the changes in the percentage of TGF-ß1-producing macrophages along disease course. Variation in the number of TGF-ß1-producing macrophages resulted from differential activation state of the same cells, which displayed phenotypic and functional heterogeneity throughout the clinical course of HD. We further demonstrated that, similar to the periphery, the number of TGF-ß1-immunoreactive cells in human post-mortem brain with HD, varied with neuropathological changes. CONCLUSIONS: Our data indicate that reduced bioavailability of TGF-ß1 in the serum of HD subjects is attributable to the variation of the number of TGF-ß1-producing macrophages. Macrophages display a differential ability to produce TGF-ß1, which reflects diversity in cells polarization throughout the disease course. Besides elucidating the biochemical origin of TGF-ß1 fluctuations in HD, our study highlights an interesting parallelism between periphery and central compartment and underlines the potential of TGF-ß1 as a possible indicator suitable for prediction of disease onset in HD.