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Although human cerebellum is known to be neuropathologically impaired in Alzheimer's disease (AD) and AD-related dementias (ADRD), the cell type-specific transcriptional and epigenomic changes that contribute to this pathology are not well understood. Here, we report single-nucleus multiome (snRNA-seq and snATAC-seq) analysis of 103,861 nuclei isolated from cerebellum from 9 human cases of AD/ADRD and 8 controls, and with frontal cortex of 6 AD donors for additional comparison. Using peak-to-gene linkage analysis, we identified 431,834 significant linkages between gene expression and cell subtype-specific chromatin accessibility regions enriched for candidate cis-regulatory elements (cCREs). These cCREs were associated with AD/ADRD-specific transcriptomic changes and disease-related gene regulatory networks, especially for RAR Related Orphan Receptor A (RORA) and E74 Like ETS Transcription Factor 1 (ELF1) in cerebellar Purkinje cells and granule cells, respectively. Trajectory analysis of granule cell populations further identified disease-relevant transcription factors, such as RORA, and their regulatory targets. Finally, we prioritized two likely causal genes, including Seizure Related 6 Homolog Like 2 (SEZ6L2) in Purkinje cells and KAT8 Regulatory NSL Complex Subunit 1 (KANSL1) in granule cells, through integrative analysis of cCREs derived from snATAC-seq, genome-wide AD/ADRD loci, and Hi-C looping data. This first cell subtype-specific regulatory landscape in the human cerebellum identified here offer novel genomic and epigenomic insights into the neuropathology and pathobiology of AD/ADRD and other neurological disorders if broadly applied.
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Despite numerous neuropathological criteria for the evaluation of microscopic tissue slides, there are no systemic standards for sectioning postmortem human brain tissue. Here, we present a protocol for postmortem brain hybrid structured-light scanning to facilitate 3D printing of sectioning matrices. We describe steps for tissue preparation, 3D scanning and printing, and matrix-guided sectioning. This protocol can be used for streamlining tissue histopathology as well as in brain morphology volumetric analyses and applications in medical education. For complete details on the use and execution of this protocol, please refer to Barannikov et al.1.
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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.
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Cortical synaptic loss has emerged as an early abnormality in Alzheimer's disease (AD) with a strong relationship to cognitive performance. However, the status of synapses in frontotemporal lobar degeneration (FTLD) has received meager experimental attention. The purpose of this study was to investigate changes in cortical synaptic proteins in FTLD with tar DNA binding protein-43 (TDP-43) proteinopathy. A second aim was to study phagocytosis of synaptic proteins by microglia as a surrogate for synaptic pruning. Western blot analysis in frozen tissue from the middle frontal gyrus revealed decreased levels of the presynaptic protein synaptophysin, but slightly increased levels of the postsynaptic density protein 95 (PSD95) in FTLD-TDP. Levels of the dendritic spine protein spinophilin displayed the largest decrease. Double immunofluorescent staining visualized aggregate or punctate synaptic protein immunoreactivity in microglia. Overall, the proportion of microglia containing synaptic proteins was larger in FTLD-TDP when compared with normal controls. The increase in PSD95 levels may represent reactive upregulation of this protein, as suggested in AD. While greater numbers of microglia containing synaptic proteins is consistent with loss of synapses in FTLD-TDP, it may also be an indication of abnormal synaptic pruning by microglia.
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Doença de Alzheimer , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Proteinopatias TDP-43 , Humanos , Microglia/metabolismo , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/metabolismo , Proteinopatias TDP-43/genética , Lobo Frontal/metabolismoRESUMO
In recent years, brain banks have become valuable resources for examining the molecular underpinnings of various neurological and psychological disorders including Alzheimer disease and Parkinson disease. However, the availability of brain tissue has significantly declined. Proper collection, preparation, and preservation of postmortem autopsy tissue are essential for optimal downstream brain tissue distribution and experimentation. Collaborations between brain banks through larger networks such as NeuroBioBank with centralized sample request mechanisms promote tissue distribution where brain donations are disproportionately lower. Collaborations between brain banking networks also help to standardize the brain donation and sample preparation processes, ensuring proper distribution and experimentation. Ethical brain donation and thorough processing enhances the responsible conduct of scientific studies. Education and outreach programs that foster collaboration between hospitals, nursing homes, neuropathologists, and other research scientists help to alleviate concerns among potential brain donors. Furthermore, ensuring that biorepositories accurately reflect the true demographics of communities will result in research data that reliably represent populations. Implementing these measures will grant scientists improved access to brain tissue, facilitating a deeper understanding of the neurological diseases that impact millions.
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Doenças do Sistema Nervoso , Bancos de Tecidos , Humanos , Estados Unidos , Encéfalo , Doadores de Tecidos , Europa (Continente)RESUMO
Pick's disease (PiD) is a subtype of the tauopathy form of frontotemporal lobar degeneration (FTLD-tau) characterized by intraneuronal 3R-tau inclusions. PiD can underly various dementia syndromes, including primary progressive aphasia (PPA), characterized by an isolated and progressive impairment of language and left-predominant atrophy, and behavioral variant frontotemporal dementia (bvFTD), characterized by progressive dysfunction in personality and bilateral frontotemporal atrophy. In this study, we investigated the neocortical and hippocampal distributions of Pick bodies in bvFTD and PPA to establish clinicopathologic concordance between PiD and the salience of the aphasic versus behavioral phenotype. Eighteen right-handed cases with PiD as the primary pathologic diagnosis were identified from the Northwestern University Alzheimer's Disease Research Center brain bank (bvFTD, N = 9; PPA, N = 9). Paraffin-embedded sections were stained immunohistochemically with AT8 to visualize Pick bodies, and unbiased stereological analysis was performed in up to six regions bilaterally [middle frontal gyrus (MFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), anterior temporal lobe (ATL), dentate gyrus (DG) and CA1 of the hippocampus], and unilateral occipital cortex (OCC). In bvFTD, peak neocortical densities of Pick bodies were in the MFG, while the ATL was the most affected in PPA. Both the IPL and STG had greater leftward pathology in PPA, with the latter reaching significance (p < 0.01). In bvFTD, Pick body densities were significantly right-asymmetric in the STG (p < 0.05). Hippocampal burden was not clinicopathologically concordant, as both bvFTD and PPA cases demonstrated significant hippocampal pathology compared to neocortical densities (p < 0.0001). Inclusion-to-neuron analyses in a subset of PPA cases confirmed that neurons in the DG are disproportionately burdened with inclusions compared to neocortical areas. Overall, stereological quantitation suggests that the distribution of neocortical Pick body pathology is concordant with salient clinical features unique to PPA vs. bvFTD while raising intriguing questions about the selective vulnerability of the hippocampus to 3R-tauopathies.
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Doença de Alzheimer , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Doença de Pick , Tauopatias , Humanos , Doença de Pick/patologia , Demência Frontotemporal/patologia , Doença de Alzheimer/patologia , Encéfalo/patologia , Degeneração Lobar Frontotemporal/patologia , Atrofia/patologia , Tauopatias/patologiaRESUMO
OBJECTIVE: Age-related dementia syndromes are often not related to a single pathophysiological process, leading to multiple neuropathologies found at autopsy. An amnestic dementia syndrome can be associated with Alzheimer's disease (AD) with comorbid transactive response DNA-binding protein 43 (TDP-43) pathology (AD/TDP). Here, we investigated neuronal integrity and pathological burden of TDP-43 and tau, along the well-charted trisynaptic hippocampal circuit (dentate gyrus [DG], CA3, and CA1) in participants with amnestic dementia due to AD/TDP, amnestic dementia due to AD alone, or non-amnestic dementia due to TDP-43 proteinopathy associated with frontotemporal lobar degeneration (FTLD-TDP). METHODS: A total of 48 extensively characterized cases (14 AD, 16 AD/TDP, 18 FTLD-TDP) were analyzed using digital HALO software (Indica Labs, Albuquerque, NM, USA) to quantify pathological burden and neuronal loss. RESULTS: In AD/TDP and FTLD-TDP, TDP-43 immunoreactivity was greatest in the DG. Tau immunoreactivity was significantly greater in DG and CA3 in AD/TDP compared with pure AD. All clinical groups showed the highest amounts of neurons in DG, followed by CA3, then CA1. The AD and AD/TDP groups showed lower neuronal counts compared with the FTLD-TDP group across all hippocampal subregions consistent with the salience of the amnestic phenotype. INTERPRETATION: We conclude that AD/TDP can be distinguished from AD and FTLD-TDP based on differential regional distributions of hippocampal tau and TDP-43. Findings suggest that tau aggregation in AD/TDP might be enhanced by TDP-43. ANN NEUROL 2023;94:1036-1047.
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Doença de Alzheimer , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Humanos , Doença de Alzheimer/patologia , Demência Frontotemporal/patologia , Degeneração Lobar Frontotemporal/patologia , Hipocampo/patologia , Proteínas de Ligação a DNA/metabolismo , Proteínas tau/metabolismoRESUMO
BACKGROUND: Decedents with late-life dementia are often found at autopsy to have vascular pathology, cortical Lewy bodies, hippocampal sclerosis, and/or TDP-43 encephalopathy alone or with concurrent Alzheimer's disease (AD) lesions. Nonetheless, it is commonly believed that AD neuropathologic changes (NC) are the dominant or exclusive drivers of late-life dementia. OBJECTIVE: Assess associations of end-of-life cognitive impairment with any one or any combination of five distinct NC. Assess impairment prevalence among subjects having natural resistance to each type of NC. METHODS: Brains from 1,040 autopsied participants of the Honolulu-Asia Study, the Nun Study, and the 90â+âStudy were examined for NC of AD, Lewy body dementia, microvascular brain injury, hippocampal sclerosis, and limbic predominate TDP-43 encephalopathy. Associations with impairment were assessed for each NC and for NC polymorbidity (variable combinations of 2-5 concurrent NC). RESULTS: Among 387 autopsied decedents with severe cognitive impairment, 20.4% had only AD lesions (ADNC), 25.3% had ADNC plus 1 other NC, 11.1% had ADNC plus 2 or more other NC, 28.7% had no ADNC but 1-4 other NC, and 14.5% had no/negligible NC. Combinations of any two, three, or four NC were highly frequent among the impaired. Natural resistance to ADNC or any other single NC had a modest impact on overall cohort impairment levels. CONCLUSION: Polymorbidity involving 1-5 types of concurrent NC is a dominant neuropathologic feature of AD and related dementias. This represents a daunting challenge to future prevention and could explain failures of prior preventive intervention trials and of efforts to identify risk factors.
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Doença de Alzheimer , Disfunção Cognitiva , Doença por Corpos de Lewy , Humanos , Doença de Alzheimer/patologia , Encéfalo/patologia , Disfunção Cognitiva/patologia , Doença por Corpos de Lewy/patologia , Proteínas de Ligação a DNARESUMO
The anatomical distribution of most neurodegenerative diseases shows considerable interindividual variations. In contrast, frontotemporal lobar degeneration with transactive response DNA-binding protein type C (TDP-C) shows a consistent predilection for the anterior temporal lobe (ATL). The relatively selective atrophy of ATL in TDP-C patients has highlighted the importance of this region for complex cognitive and behavioral functions. This review includes observations on 28 TDP-C patients, 18 with semantic primary progressive aphasia and 10 with other syndromes. Longitudinal imaging allowed the delineation of progression trajectories. At post-mortem examination, the pathognomonic feature of TDP-C consisted of long, thick neurites found predominantly in superficial cortical layers. These neurites may represent dystrophic apical dendrites of layer III and V pyramidal neurons that are known to play pivotal roles in complex cortical computations. Other types of frontotemporal lobar degeneration TDP, such as TDP-A and TDP-B, are not associated with long dystrophic neurites in the cerebral cortex, and do not show similar predilection patterns for ATL. Research is beginning to identify molecular, structural, and immunological differences between pathological TDP-43 in TDP-C versus TDP-A and B. Parallel investigations based on proteomics, somatic mutations, and genome-wide association studies are detecting molecular features that could conceivably mediate the selective vulnerability of ATL to TDP-C. Future work will focus on characterizing the distinctive features of the abnormal TDP-C neurites, the mechanisms of neurotoxicity, initial cellular targets within the ATL, trajectory of spread, and the nature of ATL-specific markers that modulate vulnerability to TDP-C. ANN NEUROL 2023;94:1-12.
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Demência Frontotemporal , Degeneração Lobar Frontotemporal , Humanos , Estudo de Associação Genômica Ampla , Encéfalo/patologia , Demência Frontotemporal/metabolismo , Lobo Temporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Atrofia/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismoRESUMO
Host responses to anti-amyloid-ß (Aß) antibody therapy are evident in neuroimaging changes and clinical symptoms in a subset of clinical trial subjects receiving such therapy. The pathological basis for the imaging changes and clinical symptoms is not known, nor is the precise mechanism of Aß clearing. We report the autopsy findings in a 65-year-old woman who received three open label infusions of the experimental anti-Aß drug lecanemab over about one month. Four days after the last infusion, she was treated with tissue plasminogen activator for acute stroke symptoms and died several days later with multifocal hemorrhage. Neuropathological examination demonstrated histiocytic vasculitis involving blood vessels with cerebral amyloid angiopathy. Fragmentation and phagocytosis of vascular Aß were present throughout the cerebral cortex. Phagocytosis of parenchymal Aß plaques was noted. Changes suggestive of Aß and phosphorylated tau "clearing" were also noted. The findings overall suggest that anti-Aß treatment stimulated a host response to Aß, i.e., target engagement. The findings also provide evidence that amyloid-related imaging abnormalities might be indicative of an Aß phagocytic syndrome within cerebral vasculature and parenchymal brain tissue in some cases.
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Doença de Alzheimer , Angiopatia Amiloide Cerebral , Feminino , Humanos , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/terapia , Ativador de Plasminogênio Tecidual , Peptídeos beta-Amiloides/metabolismo , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Angiopatia Amiloide Cerebral/terapia , Angiopatia Amiloide Cerebral/etiologia , Encéfalo/patologia , Imunoterapia/efeitos adversosRESUMO
INTRODUCTION: European local ancestry (ELA) surrounding apolipoprotein E (APOE) ε4 confers higher risk for Alzheimer's disease (AD) compared to African local ancestry (ALA). We demonstrated significantly higher APOE ε4 expression in ELA versus ALA in AD brains from APOE ε4/ε4 carriers. Chromatin accessibility differences could contribute to these expression changes. METHODS: We performed single nuclei assays for transposase accessible chromatin sequencing from the frontal cortex of six ALA and six ELA AD brains, homozygous for local ancestry and APOE ε4. RESULTS: Our results showed an increased chromatin accessibility at the APOE ε4 promoter area in ELA versus ALA astrocytes. This increased accessibility in ELA astrocytes extended genome wide. Genes with increased accessibility in ELA in astrocytes were enriched for synapsis, cholesterol processing, and astrocyte reactivity. DISCUSSION: Our results suggest that increased chromatin accessibility of APOE ε4 in ELA astrocytes contributes to the observed elevated APOE ε4 expression, corresponding to the increased AD risk in ELA versus ALA APOE ε4/ε4 carriers.
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Doença de Alzheimer , Apolipoproteína E4 , Humanos , Apolipoproteína E4/genética , Doença de Alzheimer/genética , Doença de Alzheimer/complicações , Cromatina , Heterozigoto , Expressão GênicaRESUMO
Octopamine is a well-established invertebrate neurotransmitter involved in fight or flight responses. In mammals, its function was replaced by epinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here, through a multidisciplinary approach utilizing in vitro and in vivo models of α-synucleinopathy, we uncovered an unprecedented role for octopamine in driving the conversion from toxic to neuroprotective astrocytes in the cerebral cortex by fostering aerobic glycolysis. Physiological levels of neuron-derived octopamine act on astrocytes via a trace amine-associated receptor 1-Orai1-Ca2+-calcineurin-mediated signaling pathway to stimulate lactate secretion. Lactate uptake in neurons via the monocarboxylase transporter 2-calcineurin-dependent pathway increases ATP and prevents neurodegeneration. Pathological increases of octopamine caused by α-synuclein halt lactate production in astrocytes and short-circuits the metabolic communication to neurons. Our work provides a unique function of octopamine as a modulator of astrocyte metabolism and subsequent neuroprotection with implications to α-synucleinopathies.
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Octopamina , alfa-Sinucleína , Animais , alfa-Sinucleína/metabolismo , Astrócitos/metabolismo , Calcineurina/metabolismo , Lactatos/metabolismo , Mamíferos/metabolismo , Neuroproteção , Neurotransmissores/metabolismo , Octopamina/metabolismoRESUMO
BACKGROUND: Phosphorylated cytoplasmic tau inclusions correlate with and precede cognitive deficits in Alzheimer's disease (AD). However, pathological tau accumulation and relationships to synaptic changes remain unclear. OBJECTIVE: To address this, we examined postmortem brain from 50 individuals with the full spectrum of AD (clinically and neuropathologically). Total tau, pTau231, and AMPA GluR1 were compared across two brain regions (entorhinal and middle frontal cortices), as well as clinically stratified groups (control, amnestic mild cognitive impairment, AD dementia), NIA-AA Alzheimer's Disease Neuropathologic Change designations (Not, Low, Intermediate, High), and Braak tangle stages (1-6). Significant co-existing pathology was excluded to isolate changes attributed to pathologic AD. METHODS: Synaptosomal fractionation and staining were performed to measure changes in total Tau, pTau231, and AMPA GluR1. Total Tau and pTau231 were quantified in synaptosomal fractions using Quanterix Simoa HD-X. RESULTS: Increasing pTau231 in frontal postsynaptic fractions correlated positively with increasing clinical and neuropathological AD severity. Frontal cortex is representative of early AD, as it does not become involved by tau tangles until late in AD. Entorhinal total tau was significantly higher in the amnestic mild cognitive impairment group when compared to AD, but only after accounting for AD associated synaptic changes. Alterations in AMPA GluR1 observed in the entorhinal cortex, but not middle frontal cortex, suggest that pTau231 mislocalization and aggregation in postsynaptic structures may impair glutamatergic signaling by promoting AMPA receptor dephosphorylation and internalization. CONCLUSION: Results highlight the potential effectiveness of early pharmacological interventions targeting pTau231 accumulation at the postsynaptic density.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/patologia , Proteínas tau/metabolismo , Densidade Pós-Sináptica/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico , Encéfalo/patologia , Disfunção Cognitiva/patologiaAssuntos
Anticorpos Monoclonais Humanizados , Hemorragia Cerebral , Fibrinolíticos , Acidente Vascular Cerebral , Ativador de Plasminogênio Tecidual , Humanos , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/tratamento farmacológico , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/diagnóstico por imagem , Fibrinolíticos/efeitos adversos , Fibrinolíticos/uso terapêutico , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/diagnóstico por imagem , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/efeitos adversos , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do Tratamento , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
Digital pathology (DP) has transformative potential, especially for Alzheimer disease and related disorders. However, infrastructure barriers may limit adoption. To provide benchmarks and insights into implementation barriers, a survey was conducted in 2019 within National Institutes of Health's Alzheimer's Disease Centers (ADCs). Questions covered infrastructure, funding sources, and data management related to digital pathology. Of the 35 ADCs to which the survey was sent, 33 responded. Most respondents (81%) stated that their ADC had digital slide scanner access, with the most frequent brand being Aperio/Leica (62.9%). Approximately a third of respondents stated there were fees to utilize the scanner. For DP and machine learning (ML) resources, 41% of respondents stated none was supported by their ADC. For scanner purchasing and operations, 50% of respondents stated they received institutional support. Some were unsure of the file size of scanned digital images (37%) and total amount of storage space files occupied (50%). Most (76%) were aware of other departments at their institution working with ML; a similar (76%) percentage were unaware of multiuniversity or industry partnerships. These results demonstrate many ADCs have access to a digital slide scanner; additional investigations are needed to further understand hurdles to implement DP and ML workflows.
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Doença de Alzheimer , Humanos , Fluxo de Trabalho , Aprendizado de Máquina , Inquéritos e QuestionáriosRESUMO
The dentate gyrus (DG), a key hippocampal subregion in memory processing, generally resists phosphorylated tau accumulation in the amnestic dementia of the Alzheimer's type due to Alzheimer's disease (DAT-AD), but less is known about the susceptibility of the DG to other tauopathies. Here, we report stereologic densities of total DG neurons and tau inclusions in thirty-two brains of human participants with autopsy-confirmed tauopathies with distinct isoform profiles-3R Pick's disease (PiD, N = 8), 4R corticobasal degeneration (CBD, N = 8), 4R progressive supranuclear palsy (PSP, N = 8), and 3/4R AD (N = 8). All participants were diagnosed during life with primary progressive aphasia (PPA), an aphasic clinical dementia syndrome characterized by progressive deterioration of language abilities with spared non-language cognitive abilities in early stages, except for five patients with DAT-AD as a comparison group. 51% of total participants were female. All specimens were stained immunohistochemically with AT8 to visualize tau pathology, and PPA cases were stained for Nissl substance to visualize neurons. Unbiased stereological analysis was performed in granule and hilar DG cells, and inclusion-to-neuron ratios were calculated. In the PPA group, PiD had highest mean total (granule + hilar) densities of DG tau pathology (p < 0.001), followed by CBD, AD, then PSP. PPA-AD cases showed more inclusions in hilar cells compared to granule cells, while the opposite was true in PiD and CBD. Inclusion-to-neuron ratios revealed, on average, 33% of all DG neurons in PiD cases contained a tau inclusion, compared to ~ 7% in CBD, 2% in AD, and 0.4% in PSP. There was no significant difference between DAT-AD and PPA-AD pathologic tau burden, suggesting that differences in DG burden are not specific to clinical phenotype. We conclude that the DG is differentially vulnerable to pathologic tau accumulation, raising intriguing questions about the structural integrity and functional significance of hippocampal circuits in neurodegenerative dementias.
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Doença de Alzheimer , Degeneração Corticobasal , Paralisia Supranuclear Progressiva , Tauopatias , Humanos , Feminino , Masculino , Proteínas tau/metabolismo , Tauopatias/patologia , Doença de Alzheimer/patologia , Paralisia Supranuclear Progressiva/patologia , Giro Denteado/metabolismoRESUMO
Concerns about the costs associated with autopsy assessment of Alzheimer disease and related dementias according to 2012 NIA-AA Guidelines have been expressed since the publication of those guidelines. For this reason, we designed and validated a Condensed Protocol for the neuropathologic diagnoses of Alzheimer disease neuropathologic change, Lewy Body disease neuropathologic change, as well as chronic microvascular lesions, hippocampal sclerosis of aging, and cerebral amyloid angiopathy. In this study, the Condensed Protocol is updated to include frontotemporal lobar degeneration [FTLD] tau (corticobasal degeneration, progressive supranuclear palsy, and Pick disease), FTLD-TDP, and limbic-predominant, age-related TDP-43 encephalopathy. The same 20 brain regions are sampled and processed in 5 tissue cassettes, which reduces reagent costs by approximately 65%. Three board-certified neuropathologists were blinded to the original Northwestern University Alzheimer's Disease Research Center Original Protocol neuropathological diagnoses and all clinical history information. The results yielded near uniform agreement with the original comprehensive Alzheimer's Disease Research Center neuropathologic assessments. Diagnostic sensitivity was not impacted. In summary, our recent results show that our updated Condensed Protocol is also an accurate and less expensive alternative to the comprehensive protocols for the additional neuropathologic diagnoses of FTLD Tau and TDP43 proteinopathies.
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Doença de Alzheimer , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Doença de Pick , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Neuropatologia , Degeneração Lobar Frontotemporal/patologia , Doença de Pick/patologia , Proteínas tauRESUMO
An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.
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Doença de Alzheimer , Esclerose Lateral Amiotrófica , Demência Frontotemporal , Humanos , Doença de Alzheimer/patologia , Demência Frontotemporal/patologia , Esclerose Lateral Amiotrófica/patologia , Proteínas de Ligação a DNA/genéticaRESUMO
Translating human genetic findings (genome-wide association studies [GWAS]) to pathobiology and therapeutic discovery remains a major challenge for Alzheimer's disease (AD). We present a network topology-based deep learning framework to identify disease-associated genes (NETTAG). We leverage non-coding GWAS loci effects on quantitative trait loci, enhancers and CpG islands, promoter regions, open chromatin, and promoter flanking regions under the protein-protein interactome. Via NETTAG, we identified 156 AD-risk genes enriched in druggable targets. Combining network-based prediction and retrospective case-control observations with 10 million individuals, we identified that usage of four drugs (ibuprofen, gemfibrozil, cholecalciferol, and ceftriaxone) is associated with reduced likelihood of AD incidence. Gemfibrozil (an approved lipid regulator) is significantly associated with 43% reduced risk of AD compared with simvastatin using an active-comparator design (95% confidence interval 0.51-0.63, p < 0.0001). In summary, NETTAG offers a deep learning methodology that utilizes GWAS and multi-genomic findings to identify pathobiology and drug repurposing in AD.