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Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) share many clinical, pathological, and genetic features, but a detailed understanding of their associated transcriptional alterations across vulnerable cortical cell types is lacking. Here, we report a high-resolution, comparative single-cell molecular atlas of the human primary motor and dorsolateral prefrontal cortices and their transcriptional alterations in sporadic and familial ALS and FTLD. By integrating transcriptional and genetic information, we identify known and previously unidentified vulnerable populations in cortical layer 5 and show that ALS- and FTLD-implicated motor and spindle neurons possess a virtually indistinguishable molecular identity. We implicate potential disease mechanisms affecting these cell types as well as non-neuronal drivers of pathogenesis. Finally, we show that neuron loss in cortical layer 5 tracks more closely with transcriptional identity rather than cellular morphology and extends beyond previously reported vulnerable cell types.
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Esclerose Lateral Amiotrófica , Degeneração Lobar Frontotemporal , Córtex Pré-Frontal , Animais , Humanos , Camundongos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Demência Frontotemporal/genética , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Perfilação da Expressão Gênica , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Análise da Expressão Gênica de Célula ÚnicaRESUMO
The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N6-methyladenosine (m6A) modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m6A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m6A and the m6A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice. These results reveal a complex containing oTau, HNRNPA2B1, and m6A that contributes to the integrated stress response of oTau.
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Adenosina/análogos & derivados , Doença de Alzheimer/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Processamento Pós-Transcricional do RNA , RNA/metabolismo , Proteínas tau/metabolismo , Adenosina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Estudos de Casos e Controles , Modelos Animais de Doenças , Progressão da Doença , Feminino , Células HEK293 , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Humanos , Masculino , Metilação , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Agregados Proteicos , Agregação Patológica de Proteínas , RNA/genética , Índice de Gravidade de Doença , Proteínas tau/genéticaRESUMO
Given the prevalence of dementia and the development of pathology-specific disease-modifying therapies, high-value biomarker strategies to inform medical decision-making are critical. In vivo tau-PET is an ideal target as a biomarker for Alzheimer's disease diagnosis and treatment outcome measure. However, tau-PET is not currently widely accessible to patients compared to other neuroimaging methods. In this study, we present a convolutional neural network (CNN) model that imputes tau-PET images from more widely available cross-modality imaging inputs. Participants (n = 1192) with brain T1-weighted MRI (T1w), fluorodeoxyglucose (FDG)-PET, amyloid-PET and tau-PET were included. We found that a CNN model can impute tau-PET images with high accuracy, the highest being for the FDG-based model followed by amyloid-PET and T1w. In testing implications of artificial intelligence-imputed tau-PET, only the FDG-based model showed a significant improvement of performance in classifying tau positivity and diagnostic groups compared to the original input data, suggesting that application of the model could enhance the utility of the metabolic images. The interpretability experiment revealed that the FDG- and T1w-based models utilized the non-local input from physically remote regions of interest to estimate the tau-PET, but this was not the case for the Pittsburgh compound B-based model. This implies that the model can learn the distinct biological relationship between FDG-PET, T1w and tau-PET from the relationship between amyloid-PET and tau-PET. Our study suggests that extending neuroimaging's use with artificial intelligence to predict protein specific pathologies has great potential to inform emerging care models.
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Inteligência Artificial , Aprendizado Profundo , Neuroimagem , Tauopatias , Humanos , Proteínas Amiloidogênicas , Biomarcadores , Fluordesoxiglucose F18 , Neuroimagem/métodos , Tauopatias/diagnóstico por imagemRESUMO
Rare and common GBA variants are risk factors for both Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the degree to which GBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rare GBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen, ventrolateral substantia nigra neuronal loss, Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, phospho-ubiquitin (pS65-Ub) level, TDP-43 pathology, and vascular disease. Sequencing of GBA exons revealed a total of 42 different variants (4 common [MAF > 0.5%], 38 rare [MAF < 0.5%]) in our series, and 165 cases (17.5%) had a copy of the minor allele for ≥ 1 variant. In analysis of common variants, p.L483P was associated with a lower Braak NFT stage (OR = 0.10, P < 0.001). In gene-burden analysis, presence of the minor allele for any GBA variant was associated with increased odds of a high likelihood of DLB (OR = 2.00, P < 0.001), a lower Braak NFT stage (OR = 0.48, P < 0.001), a lower Thal amyloid phase (OR = 0.55, P < 0.001), and a lower pS65-Ub level (ß: -0.37, P < 0.001). Subgroup analysis revealed that GBA variants were most common in LBD cases with a combination of transitional/diffuse LBD and Braak NFT stage 0-II or Thal amyloid phase 0-1, and correspondingly that the aforementioned associations of GBA gene-burden with a decreased Braak NFT stage and Thal amyloid phase were observed only in transitional or diffuse LBD cases. Our results indicate that in LBD, GBA variants occur most frequently in cases with greater LB pathology and low AD pathology, further informing disease-risk associations of GBA in PD, PD dementia, and DLB.
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Doença de Alzheimer , Doença por Corpos de Lewy , Doença de Parkinson , Humanos , Doença por Corpos de Lewy/patologia , Doença de Parkinson/patologia , Doença de Alzheimer/patologia , Substância Negra/patologia , Emaranhados Neurofibrilares/patologiaRESUMO
BACKGROUND: Primary progressive aphasia (PPA) defines a group of neurodegenerative disorders characterised by language decline. Three PPA variants correlate with distinct underlying pathologies: semantic variant PPA (svPPA) with transactive response DNA-binding protein of 43 kD (TDP-43) proteinopathy, agrammatic variant PPA (agPPA) with tau deposition and logopenic variant PPA (lvPPA) with Alzheimer's disease (AD). Our objectives were to differentiate PPA variants using clinical and neuroimaging features, assess progression and evaluate structural MRI and a novel 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) image decomposition machine learning algorithm for neuropathology prediction. METHODS: We analysed 82 autopsied patients diagnosed with PPA from 1998 to 2022. Clinical histories, language characteristics, neuropsychological results and brain imaging were reviewed. A machine learning framework using a k-nearest neighbours classifier assessed FDG-PET scans from 45 patients compared with a large reference database. RESULTS: PPA variant distribution: 35 lvPPA (80% AD), 28 agPPA (89% tauopathy) and 18 svPPA (72% frontotemporal lobar degeneration-TAR DNA-binding protein (FTLD-TDP)). Apraxia of speech was associated with 4R-tauopathy in agPPA, while pure agrammatic PPA without apraxia was linked to 3R-tauopathy. Longitudinal data revealed language dysfunction remained the predominant deficit for patients with lvPPA, agPPA evolved to corticobasal or progressive supranuclear palsy syndrome (64%) and svPPA progressed to behavioural variant frontotemporal dementia (44%). agPPA-4R-tauopathy exhibited limited pre-supplementary motor area atrophy, lvPPA-AD displayed temporal atrophy extending to the superior temporal sulcus and svPPA-FTLD-TDP had severe temporal pole atrophy. The FDG-PET-based machine learning algorithm accurately predicted clinical diagnoses and underlying pathologies. CONCLUSIONS: Distinguishing 3R-taupathy and 4R-tauopathy in agPPA may rely on apraxia of speech presence. Additional linguistic and clinical features can aid neuropathology prediction. Our data-driven brain metabolism decomposition approach effectively predicts underlying neuropathology.
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PURPOSE: PreOperative radiotherapy (RT) is commonly used in the treatment of brain metastasis and different cancer types but has never been used in primary glioblastoma (GBM). Here, we aim to establish, describe, and validate the use of PreOperative RT for the treatment of GBM in a preclinical model. METHODS: Rat brains were locally irradiated with 30-Gy, hypofractionated in five doses 2 weeks before or after the resection of intracranial GBM. Kaplan-Meier analysis determined survival. Hematoxylin-eosin staining was performed, and nuclei size and p21 senescence marker were measured in both resected and recurrent rodent tumors. Immunohistochemistry assessed microglia/macrophage markers, and RNAseq analyzed gene expression changes in recurrent tumors. Akoya Multiplex Staining on two human patients from our ongoing Phase I/IIa trial served as proof of principle. RESULTS: PreOperative RT group median survival was significantly higher than PostOperative RT (p < 0.05). Radiation enlarged cytoplasm and nuclei in PreOperative RT resected tumors (p < 0.001) and induced senescence in PostOperative RT recurrent tumors (p < 0.05). Gene Set Enrichment Analysis (GSEA) suggested a more proliferative profile in PreOperative RT group. PreOperative RT showed lower macrophage/microglia recruitment in recurrent tumors (p < 0.01) compared to PostOperative RT. Akoya Multiplex results indicated TGF-ß accumulation in the cytoplasm of TAMs and CD4 + lymphocyte predominance in PostOperative group. CONCLUSIONS: This is the first preclinical study showing feasibility and longer overall survival using neoadjuvant radiotherapy before GBM resection in a mammalian model. This suggests strong superiority for new clinical radiation strategies. Further studies and trials are required to confirm our results.
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OBJECTIVE: To determine whether poorer performance on the Boston Naming Test (BNT) in individuals with transactive response DNA-binding protein 43 pathology (TDP-43+) is due to greater loss of word knowledge compared to retrieval-based deficits. METHODS: Retrospective clinical-pathologic study of 282 participants with Alzheimer's disease neuropathologic changes (ADNC) and known TDP-43 status. We evaluated item-level performance on the 60-item BNT for first and last available assessment. We fit cross-sectional negative binomial count models that assessed total number of incorrect items, number correct of responses with phonemic cue (reflecting retrieval difficulties), and number of "I don't know" (IDK) responses (suggestive of loss of word knowledge) at both assessments. Models included TDP-43 status and adjusted for sex, age, education, years from test to death, and ADNC severity. Models that evaluated the last assessment adjusted for number of prior BNT exposures. RESULTS: 43% were TDP-43+. The TDP-43+ group had worse performance on BNT total score at first (p = .01) and last assessments (p = .01). At first assessment, TDP-43+ individuals had an estimated 29% (CI: 7%-56%) higher mean number of incorrect items after adjusting for covariates, and a 51% (CI: 15%-98%) higher number of IDK responses compared to TDP-43-. At last assessment, compared to TDP-43-, the TDP-43+ group on average missed 31% (CI: 6%-62%; p = .01) more items and had 33% more IDK responses (CI: 1% fewer to 78% more; p = .06). CONCLUSIONS: An important component of poorer performance on the BNT in participants who are TDP-43+ is having loss of word knowledge versus retrieval difficulties.
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While plasma biomarkers for Alzheimer's disease (AD) are increasingly being evaluated for clinical diagnosis and prognosis, few population-based autopsy studies have evaluated their utility in the context of predicting neuropathological changes. Our goal was to investigate the utility of clinically available plasma markers in predicting Braak staging, neuritic plaque score, Thal phase, and overall AD neuropathological change (ADNC).We utilized a population-based prospective study of 350 participants with autopsy and antemortem plasma biomarker testing using clinically available antibody assay (Quanterix) consisting of Aß42/40 ratio, p-tau181, GFAP, and NfL. We utilized a variable selection procedure in cross-validated (CV) logistic regression models to identify the best set of plasma predictors along with demographic variables, and a subset of neuropsychological tests comprising the Mayo Clinic Preclinical Alzheimer Cognitive Composite (Mayo-PACC). ADNC was best predicted with plasma GFAP, NfL, p-tau181 biomarkers along with APOE ε4 carrier status and Mayo-PACC cognitive score (CV AUC = 0.798). Braak staging was best predicted using plasma GFAP, p-tau181, and cognitive scores (CV AUC = 0.774). Neuritic plaque score was best predicted using plasma Aß42/40 ratio, p-tau181, GFAP, and NfL biomarkers (CV AUC = 0.770). Thal phase was best predicted using GFAP, NfL, p-tau181, APOE ε4 carrier status and Mayo-PACC cognitive score (CV AUC = 0.754). We found that GFAP and p-tau provided non-overlapping information on both neuritic plaque and Braak stage scores whereas Aß42/40 and NfL were mainly useful for prediction of neuritic plaque scores. Separating participants by cognitive status improved predictive performance, particularly when plasma biomarkers were included. Plasma biomarkers can differentially inform about overall ADNC pathology, Braak staging, and neuritic plaque score when combined with demographics and cognitive variables and have significant utility for earlier detection of AD.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Placa Amiloide/patologia , Estudos Prospectivos , Apolipoproteína E4 , Biomarcadores , Proteínas tau , Peptídeos beta-AmiloidesRESUMO
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
Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a complex heterogeneous neurodegenerative disorder for which mechanisms are poorly understood. To explore transcriptional changes underlying FTLD-TDP, we performed RNA-sequencing on 66 genetically unexplained FTLD-TDP patients, 24 FTLD-TDP patients with GRN mutations and 24 control participants. Using principal component analysis, hierarchical clustering, differential expression and coexpression network analyses, we showed that GRN mutation carriers and FTLD-TDP-A patients without a known mutation shared a common transcriptional signature that is independent of GRN loss-of-function. After combining both groups, differential expression as compared to the control group and coexpression analyses revealed alteration of processes related to immune response, synaptic transmission, RNA metabolism, angiogenesis and vesicle-mediated transport. Deconvolution of the data highlighted strong cellular alterations that were similar in FTLD-TDP-A and GRN mutation carriers with NSF as a potentially important player in both groups. We propose several potentially druggable pathways such as the GABAergic, GDNF and sphingolipid pathways. Our findings underline new disease mechanisms and strongly suggest that affected pathways in GRN mutation carriers extend beyond GRN and contribute to genetically unexplained forms of FTLD-TDP-A.
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Demência Frontotemporal , Degeneração Lobar Frontotemporal , Progranulinas , Encéfalo/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mutação , Progranulinas/genética , Progranulinas/metabolismo , TranscriptomaRESUMO
BACKGROUND: Neuropathologically, Alzheimer's disease (AD) is characterized by the presence of senile plaques composed of beta-amyloid (Aß) and neurofibrillary tangles made of hyperphosphorylated tau. Aß and p-tau have been shown to impact endoplasmic reticulum homeostasis, DNA damage response and autophagic functions. Intriguingly, alterations in these systems have also been connected to dysfunctions in UFMylation, a ubiquitin-like posttranslational modification. Analogous to ubiquitin, UFM1, is conjugated to substrates via a catalytic cascade involving UFM1-specific set of E1 (UBA5), E2 (UFC1), and a complex that consists of E3 ligase (UFL1), DDRGK1 and CDK5RAP3. UFMylation is reversible, and this is mediated by UFSP2. The UFMylation pathway is essential for brain development as complete loss of function of any of its components result in severe neurodevelopmental disorders. However, alterations in UFMylation and their role in and significance for age-related AD remains unknown. METHOD: We performed Western blot and Meso Scale Discovery based ELISA to measure the protein level of UFM1, UFSP2, tau, p-tau and other UFMylation pathway components in human post-mortem brain. Analyses were performed with RIPA- and 2% SDS-soluble fraction from frontal cortex. To validate our finding in human tissues, we knocked out UFM1 and UFSP2 in ReN cells, a neural progenitor cell model that has already been used to study AD and that can be terminally differentiated in neurons. RESULT: We found a significant reduction of RIPA UFSP2, but an increase of RIPA and SDS UFM1 in AD compared to controls. Strikingly, RIPA UFSP2 had a strong negative correlation with both RIPA and SDS UFM1. Furthermore. UFM1 was significantly increased in UFSP2-KO neurons compared to WT, mirroring the negative correlation between UFM1 and UFSP2 observed in human brain. In addition, RIPA and SDS UFM1 had a strong positive correlation with p-tau, indicating that dysfunctional UFMylation might play an important role for disease pathogenesis. CONCLUSION: Reduction of RIPA soluble UFSP2 in human AD frontal cortex might result in the abnormal accumulation of UFM1 and this might further facilitate the AD pathogenesis. Because of its role for several central AD-relevant pathways, the UFMylation pathway might be a potential therapeutic target for AD.
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Doença de Alzheimer , Proteínas tau , Humanos , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Proteínas tau/metabolismo , Encéfalo/patologia , Encéfalo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Masculino , Animais , Enzimas Ativadoras de Ubiquitina/metabolismo , Enzimas Ativadoras de Ubiquitina/genética , Neurônios/metabolismo , Neurônios/patologia , ProteínasRESUMO
INTRODUCTION: We aimed to describe baseline amyloid-beta (Aß) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD). METHODS: We analyzed baseline [18F]Florbetaben (Aß) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aß+) from EOnonAD (Aß-) based on the combination of visual read by expert reader and image quantification. RESULTS: 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants. DISCUSSION: LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD. HIGHLIGHTS: 72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Feminino , Doença de Alzheimer/metabolismo , Elétrons , Estudos Prospectivos , Proteínas tau/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Amiloide/metabolismo , BiomarcadoresRESUMO
INTRODUCTION: Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS: We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS: The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. DISCUSSION: The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. HIGHLIGHTS: We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Reprodutibilidade dos Testes , Lobo Temporal/patologia , Imageamento por Ressonância Magnética/métodos , Atrofia/patologia , BiomarcadoresRESUMO
INTRODUCTION: One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants. METHODS: LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study. RESULTS: Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases. DISCUSSION: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases. HIGHLIGHTS: Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Proteína C9orf72/genética , Testes Genéticos , Estudos Longitudinais , Mutação , Presenilina-1/genética , Presenilina-2/genéticaRESUMO
INTRODUCTION: We used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD). METHODS: We included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden. RESULTS: EOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non-carriers also had greater gray matter atrophy than female ε4 carriers. DISCUSSION: The effects of sex and APOE ε4 must be considered when studying these populations. HIGHLIGHTS: Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE ε4) carrier status on neuroimaging biomarkers among early-onset Alzheimer's disease (EOAD), early-onset non-AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.
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Doença de Alzheimer , Humanos , Masculino , Feminino , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Neuroimagem , Biomarcadores , Proteínas Amiloidogênicas , Atrofia , Peptídeos beta-AmiloidesRESUMO
INTRODUCTION: We compared white matter hyperintensities (WMHs) in early-onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early-onset amyloid-negative cognitively impaired (EOnonAD) groups in the Longitudinal Early-Onset Alzheimer's Disease Study. METHODS: We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t-tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden. RESULTS: EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group. DISCUSSION: EOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD. HIGHLIGHTS: This study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early-onset amyloid-negative cognitively impaired (EOnonAD) groups across all brain regions.
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Doença de Alzheimer , Disfunção Cognitiva , Substância Branca , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/complicações , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Imageamento por Ressonância Magnética , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/complicações , Proteínas Amiloidogênicas , AmiloideRESUMO
INTRODUCTION: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD). METHODS: Cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated. RESULTS: Biomarkers were correlated with one another. Levels of CSF Aß42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aß42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure. DISCUSSION: This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3 , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Estudos Longitudinais , Biomarcadores/líquido cefalorraquidiano , Neurogranina/líquido cefalorraquidianoRESUMO
INTRODUCTION: We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS). METHODS: Baseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n = 70). RESULTS: Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD. DISCUSSION: Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD.
Assuntos
Doença de Alzheimer , Humanos , Idoso , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Estudos Longitudinais , Coleta de DadosRESUMO
INTRODUCTION: The Rey Auditory Verbal Learning Test (RAVLT) is a useful neuropsychological test for describing episodic memory impairment in dementia. However, there is limited research on its utility in early-onset Alzheimer's disease (EOAD). We assess the influence of amyloid and diagnostic syndrome on several memory scores in EOAD. METHODS: We transcribed RAVLT recordings from 303 subjects in the Longitudinal Early-Onset Alzheimer's Disease Study. Subjects were grouped by amyloid status and syndrome. Primacy, recency, J-curve, duration, stopping time, and speed score were calculated and entered into linear mixed effects models as dependent variables. RESULTS: Compared with amyloid negative subjects, positive subjects exhibited effects on raw score, primacy, recency, and stopping time. Inter-syndromic differences were noted with raw score, primacy, recency, J-curve, and stopping time. DISCUSSION: RAVLT measures are sensitive to the effects of amyloid and syndrome in EOAD. Future work is needed to quantify the predictive value of these scores. HIGHLIGHTS: RAVLT patterns characterize various presentations of EOAD and EOnonAD Amyloid impacts raw score, primacy, recency, and stopping time Timing-based scores add value over traditional count-based scores.
Assuntos
Doença de Alzheimer , Memória Episódica , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Testes Neuropsicológicos , Transtornos da Memória/diagnóstico , Transtornos da Memória/etiologia , Estudos Longitudinais , Proteínas AmiloidogênicasRESUMO
OBJECTIVE: The Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early-onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data-collection mid-point. METHODS: Data from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid-positive EOAD [n = 212], and amyloid-negative early-onset non-Alzheimer's disease [EOnonAD; n = 70]). RESULTS: Cognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures. CONCLUSIONS: We present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant. HIGHLIGHTS: Findings represent the most comprehensive baseline characterization of sporadic early-onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present.