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OBJECTIVE: Microtubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers. METHODS: We compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles. RESULTS: Symptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline. INTERPRETATION: Network connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632-646.
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Demência Frontotemporal , Proteínas tau , Humanos , Estudos Transversais , Proteínas tau/genética , Encéfalo/diagnóstico por imagem , Mutação/genética , Substância Cinzenta/diagnóstico por imagem , Imageamento por Ressonância Magnética , Demência Frontotemporal/genética , BiomarcadoresRESUMO
BACKGROUND: Clinical trials for upcoming disease-modifying therapies of spinocerebellar ataxias (SCA), a group of rare movement disorders, lack endpoints sensitive to early disease progression, when therapeutics will be most effective. In addition, regulatory agencies emphasize the importance of biological outcomes. OBJECTIVES: READISCA, a transatlantic clinical trial readiness consortium, investigated whether advanced multimodal magnetic resonance imaging (MRI) detects pathology progression over 6 months in preataxic and early ataxic carriers of SCA mutations. METHODS: A total of 44 participants (10 SCA1, 25 SCA3, and 9 controls) prospectively underwent 3-T MR scanning at baseline and a median [interquartile range] follow-up of 6.2 [5.9-6.7] months; 44% of SCA participants were preataxic. Blinded analyses of annual changes in structural, diffusion MRI, MR spectroscopy, and the Scale for Assessment and Rating of Ataxia (SARA) were compared between groups using nonparametric testing. Sample sizes were estimated for 6-month interventional trials with 50% to 100% treatment effect size, leveraging existing large cohort data (186 SCA1, 272 SCA3) for the SARA estimate. RESULTS: Rate of change in microstructural integrity (decrease in fractional anisotropy, increase in diffusivities) in the middle cerebellar peduncle, corona radiata, and superior longitudinal fasciculus significantly differed in SCAs from controls (P < 0.005), with high effect sizes (Cohen's d = 1-2) and moderate-to-high responsiveness (|standardized response mean| = 0.6-0.9) in SCAs. SARA scores did not change, and their rate of change did not differ between groups. CONCLUSIONS: Diffusion MRI is sensitive to disease progression at very early-stage SCA1 and SCA3 and may provide a >5-fold reduction in sample sizes relative to SARA as endpoint for 6-month-long trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Our results (i) confirmed SCA6 being considered as a pure cerebellar grey matter disease, (ii) emphasise the involvement of cerebellar white matter in the neuropathology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.
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Cerebelo , Imageamento por Ressonância Magnética , Humanos , Masculino , Feminino , Cerebelo/patologia , Cerebelo/diagnóstico por imagem , Pessoa de Meia-Idade , Adulto , Estudos Transversais , Idoso , Índice de Gravidade de Doença , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/patologia , Ataxias Espinocerebelares/genética , Atrofia/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Tamanho do Órgão , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologiaRESUMO
The Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) manifests as impaired executive control, linguistic processing, visual spatial function, and affect regulation. The CCAS has been described in the spinocerebellar ataxias (SCAs), but its prevalence is unknown. We analyzed results of the CCAS/Schmahmann Scale (CCAS-S), developed to detect and quantify CCAS, in two natural history studies of 309 individuals Symptomatic for SCA1, SCA2, SCA3, SCA6, SCA7, or SCA8, 26 individuals Pre-symptomatic for SCA1 or SCA3, and 37 Controls. We compared total raw scores, domain scores, and total fail scores between Symptomatic, Pre-symptomatic, and Control cohorts, and between SCA types. We calculated scale sensitivity and selectivity based on CCAS category designation among Symptomatic individuals and Controls, and correlated CCAS-S performance against age and education, and in Symptomatic patients, against genetic repeat length, onset age, disease duration, motor ataxia, depression, and fatigue. Definite CCAS was identified in 46% of the Symptomatic group. False positive rate among Controls was 5.4%. Symptomatic individuals had poorer global CCAS-S performance than Controls, accounting for age and education. The domains of semantic fluency, phonemic fluency, and category switching that tap executive function and linguistic processing consistently separated Symptomatic individuals from Controls. CCAS-S scores correlated most closely with motor ataxia. Controls were similar to Pre-symptomatic individuals whose nearness to symptom onset was unknown. The use of the CCAS-S identifies a high CCAS prevalence in a large cohort of SCA patients, underscoring the utility of the scale and the notion that the CCAS is the third cornerstone of clinical ataxiology.
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Ataxias Espinocerebelares , Humanos , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/psicologia , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/fisiopatologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Função Executiva/fisiologia , Testes Neuropsicológicos , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/psicologia , Estudos de CoortesRESUMO
INTRODUCTION: The pace of innovation has accelerated in virtually every area of tau research in just the past few years. METHODS: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. RESULTS: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research. DISCUSSION: The virtual meeting provided an opportunity to foster cross-sector collaboration and partnerships as well as a forum for updating colleagues on research-advancing tools and programs that are steadily moving the field forward.
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Doença de Alzheimer , Tauopatias , Humanos , Proteínas tauRESUMO
OBJECTIVE: This study was undertaken to identify magnetic resonance (MR) metrics that are most sensitive to early changes in the brain in spinocerebellar ataxia type 1 (SCA1) and type 3 (SCA3) using an advanced multimodal MR imaging (MRI) protocol in the multisite trial setting. METHODS: SCA1 or SCA3 mutation carriers and controls (n = 107) underwent MR scanning in the US-European READISCA study to obtain structural, diffusion MRI, and MR spectroscopy data using an advanced protocol at 3T. Morphometric, microstructural, and neurochemical metrics were analyzed blinded to diagnosis and compared between preataxic SCA (n = 11 SCA1, n = 28 SCA3), ataxic SCA (n = 14 SCA1, n = 37 SCA3), and control (n = 17) groups using nonparametric testing accounting for multiple comparisons. MR metrics that were most sensitive to preataxic abnormalities were identified using receiver operating characteristic (ROC) analyses. RESULTS: Atrophy and microstructural damage in the brainstem and cerebellar peduncles and neurochemical abnormalities in the pons were prominent in both preataxic groups, when patients did not differ from controls clinically. MR metrics were strongly associated with ataxia symptoms, activities of daily living, and estimated ataxia duration. A neurochemical measure was the most sensitive metric to preataxic changes in SCA1 (ROC area under the curve [AUC] = 0.95), and a microstructural metric was the most sensitive metric to preataxic changes in SCA3 (AUC = 0.92). INTERPRETATION: Changes in cerebellar afferent and efferent pathways underlie the earliest symptoms of both SCAs. MR metrics collected with a harmonized advanced protocol in the multisite trial setting allow detection of disease effects in individuals before ataxia onset with potential clinical trial utility for subject stratification. ANN NEUROL 2022.
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Spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders, but there is no metric that predicts disease severity over time. We hypothesized that by developing a new metric, the Severity Factor (S-Factor) using immutable disease parameters, it would be possible to capture disease severity independent of clinical rating scales. Extracting data from the CRC-SCA and READISCA natural history studies, we calculated the S-Factor for 438 participants with symptomatic SCA1, SCA2, SCA3, or SCA6, as follows: ((length of CAG repeat expansion - maximum normal repeat length) /maximum normal repeat length) × (current age - age at disease onset) × 10). Within each SCA type, the S-Factor at the first Scale for the Assessment and Rating of Ataxia (SARA) visit (baseline) was correlated against scores on SARA and other motor and cognitive assessments. In 281 participants with longitudinal data, the slope of the S-Factor over time was correlated against slopes of scores on SARA and other motor rating scales. At baseline, the S-Factor showed moderate-to-strong correlations with SARA and other motor rating scales at the group level, but not with cognitive performance. Longitudinally the S-Factor slope showed no consistent association with the slope of performance on motor scales. Approximately 30% of SARA slopes reflected a trend of non-progression in motor symptoms. The S-Factor is an observer-independent metric of disease burden in SCAs. It may be useful at the group level to compare cohorts at baseline in clinical studies. Derivation and examination of the S-factor highlighted challenges in the use of clinical rating scales in this population.
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Ataxias Espinocerebelares , Humanos , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/epidemiologia , Gravidade do Paciente , Progressão da DoençaRESUMO
OBJECTIVE: Investigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without ß-amyloid positivity METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses. HIGHLIGHTS: Learning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides , Amiloide , Aprendizagem , Proteínas AmiloidogênicasRESUMO
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.
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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.
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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.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Apolipoproteínas E/genética , Estudos Longitudinais , Apolipoproteína E4/genética , Coleta de DadosRESUMO
Frontotemporal dementia (FTD) is one of the leading causes of dementia before age 65 and often manifests as abnormal behavior (in behavioral variant FTD) or language impairment (in primary progressive aphasia). FTD's exact clinical presentation varies by culture, language, education, social norms, and other socioeconomic factors; current research and clinical practice, however, is mainly based on studies conducted in North America and Western Europe. Changes in diagnostic criteria and procedures as well as new or adapted cognitive tests are likely needed to take into consideration global diversity. This perspective paper by two professional interest areas of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment examines how increasing global diversity impacts the clinical presentation, screening, assessment, and diagnosis of FTD and its treatment and care. It subsequently provides recommendations to address immediate needs to advance global FTD research and clinical practice.
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Doença de Alzheimer , Demência Frontotemporal , Humanos , Idoso , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/terapia , Demência Frontotemporal/psicologia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/terapia , Testes Neuropsicológicos , Idioma , Europa (Continente)RESUMO
OBJECTIVES: Generalization (or near-transfer) effects of an intervention to tasks not explicitly trained are the most desirable intervention outcomes. However, they are rarely reported and even more rarely explained. One hypothesis for generalization effects is that the tasks improved share the same brain function/computation with the intervention task. We tested this hypothesis in this study of transcranial direct current stimulation (tDCS) over the left inferior frontal gyrus (IFG) that is claimed to be involved in selective semantic retrieval of information from the temporal lobes. MATERIALS AND METHODS: In this study, we examined whether tDCS over the left IFG in a group of patients with primary progressive aphasia (PPA), paired with a lexical/semantic retrieval intervention (oral and written naming), may specifically improve semantic fluency, a nontrained near-transfer task that relies on selective semantic retrieval, in patients with PPA. RESULTS: Semantic fluency improved significantly more in the active tDCS than in the sham tDCS condition immediately after and two weeks after treatment. This improvement was marginally significant two months after treatment. We also found that the active tDCS effect was specific to tasks that require this IFG computation (selective semantic retrieval) but not to other tasks that may require different computations of the frontal lobes. CONCLUSIONS: We provided interventional evidence that the left IFG is critical for selective semantic retrieval, and tDCS over the left IFG may have a near-transfer effect on tasks that depend on the same computation, even if they are not specifically trained. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT02606422.
Assuntos
Afasia Primária Progressiva , Estimulação Transcraniana por Corrente Contínua , Humanos , Córtex Pré-Frontal , Semântica , Lobo Temporal , Afasia Primária Progressiva/diagnóstico por imagem , Afasia Primária Progressiva/terapiaRESUMO
BACKGROUND: Lifestyle could influence the course of hereditary ataxias, but representative data are missing. OBJECTIVE: The objective of this study was to characterize lifestyle in spinocerebellar ataxia type 3 (SCA3) and investigate possible associations with disease parameters. METHODS: In a prospective cohort study, data on smoking, alcohol consumption, physical activity, physiotherapy, and body mass index (BMI) were collected from 243 patients with SCA3 and 119 controls and tested for associations with age of onset, disease severity, and progression. RESULTS: Compared with controls, patients with SCA3 were less active and consumed less alcohol. Less physical activity and alcohol abstinence were associated with more severe disease, but not with progression rates or age of onset. Smoking, BMI, or physiotherapy did not correlate with disease parameters. CONCLUSION: Differences in lifestyle factors of patients with SCA3 and controls as well as associations of lifestyle factors with disease severity are likely driven by the influence of symptoms on behavior. No association between lifestyle and disease progression was detected. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.