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1.
Ann Neurol ; 96(3): 526-538, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38888142

RESUMO

OBJECTIVE: To determine whether plasma phosphorylated-Tau181 (pTau181) could be used as a diagnostic biomarker of concurrent Alzheimer's disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in Lewy body disease (LBD). METHODS: We studied 565 participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 with Alzheimer's disease, and 274 cognitively normal. Plasma pTau181 levels were measured with the Lumipulse G platform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with Receiver Operating Characteristic curves in a subset of participants with CSF pTau181/Aß42, and CSF Aß42/Aß40 or amyloid-ß PET, respectively. Linear mixed effects models were used to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes. RESULTS: Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In LBD patients with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCA and CDR-SB, as well as accelerated decline in CDR-SB. Additionally, in this group, rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR-SB and memory. In LBD patients with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment. INTERPRETATION: Our findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD. ANN NEUROL 2024;96:526-538.


Assuntos
Doença de Alzheimer , Biomarcadores , Doença por Corpos de Lewy , Proteínas tau , Humanos , Feminino , Masculino , Idoso , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano , Doença por Corpos de Lewy/sangue , Doença por Corpos de Lewy/patologia , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Fosforilação , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Pessoa de Meia-Idade , Disfunção Cognitiva/sangue , Amiloidose/sangue , Prognóstico
2.
Alzheimers Dement ; 20(8): 5299-5310, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38962867

RESUMO

INTRODUCTION: Amyloid positron emission tomography (PET) acquisition timing impacts quantification. METHODS: In florbetaben (FBB) PET scans of 245 adults with and without cognitive impairment, we investigated the impact of post-injection acquisition time on Centiloids (CLs) across five reference regions. CL equations for FBB were derived using standard methods, using FBB data collected between 90 and 110 min with paired Pittsburgh compound B data. Linear mixed models and t-tests evaluated the impact of acquisition time on CL increases. RESULTS: CL values increased significantly over the scan using the whole cerebellum, cerebellar gray matter, and brainstem as reference regions, particularly in amyloid-positive individuals. In contrast, CLs based on white matter-containing reference regions decreased across the scan. DISCUSSION: The quantification of CLs in FBB PET imaging is influenced by both the overall scan acquisition time and the choice of reference region. Standardized acquisition protocols or the application of acquisition time-specific CL equations should be implemented in clinical protocols. HIGHLIGHTS: Acquisition timing affects florbetaben positron emission tomography (PET) scan quantification, especially in amyloid-positive participants. The impact of acquisition timing on quantification varies across common reference regions. Consistent acquisitions and/or appropriate post-injection adjustments are needed to ensure comparability of PET data.


Assuntos
Compostos de Anilina , Tomografia por Emissão de Pósitrons , Estilbenos , Humanos , Masculino , Feminino , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Pessoa de Meia-Idade , Disfunção Cognitiva/diagnóstico por imagem , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Fatores de Tempo
3.
BMC Med ; 21(1): 156, 2023 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-37138290

RESUMO

BACKGROUND: Alzheimer's disease (AD) pathology impairs cognitive function. Yet some individuals with high amounts of AD pathology suffer marked memory impairment, while others with the same degree of pathology burden show little impairment. Why is this? One proposed explanation is cognitive reserve i.e., factors that confer resilience against, or compensation for the effects of AD pathology. Deep NREM slow wave sleep (SWS) is recognized to enhance functions of learning and memory in healthy older adults. However, that the quality of NREM SWS (NREM slow wave activity, SWA) represents a novel cognitive reserve factor in older adults with AD pathology, thereby providing compensation against memory dysfunction otherwise caused by high AD pathology burden, remains unknown. METHODS: Here, we tested this hypothesis in cognitively normal older adults (N = 62) by combining 11C-PiB (Pittsburgh compound B) positron emission tomography (PET) scanning for the quantification of ß-amyloid (Aß) with sleep electroencephalography (EEG) recordings to quantify NREM SWA and a hippocampal-dependent face-name learning task. RESULTS: We demonstrated that NREM SWA significantly moderates the effect of Aß status on memory function. Specifically, NREM SWA selectively supported superior memory function in individuals suffering high Aß burden, i.e., those most in need of cognitive reserve (B = 2.694, p = 0.019). In contrast, those without significant Aß pathological burden, and thus without the same  need for cognitive reserve, did not similarly benefit from the presence of NREM SWA (B = -0.115, p = 0.876). This interaction between NREM SWA and Aß status predicting memory function was significant after correcting for age, sex, Body Mass Index, gray matter atrophy, and previously identified cognitive reserve factors, such as education and physical activity (p = 0.042). CONCLUSIONS: These findings indicate that NREM SWA is a novel cognitive reserve factor providing resilience against the memory impairment otherwise caused by high AD pathology burden. Furthermore, this cognitive reserve function of NREM SWA remained significant when accounting both for covariates, and factors previously linked to resilience, suggesting that sleep might be an independent cognitive reserve resource. Beyond such mechanistic insights are potential therapeutic implications. Unlike many other cognitive reserve factors (e.g., years of education, prior job complexity), sleep is a modifiable factor. As such, it represents an intervention possibility that may aid the preservation of cognitive function in the face of AD pathology, both present moment and longitudinally.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Reserva Cognitiva , Sono de Ondas Lentas , Humanos , Idoso , Doença de Alzheimer/patologia , Imageamento por Ressonância Magnética , Peptídeos beta-Amiloides , Sono , Tomografia por Emissão de Pósitrons
4.
Alzheimers Dement ; 19(5): 2182-2196, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36642985

RESUMO

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Encéfalo/patologia , Biomarcadores , Progressão da Doença
5.
J Neurosci ; 41(36): 7687-7696, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34290080

RESUMO

Alzheimer's disease is associated with poor sleep, but the impact of tau and ß-amyloid (Aß) pathology on sleep remains largely unknown. Here, we test the hypothesis that tau and Aß predict unique impairments in objective and self-perceived human sleep under real-life, free-living conditions. Eighty-nine male and female cognitively healthy older adults received 18F-FTP-tau and 11C-PIB-Aß PET imaging, 7 nights of sleep actigraphy and questionnaire measures, and neurocognitive assessment. Tau burden, but not Aß, was associated with markedly worse objective sleep. In contrast, Aß and tau were associated with worse self-reported sleep quality. Of clinical relevance, Aß burden predicted a unique perceptual mismatch between objective and subject sleep evaluation, with individuals underestimating their sleep. The magnitude of this mismatch was further predicted by worse executive function. Thus, early-stage tau and Aß deposition are linked with distinct phenotypes of real-world sleep impairment, one that includes a cognitive misperception of their own sleep health.SIGNIFICANCE STATEMENT Alzheimer's disease is associated with sleep disruption, often before significant memory decline. Thus, real-life patterns of sleep behavior have the potential to serve as a window into early disease progression. In 89 cognitive healthy older adults, we found that tau burden was associated with worse wristwatch actigraphy-measured sleep quality, and that both tau and ß-amyloid were independently predictive of self-reported sleep quality. Furthermore, individuals with greater ß-amyloid deposition were more likely to underestimate their sleep quality, and sleep quality underestimation was associated with worse executive function. These data support the role of sleep impairment as a key marker of early Alzheimer's disease, and offer the possibility that actigraphy may be an affordable and scalable tool in quantifying Alzheimer's disease-related behavioral changes.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Sono/fisiologia , Proteínas tau/metabolismo , Actigrafia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Autorrelato , Inquéritos e Questionários
6.
Neuroimage ; 263: 119658, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36191755

RESUMO

Higher neuroticism is a risk factor for Alzheimer's disease (AD), and is implicated in disordered stress responses. The locus coeruleus (LC)-catecholamine system is activated during perceived threat and is a centerpiece of developing models of the pathophysiology of AD, as it is the first brain region to develop abnormal tau. We examined relationships among the "Big 5" personality traits, LC catecholamine synthesis capacity measured with [18F]Fluoro-m-tyrosine PET, and tau burden measured with [18F]Flortaucipir PET in cognitively normal older adults (n = 47). ß-amyloid (Aß) status was determined using [11C]Pittsburgh compound B PET (n = 14 Aß positive). Lower LC catecholamine synthesis capacity was associated with higher neuroticism, more depressive symptoms as measured by the Geriatric Depression Scale, and higher amygdala tau-PET binding. Exploratory analyses with other personality traits revealed that low trait conscientiousness was also related to both lower LC catecholamine synthesis capacity, and more depressive symptoms. A significant indirect path linked both high neuroticism and low conscientiousness to greater amygdala tau burden via their mutual association with low LC catecholamine synthesis capacity. Together, these findings reveal LC catecholamine synthesis capacity to be a promising marker of affective health and pathology burden in aging, and identifies candidate neurobiological mechanisms for the effect of personality on increased vulnerability to dementia.


Assuntos
Doença de Alzheimer , Locus Cerúleo , Humanos , Idoso , Locus Cerúleo/metabolismo , Proteínas tau/metabolismo , Catecolaminas/metabolismo , Neuroticismo , Doença de Alzheimer/patologia , Envelhecimento/patologia , Peptídeos beta-Amiloides/metabolismo , Tomografia por Emissão de Pósitrons
7.
Ann Neurol ; 90(6): 988-993, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34590340

RESUMO

Difficulty retrieving proper names is common in older adults, coinciding with the accumulation of aggregated proteins in mid-life. We investigated the ability of healthy older adults to retrieve the names of famous faces in relation to positron emission tomography measurements of amyloid-ß plaques and tau neurofibrillary tangles. More tau in the left fusiform and parahippocampal gyrus was related to reduced proper name retrieval performance and this effect was potentiated by amyloid-ß. These findings provide an explanation for a common complaint of older adults and link proper name retrieval to neural systems involved in face perception, memory, and naming. ANN NEUROL 2021;90:988-993.


Assuntos
Envelhecimento/metabolismo , Rememoração Mental/fisiologia , Lobo Temporal/metabolismo , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/psicologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Fosforilação , Tomografia por Emissão de Pósitrons , Lobo Temporal/diagnóstico por imagem
8.
J Neurosci ; 39(32): 6315-6324, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209175

RESUMO

Recent proposals suggest that sleep may be a factor associated with accumulation of two core pathological features of Alzheimer's disease (AD): tau and ß-amyloid (Aß). Here we combined PET measures of Aß and tau, electroencephalogram sleep recordings, and retrospective sleep evaluations to investigate the potential utility of sleep measures in predicting in vivo AD pathology in male and female older adults. Regression analyses revealed that the severity of impaired slow oscillation-sleep spindle coupling predicted greater medial temporal lobe tau burden. Aß burden was not associated with coupling impairment but instead predicted the diminished amplitude of <1 Hz slow-wave-activity, results that were statistically dissociable from each other. Additionally, comparisons of AD pathology and retrospective, self-reported changes in sleep duration demonstrated that changes in sleep across the lifespan can predict late-life Aß and tau burden. Thus, quantitative and qualitative features of human sleep represent potential noninvasive, cost-effective, and scalable biomarkers (current and future forecasting) of AD pathology, and carry both therapeutic and public health implications.SIGNIFICANCE STATEMENT Several studies have linked sleep disruption to the progression of Alzheimer's disease (AD). Tau and ß-amyloid (Aß), the primary pathological features of AD, are associated with both objective and subjective changes in sleep. However, it remains unknown whether late life tau and Aß burden are associated with distinct impairments in sleep physiology or changes in sleep across the lifespan. Using polysomnography, retrospective questionnaires, and tau- and Aß-specific PET, the present study reveals human sleep signatures that dissociably predict levels of brain tau and Aß in older adults. These results suggest that a night of polysomnography may aid in evaluating tau and Aß burden, and that treating sleep deficiencies within decade-specific time windows may serve in delaying AD progression.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/análise , Proteínas do Tecido Nervoso/análise , Transtornos Intrínsecos do Sono/metabolismo , Fases do Sono/fisiologia , Lobo Temporal/química , Proteínas tau/análise , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Compostos de Anilina , Biomarcadores , Carbolinas , Radioisótopos de Carbono , Eletroencefalografia , Feminino , Radioisótopos de Flúor , Humanos , Imageamento por Ressonância Magnética , Masculino , Modelos Neurológicos , Polissonografia , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Prognóstico , Compostos Radiofarmacêuticos , Transtornos Intrínsecos do Sono/diagnóstico por imagem , Transtornos Intrínsecos do Sono/patologia , Tiazóis
9.
J Alzheimers Dis ; 97(2): 567-572, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38250779

RESUMO

With the FDA approval of aducanumab and lecanemab, and with the recent statistically significant phase 3 clinical trial for donanemab, there is growing enthusiasm for anti-amyloid antibodies in the treatment of Alzheimer's disease. Here, we discuss three substantial limitations regarding recent anti-amyloid clinical trials: 1) there is little evidence that amyloid reduction correlates with clinical outcome, 2) the reported efficacy of anti-amyloid therapies may be explained by functional unblinding, and 3) donanemab had no effect on tau burden in its phase 3 trial. Taken together, these observations call into question the efficacy of anti-amyloid therapies.


Assuntos
Doença de Alzheimer , Proteínas Amiloidogênicas , Anticorpos Monoclonais Humanizados , Humanos , Doença de Alzheimer/tratamento farmacológico , Emoções
10.
Alzheimers Res Ther ; 16(1): 35, 2024 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-38355598

RESUMO

BACKGROUND: Sleep-wake regulating circuits are affected during prodromal stages in the pathological progression of both Alzheimer's disease (AD) and Parkinson's disease (PD), and this disturbance can be measured passively using wearable devices. Our objective was to determine whether accelerometer-based measures of 24-h activity are associated with subsequent development of AD, PD, and cognitive decline. METHODS: This study obtained UK Biobank data from 82,829 individuals with wrist-worn accelerometer data aged 40 to 79 years with a mean (± SD) follow-up of 6.8 (± 0.9) years. Outcomes were accelerometer-derived measures of 24-h activity (derived by cosinor, nonparametric, and functional principal component methods), incident AD and PD diagnosis (obtained through hospitalization or primary care records), and prospective longitudinal cognitive testing. RESULTS: One hundred eighty-seven individuals progressed to AD and 265 to PD. Interdaily stability (a measure of regularity, hazard ratio [HR] per SD increase 1.25, 95% confidence interval [CI] 1.05-1.48), diurnal amplitude (HR 0.79, CI 0.65-0.96), mesor (mean activity; HR 0.77, CI 0.59-0.998), and activity during most active 10 h (HR 0.75, CI 0.61-0.94), were associated with risk of AD. Diurnal amplitude (HR 0.28, CI 0.23-0.34), mesor (HR 0.13, CI 0.10-0.16), activity during least active 5 h (HR 0.24, CI 0.08-0.69), and activity during most active 10 h (HR 0.20, CI 0.16-0.25) were associated with risk of PD. Several measures were additionally predictive of longitudinal cognitive test performance. CONCLUSIONS: In this community-based longitudinal study, accelerometer-derived metrics were associated with elevated risk of AD, PD, and accelerated cognitive decline. These findings suggest 24-h rhythm integrity, as measured by affordable, non-invasive wearable devices, may serve as a scalable early marker of neurodegenerative disease.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doença de Parkinson/epidemiologia , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/complicações , Estudos Longitudinais , Estudos Prospectivos , Disfunção Cognitiva/psicologia
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