Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
1.
Alzheimers Dement ; 19(7): 2831-2841, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36583547

RESUMEN

INTRODUCTION: With increasing age, neuropathological substrates associated with Alzheimer's disease (AD) accumulate in brains of cognitively healthy individuals-are they resilient, or resistant to AD-associated neuropathologies? METHODS: In 85 centenarian brains, we correlated NIA (amyloid) stages, Braak (neurofibrillary tangle) stages, and CERAD (neuritic plaque) scores with cognitive performance close to death as determined by Mini-Mental State Examination (MMSE) scores. We assessed centenarian brains against 2131 brains from AD patients, non-AD demented, and non-demented individuals in an age continuum ranging from 16 to 100+ years. RESULTS: With age, brains from non-demented individuals reached the NIA and Braak stages observed in AD patients, while CERAD scores remained lower. In centenarians, NIA stages varied (22.4% were the highest stage 3), Braak stages rarely exceeded stage IV (5.9% were V), and CERAD scores rarely exceeded 2 (4.7% were 3); within these distributions, we observed no correlation with the MMSE (NIA: P = 0.60; Braak: P = 0.08; CERAD: P = 0.16). DISCUSSION: Cognitive health can be maintained despite the accumulation of high levels of AD-related neuropathological substrates. HIGHLIGHTS: Cognitively healthy elderly have AD neuropathology levels similar to AD patients. AD neuropathology loads do not correlate with cognitive performance in centenarians. Some centenarians are resilient to the highest levels of AD neuropathology.


Asunto(s)
Enfermedad de Alzheimer , Ovillos Neurofibrilares , Anciano de 80 o más Años , Humanos , Anciano , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Ovillos Neurofibrilares/patología , Placa Amiloide/patología , Centenarios , Enfermedad de Alzheimer/patología , Encéfalo/patología
2.
Alzheimers Dement ; 19(11): 5036-5047, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37092333

RESUMEN

INTRODUCTION: Neuropathological substrates associated with neurodegeneration occur in brains of the oldest old. How does this affect cognitive performance? METHODS: The 100-plus Study is an ongoing longitudinal cohort study of centenarians who self-report to be cognitively healthy; post mortem brain donation is optional. In 85 centenarian brains, we explored the correlations between the levels of 11 neuropathological substrates with ante mortem performance on 12 neuropsychological tests. RESULTS: Levels of neuropathological substrates varied: we observed levels up to Thal-amyloid beta phase 5, Braak-neurofibrillary tangle (NFT) stage V, Consortium to Establish a Registry for Alzheimer's Disease (CERAD)-neuritic plaque score 3, Thal-cerebral amyloid angiopathy stage 3, Tar-DNA binding protein 43 (TDP-43) stage 3, hippocampal sclerosis stage 1, Braak-Lewy bodies stage 6, atherosclerosis stage 3, cerebral infarcts stage 1, and cerebral atrophy stage 2. Granulovacuolar degeneration occurred in all centenarians. Some high performers had the highest neuropathology scores. DISCUSSION: Only Braak-NFT stage and limbic-predominant age-related TDP-43 encephalopathy (LATE) pathology associated significantly with performance across multiple cognitive domains. Of all cognitive tests, the clock-drawing test was particularly sensitive to levels of multiple neuropathologies.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Anciano de 80 o más Años , Humanos , Péptidos beta-Amiloides/metabolismo , Centenarios , Estudios Longitudinales , Enfermedad de Alzheimer/patología , Encéfalo/patología , Ovillos Neurofibrilares/patología , Neuropatología , Cognición
3.
J Neurochem ; 151(4): 435-445, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-30289976

RESUMEN

Dementias are prevalent brain disorders in the aged population. Dementias pose major socio-medical burden, but currently there is no cure available. Novel proteomics approaches hold promise to identify alterations of the brain proteome that could provide clues on disease etiology, and identify candidate proteins to develop further as a biomarker. In this review, we focus on recent proteomics findings from brains affected with Alzheimer's Disease, Parkinson Disease Dementia, Frontotemporal Dementia, and Amyotrophic Lateral Sclerosis. These studies confirmed known cellular changes, and in addition identified novel proteins that may underlie distinct aspects of the diseases. This article is part of the special issue "Proteomics".


Asunto(s)
Encéfalo/metabolismo , Demencia/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Proteoma/metabolismo , Proteómica , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/metabolismo , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/metabolismo , Biomarcadores/metabolismo , Demencia/complicaciones , Progresión de la Enfermedad , Demencia Frontotemporal/complicaciones , Demencia Frontotemporal/metabolismo , Humanos , Enfermedades Neurodegenerativas/complicaciones , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/metabolismo
4.
Acta Neuropathol Commun ; 10(1): 100, 2022 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-35799292

RESUMEN

Frontotemporal dementia is characterized by progressive atrophy of frontal and/or temporal cortices at an early age of onset. The disorder shows considerable clinical, pathological, and genetic heterogeneity. Here we investigated the proteomic signatures of frontal and temporal cortex from brains with frontotemporal dementia due to GRN and MAPT mutations to identify the key cell types and molecular pathways in their pathophysiology. We compared patients with mutations in the GRN gene (n = 9) or with mutations in the MAPT gene (n = 13) with non-demented controls (n = 11). Using quantitative proteomic analysis on laser-dissected tissues we identified brain region-specific protein signatures for both genetic subtypes. Using published single cell RNA expression data resources we deduced the involvement of major brain cell types in driving these different protein signatures. Subsequent gene ontology analysis identified distinct genetic subtype- and cell type-specific biological processes. For the GRN subtype, we observed a distinct role for immune processes related to endothelial cells and for mitochondrial dysregulation in neurons. For the MAPT subtype, we observed distinct involvement of dysregulated RNA processing, oligodendrocyte dysfunction, and axonal impairments. Comparison with an in-house protein signature of Alzheimer's disease brains indicated that the observed alterations in RNA processing and oligodendrocyte function are distinct for the frontotemporal dementia MAPT subtype. Taken together, our results indicate the involvement of different brain cell types and biological mechanisms in genetic subtypes of frontotemporal dementia. Furthermore, we demonstrate that comparison of proteomic profiles of different disease entities can separate general neurodegenerative processes from disease-specific pathways, which may aid the development of disease subtype-specific treatment strategies.


Asunto(s)
Demencia Frontotemporal , Enfermedad de Pick , Células Endoteliales/metabolismo , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Mutación/genética , Progranulinas/genética , Proteómica , Proteínas tau/genética , Proteínas tau/metabolismo
5.
Acta Neuropathol Commun ; 6(1): 64, 2018 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-30037350

RESUMEN

With aging, the incidence of neuropathological hallmarks of neurodegenerative diseases increases in the brains of cognitively healthy individuals. It is currently unclear to what extent these hallmarks associate with symptoms of disease at extreme ages. Forty centenarians from the 100-plus Study cohort donated their brain. Centenarians self-reported to be cognitively healthy at baseline, which was confirmed by a proxy. Objective ante-mortem measurements of cognitive performance were associated with the prevalence, distribution and quantity of age- and AD-related neuropathological hallmarks. Despite self-reported cognitive health, objective neuropsychological testing suggested varying levels of ante-mortem cognitive functioning. Post-mortem, we found that neuropathological hallmarks related to age and neurodegenerative diseases, such as Aß and Tau pathology, as well as atherosclerosis, were abundantly present in most or all centenarians, whereas Lewy body and pTDP-43 pathology were scarce. We observed that increased pathology loads correlated across pathology subtypes, and an overall trend of higher pathology loads to associate with a lower cognitive test performance. This trend was carried especially by the presence of neurofibrillary tangles (NFTs) and granulovacuolar degeneration (GVD) and to a lesser extent by Aß-associated pathologies. Cerebral Amyloid Angiopathy (CAA) specifically associated with lower executive functioning in the centenarians. In conclusion, we find that while the centenarians in this cohort escaped or delayed cognitive impairment until extreme ages, their brains reveal varying levels of disease-associated neuropathological hallmarks, some of which associate with cognitive performance.


Asunto(s)
Envejecimiento/patología , Encéfalo/patología , Disfunción Cognitiva/patología , Disfunción Cognitiva/psicología , Neuropatología , Autoinforme , Anciano de 80 o más Años , Péptidos beta-Amiloides/metabolismo , Autopsia , Quinasa Idelta de la Caseína/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Estudios de Cohortes , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Escala del Estado Mental , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA