Neuropathology and cognitive performance in centenarians

Abstract

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 agreed to post-mortem brain donation. Centenarians self-reported to be cognitive 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 most neuropathological hallmarks related to age and neurodegenerative diseases such as Aβ 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 Aβ-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.

Untangling the origin and function of granulovacuolar degeneration bodies in neurodegenerative proteinopathies

“…Interestingly, although the hippocampal GVB burden increases with age in subjects without clinical symptoms [9,31,125,144], GVBs are also observed in the brains of young patients with tau pathology. For example, GVBs were found to accompany tau pathology/argentophilic NFTs in a 13-year-old patient with tuberous sclerosis [41], a 15-year-old patient with subacute sclerosing panencephalitis [86], a 15-year-old patient with Down syndrome [55], 34-and 41-year-old patients with different lysosomal storage disorders [6,127] and young patients with Fukuyama-type congenital muscular dystrophy (age range: 14-34 years) [115].…”

“…The GVB-type lysosomal response may have a similar beneficial outcome. In favor of a protective role, highly abundant GVBs were reported in a cohort of cognitively healthy individuals over 100-yearsof-age [31]. This may suggest that in healthy centenarians, a high GVB load is associated with protection from neurodegeneration and clinical symptoms.…”