Neuropathology and cognitive performance in self-reported cognitively healthy centenarians

Ganz, Andrea B; Beker, Nina; Hulsman, Marc; Sikkes, Sietske A.M.; Bank, null Netherlands Brain; Scheltens, Philip; Smit, August B.; Rozemüller, Annemieke; Hoozemans, Jeroen J. M.; Holstege, Henne

doi:10.1186/s40478-018-0558-5

Cited by 43 publications

(62 citation statements)

References 56 publications

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“…In our present study, a sharp increase in neocortical Sub NFT (as well as a trend in Amy and Ent) was observed in the severe dementia cases (GDS 6-7), consistent with Braak and Braak's description of neuropathological staging of AD [38]. Neocortical NFT has been consistently associated with dementia status across other studies in the oldest old [9,10,14,24,42,55]. We did not observe a significant increase in NP in neocortices or NFT in other brain regions except Sub during earlier stages of AD as observed in younger old adults [50].…”

Section: Ad-type Pathology In Non-demented and Demented Centenarianssupporting

confidence: 91%

“…Our observations underline the heterogeneity of neuropathology and the possibility of living beyond 100 years without clinical manifestation of cognitive decline or dementia under certain degrees of neuropathological changes [5]. In line with our findings, an analysis in postmortem brains from 40 centenarians from the 100-Plus Study whose premortem MMSE score were 23.7 ± 4.6 (MMSE score: 24-30 = normal cognition; 19-23 = mild; 10-18 = moderate; or ≤9 = severe cognitive impairment) also demonstrated a wide range of AD-type pathology, but none had Braak staging V-VI [24,43]. Two out of six non-demented centenarians from the NECS also had significant AD neuropathological changes, but Braak staging was also limited to ≤IV [25].…”

Section: Ad-type Pathology In Non-demented and Demented Centenarianssupporting

confidence: 85%

“…Similar to GDS, which was subjectively assessed by geriatric psychologists in the GCS, we observed that neocortical NFT, and to a lesser extent for NP, was related to poor performance in multiple cognitive domains and activities of daily living measured by cognitive performance tests. Apart from our study, only one other centenarian study, the 100-Plus Study, reported CP correlations with different cognitive domains [24]. In the 100-Plus Study, advanced Braak staging, and to a much lesser extent for A␤ pathology, were associated with lower performance on the MMSE, the Visual Association Test (VAT), and the Clock Drawing Test (CDT), though these associations did not reach statistical significance.…”

Section: Neuropathology and Objective Test Performancecontrasting

confidence: 61%

“…It is important to point out that GDS rating does not distinguish among types of dementia [30]. Previous analysis demonstrated extensive concurrence of cerebrovascular disease, AD, HS, and Lewy body dementia pathologies in nonagenarian, centenarian, and supercentenarian (≥110 years) brains [11,19,24,42]. Although single neuropathological entities (except neocortical NFT) were not associated with dementia rating in the GCS (Table 2), all centenarians who were absent of dementia (GDS 1-3) also had low degree of neuronal loss (absent of ventricular dilation and absent or low cerebral atrophy).…”

Section: Ad-type Pathology In Non-demented and Demented Centenariansmentioning

confidence: 99%

“…Previous CP studies often combined centenarians with younger old adults (<90 years old), but findings from these studies raised questions regarding the confounding effect from longevity-associated characteristics of the oldest old [20][21][22][23]. There have been limited reports on CP correlations exclusively in 40 centenarians from the 100-Plus Study of Dutch centenarians who were all cognitively intact at the enrollment [24], 14 centenarians from the New England Centenarian Study (NECS) [25], and others with very limited numbers of subjects [9][10][11][26][27][28]. Findings from the GCS will expand our understanding of CP correlation as it is one of the keys to identify pathology and factors contributing to the prevention or delay of age-related cognitive decline and, distinctively in centenarians, successful aging.…”

Section: Introductionmentioning

confidence: 99%

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Clinico-Neuropathological Findings in the Oldest Old from the Georgia Centenarian Study

Tanprasertsuk

Johnson

et al. 2019

JAD

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Background: Centenarian studies are important sources for understanding of factors that contribute to longevity and healthy aging. Clinico-neuropathological finding is a key in identifying pathology and factors contributing to age-related cognitive decline and dementia in the oldest old. Objective: To characterize the cross-sectional relationship between neuropathologies and measures of premortem cognitive performance in centenarians. Methods: Data were acquired from 49 centenarians (≥98 years) from the Georgia Centenarian Study. Cognitive assessment from the time point closest to mortality was used (<1 year for all subjects) and scores for cognitive domains were established. Neuropathologies [cerebral atrophy, ventricular dilation, atherosclerosis, cerebral amyloid angiopathy (CAA), Lewy bodies, hippocampal sclerosis (HS), hippocampal TDP-43 proteinopathy, neuritic plaque (NP) and neurofibrillary tangle (NFT) counts, Braak staging, and National Institute on Aging-Reagan Institute (NIARI) criteria for the neuropathological diagnosis of Alzheimer's disease (AD)] were compared among subjects with different ratings of dementia. Linear regression was applied to evaluate the association between cognitive domain scores and neuropathologies. Results: Wide ranges of AD-type neuropathological changes were observed in both non-demented and demented subjects. Neocortical NFT and Braak staging were related to clinical dementia rating. Neocortical NFT and NP, Braak and NIARI staging, cerebral and ventricular atrophy, HS, CAA, and TDP-43 proteinopathy were differentially associated with poor performance in multiple cognitive domains and activities of daily living. Conclusion: AD-type pathology was associated with severe dementia and poor cognition but was not the only variable that explained cognitive impairment, indicating the complexity and heterogeneity of pathophysiology of dementia in the oldest old.

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Section: Ad-type Pathology In Non-demented and Demented Centenarianssupporting

confidence: 91%

Section: Ad-type Pathology In Non-demented and Demented Centenarianssupporting

confidence: 85%

Section: Neuropathology and Objective Test Performancecontrasting

confidence: 61%

Section: Ad-type Pathology In Non-demented and Demented Centenariansmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinico-Neuropathological Findings in the Oldest Old from the Georgia Centenarian Study

Tanprasertsuk

Johnson

et al. 2019

JAD

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Longitudinal Maintenance of Cognitive Health in Centenarians in the 100-plus Study

et al. 2020

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IMPORTANCE Some individuals who reach ages beyond 100 years in good cognitive health may be resilient against risk factors associated with cognitive decline. Exploring the processes underlying resilience may contribute to the development of therapeutic strategies that help to maintain cognitive health while aging. OBJECTIVE To identify individuals who escape cognitive decline until extreme ages and to investigate the prevalence of associated risk factors. DESIGN, SETTING, AND PARTICIPANTS The 100-plus Study is a prospective observational cohort study of community-based Dutch centenarians enrolled between 2013 and 2019 who were visited annually until death or until participation was no longer possible. The centenarians self-reported their cognitive health, as confirmed by a proxy. Of the 1023 centenarians approached for study inclusion, 340 fulfilled the study criteria and were included in analyses. Data analysis was performed from April 2019 to December 2019. MAIN OUTCOMES AND MEASURES Cognition was assessed using the Mini-Mental State Examination (MMSE). To identify centenarians who escape cognitive decline, this study investigated the association of baseline cognition with survivorship and cognitive trajectories for at least 2 years of follow-up using linear mixed models, adjusted for sex, age, and education. This study investigated the prevalence of apolipoprotein E (APOE) genotypes and cardiovascular disease as risk factors associated with cognitive decline. RESULTS At baseline, the median age of 340 centenarians was 100.5 years (range, 100.0-108.2 years); 245 participants (72.1%) were female. The maximum survival estimate plateaued at 82% per year (95% CI, 77% to 87%) across centenarians who scored 26 to 30 points on the baseline MMSE (hazard ratio, 0.56; 95% CI, 0.42 to 0.75; P < .001), suggesting that an MMSE score of 26 or higher is representative of both cognitive and physical health. Among the 79 centenarians who were followed up for 2 years or longer, those with baseline MMSE score less than 26 experienced a decline in MMSE score of 1.68 points per year (95% CI, −2.45 to −0.92 points per year; P = .02), whereas centenarians with MMSE scores of 26 or higher at baseline experienced a decline of 0.71 point per year (95% CI, −1.08 to −0.35 points per year). For 73% of the centenarians with baseline MMSE scores of 26 or higher, no cognitive changes were observed, which often extended to ensuing years or until death. It is estimated that this group is representative of less than 10% of Dutch centenarians. In this group, 18.6% carried at least 1 APOE-ε4 allele, compared with 5.6% of the centenarians with lower and/or declining cognitive performance. CONCLUSIONS AND RELEVANCE Most centenarians who scored 26 or higher on the MMSE at baseline maintained high levels of cognitive performance for at least 2 years, in some cases despite (continued) Key Points Question Is it possible to identify centenarians who escape cognitive decline? Findings In this cohort study of 340 centenarians, most individuals who scored 2...

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Association of Cognitive Function Trajectories in Centenarians With Postmortem Neuropathology, Physical Health, and Other Risk Factors for Cognitive Decline

et al. 2021

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IMPORTANCE Understanding mechanisms associated with prolonged cognitive health in combination with exceptional longevity might lead to approaches to enable successful aging. OBJECTIVE To investigate trajectories of cognitive functioning in centenarians across domains, and to examine the association of these trajectories with factors underlying cognitive reserve, physical health, and postmortem levels of Alzheimer disease (AD)-associated neuropathology. DESIGN, SETTING, AND PARTICIPANTS This cohort study used neuropsychological test data and postmortem neuropathological reports from Dutch centenarians who were drawn from the 100-plus Study between January 2013 and April 2019. Eligible participants self-reported being cognitively healthy, which was confirmed by a proxy. Data analysis was performed between June 2019 and June 2020. EXPOSURES Age, sex, APOE ε genotype, factors of cognitive reserve, physical health, and AD-associated neuropathology (ie, amyloid-β, neurofibrillary tangles, and neuritic plaques). MAIN OUTCOMES AND MEASURESIn annual visits (until death or until participation was no longer possible), centenarians underwent an extensive neuropsychological test battery, from which an mean z score of global cognition, memory, executive functions, verbal fluency, visuospatial functions, and attention/processing speed was calculated. Linear mixed models with a random intercept and time as independent variable were used to investigate cognitive trajectories, adjusted for sex, age, education, and vision and hearing capacities. In a second step, linear mixed models were used to associate cognitive trajectories with factors underlying cognitive reserve, physical health at baseline, and AD-associated neuropathology. RESULTSOf the 1023 centenarians approached, 340 were included in the study. We analyzed 330 centenarians for whom cognitive tests were available at baseline (239 [72.4%] women; median [interquartile range] age of 100.5 [100.2-101.7] years), with a mean (SD) follow-up duration of 1.6 (0.8) years. We observed no decline across investigated cognitive domains, with the exception of a slight decline in memory function (β, −0.10 SD per year; 95% CI, −0.14 to −0.05 SD; P < .001).

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Neuropathology and cognitive performance in self-reported cognitively healthy centenarians

Cited by 43 publications

References 56 publications

Clinico-Neuropathological Findings in the Oldest Old from the Georgia Centenarian Study

Clinico-Neuropathological Findings in the Oldest Old from the Georgia Centenarian Study

Longitudinal Maintenance of Cognitive Health in Centenarians in the 100-plus Study

Association of Cognitive Function Trajectories in Centenarians With Postmortem Neuropathology, Physical Health, and Other Risk Factors for Cognitive Decline

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