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. 2018 Jul 23;6(1):64.
doi: 10.1186/s40478-018-0558-5.

Neuropathology and Cognitive Performance in Self-Reported Cognitively Healthy Centenarians

Free PMC article

Neuropathology and Cognitive Performance in Self-Reported Cognitively Healthy Centenarians

Andrea B Ganz et al. Acta Neuropathol Commun. .
Free PMC article


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 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.

Keywords: 100-plus Study; Alzheimer’s disease; Clinicopathological correlation; Cognitively healthy centenarians; Healthy aging; Neuropathology.

Conflict of interest statement

Ethics approval and consent to participate

The 100-Plus Study was approved by the Medical Ethical Committee of the VU University Medical Center. Informed consent was obtained from all study participants. The detailed study protocol is described elsewhere [19].

Consent for publication

All authors and co-authors have reviewed and approved the manuscript for submission.

Competing interests

The authors declare that they have no competing interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Fig. 1
Fig. 1
Distribution and severities of pathology within the group of centenarians. For atrophy and atherosclerosis, n = 40. n = 35 for Thal stage GVD* and pTDP-43 stage, for all other pathologies, n = 26. Thal stage GVD* indicates a staging system adapted from Thal et al., 2011 [44]
Fig. 2
Fig. 2
Distribution of performance on selected neuropsychological tests within the group of centenarians at baseline and last visit. For all neuropsychological tests, n = 40. If a test was not administered or not completed, the score was indicated as not available (N/A), set apart from the scores by a dashed line. Dots are scattered to ensure visibility of all points. Cases for which only baseline data is available (T0) are shown as black circles, cases with one (T1), two (T2) or three (T3) follow-up visit are shown as blue squares and red or green triangles respectively
Fig. 3
Fig. 3
Pearson correlation plot with false discovery rate (fdr). Color and size of the circles indicate the strength of the Pearson correlation coefficient (for Pearson correlation coefficient, p-value and numerical fdr see Additional file 3: Table S3a-c), asterisks indicate the false discovery rate (* < 20%, ** < 10%, *** < 5%), X indicates no correlation. Correlations between the same test at baseline and last visit were performed for 20 cases with at least one follow up visit. Thal stage GVD* indicates that we utilized a staging system for GVD adapted from Thal et al., 2011 [44]
Fig. 4
Fig. 4
Dynamic [11C]PiB-PET and MRI scan of case 100069. The scan was performed by the ECAT EXACT HR1 scanner (Siemens/CTI) 1 month after study inclusion. PET scan for amyloid is positive in the frontal area, MRI shows moderate hippocampal atrophy (MTA score 2) as well as vascular lesions in the white matter (Fazekas score II), suggesting amyloid angiopathy
Fig. 5
Fig. 5
Representative neuropathological lesions found in the hippocampus (a, d, g, j), middle temporal lobe cortex (b, e, h, i, k), amygdala (c) and frontal lobe cortex (f) of case 100069. Shown are exemplary pTDP-43 accumulations (a-c) in the hippocampal subregion CA1 (a1) and dentate gyrus (DG) (a2), temporal pole cortex (T) (b) and Amygdala (Amy) (c), Aβ positivity (d-f) in the form of diffuse and classical plaques in the hippocampal CA1 region (d) and temporal pole cortex (e), as well as CAA of large vessels and capillaries in the frontal lobe (F2) (f). pTau immuno-staining (g-i) is shown as (pre)tangles and neuritic plaque like structures in the hippocampal CA1 region (g) and temporal pole cortex (h1 and h2), as well as astroglial pTau in ARTAG in the temporal pole cortex (i1 and i2). GVD (CK1δ granules) (j-k) is shown in the hippocampus (j) and temporal pole cortex (k). Scale bar 25 μm

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