Biology subjects

Hulsman, M.

Publications and source records attributed to Hulsman, M..

4 recordsLinked to original sources

bioRxiv2018

Neuropsychological Test Performance of Cognitively Healthy Centenarians: Normative data from the Dutch 100-plus Study

BackgroundThe population who reaches the extreme age of 100 years is growing. At this age, dementia incidence is high and cognitive functioning is variable and influenced by sensory impairments. Appropriate cognitive testing requires normative data generated specifically for this group. Currently, these are lacking. We set out to generate norms for neuropsychological tests in cognitively healthy centenarians while taking sensory impairments into account.\n\nMethodsWe included 235 centenarians (71.5% female) from the 100-plus Study, who self-reported to be cognitively healthy, which was confirmed by an informant and a trained researcher. Normative data were generated for 15 tests that evaluate global cognition, pre-morbid intelligence, attention, language, memory, executive and visuo-spatial functions by multiple linear regressions and/or percentiles. Centenarians with vision and/or hearing impairments were excluded for tests that required these faculties.\n\nResultsSubjects scored on average 25.6{+/-}3.1 (range 17-30, interquartile-range 24-28) points on the MMSE. Vision problems and fatigue often complicated the ability to complete tests, and these problems explained 41% and 22% of the missing test scores respectively, whereas hearing problems (4%) and task incomprehension (6%) only rarely did. Sex and age showed a limited association with test performance, whereas educational level was associated with performance on the majority of the tests.\n\nConclusionsNormative data for the centenarian population is provided, while taking age-related sensory impairments into consideration. Results indicate that, next to vision impairments, fatigue and education level should be taken into account when assessing cognitive functioning in centenarians.

epidemiology↗

bioRxiv2018

Centenarian Controls Increase Variant Effect-sizes by an average two-fold in an Extreme Case-Extreme Control Analysis of Alzheimer’s Disease

The detection of genetic loci associated with Alzheimers disease (AD) requires large numbers of cases and controls because variant effect-sizes are mostly small. We hypothesized that variant effect-sizes should increase when individuals who represent the extreme ends of a disease spectrum are considered, as their genomes are assumed to be maximally enriched or depleted with disease-associated genetic variants.\n\nWe used 1,073 extensively phenotyped AD cases with relatively young age at onset as extreme cases (66.3{+/-}7.9 years), 1,664 age-matched controls (66.0{+/-}6.5 years) and 255 cognitively healthy centenarians as extreme controls (101.4{+/-}1.3 years). We estimated the effect-size of 29 variants that were previously associated with AD in genome-wide association studies.\n\nComparing extreme AD-cases with centenarian-controls increased the variant effect-size relative to published effect-sizes by on average 1.90-fold (SE=0.29, p=9.0x10-4). The effect-size increase was largest for the rare high-impact TREM2 (R74H) variant (6.5-fold), and significant for variants in/near ECHDC3 (4.6-fold), SLC24A4-RIN3 (4.5-fold), NME8 (3.8-fold), PLCG2 (3.3-fold), APOE-{varepsilon}2 (2.2-fold) and APOE-{varepsilon}4 (2.0-fold). Comparing extreme phenotypes enabled us to replicate the AD association for 10 variants (p<0.05) in relatively small samples. The increase in effect-sizes depended mainly on using centenarians as extreme controls: the average variant effect-size was not increased in a comparison of extreme AD cases and age-matched controls (0.94-fold, p=6.8x10-1), suggesting that on average the tested genetic variants did not explain the extremity of the AD-cases. Concluding, using centenarians as extreme controls in AD case-controls studies boosts the variant effect-size by on average two-fold, allowing the replication of disease-association in relatively small samples.

genetics↗

bioRxiv2018

Neuropathology and cognitive performance in centenarians

AbstractWith 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 A{beta} 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 A{beta}-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.

neuroscience↗

bioRxiv2018

The 100-plus Study of Dutch cognitively healthy centenarians: rationale, design and cohort description

RATIONALEAlthough the incidence of dementia increases exponentially with age, some individuals reach >100 years with fully retained cognitive abilities. To identify the characteristics associated with the escape or delay of cognitive decline, we initiated the 100-plus Study (www.100plus.nl).\n\nDESIGNThe 100-plus Study is an on-going prospective cohort study of Dutch centenarians who self-reported to be cognitively healthy, their first-degree family members and their respective partners. We collect demographics, life history, medical history, genealogy, neuropsychological data and blood samples. Centenarians are followed annually until death. PET-MRI scans and feces donation are optional. Almost 30% of the centenarians agreed to post-mortem brain donation.\n\nCOHORT DESCRIPTIONTo date (September 2018), 332 centenarians were included in the study. We analyzed demographic statistics of the first 300 centenarians (25% males) included in the cohort. Centenarians came from higher socio-economic classes and had higher levels of education compared to their birth cohort; alcohol consumption of centenarians was similar, and most males smoked during their lifetime. At baseline, the centenarians had a median MMSE score of 25 points (IQR: 22.0-27.5); the large majority lived independently, retained hearing and vision abilities and was independently mobile. Mortality was associated with cognitive functioning: centenarians with a baseline MMSE score [≥]26 and <26 points had a mortality percentage of respectively 17% and 42% per annual year in the second year after baseline (p=0.003). The cohort was 2.1-fold enriched with the neuroprotective APOE-{varepsilon}2 allele relative to 60-80 year-old population controls (p=4.8x10-7), APOE-{varepsilon}3 was unchanged and the APOE-{varepsilon}4 allele was 2.3-fold depleted (p=6.3x10-7).\n\nCONCLUSIONSComprehensive characterization of the 100-plus cohort of cognitively healthy centenarians might reveal protective factors that explain the physiology of long-term preserved cognitive health.

neuroscience↗