Michelle Heleen Zonneveld

Background: The 1-HMR metabolomics-based MetaboHealth score, comprised of 14 serum metabolic markers, associates with disease-specific mortality, but it is unclear whether the score also reflects cognitive changes and functional impairment. Objectives: Assess the associations between the MetaboHealth score with cognitive and daily functioning, and cognitive and functional decline in older people at increased cardiovascular risk. Methods: 5292 older people free of dementia at baseline with mean age 75.3 years (standard deviation=3.4) from the Prospective Study of Pravastatin in the Elderly (PROSPER). MetaboHealth score was measured at baseline, and cognitive function and functional independence were measured at baseline and every 3 months during up to 2.5-years follow-up. Cognitive function was assessed using the Stroop test (selective attention), the Letter Digit Coding test (LDCT) (processing speed), and the two versions of the Picture Learning test (delayed and immediate; memory). Two tests of functional independence were used: Barthel Index (BI) and instrumental activities at daily living (IADL). Results: A higher MetaboHealth score was associated with worse cognitive function (in all domains) and with worse functional independence. For example, after full adjustments, a 1-SD higher MetaboHealth score was associated with 9.02 (95%CI 7.29, 10.75) seconds slower performance on the Stroop test and 2.79 (-3.26,-2.21) less digits coded on the LDCT. During follow-up, 1-SD higher MetaboHealth score was associated with an additional decline of 0.53 (0.23,0.83) seconds on the Stroop test and -0.08 (-0.11,-0.06) points on the IADL. Conclusion: Metabolic disturbance, as reflected by an increased metabolomics-based health score, may mark future cognitive and functional decline.

Prospective cohort studies have implied associations between blood levels of troponin T, troponin I, NT-proBNP, GDF15, dementia, and cognitive function, without providing evidence favoring possible causality. We aimed to assess the causal associations of these cardiac blood biomarkers with dementia and cognition using two-sample Mendelian randomization (MR). Independent genetic instruments (p < 5e⁻⁷) for troponin T and I, N-terminal pro B-type natriuretic peptide (NT-proBNP) and growth-differentiation factor 15 (GDF15) were obtained from previously-performed genome-wide association studies of predominantly European ancestry. Summary statistics for gene-outcome associations in European-ancestry participants, for the two-sample MR analyses, were obtained for general cognitive performance (n = 257,842) and dementia (n = 111,326 clinically diagnosed and “proxy” AD cases, and 677,663 controls). Two-sample MR analyses were performed using inverse variance-weighted (IWV) analyses. Sensitivity analyses to evaluate horizontal pleiotropy included weighted median estimator, MR-Egger, and MR using cis-SNPs only. Using IVW, we did not find evidence for possible causal associations between genetically influenced cardiac biomarkers with cognition and dementia. For example, per standard deviation (SD) higher cardiac blood biomarker, the odds ratio for risk of dementia was 1.06 (95%CI 0.90; 1.21) for troponin T, 0.98 (95%CI 0.72; 1.23) for troponin I, 0.97 (95%CI 0.90; 1.06) for NT-proBNP and 1.07 (95%CI 0.93; 1.21) for GDF15. Sensitivity analyses showed higher GDF15 was significantly associated with higher dementia risk and worse cognitive function. We did not find strong evidence that cardiac biomarkers causally influence dementia risk. Future research should aim at elucidating the biological pathways through which cardiac blood biomarkers associate with dementia.

Objective: to investigate the association between variability and loss of body weight with subsequent cognitive performance and activities of daily living in older individuals.Design: cross-sectional cohort study.Setting: PROspective Study of Pravastatin in the Elderly at Risk, multicentre trial with participants from Scotland, Ireland and the Netherlands.Subjects: 4,309 participants without severe cognitive dysfunction (mean age 75.1 years, standard deviation (SD) = 3.3), at higher risk for cardiovascular disease (CVD).Methods: body weight was measured every 3 months for 2.5 years. Weight loss was defined as an average slope across all weight measurements and as ≥5% decrease in baseline body weight during follow-up. Visit-to-visit variability was defined as the SD of weight measurements (kg) between visits. Four tests of cognitive function were examined: Stroop test, letter-digit coding test (LDCT), immediate and delayed picture-word learning tests. Two measures of daily living activities: Barthel Index (BI) and instrumental activities of daily living (IADL). All tests were examined at month 30.Results: both larger body weight variability and loss of ≥5% of baseline weight were independently associated with worse scores on all cognitive tests, but minimally with BI and IADL. Compared with participants with stable weight, participants with significant weight loss performed 5.83 seconds (95% CI 3.74; 7.92) slower on the Stroop test, coded 1.72 digits less (95% CI −2.21; −1.13) on the LDCT and remembered 0.71 pictures less (95% CI -0.93; −0.48) on the delayed picture-word learning test.Conclusion: in older people at higher risk for CVD, weight loss and variability are independent risk-factors for worse cognitive function.

Elevated cardiac troponin, a biomarker of myocardial injury, has been found in individuals with brain damage and lower cognitive function. We conducted a systematic review to examine the association of troponin with cognitive function, incidence of dementia and dementia-related outcomes. PubMed, Web of Science and EMBASE were searched from inception to August 2022. Inclusion criteria were: (i) population-based cohort studies; (ii) troponin measured as determinant; and (iii) cognitive function in any metric or diagnosis of any type of dementia or dementia-related measures as outcomes. Fourteen studies were identified and included, with a combined total of 38,286 participants. Of these studies, four examined dementia-related outcomes, eight studies examined cognitive function, and two studies examined both dementia-related outcomes and cognitive function. Studies report higher troponin to be associated with higher prevalence of cognitive impairment (n=1), incident dementia (n=1), increased risk of dementia hospitalization (specifically due to vascular dementia) (n=1), but not with incident Alzheimer's Disease (n=2). Majority of studies on cognitive function found elevated troponin also associated with worse global cognitive function (n=3), attention (n=2), reaction time (n=1) and visuomotor speed (n=1), both cross-sectionally and prospectively. Evidence regarding the association between higher troponin and memory, executive function, processing speed, language and visuospatial function was mixed. This was the first systematic review on the association between troponin, cognitive function, and dementia. Higher troponin is associated with subclinical cerebrovascular damage and might act as a risk-marker of cognitive vulnerability.

We aimed to investigate the cross-sectional and longitudinal associations of electrocardiogram (ECG)-based QT, QTc, JT, JTc, and QRS intervals with cognitive function and brain magnetic resonance imaging (MRI) measurements in a cohort of older individuals at increased risk for cardiovascular disease, but free of known arrhythmias. We studied 4627 participants (54% female, mean age 75 years) enrolled in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Ten-second ECGs were conducted at baseline. Cognitive function was tested at baseline and repeated during a mean follow-up time of 3.2 years. Structural MRIs were conducted in a subgroup of 535 participants. Analyses were performed with multivariable (repeated) linear regression models and adjusted for cardiovascular risk-factors, co-morbidities, and cardiovascular drug use. At baseline, longer QT, JT, JTc—but not QTc and QRS intervals—were associated with a worse cognitive performance. Most notably, on the Stroop Test, participants performed 3.02 (95% CI 0.31; 5.73) seconds worse per standard deviation higher QT interval, independent of cardiovascular risk factors and medication use. There was no association between longer ventricular de- or repolarization and structural brain measurements. Therefore, specifically ventricular repolarization was associated with worse cognitive performance in older individuals at baseline but not during follow-up.