Biology subjects

Kievit, R. A.

Publications and source records attributed to Kievit, R. A..

22 records · Page 2Linked to original sources

bioRxiv2018

Application of mechanistic methods to clinical trials in multiple sclerosis: the simvastatin case

The analysis of clinical trials is limited to pre-specified outcomes, thereby precluding a mechanistic understanding of the treatment response. Multivariate mechanistic models can elucidate the causal chain of events by simultaneous analysis of multimodal data that link intermediate variables to outcomes of interest. A double-blind, randomised, controlled, phase 2 clinical trial in secondary progressive multiple sclerosis (MS-STAT, NCT00647348) demonstrated that simvastatin (80mg/day) over two years reduced the brain atrophy rate and was associated with beneficial effects on cognitive and disability outcomes. Therefore, this trial offers an opportunity to apply mechanistic models to investigate the hypothesised pathways that link simvastatin to clinical outcome measures, either directly or indirectly via changes in serum total cholesterol levels and to determine which is the more likely.

neuroscience↗

bioRxiv2018

Cardiovascular risk factors for micro- and macro-structural brain changes in healthy ageing

Cardiovascular health declines with age, increasing the risk of hypertension and elevated heart rate in middle- and old age. Here, we used multivariate techniques to investigate the associations between cardiovascular health (diastolic blood pressure, systolic blood pressure and heart rate) and white matter macrostructure (lesion volume and number), and microstructure (as measured by Diffusion Weighted Imaging) in the cross-sectional, population-based Cam-CAN cohort (N = 667, aged 18 to 88). We found that cardiovascular health and age made approximately similar contributions to white matter health and explained up to 56% of variance. Lower diastolic blood pressure, higher systolic blood pressure and higher heart rate were each strongly, and independently, associated with white matter abnormalities on all indices. Body mass and exercise were associated with white matter health, both directly and indirectly via cardiovascular health. These results highlight the importance of cardiovascular risk factors for white matter health across the adult lifespan and suggest that systolic blood pressure, diastolic blood pressure and heart rate affect white matter via separate mechanisms.

neuroscience↗

bioRxiv2017

Age differentiation within grey matter, white matter and between memory and white matter in an adult lifespan cohort

It is well-established that brain structures and cognitive functions change across the lifespan. A longstanding hypothesis called age differentiation additionally posits that the relations between cognitive functions also change with age. To date however, evidence for age-related differentiation is mixed, and no study has examined differentiation of the relationship between brain and cognition. Here we use multi-group Structural Equation Modeling and SEM Trees to study differences within and between brain and cognition across the adult lifespan (18-88 years) in a large (N>646, closely matched across sexes), population-derived sample of healthy human adults from the Cambridge Centre for Ageing and Neuroscience (www.cam-can.org). After factor analyses of grey-matter volume (from T1- and T2-weighted MRI) and white-matter organisation (fractional anisotropy from Diffusion-weighted MRI), we found evidence for differentiation of grey and white matter, such that the covariance between brain factors decreased with age. However, we found no evidence for age differentiation between fluid intelligence, language and memory, suggesting a relatively stable covariance pattern between cognitive factors. Finally, we observed a specific pattern of age differentiation between brain and cognitive factors, such that a white matter factor, which loaded most strongly on the hippocampal cingulum, became less correlated with memory performance in later life. These patterns are compatible with reorganization of cognitive functions in the face of neural decline, and/or with the emergence of specific subpopulations in old age.\n\nSignificance statementThe theory of age differentiation posits age-related changes in the relationships between brain structures and cognitive domains, either weakening (differentiation) or strengthening (de-differentiation), but evidence for this hypothesis is mixed. Using age-varying covariance models in a large cross-sectional adult lifespan sample, we found age-related reductions in the covariance among both brain measures (neural differentiation), but no covariance change between cognitive factors of fluid intelligence, language and memory. We also observed evidence of uncoupling (differentiation) between a white matter factor and cognitive factors in older age, most strongly for memory. Together, our findings support age-related differentiation as a complex, multifaceted pattern that differs for brain and cognition, and discuss several mechanisms that might explain the changing relationship between brain and cognition.

neuroscience↗

bioRxiv2017

Symptoms of Depression in a Large Healthy Population Cohort are related to Subjective Memory Complaints and Memory Performance in Negative Contexts

Decades of research have investigated the impact of clinical depression on memory, which has revealed biases and in some cases impairments. However, little is understood about the effects of sub-clinical symptoms of depression on memory performance in the general population. Here we report the effects of symptoms of depression on memory problems in a large population-derived cohort (N = 2544), 87% of whom reported at least one symptom of depression. Specifically, we investigate the impact of depressive symptoms on subjective memory complaints, objective memory performance on a standard neuropsychological task and, in a subsample (n = 288), objective memory in affective contexts. There was a dissociation between subjective and objective memory performance, with depressive symptoms showing a robust relationship with self-reports of memory complaints, even after adjusting for age, gender, general cognitive ability and symptoms of anxiety, but not with performance on the standardised measure of verbal memory. Contrary to our expectations, hippocampal volume (assessed in a subsample, n = 592) did not account for significant variance in subjective memory, objective memory or depressive symptoms. Nonetheless, depressive symptoms were related to poorer memory for pictures presented in negative contexts, even after adjusting for memory for pictures in neutral contexts. Thus the symptoms of depression, associated with subjective memory complaints, appear better assessed by memory performance in affective contexts, rather than standardised memory measures. We discuss the implications of these findings for understanding the impact of depressive symptoms on memory functioning in the general population.

neuroscience↗