Biology subjects

Jones, D. K.

Publications and source records attributed to Jones, D. K..

4 recordsLinked to original sources

bioRxiv2018

The causal structure of age-dependent limbic decline: fornix white matter glia damage causes hippocampal grey matter damage, not vice versa.

Aging leads to gray and white matter decline but their causation remains unclear. We explored two broad classes of models of age and dementia risk related brain changes. The first class of models emphasises the importance of gray matter: age and risk-related processes cause neurodegeneration and this causes damage in associated white matter tracts. The second class of models reverses the direction of causation: aging and risk factors cause white matter damage and this leads to gray matter damage. We compared these models with linear mediation analysis and quantitative multi-modal MRI indices (from diffusion, quantitative magnetization transfer and relaxometry imaging) of tissue properties in two limbic structures implicated in age-related memory decline: the hippocampus and the fornix in 166 asymptomatic individuals (aged 38 - 71 years). Aging was associated with apparent glia but not axon density damage in the fornix. Mediation analysis unambiguously supported white matter damage causing gray matter decline; controlling for fornix glia damage, the correlation between age and hippocampal damage disappears, but not vice versa. Fornix and hippocampal tissue loss were both associated with reductions in episodic memory performance. The implications of these findings for neuroglia and neurodegenerative models of aging and late onset dementia are discussed.

neuroscience↗

bioRxiv2018

Adipokines contribute to central-obesity related reductions in myelin-sensitive MRI indices in the fornix.

Midlife obesity is a risk factor of late onset Alzheimers disease (LOAD) but why this is the case remains unknown. As systemic inflammation is involved in both conditions, one possibility is that obesity-related neuroinflammation may contribute to the development of LOAD. Neuroinflammation is closely linked to white matter myelin loss, and this can be measured in vivo with quantitative magnetization transfer (qMT) imaging. Here, we investigated whether differences in obesity measures, i.e., in Waist Hip Ratio (WHR), abdominal visceral and subcutaneous fat volume fractions and Body Mass Index (BMI), were associated with reductions in qMT indices of apparent myelin in temporal white matter pathways involved in LOAD (i.e., the fornix, the parahippocampal cingulum and the uncinate fasciculus compared with whole brain and cortico-spinal white matter) in 166 cognitively healthy individuals (38-71 years of age). Obesity-related effects on myelin-sensitive markers were contrasted with differences in apparent axon density from dual-shell diffusion Neurite Orientation Dispersion and Density Imaging (NODDI). Differences in WHR and in visceral fat volume fractions were negatively correlated with differences in qMT estimates of apparent myelin and tissue metabolism in the fornix but not with any other microstructural components. These correlations were not explained by demographic (age, sex, education), health (hypertension, alcohol consumption, sedentary lifestyle) or genetic (APOE genotype, family history of dementia) risk factors of LOAD. Furthermore, differences in the ratio of plasma concentrations of leptin and adiponectin were also positively correlated with differences in C-Reactive Protein concentrations, and contributed significantly to the correlations between central obesity and myelin-sensitive metrics in the fornix. These results are consistent with the view that visceral fat-related chronic inflammation may damage white matter myelin in limbic regions, known to be vulnerable to LOAD pathology.

neuroscience↗

bioRxiv2018

Genetic risk for schizophrenia and developmental delay is associated with shape and microstructure of midline white matter structures

Genomic copy number variants (CNVs) are amongst the most highly penetrant genetic risk factors for neuropsychiatric disorders. The scarcity of carriers of individual CNVs and their phenotypical heterogeneity limits investigations of the associated neural mechanisms and endophenotypes. We applied a novel design based on CNV penetrance for schizophrenia and developmental delay that allows us to identify structural sequelae that are most relevant to neuropsychiatric disorders. Our focus on brain structural abnormalities was based on the hypothesis that convergent mechanisms contributing to neurodevelopmental disorders would likely manifest in the macro- and microstructure of white matter and cortical and subcortical grey matter. 21 adult participants carrying neuropsychiatric risk CNVs (including those located at 22q11.2, 15q11.2, 1q21.1, 16p11.2, and 17q12) and 15 age- and gender matched controls underwent T1-weighted structural, diffusion and quantitative T1 relaxometry MRI.\n\nThe macro- and microstructural properties of the cingulum bundles were associated with penetrance for both developmental delay and schizophrenia, in particular curvature along the anterior-posterior axis (Sz: pcorr=0.026; DD: pcorr=0.035) and intracellular volume fraction (Sz: pcorr=0.019; DD: pcorr=0.064) Further principal component analysis showed alterations in the interrelationships between the volumes of several mid-line white matter structures (Sz: pcorr=0.055; DD, pcorr=0.027). In particular, the ratio of volumes in the splenium and body of the corpus callosum was significantly associated with both penetrance scores (Sz: p=0.037; DD; p=0.006). Our results are consistent with the notion that a significant alteration in developmental trajectories of mid-line white-matter structures constitutes a common neurodevelopmental aberration contributing to risk for schizophrenia and intellectual disability.

neuroscience↗

bioRxiv2018

Superoanterior Fasciculus (SAF): Novel fiber tract revealed by diffusion MRI fiber tractography

Substantial progress in acquisition, processing, and analysis boosted the reliability of diffusion-weighted MRI and increased the accuracy of mapping white matter pathways with fiber tractography. Since the introduction of region of interest (ROI) based virtual dissection by Conturo et al. in 1999, researchers have used tractography to identify white matter pathways, which faithfully represented previously known structures revealed by dyeing studies or post-mortem descriptions. The reconstructed streamlines are subjects of bundle-specific in vivo investigations to show differences between groups (e.g., comparing fractional anisotropy (FA) between patients and healthy controls) or to describe the relation between diffusion scalars and metrics of interest (e.g.: normal aging or changes due to learning). By applying a reverse strategy in using diffusion-weighted MRI tractography first, then supporting the findings with other techniques, we have identified a bilateral tract in the frontal cortex - the superoanterior fasciculus (SAF). The tract resembles the anterior shape of the cingulum bundle, but is located more frontally. To erase the chance that our findings are confounded by acquisition, processing or modeling artifacts, we analyzed a total of 421 subjects from four cohorts with different acquisition schemes and diverse processing pipelines. The findings were also completed with other non-MRI techniques, such as polarized light microscopy and dissection. Tractography results demonstrate a long pathway and are consistent among cohorts, while dissection indicates a series of U-shaped fibers connecting adjacent gyri. In conclusion, we hypothesize that these consecutive U-shaped fibers emerge to form a pathway, thereby resulting in a multicomponent bundle.

neuroscience↗