Biology subjects

Chappell, F. M.

Publications and source records attributed to Chappell, F. M..

3 recordsLinked to original sources

bioRxiv2026

APOE4 genotype, blood-brain barrier leakage and ischaemic stroke subtype and location

BackgroundApolipoprotein E (APOE) has been implicated in blood-brain barrier (BBB) dysfunction and may influence ischaemic cerebrovascular disease and cerebral small-vessel disease (cSVD). This study examined associations between APOE genotype, BBB permeability, and infarct distribution in patients with mild ischemic stroke. MethodsWe recruited patients with mild ischemic stroke who underwent structural and dynamic contrast-enhanced MRI (DCE-MRI) and APOE genotyping. Infarct type and location, white matter hyperintensities (WMH), and perivascular spaces (PVS) were assessed. BBB-related metrics were quantified using fractional plasma volume (vP) and permeability-surface area product (PS) across five brain regions of interest: deep grey matter (DGM), hippocampus, thalamus, normal-appearing white matter (NAWM), and WMH. Associations between genotype, BBB metrics, vascular risk factors, and age were evaluated using linear mixed-effects models. Binary logistic regression was also applied to assess the association between APOE status and infarct location by vascular territory (anterior vs posterior circulation). ResultsAmong 147 patients with APOE genotype and BBB measures, APOE4 carriers (n=44) demonstrated a greater proportion of posterior circulation infarcts than E3/E3 individuals (n=80; 56.4% versus 32.9%), including higher frequencies of posterior cerebral artery cortical, posterior borderzone, and thalamic infarcts. Mean PS and vP did not differ significantly by genotype. Increasing age was associated with lower PS across multiple regions and lower vP in WMH, while higher vascular risk burden was associated with lower vP in NAWM and WMH. Inclusion of regional BBB metrics did not substantially alter APOE4 effect estimates in infarct-location models. ConclusionsAPOE4 carriers showed a posterior-predominant infarct distribution despite similar BBB permeability and vascularity measures. Age and vascular risk burden were more strongly associated with BBB-related imaging metrics than APOE genotype. These findings add to evidence suggesting that APOE genotype may influence regional cerebrovascular vulnerability and that this effect is unlikely to be fully explained by DCE-MRI-derived measures of BBB permeability and vascularity alone.

neuroscience↗

bioRxiv2019

Intracranial functional haemodynamic relationships in patients with cerebral small vessel disease

BackgroundCerebral small vessel disease (SVD) is a major cause of stroke and dementia. The underlying cerebrovascular dysfunction is poorly understood. We investigated cerebrovascular reactivity, blood flow, vascular and cerebrospinal fluid (CSF) pulsatility, and their independent relationship to SVD features, in patients with minor ischaemic stroke and MRI evidence of SVD.\n\nMethodsWe recruited patients with minor ischaemic stroke and assessed CVR using Blood Oxygen Level Dependent (BOLD) MRI during a hypercapnic challenge, cerebral blood flow, vascular and CSF pulsatility using phase contrast MRI, and structural MR brain imaging to quantify white matter hyperintensities (WMH) and perivascular spaces (PVS). We quantified CVR in seven white matter and six subcortical grey matter regions, measured blood flow in carotid and vertebral arteries, intracranial venous sinuses, internal jugular veins and CSF flow at the aqueduct and foramen magnum. We used multiple regression to identify SVD features, blood flow and pulsatility parameters associated with CVR, controlling for patient characteristics.\n\nResultsIn 53 of 60 patients with complete data (age 68.0{+/-}8.8, 74% male, 75% hypertensive), CVR in grey and white matter decreased with increasing blood pressure (BP, respectively -0.001%/mmHg, p=0.01 and -0.006%/mmHg, p=0.01, per mmHg increase in BP). After controlling for age, gender and systolic BP, white matter CVR decreased with increasing WMF volume (-0.01%/mmHg per log10 increase in WMH volume, p=0.02) and basal ganglia PVS (-0.01%/mmHg per point increase in PVS score, p=0.02). White matter CVR decreased with increasing venous pulsatility (superior sagittal sinus -0.03%/mmHg, p=0.02, per unit increase in pulsatility index) but not with cerebral blood flow (p=0.58). Lower foramen magnum CSF stroke volume was associated with worse white matter CVR (0.04%/mmHg per ml increase in stroke volume, p=0.04) and increased basal ganglia PVS.\n\nConclusionsContemporaneous assessment of CVR, intracranial vascular and CSF pulsatility demonstrates important interrelationships of these vascular functions in humans. Decreased CVR, increased venous pulsatility and reduced foramen magnum CSF stroke volume suggests that dynamic vascular dysfunctions underpin PVS dysfunction and WMH development. Improved understanding of microvascular dysfunction and CSF dynamics offers new intervention targets to reduce SVD lesion development and their impact on cognitive dysfunction and stroke.

neuroscience↗

bioRxiv2018

Spatial Gradient of Microstructural Changes in Normal-Appearing White Matter in Tracts Affected by White Matter Hyperintensities in Older Age

Brain white matter hyperintensities (WMH), common in older adults, may contribute to cortical disconnection and cognitive dysfunction. The presence of WMH within white matter (WM) tracts indicates underlying microstructural WM changes that may also affect the normal-appearing WM (NAWM) of a tract. We performed an exploratory study using diffusion magnetic resonance imaging of 52 healthy participants from the Lothian Birth Cohort 1936 (age 72.2 {+/-} 0.7 years) selected to include a range of WMH burden, to quantify microstructural changes of tracts intersecting WMH. We reconstructed tracts using automated tractography and identified intersections with WMH. Tissue volumes and water diffusion tensor parameters (mean diffusivity (MD) and fractional anisotropy (FA)) were established for tract-WMH and tract-NAWM. MD and FA were also measured for tract-NAWM at 2 mm incremental distances from the tract-WMH edge, and from the edge of nearby, non-intersecting, WMH. We observed microstructural changes in tract-WMH suggestive of tissue damage. Tract-NAWM also showed a spatial gradient of FA and MD abnormalities, which diminished with distance from the tract-WMH. Nearby WMH lesions, not directly crossed by the tract, also affected tract microstructure with a similar pattern. Additionally, both FA and MD changes in tract-NAWM were predicted by FA and MD changes respectively in tract-WMH. FA was also predicted by tract-WMH overlap volume, whereas MD was better predicted by whole-brain WMH load. These results suggest that tract-NAWM microstructure is affected by the pathological process underlying WMH, when WMH are either within or near to the tract. The changes in NAWM tract tissue may indicate future lesion progression and may play an important role in cognitive ageing.

neuroscience↗