Biology subjects

Detre, J. A.

Publications and source records attributed to Detre, J. A..

22 records · Page 2Linked to original sources

bioRxiv2019

Disconnectome Associated with Progressive Ischemic Periventricular White Matter Lesions

Periventricular white matter (PVWM) hyperintensities on T2-weighted MRI are ubiquitous in older adults and associated with dementia. Efforts to determine how PVWM lesions impact structural connectivity to impinge on brain function remain challenging in part because white matter tractography algorithms for diffusion tensor imaging (DTI) may lose fidelity in the presence of lesions. We used a "virtual lesion" approach to characterize the "disconnectome" associated with periventricular white matter (PVWM) lesions. We simulated progressive ischemic PVWM lesions using sub-threshold cerebral blood flow (CBF) masks derived from a previously published group-averaged map acquired from N=436 middle aged subjects in which the lowest CBF values were seen in PVWM and morphologically recapitulated the spatial pattern of PVWM hyperintensities seen in typical aging. We mimicked the age-dependent evolution of PVWM lesion burden by varying the threshold applied to the CBF map. We found that the optic radiations, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, corpus callosum, temporopontine tract and fornix were affected in early simulated PVWM lesion burdens, and that the connectivity of subcortical, cerebellar, and visual regions were significantly disrupted with increasing simulated PVWM lesion burdens. We also validated the use of virtual lesions to simulate the disconnectome due to WM hyperintensities in a cognitively normal elderly cohort (N=46) by evaluating correlations between structural and functional connectomes. The virtual lesion approach provides new insights into the spatial-temporal changes of the brain structural connectome under progressive PVWM burdens during normal aging. Significance StatementWe determined the disconnectomes caused by periventricular white matter (PVWM) lesions using the "virtual lesion" approach. We validated the approach using lesions, DTI and resting-state fMRI data from elderly subjects. We simulated disconnectome of progressive PVWM lesions using cerebral blood flow (CBF) masks in PVWM region with normative DTI data, which provides specificity for an ischemic mechanism and begins to address the possibility that connectivity may be affected by reduced CBF prior to the development of overt lesions on T2-weighted FLAIR MRI. The current study presented new insights into the spatial-temporal evolutions of the brain structural connectome under progressive PVWM burdens under normal aging.

neuroscience↗

bioRxiv2019

Preserved global cerebral blood flow accounts for youthful processing speed in older adults

Preserved cognitive performance is one of the key contributors to successful aging. The processing speed theory and prefrontal executive theory - are competing theories regarding the general causes of cognitive aging. Here, we used a theoretically-driven framework to investigate the neural correlates of older adults with preserved processing speed. Older adults with youth-like processing speed (SuperAgers) were compared with normal aged adults (TypicalAgers) using neuroimaging methods. Global cerebral blood flow (CBF) accounted for approximately 45% of the variance in processing speed, while neither regional CBF nor other structural measures predicted additional variance. In addition, despite having significantly cortical thinning, SuperAgers still shown comparable global CBF levels with young adults. These results support the global mechanism suggested by processing speed theory and indicate that global CBF may serve as a biomarker of cognitive aging.

neuroscience↗

bioRxiv2019

Multimodal parameters of brain structure and function related to sex differences in cognitive performance.

The Parieto-Frontal Integration Theory (PFIT) identified a fronto-parietal network of regions where individual differences in brain parameters most strongly relate to cognitive performance. PFIT was supported and extended in adult samples, but not in youths or within single-scanner well-powered multimodal studies. We performed multimodal neuroimaging in 1601 youths age 8-22 on the same 3-Tesla scanner with contemporaneous neurocognitive assessment, measuring volume, gray matter density (GMD), mean diffusivity (MD), cerebral blood flow (CBF), resting-state functional MRI measures of amplitude of low frequency fluctuations (ALFF) and regional homogeneity (ReHo), and activation to a working memory and a social cognition task. Across age and sex groups, better performance was associated with higher volumes, greater GMD, lower MD, lower CBF, higher ALFF and ReHo and greater activation for the working memory task in PFIT regions. However, additional cortical, striatal, limbic and cerebellar regions showed comparable effects, hence PFIT needs expansion into an Extended PFIT (ExtPFIT) network incorporating nodes that support motivation and affect. Associations of brain parameters became stronger with advancing age group from childhood to adolescence to young adulthood, effects occurring earlier in females. This ExtPFIT network is developmentally fine-tuned, optimizing abundance and integrity of neural tissue while maintaining low resting energy state.

neuroscience↗

bioRxiv2018

Variability in the Analgesic Response to Ibuprofen Following Third-Molar Extraction is Associated with Differences in Activation of the Cyclooxygenase Pathway

The analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) has long been recognized to be limited by substantial interindividual variability in pain relief, but the underlying mechanisms are not well understood. We performed pain phenotyping, functional neuroimaging, pharmacokinetic/pharmacodynamic assessments, inflammation biomarkers, and gene expression profiling in healthy subjects who underwent surgical extraction of bony impacted third molars, in order to characterize factors associated with heterogeneity in response to ibuprofen.\n\nSubjects were treated with rapid-acting ibuprofen (400 mg; N=19) or placebo (N=10) in a randomized, double-blind design. Compared to placebo, ibuprofen-treated subjects exhibited greater reduction in pain scores, alterations in regional cerebral blood flow in brain regions associated with pain processing, and inhibition of ex vivo cyclooxygenase activity and urinary prostaglandin metabolite excretion as indices of biochemical drug action (p<0.05). As expected, ibuprofen-treated subjects could be stratified into partial responders (N=9, required rescue medication within the dosing interval) and complete responders (N=10, no rescue medication). This was also reflected by differences in pain scores (p<0.01) as early as 30 minutes following drug administration (p<0.05). Variability in analgesic efficacy was not associated with demographic or clinical characteristics, ibuprofen pharmacokinetics, metabolizing enzyme genotype, or the degree of cyclooxygenase inhibition by ibuprofen. However, complete responders had higher concentrations of inflammatory biomarkers in urine and serum, than partial responders. Specifically, a stable urinary prostaglandin E2 metabolite, serum TNF and IL-8 were higher in patients who did not require rescue medication compared those who did (p < 0.05). RNAseq gene expression analysis in PBMCs collected after surgery and ibuprofen administration showed enrichment of inflammation related pathways among genes differentially expressed (q < 0.2) between complete and partial responders\n\nThese findings suggest that patients who receive substantial pain relief from ibuprofen have a more pronounced activation of the prostanoid biosynthetic pathway and regulation of the inflammatory pain phenotype differs from those patients who are insufficiently treated with ibuprofen alone and may require an opioid or other therapeutic intervention.

genomics↗