Biology subjects

McEvoy, L. K.

Publications and source records attributed to McEvoy, L. K..

5 recordsLinked to original sources

bioRxiv2022

Decline of intrinsic cerebrospinal fluid outflow in healthy humans with age detected by non-contrast spin-labeling MRI

BackgroundClearance of cerebrospinal fluid (CSF) is important for the removal of toxins from the brain, with implication for neurodegenerative diseases. Imaging evaluation of CSF outflow in humans has been limited, relying on injections of contrast agents. Objective of this study was to introduce a novel spin-labeling magnetic resonance imaging (MRI) technique to detect and quantify the movement of endogenously tagged CSF without administration of tracer or contrast media, and use the technique to evaluate CSF outflow in normal human subjects with varying ages. MethodsThis study was performed on a clinical 3-Tesla MRI scanner in healthy subjects (10 males and 6 females; mean age, 47.6 {+/-} 18.9 years; range, 19-71 years) with informed consent. Our non-contrast spin-labeling MRI technique applies a tag pulse on the brain hemisphere, including subarachnoid space, dura mater, brain parenchyma, and images the outflow of the tagged CSF into the superior sagittal sinus. We obtained 3-dimensional images in real time, which was analyzed to determine tagged-signal changes in different regions of the brain involved in CSF outflow or clearance. Additionally, the signal changes over time were fit to a signal curve to determine quantitative flow metrics such as relative CSF flow and volume. These were correlated against subject age to determine aging effects. ResultsWe observed the signal of the tagged CSF moving from the subarachnoid space to the dura mater and parasagittal dura, and finally draining into the superior sagittal sinus. In addition, there was strong evidence of a direct pathway by which tagged CSF flows directly from the subarachnoid space to the superior sagittal sinus, via the lateral wall of superior sagittal sinus. Furthermore, quantitative CSF outflow metrics were shown to decrease significantly with age. ConclusionsWe demonstrated a novel non-invasive MRI technique to evaluate CSF clearance in humans. In this study, we identified possible two CSF clearance pathways, and determined normative values and decline of CSF flow metrics in normal ages. Our work provides a new opportunity to better understand the relationships of these CSF clearance pathways in ages, which may be a significant factor in the age-related prevalence of neurodegenerative diseases. FundingThis study was supported by the National Institutes of Health grants: RF1AG076692 (MM) and R01HL154092 (MM); and made possible by a grant from Canon Medical Systems. Corp., Japan. Clinical trialNot applicable.

neuroscience↗

bioRxiv2021

The genetic etiology of longitudinal measures of predicted brain ageing in a population-based sample of mid to late-age males

Magnetic resonance imaging data are being used in statistical models to predicted brain ageing (PBA) and as biomarkers for neurodegenerative diseases such as Alzheimers Disease. Despite their increasing application, the genetic and environmental etiology of global PBA indices is unknown. Likewise, the degree to which genetic influences in PBA are longitudinally stable and how PBA changes over time are also unknown. We analyzed data from 734 men from the Vietnam Era Twin Study of Aging with repeated MRI assessments between the ages 52 to 72 years. Biometrical genetic analyses twin models revealed significant and highly correlated estimates of additive genetic heritability ranging from 59% to 75%. Multivariate longitudinal modelling revealed that covariation between PBA at different timepoints could be explained by a single latent factor with 73% heritability. Our results suggest that genetic influences on PBA are detectable in midlife or earlier, are longitudinally very stable, and are largely explained by common genetic influences. HighlightsWe explored the genetic and environmental etiology of MRI-based predicted brain age (PBA) in a longitudinal sample of males starting in midlife. Genetic influences on PBA are detectable in midlife or earlier, are longitudinally very stable, and largely explained by common genetic influences.

genetics↗

bioRxiv2019

Sex-dependent polygenic effects on the clinical progressions of Alzheimer’s disease

Sex differences in the manifestations of Alzheimers disease (AD) are under intense investigations 1,2. Despite the emerging importance of polygenic predictions for AD 3-8, the sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on AD can be revealed by characterizing disease progress via the hazard function. We first performed sex-stratified genome-wide associations, and then applied derived sex-dependent weights to two independent cohorts. Sex-matched polygenic hazard scores (PHS) have significantly stronger associations with age-at-disease-onset, clinical progressions, amyloid depositions, neurofibrillary tangles, and composite neuropathological scores, than sex-mismatched PHS, independent of apolipoprotein E. Models without using hazard weights, i.e. polygenic risk scores (PRS), have lower predictive power than PHS and show no evidence for sex differences. Our results indicate revealing sex-dependent genetic architecture requires the consideration of temporal processes of AD. This has strong implications not only for the genetic underpinning of AD but also for how we estimate sex-dependent polygenic effects for clinical use.

genetics↗

bioRxiv2017

Polygenic hazard score: an enrichment marker for Alzheimer’s associated amyloid and tau deposition

BackgroundThere is an urgent need for the early identification of nondemented individuals at the highest risk of progressing to Alzheimers disease (AD) dementia for early therapeutic interventions. Our goal was to evaluate whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo CSF or PET biomarkers of amyloid or tau pathology to prospectively predict cognitive decline and clinical progression to AD dementia in nondemented older individuals.\n\nMethodsWe evaluated 347 cognitive normal (CN) and 599 mild cognitively impaired (MCI) individuals. We first investigated whether PHS can predict CSF or PET amyloid and tau deposition. We evaluated differences in positive and negative predictive values of biomarker status, as a function of PHS risk. Next, we used linear mixed-effects (LME) to examine if PHS and biomarker status in conjunction, best predict longitudinal cognitive and clinical progression. Lastly, we used survival analysis to investigate whether a combination of PHS and biomarker positivity predicts progression to AD dementia better than using PHS or biomarker positivity alone.\n\nFindingsIn CN and MCI individuals, we found that amyloid and total tau positivity systematically varies as a function of PHS. For individuals in greater than the 50th percentile PHS, the positive predictive value for amyloid approached 100%. Similarly, for individuals in less than the 25th percentile PHS, the negative predictive value for total tau approached 85%. Beyond APOE, high PHS individuals with amyloid and tau pathology showed the fastest rate of longitudinal cognitive decline and time to AD dementia progression. Among the CN subgroup, we similarly found that PHS was strongly associated with amyloid positivity and the combination of PHS and biomarker status significantly predicted longitudinal clinical progression.\n\nInterpretationAmong asymptomatic and mildly symptomatic older individuals, PHS considerably improves the predictive value of CSF or PET amyloid and tau biomarkers. Beyond APOE, PHS may be useful for risk stratification and cohort enrichment for MCI and preclinical AD therapeutic trials.

genetics↗

bioRxiv2017

Polygenic hazard scores in preclinical Alzheimer’s disease

Identifying asymptomatic older individuals at elevated risk for developing Alzheimers disease (AD) is of clinical importance. Among 1,081 asymptomatic older adults, a recently validated polygenic hazard score (PHS) significantly predicted time to AD dementia and steeper longitudinal cognitive decline, even after controlling for APOE {varepsilon}4 carrier status. Older individuals in the highest PHS percentiles showed the highest AD incidence rates. PHS predicted longitudinal clinical decline among older individuals with moderate to high CERAD (amyloid) and Braak (tau) scores at autopsy, even among APOE {varepsilon}4 non-carriers. Beyond APOE, PHS may help identify asymptomatic individuals at highest risk for developing Alzheimers neurodegeneration.

genetics↗