Biology subjects

McDonald, S. J.

Publications and source records attributed to McDonald, S. J..

3 recordsLinked to original sources

bioRxiv2025

Factor Analysis of Multimodal MRI, Biofluid and Vascular Health Biomarkers Reveals Latent Constructs of Brain Health

Individual imaging and fluid biomarkers provide insights into specific components of brain health, but integrated multimodal approaches are necessary to capture the complex, interrelated biological systems that contribute to brain homeostasis and neurodegenerative disease. Using data from the Brain and Cognitive Health (BACH) cohort study (N=127; mean age=67 years, 68% women), we performed an exploratory factor analysis to identify latent constructs of brain health. We included multimodal neurovascular imaging markers, brain atrophy metrics, plasma Alzheimers disease (AD) biomarkers and cardiovascular risk factors. Five constructs emerged: "Brain & Vascular Health" (greater hippocampal volume, basal ganglia enlarged perivascular spaces [ePVS], cerebral blood flow and HDL cholesterol; lower ventricle volume and BMI); "Structural Integrity" (greater cortical thickness, fractional anisotropy and basal ganglia ePVS); "Fluid Transport" (greater white matter ePVS and Free Water); "AD Biomarkers" (higher phosphorylated tau [pTau]181 and pTau217; lower amyloid-beta 42/40 ratio); and "Neuronal Injury" (higher glial fibrillary acidic protein and neurofilament light chain). All constructs were associated with age ({beta}=-0.70-0.39, p[≤].014), except for Fluid Transport (p>.05). Brain & Vascular Health and Structural Integrity (partial r=.305, p<.001), and AD Biomarkers and Neuronal Injury (partial r=.248, p=.005) were positively correlated. Only Brain & Vascular Health was associated with global cognition ({beta}=0.27, SE=0.13, p=.043). These findings provide a data-driven framework for examining distinct constructs underlying vascular health, fluid regulation and neurodegenerative pathology. We demonstrate the utility of using multiple biomarkers to probe these biological systems, paving the way for future research to explore how these systems change across diverse neurodegenerative conditions.

neuroscience↗

bioRxiv2025

Plasma pTau-217 Correlates with Brain Atrophy, Cognition, and CSF Biomarkers in a Cognitively Healthy Community Cohort

Plasma biomarkers are promising for detecting Alzheimers disease (AD) pathology, but their role in cognitively healthy individuals remains unclear. Plasma pTau-217 has high diagnostic accuracy for clinical and prodromal AD, yet its relevance in preclinical stages is underexplored. We examined if plasma biomarkers of AD, neurodegeneration, and neuroinflammation were associated with cognition, brain structure, and their cerebrospinal fluid (CSF) counterparts in dementia-free older adults. We studied community-based, dementia-free older adults from the Brain and Cognitive Health (BACH) cohort. Neuropsychological testing assessed global cognition (MMSE), memory (Logical Memory II), visual processing (Hooper Visual Organization Test), processing speed (Trail Making Test-A), and reasoning (Similarities). Paired plasma and CSF biomarkers (pTau-217, pTau-181, GFAP, NfL, A{beta}42/40) were measured using SIMOA. MRI-derived cortical thickness was used as a neurodegeneration marker. Multivariable linear regression assessed associations between log10-transformed plasma biomarker levels, cognition (adjusted for age, sex, education, hypertension, hyperlipidemia, diabetes), and cortical thickness (adjusted for age, sex, education, and intracranial volume). Pearsons correlations and Bland-Altman plots evaluated plasma-CSF agreement. There were 147 dementia-free participants (mean age{+/-}SD: 66.7{+/-}7.7 years; 56 % women). Higher plasma pTau-217 levels associated with lower global cognition scores ({beta} -0.80, 95% C.I. -1.56, -0.03, p=0.041) and abstract reasoning ({beta} -0.86, 95% confidence interval [C.I.] -1.62, -0.09, p=0.028). Greater plasma pTau-217 also associated with lower global cortical thickness ({beta}eta [{beta}] -0.21, 95% confidence interval [C.I]. -0.37, -0.06, per log unit change; p=0.006). No associations were found between the plasma biomarkers and processing speed or visual processing (p>0.05 for all). Among 47 participants with paired plasma-CSF biomarkers, plasma pTau-217 showed the strongest correlation with its CSF counterpart (R=0.76, p<0.0001), outperforming pTau-181 (R=0.61, p<0.0001), GFAP (R=0.66, p<0.0001), NfL (R=0.56, p<0.0001), and A{beta}42/40 (R=0.53, p=0.0001). In conclusion, plasma pTau-217 levels were associated with both cognition and cortical thickness in dementia-free older adults. All plasma biomarkers correlated significantly with their CSF counterpart. These findings reinforce the utility of plasma biomarkers, particularly pTau-217, as indicators of neurodegenerative processes, even in asymptomatic individuals.

neuroscience↗

bioRxiv2025

Fos expression in the periaqueductal gray, but not the ventromedial hypothalamus, is correlated with psychosocial stress-induced cocaine-seeking behavior in rats

Psychosocial stressors are known to promote cocaine craving and relapse in humans but are infrequently employed in preclinical relapse models. Consequently, the underlying neural circuitry by which these stressors drive cocaine seeking has not been thoroughly explored. Using Fos expression analyses, we sought to examine whether the ventromedial hypothalamus (VMH) or periaqueductal gray (PAG), two critical components of the brains hypothalamic defense system, are activated during psychosocial stress-induced cocaine seeking. Adult male and female rats self-administered cocaine (0.5 mg/kg/inf IV, fixed-ratio 1 schedule, 2 h/session) over 20 sessions. On sessions 11, 14, 17, and 20, a tactile cue was present in the operant chamber that signaled impending social defeat stress (n=16, 8/sex), footshock stress (n=12, 6/sex), or a no-stress control condition (n=12, 6/sex) immediately after the sessions conclusion. Responding was subsequently extinguished, and rats were tested for reinstatement of cocaine seeking during re-exposure to the tactile cue that signaled their impending stress/no-stress post-session event. All experimental groups displayed significant reinstatement of cocaine seeking, but Fos analyses indicated that neural activity within the rostrolateral PAG (rPAGl) was selectively correlated with cocaine-seeking magnitude in the socially-defeated rats. rPAGl activation was also associated with active-defense coping behaviors during social defeat encounters and with Fos expression in prelimbic prefrontal cortex and orexin-negative cells of the lateral hypothalamus/perifornical area in males, but not females. These findings suggest a potentially novel role for the rPAGl in psychosocial stress-induced cocaine seeking, perhaps in a sex-dependent manner.

neuroscience↗