Biology subjects

Mecca, A. P.

Publications and source records attributed to Mecca, A. P..

5 recordsLinked to original sources

bioRxiv2026

Greater hypoxic burden predicts weaker gray matter-CSF coordination independent of non-hypoxic arousals: Implications for glymphatic activity

Study ObjectivesObstructive sleep apnea (OSA) is a risk factor for neurodegeneration, and glymphatic impairment may be one mechanistic pathway. Anti-phase coordination between brain pulsations and CSF flow, reflecting compensatory CSF displacement during each vascular pulsation cycle, supports glymphatic activity. This study examined whether hypoxic burden and sleep fragmentation, two distinct OSA pathologies, are differentially associated with brain pulsation-CSF flow dynamics. MethodsThis cross-sectional study included 28 individuals with newly identified OSA and 8 without OSA. Participants completed in-lab polysomnography or WatchPAT testing, providing measures of hypoxic burden, quantified as time below 90% oxygen saturation (T90), and non-hypoxic sleep fragmentation, quantified as respiratory effort-related arousals (RERAs). Participants also completed 7T resting-state functional MRI to estimate global BOLD-CSF, defined as anti-phase cross-correlation between blood-oxygen-level-dependent (BOLD) signal and CSF inflow. Associations were examined using correlation and hierarchical regression. Exploratory analyses examined region-specific BOLD-CSF and brain pulsation strength, quantified as BOLD amplitude. ResultsGreater T90 was associated with weaker global BOLD-CSF, independent of RERAs and covariates ({beta}=0.08,p=0.03). Greater T90 was also associated with higher BOLD amplitude across temporal, frontal, and parietal regions, but this elevation in amplitude was not accompanied by stronger region-specific BOLD-CSF coupling ({beta}=0.001,p>0.05). In contrast, among regions where BOLD amplitude was not associated with T90, greater BOLD amplitude predicted stronger region-specific BOLD-CSF ({beta}=-0.004,p<0.001). RERAs were not associated with global BOLD-CSF or BOLD amplitude. ConclusionsIn OSA, hypoxic burden may be the primary feature associated with impaired brain pulsation and CSF dynamics that support glymphatic activity. These alterations may be pronounced in the temporal lobe, where elevated pulsations were uncoupled from compensatory CSF displacement.

neuroscience↗

bioRxiv2025

Optimized reference region and the effect on test-retest reliability and detection of Parkinson's disease with UCB-J.

[11C]UCB-J is a radioligand targeting synaptic vesicle glycoprotein 2A, used to image synaptic density. For quantification, a small-volume centrum semiovale area was previously optimized as a [11C]UCB-J reference region (CS2mL); however, its high variability resulted in reduced reliability. Herin, we evaluated an alternative reference region method to assess longitudinal test-retest reliability and detection of Parkinsons disease (PD). For estimating distribution volume ratio (DVR), CS2mL and eleven white matter (WM) reference regions (range: 0.5-200 mL) were generated using the Freesurfer WM map. Same-day and longitudinal test-retest variability (TRV) were assessed (24 healthy subjects (HS); n=10 same-day and n=20 longitudinal HRRT scans, range: 7-1028 days). Each reference region was used to evaluate the substantia nigra (SN) and caudate DVRs in HS (n=25) and PD (n=20). The 10mL WM reference region yielded [11C]UCB-J DVR measurements with reduced variability in TRV (same-day: 10mL: 1.2{+/-}5.7%, same-day: CS2mL: -0.9{+/-}9.2% longitudinal: 10mL: 1.5{+/-}7.0%, CS2mL: 1.6{+/-}11.9%,) while maintaining <10% volume of distribution difference, compared to CS2mL. Further, a significant difference between PD and HS groups in SN and caudate DVRs was found using 10mL, with greater effect size (Cohens d 0.61 for SN and 0.66 for caudate) compared to CS2mL (0.38 for SN and 0.43 for caudate).

neuroscience↗

bioRxiv2025

Basal forebrain volume is associated with cortical amyloid burden in cognitively unimpaired older adults at varying genetic risk for Alzheimers disease

BackgroundIn mild cognitive impairment and dementia due to Alzheimers disease (AD), postmortem and in vivo neuroimaging studies have demonstrated significant neuronal loss in the basal forebrain cholinergic system (BFCS), which provides the primary cholinergic input to the cerebral cortex. Within this region, atrophy is most prominent in the nucleus basalis of Meynert (nbM), a group of posteriorly clustered magnocellular neurons in the BFCS. However, less is known surrounding the relationship between amyloid deposition, BFCS atrophy, and medial temporal lobe (MTL) volume loss in the preclinical stages of AD. The current study investigates the relationship between sub-structural BFCS volume and cortical A{beta} burden in cognitively unimpaired middle-aged individuals at varying genetic risk for AD. MethodsCognitively unimpaired participants aged 50-65 with a first-degree family history for AD were genetically screened to select three groups: APOE genotype {varepsilon}4{varepsilon}4 (n=15), {varepsilon}3{varepsilon}4 (n=15), and {varepsilon}3{varepsilon}3 (n=15), matched for age and sex. Participants underwent imaging with [11C]PiB PET and structural 3T MRI. Distribution volumes ratios (DVR) with a whole cerebellum reference region were calculated for [11C]PiB PET analyses. BFCS sub-structural volumes were obtained from the SPM8 Anatomy Toolbox (Cholinergic nuclei [Ch] 1-3, Ch4). MTL subregional volumes (entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus) were extracted using Freesurfer. ResultsBFCS amyloid burden was highest among APOE {varepsilon}4 homozygotes (Ch1-3, F(2, 42)=3.26, P=0.048; Ch4, F(2, 42)=3.82, P= 0.03). Ch4 (nbM), but not Ch1-3 volume, was found to be inversely associated with global A{beta} burden (Pearson r=-0.40, P=0.007). MTL subregional volumes were not associated with global A{beta} burden in the pooled sample. Exploratory analyses in groups stratified by amyloid positivity demonstrated reduced Ch4 volume (P=0.032) and significant inverse associations between Ch4 volume and amyloid burden (Pearson r = -0.70, P=0.02) in A{beta}+ participants. ConclusionsWe observed nbM (Ch4), but not MTL volume, to be significantly inversely associated with cortical amyloid burden in cognitively unimpaired, A{beta}+, middle-aged adults at varying genetic risk for AD. These findings provide further in vivo evidence suggesting that nbM atrophy is an early structural correlate of AD pathogenesis, potentially preceding MTL atrophy.

neuroscience↗

bioRxiv2024

Assessment of the relationship between synaptic density and metabotropic glutamate receptors in early Alzheimer's disease: a multi-tracer PET study

BackgroundThe pathological effects of amyloid {beta} oligomers (A{beta}o) may be mediated through the metabotropic glutamate receptor subtype 5 (mGluR5), leading to synaptic loss in Alzheimers disease (AD). Positron emission tomography (PET) studies of mGluR5 using [18F]FPEB indicate a reduction of receptor binding that is focused in the medial temporal lobe in AD. Synaptic loss due to AD measured through synaptic vesicle glycoprotein 2A (SV2A) quantification with [11C]UCB-J PET is also focused in the medial temporal lobe, but with clear widespread reductions is commonly AD-affected neocortical regions. In this study, we used [18F]FPEB and [11C]UCB-J PET to investigate the relationship between mGluR5 and synaptic density in early AD. MethodsFifteen amyloid positive participants with early AD and 12 amyloid negative, cognitively normal (CN) participants underwent PET scans with both [18F]FPEB to measure mGluR5 and [11C]UCB-J to measure synaptic density. Parametric DVR images using equilibrium methods were generated from dynamic. For [18F]FPEB PET, DVR was calculated using equilibrium methods and a cerebellum reference region. For [11C]UCB-J PET, DVR was calculated with a simplified reference tissue model - 2 and a whole cerebellum reference region. ResultA strong positive correlation between mGluR5 and synaptic density was present in the hippocampus for participants with AD (r = 0.81, p < 0.001) and in the CN group (r = 0.74, p = 0.005). In the entorhinal cortex, there was a strong positive correlation between mGluR5 and synaptic in the AD group (r = 0.85, p <0.001), but a weaker non-significant correlation in the CN group (r = 0.36, p = 0.245). Exploratory analyses within and between other brain regions suggested significant positive correlations between mGluR5 in the medial temporal lobe and synaptic density in a broader set of commonly AD-affected regions. ConclusionMedial temporal loss of mGluR5 in AD is associated with synaptic loss in both medial temporal regions and more broadly in association cortical regions, indicating that mGluR5 mediated A{beta}o toxicity may lead to early synaptic loss more broadly in AD-affected networks. In CN individuals, an isolated strong association between lower mGluR5 and lower synaptic density may indicate non-AD related synaptic loss.

pathology↗

bioRxiv2022

Altered CD8+ T cell associated aging gene signature in the peripheral blood of patients with Alzheimer's disease.

INTRODUCTIONEffector memory (EM) CD8+ T cells have been associated with poor cognition in Alzheimers disease (AD). Our lab recently discovered an age-associated gene expression signature of IL-7 receptor alpha (IL-7R)low EM CD8+ T cells. We hypothesized that individuals with AD have altered levels of this IL-7Rlow aging gene expression. METHODSForty genes associated with IL-7Rlow EM CD8+ T cells, AD, or memory, were analyzed in peripheral blood of participants with normal cognition, mild cognitive impairment, and dementia by qPCR. RESULTSOf the eight genes that were found to be differentially expressed based on clinical diagnosis, 5 genes (62.5%) were IL-7Rlow aging genes. Principal component analysis revealed 3 clusters of participants with dementia which had distinct expression levels of IL-7Rlow aging genes and cognitive function. DISCUSSIONOur findings support the possible relationship of the IL-7Rlow EM CD8+ T cell aging signature with cognition in individuals with dementia due to AD.

immunology↗