Browsing by Author "Norris, Christopher M."

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    Frontal Memory‐related Brainwaves Differentially Correlate with AD and Astrocyte Plasma Biomarkers
    (Wiley, 2025-01-09) Jiang, Yang; Wu, Xian; Katsumata, Yuriko; Clark, Maria F.; Foley, Kate E.; Wang, Baoxi; Sudduth, Tiffany L.; Wilcock, Donna M.; Jicha, Gregory A.; Norris, Christopher M.; Neurology, School of Medicine
    Background: We currently lack in the dementia field accurate, noninvasive, quick, and affordable screening tools for brain dysfunctions associated with early subtle risk of mild cognitive impairment (MCI). Our Kentucky aging cohort demonstrates that asymptomatic older individuals with MCI‐like frontal memory‐related brainwave patterns convert to MCI within a short 5‐year period, as opposed to individuals with NC‐like patterns (1) that remain normal 10 years later (2). Astrocyte reactivity influences amyloid‐β effects on tau pathology in preclinical Alzheimer’s disease (3). Leveraging blood‐based AD and astrocyte biomarkers and the cognitive electroencephalogram (EEG) signatures (4), we test the hypothesis that predictive frontal memory‐related EEG changes correlate with preclinical and early AD plasma biomarkers. Method: 34 (19 women) older volunteers with or without MCI, average age 79 (SD 8.53) years old, from a longitudinal cohort followed by University of Kentucky ADRC participated. Each participant’s EEG was recorded (64‐ or 14‐channels) during a working memory (modified delayed match‐to‐sample) task. Principal component analysis (PCA) was performed on 64‐channel EEG data to create PC scores (PC1 & PC2). For multiple linear regression of EEG PC scores on multiple neurodegenerative plasma biomarkers including Aβ42/40, pTau181, total Tau, and GFAP (Astrocyte reactivity), we adjusted age, sex, education, and gap years between collection dates. Result: The 61% of variance in frontal signals can be explained by PC1 in normal cognition (NC) and MCI individuals, and PC2 counts for 35% of variance (Figure 1). The decreased brainwaves (MCI‐like) seen in left frontal sites significantly correlate with increased pTau181, GFAP, and PC2 (Figure 2). Curiously, right frontal EEG relations with pTau181, GFAP showed the opposite trend. Bilateral frontal signals showed negative correlations with Aβ42/40 and positive correlations with total Tau. Conclusion: Our results indicate that GFAP & pTau181 trend in similar asymmetry ways with frontal cognitive brainwaves, but Aβ42/40 & total Tau correlate to a different component of frontal EEG. That is, distinct cognitive brainwaves correlate with astrocyte reactivity differentially that influence pathologies of beta‐amyloid accumulations and Tau development. Cognitive pathophysiological signatures and AD–Astrocyte plasma biomarkers have great potential for predicting subtle cognitive decline and specific dementia risk in healthy normal individuals.
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    The Effect of Sex‐Differences on the Relationship Between White Matter Hyperintensity, Cerebrovascular Reactivity, and Fluid Biomarkers
    (Wiley, 2025-01-09) Bahrani, Ahmed A.; Jiang, Yang; Powell, David K.; Katsumata, Yuriko; Nahvi, Azadeh; Lee, Tiffany; Gold, Brian T.; Goldstein, Larry B.; Wilcock, Donna M.; Jicha, Gregory A.; Nelson, Peter T.; Norris, Christopher M.; Neurology, School of Medicine
    Background: Alzheimer’s disease (AD) and vascular cognitive impairment and dementia (VCID) are the predominant types of dementia in older adults, associated with memory loss and cognitive deficits. White matter hyperintensities (WMH) are linked to both AD and VCID. Astrocytes play a crucial role in WM integrity, encompassing functions like neuroinflammation, oxidative stress, and Aβ clearance. Poorly reactive astrocytes could lead to implications, like WMH or vascular damage. This study aims to explore sex‐differences effect on the correlation between fluid biomarkers, WMH, and cerebrovascular reactivity (CVR). Method: Twenty‐seven participants (mean age 76.8±6.4 years, Female=15) preliminary data were collected from UK‐ADRC/MarkVCID cohorts. A correlation test was employed to examine sex‐differences based on the correlation of fluid inflammatory (GFAP, IL6, IL8, IL10), angiogenic (TDP‐43, and PlGF) biomarkers, and Aβ40 and 42, to global and regional CVR and WMH. Results: We observed several sex‐differences: the female group showed a significant correlation between WMH at occipital lobe and IL6 (P=0.031), IL10 (P=0.036), and GFAP (P=0.037), while male group only showed a significant correlation between Aβ42 and WMH at the occipital lobe (P=0.039). CVR data of the female group exhibited a correlation at the parietal lobe (right‐hemisphere) and IL8 (P=0.037) and Aβ40 (P=0.038) and between Aβ40 and CVR temporal lobe (right‐hemisphere, P=0.021). The male group showed a significant correlation between IL6 and CVR at the occipital lobe (left‐hemisphere, P=0.012. Generally, the female group showed higher mean values for all biomarkers except for IL10 and PIGF, but only significant at GFAP and TDP43. Additionally, the correlation test adjusted for age and sex showed that TDP‐43 had a significant correlation with WMH in the temporal (P=0.041), occipital (P=0.024), and parietal (P=0.024) lobes, while GFAP displayed a significant correlation only with WMH in the frontal lobe (P=0.013). Conclusions: Despite the small sample size, which warrants expansion in future studies, we observed interesting findings of sex‐differences in specific brain regions in relation to fluid biomarkers. These biomarkers may arise, in part, from reactive astrocytes, commonly found near many brain lesions, including WM pathology. Further studies are needed to gain deeper insight into astrocyte activities in diseases associated with WMH and CVR, like AD.
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    Using digital pathology to analyze the murine cerebrovasculature
    (Sage, 2024) Niedowicz, Dana M.; Gollihue, Jenna L.; Weekman, Erica M.; Phe, Panhavuth; Wilcock, Donna M.; Norris, Christopher M.; Nelson, Peter T.; Neurology, School of Medicine
    Research on the cerebrovasculature may provide insights into brain health and disease. Immunohistochemical staining is one way to visualize blood vessels, and digital pathology has the potential to revolutionize the measurement of blood vessel parameters. These tools provide opportunities for translational mouse model research. However, mouse brain tissue presents a formidable set of technical challenges, including potentially high background staining and cross-reactivity of endogenous IgG. Formalin-fixed paraffin-embedded (FFPE) and fixed frozen sections, both of which are widely used, may require different methods. In this study, we optimized blood vessel staining in mouse brain tissue, testing both FFPE and frozen fixed sections. A panel of immunohistochemical blood vessel markers were tested (including CD31, CD34, collagen IV, DP71, and VWF), to evaluate their suitability for digital pathological analysis. Collagen IV provided the best immunostaining results in both FFPE and frozen fixed murine brain sections, with highly-specific staining of large and small blood vessels and low background staining. Subsequent analysis of collagen IV-stained sections showed region and sex-specific differences in vessel density and vessel wall thickness. We conclude that digital pathology provides a useful tool for relatively unbiased analysis of the murine cerebrovasculature, provided proper protein markers are used.