Browsing by Author "Katsumata, Yuriko"

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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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    Genome-wide association study of brain arteriolosclerosis
    (Sage, 2022) Shade, Lincoln M. P.; Katsumata, Yuriko; Hohman, Timothy J.; Nho, Kwangsik; Saykin, Andrew J.; Mukherjee, Shubhabrata; Boehme, Kevin L.; Kauwe, John S. K.; Farrer, Lindsay A.; Schellenberg, Gerard D.; Haines, Jonathan L.; Mayeux, Richard P.; Schneider, Julie A.; Nelson, Peter T.; Fardo, David W.; Radiology and Imaging Sciences, School of Medicine
    Brain arteriolosclerosis (B-ASC) is characterized by pathologically altered brain parenchymal arterioles. B-ASC is associated with cognitive impairment and increased likelihood of clinical dementia. To date, no study has been conducted on genome-wide genetic risk of autopsy-proven B-ASC. We performed a genome-wide association study (GWAS) of the B-ASC phenotype using multiple independent aged neuropathologic cohorts. Included in the study were participants with B-ASC autopsy and genotype data available from the NACC, ROSMAP, ADNI, and ACT data sets. Initial Stage 1 GWAS (n = 3382) and Stage 2 mega-analysis (n = 4569) were performed using data from the two largest cohorts (NACC and ROSMAP). Replication of top variants and additional Stage 3 mega-analysis were performed incorporating two smaller cohorts (ADNI and ACT). Lead variants in the top two loci in the Stage 2 mega-analysis (rs7902929, p =  1.8×10−7 ; rs2603462, p =  4×10−7 ) were significant in the ADNI cohort (rs7902929, p =  0.012 ; rs2603462, p = 0.012 ). The rs2603462 lead variant colocalized with ELOVL4 expression in the cerebellum (posterior probability = 90.1%). Suggestive associations were also found near SORCS1 and SORCS3. We thus identified putative loci associated with B-ASC risk, but additional replication is needed.
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    GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia
    (Springer Nature, 2024) Shade, Lincoln M. P.; Katsumata, Yuriko; Abner, Erin L.; Aung, Khine Zin; Claas, Steven A.; Qiao, Qi; Aguzzoli Heberle, Bernardo; Brandon, J. Anthony; Page, Madeline L.; Hohman, Timothy J.; Mukherjee, Shubhabrata; Mayeux, Richard P.; Farrer, Lindsay A.; Schellenberg, Gerard D.; Haines, Jonathan L.; Kukull, Walter A.; Nho, Kwangsik; Saykin, Andrew J.; Bennett, David A.; Schneider, Julie A.; National Alzheimer’s Coordinating Center; Ebbert, Mark T. W.; Nelson, Peter T.; Fardo, David W.; Radiology and Imaging Sciences, School of Medicine
    Genome-wide association studies (GWAS) have identified >80 Alzheimer's disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer's Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk.
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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.