Browsing by Author "Klinedinst, Brandon S."

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    APOE, TOMM40, and Sex Interactions on Neural Network Connectivity
    (Elsevier, 2022) Li, Tianqi; Pappas, Colleen; Le, Scott T.; Wang, Qian; Klinedinst, Brandon S.; Larsen, Brittany; Pollpeter, Amy; Lee, Ling Yi; Lutz, Mike W.; Gottschalk, William K.; Swerdlow, Russell H.; Nho, Kwangsik; Willette, Auriel A.; Radiology and Imaging Sciences, School of Medicine
    The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer‟s disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs2075650 (‘650) G vs. A carriage is consistently related to neural and cognitive outcomes, but it is unclear if and how it interacts with APOE. We examined 21 orthogonal neural networks among 8,222 middle-aged to aged participants in the UK Biobank cohort. ANOVA and multiple linear regression tested main effects and interactions with APOE and TOMM40 ‘650 genotypes, and if age and sex acted as moderators. APOE ε4 was associated with less strength in multiple networks, while ‘650 G vs. A carriage was related to more language comprehension network strength. In APOE ε4 carriers, ‘650 G-carriage led to less network strength with increasing age, while in non G-carriers this was only seen in women but not men. TOMM40 may shift what happens to network activity in aging APOE ε4 carriers depending on sex.
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    Association of amyloid and cardiovascular risk with cognition: Findings from KBASE
    (Wiley, 2024) Chaudhuri, Soumilee; Dempsey, Desarae A.; Huang, Yen-Ning; Park, Tamina; Cao, Sha; Chumin, Evgeny J.; Craft, Hannah; Crane, Paul K.; Mukherjee, Shubhabrata; Choi, Seo-Eun; Scollard, Phoebe; Lee, Michael; Nakano, Connie; Mez, Jesse; Trittschuh, Emily H.; Klinedinst, Brandon S.; Hohman, Timothy J.; Lee, Jun-Young; Kang, Koung Mi; Sohn, Chul-Ho; Kim, Yu Kyeong; Yi, Dahyun; Byun, Min Soo; Risacher, Shannon L.; Nho, Kwangsik; Saykin, Andrew J.; Lee, Dong Young; KBASE Research Group; Radiology and Imaging Sciences, School of Medicine
    Background: Limited research has explored the effect of cardiovascular risk and amyloid interplay on cognitive decline in East Asians. Methods: Vascular burden was quantified using Framingham's General Cardiovascular Risk Score (FRS) in 526 Korean Brain Aging Study (KBASE) participants. Cognitive differences in groups stratified by FRS and amyloid positivity were assessed at baseline and longitudinally. Results: Baseline analyses revealed that amyloid-negative (Aβ-) cognitively normal (CN) individuals with high FRS had lower cognition compared to Aβ- CN individuals with low FRS (p < 0.0001). Longitudinally, amyloid pathology predominantly drove cognitive decline, while FRS alone had negligible effects on cognition in CN and mild cognitive impairment (MCI) groups. Conclusion: Our findings indicate that managing vascular risk may be crucial in preserving cognition in Aβ- individuals early on and before the clinical manifestation of dementia. Within the CN and MCI groups, irrespective of FRS status, amyloid-positive individuals had worse cognitive performance than Aβ- individuals. Highlights: Vascular risk significantly affects cognition in amyloid-negative older Koreans. Amyloid-negative CN older adults with high vascular risk had lower baseline cognition. Amyloid pathology drives cognitive decline in CN and MCI, regardless of vascular risk. The study underscores the impact of vascular health on the AD disease spectrum.
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    Associations between Amyloid, Cardiovascular Risk, and Cognitive Function in Korean Older Adults: Insights from the KBASE Cohort
    (Wiley, 2025-01-09) Chaudhuri, Soumilee; Dempsey, Desarae A.; Huang, Yen-Ning; Cao, Sha; Chumin, Evgeny J.; Craft, Hannah; Crane, Paul K.; Mukherjee, Shubhabrata; Choi, Seo-Eun; Lee, Michael L.; Scollard, Phoebe; Mez, Jesse; Trittschuh, Emily H.; Klinedinst, Brandon S.; Nakano, Connie; Hohman, Timothy J.; Yi, Dahyun; Byun, Min Soo; Risacher, Shannon L.; Nho, Kwangsik; Saykin, Andrew J.; Lee, Dong Young; Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE); Radiology and Imaging Sciences, School of Medicine
    Background: Understanding the relationship between cardiovascular burden, amyloid, and cognition in Alzheimer’s disease (AD) is essential for targeted interventions, especially in ethnically diverse populations where research remains limited. This study aimed to investigate these relationships in a cohort of Korean older adults along the AD spectrum. Method: 526 participants from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort were included in this study. Vascular burden was quantified using Framingham Risk Score (FRS) and participants were categorized into four groups based on combinations of FRS (FRS High or FRS Low with a median split) and amyloid status (Aβ+ or Aβ‐ based on a cut‐off of 1.2373). Cognitive function was evaluated using standardized neuropsychological tests processed with structural equation models to produce domain scores for memory, executive functioning, language, and visuospatial. ANOVA was employed at baseline to analyze cognitive differences among these groups and within each clinical diagnosis. Longitudinal mixed effects models spanning a period of four years from the initial visit captured cognitive changes over time within these groups (Figure 1). Result: Significant group and pairwise differences were observed among the four groups in all cognitive domains (p < 0.0001). Stratified analysis within each clinical diagnoses group revealed that CN individuals in FRS high Aβ‐ demonstrated significantly lower memory scores compared to those with FRS low Aβ‐ (p < 0.0001), this trend was absent from MCI and AD groups (Figure 2). Longitudinally, FRS high Aβ+ and FRS low Aβ+ groups consistently demonstrated lower memory scores compared to the FRS low Aβ‐ group. Interestingly, no significant difference in cognition was observed between FRS high Aβ‐ and FRS low Aβ‐ groups over time. However, the most pronounced divergence in longitudinal cognition of the four FRS and Amyloid groups was observed within the MCI diagnosis group (Figure 3). Conclusion: This study highlights the differential impact of cardiovascular risk on cognition depending on amyloid status and clinical diagnosis group. This underscores the importance of considering both cardiovascular risk factors and amyloid pathology early‐on in understanding clinical manifestation and cognitive decline in the AD spectrum, particularly in ethnically diverse populations.
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    Characterization of Language Profiles in Cognitively‐Defined Subgroups of Alzheimer’s Disease
    (Wiley, 2025-01-03) Gallée, Jeanne; Gibbons, Laura E.; Mukherjee, Shubhabrata; Scollard, Phoebe; Choi, Seo-Eun; James, Bryan D.; Klinedinst, Brandon S.; Lee, Michael L.; Mez, Jesse; Trittschuh, Emily H.; Saykin, Andrew J.; Crane, Paul K.; Medical and Molecular Genetics, School of Medicine
    Background: The relationship between Alzheimer’s disease (AD) pathology and the associated clinical syndrome a patient presents with remains indeterminate. Cognitively‐defined subgroups of AD have revealed distinctions based on relative cognitive impairments, including AD‐Language, where challenges in language are substantial, and AD‐No Domain, where no relative asymmetries across cognitive domains occur. Pathological features of AD have been associated as the primary neuropathology of the logopenic variant of primary progressive aphasia (lvPPA). Hallmark clinical features of lvPPA include relatively spared comprehension in the face of decline in naming and repetition abilities. This work aimed to test the hypothesis that the lvPPA language profile was overrepresented in AD‐Language when compared to AD‐No Domain. Method: Measures of verbal comprehension, confrontation naming, and phrase‐level repetition were obtained from all participants from the Religious Orders Study (ROS), the RUSH Memory and Aging Project (MAP) and the Minority Aging Research Study (MARS) using confirmatory factor analyses. We subsetted the data to include participants belonging to the AD‐Language and AD‐No Domain groups at their initial AD diagnosis visit. We compared patterns of language profiles based on strengths and weaknesses in comprehension, naming, and repetition. Pearson’s Chi‐squared tests with Yates continuity correction was used to test if the language patterns were statistically different between the two AD subgroups. Results: We analyzed language performance in 642 participants across AD‐Language (31.8%) and AD‐No Domain (68.2%) groups (Table 1). Thresholds were based on AD‐No Domain and set as the median for each subdomain (comprehension = ‐.101, naming = ‐.957, repetition = .233) to establish whether a score represented a relative strength or weakness in the language profile. Eight patterns of language profiles based on strengths and weaknesses in comprehension, naming, and repetition were formed (Figure 1). The distribution of language patterns differed significantly between AD‐Language and AD‐No Domain (χ2 = 97.6, p <.001). Furthermore, the lvPPA pattern was found more frequently in AD‐Language (χ2 = 28.1, p <.001). Conclusion: Heterogeneity within the AD‐Language spectrum includes a significant proportion that is consistent with the language profile of lvPPA. Relative performance in domains of verbal comprehension, confrontation naming, and phrase‐level repetition varied by AD subgroup.
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    Evaluating the association of APOE genotype and cognitive resilience in SuperAgers
    (medRxiv, 2025-01-07) Durant, Alaina; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Klinedinst, Brandon S.; Trittschuh, Emily H.; Mez, Jesse; Farrer, Lindsay A.; Gifford, Katherine A.; Cruchaga, Carlos; Hassenstab, Jason; Naj, Adam C.; Wang, Li-San; Johnson, Sterling C.; Engelman, Corinne D.; Kukull, Walter A.; Keene, C. Dirk; Saykin, Andrew J.; Cuccaro, Michael L.; Kunkle, Brian W.; Pericak-Vance, Margaret A.; Martin, Eden R.; Bennett, David A.; Barnes, Lisa L.; Schneider, Julie A.; Bush, William S.; Haines, Jonathan L.; Mayeux, Richard; Vardarajan, Badri N.; Albert, Marilyn S.; Thompson, Paul M.; Jefferson, Angela L.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Genetics Consortium (ADGC); The Alzheimer’s Disease Sequencing Project (ADSP); Crane, Paul K.; Dumitrescu, Logan; Archer, Derek B.; Hohman, Timothy J.; Gaynor, Leslie S.; Radiology and Imaging Sciences, School of Medicine
    Importance: "SuperAgers" are oldest-old adults (ages 80+) whose memory performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary memory are underexplored in large, racially diverse cohorts. Objective: To determine the frequency of APOE genotypes in non-Hispanic Black and non-Hispanic White SuperAgers compared to middle-aged (ages 50-64), old (ages 65-79), and oldest-old (ages 80+) controls and Alzheimer's disease (AD) dementia cases. Design: This multicohort study selected data from eight longitudinal cohort studies of normal aging and AD. Setting: Variable recruitment criteria and follow-up intervals, including both population-based and clinical-based samples. Participants: Inclusion in our analyses required APOE genotype, that participants be age 50+, and are identified as either non-Hispanic Black or non-Hispanic White. In total, 18,080 participants were included in the present study with a total of 78,549 datapoints. Main outcomes and measures: Harmonized, longitudinal memory, executive function, and language scores were obtained from the Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC). SuperAgers, controls, and AD dementia cases were identified by cognitive scores using a residual approach and clinical diagnoses across multiple timepoints when available. SuperAgers were compared to AD dementia cases and cognitively normal controls using age-defined bins (middle-aged, old, oldest-old). Results: Across racialized groups, SuperAgers had significantly higher proportions of APOE-ε2 alleles and lower proportions of APOE-ε4 alleles compared to cases. Similar differences were observed between SuperAgers and middle-aged and old controls. Non-Hispanic White SuperAgers had significantly lower proportions of APOE-ε4 alleles and significantly higher proportions of APOE-ε2 alleles compared to all cases and controls, including oldest-old controls. In contrast, non-Hispanic Black SuperAgers had significantly lower proportions of APOE-ε4 alleles compared to cases and younger controls, and significantly higher proportions of APOE-ε2 alleles compared only to cases. Conclusions and relevance: In the largest study to date, we demonstrated strong evidence that the frequency of APOE-ε4 and -ε2 alleles differ between non-Hispanic White SuperAgers and AD dementia cases and cognitively normal controls. Differences in the role of APOE in SuperAging by race underlines distinctions in mechanisms conferring resilience across race groups given likely differences in genetic ancestry.
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    Patterns of Tau Deposition by Cognitive Subtype in the Alzheimer's Disease Neuroimaging Initiative
    (Wiley, 2025-01-09) Scollard, Phoebe; Gibbons, Laura E.; Choi, Seo-Eun; Lee, Michael L.; Klinedinst, Brandon S.; Trittschuh, Emily H.; Mez, Jesse; Saykin, Andrew J.; Nakano, Connie; Sanders, Elizabeth; Lila, Eardi; Risacher, Shannon L.; Mormino, Elizabeth; Smith, Viktorija; Carlson, Mackenzie L.; Young, Christina B.; Crane, Paul K.; Mukherjee, Shubhabrata; Radiology and Imaging Sciences, School of Medicine
    Background: Cognitive subtypes of Alzheimer’s Dementia (AD), defined by a relative impairment in a particular domain of cognition, have previously been shown to be associated with patterns of gray matter atrophy. Here we assessed the association of these subtypes with patterns of tau deposition measured in vivo using tau PET imaging in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Method: We included amyloid positive individuals with AD and Mild Cognitive Impairment (MCI). We selected the first diagnosis visit for AD and the most recent visit for MCI. Previously, AD individuals were categorized into AD‐Memory, AD‐Language, AD‐Executive, AD‐Visuospatial, AD‐Multiple domains, or AD‐No domain subtypes based on a relative cognitive impairment. These methods were extended to categorize MCI individuals. The AD/MCI‐Memory, AD/MCI‐Visuospatial, and AD/MCI‐No domain groups were large enough for our analyses. The tau PET scan closest to the subtyping visit was selected (median 49 days between scan and visit). Tau deposition for 35 brain regions (left and right sides averaged) were included as predictors. Separate five‐fold cross validated LASSO regressions were run for each of the three pairwise comparisons. Each model was repeated 100 times with different random fold selections to assess the stability of results. Result: We included 240 individuals (118 AD; 122 MCI) in our analyses (Table 1). There was some variation in the chosen models across repetitions with the AD/MCI‐Visuospatial versus AD/MCI‐No domain comparison varying the most (Table 2). We limit interpretation to those regions that appeared in ≥70% of repetitions. The amygdala was consistently selected in all pair‐wise comparisons. Higher tau deposition in this region was associated with a higher likelihood of being in AD/MCI‐Memory. Higher tau deposition in the postcentral region was associated with a lower likelihood of being in AD/MCI‐Memory compared to AD/MCI‐Visuospatial. Coefficients on consistently selected regions in the AD/MCI‐visuospatial versus AD/MCI‐No domain comparison were small. Figure 1 summarizes the top results from our analyses. Conclusion: We found heterogeneity in regional tau deposition among three cognitive subtypes. Future work will make use of additional cohorts with harmonized cognitive and imaging data. We plan to incorporate all cognitive subtypes and evaluate lateral asymmetry.
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    Uncovering the role of white matter microstructure in longitudinal memory and executive function decline: insights from a multi‐site study of 2,220 participants across 4,918 paired imaging‐cognition sessions
    (Wiley, 2025-01-09) Archer, Derek B.; Peter, Chris; Sathe, Aditi; Yang, Yisu; Durant, Alaina; Shashikumar, Niranjana; Pechman, Kimberly R.; Dumitrescu, Logan C.; Gifford, Katherine A.; Mukherjee, Shubhabrata; Klinedinst, Brandon S.; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Trittschuh, Emily H.; Risacher, Shannon L.; Beason-Held, Lori L.; An, Yang; Schilling, Kurt; Landman, Bennett A.; Schneider, Julie A.; Barnes, Lisa L.; Bennett, David A.; Crane, Paul K.; Kukull, Walter A.; Johnson, Sterling C.; Albert, Marilyn S.; Jefferson, Angela L.; Resnick, Susan M.; Saykin, Andrew J.; Hohman, Timothy J.; Alzheimer's Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of Medicine
    Background: Recent research emphasizes the significance of white matter tracts and the free‐water (FW) component in understanding cognitive decline. The goal of this study is to conduct a large‐scale assessment on the role of white matter microstructure on longitudinal cognitive decline. Method: This study used a cohort collated from seven longitudinal cohorts of aging (ADNI, BIOCARD, BLSA, NACC, ROS/MAP/MARS, VMAP, and WRAP). In total, this dataset included 2,220 participants aged 50+ who had both diffusion MRI and harmonized composites of memory performance and executive function. This dataset included a total of 4,918 imaging sessions with corresponding cognitive data (mean number of visits per participant: 1.69 ± 1.67, interval range: 1‐10 years). Diffusion MRI was preprocessed using the PreQual pipeline and FW correction was used to create FW and FW‐corrected intracellular metrics. Conventional and FW‐corrected measures were harmonized using the Longitudinal ComBat package. Linear mixed effects regression was used for longitudinal analysis, in which we covaried for age, age squared, education, sex, race/ethnicity, diagnosis at baseline, APOE‐ε4 status, and APOE‐ε2 status. All models were corrected for multiple comparisons using the FDR approach. Result: For longitudinal memory performance, we found global associations with conventional diffusion MRI metrics, in which abnormalities were associated with lower memory performance. Following FW correction, we found that the FW metric itself was strongly associated with memory performance, in which higher FW was associated with lower memory performance and exacerbated decline. Interestingly, following FW‐correction the intracellular contributions were largely mitigated. As illustrated in Figure 1A, the most significant effects were found in the limbic tracts, with the most significant associations found for cingulum bundle FW (p=5.80x10‐45). Figure 1B illustrates the association between cingulum FW and longitudinal memory performance. Findings for longitudinal executive function performance are shown in Figure 2. Conclusion: To date, this is the largest study combining FW‐corrected diffusion MRI data and harmonized cognitive composites to understand cognitive trajectories in aging. Future studies evaluating how white matter microstructure may be incorporated into models of AD may further our knowledge into the neurodegenerative cascade of AD.