Browsing by Author "Clark, David G."

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    Amyloid and Tau Pathology are Associated with Cerebral Blood Flow in a Mixed Sample of Nondemented Older Adults with and without Vascular Risk Factors for Alzheimer’s Disease
    (Elsevier, 2023) Swinford, Cecily G.; Risacher, Shannon L.; Vosmeier, Aaron; Deardorff, Rachael; Chumin, Evgeny J.; Dzemidzic, Mario; Wu, Yu-Chien; Gao, Sujuan; McDonald, Brenna C.; Yoder, Karmen K.; Unverzagt, Frederick W.; Wang, Sophia; Farlow, Martin R.; Brosch, Jared R.; Clark, David G.; Apostolova, Liana G.; Sims, Justin; Wang, Danny J.; Saykin, Andrew J.; Radiology and Imaging Sciences, School of Medicine
    Identification of biomarkers for the early stages of Alzheimer's disease (AD) is an imperative step in developing effective treatments. Cerebral blood flow (CBF) is a potential early biomarker for AD; generally, older adults with AD have decreased CBF compared to normally aging peers. CBF deviates as the disease process and symptoms progress. However, further characterization of the relationships between CBF and AD risk factors and pathologies is still needed. We assessed the relationships between CBF quantified by arterial spin-labeled magnetic resonance imaging, hypertension, APOEε4, and tau and amyloid positron emission tomography in 77 older adults: cognitively normal, subjective cognitive decline, and mild cognitive impairment. Tau and amyloid aggregation were related to altered CBF, and some of these relationships were dependent on hypertension or APOEε4 status. Our findings suggest a complex relationship between risk factors, AD pathologies, and CBF that warrants future studies of CBF as a potential early biomarker for AD.
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    BrainAGE Estimation: Influence of Field Strength, Voxel Size, Race, and Ethnicity
    (medRxiv, 2023-12-05) Dempsey, Desarae A.; Deardorff, Rachael; Wu, Yu-Chien; Yu, Meichen; Apostolova, Liana G.; Brosch, Jared; Clark, David G.; Farlow, Martin R.; Gao, Sujuan; Wang, Sophia; Saykin, Andrew J.; Risacher, Shannon L.; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of Medicine
    The BrainAGE method is used to estimate biological brain age using structural neuroimaging. However, the stability of the model across different scan parameters and races/ethnicities has not been thoroughly investigated. Estimated brain age was compared within- and across- MRI field strength and across voxel sizes. Estimated brain age gap (BAG) was compared across demographically matched groups of different self-reported races and ethnicities in ADNI and IMAS cohorts. Longitudinal ComBat was used to correct for potential scanner effects. The brain age method was stable within field strength, but less stable across different field strengths. The method was stable across voxel sizes. There was a significant difference in BAG between races, but not ethnicities. Correction procedures are suggested to eliminate variation across scanner field strength while maintaining accurate brain age estimation. Further studies are warranted to determine the factors contributing to racial differences in BAG.
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    Evaluating Depressive Symptoms, BDNF Val66Met, and APOE-ε4 as Moderators of Response to Computerized Cognitive Training in Heart Failure
    (Elsevier, 2023) Pressler, Susan J.; Jung, Miyeon; Giordani, Bruno; Titler, Marita G.; Gradus-Pizlo, Irmina; Reid Lake, Kittie; Wierenga, Kelly L.; Clark, David G.; Perkins, Susan M.; Smith, Dean G.; Mocci, Evelina; Dorsey, Susan G.; School of Nursing
    Background: Depressive symptoms, brain-derived neurotrophic factor (BDNF) Val66Met, and apolipoprotein (APOE)-ε4 may moderate response to computerized cognitive training (CCT) interventions among patients with heart failure (HF). Objectives: The purpose of this study was to examine moderators of intervention response to CCT over 8 months among patients with HF enrolled in a 3-arm randomized controlled trial. Outcomes were memory, serum BDNF, working memory, instrumental activities of daily living (IADLs), and health-related quality of life (HRQL). Methods: 256 patients with HF were randomized to CCT, computerized crossword puzzles active control, and usual care control groups for 8 weeks. Data were collected at enrollment, baseline, 10 weeks, and 4 and 8 months. Mixed effects models were computed to evaluate moderators. Results: As previously reported, there were no statistically significant group by time effects in outcomes among the 3 groups over 8 months. Tests of moderation indicated that depressive symptoms and presence of BDNF Val66Met and APOE-ε4 were not statistically significant moderators of intervention response in outcomes of delayed recall memory, serum BDNF, working memory, IADLs, and HRQL. In post hoc analysis evaluating baseline global cognitive function, gender, age, and HF severity as moderators, no significant effects were found. HF severity was imbalanced among groups (P = .049) which may have influenced results. Conclusions: Studies are needed to elucidate biological mechanisms of cognitive dysfunction in HF and test novel interventions to improve memory, serum BDNF, working memory, IADLs and HRQL. Patients may need to be stratified or randomized by HF severity within intervention trials.
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    Optimizing differential identifiability improves connectome predictive modeling of cognitive deficits from functional connectivity in Alzheimer's disease
    (Wiley, 2021-08) Svaldi, Diana O.; Goñi, Joaquín; Abbas, Kausar; Amico, Enrico; Clark, David G.; Muralidharan, Charanya; Dzemidzic, Mario; West, John D.; Risacher, Shannon L.; Saykin, Andrew J.; Apostolova, Liana G.; Medicine, School of Medicine
    Functional connectivity, as estimated using resting state functional MRI, has shown potential in bridging the gap between pathophysiology and cognition. However, clinical use of functional connectivity biomarkers is impeded by unreliable estimates of individual functional connectomes and lack of generalizability of models predicting cognitive outcomes from connectivity. To address these issues, we combine the frameworks of connectome predictive modeling and differential identifiability. Using the combined framework, we show that enhancing the individual fingerprint of resting state functional connectomes leads to robust identification of functional networks associated to cognitive outcomes and also improves prediction of cognitive outcomes from functional connectomes. Using a comprehensive spectrum of cognitive outcomes associated to Alzheimer's disease (AD), we identify and characterize functional networks associated to specific cognitive deficits exhibited in AD. This combined framework is an important step in making individual level predictions of cognition from resting state functional connectomes and in understanding the relationship between cognition and connectivity.
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    Patient and caregiver assessment of the benefits from the clinical use of amyloid PET imaging
    (Wolters Kluwer, 2018-01) Mustafa, Rafid; Brosch, Jared R.; Rabinovici, Gil D.; Dickerson, Brad; Carrillo, Maria C.; Glazier, Brad; Gao, Sujuan; Tierney, Martha; Fargo, Keith N.; Austrom, Mary G.; De Santi, Susan; Clark, David G.; Apostolova, Liana; Neurology, School of Medicine
    INTRODUCTION: Few studies to date have explored patient and caregiver views on the clinical use of amyloid positron emission tomography (PET). METHODS: A 7-item questionnaire assessing patient and caregiver views (510 total respondents) toward amyloid PET imaging was advertised broadly through alz.org/trialmatch. RESULTS: We received 510 unique responses from 48 US states, 2 Canadian provinces, the Dominican Republic, and Greece. Both patients and caregivers indicated that they would want to receive amyloid imaging if offered the opportunity. Over 88% of respondents had a positive response (∼10% with neutral and 2% with negative responses) to whether amyloid PET should be offered routinely and be reimbursed. Such information was felt to be useful for long-term legal, financial, and health care planning. Respondents identifying with early age cognitive decline (younger than 65 y) were more likely to explore options for disability insurance (P=0.03). Responders from the Midwest were more likely to utilize information from amyloid imaging for legal planning (P=0.02), disability insurance (P=0.02), and life insurance (P=0.04) than other US regions. DISCUSSION: Patients and caregivers supported the use of amyloid PET imaging in clinical practice and felt that the information would provide significant benefits particularly in terms of future planning.
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    Randomized Controlled Trial of a Cognitive Intervention to Improve Memory in Heart Failure
    (Elsevier, 2022) Pressler, Susan J.; Jung, Miyeon; Gradus-Pizlo, Irmina; Titler, Marita G.; Smith, Dean G.; Gao, Sujuan; Lake, Kittie Reid; Burney, Heather; Clark, David G.; Wierenga, Kelly L.; Dorsey, Susan G.; Giordani, Bruno; School of Nursing
    Background: The objective of this 3-arm randomized controlled trial was to evaluate the efficacy of computerized cognitive training (CCT) in improving primary outcomes of delayed-recall memory and serum brain-derived neurotrophic factor (BDNF) levels; and the secondary outcomes were working memory, instrumental activities of daily living (IADLs) and health-related quality of life (HRQL) in patients with heart failure (HF). Methods and results: Patients (n = 256) were randomly assigned to 8 weeks of CCT using BrainHQ, computerized crossword puzzles active control intervention, and usual care. All patients received weekly nurse-enhancement interventions. Data were collected at enrollment and baseline visits and at 10 weeks and 4 and 8 months. In mixed effects models, there were no statistically significant group or group-by-time differences in outcomes. There were statistically significant differences over time in all outcomes in all groups. Patients improved over time on measures of delayed-recall memory, working memory, IADLs, and HRQL and had decreased serum BDNF. Conclusions: CCT did not improve outcomes compared with the active control intervention and usual care. Nurse-enhancement interventions may have led to improved outcomes over time. Future studies are needed to test nurse-enhancement interventions in combination with other cognitive interventions to improve memory in persons with HF.
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    Spatial transcriptomic patterns underlying amyloid-β and tau pathology are associated with cognitive dysfunction in Alzheimer’s disease
    (Elsevier, 2024) Yu, Meichen; Risacher, Shannon L.; Nho, Kwangsik T.; Wen, Qiuting; Oblak, Adrian L.; Unverzagt, Frederick W.; Apostolova, Liana G.; Farlow, Martin R.; Brosch, Jared R.; Clark, David G.; Wang, Sophia; Deardorff, Rachael; Wu, Yu-Chien; Gao, Sujuan; Sporns, Olaf; Saykin, Andrew J.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of Medicine
    Amyloid-β (Aβ) and tau proteins accumulate within distinct neuronal systems in Alzheimer's disease (AD). Although it is not clear why certain brain regions are more vulnerable to Aβ and tau pathologies than others, gene expression may play a role. We study the association between brain-wide gene expression profiles and regional vulnerability to Aβ (gene-to-Aβ associations) and tau (gene-to-tau associations) pathologies by leveraging two large independent AD cohorts. We identify AD susceptibility genes and gene modules in a gene co-expression network with expression profiles specifically related to regional vulnerability to Aβ and tau pathologies in AD. In addition, we identify distinct biochemical pathways associated with the gene-to-Aβ and the gene-to-tau associations. These findings may explain the discordance between regional Aβ and tau pathologies. Finally, we propose an analytic framework, linking the identified gene-to-pathology associations to cognitive dysfunction in AD at the individual level, suggesting potential clinical implication of the gene-to-pathology associations.