Browsing by Author "Clark, David G."
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Item 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 MedicineIdentification 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.Item Association Between MIND Diet Score and Cortical Thickness in an Aging Population(Wiley, 2025-01-09) Dempsey, Desarae A.; Apostolova, Liana G.; Brosch, Jared R.; Clark, David G.; Farlow, Martin R.; Mathew, Sunu; Unverzagt, Frederick; Wang, Sophia; Gao, Sujuan; Clark, Daniel; Saykin, Andrew J.; Risacher, Shannon L.; Neurology, School of MedicineBackground The Mediterranean diet has been associated with decreased brain atrophy (Staubo et al. 2016,Alz&Dem), but the MIND (Mediterranean‐Dietary Approaches to Stop Hypertension (DASH) Intervention for Neurodegenerative Delay) diet, designed for dementia prevention (Morris et al. 2015, Alz&Dem), remains underexplored for its impact on brain atrophy. We investigated the MIND diet’s association with cortical thickness (CT) in the Indiana Alzheimer’s Disease Research Center (IADRC) sample. Methods 134 participants (49 CN, 45 SCD, 30 MCI, 10 AD/other) completed a self‐report MIND diet questionnaire at the IADRC, which was coded into high, medium, or low intake groups for each food (5 ‘unhealthy’ food groups were reverse scored) and completed an MRI scan on a 3T scanner. The cortical surface was parcellated using FreeSurfer v6. We selected two regions of interest (ROIs) reflecting AD‐associated neurodegeneration: temporal and global CT. We examined the association of MIND diet scores (0‐15) and food groups with CT using regression models adjusted for age, sex, race, education, and diagnosis. Results Higher MIND diet scores were associated with greater mean temporal CT (r = 0.269, p = 0.002) and greater mean global CT (r = 0.230, p = 0.008). In multivariable‐adjusted models, the association persisted for temporal but not global CT. Among the 15 food components, greater olive oil (r = 0.034, p<0.001), fish (r = 0.181, p = 0.040), beans (r = 0.237, p = 0.008), and nuts (r = 0.214, p = 0.014), and reduced fast food intake (r = 0.188, p = 0.035) were significantly associated with temporal CT. These associations, except for nuts, remained significant in multivariable‐adjusted models, with an additional relationship found for chicken (r = 0.189, p = 0.038). Among the 15 food components, greater olive oil (r = 0.243, p = 0.008), and beans (0.180, p = 0.044), and reduced fast food (r = 0.212, p = 0.017) were significantly associated with global CT. Only reduced fast food retained significance in the multivariable‐adjusted models. Conclusions Greater adherence to the MIND diet was associated with greater CT in both global and temporal regions. Specific components, including increased olive oil, beans, nuts, fish, and reduced fast food, showed significant associations with CT, suggesting elements within the diet driving this association. These findings highlight the potential neuroprotective effects of the MIND diet, emphasizing the importance of dietary patterns in preserving brain health during aging.Item 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 MedicineThe 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.Item Computerized Cognitive Training and 24-Month Mortality in Heart Failure(Wolters Kluwer, 2024) Jung, Miyeon; Smith, Asa B.; Giordani, Bruno; Clark, David G.; Gradus-Pizlo, Irmina; Wierenga, Kelly L.; Lake, Kittie Reid; Pressler, Susan J.; School of NursingBackground: Cognitive dysfunction predicts mortality in heart failure (HF). Computerized cognitive training (CCT) has shown preliminary efficacy in improving cognitive function. However, the relationship between CCT and mortality is unclear. Aims were to evaluate (1) long-term efficacy of CCT in reducing 24-month mortality and (2) age, HF severity, global cognition, memory, working memory, depressive symptoms, and health-related quality of life as predictors of 24-month mortality among patients with HF. Methods: In this prospective longitudinal study, 142 patients enrolled in a 3-arm randomized controlled trial were followed for 24 months. Logistic regression was used to achieve the aims. Results: Across 24 months, 16 patients died (CCT, 8.3%; control groups, 12.8%). Computerized cognitive training did not predict 24-month mortality (odds ratio [OR], 0.65). Older age (OR, 1.08), worse global cognition (OR, 0.73), memory (OR, 0.81), and depressive symptoms (OR, 1.10) at baseline predicted 24-month mortality. Conclusions: Efficacious interventions are needed to improve global cognition, memory, and depressive symptoms and reduce mortality in HF.Item 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 NursingBackground: 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.Item Influence of amyloid and diagnostic syndrome on non-traditional memory scores in early-onset Alzheimer's disease(Wiley, 2023) Bushnell, Justin; Hammers, Dustin B.; Aisen, Paul; Dage, Jeffrey L.; Eloyan, Ani; Foroud, Tatiana; Grinberg, Lea T.; Iaccarino, Leonardo; Jack, Clifford R., Jr.; Kirby, Kala; Kramer, Joel; Koeppe, Robert; Kukull, Walter A.; La Joie, Renaud; Mundada, Nidhi S.; Murray, Melissa E.; Nudelman, Kelly; Rumbaugh, Malia; Soleimani-Meigooni, David N.; Toga, Arthur; Touroutoglou, Alexandra; Vemuri, Prashanthi; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph; Mendez, Mario; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Steven; Sha, Sharon; Turner, Raymond S.; Wingo, Thomas S.; Wolk, David A.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; Clark, David G.; LEADS Consortium; Neurology, School of MedicineIntroduction: The Rey Auditory Verbal Learning Test (RAVLT) is a useful neuropsychological test for describing episodic memory impairment in dementia. However, there is limited research on its utility in early-onset Alzheimer's disease (EOAD). We assess the influence of amyloid and diagnostic syndrome on several memory scores in EOAD. Methods: We transcribed RAVLT recordings from 303 subjects in the Longitudinal Early-Onset Alzheimer's Disease Study. Subjects were grouped by amyloid status and syndrome. Primacy, recency, J-curve, duration, stopping time, and speed score were calculated and entered into linear mixed effects models as dependent variables. Results: Compared with amyloid negative subjects, positive subjects exhibited effects on raw score, primacy, recency, and stopping time. Inter-syndromic differences were noted with raw score, primacy, recency, J-curve, and stopping time. Discussion: RAVLT measures are sensitive to the effects of amyloid and syndrome in EOAD. Future work is needed to quantify the predictive value of these scores. Highlights: RAVLT patterns characterize various presentations of EOAD and EOnonAD Amyloid impacts raw score, primacy, recency, and stopping time Timing-based scores add value over traditional count-based scores.Item Influence of tau on non‐traditional memory scores in early‐onset Alzheimer’s disease(Wiley, 2025-01-09) Kostadinova, Ralitsa V.; Bushnell, Justin; Hammers, Dustin B.; Apostolova, Liana G.; Clark, David G.; Neurology, School of MedicineBackground: A common neuropsychological test for assessing episodic memory is the Rey Auditory Verbal Learning Test (RAVLT), a sequence of 8 word‐list learning and recall tasks (five learning trials, immediate recall of an intrusion list, short‐delay and long‐delay recall). There is extensive research correlating patterns of RAVLT performance with clinical dementia syndromes, but little work relating these patterns to biomarkers in early‐onset dementia. Here, we analyze the relationship between patterns of tau deposition and RAVLT performance in early‐onset populations. Method: We transcribed RAVLT recordings from 249 subjects in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS). We calculated three composite scores from scores on the individual RAVLT tasks: learning ratio, raw learning score, and recency ratio. We then performed principle components analysis (PCA) on tau measurements in 108 regions of interest, identifying five components accounting for 90.9% of the variance. We entered RAVLT composite scores as dependent variables in a series of linear regression models. The PCA components, along with diagnostic syndrome and nuisance variables (age, sex, education), were entered as independent variables. Result: Principal component 1 loaded positively in all ROIs in both hemispheres, with weaker loadings in the motor strip, occipital region, and subcortical nuclei. Principal component 5 loaded positively on left > right temporal lobes and white matter. These two were significant predictors of both learning ratio and raw learning score, showing that an increase in tau affects the performance of these RAVLT metrics. Loadings for principal component 4 were more complex, but in general were positive in the right > left hemisphere, including parietal lobes and superior temporal gyri, with negative loadings elsewhere in the temporal lobes. This component was a significant predictor of recency ratio. In all cases, regression coefficients were negative, indicating that tau within ROIs with positive loadings was negatively correlated with the memory score in question. Conclusion: RAVLT measures are sensitive to the effects of tau deposition in early‐onset Alzheimer’s disease. Further work is needed to evaluate these scores as predictors of specific forms of pathology in early‐onset dementia.Item 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 MedicineFunctional 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.Item 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 MedicineINTRODUCTION: 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.Item 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 NursingBackground: 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.