Browsing by Subject "Alzheimer’s disease (AD)"
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Item Association of brain amyloidosis with the incidence and frequency of neuropsychiatric symptoms in ADNI: a multisite observational cohort study(BMJ Journals, 2019-12-18) Goukasian, Naira; Hwang, Kristy S.; Romero, Tamineh; Grotts, Jonathan; Do, Triet M.; Groh, Jenna R.; Bateman, Daniel R.; Apostolova, Liana G.; Neurology, School of MedicineObjective To investigate the relationship between amyloid burden and frequency of existing and incidence of new neuropsychiatric symptoms (NPS) in elderly with and without cognitive decline. Methods 275 cognitively normal controls (NC), 100 subjective memory complaint (SMC), 559 mild cognitive impairment (MCI) and 143 Alzheimer’s disease dementia subjects from the Alzheimer’s Disease Neuroimaging Initiative received (18F)-florbetapir positron emission tomography (PET) scans. Yearly neuropsychiatric inventory (Neuropsychiatric Inventory (NPI)/NPI-Questionnaire) data were collected from the study partners at each visit. Mean standard uptake volume ratios (SUVR) normalised to whole cerebellum were obtained. Positive amyloid PET scan was defined as mean SUVR ≥1.17. Fisher’s exact test was used to compare frequency and incidence between amyloid positive and amyloid negative subjects. Survival analyses were used to estimate of neuropsychiatric symptoms (NPS) between amyloid positive and amyloid negative subjects. Survival analyses were used to estimate hazard ratios for developing the most common NPS by amyloid status. Results No differences in NPS frequency were seen between amyloid positive and amyloid negative NC, SMC, MCI or dementia groups. MCI subjects with amyloid pathology however tended to have greater frequency x severity (FxS) of anxiety, hallucinations, delusions, apathy, disinhibition, irritability, aberrant motor behavior, and appetite, but not agitation, depression, night-time disturbances, or elation. MCI subjects with amyloid pathology were at greater risk for developing apathy, anxiety and agitation over time. Baseline presence of agitation and apathy and new onset agitation, irritability and apathy predicted faster conversion to dementia among MCI subjects. Conclusions Amyloid pathology is associated with greater rate of development of new NPS in MCI. Anxiety and delusions are significant predictors of amyloid pathology. Agitation, irritability and apathy are significant predictors for conversion from MCI to dementia.Item Association of plasma and cortical beta-amyloid is modulated by APOE ε4 status.(Elsevier, 2014-01) Swaminathan, Shanker; Risacher, Shannon L.; Yoder, Karmen K.; West, John D.; Shen, Li; Kim, Sungeun; Inlow, Mark; Foroud, Tatiana; Jagust, William J.; Koeppe, Robert A.; Mathis, Chester A.; Shaw, Leslie M.; Trojanowski, John Q.; Soares, Holly; Aisen, Paul S.; Petersen, Ronald C.; Weiner, Michael W.; Saykin, Andrew J.; Department of Radiology and Imaging Sciences, IU School of MedicineBackground: APOE ε4’s role as a modulator of the relationship between soluble plasma beta-amyloid (Aβ) and fibrillar brain Aβ measured by Pittsburgh Compound-B positron emission tomography ([11C]PiB PET) has not been assessed. Methods: Ninety-six Alzheimer’s Disease Neuroimaging Initiative participants with [11C]PiB scans and plasma Aβ1-40 and Aβ1-42 measurements at time of scan were included. Regional and voxel-wise analyses of [11C]PiB data were used to determine the influence of APOE ε4 on association of plasma Aβ1-40, Aβ1-42, and Aβ1-40/Aβ1-42 with [11C]PiB uptake. Results: In APOE ε4− but not ε4+ participants, positive relationships between plasma Aβ1-40/Aβ1-42 and [11C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ1-40/Aβ1-42 improved the explained variance in [11C]PiB binding compared to using APOE and plasma Aβ1-40/Aβ1-42 as separate terms. Conclusions: The results suggest that plasma Aβ is a potential Alzheimer’s disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels.Item Associations Between Clinical Functioning and Ad Biomarkers Among Hispanic and White Non-Hispanic Older Adults(Oxford University Press, 2023-12-21) Rodriguez, Miriam; Mendoza, Lisandra; Garcia, Patricia; Duart, Andres; Padron, Dilianna; Marsiske, Michael; Fiala, Jacob; Duara, Ranjan; Neurology, School of MedicineObjectives: Hispanics are 1.5x more likely to develop Alzheimer’s disease (AD) when compared to White non-Hispanics (WNHs). There is also evidence to support that cognitive performance disproportionately reflects neuropathology among Hispanics and that functional decline is concurrent with the accumulation of AD biomarkers. The current study aimed to examine relationships between AD biomarkers and a functional measure among Hispanic and WNH older adults. It was hypothesized that the functional measure would be strongly related to AD biomarkers among Hispanics. Methods: The modified clinical dementia rating scale (mCDR) was administered in the participants primary language (English or Spanish) to WNH (n=203) and Hispanic (n=258) older adults who were cognitive normal or diagnosed with Mild Cognitive Impairment (MCI) or dementia. Invariance SEM models were used to compare the pattern of relationships between the mCDR and neurocognitive test performance, MRI volumes, and amyloid load adjusting for age, education, ApoE4 status, and intracranial volume. Results: Model fit was good and not significantly worsened by imposing strict structural invariance. Nested model comparisons indicated that regression weights and correlations among measures differed by group, suggestive of moderation by Hispanic status. Among Hispanic participants, sex (♌=-0.17, p<.05) and Amyloid load (♌=0.25, p<.001) significantly predicted mCDR scores. MRI volumes significantly predicted MCDR scores among both Hispanic (♌=-0.51, p<.001) and WNH participants (♌= -0.42, p<.001). Conclusions: Functional measures like the mCDR may better correlate with Amyloid load among Hispanic older adults than among WNHs, while the correlation with MRI volumes may be comparable in both groups.Item Data Mining and Quantitative Structure-Activity Relationships of Inhibitors for Treating Alzheimer's Disease(Office of the Vice Chancellor for Research, 2012-04-13) Nastase, Anthony F.; Boyd, Donald B.Amyloid cleaving enzyme-1 (BACE1) is a target of interest for treating patients with Alzheimer’s disease (AD). As of 2007, more than 37 million people worldwide are afflicted with the disease. Incidence of the disease keeps increasing as the population ages and fewer people die of other diseases. ß-Amyloid precursor protein (APP) is a natural protein associated with neurons of the brain. In Alzheimer's disease, APP is cleaved by BACE1 at the beta-site, resulting in short 42 amino acid segments called amyloid-ß (Aß). Aggregation of Aß into plaques results in the death of neurons and is associated with AD. Inhibition of the BACE1 enzyme may prevent Aß formation and prevent the development or progression of AD. Known BACE1 inhibitors are analyzed using computational chemistry techniques, and quantitative structure-activity relationships (QSAR) are developed.Item EXPERIENCING POSITIVE ASPECTS IN BEING A SPOUSAL CAREGIVER IN PARKINSON’S AND ALZHEIMER’S DISEASE(Office of the Vice Chancellor for Research, 2010-04-09) Habermann, Barbara; Davis, Linda LindseyAim: A primary aim of this study was to describe caregiver appraisal and coping strategies in caregivers of family members with Parkinson’s (PD) or Alzheimer’s disease (AD). This study was part of a larger randomized clinical trial of a skill building intervention for caregivers. Method: To achieve this aim, 84 spousal caregivers who were consecutively enrolled in the study were interviewed at baseline. The interview focused on specific caregiving situations where the caregiver was asked to describe a positive or meaningful caregiving event. Interviews were semi-structured and included probes to elicit the full narrative of the events. Interviews were transcribed verbatim and analyzed by the research team utilizing a thematic analysis. Results: Of the 84 caregivers, 48% (N=44) were PD caregivers and 52% (N=40) were AD caregivers. Male caregivers comprised 17% (N=14) of the sample. The mean age of the caregivers was 63.7 years (SD ±26.8) with the mean age of their spouses being 75.5 years (SD ± 7.2). The core theme identified was “time spent together”. Within this core theme were several relational sub-themes including turning back the hands of time, being able to rely on the caregiver, and experiencing moments of joy when the family member can participate. Conclusions: Differences existed in both how easily caregivers could identify positive or meaningful aspects to caregiving and how many aspects they could identify. However, the majority of caregivers were able to identify a positive or a meaningful aspect to spousal caregiving. Future intervention studies with spousal caregivers might consider developing targeted interventions based on positive meaningful caregiving situations and building on this relational aspect.Item Genome-wide pathway analysis of memory impairment in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort(Office of the Vice Chancellor for Research, 2012-04-13) Ramanan, Vijay K.; Kim, Sungeun; Holohan, Kelly; Shen, Li; Nho, Kwangsik; Risacher, Shannon L.; Foroud, Tatiana M.; Mukherjee, Shubhabrata; Crane, Paul K.; Aisen, Paul S.; Petersen, Ronald C.; Weiner, Michael W.; Saykin, Andrew J.Memory deficits are prominent features of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). The genetic architecture underlying these memory deficits likely involves the combined effects of multiple genetic variants operative within numerous biological pathways. In order to identify functional pathways associated with memory impairment, we performed a pathway enrichment analysis on genome-wide association data from 742 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants. A composite measure of memory was generated as the phenotype for this analysis by applying modern psychometric theory to item-level data from the ADNI neuropsychological test battery. Using the GSA-SNP software tool, we identified 27 canonical, expertly-curated pathways with enrichment (FDR-corrected p-value < 0.05) against this composite memory score. Processes classically understood to be involved in memory consolidation, such as neurotransmitter receptor-mediated calcium signaling and long-term potentiation, were highly represented among the enriched pathways. In addition, pathways related to cell adhesion, neuronal differentiation and guided outgrowth, and glucose- and inflammation-related signaling were also enriched. Among genes that were highly-represented in these enriched pathways, we found indications of coordinated relationships, including one large gene set that is subject to regulation by the SP1 transcription factor, and another set that displays co-localized expression in normal brain tissue along with known AD risk genes. These results 1) highlight key pathways and their candidate genes that appear to underlie susceptibility to memory impairment in this population, 2) suggest mechanistic targets for future studies related to diagnosis and treatment of memory deficits, and 3) validate the promise of pathway analysis in elucidating key processes underlying complex traits.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 Sex-specific genetic predictors of memory, executive function, and language performance(Wiley, 2022) Eissman, Jaclyn M.; Smith, Alexandra N.; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Trittschuh, Emily H.; Mez, Jesse B.; Bush, William S.; Engelman, Corinne D.; Lu, Qiongshi; Fardo, David W.; Widaman, Keith F.; Buckley, Rachel F.; Mormino, Elizabeth C.; Kunkle, Brian W.; Naj, Adam C.; Clark, Lindsay R.; Gifford, Katherine A.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Genetics Consortium (ADGC); A4 Study Team; The Alzheimer’s Disease Sequencing Project (ADSP); Cuccaro, Michael L.; Cruchaga, Carlos; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li-San; Schellenberg, Gerard D.; Haines, Jonathan L.; Jefferson, Angela L.; Johnson, Sterling C.; Kukull, Walter A.; Albert, Marilyn S.; Keene, C. Dirk; Saykin, Andrew J.; Larson, Eric B.; Sperling, Reisa A.; Mayeux, Richard; Thompson, Paul M.; Martin, Eden R.; Bennett, David A.; Barnes, Lisa L.; Schneider, Julie A.; Crane, Paul K.; Hohman, Timothy J.; Dumitrescu, Logan; Radiology and Imaging Sciences, School of MedicineBackground: Alzheimer’s disease (AD) is more prevalent in women than men, and robust evidence shows sex differences in the biological response to the AD neuropathological cascade. However, there is a lack of large-scale genetic studies on sex-specific genetic predictors of AD-related cognitive outcomes. Thus, we sought to elucidate the sex-specific genetic etiology of memory, executive function, and language performance. Method: This study included six cohorts of cognitive aging (Nmales=7,267, Nfemales=9,518). We applied psychometric approaches to build harmonized memory, executive function, and language composite scores. Next, for all domains, we calculated slopes from the cognitive scores (two or more timepoints) with linear mixed effects models. Then we performed sex-stratified and sex-interaction GWAS on these phenotypes, covarying for baseline age and the first three genetic principal components. We meta-analyzed across cohorts with a fixed-effects model. Sensitivity analyses for all models restricted the sample to cognitively unimpaired individuals. Result: In addition to well-established associations with cognition at the APOE locus, we identified three genetic loci that showed sex-specific effects with cognition. A chromosome 16 locus (rs114106271), a splicing-quantitative trait locus for RP11-152O14.4 and LINC02180 in the testis (GTEx), associated with baseline memory performance in men (β=0.13, P=2.40×10-8; PInteraction=8.96×10-6; Figures 1-2) but not in women (β=-0.01, P=0.76). A chromosome 14 locus (rs34074573), an expression-quantitative trait locus (GTEx) for HOMEZ (a homeobox gene), and for BCL2L2 (a previously reported AD risk gene), associated with longitudinal memory performance in men (β=-0.01, P=4.15×10-8; PInteraction=5.83×10-7; Figures 3-4) but not in women (β=0.001, P=0.09). Finally, a chromosome 6 locus (rs9382966) associated with longitudinal language performance in men with near genome-wide significance (β=-0.004, P=6.29×10-8; PInteraction=2.01×10-4) but not in women (β=-0.0003, P=0.61). Conclusion: Our results highlight some key sex differences in the genetic architecture of cognitive outcomes. Findings further suggest that some sex-specific genetic predictors have domain-specific associations, providing an exciting opportunity to better understand the molecular basis of memory, executive function, and language through genomic analysis. Although our findings need to be replicated, our GWAS analyses highlight the contribution of sex-specific genetic predictors beyond the APOE locus in conferring risk for late-life cognitive decline.Item Sources of Burden in Caregivers of Persons with Early- and Late-Onset Alzheimer’s Disease(Oxford University Press, 2023) Crouch, Adele; Massimo, Lauren; School of NursingFunctional impairment and neuropsychiatric symptoms (NPS) are common in Alzheimer’s disease (AD) and contribute to caregiver burden. Persons with early-onset AD (EOAD) on average experience greater functional impairment and NPS compared to late-onset AD (LOAD), yet their contribution to caregiver burden have not been explored. Objectives were to: 1) compare functional impairment, NPS, and caregiving burden in EOAD and LOAD; 2) identify sources of caregiver burden including functional impairment and NPS in EOAD and LOAD. Caregivers of 85 persons with EOAD (n=63) and LOAD (n=22) completed questionnaires [Functional Activities Questionnaire, Neuropsychiatric Inventory, Zarit Burden Inventory]. T-tests compared group differences in function, NPS, and caregiver burden. Persons with EOAD had greater NPS frequency than LOAD (t= 2.275, p=0.026). There were no significant differences between groups in function or caregiver burden. Multivariate regression analyses were performed in AD groups, with function and NPS frequency as predictors of caregiver burden covarying for age, caregiver sex, and global cognitive function (MMSE). In the total AD sample, the model explained 12.6% of the variance in caregiver burden [F(5,52)=2.64, adjusted R2=0.126; p=0.033] and poor function was a significant predictor (standardized B=0.42, p=0.003) of caregiver burden. In EOAD, the model explained 17% of the variance in caregiver burden [F(5,35)=2.64, adjusted R2=0.17; p=0.04], and poor function was a significant (standardized B=0.42, p=0.015) predictor of caregiver burden; however this was not the case in LOAD. Results suggest poor function predicts caregiver burden in EOAD. Although NPS in EOAD are more frequent, this was not a predictor of caregiver burden.Item Variants in the Mitochondrial Intermediate Peptidase (MIPEP) Gene are Associated with Gray Matter Density in the Alzheimer’s Disease Neuroimaging Initiative Cohort(Office of the Vice Chancellor for Research, 2015-04-17) Nudelman, Kelly N. H.; Risacher, Shannon L.; West, John D.; McDonald, Brenna C.; Gao, Su; Saykin, Andrew J.Cancer and Alzheimer’s disease (AD) incidence is inversely correlated, but the genetic underpinnings of this relationship remain to be elucidated. Recent findings identified lower gray matter density in frontal regions of participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with cancer history compared to those without such history, across diagnostic groups (Nudelman et al., 2014). Pathways proposed to impact cancer and AD, including metabolism and survival, may play an important role in the observed difference. To test this hypothesis, a genome-wide association study (GWAS) using mean frontal gray matter cluster values was performed for all Caucasian participants in this cohort with neuroimaging and genetic data (n=1405). Analysis covaried for age, sex, AD, and cancer history. Of the two genes with the most significant SNPs (p<10-5), WD repeat domain 5B (WDR5B) and mitochondrial intermediate peptidase (MIPEP), MIPEP was selected for further analysis given the hypothesis focus on metabolism. ANOVA analysis of MIPEP top SNP rs8181878 with frontal gray matter cluster values in SPSS indicated that while this SNP is significantly associated with gray matter density (p=2x10-6), no interaction was observed with cancer history or AD diagnosis. Furthermore, whole brain gray matter voxel-wise analysis of this SNP using Statistical Parametric Mapping 8 software showed that minor allele(s) of this SNP were significantly (PFWE<0.05) associated with higher gray matter density. These results suggest that the minor allele of MIPEP SNP rs8181878 may be protective against gray matter density loss, highlighting the importance of metabolic processes in aging and disease.