Browsing by Subject "Alzheimer’s"

Now showing 1 - 8 of 8
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    Adherence and Tolerability of Alzheimer's Disease Medications: A Pragmatic Randomized Trial
    (Wiley, 2017-07) Campbell, Noll L.; Perkins, Anthony J.; Gao, Sujuan; Skaar, Todd C.; Li, Lang; Hendrie, Hugh C.; Fowler, Nicole; Callahan, Christopher M.; Boustani, Malaz A.; Department of Medicine, IU School of Medicine
    BACKGROUND/OBJECTIVES: Post-marketing comparative trials describe medication use patterns in diverse, real-world populations. Our objective was to determine if differences in rates of adherence and tolerability exist among new users to acetylcholinesterase inhibitors (AChEI's). DESIGN: Pragmatic randomized, open label comparative trial of AChEI's currently available in the United States. SETTING: Four memory care practices within four healthcare systems in the greater Indianapolis area. PARTICIPANTS: Eligibility criteria included older adults with a diagnosis of possible or probable Alzheimer's disease (AD) who were initiating treatment with an AChEI. Participants were required to have a caregiver to complete assessments, access to a telephone, and be able to understand English. Exclusion criteria consisted of a prior severe adverse event from AChEIs. INTERVENTION: Participants were randomized to one of three AChEIs in a 1:1:1 ratio and followed for 18 weeks. MEASUREMENTS: Caregiver-reported adherence, defined as taking or not taking study medication, and caregiver-reported adverse events, defined as the presence of an adverse event. RESULTS: 196 participants were included with 74.0% female, 30.6% African Americans, and 72.9% who completed at least twelfth grade. Discontinuation rates after 18 weeks were 38.8% for donepezil, 53.0% for galantamine, and 58.7% for rivastigmine (P = .063) in the intent to treat analysis. Adverse events and cost explained 73.1% and 25.4% of discontinuation. No participants discontinued donepezil due to cost. Adverse events were reported by 81.2% of all participants; no between-group differences in total adverse events were statistically significant. CONCLUSIONS: This pragmatic comparative trial showed high rates of adverse events and cost-related non-adherence with AChEIs. Interventions improving adherence and persistence to AChEIs may improve AD management. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01362686 (https://clinicaltrials.gov/ct2/show/NCT01362686).
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    Amyloid and Tau Pathology Associations With Personality Traits, Neuropsychiatric Symptoms, and Cognitive Lifestyle in the Preclinical Phases of Sporadic and Autosomal Dominant Alzheimer’s Disease
    (Elsevier, 2021) Pichet Binette, Alexa; Vachon-Presseau, Étienne; Morris, John; Bateman, Randall; Benzinger, Tammie; Collins, D. Louis; Poirier, Judes; Breitner, John C. S.; Villeneuve, Sylvia; Dominantly Inherited Alzheimer Network (DIAN); PREVENT-AD Research Group; Psychiatry, School of Medicine
    Background: Major prevention trials for Alzheimer's disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-β, and tau deposits. Methods: A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. Results: In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology. Conclusions: In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression.
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    Barriers and Facilitators of Health and Well-Being in Informal Caregivers of Dementia Patients: A Qualitative Study
    (MDPI, 2023-02-28) Duplantier, Sally C.; Williamson, Francesca A.; Pediatrics, School of Medicine
    Background: Given the dramatic projected increase in Alzheimer's disease globally and the increased risk of morbidity and mortality for family caregivers of these patients, there is an urgent need to provide more targeted, timely resources to support the health and well-being of these informal caregivers. Few studies have investigated the barriers to health and well-being and potential strategies to facilitate better self-care from the unique perspective of the caregivers themselves. Purpose: This qualitative study aimed to identify barriers and facilitators to health and well-being for informal caregivers of family members with Alzheimer's. Method: We conducted semi-structured interviews with eight informal caregivers, including daughters, wives, and one husband, ages 32 to 83. Using Reflexive Thematic Analysis, we identified three main themes and subthemes across caregivers' experiences. Findings: We found that caregivers (1) prioritized mental and social well-being over physical health or health behaviors; (2) characterized the subjective burden of caregiving as a "mantle of responsibility" that could not easily be shed due to the complex subjective burden of loss, grief, guilt, resentment, isolation, loneliness, and lack of agency; (3) sought to be recognized as "additional patients", instead of being viewed as invisible patients, with support services tailored to their life stage and challenges. Conclusions: The findings suggest that the subjective burden of strain experienced by family caregivers of Alzheimer's patients has a profound impact on their health and well-being, even more so than the objective burden of strain that is the result of their day-to-day caregiving activities.
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    Detection of β-amyloid positivity in Alzheimer’s Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers
    (Oxford University Press, 2021-02-02) Tosun, Duygu; Veitch, Dallas; Aisen, Paul; Jack, Clifford R., Jr.; Jagust, William J.; Petersen, Ronald C.; Saykin, Andrew J.; Bollinger, James; Ovod, Vitaliy; Mawuenyega, Kwasi G.; Bateman, Randall J.; Shaw, Leslie M.; Trojanowski, John Q.; Blennow, Kaj; Zetterberg, Henrik; Weiner, Michael W.; Radiology and Imaging Sciences, School of Medicine
    In vivo gold standard for the ante-mortem assessment of brain β-amyloid pathology is currently β-amyloid positron emission tomography or cerebrospinal fluid measures of β-amyloid42 or the β-amyloid42/β-amyloid40 ratio. The widespread acceptance of a biomarker classification scheme for the Alzheimer's disease continuum has ignited interest in more affordable and accessible approaches to detect Alzheimer's disease β-amyloid pathology, a process that often slows down the recruitment into, and adds to the cost of, clinical trials. Recently, there has been considerable excitement concerning the value of blood biomarkers. Leveraging multidisciplinary data from cognitively unimpaired participants and participants with mild cognitive impairment recruited by the multisite biomarker study of Alzheimer's Disease Neuroimaging Initiative, here we assessed to what extent plasma β-amyloid42/β-amyloid40, neurofilament light and phosphorylated-tau at threonine-181 biomarkers detect the presence of β-amyloid pathology, and to what extent the addition of clinical information such as demographic data, APOE genotype, cognitive assessments and MRI can assist plasma biomarkers in detecting β-amyloid-positivity. Our results confirm plasma β-amyloid42/β-amyloid40 as a robust biomarker of brain β-amyloid-positivity (area under curve, 0.80-0.87). Plasma phosphorylated-tau at threonine-181 detected β-amyloid-positivity only in the cognitively impaired with a moderate area under curve of 0.67, whereas plasma neurofilament light did not detect β-amyloid-positivity in either group of participants. Clinical information as well as MRI-score independently detected positron emission tomography β-amyloid-positivity in both cognitively unimpaired and impaired (area under curve, 0.69-0.81). Clinical information, particularly APOE ε4 status, enhanced the performance of plasma biomarkers in the detection of positron emission tomography β-amyloid-positivity by 0.06-0.14 units of area under curve for cognitively unimpaired, and by 0.21-0.25 units for cognitively impaired; and further enhancement of these models with an MRI-score of β-amyloid-positivity yielded an additional improvement of 0.04-0.11 units of area under curve for cognitively unimpaired and 0.05-0.09 units for cognitively impaired. Taken together, these multi-disciplinary results suggest that when combined with clinical information, plasma phosphorylated-tau at threonine-181 and neurofilament light biomarkers, and an MRI-score could effectively identify β-amyloid+ cognitively unimpaired and impaired (area under curve, 0.80-0.90). Yet, when the MRI-score is considered in combination with clinical information, plasma phosphorylated-tau at threonine-181 and plasma neurofilament light have minimal added value for detecting β-amyloid-positivity. Our systematic comparison of β-amyloid-positivity detection models identified effective combinations of demographics, APOE, global cognition, MRI and plasma biomarkers. Promising minimally invasive and low-cost predictors such as plasma biomarkers of β-amyloid42/β-amyloid40 may be improved by age and APOE genotype.
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    From the Mind to the Spine: The Intersecting World of Alzheimer's and Osteoporosis
    (Springer, 2024) Margetts, Tyler J.; Wang, Hannah S.; Karnik, Sonali J.; Plotkin, Lilian I.; Movila, Alexandru; Oblak, Adrian L.; Fehrenbacher, Jill C.; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
    Purpose of review: This comprehensive review delves into the intricate interplay between Alzheimer's disease (AD) and osteoporosis, two prevalent conditions with significant implications for individuals' quality of life. The purpose is to explore their bidirectional association, underpinned by common pathological processes such as aging, genetic factors, inflammation, and estrogen deficiency. Recent findings: Recent advances have shown promise in treating both Alzheimer's disease (AD) and osteoporosis by targeting disease-specific proteins and bone metabolism regulators. Monoclonal antibodies against beta-amyloid and tau for AD, as well as RANKL and sclerostin for osteoporosis, have displayed therapeutic potential. Additionally, ongoing research has identified neuroinflammatory genes shared between AD and osteoporosis, offering insight into the interconnected inflammatory mechanisms. This knowledge opens avenues for innovative dual-purpose therapies that could address both conditions, potentially revolutionizing treatment approaches for AD and osteoporosis simultaneously. This review underscores the potential for groundbreaking advancements in early diagnosis and treatment by unraveling the intricate connection between AD and bone health. It advocates for a holistic, patient-centered approach to medical care that considers both cognitive and bone health, ultimately aiming to enhance the overall well-being of individuals affected by these conditions. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.
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    Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer's disease related proteins
    (BMC, 2023-01-07) Oatman, Stephanie R.; Reddy, Joseph S.; Quicksall, Zachary; Carrasquillo, Minerva M.; Wang, Xue; Liu, Chia‑Chen; Yamazaki, Yu; Nguyen, Thuy T.; Malphrus, Kimberly; Heckman, Michael; Biswas, Kristi; Nho, Kwangsik; Baker, Matthew; Martens, Yuka A.; Zhao, Na; Kim, Jun Pyo; Risacher, Shannon L.; Rademakers, Rosa; Saykin, Andrew J.; DeTure, Michael; Murray, Melissa E.; Kanekiyo, Takahisa; Alzheimer’s Disease Neuroimaging Initiative; Dickson, Dennis W.; Bu, Guojun; Allen, Mariet; Ertekin‑Taner, Nilüfer; Radiology and Imaging Sciences, School of Medicine
    Background: Alzheimer's disease (AD) is neuropathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The main protein components of these hallmarks include Aβ40, Aβ42, tau, phosphor-tau, and APOE. We hypothesize that genetic variants influence the levels and solubility of these AD-related proteins in the brain; identifying these may provide key insights into disease pathogenesis. Methods: Genome-wide genotypes were collected from 441 AD cases, imputed to the haplotype reference consortium (HRC) panel, and filtered for quality and frequency. Temporal cortex levels of five AD-related proteins from three fractions, buffer-soluble (TBS), detergent-soluble (Triton-X = TX), and insoluble (Formic acid = FA), were available for these same individuals. Variants were tested for association with each quantitative biochemical measure using linear regression, and GSA-SNP2 was used to identify enriched Gene Ontology (GO) terms. Implicated variants and genes were further assessed for association with other relevant variables. Results: We identified genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD-related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. Conclusions: Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.
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    A Longitudinal Imaging Genetics Study of Neuroanatomical Asymmetry in Alzheimer's Disease
    (Elsevier, 2018-10-01) Wachinger, Christian; Nho, Kwangsik; Saykin, Andrew J.; Reuter, Martin; Rieckmann, Anna; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of Medicine
    Neuroanatomical asymmetries have recently been associated with the progression of Alzheimer’s disease (AD) but the biological basis of asymmetric brain changes in disease remains unknown. Methods We investigated genetic influences on brain asymmetry by identifying associations between MRI-derived measures of asymmetry and candidate single-nucleotide polymorphisms (SNPs) that have previously been identified in genome-wide association studies (GWAS) for AD diagnosis and for brain subcortical volumes. For the longitudinal neuroimaging data (1,241 individuals; 6,395 scans), we use a mixed effects model with interaction between genotype and diagnosis. Results We found significant associations between asymmetry of amygdala, hippocampus, and putamen and SNPs in the genes BIN1, CD2AP, ZCWPW1, ABCA7, TNKS, and DLG2. For AD candidate SNPs, we demonstrated an asymmetric effect on subcortical brain structures. Conclusions The associations between SNPs in the genes TNKS and DLG2 and AD-related increases in shape asymmetry are of particular interest; these SNPs have previously been associated with subcortical volumes of amygdala and putamen but have not yet been associated with Alzheimer’s pathology. This provides novel evidence about the biological underpinnings of brain asymmetry as a disease marker. Contralateral brain structures represent a unique, within-patient, reference element for disease and asymmetries can provide a personalized measure of the accumulation of past disease processes.
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    The Pivotal Role of NF-kB in the Pathogenesis and Therapeutics of Alzheimer’s Disease
    (MDPI, 2022-08-11) Sun, Emily; Motolani, Aishat; Campos, Leonardo; Lu, Tao; Pharmacology and Toxicology, School of Medicine
    Alzheimer's Disease (AD) is the most common neurodegenerative disease worldwide, with a high prevalence that is expected to double every 20 years. Besides the formation of Aβ plaques and neurofibrillary tangles, neuroinflammation is one the major phenotypes that worsens AD progression. Indeed, the nuclear factor-κB (NF-κB) is a well-established inflammatory transcription factor that fuels neurodegeneration. Thus, in this review, we provide an overview of the NF-κB role in the pathogenesis of AD, including its interaction with various molecular factors in AD mice models, neurons, and glial cells. Some of these cell types and molecules include reactive microglia and astrocytes, β-secretase, APOE, glutamate, miRNA, and tau protein, among others. Due to the multifactorial nature of AD development and the failure of many drugs designed to dampen AD progression, the pursuit of novel targets for AD therapeutics, including the NF-κB signaling pathway, is rising. Herein, we provide a synopsis of the drug development landscape for AD treatment, offering the perspective that NF-κB inhibitors may generate widespread interest in AD research in the future. Ultimately, the additional investigation of compounds and small molecules that target NF-κB signaling and the complete understanding of NF-κB mechanistic activation in different cell types will broaden and provide more therapeutic options for AD patients.