Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Nidadavolu, Lolita S. | Feger, Danielle | Wu, Yuqiong | Grodstein, Francine | Gross, Alden L. | Bennett, David A. | Walston, Jeremy D. | Oh, Esther S. | Abadir, Peter M.

Article Type: Research Article

Abstract: Background: Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death and turnover, releasing circulating cell-free DNA (ccf-DNA). Objective: The goal of this study is to determine if serum genomic cell-free DNA (ccf-gDNA) is associated with physical and cognitive decline in older adults. Methods: We used serum from 631 community-dwelling individuals from the Religious Orders Study or Rush Memory and Aging Project who were without cognitive impairment at baseline. ccf-gDNA fragments in serum were quantified using digital PCR. An array of cognitive and physical traits, risk of dementia, global cognition, and frailty at …or nearest the time of blood draw were regressed on ccf-DNA, with adjustment for age, sex, race, and education. Results: Cross-sectionally, higher ccf-gDNA levels were associated with lower global cognition score and slower gait speed at the evaluation nearest to blood draw. Higher ccf-gDNA levels were associated with increased odds of incident dementia (OR 1.27, 95% CI 1.05, 1.54). Longitudinally, higher levels of ccf-gDNA were associated with steeper general cognitive decline and worsening frailty over eight years of follow up. Conclusion: This study demonstrates that ccf-gDNA fragments have utility for identifying persons at higher risk of developing dementia and worsening cognition and frailty. Show more

Keywords: Cell-free DNA, cell death, cognitive dysfunction, dementia, frailty

DOI: 10.3233/JAD-220301

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2022

Authors: Zawar, Ifrah | Mattos, Meghan K. | Manning, Carol | Quigg, Mark

Article Type: Research Article

Abstract: Background: While sleep disturbances appear to be risk factors in Alzheimer’s disease (AD) progression, information such as the prevalence across dementia severity and the influence on the trajectory of cognitive decline is unclear. Objective: We evaluate the hypotheses that the prevalence of insomnia differs by cognitive impairment, that sleep disturbances track with AD biomarkers, and that longitudinal changes in sleep disorders affect cognition. Methods: We used the National Alzheimer’s Coordinating Center Database to determine the prevalence of clinician-identified insomnia and nighttime behaviors in normal, mild cognitive impairment (MCI), and demented individuals. We evaluated mean Montreal Cognitive …Assessment (MoCA) scores, hippocampal volumes (HV), and CSF phosphorylated tau:amyloid-β ratios at first visit using analysis of variance with age as a covariate. In longitudinal evaluations, we assessed changes in MoCA scores and HV in insomnia and nighttime behaviors between the first and last visits. Results: Prevalence of insomnia was 14%, 16%, and 11% for normal, MCI, and dementia groups. Prevalence of nighttime behaviors was 14%, 21%, and 29% respectively. Insomnia patients had higher MoCA scores, larger HV, and lower pTauBeta than individuals without insomnia, indicating less neurodegeneration. In contrast, nighttime behaviors were associated with worse cognition, smaller HV, and higher pTauBeta. Similar findings were seen between longitudinal associations of sleep disorders and cognition and HV. Conclusion: Our findings suggest that insomnia is unreliably recognized in patients with cognitive impairment. Nighttime behaviors may better indicate the presence of sleep disturbances and have diagnostic specificity in AD over insomnia. Show more

Keywords: Dementia, hippocampus, insomnia, sleep, sleep insufficiency

DOI: 10.3233/JAD-220664

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2022

Authors: Shkirkova, Kristina | Lamorie-Foote, Krista | Zhang, Nathan | Li, Andrew | Diaz, Arnold | Liu, Qinghai | Thorwald, Max A. | Godoy-Lugo, Jose A. | Ge, Brandon | D’Agostino, Carla | Zhang, Zijiao | Mack, Wendy J. | Sioutas, Constantinos | Finch, Caleb E. | Mack, William J. | Zhang, Hongqiao

Article Type: Research Article

Abstract: Background: Air pollution particulate matter (PM) is strongly associated with risks of accelerated cognitive decline, dementia and Alzheimer’s disease. Ambient PM batches have variable neurotoxicity by collection site and season, which limits replicability of findings within and between research groups for analysis of mechanisms and interventions. Diesel exhaust particles (DEP) offer a replicable model that we define in further detail. Objective: Define dose- and time course neurotoxic responses of mice to DEP from the National Institute of Science and Technology (NIST) for neurotoxic responses shared by DEP and ambient PM. Methods: For dose-response, adult C57BL/6 male …mice were exposed to 0, 25, 50, and 100μg/m3 of re-aerosolized DEP (NIST SRM 2975) for 5 h. Then, mice were exposed to 100μg/m3 DEP for 5, 100, and 200 h and assayed for amyloid-β peptides, inflammation, oxidative damage, and microglial activity and morphology. Results: DEP exposure at 100μg/m3 for 5 h, but not lower doses, caused oxidative damage, complement and microglia activation in cerebral cortex and corpus callosum. Longer DEP exposure for 8 weeks/200 h caused further oxidative damage, increased soluble Aβ, white matter injury, and microglial soma enlargement that differed by cortical layer. Conclusion: Exposure to 100μg/m3 DEP NIST SRM 2975 caused robust neurotoxic responses that are shared with prior studies using DEP or ambient PM0.2. DEP provides a replicable model to study neurotoxic mechanisms of ambient PM and interventions relevant to cognitive decline and dementia. Show more

Keywords: Air pollution, Alzheimer’s disease, brain, dementia, diesel exhaust particle, neurotoxicity

DOI: 10.3233/JAD-220493

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2022

Authors: Bardenheier, Barbara Helen | Resnik, Linda J. | Jutkowitz, Eric | Gravenstein, Stefan

Article Type: Research Article

Abstract: Background: To reduce the increasing societal and financial burden of Alzheimer’s disease and related dementias (ADRD), prevention is critical. Even small improvements of the modifiable dementia risk factors on the individual level have the potential to lead to a substantial reduction of dementia cases at the population level. Objective: To determine if pattern(s) of functional decline in midlife associate with late-onset ADRD years later. Methods: Using a longitudinal study of adults aged 51–59 years in 1998 without symptoms of ADRD by 2002 and followed them from 2002 to 2016 (n  = 5404). The outcome was incident ADRD …identified by the Lange-Weir algorithm, death, or alive with no ADRD. We used cluster analysis to identify patterns of functional impairment at baseline and multinomial regression to assess their association with future ADRD. Results: Three groups of adults with differing patterns of functional impairment were at greater risk of future ADRD. Difficulty with climbing one flight of stairs was observed in all adults in two of these groups. In the third group, 100% had difficulty with lifting 10 pounds and pushing or pulling a large object, but only one-fourth had difficulty in climbing stairs. Conclusion: Results imply that improved large muscle strength could decrease future risk of ADRD. If confirmed in other studies, screening for four self-reported measures of function among adults in midlife may be used for targeted interventions. Show more

Keywords: Alzheimer’s disease and related dementias, Health and Retirement Study, late midlife, physical function limitation

DOI: 10.3233/JAD-220573

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2022

Authors: Guo, Rong | Ou, Ya-Nan | Hu, He-Ying | Ma, Ya-Hui | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: The relationship between osteoarthritis (OA) and risk of dementia and cognitive impairment (CIM) has long been debated; however, uncertainties still persist. Objective: The aim of our present meta-analysis and systematic review was to roundly illuminate the association between OA and the risk of dementia and CIM. Methods: We identified relevant studies by searching PubMed, Embase, and Web of Science up to October 2021. The relative risk (RR) or odds ratio (OR) with 95% confidence interval (CI) were aggregated using random-effects methods. Credibility of each meta-analysis was assessed. Meta-regression and subgroup analyses were conducted. Publication bias …was explored using funnel plot. Results: Of 21,925 identified literatures, 8 were eligible for inclusion in the systematic review and 19 observational studies involving 724,351 individuals were included in the meta-analysis. The risk of developing dementia and CIM among OA patients was demonstrated in 11 prospective studies (RR = 1.42, 95% CI = 1.07–1.86, I2  = 98.9%, p  <  0.001), 2 retrospective cohort studies (RR = 1.35, 95% CI = 1.19–1.52, I2  = 61.0%, p  = 0.109), 3 retrospective case-control studies (OR = 1.21, 95% CI = 0.96–1.53, I2  = 95.2%, p  <  0.001), and 4 cross-sectional studies (OR = 1.51, 95% CI = 1.09–2.09, I2  = 75.8%, p  = 0.006). Meta-regression analyses did not find any valid moderators. Heterogeneity in subgroup analyses for population age, OA location, year of publication, outcome type, adjusted for BMI, depression, and comorbidity decreased to zero. No significant evidence of publication bias was found. Conclusion: OA associated with an increased risk of dementia and CIM. Effective interventions in OA patients may decrease new incidence of dementia or CIM. Show more

Keywords: Dementia, meta-analysis, osteoarthritis, systematic review

DOI: 10.3233/JAD-220568

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2022

Authors: Perales-Puchalt, Jaime | Townley, Ryan | Niedens, Michelle | Vidoni, Eric D. | Greiner, K. Allen | Zufer, Tahira | Schwasinger-Schmidt, Tiffany | McGee, Jerrihlyn L. | Arreaza, Hector | Burns, Jeffrey M.

Article Type: Research Article

Abstract: Background: Optimal care can improve lives of families with dementia but remains under-implemented. Most healthcare professional training is in person, time-intensive, and does not focus on key aspects such as early detection, and cultural competency. Objective: We explored the acceptability and preliminary effectiveness of a training, The Dementia Update Course, which addressed these issues. We hypothesized that the training would lead to increased levels of perceived dementia care competency among key healthcare workers, namely primary care providers (PCPs) and health navigators (HNs). Methods: We conducted pre-post training assessments among 22 PCPs and 32 HNs. The 6.5-h …training was remote, and included didactic lectures, case discussion techniques, and materials on dementia detection and care. Outcomes included two 5-point Likert scales on acceptability, eleven on perceived dementia care competency, and the three subscales of the General Practitioners Confidence and Attitude Scale for Dementia. We used paired samples t -tests to assess the mean differences in all preliminary effectiveness outcomes. Results: The training included 28.6% of PCPs and 15.6% of HNs that self-identified as non-White or Latino and 45.5% of PCPs and 21.9% of HNs who served in rural areas. PCPs (84.2%) and HNs (91.7%) reported a high likelihood to recommend the training and high satisfaction. Most preliminary effectiveness outcomes analyzed among PCPs (11/14) and all among HNs (8/8) experienced an improvement from pre- to post-training (p  <  0.05). Conclusion: A relatively brief, remote, and inclusive dementia training was associated with high levels of acceptability and improvements in perceived dementia care competency among PCPs and HNs. Show more

Keywords: Attitude of health personnel, dementia, education, healthcare professionals

DOI: 10.3233/JAD-220235

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2022

Authors: Wawrziczny, Emilie | Picard, Sandrine | Buquet, Amandine | Traversac, Elodie | Puisieux, François | Pasquier, Florence | Huvent-Grelle, Dominique | Doba, Karyn

Article Type: Research Article

Abstract: Background: Dementia has a negative impact on the quality of life of the person with dementia and their spouse caregivers, as well as on the couple’s relationship, which can lead to high levels of distress for both partners. Hypnosis has been shown to be effective in managing distress and increasing the quality of the relationship. Objective: The aim was to develop a standardized hypnosis intervention for couples confronted with Alzheimer’s disease and evaluate its feasibility, acceptability, and helpfulness in managing the distress of both partners and increasing the quality of the relationship. Methods: In a single-arm …study, sixteen couples received the 8-week intervention. Qualitative and quantitative assessments were conducted pre- and post-intervention as well as three months after. Results: 88.9% of couples (n  = 16) of the final sample (n  = 18) completed the intervention. Despite the negative representations of hypnosis, several factors led couples to accept to participate in this study: positive expectations, professional endorsement, medical application, non-drug approach, home-based, free, flexible, and couple-based intervention. The results showed a significant decrease in distress for both partners. These effects were maintained three months after the intervention. Couples felt more relaxed, had fewer negative emotions, accepted difficulties more easily, were more patient, and reported better communication and more affection in the relationship. Conclusion: Overall, this pilot study shows the feasibility and acceptability of hypnosis with couples confronted with Alzheimer’s disease. Although measures of the preliminary pre- and post-intervention effects are encouraging, confirmatory testing with a randomized controlled trial is needed. Show more

Keywords: Alzheimer’s disease, couple, distress, hypnosis

DOI: 10.3233/JAD-220430

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2022

Authors: Kanagasingam, Shalini | von Ruhland, Christopher | Welbury, Richard | Singhrao, Sim K.

Article Type: Research Article

Abstract: Background: Tau is an established substrate for gingipains secreted by Porphyromonas gingivalis . Hyperphosphorylation of tau and neurofibrillary tangle (NFT) formation is a defining lesion of Alzheimer’s disease (AD) where NFT distribution is related to Braak stage and disease severity. Objective: To assess gingipains’-fragmented tau peptides for their antimicrobial properties and for the likelihood of paired helical/straight filament (PHF/SF) formation with implications for the NFT lesion. Methods: Seven non-phosphorylated (A-G) and three phosphorylated (A-C) tau peptides, were tested for antimicrobial properties against P. gingivalis . Polarizing light properties were determined using Congo Red staining. Secondary and …tertiary structures of peptides B-F were determined using transmission electron microscopy (TEM) and circular dichroism (CD) was undertaken for the soluble peptides A in phosphorylated and non-phosphorylated states. Results: Phosphorylated tau peptide A displayed a significant effect against planktonic P. gingivalis . The CD results demonstrated that both peptides A, in phosphorylated and non-phosphorylated states, in aqueous solution, adopted mainly β-type structures. Non-phosphorylated peptides B-F and phosphorylated peptides B-C were insoluble and fibrillar under the TEM. The secondary and tertiary structures of the non-phosphorylated peptide B demonstrated fewer helical twists, whereas peptide C displayed significantly more helical twists along the whole fiber(s) length following its phosphorylation. Conclusion: Phosphorylated peptide A reduced P. gingivalis viability. CD spectroscopy demonstrated the phosphorylated and the non-phosphorylated peptide A predominantly formed from β-sheet structures in aqueous solution with potential antimicrobial activity. Phosphorylation of tau peptides physically changed their tertiary structure into PHFs with potential for self-aggregation and binding to the NFT lesion. Show more

Keywords: Antimicrobial, β-sheet, birefringence, gingipains, neurofibrillary tangles, Porphyromonas gingivalis, tau

DOI: 10.3233/JAD-220486

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2022

Authors: Kurasz, Andrea M. | De Wit, Liselotte | Smith, Glenn E. | Armstrong, Melissa J.

Article Type: Research Article

Abstract: Background: Survival and associated clinical and pathological characteristics in Lewy body disease (LBD)-related dementias are understudied. Available studies focus primarily on white non-Hispanic samples. Objective: We investigated demographic, clinical, and pathological correlates of survival by race and ethnicity in an autopsy-confirmed cohort of LBD cases. Methods: Using National Alzheimer’s Coordinating Center data, we selected participants who self-identified as Black, Hispanic, or white who had neuropathological assessments showing transitional or diffuse LBD pathology. We used Kruskal-Wallis and Pearson χ2 analyses to investigate group differences in demographic and presenting clinical and pathological characteristics. We used linear regressions …to identify predictors of survival with sex, age at symptom onset, education, ethnoracial status, LBD pathology type, and Braak tangle stage included in the model. Results: Data from 1,441 white, 60 Black, and 54 Hispanic participants were available for analysis. Hispanics were more likely to have transitional LBD pathology and had a longer survival than white and Black participants. After controlling for demographic and pathological variables, length of survival did not differ between Hispanics and Black or white participants. Additional key findings demonstrated discrepancies between clinical diagnoses received at last visit and pathological findings, particularly among Black participants. Conclusion: LBD survival differences by race and ethnicity can be accounted for by LBD pathology type and co-occurring Alzheimer’s disease pathology. The discrepancies between clinical diagnoses and pathological findings raise concern that dementia with Lewy bodies is underdiagnosed in NACC, especially for Black older adults. Show more

Keywords: Cognitive dysfunction, dementia, ethnicity, Lewy body disease, neuropathology, racial groups

DOI: 10.3233/JAD-220297

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022

Authors: Berdyński, Mariusz | Ludwiczak, Jan | Barczak, Anna | Barcikowska-Kotowicz, Maria | Kuźma-Kozakiewicz, Magdalena | Dunin-Horkawicz, Stanisław | Żekanowski, Cezary | Borzemska, Beata

Article Type: Research Article

Abstract: Background: Homozygous variants of the TREM2 and TYROBP genes have been shown to be causative for multiple bone cysts and neurodegeneration leading to progressive dementia (NHD, Nasu-Hakola disease). Objective: To determine if biallelic variants of these genes and/or oligogenic inheritance could be responsible for a wider spectrum of neurodegenerative conditions. Methods: We analyzed 52 genes associated with neurodegenerative disorders using targeted next generation sequencing in a selected group of 29 patients (n  = 14 Alzheimer’s disease, n  = 8 frontotemporal dementia, n  = 7 amyotrophic lateral sclerosis) carrying diverse already determined rare variants in exon 2 of …TREM2. Molecular modeling was used to get an insight into the potential effects of the mutation. Results: We identified a novel mutation c.401_406delinsTCTAT; p.(Asp134Valfs*55) in exon 3 of TREM2 in an Alzheimer’s disease patient also carrying the p.Arg62His TREM2 variant. Molecular modeling revealed that the identified mutation prevents anchoring of the TREM2 protein in the membrane, leaving the core of the Ig-like domain intact. Conclusion: Our results expand the spectrum of neurodegenerative diseases, where the carriers of biallelic mutations in TREM2 have been described for Alzheimer’s disease, and highlight the impact of variant burden in other genes on phenotypic heterogeneity. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, behavioral variant of frontotemporal dementia, compound heterozygosity, TREM2, TYROBP, variant burden

DOI: 10.3233/JAD-220210

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022