Journal of Alzheimer's Disease - Volume 87, issue 4

Authors: McGrath, Emer R. | Beiser, Alexa S. | O’Donnell, Adrienne | Yang, Qiong | Ghosh, Saptaparni | Gonzales, Mitzi M. | Himali, Jayandra J. | Satizabal, Claudia L. | Johnson, Keith A. | Tracy, Russell P. | Seshadri, Sudha

Article Type: Research Article

Abstract: Background: Plasma phosphorylated-tau181 (p-tau181) is a promising biomarker for Alzheimer’s disease (AD) and may offer utility for predicting preclinical disease. Objective: To evaluate the prospective association between plasma p-tau181 and amyloid-β (Aβ) and tau-PET deposition in cognitively unimpaired individuals. Methods: Plasma p-tau181 levels were measured at baseline in 52 [48% women, mean 64.4 (SD 5.5) years] cognitively unimpaired Framingham Offspring cohort participants using samples stored between 2011–2014 who subsequently underwent 11 C-Pittsburgh Compound-B (PiB)-PET and/or 18 F-Flortaucipir (FTP)-PET scans (n  = 18 with tau-PET) a mean of 6.8 (SD 0.6) years later. Our primary outcomes included Aβ-precuneus, …Aβ-FLR (frontal, lateral, and retrosplenial cortices) and tau-global composite region PET deposition. Secondary outcomes included individual regional Aβ and tau PET-deposition. P-tau181 was compared with plasma neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) in predicting PET outcomes. Results: P-tau181 was associated with increased Aβ deposition in the FLR (β±SE, 1.25±0.30, p  < 0.0001), precuneus (1.35±0.29, p  < 0.001), and other cortical regions. Plasma NFL (1.30±0.49, p  = 0.01) and GFAP (1.46±0.39, p  < 0.001) were also associated with FLR Aβ deposition. In models including all three biomarkers adjusted for age, sex, APOE E4 allele, AD polygenic risk score and cortical atrophy score, p-tau181 (0.93±0.31, p  < 0.01, R2  = 0.18) and GFAP (0.93±0.41, p  = 0.03, R2  = 0.11), but not NFL (0.25±0.51, p  = 0.62, R2  = 0.01), were associated with FLR-Aβ deposition. Plasma p-tau181 was not associated with tau-PET burden. Conclusion: In cognitively unimpaired adults, elevated plasma p-tau181 is associated with future increased Aβ deposition across multiple brain regions. Our results highlight the potential utility of p-tau181 as a blood-biomarker to screen for brain-amyloid deposition in cognitively healthy individuals in a community-setting. Show more

Keywords: Dementia, brain positron emission tomography, Aβ-PET, tau-PET, biomarkers

DOI: 10.3233/JAD-215639

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1517-1526, 2022

Authors: Dias, Irundika H.K. | Shokr, Hala | Shephard, Freya | Chakrabarti, Lisa

Article Type: Research Article

Abstract: Background: Brain cholesterol levels are tightly regulated but increasing evidence indicates that cholesterol metabolism may drive Alzheimer’s disease (AD)-associated pathological changes. Recent advances in understanding of mitochondrial dysfunction in AD brain have presented a vital role played by mitochondria in oxysterol biosynthesis and their involvement in pathophysiology. Oxysterol accumulation in brain is controlled by various enzymatic pathways including sulfation. While research into oxysterol is under the areas of active investigation, there is less evidence for oxysterol sulfate levels in human brain. Objective: This study investigates the hypothesis that AD brain oxysterol detoxification via sulfation is impaired in later …stages of disease resulting in oxysterol accumulation. Methods: Lipids were extracted from postmortem frozen brain tissue and cerebrospinal (CSF) from late- (Braak stage III-IV) and early- (Braak stage I-II) stage AD patients. Samples were spiked with internal standards prior to lipid extraction. Oxysterols were enriched with a two-step solid phase extraction using a polymeric SPE column and further separation was achieved by LC-MS/MS. Results: Oxysterols, 26-hydroxycholesterol (26-OHC), 25-hydroxycholesterol (25-OHC), and 7-oxycholesterol levels were higher in brain tissue and mitochondria extracted from late-stage AD brain tissue except for 24S-hydroxycholesterol, which was decreased in late AD. However, oxysterol sulfates are significantly lower in the AD frontal cortex. Oxysterols, 25-OHC, and 7-oxocholesterol was higher is CSF but 26-OHC and oxysterol sulfate levels were not changed. Conclusion: Our results show oxysterol metabolism is altered in AD brain mitochondria, favoring synthesis of 26-OHC, 25-OHC, and 7-oxocholesterol, and this may influence brain mitochondrial function and acceleration of the disease. Show more

Keywords: Alzheimer’s disease, brain, cholesterol, mitochondria, oxidative stress, oxysterols

DOI: 10.3233/JAD-220083

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1527-1536, 2022

Authors: McCarter, Stuart J. | Lesnick, Timothy G. | Lowe, Val J. | Rabinstein, Alejandro A. | Przybelski, Scott A. | Algeciras-Schimnich, Alicia | Ramanan, Vijay K. | Jack Jr., Clifford R. | Petersen, Ronald C. | Knopman, David S. | Boeve, Bradley F. | Kantarci, Kejal | Vemuri, Prashanthi | Mielke, Michelle M. | Graff-Radford, Jonathan

Article Type: Research Article

Abstract: Background: Cerebral microbleeds (CMBs) are a common vascular pathology associated with future intracerebral hemorrhage. Plasma biomarkers of amyloid, tau, and neurodegeneration may provide a screening avenue to identify those with CMBs, but evidence is conflicting. Objective: To determine the association between plasma biomarkers (Aβ40 , Aβ42 , t-tau, p-tau181 , p-tau217 , neurofilament light chain (NfL)) and CMBs in a population-based study of aging and whether these biomarkers predict higher signal on Aβ-PET imaging in patients with multiple CMBs. Methods: 712 participants from the Mayo Clinic Study of Aging with T2* GRE MRI and plasma …biomarkers were included. Biomarkers were analyzed utilizing Simoa (Aβ40 , Aβ42 , t-tau, NfL) or Meso Scale Discovery (p-tau181 , p-tau217) platforms. Cross-sectional associations between CMBs, plasma biomarkers and Aβ-PET were evaluated using hurdle models and multivariable regression models. Results: Among the 188 (26%) individuals with≥1 CMB, a lower plasma Aβ42 /Aβ40 ratio was associated with more CMBs after adjusting for covariables (IRR 568.5 95% CI 2.8–116,127). No other biomarkers were associated with risk or number CMBs. In 81 individuals with≥2 CMBs, higher plasma t-tau, p-tau181 , and p-tau217 all were associated with higher Aβ-PET signal, with plasma p-tau217 having the strongest predictive value (r2 0.603, AIC –53.0). Conclusion: Lower plasma Aβ42 /Aβ40 ratio and higher plasma p-tau217 were associated with brain amyloidosis in individuals with CMBs from the general population. Our results suggest that in individuals with multiple CMBs and/or lobar intracranial hemorrhage that a lower plasma Aβ42 /Aβ40 ratio or elevated p-tau217 may indicate underlying cerebral amyloid angiopathy. Show more

Keywords: Amyloid-β, biomarker, cerebral microbleed, PiB-PET, plasma, tau

DOI: 10.3233/JAD-220158

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1537-1547, 2022

Authors: Dong, Liling | Liu, Caiyan | Sha, Longze | Mao, Chenhui | Li, Jie | Huang, Xinying | Wang, Jie | Chu, Shanshan | Peng, Bin | Cui, Liying | Xu, Qi | Gao, Jing

Article Type: Research Article

Abstract: Background: The established causative mutations in the APP , PSEN1 , and PSEN2 can explain less than 1%,Alzheimer’s disease (AD) patients. Of the identified variants, the PSEN2 mutations are even less common. Objective: With the genetic study from the dementia cohort of Peking Union Medical College Hospital (PUMCH), we aim to illustrate the PSEN2 mutation spectrum and novel functionally validated mutations in Chinese AD patients. Methods: 702 AD participants, aged 30–85, were identified in PUMCH dementia cohort. They all received history inquiry, physical examination, biochemical test, cognitive evaluation, brain CT/MRI, and next-generation DNA …sequencing. Functional analysis was achieved by transfection of the HEK293 cells with plasmids harboring the wild-type PSEN2 or candidate mutations. Results: Nine PSEN2 rare variants were found, including two reported (M239T, R62C) and seven novel variants (N141S, I368F, L396I, G117X, I146T, S147N, H220Y). The HEK293 cells transfected with the PSEN2 N141S, M239T, I368F plasmids showed higher Aβ42 and Aβ42 /Aβ40 levels relative to the wild-type PSEN2 . The PSEN2 L396I, G117X, S147N, H220Y, and R62C did not alter Aβ42 , Aβ40 levels, or Aβ42 /Aβ40 ratio. 1.9%,(13/702) subjects harbored rare PSEN2 variants. 0.4%,(3/702) subjects carried pathogenic/likely pathogenic PSEN2 mutations. The three subjects with the functionally validated PSEN2 mutations were all familial early-onset AD patients. The common symptoms included amnesia and mental symptom. Additionally, the M239T mutation carrier presented with dressing apraxia, visuospatial agraphia, dyscalculia and visual mislocalization. Conclusion: The PSEN2 N141S, M239T, and I368F are functionally validated mutations. Show more

Keywords: Alzheimer’s disease, pathogenic mutations, PSEN2

DOI: 10.3233/JAD-220194

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1549-1556, 2022

Authors: Salazar, Christian R. | Ritchie, Marina | Gillen, Daniel L. | Grill, Joshua D.

Article Type: Research Article

Abstract: Background: Best approaches for retaining research participants in Alzheimer’s disease cohort studies are understudied. Objective: Using data from the National Alzheimer’s Coordinating Center Uniform Data Set, we evaluated the associations of unique strategies with participant retention across Alzheimer’s Disease Research Centers and explored potential effect modification by race, ethnicity and diagnostic group. Methods: We examined retention at the first follow-up visit among participants enrolled during 2015–2017. Structured surveys ascertained 95 retention tactics among 12 strategies. Strategy-specific summary scores were created based on the number of implemented tactics for each strategy and grouped into tertiles. Generalized estimating …equations were constructed to evaluate associations between strategy scores and the odds of retention, controlling for age, sex, education, study partner type, marital status, visit length, battery length, diagnostic group, race and ethnicity. Separate models were stratified by race, ethnicity and diagnostic group. Effect modification was formally tested with interaction terms. Results: Among 5,715 total participants enrolled, 4,515 were Non-Hispanic White (79%), 335 were Hispanic/Latino (6%), 651 were Non-Hispanic Black (11%), and 214 were Non-Hispanic Asian (4%). Compared to the lowest tertile of scores, the highest tertile of scores involving improvement in study personnel and communication of study requirements and details were associated with 61% higher odds of retention in fully adjusted models (adjusted Odds Ratios [aOR] = 1.61, 95% Confidence Interval [CI] = 1.05–2.47 and aOR = 1.55, 95% CI = 1.03–2.35, respectively). We did not find evidence for effect modification. Conclusion: In the setting of limited resources, specific retention strategies may be more valuable than others. Show more

Keywords: Alzheimer’s disease, diagnostic-related group, ethnicity, patient dropouts, patient participation, race

DOI: 10.3233/JAD-215537

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1557-1566, 2022

Authors: Kim, Hyun | Levine, Alina | Cohen, Daniel | Gehrman, Philip | Zhu, Xi | Devanand, Davangere P. | Lee, Seonjoo | Goldberg, Terry E. | on behalf of the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The association between sleep and Alzheimer’s disease (AD) biomarkers are well-established, but little is known about how they interact to change the course of AD. Objective: To determine the potential interaction between sleep disturbance and Aβ, tau, and APOE4 on brain atrophy and cognitive decline. Methods: Sample included 351 participants (mean age 72.01 ± 6.67, 50.4%female) who were followed for approximately 5 years as part of the Alzheimer’s Disease Neuroimaging Initiative. Informant-reported sleep disturbance (IRSD) was measured using the Neuropsychiatric Inventory (NPI). Changes in magnetic resonance imaging (MRI)-measured AD signature brain regions and cognitive …performance and IRSD’s interaction with cerebrospinal fluid amyloid-β (Aβ42 ) and p-Tau depositions and APOE4 status were examined using the linear mixed models. Results: Baseline IRSD was not significantly associated with the rate of atrophy after adjusting for covariates (age, sex, education, total NPI severity score, and sleep medications). However, there was a significant interaction between IRSD and AD biomarkers on faster atrophy rates in multiple brain regions, including the cortical and middle temporal volumes. Post-hoc analyses indicated that Aβ and p-Tau/Aβ predicted a faster decline in these regions/domains in IRSD, compared with biomarker-negative individuals with IRSD (p s≤0.001). There was a significant IRSD*APOE4 interaction for brain atrophy rate (p s≤0.02) but not for cognition. Conclusion: IRSD may increase the future risk of AD by contributing to faster brain atrophy and cognitive decline when combined with the presence of AD biomarkers and APOE4 . Early intervention for sleep disturbance could help reduce the risk of developing AD. Show more

Keywords: All sleep disorders, Alzheimer’s disease, cognitive aging, insomnia, volumetric MRI

DOI: 10.3233/JAD-215417

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1567-1580, 2022

Authors: Zhao, Xing | Du, Wenying | Jiang, Jiehui | Han, Ying

Article Type: Research Article

Abstract: Background: Sleep appears to be a sensitive biomarker that facilitates early detection and effective intervention for Alzheimer’s disease, while subjective cognitive decline (SCD) is a risk factor for Alzheimer’s disease. Prefrontal cortex atrophy is associated with both sleep disruption and cognitive decline. Transcranial brain photobiomodulation (PBM) therapy can enhance frontal cortex oxygen consumption, increasing frontal cortex mediated memory function. Objective: This study aimed to test whether PBM therapy targeting the frontal cortex could improve sleep and cognitive function in SCD. Methods: Fifty-eight SCDs were divided into the PBM group (N  = 32) in which real light therapy …was administered and a sham light therapy group (N  = 26). All the participants received either real light or sham light therapy for 6 days consecutively, while the sleep data were recorded. The n-back task was employed to measure each participant’s working memory. Results: We found no differences in sleep efficiency change (F  = 211, p  = 0.279), REM stage percent change (F  = 420, p  = 0.91), and wake-up time (F  = 212, p  = 0.277) between the two groups. The sleep efficiency and REM were improved within the true light group on the fifth day. The true light group perform better than the control group in the n-back test, the accuracy was higher in the 2-back test (88.6% versus 79.6%, p  = 0.001), and the reaction time in 1-back was shorter (544.80±202.00 versus 592.87±222.05, p  = 0.003). Conclusion: After five days of PBM therapy targeting the prefrontal cortex, sleep efficiency and N-back cognitive performance were improved on the fifth day. Show more

Keywords: Alzheimer’s disease, photobiomodulation, sleep, subjective cognitive decline

DOI: 10.3233/JAD-215715

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1581-1589, 2022

Authors: Troxel, Wendy M. | Haas, Ann | Dubowitz, Tamara | Ghosh-Dastidar, Bonnie | Butters, Meryl A. | Gary-Webb, Tiffany L. | Weinstein, Andrea M. | Rosso, Andrea L.

Article Type: Research Article

Abstract: Background: Sleep problems may contribute to the disproportionate burden of Alzheimer’s disease and related dementias (ADRD) among African Americans (AAs). Objective: To examine the role of sleep problems in contributing to cognitive function and clinically adjudicated cognitive impairment in a predominantly AA sample. Methods: This study (n  = 216, 78.8% female; mean age = 67.7 years) examined associations between 1) the level (i.e., measured in 2018) and 2) change over time (from 2013 to 2018; n  = 168) in actigraphy-assessed sleep with domain-specific cognitive function and clinically adjudicated cognitive impairment (2018) in a community-dwelling, predominantly AA (96.9%) sample. A comprehensive …cognitive battery assessed global cognitive function (3MS) and domain-specific cognitive function (attention, visuo-spatial ability, language, delayed recall, immediate recall, and executive function) in 2018. Sleep was measured in 2013 and 2018 via actigraphy. Results: Higher sleep efficiency and less wakefulness after sleep onset (WASO; measured in 2018) were associated with greater attention, executive function, and visuospatial ability. Increases in sleep efficiency between 2013 and 2018 were associated with better executive function, language, immediate recall, and visuospatial ability, whereas increases in WASO (2013–2018) were associated with poorer attention, executive function, and visuospatial ability. Level or change in sleep duration were not associated with domain-specific cognitive function, nor were any sleep measures associated with clinically adjudicated cognitive impairment. Conclusion: In a predominantly AA sample of older adults, both the level and change (i.e., worsening) of sleep efficiency and WASO were associated with poorer cognitive function. Improving sleep health may support ADRD prevention and reduce health disparities. Show more

Keywords: Actigraphy, African Americans, Alzheimer’s disease, cognitive function, disparities, race, sleep, structural racism

DOI: 10.3233/JAD-215530

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1591-1601, 2022

Authors: Tongsiri, Sirinart | Levkoff, Sue | Gallagher-Thompson, Dolores | Teri, Linda | Hinton, Ladson | Wisetpholchai, Bussabong | Chuengsatiansup, Komatra | Sihapark, Siranee | Fritz, Stacy | Chen, Hongtu

Article Type: Research Article

Abstract: Background: The Reducing Disability in Alzheimer’s Disease (RDAD) program is an evidence-based intervention found to be feasible for implementation in community settings in the United States, and effective in reducing depression, one of the major behavioral and psychological symptoms of dementia (BPSD). Objective: The goal of the study is to culturally adapt the RDAD for persons with dementia living in community settings of Thailand. Methods: Key adaptation steps included: 1) assess the community, 2) understand/select the intervention, 3) consult with experts/stakeholders, 4) decide what needs to be adapted, 5) adapt the original program, 6) train staff, …and 7) pilot test the adapted materials. Results: Modifications to the original RDAD protocol included changes in number of sessions, mode of delivery, and the specific pleasant activities targeted. The pilot test demonstrated the feasibility and acceptance of the adapted RDAD intervention protocol. Implementers were able to comprehend and implement the core components of the intervention, while family members demonstrated ability to follow instructions, gain knowledge about dementia, and improve skills for setting up realistic goals. Conclusion: Following the key adaptation steps outlined above, we were able to successfully modify the RDAD for the Thai cultural context, maintaining core components of the original protocol. Program implementers demonstrated their ability to supervise family caregivers and help them gain the knowledge and skills needed to provide care for older adults with dementia. Findings from the pilot studies were incorporated into final training and intervention protocols currently being implemented and evaluated in a randomized implementation trial in Thailand. Show more

Keywords: Behavioral and psychological symptoms of dementia, care provision, cultural adaptation, dementia, depression, family caregivers, reducing disability in Alzheimer’s Disease

DOI: 10.3233/JAD-215253

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1603-1614, 2022

Authors: Mühlichen, Franka | Michalowsky, Bernhard | Rädke, Anika | Platen, Moritz | Mohr, Wiebke | Thyrian, Jochen René | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Recent studies have demonstrated the efficiency of collaborative dementia care, which aims to improve post-diagnostic support. However, tasks carried out of such models are currently unknown, hindering its implementation. Objective: To describe tasks of a collaborative model of dementia care, analyze the association between specific task subgroups and number of tasks with patients’ and caregivers’ characteristics and the impact of specific tasks on health-related quality of life (HRQoL). Methods: The analysis was based on 183 persons with dementia (PwD) who received dementia care management conducted by dementia-specific qualified nurses. A standardized, computer-assisted assessment was used …to identify patients’ and caregivers’ unmet needs. Tasks carried out to address unmet needs were documented, categorized, and descriptively analyzed. We used multivariate regression models to identify socio-demographic and clinical factors associated with a specific subgroup of tasks or a higher number of tasks. Results: On average, 20.5 tasks were carried out per dyad (PwD and caregiver). 41% of tasks were categorized to cooperation with other healthcare providers, 39% to nursing care, and 19% to social support. Lower HRQoL and higher age, cognitive impairment, deficits in daily living activities, and depressive symptoms were significantly associated with a higher number of tasks. A higher number of cooperation tasks were associated with a higher gain in HRQoL. Conclusion: Patients’ characteristics and HRQoL significantly determine the intensity of collaborative care interventions. Variability of the intensity should be considered in developing future studies and in the implementation into routine care. ClinicalTrials.gov Identifier: NCT01401582 Show more

Keywords: Dementia, health services needs and demand, home health nursing, nurses, patient-centered care, primary care nursing, progressive patient care

DOI: 10.3233/JAD-215656

Citation: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1615-1625, 2022