Journal of Alzheimer's Disease - Volume 99, issue 1

Authors: Wu, Yaxuan | Tan, Ming | Gao, Yanling | Geng, Na | Zhong, Weibin | Sun, Hairong | Li, Zhenguang | Wu, Chenxi | Li, Xuemei | Zhang, Jinbiao

Article Type: Research Article

Abstract: Background: The complement system plays crucial roles in cognitive impairment and acute ischemic stroke (AIS). High levels of complement proteins in plasma astrocyte-derived exosomes (ADEs) were proven to be associated with Alzheimer’s disease. We aimed to investigate the relationship of complement proteins in serum ADEs with poststroke cognitive impairment in type 2 diabetes mellitus (T2DM) patients. Methods: This study analyzed 197 T2DM patients who suffered AIS. The Beijing version of the Montreal Cognitive Assessment (MoCA) was used to assess cognitive function. Complement proteins in serum ADEs were quantified using ELISA kits. Results: Mediation analyses showed that …C5b-9 and C3b in serum ADEs partially mediate the impact of obstructive sleep apnea (OSA), depression, small vessel disease (SVD), and infarct volume on cognitive function at the acute phase of AIS in T2DM patients. After adjusting for age, sex, time, and interaction between time and complement proteins in serum ADEs, the mixed linear regression showed that C3b and complement protein Factor B in serum ADEs were associated with MoCA scores at three-, six-, and twelve-months after AIS in T2DM patients. Conclusions: Our study suggested that the impact of OSA, depression, SVD, and infarct volume on cognitive impairment in the acute stage of AIS may partially mediate through the complement proteins in serum ADEs. Additionally, the complement proteins in serum ADEs at the acute phase of AIS associated with MoCA scores at three-, six-, twelve months after AIS in T2DM patients. REGISTRATION: URL: http://www.chictr.org.cn/,ChiCTR1900021544 Show more

Keywords: Keywords: Alzheimer’s disease, astrocyte-derived exosomes, complement proteins, post stroke cognitive impairment, type 2 diabetes mellitus

DOI: 10.3233/JAD-231235

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 291-305, 2024

Authors: Butler, Tracy | Wang, Xiuyuan | Chiang, Gloria | Xi, Ke | Niogi, Sumit | Glodzik, Lidia | Li, Yi | Razlighi, Qolamreza Ray | Zhou, Liangdong | Hojjati, Seyed Hani | Ozsahin, Ilker | Mao, Xiangling | Maloney, Thomas | Tanzi, Emily | Rahmouni, Nesrine | Tissot, Cécile | Lussier, Firoza | Shah, Sudhin | Shungu, Dikoma | Gupta, Ajay | De Leon, Mony | Mozley, P. David | Pascoal, Tharick A. | Rosa-Neto, Pedro

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) pathology is considered to begin in the brainstem, and cerebral microglia are known to play a critical role in AD pathogenesis, yet little is known about brainstem microglia in AD. Translocator protein (TSPO) PET, sensitive to activated microglia, shows high signal in dorsal brainstem in humans, but the precise location and clinical correlates of this signal are unknown. Objective: To define age and AD associations of brainstem TSPO PET signal in humans. Methods: We applied new probabilistic maps of brainstem nuclei to quantify PET-measured TSPO expression over the whole brain including brainstem …in 71 subjects (43 controls scanned using 11 C-PK11195; 20 controls and 8 AD subjects scanned using 11 C-PBR28). We focused on inferior colliculi (IC) because of visually-obvious high signal in this region, and potential relevance to auditory dysfunction in AD. We also assessed bilateral cortex. Results: TSPO expression was normally high in IC and other brainstem regions. IC TSPO was decreased with aging (p  = 0.001) and in AD subjects versus controls (p  = 0.004). In cortex, TSPO expression was increased with aging (p  = 0.030) and AD (p  = 0.033). Conclusions: Decreased IC TSPO expression with aging and AD—an opposite pattern than in cortex—highlights underappreciated regional heterogeneity in microglia phenotype, and implicates IC in a biological explanation for strong links between hearing loss and AD. Unlike in cerebrum, where TSPO expression is considered pathological, activated microglia in IC and other brainstem nuclei may play a beneficial, homeostatic role. Additional study of brainstem microglia in aging and AD is needed. Show more

Keywords: Alzheimer’s disease, inferior colliculus, inflammation, neuroinflammation, reticular formation, TSPO PET

DOI: 10.3233/JAD-231312

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 307-319, 2024

Authors: Duff, Kevin | Hammers, Dustin B. | Koppelmans, Vincent | King, Jace B. | Hoffman, John M.

Article Type: Research Article

Abstract: Background: Practice effects on cognitive testing in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) remain understudied, especially with how they compare to biomarkers of AD. Objective: The current study sought to add to this growing literature. Methods: Cognitively intact older adults (n  = 68), those with amnestic MCI (n  = 52), and those with mild AD (n  = 45) completed a brief battery of cognitive tests at baseline and again after one week, and they also completed a baseline amyloid PET scan, a baseline MRI, and a baseline blood draw to obtain APOE ɛ4 …status. Results: The intact participants showed significantly larger baseline cognitive scores and practice effects than the other two groups on overall composite measures. Those with MCI showed significantly larger baseline scores and practice effects than AD participants on the composite. For amyloid deposition, the intact participants had significantly less tracer uptake, whereas MCI and AD participants were comparable. For total hippocampal volumes, all three groups were significantly different in the expected direction (intact > MCI > AD). For APOE ɛ4, the intact had significantly fewer copies of ɛ4 than MCI and AD. The effect sizes of the baseline cognitive scores and practice effects were comparable, and they were significantly larger than effect sizes of biomarkers in 7 of the 9 comparisons. Conclusion: Baseline cognition and short-term practice effects appear to be sensitive markers in late life cognitive disorders, as they separated groups better than commonly-used biomarkers in AD. Further development of baseline cognition and short-term practice effects as tools for clinical diagnosis, prognostic indication, and enrichment of clinical trials seems warranted. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, brain imaging, effect sizes, mild cognitive impairment, neuropsychological testing, practice effects

DOI: 10.3233/JAD-231392

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 321-332, 2024

Authors: Alrouji, Mohammed | Yasmin, Sabina | Furkan, Mohammad | Alhumaydhi, Fahad A. | Sharaf, Sharaf E. | Khan, Rizwan Hasan | Shamsi, Anas

Article Type: Research Article

Abstract: Background: Neurodegeneration is a term describing an irreversible process of neuronal damage. In recent decades, research efforts have been directed towards deepening our knowledge of numerous neurodegenerative disorders, with a particular focus on conditions such as Alzheimer’s disease (AD). Human transferrin (htf) is a key player in maintaining iron homeostasis within brain cells. Any disturbance in this equilibrium gives rise to the emergence of neurodegenerative diseases and associated pathologies, particularly AD. Limonene, a natural compound found in citrus fruits and various plants, has shown potential neuroprotective properties. Objective: In this study, our goal was to unravel the binding …of limonene with htf, with the intention of comprehending the interaction mechanism of limonene with htf. Methods: Binding was scrutinized using fluorescence quenching and UV-Vis spectroscopic analyses. The binding mechanism of limonene was further investigated at the atomic level through molecular docking and extensive 200 ns molecular dynamic simulation (MD) studies. Results: Molecular docking uncovered that limonene interacted extensively with the deep cavity located within the htf binding pocket. MD results indicated that binding of limonene to htf did not induce substantial structural alterations, ultimately forming stable complex. The findings from fluorescence binding indicated a pronounced interaction between limonene and htf, limonene binds to htf with a binding constant (K ) of 0.1×105  M–1 . UV spectroscopy also advocated stable htf-limonene complex formation. Conclusions: The study deciphered the binding mechanism of limonene with htf, providing a platform to use limonene in AD therapeutics in context of iron homeostasis. Show more

Keywords: Alzheimer’s disease, fluorescence spectroscopy, molecular dynamic simulation, natural compounds

DOI: 10.3233/JAD-240072

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 333-343, 2024

Authors: Kim, Donghyun | Jamrasi, Parivash | Li, Xinxing | Ahn, Soyoung | Sung, Yunho | Ahn, Seohyun | Kang, Yuseon | Song, Wook

Article Type: Research Article

Abstract: Background: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been demonstrated to have high diagnostic accuracy in differentiating Alzheimer’s disease (AD) patients from healthy individuals. However, it is yet unclear whether exercise can lower the level of AD7c-NTP in urine among active Korean elderly. Objective: To assess the effect of exercise on AD7c-ntp levels in urine and cognitive function among active Korean elderly. Methods: In total, 40 Korean elderly (≥65 years) were divided into Active Control group (CG, n  = 10), Aerobic exercise group (AG, n  = 18), and combined Resistance/Aerobic exercise group (RAG, n  = 12). A total of 12 …weeks of exercise intervention was implemented. At week 0 and 12, cognitive performance (Korean Mini-Mental State Examination, Korean-Color Word Stroop test), grip strength, and body composition (muscle mass and body fat percentage) were measured. Also, a morning urine sample was obtained from each subject. The level of AD7c-NTP was measured using competitive enzyme-linked immunosorbent assay (ELISA). Results: After 12 weeks of exercise intervention, there was a significant difference of AD7c-NTP levels between RAG and CG (p  = 0.026), AG and CG (p  = 0.032), respectively. Furthermore, the AD7c-NTP levels in urine showed negative correlation with K-MMSE scores (r  = –0.390, p  = 0.013) and grip strength (r  = –0.376, p  = 0.017), among all participants after exercise intervention. Conclusions: This is the first study to investigate urine biomarker through exercise intervention. In future stuides, participants who have low cognitive function and low activity levels need to be recruited to observe more significant ‘Exercise’ effect. Show more

Keywords: AD7C-NTP, Alzheimer’s disease, cognitive function, exercise, urine biomarker

DOI: 10.3233/JAD-230946

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 345-362, 2024

Authors: Gjøra, Linda | Strand, Bjørn Heine | Bergh, Sverre | Bosnes, Ingunn | Johannessen, Aud | Livingston, Gill | Skjellegrind, Håvard Kjesbu | Selbæk, Geir

Article Type: Research Article

Abstract: Background: A timely diagnosis of dementia can be beneficial for providing good support, treatment, and care, but the diagnostic rate remains unknown and is probably low. Objective: To determine the dementia diagnostic rate and to describe factors associated with diagnosed dementia. Methods: This registry linkage study linked information on research-based study diagnoses of all-cause dementia and subtypes of dementias, Alzheimer’s disease, and related dementias, in 1,525 participants from a cross-sectional population-based study (HUNT4 70+) to dementia registry diagnoses in both primary-care and hospital registries. Factors associated with dementia were analyzed with multiple logistic regression. …Results: Among those with research-based dementia study diagnoses in HUNT4 70+, 35.6% had a dementia registry diagnosis in the health registries. The diagnostic rate in registry diagnoses was 19.8% among home-dwellers and 66.0% among nursing home residents. Of those with a study diagnosis of Alzheimer’s disease, 35.8% (95% confidence interval (CI) 32.6–39.0) had a registry diagnosis; for those with a study diagnosis of vascular dementia, the rate was 25.8% (95% CI 19.2–33.3) and for Lewy body dementias and frontotemporal dementia, the diagnosis rate was 63.0% (95% CI 48.7–75.7) and 60.0% (95% CI 43.3–75.1), respectively. Factors associated with having a registry diagnosis included dementia in the family, not being in the youngest or oldest age group, higher education, more severe cognitive decline, and greater need for help with activities of daily living. Conclusions: Undiagnosed dementia is common, as only one-third of those with dementia are diagnosed. Diagnoses appear to be made at a late stage of dementia. Show more

Keywords: Alzheimer’s disease, dementia, diagnosis, population-based, health registry

DOI: 10.3233/JAD-240037

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 363-375, 2024

Authors: Lissek, Vanessa J. | Orth, Stefan | Suchan, Boris

Article Type: Research Article

Abstract: Background: Cognitive training and physical exercise show positive effects on cognitive decline in subjects with mild cognitive impairment (MCI). Multimodal interventions for MCI patients, combining physical and cognitive training in a social context seem to slow down cognitive decline. Objective: Based on a previous study, a new mobile gamification tool (go4cognition; https://www.ontaris.de/go4cognition) has been developed to train cognitive and physical functions simultaneously in a group setting. It involves tasks targeting various cognitive functions (short-term memory, working memory, executive functions). The computer-based setup allows for individual performance analysis. This study evaluated the effects of this tool. Methods: …30 participants with MCI, as defined by the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) cut-off-score, aged between 66 and 89 years, trained for one hour two days a week for twelve weeks. Additionally, standard neuropsychological assessment of memory and attention was carried out before and after the intervention. Results: The go4cognition device is highly effective in improving various cognitive functions. A significant improvement in the CERAD total score resulting in re-classification of 70% of former MCI patients into non-MCI patients was found. Additionally, an improvement of verbal fluency, verbal memory, spatial memory, and attention was observed. Furthermore, the CERAD total score was significantly correlated with performance in the go4cognition tool. Conclusions: The results of the intervention support the idea of the effectiveness of a combined cognitive and motor intervention by incorporating neuropsychological paradigms in a group setting and suggest a close relation between combined cognitive and physical exercise and cognitive performance. Show more

Keywords: Alzheimer’s disease, CERAD total score, cognitive training, gamification, mild cognitive impairment, multimodal intervention, physiological intervention, simultaneous stimulation of cognitive and physical abilities, social contact

DOI: 10.3233/JAD-230802

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 377-392, 2024

Authors: Peng, Lang | Xiang, Qingwei | Zhou, Yong | Yin, Renyi

Article Type: Research Article

Abstract: Background: The joint associations of handgrip strength (HGS) weakness and asymmetry with cognitive decline remain understudied in older adults. Objective: To investigate the associations between HGS weakness, asymmetry, and lower cognitive function in a nationally representative sample of older Americans. Methods: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey 2011–2014. Weakness was defined as HGS <26 kg for men and <16 kg for women. Asymmetry was determined by calculating the ratio of dominant to non-dominant HGS. Participants with an HGS ratio <0.90 or >1.10 were classified as having any HGS …asymmetry. Those with an HGS ratio >1.10 exhibited dominant HGS asymmetry, while those with an HGS ratio <0.90 displayed nondominant HGS asymmetry, respectively. Lower cognitive functioning was defined as global cognitive composite scores more than 1 standard deviation below the mean. Covariate-adjusted logistic regression models were used to analyze the associations between HGS asymmetry/weakness and lower cognitive functioning. Results: Compared to individuals with non-weak and symmetric HGS, those with any HGS asymmetry alone and weakness alone had 1.017 (95% confidence interval [CI]: 0.707–1.463) and 1.391 (95% CI: 0.542–3.571) greater odds for cognitive decline, while co-occurrence of both HGS asymmetry and weakness was associated with 3.724 (95% CI: 1.711–8.107) greater odds for lower cognitive function after controlling for confounders. Cnclusions: Individuals exhibiting both diminished and asymmetrical HGS demonstrated an elevated susceptibility to cognitive impairment, thereby implying that the inclusion of HGS asymmetry assessment in conjunction with weakness evaluation may enhance the accuracy of prognosticating cognitive decline. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, cross-sectional study, geriatrics, handgrip strength

DOI: 10.3233/JAD-231375

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 393-402, 2024

Authors: Nakanishi, Miharu | Yamasaki, Syudo | Nakashima, Taeko | Miyamoto, Yuki | Cooper, Claudia | Richards, Marcus | Stanyon, Daniel | Sakai, Mai | Yoshii, Hatsumi | Nishida, Atsushi

Article Type: Research Article

Abstract: Background: The emotional impact of the coronavirus disease 2019 (COVID-19) pandemic on people with dementia has been quantified. However, little is known about the impact of change in home-care use owing to the pandemic. Objective: To determine the longitudinal association between dementia, change in home-care use, and depressive symptoms during the pandemic. Methods: We included data of 43,782 home-dwelling older adults from the English Longitudinal Study of Ageing (ELSA), Study of Health, Ageing and Retirement in Europe (SHARE), and National Health and Aging Trends Study (NHATS). This study considered the latest main wave …survey prior to the pandemic as the baseline, and the COVID-19 survey as follow-up. In a series of coordinated analyses, multilevel binomial logistic regression model was used to examine the association between baseline dementia, change in home-care use at follow-up, and presence of depressive symptoms. Results: Dementia, using the ELSA, SHARE, and NHATS datasets, was identified in 2.9%, 2.3%, and 6.5% of older adults, and home-care use reduced in 1.7%, 2.8%, and 1.1% of individuals with dementia, respectively. Dementia was significantly associated with the increased risk of depressive symptoms in all three cohorts. However, the interaction between dementia and period (follow-up) was non-significant in SHARE and NHATS. Across all three cohorts, home-care use during the pandemic, regardless of change in amount, was significantly associated with increased depressive symptoms, compared to the non-use of home care. Conclusions: These results highlight the need for tailoring dementia care at home to promote independence and provide sustainable emotional support. Show more

Keywords: Alzheimer’s disease, cohort studies, dementia, depression, home care services, SARS-CoV 2, social interaction

DOI: 10.3233/JAD-240097

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 403-415, 2024

Authors: Thomas, Kelsey R. | Clark, Alexandra L. | Weigand, Alexandra J. | Edwards, Lauren | Durazo, Alin Alshaheri | Membreno, Rachel | Luu, Britney | Rantins, Peter | Ly, Monica T. | Rotblatt, Lindsay J. | Bangen, Katherine J. | Jak, Amy J.

Article Type: Research Article

Abstract: Background: Within older Veterans, multiple factors may contribute to cognitive difficulties. Beyond Alzheimer’s disease (AD), psychiatric (e.g., PTSD) and health comorbidities (e.g., TBI) may also impact cognition. Objective: This study aimed to derive subgroups based on objective cognition, subjective cognitive decline (SCD), and amyloid burden, and then compare subgroups on clinical characteristics, biomarkers, and longitudinal change in functioning and global cognition. Methods: Cluster analysis of neuropsychological measures, SCD, and amyloid PET was conducted on 228 predominately male Vietnam-Era Veterans from the Department of Defense-Alzheimer’s Disease Neuroimaging Initiative. Cluster-derived subgroups were compared on baseline …characteristics as well as 1-year changes in everyday functioning and global cognition. Results: The cluster analysis identified 3 groups. Group 1 (n  = 128) had average-to-above average cognition with low amyloid burden. Group 2 (n  = 72) had the lowest memory and language, highest SCD, and average amyloid burden; they also had the most severe PTSD, pain, and worst sleep quality. Group 3 (n  = 28) had the lowest attention/executive functioning, slightly low memory and language, elevated amyloid and the worst AD biomarkers, and the fastest rate of everyday functioning and cognitive decline. CONCLUSIONS: Psychiatric and health factors likely contributed to Group 2’s low memory and language performance. Group 3 was most consistent with biological AD, yet attention/executive function was the lowest score. The complexity of older Veterans’ co-morbid conditions may interact with AD pathology to show attention/executive dysfunction (rather than memory) as a prominent early symptom. These results could have important implications for the implementation of AD-modifying drugs in older Veterans. Show more

Keywords: Alzheimer’s disease, amyloid, cognition, phenotypes, PTSD, Veterans

DOI: 10.3233/JAD-240077

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 417-427, 2024