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

Authors: Park, Jaehong | Kim, Tae Jun | Song, Joo Hye | Jang, Hyemin | Kim, Ji Sun | Kang, Sung Hoon | Kim, Hang-Rai | Hwangbo, Song | Shin, Hee Young | Na, Duk L. | Seo, Sang Won | Kim, Hee Jin | Kim, Jae J.

Article Type: Research Article

Abstract: Background: An association between Helicobacter pylori (H. pylori ) infection and dementia was reported in previous studies; however, the evidence is inconsistent. Objective: In the present study, the association between H. pylori infection and brain cortical thickness as a biomarker of neurodegeneration was investigated. Methods: A cross-sectional study of 822 men who underwent a medical health check-up, including an esophagogastroduodenoscopy and 3.0 T magnetic resonance imaging, was performed. H. pylori infection status was assessed based on histology. Multiple linear regression analyses were conducted to evaluate the relationship between H. pylori infection and …brain cortical thickness. Results: Men with H. pylori infection exhibited overall brain cortical thinning (p  = 0.022), especially in the parietal (p  = 0.008) and occipital lobes (p  = 0.050) compared with non-infected men after adjusting for age, educational level, alcohol intake, smoking status, and intracranial volume. 3-dimentional topographical analysis showed that H. pylori infected men had cortical thinning in the bilateral lateral temporal, lateral frontal, and right occipital areas compared with non-infected men with the same adjustments (false discovery rate corrected, Q  <  0.050). The association remained significant after further adjusting for inflammatory marker (C-reactive protein) and metabolic factors (obesity, dyslipidemia, fasting glucose, and blood pressure). Conclusion: Our results indicate H. pylori infection is associated with neurodegenerative changes in cognitive normal men. H. pylori infection may play a pathophysiologic role in the neurodegeneration and further studies are needed to validate this association. Show more

Keywords: Cognitive impairment, dementia, H. pylori, neurodegeneration

DOI: 10.3233/JAD-210119

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Yao, Weina | Chen, Haifeng | Sheng, Xiaoning | Zhao, Hui | Xu, Yun | Bai, Feng | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Abnormal default mode network (DMN) was associated with the progress of Alzheimer’s disease (AD). Rather than treat the DMN as a unitary network, it can be further divided into three subsystems with different functions. Objective: It remains unclear the interactions of DMN subsystems associated with the progress of cognitive impairments and AD pathological features. Methods: This study has recruited 187 participants, including test data and verification data. Firstly, an imaging analysis approach was utilized to investigate disease-related differences in the interactions of DMN subsystems in test data (n  = 149), including 42 cognitively normal subjects, 43 …early mild cognitive impairment (EMCI), 32 late mild cognitive impairment (LMCI), and 32 AD patients. Brain-behavior-pathological relationships regarding to the interactions among DMN subsystems were then further examined. Secondly, DMN subsystems abnormalities for classifying AD spectrum population in the independent verification data (n  = 38). Results: This study found that the impaired cognition relates to disturbances in the interactions between DMN subsystems but preferentially in core subsystem, and the abnormal regulatory processes of core subsystem were significantly associated with the levels of cerebrospinal fluid Aβ and tau in AD-spectrum patients. Meantime, the nonlinear relationship between dysfunctional core subsystem and impaired cognition was observed as one progresses through the stages of MCI to AD. Importantly, this classification presented a higher sensitivity and specificity dependent on the core-centered connection abnormalities. Conclusion: The abnormal interaction patterns of DMN subsystems at an early stage of AD appeared and presented as core-centered connection abnormalities, which were the potential neuroimaging features for monitoring the development of AD. Show more

Keywords: Alzheimer’s disease, classification, cognitive impairment, default mode network, regulation, subsystems

DOI: 10.3233/JAD-210481

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Shang, Xianwen | Hodge, Allison M. | Hill, Edward | Zhu, Zhuoting | He, Mingguang

Article Type: Research Article

Abstract: Background: A few studies have linked dietary patterns and sleep to cognitive decline. Objective: To examine the independent and joint associations of dietary patterns and sleep with cognitive decline. Methods: Our analysis included 2,307 participants aged 55– 89 years at baseline from the China Health and Nutrition Survey. Dietary intake was assessed using weighing methods in combination with 24 h dietary recalls for three consecutive days. Exploratory factor analysis was applied to identify major dietary factors. Cognition was assessed in 1997, 2000, 2004, 2006, and 2015. Results: Five dietary patterns were identified: dairy-fruits-fast foods, grains-vegetables-pork, …plant-based food, beans-mushroom, and beverages-nuts patterns. Beans-mushroom pattern and sleep duration of 8 h/day were defined as healthy habits. There was a positive association between the beans-mushroom pattern and change in the global cognitive Z-score over seven years (β (95% CI) for quintile 5 versus quintile 1:0.17 (0.05, 0.30)). Compared to individuals with sleep duration of 8 h/day, those with sleep duration of≤5 h/day (β (95% CI): – 0.23 (– 0.45, – 0.00)) or >  10 h/day (– 0.52 (– 0.73, – 0.32)) had a greater decrease in global cognitive Z-score. Compared to individuals with no healthy patterns, those with a healthy dietary pattern only (β (95% CI): 0.18 (0.08, 0.28)), healthy sleep pattern only (0.13 (0.04, 0.23), and both healthy dietary and sleep patterns (0.19 (0.08, 0.31)) had a relative increase in global cognitive Z-score. Conclusion: Our findings highlight the importance of involving both diet and sleep as intervention priorities for the potential prevention of cognitive decline. Show more

Keywords: Cognitive decline, dietary pattern, sleep duration

DOI: 10.3233/JAD-201329

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Chao, Linda L. | Lee, Jennifer A. | Martinez, Steven | Barlow, Cody | Chesney, Margaret A. | Mehling, Wolf E. | Barnes, Deborah E.

Article Type: Research Article

Abstract: Background: Preventing Loss of Independence through Exercise (PLIÉ) is a group movement program initially developed for people with mild-to-moderate dementia that integrates principles from several well-established traditions to specifically addresses the needs of people with cognitive impairment. Objective: To investigate whether PLIÉ would benefit cognitive and behavioral outcomes and functional brain connectivity in older adults with milder forms of cognitive impairment. Methods: Participants (≥55 y) with subjective memory decline (SMD) or mild cognitive impairment (MCI) were assessed with tests of cognitive and physical function, self-report questionnaires, and resting state functional magnetic resonance imaging (rs-fMRI) on a …3 Tesla scanner before and after participating in twice weekly PLIÉ classes for 12 weeks at the San Francisco Veterans Affairs Medical Center. Results: Eighteen participants completed the pre-post intervention pilot trial. We observed significant improvements on the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog; effect size 0.34, p  = 0.002) and enhanced functional connections between the medial prefrontal cortex (mPFC) and other nodes of the default mode network (DMN) after PLIÉ. Improvements (i.e., lower scores) on ADAS-cog were significantly correlated with enhanced functional connectivity between the mPFC and left lateral parietal cortex (Spearman’s ρ = –0.74, p  = 0.001) and between the mPFC and right hippocampus (Spearman’s ρ = –0.83, p  = 0.001). After completing PLIÉ, participants reported significant reductions in feelings of social isolation and improvements in well-being and interoceptive self-regulation. Conclusion: These preliminary findings of post-PLIÉ improvements in DMN functional connectivity, cognition, interoceptive self-regulation, well-being and reduced feelings of social isolation warrant larger randomized, controlled trials of PLIÉ in older adults with SMD and MCI. Show more

Keywords: Aging, cognitive dysfunction, exercise therapy, memory disorders, mild cognitive impairment, mind-body therapies, self-report

DOI: 10.3233/JAD-210159

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Sakakibara, Yasufumi | Hirota, Yu | Ibaraki, Kyoko | Takei, Kimi | Chikamatsu, Sachie | Tsubokawa, Yoko | Saito, Takashi | Saido, Takaomi C. | Sekiya, Michiko | Iijima, Koichi M.

Article Type: Research Article

Abstract: Background: The locus coeruleus (LC), a brainstem nucleus comprising noradrenergic neurons, is one of the earliest regions affected by Alzheimer’s disease (AD). Amyloid-β (Aβ) pathology in the cortex in AD is thought to exacerbate the age-related loss of LC neurons, which may lead to cortical tau pathology. However, mechanisms underlying LC neurodegeneration remain elusive. Objective: Here, we aimed to examine how noradrenergic neurons are affected by cortical Aβ pathology in App NL -G -F /NL -G -F knock-in mice. Methods: The density of noradrenergic axons in LC-innervated regions and the LC neuron number were …analyzed by an immunohistochemical method. To explore the potential mechanisms for LC degeneration, we also examined the occurrence of tau pathology in LC neurons, the association of reactive gliosis with LC neurons, and impaired trophic support in the brains of App NL -G -F /NL -G -F mice. Results: We observed a significant reduction in the density of noradrenergic axons from the LC in aged App NL -G -F /NL -G -F mice without neuron loss or tau pathology, which was not limited to areas near Aβ plaques. However, none of the factors known to be related to the maintenance of LC neurons (i.e., somatostatin/somatostatin receptor 2, brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3) were significantly reduced in App NL -G -F /NL -G -F mice. Conclusion: This study demonstrates that cortical Aβ pathology induces noradrenergic neurodegeneration, and further elucidation of the underlying mechanisms will reveal effective therapeutics to halt AD progression. Show more

Keywords: Alzheimer’s disease, amyloid-β , locus coeruleus, neurotrophic factors, noradrenaline, somatostatin, tau

DOI: 10.3233/JAD-210385

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2021

Authors: Chaudhary, Suman | Ashok, Ajay | McDonald, Dallas | Wise, Aaron S. | Kritikos, Alexander E. | Rana, Neil A. | Harding, Clifford V. | Singh, Neena

Article Type: Research Article

Abstract: Background: Accumulation of iron is a consistent feature of Alzheimer’s disease (AD) brains. The underlying cause, however, remains debatable. Objective: To explore whether local hepcidin synthesized by brain cells contributes to iron accumulation in AD brains. Methods: Brain tissue from the cingulate cortex of 33 cases of AD pre-assigned to Braak stage I-VI, 6 cases of non-dementia, and 15 cases of non-AD dementia were analyzed for transcriptional upregulation of hepcidin by RT-qPCR and RT-PCR. Change in the expression of ferritin, ferroportin (Fpn), microglial activation marker Iba1, IL-6, and TGFβ 2 was determined by western blotting. Total …tissue iron was determined by colorimetry. Results: Significant transcriptional upregulation of hepcidin was observed in Braak stage III-VI relative to Braak stage I and II, non-AD dementia, and non-dementia samples. Ferritin was increased in Braak stage V, and a significant increase in tissue iron was evident in Braak stage III-VI. The expression of Iba1 and IL-6 was also increased in Braak stage III-VI relative to Braak stage I and II and non-AD dementia samples. Amyloid-β plaques were absent in most Braak stage I and II samples, and present in Braak stage III-VI samples with few exceptions. Conclusion: These observations suggest that upregulation of brain hepcidin is mediated by IL-6, a known transcriptional activator of hepcidin. The consequent downregulation of Fpn on neuronal and other cells results in accumulation of iron in AD brains. The increase in hepcidin is disease-specific, and increases with disease progression, implicating AD-specific pathology in the accumulation of iron. Show more

Keywords: Alzheimer’s disease, ferritin, hepcidin, IL-6, iron, oxidative stress

DOI: 10.3233/JAD-210221

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Kang, Sarang | Gim, Jungsoo | Lee, Jiwoon | Gunasekaran, Tamil Iniyan | Choi, Kyu Yeong | Lee, Jang Jae | Seo, Eun Hyun | Ko, Pan-Woo | Chung, Ji Yeon | Choi, Seong-Min | Lee, Young Min | Jeong, Jee Hyang | Park, Kyung Won | Song, Min Kyung | Lee, Ho-Won | Kim, Ki Woong | Choi, Seong Hye | Lee, Dong Young | Kim, Sang Yun | Kim, Hoowon | Kim, Byeong C. | Ikeuchi, Takeshi | Lee, Kun Ho

Article Type: Short Communication

Abstract: The present study reports two novel genome-wide significant loci for late-onset Alzheimer’s disease (LOAD) identified from APOE ε4 non-carrier subjects of East Asian origin. A genome-wide association study of Alzheimer’s disease was performed in 2,291 Korean seniors in the discovery phase, from the Gwangju Alzheimer’ and Related Dementias (GARD) cohort study. The study was replicated in a Japanese cohort of 1,956 subjects that suggested two novel susceptible SNPs in two genes: LRIG1 and CACNA1A. This study demonstrates that the discovery of AD-associated variants is feasible in non-European ethnic groups using samples comprising fewer subjects from the more homogeneous genetic …background. Show more

Keywords: Alzheimer’s disease, APOE, genome-wide association study, late-onset Alzheimer’s disease, stratified genome analysis

DOI: 10.3233/JAD-210145

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Herd, Pamela | Sicinski, Kamil | Asthana, Sanjay

Article Type: Research Article

Abstract: Background: There is a robust consensus, most recently articulated in the 2020 Lancet Commission, that the roots of dementia can be traced to early life, and that the path to prevention may start there as well. Indeed, a growing body of research demonstrates that early life disadvantage may influence the risk for later life dementia and cognitive decline. A still understudied risk, however, is early life rural residence, a plausible pathway given related economic and educational disadvantages, as well as associations between later life rural living and lower levels of cognitive functioning. Objective: We aim to examine whether …living in rural environments during early life has long term implications for cognitive health in later life. Methods: We employed the Wisconsin Longitudinal Study, which tracked 1 in every 3 high school graduates from the class of 1957, from infancy to ∼age 72. The data include a rich array of prospectively collected early life data, unique among existing studies, as well as later life measures of cognitive functioning. Results: We found a robust relationship between early life rural residence, especially living on a farm, and long-term risk for reduced cognitive performance on recall and fluency tasks. Controls for adolescent cognitive functioning, APOE ɛ 2 and APOE ɛ 4, as well as childhood and adult factors, ranging from early life socioeconomic conditions to later life health and rural and farm residency, did not alter the findings. Conclusion: Rural living in early life is an independent risk for lower levels of cognitive functioning in later life. Show more

Keywords: Aging, cognitive function, early life, rural, socioeconomic status

DOI: 10.3233/JAD-210224

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Solomon, Alina | Handels, Ron | Wimo, Anders | Antikainen, Riitta | Laatikainen, Tiina | Levälahti, Esko | Peltonen, Markku | Soininen, Hilkka | Strandberg, Timo | Tuomilehto, Jaakko | Kivipelto, Miia | Ngandu, Tiia

Article Type: Research Article

Abstract: We investigated the effect of a multidomain lifestyle intervention on the risk of dementia estimated using the validated CAIDE risk score (post-hoc analysis). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a 2-year randomized controlled trial among 1,260 at-risk older adults (60–77 years). Difference in the estimated mean change in CAIDE score at 2 years in the intervention compared to the control group was –0.16 (95 %CI –0.31 to 0.00) (p  = 0.013), corresponding to a relative dementia risk reduction between 6.04–6.50%. This could be interpreted as a reflection of the prevention potential of the …intervention. Show more

Keywords: Clinical trial, dementia, dementia risk score, lifestyle intervention, prevention

DOI: 10.3233/JAD-210331

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2021

Authors: Li, Wenwen | Wang, Shiyuan | zhang, Heng | Li, Bingqiu | Xu, Lingzhi | Li, Yan | Kong, Chaojun | Jiao, Haishan | Wang, Yan | Pang, Yana | Qin, Wei | Jia, Longfei | Jia, Jianping

Article Type: Research Article

Abstract: Background: Dysfunction of microglia has been increasingly recognized as a causative factor in Alzheimer’s disease (AD); thus, developing medicines capable of restoring microglial functions is critically important and constitutes a promising therapeutic strategy. Honokiol is a natural neuroprotective compound extracted from Magnolia officinalis, which may play roles in AD therapy. Objective: This study aimed to evaluate the role and the underlying mechanisms of honokiol in microglial phagocytosis. Methods: MTT and flow cytometry were used to assess the cell viability and apoptosis, respectively. Phagocytic capacity, mitochondrial reactive oxygen species production, and membrane potential were evaluated using fluorescence …microscopy. Seahorse XF24 extracellular flux analyzer was for cell glycolysis and oxidative phosphorylation (OXPHOS) detection. Mass spectrometry was applied for metabolites measurement. Quantitative real-time polymerase chain reaction and western blotting were performed to detect the mRNA and protein level of PPARγ and PGC1α, respectively. Results: Honokiol alleviated Aβ 42 -induced BV2 neurotoxicity. Honokiol promoted phagocytic efficiency of BV2 cells through reversing a metabolic switch from OXPHOS to anaerobic glycolysis and enhancing ATP production. Meanwhile, honokiol reduced mitochondrial reactive oxygen species (ROS) production and elevated mitochondrial membrane potential. Moreover, honokiol increased the expression of PPARγ and PGC1α, which might play positive roles in energy metabolism and microglial phagocytosis. Conclusion: In this study, honokiol was identified as an effect natural product capable of enhancing mitochondrial function thus promoting microglial phagocytic function. Show more

Keywords: Honokiol, metabolic reprogramming, microglial phagocytosis, mitochondria

DOI: 10.3233/JAD-210177

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021