Journal of Alzheimer's Disease - Volume 76, issue 1

Authors: Rabipour, Sheida | Rajagopal, Sricharana | Yu, Elsa | Pasvanis, Stamatoula | Lafaille-Magnan, Marie-Elyse | Breitner, John | PREVENT-AD Research Group | Rajah, M. Natasha

Article Type: Research Article

Abstract: Background: Episodic memory decline is one of the earliest symptoms of late-onset Alzheimer’s disease (AD). Older adults with the apolipoprotein E ɛ 4 (+APOE4 ) genetic risk factor for AD may exhibit altered patterns of memory-related brain activity years prior to initial symptom onset. Objective: Here we report the baseline episodic memory task functional MRI results from the PRe-symptomatic EValuation of Experimental or Novel Treatments for Alzheimer’s Disease cohort in Montreal, Canada, in which 327 healthy older adults were scanned within 15 years of their parent’s conversion to AD. Methods: Volunteers were scanned as they encoded …and retrieved object-location spatial source associations. The task was designed to discriminate between brain activity related to spatial source recollection and object-only (recognition) memory. We used multivariate partial least squares (PLS) to test the hypothesis that +APOE4 adults with family history of AD would exhibit altered patterns of brain activity in the recollection-related memory network, comprised of medial frontal, parietal, and medial temporal cortices, compared to APOE4 non-carriers (–APOE4 ). We also examined group differences in the correlation between event-related brain activity and memory performance. Results: We found group similarities in memory performance and in task-related brain activity in the recollection network, but differences in brain activity-behavior correlations in ventral occipito-temporal, medial temporal, and medial prefrontal cortices during episodic encoding. Conclusion: These findings are consistent with previous literature on the influence of APOE4 on brain activity and provide new perspective on potential gene-based differences in brain-behavior relationships in people with first-degree family history of AD. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E polymorphism, associative learning, brain-behavior relationships, episodic memory, familial history, task-related functional MRI

DOI: 10.3233/JAD-191292

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 97-119, 2020

Authors: Parizkova, Martina | Lerch, Ondrej | Andel, Ross | Kalinova, Jana | Markova, Hana | Vyhnalek, Martin | Hort, Jakub | Laczó, Jan

Article Type: Research Article

Abstract: Background: The hippocampus, entorhinal cortex, and basal forebrain are among the first brain structures affected by Alzheimer’s disease (AD). They play an essential role in spatial pattern separation, a process critical for accurate encoding of similar spatial information. Objective: Our aim was to examine spatial pattern separation and its association with volumetric changes of the hippocampus, entorhinal cortex, and basal forebrain nuclei projecting to the hippocampus (the medial septal nuclei and vertical limb of the diagonal band of Broca – Ch1-2 nuclei) in the biomarker-defined early clinical stages of AD. Methods: A total of 98 older …adults were recruited from the Czech Brain Aging Study cohort. The participants with amnestic mild cognitive impairment (aMCI) due to AD (n  = 44), mild AD dementia (n  = 31), and cognitively normal older adults (CN; n  = 23) underwent spatial pattern separation testing, comprehensive cognitive assessment, and MRI brain volumetry. Results: Spatial pattern separation accuracy was lower in the early clinical stages of AD compared to the CN group (p  < 0.001) and decreased with disease severity (CN > aMCI due to AD > AD dementia). Controlling for general memory and cognitive performance, demographic characteristics and psychological factors did not change the results. Hippocampal and Ch1-2 volumes were directly associated with spatial pattern separation performance while the entorhinal cortex operated on pattern separation indirectly through the hippocampus. Conclusion: Smaller volumes of the hippocampus, entorhinal cortex, and basal forebrain Ch1-2 nuclei are linked to spatial pattern separation impairment in biomarker-defined early clinical AD and may contribute to AD-related spatial memory deficits. Show more

Keywords: Basal forebrain, entorhinal cortex, hippocampus, memory, mild cognitive impairment

DOI: 10.3233/JAD-200093

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 121-138, 2020

Authors: Palta, Priya | Heiss, Gerardo | Sharrett, A. Richey | Gabriel, Kelley Pettee | Walker, Keenan | Evenson, Kelly R. | Knopman, David | Mosley, Thomas H. | Wong, Dean F. | Gottesman, Rebecca F.

Article Type: Research Article

Abstract: Background: Physical activity (PA) may slow the development of dementia by reducing the accumulation of amyloid. Objective: We tested the hypothesis that higher levels of leisure-time PA in mid- or late-life were associated with lower brain amyloid burden in late-life among 326 non-demented participants from the Atherosclerosis Risk in Communities Study of brain florbetapir positron emission tomography (ARIC-PET) ancillary. Methods: Self-reported PA was quantified using a past-year recall, interviewer-administered questionnaire in mid-life (1987-1989, aged 45–64 years) and late-life (2011-2013, aged 67–89 years). Continuous PA estimates were classified as 1) any leisure-time PA participation (yes/no); 2) meeting …the 2018 United States’ PA guidelines (yes/no); and 3) per 1 standard deviation (SD) higher metabolic equivalent of task (MET) minutes per week (MET·min·wk-1 ). A brain magnetic resonance imaging scan with Florbetapir PET was performed in late-life. Adjusted odds ratios (OR) of elevated amyloid burden, defined as a global cortical standardized uptake value ratio (>1.2), compared to no elevated amyloid burden were estimated according to PA measures. Results: Among the 326 participants (mean age: 76 years, 42% male, 41% Black), 52% had elevated brain amyloid burden. Mid-life leisure-time PA did not show a statistically significant lower odds of elevated late-life amyloid burden (OR = 0.71, 95% CI: 0.43–1.18). A 1 SD (970 MET. min. wk–1 ) higher PA level in mid-life was also not significantly associated with elevated amyloid burden (OR = 0.89, 95% CI: 0.69–1.15). Similar estimates were observed for meeting versus not meeting PA guidelines in both mid- and late-life. Conclusion: Self-reported higher mid- and late-life leisure-time PA were not significantly associated with lower amyloid burden. Data show a trend of an association, which is, however, imprecise, suggesting replication in larger studies. Show more

Keywords: Amyloid, cohort study, epidemiology, imaging, PET, physical activity

DOI: 10.3233/JAD-200152

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 139-147, 2020

Authors: Su, Ya | Fu, Jiayu | Yu, Jintai | Zhao, Qianhua | Guan, Yihui | Zuo, Chuantao | Li, Ming | Tan, Haibo | Cheng, Xin

Article Type: Research Article

Abstract: Background: Flortaucipir (AV-1451) and pyridinyl-butadienyl-benzothiazole 3 (PBB3) are newly developed and commonly used positron emission tomography (PET) tracers to detect tau deposition in tauopathies, including frontotemporal dementia (FTD). [18 F]PM-PBB3, as a second-generation compound, has not been described in FTD so far. Objective: We aim to explore the in vivo performance of [18 F]PM-PBB3 tau PET in an FTD case caused by microtubule-associated protein tau (MAPT) mutation and compare the binding to different tau strains between AV-1451 and PBB3. Methods: We reported the clinical and FDG, [18 F]AV45 amyloid and [18 F]PM-PBB3 tau PET findings …in a patient with FTD of P301L MAPT mutation. Based on our results and published data, we summarized and compared the different utilities of tau PET tracers of AV-1451 and PBB3 in FTD with MAPT mutation. Results: The patient demonstrated slightly diffuse [18 F]PM-PBB3 tau deposition in cerebral lobes especially in the left frontal lobe overlapping with the hypometabolic region detected by FDG PET. From our analysis of 35 FTD patients with MAPT mutation who underwent tau PET, AV-1451 was positive in all (n  = 11) patients with mutations known to cause three and four repeat (3R/4R) tau deposition and in 14.3% (n  = 2/14) of 4R tauopathies, while positive PBB3 retention was found in all patients with both 3R/4R (n  = 2) and 4R (n  = 8) tau. Conclusions: [18 F]PM-PBB3 tau PET assisted the diagnosis of FTD with P301L MAPT mutation, and might be useful in the in vivo detection of both 3R/4R and 4R tau domains in the brain of FTD with MAPT mutation. Show more

Keywords: [18F]PM-PBB3, AV-1451, frontotemporal dementia, MAPT mutation, positron emission tomography

DOI: 10.3233/JAD-200287

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 149-157, 2020

Authors: Kridawati, Atik | Hardinsyah, Hardinsyah | Sulaeman, Ahmad | Rahardjo, Tri Budi W. | Hogervorst, Eef

Article Type: Research Article

Abstract: Background: Estrogens have been found to reduce amyloid-β (Aβ) levels, a risk factor associated with dementia. We hypothesized that phytoestrogenic soybean products such as tempe and tofu might show similar effects. Objective: The aim of this study were to analyze the effect of tempe and tofu flour on Aβ1-40 serum levels in ovariectomized rats. Methods: This research was conducted on female Sprague Dawley rats, aged 12 months. Before the intervention rats underwent ovariectomy (OVx) and were grouped into 5 intervention groups which were given tempe flour, tofu flour, estradiol, or casein as an active control. …There was also a non-OVx control group which was fed a normal diet. Results: The intake of tempe and tofu flour decreased Aβ serum levels in all estrogen and phytoestrogenic treatment groups, offsetting effects of OVx (but not in the casein group, where Aβ levels rise). Conclusion: The tempe flour group showed the strongest decrease in serum Aβ levels compared to the other groups. Future studies should investigate whether tempe can reduce Aβ levels in patients with dementia. Show more

Keywords: Amyloid-β , ovariectomized rats, tempe flour, tofu flour

DOI: 10.3233/JAD-200220

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 159-163, 2020

Authors: Akhter, Firoz | Chen, Doris | Akhter, Asma | Sosunov, Alexander A. | Chen, Allen | McKhann, Guy M. | Yan, Shi Fang | Yan, Shirley ShiDu

Article Type: Research Article

Abstract: Background: Advanced glycation end products (AGEs) are an important risk factor for the development of cognitive decline in aging and late-onset neurodegenerative diseases including Alzheimer’s disease. However, whether and how dietary AGEs exacerbate cognitive impairment and brain mitochondrial dysfunction in the aging process remains largely unknown. Objective: We investigated the direct effects of dietary AGEs on AGE adducts accumulation, mitochondrial function, and cognitive performance in mice. Methods: Mice were fed the AGE+ diet or AGE– diet. We examined levels of AGE adducts in serum and cerebral cortexes by immunodetection and immunohistochemistry, determined levels of reactive oxygen …species by biochemical analysis, detected enzyme activity associated with mitochondrial respiratory chain complexes I & IV and ATP levels, and assessed learning and memory ability by Morris Water Maze and nesting behavior. Results: Levels of AGE adducts (MG-H1 and CEL) were robustly increased in the serum and brain of AGE+ diet fed mice compared to the AGE– group. Furthermore, greatly elevated levels of reactive oxygen species, decreased activities of mitochondrial respiratory chain complexes I & IV, reduced ATP levels, and impaired learning and memory were evident in AGE+ diet fed mice compared to the AGE– group. Conclusion: These results indicate that dietary AGEs are important sources of AGE accumulation in vivo , resulting in mitochondrial dysfunction, impairment of energy metabolism, and subsequent cognitive impairment. Thus, reducing AGEs intake to lower accumulation of AGEs could hold therapeutic potential for the prevention and treatment of AGEs-induced mitochondrial dysfunction linked to cognitive decline. Show more

Keywords: Advanced glycation end products, methylglyoxal, mitochondrial and cognitive dysfunction

DOI: 10.3233/JAD-191236

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 165-178, 2020

Authors: Falck, Ryan S. | Davis, Jennifer C. | Best, John R. | Chan, Patrick C.Y. | Li, Linda C. | Wyrough, Anne B. | Bennett, Kimberly J. | Backhouse, Daniel | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: Poor sleep is common among older adults with mild cognitive impairment (MCI) and may contribute to further cognitive decline. Whether multimodal lifestyle intervention that combines bright light therapy (BLT), physical activity (PA), and good sleep hygiene can improve sleep in older adults with MCI and poor sleep is unknown. Objective: To assess the effect of a multimodal lifestyle intervention on sleep in older adults with probable MCI and poor sleep. Methods: This was a 24-week proof-of-concept randomized trial of 96 community-dwelling older adults aged 65–85 years with probable MCI (<26/30 on the Montreal Cognitive Assessment) …and poor sleep (>5 on the Pittsburgh Sleep Quality Index [PSQI]). Participants were allocated to either a multimodal lifestyle intervention (INT); or 2) education + attentional control (CON). INT participants received four once-weekly general sleep hygiene education classes, followed by 20-weeks of: 1) individually-timed BLT; and 2) individually-tailored PA promotion. Our primary outcome was sleep efficiency measured using the MotionWatch8© (MW8). Secondary outcomes were MW8-measured sleep duration, fragmentation index, wake-after-sleep-onset, latency, and PSQI-measured subjective sleep quality. Results: There were no significant between-group differences in MW8 measured sleep efficiency at 24-weeks (estimated mean difference [INT –CON]: 1.18%; 95% CI [–0.99, 3.34]), or any other objective-estimate of sleep. However, INT participants reported significantly better subjective sleep quality at 24-weeks (estimated mean difference: –1.39; 95% CI [–2.72, –0.06]) compared to CON. Conclusion: Among individuals with probable MCI and poor sleep, a multimodal lifestyle intervention improves subjective sleep quality, but not objectively estimated sleep. Show more

Keywords: Bright light therapy, chronotherapy, mild cognitive impairment, older adults, physical activity, sleep, sleep hygiene, ClinicalTrials.gov, NCT02926157, Registered on 6 October 2016

DOI: 10.3233/JAD-200383

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 179-193, 2020

Authors: Chen, Shuoqi | Jia, Jianping

Article Type: Research Article

Abstract: Background: Inflammation and oxidative stress are believed to play an important role in the pathogenesis of Alzheimer’s disease (AD). Tenuifolin (TEN) is a natural neuroprotective compound extracted from Polygala tenuifolia Willd , which may improve cognitive symptoms. Objective: This study was designed to evaluate the protective effect of TEN on inflammatory and oxidative stress induced by amyloid-β (Aβ)42 oligomers in BV2 cells, and to explore the underlying mechanisms. Methods: We conducted cell viability assays to estimate drug toxicity and drug effects on cells. Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays were performed to …detect the release of inflammatory factors. Nitric oxide (NO) assays were used to measure the degree of oxidative stress. Western blot and immunofluorescence analysis were used to explore the influence of TEN on the nuclear factor-κ B (NF-κ B) pathway. Results: Pretreatment of BV2 microglial cells with TEN inhibited the release of tumor necrosis factor-α , interleukin-6, and interleukin-1β, alleviated NO-induced oxidative stress by inhibiting the expression of inducible nitric oxide synthase and cyclo-oxygenase-2, and protected SH-SY5Y cells from the toxicity induced by the medium conditioned by BV2 cells previously exposed to Aβ42 oligomers. Moreover, TEN suppressed upstream activators of NF-κ B, as well as NF-κ B translocation to the nucleus in BV2 microglial cells. Conclusion: This study demonstrates that TEN can protect SH-SY5Y cells from Aβ42 oligomer-induced microglia-mediated inflammation, and oxidative stress by downregulating the NF-κ B signaling pathway. Show more

Keywords: Alzheimer disease, amyloid-β protein, inflammation, nuclear factor-κB, microglia

DOI: 10.3233/JAD-200077

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 195-205, 2020

Authors: Schwaber, Eric J. | Thompson, Atalie C. | Smilnak, Gordon | Stinnett, Sandra S. | Whitson, Heather E. | Lad, Eleonora M.

Article Type: Research Article

Abstract: Background: Previous epidemiologic studies have suggested an association between AMD and AD, and several therapeutic agents are being developed based on this principle. However, prior studies have provided conflicting results due in part to their reliance on clinical diagnoses that are not based on gold-standard histopathology. Objective: To use histopathologic standards for diagnosis in order to determine the co-prevalence of AD among patients with and without AMD. Methods: This is a cross-sectional study of 157 autopsy ocular specimens from patients with and without AMD that were greater than 75 years of age at death. Sarks staging …was used to document the severity of AMD, and Braak and Braak staging was used to assess the severity of AD in corresponding brain specimens. The prevalence of AD within different severities of AMD was determined using univariable and multivariable logistic regression. Results: 58% of autopsy eyes had AMD. The prevalence of AD was lower in AMD subjects (63%) compared to non-AMD subjects (73%), even when grouped by severity (all p  > 0.15). The likelihood of AD was significantly less in AMD subjects, even after adjusting for age and sex in multivariable analysis (OR 0.47, p  = 0.049). Conclusion: Histopathologic diagnoses fail to support an increase in prevalence of AD among subjects with AMD, even when disease severity is considered. Show more

Keywords: Age-related macular degeneration, Alzheimer’s disease, dementia, epidemiology, histopathology

DOI: 10.3233/JAD-200111

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 207-215, 2020

Authors: Wang, Xin | Zimmermann, Helena R. | Lockhart, Samuel N. | Craft, Suzanne | Ma, Tao

Article Type: Research Article

Abstract: Background: There is an urgent need to develop feasible biomarkers for diagnosis and prognosis of Alzheimer’s disease (AD). Mounting evidence implicates that dysregulation of energy metabolism is a key and early event in AD pathogenesis. AMP-activated protein kinase (AMPK) is a central molecular sensor that plays a critical role in maintaining cellular energy homeostasis, and aberrant brain AMPK activities are linked to AD pathophysiology. Objective: We aimed to investigated protein levels of AMPKα isoforms, AMPKα 1 and AMPKα 2, in plasma samples from patients clinically diagnosed with mild cognitive impairment (MCI) or AD, along with age-matched healthy …controls. Methods: 30 participants (10 MCI, 10 AD, and 10 controls) were included in our pilot study. Plasma levels of AMPKα 1 and AMPKα 2 were determined by ELISA. Receiver operating characteristic (ROC) analysis was used to assess sensitivity and specificity. Linear regression was used to assess the correlation between levels of AMPKα isoforms and other biomarkers. Results: Plasma levels of AMPKα 1 were decreased in MCI and AD patients, while levels of AMPKα 2 were unaltered as compared to controls. ROC analysis showed relatively high sensitivity and specificity for AMPKα 1 to distinguish MCI and AD from controls. Linear regression analysis showed that plasma levels of AMPKα 1 were correlated with a brain imaging biomarker (AD signature cortical thicknesses). Conclusion: Plasma levels of AMPKα 1 were decreased in MCI and AD patients. Future endeavor to explore whether blood AMPKα 1 protein expression has the value as a potential biomarker for AD and MCI diagnosis shall be encouraged. Show more

Keywords: Alzheimer’s disease, AMPK, biomarker, isoform, mild cognitive impairment, plasma

DOI: 10.3233/JAD-191189

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 217-224, 2020