Journal of Alzheimer's Disease - Volume 64, issue 2

Authors: Croteau, Etienne | Castellano, Christian-Alexandre | Richard, Marie Anne | Fortier, Mélanie | Nugent, Scott | Lepage, Martin | Duchesne, Simon | Whittingstall, Kevin | Turcotte, Éric E. | Bocti, Christian | Fülöp, Tamàs | Cunnane, Stephen C.

Article Type: Research Article

Abstract: Background : In Alzheimer’s disease (AD), it is unknown whether the brain can utilize additional ketones as fuel when they are derived from a medium chain triglyceride (MCT) supplement. Objective : To assess whether brain ketone uptake in AD increases in response to MCT as it would in young healthy adults. Methods : Mild-moderate AD patients sequentially consumed 30 g/d of two different MCT supplements, both for one month: a mixture of caprylic (55%) and capric acids (35%) (n = 11), followed by a wash-out and then tricaprylin (95%; n = 6). Brain ketone …(11 C-acetoacetate) and glucose (FDG) uptake were quantified by PET before and after each MCT intervention. Results : Brain ketone consumption doubled on both types of MCT supplement. The slope of the relationship between plasma ketones and brain ketone uptake was the same as in healthy young adults. Both types of MCT increased total brain energy metabolism by increasing ketone supply without affecting brain glucose utilization. Conclusion : Ketones from MCT compensate for the brain glucose deficit in AD in direct proportion to the level of plasma ketones achieved. Show more

Keywords: Acetoacetate, Alzheimer’s disease, beta-hydroxybutyrate, brain energy metabolism, [11C]-acetoacetate, cerebral blood flow, [18F]-fluorodeoxyglucose, ketones, medium chain triglycerides

DOI: 10.3233/JAD-180202

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 551-561, 2018

Authors: Kawanishi, Shohei | Takata, Kazuyuki | Itezono, Shouma | Nagayama, Hiroko | Konoya, Sayaka | Chisaki, Yugo | Toda, Yuki | Nakata, Susumu | Yano, Yoshitaka | Kitamura, Yoshihisa | Ashihara, Eishi

Article Type: Research Article

Abstract: Microglia, the primary immune cells in the brain, sense pathogens and tissue damage, stimulate cytokine production, and phagocytosis to maintain homeostasis. Accumulation of amyloid-β peptides (Aβ) in the brain triggers the onset of Alzheimer’s disease (AD). Accordingly, promotion of Aβ clearance represents a promising strategy for AD therapy. We previously demonstrated that primary-cultured rat microglia phagocytose Aβ, and that transplantation of these cells ameliorates the Aβ burden in brains of Aβ-injected rats. In this study, we demonstrate that stimulation with colony-stimulating factor-1 efficiently differentiates mouse bone marrow cells into bone marrow-derived microglia-like (BMDML) cells that express markers for microglia, including …the recently identified transmembrane protein 119. BMDML cells effectively phagocytose Aβ in vitro , with effects comparable to primary-cultured mouse microglia and greater than peritoneal macrophages. RT-qPCR analysis for cytokine mRNA levels revealed that BMDML cells polarize to a relatively anti-inflammatory state under non-stimulated and inflammatory conditions but exert a pro-inflammatory reaction after lipopolysaccharide treatment. Moreover, BMDML cells hippocampally injected into a mouse model of AD are morphologically similar to the ramified and amoeboid types of residential microglia. Comparisons with simulations assuming a uniform distribution of cells suggest that BMDML cells migrate directionally toward Aβ plaques. We also detected Aβ phagocytosis by BMDML cells, concomitant with a reduction in the number and area of Aβ plaques. Finally, we observed amelioration of cognitive impairment in a mouse model of AD after hippocampal injection of BMDML cells. Our results suggest that BMDML cells have potential as a cell-based disease-modifying therapy against AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, bone-marrow-derived cells, microglia

DOI: 10.3233/JAD-170994

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 563-585, 2018

Authors: Haapala, Eero A. | Paananen, Jussi | Hiltunen, Mikko | Lakka, Timo A.

Article Type: Research Article

Abstract: We investigated the associations of genetic risk score (GRS) for Alzheimer’s disease and apolipoprotein E (APOE ) ɛ variant with cardiometabolic risk factors during 2-year follow-up in children and whether body fat percentage (BF%) modify these associations. A population-based sample of 469 children (246 boys, 223 girls) at baseline and 398 children (201 boys, 197 girls) at 2-year follow-up participated in the study. Genotyping was performed using the Illumina Custom Infinium CardioMetabo BeadChip and the Illumina Infinium HumanCoreExome BeadChip. The GRS was calculated using information on nine independent gene variants available in our genomic data. We assessed BF%, waist …circumference, insulin, glucose, triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and systolic and diastolic blood pressure. We computed a cardiometabolic risk score and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). In boys, the GRS was not associated with cardiometabolic risk factors. In girls, GRS was directly associated with LDL cholesterol (β = 0.133, 95% CI = 0.002 to 0.262) at baseline and with a higher cardiometabolic risk score (β = 0.154, 95% CI = 0.015 to 0.294), glucose (β = 0.143, 95% CI = 0.003 to 0.284), and HOMA-IR (β = 0.141, 95% CI = 0.004 to 0.278) at 2-year follow-up. GRS was directly associated with a cardiometabolic risk score at baseline and 2-year follow-up among girls in the highest third of BF% at baseline, but not in other girls (p < 0.05 for interaction). Children with the APOE ɛ 3/3 genotype had higher LDL cholesterol at and 2-year follow-up than those with the APOE ɛ 2/3 genotype. In conclusion, GRS was associated with increased cardiometabolic risk in girls and especially those with higher BF%. Show more

Keywords: Alzheimer’s disease, child, genetics, insulin resistance, metabolic syndrome

DOI: 10.3233/JAD-180216

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 587-595, 2018

Authors: Leoutsakos, Jeannie-Marie S. | Yan, Haijuan | Anderson, William S. | Asaad, Wael F. | Baltuch, Gordon | Burke, Anna | Chakravarty, M. Mallar | Drake, Kristen E. | Foote, Kelly D. | Fosdick, Lisa | Giacobbe, Peter | Mari, Zoltan | McAndrews, Mary Pat | Munro, Cynthia A. | Oh, Esther S. | Okun, Michael S. | Pendergrass, Jo Cara | Ponce, Francisco A. | Rosenberg, Paul B. | Sabbagh, Marwan N. | Salloway, Stephen | Tang-Wai, David F. | Targum, Steven D. | Wolk, David | Lozano, Andres M. | Smith, Gwenn S. | Lyketsos, Constantine G.

Article Type: Research Article

Abstract: Background: Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years. Objective: To examine the long-term safety and clinical effects of sustained …and delayed-on DBS-f treatment of mild AD after two years. Methods: 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial. Results: DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants. Conclusion: DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65. Show more

Keywords: Alzheimer’s disease, deep brain stimulation, dementia, delayed start, fornix, treatment

DOI: 10.3233/JAD-180121

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 597-606, 2018

Authors: Bae, Jong Bin | Han, Ji Won | Kwak, Kyung Phil | Kim, Bong Jo | Kim, Shin Gyeom | Kim, Jeong Lan | Kim, Tae Hui | Ryu, Seung-Ho | Moon, Seok Woo | Park, Joon Hyuk | Youn, Jong Chul | Lee, Dong Young | Lee, Dong Woo | Lee, Seok Bum | Lee, Jung Jae | Jhoo, Jin Hyeong | Kim, Ki Woong

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a cognitive state that lies on the continuum between normal aging and dementia, and the prevalence of MCI is higher than dementia. However, the risk for mortality of people with MCI has been far less studied than that of people with dementia, and the population attributable risk percent (PAR%) of death attributable to MCI has not been estimated yet. Objective: To investigate the impact of MCI on mortality and the cause of death in the elderly, and to estimate the PAR% of deaths attributable to MCI. Methods: Data came from …7,315 elderly subjects aged ≥60 years without dementia from two cohort studies with diagnostic assessments of MCI at baseline. Deaths among participants were confirmed through the nationwide mortality database of Statistics Korea. Results: MCI increased the risk of mortality in a multivariate Cox proportional model adjusting for age, sex, education, smoking, alcohol drinking, chronic illness, depression, vascular components, and cohort (hazard ratio = 1.59, 95% confidence interval 1.30, 1.94). PAR% of death attributable to MCI was 10.7% for age 65–74 years, 16.0% for age 75–84 years, and 24.2% for age ≥85 years. In the elderly with MCI, mortality risks from cerebrovascular disease, respiratory disease, and external causes were higher than in the cognitively normal elderly. Conclusions: Our results suggest that the mortality risk of MCI in Asian countries may be comparable to that in Western countries, and MCI can contribute to the death of the elderly as much as dementia. Show more

Keywords: Cause of death, cognitive dysfunction, death, epidemiology, neurocognitive disorders, mortality

DOI: 10.3233/JAD-171182

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 607-616, 2018

Authors: Craven, Kristen M. | Kochen, William R. | Hernandez, Carlos M. | Flinn, Jane M.

Article Type: Research Article

Abstract: Hyperphosphorylated tau protein is a key pathology in Alzheimer’s disease (AD), frontotemporal dementia, chronic traumatic encephalopathy, and Parkinson’s disease. The essential trace element zinc exacerbates tauopathy in vitro as well as in a Drosophila model of AD. However, the interaction has never been assessed behaviorally or biochemically in mammals. Zinc supplementation is prevalent in society, finding use as a treatment for macular degeneration and cataracts, and is also taken as an immune system booster with high levels appearing in multivitamins marketed toward the elderly. Using a transgenic mouse model that contains the human gene for tau protein (P301L), …we assessed the effects of excess chronic zinc supplementation on tau pathology. Behavioral tests included nest building, circadian rhythm, Morris Water Maze, fear conditioning, and open field. Biochemically, total tau and Ser396 phosphorylation were assessed using western blot. Number of tangles were assessed by Thioflavin-S and free zinc levels were assessed by Zinpyr-1. Tau mice demonstrated behavioral deficits compared to control mice. Zinc supplementation exacerbated tauopathic deficits in circadian rhythm, nesting behavior, and Morris Water Maze. Biochemically, zinc-supplemented tau mice showed increased phosphorylation at pSer396. Zinc supplementation in tau mice also increased tangle numbers in the hippocampus while decreasing free-zinc levels, demonstrating that tangles were sequestering zinc. These results show that zinc intensified the deficits in behavior and biochemistry caused by tau. Show more

Keywords: Circadian rhythm, spatial memory, tau proteins, tauopathies, western blotting, zinc

DOI: 10.3233/JAD-180151

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 617-630, 2018

Authors: Barnes, Josephine | Bartlett, Jonathan W. | Wolk, David A. | van der Flier, Wiesje M. | Frost, Chris

Article Type: Research Article

Abstract: Health-care professionals, patients, and families seek as much information as possible about prognosis for patients with Alzheimer’s disease (AD); however, we do not yet have a robust understanding of how demographic factors predict prognosis. We evaluated associations between age at presentation, age of onset, and symptom length with cognitive decline as measured using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating sum-of-boxes (CDR-SOB) in a large dataset of AD patients. Age at presentation was associated with post-presentation decline in MMSE (p < 0.001), with younger patients showing faster decline. There was little evidence of an association with change …in CDR-SOB. Symptom length, rather than age, was the strongest predictor of MMSE and CDR-SOB at presentation, with increasing symptom length associated with worse outcomes. The evidence that younger AD patients have a more aggressive disease course implies that early diagnosis is essential. Show more

Keywords: Age factors, age of onset, Alzheimer’s disease, cognition, cognitive decline

DOI: 10.3233/JAD-170841

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 631-642, 2018

Authors: Thomann, Alessandra E. | Goettel, Nicolai | Monsch, Raphael J. | Berres, Manfred | Jahn, Thomas | Steiner, Luzius A. | Monsch, Andreas U.

Article Type: Research Article

Abstract: Background: The Montreal Cognitive Assessment (MoCA) is used to evaluate multiple cognitive domains in elderly individuals. However, it is influenced by demographic characteristics that have yet to be adequately considered. Objective: The aim of our study was to investigate the effects of age, education, and sex on the MoCA total score and to provide demographically adjusted normative values for a German-speaking population. Methods: Subjects were recruited from a registry of healthy volunteers. Cognitive health was defined using the Mini-Mental State Examination (score ≥27/30 points) and the Consortium to Establish a Registry for Alzheimer’s Disease-Neuropsychological Assessment Battery …(total score ≥85.9 points). Participants were assessed with the German version of the MoCA. Normative values were developed based on regression analysis. Covariates were chosen using the Predicted Residual Sums of Squares approach. Results: The final sample consisted of 283 participants (155 women, 128 men; mean (SD) age = 73.8 (5.2) years; education = 13.6 (2.9) years). Thirty-one percent of participants scored below the original cut-off (<26/30 points). The MoCA total score was best predicted by a regression model with age, education, and sex as covariates. Older age, lower education, and male sex were associated with a lower MoCA total score (p  < 0.001). Conclusion: We developed a formula to provide demographically adjusted standard scores for the MoCA in a German-speaking population. A comparison with other MoCA normative studies revealed considerable differences with respect to selection of volunteers and methods used to establish normative data. Show more

Keywords: Elderly individuals, healthy participants, mild cognitive impairment, Montreal Cognitive Assessment, regression analysis

DOI: 10.3233/JAD-180080

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 643-655, 2018

Authors: Larsson, Susanna C. | Markus, Hugh S.

Article Type: Research Article

Abstract: Background: Epidemiological evidence has associated Alzheimer’s disease (AD) with vascular risk factors (VRFs), but whether treatment of VRFs reduces the incidence of dementia and AD is uncertain. Objective: To conduct a systematic review and meta-analysis to summarize available data on the impact of treatment of VRFs on dementia and AD incidence. Methods: Pertinent studies published until 1 January 2018 were identified from PubMed. Both randomized controlled trials (RCT) and prospective studies that investigated the impact of treatment of VRFs on dementia or AD incidence were included. Results: …Eight RCTs and 52 prospective studies were identified. Antihypertensive treatment was associated with a non-significant reduced risk of dementia in RCTs (n = 5; relative risk [RR], 0.84; 95% confidence interval [CI], 0.69–1.02) and prospective studies (n = 3; RR, 0.77; 95% CI, 0.58–1.01) and with reduced AD risk in prospective studies (n = 5; RR = 0.78; 95% CI, 0.66–0.91). In prospective studies, treatment of hyperlipidemia with statins, but not nonstatin lipid-lowering agents, was associated with reduced risk of dementia (n = 17; RR, 0.77; 95% CI, 0.63–0.95) and AD (n = 13; RR, 0.86; 95% CI, 0.80–0.92). The single RCT on statins and dementia incidence showed no association. Data from one RCT and six prospective studies did not support a beneficial impact of antidiabetic drugs or insulin therapy on dementia risk. Conclusion: Current evidence indicates that antihypertensives and statins might reduce the incidence of dementia and AD. Further trials to determine the effect of VRF on AD are needed. Show more

Keywords: Alzheimer’s disease, dementia, meta-analysis, prevention, prospective studies, randomized controlled trials, risk factors, systematic review

DOI: 10.3233/JAD-180288

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 657-668, 2018

Authors: Mandal, Pravat K. | Shukla, Deepika

Article Type: Correction

DOI: 10.3233/JAD-189005

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 669-670, 2018