Journal of Alzheimer's Disease - Volume 78, issue 4

Authors: Pelcher, Isabelle | Puzo, Christian | Tripodis, Yorghos | Aparicio, Hugo J. | Steinberg, Eric G. | Phelps, Alyssa | Martin, Brett | Palmisano, Joseph N. | Vassey, Elizabeth | Lindbergh, Cutter | McKee, Ann C. | Stein, Thor D. | Killiany, Ronald J. | Au, Rhoda | Kowall, Neil W. | Stern, Robert A. | Mez, Jesse | Alosco, Michael L.

Article Type: Research Article

Abstract: Background: The Framingham Stroke Risk Profile (FSRP) was created in 1991 to estimate 10-year risk of stroke. It was revised in 2017 (rFSRP) to reflect the modern data on vascular risk factors and stroke risk. Objective: This study examined the association between the rFSRP and cognitive and brain aging outcomes among participants from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS). Methods: Cross-sectional rFSRP was computed at baseline for 19,309 participants (mean age = 72.84, SD = 8.48) from the NACC-UDS [9,697 (50.2%) normal cognition, 4,705 (24.4%) MCI, 4,907 (25.4%) dementia]. Multivariable linear, logistic, or ordinal regressions examined …the association between the rFSRP and diagnostic status, neuropsychological test performance, CDR® Sum of Boxes, as well as total brain volume (TBV), hippocampal volume (HCV), and log-transformed white matter hyperintensities (WMH) for an MRI subset (n  = 1,196). Models controlled for age, sex, education, racial identity, APOE ɛ 4 status, and estimated intracranial volume for MRI models. Results: The mean rFSRP probability was 10.42% (min = 0.50%, max = 95.71%). Higher rFSRP scores corresponded to greater CDR Sum of Boxes (β= 0.02, p  = 0.028) and worse performance on: Trail Making Test A (β= 0.05, p  < 0.001) and B (β= 0.057, p  < 0.001), and Digit Symbol (β= –0.058, p  < 0.001). Higher rFSRP scores were associated with increased odds for a greater volume of log-transformed WMH (OR = 1.02 per quartile, p  = 0.015). No associations were observed for diagnosis, episodic memory or language test scores, HCV, or TBV. Conclusion: These results support the rFSRP as a useful metric to facilitate clinical research on the associations between cerebrovascular disease and cognitive and brain aging. Show more

Keywords: Alzheimer’s disease, cardiovascular disease, cerebrovascular disease, framingham stroke risk profile, stroke risk

DOI: 10.3233/JAD-200803

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1393-1408, 2020

Authors: Blair, Emilie M. | Zahuranec, Darin B. | Langa, Kenneth M. | Forman, Jane | Reale, Bailey K. | Kollman, Colleen | Giordani, Bruno | Levine, Deborah A.

Article Type: Research Article

Abstract: Background: Older patients with mild cognitive impairment (MCI) should receive evidence-based treatments when clinically indicated. However, patients with MCI appear less likely than cognitively normal patients to receive evidence-based treatments. Objective: To explore the influence of a patient’s MCI diagnosis on physician decision-making. Methods: Qualitative study of 18 physicians from cardiology, neurology, and internal medicine using semi-structured interviews. We sought to understand whether and how a patient’s having MCI has influenced physicians’ decisions about five categories of treatments or tests (surgery, invasive tests, non-invasive tests, rehabilitation, and preventive medication). We used qualitative content analysis to identify …the unifying and recurrent themes. Results: Most physician participants described MCI as influencing their recommendations for at least one treatment or test. We identified two major themes as factors that influenced physician recommendations in patients with MCI: Physicians assume that MCI patients’ decreased cognitive ability will impact treatment; and physicians assume that MCI patients have poor health status and physical functioning that will impact treatment. These two themes were representative of physician beliefs that MCI patients have impaired independent decision-making, inability to adhere to treatment, inability to communicate treatment preferences, and increased risk and burden from treatment. Conclusion: A patient’s MCI diagnosis influences physician decision-making for treatment. Some physician assumptions about patients with MCI were not evidence-based. This phenomenon potentially explains why many patients with MCI get fewer effective treatments or tests than cognitively normal patients. Interventions that improve how physicians understand MCI and make decisions for treatments in patients with MCI are needed. Show more

Keywords: Aging, decision making, mild cognitive impairment, treatment

DOI: 10.3233/JAD-200700

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1409-1417, 2020

Authors: Ghoweri, Adam O. | Ouillette, Lara | Frazier, Hilaree N. | Anderson, Katie L. | Lin, Ruei-Lung | Gant, John C. | Parent, Rachel | Moore, Shannon | Murphy, Geoffrey G. | Thibault, Olivier

Article Type: Research Article

Abstract: Background: In animal models and tissue preparations, calcium dyshomeostasis is a biomarker of aging and Alzheimer’s disease that is associated with synaptic dysfunction, neuritic pruning, and dysregulated cellular processes. It is unclear, however, whether the onset of calcium dysregulation precedes, is concurrent with, or is the product of pathological cellular events (e.g., oxidation, amyloid-β production, and neuroinflammation). Further, neuronal calcium dysregulation is not always present in animal models of amyloidogenesis, questioning its reliability as a disease biomarker. Objective: Here, we directly tested for the presence of calcium dysregulation in dorsal hippocampal neurons in male and female 5×FAD …mice on a C57BL/6 genetic background using sharp electrodes coupled with Oregon-green Bapta-1 imaging. We focused on three ages that coincide with the course of amyloid deposition: 1.5, 4, and 10 months old. Methods: Outcome variables included measures of the afterhyperpolarization, short-term synaptic plasticity, and calcium kinetics during synaptic activation. Quantitative analyses of spatial learning and memory were also conducted using the Morris water maze. Main effects of sex, age, and genotype were identified on measures of electrophysiology and calcium imaging. Results: Measures of resting Oregon-green Bapta-1 fluorescence showed significant reductions in the 5×FAD group compared to controls. Deficits in spatial memory, along with increases in Aβ load, were detectable at older ages, allowing us to test for temporal associations with the onset of calcium dysregulation. Conclusion: Our results provide evidence that reduced, rather than elevated, neuronal calcium is identified in this 5×FAD model and suggests that this surprising result may be a novel biomarker of AD. Show more

Keywords: 5×FAD, afterhyperpolarization, aging, Alzheimer’s disease, calcium, electrophysiology, hippocampus, hyperactivity, intracellular, sex

DOI: 10.3233/JAD-200109

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1419-1438, 2020

Authors: Walker, Jennifer D. | Spiro, Grace | Loewen, Kassandra | Jacklin, Kristen

Article Type: Research Article

Abstract: Background: There remains a lack of information and understanding of the prevalence and incidence of Alzheimer’s disease and related dementia in Indigenous populations. Little evidence available suggests that Indigenous peoples may have disproportionately high rates of Alzheimer’s disease and related dementia (ADRD). Objective: Given this information, this study systematically explores what risk factors may be associated with ADRD in Indigenous populations. Methods: A search of all published literature was conducted in October 2016, March 2018, and July 2019 using Medline, Embase, and PsychINFO. Subject headings explored were inclusive of all terms related to Indigenous persons, dementia, …and risk. All relevant words, phrases, and combinations were used. To be included in this systematic review, articles had to display an association of a risk factor and ADRD. Only studies that reported a quantifiable measure of risk, involved human subjects, and were published in English were included. Results: Of 237 articles originally identified through database searches, 45 were duplicates and 179 did not meet a priori inclusion criteria, resulting in 13 studies eligible for inclusion in this systematic review. Conclusion: The large number of potentially modifiable risk factors reported relative to non-modifiable risk factors illustrates the importance of socioeconomic context in the pathogenesis of ADRD in Indigenous populations. The tendency to prioritize genetic over social explanations when encountering disproportionately high disease rates in Indigenous populations can distract from modifiable proximal, intermediate, and distal determinants of health. Show more

Keywords: Alzheimer’s disease, indigenous population, neurocognitive disorders, social determinants of health

DOI: 10.3233/JAD-200704

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1439-1451, 2020

Authors: Armstrong, Tyler D. | Suwannasual, Usa | Kennedy, Conner L. | Thasma, Akshaykumar | Schneider, Leah J. | Phillippi, Danielle | Lund, Amie K.

Article Type: Research Article

Abstract: Background: Multiple studies report a strong correlation between traffic-generated air pollution-exposure and detrimental outcomes in the central nervous system (CNS), including Alzheimer’s disease (AD). Incidence of AD is rapidly increasing and, worldwide, many live in regions where pollutants exceed regulatory standards. Thus, it is imperative to identify environmental pollutants that contribute to AD, and the mechanisms involved. Objective: We investigated the effects of mixed gasoline and diesel engine emissions (MVE) on the expression of factors involved in progression of AD in the hippocampus and cerebrum in a young versus aged mouse model. Methods: Young (2 months …old) and aged (18 months old) male C57BL/6 mice were exposed to either MVE (300μ g/m3 PM) or filtered air (FA) for 6 h/d, 7 d/wk, for 50 d. Immunofluorescence and RT-qPCR were used to quantify oxidative stress (8-OHdG) and expression of amyloid-β protein precursor (Aβ PP), β secretase (BACE1), amyloid-β (Aβ ), aryl hydrocarbon receptor (AhR), cytochrome P450 (CYP) 1B1, angiotensin-converting enzyme (ACE1), and angiotensin II type 1 (AT1) receptor in the cerebrum and hippocampus, in addition to cerebral microvascular tight junction (TJ) protein expression. Results: We observed age-related increases in oxidative stress, AhR, CYP1B1, Aβ , BACE1, and AT1 receptor in the CA1 region of the hippocampus, and elevation of cerebral Aβ PP, AhR, and CYP1B1 mRNA, associated with decreased cerebral microvascular TJ protein claudin-5. MVE-exposure resulted in further promotion of oxidative stress, and significant increases in AhR, CYP1B1, BACE1, ACE1, and Aβ , compared to the young and aged FA-exposed mice. Conclusion: Such findings suggest that MVE-exposure exacerbates the expression of factors in the CNS associated with AD pathogenesis in aged populations. Show more

Keywords: Air pollution, Alzheimer’s disease, amyloid-β , AT1 receptor, reactive oxygen species

DOI: 10.3233/JAD-200929

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1453-1471, 2020

Authors: Laczó, Jan | Cechova, Katerina | Parizkova, Martina | Lerch, Ondrej | Andel, Ross | Matoska, Vaclav | Kaplan, Vojtech | Matuskova, Veronika | Nedelska, Zuzana | Vyhnalek, Martin | Hort, Jakub

Article Type: Research Article

Abstract: Background: The apolipoprotein E (APOE ) ɛ 4 allele is associated with episodic memory and spatial navigation deficits. The brain-derived neurotrophic factor (BDNF ) Met allele may further worsen memory impairment in APOE ɛ 4 carriers but its role in APOE ɛ 4-related spatial navigation deficits has not been established. Objective: We examined influence of APOE and BDNF Val66Met polymorphism combination on spatial navigation and volumes of selected navigation-related brain regions in cognitively unimpaired (CU) older adults and those with amnestic mild cognitive impairment (aMCI). Methods: 187 participants (aMCI [n  = 116] and …CU [n  = 71]) from the Czech Brain Aging Study were stratified based on APOE and BDNF Val66Met polymorphisms into four groups: ɛ 4– /BDNF Val/Val , ɛ 4– /BDNF Met , ɛ 4+ /BDNF Val/Val , and ɛ 4+ /BDNF Met . The participants underwent comprehensive neuropsychological examination, brain MRI, and spatial navigation testing of egocentric, allocentric, and allocentric delayed navigation in a real-space human analogue of the Morris water maze. Results: Among the aMCI participants, the ɛ 4+ /BDNF Met group had the least accurate egocentric navigation performance (p  < 0.05) and lower verbal memory performance than the ɛ 4– /BDNF Val/Val group (p  = 0.007). The ɛ 4+ /BDNF Met group had smaller hippocampal and entorhinal cortical volumes than the ɛ 4– /BDNFVal/Val (p ≤0.019) and ɛ 4– /BDNFMet (p ≤0.020) groups. Among the CU participants, the ɛ 4+ /BDNF Met group had less accurate allocentric and allocentric delayed navigation performance than the ɛ 4– /BDNFVal/Val group (p  < 0.05). Conclusion: The combination of APOE ɛ 4 and BDNF Met polymorphisms is associated with more pronounced egocentric navigation impairment and atrophy of the medial temporal lobe regions in individuals with aMCI and less accurate allocentric navigation in CU older adults. Show more

Keywords: Alzheimer’s disease, apolipoproteins E, brain-derived neurotrophic factor, entorhinal cortex, episodic memory, gene polymorphism, magnetic resonance imaging, mild cognitive impairment, Morris water maze, spatial navigation

DOI: 10.3233/JAD-200615

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1473-1492, 2020

Authors: Satoh, Masayuki | Ogawa, Jun-ichi | Tokita, Tomoko | Matsumoto, Yoshimi | Nakao, Koji | Tabei, Ken-ichi | Kato, Natsuko | Tomimoto, Hidekazu

Article Type: Research Article

Abstract: Background: We previously reported the enhanced effects of physical exercise when combined with music (ExM) on cognitive function in community-dwelling normal elderly people compared to exercise alone. Following that study, participants voluntarily continued the ExM classes for 5 years. Objective: To identify the effects of a 5-year ExM intervention on cognitive function in normal elderly people. Methods: Fifty-four subjects continued the ExM classes once a week for 5 years (ExM group). Thirty-three subjects retired from the ExM class during the 5 years (Retired group). Twenty-one subjects never participated in any intervention over the 5 years (No-exercise …group). Cognitive function and ADLs were assessed using neuropsychological batteries and the functional independence measure (FIM), respectively. The voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) was used to investigate medial temporal lobe atrophy. Results: Analyses of the raw scores after the 5-year intervention showed significant differences between the ExM and No-exercise groups in their MMSE scores, Raven’s colored progressive matrices (RCPM) time, logical memory (LM)-I, as well as the total and physical exercise sub-scores of the FIM. Analysis of subjects aged 70– 79 years at the beginning of this project showed significantly quicker performance on the RCPM in the ExM compared to No-exercise groups. The correlation coefficients between the total number of ExM sessions attended and the degree of changes in physical, neuropsychological, and VSRAD scores were significant for RCPM performance time and LM-I scores. Conclusion: Long-term ExM intervention reinforces multifaceted cognitive function in normal elderly people, and is especially beneficial for psychomotor speed. Show more

Keywords: functional independence measure, long-term effect, neuropsychological assessments, physical exercise with music, psychomotor speed

DOI: 10.3233/JAD-200480

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1493-1507, 2020

Authors: Yang, Tong | Wang, Hualou | Xiong, Ying | Chen, Chong | Duan, Keran | Jia, Jingya | Ma, Fei

Article Type: Research Article

Abstract: Background: Cognitive decline in older adults is a serious public health problem today. Association between vitamin D supplementation and cognition remains controversial. Objective: To determine whether a 12-month vitamin D supplementation improves cognitive function in elderly subjects with mild cognitive impairment (MCI), and whether it is mediated through the mechanism in which telomere length (TL) regulate oxidative stress. Methods: This was a double-blind, randomized, placebo-controlled trial in Tianjin, China. Participants were all native Chinese speakers aged 65 years and older with MCI. 183 subjects were randomized to an intervention group (vitamin D 800 IU/day, n  = 93) …or a placebo group (the matching starch granules, n  = 90), and followed up for 12 months. Tests of cognitive function and mechanism-related biomarkers were evaluated at baseline, 6 months, and 12 months. Results: Repeated-measures ANOVA showed substantial improvements in the full scale intelligence quotient (FSIQ), information, digit span, vocabulary, block design, and picture arrangement scores in the vitamin D group over the placebo group (p  < 0.001). Leukocyte TL was significantly higher, while serum 8-OXO-dG, OGG1mRNA, and P16INK4a mRNA revealed greater decreases in the vitamin D group over the placebo group (p  < 0.001). According to mixed-model repeated-measures ANOVA analysis, vitamin D group showed a significant enhancement in the FSIQ score for 12 months compared with the control (estimate value = 5.132, p  < 0.001). Conclusion: Vitamin D supplementation for 12 months appears to improve cognitive function through reducing oxidative stress regulated by increased TL in order adults with MCI. Vitamin D may be a promising public health strategy to prevent cognitive decline. Show more

Keywords: Cognitive performance, oxidative stress, telomere, vitamin D

DOI: 10.3233/JAD-200926

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1509-1518, 2020

Authors: Chen, J.Q. Alida | Scheltens, Philip | Groot, Colin | Ossenkoppele, Rik

Article Type: Research Article

Abstract: Background: Epidemiologic studies have provided inconclusive evidence for a protective effect of caffeine consumption on risk of dementia and cognitive decline. Objective: To summarize literature on the association between caffeine and 1) the risk of dementia and/or cognitive decline, and 2) cognitive performance in individuals with mild cognitive impairment (MCI) or dementia, and 3) to examine the effect of study characteristics by categorizing studies based on caffeine source, quantity and other possible confounders. Methods: We performed a systematic review of caffeine effects by assessing overall study outcomes; positive, negative or no effect. Our literature search identified …61 eligible studies performed between 1990 and 2020. Results: For studies analyzing the association between caffeine and the risk of dementia and/or cognitive decline, 16/57 (28%) studies including a total of 40,707/153,070 (27%) subjects reported positive study outcomes, and 30/57 (53%) studies including 71,219/153,070 (47%) subjects showed positive results that were dependent on study characteristics. Caffeine effects were more often positive when consumed in moderate quantities (100–400 mg/d), consumed in coffee or green tea, and in women. Furthermore, four studies evaluated the relationship between caffeine consumption and cognitive function in cognitively impaired individuals and the majority (3/4 [75% ]) of studies including 272/289 subjects (94%) reported positive outcomes. Conclusion: This review suggests that caffeine consumption, especially moderate quantities consumed through coffee or green tea and in women, may reduce the risk of dementia and cognitive decline, and may ameliorate cognitive decline in cognitively impaired individuals. Show more

Keywords: Caffeine, coffee, cognition, dementia, review, tea

DOI: 10.3233/JAD-201069

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1519-1546, 2020

Authors: de la Fuente Garcia, Sofia | Ritchie, Craig W. | Luz, Saturnino

Article Type: Research Article

Abstract: Background: Language is a valuable source of clinical information in Alzheimer’s disease, as it declines concurrently with neurodegeneration. Consequently, speech and language data have been extensively studied in connection with its diagnosis. Objective: Firstly, to summarize the existing findings on the use of artificial intelligence, speech, and language processing to predict cognitive decline in the context of Alzheimer’s disease. Secondly, to detail current research procedures, highlight their limitations, and suggest strategies to address them. Methods: Systematic review of original research between 2000 and 2019, registered in PROSPERO (reference CRD42018116606). An interdisciplinary search covered six databases on …engineering (ACM and IEEE), psychology (PsycINFO), medicine (PubMed and Embase), and Web of Science. Bibliographies of relevant papers were screened until December 2019. Results: From 3,654 search results, 51 articles were selected against the eligibility criteria. Four tables summarize their findings: study details (aim, population, interventions, comparisons, methods, and outcomes), data details (size, type, modalities, annotation, balance, availability, and language of study), methodology (pre-processing, feature generation, machine learning, evaluation, and results), and clinical applicability (research implications, clinical potential, risk of bias, and strengths/limitations). Conclusion: Promising results are reported across nearly all 51 studies, but very few have been implemented in clinical research or practice. The main limitations of the field are poor standardization, limited comparability of results, and a degree of disconnect between study aims and clinical applications. Active attempts to close these gaps will support translation of future research into clinical practice. Show more

Keywords: Alzheimer’s disease, artificial intelligence, cognitive decline, computational linguistics, dementia, machine learning, screening, speech processing

DOI: 10.3233/JAD-200888

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1547-1574, 2020