Journal of Alzheimer's Disease - Volume 75, issue 3

Authors: Wang, Chenchen | Huang, Xi | Tian, Sai | Huang, Rong | Guo, Dan | Lin, Hongyan | Wang, Jiaqi | Wang, Shaohua

Article Type: Research Article

Abstract: Background: Metabolic disorders, including insulin resistance, obesity, and hyperlipidemia occur frequently prior to hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and cause mild cognitive impairment (MCI). Objective: We investigated the involvement of resistin in these metabolic abnormalities contributes to MCI in patients with T2DM. Methods: A total of 138 hospitalized patients with T2DM were enrolled and categorized into MCI and non-MCI groups according to the Montreal Cognitive Assessment (MoCA) score. Metabolic indicators and cognitive state were assessed, and plasma resistin levels were determined by ELISA. Results: The resistin levels and homeostasis model …assessment of insulin resistance (HOMA-IR) scores of MCI and gender-stratified subgroups were significantly higher than those of controls without MCI (all p  < 0.01). Correlation analysis showed that the resistin level was negatively associated with majority of cognitive domains, e.g., MoCA (r  = –0.693, p  < 0.001) and Mini-Mental State Examination (r  = –0.571, p  < 0.001), and was related to HOMA-IR (r  = 0.667, p  < 0.001) but not to obesity and lipid indices. Multivariable regression analysis indicated that resistin (β = –0.675, p  < 0.001) and educational level (β = 0.177, p  = 0.003) were independent risk factors of MoCA in patients with T2DM. Conclusions: High plasma resistin levels portend the insulin resistance-related susceptibility to early cognitive decline in Chinese patients with T2DM. The involvement of this adipokine in other metabolic disorders leading to diabetic MCI and its clinical value for early disease screening must be further studied. Show more

Keywords: Alzheimer’s disease, insulin resistance, mild cognitive impairment, resistin, type 2 diabetes

DOI: 10.3233/JAD-200074

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 807-815, 2020

Authors: Sultana, Munira | Bryant, Dianne | Orange, J.B. | Beedie, Taylor | Montero-Odasso, Manuel

Article Type: Research Article

Abstract: Background: Exercise is beneficial to maintain balance. Wii Fit©, a video game-based exercise, offers an enjoyable way to exercise and is feasible for older adults with neurocognitive disorders (NCD). Objective: To evaluate the effects of Wii Fit© exercise training on the balance of older adults with NCD. Methods: Systematic review and meta-analysis of randomized control trials using Cochrane collaboration tools. The participants were older adults (60 years and over) with NCD. Balance was measured with Berg Balance Scale (BBS) and Timed Up and Go (TUG). Two reviewers independently searched, selected, extracted data, assessed risk of biases, …and determined the quality of evidence. Outcomes were evaluated using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). A meta-analysis was performed. Results: The literature search identified 522 source documents of which titles and abstracts were reviewed for 428 after removing 94 duplicates. The reviewers selected five studies out of 50 after a full text review. The overall effect of Wii Fit© exercise training on BBS was moderate, significant, and clinically meaningful (standardized mean difference [SMD] = 0.5 standard deviation [SD] [95% confidence interval CI] 0.08, 0.84]). No effect was observed with TUG scores (SMD = 0.00 SD [95% CI –0.44, 0.44]). The GRADE quality of evidence was very low. Conclusion: Wii Fit© exercise training has a positive effect on balance in older adults with NCD. However, further research with sufficient power is needed to evaluate its effectiveness. Show more

Keywords: Aged, neurocognitive disorders, postural balance, video games

DOI: 10.3233/JAD-191301

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 817-826, 2020

Authors: Kaur, Gurjeet | Poljak, Anne | Braidy, Nady | Crawford, John D. | Lo, Jessica | Sachdev, Perminder S.

Article Type: Research Article

Abstract: Background: Numerous studies have reported on cerebrospinal fluid (CSF) and blood biomarkers of Alzheimer’s disease (AD); however, to date, none has compared biomarker patterns across the early-onset subtypes, i.e., early onset sporadic AD (EOsAD) and autosomal dominant AD (ADAD), qualitatively and quantitatively. Objective: To compare the fluid biomarker patterns in early-onset subtypes of AD; EOsAD and ADAD. Methods: Six scientific databases were searched for peer-reviewed research publications. The total number of individuals used in all the meta-analysis were 2,427, comprised of 1,337 patients and 1,090 controls. Results: In the subset of EOsAD cases without …APP , PSEN1 /PSEN2 mutations, CSF Aβ42 and tau levels were higher when compared to the EOsAD group as a whole. Prevalence of the APOE ɛ 4 allele was more elevated in EOsAD relative to controls, and not significantly elevated in ADAD cases. Conclusion: Established CSF biomarkers confirmed quantitative differences between variants of EOAD. EOsAD is enriched with APOE ɛ 4, but the level is not higher than generally reported in late-onset AD. The results prompt further exploration of the etiopathogenesis of EOsAD, which accounts for ∼4–10% of all AD cases, but the reasons for the early onset remain poorly understood. Show more

Keywords: Amyloid-β42 , APOE ɛ4, APP/PSEN, early onset Alzheimer’s disease, neurodegeneration biomarkers, tau

DOI: 10.3233/JAD-200052

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 827-843, 2020

Authors: Devanand, D. P. | Liu, Xinhua | Chunga, Richard E. | Cohen, Hannah | Andrews, Howard | Schofield, Peter W. | Stern, Yaakov | Huey, Edward D. | Choi, Jongwoo | Pelton, Gregory H.

Article Type: Research Article

Abstract: Background: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer’s disease (AD) pathology, and short-term change in odor identification impairment with cholinesterase inhibitor (CheI) treatment may predict longer term cognitive outcomes. Objective: In patients with mild cognitive impairment (MCI) treated prospectively with donepezil, a CheI, for 52 weeks, to determine if 1) acute decline in odor identification ability with anticholinergic challenge can predict cognitive improvement, and 2) change in odor identification over 8 weeks can predict cognitive improvement. Methods: MCI was diagnosed clinically without AD biomarkers. At baseline, the University of Pennsylvania Smell identification Test …(UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and this dose was maintained for 52 weeks. Main outcomes were ADAS-Cog total score and Selective Reminding Test (SRT) total immediate recall score measured at baseline, 26 and 52 weeks. Results: In 100 study participants, mean age 70.14 (SD 9.35) years, atropine-induced decrease in UPSIT score at baseline was not associated with change in ADAS-Cog or SRT scores over 52 weeks. Change in UPSIT score from 0 to 8 weeks did not show a significant association with change in the ADAS-Cog or SRT measures over 52 weeks. Conclusion: These negative findings in a relatively large sample of patients with MCI did not replicate results in much smaller samples. Change in odor identification with anticholinergic challenge, and over 8 weeks, may not be useful predictors of cognitive improvement with CheI in patients with MCI. Show more

Keywords: Acetylcholine, Alzheimer’s disease, atropine, mild cognitive impairment, olfaction

DOI: 10.3233/JAD-200021

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 845-854, 2020

Authors: Marmarelis, Vasilis Z. | Shin, Dae C. | Zhang, Rong

Article Type: Research Article

Abstract: Background: Significant reduction of dynamic vasomotor reactivity (DVR) was recently reported in patients with amnestic mild cognitive impairment (MCI) relative to age-matched controls. These results were obtained via a novel approach that utilizes data-based predictive dynamic models to quantify DVR. Objective: Using the same methodological approach, we seek to quantify the dynamic effects of the CO2-driven chemoreflex and baroreflex upon heart-rate in order to examine their possible correlation with the observed DVR impairment in each MCI patient. Methods: The employed approach utilizes time-series data to obtain subject-specific predictive input-output models of the dynamic effects of changes …in arterial blood pressure and end-tidal CO2 (putative “inputs”) upon cerebral blood flow velocity in large cerebral arteries, cortical tissue oxygenation, and heart-rate (putative “outputs”). Results: There was significant dysregulation of CO2-driven heart-rate chemoreflex (p  = 0.0031), but not of baroreflex (p  = 0.5061), in MCI patients relative to age-matched controls. The model-based index of CO2-driven heart-rate chemoreflex gain (CRG) correlated significantly with the DVR index in large cerebral arteries (p  = 0.0146), but not with the DVR index in small/micro-cortical vessels (p  = 0.1066). This suggests that DVR impairment in small/micro-cortical vessels is not mainly due to CO2-driven heart-rate chemoreflex dysregulation, but to other factors (possibly dysfunction of neurovascular coupling). Conclusion: Improved delineation between MCI patients and controls is achieved by combining the DVR index for small/micro-cortical vessels with the CRG index (p  = 2×10–5 ). There is significant correlation (p  < 0.01) between neuropsychological test scores and model-based DVR indices. Combining neuropsychological scores with DVR indices reduces the composite diagnostic index p -value (p ∼10–10 ). Show more

Keywords: cerebral blood flow regulation, cerebrovascular regulation, dynamic vasomotor reactivity, heart-rate chemoreflex modeling, mild cognitive impairment.

DOI: 10.3233/JAD-191238

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 855-870, 2020

Authors: Rodrigo-Herrero, Silvia | Sánchez-Benavides, Gonzalo | Ainz-Gómez, Leire | Luque-Tirado, Andrea | Graciani-Cantisán, Eugenia | Sánchez-Arjona, María Bernal | Maillet, Didier | Jiménez-Hernández, María Dolores | Franco-Macías, Emilio

Article Type: Research Article

Abstract: Background: TMA-93 examines binding by images, a potential advantage for less-educated individuals. Objective: To obtain norms from older Spanish adults for TMA-93. Methods: A cross-sectional normative study was undertaken in a general neurology outpatient clinic of a university hospital in the Southern Spanish region of Andalusia. Partners of patients who attended the clinic were systematically recruited when eligible: aged 50 and over, no memory complaints, and a total score equal or above percentile 10 on Phototest. Age, gender, and educational attainment were considered as sociodemographic variables. TMA-93 was administered and the total score was registered. …Results: The final sample contained 1,131 participants (mean age = 65.7, SD = 9.2), including 305 individuals (27%) who did not completed primary studies. The total score on TMA-93 showed a non-normal, left asymmetric, and leptokurtic distribution (median = 29, interquartile range = 27–30, range = 16–30) mitigated by lower education and older age. Stratified analysis by age and education showed wide variations of the scores for the 5-percentile. Conclusion: TMA-93 runs with a ceiling effect in non-cognitively impaired older Spanish adults. The score for the 5-percentile depends on age and education. The test is feasible for low-educated individuals. Show more

Keywords: Associative memory, cognitive assessment, cross-cultural neuropsychology, memory test

DOI: 10.3233/JAD-191235

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 871-878, 2020

Authors: Espenes, Ragna | Kirsebom, Bjørn-Eivind | Eriksson, Cecilia | Waterloo, Knut | Hessen, Erik | Johnsen, Stein Harald | Selnes, Per | Fladby, Tormod

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is associated with an increased risk of Alzheimer’s disease (AD). However, patients reporting SCD to their general practitioner are not always referred to a memory clinic. Objective: To investigate whether prior history of medical help-seeking is associated with AD biomarker abnormality, worse cognitive performance, and/or depressive symptoms in SCD. Methods: We compared levels of cerebrospinal fluid (CSF) Aβ 1 - 42 , cognitive performance, and depressive symptoms (15-item Geriatric Depression Scale, GDS-15) between healthy controls (n  = 88), SCD with a history of medical help seeking (SCD-HS, n  = 67), and SCD non help-seekers (SCD-NHS, …n  = 44). Cases with evidence of amyloid plaques (CSF Aβ 1 - 42 ≤708 ng/l) and symptoms of depression (GDS-15≥6) were determined in both SCD groups. Results: The SCD-HS group had lower CSF Aβ 1 - 42 (p  < 0.01), lower word list learning and memory recall (p  < 0.0001), and an increased level of depressive symptoms (p  < 0.0001) compared to controls and SCD-NHS cases. The SCD-HS group had more cases with symptoms of depression (n  = 12, 18%) and amyloid plaques (n  = 18, 27%) compared to SCD-NHS (n  = 1, 2% and n  = 7, 16%, respectively). None of the SCD-HS cases and only one SCD-NHS case had concurrent symptoms of depression and amyloid plaques. The SCD-HS cases showed equal word list learning and memory performance regardless of amyloid status or symptoms of depression. Conclusion: Medical help-seeking in SCD is associated with an increased risk of AD pathology or symptoms of depression. However, subtle memory deficits are seen in SCD help-seekers, also without amyloid plaques or symptoms of depression. Show more

Keywords: Alzheimer’s disease, amyloid plaques, cerebrospinal fluid Aβ1 - 42 , cognitive symptoms, early diagnosis, help-seeking behavior, medical help-seeking, neuropsychiatric symptoms, neuropsychological tests, subjective cognitive decline

DOI: 10.3233/JAD-190712

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 879-890, 2020

Authors: Wimo, Anders | Handels, Ron | Winblad, Bengt | Black, Christopher M. | Johansson, Gunilla | Salomonsson, Stina | Eriksdotter, Maria | Khandker, Rezaul K.

Article Type: Research Article

Abstract: Background: A long-term horizon is necessary when the socioeconomic consequences and the potential effects of interventions in Alzheimer’s disease (AD) are estimated. Objectives: To illustrate the potential societal costs of AD across the disease continuum and to illustrate the potential cost-effectiveness of a hypothetical intervention with disease modifying treatment (DMT). Methods: Based on the Swedish dementia registry, a Markov model was used to simulate a virtual cohort of 100,000 people with mild cognitive impairment (MCI) due to AD (AD-MCI) in Sweden for 40 years starting at the age of 60. A simulated hypothetical intervention assumed a …25% reduction in progression rate during AD-MCI and mild AD-dementia. A comprehensive set of sensitivity analyses was included. Results: The cumulative risk to develop dementia was 96%. The mean simulated survival was 19.0 years. The net present value for a person year with dementia was 252,843 SEK (about 29,500 US$). The cost effectiveness model illustrated how the hypothetical scenario of a 25% reduction in progression to AD-dementia would require 41 AD-MCI patients to be treated to prevent one case of AD-dementia (2,447 avoided AD-dementia cases of 100,000 with AD-MCI). Most scenarios illustrated hypothetical cost effectiveness (based on a willingness to pay level of 600,000 SEK (70,000 US$) per gained QALY), but not cost savings. Discussion: Lifetime societal costs of AD are substantial. A future DMT may be potentially cost-effective given assumed treatment effects and costs, but cost savings are unlikely. Show more

Keywords: Alzheimer’s disease, cost analysis, cost effectiveness, costs, dementia, disease-modifying treatment, economics

DOI: 10.3233/JAD-191055

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 891-902, 2020

Authors: Wroolie, Tonita | Roat-Shumway, Siena | Watson, Katie | Reiman, Eric | Rasgon, Natalie

Article Type: Research Article

Abstract: Background: The apolipoprotein epsilon 4 (APOE4 ) allele is a well-established genetic risk factor for Alzheimer’s disease (AD). However, there are mixed findings as to how the APOE4 allele modifies the effects of both higher low-density lipoprotein cholesterol (LDL) and statin use on cognitive functioning. Objective: This study sought to examine the effects of LDL levels and statin use on verbal learning and memory, as modified by the presence of the APOE4 allele, in a sample of cognitively unimpaired, older adults at risk for AD. Methods: Neuropsychological, LDL, statin use, and APOE4 data …were extracted from an ongoing longitudinal study at the Banner Alzheimer’s Institute in Arizona. Participants were cognitively unimpaired based on Mini-Mental State Examination scores within a normal range, aged 47–75, with a family history of probable AD in at least one first-degree relative. Results: In the whole sample, higher LDL was associated with worse immediate verbal memory in APOE4 non-carriers, but did not have an effect on immediate verbal memory in APOE4 carriers. In APOE4 non-carriers, statin use was associated with better verbal learning, but did not have an effect on verbal learning in APOE4 carriers. Among women, higher LDL in APOE4 carriers was associated with worse verbal learning than in APOE4 non-carriers, and statin use in APOE4 non-carriers was associated with better verbal learning and immediate and delayed verbal memory but worse performances on these tasks in APOE4 carriers. Conclusion: LDL and statin use may have differential effects on verbal learning and/or memory depending on genetic risk for AD. Women appear to be particularly vulnerable to statin use depending on their APOE4 status. Show more

Keywords: APOE4 , at risk for alzheimer’s disease, immediate and delayed verbal memory, LDL cholesterol, statins, verbal learning

DOI: 10.3233/JAD-191090

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 903-910, 2020

Authors: Sahin, Levent | Figueiro, Mariana G.

Article Type: Research Article

Abstract: Background: Coherent 40 Hz (gamma) neural oscillation indicates healthy brain activity and is known to be disrupted in Alzheimer’s disease (AD) patients. 40 Hz entrainment by flickering light is known to significantly attenuate AD pathology in mice. Objective: To demonstrate the feasibility of using a lighting intervention to promote coherent 40 Hz neural oscillation, improved working memory performance, and reduced subjective sleepiness among a population of healthy young adults. If successful, the intervention could be extended to address cognitive impairment associated with mild cognitive impairment and AD. Methods: Nine healthy participants (median age 22 years, five females) were exposed …to one of two lighting conditions per session in a within-subjects counterbalanced manner. The study’s two sessions were separated by 1 week. Custom-built light masks provided either a 40 Hz flickering red light (FRL) intervention or a dark control condition (i.e., total darkness, light mask not energized) at participants’ eyes. Data were collected four times per session: pre-exposure, after 25-min exposure, after 50-min exposure, and post-exposure. Each data collection period included a Karolinska Sleepiness Scale report, an electroencephalogram, and working memory (n -back) auditory performance testing. Results: The FRL intervention induced a significant increase in 40 Hz power and a modest increase in low gamma power. The intervention had no significant impact on working memory performance and subjective sleepiness compared to the control. However, increases in 40 Hz power were significantly correlated with reduced subjective sleepiness. Conclusion: The results clearly demonstrate the feasibility of using a flickering light to increase 40 Hz power. Show more

Keywords: 40 Hz neural oscillation, Alzheimer’s disease, electroencephalography, flickering red light, subjective sleepiness, working memory performance testing

DOI: 10.3233/JAD-200179

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 911-921, 2020