Journal of Alzheimer's Disease - Volume 67, issue 2

Authors: Farlow, Martin R. | Thompson, Richard E. | Wei, Lee-Jen | Tuchman, Alan J. | Grenier, Elaine | Crockford, David | Wilke, Susanne | Benison, Jeffrey | Alkon, Daniel L.

Article Type: Research Article

Abstract: Background: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-β oligomers, and anti-hyperphosphorylated tau. Objectives: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer’s disease (AD) patients. Methods: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.v. bryostatin for 150 advanced AD patients (55–85) with MMSE-2 of 4–15, randomized 1:1:1 into 20 μg and 40 μg bryostatin, and placebo arms. The Full Analysis Set (FAS) and the Completer Analysis Set (CAS) were pre-specified alternative assessments (1-sided, p  < 0.1 for primary efficacy, and 2-sided, p  < 0.05 for pre-specified and post hoc exploratory …analyses). Results: The safety profile was similar for 20 μg treatment and placebo patients. The 40 μg patients showed safety and drop-out issues, but no efficacy. Primary improvement of Severe Impairment Battery (SIB) scores at 13 weeks was not significant (p  = 0.134) in the FAS, although in the CAS, the SIB comparison favored 20 μg bryostatin compared to placebo patients (p  < 0.07). Secondary analyses at weeks 5 and 15 (i.e., 30 days post-final dosing) also favored 20 μg bryostatin compared to placebo patients. A pre-specified ANCOVA for baseline memantine blocking bryostatin and positive post-hoc trend analyses were statistically significant (2-sided, p < 0.05). Conclusion: Although the primary endpoint was not significant in the FAS, primary and secondary analyses in the CAS, and pre-specified and post-hoc exploratory analyses did favor bryostatin 20 μg compared to the placebo cohort. These promising Phase II results support further trials of 20 μg bryostatin— without memantine— to treat AD. Show more

Keywords: Bryostatin, memantine, neurorestorative, PKC (Protein Kinase C), severe Alzheimer’s disease, severe impairment battery, synaptic growth factors, synaptogenesis

DOI: 10.3233/JAD-180759

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 555-570, 2019

Authors: Zhou, Yajun | Deng, Jiangshan | Chu, Xiuli | Zhao, Yuwu | Guo, Yong

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease prevalent in aged people, clinically characterized by progressive memory loss, behavioral and learning dysfunction, and cognitive deficits. The pathogenesis of AD is hallmarked by formation of amyloid-β peptide aggregates (Aβ) and intraneuronal neurofibrillary tangles (NFTs), which are induced by hyperphosphorylation of amyloid-β protein precursor and tau protein, respectively. The hyperphosphorylation is controlled by cyclin-dependent kinase-5 (CDK5), the aberrant activation of which is mediated by calpain (CAPN)-induced cleavage of p35 into p25. However, the regulation of CAPN in AD remains largely unknown. Here, we studied the post-transcriptional control of CAPN1 by microRNAs (miRNAs) in …the setting of AD. We found that miR-124-3p, previously reported as a miRNA that was downregulated in AD, was a CAPN1-targeting miRNA that functionally inhibited the protein translation of CAPN1 in a human neural cell line, HCN-2. In vitro , transfection with miR-124-3p reduced the levels of CAPN1 protein, the cleavage of p35 into p25, and cell apoptosis dose-dependently in HCN-2 cells. Moreover, a significant inverse correlation was detected between the levels of miR-124-3p and CAPN1 in AD specimens. Furthermore, intracranial injection of adeno-associated virus expressing miR-124-3p into APP/PS1-AD mice significantly reduced Aβ deposition and significantly improved the AD-mouse behavior in the social recognition test and plus-maze discriminative avoidance task. Together, our data suggest that post-transcriptional control of calpain by miR-124-3p plays an essential role in the development of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide aggregates, calpain 1, CDK5, miR-124-3p

DOI: 10.3233/JAD-181053

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 571-581, 2019

Authors: Chen, Xi | Maguire, Brook | Brodaty, Henry | O’Leary, Fiona

Article Type: Research Article

Abstract: While the role of diet and nutrition in cognitive health and prevention of dementia in older adults has attracted much attention, the efficacy of different dietary patterns remains uncertain. Previous reviews have mainly focused on the Mediterranean diet, but either omitted other dietary patterns, lacked more recent studies, were based on cross-sectional studies, or combined older and younger populations. We followed PRISMA guidelines, and examined the efficacy of current research from randomized controlled trials and cohort studies on the effects of different dietary patterns. We reviewed the Mediterranean diet, Dietary Approach to Stop Hypertension (DASH) diet, the Mediterranean-DASH diet Intervention …for Neurodegenerative Delay (MIND) diet, Anti-inflammatory diet, Healthy diet recommended by guidelines via dietary index, or Prudent healthy diet s generated via statistical approaches, and their impact on cognitive health among older adults. Of 37 studies, the Mediterranean diet was the most investigated with evidence supporting protection against cognitive decline among older adults. Evidence from other dietary patterns such as the MIND, DASH, Anti-inflammatory, and Prudent healthy diets was more limited but showed promising results, especially for those at risk of cardiovascular disease. Overall, this review found positive effects of dietary patterns including the Mediterranean, DASH, MIND, and Anti-inflammatory diets on cognitive health outcomes in older adults. These dietary patterns are plant-based, rich in poly- and mono-unsaturated fatty acids with lower consumption of processed foods. Better understanding of the underlying mechanisms and effectiveness is needed to develop comprehensive and practical dietary recommendations against age-related cognitive decline among older adult. Show more

Keywords: Alzheimer’s disease, anti-inflammatory, cognitive decline, DASH, dementia, dietary pattern, mild cognitive impairment, Mediterranean, MIND, nutrition

DOI: 10.3233/JAD-180468

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 583-619, 2019

Authors: Takahashi, Yukako | Saito, Satoshi | Yamamoto, Yumi | Uehara, Toshiyuki | Yokota, Chiaki | Sakai, Go | Nishida, Norifumi | Takahashi, Ryosuke | Kalaria, Raj N. | Toyoda, Kazunori | Nagatsuka, Kazuyuki | Ihara, Masafumi

Article Type: Research Article

Abstract: Background: Time and resource limitations prevent cognitive assessment in acute-to-subacute settings, even in comprehensive stroke centers. Objective: To assess cognitive function in acute stroke patients undergoing routine clinical, laboratory, and radiological investigations, with a view to improving post-stroke care and treatment. Methods: Sixty-nine patients (72.6±11.1 years; 65% male) were prospectively enrolled within 14 days of acute ischemic stroke. Patients with altered consciousness, aphasia, or dysarthria were excluded. Clinical features including modified Rankin and NIH stroke scales, and vascular risk factors were assessed, as well as neuroimaging parameters by semi-quantitative evaluation of medial temporal …lobe atrophy (MTLA) using MRA source images, FLAIR images for white matter changes (Fazekas scores), and T2∗ images for cerebral microbleeds. Neuropsychological screening was conducted using the Montreal Cognitive Assessment (MoCA) test. Univariate and multivariate analyses were used to evaluate the influence of variables on MoCA total and subscale scores. Results: Lower MoCA scores of 22 or less were associated with MTLA [OR (95% CI), 5.3 (1.0–27.5); p  = 0.045], education years [OR (95% CI), 0.71 (0.55–0.91); p  = 0.007], and modified Rankin scale at discharge [OR (95% CI), 2.4 (1.3–4.5); p  = 0.007]. The delayed recall MoCA score was correlated with MTLA (r  = – 0.452, p  < 0.001), periventricular (r  = – 0.273, p  = 0.024), and deep (r  = – 0.242, p  = 0.046), white matter changes. Conclusions: MTLA, together with lower educational history, are quick indicators of amnestic cognitive impairment after stroke. The association between cognitive impairment and physical disability at discharge may signify the importance of earlier cognitive assessment. Show more

Keywords: Comprehensive stroke center, dementia, medial temporal lobe atrophy, Montreal Cognitive Assessment, post-stroke dementia, stroke

DOI: 10.3233/JAD-180976

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 621-629, 2019

Authors: Levendowski, Daniel J. | Gamaldo, Charlene | St. Louis, Erik K. | Ferini-Strambi, Luigi | Hamilton, Joanne M. | Salat, David | Westbrook, Philip R. | Berka, Chris

Article Type: Research Article

Abstract: Background: The characterization of sleep in those with neurodegenerative disease (NDD) is essential in understanding the potential neurobiological mechanisms that underlie the connection between sleep disruption and NDD manifestations and progression. Objective: Explore the inter-relationships between NDD and age, sex, diagnosis of obstructive sleep apnea, snoring, and duration of sleep time with the head in the supine and non-supine positions. Methods: A case-control design was used to evaluate differences in sleep position obtained from multi-night, in-home Sleep Profiler recordings in 45 patients with diagnosed NDD (24 with mild cognitive impairment, 15 with Alzheimer’s …disease, and 6 with Lewy Body, Parkinson’s, or other dementias) and 120 age-sex matched controls with normal cognition (NC). Results: The frequency of supine sleep >2 h/night was significantly greater in the NDD than in the NC group (p  < 0.001, odds ratio = 3.7), and remained significant after controlling for age, sex, snoring, and obstructive sleep apnea diagnosis (p  = 0.01). There were no group differences in nocturnal mobility i.e., number of head position changes/h. Conclusion: This study demonstrates the utility of in-home measurements of sleep in defining the association of supine sleep position with neurodegenerative disorders. Our findings warrant further investigation, particularly in light of the recent evidence suggesting that sleep may an active role in the brain’s ability to clear CNS neurotoxins and metabolites. Show more

Keywords: Head position, neurodegeneration, obstructive sleep apnea, sleep, supine

DOI: 10.3233/JAD-180697

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 631-638, 2019

Authors: Khoonsari, Payam Emami | Shevchenko, Ganna | Herman, Stephanie | Remnestål, Julia | Giedraitis, Vilmantas | Brundin, RoseMarie | Degerman Gunnarsson, Malin | Kilander, Lena | Zetterberg, Henrik | Nilsson, Peter | Lannfelt, Lars | Ingelsson, Martin | Kultima, Kim

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ42 , total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD. Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects. Methods: We applied ELISA, mass spectrometry, and multivariate modeling to investigate …classical biomarkers and the CSF proteome in subjects (n  = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4–9 years and 21 of these converted to AD, whereas 53 remained stable. Results: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively. Conclusions: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, ELISA, mass spectrometry, mild cognitive impairment, proteomics

DOI: 10.3233/JAD-180855

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 639-651, 2019

Authors: Özbe, Dominik | Graessel, Elmar | Donath, Carolin | Pendergrass, Anna

Article Type: Research Article

Abstract: Background: There is no curative medical treatment for dementia. Therefore, researchers turned their attention to non-pharmacological treatment approaches. Many reviews analyzed the efficacy of single-component interventions, but there has been no systematic review of multicomponent interventions so far. Objective: The aim was to systematically review studies using standardized multicomponent group interventions for persons with dementia or persons with mild cognitive impairment (MCI) and to analyze their immediate intervention effects. Methods: The databases PubMed, PsycINFO, PSYNDEX, and CINAHL were systematically searched. We included randomized controlled trials with people with MCI or dementia, which implemented interventions with at …least two components that targeted different outcome domains. Additionally, the intervention had to be standardized and in a group setting. Results: Nine studies met the inclusion criteria with a total sample size of N = 513 participants. Six studies applied two, two studies applied three, and one study applied four components. Four studies, which combined at least a physical and a cognitive component, had a positive effect on non-cognitive symptoms of dementia. Two of these interventions additionally had a positive effect on cognitive abilities. One study reported a positive effect on activities of daily living and another study showed an effect on quality of life. Conclusion: In spite of the heterogeneity of the studies, multicomponent interventions suggest a positive effect on non-cognitive symptoms, especially the combination of cognitive and physical components. Single studies had also an effect on additional outcome domains. By trend the effects are dependent on application rate and used assessments. Show more

Keywords: Behavioral symptoms, cognitive dysfunction, dementia, multicomponent intervention, review

DOI: 10.3233/JAD-180980

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 653-670, 2019

Authors: Alfini, Alfonso J. | Weiss, Lauren R. | Nielson, Kristy A. | Verber, Matthew D. | Smith, J. Carson

Article Type: Research Article

Abstract: Background: Exercise training has been associated with greater cerebral blood flow (CBF) in cognitively normal older adults (CN). Alterations in CBF, including compensatory perfusion in the prefrontal cortex, may facilitate changes to the brain’s neural infrastructure. Objective: To examine the effects of a 12-week aerobic exercise intervention on resting CBF and cognition in CN and those with mild cognitive impairment (MCI). We hypothesized individuals with MCI (versus CN) would exhibit greater whole brain CBF at baseline and that exercise would mitigate these differences. We also expected CBF changes to parallel cognitive improvements. Methods: Before and after …a 12-week exercise intervention, 18 CN and 17 MCI participants (aged 61–88) underwent aerobic fitness testing, neuropsychological assessment, and an MRI scan. Perfusion-weighted images were collected using a GE 3T MR system. Repeated measures analyses of covariance were used to test within- and between-group differences over time, followed by post-hoc analyses to examine links between CBF changes and cognitive improvement. Results: At baseline, individuals with MCI (versus CN) exhibited significantly elevated perfusion in the left insula. Twelve weeks of aerobic exercise reversed this discrepancy. Additionally, exercise improved working memory (measured by the Rey Auditory Verbal Learning Test) and verbal fluency (measured by the Controlled Oral Word Association Test) and differentially altered CBF depending on cognitive status. Among those with MCI, decreased CBF in the left insula and anterior cingulate cortex was associated with improved verbal fluency. Conclusions: Exercise training alters CBF and improves cognitive performance in older adults with and without cognitive impairment. Future studies must evaluate the mediating effects of CBF on the association between exercise training and cognition. Show more

Keywords: Aging, cerebral blood flow, exercise, magnetic resonance imaging, mild cognitive impairment, neuroimaging

DOI: 10.3233/JAD-180728

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 671-684, 2019

Authors: Reisberg, Barry | Torossian, Carol | Shulman, Melanie B. | Monteiro, Isabel | Boksay, Istvan | Golomb, James | Guillo Benarous, Francoise | Ulysse, Anaztasia | Oo, Thet | Vedvyas, Alok | Rao, Julia A. | Marsh, Karyn | Kluger, Alan | Sangha, Jaspreet | Hassan, Mudasar | Alshalabi, Munther | Arain, Fauzia | Shaikh, Naveed | Buj, Maja | Kenowsky, Sunnie | Masurkar, Arjun V. | Rabin, Laura | Noroozian, Maryam | Sánchez-Saudinós, Mar&a Belén | Blesa, Rafael | Auer, Stefanie | Zhang, Yian | de Leon, Mony | Sadowski, Martin | Wisniewski, Thomas | Gauthier, Serge | Shao, Yongzhao

Article Type: Research Article

Abstract: Background: Little is known with respect to behavioral markers of subjective cognitive decline (SCD), a condition initially described in association with Global Deterioration Scale (GDS) stage 2. Objective: Two-year interval behavioral markers were investigated herein. Methods: Subjects from a published 7-year outcome study of GDS stage 2 subjects were selected. This study had demonstrated a hazard ratio of 4.5 for progression of GDS stage 2, in comparison with GDS stage 1 (no subjective or objective cognitive decline) subjects, after controlling for demographic and temporal variables. Because GDS 2 subjects have previously demonstrated impairment in comparison with …healthy persons free of complaints, we herein suggest the terminology “SCD(I)” for these persons. 98 SCD(I) persons, 63 women and 35 men, mean baseline age, 67.12±8.75 years, with a mean educational background of 15.55±2.60 years, and mean baseline MMSE scores of 28.9±1.24 were followed for 2.13±0.30 years. Results: Observed annual decline on the GDS was 6.701% per annum, very close to a 1986 published estimate. At follow up, the MMSE, and 7 of 8 psychometric tests did not decline significantly. Of 21 Hamilton Depression Scale items, 2 improved and the remainder were unchanged. Anxieties declined from multiple perspectives. The Brief Cognitive Rating Scale (BCRS) declined significantly (p  < 0.001), with component declines in Remote memory (p  < 0.01), and Functioning/self-care (p  = 0.01). Conclusion: SCD(I) persons decline at an annual rate of approximately 6.7% /year from several recent studies. The BCRS assessments and the Digit Symbol Substitution Test can be sensitive measures for future studies of progression mitigation. Show more

Keywords: Aging, behavioral disturbances, cognition, cognitive decline, cognitive impairments, longitudinal studies,, memory, prognosis, psychometric testing, remote memory

DOI: 10.3233/JAD-180341

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 685-705, 2019

Authors: Huisa, Branko N. | Thomas, Ronald G. | Jin, Shelia | Oltersdorf, Tilman | Taylor, Curtis | Feldman, Howard H.

Article Type: Research Article

Abstract: Background: Acetylcholinesterase inhibitors (AChEIs) and memantine are commonly prescribed medications for Alzheimer’s disease (AD). Their concurrent use in AD randomized clinical trials (RCTs) is generally allowed but their effect in outcome measures is unsettled. Objective: To evaluate whether use of AChEIs and/or memantine across AD RCTs are associated with different rates of cognitive/functional decline. Methods: We pooled data from 5 RCTs of mild to moderate AD conducted by the Alzheimer’s Disease Cooperative Study (ADCS) between 2002-2013. 1,423 participants with MMSE of 14–26 and completion of 12–18 months follow-up visits were analyzed. Trials did …not randomize with respect to AChEIs or memantine. We defined 4 groups: AChEI (27%), memantine (16%), AChEIs+memantine (46%), and non-users (11%). Outcome measures were change in ADAS-cog-11, ADCS-ADL, and MMSE from baseline to 18 months. Fisher’s exact test, Wilcoxon signed rank, and Spearman’s tests were used to identify confounding variables. Mixed model repeated measures were used for adjustments and pairwise tests for comparing change in scores. Results: Age, apolipoprotein E, and initial MMSE were identified as covariates. Memantine and/or AChEIs users had greater impairment at entry than non-users. There was a significant decline on the ADAS-cog-11 in the memantine (estimate –4.2 p  < 0.0001) and AChEIs+memantine groups (estimate –3.5 p  < 0.0001) than non-users, while there was significantly more decline in MMSE (estimate 2.5 p  < 0.0001) and ADCS-ADL in the AChEIs+memantine group (estimate 4.3 p  < 0.0001) Conclusion: Memantine monotherapy or combined with AChEIs are associated with more rapid cognitive and functional decline than non-users. We postulated a potential selection bias by indication. Show more

Keywords: Acetylcholinesterase inhibitors, Alzheimer’s disease, memantine, randomized clinical trials

DOI: 10.3233/JAD-180684

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 707-713, 2019