Journal of Alzheimer's Disease - Volume 56, issue 4

Authors: Lu, Yujiao | Dong, Yan | Tucker, Donovan | Wang, Ruimin | Ahmed, Mohammad Ejaz | Brann, Darrell | Zhang, Quanguang

Article Type: Research Article

Abstract: Recent work has suggested that exercise may be beneficial in preventing or ameliorating symptoms of several neurological disorders, although the mechanism is not entirely understood. The current study was designed to examine the potential beneficial effect of treadmill exercise upon cognitive function in a streptozotocin (STZ)-induced rat model of Alzheimer’s disease (AD). Animals underwent treadmill exercise (30 min/day, 5 days/week) for 4 weeks after bilateral STZ intracerebroventricular injection (2.4 mg/kg). We demonstrated that treadmill exercise significantly attenuated STZ-induced neurodegeneration in the rat hippocampal CA1 region and strongly preserved hippocampal-dependent cognitive functioning. Further mechanistic investigation displayed a marked suppression of STZ-induced amyloid-β accumulation …and tau phosphorylation. Intriguingly, treadmill exercise remarkably inhibited reactive gliosis following STZ insult and effectively shifted activated microglia from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype, which was correlated with a significantly reduced expression of pro-inflammatory mediators and a corresponding enhancement of anti-inflammatory cytokine expression in the hippocampus. Furthermore, treadmill exercise caused a robust suppression of oxidative damage as evidenced by significantly reduced peroxynitrite production, lipid peroxidation, and oxidized DNA damage. Finally, treadmill exercise strongly attenuated STZ-induced mitochondrial dysfunction manifested by a dramatically elevated intra-mitochondrial cytochrome c oxidase activity and ATP synthesis, and markedly inhibited neuronal apoptosis in the hippocampus. These findings demonstrate that treadmill exercise has a multifactorial effect to attenuate many of the pathological processes that play a key role in AD, and provide further support for the beneficial role of exercise as a potential therapeutic option in AD treatment. Show more

Keywords: Alzheimer’s disease, cognition, exercise, inflammation, microglia, oxidative stress, streptozotocin

DOI: 10.3233/JAD-160869

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1469-1484, 2017

Authors: Yu, Lei | Wilson, Robert S. | Schneider, Julie A. | Bennett, David A. | Boyle, Patricia A.

Article Type: Research Article

Abstract: Background: Domain specific literacy is a multidimensional construct that requires multiple resources including cognitive and non-cognitive factors. Objective: We test the hypothesis that domain specific literacy is associated with Alzheimer’s disease (AD) dementia and AD pathology after controlling for cognition. Methods: Participants were community-based older persons who completed a baseline literacy assessment, underwent annual clinical evaluations for up to 8 years, and agreed to organ donation after death. Financial and health literacy was measured using 32 questions and cognition was measured using 19 tests. Annual diagnosis of AD dementia followed standard criteria. AD pathology was …examined postmortem by quantifying plaques and tangles. Cox models examined the association of literacy with incident AD dementia. Performance of model prediction for incident AD dementia was assessed using indices for integrated discrimination improvement and continuous net reclassification improvement. Linear regression models examined the independent association of literacy with AD pathology in autopsied participants. Results: All 805 participants were free of dementia at baseline and 102 (12.7%) developed AD dementia during the follow-up. Lower literacy was associated with higher risk for incident AD dementia (p  < 0.001), and the association persisted after controlling for cognition (hazard ratio = 1.50, p  = 0.004). The model including the literacy measure had better predictive performance than the one with demographics and cognition only. Lower literacy also was associated with higher burden of AD pathology after controlling for cognition (β= 0.07, p  = 0.035). Conclusion: Literacy predicts incident AD dementia and AD pathology in community-dwelling older persons, and the association is independent of traditional measures of cognition. Show more

Keywords: Alzheimer’s disease, cognition, dementia, domain specific literacy, pathology

DOI: 10.3233/JAD-161132

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1485-1493, 2017

Authors: Jia, Jianping | Wei, Cuibai | Jia, Longfei | Tang, Yi | Liang, Junhua | Zhou, Aihong | Li, Fangyu | Shi, Lu | Doody, Rachelle S.

Article Type: Research Article

Abstract: Background : Donepezil has been used worldwide for the treatment of severe Alzheimer’s disease (AD). Whether it is also appropriate for severe AD in Chinese patients remains unknown. Objective: To determine whether donepezil is effective and tolerable for Chinese patients with severe AD. Methods : The present study was a 24-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group study conducted at 38 investigational hospitals in China. Patients with severe AD were enrolled in this trial. Patients were randomly assigned in a 1:1 ratio to receive either donepezil or placebo (5 mg for 6 weeks and10 mg for the remaining 18 weeks). …The efficacy for donepezil were evaluated by the SIB, the Clinician’s Interview-Based Impression of Change-Plus caregiver input (CIBIC-plus) and the MMSE. Safety parameters were monitored throughout. Results : A total of 313 patients included the donepezil (n  = 157) and the placebo groups (n  = 156). Donepezil group improved more in SIB scores (least squares [LS] mean difference: 4.8, 95% CI 1.56 to 8.08, p  = 0.004) and CIBIC-plus scores (drug-placebo difference: –0.4, 95% CI –0.66 to 0.03, p  = 0.04) than placebo groups at Week 24. The MMSE scores between drug and placebo groups did not differ significantly. Twenty-nine patients with serious adverse events (SAEs) were reported in donepezil (n  = 11) and placebo groups (n  = 18) (p  = 0.08). Most SAEs were not considered drug-related. Conclusion : Donepezil for 24 weeks was more effective than placebo and showed good safety and tolerability in Chinese patients with severe AD. This study supports utility of the drug in severe stages of AD in the Chinese population. Show more

Keywords: Alzheimer’s disease, Chinese population, clinical trial, donepezil

DOI: 10.3233/JAD-161117

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1495-1504, 2017

Authors: Gelfo, Francesca | Cutuli, Debora | Nobili, Annalisa | De Bartolo, Paola | D’Amelio, Marcello | Petrosini, Laura | Caltagirone, Carlo

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is an age-related neurodegenerative disorder with multifactorial etiopathogenesis, characterized by progressive loss of memory and other cognitive functions. A fundamental neuropathological feature of AD is the early and severe brain cholinergic neurodegeneration. Lithium is a monovalent cation classically utilized in the treatment of mood disorders, but recent evidence also advances a beneficial potentiality of this compound in neurodegeneration. Interestingly, lithium acts on several processes whose alterations characterize the brain cholinergic impairment at short and long term. On this basis, the aim of the present research was to evaluate the potential beneficial effects of a chronic lithium treatment …in preventing the damage that a basal forebrain cholinergic neurodegeneration provokes, by investigating memory functions and neurodegeneration correlates. Adult male rats were lesioned by bilateral injections of the immunotoxin 192 IgG-Saporin into the basal forebrain. Starting 7 days before the surgery, the animals were exposed to a 30-day lithium treatment, consisting of a 0.24% Li2 CO3 diet. Memory functions were investigated by the open field test with objects, the sociability and preference for social novelty test, and the Morris water maze. Hippocampal and neocortical choline acetyltransferase (ChAT) levels and caspase-3 activity were determined. Cholinergic depletion significantly impaired spatial and social recognition memory, decreased hippocampal and neocortical ChAT levels and increased caspase-3 activity. The chronic lithium treatment significantly rescued memory performances but did not modulate ChAT availability and caspase-3 activity. The present findings support the lithium protective effects against the cognitive impairment that characterizes the brain cholinergic depletion. Show more

Keywords: 192 IgG-Saporin, basal forebrain, cholinergic depletion, lithium, memory deficits, neuroprotection

DOI: 10.3233/JAD-160892

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1505-1518, 2017

Authors: Jacob, Louis | Bohlken, Jens | Kostev, Karel

Article Type: Research Article

Abstract: Background: Dementia is a chronic disease associated with numerous cardiovascular disorders. Objective: To analyze the prevalence of cardiovascular drug use in dementia patients treated in general practices in Germany. Methods: The present study included patients who were diagnosed with dementia (Alzheimer’s disease, vascular dementia, or unspecified dementia) in 2015. The main outcome measure was the proportion of patients using cardiovascular drugs. Demographical and clinical variables included age, sex, dementia type, and cardiovascular co-diagnoses. A multivariate logistic regression model was used to analyze the association between cardiovascular drug use and these variables. Results: We …identified 7,987 and 1,268 dementia patients with and without prescriptions for cardiovascular drugs, respectively. The share of individuals who received cardiovascular treatments was 86.3%. Diuretics (20.9%), beta blocking agents (20.0%), and ACE inhibitors (17.4%) were the three most commonly prescribed types of medications. Patients between the ages of 71–80 (OR = 1.59), 81–90 (OR = 1.61), and over 90 years (OR = 1.48) were more likely to receive cardiovascular drugs than patients under the age of 70 years. Moreover, compared to those with unspecified dementia, individuals with Alzheimer’s disease had a lower chance while those with vascular dementia had a higher chance of being prescribed these drugs (ORs equal to 0.81 and 1.22, respectively). Finally, we found a positive association between the use of cardiovascular drugs and all co-diagnoses (ORs ranging from 1.23 to 7.12). Conclusion: The prevalence of cardiovascular drug use in dementia patients was around 86%. This use was significantly associated with such factors as age, type of dementia, and co-diagnoses. Show more

Keywords: Cardiovascular diseases, cardiovascular drugs, dementia, Germany, risk factors

DOI: 10.3233/JAD-161234

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1519-1524, 2017

Authors: Wang, Qian | Li, Wen-Xing | Dai, Shao-Xing | Guo, Yi-Cheng | Han, Fei-Fei | Zheng, Jun-Juan | Li, Gong-Hua | Huang, Jing-Fei

Article Type: Research Article

Abstract: Many lines of evidence suggest that Parkinson’s disease (PD) and Alzheimer’s disease (AD) have common characteristics, such as mitochondrial dysfunction and oxidative stress. As the underlying molecular mechanisms are unclear, we perform a meta-analysis with 9 microarray datasets of PD studies and 7 of AD studies to explore it. Functional enrichment analysis revealed that PD and AD both showed dysfunction in the synaptic vesicle cycle, GABAergic synapses, phagosomes, oxidative phosphorylation, and TCA cycle pathways, and AD had more enriched genes. Comparing the differentially expressed genes between AD and PD, we identified 54 common genes shared by more than six tissues. …Among them, 31 downregulated genes contained the antioxidant response element (ARE) consensus sequence bound by NRF2. NRF2 is a transcription factor, which protects cells against oxidative stress through coordinated upregulation of ARE-driven genes. To our surprise, although NRF2 was upregulated, its target genes were all downregulated. Further exploration found that MAFF was upregulated in all tissues and significantly negatively correlated with the 31 NRF2-dependent genes in diseased conditions. Previous studies have demonstrated over-expressed small MAFs can form homodimers and act as transcriptional repressors. Therefore, MAFF might play an important role in dysfunction of NRF2 regulatory network in PD and AD. Show more

Keywords: Parkinson’s disease, Alzheimer’s disease, meta-analysis, MAFF, NRF2

DOI: 10.3233/JAD-161032

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1525-1539, 2017

Article Type: Other

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1541-1558, 2017