Journal of Alzheimer's Disease - Volume 43, issue 2

Authors: Benke, Thomas | Sanin, Günter | Lechner, Anita | Dal-Bianco, Peter | Ransmayr, Gerhard | Uranüs, Margarete | Marksteiner, Josef | Gaudig, Maren | Schmidt, Reinhold | on behalf of the PRODEM Study Group

Article Type: Research Article

Abstract: Background: Patient dependence has rarely been studied in mild-to-moderate Alzheimer's disease (AD). Objective: To identify factors which predict patient dependence in mild-to-moderate AD. Methods: We studied 398 non-institutionalized AD patients (234 females) of the ongoing Prospective Registry on Dementia (PRODEM) in Austria. The Dependence Scale (DS) was used to assess patient dependence. Patient assessment comprised functional abilities, neuropsychiatric symptoms and cognitive functions. A multiple linear regression analysis was performed to identify predictors of patient dependence. Results: AD patients were mildly-to-moderately impaired (mean scores and SDs were: CDR 0.84 ± 0.43; DAD 74.4 ± 23.3, …MMSE = 22.5 ± 3.6). Psychopathology and caregiver burden were in the low range (mean NPI score 13.2, range 0 to 98; mean ZBI score 18, range 0–64). Seventy five percent of patients were classified as having a mild level of patient dependence (DS sum score 0 to 6). Patient dependence correlated significantly and positively with age, functional measures, psychopathology and depression, disease duration, and caregiver burden. Significant negative, but low correlations were found between patient dependence, cognitive variables, and global cognition. Activities of daily living, patient age, and disease severity accounted for 63% of variance in patient dependence, whereas cognitive variables accounted for only 11%. Conclusion: Dependence in this cohort was mainly related to age and functional impairment, and less so to cognitive and neuropsychiatric variables. This differs from studies investigating patients in more advanced disease stages which found abnormal behavior and impairments of cognition as main predictors of patient dependence. Show more

Keywords: Alzheimer's disease, patient dependence

DOI: 10.3233/JAD-140099

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 443-449, 2015

Authors: Wang, Yongfu | Wu, Long | Li, Jianping | Fang, Du | Zhong, Changjia | Chen, John Xi | Yan, Shirley ShiDu

Article Type: Research Article

Abstract: Diabetes is considered to be a risk factor in Alzheimer's disease (AD) pathogenesis. Although recent evidence indicates that diabetes exaggerates pathologic features of AD, the underlying mechanisms are not well understood. To determine whether mitochondrial perturbation is associated with the contribution of diabetes to AD progression, we characterized mouse models of streptozotocin (STZ)-induced type 1 diabetes and transgenic AD mouse models with diabetes. Brains from mice with STZ-induced diabetes revealed a significant increase of cyclophilin D (CypD) expression, reduced respiratory function, and decreased hippocampal long-term potentiation (LTP); these animals had impaired spatial learning and memory. Hyperglycemia exacerbated the upregulation of …CypD, mitochondrial defects, synaptic injury, and cognitive dysfunction in the brains of transgenic AD mice overexpressing amyloid-β as shown by decreased mitochondrial respiratory complex I and IV enzyme activity and greatly decreased mitochondrial respiratory rate. Concomitantly, hippocampal LTP reduction and spatial learning and memory decline, two early pathologic indicators of AD, were enhanced in the brains of diabetic AD mice. Our results suggest that the synergistic interaction between effects of diabetes and AD on mitochondria may be responsible for brain dysfunction that is in common in both diabetes and AD. Show more

Keywords: Alzheimer's disease, cognitive impairment, diabetes, long-term potentiation, mitochondria, synaptic injury

DOI: 10.3233/JAD-140972

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 451-463, 2015

Authors: Wang, Ju | Shi, Zi-Qi | Zhang, Mu | Xin, Gui-Zhong | Pang, Tao | Zhou, Ping | Chen, Jun | Qi, Lian-Wen | Yang, Hua | Xu, Xiaojun | Li, Ping

Article Type: Research Article

Abstract: Compounds derived from natural products are becoming promising alternative drugs/tools in Alzheimer's disease (AD) therapeutics. From an in-house natural products library, seventeen hits were selected for their inhibitory effect on the production of amyloid-β (Aβ) with IC50 lower than 10 μM without causing obvious toxicity. Among these compounds, camptothecin (CPT) and its analogs showed inhibitory effects on amyloid-β 1-42 (Aβ42 ) with the IC50 value in the nanomolar range in HEKsw cells and SHSY5Ysw cells. Further studies showed that CPT and its analogs inhibited Aβ42 via a p53 dependent pathway. Meanwhile, CPT and its analogs could also …inhibit Aβ42 induced IL-1β production in the THP-1 cells. Taken together, our results indicate that CPT and its analogs would be a promising therapeutic candidates for AD. Show more

Keywords: Alzheimer's disease, amyloid-β, camptothecin, IL-1β, p53

DOI: 10.3233/JAD-140078

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 465-477, 2015

Authors: Zhou, Jing | Yu, Jin-Tai | Wang, Hui-Fu | Meng, Xiang-Fei | Tan, Chen-Chen | Wang, Jun | Wang, Chong | Tan, Lan

Article Type: Research Article

Abstract: Alzheimer's disease (AD) and stroke are common disorders of aging, but the relationship between these two disorders remains uncertain. Recent evidence recognized that they frequently co-occur and are influenced by each other, while other studies have produced inconsistent results. We conducted this systematic review and meta-analysis of stroke on risk for AD and AD on risk for stroke subtypes to clarify the relation between these two disorders on the basis of the studies published from 1975 to November 2013 in the PubMed, EMBASE, and Cochrane Library databases. In total, 7 cohort studies and 2 nested case-control studies met the inclusion …criteria for meta-analysis. For stroke, the pooled effect size for AD risk was 1.59 (95% CI 1.25–2.02; z = 3.76; p = 0.000). For AD dementia, it was not associated with risk of all strokes or ischemic stroke (IS), but the risk of intracerebral hemorrhage (ICH was higher among persons with AD. The pooled RR for AD in relation to incident IS did not indicate a significant association (RR: 1.13; 95% CI 0.75–1.70; z = 0.58; p = 0.565). The pooled effect size for AD and ICH risk was 1.41 (95% CI 1.21–1.66; z = 4.27; p < 0.001). Stroke significantly and independently increased risk for AD and in turn AD increased risk for ICH. These results confirm that AD and ICH may have common pathogenesis and share preventive treatment measures. Show more

Keywords: Alzheimer's disease, meta-analysis, risk, stroke

DOI: 10.3233/JAD-140666

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 479-489, 2015

Authors: Khan, Tapan K. | Sen, Abhik | Hongpaisan, Jarin | Lim, Chol S. | Nelson, Thomas J. | Alkon, Daniel L.

Article Type: Research Article

Abstract: In Alzheimer's disease (AD) transgenic mice, activation of synaptogenic protein kinase C ε (PKCε) was found to prevent synaptotoxic amyloid-β (Aβ)-oligomer elevation, PKCε deficits, early synaptic loss, cognitive deficits, and amyloid plaque formation. In humans, to study the role of PKCε in the pathophysiology of AD and to evaluate its possible use as an early AD-biomarker, we examined PKCε and Aβ in the brains of autopsy-confirmed AD patients (n = 20) and age-matched controls (AC, n = 19), and in skin fibroblast samples from AD (n = 14), non-AD dementia patients (n = 14), and AC (n = 22). Intraneuronal …Aβ levels were measured immunohistochemically (using an Aβ-specific antibody) in hippocampal pyramidal cells of human autopsy brains. PKCε was significantly lower in the hippocampus and temporal pole areas of AD brains, whereas Aβ levels were significantly higher. The ratio of PKCε to Aβ in individual CA1 pyramidal cells was markedly lower in the autopsy AD brains versus controls. PKCε was inversely correlated with Aβ levels in controls, whereas in AD patients, PKCε showed no significant correlation with Aβ. In autopsy brains, PKCε decreased as the Braak score increased. Skin fibroblast samples from AD patients also demonstrated a deficit in PKCε compared to controls and an AD-specific change in the Aβ-oligomer effects on PKCε. Together, these data demonstrate that the relationship between Aβ levels and PKCε is markedly altered in AD patients' brains and skin fibroblasts, reflecting a loss of protective effect of PKCε against toxic Aβ accumulation. These changes of PKCε levels in human skin fibroblasts may provide an accurate, non-invasive peripheral AD biomarker. Show more

Keywords: Alzheimer's disease, amyloid-β oligomers, diagnostic assay, peripheral biomarker, PKCε

DOI: 10.3233/JAD-141221

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 491-509, 2015

Authors: Zeng, Fan | Xie, Wan-Ting | Wang, Yan-Jiang | Luo, Hong-Bo | Shi, Xiang-Qun | Zou, Hai-Qiang | Zeng, Yue-Qing | Li, Ya-Fei | Zhang, Shao-Rong | Lian, Yan

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common type of dementia affecting the aged population worldwide, yet its social perceptions have been less studied. To investigate the perceptions and attitudes toward AD in the Chinese population, a cross-sectional face-to-face survey of 2,000 randomly selected adults was conducted in five representative cities of China. This survey focused on the fear of AD, and the relationship between this variable and each studied factor was analyzed using univariate analysis and multivariate regression analysis. In general, 76.6% of the total respondents had personal fear of developing AD, and such fear was closely related to the …proximity to AD and perceived severity of AD, as well as other factors such as gender and self-perceived health. The results strongly suggested that more attention should be paid to public health education of AD, which can only be achieved with the cooperation of government, media, medical institutions, and the community so as to eliminate people's confusion about AD, relieve their psychological burden, and optimize their health-seeking behavior. Show more

Keywords: Alzheimer's disease, attitude, China, fear, perception

DOI: 10.3233/JAD-141371

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 511-518, 2015

Authors: Wang, Dayong | Hui, Yang | Peng, Yahui | Tang, Lu | Jin, Jianfeng | He, Rongzhang | Li, Yanze | Zhang, Shuai | Li, Lisha | Zhou, You | Li, Jing | Ma, Ning | Li, Jihong | Li, Sijia | Gao, Xu | Luo, Shanshun

Article Type: Research Article

Abstract: The stress protein heme oxygenase-1 (HO-1) is upregulated and co-localizes to pathological features, including tauopathies in the brains of individuals with Alzheimer's disease. However, the relationship between HO-1 and Alzheimer's disease remains unclear. In our previous research, the long-term overexpression of HO-1 was shown to promote tau aggregation by inducing tau phosphorylation in the mouse brain. In this study, we found that the long-term overexpression of HO-1 led to cognitive decline in transgenic mice, as determined by the water maze test, and that HO-1 can affect two pathways for tauopathy. Through one pathway, HO-1 promotes the expression of CDK5 by …accumulating reactive oxygen species, which are produced by HO-1 downstream products of iron in neuro2a cell lines and mouse brain. Through the second pathway, HO-1 induces tau truncation at D421 in vivo and in vitro. Clearly, there is a HO-1-dependent mechanism responsible for tau protein phosphorylation and tau truncation in vivo and in vitro. Taken together, our results suggest that HO-1 plays an important role in the disease process of tauopathies in AD. Show more

Keywords: Alzheimer's disease, CDK5, heme oxygenase-1, iron, tau truncation, tauopathies

DOI: 10.3233/JAD-140567

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 519-534, 2015

Authors: Li, Jiang-chao | Han, Lu | Wen, Yin-xin | Yang, Yong-xia | Li, Shuai | Li, Xue-song | Zhao, Chang-jiang | Wang, Ting-yu | Chen, Hui | Liu, Ying | Qi, Cui-ling | He, Xiao-dong | Gu, Qu-liang | Ye, Yu-xiang | Zhang, Yu | Huang, Ren | Wu, Yu-e | He, Rong-rong | Kurihara, Hiroshi | Song, Xiao-yu | Cao, Liu | Wang, Li-jing

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurological disorder that primarily affects memory, and its prevalence is rising. Increasing evidence suggests that dysfunction of the blood-brain barrier (BBB) may be involved in AD and other neurodegenerative diseases. Herein, we report that the permeability of the BBB is increased and that AD-like alterations are present in Slit-2 overexpressing transgenic mice. We found that behavioral change and the corresponding molecular diagnostic markers of AD, such as hippocampal neuron apoptosis, amyloid-β (Aβ) protein deposition, and acetylcholinesterase expression, were increased in the Slit-2 transgenic mice. Moreover, the endothelial cells were dysfunctional, the size of the …lateral ventricle cavity increased, and the permeability of the BBB increased. Additionally, there was an increased serum level of glutamate indicating that the BBB is related to AD. Finally, histopathological analysis of other organs in the Slit-2 overexpressing mice did not show any marked abnormalities. These findings demonstrate that Slit2 overexpression may be responsible for AD-like alterations and the increased BBB permeability in these mice. Our study provides a potential novel mechanism for the development of AD. Show more

Keywords: Alzheimer's disease, blood-brain barrier, Slit homolog 2 protein, transgenic mice

DOI: 10.3233/JAD-141215

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 535-548, 2015

Authors: Zhao, Xuemei | Lejnine, Serguei | Spond, Jeffrey | Zhang, Chunsheng | Ramaraj, T.C. | Holder, Daniel J. | Dai, Hongyue | Weiner, Russell | Laterza, Omar F.

Article Type: Research Article

Abstract: Biomarkers currently used in the aid for the diagnosis of Alzheimer's disease (AD) are cerebrospinal fluid (CSF) protein markers and brain neuroimaging markers. These biomarkers, however, either involve semi-invasive procedures or are costly to measure. Thus, AD biomarkers from more easily accessible body fluids, such as plasma, are very enticing. Using an aptamer-based proteomic technology, we profiled 1,129 plasma proteins of AD patients and non-demented control individuals. A 5-protein classifier for AD identification was constructed in the discovery study with excellent 10-fold cross-validation performance (90.1% sensitivity, 84.2% specificity, 87.9% accuracy, and AUC as 0.94). In an independent validation study, the …classifier was applied and correctly predicted AD with 100.0% sensitivity, 80.0% specificity, and 90.0% accuracy, matching or outperforming the CSF Aβ42 and tau biomarkers whose performance were assessed in individual-matched CSF samples obtained at the same visit as plasma sample collection. Moreover, the classifier also correctly predicted mild cognitive impairment, an early pre-dementia state of the disease, with 96.7% sensitivity, 80.0% specificity, and 92.5% accuracy. These studies demonstrate that plasma proteins could be used effectively and accurately to contribute to the clinical diagnosis of AD. Although additional and more diverse cohorts are needed for further validation of the robustness, including the support of postmortem diagnosis, the 5-protein classifier appears to be a promising blood test to contribute diagnosis of AD. Show more

Keywords: Alzheimer's disease, biomarkers, blood, aptamers, proteome

DOI: 10.3233/JAD-141149

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 549-563, 2015

Authors: Martiskainen, Henna | Helisalmi, Seppo | Viswanathan, Jayashree | Kurki, Mitja | Hall, Anette | Herukka, Sanna-Kaisa | Sarajärvi, Timo | Natunen, Teemu | Kurkinen, Kaisa M.A. | Huovinen, Jaakko | Mäkinen, Petra | Laitinen, Marjo | Koivisto, Anne M. | Mattila, Kari M. | Lehtimäki, Terho | Remes, Anne M. | Leinonen, Ville | Haapasalo, Annakaisa | Soininen, Hilkka | Hiltunen, Mikko

Article Type: Research Article

Abstract: Background: Several risk loci for Alzheimer's disease (AD) have been identified during recent years in large-scale genome-wide association studies. However, little is known about the mechanisms by which these loci influence AD pathogenesis. Objective: To investigate the individual and combined risk effects of the newly identified AD loci. Methods: Association of 12 AD risk loci with AD and AD-related cerebrospinal fluid (CSF) biomarkers was assessed. Furthermore, a polygenic risk score combining the effect sizes of the top 22 risk loci in AD was calculated for each individual among the clinical and neuropathological cohorts. Effects of individual …risk loci and polygenic risk scores were assessed in relation to CSF biomarker levels as well as neurofibrillary pathology and different biochemical measures related to AD pathogenesis obtained from the temporal cortex. Results: Polygenic risk scores associated with CSF amyloid-β42 (Aβ42 ) levels in the clinical cohort, and with soluble Aβ42 levels and γ-secretase activity in the neuropathological cohort. The γ-secretase effect was independent of APOE. APOE-ε4 associated with CSF Aβ42 (p < 0.001) levels. For the other risk loci, no significant associations with AD risk or CSF biomarkers were detected after multiple testing correction. Conclusions: AD risk loci polygenically contribute to Aβ pathology in the CSF and temporal cortex, and this effect is potentially associated with increased γ-secretase activity. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, biomarker, cerebrospinal fluid, polygenic risk score, risk gene, tau protein

DOI: 10.3233/JAD-140777

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 565-573, 2015