Journal of Alzheimer's Disease - Volume 44, issue 2

Authors: Yu, Jun | Luo, Xiaobin | Xu, Hua | Ma, Quan | Yuan, Jianhui | Li, Xuling | Chang, Raymond Chuen-Chung | Qu, Zhongsen | Huang, Xinfeng | Zhuang, Zhixiong | Liu, Jianjun | Yang, Xifei

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by a progressive impairment of cognitive functions including spatial learning and memory. Excess copper exposure accelerates the development of AD; however, the potential mechanisms by which copper exacerbates the symptoms of AD remain unknown. In this study, we explored the effects of chronic copper exposure on cognitive function by treating 6 month-old triple AD transgenic (3xTg-AD) mice with 250 ppm copper sulfate in drinking water for 6 months, and identified several potential key molecules involved in the effects of chronic copper exposure on memory by proteomic analysis. The behavioral test …showed that chronic copper exposure aggravated memory impairment of 3xTg-AD mice. Two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry revealed a total of 44 differentially expressed proteins (18 upregulated and 26 down-regulated) in hippocampus between the wild-type (WT) mice and non-exposed 3xTg-AD mice. A total of 40 differentially expressed proteins were revealed (20 upregulated and 20 down-regulated) in hippocampus between copper exposed and non-exposed 3xTg-AD mice. Among these differentially expressed proteins, complexin-1 and complexin-2, two memory associated proteins, were significantly decreased in hippocampus of 3xTg-AD mice compared with the WT mice. Furthermore, the expression of these two proteins was further down-regulated in 3xTg-AD mice when exposed to copper. The abnormal expression of complexin-1 and complexin-2 identified by proteomic analysis was verified by western blot analysis. Taken together, our data showed that chronic copper exposure accelerated memory impairment and altered the expression of proteins in hippocampus in 3xTg-AD mice. The functional analysis on the differentially expressed proteins suggested that complexin-1 and complexin-2 may be the key molecules involved in chronic copper exposure-aggravated memory impairment in AD. Show more

Keywords: Alzheimer's disease, copper, memory impairment, two-dimensional fluorescence difference gel electrophoresis

DOI: 10.3233/JAD-141776

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 455-469, 2015

Authors: Olde Rikkert, Marcel G.M. | Verhey, Frans R. | Blesa, Rafael | von Arnim, Christine A.F. | Bongers, Anke | Harrison, John | Sijben, John | Scarpini, Elio | Vandewoude, Maurits F.J. | Vellas, Bruno | Witkamp, Renger | Kamphuis, Patrick J.G.H. | Scheltens, Philip

Article Type: Research Article

Abstract: Background: The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to improve synapse formation and function in patients with Alzheimer's disease (AD). Two double-blind randomized controlled trials (RCT) with Souvenaid of 12 and 24 week duration (Souvenir I and Souvenir II) showed that memory performance was improved in drug-naïve mild AD patients, whereas no effects on cognition were observed in a 24-week RCT (S-Connect) in mild to moderate AD patients using AD medication. Souvenaid was well-tolerated in all RCTs. Objective: In this 24-week open-label extension (OLE) study to the 24-week Souvenir II RCT, long-term …safety and intake adherence of the medical food Souvenaid was evaluated. Methods: Patients with mild AD (n = 201) received Souvenaid once-daily during the OLE. Main outcome parameters were safety and product intake adherence. The memory domain z-score from a revised neuropsychological test battery was continued as exploratory parameter. Results: Compared to the RCT, a similar (low) incidence and type of adverse events was observed, being mainly (68.3%) of mild intensity. Pooled data (RCT and OLE) showed that 48-week use of Souvenaid was well tolerated with high intake adherence (96.1%). Furthermore, a significant increase in the exploratory memory outcome was observed in both the active-active and control-active groups during Souvenaid intervention. Conclusion: Souvenaid use for up to 48-weeks was well tolerated with a favorable safety profile and high intake adherence. The findings in this OLE study warrant further investigation toward the long-term safety and efficacy of Souvenaid in a well-controlled, double-blind RCT. Show more

Keywords: Alzheimer's disease, clinical trial, dietary management, intervention studies, long-term, medical nutrition therapy, memory, patient adherence, safety

DOI: 10.3233/JAD-141305

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 471-480, 2015

Authors: MacPherson, Sarah E. | Parra, Mario A. | Moreno, Sonia | Lopera, Francisco | Della Sala, Sergio

Article Type: Research Article

Abstract: Patients with sporadic Alzheimer's disease (AD) are impaired in their ability to perform two tasks concurrently compared to healthy younger and older adults, despite being able to successfully perform the tasks on their own reasonably well. Dual task impairments have also been found in those individuals with an E280A presenilin-1 genetic mutation but who do not yet meet the criteria for AD. The aim of the current study is to determine whether this dual task deficit is specific to the given combination of tasks performed simultaneously or whether it reflects a general deficit in the ability to coordinate two tasks. …Thirty-one carriers of the gene mutation who did not meet the criteria for AD and 38 non-carriers were asked to perform two memory tasks simultaneously. The familial AD carriers showed significant dual task decrements compared to those family members without the gene mutation. The findings support the notion that a deficit in the mechanism responsible for coordinating the performance of two tasks may be a clinical marker for the early detection of AD due to the E280A presenilin-1 gene mutation. Show more

Keywords: Dual task, familial Alzheimer disease, human, presenilin 1 (Alzheimer disease 3), working memory

DOI: 10.3233/JAD-140990

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 481-492, 2015

Authors: Cuesta, Pablo | Garcés, Pilar | Castellanos, Nazareth P. | López, Maria Eugenia | Aurtenetxe, Sara | Bajo, Ricardo | Pineda-Pardo, José Angel | Bruña, Ricardo | Marín, Antonio García | Delgado, Marisa | Barabash, Ana | Ancín, Inés | Cabranes, Jose Antonio | Fernandez, Alberto | del Pozo, Francisco | Sancho, Miguel | Marcos, Alberto | Nakamura, Akinori | Maestú, Fernando

Article Type: Research Article

Abstract: The apolipoprotein E (APOE) ε4 allele constitutes the major genetic risk for the development of late onset Alzheimer's disease (AD). However, its influence on the neurodegeneration that occurs in early AD remains unresolved. In this study, the resting state magnetoencephalography(MEG) recordings were obtained from 27 aged healthy controls and 36 mild cognitive impairment (MCI) patients. All participants were divided into carriers and non-carriers of the ε4 allele. We have calculated the functional connectivity (FC) in the source space along brain regions estimated using the Harvard-Oxford atlas and in the classical bands. Then, a two way ANOVA analysis (diagnosis and APOE) …was performed in each frequency band. The diagnosis effect consisted of a diminished FC within the high frequency bands in the MCI patients, affecting medial temporal and parietal regions. The APOE effect produced a decreased long range FC in delta band in ε4 carriers. Finally, the interaction effect showed that the FC pattern of the right frontal-temporal region could be reflecting a compensatory/disruption process within the ε4 allele carriers. Several of these results correlated with cognitive decline and neuropsychological performance. The present study characterizes how the APOE ε4 allele and MCI status affect the brain's functional organization by analyzing the FC patterns in MEG resting state in the sources space. Therefore a combination of genetic, neuropsychological, and neurophysiological information might help to detect MCI patients at higher risk of conversion to AD and asymptomatic subjects at higher risk of developing a manifest cognitive deterioration. Show more

Keywords: Aging, APOE ε4, functional connectivity, magnetoencephalography, mild cognitive impairment, source analysis

DOI: 10.3233/JAD-141872

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 493-505, 2015

Authors: Meunier, Johann | Borjini, Nozha | Gillis, Cyril | Villard, Vanessa | Maurice, Tangui

Article Type: Research Article

Abstract: Aftins (amyloid forty-two inducers) represent a novel class of tri-substituted purines derived from roscovitine, able to promote the generation of amyloid-β (Aβ)1-42 from amyloid-β protein precursor through γ-secretase activation in cell cultures. We here examined whether aftin-4 could provoke an amyloid-like toxicity in vivo in mice. The intracerebroventricular administration of aftin-4 (3–20 nmol) increased Aβ1-42 , but not Aβ1-40 , content in the mouse hippocampus, between 5 and 14 days after injection. Aftin-4 injection increased lipid peroxidation levels in the hippocampus, an index of oxidative stress. It increased brain contents in pro-inflammatory cytokines, IL-1β, IL-6, and TNFα, and GFAP …immunolabeling, showing astrocytic reaction. Expression of the synaptic marker synaptophysin was decreased by aftin-4. Finally, the treatment provoked marked learning deficits, observed using different memory procedures: Spontaneous alternation in the Y-maze, place learning in the water-maze, and passive avoidance response. The systemic intraperitoneal injection of aftin-4 in the 3-30 mg/kg dose range also induced oxidative stress and learning deficits. All these alterations could be blocked by pre-treatment with the γ-secretase inhibitor BMS-299,897, confirming that the mechanism of action of aftin-4 involves secretase activity. Furthermore, we examined if the cholinesterase inhibitor donepezil and the non-steroidal anti-inflammatory drug ibuprofen could prevent aftin-4-induced memory impairments, cytokine release, and lipid peroxidation. Donepezil prevented all alterations, whereas ibuprofen prevented the increases in cytokine release and lipid peroxidation, but only marginally the memory impairments. As a whole, this study showed that in vivo injection of aftin-4 results in a rapid, acute Alzheimer's disease-like toxicity in the rodent brain. Show more

Keywords: Aβ1-42, aftins, Alzheimer's disease, amyloid toxicity in vivo, memory deficits

DOI: 10.3233/JAD-140711

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 507-524, 2015

Authors: Seeburger, Jeffrey L. | Holder, Daniel J. | Combrinck, Marc | Joachim, Catharine | Laterza, Omar | Tanen, Michael | Dallob, Aimee | Chappell, Derek | Snyder, Karen | Flynn, Mary | Simon, Adam | Modur, Vijay | Potter, William Z. | Wilcock, Gordon | Savage, Mary J. | Smith, A. David

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau have been studied as markers of Alzheimer's disease (AD). Combined Aβ42 and t-tau distinguishes AD from healthy controls with a sensitivity and specificity (sens/spec) near 89% across studies. This study examined these markers in the homogeneous OPTIMA cohort, using extensive longitudinal follow up and postmortem evaluation to confirm clinicopathological status. Baseline CSF was analyzed from 227 participants with AD (97% autopsy-confirmed), mild cognitive impairment (MCI; 73% confirmed), other dementia syndrome (ODS; 100% confirmed), and controls (CTL; 27% confirmed, follow up approximately 9–13 years). Biomarker concentrations were analyzed using validated ELISAs. AD patients …had lower CSF Aβ42 and higher t-tau, p-tau, t-tau/Aβ42 , and t-tau/Aβ40 compared to CTLs, with MCI intermediate. CTL and MCI participants who progressed to AD demonstrated more AD-like profiles. Aβ40 , sAβPPα, and sAβPPβ were lower in AD compared to CTL. High-level discriminators of AD from CTL were t-tau/Aβ40 (AUROC 0.986, sens/spec of 92%/94%), p-tau/Aβ42 (AUROC 0.972, sens/spec of 94%/90%), and Aβ42 (AUROC 0.941, sens/spec of 88%). For discriminating AD from ODS, p-tau/Aβ42 demonstrated sens/spec of 88%/100% (95%/86% at the AD versus CTL cutoff) and Aβ42 demonstrated sens/spec of 84%/100% (88%/100% at the AD versus CTL cutoff). In a well-characterized, homogeneous population, a single cutoff for baseline CSF Aβ and tau markers can distinguish AD with a high level of sens/spec compared to other studies. It may be important to characterize sources of demographic and biological variability to support the effective use of CSF diagnostic assays in the broader AD population. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarker, cerebrospinal fluid, frontotemporal dementia, mild cognitive impairment, postmortem examination, tau

DOI: 10.3233/JAD-141725

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 525-539, 2015

Authors: Piguet, Olivier | Leyton, Cristian E. | Gleeson, Liam D. | Hoon, Chris | Hodges, John R.

Article Type: Research Article

Abstract: Background: The two non-semantic variants of primary progressive aphasia (PPA), nonfluent/agrammatic PPA (nfv-PPA) and logopenic variant PPA (lv-PPA), share language features despite their different underlying pathology, and may be difficult to distinguish for non-language experts. Objective: To improve diagnostic accuracy of nfv-PPA and lv-PPA using tasks measuring non-language cognition and emotion processing. Methods: Thirty-eight dementia patients meeting diagnostic criteria for PPA (nfv-PPA 20, lv-PPA 18) and 21 matched healthy Controls underwent a comprehensive assessment of cognition and emotion processing, as well as a high-resolution structural MRI and a PiB-PET scan, a putative biomarker of Alzheimer's disease. …Task performances were compared between the groups and those found to differ significantly were entered into a logistic regression analysis. Results: Analyses revealed a double dissociation between nfv-PPA and lv-PPA. nfv-PPA exhibited significant emotion processing disturbance compared to lv-PPA and Controls. In contrast, only the lv-PPA group was significantly impaired on tasks of episodic memory. Logistic regression analyses showed that 87% of patients were correctly classified using emotion processing and episodic memory composite scores, together with a measure of visuospatial ability. Conclusions: Non-language presenting features can help differentiate between the two non-semantic PPA syndromes, with a double dissociation observed on tasks of episodic memory and emotion processing. Based on performance on these tasks, we propose a decision tree as a complementary method to differentiate between the two non-semantic variants. These findings have important clinical implications, with identification of patients who may potentially benefit existing therapeutic interventions currently available for Alzheimer's disease. Show more

Keywords: Alzheimer disease, frontotemporal dementia, episodic memory, emotions

DOI: 10.3233/JAD-141854

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 541-547, 2015

Authors: Bowen, Richard L. | Perry, George | Xiong, Chengjie | Smith, Mark A. | Atwood, Craig S.

Article Type: Research Article

Abstract: To test the efficacy and safety of leuprolide acetate (Lupron Depot® ) in the treatment of Alzheimer's disease (AD), we conducted a 48-week, double-blind, placebo-controlled, dose-ranging study in women aged 65 years or older with mild to moderate AD. A total of 109 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 24 inclusive were randomized to low dose Lupron Depot® (11.25 mg leuprolide acetate), high dose Lupron Depot® (22.5 mg leuprolide acetate), or placebo injections every 12 weeks. There were no statistically significant differences in primary efficacy parameters (ADAS-Cog and ADCS-CGIC), …although there was a non-statistically significant trend in favor of the high dose Lupron group on the ADAS-Cog. There were no statistically significant differences in secondary efficacy parameters (NPI, ADCS-ADL, BI, and ADCS-Severity Rating). However, in the a priori designated subgroup analysis of patients taking an acetylcholinesterase inhibitor (AChEI), there was a statistically significant benefit in the high dose group compared to both the low dose and placebo groups as determined by ADAS-Cog (mean decline: 0.18, 4.21, and 3.30), ADCS-CGIC (% subjects experiencing decline: 38, 82, and 63), and ADCS-ADL (mean decline: −0.54, −8.00, and −6.85), respectively. No differences between treatment groups were seen on the NPI, ADCS-CGI Severity Rating, or the BI in the subgroup analysis. These data indicate that cognitive function is preserved in patients treated with high dose Lupron who were already using AChEIs. The positive interaction between Lupron and AChEIs warrants further investigation for the treatment of AD. Show more

Keywords: 17β-estradiol, acetylcholinesterase inhibitor, Alzheimer's disease, apolipoprotein E, clinical trial, cognitive testing, gonadotropin-releasing hormone, Lupron, luteinizing hormone, women

DOI: 10.3233/JAD-141626

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 549-560, 2015

Authors: Walker, Jennifer M. | Klakotskaia, Diana | Ajit, Deepa | Weisman, Gary A. | Wood, W. Gibson | Sun, Grace Y. | Serfozo, Peter | Simonyi, Agnes | Schachtman, Todd R.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive, age-dependent neurodegenerative disorder affecting specific brain regions that control memory and cognitive functions. Epidemiological studies suggest that exercise and dietary antioxidants are beneficial in reducing AD risk. To date, botanical flavonoids are consistently associated with the prevention of age-related diseases. The present study investigated the effects of 4 months of wheel-running exercise, initiated at 2-months of age, in conjunction with the effects of the green tea catechin (-)-epigallocatechin-3-gallate (EGCG) administered orally in the drinking water (50 mg/kg daily) on: 1) behavioral measures: learning and memory performance in the Barnes maze, nest building, open-field, anxiety …in the light-dark box; and 2) soluble amyloid-β (Aβ) levels in the cortex and hippocampus in TgCRND8 (Tg) mice. Untreated Tg mice showed hyperactivity, relatively poor nest building behaviors, and deficits in spatial learning in the Barnes maze. Both EGCG and voluntary exercise, separately and in combination, were able to attenuate nest building and Barnes maze performance deficits. Additionally, these interventions lowered soluble Aβ1-42 levels in the cortex and hippocampus. These results, together with epidemiological and clinical studies in humans, suggest that dietary polyphenols and exercise may have beneficial effects on brain health and slow the progression of AD. Show more

Keywords: AβPP transgenic mice, Alzheimer's disease, behavior, exercise, EGCG, learning

DOI: 10.3233/JAD-140981

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 561-572, 2015

Authors: Jung, Chau-Ren | Lin, Yu-Ting | Hwang, Bing-Fang

Article Type: Research Article

Abstract: Several studies with animal research associate air pollution in Alzheimer's disease (AD) neuropathology, but the actual impact of air pollution on the risk of AD is unknown. Here, this study investigates the association between long-term exposure to ozone (O3 ) and particulate matter (PM) with an aerodynamic diameter equal to or less than 2.5 μm (PM2.5 ), and newly diagnosed AD in Taiwan. We conducted a cohort study of 95,690 individuals' age ≥ 65 during 2001–2010. We obtained PM10 and O3 data from Taiwan Environmental Protection Agency during 2000–2010. Since PM2.5 data is only accessible entirely after …2006, we used the mean ratio between PM2.5 and PM10 during 2006–2010 (0.57) to estimate the PM2.5 concentrations from 2000 to 2005. A Cox proportional hazards model was used to evaluate the associations between O3 and PM2.5 at baseline and changes of O3 and PM2.5 during the follow-up period and AD. The adjusted HR for AD was weakly associated with a raised concentration in O3 at baseline per increase of 9.63 ppb (adjusted HR 1.06, 95% confidence interval (CI) 1.00–1.12). Further, we estimated a 211% risk of increase of AD per increase of 10.91 ppb in O3 over the follow-up period (95% CI 2.92–3.33). We found a 138% risk of increase of AD per increase of 4.34 μg/m3 in PM2.5 over the follow-up period (95% CI 2.21–2.56). These findings suggest long-term exposure to O3 and PM2.5 above the current US EPA standards are associated with increased the risk of AD. Show more

Keywords: Air pollution, Alzheimer's disease, neurodevelopment, ozone, particulate matter

DOI: 10.3233/JAD-140855

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 573-584, 2015