Journal of Alzheimer's Disease - Volume 42, issue 3

Authors: Freund-Levi, Yvonne | Vedin, Inger | Hjorth, Erik | Basun, Hans | Faxén Irving, Gerd | Schultzberg, Marianne | Eriksdotter, Maria | Palmblad, Jan | Vessby, Bengt | Wahlund, Lars-Olof | Cederholm, Tommy | Basu, Samar

Article Type: Research Article

Abstract: Background: Oxidative stress and inflammation are two key mechanisms suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Omega-3 fatty acids (ω-3 FAs) found in fish and fish oil have several biological properties that may be beneficial in AD. However, they may also auto-oxidize and induce in vivo lipid peroxidation. Objective: TThe objective of this study was to evaluate systemic oxidative stress and inflammatory biomarkers following oral supplementation of dietary ω-3 FA. Methods: Forty patients with moderate AD were randomized to receive 1.7 g DHA (22:6) and 0.6 g EPA (20:5) or placebo for …6 months. Urinary samples were collected before and after supplementation. The levels of the major F2 -isoprostane, 8-iso-PGF2α , a consistent in vivo biomarker of oxidative stress, and 15-keto-dihydro-PGF2α , a major metabolite of PGF2α and biomarker of inflammatory response, were measured. Results: F2 -isoprostane in urine increased in the placebo group after 6 months, but there was no clear difference in treatment effect between supplemented and non-supplemented patients on the urinary levels of F2 -isoprostanes and 15-keto-dihydro-PGF2α . At baseline, the levels of 15-keto-dihydro-PGF2α showed negative correlative relationships to ω-3 FAs, and a positive correlation to linoleic acid. 8-iso-PGF2α correlated negatively to the ω-6 FA arachidonic acid. Conclusion: The findings indicate that supplementation of ω-3 FAs to patients with AD for 6 months does not have a clear effect on free radical-mediated formation of F2 -isoprostane or cyclooxygenase-mediated formation of prostaglandin F2α . The correlative relationships to FAs indicate a potential role of FAs in immunoregulation. Show more

Keywords: Alzheimer's disease, eicosanoids, F2-isoprostane, inflammation, lipids, omega-3 fatty acids, oxidative stress, prostaglandin F2α

DOI: 10.3233/JAD-132042

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 823-831, 2014

Authors: Appleby, Brian S. | Rincon-Beardsley, Tonya D. | Appleby, Kristin K. | Crain, Barbara J. | Wallin, Mitchell T.

Article Type: Research Article

Abstract: Background: Prion diseases are rapidly progressive neurodegenerative diseases that frequently mimic other forms of dementia making them difficult to diagnose. Objective: To explore factors associated with the initial diagnoses of cases later determined to be caused by prion disease in an attempt to recognize key clinical variables that impact the timely diagnosis of prion disease. Methods: A retrospective chart review performed at Johns Hopkins Medicine and the Department of Veterans Affairs Health Care System (1995–2008) was conducted. Ninety-two subjects with definite or probable prion disease were included in the analyses. Demographic, clinical, diagnostic test results, neuropathologic, …molecular, and genetic data were collected using a standardized instrument and compared between initial diagnosis groups. Results: Cases were separated into five broad categories pertaining to their initial diagnoses: prion disease, non-prion-related dementia, psychiatric disorder, stroke, and other. The majority of cases did not receive an initial diagnosis of prion disease (n = 76, 83%). The plurality of subjects received an initial diagnosis of a non-prion disease related dementia (n = 33, 36%). Mean survival times varied between initial diagnosis groups (p = 0.042). Times to cerebrospinal fluid 14-3-3 analysis and electroencephalogram also differed between initial diagnosis groups. Conclusions: Most patients with prion disease are initially diagnosed with a non-prion disease related dementia. Several clinical features were associated with initial diagnoses including survival time, onset of specific symptoms, and times to 14-3-3 analyses and electroencephalogram. Expanding our knowledge of the various clinical presentations of prion disease, especially dementia, may aid in the earlier diagnoses of these rapidly progressive diseases. Show more

Keywords: Creutzfeldt-Jakob disease, Creutzfeldt-Jakob syndrome, dementia, diagnosis, diagnostic errors, fatal familial insomnia, Gerstmann-Straussler-Scheinker Disease, mean survival time, phenotype, prion diseases, sporadic

DOI: 10.3233/JAD-132465

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 833-839, 2014

Authors: Chen, Yaojing | Wang, Jun | Zhang, Junying | Zhang, Ting | Chen, Kewei | Fleisher, Adam | Wang, Yongyan | Zhang, Zhanjun

Article Type: Research Article

Abstract: Silent or asymptomatic lacunar infarcts (LACI) are common in elderly individuals, but it remains largely unclear how these often neglected silent brain infarcts lead to multiple domain cognitive deficits and even Alzheimer's disease (AD). In this study, we investigated the difference between patients with silent LACI in basal ganglia region and healthy controls for the structural and functional changes in the aspects of alterations of gray matter (GM) volume and intra-/inter-default mode network (DMN) and salience network (SN) connectivity. Thirty patients with silent LACI in the basal ganglia region and thirty healthy controls participated in the study. Voxel-based morphometry analysis …was employed to measure the GM volume. We further investigated the intra/inter-network connectivity of DMN and SN using resting-state functional magnetic resonance imaging. Compared with healthy controls, patients performed worse in cognitive function in the aspects of general mental status, attention, and memory. The LACIs showed more severe GM atrophy in insula, anterior cingulate cortex, caudate, and superior temporal pole than controls. The connectivity within and between two networks was also reduced in patients. Importantly, the disrupted connectivity correlated with the patients' cognitive performance. Our findings support the hypothesis that silent lacunar infarcts result in cognitive decline, GM, and functional connectivity loss. Show more

Keywords: Cognition, functional connectivity, gray matter, network, silent stroke

DOI: 10.3233/JAD-140948

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 841-850, 2014

Authors: Polito, Letizia | Chierchia, Armando | Tunesi, Marta | Bouybayoune, Ihssane | Kehoe, Patrick Gavin | Albani, Diego | Forloni, Gianluigi

Article Type: Research Article

Abstract: Environmental enrichment (EE) is a non-pharmacological intervention reported to counteract pathological signs in models of Alzheimer's disease (AD). We developed EE protocols in APP23 mice and evaluated how they influenced cognitive decline and brain amyloid-β (Aβ) burden. We also investigated the involvement of sirtuins (SIRTs) as a possible molecular mediator of EE, by assessing hippocampal and cortical mRNA and protein levels of the SIRT family members (SIRT1 to SIRT7). APP23 transgenic mice were moved to EE cages (TG-EEs) starting from 3 months of age. TG-EEs were compared to transgenic mice housed in standard cages (TG-SHs) and to wild-type littermates in …the two housing conditions (WT-EEs and WT-SHs). At 7 months of age, all mice were tested for behavioral performance with Morris Water Maze (MWM) and visual novel Object Recognition Test (vORT). After a month, a group underwent biochemical analyses, while another group continued in the EE environment till 18 months of age, when Aβ plaque load was assessed. At 7 months, TG-SHs had impaired behavioral performance in MWM and vORT. In contrast, TG-EE mice had restored behavioral performance. At 8 months, EE did not affect AβPP expression or processing, Aβ40/42 , pGlu-Aβ3-40 /3-42 , or Aβ oligomer level. The expression of two Aβ degrading enzymes (insulin degrading enzyme and neprilysin) was not modulated by EE. Brain sirtuin mRNA and protein levels were unchanged, while brain-derived neurotrophic factor expression increased after EE. Aβ deposition was attenuated in 18-month-old TG-EE mice, without apparent reduction of neuroinflammatory signs. We suggest that EE had a beneficial effect on cognitive performance and lessened long-term Aβ accumulation, but brain sirtuin expression was not modulated when cognitive impairment was restored. Show more

Keywords: Alzheimer's disease, APP23 mice, cognitive impairment, environmental enrichment, sirtuin

DOI: 10.3233/JAD-131430

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 851-864, 2014

Authors: Tong, Yawei | Yang, Huan | Tian, Xiaosheng | Wang, Hecheng | Zhou, Ting | Zhang, Shouzi | Yu, Jia | Zhang, Tao | Fan, Dongshen | Guo, Xiangyang | Tabira, Takeshi | Kong, Fanjun | Chen, Zheng | Xiao, Weizhong | Chui, Dehua

Article Type: Research Article

Abstract: Excess manganese (Mn) in brain can be neurotoxic, implicated in several neurodegenerative disorders such as sporadic Alzheimer's disease (AD). However, little is known about the altered metal environment including elevated Mn in the progressive cognitive impairment of AD. Indeed, whether high Mn is associated with AD risk remains elusive. In the study, we recruited 40 Chinese elders with different cognitive statuses and investigated concentrations of Mn in whole blood and plasma amyloid-β (Aβ) peptides. Surprisingly, there were significant correlations of Mn with Mini-Mental State Examination score and Clinical Dementia Rating Scale score. In addition, plasma Aβ peptides increased with elevated …Mn. Further studies both in vitro and in vivo demonstrated dose-related neurotoxicity and increase of Aβ by Mn treatment, which was probably caused by disrupted Aβ degradation. These data suggested that high Mn may be involved in the progress of AD as an essential pathogenic factor. Show more

Keywords: High manganese (Mn), cognitive impairment, amyloid-beta (Abeta), Alzheimer's disease (AD), Aβ degradation

DOI: 10.3233/JAD-140534

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 865-878, 2014

Authors: Lanza, Claudia | Knörzer, Oliver | Weber, Michael | Riepe, Matthias W.

Article Type: Research Article

Abstract: Background/Objective: Spatial orientation declines early in patients with Alzheimer’s disease (AD) and is a major cause for institutionalization of patients. Methods: Use of either an aerial map or an assistive device to get from start to goal zone, both located on the campus of the hospital (distance between start and goal zone 300 m to 500 m). Use of the assistive device was trained for 15 minutes prior to the task. Results: We assessed 14 patients with mild to moderate AD (DSM-IV and NINCDS-ADRDA criteria; 9 female patients, 5 male patients; age 71.9 ± 7.4 years; …MMSE 21.7 ± 2.9 (mean ± SD), range 16–26). Each patient had to find the way for three different routes with different start and goal zones. None of the patients found their way to the goal zone for any of the routes when using an aerial map in which the way was highlighted. With use of the assistive device, patients found their way from start to goal zones autonomously for 20 of 42 routes (3 routes each for 14 patients). For 22 of 42 routes intermediate re-assurance was necessary, but herewith routes were completed. Conclusion: This study lays ground for the use of mobile technical devices in patients with mild to moderate AD. Mobile assistive devices may enable patients with mild to moderate AD to maintain autonomous spatial orientation in unfamiliar environments. Improvement of the familiarization of patients with the device and further sophistication of assistive cues is likely to further improve autonomous use of navigational devices in patients with mild to moderate AD. Show more

Keywords: Alzheimer's disease, assistive devices, spatial orientation

DOI: 10.3233/JAD-140063

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 879-884, 2014

Authors: Elias, Alby | Woodward, Michael | Rowe, Christopher C.

Article Type: Research Article

Abstract: Background: 2-[18F]fluoro-2-Deoxy-D-glucose (FDG) positron emission tomography (PET) may assist the diagnosis of dementia but it is an expensive investigation. Objective: To obtain management impact data for FDG-PET in dementia. Methods: This was a prospective study of 194 consecutive patients referred from a memory clinic for FDG-PET at the discretion of the dementia specialists. Diagnosis and management plans formulated at a multidisciplinary patient review meeting were compared before and after the release of PET findings. Results: FDG-PET had moderate to high impact on the diagnosis and management in 85 (44%) participants. Diagnosis changed from probable …neurodegenerative disease in 27 patients to a non-degenerative diagnosis and vice versa in 12 patients. PET changed the type of dementia in another 29 (15%) participants and prescription of cholinesterase inhibitors in 33 patients (17%). Number of uncertain diagnoses reduced from 58 to 35 (p < 0.001, χ2 = 15.12), differential diagnoses reduced from 127 to 55 (p = 0.003) and very probable diagnoses increased from 5 to 42 (p ≤ 0.001, χ2 = 1.01). Mini-Mental State Examination score was higher in those where PET had high diagnostic impact (26.3 ± 3.1 versus 23.9 ± 5.1, p ≤ 0.05). The degree of impact correlated with the pre-scan level of diagnostic uncertainty (ρ = −0.258, p < 0.001). Discussion: The management impact was higher in those with greater diagnostic uncertainty and in those with less severe cognitive impairment. The findings suggest that FDG-PET is a useful adjunct for the management of suspected dementing disorders in appropriately selected patients. Show more

Keywords: Alzheimer's disease, diagnostic impact, FDG-PET, memory clinic

DOI: 10.3233/JAD-132729

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 885-892, 2014

Authors: Shen, Xiao-Li | Yu, Jian-Han | Zhang, Dong-Feng | Xie, Jun-Xia | Jiang, Hong

Article Type: Research Article

Abstract: An imbalance of metal ions is implicated in the development of Alzheimer's disease (AD). We investigated the relationship between the annual mortality of AD and ionic concentration (iron, zinc, copper, and aluminum) in the soil in mainland China. The AD annual mortality data were from 26 provinces and 3 municipal districts within mainland China between the years 1991 and 2000 and provided by the National Death Cause Surveillance Database of China. The ionic concentration in soil was provided by the China State Environmental Protection Bureau, which was published in 1990. The results showed that the relative risk of mortality in …the regions with the highest copper concentrations (60–80 mg/kg) reached 2.634 (95% CI: 2.626–2.642) compared with the regions that had the lowest copper concentrations. The relative risk was 1.292 (95% CI: 1.290–1.294) and 1.248 (95% CI: 1.245–1.251) when the soil iron concentrations exceeded 3 mg/kg and 4 mg/kg, respectively. When the soil zinc concentration was over 100 mg/kg and 200 mg/kg, the relative risk was 1.870 (95% CI: 1.859–1.881) and 2.289 (95% CI: 2.276–2.304), respectively. However, the relative risk was 0.560 (95% CI: 0.559–0.561), 0.604 (95% CI: 0.603–0.605), and 0.267 (95% CI: 0.265–0.268) when the soil aluminum concentration was over 6 mg/kg, 7 mg/kg, and 8 mg/kg, respectively. This study suggests that high concentrations of iron and copper in the soil might be associated with the high AD annual mortality in this region in China, while aluminum had no association with AD mortality. Show more

Keywords: Alzheimer's disease, annual mortality, metals, soil

DOI: 10.3233/JAD-140153

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 893-900, 2014

Authors: Antonell, Anna | Mansilla, Alicia | Rami, Lorena | Lladó, Albert | Iranzo, Alex | Olives, Jaume | Balasa, Mircea | Sánchez-Valle, Raquel | Molinuevo, José Luis

Article Type: Research Article

Abstract: Background: An increase in YKL-40 levels seems to correlate with disease severity and poor prognosis in many diseases, including several neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease (AD). Specifically, YKL-40 protein is increased in mild AD with respect to controls, both in cerebrospinal fluid (CSF) and plasma. Objective: We hypothesize that subjects in the preclinical (Pre-AD) and prodromal (Prod-AD) stage of AD could already present an increase in CSF YKL-40 levels with respect to healthy controls and idiopathic REM sleep behavior disorder (iRBD) subjects, included as a control group of a distinct neurological …disease. Methods: We measured CSF YKL-40 levels using a commercial ELISA kit in a cohort of 95 subjects, consisting of controls (n = 43), Pre-AD (n = 18), Prod-AD (n = 22), and iRBD (n = 12) subjects. We explored for possible correlations of YKL-40 levels with demographic characteristics, a wide battery of neuropsychological tests, and the AD CSF biomarkers: amyloid-β42 (Aβ42 ), total-tau protein (t-tau), and phosphorylated-tau protein (p-tau). Results: We detected statistically significant differences between Prod-AD patients and controls. YKL-40 levels showed a significant correlation with t-tau and p-tau levels in the predementia AD continuum and the Pre-AD group. We also observed significant correlations with the MMSE, FCSRT, and M@T tests within the AD continuum, but not in iRBD subjects. Conclusion: Our data suggest that CSF YKL-40 levels, although not useful as a diagnostic marker for Prod-AD, may be a valuable marker to detect early physiopathological changes potentially linked with the neurodegenerative process. Show more

Keywords: Alzheimer's disease, amyloid-β42, cerebrospinal fluid, correlation, neuropsychological tests, preclinical, tau protein, YKL-40

DOI: 10.3233/JAD-140624

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 901-908, 2014

Authors: Williams, Michael A. | Silvestri, Vittorio | Craig, David | Passmore, A. Peter | Silvestri, Giuliana

Article Type: Research Article

Abstract: Background: Age-related macular degeneration (AMD) and Alzheimer’s disease (AD) share several features, including the presence of extracellular abnormal deposits associated with neuronal degeneration, drusen, and plaques, respectively. Investigation of any association of AMD and specifically AD is worthwhile but has rarely been done. Objectives: The aim of this study was to determine the prevalence of AMD in subjects with AD in comparison with an age-matched cognitively normal cohort. Methods: Cases were defined as those diagnosed with AD using standardized criteria as part of their clinical care, while controls were cognitively intact individuals aged 65 years or …more. Dilated retinal photographs were taken, and a range of potentially confounding factors measured including APOE genotype. AMD features were recorded and AMD grades given. Results: Data was collected on 322 controls and 258 cases. While AMD was associated with AD, and the proportion of cases of advanced AMD in AD cases was twice that of controls, when corrected the association was lost. AD was associated with age, the presence of an APOE allele, and smoking, while being ‘generally unwell recently’ was associated with a reduced risk of AD. Conclusion: AD and AMD are both associated with age, but our study does not find evidence they are associated with each other. However the retina offers an opportunity to non-invasively image neuronal tissue, and more sophisticated imaging techniques may shed light on ocular biomarkers of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, macular degeneration, retinal drusen

DOI: 10.3233/JAD-140243

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 909-914, 2014

Authors: Ma, Hui | Huang, Yinglin | Cong, Zhengtu | Wang, Yuan | Jiang, Wenhai | Gao, Shuhe | Zhu, Gang

Article Type: Research Article

Abstract: Background: The application of atypical antipsychotics (SGAs) for treatment of psychiatric and behavioral symptoms of dementia is controversial since their efficacy might be offset by their adverse events (AEs). Objective: To assess the efficacy, safety, and tolerability of SGAs for treatment of psychological and behavioral symptoms of dementia. Methods: Two researchers searched MEDLINE, PsychINFO, and the Cochrane Central Register of Controlled Trials independently for double-blind, placebo-controlled, randomized controlled trials (DB-PC-RCTs) as of June 2013, written in English. Efficacy was measured using the Brief Psychiatric Rating Scale (BPRS), Cohen-Mansfield Agitation Inventory (CMAI), Neuropsychiatric Inventory (NPI), Clinical Global …Impression of Change (CGI-C), and (or) Clinical Global Impression of Severity (CGI-S). Safety and tolerability were measured by frequencies of drop-outs, AEs, and death. In total, 19 treatment comparisons drawn from 16 DB-PC-RCTs were included, and 3,343 patients randomized to the antipsychotic group and 1,707 to the placebo group were assessed. Results: This meta-analysis demonstrated a significant efficacy of atypical antipsychotics on BPRS (MD = −1.58, 95% CI = −2.52 - −0.65), CMAI (−1.84, −3.01 - −0.61), NPI (−2.81, −4.35 - −1.28), CGI-C (−0.32, −0.44 - −0.20), and CGI-S (−0.19, −0.30 - −0.09), compared to placebo (p < 0.01 for all). Patients receiving atypical antipsychotics showed no difference in risk for discontinuation (p > 0.05), significantly higher risks (p < 0.05 for all) for somnolence (OR = 2.95), extrapyramidal symptoms (1.74), cerebrovascular AEs (2.50), urinary tract infection (1.35), edema (1.80), gait abnormality (3.35), and death (1.52), and a lower risk for agitation (OR = 0.80, p = 0.03). Conclusions: The higher risks for AEs and mortality may offset the efficacy of atypical antipsychotics for treatment of dementia. Efficacy, safety, and tolerability thus should be carefully considered against clinical need. Show more

Keywords: Antipsychotic, clinical trial, dementia, meta-analysis

DOI: 10.3233/JAD-140579

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 915-937, 2014

Authors: Puoti, Gianfranco | Lerza, Maria Cristina | Ferretti, Maria Giulia | Bugiani, Orso | Tagliavini, Fabrizio | Rossi, Giacomina

Article Type: Research Article

Abstract: Frontotemporal lobar degeneration (FTLD) is a very heterogeneous disorder. It is genetically linked to three major genes: microtubule-associated protein tau (MAPT), progranulin (GRN), and C9ORF72. In particular, mutations in GRN account for 5–10% of all cases and give rise to a wide spectrum of clinical phenotypes, ranging from behavioral frontotemporal dementia (bvFTD) to primary progressive aphasia, including progressive non-fluent aphasia (PNFA) and semantic dementia, and corticobasal syndrome (CBS). We studied a family affected by FTLD whose members showed three different phenotypes: bvFTD, PNFA, and CBS. We performed plasma progranulin measurement before any genetic analyses and, due to the low level …detected, we sequenced GRN and found the new mutation EX0-5′ splice site A > G in the 5′-UTR region, where no pathogenic mutations had been previously demonstrated. Genetic analyses of MAPT and C9ORF72 were normal. GRN mRNA expression showed about 50% reduction caused by this mutation, and similar results were found for progranulin level. Testing of nonsense mediated RNA decay gave negative results, suggesting a different mechanism of mRNA degradation. In summary, the EX0-5′ splice site A > G mutation widens the GRN regions affected by null mutations, including the 5′-UTR, and confirms once more the large phenotypic variability linked to GRN mutations. Show more

Keywords: Frontotemporal lobar degeneration, GRN, haploinsufficiency, mutation, phenotype, progranulin

DOI: 10.3233/JAD-140717

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 939-947, 2014

Authors: Michalowsky, Bernhard | Eichler, Tilly | Thyrian, Jochen René | Hertel, Johannes | Wucherer, Diana | Laufs, Sebastian | Fleßa, Steffen | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Results of cost-of-illness studies in dementia have shown a considerable divergence in costs of medication for persons with dementia. However, detailed economic analyses of medication costs for community-dwelling persons with dementia are currently still missing, especially on the basis of primary data. Objective: To determine medication cost, cost per drug, and number of drugs taken of community-dwelling persons with dementia and analyze their associated factors; to estimate the current price reduction of anti-dementia drugs due to implementation of low-priced generics. Method: The present analysis included 205 patients screened positive for dementia. Medication data were assessed …within a medication review. To estimate the cost effect of implementing generics, the most favorable equivalent generic was assigned to each anti-dementia drug. Factors associated with medication cost, cost per drug, and number of drugs taken were evaluated using multiple regression models. Results: Medication cost and cost per drug were higher and the number of taken drugs lower in advanced stages of cognitive impairment. Prescription of anti-dementia generics could decrease overall medication cost by 28%. Medication cost was associated with number of diagnoses, deficits in activities of daily living, and age. Dementia severity was related to cost per drug and number of drugs taken. Conclusion: Medication cost increases with the number of diagnoses and growing deficits in activities of daily living and decreases with age. Severely cognitively impaired persons are treated with a small number of high-priced drugs, which could suggest inadequate medication of multimorbid persons. Show more

Keywords: Dementia, drug substitution, drug therapy, economics, pharmaceutical economics

DOI: 10.3233/JAD-140804

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 949-958, 2014

Authors: Haig, George M. | Pritchett, Yili | Meier, Andreas | Othman, Ahmed A. | Hall, Coleen | Gault, Laura M. | Lenz, Robert A.

Article Type: Research Article

Abstract: Background: ABT-288, a highly selective histamine-3 receptor antagonist, demonstrated efficacy across several preclinical cognitive domains, and safety in healthy subjects and elderly volunteers. Objective: Evaluate the efficacy and safety of ABT-288 in subjects with mild-to-moderate Alzheimer’s dementia. Methods: The study used a randomized, double-blind, placebo- and active-controlled, parallel group design with pre-defined futility criteria to permit early study termination. A total of 242 subjects were randomized in an equal ratio to ABT-288 1 mg or 3 mg, donepezil 10 mg, or placebo once daily for 12 weeks. The primary efficacy endpoint was the change from baseline …to final evaluation on the 13-item Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score. Results: The study was prematurely terminated because futility criteria were met. Point estimates on the ADAS-Cog scores for both ABT-288 dose groups were numerically inferior to placebo but no statistical differences were detected. Donepezil demonstrated statistically significant improvement. Adverse events were generally mild and self-limiting. Conclusion: ABT-288 did not demonstrate efficacy in the symptomatic treatment of Alzheimer’s dementia. Show more

Keywords: ABT-288, Alzheimer's dementia, cognition, drug therapy, H3 antagonists, humans

DOI: 10.3233/JAD-140291

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 959-971, 2014

Authors: Cao, Chuanhai | Li, Yaqiong | Liu, Hui | Bai, Ge | Mayl, Jonathan | Lin, Xiaoyang | Sutherland, Kyle | Nabar, Neel | Cai, Jianfeng

Article Type: Research Article

Abstract: The purpose of this study was to investigate the potential therapeutic qualities of Δ9 -tetrahydrocannabinol (THC) with respect to slowing or halting the hallmark characteristics of Alzheimer's disease. N2a-variant amyloid-β protein precursor (AβPP) cells were incubated with THC and assayed for amyloid-β (Aβ) levels at the 6-, 24-, and 48-hour time marks. THC was also tested for synergy with caffeine, in respect to the reduction of the Aβ level in N2a/AβPPswe cells. THC was also tested to determine if multiple treatments were beneficial. The MTT assay was performed to test the toxicity of THC. Thioflavin T assays and western blots …were performed to test the direct anti-Aβ aggregation significance of THC. Lastly, THC was tested to determine its effects on glycogen synthase kinase-3β (GSK-3β) and related signaling pathways. From the results, we have discovered THC to be effective at lowering Aβ levels in N2a/AβPPswe cells at extremely low concentrations in a dose-dependent manner. However, no additive effect was found by combining caffeine and THC together. We did discover that THC directly interacts with Aβ peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3β levels and phosphorylated GSK-3β in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin's enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer's disease through multiple functions and pathways. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, cannabinoid, CB1 receptor, CB2 receptor, delta(9)-tetrahydrocannabinol, neurodegeneration

DOI: 10.3233/JAD-140093

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 973-984, 2014

Authors: Goto, Seiko | Kamal, Naveed | Puzio, Helene | Kobylarz, Fred | Herrup, Karl

Article Type: Research Article

Abstract: The purpose of this study was to determine the responses of individuals with advanced dementia to two novel sensory environments in a nursing home facility. The first was a multisensory Snoezelen room; the second was a temporary Japanese garden. Subjects viewed each environment twice a week for 15 minutes during the study. Stress was measured using heart rate and informant-based behavioral changes. By these criteria, the garden-viewing group showed positive behavioral changes while the responses of the subjects in the Snoezelen group were more negative. The response of the subjects' pulse rate was most dramatic. During the 15 minutes in …the garden, the average rate (all subjects/all visits) was significantly less than in their residential room. In the Snoezelen room, we detected little or no change. The impact of the garden could also be seen in the negative behavioral signs elicited upon returning the subjects to the garden room after the installation had been replaced with plants and furniture arranged with no formal design. We propose that exposure to a small interior Japanese garden could be an effective intervention for individuals suffering from late stage Alzheimer's disease. Show more

Keywords: Dementia, heart rate, Japanese garden, nursing home, Snoezelen room

DOI: 10.3233/JAD-131379

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 985-998, 2014

Authors: Libon, David J. | Drabick, Deborah A.G. | Giovannetti, Tania | Price, Catherine C. | Bondi, Mark W. | Eppig, Joel | Devlin, Kathryn | Nieves, Christine | Lamar, Melissa | Delano-Wood, Lisa | Nation, Daniel A. | Brennan, Laura | Au, Rhoda | Swenson, Rod

Article Type: Research Article

Abstract: Background: Epidemiologic autopsy studies show mixed Alzheimer’s disease (AD)/vascular pathology in many patients. Moreover, clinical research shows that it is not uncommon for AD and vascular dementia (VaD) patients to be equally impaired on memory, executive, or other neurocognitive tests. However, this clinical heterogeneity has not been incorporated into the new diagnostic criteria for AD (Dubois et al., 2010; McKhann et al., 2011). Objective: The current research applied Latent Class Analysis (LCA) to a protocol of six neuropsychological parameters to identify phenotypic subtypes from a large group of AD/VaD participants. Follow-up analyses examined difference between groups on neuroradiological …parameters and neuropsychological measures of process and errors. Methods: 223 AD/VaD patients were administered a comprehensive neuropsychological protocol. Measures of whole brain and hippocampal volume were available for a portion of the sample (n = 76). Results: LCA identified four distinct groups: moderate/mixed dementia (n = 54; 24.21%), mild/mixed dementia (n = 91; 40.80%); dysexecutive (n = 49, 21.97%), and amnestic (n = 29, 13.00%). Follow-up analyses comparing the groups on neuropsychological process and error scores showed that the dysexecutive group exhibited difficulty sustaining mental set. The moderate/mixed group evidenced pronounced impairment on tests of lexical retrieval/naming along with significant amnesia. Amnestic patients also presented with gross amnesia, but showed relative sparing on other neuropsychological measures. Mild/mixed patients exhibited milder memory deficits that were intermediary between the amnestic and moderate/mixed groups. Conclusions: There are distinct neuropsychological profiles in patients independent of clinical diagnosis, suggesting that the two are not wholly separate and that this information should be integrated into new AD diagnostic paradigms. Show more

Keywords: Alzheimer's disease, latent class analysis, mixed dementia, vascular dementia

DOI: 10.3233/JAD-132147

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 999-1014, 2014

Authors: Guerini, Franca Rosa | Agliardi, Cristina | Sironi, Manuela | Arosio, Beatrice | Calabrese, Elena | Zanzottera, Milena | Bolognesi, Elisabetta | Ricci, Cristian | Costa, Andrea Saul | Galimberti, Daniela | Griffanti, Ludovica | Bianchi, Anna | Savazzi, Federica | Mari, Daniela | Scarpini, Elio | Baglio, Francesca | Nemni, Raffaello | Clerici, Mario

Article Type: Research Article

Abstract: Synaptosomal-associated protein of 25 kDa (SNAP-25) is an age-regulated vesicular SNARE protein involved in the exocytosis of neurotransmitters from synapses, a process that is altered in Alzheimer's disease (AD). Changes in SNAP-25 levels are suggested to contribute to age-related decline of cognitive function, and single nucleotide polymorphisms (SNPs) in the SNAP-25 gene are present in neuropsychiatric conditions and play a role in determining IQ phenotypes. To verify a possible role of SNAP-25 in AD, we analyzed five gene polymorphisms in patients with AD (n = 607), replicating the study in subjects with amnestic mild cognitive impairment (aMCI) (n = 148) …and in two groups of age-matched healthy controls (HC1: n = 615 and HC2: n = 310). Results showed that the intronic rs363050 (A) and rs363043 (T) alleles, as well as the rs363050/rs363043 A-T haplotype are significantly more frequent in AD and aMCI and are associated with pathological scores of categorical fluency in AD. Notably, functional MRI analyses indicated that SNAP-25 genotypes correlate with a significantly decreased brain activity in the cingulate cortex and in the frontal (middle and superior gyri) and the temporo-parietal (angular gyrus) area. SNAP-25 polymorphisms may be associated with AD and correlate with alterations in categorical fluency and a reduced localized brain activity. SNAP-25 polymorphisms could be used as surrogate markers for the diagnosis of AD and of cognitive deficit; these SNPs might also have a possible predictive role in the natural history of AD. Show more

Keywords: Alzheimer's disease, categorical fluency, cognitive impairment, functional MRI, genetic polymorphisms, SNAP-25

DOI: 10.3233/JAD-140057

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 1015-1028, 2014

Authors: Xia, Yiyuan | Liu, Rong | Chen, Rong | Tian, Qing | Zeng, Kuan | Hu, Jichang | Liu, Xinghua | Wang, Qun | Wang, Peng | Wang, Xiao-Chuan | Wang, Jian-Zhi

Article Type: Research Article

Abstract: Alzheimer's disease (AD) has multiple etiopathogenic factors, yet the definitive cause remains unclear and the therapeutic strategies have been elusive. Combination therapy, as one of the promising treatments, has been studied for years and may exert synergistic beneficial effects on AD through polytherapeutic targets. In this study, we tested the effects of a synthesized juxtaposition (named SCR1693) composed of an acetylcholinesterase inhibitor (AChEI) and a calcium channel blocker (CCB) on the hyperhomocysteinemia (HHcy)-induced AD rat model, and found that SCR1693 remarkably improved the HHcy-induced memory deficits and preserved dendrite morphologies as well as spine density by upregulating synapse-associated proteins PSD95 …and synapsin-1. In addition, SCR1693 attenuated HHcy-induced tau hyperphosphorylation at multiple AD-associated sites by regulating the activity of protein phosphatase-2A and glycogen synthase kinase-3β. Furthermore, SCR1693 was more effective than individual administration of both donepezil and nilvadipine which were used as AChEI and CCB, respectively, in the clinical practice. In conclusion, our data suggest that the polytherapeutic targeting juxtaposition SCR1693 (AChEI-CCB) is a promising therapeutic candidate for AD. Show more

Keywords: Alzheimer's disease, GSK-3β, hyperhomocysteinemia, PP2A, SCR1693, tau

DOI: 10.3233/JAD-140597

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 1029-1039, 2014

Authors: Struhal, Walter | Javor, Andrija | Brunner, Cornelia | Benesch, Thomas | Schmidt, Verena | Vosko, Milan R. | Ransmayr, Gerhard

Article Type: Research Article

Abstract: Background: Patients with autonomic failure may experience postural dizziness, syncope, and falls. Identifying symptomatic dysautonomia in dementia is of importance to ensure appropriate management and reduce risk of falls. Objective: The aim of this prospective study is to identify cardiovascular autonomic dysfunction in patients suffering from behavioral variant of frontotemporal dementia (bvFTD), compared to Alzheimer’s disease (AD). Methods: Patients were prospectively recruited from 2009 until 2013. Clinical autonomic function tests were carried out in an Autonomic Unit according to Ewing’s cardiovascular battery. Parasympathetic tests included resting heart rate variability, deep breathing, and Valsalva. Sympathetic function tests …compromised blood pressure regulation on valsalva, cutaneous cold stimulation, and 70° head up tilt including of plasma noradrenaline. Results: 26 patients (17 female) with bvFTD and 18 patients (10 female) with AD were examined. Mean age of bvFTD was 69 ± 11 years, AD 74 ± 9 years. History taking was often not conclusive and did not correlate with autonomic signs. In 42% bvFTD patients and 44% AD patients, autonomic dysfunction was demonstrated. Manifest orthostatic hypotension (OH) was present in 19% of bvFTD and 33% AD patients. Frequency of autonomic dysfunction and orthostatic hypotension did not differ between bvFTD and AD, but were significantly higher than in healthy controls. Autonomic dysfunction was associated with an increased risk of falling (assessed with Tinetti Score). Conclusion: This is the first prospective study to elucidate autonomic dysfunction in bvFTD patients. There is a considerable higher frequency of cardiovascular dysfunction and OH in bvFTD. History taking may be not conclusive thus cannot exclude cardiovascular dysautonomia. Show more

Keywords: Alzheimer's disease, autonomic dysfunction, autonomic nervous system, dementia, frontotemporal dementia

DOI: 10.3233/JAD-140531

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 1041-1046, 2014

Article Type: Other

DOI: 10.3233/JAD-140532

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 1047-1049, 2014