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

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