Journal of Alzheimer's Disease - Volume 46, issue 3

Authors: O’Day, Danton H. | Eshak, Kristeen | Myre, Michael A.

Article Type: Review Article

Abstract: The small, calcium-sensor protein, calmodulin, is ubiquitously expressed and central to cell function in all cell types. Here the literature linking calmodulin to Alzheimer’s disease is reviewed. Several experimentally-verified calmodulin-binding proteins are involved in the formation of amyloid-β plaques including amyloid-β protein precursor, β-secretase, presenilin-1, and ADAM10. Many others possess potential calmodulin-binding domains that remain to be verified. Three calmodulin binding proteins are associated with the formation of neurofibrillary tangles: two kinases (CaMKII, CDK5) and one protein phosphatase (PP2B or calcineurin). Many of the genes recently identified by genome wide association studies and other studies encode proteins that contain putative …calmodulin-binding domains but only a couple (e.g., APOE, BIN1) have been experimentally confirmed as calmodulin binding proteins. At least two receptors involved in calcium metabolism and linked to Alzheimer’s disease (mAchR; NMDAR) have also been identified as calmodulin-binding proteins. In addition to this, many proteins that are involved in other cellular events intimately associated with Alzheimer’s disease including calcium channel function, cholesterol metabolism, neuroinflammation, endocytosis, cell cycle events, and apoptosis have been tentatively or experimentally verified as calmodulin binding proteins. The use of calmodulin as a potential biomarker and as a therapeutic target is discussed. Show more

Keywords: Alzheimer’s disease, calcium, calcium channels, calmodulin, calmodulin binding proteins, cholesterol metabolism, endocytosis, genome wide association studies, neuroinflammation

DOI: 10.3233/JAD-142772

Citation: Journal of Alzheimer's Disease, vol. 46, no. 3, pp. 553-569, 2015

Authors: Villa, Chiara | Ferini-Strambi, Luigi | Combi, Romina

Article Type: Review Article

Abstract: Sleep disorders are frequently reported in Alzheimer’s disease (AD), with a significant impact on patients and caregivers and a major risk factor for early institutionalization. Although changes in sleep organization are a hallmark of the normal aging processes, sleep macro- and micro-architectural alterations are more evident in patients affected by AD. Degeneration of neural pathways regulating sleep-wake patterns and sleep architecture may contribute to sleep alterations. In return, several recent studies suggested that common sleep disorders may precede clinical symptoms of dementia and represent risk factors for cognitive decline, through impairment of sleep-dependent memory consolidation processes. Thus, a close relationship …between sleep disorders and AD has been largely hypothesized. Here, sleep alterations in AD and its pre-dementia stage, mild cognitive impairment, and their complex interactions are reviewed. Show more

Keywords: Alzheimer’s disease, amyloid-β , mild cognitive impairment, sleep disorders

DOI: 10.3233/JAD-150138

Citation: Journal of Alzheimer's Disease, vol. 46, no. 3, pp. 571-580, 2015

Authors: Bhat, Narayan R.

Article Type: Review Article

Abstract: Using a variety of animal models of Alzheimer’s disease (AD), there have been a number of recent studies reporting varying degrees of success with anti-AD therapeutics. The efficacies are often discussed in terms of the modulatory effects of the compounds tested on identified or assumed targets among the known (or proposed) pathogenic and neuroprotective mechanisms, largely within the context of the dominant amyloid cascade hypothesis. However, it is clear that several of the relatively more efficacious treatments tend to be multifunctional and target multiple pathological processes associated with AD including most commonly, oxidative and metabolic stress and neuroinflammation. Increasing evidence …suggests that vascular and neurodegenerative pathologies often co-exist and that neurovascular dysfunction plays a critical role in the development or progression of AD. In this review, we will discuss the significance of vasculoprotection or neurovascular unit integrity as a common, multi-targeted mechanism underlying the reported efficacy of a majority of anti-AD therapeutics— amyloid-targeted or otherwise— while providing a strong support for future neurovascular-based treatment strategies and interventions. Show more

Keywords: Anti-AD therapeutics, blood-brain barrier, cerebrovascular dysfunction, neurovascular unit, type 2-diabetes, vascular risk factors

DOI: 10.3233/JAD-150098

Citation: Journal of Alzheimer's Disease, vol. 46, no. 3, pp. 581-591, 2015

Authors: Brewer, George J.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is at epidemic proportions in developed countries, with a steady increase in the early 1900 s, and then exploding over the last 50 years. This epidemiology points to something causative in the environment of developed countries. This paper will review the considerable evidence that that something could be inorganic copper ingestion. The epidemic parallels closely the spread of copper plumbing, with copper leached from the plumbing into drinking water being a main causal feature, aided by the increasingly common use of supplement pills containing copper. Inorganic copper is divalent copper, or copper-2, while we now know that organic …copper, or copper in foods, is primarily monovalent copper, or copper-1. The intestinal transport system, Ctr1, absorbs copper-1 and the copper moves to the liver, where it is put into safe channels. Copper-2 is not absorbed by Ctr1, and some of it bypasses the liver and goes directly into the blood, where it appears to be exquisitely toxic to brain cognition. Thus, while aggregation of amyloid-β has been postulated to be the cause of AD under current dogma, the great increase in prevalence over the last century appears to be due to ingestion of copper-2, which may be causing the aggregation, and/or increasing the oxidant toxicity of the aggregates. An alternative hypothesis proposes that oxidant stress is the primary injuring agent, and under this hypothesis, copper-2 accumulation in the brain may be a causal factor of the oxidant injury. Thus, irrespective of which hypothesis is correct, AD can be classified, at least in part, as a copper-2 toxicity disease. It is relatively easy to avoid copper-2 ingestion, as discussed in this review. If most people begin avoiding copper-2 ingestion, perhaps the epidemic of this serious disease can be aborted. Show more

Keywords: Alzheimer’s disease, copper-2, copper plumbing, copper supplement pills, dementia, inorganic copper

DOI: 10.3233/JAD-143123

Citation: Journal of Alzheimer's Disease, vol. 46, no. 3, pp. 593-604, 2015

Authors: Müller, Mareike | Claassen, Jurgen A. | Kuiperij, H. Bea | Verbeek, Marcel M.

Article Type: Short Communication

Abstract: Neuronal Cell Adhesion Molecule (NrCAM) is a proposed new cerebrospinal fluid (CSF) biomarker in Alzheimer’s disease (AD). In this pilot study, we aimed to validate and extend previous results and measured NrCAM by ELISA in CSF of patients with AD, frontotemporal dementia, dementia with Lewy bodies, and non-demented controls. NrCAM levels were comparable in all groups, but correlated positively with total tau and phosphorylated tau levels. Furthermore, NrCAM had no significant additional diagnostic value when combined with amyloid-β42 , total tau, and phosphorylated tau proteins. Therefore, NrCAM is not a suitable CSF biomarker to differentiate between dementia groups.

Keywords: Alzheimer’s disease, biological markers, cerebrospinal fluid, dementia with Lewy bodies, frontotemporal dementia, NrCAM

DOI: 10.3233/JAD-142901

Citation: Journal of Alzheimer's Disease, vol. 46, no. 3, pp. 605-609, 2015

Authors: Sun, Jia-Hao | Tan, Lan | Wang, Hui-Fu | Tan, Meng-Shan | Tan, Lin | Li, Jie-Qiong | Xu, Wei | Zhu, Xi-Chen | Jiang, Teng | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Vascular dementia (VaD) is the second most common type of dementia. So far, little is known about the contribution of genetic polymorphisms to the risk of VaD. Many candidate genetic polymorphisms have been examined in a large number of studies. However, due to the conflicting results, the genetics of VaD is still behind the shadow. Objective: We conducted a comprehensive meta-analysis on associations between genetic polymorphisms of any gene and VaD to investigate the genetics of VaD. Method: We sought the published studies of associations between any genetic polymorphism and VaD …and critically appraised them. We assessed the effects of genetic models by calculating pooled odds ratios (ORs), investigating the origin of heterogeneity by subgroup analysis, and testing the robustness by random effect model and sensitivity analysis. Results: 69 studies with 4,462 cases and 11,583 controls were included. We identified APOE ɛ 2/ɛ 3/ɛ 4 and additional four genetic polymorphisms including MTHFR C677T, PON1 L55M, TGF-β 1 +29C/T, and TNF-α −850C/T associated with VaD. Tested by random effect model and sensitivity analysis, the pooled results show nice robustness. Conclusions: Our comprehensive meta-analysis highlighted the genetic contribution to sporadic VaD. Because of the small amount of data on associations between genetic polymorphisms, except for APOE, and VaD, more studies are needed to test the existing genetic polymorphisms and detect other related genetic variants. Show more

Keywords: Apolipoprotein E, dementia, genetics, polymorphism, vascular dementia

DOI: 10.3233/JAD-143102

Citation: Journal of Alzheimer's Disease, vol. 46, no. 3, pp. 611-629, 2015

Authors: Pusswald, Gisela | Lehrner, Johann | Hagmann, Michael | Dal-Bianco, Peter | Benke, Thomas | Marisa Loitfelder, | Marksteiner, Josef | Mosbacher, Jochen | Ransmayr, Gerhard | Sanin, Guenter | Schmidt, Reinhold | and PRODEM Study Group

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is one of the most common age-related diseases in the western world. Gender differences in neuropsychological functions are seldom evaluated in AD. Objective: Recent investigations suggested that gender may be an important modifying factor in the development and progression of AD. We examined gender-specific differences in the pattern of cognitive dysfunction of patients with mild to moderate AD. Methods: We examined 113 males (mean age 78) and 173 females (mean age 80) of the prospective registry on dementia in Austria (PRODEM). We analyzed differences in the cognitive profile between male and …female AD patients on the CERAD-Plus test battery. Results: We found gender-related differences in the neuropsychological domains of verbal learning; the women tended to perform worse than men. Controlling for depression, stage and duration of dementia, and the level of education, there was still a significant effect of gender on verbal episodic memory. Conclusion: There is an interaction between gender and cognitive function, most notable in verbal episodic memory; female patients in the early stage of AD performed worse on verbal episodic memory than men. This indicates that the gender-specificities of neuropsychological functions should be given careful consideration in clinical diagnosis of dementia. Show more

Keywords: Alzheimer’s dementia, Alzheimer’s disease, cognitive function, episodic memory, gender differences

DOI: 10.3233/JAD-150188

Citation: Journal of Alzheimer's Disease, vol. 46, no. 3, pp. 631-637, 2015

Authors: Moodley, Kuven K. | Perani, Daniela | Minati, Ludovico | Anthony Della Rosa, Pasquale | Pennycook, Frank | Dickson, John C. | Barnes, Anna | Elisa Contarino, Valeria | Michopoulou, Sofia | D’Incerti, Ludovico | Good, Catriona | Fallanca, Federico | Giovanna Vanoli, Emilia | Ell, Peter J. | Chan, Dennis

Article Type: Research Article

Abstract: Background: Simultaneous PET-MRI is used to compare patterns of cerebral hypometabolism and atrophy in six different dementia syndromes. Objectives: The primary objective was to conduct an initial exploratory study regarding the concordance of atrophy and hypometabolism in syndromic variants of Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The secondary objective was to determine the effect of image analysis methods on determination of atrophy and hypometabolism. Method: PET and MRI data were acquired simultaneously on 24 subjects with six variants of AD and FTD (n  = 4 per group). Atrophy was rated visually and also quantified with …measures of cortical thickness. Hypometabolism was rated visually and also quantified using atlas- and SPM-based approaches. Concordance was measured using weighted Cohen’s kappa. Results: Atrophy-hypometabolism concordance differed markedly between patient groups; kappa scores ranged from 0.13 (nonfluent/agrammatic variant of primary progressive aphasia, nfvPPA) to 0.49 (posterior cortical variant of AD, PCA). Heterogeneity was also observed within groups; the confidence intervals of kappa scores ranging from 0–0.25 for PCA to 0.29–0.61 for nfvPPA. More widespread MRI and PET changes were identified using quantitative methods than on visual rating. Conclusion: The marked differences in concordance identified in this initial study may reflect differences in the molecular pathologies underlying AD and FTD syndromic variants but also operational differences in the methods used to diagnose these syndromes. The superior ability of quantitative methodologies to detect changes on PET and MRI, if confirmed on larger cohorts, may favor their usage over qualitative visual inspection in future clinical diagnostic practice Show more

Keywords: Alzheimer’s disease, atrophy, frontotemporal dementia, hypometabolism, NEUROSTAT, simultaneous PET-MRI, statistical parametric mapping, visual rating

DOI: 10.3233/JAD-150151

Citation: Journal of Alzheimer's Disease, vol. 46, no. 3, pp. 639-653, 2015

Authors: Licastro, Federico | Raschi, Elena | Carbone, Ilaria | Porcellini, Elisa

Article Type: Research Article

Abstract: A gene association study of factors regulating antiviral response such as interferon (IFN)-λ3, also known as IL-28B, mediator complex (Med) 23, and interferon regulatory factor (IRF) 7 with cognitive deterioration and Alzheimer’s disease (AD) was performed. Differences in the TT genotype distribution of IL-28B single nucleotide polymorphism (SNP) between AD patients and controls were found. The GG genotype of Med23 gene appeared to influence the progression of the disease, being more frequent in the APOE ɛ 4 negative elderly that developed AD during the five year follow-up. Leukocyte positivity for Epstein Barr virus (EBV) and human herpes virus (HHV)-6 DNA …was analyzed. Med23 GG genotype correlated with the positivity to HHV-6 DNA. EBV and HHV-6 plasma IgG levels were also investigated and EBV IgG levels were increased in AD with the IRF7 GG genotype. A differential genetic background in genes regulating anti-virus responses was associated with an increased risk of cognitive decline and AD. EBV and HHV-6 appeared to be risk factors for AD in genetically susceptible elderly. Show more

Keywords: Alzheimer’s disease, antiviral genes, case-control study, gene polymorphisms, herpes virus infection

DOI: 10.3233/JAD-142718

Citation: Journal of Alzheimer's Disease, vol. 46, no. 3, pp. 655-663, 2015

Authors: Zhang, Junying | Xu, Kai | Wei, Dongfeng | Guo, Rongjuan | Li, He | Wang, Yongyan | Zhang, Zhanjun

Article Type: Research Article

Abstract: Background: Observing the effects of a drug on episodic memory and the underlying brain function has extreme significance in evaluating its therapeutic value in treating amnestic mild cognitive impairment (aMCI). Objective: To observe the effects of Bushen capsule (BSC), a Chinese herbal medicine, on episodic memory in aMCI and further explore the underlying mechanism. Methods: 44 aMCI patients from hospitals and local communities in Beijing were randomly divided into the BSC treatment group (22 patients orally treated with BSC) and the placebo group (22 patients treated with placebo). The duration of intervention lasted for 3 …months. Before and after the 3 months treatment, neuropsychological tests and fMRI examinations were carried out to assess cognitive ability and brain activation changes, respectively. Results: Compared to the placebo group, the BSC group presented a significant increase in the AVLT(N5) (p  = 0.003) and Stroop (C-B) time (p  = 0.002). fMRI results showed a reduction of brain negative activation in the right middle temporal gyrus and a positive activation enhancement in the right putamen among the BSC group after treatment. Meanwhile, the variation in activation values in the right middle temporal gyrus was significantly correlated with the improvement in test values of AVLT(N5), and the variation in deactivation values in the right putamen was significantly correlated with the improvement in test values of Stroop (C-B) time. Conclusions: BSC can improve the behavioral performances of episodic memory in aMCI; this effect may be related to its modulation on the activations of the temporal lobe and the putamen under episodic memory encoding task. Show more

Keywords: activation, deactivation, compound Chinese medicine, episodic memory, functional magnetic resonance imaging, amnestic mild cognitive impairment

DOI: 10.3233/JAD-150004

Citation: Journal of Alzheimer's Disease, vol. 46, no. 3, pp. 665-676, 2015