Journal of Alzheimer's Disease - Volume 42, issue 4

Authors: Tan, Chen-Chen | Yu, Jin-Tai | Tan, Lan

Article Type: Review Article

Abstract: Currently, there is a pressing need to shift the focus to accurate detection of the earliest phase of increasingly preclinical Alzheimer's disease (AD). Meanwhile, the growing recognition that the pathophysiological process of AD begins many years prior to clinically obvious symptoms and the concept of a presymptomatic or preclinical stage of AD are becoming more widely accepted. Advances in clinical identification of new measurements will be critical not only in the discovery of sensitive, specific, and reliable biomarkers of preclinical AD but also in the development of tests that will aid in the early detection and differential diagnosis of dementia …and in monitoring disease progression. The goal of this review is to provide an overview of biomarkers for preclinical AD, with emphasis on neuroimaging and neurochemical biomarkers. We conclude with a discussion of emergent directions for AD biomarker research. Show more

Keywords: Biomarker, blood, cerebrospinal fluid biomarkers, clinical biomarkers, genetic biomarkers, neuroimaging, preclinical Alzheimer's disease

DOI: 10.3233/JAD-140843

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1051-1069, 2014

Authors: Monacelli, Fiammetta | Rosa, Gianmarco

Article Type: Review Article

Abstract: Alzheimer's disease is a life shortening disease, and the lack of disease modifying therapy implies a huge impact on life expectancy as well as an outgrowing financial and socioeconomic burden. Cholinesterase inhibitors (ChEIs) represent the first line symptomatic therapy, whose benefit to harm ratio is still a matter of debate. Acetylcholinesterase enzyme is a core interest for pharmacological and toxicological research to unmask the fine balance between therapeutic drug efficacy, tolerability, safety, and detrimental effects up to adverse drug reaction. So far, a body of evidence advocated that an increased vagal tone was associated to an increased risk of gastrointestinal …and cardiac side effects (negative chronotropic, arrhytmogenic, hypotensive effects), able to hamper ChEIs effects on cognition, reducing administration feasibility and compliance, especially in older and comorbid patients. Conversely, a growing body of evidence is indicating a protective role of ChEIs on overall cardiovascular mortality in patients with dementia, through a series of in vitro and in vivo investigations. The present review is aimed to report the up to date literature in the controversial field of ChEIs and cardioprotection in dementia, offering a state of the art, which may constitute the conceptual framework to be enlarged in order to build higher evidence. Chronic vagal nerve stimulation acted upon by donepezil might improve long term survival through pharmacological properties apart from cholinesterase inhibition, able to offer cardioprotection, abating the overall cardiovascular risk, and, thus profiling a new line of therapeutic intervention for ChEI drug class. Show more

Keywords: Alzheimer's disease, cardioprotection, cholinesterase inhibitors, increased survival

DOI: 10.3233/JAD-141089

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1071-1077, 2014

Authors: Froestl, Wolfgang | Pfeifer, Andrea | Muhs, Andreas

Article Type: Review Article

Abstract: Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers, are very productive. The review “Drugs interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs” was accepted in October 2012. In the last 20 months, new targets for the potential treatment of Alzheimer's disease were identified. Enormous progress was realized in the pharmacological characterization of natural products with cognitive enhancing properties. This review covers the evolution of research in this field through May 2014.

Keywords: Amyloid-β aggregation inhibitors, antibodies, antioxidants, cognitive enhancers, metal chelators, natural products, nootropics, peptides, psychostimulants, stem cells, tau, vaccines

DOI: 10.3233/JAD-141206

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1079-1149, 2014

Authors: D'Alton, Simon | Hunter, Sally | Whitehouse, Peter | Brayne, Carol | George, Daniel

Article Type: Research Article

Abstract: For the last several decades, Alzheimer's disease (AD) has been widely regarded as a late life event, but is now being redefined as a chronic condition that develops over decades. Concurrently, a preponderance of evidence emerging from basic and clinical research in diverse fields such as cardiovascular, endocrine, and mental health has suggested that the environmental component of clinical AD is not only multifactorial in populations and in individuals, but is also modifiable across the life-course, from conception until death. Re-conceptualizing the environmental component of AD to account for these observations necessitates an approach to brain health that eschews singular, …short- and medium-term methodology and instead reflects long-term complexity. Such thinking is consistent with the ecological models of public health, which emphasize the development of community infrastructure that can foster population and individual health over the life-course by minimizing risk through multifaceted, systemic approaches. Show more

Keywords: Alzheimer's disease, amyloid, dementia, epidemiology, public heath, risk factors, social policy

DOI: 10.3233/JAD-140213

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1151-1163, 2014

Authors: Miura, Yumako | Miyaji, Kazuki | Chai, Yuek Ling | Chen, Christopher L.H. | Lai, Mitchell K.P. | Yuki, Nobuhiro

Article Type: Research Article

Abstract: A few studies have reported the association of autoantibodies to GM1 or GQ1bα with Alzheimer's disease (AD) or vascular dementia. Here we investigated whether patients with AD or vascular dementia had high titers of the anti-ganglioside antibodies. Sera were obtained from patients with AD (n = 22), vascular dementia (n = 14), Guillain–Barré syndrome, and multifocal motor neuropathy as well as normal controls. Enzyme-linked immunosorbent assay showed titers of IgG and IgM anti-GM1, anti-GQ1bα, and anti-GT1aα antibodies did not differ among AD, vascular dementia, and normal controls, and being remarkably lower than those in Guillain–Barré syndrome and multifocal motor neuropathy. …The anti-ganglioside antibodies are not biological markers of AD. Show more

Keywords: Alzheimer's disease, anti-ganglioside antibody, biological marker, ganglioside

DOI: 10.3233/JAD-140474

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1165-1169, 2014

Authors: Vita, Maria Gabriella | Marra, Camillo | Spinelli, Pietro | Caprara, Alessia | Scaricamazza, Eugenia | Castelli, Diana | Canulli, Serena | Gainotti, Guido | Quaranta, Davide

Article Type: Research Article

Abstract: Semantic and, to a lesser extent, phonological verbal fluency tasks are impaired in Alzheimer's disease (AD) and in amnesic mild cognitive impairment (aMCI). Furthermore, both fluency tasks have been considered as possible markers of conversion from aMCI to AD. Up to recent years, the use of fluency tasks has been limited to word count, but, more recently, linguistic variables, such as word frequency, age of acquisition, familiarity, and typicality, have also been considered. In particular, attention has been focused on typicality of words produced on semantic verbal fluency tasks, because the tendency to produce only the more typical members of …various categories points to an impoverishment of semantic memory. The aim of our study was to compare in aMCI, AD, and control subjects a lexical (word frequency) and a lexical-semantic variable (item typicality) in a semantic verbal fluency task, and to evaluate the possible value of these variables in predicting conversion from aMCI to AD during a 2 years follow-up period. We found no difference in mean typicality of words produced by aMCI and AD subjects whereas both groups produced words of higher mean typicality than control subjects. Furthermore, to assess the relationship between typicality values and risk of conversion to AD, the aMCI group was split in two subgroups, including subjects who obtained a mean typicality value lower or higher than the median value of the whole aMCI group. Consistent with our hypothesis, conversion to AD was significantly more frequent in high typicality than in low typicality subjects. Show more

Keywords: Alzheimer's disease, frequency of use, mild cognitive impairment, semantic disturbance, semantic fluency, typicality

DOI: 10.3233/JAD-140570

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1171-1178, 2014

Authors: Laursen, Bettina | Mørk, Arne | Kristiansen, Uffe | Bastlund, Jesper Frank

Article Type: Research Article

Abstract: P300 (P3) event-related potentials (ERPs) have been suggested to be an endogenous marker of cognitive function and auditory oddball paradigms are frequently used to evaluate P3 ERPs in clinical settings. Deficits in P3 amplitude and latency reflect some of the neurological dysfunctions related to several psychiatric and neurological diseases, e.g., Alzheimer's disease (AD). However, only a very limited number of rodent studies have addressed the back-translational validity of the P3-like ERPs as suitable markers of cognition. Thus, the potential of rodent P3-like ERPs to predict pro-cognitive effects in humans remains to be fully validated. The current study characterizes P3-like ERPs …in the 192-IgG-SAP (SAP) rat model of the cholinergic degeneration associated with AD. Following training in a combined auditory oddball and lever-press setup, rats were subjected to bilateral intracerebroventricular infusion of 1.25 μg SAP or PBS (sham lesion) and recording electrodes were implanted in hippocampal CA1. Relative to sham-lesioned rats, SAP-lesioned rats had significantly reduced amplitude of P3-like ERPs. P3 amplitude was significantly increased in SAP-treated rats following pre-treatment with 1 mg/kg donepezil. Infusion of SAP reduced the hippocampal choline acetyltransferase activity by 75%. Behaviorally defined cognitive performance was comparable between treatment groups. The present study suggests that AD-like deficits in P3-like ERPs may be mimicked by the basal forebrain cholinergic degeneration induced by SAP. SAP-lesioned rats may constitute a suitable model to test the efficacy of pro-cognitive substances in an applied experimental setup. Show more

Keywords: Alzheimer's disease, donepezil, 192-IgG-SAP, P300 event-related potential, rat

DOI: 10.3233/JAD-131502

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1179-1189, 2014

Authors: Nolan, John M. | Loskutova, Ekaterina | Howard, Alan N. | Moran, Rachel | Mulcahy, Riona | Stack, Jim | Bolger, Maggie | Dennison, Jessica | Akuffo, Kwadwo Owusu | Owens, Niamh | Thurnham, David I. | Beatty, Stephen

Article Type: Research Article

Abstract: Background: The macula (central retina) contains a yellow pigment, comprising the dietary carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin, known as macular pigment (MP). The concentrations of MP’s constituent carotenoids in retina and brain tissue correlate, and there is a biologically-plausible rationale, supported by emerging evidence, that MP’s constituent carotenoids are also important for cognitive function. Objective: To investigate if patients with Alzheimer’s disease (AD) are comparable to controls in terms of MP and visual function. Methods: 36 patients with moderate AD and 33 controls with the same age range participated. MP was measured using dual-wavelength …autofluorescence (Heidelberg Spectralis® ); cognitive function was assessed using a battery of cognition tests (including Cambridge Neuropsychological Test Automated Battery). Visual function was recorded by measuring best corrected visual acuity (BCVA) and contrast sensitivity (CS). Serum L and Z concentrations (by HPLC) and age-related macular degeneration (AMD, by retinal examination) status were also assessed. Results: In the AD group, central MP (i.e., at 0.23°) and MP volume were significantly lower than the control group (p < 0.001 for both), as were measures of BCVA, CS, and serum L and Z concentrations (p < 0.05, for all). Conclusion: AD patients were observed to exhibit significantly less MP, lower serum concentrations of L and Z, poorer vision, and a higher occurrence of AMD when compared to control subjects. A clinical trial in AD patients designed to investigate the impact of macular carotenoid supplementation with respect to MP, visual function, and cognitive function is merited. Show more

Keywords: Age-related macular degeneration, Alzheimer's disease, cognitive function, contrast sensitivity, lutein, meso-zeaxanthin, visual function, zeaxanthin

DOI: 10.3233/JAD-140507

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1191-1202, 2014

Authors: Godefroy, Olivier | Martinaud, Olivier | Verny, Marc | Mosca, Chrystèle | Lenoir, Hermine | Bretault, Eric | Roussel, Martine | GREFEX Study Group

Article Type: Research Article

Abstract: Background: Dysexecutive disorders are common in early-stage Alzheimer’s disease (AD) but have yet to be characterized in detail. Objective: The objectives of the present study based on validated diagnostic criteria were to determine the frequency and characterize the profile of behavioral and cognitive dysexecutive disorders in AD. Methods: 102 patients with AD (mild: n = 92; moderate: n = 10; mean MMSE score: 23.2) were examined with the GREFEX battery. Neuropsychological data were interpreted within a validated framework based on the performance levels of 780 control participants from the GREFEX study. Results: Dysexecutive syndrome …was observed in 87.5% (95%CI: 79–96) of the AD patients (p = 0.0001). The dysexecutive disorder profile was characterized by prominent impairments of planning, inhibition flexibility and generation in the cognitive domain (p = 0.0001 as compared to controls for all) and global hypoactivity in the behavioral domain (p = 0.0001 as compared to controls). Conclusions: Dysexecutive syndrome is observed in over 80% of AD patients and has a distinct profile. Show more

Keywords: Alzheimer disease, attention, dementia, executive function, mild cognitive impairment

DOI: 10.3233/JAD-140585

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1203-1208, 2014

Authors: Porquet, David | Griñán-Ferré, Christian | Ferrer, Isidre | Camins, Antoni | Sanfeliu, Coral | del Valle, Jaume | Pallàs, Mercè

Article Type: Research Article

Abstract: The amyloid-β protein precursor/presenilin 1 (AβPP/PS1) mouse model of Alzheimer's disease (AD) has provided robust neuropathological hallmarks of familial AD-like pattern. AD is a neurodegenerative process that causes severe cognitive impairment; it is characterized by the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau forms and by oxidative and inflammatory processes in brain. Currently, efforts are made to understand biochemical pathways because there is no effective therapy for AD. Resveratrol is a polyphenol that induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of oral resveratrol administration on …AβPP/PS1 mice. Long-term resveratrol treatment significantly prevented memory loss as measured by the object recognition test. Moreover, resveratrol reduced the amyloid burden and increased mitochondrial complex IV protein levels in mouse brain. These protective effects of resveratrol were mainly mediated by increased activation of Sirtuin 1 and AMPK pathways in mice. However, an increase has been observed in IL1β and TNF gene expression, indicating that resveratrol promoted changes in inflammatory processes, although no changes were detected in other key actors of the oxidative stress pathway. Taken together, our findings suggest that resveratrol is able to reduce the harmful process that occurs in AβPP/PS1 mouse hippocampus, preventing memory loss. Show more

Keywords: AMPK, inflammation, mitochondria, resveratrol, sirtuin 1

DOI: 10.3233/JAD-140444

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1209-1220, 2014