Journal of Alzheimer's Disease - Volume 38, issue 4

Authors: de Souza Rolim, Thaís | Fabri, Gisele Maria Campos | Nitrini, Ricardo | Anghinah, Renato | Teixeira, Manoel Jacobsen | de Siqueira, José Tadeu T. | Cestari, José Augusto Ferrari | de Siqueira, Silvia Regina Dowgan T.

Article Type: Research Article

Abstract: Background: Dental infections are frequent and have recently been implicated as a possible risk factor for Alzheimer’s disease (AD). Despite a lack of studies investigating orofacial pain in this patient group, dental conditions are known to be a potential cause of pain and to affect quality of life and disease progression. Objectives: To evaluate oral status, mandibular function and orofacial pain in patients with mild AD versus healthy subjects matched for age and gender. Methods: Twenty-nine patients and 30 control subjects were evaluated. The protocol comprised a clinical questionnaire and dental exam, research diagnostic criteria for …temporomandibular disorders, the McGill Pain Questionnaire, the decayed, missing, and filled teeth index, and included a full periodontal evaluation. AD signs and symptoms as well as associated factors were evaluated by a trained neurologist. Results: A higher prevalence of orofacial pain (20.7%, p < 0.001), articular abnormalities in temporomandibular joints (p < 0.05), and periodontal infections (p = 0.002) was observed in the study group compared to the control group. Conclusion: Orofacial pain and periodontal infections were more frequent in patients with mild AD than in healthy subjects. Orofacial pain screening and dental and oral exams should be routinely performed in AD patients in order to identify pathological conditions that need treatment thus improving quality of life compromised due to dementia. Show more

Keywords: Alzheimer's disease, oral infections, orofacial pain, periodontitis, TMD

DOI: 10.3233/JAD-131283

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 823-829, 2014

Authors: Taher, Noor | McKenzie, Courtney | Garrett, Rebecca | Baker, Matthew | Fox, Nena | Isaacs, Gary D.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by neurofibrillary tangles and extracellular amyloid-β plaques (Aβ). Despite ongoing research, some ambiguity remains surrounding the role of Aβ in the pathogenesis of this neurodegenerative disease. While several studies have focused on the mutations associated with AD, our understanding of the epigenetic contributions to the disease remains less clear. To that end, we determined the changes in DNA methylation in differentiated human neurons with and without Aβ treatment. DNA was isolated from neurons treated with Aβ or vehicle, and the two samples were digested with either a methylation-sensitive (HpaII) or a methylation-insensitive (MspI) restriction endonuclease. …The fragments were amplified and co-hybridized to a commercial promoter microarray. Data analysis revealed a subset of genomic loci that shows a significant change in DNA methylation following Aβ treatment in comparison to the control group. After mapping these loci to nearby genes, we discovered high enrichment for cell-fate genes that control apoptosis and neuronal differentiation. Finally, we incorporated three of those genes in a possible model suggesting the means by which Aβ contributes to the brain shrinkage and memory loss seen in AD. Show more

Keywords: Alzheimer's disease, amyloid-β fragment 1-40, DNA methylation, neurogenesis

DOI: 10.3233/JAD-131061

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 831-844, 2014

Authors: Chakrabarti, Arunabha | Roy, Kasturi | Mukhopadhyay, Debashis

Article Type: Research Article

Abstract: Amyloid-β protein precursor intracellular domain (AICD), which exerts intracellular effects by interacting with proteins involved in a plethora of biological processes, is a key player behind the pathophysiology of Alzheimer's disease (AD). Keeping in mind that overwhelming presence of AICD would mimic AD-like conditions in neuroblastoma cell lines, we hypothesized alteration in the proteomic expression pattern in these cells in the presence of AICD compared to their normal proteome. The rationale behind the study was to distinguish between symptomatic pathophysiological effects as opposed to any artifactual consequence due to protein overload in the cell lines. Using 2D-DIGE analysis and MALDI-MS …identifications in neuro2A (mouse) and SHSY5Y (human) cell lines, we have identified several proteins belonging to different functional classes and involved in several biological pathways including protein folding, cytoskeletal dynamics, metabolism, and stress. Many of these were being upregulated or downregulated due to AICD effects and could be correlated directly with AD phenotypes. Show more

Keywords: Alzheimer's disease, AβPP intracellular domain, 2D-DIGE, MALDI-MS, transfection

DOI: 10.3233/JAD-130695

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 845-855, 2014

Authors: Naismith, Sharon L. | Hickie, Ian B. | Terpening, Zoe | Rajaratnam, Shanthakumar W. | Hodges, John R. | Bolitho, Samuel | Rogers, Naomi L. | Lewis, Simon J.G.

Article Type: Research Article

Abstract: Background: While it is evident that Alzheimer’s disease is associated with disturbed sleep and circadian rhythms, the extent to which such changes are evident in older people ‘at risk’ of developing dementia is unknown. Objective: In this study, we aimed to determine whether patients with mild cognitive impairment (MCI) demonstrated significant alterations in the timing of melatonin secretion onset and amount, as well as sleep architecture. Methods: Thirty patients with MCI and 28 age-matched controls underwent psychiatric, medical, and neuropsychological assessment, followed by overnight polysomnography and dim light melatonin onset assessment. Participants also performed an episodic …memory task while in the laboratory. Dim light melatonin onset was computed using a standardized algorithm, and area under the curve was computed for melatonin secretion. Sleep architecture measures including wake after sleep onset and latency to rapid eye movement sleep were derived. Results: Patients with MCI had advanced timing of their melatonin secretion onset relative to controls, but the levels of melatonin secreted did not differ between groups. The MCI group also had greater wake after sleep onset and increased rapid eye movement sleep latency. There were differential associations between dim light melatonin onset and cognition between the two groups, with earlier dim light melatonin onset being associated with poorer memory performance in MCI patients. Conclusion: Circadian misalignment and sleep disruption is evident in patients with MCI, and is consistent with changes observed in Alzheimer’s disease. Such findings could be a marker for disease trajectory, and may even be implicated in disease pathogenesis. Show more

Keywords: Circadian, melatonin, mild cognitive impairment, salivary, sleep

DOI: 10.3233/JAD-131217

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 857-866, 2014

Authors: Nelson, Amy R. | Kolasa, Krystyna | McMahon, Lori L.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaques, hyperphosphorylated tau neurofibrillary tangles, and cholinergic dysfunction. Cholinergic degeneration can be mimicked in rats by lesioning medial septum cholinergic neurons. Hippocampal cholinergic denervation disrupts retrograde nerve growth factor (NGF) transport, leading to its accumulation, which subsequently triggers sprouting of noradrenergic sympathetic fibers from the superior cervical ganglia into hippocampus. Previously we reported that coincident with noradrenergic sprouting is the partial reinnervation of hippocampus with cholinergic fibers and the maintenance of a M1 muscarinic acetylcholine receptor (M1 mAChR) dependent long-term depression at CA3-CA1 synapses that is lost in the absence of sprouting. …These findings suggest that sympathetic sprouting and the accompanying cholinergic reinnervation maintains M1 mAChR function. Importantly, noradrenergic sympathetic and cholinergic sprouting have been demonstrated in human postmortem AD hippocampus. Furthermore, M1 mAChRs are a recent focus as a therapeutic target for AD given their role in cognition and non-amyloidogenic processing of amyloid-β protein precursor (AβPP). Here we tested the hypotheses that noradrenergic sympathetic sprouting is triggered by NGF, that sprouting maintains non-amyloidogenic AβPP processing, and that sprouting is prevented by intrahippocampal Aβ42 infusion. We found that NGF stimulates sprouting, that sprouting maintains non-amyloidogenic AβPP processing, and that Aβ42 is not only toxic to central cholinergic fibers innervating hippocampus but it prevents and reverses noradrenergic sympathetic sprouting and the accompanying cholinergic reinnervation. These findings reiterate the clinical implications of sprouting as an innate compensatory mechanism and emphasize the importance of M1 mAChRs as an AD therapeutic target. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, cholinergic fibers, muscarinic receptor M1, nerve growth factor

DOI: 10.3233/JAD-130608

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 867-879, 2014

Authors: Roy, Kasturi | Raychaudhuri, Mithu | Chakrabarti, Oishee | Mukhopadhyay, Debashis

Article Type: Research Article

Abstract: The ascertainment of elevated levels of amyloid-β protein precursor intracellular domain (AICD) in Alzheimer's disease (AD) brains and the fact that it contributes to AD-like pathology has geared the search toward a new paradigm. While studying endogenous as well as overexpressed Grb2-AICD interaction in AD cell models, it was found that Grb2 co-localized to compartments along with AICD. We report now that these vesicles form in a clathrin and dynamin independent manner. Both types of vesicles mature into autophagosomes, merge with lysosomes, and relieve the cells of AICD overload. Inhibiting autophagosome formation results in vesicle accumulation. AICD-level is reduced in …Grb2 excess condition in Cycloheximide Chase setup. Reduced caspase activity and apoptosis point toward the fact that the cytotoxic effect of AICD is alleviated by its sequestration in autolysosomes. Hence we state that the entrapping of AICD in Grb2 vesicles and its clearance via autophagosomes is a survival contrivance on the part of the cell. This study unravels, for the first time, the roles of Grb2 in autophagy and in handling toxic protein overload in an AD-like scenario. Show more

Keywords: Amyloid-β protein precursor protein, autophagy, CD63, clathrin, dynamin, Grb2, LC3 protein

DOI: 10.3233/JAD-130929

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 881-895, 2014

Authors: Lupton, Michelle K. | Proitsi, Petroula | Lin, Kuang | Hamilton, Gillian | Daniilidou, Makrina | Tsolaki, Magda | Powell, John F.

Article Type: Research Article

Abstract: The ATP-binding cassette, sub-family A, member 1 gene (ABCA1) is a candidate risk gene for late onset Alzheimer's disease (LOAD) as a consequence of its role in cholesterol transport and metabolism, which is implicated in LOAD risk. ABCA1 has been shown in mouse models to enable the clearance of amyloid-β peptide from the brain, through its role in the lipidation of apolipoprotein (APOE). Although recent large scale genome wide association studies (GWAS) have failed to find significant associations with common genetic variants in this gene and LOAD, rare variants in ABCA1 have been shown to influence plasma high-density lipoprotein cholesterol …levels. Using next generation sequencing of pooled DNA samples, we sequenced all the coding regions of ABCA1 in 311 LOAD cases and 360 control individuals drawn from the Greek population to identify low frequency non-synonymous variation. There were a significantly higher proportion of rare non-synonymous variants in control individuals compared to AD cases, suggestive of a protective effect. These findings provide new evidence of an effect of ABCA1 variants on AD risk. In addition they highlight the importance of high throughput sequencing in the identification of rare variation undetected by GWAS, but with the potential to have a strong effect on risk of LOAD. Show more

Keywords: Alzheimer's disease, ATP-binding cassette transporters, ATP-binding cassette sub-family A (ABC1) member 1, candidate gene analyses, cholesterol, genetic association studies, high-throughput nucleotide sequencing

DOI: 10.3233/JAD-131121

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 897-906, 2014

Authors: Percy, Maire | Somerville, Martin J. | Hicks, Mark | Colelli, Teresa | Wright, Emily | Kitaygorodsky, Julia | Jiang, Amy | Ho, Valerie | Parpia, Alyssa | Wong, Michael K. | Garcia, Angeles

Article Type: Research Article

Abstract: Risk factors for dementia development are not well-defined. We evaluated several factors alone and in combination in a unique cohort of Caucasian volunteers over an approximately 6-year observation window using a nested case/control design. Factors included: apolipoprotein E (ApoE) gene variants (the E4 allele is the strongest confirmed genetic predisposing factor for Alzheimer's disease), the hemochromatosis-HFE gene mutations (H63D and C282Y), diabetes, and stroke. At study entry, subjects were ≥65 years of age (M ± SD = 73.0 ± 4.9), had an MMSE score ≥24, and no evidence of cerebrovascular disease or current depression. Genotyping was completed on 163 available …DNA samples from three different groups at the study end: those who still had normal cognitive function; those who had developed dementia; and those with Mild Cognitive Impairment (MCI). Analyses were interpreted at the 95% confidence level without Bonferroni corrections. In the subgroup with dementia, all cases of diabetes were type 2 and present at study entry, whereas all strokes occurred during the study. The results highlight apparently synergistic interactions between genetic and medical risk factors for dementia development, gender differences in risk factors, and involvement of HFE mutations. Having E4 (i.e., either of E3/4 or E4/4), C282Y, H63D, diabetes, or stroke alone did not attain significance. Significant predisposing factors with post-hoc power ≥80% were: E4 homozygosity (E4/4)males+females, odds ratio (OR) = 56.0); E4+diabetes (males+females, OR = 13.7; E4+H63D+diabetes (females, OR = 52.0); E4+stroke (males, OR = 46.5). The importance of preventing diabetes and stroke to ward off dementia and the possible role of iron dysmetabolism in dementia are discussed. Show more

Keywords: Alzheimer's disease, apolipoprotein E, C282Y, cohort study, dementia, HFE mutations, H63D, hemochromatosis, iron, mild cognitive impairment, risk factors, stroke, type 2 diabetes mellitus

DOI: 10.3233/JAD-131409

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 907-922, 2014

Authors: Ben-David, Boaz M. | Tewari, Anita | Shakuf, Vered | Van Lieshout, Pascal H.H.M.

Article Type: Research Article

Abstract: Selective attention, an essential part of daily activity, is often impaired in people with Alzheimer's disease (AD). Usually, it is measured by the color-word Stroop test. However, there is no universal agreement whether performance on the Stroop task changes significantly in AD patients; or if so, whether an increase in Stroop effects reflects a decrease in selective attention, a slowing in generalized speed of processing (SOP), or is the result of degraded color-vision. The current study investigated the impact of AD on Stroop performance and its potential sources in a meta-analysis and mathematical modeling of 18 studies, comparing 637 AD …patients with 977 healthy age-matched participants. We found a significant increase in Stroop effects for AD patients, across studies. This AD-related change was associated with a slowing in SOP. However, after correcting for a bias in the distribution of latencies, SOP could only explain a moderate portion of the total variance (25%). Moreover, we found strong evidence for an AD-related increase in the latency difference between naming the font-color and reading color-neutral stimuli (r2 = 0.98). This increase in the dimensional imbalance between color-naming and word-reading was found to explain a significant portion of the AD-related increase in Stroop effects (r2 = 0.87), hinting on a possible sensory source. In conclusion, our analysis highlights the importance of controlling for sensory degradation and SOP when testing cognitive performance and, specifically, selective attention in AD patients. We also suggest possible measures and tools to better test for selective attention in AD. Show more

Keywords: Aging, Alzheimer's disease, color vision, selective attention, sensory and cognitive interaction, speed of processing, Stroop test, visual perception

DOI: 10.3233/JAD-131244

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 923-938, 2014

Authors: Scrascia, Federica | Curcio, Giuseppe | Ursini, Francesca | Trotta, Laura | Quintiliani, Livia | Migliore, Simone | Altamura, Claudia | Pitocco, Francesca | Altavilla, Riccardo | Melgari, Jean-Marc | Quattrocchi, Carlo Cosimo | Vernieri, Fabrizio

Article Type: Research Article

Abstract: Magnetic resonance (MR) diffusion tensor imaging (DTI) can detect microstructural alterations by means of fractional anisotropy (FA) in patients with dementia, also in relation to cognitive status. The present study aimed at investigating the possible relation among white matter damage in DTI, quantitative electroencephalography (EEG) spectral power, and cognitive status in Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients. Forty-seven subjects (8 moderate AD, 18 mild AD, 12 MCI, and 9 healthy controls) underwent brain MR, neuropsychological evaluation, and resting EEG recording. A progressive increase of EEG delta and theta spectral power was observed from controls to patients, mainly …in more anterior areas, with a parallel widespread decrease of beta power. Moreover, a progressive decrease of FA from controls to patients in frontal areas and in the corpus callosum (genu) was observed. Correlation analyses indicated convergence among EEG rhythms changes, DTI values, and cognitive status mainly over anterior areas. The decrease of FA values and EEG spectral power changes might represent markers of neurodegenerative dysfunction, possibly preceding macrostructural atrophy. Show more

Keywords: Alzheimer's disease, brain activity, dementia, diffusion tensor imaging, mild cognitive impairment

DOI: 10.3233/JAD-130788

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 939-950, 2014