Journal of Alzheimer's Disease - Volume 30, issue 4

Authors: Perry, George

Article Type: Editorial

DOI: 10.3233/JAD-2012-129909

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 735-735, 2012

Authors: Popovics, Petra | Stewart, Alan J.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is associated with altered neuronal Ca2+ homeostasis. Ca2+ is known to accumulate in AD-affected neurons leading to deficits in neurological activity that are characteristic of the disease. This has led to the coinage of the term “calciumopathy”. However, the mechanisms of how and why Ca2+ levels are increased in the AD-affected brain remain unknown. Identifying these mechanisms is crucial for our ability to treat and understand the disease processes that are occurring. Recent work has revealed the existence of a novel signaling pathway that may contribute toward this calciumopathy. Phospholipase C-η enzymes have recently …been implicated in the modulation and amplification of Ca2+ signals and are known to be expressed in neuronal regions of the brain associated with cognition and memory. In this article their potential impact on neuronal Ca2+ signaling and AD pathogenesis is discussed. Show more

Keywords: Calcium, dementia, inositol 1, 4, 5-triphosphate, phospholipases, signal amplification

DOI: 10.3233/JAD-2012-120241

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 737-744, 2012

Authors: Albani, Diego | Boneschi, Filippo Martinelli | Biella, Gloria | Giacalone, Giacomo | Lupoli, Sara | Clerici, Francesca | Benussi, Luisa | Ghidoni, Roberta | Galimberti, Daniela | Squitti, Rosanna | Mariani, Stefania | Confaloni, Annamaria | Bruno, Giuseppe | Mariani, Claudio | Scarpini, Elio | Binetti, Giuliano | Magnani, Giuseppe | Franceschi, Massimo | Forloni, Gianluigi

Article Type: Short Communication

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder often treated with donepezil, an acetylcholinesterase inhibitor. Response to donepezil is variable, probably based on patients' genetic background in donepezil metabolizing enzymes, including cytochrome 2D6 (CYP2D6). We evaluated the association between clinical response to donepezil and a common variant (rs1080985) of CYP2D6, previously reported to be associated with poor response to the drug. In a sample of 415 AD cases, we found evidence of association between rs1080985 and response to donepezil after 6 months of therapy (OR [95% CI]: 1.74 [1.01–3.00], p = 0.04). Rs1080985 might be useful as predictor of poor response …to short-term donepezil treatment. Show more

Keywords: Alzheimer's disease, apolipoprotein E, CYP2D6, donepezil, pharmacogenetics, rs1080985

DOI: 10.3233/JAD-2012-112123

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 745-749, 2012

Authors: Schmidt, Christian | Haïk, Stephane | Satoh, Katsuya | Rábano, Alberto | Martinez-Martin, Pablo | Roeber, Sigrun | Brandel, Jean-Philippe | Calero-Lara, Miguel | de Pedro-Cuesta, Jesús | Laplanche, Jean-Louis | Hauw, Jean-Jaques | Kretzschmar, Hans | Zerr, Inga

Article Type: Research Article

Abstract: The objective was to characterize a rapidly progressive subtype of Alzheimer's disease (rpAD). Multicenter (France, Germany, Japan, Spain) retrospective analyses of neuropathologically confirmed rpAD cases initially classified as prion disease due to their clinical phenotype were performed. Genetic properties, cerebrospinal fluid biomarkers, neuropathology, and clinical features were examined. Eighty-nine patients were included (median survival 10 months). APOE and PRNP codon 129 genotype distribution paralleled a healthy control group. APOE ε4 homozygosity was absent. Cerebrospinal fluid biomarkers were abnormal, but within a range as expected for classic AD, except for proteins 14-3-3, which were detectable in 42%. Thus, evidence of the …existence of rpAD is accumulating. The APOE profile is intriguing, suggesting that this very rapid disease form might represent a distinct subtype of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, heterogeneity, rapid decline

DOI: 10.3233/JAD-2012-120007

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 751-756, 2012

Authors: Mortimer, James A. | Ding, Ding | Borenstein, Amy R. | DeCarli, Charles | Guo, Qihao | Wu, Yougui | Zhao, Qianhua | Chu, Shugang

Article Type: Research Article

Abstract: Physical exercise has been shown to increase brain volume and improve cognition in randomized trials of non-demented elderly. Although greater social engagement was found to reduce dementia risk in observational studies, randomized trials of social interventions have not been reported. A representative sample of 120 elderly from Shanghai, China was randomized to four groups (Tai Chi, Walking, Social Interaction, No Intervention) for 40 weeks. Two MRIs were obtained, one before the intervention period, the other after. A neuropsychological battery was administered at baseline, 20 weeks, and 40 weeks. Comparison of changes in brain volumes in intervention groups with the No …Intervention group were assessed by t-tests. Time-intervention group interactions for neuropsychological measures were evaluated with repeated-measures mixed models. Compared to the No Intervention group, significant increases in brain volume were seen in the Tai Chi and Social Intervention groups (p < 0.05). Improvements also were observed in several neuropsychological measures in the Tai Chi group, including the Mattis Dementia Rating Scale score (p = 0.004), the Trailmaking Test A (p = 0.002) and B (p = 0.0002), the Auditory Verbal Learning Test (p = 0.009), and verbal fluency for animals (p = 0.01). The Social Interaction group showed improvement on some, but fewer neuropsychological indices. No differences were observed between the Walking and No Intervention groups. The findings differ from previous clinical trials in showing increases in brain volume and improvements in cognition with a largely non-aerobic exercise (Tai Chi). In addition, intellectual stimulation through social interaction was associated with increases in brain volume as well as with some cognitive improvements. Show more

Keywords: Cognition, exercise, intervention studies, magnetic resonance imaging, pilot study, Tai Chi

DOI: 10.3233/JAD-2012-120079

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 757-766, 2012

Authors: Mattsson, Niklas | Portelius, Erik | Rolstad, Sindre | Gustavsson, Mikael | Andreasson, Ulf | Stridsberg, Mats | Wallin, Anders | Blennow, Kaj | Zetterberg, Henrik

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) measurements of amyloid-β42 (Aβ42 ), total-tau (T-tau), and phosphorylated tau (P-tau) may be used to predict future Alzheimer's disease (AD) dementia in patients with mild cognitive impairment (MCI). The precise temporal development of these biomarkers in relation to clinical progression is unclear. Earlier studies have been hampered by short follow-up. In an MCI cohort, we selected 15 patients who developed AD (MCI-AD) and 15 who remained cognitively stable during 4 years of follow-up. CSF was sampled at three serial occasions from each patient and analyzed for Aβ peptides, the soluble amyloid-β protein precursor protein fragments sAβPPα …and sAβPPβ, T-tau, P-tau, and chromogranin B, which is a protein linked to regulated neuronal secretion. We also measured, for the first time in MCI patients, an extended panel of Aβ peptides by matrix-assisted-laser-desorption/ionization time-of-flight mass spectrometry (MS). Most biomarkers were surprisingly stable over the four years with coefficients of variation below or close to 10%. However, MCI-AD patients decreased in CSF AβX-40 and chromogranin B concentrations, which may indicate a reduced number of functional neurons or synapses with disease progression. The MS Aβ peptide panel was more useful than any single Aβ peptide to identify MCI-AD patients already at baseline. Knowledge on these biomarkers and their trajectories may facilitate early diagnosis of AD and be useful in future clinical trials to track effects of disease modifying drugs. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarkers, cerebrospinal fluid, chromogranin, mild cognitive impairment, tau

DOI: 10.3233/JAD-2012-120019

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 767-778, 2012

Authors: Guzman-Sanchez, Fernando | Valdivieso, Fernando | Burgos, Javier S.

Article Type: Research Article

Abstract: To date, the main advances in understanding Alzheimer's disease (AD) have revolved around the genetic variants associated with the familial form of the disease, yet the majority of cases are sporadic. The main risk factor for AD is aging, followed by production of the E4 isoform of apolipoprotein E (APOE). Female gender also increases the risk of developing AD. Herpes simplex virus type 1 (HSV-1) has been epidemiologically and experimentally associated with AD, although no studies on its effects over aging have been undertaken. To assess the potential aging-related consequences of HSV-1 brain infection, 2 month-old wild-type and apoE-deficient mice …were infected with the virus, and over the next 16 months analyses made of cerebral viral load, neuropathological, morphological, and metabolic changes in the brain, and cognitive performance. Viral load in the central nervous system (CNS) increased with age. The viral load in the brains of aged apoE+/+ female mice was 43 times that seen in apoE−/− male mice. No MRI-detectable morphological differences nor any clear neuropathological differences were seen between 18 month-old infected and mock-infected mice, although differences were seen in younger animals. Neuroinfection was associated with memory deficit and a reduction in metabolic indicators of CNS health. Show more

Keywords: Aging, apolipoprotein E, brain, HSV-1 infection, gender, mouse, MRI

DOI: 10.3233/JAD-2012-120070

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 779-790, 2012

Authors: Johnstone, Daniel M. | Graham, Ross M. | Trinder, Debbie | Riveros, Carlos | Olynyk, John K. | Scott, Rodney J. | Moscato, Pablo | Milward, Elizabeth A.

Article Type: Research Article

Abstract: Iron abnormalities are observed in the brains of Alzheimer's disease (AD) patients, but it is unclear whether common disorders of systemic iron overload such as hemochromatosis alter risks of AD. We used microarrays and real-time reverse transcription-PCR to investigate changes in the brain transcriptome of adult Hfe−/− mice, a model of hemochromatosis, relative to age- and gender-matched wildtype controls. Classification by functional pathway analysis revealed transcript changes for various genes important in AD. There were decreases of up to 9-fold in transcripts for amyloid-β protein precursor, tau, apolipoprotein E, presenilin 1, and various other γ-secretase components, as well as …Notch signaling pathway molecules. This included decreased transcripts for ‘hairy and enhancer of split’ Hes1 and Hes5, downstream targets of Notch canonical signaling. The reductions in Hes1 and Hes5 transcripts provide evidence that the changes in levels of transcripts for γ-secretase components and Notch signaling genes have functional consequences. The effects appeared relatively specific for AD in that few genes pertaining to other important neurodegenerative diseases, notably Parkinson's disease and Huntington's disease, or to inflammation, oxidative stress, or apoptosis, showed altered transcript levels. The observed effects on AD-related gene transcripts do not appear to be consistent with increased AD risk in HFE hemochromatosis and might, if anything, be predicted to protect against AD to some extent. As Hfe−/− mice did not have higher brain iron levels than wildtype controls, these studies highlight the need for further research in models of more severe hemochromatosis with brain iron loading. Show more

Keywords: Amyloid-β protein precursor, γ-secretase, hemochromatosis, HFE, iron, notch signaling

DOI: 10.3233/JAD-2012-112183

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 791-803, 2012

Authors: Gommer, Erik D. | Martens, Esther G.H.J. | Aalten, Pauline | Shijaku, Eri | Verhey, Frans R.J. | Mess, Werner H. | Ramakers, Inez H.G.B. | Reulen, Jos P.H.

Article Type: Research Article

Abstract: Cerebrovascular dysfunction plays a role not only in vascular causes of cognitive impairment but also in Alzheimer's disease (AD). We hypothesized that cerebral autoregulation is impaired in patients with AD compared to subjects with mild cognitive impairment (MCI) and controls. Dynamic cerebral autoregulation (dCA) was investigated in 17 AD patients, 19 MCI subjects, and 20 controls (C). Groups were matched for age, gender, and level of education. Electrocardiogram and non-invasive finger arterial blood pressure were measured and transcranial doppler ultrasonography was used to measure cerebral blood flow velocity in right and left middle cerebral artery (MCA). Cerebrovascular resistance index (CVRi) …was also computed. dCA in supine position was quantified based on spontaneous blood pressure variations by computation of the linear transfer function between arterial blood pressure and MCA cerebral blood flow velocity. dCA gain and phase were evaluated for different frequency bands. Results were also evaluated using a 3-parameter windkessel model (WKM). CVRi was significantly higher in AD (2.9 ± 0.2) compared to both MCI (2.3 ± 0.1, p = 0.02) and C (2.1 ± 0.1 mmHgs/cm, p = 0.002). Five MCI patients who converted to AD during the course of the study also had higher CVRi compared to non-converters (2.8 ± 0.6 versus 2.1 ± 0.5 mmHgs/cm, p < 0.05). No significant differences in dCA gain and phase were found. In terms of the WKM approach, in the order C→MCI→AD groups showed about equal arterial resistance and peripheral compliance, but increased peripheral vasculature resistance (26 ± 2 versus 36 ± 3 mmHgs/ml in C resp. AD, p = 0.004). In conclusion, AD patients compared to MCI patients and controls have increased CVRi, whereas dCA parameters do not seem to differentiate AD patients. For MCI patients, CVRi might have predictive value in developing AD. Show more

Keywords: Alzheimer's disease, autoregulation, cerebral blood flow, mild cognitive impairment, transcranial doppler ultrasonography, transfer function analysis, windkessel model

DOI: 10.3233/JAD-2012-111628

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 805-813, 2012

Authors: Santana, Soraya | Bullido, Maria Jesús | Recuero, Maria | Valdivieso, Fernando | Aldudo, Jesus

Article Type: Research Article

Abstract: Autophagy is a homeostatic process involved in the turnover or elimination of cytoplasmic components, damaged organelles, and protein aggregates via a lysosomal degradation mechanism. Autophagy also provides a mechanism of innate immunity, known as xenophagy, designed to protect cells from intracellular pathogens, but it may unfortunately be subverted to act as a pro-viral pathway facilitating the replication of certain viruses. Herpes simplex virus type I (HSV-1) is a neurotropic virus that remains latent in host neurons; it is the most common cause of sporadic viral encephalitis. Moreover, HSV-1 has been related to the pathogenesis of Alzheimer's disease. HSV-1 can modulate …the autophagic process through a mechanism mediated by the viral protein ICP34.5. Here we report that HSV-1 induces a strong increase in GFP-LC3 and endogenous LC3 lipidation, and triggers the accumulation of intracellular autophagic compartments (mainly autophagosomes) without enhancing autophagic long-lived protein degradation in the late stages of infection. Autophagy inhibition mediated by ATG5 gene silencing had no effect on viral growth. The present results suggest that HSV-1 infection activates the host autophagic machinery and strongly controls the autophagic process, blocking the fusion of autophagosomes with lysosomes. These events might be important in the neurodegenerative process associated with HSV-1 infection. Show more

Keywords: ATG5, autophagy, HSV-1, LC3, lysosome, neurodegeneration

DOI: 10.3233/JAD-2012-112000

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 815-831, 2012