Journal of Alzheimer's Disease - Volume 36, issue 2

Authors: Tauber, Clovis | Beaufils, Emilie | Hommet, Caroline | Ribeiro, Maria Joao | Vercouillie, Johnny | Vierron, Emilie | Mondon, Karl | Cottier, Jean Philippe | Gissot, Valérie | Guilloteau, Denis | Camus, Vincent

Article Type: Research Article

Abstract: Background: Positron emission tomography (PET) imaging of brain amyloid (Aβ) and neurofibrillary tangle (NFT) load is a candidate biomarker of Alzheimer’s disease (AD). Objectives: To compare brain Aβ and NFT load and glucose metabolism in advanced elderly (70 years and older) patients with AD and healthy controls (HCs) by PET with [18 F]FDDNP and [18 F]FDG. Methods: Seven AD patients (mean ± SD age 79.3 ± 3.6 y, Mini-Mental State Examination (MMSE) score 22.1 ± 2.5) and eight HCs (mean age ± SD, 75.7 ± 3.9 y; MMSE score 29.0 ± 1.2) underwent PET with [18 …F]FDDNP and [18 F]FDG. Results: Global [18 F]FDDNP uptake was significantly higher (p < 0.05) in AD patients (1.15 ± 0.04) than in HCs (1.10 ± 0.06), while global brain metabolism was lower in AD patients than in HCs (AD patients 0.96 ± 0.09; HCs 1.13 ± 0.11; p < 0.05). In HCs, brain glucose metabolism was correlated with age for both the global [18 F]FDG SUVr and in the parietal and posterior cingulate regions, while no correlation was found between age and [18 F]FDDNP uptake. In AD patients, global [18 F]FDDNP uptake and uptake in the frontal and anterior cingulate regions of interest were correlated with MMSE score, while no correlation was observed with brain glucose metabolism. Conclusion: Imaging Aβ load and NFT with [18 F]FDDNP can distinguish AD patients from HCs in an advanced elderly population. It seems to be less sensitive than [18 F]FDG to the brain changes observed with normal aging, but more sensitive to cognitive decline in advanced elderly AD patients. Show more

Keywords: Alzheimer's disease, amyloid, diagnostic, imaging, PET scan

DOI: 10.3233/JAD-122068

Citation: Journal of Alzheimer's Disease, vol. 36, no. 2, pp. 311-320, 2013

Authors: Hong, Ingie | Kang, Taewook | Yoo, YongCheol | Park, Royun | Lee, Junuk | Lee, Sukwon | Kim, Jeongyeon | Song, Boemjong | Kim, Se-Young | Moon, Minho | Yun, Ki Na | Kim, Jin Young | Mook-Jung, Inhee | Park, Young Mok | Choi, Sukwoo

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by progressive memory loss accompanied by synaptic and neuronal degeneration. Although research has shown that substantial neurodegeneration occurs even during the early stages of AD, the detailed mechanisms of AD pathogenesis are largely unknown because of difficulties in diagnosis and limitations of the analytical methods. The 5XFAD mouse model harbors five early-onset familial AD (FAD) mutations and displays substantial amyloid plaques and neurodegeneration. Here, we use quantitative mass spectrometry to identify proteome-wide changes in the 5XFAD mouse hippocampus during the early stages of AD pathology. A subset of the results was validated with immunoblotting. We …found that the 5XFAD mice display higher expression of ApoE, ApoJ (clusterin), and nicastrin, three important proteins in AD that are known to participate in amyloid-β processing and clearance, as well as the neurological damage/glial marker protein GFAP and other proteins. A large subset of the proteins that were up- or downregulated in 5XFAD brains have been implicated in neurological disorders and cardiovascular disease, suggesting an association between cardiovascular disease and AD. Common upstream regulator analysis of upregulated proteins suggested that the XBP1, NRF2, and p53 transcriptional pathways were activated, as was IGF-1R signaling. Protein interactome analysis revealed an interconnected network of regulated proteins, with two major sub-networks centered on AβPP processing membrane complexes and mitochondrial proteins. Together with a recent study on the transcriptome of 5XFAD mice, our study allows a comprehensive understanding of the molecular events occurring in 5XFAD mice during the early stages of AD pathology. Show more

Keywords: Alzheimer's disease, amyloid-β, memory, mild cognitive impairment, PS1, proteomics, transgenic mice

DOI: 10.3233/JAD-130311

Citation: Journal of Alzheimer's Disease, vol. 36, no. 2, pp. 321-334, 2013

Authors: Handattu, Shaila P. | Monroe, Candyce E. | Nayyar, Gaurav | Palgunachari, Mayakonda N. | Kadish, Inga | van Groen, Thomas | Anantharamaiah, G.M. | Garber, David W.

Article Type: Research Article

Abstract: Background: Apolipoprotein E (ApoE) is the major apolipoprotein present in the high-density lipoprotein-like particles in the central nervous system (CNS). ApoE is involved in various protective functions in CNS including cholesterol transport, anti-inflammatory, and antioxidant effects. An ApoE peptide would be expected to exert protective effects on neuroinflammation. Objective: To determine the effects of an ApoE mimetic peptide Ac-hE18A-NH2 on amyloid-β pathology. Method: Using human APP/PS1ΔE9 transgenic mice and in vitro studies, we have evaluated the effect of an ApoE mimetic peptide, Ac-hE18A-NH2 , on amyloid plaque deposition and inflammation. Results: Administration of …Ac-hE18A-NH2 to APP/PS1ΔE9 mice for 6 weeks (50 µg/mouse, 3 times a week) significantly improved cognition with a concomitant decrease in amyloid plaque deposition and reduced activated microglia and astrocytes, and increased brain ApoE levels. Oligomeric Aβ42 (oAβ42 ) and oxidized PAPC (ox-PAPC) inhibited secretion of ApoE in U251 cells, a human astrocyte cell line, and this effect was ameliorated in the presence of peptide Ac-hE18A-NH2 . The peptide also increased Aβ42 uptake in a cell line of human macrophages. Conclusions: Peptide Ac-hE18A-NH2 attenuates the effects of oxidative stress on ApoE secretion, inhibits amyloid plaque deposition, and thus could be beneficial in the treatment of Alzheimer’s disease. Show more

Keywords: Alzheimer's disease, amyloid-β, apolipoprotein E, blood-brain barrier, oxidized phospholipid, peptide mimetics

DOI: 10.3233/JAD-122377

Citation: Journal of Alzheimer's Disease, vol. 36, no. 2, pp. 335-347, 2013

Authors: Delerue, Fabien | Sjollema, Geoff | Whittle, Belinda | Krüger, Sarah | Andrews, Dan | Götz, Jürgen

Article Type: Research Article

Abstract: One of the major challenges in neurodegenerative research is modeling systemic aging. Here, senescence-accelerated mice such as the multigenic SAMP8 (senescence accelerated prone 8) mice are useful as they are characterized by an early manifestation of senescence that includes a shortened lifespan and impaired brain and immune functions. While SAMP8 mice are widely used tools to address aging and neurodegenerative conditions such as Alzheimer's disease (AD), the underlying gene mutations are not known. To make the SAMP8 strain a more versatile and useful research tool, we performed exome sequencing, using SAMR1 (senescence accelerated mouse resistant 1) mice as controls. We …identified 51 SNVs (single nucleotide variants) that discriminate SAMP8 from SAMR1 mice. Using the prediction tool Polyphen2, we were able to subdivide the SNVs into four categories: splice variants, probably damaging, possibly damaging, and benign. Of these genes, a significant fraction is predicted to be expressed in the brain. Our data present these genes for a more detailed analysis in aging and neurodegeneration studies. They underscore the usefulness of SAMP8 mice as an animal model to study fundamental mechanisms of both aging and the pathogenesis of AD. Show more

Keywords: Alzheimer's disease, exome sequencing, mouse, senescence, sequence nucleotide variants

DOI: 10.3233/JAD-130089

Citation: Journal of Alzheimer's Disease, vol. 36, no. 2, pp. 349-363, 2013

Authors: Li, He | Liang, Ying | Chen, Kewei | Li, Xin | Shu, Ni | Zhang, Zhanjun | Wang, Yongyan | for the BGBH Study Group

Article Type: Research Article

Abstract: Amnestic mild cognitive impairment (aMCI) is recognized as the prodromal phase of Alzheimer's disease (AD). Evidence showed that patients with multiple-domain (MD) aMCI were at higher risk of converting to dementia and exhibited more severe gray matter atrophy than single-domain (SD) aMCI. The investigation of the microstructural abnormalities of white matter (WM) among different subtypes of aMCI and their relations with cognitive performances can help to understand the variations among aMCI subtypes and to construct potential imaging based biomarkers to monitor the progression of aMCI. Diffusion-weighted MRI data were acquired from 40 patients with aMCI (aMCI-SD: n = 19; aMCI-MD: …n = 21) and 37 healthy controls (HC). Voxel-wise and atlas-based analyses of whole-brain WM were performed among three groups. The correlations between the altered diffusion metrics of the WM tracts and the neuropsychological scores in each subtype of aMCI were assessed. The aMCI-MD patients showed disrupted integrity in multiple WM tracts across the whole-brain when compared with HCs or with aMCI-SD. In contrast, only few WM regions with diffusion changes were found in aMCI-SD as compared to HCs and with less significance. For neuropsychological correlations, only aMCI-MD patients exhibited significant associations between disrupted WM connectivity (in the body of the corpus callosum and the right anterior internal capsules) and cognitive impairments (MMSE and Digit Symb-Coding scores), whereas no such correlations were found in aMCI-SD. These findings indicate that the degeneration extensively exists in WM tracts in aMCI-MD that precedes the development of AD, whereas underlying WM pathology in aMCI-SD is imperceptible. The results are consistent with the view that aMCI is not a uniform disease entity and presents heterogeneity in the clinical progression. Show more

Keywords: Amnestic mild cognitive impairment, diffusion tensor imaging, multiple-domain, single-domain, TBSS, white matter

DOI: 10.3233/JAD-122023

Citation: Journal of Alzheimer's Disease, vol. 36, no. 2, pp. 365-376, 2013

Authors: Kapay, Nadezhda A. | Popova, Olga V. | Isaev, Nikolay K. | Stelmashook, Elena V. | Kondratenko, Rodion V. | Zorov, Dmitry B. | Skrebitsky, Vladimir G. | Skulachev, Vladimir P.

Article Type: Research Article

Abstract: Bath application of 200 nM amyloid-β1-42 (Aβ) to rat hippocampal slices impairs induction of long-term potentiation (LTP) of the population spike in pyramidal layer of the CA1 field of the hippocampus. Intraperitoneal injection of mitochondria-targeted plastoquinone derivative SkQ1 at very low concentrations (250 nmol/kg body weight) given 24 h before the slice preparation or 1 h treatment of hippocampal slices with 250 nM SkQ1 prevents the deleterious effect of Aβ on LTP. To elucidate which part of the molecule is responsible for this type of neuroprotective activity, the effect of the analog of SkQ1 lacking plastoquinone (C12 TPP) was …studied. It was found that C12 TPP was much less efficient in LTP protection than SkQ1 itself. It means that the plastoquinone part of the SkQ1 molecule is responsible for the LTP rescue. To summarize, in vivo and in vitro injection of SkQ1 compensates for Aβ-induced oxidative damage of long-term synaptic plasticity in the hippocampus, which is considered to be the main reason of memory loss and impairment of other cognitive functions associated with Alzheimer's disease. Therefore, SkQ1 may be considered as a promising candidate for the treatment of early-stage Alzheimer's disease. Show more

Keywords: Alzheimer's disease, amyloid-β, C12TPP, hippocampus, long-term potentiation, memory, mitochondria-targeted antioxidants, SkQ1

DOI: 10.3233/JAD-122428

Citation: Journal of Alzheimer's Disease, vol. 36, no. 2, pp. 377-383, 2013

Authors: Wimo, Anders | Reed, Catherine C. | Dodel, Richard | Belger, Mark | Jones, Roy W. | Happich, Michael | Argimon, Josep M. | Bruno, Giuseppe | Novick, Diego | Vellas, Bruno | Haro, Josep Maria

Article Type: Research Article

Abstract: To address socioeconomic challenges associated with its increasing prevalence, data are needed on country-level resource use and costs associated with Alzheimer's disease (AD). GERAS is an 18-month observational study being conducted in France, Germany, and the UK (with an 18-month extension in France and Germany), aimed at determining resource use and total costs associated with AD, stratified by AD severity at baseline. Resource use information and time spent on informal care by non-professional caregivers was obtained using the Resource Utilization in Dementia instrument. Total baseline societal costs were based on four cost components: patient health care costs, patient social care …costs, caregiver health care costs, and caregiver informal care costs. Overall, 1,497 community-dwelling patients with AD were analyzed at baseline. Estimated mean monthly total societal costs per patient at baseline differed significantly between groups with mild, moderate, and moderately severe/severe AD (p < 0.001 in each country): €1,418, €1,737, and €2,453 in France; €1,312, €2,412, and €3,722 in Germany; and €1,621, €1,836, and €2,784 in the UK, respectively. All cost components except caregiver health care costs increased with AD severity. Informal caregiver costs were the largest cost component accounting for about half to just over 60% of total societal costs, depending on country and AD severity group. In conclusion, GERAS study baseline results showed that country-specific costs increase with AD severity. Informal care costs formed the greatest proportion of total societal costs, increasing with AD severity independent of costing method. Longitudinal data will provide information on cost trends with disease progression. Show more

Keywords: Alzheimer's disease, caregivers, cohort study, cost, dementia, Europe, informal care, Mini-Mental State examination, observational study, resource use

DOI: 10.3233/JAD-122392

Citation: Journal of Alzheimer's Disease, vol. 36, no. 2, pp. 385-399, 2013

Authors: Alexopoulos, Panagiotis | Guo, Liang-Hao | Jiang, Meizi | Bujo, Hideaki | Grimmer, Timo | Förster, Stefan | Drzezga, Alexander | Kurz, Alexander | Perneczky, Robert

Article Type: Research Article

Abstract: Background: Biomarker relationships in early stages of Alzheimer’s disease (AD) are elusive. Cerebrospinal fluid (CSF) levels of amyloid-β 1-42 (Aβ42 ) and total tau (tTau) as well as 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) contribute to help unravel AD pathology. Furthermore, peptides related to amyloid-β protein precursor (AβPP) processing [e.g., soluble AβPPα and β (sAβPPα and sAβPPβ, respectively); sortilin-related receptor with A-type repeats (SORL1, also called LR11 or SORLA)] are factors crucially implicated in the formation of pathological hallmarks of AD. Objective: To unveil differences in CSF concentrations of Aβ42 , sAβPPα, sAβPPβ, tTau, and SORL1 between patients …with mild cognitive impairment (MCI) who were categorized according to expert interpretation of FDG scans. Methods: PET results were classified as suggesting high likelihood for AD (MCI-AD high), intermediate likelihood for AD (MCI-AD intermediate), or little likelihood for AD (MCI-AD unlikely). An AD dementia group was also included. Differences between the groups were tested by Kruskal- Wallis test, Mann-Whitney test, or χ2 . Provided statistically significant differences were detected, multiple linear regression models were employed. Results: Aβ42 levels in patients with MCI-AD high (n = 15) were lower compared to MCI-AD intermediate (n = 18) and MCI-AD unlikely patients (n = 25) (p = 0.002), while they did not differ from patients with AD dementia (n = 17). The regression model revealed a significant impact of the metabolic pattern on Aβ42 concentrations. SORL1, tTau, sAβPPα, and sAβPPβ concentrations did not differ between the groups. Conclusion: These findings point to linkages between plaque pathology and glucose cerebral hypometabolism. Show more

Keywords: Amyloid-β, mild cognitive impairment, sAβPPα, sAβPPβ, SORL1, total tau

DOI: 10.3233/JAD-122329

Citation: Journal of Alzheimer's Disease, vol. 36, no. 2, pp. 401-408, 2013

Article Type: Other

DOI: 10.3233/JAD-130091

Citation: Journal of Alzheimer's Disease, vol. 36, no. 2, pp. 409-411, 2013