Pages 225-232
Editorial
Peter Whitehouse
The Challenges of Cognitive Aging: Integrating Approaches from Science to Intergenerational Relationships
Abstract: The individual and social challenges created by population aging and especially the growing number of people labeled with dementia demand new innovative and comprehensive approaches. A broader integrative biology needs to replace reductionist, overly simplistic biomedical solutions that dominate today’s scientific discourse, particularly with regards to cognitive aging. Alzheimer’s disease is a heterogeneous syndrome characterized more fully at a system rather than molecular level. Coordinated scientific and community responses are needed including new attention to intergenerational relationships, innovative learning organizations, and empowering health practices. The Intergenerational School is a successful public charter school which provides learning opportunities for elementary school children and adults of various ages, including those with dementia. InterWell is a planned primary care and public health practice to be associated with the school. Both represent innovations that balance the sciences and the humanities in address growing social challenges associated with changes in population demographics and climate.
Pages 233-238
Short Communication
Chelsea Cavanagh*, Jessica Colby-Milley*, David Bouvier, Mark Farso, Jean-Guy Chabot, Rémi Quirion, Slavica Krantic *These authors contributed equally to this manuscript.
βCTF-Correlated Burst of Hippocampal TNFα Occurs at a Very Early, Pre-Plaque Stage in the TgCRND8 Mouse Model of Alzheimer’s Disease
Abstract: Tumor necrosis factor-alpha (TNFα) regulates neuronal excitability. We investigated whether alterations in the level of TNFα occur at a time point that precedes the reported seizure-associated hyperexcitability of hippocampal networks in pre-plaque models of Alzheimer’s disease (AD). Western blot and ELISA experiments indicated a significant increase in hippocampal TNFα expression in 1-month-old TgCRND8 mice that correlated with levels of the β-C-terminal fragment (βCTF) of amyloid-β protein precursor. CD11b labeling indicated changes in microglial morphology toward an activated state, suggesting that these cells may be a putative source of the observed TNFα increase during this pre-symptomatic stage of AD-like pathology.
Pages 239-243
Short Communication
Colin J. Mahoney, Laura E. Downey, Jon Beck, Yuying Liang, Simon Mead, Richard J. Perry, Jason D. Warren (Handling Associate Editor: Amalia Bruni)
The Presenilin 1 P264L Mutation Presenting as non-Fluent/Agrammatic Primary Progressive Aphasia
Abstract: Primary progressive aphasia (PPA) represents a diverse group of language-led dementias most often due to frontotemporal lobar degeneration. We report clinical, neuropsychological, and neuroimaging data in the case of a 47-year-old woman presenting with non-fluent PPA due to a genetically confirmed pathogenic Presenilin 1 P264L mutation. This case highlights an unusual clinical presentation of familial Alzheimer’s disease and a novel presentation of the P264L mutation. The case adds to accumulating evidence that particular mutations can promote specific brain network degeneration, with wider implications for understanding the sporadic forms of Alzheimer’s disease and PPA.
Pages 245-251
Jun-Peng Zhuang*, Rong Fang1, Xia Feng, Xu-Hua Xu, Li-Hua Liu, Qing-Ke Bai, Hui-Dong Tang, Zhen-Guo Zhao, Sheng-Di Chen *These authors contributed equally to this work.
The Impact of Human-Computer Interaction-Based Comprehensive Training on the Cognitive Functions of Cognitive Impairment Elderly Individuals in a Nursing Home
Abstract: Background: Given the increasing prevalence of dementia, any intervention that can effectively slow the deterioration of cognitive function is of great importance. Objective: This study investigated the efficacy of a human-computer interaction-based comprehensive cognitive training program in cognitively impaired elderly individuals living in a nursing home.Methods: All subjects, who were aged ≥70 years and had cognitive impairment, were randomly allocated to an intervention group (n = 19) or a control group (n = 14). The intervention group received human-computer interaction-based comprehensive cognitive training for 24 weeks. Neuropsychological examinations were conducted before and after this period. The intervention group was subdivided into two groups according to the scores of global cortical atrophy (GCA) to evaluate the impact of training effectiveness on GCA. Results: After 24 weeks, neither group showed a significant change compared with baseline cognitive examinations. However, there was a tendency for greater improvement in memory, language, and visuospatial abilities for the intervention group as compared with controls. Patients with mild cognitive impairment showed improvements in language and visuospatial capacity, while patients with dementia showed improvements in attention/orientation, memory, language, and fluency. However, none of these findings were statistically significant. The results for the intervention subgroups showed that visuospatial ability improvement was significantly greater among those with a global cortical atrophy score of ≤15 (p<0.05). Conclusion: Human-computer interaction-based comprehensive training may improve cognitive functions among cognitively impaired elderly individuals. The training effect was most prominent among those with milder cerebral atrophy.
Pages 253-260
Patrícia Regina Manzine, Elisabeth Joan Barham, Francisco de Assis Carvalho do Vale, Heloisa Sobreiro Selistre-de-Araújo, Sofia Cristina Iost Pavarini, Márcia Regina Cominetti(Handling Associate Editor: Barbara Borroni)
Correlation between Mini-Mental State Examination and Platelet ADAM10 Expression in Alzheimer’s Disease
Abstract: Background: Previous studies have demonstrated a decrease in platelet ADAM10 expression among patients with Alzheimer’s disease (AD) and healthy matched subjects. The association between cognitive tests and molecular biomarkers, such as platelet ADAM10, may contribute to an accurate AD diagnosis. Objective: The aim of this research was to investigate whether cognitive deficits in AD, assessed by Mini-Mental State Exam (MMSE), correlate with ADAM10 platelet levels and if that contributes to a more effective AD diagnosis. Methods:Elderly patients with probable AD (n=30) and a non-AD control group (n=25), matched by age, gender, and education level were evaluated. Platelet proteins were analyzed on SDS-PAGE (10%) and ADAM10 expression was identified by western blotting. β-actin was used as the endogenous control. The Spearman correlation coefficient between ADAM10 and MMSE ratio was obtained for each group. Results: The MMSE ratio of AD subjects (0.45±0.32) was significantly different (p < 0.001) compared to the non-AD group (1.14±0.07). The relationship between MMSE ratio and ADAM10 expression was significant (r = 0.62, p = 0.0003) for the AD group. The combination of ADAM10 and MMSE at a cutoff ≤ 0.87 presented a sensitivity of 85%, and a specificity of 97% (AUC 0.99, 95% CI 0.92 -1.00), which was significantly better for AD diagnosis than the AUCs of MMSE (p = 0.05) and ADAM10 expression (p = 0.18) separately. Conclusions: The association of MMSE and ADAM10 expression was significantly better compared with MMSE and ADAM10 expression separately, thus providing and additional diagnostic tool for AD.
Pages 261-274
Lojze M. Smid, Vladimir Kepe, Harry V. Vinters, Mara Bresjanac, Tatsushi Toyokuni, Nagichettiar Satyamurthy, Koon-Pong Wong, Sung-Cheng Huang, Daniel H.S. Silverman, Karen Miller, Gary W. Small, Jorge R. Barrio (Handling Associate Editor: J. Wesson Ashford)
Postmortem3-D Brain Hemisphere Cortical Tau and Amyloid-β Pathology Mapping and Quantification as a Validation Method of Neuropathology Imaging
Abstract: This work is aimed at correlating pre-mortem [18F]FDDNP positron emission tomography (PET) scan results in a patient with dementia with Lewy bodies (DLB), with cortical neuropathology distribution determined postmortemin three physical dimensions in whole brain coronal sections. Analysis of total amyloid-β (Aβ) distribution in frontal cortex and posterior cingulate gyrus confirmed its statistically significant correlation with cortical [18F]FDDNP PET binding values (distribution volume ratios, DVR) (p<0.001, R=0.97, R2=0.94). Neurofibrillary tangle (NFT) distribution correlated significantly with cortical [18F]FDDNP PET DVR in the temporal lobe (p<0.001, R=0.87, R2=0.76). Linear combination of Aβ and NFT densities was highly predictive of [18F]FDDNP PET DVR through all analyzed regions of interest (p<0.0001, R=0.92, R2=0.85), and both densities contributed significantly to the model. Lewy bodies were present at a much lower level than either Aβ or NFTs and did not significantly contribute to thein vivo signal. [18F]FDG PET scan results in this patient were consistent with the distinctive DLB pattern of hypometabolism. This work offers a mapping brain model applicable to all imaging probes for verification of imaging results with Aβ and/or tau neuropathology brain distribution using immunohistochemistry, fluorescence microscopy, and autoradiography.
Pages 275-284
Barbara Caracciolo Margaret Gatz, Weili Xu, Alessandra Marengoni, Nancy L. Pedersen, Laura Fratiglioni (Handling Associate Editor: Julián Benito-León)
Relationship of Subjective Cognitive Impairment and Cognitive Impairment No Dementia to Chronic Disease and Multimorbidity in a Nation-Wide Twin Study
Abstract: We investigated the relation of subjective cognitive impairment (SCI) and cognitive impairment no dementia (CIND) to common chronic diseases of the elderly and multimorbidity, and assessed the contribution of genetic background and shared familial environment to these associations. Subjects were 11,379 dementia-free twin individuals aged ≥ 65 from the Swedish Twin Registry. SCI was defined as subjective complaint of cognitive change without objective cognitive impairment and CIND was defined according to current criteria. In unmatched, fully-adjusted regression models, mental, musculoskeletal, respiratory, and urological diseases were all significantly associated with increased odds ratios (ORs) of SCI and CIND. Circulatory and gastrointestinal diseases were related to SCI only, while endocrine diseases were associated with CIND. The adjusted ORs of multimorbidity were 2.1 [95% confidence intervals (95% CI): 1.8-2.3] for SCI and 1.5 for CIND (95% CI: 1.3-1.8). A dose-dependent relationship was observed between number of chronic diseases and ORs for SCI but not for CIND. In co-twin control analyses, the chronic diseases-SCI association was largely unchanged. On the other hand, the chronic diseases-CIND association was no longer statistically significant, except for cancer, where an increased OR was observed. In conclusion, chronic morbidity is associated with both SCI and CIND but disease profiles do not always overlap between the two cognitive syndromes. The association is stronger when diseases co-occur, especially for SCI. Genetic and early-life environmental factors may partially explain the association of CIND but not that of SCI with chronic diseases.
Pages 285-295
Maria Manczak, P. Hemachandra Reddy
Abnormal Interaction of Oligomeric Amyloid-β with Phosphorylated Tau: Implications for Neuronal Damage in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative mental illness characterized by memory loss, multiple cognitive impairments, and changes in personality and behavior. The purpose of our study was to determine the interaction between monomeric and oligomeric amyloid-β (Aβ) and phosphorylated tau in AD neurons. Using postmortem brains from AD patients at different stages of disease progression and control subjects, and also from AβPP, AβPPxPS1, and 3xTg-AD mice, we studied the physical interaction between Aβ and phosphorylated tau. Using immunohistological and double-immunofluorescence analyses, we also studied the localization of monomeric and oligomeric Aβ with phosphorylated tau. We found monomeric and oligomeric Aβ interacted with phosphorylated tau in neurons affected by AD. Further, these interactions progressively increased with the disease process. These findings led us to conclude that Aβ interacts with phosphorylated tau and may damage neuronal structure and function, particularly synapses, leading to cognitive decline in AD patients. Our findings suggest that binding sites between Aβ and phosphorylated tau need to be identified and molecules developed to inhibit this interaction.
Pages 297-302
Javier Olazarán, Belén González, Jorge López, Alessandro Castagna, Emma Osa-Ruiz, Vanesa Herrero-Cano, Luis Agüera-Ortiz, Salvatore Rinaldi, Pablo Martínez-Martín, AD Research Unit Investigators
Motor Effects of REAC in Advanced Alzheimer’s Disease: Results from a Pilot Trial
Abstract: We conducted a pilot, randomized, controlled trial to mainly investigate the feasibility, safety, and short-term motor effects of brain stimulation with radio electric asymmetric conveyer (REAC) technology in patients with advanced Alzheimer’s disease (AD) who also experience some gait dysfunction. Neuropostural optimization (NPO) or sham protocol was administered to 31 nursing home patients (mean [SD] age 84.7 [7.0], 77.4% female, 6.5% moderate dementia, 51.6% moderately severe dementia, and 41.9% severe dementia). Motor, cognitive, functional, and behavioral measures were conducted at baseline (T1), immediately after treatment (T2), and 1-3 weeks after treatment (T3). There was transitory dysfunction in axial movements at T2 in the experimental group with no other differences between the experimental group and the control group in the planned analyses. However, after reanalysis of data based on outcome, improvement in capacity of walking was observed at T3 in the experimental group (p<0.05). NPO administration was comfortable and safe. These results warrant further research with NPO and other REAC protocols to improve motor deterioration in AD.
Pages 303-309
Luisa Ientile, Riccardo De Pasquale, Fiammetta Monacelli, Patrizio Odetti, Nicola Traverso, Sergio Cammarata, Massimo Tabaton, Babette Dijk (Handling Associate Editor: Daniela Galimberti)
Survival Rate in Patients Affected by Dementia Followed by Memory Clinics (UVA) in Italy
Abstract: People affected by dementia experienced decreased life expectancy with a 2-4 times higher risk of death at a given age compared to non-demented people. Dementia represents a major cost to health care and society in the Western world and, particularly in Italy, is projected to become a high-resource demanding chronic disease. The present study aimed to estimate the average survival rate of a group of community dwelling elderly affected by dementia in Italy, and to assess the predictive variables associated with survival length. This retrospective study collected the data of patients (n=290) who died from 2008 to 2012. The data were extracted from a cohort of over 2,000 patients from three outpatient Dementia Clinics of Genoa (Italy). Demographic data and other clinical parameters listed in the patients’ clinical records were collected. The mean survival rate after dementia diagnosis was 3.3 ± 0.1 years, lower compared to the age-matched healthy population. The survival rate of these patients showed a significant correlation with age (n=290; r=-0.16: p<0.006), with the cognitive status (n=285; r=0.16: p<0.007), with education (n=204; r=0.23: p<0.001), with comorbidity (n=138;r=-0.41: p<0.0001), with depressive mood (n=74; r=0.44: p<0.0001), and with the functional status (ADL: n=242, r=0.29: p<0.0001; IADL: n=243; r=0.25: p<0.0001). Multivariate regression revealed age, gender, and functional status as the main determinants informing patient survival. The study provides interesting and reliable data on the pivotal value of early dementia diagnosis in predicting longer survival and addresses comprehensive geriatric assessment, which encompasses most of the predictive variables provided by the study, as a remarkable tool in estimating life expectancy of patients with dementia.
Pages 311-320
Clovis Tauber, Emilie Beaufils, Caroline Hommet, Maria Joao Ribeiro, Johnny Vercouillie, Emilie Vierron, Karl Mondon, Jean Philippe Cottier, Valérie Gissot, Denis Guilloteau, Vincent Camus (Handling Associate Editor: Gary Small)
Brain [18F]FDDNP Binding and Glucose Metabolism in Advanced Elderly Healthy Subjects and Alzheimer’s Disease Patients
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 [18F]FDDNP and [18F]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 [18F]FDDNP and [18F]FDG. Results: Global [18F]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 [18F]FDG SUVr and in the parietal and posterior cingulate regions, while no correlation was found between age and [18F]FDDNP uptake. In AD patients, global [18F]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 [18F]FDDNP can distinguish AD patients from HCs in an advanced elderly population. It seems to be less sensitive than [18F]FDG to the brain changes observed with normal aging, but more sensitive to cognitive decline in advanced elderly AD patients.
Pages 321-334
Ingie Hong*, Taewook Kang*, YongCheol Yoo*, Royun Park*, Junuk Lee, Sukwon Lee, Jeongyeon Kim, Boemjong Song, Se-Young Kim, Minho Moon, Ki Na Yun, Jin Young Kim, Inhee Mook-Jung, Young Mok Park, Sukwoo Choi (Handling Associate Editor: Bhumsoo Kim)*These authors contributed equally to this work.
Quantitative Proteomic Analysis of the Hippocampus in the 5XFAD Mouse Model at Early Stages of Alzheimer’s Disease Pathology
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.
Pages 335-347
Shaila P. Handattu, Candyce E. Monroe, Gaurav Nayyar, Mayakonda N. Palgunachari, Inga Kadish, Thomas van Groen, Gattadahalli M. Anantharamaiah, David W. Garber
In Vivo and In Vitro Effects of an Apolipoprotein E Mimetic Peptide on Amyloid-β Pathology
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 andin 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.
Pages 349-363
Fabien Delerue, Geoff Sjollema, Belinda Whittle, Sarah Krüger, Dan Andrews, Jürgen Götz(Handling Associate Editor: Michal Novak)
Single Nucleotide Variants (SNVs) Define Senescence-Accelerated SAMP8 Mice, a Model of a Geriatric Condition
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.
Pages 365-376
He Li*, Ying Liang*, Kewei Chen, Xin Li, Ni Shu, Zhanjun Zhang, Yongyan Wang, for the BGBH Study Group (Handling Associate Editor: Anna Zimny) *These authors contributed equally to the manuscript.
Different Patterns of White Matter Disruption among Amnestic Mild Cognitive Impairment Subtypes: Relationship with Neuropsychological Performance
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.
Pages 377-383
Nadezhda A. Kapay, Olga V. Popova , Nikolay K. Isaev, Elena V. Stelmashook, Rodion V. Kondratenko, Dmitry B. Zorov, Vladimir G. Skrebitsky, Vladimir P. Skulachev
Mitochondria-Targeted Plastoquinone Antioxidant SkQ1 Prevents Amyloid-β-Induced Impairment of Long-Term Potentiation in Rat Hippocampal Slices
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 SkQ1at 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 (C12TPP) was studied. It was found that C12TPP 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.
Pages 385-399
Anders Wimo, Catherine C Reed, Richard Dodel, Mark Belger, Roy W. Jones, Michael Happich, Josep M. Argimon, Giuseppe Bruno, Diego Novick, Bruno Vellas, Josep Maria Haro
The GERAS Study: A Prospective Observational Study of Costs and Resource Use in Community Dwellers with Alzheimer’s Disease in Three European Countries – Study Design and Baseline Findings
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.
Pages 401-408
Panagiotis Alexopoulos, Liang-Hao Guo, Meizi Jiang, Hideaki Bujo, Timo Grimmer, Stefan Förster, Alexander Drzezga, Alexander Kurz, Robert Perneczky
Amyloid Cascade and Tau Pathology Cerebrospinal Fluid Markers in Mild Cognitive Impairment with regards to Alzheimer’s Disease Cerebral Metabolic Signature
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 18F-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 (sΑβΡΡα and sΑβΡΡβ, 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.
