Journal of Alzheimer's Disease - Volume 48, issue 1

Authors: Papuć, Ewa | Kurys-Denis, Ewa | Krupski, Witold | Tatara, Marcin | Rejdak, Konrad

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is known to exhibit well characterized pathologies including the extracellular accumulation of amyloid plaques, intra-axonal presence of neurofibrillary tangles, and glial hypertrophy. Nevertheless, the nature of myelin pathology in AD has not been well studied. Recent studies on animal models of AD, however, revealed focal demyelination within amyloid-β plaques in hippocampus. Objectives: In a view of this finding, we decided to assess humoral response against proteins of myelin sheath in AD, in the hope of identifying early biomarkers of memory loss and neuropathological process characteristic of AD. Methods: We assessed …antibodies levels against proteins of the myelin sheath: myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), myelin-associated glycoprotein (MAG), and proteolipoprotein (PLP) in sera of 26 AD patients and 26 healthy controls, using commercially available ELISA system (Mediagnost, Germany). Results: In the AD patient subgroup, significantly higher titers were observed for all types of assessed IgG autoantibodies compared to healthy control subjects (anti-MOG, anti-MAG, anti-MBP, anti-PLP). The titers of most of the investigated IgM antibodies were also higher in AD patients (p  <  0.05), with the exception of anti-MAG IgM antibodies (p  >  0.05). Conclusion: The study provides the evidence for the significantly increased production of autoantibodies against proteins of myelin sheath in AD. These results can be of importance in the light of emerging data from animal models of AD, indicating early demyelination of hippocampal region. Further studies on larger population are necessary to confirm whether these autoantibodies could serve as early biomarkers of AD in humans. Show more

Keywords: Alzheimer’s disease, autoantibodies, glial cells, humoral response, immune system, oligodendrocytes

DOI: 10.3233/JAD-150309

Citation: Journal of Alzheimer's Disease, vol. 48, no. 1, pp. 115-121, 2015

Authors: Kemppainen, Nina | Joutsa, Juho | Johansson, Jarkko | Scheinin, Noora M. | Någren, Kjell | Rokka, Johanna | Parkkola, Riitta | Rinne, Juha O.

Article Type: Research Article

Abstract: The aim of this longitudinal positron emission tomography (PET) study was to evaluate the interrelationship between brain metabolism and amyloid accumulation during the disease process from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Nine MCI patients, who converted to AD between two and five years, and nine healthy subjects underwent [11 C]PIB and [18 F]FDG PET scans at baseline and at 5 years. [11 C]PIB uptake was clearly higher in MCI patients at baseline compared to controls and spread extensively to the cerebral cortex during the conversion to AD. [18 F]FDG uptake was reduced especially in the temporal-parietal regions …in MCI compared to controls at baseline, and widely over the cortex at the 5-year follow-up. The reduction in metabolism during the follow-up was significant in the posterior brain regions. In addition, brain amyloid load was positively associated with metabolism in posterior brain regions in MCI, but not after conversion to AD. The results suggest that there are interactions between brain amyloid accumulation and metabolism during the AD process, including a possible compensatory upregulation of posterior brain metabolism in the early phase. Show more

Keywords: Alzheimer’s disease, [11C]PIB, [18F]FDG, follow-up, mild cognitive impairment, PET

DOI: 10.3233/JAD-150190

Citation: Journal of Alzheimer's Disease, vol. 48, no. 1, pp. 123-133, 2015

Authors: Hutchings, Rosalind | Hodges, John R. | Piguet, Olivier | Kumfor, Fiona

Article Type: Research Article

Abstract: Background: Skills such as empathy and emotion recognition rely on a multi-dimensional socio-emotional system. Increasingly, evidence suggests that socio-emotional cognition is affected in frontotemporal dementia and Alzheimer’s disease (AD), to varying degrees. However, the specific dimensions of socio-emotional behavior and their neuroanatomical correlates have been relatively unexplored. Objective: The current study aimed to: (i) determine how different dimensions of socio-emotional cognition are affected in behavioral-variant frontotemporal dementia (bvFTD), semantic dementia (SD), and AD; (ii) investigate insight into socio-emotional cognition; (iii) identify the neural correlates subserving dimensions of socio-emotional cognition. Methods: Sixteen bvFTD, …15 SD, 10 AD patients, and 17 controls were included. Each participant and a nominated ‘informant’ completed the socio-emotional questionnaire; a 30-item rating scale assessing five dimensions of socio-emotional cognition (empathy, emotion recognition, social conformity, antisocial behavior, sociability). Results: SD and bvFTD participants were rated lower on measures of empathy and emotion recognition compared to AD participants and Controls, while other dimensions were relatively intact. In contrast, participants with AD were rated similarly to Controls across all dimensions. SD and bvFTD groups demonstrated reduced insight into socio-emotional dysfunction. Grey matter intensity in the temporal regions correlated with empathy and emotion recognition. Social conformity was associated with the orbitofrontal cortex and amygdala. Conclusion: Distinct profiles in typically presenting bvFTD, SD, and AD illustrate preliminary evidence of the utility of socio-emotional cognition in diagnostic clarification. This is an important starting point in understanding socio-emotional functioning in younger-onset dementia, paving the way for targeted management and interventions. Show more

Keywords: Alzheimer’s disease, carer, cognition, frontotemporal dementia, social behavior, temporal pole

DOI: 10.3233/JAD-150245

Citation: Journal of Alzheimer's Disease, vol. 48, no. 1, pp. 135-147, 2015

Authors: Hosono, Takashi | Mouri, Akihiro | Nishitsuji, Kazuchika | Jung, Cha-Gyun | Kontani, Masanori | Tokuda, Hisanori | Kawashima, Hiroshi | Shibata, Hiroshi | Suzuki, Toshiharu | Nabehsima, Toshitaka | Michikawa, Makoto

Article Type: Research Article

Abstract: It is believed that the amyloid β -protein (Aβ ) plays a causative role in the development of Alzheimer’s disease (AD). The amyloid-β protein precursor (Aβ PP), a substrate of Aβ , and β -secretase and γ -secretase complex proteins, which process Aβ PP to generate Aβ , are all membrane proteins. Thus, it is reasonable to assume that alterations in brain lipid metabolism modulate Aβ PP and/or Aβ metabolism. However, the role of cellular polyunsaturated fatty acids in Aβ PP processing has not been completely understood yet. We report here that 4 months of treatment of Tg2576 …mice with an arachidonic acid (ARA)- or a docosahexaenoic acid (DHA)-containing (ARA+ or DHA+) diet prevented memory impairment at 13 months of age. Although, Aβ PP processing to generate soluble Aβ PP and induce Aβ synthesis was enhanced, Aβ 1 - 42 /Aβ 1 - 40 ratio decreased in 14-month-old Tg2576 mice fed with the ARA+ or DHA+ diet. The ARA+ or DHA+ diet did not alter the Aβ PP levels and the expression levels of Aβ -degrading enzymes. In cortical primary neuron cultures, ARA or DHA treatment also increased soluble Aβ PP and Aβ 1 - 40 levels, and decreased Aβ 1 - 42 /Aβ 1 - 40 ratio, which are similar to what were observed in Tg2576 mice fed with ARA+ or DHA+ diet. These findings suggest that not only the DHA+ diet, but also the ARA+ diet could prevent cognitive dysfunction in Tg2576 mice through the alteration of Aβ PP processing. Show more

Keywords: Alzheimer’s disease, amyloid β-protein, amyloid β-protein precursor, arachidonic acid, docosahexaenoic acid, memory impairment

DOI: 10.3233/JAD-150341

Citation: Journal of Alzheimer's Disease, vol. 48, no. 1, pp. 149-162, 2015

Authors: Serna, Adriana | Contador, Israel | Bermejo-Pareja, Félix | Mitchell, Alex J. | Fernández-Calvo, Bernardino | Ramos, Francisco | Villarejo, Alberto | Benito-León, Julián

Article Type: Research Article

Abstract: Early separation of mild cognitive impairment (MCI) from normal aging and mild cases of dementia remains a challenge, especially in the general population. We aimed to analyze the diagnostic accuracy of a brief neuropsychological battery (BNB) in dementia and MCI cases from the Neurological Disorders in Central Spain (NEDICES) population-based cohort study. We screened 3,891 participants into dementia and non-dementia groups using a two-phase procedure: screening (MMSE-37 and Pfeffer-11) and clinical diagnosis by specialists (DSM-IV criteria). We selected subsequently a subsample of dementia (n  = 98), MCI (n  = 71), and cognitively healthy (n  = 123) participants matched in socio-demographic characteristics. The clinical …validity of each test of the BNB was determined by the area under the ROC curve. We determined the best combination of tests to classify individuals into the diagnostic groups by logistic regression analyses. The results indicated that dementia and MCI groups could be best discriminated from the healthy control group on the basis of their scores on the semantic verbal fluency and delayed recall subtests of the BNB. As for discriminating the MCI group from the dementia group, immediate recall tasks (stories and pictures) yielded the highest level of accuracy. Probably the most interesting finding is that the verbal fluency task consistently allowed discrimination among the diagnostic groups. Overall, subtests of the BNB are more accurate in differentiating dementia patients than MCI patients from healthy controls. In this population-based sample, a more fine-grained discrimination that includes MCI patients should follow a systematic subtest-wise analysis and decision. Show more

Keywords: Dementia, memory, mild cognitive impairment, neuropsychological assessment, population based-study, test accuracy

DOI: 10.3233/JAD-150086

Citation: Journal of Alzheimer's Disease, vol. 48, no. 1, pp. 163-173, 2015

Authors: Li, Qiao-Xin | Villemagne, Victor L. | Doecke, James D. | Rembach, Alan | Sarros, Shannon | Varghese, Shiji | McGlade, Amelia | Laughton, Katrina M. | Pertile, Kelly K. | Fowler, Christopher J. | Rumble, Rebecca L. | Trounson, Brett O. | Taddei, Kevin | Rainey-Smith, Stephanie R. | Laws, Simon M. | Robertson, Joanne S. | Evered, Lisbeth A. | Silbert, Brendan | Ellis, Kathryn A. | Rowe, Christopher C. | Macaulay, S. Lance | Darby, David | Martins, Ralph N. | Ames, David | Masters, Colin L. | Collins, Steven | and for the AIBL Research Group

Article Type: Research Article

Abstract: Background: The cerebrospinal fluid (CSF) amyloid-β (Aβ)1-42 , total-tau (T-tau), and phosphorylated-tau (P-tau181P ) profile has been established as a valuable biomarker for Alzheimer’s disease (AD). Objective: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands. Methods: Aβ pathology was determined by PET imaging, utilizing 11 C-Pittsburgh Compound B, 18 F-flutemetamol, or 18 F-florbetapir, in 157 AIBL …participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ1-42 >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a “positive” CSF in the sub-cohort of amyloid-PET negative healthy participants (n  = 97), and compared with the presence of PET demonstrated AD pathology. Results: CSF Aβ1-42 was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aβ1-42 provided greater accuracy, predicting MCI/AD with Aβ pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aβ1-42 to predict MCI/AD, reached ≥92% sensitivity and specificity. Conclusions: CSF Aβ1-42 levels and analyte combination ratios demonstrated very high correlation with PET Aβ imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage. Show more

Keywords: Alzheimer’s disease, amyloid-β, cerebrospinal fluid biomarkers, positron emission tomography Aβ imaging, tau

DOI: 10.3233/JAD-150247

Citation: Journal of Alzheimer's Disease, vol. 48, no. 1, pp. 175-187, 2015

Authors: Schmidt, Christian | Gerlach, Nicole | Schmitz, Matthias | Thom, Tobias | Kramer, Katharina | Friede, Tim | Zerr, Inga

Article Type: Research Article

Abstract: Background/Objective: Apolipoprotein E (ApoE) has an active part in the pathogenesis of Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) and plasma level alterations have been reported in AD patients. In search of a biomarker potentially predictive of cognitive, functional, or motor decline, we analyzed the CSF to serum ratios of ApoE levels (CSF/serum ApoE) in AD patients in this regard. Methods: Subjects with newly diagnosed AD were followed within a longitudinal observational study (rpAD study). Annual neuropsychological testing and physical examination were performed. Multiple regression analyses were used to determine possible associations of the ApoE CSF/serum concentration ratios …and velocity of decline on a variety of cognitive, functional and motor scales (MMSE, iADL, bADL, GDS, UPDRSIII) adjusted for relevant co-variables. Results: CSF/serum ratios of ApoE levels were associated with progression on the UPDRSIII (change of UPDRSIII slope [pt/yr] per unit of ApoE CSF/serum = –0.06, p  <  0.01) and instrumental ADL scale (change of iADL slope [pt/yr] per unit of ApoE CSF/serum = 0.01, p  = 0.01) (“the lower the ratio, the faster the deterioration” and vice versa). Secondarily, higher age at onset was associated with faster UPDRSIII progression, antidepressant use with faster iADL decline, and better baseline function with more rapid decline on either MMSE, iADL, or GDS scale. Conclusion: Here, CSF/serum ApoE at time of AD diagnosis was shown to be inversely associated with medium-term functional and motor progression. Whether this ratio qualifies for the use as a predictive biomarker must be validated in larger cohort studies over the long term. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, biomarker, cerebrospinal fluid, cognition

DOI: 10.3233/JAD-150286

Citation: Journal of Alzheimer's Disease, vol. 48, no. 1, pp. 189-196, 2015

Authors: Brueggen, Katharina | Dyrba, Martin | Barkhof, Frederik | Hausner, Lucrezia | Filippi, Massimo | Nestor, Peter J. | Hauenstein, Karlheinz | Klöppel, Stefan | Grothe, Michel J. | Kasper, Elisabeth | Teipel, Stefan J. | and the EDSD study group

Article Type: Research Article

Abstract: Background: Hippocampal grey matter (GM) atrophy predicts conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Pilot data suggests that mean diffusivity (MD) in the hippocampus, as measured with diffusion tensor imaging (DTI), may be a more accurate predictor of conversion than hippocampus volume. In addition, previous studies suggest that volume of the cholinergic basal forebrain may reach a diagnostic accuracy superior to hippocampal volume in MCI. Objective: The present study investigated whether increased MD and decreased volume of the hippocampus, the basal forebrain and other AD-typical regions predicted time to conversion from MCI …to AD dementia. Methods: 79 MCI patients with DTI and T1 -weighted magnetic resonance imaging (MRI) were retrospectively included from the European DTI Study in Dementia (EDSD) dataset. Of these participants, 35 converted to AD dementia after 6–46 months (mean: 21 months). We used Cox regression to estimate the relative conversion risk predicted by MD values and GM volumes, controlling for age, gender, education and center. Results: Decreased GM volume in all investigated regions predicted an increased risk for conversion. Additionally, increased MD in the right basal forebrain predicted increased conversion risk. Reduced volume of the right hippocampus was the only significant predictor in a stepwise model combining all predictor variables. Conclusion: Volume reduction of the hippocampus, the basal forebrain and other AD-related regions was predictive of increased risk for conversion from MCI to AD. In this study, volume was superior to MD in predicting conversion. Show more

Keywords: Diffusion tensor imaging, magnetic resonance imaging, Mild Cognitive Impairment, Alzheimer’s disease, atrophy, basal forebrain, cholinergic, early diagnosis

DOI: 10.3233/JAD-150063

Citation: Journal of Alzheimer's Disease, vol. 48, no. 1, pp. 197-204, 2015

Authors: Hanson, Angela J. | Bayer, Jennifer L. | Baker, Laura D. | Cholerton, Brenna | VanFossen, Brian | Trittschuh, Emily | Rissman, Robert A. | Donohue, Michael C. | Moghadam, Setareh H. | Plymate, Stephen R. | Craft, Suzanne

Article Type: Research Article

Abstract: Background: High intake of saturated fat (SF) and glycemic index (GI) foods is a risk factor for sporadic Alzheimer’s disease. Meal challenges may elucidate mechanisms that contribute to this risk, enabling development of targeted interventions. Objective: To assess cognitive and metabolic changes after a meal high in SF and GI calories (HIGH) versus a meal low in these macronutrients (LOW) in older adults with and without cognitive impairment, and with and without the apolipoprotein E4 risk factor. Methods: 46 adults with either cognitive impairment (CI) or normal cognition (NC) ingested a LOW …(25% total fat, 7% SF, GI <55) and a HIGH meal (50% total fat, 25% SF, GI >70) in a blinded random fashion. Participants then underwent cognitive testing and blood sampling for metabolic and Alzheimer’s disease biomarkers. Data were analyzed using repeated measures ANOVA and Spearman correlations. Results: E4–adults with NC demonstrated lower delayed memory scores after the HIGH compared to the LOW meal, whereas normal E4+ and CI E4– groups had higher scores after the HIGH meal (ANOVA p  = 0.03). These findings were associated with meal-induced changes in glucose (p  = 0.05), insulin (p  = 0.004), triglycerides (p  <  0.01), and plasma Aβ42 (p  = 0.05). Conclusions: These preliminary data suggest that cognitive performance of adults without CI may worsen following high SF and sugar meals, whereas adults with CI or those at risk for CI due to E4 status may benefit acutely from such meals. Furthermore, plasma Aβ was affected by meal type, suggesting a relationship between metabolic response and amyloid regulation. Show more

Keywords: Alzheimer’s disease, APOE genotype, glycemic index, insulin, plasma amyloid, saturated fat, triglycerides

DOI: 10.3233/JAD-150273

Citation: Journal of Alzheimer's Disease, vol. 48, no. 1, pp. 205-218, 2015

Authors: Alam, John J.

Article Type: Research Article

Abstract: Background: P38 mitogen activated protein kinase (MAPK) α modulates microglia-mediated inflammatory responses and a number of neuronal physiological processes. Objective: To evaluate pre-clinically the pharmacological effects in the brain of p38 MAPKα inhibition with a brain-penetrant specific chemical antagonist. Methods: VX-745, a blood-brain barrier penetrant, highly selective p38 MAPKα inhibitor, and clinical stage investigational drug, was utilized. Initially, a pilot study in 26-month-old Tg2576 mice was conducted. Subsequently, a definitive dose-response study was conducted in aged (20–22 months) rats with identified cognitive deficits; n  = 15 per group: vehicle, 0.5, 1.5, and 4.5 mg/kg …VX-745 by oral gavage twice daily for 3 weeks. Assessments in aged rats included IL-1β, PSD-95, TNFα protein levels in hippocampus; and Morris water maze (MWM) test for cognitive performance. Results: Drug effect could not be assessed in Tg2576 mice, as little inflammation was evident. In cognitively-impaired aged rats, VX-745 led to significantly improved performance in the MWM and significant reduction in hippocampal IL-1β protein levels, though the effects were dissociated as the MWM effect was evident at a lower dose level than that required to lower IL-1β. Drug concentration-effect relationships and predicted human doses were determined. Conclusions: Selective inhibition of p38 MAPKα with VX-745 in aged rats reduces hippocampal IL-1β levels and improves performance in the MWM. As the two effects occur at different dose levels, the behavioral effect appears to be via a mechanism that is independent of reducing cytokine production. The predicted human doses should minimize risks of systemic toxicity. Show more

Keywords: Aged rats, Alzheimer’s disease, amyloid plaque, cognition, IL-1β , p38 MAPKα , Tg2576 mouse

DOI: 10.3233/JAD-150277

Citation: Journal of Alzheimer's Disease, vol. 48, no. 1, pp. 219-227, 2015