Journal of Alzheimer's Disease - Volume 41, issue 1

Authors: Siervo, Mario | Harrison, Stephanie L. | Jagger, Carol | Robinson, Louise | Stephan, Blossom C.M.

Article Type: Research Article

Abstract: Background: Metabolic syndrome (MetS) is associated with an increased risk of coronary heart diseases and stroke. Results on the association of MetS with dementia and cognitive decline have been inconsistent. Objective: The aim of this study was to examine the association between MetS and longitudinal changes in cognitive function. Methods: Medline, EMBASE, and Scopus databases were searched from inception to June 2013. Longitudinal cohort studies that reported on the association between MetS and change in cognitive function (over two or more time points), were included. Results: Random-effects models were used to assess the pooled …effect sizes of longitudinal changes in cognitive function associated with MetS. Thirteen studies were included. The total sample size was 19,522 subjects. Follow up duration ranged from 1 to 16 years. In the total sample, a small association of MetS with cognitive decline was observed (SDM 0.06, 95%CI: −0.001, 0.12; p = 0.05). When age-stratified, a marginal significant association between MetS and cognitive decline was observed in the younger old group (≤70 years; SDM = 0.09, 95%CI: −0.003, 0.19; p = 0.05) but not in the older group (>70 years; SDM = 0.03, 95%CI: −0.05, 0.11; p = 0.48). The meta-regression showed that duration of follow up was not associated with changes in cognitive estimates (β = 0.005; p = 0.30). Conclusions: Age appears to modify the association between MetS and cognitive decline. These results emphasize the importance of age-stratified risk prediction models of dementia in subjects with chronic metabolic disorders. Show more

Keywords: Aging, cognition, cohort studies, metabolic syndrome, risk prediction, systematic review

DOI: 10.3233/JAD-132279

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 151-161, 2014

Authors: Frisardi, Vincenza

Article Type: Research Article

Abstract: Metabolic syndrome (MetS) has been found to be a risk factor for dementia, mild cognitive impairment, and its associated states. However, a definitive conclusion cannot be drawn from the available data. Discrepancies between the results are due to several factors, e.g., study design, heterogeneity of the population enrolled, reliability and sensitivity of detection tools for cognitive changes, cut-offs and criteria used to diagnose MetS, the outcome measures considered, MetS duration before the onset of cognitive decline, and also the analytical approach performed. Recently, a systematic review and meta-analysis including 19,522 subjects aged 59–85 years from 13 longitudinal population-based studies has …been conducted to examine the association between MetS and longitudinal changes in cognitive functions. While a marginal significant association was found in the younger old group, this relationship was not observed in older group (>70 years). It is not yet clear how age can influence this relationship. Apart from methodological issues, other biological factors are likely involved in this direction reversal. Show more

Keywords: Alzheimer's disease, dementia, late-life cognitive decline, metabolic syndrome

DOI: 10.3233/JAD-140389

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 163-167, 2014

Authors: Kim, Geon Ha | Kim, Jung-Eun | Choi, Kyoung-Gyu | Lim, Soo Mee | Lee, Jong-Min | Na, Duk L. | Jeong, Jee Hyang

Article Type: Research Article

Abstract: Background: The most-widely used visual rating scale (VRS) for medial temporal atrophy is the T1-weighted (T1W) coronal VRS developed by Scheltens et al. However, it is often difficult to use the T1W-coronal VRS in cases with limitations in obtaining T1W-coronal images. To overcome this issue, we modified the T1W-coronal VRS onto the axial plane. Objective: The purposes of this study were to validate our T1W-axial VRS by examining its compatibility with the original T1W-coronal VRS and by investigating the correlation with the cognitive functions and hippocampal volumes. Methods: Participants were 50 patients with Alzheimer’s disease dementia …and 30 elderly with normal cognition. We transposed each component of the T1W-coronal VRS onto T1W-axial images (i.e., the largest height of the hippocampal formation into the width of the medial temporal lobe). The compatibility of T1W-axial VRS with T1W-coronal one was determined using the kappa value. The correlations of T1W-axial VRS with cognitive performance or the hippocampal volumes were analyzed with age, gender, and education as covariates. Results: The kappa value between the T1W-axial and T1W-coronal VRS was 0.772 (p < 0.045). The T1W-axial VRS showed a significant correlation with the scores of cognitive functions, including verbal memory tests (−0.601, p < 0.001 for the left). Furthermore, the T1W-axial VRS also correlated well with hippocampal volumes (−0.576, p < 0.001). Conclusions: The T1W-axial VRS showed good agreement with T1W-coronal VRS and correlated well with cognitive functions as well as hippocampal volumes, which suggests that the T1-axial VRS may replace the original T1W-coronal one. Show more

Keywords: Alzheimer's disease, medial temporal atrophy, visual rating scale

DOI: 10.3233/JAD-132333

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 169-178, 2014

Authors: Harris, Christopher J. | Voss, Kellen | Murchison, Charles | Ralle, Martina | Frahler, Kate | Carter, Raina | Rhoads, Allison | Lind, Betty | Robinson, Emily | Quinn, Joseph F.

Article Type: Research Article

Abstract: The aggregation of amyloid-β in Alzheimer's disease can be affected by free transition metals such as copper and zinc in the brain. Addition of copper and zinc with amyloid acts to increase aggregation and copper additionally promotes the formation of reactive oxygen species. We propose that reduction of brain copper by blocking uptake of copper from the diet is a viable strategy to regulate the formation of insoluble amyloid-β in the brain of Tg2576 mice. Mice were treated with regimens of zinc acetate, which acts with metallothionein to block copper uptake in the gut, at various times along their lifespan …to model prevention and treatment paradigms. We found that the mice tolerated zinc acetate well over the six month course of study. While we did not observe significant changes in cognition and behavior, there was a reduction in insoluble amyloid-β in the brain. This observation coincided with a reduction in brain copper and interestingly no change in brain zinc. Our findings show that blocking copper uptake from the diet can redistribute copper from the brain and reduce amyloid-β aggregation. Show more

Keywords: Alzheimer's disease, amyloid-β protein, copper, transgenic mice

DOI: 10.3233/JAD-131703

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 179-192, 2014

Authors: Scheinin, Noora M. | Wikman, Kristina | Jula, Antti | Perola, Markus | Vahlberg, Tero | Rokka, Johanna | Någren, Kjell | Viitanen, Matti | Rinne, Juha O.

Article Type: Research Article

Abstract: Background/Objective: Our aim was to elucidate factors that contribute to amyloid-β (Aβ) accumulation in the brains of the seemingly healthy elderly population, and whether there is interplay between those factors. Methods: We conducted a cross-sectional positron emission tomography (PET) study with the amyloid tracer 11 C-PIB, in 64 cognitively healthy subjects (54–89 years). In addition to PET, magnetic resonance imaging, neuropsychological testing, and APOE genotyping was performed. The results were assessed with a statistical general linear model as well as with Statistical Parametric Mapping (SPM). Results: The effects of age (p < 0.001), APOE ε4 carrier …status (p = 0.003), and gender (p = 0.001) on composite cortical 11 C-PIB uptake were all significant. The effect of educational level was non-significant (p = 0.37). No significant interactions were found between any of the factors. Cortical 11 C-PIB uptake increased, on the average, by 0.015 cortex/cerebellar cortical ratio unit, with every year of age. APOE ε4 positive subjects exhibited higher cortical 11 C-PIB uptake than APOE ε4 negative subjects (unadjusted means 1.49 ± 0.34 versus 1.29 ± 0.26) and males had higher uptake than females (1.49 ± 0.39 versus 1.29 ± 0.22), irrespective of age. The results of the voxel-based (SPM) analysis were similar. In addition, SPM analysis showed that lower CERAD score was associated with higher 11 C-PIB uptake in the frontal cortex. Conclusions: Age and APOE ε4 genotype were associated with higher 11 C-PIB uptake. In this sample of cognitively healthy elderly individuals, men exhibited higher 11 C-PIB uptake than women. Possible gender differences in Aβ accumulation have not been addressed in detail in previous studies, and deeper evaluation in the future is warranted. Show more

Keywords: Aging, amyloid, APOE, gender, PET, PIB, positron emission tomography

DOI: 10.3233/JAD-132783

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 193-202, 2014

Authors: Al-khateeb, Eman | Al-zayadneh, Ebaa | Al-dalahmah, Osama | Alawadi, Zeinab | khatib, Faisal | Naffa, Randa | Shafagoj, Yanal

Article Type: Research Article

Abstract: The purpose of the current study was to examine the association of serum copper and lipid concentrations with changes in cognitive function in elderly Jordanian individuals. The study population consisted of two groups: 52 dementia patients and 50 control subjects. All individuals were screened using the Mini-Mental State Examination and Clock Drawing Test. Serum copper and lipid profile were also assessed. Results were statistically evaluated at p < 0.05 level of significance. The dementia group had 10.1% higher copper level than control subjects that was not statistically significant. No significant differences could be found between the two groups in lipid …profile levels. There was no significant correlation between serum copper, lipid profile, and cognitive decline in elderly Jordanians. Demographic variables indicated that educational level less than 12 years and illiterate demonstrated a 3.29 fold (p = 0.026) and 6.29 fold (p = 0.002) increase in risk of developing dementia, respectively. Coffee intake demonstrated a protective effect against cognitive decline with 6.25 fold lower risk with increased coffee intake. Show more

Keywords: Alzheimer's disease, cholesterol, coffee, copper, dementia, lipid profile

DOI: 10.3233/JAD-132180

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 203-211, 2014

Authors: Romero, Juan Pablo | Benito-León, Julián | Louis, Elan D. | Bermejo-Pareja, Félix

Article Type: Research Article

Abstract: The purpose of this review is to assess the extent to which dementia is omitted as a cause of death from the death certificates of patients with dementia. A systematic literature search was performed to identify population-based cohort studies in which all participants were examined or screened for symptoms of dementia with a validated instrument followed by confirmation of any suspected cases with a clinical examination (two-phase investigation). Data were extracted in a standardized manner and assessed through the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative. Seven studies met the selection criteria. These were from the Americas …(5 articles: 2 from Canada, 2 from the US, and 1 from Brazil) and Europe (2 articles: 1 from the UK and 1 from Spain). Each met at least 83% of the STROBE criteria. The reporting of dementia on death certificates was poor in these 7 studies, ranging from 7.2%–41.8%. Respiratory or circulatory-related problems were the most frequently reported causes of death among people who were demented but who were not reported as demented on death certificates. The use of death certificates for studying dementia grossly underestimates the occurrence of dementia in the population. The poor reporting of dementia on these certificates suggests a lack of awareness of the importance of dementia as a cause of death among medical personnel. There is an urgent need to provide better education on the importance of codification of dementia on death certificates in order to minimize errors in epidemiological studies on dementia. Show more

Keywords: Death certificates, elderly, epidemiology, population-based study, systematic review

DOI: 10.3233/JAD-132765

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 213-221, 2014

Authors: Lodeiro, María | Ibáñez, Clara | Cifuentes, Alejandro | Simó, Carolina | Cedazo-Mínguez, Ángel

Article Type: Research Article

Abstract: Increasing evidence suggest that Alzheimer's disease (AD) is a heterogeneous disorder that includes several subtypes with different etiology and progression. Cerebrospinal fluid (CSF) is being used to find new biomarkers reflecting the complexity of the pathological pathways within this disease. We used CSF and clinical data from patients to investigate the status of asymmetric dimethyl–L-arginine, creatine, suberylglycine, and L-carnitine along AD progression. These molecules play important roles in mitochondrial function and dysfunction in mitochondrial metabolism are involved in AD pathology. We found that non-APOE4 carriers show lower levels of L-carnitine in CSF early in AD. L-carnitine levels correlate with amyloid-β …(Aβ) levels and Mini-Mental State Examination score, but do not add to the specificity or sensitivity of the classical AD CSF biomarkers, Aβ42 , phospho-tau, and total-tau. Our results suggest APOE genotype-dependent differences in L-carnitine synthesis or metabolism along AD, and insinuate that L-carnitine treatments would be more beneficial for AD patients not carrying the APOE4 isoform. Show more

Keywords: Alzheimer's disease, APOE4, biomarkers, cerebrospinal fluid, L-carnitine

DOI: 10.3233/JAD-132063

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 223-232, 2014

Authors: Moon, Minho | Cha, Moon-Yong | Mook-Jung, Inhee

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is an age-related neurological disorder characterized by the deposition of amyloid-β (Aβ), cognitive deficits, and neuronal loss. The decline in neurogenic capacity could participate in neuronal vulnerability and contribute to memory impairment in AD. In our longitudinal study with AD model mice (5XFAD mice), we found that the number of doublecortin (neurogenesis marker)-positive cells in 5XFAD mice was significantly decreased compared to wild-type littermate mice. Using Aβ immunostaining with 4G8 antibody, we observed that impairment in neurogenesis might be associated with the deposits of amyloid plaques. To investigate the effect of the neurogenic hormone ghrelin on defective …neurogenesis in the AD brain, 5XFAD mice were administered peripherally with ghrelin. We found that treatment with ghrelin increased the number of doublecortin, HH3, and calretinin-stained cells in the hippocampus of 5XFAD mice. In 5XFAD mice treated with ghrelin, the 4G8-positive area was not significantly different from the saline-treated 5XFAD mice. Together, these findings suggest that hippocampal neurogenesis is impaired in 5XFAD mice and that treatment with ghrelin successfully rescued the abnormality of neurogenesis in 5XFAD mice without affecting Aβ pathology. Show more

Keywords: Alzheimer's disease, 5XFAD mice, amyloid plaque, adult neurogenesis, hippocampus, ghrelin

DOI: 10.3233/JAD-132417

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 233-241, 2014

Authors: Yu, Yun-Zhou | Wang, Wen-Bin | Chen, Ao | Chang, Qing | Liu, Si | Zhao, Meng | Wang, Shuang | Qiu, Wei-Yi | Pang, Xiao-Bin | Xu, Qing | Sun, Zhi-Wei

Article Type: Research Article

Abstract: Targeting on the amyloid-β (Aβ) is a promising immunotherapeutic strategy for Alzheimer's disease (AD). However, Aβ1-15 sequence alone induces low antibody response and poor protection against AD. We describe here the immunological characterization and protective efficacy of several recombinant chimeric vaccines with hexavalent foldable Aβ1-15 (6Aβ15) fused to PADRE or toxin-derived carrier proteins. Immunization with these chimeric antigens generated robust Th2 immune responses with high anti-Aβ42 antibody titers in different mice, which recognized neurotoxic Aβ42 oligomers, but did not stimulate Aβ42 -specific T cell responses. These 6Aβ15 chimeric vaccines markedly reduced Aβ pathology and prevented development …of behavioral deficits in immunized older AD mice. Importantly, toxin-derived carrier proteins as molecular adjuvants of chimeric vaccines could substantially boost immune responses and overcome Aβ- and old age-associated hypo-responsiveness, and elicit long-term Aβ-specific antibody response, which in turn inhibited Aβ-mediated pathology and improved acquisition and retention of spatial memory in immunized AD mice. These data indicate that toxin fragments as molecular adjuvants are promising new tools for the rational design and development of prototype chimeric vaccines for AD and this type of chimeric vaccine design has the added advantage of overcoming hypo-responsiveness in elderly AD patients with pre-existing memory Th cells from tetanus toxin. Show more

Keywords: Alzheimer's disease, carrier protein, chimeric vaccines, immunotherapy, molecular adjuvant

DOI: 10.3233/JAD-132177

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 243-260, 2014