Journal of Alzheimer's Disease - Volume 48, issue 4

Authors: Bilello, Michel | Doshi, Jimit | Nabavizadeh, S. Ali | Toledo, Jon B. | Erus, Guray | Xie, Sharon X. | Trojanowski, John Q. | Han, Xiaoyan | Davatzikos, Christos

Article Type: Research Article

Abstract: Background: Vascular risk factors are increasingly recognized as risks factors for Alzheimer’s disease (AD) and early conversion from mild cognitive impairment (MCI) to dementia. While neuroimaging research in AD has focused on brain atrophy, metabolic function, or amyloid deposition, little attention has been paid to the effect of cerebrovascular disease to cognitive decline. Objective: To investigate the correlation of brain atrophy and white matter lesions with cognitive decline in AD, MCI, and control subjects. Methods: Patients with AD and MCI, and healthy subjects were included in this study. Subjects had a baseline MRI scan, and …baseline and follow-up neuropsychological battery (CERAD). Regional volumes were measured, and white matter lesion segmentation was performed. Correlations between rate of CERAD score decline and white matter lesion load and brain structure volume were evaluated. In addition, voxel-based correlations between baseline CERAD scores and atrophy and white matter lesion measures were computed. Results: CERAD rate of decline was most significantly associated with lesion loads located in the fornices. Several temporal lobe ROI volumes were significantly associated with CERAD decline. Voxel-based analysis demonstrated strong correlation between baseline CERAD scores and atrophy measures in the anterior temporal lobes. Correlation of baseline CERAD scores with white matter lesion volumes achieved significance in multilobar subcortical white matter. Conclusion: Both baseline and declines in CERAD scores correlate with white matter lesion load and gray matter atrophy. Results of this study highlight the dominant effect of volume loss, and underscore the importance of small vessel disease as a contributor to cognitive decline in the elderly. Show more

Keywords: Alzheimer’s disease, atrophy, cognitive decline, mild cognitive impairment, vascular disease, white matter lesions

DOI: 10.3233/JAD-150400

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 987-994, 2015

Authors: Zheng, Weihao | Yao, Zhijun | Hu, Bin | Gao, Xiang | Cai, Hanshu | Moore, Philip | and for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Brain network occupies an important position in representing abnormalities in Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Currently, most studies only focused on morphological features of regions of interest without exploring the interregional alterations. In order to investigate the potential discriminative power of a morphological network in AD diagnosis and to provide supportive evidence on the feasibility of an individual structural network study, we propose a novel approach of extracting the correlative features from magnetic resonance imaging, which consists of a two-step approach for constructing an individual thickness network with low computational complexity. Firstly, multi-distance combination is utilized for …accurate evaluation of between-region dissimilarity; and then the dissimilarity is transformed to connectivity via calculation of correlation function. An evaluation of the proposed approach has been conducted with 189 normal controls, 198 MCI subjects, and 163 AD patients using machine learning techniques. Results show that the observed correlative feature suggests significant promotion in classification performance compared with cortical thickness, with accuracy of 89.88% and area of 0.9588 under receiver operating characteristic curve. We further improved the performance by integrating both thickness and apolipoprotein E ɛ 4 allele information with correlative features. New achieved accuracies are 92.11% and 79.37% in separating AD from normal controls and AD converters from non-converters, respectively. Differences between using diverse distance measurements and various correlation transformation functions are also discussed to explore an optimal way for network establishment. Show more

Keywords: Alzheimer’s disease, combined distance, correlation calculation function, cortical thickness network, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-150311

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 995-1008, 2015

Authors: Binukumar, B.K. | Shukla, Varsha | Amin, Niranjana D. | Bhaskar, Manju | Skuntz, Suzanne | Steiner, Joseph | Winkler, Dirk | Pelech, Steven L. | Pant, Harish C.

Article Type: Research Article

Abstract: Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles, it is well documented that cyclin-dependent kinase 5 (CDK5), a critical neuronal protein kinase in nervous system development, function, and survival, when deregulated and hyperactivated induces Alzheimer’s disease (AD) and amyotrophic lateral sclerosis and Parkinson’s disease-like phenotypes in mice. In a recent study, we demonstrated that p5, a small, truncated fragment of 24 amino acid residues derived from the CDK5 activator protein 35 (NCK5A, p35), selectively inhibited deregulated CDK5 hyperactivity and ameliorated AD phenotypes in model mice. In this study, we identified the most inhibitory elements in the p5 peptide …fragment. Each amino acid residue in p5 was systematically replaced with its homologous residues that may still be able to functionally substitute. The effects of these p5 peptide analogs were studied on the phosphotransferase activities of CDK5/p35, CDK5/p25, ERK1, and GSK3β. The mimetic p5 peptide (A/V substitution at the C-terminus of the peptide) in the sequence, KNAFYERALSIINLMTSKMVQINV (p5-MT) was the most effective inhibitor of CDK5 kinase activity of 79 tested mimetic peptides including the original p5 peptide, KEAFWDRCLSVINLMSSKMLQINA (p5-WT). Replacement of the residues in C-terminus end of the peptide affected CDK5 phosphotransferase activity most significantly. These peptides were strong inhibitors of CDK5, but not the related proline-directed kinases, ERK1 and GSK3β. Show more

Keywords: Alzheimer’s disease, CDK5 activator protein 35, cyclin-dependent kinase 5, phosphorylation

DOI: 10.3233/JAD-150412

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 1009-1017, 2015

Authors: Liu, Hui | Qiu, Hongyan | Xiao, Qian | Le, Weidong

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common form of dementia with the accumulation of senile plaques and neurofibrillary tangles in the brain. Autophagy is the key machinery for mammalian cells to degrade damaged organelles and abnormal proteins. Enormous evidence suggests that the autophagy pathway is impaired in AD. Our previous study revealed that hypoxia induced autophagic activation leading to more amyloid-β production in vitro . In this study, we investigated whether autophagic dysfunction is involved in the hypoxia mediated-pathogenesis of AD. We used APPSwe /PS1dE9 transgenic (Tg) mice and wildtype (Wt) littermates. We documented that chronic hypoxia caused more …and larger senile plaques in the brains of Tg mice. In addition, chronic hypoxia induced activation of autophagy in the brains of both Wt and Tg mice, and compared to the normal autophagic flux in Wt mice, the autophagic flux was impaired in the brains of H-Tg mice with a large amount of autophagic vacuole accumulation and significant high level of P62. In an in vitro study, we showed that hypoxia-induced autophagy significantly elevated the level of hAβ42 . Furthermore, we found that chronic hypoxia activated AMPK and further inhibited the mTOR signaling pathway, while inhibition of AMPK attenuated autophagy induction through the enhancement of mTOR phosphorylation. In short, our study provides new insight into the mechanism underlying chronic hypoxia-mediated AD pathogenesis. Show more

Keywords: Alzheimer’s disease, AMPK, autophagy, chronic hypoxia, mTOR

DOI: 10.3233/JAD-150303

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 1019-1032, 2015

Authors: Törmälehto, Soili M. | Martikainen, Janne A. | Väätäinen, Saku T. | Hallikainen, Ilona T. | Hallikainen, Merja | Bell, J. Simon | Koivisto, Anne M. | and on the behalf of the ALSOVA study group

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by deterioration in cognition, decline in physical function, and increase in behavioral disturbances. These symptoms are associated with dependence. Objective: We investigated the use of anti-dementia drugs in relation to change in cognition, function, and behavior over a 3-year period. Methods: Data were collected as part of the prospective follow-up ALSOVA study. All study participants (n  = 236) had very mild or mild AD at baseline. All participants and their informal caregivers underwent annual clinical and medication assessments. Repeated measures logistic regression was used to compute odds ratios (ORs) and …95% confidence intervals (CIs) for factors associated with anti-dementia drug use and disease progression measures over time. Results: The overall prevalence of anti-dementia drug use remained stable (from 89% to 92%) during the follow-up period. The use of memantine and cholinesterase inhibitor-memantine combination treatment increased with disease severity. After adjustment for confounding, a one-point increase in the disease severity scale (CDR-SOB) was associated with 15.6% increased odds of memantine use. A one-point decrease in CERAD Neuropsychological battery (CERAD-NB) total score was associated with 2.4% increased odds of memantine use. The overall unadjusted rate of switching between anti-dementia drugs was 9.17 (95% CI 7.10 to 11.88) changes per 100 person-years. Conclusion: Nearly 90% of newly diagnosed persons with AD were prescribed anti-dementia drugs. Use of memantine was found to be associated with disease progression. Switching and use of anti-dementia drugs was consistent with Finnish and European clinical practice guidelines for AD. Show more

Keywords: ALSOVA, Alzheimer’s disease, cholinesterase inhibitor, dementia, drug utilization, memantine

DOI: 10.3233/JAD-150092

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 1033-1041, 2015

Authors: Kim, Hyeong Jun | Park, Kyung Won | Kim, Tae Eun | Im, Ji Young | Shin, Ho Sik | Kim, Saeromi | Lee, Dong Hyun | Ye, Byoung Seok | Kim, Jong Hun | Kim, Eun-Joo | Park, Kee Hyung | Han, Hyun Jeong | Jeong, Jee Hyang | Choi, Seong Hye | Park, Sun Ah

Article Type: Research Article

Abstract: Background: Although plasma amyloid-β (Aβ) levels have been evaluated as a possible diagnostic marker of Alzheimer’s disease (AD), the findings are inconsistent. Objective: The present study aimed to validate plasma levels of Aβ40 , Aβ42 , and the Aβ40 /Aβ42 ratio as biomarkers of AD in subjects with early-onset AD (EOAD) without familial AD genetic mutations. Methods: Patients with sporadic EOAD (sEOAD) were prospectively recruited by nine neurology clinics. Plasma levels of Aβ40 and Aβ42 were measured using a sandwich enzyme-linked immunosorbent assay (ELISA) in 100 sEOAD (50–69 year-old) and 46 age-matched …normal control subjects (50–72 year-old). Cerebrospinal fluid (CSF) was obtained from 32 sEOAD subjects and 25 controls. The integrity of the blood-brain barrier was assessed using the CSF/plasma albumin ratio. Results: The plasma levels of Aβ42 were significantly lower, while the Aβ40 /Aβ42 ratio was significantly higher in sEOAD patients than in controls. The levels of Aβ40 , Aβ42 , and the Aβ40 /Aβ42 ratio did not differ in relation to the APOE ɛ 4 allele. The CSF/plasma albumin ratio was comparable between the two groups, and the plasma parameters of Aβ proteins were not significantly associated. A multivariate analysis revealed that an increased Aβ40 /Aβ42 ratio is valuable for the discrimination of sEOAD from controls (β= 0.344, p  = 0.000). The area under the ROC curve for the Aβ40 /Aβ42 ratio was 0.76, and a cut-off ratio of 5.87 was suggested to have 70% sensitivity and 68% specificity. Conclusion: The plasma Aβ40 /Aβ42 ratio had moderate validity for the discrimination of sEOAD patients from age-matched controls. Show more

Keywords: Alzheimer’s disease, amyloid-β protein, biomarker, blood-brain barrier, plasma

DOI: 10.3233/JAD-143018

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 1043-1050, 2015

Authors: Moon, Seok Woo | Dinov, Ivo D. | Kim, Jaebum | Zamanyan, Alen | Hobel, Sam | Thompson, Paul M. | Toga, Arthur W. | and for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: This article investigates late-onset cognitive impairment using neuroimaging and genetics biomarkers for Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants. Eight-hundred and eight ADNI subjects were identified and divided into three groups: 200 subjects with Alzheimer’s disease (AD), 383 subjects with mild cognitive impairment (MCI), and 225 asymptomatic normal controls (NC). Their structural magnetic resonance imaging (MRI) data were parcellated using BrainParser, and the 80 most important neuroimaging biomarkers were extracted using the global shape analysis Pipeline workflow. Using Plink via the Pipeline environment, we obtained 80 SNPs highly-associated with the imaging biomarkers. In the AD cohort, rs2137962 was significantly associated bilaterally …with changes in the hippocampi and the parahippocampal gyri, and rs1498853, rs288503, and rs288496 were associated with the left and right hippocampi, the right parahippocampal gyrus, and the left inferior temporal gyrus. In the MCI cohort, rs17028008 and rs17027976 were significantly associated with the right caudate and right fusiform gyrus, rs2075650 (TOMM40) was associated with the right caudate, and rs1334496 and rs4829605 were significantly associated with the right inferior temporal gyrus. In the NC cohort, Chromosome 15 [rs734854 (STOML1), rs11072463 (PML), rs4886844 (PML), and rs1052242 (PML)] was significantly associated with both hippocampi and both insular cortices, and rs4899412 (RGS6) was significantly associated with the caudate. We observed significant correlations between genetic and neuroimaging phenotypes in the 808 ADNI subjects. These results suggest that differences between AD, MCI, and NC cohorts may be examined by using powerful joint models of morphometric, imaging and genotypic data. Show more

Keywords: ADNI, Alzheimer’s disease, GWAS, late-onset, mild cognitive impairment, neuroimaging

DOI: 10.3233/JAD-150335

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 1051-1063, 2015

Authors: Calderón-Garcidueñas, Lilian | Mora-Tiscareño, Antonieta | Melo-Sánchez, Gastón | Rodríguez-Díaz, Joel | Torres-Jardón, Ricardo | Styner, Martin | Mukherjee, Partha S. | Lin, Weili | Jewells, Valerie

Article Type: Research Article

Abstract: Severe air pollution exposures produce systemic, respiratory, myocardial, and brain inflammation and Alzheimer’s disease (AD) hallmarks in clinically healthy children. We tested whether hippocampal metabolite ratios are associated with contrasting levels of air pollution, APOE, and body mass index (BMI) in paired healthy children and one parent sharing the same APOE alleles. We used 1 H-MRS to interrogate bilateral hippocampal single-voxel in 57 children (12.45 ± 3.4 years) and their 48 parents (37.5 ± 6.78 years) from a low pollution city versus Mexico City (MC). NAA/Cr, Cho/Cr, and mI/Cr metabolite ratios were analyzed. The right hippocampus NAA/Cr ratio was significantly …different between cohorts (p  = 0.007). The NAA/Cr ratio in right hippocampus in controls versus APOE ɛ 4 MC children and in left hippocampus in MC APOE ɛ 4 parents versus their children was significantly different after adjusting for age, gender, and BMI (p  = 0.027 and 0.01, respectively). The NAA/Cr ratio is considered reflective of neuronal density/functional integrity/loss of synapses/higher pTau burden, thus a significant decrease in hippocampal NAA/Cr ratios may constitute a spectral marker of early neurodegeneration in young urbanites. Decreases in NAA/Cr correlate well with cognitive function, behavioral symptoms, and dementia severity; thus, since the progression of AD starts decades before clinical diagnosis, our findings support the hypothesis that under chronic exposures to fine particulate matter and ozone above the standards, neurodegenerative processes start in childhood and APOE ɛ 4 carriers are at higher risk. Gene and environmental factors are critical in the development of AD and the identification and neuroprotection of young urbanites at high risk must become a public health priority. Show more

Keywords: Air Pollution, APOE, body mass index, children, hippocampus, magnetic resonance spectroscopy, memory, NAA/Cr ratio, neuroprotection, PM2.5

DOI: 10.3233/JAD-150415

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 1065-1075, 2015

Authors: Fraga, Vanessa G. | Guimarães, Henrique C. | Lara, Vivian P. | Teixeira, Antônio L. | Barbosa, Maira T. | Carvalho, Maria G. | Caramelli, Paulo | Gomes, Karina B.

Article Type: Research Article

Abstract: Background: Inflammation and cytokine production are a common finding in aging, which probably exert influence on cognitive and functional abilities in elderly people. Transforming-growth-factor beta 1 (TGF-β1) is an important multifunctional anti-inflammatory cytokine that displays immunomodulatory activities. Objective: This prospective investigation aimed to evaluate the TGF-β1 codon 10 T>C on functional and cognitive decline in subjects aged 75+ years. Methods: The Functional Activities Questionnaire evaluated the functional performance and the cognitive assessment was evaluated through brief cognitive tests, consisting of: the Mini-Mental State Examination, animal category fluency test, and picture drawings memory test. All tests …were administered twice, with a one-year interval. Results: Carriers of Tlower allele showed significant short-term decline in cognitive and functional performance, while individuals with CChigher genotype of TGF-β1 codon 10 T>C remained stable or showed improvement. Conclusion: Our findings indicate that the lower production of TGF-β1 could predict a longitudinal functional and cognitive decline in oldest-old individuals. Show more

Keywords: Aging, cognition, functional performance, polymorphism, TGF-β1

DOI: 10.3233/JAD-150397

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 1077-1081, 2015

Authors: Bielarczyk, Hanna | Jankowska-Kulawy, Agnieszka | Höfling, Corinna | Ronowska, Anna | Gul-Hinc, Sylwia | Roßner, Steffen | Schliebs, Reinhard | Pawelczyk, Tadeusz | Szutowicz, Andrzej

Article Type: Research Article

Abstract: The pyruvate-derived acetyl-CoA is a principal direct precursor substrate for bulk energy synthesis in the brain. Deficits of pyruvate dehydrogenase in the neocortex are common features of Alzheimer’s disease and other age-related encephalopathies in humans. Therefore, amyloid-β overload in brains of diverse transgenic Alzheimer’s disease model animals was investigated as one of neurotoxic compounds responsible for pyruvate dehydrogenase inhibition yielding deficits of cholinergic neurotransmission and cognitive functions. Brains of aged, 14–16-month-old Tg2576 mice contained 0.6μ mol/kg levels of amyloid-β1 - 42 . Activities of pyruvate dehydrogenase complex, choline acetyltransferase, and several enzymes of acetyl-CoA and energy metabolism were found to be unchanged …in both forebrain mitochondria and synaptosomes of Tg2576 mice, indicating preservation of structural integrity at least in cholinergic neuronal cells. However, in transgenic brain synaptosomes, pyruvate utilization, mitochondrial levels, and cytoplasmic acetyl-CoA levels, as well as acetylcholine content and its quantal release, were all found to be decreased by 25–40% . On the contrary, activation of pyruvate utilization was detected and no alterations in acetyl-CoA content and citrate or α-ketoglutarate accumulation were observed in transgenic whole brain mitochondria. These data indicate that amyloid-β evoked deficits in acetyl-CoA are confined to mitochondrial and cytoplasmic compartments of Tg2576 nerve terminals, becoming early primary signals paving the path for further stages of neurodegeneration. On the other hand, acetyl-CoA synthesis in mitochondrial compartments of glial cells seems to be activated despite amyloid-β accumulated in transgenic brains. Show more

Keywords: Acetylcholine, acetyl-CoA, amyloid-β , choline acetyltransferase, pyruvate dehydrogenase, synaptosomes, Tg2576 mice, whole brain mitochondria

DOI: 10.3233/JAD-150327

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 1083-1094, 2015