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

Authors: Dubner, Lauren | Wang, Jun | Ho, Lap | Ward, Libby | Pasinetti, Giulio M.

Article Type: Review Article

Abstract: It is currently thought that the lackluster performance of translational paradigms in the prevention of age-related cognitive deteriorative disorders, such as Alzheimer’s disease (AD), may be due to the inadequacy of the prevailing approach of targeting only a single mechanism. Age-related cognitive deterioration and certain neurodegenerative disorders, including AD, are characterized by complex relationships between interrelated biological phenotypes. Thus, alternative strategies that simultaneously target multiple underlying mechanisms may represent a more effective approach to prevention, which is a strategic priority of the National Alzheimer’s Project Act and the National Institute on Aging. In this review article, we discuss recent strategies …designed to clarify the mechanisms by which certain brain-bioavailable, bioactive polyphenols, in particular, flavan-3-ols also known as flavanols, which are highly represented in cocoa extracts, may beneficially influence cognitive deterioration, such as in AD, while promoting healthy brain aging. However, we note that key issues to improve consistency and reproducibility in the development of cocoa extracts as a potential future therapeutic agent requires a better understanding of the cocoa extract sources, their processing, and more standardized testing including brain bioavailability of bioactive metabolites and brain target engagement studies. The ultimate goal of this review is to provide recommendations for future developments of cocoa extracts as a therapeutic agent in AD. Show more

Keywords: Amyloid, chocolate, diet therapy, Lavado, oligomerization, polyphenols, synapses

DOI: 10.3233/JAD-150536

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 879-889, 2015

Authors: Jha, Niraj Kumar | Jha, Saurabh Kumar | Kumar, Dhiraj | Kejriwal, Noopur | Sharma, Renu | Ambasta, Rashmi K. | Kumar, Pravir

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative process primarily characterized by amyloid-β (Aβ) agglomeration, neuroinflammation, and cognitive dysfunction. The prominent cause for dementia is the deposition of Aβ plaques and tau-neurofibrillary tangles that hamper the neuronal organization and function. Aβ pathology further affects numerous signaling cascades that disturb the neuronal homeostasis. For instance, Aβ deposition is responsible for altered expression of insulin encoding genes that lead to insulin resistance, and thereby affecting insulin signaling pathway and glucose metabolism in the brain. As a result, the common pathology of insulin resistance between Type-2 diabetes mellitus and AD has led AD to be …proposed as a form of diabetes and termed ‘Type-3 diabetes’. Since accumulation of Aβ is the prominent cause of neuronal toxicity in AD, its clearance is the prime requisite for therapeutic prospects. This purpose is expertly fulfilled by the potential role of Aβ degrading enzymes such as insulin degrading enzyme (IDE) and Neprilysin (NEP). Therefore, their molecular study is important to uncover the proteolytic and regulatory mechanism of Aβ degradation. Herein, (i) In silico sequential and structural analysis of IDE and NEP has been performed to identify the molecular entities for proteolytic degradation of Aβ in the AD brain, (ii) to analyze their catalytic site to demonstrate the enzymatic action played by IDE and NEP, (iii) to identify their structural homologues that could behave as putative partners of IDE and NEP with similar catalytic action and (iv) to illustrate various IDE- and NEP-mediated therapeutic approaches and factors for clearing Aβ in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , insulin degrading enzyme, Neprilysin, therapeutics

DOI: 10.3233/JAD-150379

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 891-917, 2015

Authors: Giaccone, Giorgio

Article Type: Short Communication

Abstract: The distinction between Alzheimer’s disease (AD) and Primary Age-Related Tauopathy (PART) is a hotly debated issue. As most lines of evidence support the tenet that tau pathology occurs downstream of amyloid-β deposition, it seems reasonable to consider PART as a separate disease process not necessarily related to Aβ and hence AD. Following this view, the early stages of neurofibrillary pathology may not always be the forerunner of diffuse neurofibrillary changes and AD. The ongoing debate further enhances the need for greater caution against any future predictions using tau cerebrospinal fluid and imaging biomarkers.

Keywords: Alzheimer’s disease, Braak staging, neuropathology, Primary Age-Related Tauopathy

DOI: 10.3233/JAD-150435

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 919-921, 2015

Authors: Marshall, Charles R. | Guerreiro, Rita | Thust, Steffi | Fletcher, Phillip | Rohrer, Jonathan D. | Fox, Nick C.

Article Type: Short Communication

Abstract: The authors describe a case of corticobasal syndrome led by progressive apraxia of speech, associated with a novel mutation in exon 10 of the MAPT gene. Genetic bases for progressive apraxia of speech and corticobasal syndrome are only rarely described, and have not been described in conjunction.

Keywords: Corticobasal syndrome, frontotemporal dementia, microtubule-associated protein tau, progressive apraxia of speech

DOI: 10.3233/JAD-150477

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 923-926, 2015

Authors: Moreno, Laura | Rose, Christiane | Mohanraj, Arun | Allinquant, Bernadette | Billard , Jean-Marie | Dutar, Patrick

Article Type: Research Article

Abstract: This study shows a decrease in soluble amyloid-β protein precursor-α (sAβPPα) levels, but no change in sAβPPβ, in the rat hippocampus during healthy aging, associated with the weaker expression of N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) in the CA1 area of hippocampal slices. Exogenous application of recombinant sAβPPα increases NMDAR activation in aged animals and could rescue the age-related LTP deficits described. In contrast, it does not affect basal synaptic transmission or glutamate release. These results indicate that improving synaptic sAβPPα availability at synapses helps in reducing the functional NMDAR-related deregulation of hippocampal networks linked to aging.

Keywords: Alzheimer’s disease, amyloid-β protein precursor, α-secretase, glutamate, memory, mouse hippocampus, NMDA receptors, synaptic plasticity

DOI: 10.3233/JAD-150297

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 927-935, 2015

Authors: Struyfs, Hanne | Van Hecke, Wim | Veraart, Jelle | Sijbers, Jan | Slaets, Sylvie | De Belder, Maya | Wuyts, Laura | Peters, Benjamin | Sleegers, Kristel | Robberecht, Caroline | Van Broeckhoven, Christine | De Belder, Frank | Parizel, Paul M. | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: The purpose of this explorative study was to investigate whether diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) parameter changes are reliable measures of white matter integrity changes in Alzheimer’s disease (AD) patients using a whole brain voxel-based analysis (VBA). Therefore, age- and gender-matched patients with mild cognitive impairment (MCI) due to AD (n  = 18), dementia due to AD (n  = 19), and age-matched cognitively healthy controls (n  = 14) were prospectively included. The magnetic resonance imaging protocol included routine structural brain imaging and DKI. Datasets were transformed to a population-specific atlas space. Groups were compared using VBA. Differences in diffusion …and mean kurtosis measures between MCI and AD patients and controls were shown, and were mainly found in the splenium of the corpus callosum and the corona radiata. Hence, DTI and DKI parameter changes are suggestive of white matter changes in AD. Show more

Keywords: Alzheimer’s disease, biomarker, diffusion kurtosis imaging, diffusion tensor imaging, early diagnosis, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-150253

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 937-948, 2015

Authors: Cermakova, Pavla | Johnell, Kristina | Fastbom, Johan | Garcia-Ptacek, Sara | Lund, Lars H. | Winblad, Bengt | Eriksdotter, Maria | Religa, Dorota

Article Type: Research Article

Abstract: Background: Cardiovascular diseases are leading causes of death and patients with dementia are often affected by them. Objective: Investigate associations of cardiovascular diseases with different dementia disorders and determine their impact on mortality. Methods: This study included 29,630 patients from the Swedish Dementia Registry (mean age 79 years, 59% women) diagnosed with Alzheimer’s disease (AD), mixed dementia, vascular dementia, dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), frontotemporal dementia (FTD), or unspecified dementia. Records of cardiovascular diseases come from the Swedish National Patient Register. Multinomial logistic regression and cox proportional hazard models were applied. …Results: Compared to AD, we found a higher burden of all cardiovascular diseases in mixed and vascular dementia. Cerebrovascular diseases were more associated with DLB than with AD. Diabetes mellitus was less associated with PDD and DLB than with AD. Ischemic heart disease was less associated with PDD and FTD than AD. All cardiovascular diseases predicted death in patients with AD, mixed, and vascular dementia. Only ischemic heart disease significantly predicted death in DLB patients (HR = 1.72; 95% CI = 1.16–2.55). In PDD patients, heart failure and diabetes mellitus were associated with a higher risk of death (HR = 3.06; 95% CI = 1.74–5.41 and HR = 3.44; 95% CI = 1.31–9.03). In FTD patients, ischemic heart disease and atrial fibrillation or flutter significantly predicted death (HR = 2.11; 95% CI = 1.08–4.14 and HR = 3.15; 95% CI = 1.60–6.22, respectively). Conclusion: Our study highlights differences in the occurrence and prognostic significance of cardiovascular diseases in several dementia disorders. This has implications for the care and treatment of the different dementia disorders. Show more

Keywords: Alzheimer’s disease, cardiovascular diseases, dementia, mortality

DOI: 10.3233/JAD-150499

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 949-958, 2015

Authors: Laiterä, Tiina | Kurki, Mitja I. | Pursiheimo, Juha-Pekka | Zetterberg, Henrik | Helisalmi, Seppo | Rauramaa, Tuomas | Alafuzoff, Irina | Remes, Anne M. | Soininen, Hilkka | Haapasalo, Annakaisa | Jääskeläinen, Juha E. | Hiltunen, Mikko | Leinonen, Ville

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition in which Alzheimer’s disease (AD)-related amyloid-β (Aβ) plaques are frequently observed in the neocortex. iNPH patients with prominent Aβ pathology show AD-related alterations in amyloid-β protein precursor (AβPP) processing resulting from increased γ -secretase activity. Objectives: Our goal was to assess potential alterations in the global gene expression profile in the brain of iNPH patients as compared to non-demented controls and to evaluate the levels of the identified targets in the cerebrospinal fluid (CSF) of iNPH patients. Methods: The genome-wide expression profile of ∼35,000 probes …was assessed in the RNA samples obtained from 22 iNPH patients and eight non-demented control subjects using a microarray chip. The soluble levels of sAβPPα , sAβPPβ, and transthyretin (TTR) were measured from the CSF of 102 iNPH patients using ELISA. Results: After correcting the results for multiple testing, significant differences in the expression of TTR and A βPP were observed between iNPH and control subjects. The mRNA levels of TTR were on average 17-fold lower in iNPH samples compared to control samples. Conversely, the expression level of A βPP was on average three times higher in iNPH samples as compared to control samples. Interestingly, the expression of α -secretase (ADAM10 ) was also increased in iNPH patients. In the lumbar CSF samples, soluble TTR levels showed a significant positive correlation with sAβPPα and sAβPPβ, but TTR levels did not predict the brain pathology or the shunt response. Conclusions: These findings suggest differences in the expression profile of key factors involved in AD-related cellular events in the brain of iNPH patients. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, gene expression profiling, idiopathic normal pressure hydrocephalus, transthyretin

DOI: 10.3233/JAD-150268

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 959-968, 2015

Authors: Conejero-Goldberg, Concepcion | Hyde, Thomas M. | Chen, Shufen | Herman, Mary M. | Kleinman, Joel E. | Davies, Peter | Goldberg, Terry E.

Article Type: Research Article

Abstract: Transcriptional profiling of postmortem Alzheimer’s disease (AD) brain tissue has yielded important insights into disease. We recently described a novel approach to understand transcriptional changes in AD designed to identify both neuro-susceptibility and intrinsic neuroprotective factors in young non-AD E4 carriers. Here we extend our work to APOE4 related AD itself. In temporal cortex (BA 21), a region known to be vulnerable to AD pathology, we identified over 1400 transcripts that differed between APOE4 controls and APOE4 carriers diagnosed with AD. Results from somatosensory cortex (BA 1/2/3), a region relatively preserved in AD differed strikingly from temporal cortex in that …differences were far fewer (37 vs. 1492). We also conducted another set of contrasts involving APOE3 AD cases and APOE4 AD cases to better understand what transcriptional differences were dependent on genotype, but independent of disease status and found 6 transcripts to differ. We also conducted detailed pathway analyses in BA 1/2/3 and found significant transcriptional upregulations in pro-survival gene networks (e.g., TNF and NFkB). In summary, our results indicate that many of the molecular changes identified in the brains of patients with AD reflect the non-specific consequences of neurodegeneration, rather than causative processes. Additionally, the molecular signatures specific to somatosensory cortex may make it uniquely resistant to AD pathology and thereby could provide important leads for treatment. Show more

Keywords: Alzheimer’s disease, APOE, gene expression, human brain, microarray

DOI: 10.3233/JAD-150345

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 969-978, 2015

Authors: Sparre-Sørensen, Maja | Kristensen, Gustav

Article Type: Research Article

Abstract: Background: Several studies published over the last few years have shown that malnutrition is a risk factor for developing and worsening Alzheimer’s disease (AD) and that a balanced diet can delay the onset of the disease. During the period from January 1999 to January 2007, a statistically significant increase in the number of deaths related to malnutrition was found among the elderly in Denmark. Many more may have been suffering from malnutrition, but not to such a degree that it led to their deaths. Objective: The aim of this study is to examine whether or not the …effect of the malnutrition period can be seen in the number of AD-related deaths. Methods: All Danes listed in the National Death Register from 1994 to 2012 where included in this study. Regression analyses based on the Expansion Method were used. Results: We found a sudden statistically significant rise in the number of deaths from AD associated with the period when the general nutritional state among the elderly in Denmark worsened (from 1999 to 2007). Conclusion: The study concludes that the malnutrition period resulted in an excess death rate from Alzheimer’s disease. All in all, a total of 345 extra lives were lost, and many might have developed AD earlier than they otherwise would, due to malnutrition. Show more

Keywords: Alzheimer’s disease, death rate, Expansion Method, malnutrition

DOI: 10.3233/JAD-150472

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 979-985, 2015

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

Authors: Mistridis, Panagiota | Krumm, Sabine | Monsch, Andreas U. | Berres, Manfred | Taylor, Kirsten I.

Article Type: Research Article

Abstract: Background: The identification of the type and sequence of cognitive decline in preclinical mild cognitive impairment (MCI) prior to Alzheimer’s disease (AD) is crucial for understanding AD pathogenesis and implementing therapeutic interventions. Objective: To model the longitudinal courses of different neuropsychological functions in MCI due to AD. Methods: We investigated the prodromal phase of MCI over a 12-year period in 27 initially healthy participants with subsequent MCI preceding AD (NC-MCI) and 60 demographically matched healthy individuals (NC-NC). The longitudinal courses of cognitive performance (verbal and visual episodic memory, semantic memory, executive functioning, constructional praxis, psychomotor …speed, language, and informant-based reports) were analyzed with linear mixed effects models. Results: The sequence with which different cognitive functions declined in the NC-MCI relative to the NC-NC group began with verbal memory and savings performance approximately eight years, and verbal episodic learning, visual memory, and semantic memory (animal fluency) circa four years prior to the MCI diagnosis. Executive functioning, psychomotor speed, and informant-based reports of the NC-MCI group declined approximately two years preceding the MCI diagnosis. Conclusions: Measurable neuropsychological deterioration occurs up to approximately eight years preceding MCI due to AD. Show more

Keywords: Alzheimer’s disease, cognitive decline, neuropsychology, linear mixed effects models, longitudinal course, mild cognitive impairment, prodromal

DOI: 10.3233/JAD-150137

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 1095-1107, 2015

Authors: Alegret, Montserrat | Rodríguez, Octavio | Espinosa, Ana | Ortega, Gemma | Sanabria, Angela | Valero, Sergi | Hernández, Isabel | Rosende-Roca, Maitée | Vargas, Liliana | Abdelnour, Carla | Mauleón, Ana | Gailhajanet, Anna | Martín, Elvira | Tárraga, Lluís | Rentz, Dorene M. | Amariglio, Rebecca E. | Ruíz, Agustín | Boada, Mercè

Article Type: Research Article

Abstract: BACKGROUND: Subjective memory impairment (SMI) refers to subjective awareness of initial memory decline undetectable with existing standardized cognitive tests. The Face Name Associative Memory Exam (FNAME) was created to detect memory deficits in individuals with preclinical Alzheimer’s disease (AD). We reported normative data of a Spanish version of FNAME (S-FNAME) in cognitively normal (CN) Spanish-speaking subjects >49. OBJECTIVE: To determine whether higher SMI [a modification of Memory Failures Everyday (MFE-30)] was related to worse memory performance (S-FNAME) or associated with greater affective symptoms in subjects >49; and whether MFE-30 and FNAME were able to discriminate between …CN and mild cognitive impairment (MCI) subjects. METHODS: 317 subjects (CN = 196, MCI = 121) were included in the analysis because they attended the annual “Open House Initiative” at Memory Clinic Fundació ACE, were >49 years, literate, received S-FNAME, MFE-30, and Hospital Anxiety and Depression Scale, had Mini-Mental State Examination scores ≥27, and returned to complete a comprehensive diagnostic assessment. RESULTS: MFE-30 scores were associated with affective symptoms but not with S-FNAME performance. S-FNAME scores were related to performance on memory variables of NBACE (neuropsychological battery used in Fundació ACE). Although the MCI group showed significantly higher MFE-30 and worse S-FNAME scores than the CN group, their discriminability values were similar (Sensitivity: 49.6 versus 52.9; Specificity: 85.1 versus 83.6, respectively). CONCLUSIONS: SMI was more related to depressive symptoms than to S-FNAME memory performance; and S-FNAME scores were related to other episodic memory test performances, but neither to affective symptoms nor to SMI. MFE-30 and S-FNAME are not optimal for discriminating between CN and MCI groups. Longitudinal follow-up will determine if lower S-FNAME and higher SMI are related to increased risk of AD. Show more

Keywords: Episodic memory, FNAME, neuropsychology, preclinical Alzheimer’s disease, subjective memory impairment

DOI: 10.3233/JAD-150594

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 1109-1117, 2015

Authors: Bäckman, Kristoffer | Joas, Erik | Waern, Margda | Östling, Svante | Guo, Xinxin | Blennow, Kaj | Skoog, Ingmar | Gustafson, Deborah R.

Article Type: Research Article

Abstract: Background: Overweight and obesity in mid- and late-life may increase risk for dementia, whereas a decline in body weight or body mass index (BMI) and underweight in years preceding a clinical dementia diagnosis are also associated with dementia. Little is known about the modifying effect of the APOE genotype, a major susceptibility gene for Alzheimer’s disease (AD), on the BMI-dementia adult life course trajectory. Objective: We evaluated the exposure, BMI, in relationship to the outcome, clinical dementia, over 37 years, considering the effect modification of the APOE ɛ4 allele. Methods: The Prospective Population Study of …Women (PPSW) in Sweden is a systematic sample of 1462 women born 1908, 1914, 1918, 1922, and 1930 and aged 38–60 years at baseline. Examinations occurred in 1968, 1974, 1980, 1992, 2000, and 2005; 559 women had information on dementia, BMI, and APOE ɛ4 allele status, in addition to covariates. Statistical analyses were conducted using mixed effects regression models. Results: Trajectories of BMI over 37 years differed by APOE ɛ4 allele status. While women gained BMI similarly from mid-life to age 70 years, women with at least one APOE ɛ4 allele experienced BMI decline more quickly after age 70 years compared to women without an APOE ɛ4 allele. However, upon stratifying the sample by dementia occurrence, it appeared that dementia drove the overall BMI-trajectory. There was a main effect of age, interactions of age by APOE ɛ4 allele status, and age by presence versus absence of dementia. Conclusions: Women with similar average BMI at mid-life exhibited different BMI trajectories in relation to dementia occurrence. In addition, the pattern of BMI decline in late-life differed on the basis of APOE ɛ4 allele possession. Thus, these data suggest roles for both dementia- and APOE-associated changes in BMI during the adult life course. Show more

Keywords: Alzheimer’s disease, APOE, body mass index change, dementia, prospective, risk factor

DOI: 10.3233/JAD-150326

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 1119-1127, 2015

Article Type: Other

DOI: 10.3233/JAD-150906

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 1129-1139, 2015

Article Type: Other

DOI: 10.3233/JAD-150718

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 1141-1144, 2015

Article Type: Other

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 1145-1156, 2015