Volume 48, Number 4, 2015

Pages 879-889

Lauren Dubner, Jun Wang, Lap Ho, Libby Ward, Giulio M. Pasinetti
Recommendations for Development of New Standardized Forms of Cocoa Breeds and Cocoa Extract Processing for the Prevention of Alzheimer’s Disease: Role of Cocoa in Promotion of Cognitive Resilience and Healthy Brain Aging
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.

Pages 891-917

Niraj Kumar Jha*, Saurabh Kumar Jha*, Dhiraj Kumar*, Noopur Kejriwal, Renu Sharma, Rashmi K. Ambasta, Pravir Kumar *These authors contributed equally to this work.
Impact of Insulin Degrading Enzyme and Neprilysin in Alzheimer’s Disease Biology: Characterization of Putative Cognates for Therapeutic Applications
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.

Pages 919-921
Short Communication

Giorgio Giaccone
The Existence of Primary Age-Related Tauopathy Suggests that not all the Cases with Early Braak Stages of Neurofibrillary Pathology are Alzheimer’s Disease
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.

Pages 923-926
Short Communication

Charles R Marshall, Rita Guerreiro, Steffi Thust, Phillip Fletcher, Jonathan D. Rohrer, Nick C. Fox
A Novel MAPT Mutation Causing Corticobasal Syndrome Led by Progressive Apraxia of Speech
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.

Pages 927-935
Laura Moreno, Christiane Rose, Arun Mohanraj, Bernadette Allinquant, Jean-Marie Billard, Patrick Dutar (Handling Associate Editor: Ottavio Arancio)
sAβPPα Improves Hippocampal NMDA-Dependent Functional Alterations Linked to Healthy Aging
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.

Pages 937-948
Hanne Struyfs, Wim Van Hecke, Jelle Veraart, Jan Sijbers, Sylvie Slaets, Maya De Belder, Laura Wuyts, Benjamin Peters, Kristel Sleegers, Caroline Robberecht, Christine Van Broeckhoven, Frank De Belder, Paul M. Parizel, Sebastiaan Engelborghs (Handling Associate Editor: Peter Lewczuk)
Diffusion Kurtosis Imaging: A Possible MRI biomarker for AD diagnosis?
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.

Pages 949-958
Pavla Cermakova, Kristina Johnell, Johan Fastbom, Sara Garcia-Ptacek, Lars H. Lund, Bengt Winblad, Maria Eriksdotter, Dorota Religa (Handling Associate Editor: Sotirios Giannopoulos)
Cardiovascular Diseases in ~ 30,000 Patients in the Swedish Dementia Registry
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.

Pages 959-968
Tiina Laiterä, Mitja I. Kurki, Juha-Pekka Pursiheimo, Henrik Zetterberg, Seppo Helisalmi, Tuomas Rauramaa, Irina Alafuzoff, Anne M. Remes, Hilkka Soininen, Annakaisa Haapasalo, Juha E. Jääskeläinen, Mikko Hiltunen*, Ville Leinonen* *These authors contributed equally to this work.
The Expression of Transthyretin and Amyloid-β Protein Precursor is Altered in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients
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 AβPP 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 AβPP 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.

Pages 969-978
Concepcion Conejero-Goldberg, Thomas M. Hyde, Shufen Chen, Mary M. Herman, Joel E. Kleinman, Peter Davies, Terry E. Goldberg
Cortical Transcriptional Profiles in APOE4 Carriers with Alzheimer’s Disease: Patterns of Protection and Degeneration
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 neurosusceptibility 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 1,400 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 versus 1,492). 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. When analyzing interregional differences, ten pathways differed between both brain areas in the APOE4 AD cases to APOE4 controls contrast and two pathways differed between both brain areas in the APOE4 cases to APOE3 controls contrast. Base excision repair pathway was found in common for both contrasts. 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.

Pages 979-985
Maja Sparre-Sørensen, Gustav Kristensen
Alzheimer’s Disease in the Danish Malnutrition Period 1999-2007
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.

Pages 987-994
Michel Bilello, Jimit Doshi, S. Ali Nabavizadeh, Jon B. Toledo, Guray Erus, Sharon X. Xie, John Q. Trojanowski, Xiaoyan Han, Christos Davatzikos
Correlating Cognitive Decline with White Matter Lesion and Brain Atrophy Magnetic Resonance Imaging Measurements in Alzheimer’s Disease
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.

Pages 995-1008
Weihao Zheng, Zhijun Yao, Bin Hu, Xiang Gao, Hanshu Cai, Philip Moore, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Zhanjun Zhang)
Novel Cortical Thickness Pattern for Accurate Detection of Alzheimer’s Disease
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 ε4 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.

Pages 1009-1017
Binukumar BK, Varsha Shukla, Niranjana D. Amin, Manju Bhaskar, Suzanne Skuntz, Joseph Steiner, Dirk Winkler, Steven L. Pelech, Harish C. Pant
Analysis of the Inhibitory Elements in the p5 Peptide Fragment of the CDK5 Activator, p35, CDKR1 Protein
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.

Pages 1019-1032
Hui Liu, Hongyan Qiu, Qian Xiao, Weidong Le
Chronic Hypoxia-Induced Autophagy Aggravates the Neuropathology of Alzheimer's Disease through AMPK-mTOR Signaling in the APPSwe/PS1dE9 Mouse Model
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 elevated 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 induction of autophagy through the enhancement of mTOR phosphorylation. In short, our study provides new insight into the mechanism underlying chronic hypoxia-mediated AD pathogenesis.

Pages 1033-1041
Soili M. Törmälehto1, Janne A. Martikainen1, Saku T. Väätäinen, Ilona T. Hallikainen, Merja Hallikainen, J. Simon Bell2, Anne M. Koivisto2, on the behalf of the ALSOVA study group. 1These authors contributed equally to this work. 2These authors share the last authorship.
Use of Anti-Dementia Drugs in Relation to Change in Cognition, Behavior, and Functioning in Alzheimer’s Disease over a Three-Year Period: Kuopio ALSOVA Study
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.

Pages 1043-1050
Hyeong Jun Kim*, Kyung Won Park*, Tae Eun Kim, Ji Young Im, Ho Sik Shin, Saeromi Kim, Dong Hyun Lee, Byoung Seok Ye,Jong Hun Kim, Eun-Joo Kim, Kee Hyung Park, Hyun Jeong Han, Jee Hyang Jeong, Seong Hye Choi, Sun Ah Park (Handling Associate Editor: Albert Lladó) *These two authors contributed equally to this work.
Elevation of the Plasma Aβ40/Aβ42 Ratio as a Diagnostic Marker of Sporadic Early-Onset Alzheimer’s Disease
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 ε4 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.

Pages 1051-1063
Seok Woo Moon*, Ivo D. Dinov*, Jaebum Kim, Alen Zamanyan, Sam Hobel, Paul M. Thompson, Arthur W. Toga for the Alzheimer’s Disease Neuroimaging Initiative *These authors have contributed equally to this research.
Structural Neuroimaging Genetics Interactions in Alzheimer’s Disease
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 inferor 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.

Pages 1065-1075
Lilian Calderón-Garcidueñas, Antonieta Mora-Tiscareño, Gastón Melo-Sánchez, Joel Rodríguez-Díaz, Ricardo Torres-Jardón, Martin Styner, Partha S. Mukherjee, Weili Lin, Valerie Jewells
A Critical Proton MR Spectroscopy Marker of Alzheimer’s Disease Early Neurodegenerative Change: Low Hippocampal NAA/Cr Ratio Impacts APOE ε4 Mexico City Children and Their Parents
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 1H-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 ε4 MC children and in left hippocampus in MC APOE ε4 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 ε4 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.

Pages 1077-1081
Vanessa G. Fraga, Henrique C. Guimarães, Vivian P. Lara, Antônio L. Teixeira, Maira T. Barbosa, Maria G. Carvalho, Paulo Caramelli, Karina B. Gomes (Handling Associate Editor: Beatrice Arosio)
TGF-β1 Codon 10 T>C Polymorphism Influences Short-Term Functional and Cognitive Decline in Healthy Oldest-Old Individuals: The Pietà Study
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 10T>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.

Pages 1083-1094
Hanna Bielarczyk, Agnieszka Jankowska-Kulawy, Corinna Hofling, Anna Ronowska, Sylwia Gul-Hinc, Steffen Rossner, Reinhard Schliebs, Tadeusz Pawełczyk, Andrzej Szutowicz
AβPP-Transgenic 2576 Mice Mimic Cell Type-Specific Aspects of Acetyl-CoA-Linked Metabolic Deficits in Alzheimer’s Disease
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 0.6 µmol/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 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 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.

Pages 1095-1107
Panagiota Mistridis, Sabine Krumm, Andreas U. Monsch, Manfred Berres, Kirsten I. Taylor (Handling Associate Editor: Thomas Benke)
The 12 Years Preceding Mild Cognitive Impairment Due to Alzheimer’s Disease: The Temporal Emergence of Cognitive Decline
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, 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.

Pages 1109-1117
Montserrat Alegret, Octavio Rodríguez, Ana Espinosa, Gemma Ortega, Angela Sanabria, Sergi Valero, Isabel Hernández, Maitée Rosende-Roca, Liliana Vargas, Carla Abdelnour, Ana Mauleón, Anna Gailhajanet, Elvira Martín, Lluís Tárraga, Dorene M. Rentz, Rebecca E. Amariglio, Agustín Ruíz, Mercè Boada
Concordance between Subjective and Objective Memory Impairment in Volunteer Subjects
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 Exam 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.

Pages 1119-1127
Kristoffer Bäckman, Erik Joas, Margda Waern, Svante Östling, Xinxin Guo, Kaj Blennow, Ingmar Skoog, Deborah R. Gustafson
37 Years of Body Mass Index and Dementia: Effect Modification by the APOE Genotype: Observations from the Prospective Population Study of Women in Gothenburg, Sweden
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 ε4 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 ε4 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 ε4 allele status. While women gained BMI similarly from mid-life to age 70 years, women with at least one APOE ε4 allele experienced BMI decline more quickly after age 70 years compared to women without an APOE ε4 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 ε4 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 ε4 allele possession. Thus, these data suggest roles for both dementia- and APOE-associated changes in BMI during the adult life course.