Pages 563-580
Review
Hanuma Kumar Karnati, Manas Kumar Panigrahi, Ravi Kumar Gutti, Nigel H. Greig, Ian A. Tamargo
miRNAs: Key Players in Neurodegenerative Disorders and Epilepsy
Abstract: MicroRNAs (miRNAs) are endogenous, ~22 nucleotide, non-coding RNA molecules that function as post-transcriptional regulators of gene expression. miRNA dysregulation has been observed in cancer and in neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, amyotrophic lateral sclerosis, and the neurological disorder, epilepsy. Neuronal degradation and death are important hallmarks of neurodegenerative disorders. Additionally, abnormalities in metabolism, synapsis and axonal transport have been associated with Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia. A number of recently published studies have demonstrated the importance of miRNAs in the nervous system and have contributed to the growing body of evidence on miRNA dysregulation in neurological disorders. Knowledge of the expressions and activities of such miRNAs may aid in the development of novel therapeutics. In this review, we discuss the significance of miRNA dysregulation in the development of neurodegenerative disorders and the use of miRNAs as targets for therapeutic intervention.
Pages 581-589
Review
Manuel Menéndez-González, Benito de Celis Alonso, José Salas-Pacheco, Oscar Arias-Carrión
Structural Neuroimaging of the Medial Temporal Lobe in Alzheimer's Disease Clinical Trials
Abstract: Atrophy in the medial temporal lobe (MTA) is being used as a criterion to support a diagnosis of Alzheimer’s disease (AD). There are several structural neuroimaging approaches for quantifying MTA, including semiquantitative visual rating scales, volumetry (3D), planimetry (2D), and linear measures (1D). Current applications of structural neuroimaging in Alzheimer’s disease clinical trials (ADCTs) incorporate it as a tool for improving the selection of subjects for enrollment or for stratification, for tracking disease progression, or providing evidence of target engagement for new therapeutic agents. It may also be used as a surrogate marker, providing evidence of disease-modifying effects. However, despite the widespread use of volumetric magnetic resonance imaging (MRI) in ADCTs, there are some important challenges and limitations, such as difficulties in the interpretation of results, limitations in translating results into clinical practice, and reproducibility issues, among others. Solutions to these issues may arise from other methodologies that are able to link the results of volumetric MRI from trials with conventional MRIs performed in routine clinical practice (linear or planimetric methods). Also of potential benefit are automated volumetry, using indices for comparing the relative rate of atrophy of different regions instead of absolute rates of atrophy, and combining structural neuroimaging with other biomarkers. In this review, authors present the existing structural neuroimaging approaches for MTA quantification. They then discuss solutions to the limitations of the different techniques as well as the current challenges of the field. Finally, and due to their relevance, they discuss how the current advances in AD neuroimaging can help AD diagnosis.
Pages 591-595
Short Communication
Ruth Remington, Jevin J. Lortie, Heather Hoffmann, Robert Page, Christopher Morrell, Thomas B. Shea
A Nutritional Formulation for Cognitive Performance in Mild Cognitive Impairment: A Placebo-Controlled Trial with an Open-Label Extension
Abstract: Thirty-four individuals with mild cognitive impairment were randomized for 6 months to a nutraceutical formulation (NF: folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) or indistinguishable placebo, followed by a 6-month open-label extension in which all individuals received NF. The NF cohort improved in the Dementia Rating Scale (DRS; effect size >0.7) and maintained baseline performance in CLOX-1. The placebo cohort did not improve in DRS and declined in CLOX-1, but during the open-label extension improved in DRS and ceased declining in CLOX-1. These findings extend prior studies of NF efficacy for individuals without cognitive impairment and with Alzheimer’s disease.
Pages 597-601
Short Communication
Svetlana N. Popova, Samuli Pesälä, Irina Alafuzoff (Handling Associate Editor: Sanna-Kaisa Herukka)
To Stage Alzheimer’s Disease Related Neurodegeneration Using one Section of Hippocampus
Abstract: For Braak staging of Alzheimer’s disease (AD), the assessment of only hippocampal section has been proposed. In two published modifications, the emphasis is on the pathology in Ammon’s horn. We investigated this approach in a cohort including 150 cases. A Braak stage was possible to assign in a subset of the cases, and the agreement rates varied from 60% to 36%. Thus, to reliably stage the AD-related neurodegeneration, regions such as the entorhinal, transentorhinal, temporo-occipital, and occipital cortices should be assessed as has also been recommended in 2012 by the National Institute on Aging - Alzheimer’s Association guidelines.
Pages 603-611
Zhongwei Guo, Xiaozheng Liu, Xize Jia, Hongtao Hou, Yulin Cao, Fuquan Wei, Jiapeng Li, Xingli Chen,Yingchun Zhang, Yuedi Shen , Lili Wei, Luoyi Xu, Wei Chen
Regional Coherence Changes in Alzheimer’s Disease Patients with Depressive Symptoms: A Resting-State Functional MRI Study
Abstract: Alzheimer’s disease (AD) is characterized by progressive cognitive decline along with neuropsychiatric symptoms including depression and psychosis. Depression is a common psychiatric disorder occurring in people across the lifespan. Accumulating evidence indicates that depression may be a prodrome and/or a “risk factor” for AD. However, whether AD and depression share a common pathophysiological pathway is still unclear. The aim of this study was to identify regional alterations in brain function associated with depression symptoms in mild AD patients. Thirty-two mild AD patients were evaluated using the Neuropsychiatric Inventory and Hamilton Depression Rating Scale, and were divided into two groups: 15 AD patients with depressive symptoms (D-AD) and 17 non-depressed AD (nD-AD) patients. Using the approach of regional homogeneity (ReHo), we characterized resting-state regional brain activity in D-AD and nD-AD patients. Compared with nD-AD patients, D-AD patients showed decreased ReHo in the right precentral gyrus, right superior frontal gyrus, right middle frontal gyrus, and right inferior frontal cortex. Our findings show regional brain activity alterations in D-AD patients. Thus, D-AD pathogenesis may be attributed to abnormal neural activity in multiple brain regions.
Pages 613-625
Nina Gramunt, Herman Buschke, Gonzalo Sánchez-Benavides, Richard B. Lipton, Jordi Peña-Casanova, Faustino Diéguez-Vide, Xavier Masramon, Juan D. Gispert, Karine Fauriaa, Jordi Camí, José L. Molinuevo (Handling Associate Editor: Josep Garre-Olmo)
Reference Data of the Spanish Memory Binding Test in a Midlife Population from the ALFA STUDY (Alzheimer’s and Family)
Abstract: Background: The Memory Binding Test (MBT) is a novel test based on the learning of two lists of words, developed to detect early memory impairment suggestive of Alzheimer’s disease (AD). Objective: To present and provide reference data of the Spanish MBT in a midlife population of mainly first-degree descendants of AD patients. Methods: 472 cognitively unimpaired subjects, aged 45 to 65 and participants of the ALFA STUDY, were included. Raw scores were transformed to scaled scores on which multivariate regression analysis was applied adjusting by age, gender, and education level. A standard linear regression was employed to derive the scaled score adjusted. Sociodemographic corrections were applied and an adjustment table was constructed. Results: Performance was heterogeneously influenced by sociodemographic factors. Age negatively influenced free recall. Education tends to have an influence in the results showing lower performance with lower education level. Women tend to outperform men in the learning of the first list and total recall. Only a few variables were unaffected by sociodemographic factors such as those related to semantic proactive interference (SPI) and to the retention of learned material. Our results point out that some vulnerability to SPI is expectable in cognitively healthy subjects. Close to 100% of the learned material was maintained across the delay interval. Conclusion: This study contributes with reference data for the MBT providing the necessary adjustments for sociodemographic characteristics. Our data may prove to be useful for detecting asymptomatic at-risk candidates for secondary prevention studies of AD.
Pages 627-636
Gianfranco Spalletta, Jeffrey D. Long, Robert G. Robinson, Alberto Trequattrini, Sonia Pizzoli, Carlo Caltagirone, Maria D. Orfei
Longitudinal Neuropsychiatric Predictors of Death in Alzheimer’s Disease
Abstract: Characteristics associated with life expectancy in Alzheimer’s disease (AD) are still far from known. Here we aimed at examining the ability of baseline/longitudinal clinical variables to predict time to death. One-hundred fifty AD outpatients underwent diagnostic, neuropsychiatric, and functional assessment at baseline (when ApoE ε4 was also investigated) and at each subsequent annual visit. A random effects joint modeling approach was used to simultaneously model the baseline and longitudinal trajectory of each factor and predict the time to death, adjusting for demographic covariates. An ancillary analysis of ApoE ε4 status as a predictor was also conducted. Kaplan-Meier survival curves were constructed to elucidate the relationship between each factor and the estimated probability of death over time. Shorter survival was associated with male gender, higher education, older age, lower cognition, and worse functioning in daily life, but not ApoE ε4 status. Longitudinal trajectories increased predictive power over using just baseline levels highlighting apathy, and secondarily aberrant motor behaviors and sleep disorders, as a highly reliable predictor for mortality. Apathy was the strongest neuropsychiatric predictor of time to death, which supports its role in the pathogenesis of the disorder. An increased knowledge of factors modulating survival in AD is a strategic prerequisite to plan therapeutic interventions.
Pages 637-646
Daniel Åberg, Per Johansson, Jörgen Isgaard, Anders Wallind, Jan-Ove Johanssona, Ulf Andreasson, Kaj Blennow, Henrik Zetterberg, N. David Åberg, Johan Svensson (Handling Associate Editor: Laura Baker)
Increased Cerebrospinal Fluid Level of Insulin-like Growth Factor-II in Male Patients with Alzheimer’s Disease
Abstract: Background: Insulin-like growth factor-II (IGF-II) is important for brain development. Although IGF-II is abundant also in adult life, little is known of the role of IGF-II in Alzheimer’s disease (AD). Objective and Methods: This was a cross-sectional study of 60 consecutive patients under primary evaluation of cognitive impairment and 20 healthy controls. The patients had AD dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n = 32), stable MCI (SMCI, n = 13), or other dementias (n = 15). IGF-II, IGF-binding protein-1 (IGFBP-1), and IGFBP-2 were analyzed in serum and cerebrospinal fluid (CSF). Results: Levels of IGF-II, IGFBP-1, and IGFBP-2 were similar in all groups in the total study population. Gender-specific analyses showed that in men (n = 40), CSF IGF-II level was higher in AD compared to SMCI and controls (p < 0.01 and p < 0.05, respectively). Furthermore, CSF IGFBP-2 level was increased in AD men versus SMCI men (p < 0.01) and tended to be increased versus control men (p = 0.09). There were no between-group differences in women (n = 40). In the total study population (n = 80) as well as in men (n = 40), CSF levels of IGF-II and IGFBP-2 correlated positively with CSF levels of the AD biomarkers total-tau and phosphorylated tau protein. Conclusion: In men, but not women, in the early stages of AD, CSF IGF-II level was elevated, and CSF IGFBP-2 level tended to be increased, compared to healthy controls.
Pages 647-665
Marco Magistri, Dmitry Velmeshev, Madina Makhmutova, Mohammad Ali Faghihi
Transcriptomics Profiling of Alzheimer’s Disease Reveal Neurovascular Defects, Altered Amyloid-β Homeostasis, and Deregulated Expression of Long Noncoding RNAs
Abstract: The underlying genetic variations of late-onset Alzheimer’s disease (LOAD) cases remain largely unknown. A combination of genetic variations with variable penetrance and lifetime epigenetic factors may converge on transcriptomic alterations that drive LOAD pathological process. Transcriptome profiling using deep sequencing technology offers insight into common altered pathways regardless of underpinning genetic or epigenetic factors and thus represents an ideal tool to investigate molecular mechanisms related to the pathophysiology of LOAD. We performed directional RNA sequencing on high quality RNA samples extracted from hippocampi of LOAD and age-matched controls. We further validated our data using qRT-PCR on a larger set of postmortem brain tissues, confirming downregulation of the gene encoding substance P (TAC1) and upregulation of the gene encoding the plasminogen activator inhibitor-1 (SERPINE1). Pathway analysis indicates dysregulation in neural communication, cerebral vasculature, and amyloid-β clearance. Beside protein coding genes, we identified several annotated and non-annotated long noncoding RNAs that are differentially expressed in LOAD brain tissues, three of them are activity-dependent regulated and one is induced by Aβ1-42 exposure of human neural cells. Our data provide a comprehensive list of transcriptomics alterations in LOAD hippocampi and warrant holistic approach including both coding and non-coding RNAs in functional studies aimed to understand the pathophysiology of LOAD.
Pages 667-671
Momoko Kubo, Taro Kishi, Shinji Matsunaga, Nakao Iwata
Histamine H3 Receptor Antagonists for Alzheimer’s Disease: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials
Abstract: Background: No comprehensive meta-analysis has been performed concerning the efficacy and tolerability of histamine H3 receptor antagonists (H3R-ANTs) in Alzheimer’s disease patients. Objective: We performed a systematic review and meta-analysis of double-blind randomized placebo-controlled trials (RCTs) of H3R-ANTs for Alzheimer’s disease. Methods: Relevant studies were identified through searches of PubMed®, databases of the Cochrane Library©, and PsycINFO citations up to June 19, 2015. The primary outcome was a change in the Mini-Mental State Examination (MMSE) scores. Secondary outcomes were Neuropsychiatric Inventory (NPI) scores, discontinuation rate, and individual adverse events/side effects. Risk ratios, numbers-needed-to-treat/harm, and standardized mean differences were calculated based on a random effects model. Results: The computerized search initially yielded 33 studies after excluding duplicates. We excluded 29 of these articles following a review of titles and abstracts and one RCT including healthy subjects after full-text review. We identified three RCTs (two on GSK239512 and one on ABT-288) including 402 patients. Pooled H3R-ANTs were not superior to placebo for improvement in MMSE and NPI scores. Discontinuation rate and individual adverse events/side effects did not differ among the pooled groups. Conclusions: Our results suggest that H3R-ANTs are not effective in treating cognitive dysfunction in Alzheimer’s disease. However, further studies with larger samples are required for definitive conclusions regarding responsive subpopulations.
Pages 673-686
Shunze Hu*, Huan Wang*, Kun Chen, Peng Cheng Shutao Gao, Jian Liu, Xiao Li, Xuying Sun *These authors contributed equally to this work.
MicroRNA-34c Downregulation Ameliorates Amyloid-β-Induced Synaptic Failure and Memory Deficits by Targeting VAMP2
Abstract: MicroRNAs (miRNAs) are small (∼22-nucleotide [nt]) noncoding RNAs that regulate biological processes at the post-transcriptional level. Dysregulation of specific miRNAs leads to impaired synaptic plasticity resulting in Alzheimer’s disease (AD). Amyloid-β (Aβ) accumulation is the most important pathogenic factor for AD development. Therefore, focusing on Aβ-targeted miRNAs may have therapeutic implications for AD. We found that miR-34c, a miRNA that was previously reported to be upregulated in a transgenic AD model and patients, was significantly increased in hippocampal neurons exposed to Aβ. Western blots and luciferase assay confirmed that increased miR-34c was closely related to VAMP2 reduction. Furthermore, miR-34c blockade upregulated VAMP2 expression and rescued synaptic failure as well as learning and memory deficits caused by Aβ. The Aβ-miR-34c-VAMP2 pathway mediates the sustained VAMP2 reduction in AD patients and provides a novel underlying epigenetic mechanism for attenuation of Aβ toxicity in AD.
Pages 687-702
Shelby Meier, Michelle Bell, Danielle N. Lyons, Alexandria Ingram, Jing Chen, John C. Gensel, Haining Zhu, Peter T. Nelson, Jose F. Abisambra
Identification of Novel Tau Interactions with Endoplasmic Reticulum Proteins in Alzheimer’s Disease Brain
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is pathologically characterized by the formation of extracellular amyloid plaques and intraneuronal tau tangles. We recently identified that tau associates with proteins known to participate in endoplasmic reticulum (ER)-associated degradation (ERAD); consequently, ERAD becomes dysfunctional and causes neurotoxicity. We hypothesized that tau associates with other ER proteins, and that this association could also lead to cellular dysfunction in AD. Portions of human AD and non-demented age matched control brains were fractionated to obtain microsomes, from which tau was co-immunoprecipitated. Samples from both conditions containing tau and its associated proteins were analyzed by mass spectrometry. In total, we identified 91 ER proteins that co-immunoprecipitated with tau; 15.4% were common between AD and control brains, and 42.9% only in the AD samples. The remainder, 41.8% of the proteins, was only seen in the control brain samples. We identified a variety of previously unreported interactions between tau and ER proteins. These proteins participate in over sixteen functional categories, the most abundant being involved in RNA translation. We then determined that association of tau with these ER proteins was different between the AD and control samples. We found that tau associated equally with the ribosomal protein L28 but more robustly with the ribosomal protein P0. These data suggest that the differential association between tau and ER proteins in disease could reveal the pathogenic processes by which tau induces cellular dysfunction.
Pages 703-709
Davide Guido, Gabriella Morandi, Fernando Palluzzi, Barbara Borroni
Telling the Story of Frontotemporal Dementia by Bibliometric Analysis
Abstract: In this paper, we reconstructed the medical history of frontotemporal dementia (FTD) by reviewing the literature and analyzing papers with the highest impact through citation index. Several research studies and groups involved in FTD have been reviewed. An increasing amount of knowledge has been made available in the last 20 years through a large number of publications, leading to a better definition of the genetic and clinical bases of the disease. A total of 1,436 references (articles and reviews), published in 395 journals, were retrieved through the Scopus database. The two highest publication peaks (i.e., largest number of publications) were found in 2000 and 2008. The most cited papers considering both total citation number and the number of citations within the first two years after publication refer to: (i) the genetic bases of FTD, (ii) the clinical criteria that progressively refined the different FTD phenotypes, and (iii) FTD epidemiology. Advanced neuroimaging techniques, genotype-phenotype heterogeneity, and animal models gave us a broader understanding of various aspects of the disorder. These findings confirm the great interest in FTD research. The analysis of the literature might help in guiding future goals in the field.
Pages 711-720
Flora H. Duits, Mar Hernandez-Guillamon, Joan Montaner, Jereon D.C. Goos, Alex Montañola, Mike P. Wattjes, Frederik Barkhof, Philip Scheltens, Charlotte E. Teunissen, Wiesje M. van der Flier (Handling Associate Editor: Barbara Mroczko)
Matrix Metalloproteinases in Alzheimer’s Disease and Concurrent Cerebral Microbleeds
Abstract: Matrix metalloproteinases (MMPs) are a family of enzymes able to degrade components of the extracellular matrix, which is important for normal blood-brain barrier function. Their function is regulated by tissue inhibitors of matrix metalloproteinases (TIMPs). We investigated whether MMPs and TIMPs in cerebrospinal fluid (CSF) and plasma were altered in Alzheimer’s disease (AD) and vascular dementia (VaD), and whether this effect was modified by presence of cerebral microbleeds in AD patients. In addition, we assessed associations of MMPs and TIMPs with CSF amyloid-β1-42 (Aβ42), tau, and tau phosphorylated at threonine-181 (p-tau). We measured MMP2, MMP9, and MMP10, and TIMP1 and TIMP2 in CSF and plasma of 52 AD patients, 26 matched controls, and 24 VaD patients. AD patients showed higher plasma MMP2 levels compared to VaD patients (p<0.05), and higher CSF MMP10 levels compared to controls (p<0.05). Microbleeds in AD were associated with lower CSF TIMP1, TIMP2 and MMP9 in a dose-response relation. In addition, CSF MMP2 was associated with p-tau (St.B 0.23, p<0.05), and CSF MMP10 with tau (St.B 0.38, p<0.001) and p-tau (St.B 0.40, p<0.001). Our findings suggest involvement of MMP2 and MMP10 in AD pathology. Lower levels of TIMPs in AD patients with microbleeds suggest less MMP inhibition in patients with concurrent cerebral microbleeds, which may hypothetically lead to a more vulnerable blood-brain barrier in these patients.
Pages 721-730
Myriam Soto-Gordoa, Arantzazu Arrospide, Fermín Moreno-Izco, Pablo Martínez-Lage, Iván Castilla, Javier Mar (Handling Associate Editor: Luigi Yuri Di Marco)
Projecting Burden of Dementia in Spain, 2010-2050: Impact of Modifying Risk Factors
Abstract: Risk and protective factors such as obesity, hypercholesterolemia, physical activity, and hypertension can play a role in the development of dementia. Our objective was to measure the effect of modification of risk and protective factors on the prevalence and economic burden of dementia in the aging Spanish population during 2010-2050. A discrete event simulation model including risk and protective factors according to CAIDE (Cardiovascular Risk Factors, Aging and Incidence of Dementia) Risk Score was built to represent the natural history of dementia. Prevalence of dementia was calculated from 2010 to 2050 according to different scenarios of risk factor prevalence to assess the annual social and health care costs of dementia. The model also supplied hazard ratios for dementia. Aging will increase between 49% and 16% each decade in the number of subjects with dementia. The number of working-age individuals per person with dementia will decrease to a quarter by 2050. An intervention leading to a 20% change in risk and protective factors would reduce dementia by 9%, prevent over 100,000 cases, and save nearly 4,900 million euros in 2050. Switching individuals from a group with a specific risk factor to one without it nearly halved the risk of the development of dementia. Dementia prevalence will grow unmanageable if effective prevention strategies are not developed. Interventions aiming to reduce modifiable risk factor prevalence represent valid and effective alternatives to reduce dementia burden. However, further research is needed to identify causal relationships between dementia and risk factors.
Pages 731-743
Hyun-Seok Hong, Izumi Maezawa, Jitka Petrlova, Xiao-Yan Zhao, John C. Voss, Lee-Way Jin
Tomoregulin (TMEFF2) Binds Alzheimer’s Disease Amyloid-β (Aβ) Oligomer and AβPP and Protects Neurons from Aβ-Induced Toxicity
Abstract: Amyloid-β (Aβ) protein causes neurotoxicity and its abnormal aggregation into amyloid is a pathological hallmark of Alzheimer’s disease (AD). Cellular proteins able to interact with Aβ or its precursor, AβPP (amyloid-β protein precursor), may regulate Aβ production and neurotoxicity. We identified a brain-enriched type I transmembrane protein, tomoregulin (TR), that directly binds Aβ and Aβ oligomers (AβO). TR co-immunoprecipitated with Aβ and AβO in cultured cells and co-localized with amyloid plaques and intraneuronal Aβ in the 5xFAD AD mouse model. TR was also enriched in astrocytic processes reactive to amyloid plaques. Surface plasmon resonance spectroscopy studies showed that the extracellular domain of TR binds to AβO with a high affinity (KD = 76.8 nM). Electron paramagnetic resonance spectroscopy also demonstrated a physical interaction between spin-labeled Aβ and the TR extracellular domain in solution. Furthermore, TR also interacted with AβPP and enhanced its cleavage by α-secretase. Both cellular expression of TR and application of recombinant TR extracellular domain protected N2a neurons from AβO-induced neuronal death. These data provide first evidence that neuronal and astrocytic expression of TR is intimately related to Aβ metabolism and toxicity, and could be neuroprotective through its direct interaction with Aβ and AβPP.
Pages 745-755
Jessica Foraker, Steven P. Millard, Lesley Leong, Zachary Thomson, Sunny Chen, C. Dirk Keene, Lynn M. Bekris, Chang-En Yu (Handling Associate Editor: Andre Fischer)
The APOE Gene is Differentially Methylated in Alzheimer’s Disease
Abstract: The ε4 allele of the human apolipoprotein E gene (APOE) is a well-proven genetic risk factor for the late onset form of Alzheimer’s disease (AD). However, the biological mechanisms through which the ε4 allele contributes to disease pathophysiology are incompletely understood. The three common alleles of APOE, ε2, ε3 and ε4, are defined by two single nucleotide polymorphisms (SNPs) that reside in the coding region of exon 4, which overlaps with a well-defined CpG island (CGI). Both SNPs change not only the protein codon but also the quantity of CpG dinucleotides, primary sites for DNA methylation. Thus, we hypothesize that the presence of an ε4 allele changes the DNA methylation landscape of the APOE CGI and that such epigenetic alteration contributes to AD susceptibility. To explore the relationship between APOE genotype, AD risk, and DNA methylation of the APOE CGI, we applied bisulfite pyrosequencing and evaluated methylation profiles of postmortem brain from 15 AD and 10 control subjects. We observed a tissue-specific decrease in DNA methylation with AD and identified two AD-specific differentially methylated regions (DMRs), which were also associated with APOE genotype. We further demonstrated that one DMR was completely un-methylated in a sub-population of genomes, possibly due to a subset of brain cells carrying deviated APOE methylation profiles. These data suggest that the APOE CGI is differentially methylated in AD brain in a tissue- and APOE-genotype-specific manner. Such epigenetic alteration might contribute to neural cell dysfunction in AD brain.
Pages 757-763
Kosuke Matsuzono, Kota Sato, Syoichiro Kono, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Kentaro Deguchi, Yumiko Nakano, Koji Abe
Clinical Benefits of Rivastigmine in the Real World Dementia Clinics of the Okayama Rivastigmine Study (ORS)
Abstract: Background/Objective: Alzheimer’s disease (AD) is one of the most important diseases in an aging society, but the clinical effects of rivastigmine have not been fully examined in real world domestic clinics. Methods: We performed the “Okayama Rivastigmine Study (ORS)” to retrospectively analyze the clinical effects of rivastigmine (n=75) or donepezil (n=71) on AD patients with seven dementia assessment batteries at the baseline, 3, 6, and 12 months. In addition, we divided the rivastigmine group into two subgroups at the baseline: the mild behavioral and psychological symptoms of dementia (BPSD) group (Abe’s BPSD score (ABS) < 6) and the severe BPSD group (6≤ ABS). In these two subgroups, baseline scores and changes were also retrospectively analyzed until 12 months. Results: Rivastigmine significantly improved the Mini-Mental State Examination score at 3 months (*p<0.05 versus baseline) and at 6 months (*p<0.05), the Frontal Assessment Battery (FAB) at 6 months (*p<0.05), and ABS at 3 months (**p<0.01) while donepezil only stabilized the three cognitive scores. On the other hand, the Geriatric Depression Scale and the Apathy Scale were stable until 12 months in both groups. Baseline BPSD severity-dependent analysis showed a small improvement of FAB at 6 months in the mild BPSD subgroup (*p<0.05) and a great improvement of ABS at 3 months in the severe BPSD subgroup (**p<0.01) in the rivastigmine group. Conclusions: Our present study showed that rivastigmine improved both cognitive and affective functions at 3 and 6 months, and suggested an advantage at 3 and 6 months compared to donepezil in real world dementia clinics.
Pages 765-779
Marie-Theres Pertl, Thomas Benke, Laura Zamarian, Margarete Delazer
Decision Making and Ratio Processing in Patients with Mild Cognitive Impairment
Abstract: Making advantageous decisions is important in everyday life. This study aimed at assessing how patients with mild cognitive impairment (MCI) make decisions under risk. Additionally, it investigated the relationship between decision making, ratio processing, basic numerical abilities, and executive functions. Patients with MCI (n=22) were compared with healthy controls (n=29) on a complex task of decision making under risk (Game of Dice Task-Double, GDT-D), on two tasks evaluating basic decision making under risk, on a task of ratio processing, and on several neuropsychological background tests. Patients performed significantly lower than controls on the GDT-D and on ratio processing, whereas groups performed comparably on basic decision tasks. Specifically, in the GDT-D, patients obtained lower net scores and lower mean expected values, which indicate a less advantageous performance relative to that of controls. Performance on the GDT-D correlated significantly with performance in basic decision tasks, ratio processing, and executive-function measures when the analysis was performed on the whole sample. Patients with MCI make sub-optimal decisions in complex risk situations, whereas they perform at the same level as healthy adults in simple decision situations. Ratio processing and executive functions have an impact on the decision-making performance of both patients and healthy older adults. In order to facilitate advantageous decisions in complex everyday situations, information should be presented in an easily comprehensible form and cognitive training programs for patients with MCI should focus—among other abilities—on executive functions and ratio processing.
Pages 781-791
Sisi Zhang*, Yaojing Chen*, Zhen Liu*, Junying Zhang, Xin Li, Ruixue Cui, Zhanjun Zhang (Handling Associate Editor: Hongxing Lei) *These authors contributed equally to this work.
Association of White Matter Integrity and Cognitive Functions in Chinese Non-Demented Elderly with the APOE ε4 Allele
Abstract: The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD). This study aimed to investigate abnormality of white matter integrity and its relationship to cognitive impairments in Chinese non-demented elderly with and without the ε4 allele. We assessed cognitive differences using a series of neuropsychological tests and assessed white matter integrity using tract-based spatial statistics to measure mean diffusivity and fractional anisotropy. We determined that there were no statistically significant group differences in any neuropsychological measures. However, APOE ε4 carriers without cognitive decline exhibited widespread disruption of the white matter tracts in several areas, including the cingulum, fornix, corpus callosum, and corona radiate. Furthermore, a correlation analysis in ε4 carriers indicated that disruption of the right fornix stria terminalis and the genu of the corpus callosum were positively associated with cognitive impairment, including memory, executive function, spatial processing, attention, and language. The present study reveals the deleterious effects of the ε4 allele on white matter, and this damage may potentially serve as a biomarker in preclinical investigations. Our promising results encourage further investigation using a multidimensional longitudinal approach with larger samples.
Pages 793-804
Francesca Di Stefano*, Stephane Epelbaum*, Nicola Coley, Christelle Cantet, Pierre-Jean Ousset, Harald Hampel, Hovagim Bakardjian, Simone Lista, Bruno Vellas, Bruno Dubois, Sandrine Andrieu, for the GuidAge study group (Handling Associate Editor: Francesca Baglio) *These authors contributed equally to this work.
Prediction of Alzheimer’s Disease Dementia: Data from the GuidAge Prevention Trial
Abstract: In therapeutic trials, it is crucial to identify Alzheimer’s disease (AD) at its prodromal stage. We assessed the accuracy of the free and cued selective reminding test (FCSRT) compared to other cognitive tests to predict AD dementia in subjects with subjective cognitive decline or mild cognitive impairment. Subjects from the placebo group of the GuidAge trial over 70 years old and without clinical signs of dementia at baseline who completed the 5-year follow-up free of dementia (n=840) or developed AD dementia (n=73) were included in our study. Among all the tests, the sum of the 3 free recall of the FCSRT (FCSRT-FR) and the sum of free and cued recall (FCSRT-TR) yielded the best results to predict AD dementia occurrence (all p values < 0.05 for comparison of FCSRT-FR ROC and MMSE, CDRsb, and CVF ROCs). FCSRT-FR had an area under the ROC curve of 0.799 (95%CI 0.738-0.85) and the optimal cut-off was 20 (se 68.06%, sp 81.43%, PPV 23.90%, NPV 96,75%). Concerning FCSRT-TR, the AUC was 0.776 and the optimal cut-off was 42 (se 62.5%, sp 82.26%, PPV 23.20% and NPV 96.24%). This study sets the framework for implementing the FCSRT in clinical and therapeutic trials for efficient subject selection.
Pages 805-812
Maria Eriksdotter, Inger Vedin, Farshad Falahati, Yvonne Freund-Levi, Erik Hjorth, Gerd Faxen-Irving, Lars-Olof Wahlund, Marianne Schultzberg, Hans Basun, Tommy Cederholm, Jan Palmblad
Plasma Fatty Acid Profiles in Relation to Cognition and Gender in Alzheimer’s Disease Patients During Oral Omega-3 Fatty Acid Supplementation: The OmegAD Study
Abstract: Background: ω3 fatty acids (ω3 FAs) may slow the rate of decline in cognitive performance in mild forms of cognitive impairment and Alzheimer’s disease (AD). However, the relationship between changes of plasma ω3 FA levels and cognitive performance, as well as effects of gender, are poorly known. Objective: To study the effect of 6-month administration of DHA-rich ω3 FA supplementation on plasma FA profiles in patients with mild to moderate AD in relation to cognitive performance and gender. This investigation is part of the OmegAD Study. Methods: 174 AD patients (74±9 years) were randomized to a daily intake of 2.3 g ω3 FA or placebo for 6 months; subsequently all received the ω3 FA preparation for the next 6 months. Baseline as well as changes in plasma levels of the main ω3 FAs in 165 patients, while receiving ω3 FA supplementation for 6 months, were analyzed for association to cognitive performance (assessed by ADAS-cog and MMSE scores) as well as to gender. Results: Preservation of cognitive functioning, assessed by ADAS-cog or its sub-items (but not MMSE) scores, was significantly associated to increasing plasma ω3 FA levels over time. Thus, the higher ω3 FA plasma levels rose, the lower was the rate of cognitive deterioration. This effect was not related to gender; since although females displayed higher ω3 FA plasma levels than did males after 6 months of supplementation, this difference disappeared when adjusted for body weight. Conclusions: Since our study suggests dose-response relationships between plasma levels of ω3 FA and preservation of cognition, future ω3 FA trials in patients with mild AD should consider exploring graded (and body weight adjusted) doses of ω3 FA.
Pages 813-823
Saima Hilal, Shaik Muhammad Amin, Narayanaswamy Venketasubramanian, Wiro J. Niessen, Henri Vrooman, Tien Yin Wong, Christopher Chen*, Mohammad Kamran Ikram* *Joint senior authors
Subcortical Atrophy in Cognitive Impairment and Dementia
Abstract: Background: Cortical atrophy is a key neuroimaging feature of dementia. However, the role of subcortical gray matter reduction in cognitive impairment has not been explored extensively. Objectives: We examined the risk factors of subcortical structures on neuroimaging and their association with cognitive impairment and dementia. Methods: Data from two studies were used: a subsample from the Epidemiology of Dementia in Singapore (EDIS) study of non-demented community-dwelling subjects (n=550) and a case-control study. Subjects underwent similar neuropsychological tests and brain MRI. Subcortical volumes of accumbens, amygdala, caudate, pallidum, putamen, thalamus, hippocampus, and brainstem were measured. Cognitive impairment no dementia (CIND), dementia and its subtypes, vascular cognitive impairment (VCI), were defined using accepted criteria. Cognitive function was also expressed as both composite and domain-specific Z-scores. Results: In the EDIS study, age, female gender, Malay ethnicity, diabetes, lacunar-infarcts, and white matter lesions were the most important risk factors for subcortical atrophy. Moreover, smaller volumes of accumbens, amygdala, caudate, thalamus, and brainstem were significantly associated with lower cognitive composite Z-scores. With respect to clinical outcomes in the case-control study, structures such as the accumbens, caudate, putamen, and hippocampus were associated with both CIND and dementia. Smaller caudate and pallidum volumes were related to VCI whereas amygdalar atrophy was only associated with non-VCI. Furthermore, subcortical atrophy was related to both VCI and non-VCI. Conclusion: Subcortical gray matter atrophy is not only observed in dementia, but also in the preclinical stages of cognitive impairment. Furthermore, besides VCI, subcortical structures were also related to non-VCI.
Pages 825-832
Eva Diehl-Wiesenecker, Christine A.F. von Armin, Luc Dupuis, Hans-Peter Müller, Albert C. Ludolph, Jan Kassubek
Adipose Tissue Distribution in Patients with Alzheimer’s Disease: A Whole Body MRI Case-Control Study
Abstract: Background: Total and central adiposity have been associated with increased risk of Alzheimer's disease (AD). Visceral and subcutaneous adipose tissues have different metabolic characteristics and could therefore be differentially associated with AD. Objective: To compare regional fat distribution determined by magnetic resonance imaging (MRI) in AD patients and healthy controls and investigate associations with stage of the disease and chemical markers. The investigation was performed in a prospective case-control study. Methods: We examined thirty patients with mild to moderate AD by whole-body MRI (1.5 T) and clinical questionnaires in comparison to thirty cognitively healthy age- and gender-matched study participants. Volumes of total, subcutaneous, and visceral body fat tissue were determined by an unbiased automatic analysis algorithm. Levels of leptin, ghrelin, and adiponectin were determined in serum, amyloid-β (Aβ)1-42 and tau protein levels in cerebrospinal fluid (CSF). Results: Male AD patients displayed significantly more total fat tissue than male controls. This difference was not observed in women. We observed a trend toward higher volume of visceral fat tissue in all patients (p=0.13). Severity of disease was not associated with fat distribution in our study. Increased leptin levels correlated with lower CSF Aβ1-42 in female, but not in male, AD patients. Conclusions: Fat volume is increased in male, but not in female AD patients. Negative correlation of leptin levels and CSF Aβ1-42 in females might be one co-factor for the increased AD risk of females. Further studies are required to confirm this gender difference in fat volume during AD and evaluate its pathophysiological importance.
Pages 833-847
Catherine C. Price, Jared J. Tanner, Ilona M. Schmalfuss, Babette Brumback, Kenneth M. Heilman, David J. Libon
Dissociating Statistically-Determined Alzheimer’s Disease/Vascular Dementia Neuropsychological Syndromes Using White and Gray Neuroradiological Parameters
Abstract: Background: There is remarkable heterogeneity in clinical Alzheimer’s disease (AD) or vascular dementia (VaD). Objectives: 1) To statistically exam neuropsychological data to determine dementia subgroups for individuals clinically diagnosed with AD or VaD and then 2) examine group differences in specific gray/white matter regions of interest. Methods: A k-means cluster analysis requested a 3-group solution from neuropsychological data acquired from individuals diagnosed clinically with AD/VaD. MRI measures of hippocampal, caudate, ventricular, subcortical lacunar infarction, whole brain volume, and leukoaraiosis (LA) were analyzed. Three regions of LA volumes were quantified and these included the periventricular (5 mm around the ventricles), infracortical (5 mm beneath the gray matter), and deep (between periventricular and infracortical) regions. Results: Cluster analysis sorted AD/VaD patients into single domain amnestic (n=41), single-domain dysexecutive (n=26), and multi-domain (n=26) phenotypes. Multi-domain patients exhibited worst performance on language tests; however, multi-domain patients were equally impaired on memory tests when compared to amnestic patients. Statistically-determined groups dissociated using neuroradiological parameters: amnestic and multi-domain groups presented with smaller hippocampal volume while the dysexecutive group presented with greater deep, periventricular, and whole brain LA. Neither caudate nor lacunae volume differed by group. Caudate nucleus volume negatively correlated with total LA in the dysexecutive and multi-domain groups. Conclusions: There are at least three distinct subtypes embedded within patients diagnosed clinically with AD/VaD spectrum dementia. We encourage future research to assess a) the neuroradiological substrates underlying statistically-determined AD/VaD spectrum dementia and b) how statistical modeling can be integrated into existing diagnostic criteria.
Pages 849-862
Mélanie Kuntz, Pietra Candela, Julien Saint-Pol, Yordenca Lamartinière, Marie-Christine Boucau, Emmanuel Sevin, Laurence Fenart, Fabien Gosselet (Handling Associate Editor: Maria Deli)
Bexarotene Promotes Cholesterol Efflux and Restricts Apical-to-Basolateral Transport of Amyloid-β Peptides in an In Vitro Model of the Human Blood-Brain Barrier
Abstract: One of the prime features of Alzheimer’s disease (AD) is the excessive accumulation of amyloid-β (Aβ) peptides in the brain. Several recent studies suggest that this phenomenon results from the dysregulation of cholesterol homeostasis in the brain and impaired bidirectional Aβ exchange between blood and brain. These mechanisms appear to be closely related and are controlled by the blood-brain barrier (BBB) at the brain microvessel level. In animal models of AD, the anticancer drug bexarotene (a retinoid X receptor agonist) has been found to restore cognitive functions and decrease the brain amyloid burden by regulating cholesterol homeostasis. However, the drug’s therapeutic effect is subject to debate and the exact mechanism of action has not been characterized. Therefore, the objective of this present study was to determine bexarotene’s effects on the BBB. Using an in vitro model of the human BBB, we investigated the drug’s effects on cholesterol exchange between abluminal and luminal compartments and the apical-to-basolateral transport of Aβ peptides across the BBB. Our results demonstrated that bexarotene induces the expression of ABCA1 but not ApoE. This upregulation correlates with an increase in ApoE2-, ApoE4-, ApoA-I-, and HDL-mediated cholesterol efflux. Regarding the transport of Aβ peptides, bexarotene increases the expression of ABCB1, which in turn decreases Aβ apical-to-basolateral transport. Our results showed that bexarotene not only promotes the cholesterol exchange between the brain and the blood but also decreases the influx of Aβ peptides across BBB, suggesting that bexarotene is a promising drug candidate for the treatment of AD.
Pages 863-869
S. Christine You, Christine M. Walsh, Louis A. Chiodo, Robin Ketelle, Bruce L. Miller, Joel H. Kramer
Neuropsychiatric Symptoms Predict Functional Status in Alzheimer’s Disease
Abstract: Background: Cognitive deficits are presumed to be the primary driver of functional impairment in Alzheimer’s disease (AD); however, functional impairment is likely multifactorially determined. Objective: Our objective was to determine the relative contribution of neuropsychiatric symptoms in predicting ratings of functional status. Methods: A total of 223 patients received routine neurological and neuropsychological evaluations and met criteria of probable AD dementia based on the McKhann criteria. Demographic, cognitive, and neuropsychiatric variables were entered in a hierarchical linear regression analysis to predict functional status as measured by the Functional Activities Questionnaire (FAQ). Results: The total model explained 29.7% of the variance (p<0.001) in FAQ. Importantly, neuropsychiatric variables explained 12.7% of the unique variance, with apathy and sleep as significant contributors. Conclusion: Two neuropsychiatric variables, apathy and changes in sleep/nighttime behaviors, predicted ratings of functional status in AD patients independent of age, global cognition, memory and executive function measures, and depressive symptoms. These results highlight the importance of neuropsychiatric symptoms in understanding and potentially treating the functional limitations so prevalent in AD.
