Volume 55, Number 2, 2017

Pages 447-457

Kasper Planeta Kepp (Handling Associate Editor: Francisco J. Muñoz)
Ten Challenges of the Amyloid Hypothesis of Alzheimer’s Disease
Abstract: The inability to effectively halt or cure Alzheimer’s disease (AD), exacerbated by the recent failures of high-profile clinical trials, emphasizes the urgent need to understand the complex biochemistry of this major neurodegenerative disease. In this paper, ten central, current challenges of the major paradigm in the field, the amyloid hypothesis, are sharply formulated. These challenges together show that new approaches are necessary that address data heterogeneity, increase focus on the proteome level, use available human patient data more actively, account for the aging phenotype as a background model of the disease, unify our understanding of the interplay between genetic and non-genetic risk factors, and combine into one framework both the familial and sporadic forms of the disease.

Pages 459-463
Short Communication

Harmony Duclos, Vincent de La Sayette, Anne-Laure Bonnet, Armelle Viard, Francis Eustache, Béatrice Desgranges, Mickaël Laisney (Handling Associate Editor: Maxime Bertoux)
Social Cognition in the Frontal Variant of Alzheimer's Disease: A Case Study
Abstract: Although frontal presentations of Alzheimer’s disease (fv-AD) have already been described in the literature, we still know little about patients’ social cognitive abilities, especially their theory of mind (ToM). We report the case of FT, a 61-year-old woman who was diagnosed with fv-AD. Two assessments of social cognition, using a false-belief task, the Reading the Mind in the Eyes test, and a task probing knowledge of social norms, were performed one year apart. FT exhibited cognitive ToM and social knowledge deficits from the onset. Affective ToM was initially preserved, but deteriorated as the disease progressed.

Pages 465-471
Julian Dronse*, Klaus Fliessbach*, Gérard N. Bischof, Boris von Reutern, Jennifer Faber, Jochen Hammes, Georg Kuhnert, Bernd Neumaier, Oezguer A. Onur, Juraj Kukolja, Thilo van Eimeren, Frank Jessen, Gereon R. Fink, Thomas Klockgether, Alexander Drzezga *These authors contributed equally to this work.
In vivo Patterns of Tau Pathology, Amyloid-β Burden, and Neuronal Dysfunction in Clinical Variants of Alzheimer’s Disease
Abstract: The clinical heterogeneity of Alzheimer’s disease is not reflected in the rather diffuse cortical deposition of amyloid-β. We assessed the relationship between clinical symptoms, in vivo tau pathology, amyloid distribution, and hypometabolism in variants of Alzheimer’s disease using novel multimodal PET imaging techniques. Tau pathology was primarily observed in brain regions related to clinical symptoms and overlapped with areas of hypometabolism. In contrast, amyloid-β deposition was diffusely distributed over the entire cortex. Tau PET imaging may thus serve as a valuable biomarker for the localization of neuronal injury in vivo and may help to validate atypical subtypes of Alzheimer’s disease.

Pages 473-484
Burcu F. Darst, Rebecca L. Koscik, Annie M. Racine, Jennifer M. Oh, Rachel A. Krause, Cynthia M. Carlsson, Henrik Zetterberg, Kaj Blennow, Bradley T. Christian, Barbara B. Bendlin, Ozioma C. Okonkwo, Kirk J. Hogan, Bruce P. Hermann, Mark A. Sager, Sanjay Asthana, Sterling C. Johnson, Corinne D. Engelman (Handling Associate Editor: Agustín Ruiz)
Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer’s Disease
Abstract: Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer’s disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer’s Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer’s Project’s meta-analysis, we identified clusters of genes that grouped into pathways involved in amyloid-β (Aβ) deposition and neurodegeneration: Aβ clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aβ deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging in 168 individuals, and cerebrospinal fluid Aβ deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.

Pages 485-495
Younggwang Kim, Dongkyun Lee, Kyoo Ho Cho, Jae Jung Lee, Jee Hyun Ham, Byoung Seok Ye, Seung-Koo Lee, Jong-Min Lee, Young H. Sohn, Phil Hyu Lee
Cognitive and Neuroanatomical Correlates in Early Versus Late Onset Parkinson's Disease Dementia
Abstract: Background: Aging is the most important risk factor of development of dementia in Parkinson’s disease (PD), but there are no data on clinical and radiological heterogeneity of PD dementia (PDD) depending on age at onset. Objectives: The goal of this study was to examine whether patients with PDD are clinically and radiologically heterogeneous depending on age at onset. Methods: A total of 116 patients with PD dementia and 121 age- and sex-matched normal controls were enrolled. The subjects were divided into early-onset (EOPDD; n= 39) and late-onset (LOPDD; n=77) PDD with the respective age-matched control group based on a cutoff value of 70 years. The effects of diagnosis, age, and their interaction on neuropsychological tests, cortical thickness, and substantia innominata volume were assessed using analysis of covariance. Results: EOPDD patients had a poorer cognitive performance on digit backward, forward span test (p=0.011 and 0.05), and visual recognition memory function (p=0.012) compared with LOPDD patients. Additionally, EOPDD patients exhibited cortical thinning in the left anterior cingulate gyrus and the right inferior temporal gyrus, with significantly decreased normalized substantia innominata volume (p=0.044). Conclusions: Our data demonstrated that EOPDD patients exhibit poorer cognitive performance and more severe atrophy in the cortex and substantia innominata, implying that EOPDD may be a distinct phenotype different from LOPDD.

Pages 497-507
Yan-Ping Zhang*, Rujuan Miao*, Qing Li, Tianfeng Wu, Fei Ma *These authors contributed equally to this work.
Effects of DHA Supplementation on Hippocampal Volume and Cognitive Function in Older Adults with Mild Cognitive Impairment: A 12-Month Randomized, Double-Blind, Placebo-Controlled Trial
Abstract: Docosahexaenoic acid (DHA) is important for brain function, and higher DHA intake is inversely correlated with relative risk of Alzheimer’s disease. The potential benefits of DHA supplementation in people with mild cognitive impairment (MCI) have not been fully examined. Our study aimed to determine the effect of DHA supplementation on cognitive function and hippocampal atrophy in elderly subjects with MCI. This was a randomized, double-blind, placebo-controlled trial in Tianjin, China. 240 individuals with MCI aged 65 years and over were recruited and equalized randomly allocated to the DHA or the placebo group. Participants received 12-month DHA supplementation (2 g/day) or corn oil as placebo. Both global and specific subdomains of cognitive function and hippocampal volume were measured at baseline, 6 months, and 12 months. Both changes were analyzed by repeated-measure analysis of variance (ANOVA). This trial has been registered: ChiCTR-IOR-15006058. A total of 219 participants (DHA: 110, Placebo: 109) completed the trial. The change in mean serum DHA levels was greater in the intervention group (+3.85%) compared to the control group (+1.06%). Repeated-measures analyses of covariance showed that, over 12 months, there was a significant difference in the Full-Scale Intelligence Quotient (ηp2 = 0.084; p = 0.039), Information (ηp2 = 0.439; p = 0.000), and Digit Span (ηp2 = 0.375; p = 0.000) between DHA-treated versus the placebo group. In addition, there were significant differences in volumes of left hippocampus (ηp2 = 0.121, p = 0.016), right hippocampus (ηp2 = 0.757, p = 0.008), total hippocampus (ηp2 = 0.124, p = 0.023), and global cerebrum (ηp2 = 0.145, p = 0.032) between the two groups. These findings suggest that DHA supplementation (2 g/day) for 12 months in MCI subjects can significantly improve cognitive function and slow the progression of hippocampal atrophy. Larger, longer-term confirmatory studies are warranted.

Pages 509-520
Bing Xie, Zanchao Liu, Lei Jiang, Wei Liu, Mei Song, Qingfu Zhang, Rui Zhang, Dongsheng Cui, Xueyi Wang, Shunjiang Xu (Handling Associate Editor: Ling-Qiang Zhu)
Increased Serum miR-206 Level Predicts Conversion from Amnestic Mild Cognitive Impairment to Alzheimer's Disease: A 5-Year Follow-up Study
Abstract: Evidence suggests that individuals with amnestic mild cognitive impairment (aMCI) tend to progress to probable Alzheimer's disease (AD) with aging. This study was performed to examine whether circulating miRNAs could be potential predictors for the progression of aMCI to AD. A total of 458 patients with aMCI were included in this study, and the clinical data were collected at two time points: the baseline and the follow-up assessment. These aMCI patients were classified into two groups after 5 years: aMCI-stable group (n = 330) and AD-conversion group (n = 128). The expression of miR-206 and miR-132 and the levels of BDNF and SIRT1 in serum were detected using a quantitative real-time RT-PCR (qPCR) and the ELISA method, respectively. Kaplan-Meier method (Log-rank test) was used for univariate survival analysis. Cox proportional hazard model was used to estimate the prognostic value of miRNAs in conversion from aMCI to AD. At the baseline, serum levels of miR-206 in aMCI-AD group were significantly elevated compared to aMCI-aMCI group and the same trend was found at 5-year follow-up time point as well. There were no significant differences in serum levels of miR-132 between the conversion and non-conversion group at both time points. Kaplan-Meier analysis showed significant correlation between AD conversion and higher serum levels of miR-206 for aMCI patients (HR = 3.60, 95% CI: 2.51-5.36, p < 0.001). Multivariate Cox regression analysis revealed that serum miR-206 and its target BDNF were significant independent predictors for AD conversion (HR = 4.22, p < 0.001). These results suggested that increased serum miR-206 level might be a potential predictor of conversion from aMCI to AD.

Pages 521-537
Anne Hafkemeijer, Christiane Möller, Elise G.P. Dopper, Lize C. Jiskoot, Annette A. van den Berg-Huysmans, John C. van Swieten, Wiesje M. van der Flier, Hugo Vrenken, Yolande A.L. Pijnenburg, Frederik Barkhof, Philip Scheltens, Jeroen van der Grond, Serge A.R.B. Rombouts (Handling Associate Editor: Juan Zhou)
A Longitudinal Study on Resting State Functional Connectivity in Behavioral Variant Frontotemporal Dementia and Alzheimer’s Disease
Abstract: Background/Objective: Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of early-onset dementia. We applied longitudinal resting state functional magnetic resonance imaging (fMRI) to delineate functional brain connections relevant for disease progression and diagnostic accuracy. Methods: We used two-center resting state fMRI data of 20 AD patients (65.1±8.0 years), 12 bvFTD patients (64.7±5.4 years), and 22 control subjects (63.8±5.0 years) at baseline and 1.8-year follow-up. We used whole-network and voxel-based network-to-region analyses to study group differences in functional connectivity at baseline and follow-up, and longitudinal changes in connectivity within and between groups. Results: At baseline, connectivity between paracingulate gyrus and executive control network, between cuneal cortex and medial visual network, and between paracingulate gyrus and salience network was higher in AD compared with controls. These differences were also present after 1.8 years. At follow-up, connectivity between angular gyrus and right frontoparietal network, and between paracingulate gyrus and default mode network was lower in bvFTD compared with controls, and lower compared with AD between anterior cingulate gyrus and executive control network, and between lateral occipital cortex and medial visual network. Over time, connectivity decreased in AD between precuneus and right frontoparietal network and in bvFTD between inferior frontal gyrus and left frontoparietal network. Longitudinal changes in connectivity between supramarginal gyrus and right frontoparietal network differ between both patient groups and controls. Conclusion: We found disease-specific brain regions with longitudinal connectivity changes. This suggests the potential of longitudinal resting state fMRI to delineate regions relevant for disease progression and for diagnostic accuracy, although no group differences in longitudinal changes in the direct comparison of AD and bvFTD were found.

Pages 539-549
Luís F.J.R. Miranda, Karina B. Gomes, Pedro A.L. Tito, Josianne N. Silveira, Gerson A. Pianetti, Ricardo M.D. Byrro, Patrícia R.H. Peles, Fernando H. Pereira, Thiago R. Santos, Arthur G. Assini, Valéria V. Ribeiro, Edgar N. Moraes, Paulo Caramelli (Handling Associate Editor: Andrea Slachevsky)
Clinical Response to Donepezil in Mild and Moderate Dementia: Relationship to Drug Plasma Concentration and CYP2D6 and APOE Genetic Polymorphisms
Abstract: The clinical response to donepezil in patients with mild and moderate dementia was investigated in relation to the drug plasma concentration and of APOE and CYP2D6 polymorphisms. In a prospective naturalistic observational study, 42 patients with Alzheimer’s disease (AD) and AD with cerebrovascular disease who took donepezil (10 mg) for 12 months were evaluated. Their DNA was genotyped, and the donepezil plasma concentrations were measured after 3, 6, and 12 months. Good responders scored ≥-1 on the Mini-Mental State Examination at 12 months in comparison to the baseline score. The study results indicated the good response pattern was influenced by the concentration of donepezil, but not by APOE and CYP2D6 polymorphisms.

Pages 551-558
Edward D. Huey, Seonjoo Lee, Gayathri Cheran, Jordan Grafman, Davangere P. Devanand, for the Alzheimer’s Disease Neuroimaging Initiative
Brain Regions Involved in Arousal and Reward Processing are Associated with Apathy in Alzheimer’s Disease and Frontotemporal Dementia
Abstract: Background: Apathy is a common and problematic symptom of several neurodegenerative illnesses, but its neuroanatomical bases are not understood. Objective: To determine the regions associated with apathy in subjects with mild Alzheimer’s disease (AD) using a method that accounts for the significant co-linearity of regional atrophy and neuropsychiatric symptoms. Methods: We identified 57 subjects with mild AD (CDR=1) and neuropsychiatric symptoms in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We performed a multivariate multiple regression with LASSO regularization on all symptom subscales of the Neuropsychiatric Inventory and the whole-brain ROI volumes calculated from their baseline MRIs with FreeSurfer. We compared our results to those from a previous study using the same method in patients with frontotemporal dementia (FTD) and corticobasal syndrome (CBS). Results: Of neuropsychiatric symptoms, apathy showed the most robust neuroanatomical associations in the AD subjects. Atrophy of the following regions were independently associated with apathy: the ventromedial prefrontal cortex; ventrolateral prefrontal cortex; posterior cingulate cortex and adjacent lateral cortex; and the bank of the superior temporal sulcus. These results replicate previous studies using FTD and CBS patients, mostly agree with the previous literature on apathy in AD, and correspond to the Medial and Orbital Prefrontal Cortex networks identified in non-human primates. Conclusion: The current study, previous studies from our laboratory, and the previous literature suggest that impairment of the same brain networks involved in arousal, threat response, and reward processing are associated with apathy in AD and FTD.

Pages 559-567
Rodolfo Savica, Alexandra M.V. Wennberg, Clinton Hagen, Kelly Edwards, Rosebud O. Roberts, John H. Hollman, David S. Knopman, Bradley F. Boeve, Mary M. Machulda, Ronald C. Petersen, Michelle M. Mielke
Comparison of Gait Parameters for Predicting Cognitive Decline: The Mayo Clinic Study of Aging
Abstract: Background: Previous studies reported that slower gait speed might predict cognitive impairment and dementing illnesses, supporting the role of gait speed as a possible subclinical marker of cognitive impairment. However, the predictive value of other gait parameters for cognitive decline is unclear. Objective: To investigate and compare the association with, and prediction of, specific gait parameters for cognition in a population-based sample. Methods: The analysis included 3,426 cognitively normal participants enrolled in the Mayo Clinic Study of Aging. At baseline and every 15 months (mean follow-up = 1.93 years), participants had a study coordinator evaluation, neurological examination, and a neuropsychological assessment using nine tests that covered four domains. Gait parameters were assessed with the GAITRite® instrument. General linear mixed effects models were used to compute the annualized rate of change in cognitive domain z-scores, controlling for age, sex, education, depression, comorbidities, body mass index, APOE ε4 allele, and visit number, and excluding individuals with a history of stroke, alcoholism, Parkinson's disease, subdural hematoma, and normal pressure hydrocephalus. Results: Spatial (stride length), temporal (ambulatory time, gait speed, step count, cadence, double support time), and spatiotemporal (cadence) gait parameters, and greater intraindividual variability in stride length, swing time, and stance time were associated with a significant decline in global cognition and in specific domains including memory, executive function, visuospatial, and language. Conclusions: Spatial, temporal, and spatiotemporal measures of gait and greater variability of gait parameters were associated with and predictive of both global- and domain-specific cognitive decline.

Pages 569-574
Sandra Petersen, Susan Houston, Huanying Qin, Corey Tague, Jill Studley
The Utilization of Robotic Pets in Dementia Care
Abstract: Background: Behavioral problems may affect individuals with dementia, increasing the cost and burden of care. Pet therapy has been known to be emotionally beneficial for many years. Robotic pets have been shown to have similar positive effects without the negative aspects of traditional pets. Robotic pet therapy offers an alternative to traditional pet therapy. Objective: The study rigorously assesses the effectiveness of the PARO robotic pet, an FDA approved biofeedback device, in treating dementia-related symptoms. Methods: A randomized block design with repeated measurements guided the study. Before and after measures included reliable, valid tools such as: RAID, CSDD, GDS, pulse rate, pulse oximetry, and GSR. Participants interacted with the PARO robotic pet, and the control group received standard activity programs. Five urban secure dementia units comprised the setting. Results: 61 patients, with 77% females, average 83.4 years in age, were randomized into control and treatment groups. Compared to the control group, RAID, CSDD, GSR, and pulse oximetry were increased in the treatment group, while pulse rate, pain medication, and psychoactive medication use were decreased. The changes in GSR, pulse oximetry, and pulse rate over time were plotted for both groups. The difference between groups was consistent throughout the 12-week study for pulse oximetry and pulse rate, while GSR had several weeks when changes were similar between groups. Conclusions: Treatment with the PARO robot decreased stress and anxiety in the treatment group and resulted in reductions in the use of psychoactive medications and pain medications in elderly clients with dementia.

Pages 575-583
Nozomi Okamoto, Masayuki Morikawa, Nobuko Amano, Motokazu Yanagi, Shin Takasawa, Norio Kurumatani
Effects of Tooth Loss and the Apolipoprotein E ε4 Allele on Mild Memory Impairment in the Fujiwara-kyo Study of Japan: A Nested Case-Control Study
Abstract: Background: Several studies have suggested that periodontal disease can exacerbate the pro-inflammatory status of the brain. Tooth loss is one of the alternative evaluation indices of periodontal disease. There are few data on the relationship between tooth loss and memory impairment, depending on the apolipoprotein E (APOE) ε4 genotype. Objective: To determine if tooth loss is associated with mild memory impairment (MMI) and if this association is modified by the presence of the APOE ε4 allele. Methods: A nested case-control study was conducted from 2007 to 2012 in Japan. Five hundred and thirty-seven Japanese subjects aged 65 years and over who were cognitively intact at baseline were analyzed. MMI at follow-up was evaluated. Results: The median number of teeth at baseline was significantly lower in MMI participants (n = 179) than in controls (n = 358) (MMI: median 21.0, interquartile range 10.0-25.0 versus controls: 24.0, 14.0-27.0). After adjustment for demographics, vascular risk factors, and APOE ε4 allele, the multivariate adjusted odds ratio (OR) of ≤8 teeth was 1.97 (95% confidence interval [CI], 1.13-3.44) compared to 25-32 teeth. Participants with both the presence of at least 1 APOE ε4 allele and ≤8 teeth had a higher risk of MMI compared with those with neither (OR, 2.82; 95% CI, 1.15-6.91). Those with either risk factor alone did not have a higher risk of MMI. Conclusions: A lower number of teeth is related to risk of MMI. This may be primarily true for those individuals with an APOE ε4 allele.

Pages 585-595
H. Bea Kuiperij, Alexandra A.M. Versleijen, Marijke Beenes, Nicolaas A. Verwey, Luisa Benussi, Anna Paterlini, Giuliano Binetti, Charlotte E. Teunissen, Joost Raaphorst, Helenius J. Schelhaas, Benno Küsters, Yolande A.L. Pijnenburg, Roberta Ghidoni, Marcel M. Verbeek (Handling Associate Editor: Anette Hall)
Tau rather than TDP-43 Proteins are Potential Cerebrospinal Fluid Biomarkers for Frontotemporal Lobar Degeneration Subtypes: A Pilot Study
Abstract: Background: Frontotemporal dementia (FTD) is a heterogeneous disease both at the clinical, genetic, and pathobiological level. The underlying pathological spectrum (termed FTLD, frontotemporal lobar degeneration) is in most cases defined by accumulation of either tau (FTLD-tau) or TDP-43 proteins (FTLD-TDP). Biomarkers to differentiate these subtypes are not yet available, whereas these are essential requirements to study the natural course of disease and for homogeneous inclusion of patients in clinical studies. Objective: To study if a combination of total (t-) and phosphorylated (p-)tau, and t-TDP-43 and p-TDP-43 proteins in cerebrospinal fluid (CSF) is suitable to discriminate FTLD-tau and FTLD-TDP subtypes. Methods: We developed immunoassays for the quantification of t-TDP-43 and p-TDP-43 proteins and used commercially available assays for the quantification of t-tau and p-tau proteins. We quantified these proteins in ventricular CSF samples from neuropathologically defined FTLD-tau and FTLD-TDP cases to study the reflection of underlying brain pathology in CSF composition, and in lumbar CSF samples from FTLD-tau and FTLD-TDP patients to study the diagnostic potential of CSF biomarkers. Results: In ventricular CSF, t-TDP-43 and t-tau levels, when combined into one model, were significantly different between neuropathologically-defined FTLD-tau and FTLD-TDP cases. In a pilot study using lumbar CSF, the p-tau/t-tau ratio, but not t-TDP-43 levels, were significantly different between FTLD-TDP and FTLD-tau patients. Conclusion: We conclude that with current available methods, CSF tau, rather than TDP-43 proteins, may have diagnostic value in the differentiation of FTLD patients with either tau or TDP-43 pathology.

Pages 597-612
Nor Faeizah Ibrahim, Daijiro Yanagisawa, Lina Wati Durani, Hamizah Shahirah Hamezah, Hanafi Ahmad Damanhuri, Wan Zurinah Wan Ngah, Mayumi Tsuji, Yuji Kiuchic, Kenjiro Ono, Ikuo Tooyama (Handling Associate Editor: Shun Shimohama)
Tocotrienol-Rich Fraction Modulates Amyloid Pathology and Improves Cognitive Function in AβPP/PS1 Mice
Abstract: Alzheimer’s disease (AD) is the most common cause of dementia. The cardinal neuropathological characteristic of AD is the accumulation of amyloid-β (Aβ) into extracellular plaques that ultimately disrupt neuronal function and lead to neurodegeneration. One possible therapeutic strategy therefore is to prevent Aβ aggregation. Previous studies have suggested that vitamin E analogs slow AD progression in humans. In the present study, we investigated the effects of the tocotrienol-rich fraction (TRF), a mixture of vitamin E analogs from palm oil, on amyloid pathology in vitro and in vivo. TRF treatment dose-dependently inhibited the formation of Aβ fibrils and Aβ oligomers in vitro. Moreover, daily TRF supplementation to AβPPswe/PS1dE9 double transgenic mice for 10 months attenuated Aβ immunoreactive depositions and thioflavin-S-positive fibrillar type plaques in the brain, and eventually improved cognitive function in the novel object recognition test compared with control AβPPswe/PS1dE9 mice. The present result indicates that TRF reduced amyloid pathology and improved cognitive functions, and suggests that TRF is a potential therapeutic agent for AD.

Pages 613-624
Hideomi Hamasaki, Hiroyuki Honda, Tsuyoshi Okamoto, Sachiko Koyama, Satoshi O. Suzuki, Tomoyuki Ohara, Toshiharu Ninomiya, Yutaka Kiyohara, Toru Iwaki
Recent Increases in Hippocampal Tau Pathology in the Aging Japanese Population: The Hisayama Study
Abstract: Background: The Hisayama study is a prospective cohort study of lifestyle-related diseases that commenced in 1961. Through it, a significant increasing trend in the prevalence of Alzheimer’s disease has been observed over the past 18 years. Objectives: We sought to investigate the increases in brain pathology related to Alzheimer’s disease using automated MATLAB morphometric analyses for quantifying tau pathology. Methods: We examined a series of autopsied cases from Hisayama residents obtained between 1998 and 2003 (group A: 203 cases), and between 2009 and 2014 (group B: 232 cases). We developed custom software in MATLAB to analyze abnormal tau deposits quantitatively. Specimens were immunostained with both anti-amyloid-β-protein and anti-phosphorylated tau antibodies. Results: Both the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria for senile plaques and Braak stage for NFT were higher in group B. Morphometric analyses of the hippocampi also revealed a trend toward increased tau pathology in both men and women over 80 years of age in group B. The increases were also significant when the subjects were examined independently according to high or low CERAD scores and in all levels of AD neuropathologic change according to the National Institute on Aging-Alzheimer's Association guidelines (2012). Conclusion: We revealed a recent trend of increased tauopathy in the older people, which is partly independent of amyloid-β pathology.

Pages 625-644
Amado Rivero-Santana, Daniel Ferreira, Lilisbeth Perestelo-Pérez, Eric Westman, Lars-Olof Wahlund, Antonio Sarría, Pedro Serrano-Aguilar
Cerebrospinal Fluid Biomarkers for the Differential Diagnosis between Alzheimer’s Disease and Frontotemporal Lobar Degeneration: Systematic Review, HSROC Analysis, and Confounding Factors
Abstract: Background: Differential diagnosis in dementia is at present one of the main challenges both in clinical practice and research. Cerebrospinal fluid (CSF) biomarkers are included in the current diagnostic criteria of Alzheimer’s disease (AD) but their clinical utility is still unclear. Objective: We performed a systematic review of studies analyzing the diagnostic performance of CSF Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in the discrimination between AD and frontotemporal lobar degeneration (FTLD) dementias. Methods: The following electronic databases were consulted until May 2016: Medline and PreMedline, EMBASE, PsycInfo, CINAHL, Cochrane Library, and CRD. For the first-time in the field, a Hierarchical Summary Receiver Operating Characteristic (HRSOC) model was applied, which avoids methodological problems of meta-analyses based on summary points of sensitivity and specificity values. We also investigated relevant confounders of CSF biomarkers’ diagnostic performance such as age, disease duration, and global cognitive impairment. Results: The p-tau/Aβ42 ratio showed the best diagnostic performance. No statistically significant effects of the confounders were observed. Nonetheless, the p-tau/Aβ42 ratio may be especially indicated for younger patients. P-tau may be preferable for less cognitively impaired patients (high MMSE scores) and the t-tau/Aβ42 ratio for more cognitively impaired patients (low MMSE scores). Conclusion: The p-tau/Aβ42 ratio has potential for being implemented in the clinical routine for the differential diagnosis between AD and FTLD. It is of utmost importance that future studies report information on confounders such as age, disease duration, and cognitive impairment, which should also stimulate understanding of the role of these factors in disease mechanisms and pathophysiology.

Pages 645-657
Krister Håkansson, Aurélie Ledreux, Kirk Daffner, Yvonne Terjestam, Patrick Bergman, Roger Carlsson, Miia Kivipelto, Bengt Winblad, Ann-Charlotte Granholm, Abdul Kadir H. Mohammed
BDNF Responses in Healthy Older Persons to 35 Minutes of Physical Exercise, Cognitive Training, and Mindfulness: Associations with Working Memory Function
Abstract: Brain-derived neurotrophic factor (BDNF) has a central role in brain plasticity by mediating changes in cortical thickness and synaptic density in response to physical activity and environmental enrichment. Previous studies suggest that physical exercise can augment BDNF levels, both in serum and the brain, but no other study has examined how different types of activities compare with physical exercise in their ability to affect BDNF levels. By using a balanced cross over experimental design, we exposed nineteen healthy older adults to 35-minute sessions of physical exercise, cognitive training, and mindfulness practice, and compared the resulting changes in mature BDNF levels between the three activities. We show that a single bout of physical exercise has significantly larger impact on serum BDNF levels than either cognitive training or mindfulness practice in the same persons. This is the first study on immediate BDNF effects of physical activity in older healthy humans and also the first study to demonstrate an association between serum BDNF responsivity to acute physical exercise and working memory function. We conclude that the BDNF increase we found after physical exercise more probably has a peripheral than a central origin, but that the association between post-intervention BDNF levels and cognitive function could have implications for BDNF responsivity in serum as a potential marker of cognitive health.

Pages 659-667
Vijay R. Varma, Amber Watts
Daily Physical Activity Patterns During the Early Stage of Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease that results in severe disability. Very few studies have explored changes in daily physical activity patterns during early stages of AD when components of physical function and mobility may be preserved. Objective: Our study explored differences in daily physical activity profiles, independent of the effects of non-cognitive factors including physical function and age, among individuals with mild AD compared to controls. Methods: Patients with mild AD and controls (n=92) recruited from the University of Kansas Alzheimer’s Disease Center Registry, wore the Actigraph GT3X+ for seven days, and provided objective physical function (VO2 max) and mobility data. Using multivariate linear regression, we explored whether individuals with mild AD had different daily average and diurnal physical activity patterns compared to controls independent of non-cognitive factors that may affect physical activity, including physical function and mobility. Results: We found that mild AD was associated with less moderate-intensity physical activity (p<0.05), lower peak activity (p<0.01), and lower physical activity complexity (p<0.05) particularly during the morning. Mild AD was not associated with greater sedentary activity or less lower-intensity physical activity across the day after adjusting for non-cognitive covariates. Conclusions: These findings suggest that factors independent of physical capacity and mobility may drive declines in moderate-intensity physical activity, and not lower-intensity or sedentary activity, during the early stage of AD. This underscores the importance of a better mechanistic understanding of how cognitive decline and AD pathology impact physical activity. Findings emphasize the potential value of designing and testing time-of-day specific physical activity interventions targeting individuals in the early stages of AD, prior to significant declines in mobility and physical function.

Pages 669-678
Feng Lin, Ping Ren, Raymond Y. Lo, Benjamin P. Chapman, Alanna Jacobs, Timothy M. Baran, Anton P. Porsteinsson, John J. Foxe for the Alzheimer's Disease Neuroimaging Initiative
Insula and Inferior Frontal Gyrus’ Activities Protect Memory Performance Against Alzheimer’s Disease Pathology in Old Age
Abstract: Apolipoprotein E (APOE) ε4 carriers and patients with amnestic mild cognitive impairment (MCI) have high risk of developing Alzheimer’s disease (AD). The Scaffolding Theory of Aging and Cognition proposes that recruitment of additional frontal brain regions can protect cognition against aging. This thesis has yet to be fully tested in older adults at high risk for AD. In the present study, 75 older participants (mean age: 74 years) were included. Applying a voxel-wise approach, fractional amplitude of low-frequency fluctuations (fALFF) in resting-state functional neuroimaging data were analyzed as a function of APOEε4 status (carrier versus noncarrier) and clinical status (healthy control [HC] versus MCI) using a 2×2 analysis of covariance (ANCOVA). Measures of cognition and cerebrospinal fluid levels of amyloid- β were also obtained. Three frontal regions were identified with significant interaction effects using ANCOVA (corrected p < 0.01): left-insula, left-inferior frontal gyrus (IFG), and right-precentral gyrus. The HC/APOEε4 carrier group had significantly higher fALFF in all three regions than other groups. In the entire sample, for two regions (left insula and left IFG), a significant positive relationship between amyloid-β and memory was only observed among individuals with low fALFF. Our results suggest higher activity in frontal regions may explain being cognitively normal among a subgroup of APOEε4 carriers and protect against the negative impact of AD-associated pathology on memory. This is an observation with potential implications for AD therapeutics.

Pages 679-689
Willemijn J. Jansen, Ron L.H. Handels, Pieter Jelle Visser, Pauline Aalten, Femke Bouwman, Jurgen Claassen, Peter van Domburg, Erik Hoff, Jan Hoogmoed, Albert F.G. Leentjens, Marcel Olde Rikkert, Ania M. Oleksik, Machiel Smid, Philip Scheltens, Claire Wolfs, Frans Verhey, Inez H.G.B. Ramakers
The Diagnostic and Prognostic Value of Neuropsychological Assessment in Memory Clinic Patients
Abstract: Background: Neuropsychological testing has long been embedded in daily clinical practice at memory clinics but the added value of a complete neuropsychological assessment (NPA) to standard clinical evaluation is unknown. Objective: To evaluate the added diagnostic and prognostic value of NPA to clinical evaluation only in memory clinic patients Methods: In 221 memory clinic patients of a prospective cohort study, clinical experts diagnosed clinical syndrome (subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or dementia) and etiology (Alzheimer’s disease (AD) or no AD), and provided a prognosis of disease course (decline or no decline) before and after results of NPA were made available. The reference standard was a panel consensus based on all clinical information at baseline and up to 2 follow-up assessments. Results: With NPA data available, clinicians changed their initial syndromal diagnosis in 22% of patients, and the etiological diagnosis as well as the prognosis in 15%. This led to an increase in correctly classified cases of 18% for syndromal diagnosis, 5% for etiological diagnosis, and 1% for prognosis. NPA data resulted in the largest improvement in patients initially classified as SCI (syndrome: 93.3% (n=14) correctly reclassified, etiology: net reclassification improvement [NRI]=0.61, prognosis: NRI=0.13) or MCI (syndrome: 89.3% (n=23) correctly reclassified, etiology: NRI=0.17, prognosis: NRI=0.14), while there was no improvement in patients with dementia (syndrome: 100% (n=1) correctly reclassified, etiology: NRI=-0.05, prognosis: NRI=-0.06). Overall, inclusion of NPA in the diagnostic process increased confidence in all diagnoses with 6-7%. Conclusion: Administration of a complete NPA after standard clinical evaluation has added value for diagnosing cognitive syndrome and its underlying etiology in patients regarded as non-demented based on the first clinical impression.

Pages 691-701
Diana Wucherer, Tilly Eichler, Johnanes Hertel, Ingo Kilimann, Steffen Richter, Bernhard Michalowsky, Jochen René Thyrian, Stefan Teipel, Wolfgang Hoffmann
Potentially Inappropriate Medication in Community-Dwelling Primary Care Patients who were Screened Positive for Dementia
Abstract: Background: Potentially inappropriate medication (PIM) in older people is a risk factor for adverse drug effects. This risk is even higher in older people with dementia (PWD). Objective: Our study aimed to determine (1) the prevalence of PIM among primary care patients who were screened positive for dementia and (2) the sociodemographic and clinical variables associated with the use of PIM. Methods: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg–Western Pomerania) is a general practitioner-based, cluster-randomized, controlled intervention study to implement and evaluate an innovative concept of collaborative dementia care management in Germany. The comprehensive baseline assessment includes a home medication review. The present analyses are based on the data from 448 study participants (age 70+, DemTect <9). PIMs were identified using the list of Potentially Inappropriate Medications in the Elderly (Priscus). Results: (1) A total of 99 study participants (22%) received at least one PIM. The highest prevalence was found for antidepressants, benzodiazepines, and analgetics. The most frequently prescribed PIMs were amitriptyline, etoricoxib, and doxazosin. (2) Use of a PIM was significantly associated with a diagnosis of a mental or behavioral disorder. Conclusions: The prescription rate of PIMs for community-dwelling PWD was comparable with the rates found for the general population of older people in Germany (20-29%). Antidepressants with anticholinergic properties and long-acting benzodiazepines were the most prescribed PIMs, despite having an unfavorable benefit-risk ratio. This high prevalence of PIM prescriptions in a vulnerable population of PWD indicates that standard care for dementia should include careful medication review and management.

Pages 703-716
Emilie Wawrziczny, Guillaume Berna, Francine Ducharme, Marie-Jeanne Kergoat, Florence Pasquier, Pascal Antoine
Modeling the Distress of Spousal Caregivers of People with Dementia
Abstract: Background: The progressive mobilization of spouse caregivers who take care of a person with dementia (PWD) can lead to situations of distress. Objective: The current study sought to investigate the influence of the characteristics of the caregiving context on spousal caregiver distress. Methods: 125 spousal caregivers participated in this study. The characteristics of the caregiving context were assessed using questionnaires. We examined a moderated-mediator model (Step 1) in which we hypothesized that PWD and caregiver characteristics and dyadic determinants contribute to spousal caregiver distress. This model was compared based on the age at onset of the disease and the gender of the caregiver (Step 2). Results: The model revealed that poor self-rated health and a lack of family support accentuated spousal caregiver distress, whereas the feeling of being prepared and level of confidence decreased spousal caregiver distress. Moreover, the quality of couple adjustment affected spousal caregiver distress, and this effect was mediated by the severity of the PWD's symptoms. Regarding the age at onset of the disease, the path between Couple Adjustment and the Care recipient's impairments was more important for caregivers of person with early-onset dementia (PEOD). Female caregivers who reported poor self-rated health experienced greater distress. Conclusions: It would be interesting to create a support program that would incorporate these three areas of intervention regarding the progression of the disease: first, "preparedness modules"; second, "dyadic modules" (especially for caregivers of PEOD); and third, "family modules". Specific attention should be given to female caregivers who report poor self-rated health.

Pages 717-725
Ingun Ulstein, Thomas Bøhmer
Normal Vitamin Levels and Nutritional Indices in Alzheimer’s Disease Patients with Mild Cognitive Impairment or Dementia with Normal Body Mass Indexes
Abstract: Evidence supports an association between vitamin deficiencies and cognitive decline in Alzheimer’s disease (AD). If vitamin deficiencies are causative for AD development, they should be detectable during very early stages of AD. Here we investigated nutritional factors among home-living patients diagnosed with mild cognitive impairment (MCI) or mild dementia due to AD, compared to healthy controls. Our study included 73 patients with AD (25 with MCI, 48 with dementia) and 63 cognitively intact age-matched controls. All participants underwent cognitive testing, somatic examination, and measurements of vitamins A, B1, B6, folate, B12, C, D, and E, and F2-α-isoprostane. Results are given as mean (SD). MMSE scores were 29.1 (1.0) for healthy controls, 27.4 (1.8) for patients with MCI, and 24.3 (3.2) for patients with dementia. Vitamin concentrations for the these groups, respectively, were as follows: B1 (nmol/l), 157 (29), 161 (35), and 161 (32); B6 (nmol/l), 57 (63), 71 (104), and 58 (44); folate (mmol/l), 23 (9), 26 (10), and 23 (11); B12 (pmol/l), 407 (159), 427 (116), and 397 (204); C (µmol/l), 63 (18), 61 (16), and 63 (29); A (µmol/l), 2.3 (0.6), 2.2 (0.5), and 2.3(0.5); E (µmol/l), 36 (6.3), 36 (6.9), and 36 (8.2); 25-OH vitamin D (nmol/l), 65 (18), 61 (19), and 65 (20); and 8-iso-PGFα (pg/ml), 64 (27); 60 (19), and 66 (51). These concentrations did not significantly differ (p ≤ 0.05) between the three groups. Our results do not support the hypothesis that vitamin deficiencies play a causative role in the development of early cognitive impairment.

Pages 727-735
Hoyoung An, Booyeol Choi, Kun-woo Park, Do-Hoon Kim, Dong-Won Yangf Chang Hyung Hong, Seong Yoon Kim, Seol-Heui Han
The Effect of Escitalopram on Mood and Cognition in Depressive Alzheimer’s Disease Subjects
Abstract: Background: Effective treatments to alleviate depression in Alzheimer’s disease (AD) have been scarce. Objective: To investigate the efficacy and tolerability of escitalopram in the treatment of depression in AD. Methods: In this 12-week randomized, double-blind, placebo-controlled trial with open-label, 12-week extension, AD subjects over 50 years of age, with depression defined by Olin’s provisional diagnostic criteria, were enrolled. The Cornell Scale for Depression in Dementia (CSDD), and other measures of depression and cognition were repeated. Results: 91 subjects were screened, and 84 were randomized into either the study group or placebo group (n=42 for both groups). Twenty-four subjects (29%) were unable to finish the study, yielding a per protocol population of 60 subjects (study group: n=27; placebo group: n=33). At week 12, differences in measures of depression and cognition between the two groups were not statistically significant. However, exploratory analysis suggested that further research on a subset of subjects with ‘definite major depression’ (baseline CSDD score ≥ 18) is needed. The number of treatment-related adverse-events (AE) did not differ between groups (p=0.83) and no serious treatment-related AE were observed. Conclusion: The use of escitalopram was well tolerated in depressive dementia patients. Future studies focusing on subjects with more severe levels of depression, and with more statistical power, will be needed.

Pages 737-748
Pinar Coskun, Pablo Helguera, Zahra Nemati, Ryan C. Bohannan, Jean Thomas, Samuel E. Schriner, Jocelyn Argueta, Eric Doran, Douglas C. Wallace, Ira T. Lott, Jorge Busciglio (Handling Associate Editor: Elizabeth Head)
Metabolic and Growth Rate Alterations in Lymphoblastic Cell Lines Discriminate Between Down Syndrome and Alzheimer’s Disease
Abstract: Background: Deficits in mitochondrial function and oxidative stress play pivotal roles in Down syndrome (DS) and Alzheimer’s disease (AD) and these alterations in mitochondria occur systemically in both conditions. Objective: We hypothesized that peripheral cells of elder subjects with DS exhibit disease-specific and dementia-specific metabolic features. To test this, we performed a comprehensive analysis of energy metabolism in lymphoblastic-cell-lines (LCLs) derived from subjects belonging to four groups: DS-with-dementia (DSAD), DS-without-dementia (DS), sporadic AD, and age-matched controls. Methods: LCLs were studied under regular or minimal feeding regimes with galactose or glucose as primary carbohydrate sources. We assessed metabolism under glycolysis or oxidative phosphorylation by quantifying cell viability, oxidative stress, ATP levels, mitochondrial membrane potential (MMP), mitochondrial calcium uptake, and autophagy. Results: DS and DSAD LCLs showed slower growth rates under minimal feeding. DS LCLs mainly dependent on mitochondrial respiration exhibited significantly slower growth and higher levels of oxidative stress compared to other groups. While ATP levels (under mitochondrial inhitors) and mitochondrial calcium uptake were significantly reduced in DSAD and AD cells, MMP was decreased in DS, DSAD, and AD LCLs. Finally, DS LCLs showed markedly reduced levels of the autophagy marker LC3-II, underscoring the close association between metabolic dysfunction and impaired autophagy in DS. Conclusion: There are significant mitochondrial functional changes in LCLs derived from DS, DSAD, and AD patients. Several parameters analyzed were consistently different between DS, DSAD, and AD lines suggesting that metabolic indicators between LCL groups may be utilized as biomarkers of disease progression and/or treatment outcomes.

Pages 749-762
Rachel H.L.H. Rueli, Daniel J. Torres, Andrea S.T. Dewing, Arlene C. Kiyohara, Stephanie M. Barayuga, Miyoko T. Bellinger, Jane H. Uyehara-Lock, Lon R. White, Paula I. Moreira, Marla J. Berry, George Perry, Frederick P. Bellinger
Selenoprotein S Reduces Endoplasmic Reticulum Stress-Induced Phosphorylation of Tau: Potential Role in Selenate Mitigation of Tau Pathology
Abstract: Previous studies demonstrated that selenium in the form of sodium selenate reduces neurofibrillary tangle formation in Alzheimer’s disease models. Hyperphosphorylation of tau, which leads to formation of neurofibrillary tangles in Alzheimer’s disease, is increased by endoplasmic reticulum (ER) stress. Selenoprotein S (SelS) is part of an ER membrane complex that removes misfolded proteins from the ER as a means to reduce ER stress. Selenate, as with other forms of selenium, will increase selenoprotein expression. We therefore proposed that increased SelS expression by selenate would contribute to the beneficial actions of selenate in Alzheimer’s disease. SelS expression increased with ER stress and decreased under conditions of elevated glucose concentrations in the SH-SY5Y neuronal cell line. Reducing expression of SelS with siRNA promoted cell death in response to ER stress. Selenate increased SelS expression, which significantly correlated with decreased tau phosphorylation. Restricting SelS expression during ER stress conditions increased tau phosphorylation, and also promoted aggregation of phosphorylated tau in neurites and soma. In human postmortem brain, SelS expression coincided with neurofibrillary tangles, but not with amyloid-β plaques. These results indicate that selenate can alter phosphorylation of tau by increasing expression of SelS in Alzheimer’s disease and potentially other neurodegenerative disorders.

Pages 763-776
Doortje W. Dekens, Petrus J.W. Naudé, Sebastiaan Engelborghs, Yannick Vermeiren, Debby Van Dam, Richard C. Oude Voshaar, Ulrich L.M. Eisel, Peter P. De Deyn
Neutrophil Gelatinase-Associated Lipocalin and its Receptors in Alzheimer’s Disease (AD) Brain Regions: Differential Findings in AD with and without Depression
Abstract: Co-existing depression worsens Alzheimer’s disease (AD) pathology. Neutrophil gelatinase-associated lipocalin (NGAL) is a newly identified (neuro)inflammatory mediator in the pathophysiologies of both AD and depression. This study aimed to compare NGAL levels in healthy controls, AD without depression (AD–D), and AD with co-existing depression (AD+D) patients. Protein levels of NGAL and its receptors, 24p3R and megalin, were assessed in nine brain regions from healthy controls (n=19), AD–D (n=19), and AD+D (n=21) patients. NGAL levels in AD–D patients were significantly increased in brain regions commonly associated with AD. In the hippocampus, NGAL levels were even further increased in AD+D subjects. Unexpectedly, NGAL levels in the prefrontal cortex of AD+D patients were comparable to those in controls. Megalin levels were increased in BA11 and amygdala of AD+D patients, while no changes in 24p3R were detected. These findings indicate significant differences in neuroimmunological regulation between AD patients with and without co-existing depression. Considering its known effects, elevated NGAL levels might actively promote neuropathological processes in AD with and without depression.

Pages 777-785
Lin Sun, Kathryn Chen, Xia Li, Shifu Xiao
Rapidly Progressive Frontotemporal Dementia associated with MAPT Mutation G389R
Abstract: Frontotemporal dementia includes a large spectrum of neurodegenerative disorders. Here, we report the case of a young patient with MAPT mutation G389R, who was 27 years old when he progressively developed severe behavioral disturbances. Initially, he presented with slowly progressive personality change. After 1 year, he exhibited moderate dementia with extrapyramidal and pyramidal symptoms. MRI showed frontotemporal atrophy. He rapidly progressed to severe dementia 3 years after onset. Genetic testing revealed a heterozygous guanine to cytosine mutation at the first base of codon 389 (c.1165G>A) of MAPT, the tau gene, resulting in a glycine to arginine substitution in the patient and two unaffected relatives. We predicted the model of mutant tau protein through I-TASSER software, and speculated the structural change of tau protein caused by mutant site. We also detected the MAPT gene transcript and methylation of samples from peripheral blood leucocytes in an attempt to explain the possible mechanisms of incomplete penetrance, although there were not positive findings. This case is remarkable because of the early onset and rapid progression of the disease.

Pages 787-796
Ji Won Han, Hyeonggon Lee, Jong Woo Hong, Kayoung Kim, Taehyun Kim, Hye Jin Byun, Ji Won Ko, Jong Chul Yoon, Seung-Ho Ryu, Nam-Jin Lee, Chi-Un Pae, Ki Woong Kim
Multimodal Cognitive Enhancement Therapy for Patients with Mild Cognitive Impairment and Mild Dementia: A Multi-Center, Randomized, Controlled, Double-Blind, Crossover Trial
Abstract: We developed and evaluated the effect of Multimodal Cognitive Enhancement Therapy (MCET) consisting of cognitive training, cognitive stimulations, reality orientation, physical therapy, reminiscence therapy, and music therapy in combination in older people with mild cognitive impairment (MCI) or mild dementia. This study was a multi-center, double-blind, randomized, placebo-controlled, two-period cross-over study (two 8-week treatment phases separated by a 4-week wash-out period). Sixty-four participants with MCI or dementia whose Clinical Dementia Rating was 0.5 or 1 were randomized to the MCET group or the mock-therapy (placebo) group. Outcomes were measured at baseline, week 9, and week 21. Fifty-five patients completed the study. Mini-Mental State Examination (effect size = 0.47, p = 0.013) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (effect size = 0.35, p = 0.045) scores were significantly improved in the MCET compared with mock-therapy group. Revised Memory and Behavior Problems Checklist frequency (effect size = 0.38, p = 0.046) and self-rated Quality of Life - Alzheimer's Disease (effect size = 0.39, p = 0.047) scores were significantly improved in the MCET compared with mock-therapy. MCET improved cognition, behavior, and quality of life in people with MCI or mild dementia more effectively than conventional cognitive enhancing activities did.

Pages 797-811
Richard McClure, Henry Ong, Vaibhab Janve, Shawn Barton, Meiying Zhu, Bo Li, Mary Dawes, W. Gray Jerome, Adam Anderson, Pierre Massion, John C. Gore, Wellington Pham
Aerosol Delivery of Curcumin Reduced Amyloid-β Deposition and Improved Cognitive Performance in a Transgenic Model of Alzheimer's Disease
Abstract: We report a novel approach for the delivery of curcumin to the brain via inhalation of the aerosol for the potential treatment of Alzheimer's disease. The percentage of plaque fraction in the subiculum and hippocampus reduced significantly when young 5XFAD mice were treated with inhalable curcumin over an extended period of time compared to age-matched nontreated counterparts. Further, treated animals demonstrated remarkably improved overall cognitive function, no registered systemic or pulmonary toxicity associated with inhalable curcumin observed during the course of this work.

Pages 813-822
Piotr Lewczuk*, Anja Matzen*, Kaj Blennow, Lucilla Parnetti, Jose Luis Molinuevo, Paolo Eusebi, Johannes Kornhuber, John C. Morris, Anne M. Fagan (Handling Associate Editor: Sylvain Lehmann) *These authors contributed equally to the study
Cerebrospinal Fluid Aβ42/40 Corresponds Better than Aβ42 to Amyloid PET in Alzheimer’s Disease
Abstract: Background: Decreased concentrations of amyloid-β 1-42 (Aβ42) in cerebrospinal fluid (CSF) and increased retention of Aβ tracers in the brain on positron emission tomography (PET) are considered the earliest biomarkers of Alzheimer’s disease (AD). However, a proportion of cases show discrepancies between the results of the two biomarker modalities which may reflect inter-individual differences in Aβ metabolism. The CSF Aβ42/40 ratio seems to be a more accurate biomarker of clinical AD than CSF Aβ42 alone. Objective: We tested whether CSF Aβ42 alone or the Aβ42/40 ratio corresponds better with amyloid PET status and analyzed the distribution of cases with discordant CSF-PET results. Methods: CSF obtained from a mixed cohort (n=200) of cognitively normal and abnormal research participants who had undergone amyloid PET within 12 months (n=150 PET-negative, n=50 PET-positive according to a previously published cut-off) was assayed for Aβ42 and Aβ40 using two recently developed immunoassays. Optimal CSF cut-offs for amyloid positivity were calculated, and concordance was tested by comparison of the areas under receiver operating characteristic (ROC) curves (AUC) and McNemar’s test for paired proportions. Results: CSF Aβ42/40 corresponded better than Aβ42 with PET results, with a larger proportion of concordant cases (89.4% versus 74.9%, respectively, p<0.0001) and a larger AUC (0.936 versus 0.814, respectively, p<0.0001) associated with the ratio. For both CSF biomarkers, the percentage of CSF-abnormal/PET-normal cases was larger than that of CSF-normal/PET-abnormal cases. Conclusion: The CSF Aβ42/40 ratio is superior to Aβ42 alone as a marker of amyloid-positivity by PET. We hypothesize that this increase in performance reflects the ratio compensating for general between-individual variations in CSF total Aβ.

Pages 823-833
Chao Xu Peh, Edimansyah Abdin, Janhavi A. Vaingankar, Swapna Verma, Boon Yiang Chua, Vathsala Sagayadevan, Esmond Seow, YunJue Zhang, Shazana Shahwan, Li Ling Ng, Martin Prince, Siow Ann Chong, Mythily Subramaniam (Handling Associate Editor: Brandon Gavett)
Validation of a Latent Construct for Dementia in a Population-Wide Dataset from Singapore
Abstract: Background: The latent variable δ has been proposed as a proxy for dementia. Previous validation studies have been conducted using convenience samples. It is currently unknown how δ performs in population-wide data. Objective: To validate δ in Singapore using population-wide epidemiological study data on persons aged 60 and above. Methods: δ was constructed using items from the Community Screening Instrument for Dementia (CSI’D) and World Health Organization Disability Assessment Schedule (WHODAS II). Confirmatory factor analysis (CFA) was conducted to examine δ model fit. Convergent validity was examined with the Clinical Dementia Rating scale (CDR) and GMS-AGECAT dementia. Divergent validity was examined with GMS-AGECAT depression. Results: The δ model demonstrated fit to the data, χ2(df) = 249.71(55), p < 0.001, CFI = 0.990, TLI = 0.997, RMSEA = 0.037. Latent variable δ was significantly associated with CDR and GMS-AGECAT dementia (range: β = 0.32 to 0.63), and was not associated with GMS-AGECAT depression. Compared to unadjusted models, δ model fit was poor when adjusted for age, gender, ethnicity, and education. Conclusion: The study found some support for δ as a proxy for dementia in Singapore based on population data. Both convergent and divergent validity were established. In addition, the δ model structure appeared to be influenced by age, gender, ethnicity, and education covariates.

Pages 835-847
Yijun Shen*, Yiling Xia*, Shiquan Meng*, Nastasia K.H. Lim, Wenan Wang, Fude Huang (Handling Associate Editor: Bing Zhou) *These authors contributed equally to this work.
SH2B1 is Involved in the Accumulation of Amyloid-β42 in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is characterized by deficits in learning and memory abilities, as well as pathological changes of amyloid-β (Aβ) plaque and neurofibrillary tangle formation in the brain. Insulin has been identified as a modulator of the neuronal pathways involved in learning and memory, and is also implicated as a modulator of Aβ and tau metabolism. Disrupted insulin signaling pathways are evident in AD patients and it is understood that type 2 diabetes can increase the risk of developing AD, suggesting a possible link between metabolic disorders and neurodegeneration. SH2B1 is a key protein in the insulin signaling pathway involved in regulating the activity of the insulin receptor. To further identify the role of the insulin signaling pathway in the pathology of AD, SH2B (dSH2B homologue in flies) in neurons was partially knocked out or overexpressed in an AD Drosophila model expressing Aβ42. Partial knockout of neuronal SH2B in the Aβ42-expressing Drosophila had a detrimental effect on mobility and neurotransmission, and increased levels and intraneuronal accumulation of Aβ42, as assessed by ELISA and immunostaining. Alternatively, partial overexpression of neuronal SH2B in the Aβ42-expressing Drosophila improved lifespan, mobility, and neurotransmission, as well as decreased levels and intraneuronal accumulation of Aβ42. Thus, SH2B1 may be an upstream modulator of Aβ metabolism, acting to inhibit Aβ accumulation, and has a role in the pathogenesis of AD. SH2B1 may therefore have potential as a therapeutic target for this common form of dementia.

Pages 849-864
Suzanne M. de la Monte, Ming Tong, Irio Schiano, John Didsbury
Improved Brain Insulin/IGF Signaling and Reduced Neuroinflammation with T3D-959 in an Experimental Model of Sporadic Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is associated with progressive impairments in brain insulin, insulin-like growth factor (IGF), and insulin receptor substrate (IRS) signaling through Akt pathways that regulate neuronal growth, survival, metabolism, and plasticity. The intracerebral streptozotocin (i.c. STZ) model replicates the full range of abnormalities in sporadic AD. T3D-959, an orally active PPAR-delta/gamma agonist remediates neurocognitive deficits and AD neuropathology in the i.c. STZ model. Objective: This study characterizes the effects of T3D-959 on AD biomarkers, insulin/IGF/IRS signaling through Akt pathways, and neuroinflammation in an i.c. STZ model. Methods: Long Evans rats were treated with i.c. STZ or saline, followed by daily oral doses of T3D-959 (1 mg/kg) or saline initiated 1 day (T3D-959-E) or 7 days (T3D-959-L) later through Experimental Day 28. Protein and phospho-protein expression and pro-inflammatory cytokine activation were measured in temporal lobe homogenates by duplex or multiplex bead-based ELISAs. Results: i.c. STZ treatments caused neurodegeneration with increased pTau, AβPP, Aβ42, ubiquitin, and SNAP-25, and reduced levels of synaptophysin, IGF-1 receptor (R), IRS-1, Akt, p70S6K, mTOR, and S9-GSK-3β. i.c. STZ also broadly increased neuroinflammation. T3D-959 abrogated or reduced most of the AD neuropathological and biomarker abnormalities, increased/normalized IGF-1R, IRS-1, Akt, p70S6K, and S9-GSK-3β, and decreased expression of multiple pro-inflammatory cytokines. T3D-959-E or -L effectively restored insulin/IGF signaling, whereas T3D-959-L more broadly resolved neuroinflammation. Conclusion: AD remediating effects of T3D-959 are potentially due to enhanced expression of key insulin/IGF signaling proteins and inhibition of GSK-3β and neuroinflammation. These effects lead to reduced neurodegeneration, cognitive impairment, and AD biomarker levels in the brain.