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Volume 56, Number 4, 2017

Pages 1215-1222
Short Communication

Aurelie N’Songo, Minerva M. Carrasquillo, Xue Wang, Thuy Nguyen, Yan Asmann, Steven G. Younkin, Mariet Allen, Ranjan Duara, Maria T. Greig Custo, Neill Graff-Radford, Nilüfer Ertekin-Taner
Comprehensive Screening for Disease Risk Variants in Early-Onset Alzheimer’s Disease Genes in African Americans Identifies Novel PSEN Variants
Abstract: We conducted a comprehensive screening of rare coding variants in an African American cohort to identify novel pathogenic mutations within the early-onset Alzheimer’s disease (EOAD) genes (APP, PSEN1, and PSEN2) in this understudied population. Whole-exome sequencing of 238 African American subjects identified 6 rare missense variants within the EOAD genes, which were observed in AD cases but never among controls. These variants were analyzed in an independent cohort of 300 African American subjects in which PSEN2:NM_000447:exon5:c.T331C:p.Phe111Leu and PSEN1-minilin rs777923890 variants were again not observed, indicating that these novel rare variants, may contribute to AD risk in this population.

Pages 1223-1227
Short Communication

Raffaella Valenti, Andreas Charidimou, Li Xiong, Gregoire Boulouis, Panagiotis Fotiadis, Alison Ayres, Grace Riley, Hugo J. Kuijf, Yael D. Reijmer, Leonardo Pantoni, M. Edip Gurol, Sigurros Davidsdottir, Steven M. Greenberg, Anand Viswanathan
Visuospatial Functioning in Cerebral Amyloid Angiopathy: A Pilot Study
Abstract: Cerebral amyloid angiopathy (CAA) is a contributor to cognitive impairment in the elderly. We hypothesized that the posterior cortical predilection of CAA would cause visual-processing impairment. We systematically evaluated visuospatial abilities in 22 non-demented CAA patients. Neurocognitive evaluation demonstrated visuoperceptual impairment (23% on Benton Facial Recognition Test [BFRT] and 13.6% on Benton Judgment of Line Orientation Test [BJLO]). BFRT was inversely correlated with white matter hyperintensities volume and BJLO with parietal cerebral microbleeds. This pilot study highlights the presence of visual-processing deficits in CAA. The impairment could be related to global disease severity in addition to local brain injury.

Pages 1229-1239
Shinji Matsunaga, Taro Kishi, Nakao Iwata
Combination Therapy with Zonisamide and Antiparkinson Drugs for Parkinson’s Disease: A Meta-Analysis
Abstract: Background: There is uncertainty about the efficacy and tolerability of zonisamide for Parkinson’s disease (PD). Objective: We performed a meta-analysis of zonisamide treatment in PD patients who received antiparkinson drugs such as levodopa. Methods: The primary outcome measures were the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III scores, wearing-off time, and discontinuation rate due to all causes. Secondary outcome measures were UPDRS total and subscale scores; discontinuation rates due to adverse events, inefficacy, and death; and individual adverse events. Results: Four randomized placebo-controlled trials including 1,068 PD patients were analyzed. All studies were conducted in Japan. UPDRS Part III scores were significantly lower with zonisamide than with placebo (weighted mean difference [WMD], −2.56; 95% confidence interval [CI]; −4.20 to −0.92; p=0.002). Further, zonisamide significantly decreased the wearing-off time compared with placebo (standardized mean difference, −0.24; 95%CI, −0.39 to −0.09; p=0.001). Discontinuation rates due to all causes were similar between the zonisamide and placebo groups (risk ratio, 1.29; 95%CI, 0.90 to 1.84; p=0.16). While zonisamide also decreased both UPDRS Part II (off-time) and UPDRS total scores compared to placebo (UPDRS Part II [off-time] scores: WMD, −0.79; UPDRS total scores: WMD, −2.51), there were no significant differences in other secondary outcomes between the two groups. Conclusions: Our results suggested that zonisamide combination therapy was beneficial in treating motor symptoms in PD patients receiving antiparkinson drugs and was well tolerated in Japanese patients. Future studies in populations other than the Japanese are needed.

Pages 1241-1251
Noora-Maria Suhonen, Ilona Hallikainen, Tuomo Hänninen, Jari Jokelainen, Johanna Krüger, Anette Hall, Maria Pikkarainen, Hilkka Soininen, Anne M. Remes
The Modified Frontal Behavioral Inventory (FBI-mod) for Patients with Frontotemporal Lobar Degeneration, Alzheimer’s Disease, and Mild Cognitive Impairment
Abstract: While behavioral symptoms are both early and prevalent features of behavioral variant frontotemporal dementia (bvFTD), they can be present in other types of dementia as well, including Alzheimer’s disease (AD) and even mild cognitive impairment (MCI). The Frontal Behavioral Inventory (FBI) was specifically developed to capture the behavioral and personality changes in bvFTD; it has also been modified into a self-administered caregiver questionnaire (FBI-mod). We examined the utility of the FBI-mod in differentiating bvFTD (n=26), primary progressive aphasia (PPA) (n=7), AD (n=53), and MCI (n=50) patients, and investigated how the FBI-mod may be associated with neuropsychological measures. The bvFTD patients scored significantly higher as compared to all other patient groups on the FBI-mod Total (p < 0.005), Negative (p < 0.005), and Positive (p < 0.01) scores. The cut-off point for the FBI-mod Total score that best discriminated the bvFTD and AD patients in our sample was 16, thus substantially lower than reported for the original FBI. For the bvFTD group, only mild correlations emerged between the FBI-mod and the cognitive measures. However, significant correlations between the FBI-mod and depressive symptoms as measured by the BDI-II were found for bvFTD. This suggests that while behavioral symptoms appear independent from cognitive deficits in bvFTD, they may nevertheless be interrelated with depressive symptoms. We conclude that the FBI-mod is an easily administered behavioral scale that can aid in differential diagnosis of bvFTD and should be used in clinical practice. The FBI-mod may further be considered as an outcome measure in clinical trials.

Pages 1253-1262
Nagato Kuriyama, Masafumi Ihara, Toshiki Mizuno, Etsuko Ozaki, Daisuke Matsui, Isao Watanabe, Teruhide Koyama, Masaki Kondo, Takahiko Tokuda, Aiko Tamura, Kei Yamada, Kentaro Akazawa, Kazuo Takeda, Akihiro Takada, Shigeto Mizuno, Masanori Nakagawa, Yoshiyuki Watanabe (Handling Associate Editor: Robert Friedland)
Association between Mid-Regional Proadrenomedullin Levels and Progression of Deep White Matter Lesions in the Brain Accompanying Cognitive Decline
Abstract: Background: Adrenomedullin (ADM) is a vasoreactive physiological peptide with anti-inflammatory effects and vasodilative and immunomodulatory actions that is widely distributed throughout the vascular system of the brain. Objective: To investigate mid-regional proADM (MR-proADM), a stable fragment of the ADM precursor, and cerebral deep white matter lesions (DWMLs) in association with cognitive decline. Methods: The study participants were 288 patients (194 men, 94 women) who gave consent to participate in a 5-year longitudinal survey on arteriosclerosis from 2008 to 2013. The Fazekas classification system (Grade [G] 0 [normal] to G3 [severe]) was used for the evaluation of DWMLs on brain magnetic resonance imaging (MRI). In addition, all participants were asked to undergo cognitive function tests regarding word/letter fluency, the results of which were assessed for correlations with MR-proADM levels. Results: MR-proADM levels significantly increased with DWML grade progression. The odds ratio for high MR-proADM levels was 3.08 (95% confidence interval: 1.49–5.17) in the groups graded G3 on brain MRI, suggesting that a high level of MR-proADM is an independent risk factor for DWMLs. A significant inverse correlation was observed between MR-proADM levels and cognitive test scores. MR-proADM levels were significantly increased in the G3 group in 2013 compared with 2008. Conclusion: MR-proADM levels were significantly different between the DWML groups and inversely correlated with cognitive function test scores, suggesting that high MR-proADM levels and DWMLs are associated with cognitive decline. Therefore, the MR-proADM level may be an effective candidate as a potential diagnostic surrogate marker of cognitive decline.

Pages 1263-1269
Chen Hu, Junjie Xu, Linlin Zeng, Ting Li, Mei-Zhen Cui, Xuemin Xu (Handling Associate Editor: Chengxin Gong)
Pen-2 and Presenilin are Sufficient to Catalyze Notch Processing
Abstract: Presenilin-1 (PS1) or presenilin-2 (PS2), nicastrin (NCT), anterior pharynx-defective 1 (Aph-1), and presenilin enhancer-2 (Pen-2) have been considered the minimal essential subunits required to form an active γ-secretase complex. Besides PS, which has been widely believed to function as the catalytic subunit of the complex, the functional roles of the other subunits in the γ-secretase complex remain debatable. In the current study, we set out to determine the role of Pen-2 in γ-secretase activity. To this end, using knockout cells in combination with siRNA and immunoprecipitation approaches, our results revealed that Pen-2 together with presenilin are sufficient to form a functionally active enzyme to process Notch. Specifically, our data demonstrated that Pen-2 plays a crucial role in substrate binding, a mechanism by which Pen-2 contributes directly to the catalytic mechanism of γ-secretase activity. Our data also suggested that there may be different requirements for components to process AβPP and Notch. This information would be important for therapeutic strategy aimed at inhibition or modulation of γ-secretase activity.

Pages 1271-1278
Raffaele Ferrari, Mario Grassi, Francesca Graziano, Fernando Palluzzi, Silvana Archetti, Elisa Bonomi, Amalia C. Bruni, Raffaele G. Maletta, Livia Bernardi, Chiara Cupidi, Rosanna Colao, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Daniela Galimberti, Elio Scarpini, Maria Serpente, Benedetta Nacmias, Irene Piaceri, Silvia Bagnoli, Giacomina Rossi, Giorgio Giaccone, Fabrizio Tagliavini, Luisa Benussi, Giuliano Binettil, Roberta Ghidoni, Andrew Singleton, John Hardy, Parastoo Momeni, Alessandro Padovani, Barbara Borroni (Handling Associate Editor: Estrella Gómez-Tortosa) * These authors equally contributed to this work.
Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia
Abstract: In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95%CI: -4.64 to -3.07, p<2x10-16) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.

Pages 1279-1292
Lucia Buccarello, Giuliano Grignaschi, Anna Maria Castaldo, Alessia Di Giancamillo, Cinzia Domeneghini, Roberto Cosimo Melcangi, Tiziana Borsello
Sex Impact on Tau-Aggregation and Postsynaptic Protein Levels in the P301L Mouse Model of Tauopathy
Abstract: P301L transgenic (tg) mice well mimic features of human tauopathies and provide a good model for investigating the role of tau in neurodegenerative events. We here analyzed the possible interaction among phosphorylation of tau (p-tau), spine injury, neuronal death, and sex in the P301L mouse model of tauopathy. When compared to control mice (ctr), P301L transgenic mice (tg) presented with lower body weight, reduced survival rate, hyperphosphorylated tau, spine injury, and neuronal loss in both cerebral cortex and hippocampus at 15 months of age. Importantly, we found that pathological features were more pronounced in female than male tg mice. Recent reports underlined that tau may be localized within both pre- and post-synaptic compartments, suggesting that it may possibly induce or contribute to synaptic dysfunction. Therefore, we focused our attention on tau localization at dendritic spines. We detected high levels of both tau and p-tau in dendritic spine of P301L transgenic mice. In addition, p-tau correlated with a significant reduction of post-synaptic markers, such as GluN2A, GluN2B, GluA1, GluA2, Drebrin, and PSD-95, in P301L mice. The p-tau levels are higher in female than in male mice, and the increased p-tau was consistent with a proportional decrease in the post-synaptic marker levels analyzed. The P301L-tg females presented with a more severe synaptopathy compared to males. Future investigations on the postsynaptic role of p-tau will be necessary to understand its toxic effects and provide insights into new therapeutic targets for maintaining spine integrity, highlighting the importance of tau toxicity as well as the impact of sex on tau-pathology.

Pages 1293-1299
Jeremy Molad*, Efrat Kliper*, Amos D. Korczyn, Einor Ben Assayag, Dafna Ben Bashat, Shani Shenhar-Tsarfaty, Orna Aizenstein, Ludmila Shopin, Natan M. Bornstein, Eitan Auriel *These authors contributed equally to this work.
Only White Matter Hyperintensities Predicts Post-Stroke Cognitive Performances Among Cerebral Small Vessel Disease Markers: Results from the TABASCO Study
Abstract: Background: White matter hyperintensities (WMH) were shown to predict cognitive decline following stroke or transient ischemic attack (TIA). However, WMH are only one among other radiological markers of cerebral small vessel disease (SVD). Objective: The aim of this study was to determine whether adding other SVD markers to WMH improves prediction of post-stroke cognitive performances. Methods: Consecutive first-ever stroke or TIA patients (n=266) from the Tel Aviv Acute Brain Stroke Cohort (TABASCO) study were enrolled. MRI scans were performed within seven days of stroke onset. We evaluated the relationship between cognitive performances one year following stroke, and previously suggested total SVD burden score including WMH, lacunes, cerebral microbleeds (CMB), and perivascular spaces (PVS). Results: Significant negative associations were found between WMH and cognition (p<0.05). Adding other SVD markers (lacunes, CMB, PVS) to WMH did not improve predication of post-stroke cognitive performances. Negative correlations between SVD burden score and cognitive scores were observed for global cognitive, memory, and visual spatial scores (all p<0.05). However, following an adjustment for confounders, no associations remained significant. Conclusion: WMH score was associated with poor post-stroke cognitive performance. Adding other SVD markers or SVD burden score, however, did not improve prediction.

Pages 1301-1340
Marcello Ienca, Jotterand Fabrice, Bernice Elger, Maurizio Caon, Alessandro Scoccia Pappagallo, Reto W. Kressig, Tenzin Wangmo
Intelligent Assistive Technology for Alzheimer’s Disease and Other Dementias: A Systematic Review
Abstract: Intelligent assistive technologies (IATs) have the potential of offering innovative solutions to mitigate the global burden of dementia and provide new tools for dementia care. While technological opportunities multiply rapidly, clinical applications are rare as the technological potential of IATs remains inadequately translated into dementia care. In this article, the authors present the results of a systematic review and the resulting comprehensive technology index of IATs with application in dementia care. Computer science, engineering, and medical databases were extensively searched and the retrieved items were systematically reviewed. For each IAT, the authors examined their technological type, application, target population, model of development, and evidence of clinical validation. The findings reveal that the IAT spectrum is expanding rapidly in volume and variety over time, and encompasses intelligent systems supporting various assistive tasks and clinical uses. At the same time, the results confirm the persistence of structural limitations to successful adoption including partial lack of clinical validation and insufficient focus on patients’ needs. This index is designed to orient clinicians and relevant stakeholders involved in the implementation and management of dementia care across the current capabilities, applications, and limitations of IATs and to facilitate the translation of medical engineering research into clinical practice. In addition, a discussion of the major methodological challenges and policy implications for the successful and ethically responsible implementation of IAT into dementia care is provided.

Pages 1341-1348
Ki Jung Chang, Chang Hyung Hong, Kang Soo Lee, Dae Ryong Kang, Jeong Dong Lee, Seong Hye Choi, Seong Yoon Kim, Duk L. Na, Sang Won Seo, Do-Kwan Kim, Yunhwan Lee, Young Ki Chung, Ki Young Lim, Jai Sung Noh, Jungsik Park, Sang Joon Son
Mortality Risk after Diagnosis of Early-Onset Alzheimer’s Disease versus Late-Onset Alzheimer’s Disease: A Propensity Score Matching Analysis
Abstract: Background/Objective: We aimed to compare the risk of mortality in patients with early-onset Alzheimer’s disease (EOAD) versus those with late-onset AD (LOAD) using a large number of study subjects. We applied propensity score matching (PSM) to minimize confounding biases in the comparison between EOAD and LOAD. Methods: We obtained data from elderly Korean subjects with AD (n = 3,611) at baseline from the CREDOS cohort study, which was conducted from November 2005 to July 2013. We conducted PSM to reduce the bias due to confounding variables related to survival in patients with AD. The risks of mortality associated with EOAD and LOAD were evaluated by Cox proportional hazard analyses, controlling for relevant covariates. Results: After propensity score matching, 312 subjects with EOAD and 624 subjects with LOAD were selected for further analysis. The Cox proportional hazard analysis showed that patients with EOAD are at a greater risk for mortality compared to those with LOAD (Hazard Ratio: 2.01, 95% CI: 1.01-4.00, p-value: 0.04) when controlling for the direct effect of aging on mortality. The results did not change after adjusting for age at diagnosis, general cognitive function, nutritional factor related to body mass index, and physical disability using activities of daily living. The results support the assumption that EOAD takes a more malignant course than LOAD. Conclusions: Our results provide support for the idea that EOAD takes a clinical course that is distinct from that of LOAD, especially as pertains to the risk of mortality.

Pages 1349-1372
Eeva-Liisa Kallio, Hanna Öhman, Hannu Kautiainen, Marja Hietanen, Kaisu Pitkälä (Handling Associate Editor: Kerryn Pike)
Cognitive Training Interventions for Patients with Alzheimer’s Disease: A Systematic Review
Abstract: Background: Cognitive training (CT) refers to guided cognitive exercises designed to improve specific cognitive functions, as well as enhance performance in untrained cognitive tasks. Positive effects of CT on cognitive functions in healthy elderly people and persons with mild cognitive impairment have been reported, but data regarding the effects of CT in patients with dementia is unclear. Objective: We systematically reviewed the current evidence from randomized controlled trials (RCTs) to find out if CT improves or stabilizes cognition and/or everyday functioning in patients with mild and moderate Alzheimer’s disease. Results: Altogether, 31 RCTs with CT as either the primary intervention or part of a broader cognitive or multi-component intervention were found. A positive effect was reported in 24 trials, mainly on global cognition and training-specific tasks, particularly when more intensive or more specific CT programs were used. Little evidence of improved everyday functioning was found. Conclusions: Despite some positive findings, the inaccurate definitions of CT, inadequate sample sizes, unclear randomization methods, incomplete datasets at follow-up and multiple testing may have inflated the results in many trials. Future high quality RCTs with appropriate classification and specification of cognitive interventions are necessary to confirm CT as an effective treatment option in Alzheimer's disease.

Pages 1373-1384
Andrew C. McKinnon, Shantel L. Duffy, Nathan E. Cross, Zoe Terpening, Ron R. Grunstein, Jim Lagopoulos, Jennifer Batchelor, Ian B. Hickie, Simon J.G. Lewis, James M. Shine*, Sharon L. Naismith* *Joint last authors
Functional Connectivity in the Default Mode Network is Reduced in Association with Nocturnal Awakening in Mild Cognitive Impairment
Abstract: Background: Sleep disturbance is prevalent in MCI, and is a risk factor for cognitive deterioration. Objective: To identify functional connectivity deficits in the default mode network (DMN) in patients with mild cognitive impairment (MCI) and sleep disturbance, relative to MCIs with intact sleep. Methods: Participants comprised 47 adults aged 55 years and over, recruited from the Healthy Brain Ageing Clinic at the Brain and Mind Centre, Sydney, Australia. This sample contained 15 controls and 32 participants meeting criteria for MCI. Participants underwent resting-state fMRI and actigraphy, along with comprehensive neuropsychological, medical and psychiatric assessment. MCIs were split into two groups according to average wake after sleep onset (WASO) per night. WASO equal to or greater than 1 standard deviation (SD) above the control mean was deemed to reflect disturbed sleep. There were 11 patients in the MCI sleep-disturbed group, and 21 in the MCI sleep-intact group. Results: Relative to controls, MCIs demonstrated significant connectivity reductions between parietal and temporoparietal regions, and between temporal regions. Relative to MCIs with intact sleep, MCIs with sleep disturbance demonstrated reductions in functional connectivity between temporal and parietal regions, and between temporal and temporoparietal regions. Conclusions: MCIs with nocturnal awakenings demonstrate reductions in DMN connectivity. These reductions comprise brain regions that are crucially involved in sleep and memory processes. These results strengthen our previous findings, which found reduced connectivity in MCIs with self-reported sleep disturbances. Future studies may build on these findings through incorporating complementary neuroimaging techniques and experimental manipulations of sleep.

Pages 1385-1401
Narjes Baazaoui, Michael Flory, Khalid Iqbal (Handling Associate Editor: Michal Novak)
Synaptic Compensation as a Probable Cause of Prolonged Mild Cognitive Impairment in Alzheimer’s Disease: Implications from a Transgenic Mouse Model of the Disease
Abstract: Alzheimer’s disease (AD) is a slow, progressive neurodegenerative disease in which cognitive decline takes place over a period of several years with a very variable period of mild cognitive impairment (MCI) and, in some cases, relatively long period before progression to dementia. The cognitive deficit during MCI is probably due to neuronal loss, an intermediate level of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT) and synaptosis, which is interrupted with a transient compensatory increase. We found impairment in reference memory accompanied by a decrease in the expression of synaptophysin, β-III tubulin, and MAP2 and a trend for GluR1, at 12 weeks of age in 3xTg-AD mice (hAPPSwe, P301L tau, PS1 [M146V] knock-in), a widely used transgenic model of AD. Past 12 weeks, the cross-sectional analysis of different age groups showed a compensatory increase in synaptic markers relative to that in wild type animals in a topographic and time-dependent manner. When studied across time we found that in 3xTg-AD mice, the compensatory phenomenon occurred in parallel in different regions of the brain. However, this attempt of the brain to repair itself was able to only partially rescue cognitive impairment. These findings for the first time raise the intriguing possibility that AD causing mutated transgenes may initially cause an increase in synaptic and dendritic markers as a compensatory mechanism for synaptic deficit, and this phenomenon, though transient, could be the biological basis of the period of MCI seen in AD.

Pages 1403-1417
Lin Li*, Shaofeng Xu*, Lifei Liu, Rentian Feng, Yongxiang Gong, Xuyang Zhao, Jiang Li, Jie Cai, Nan Feng, Ling Wang, Xiaoliang Wang, Ying Peng (Handling Associate Editor: Lan Zhang) *These authors contributed equally to this work.
Multifunctional Compound AD-35 Improves Cognitive Impairment and Attenuates the Production of TNF-α and IL-1β in an Aβ25-35-induced Rat Model of Alzheimer’s Disease
Abstract: The dyshomeostasis of transition metal ions, accumulation of amyloid-β (Aβ) senile plaques and neuroinflammatory response found in the brain of patients with Alzheimer’s disease (AD) have been suggested to be involved in AD pathogenesis. Novel compounds capable of targeting metal-Aβ species and neuroinflammation would be valuable. AD-35 is such a patented small-molecule compound derived from innovative modification of the chemical structure of donepezil. This compound could moderately inhibit acetylcholinesterase and metal-induced Aβ aggregation in vitro and showed disassembly of Aβ aggregates. The effects of AD-35 on cognitive impairments and neuroinflammatory changes caused by intracerebroventricular injection of Aβ25-35 were studied in rats. Compared to sham group, Aβ25-35 injection significantly led to learning and memory deficits, astrocyte activation, and pro-inflammatory cytokines releases (TNF-α and IL-1β). Further studies indicated that the phosphorylation of extracellular signal-regulated kinase was involved in astrocyte activation and pro-inflammatory cytokines production. Oral administration of AD-35 could markedly attenuate Aβ25-35 injection-induced astrocyte activation, pro-inflammatory cytokines TNF-α and IL-1β release, and memory deficits. On the contrary, donepezil only showed inhibition of IL-1β production, but failed to block astrocyte activation and TNF-α production. These results showed that AD-35 would be a novel multi-mechanism drug for the prevention and/or treatment of AD.

Pages 1419-1428
Eric L. Granholm, Matthew S. Panizzon, Jeremy A. Elman, Amy J. Jak, Richard L. Hauger, Mark W. Bondi, Michael J. Lyons, Carol E. Franz*, William S. Kremen* *Joint senior authors
Pupillary Responses as a Biomarker of Early Risk for Alzheimer’s Disease
Abstract: Task-evoked pupillary responses may be a psychophysiological biomarker of early risk for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Pupil dilation during cognitive tasks reflects cognitive effort until compensatory capacity is surpassed and performance declines are manifest, and reflects activation in the locus coeruleus, where degenerative changes have been found in the earliest stages of AD. We recorded pupillary responses during digit span recall in 918 participants ages 56-66. Despite normal performance, amnestic single-domain MCI (S-MCI) participants showed greater pupil dilation than non-amnestic S-MCI and cognitively normal (CN) participants at lower cognitive loads. Multi-domain MCI (M-MCI) participants failed to modulate effort across cognitive loads and showed poorer performance. Pupillary responses differentiated MCI and CN groups. Amnestic S-MCI participants required compensatory effort to maintain performance, consistent with increased risk for decline. Greater effort in CN individuals might indicate risk for MCI. Results are consistent with dysfunction in locus coeruleus-linked brain systems. This brief task shows promise as a biomarker for early MCI and AD risk prediction.

Pages 1429-1435
Lau Caspar Thygesen, Louise Nørreslet Gimsing, Andrea Bautz, Niels Christian Hvidt, Christoffer Johansen (Handling Associate Editor: Barbara Caracciolo)
Chronic Neurodegenerative Illnesses and Epilepsy in Danish Adventists and Baptists: A Nationwide Cohort Study
Abstract: Background: Limited knowledge of the influence of lifestyle risk factors and religious living on chronic neurological diseases exist. Seventh-day Adventists (SDA) do not consume tobacco, alcohol, or pork, and many adhere to lacto-ovo-vegetarian diet, and Baptists discourage excessive use of alcohol and tobacco. Objective: We investigated whether the incidence of four common chronic neurological illnesses: dementia, Alzheimer’s disease, Parkinson’s disease, and epilepsy in a large cohort of Danish Adventists and Baptists was different compared to the general Danish population. Three of the illnesses are neurodegenerative, whereas epilepsy can occur at any age. Methods: We compared hospital admission rates for some major neurological diseases among members of the Danish Religious Societies Health Study comprising 6,532 SDA and 3,720 Baptists with the general Danish population. Standardized incidence rates (SIR) stratified by sex, age, and calendar time were calculated. Results: SIR of dementia or Alzheimer’s disease was significantly decreased for members of both communities (SDA, 0.78; 95%CI, 0.67-0.90 and Baptists, 0.59; 0.47-0.73). The SIRs of Parkinson’s disease and epilepsy were not significantly different compared to the general population. Conclusions: We observe reduced incidence for dementia or Alzheimer’s disease in a large cohort of members of two religious communities characterized by lifestyle recommendations. More studies are needed to disentangle the interaction between such lifestyle and other components of the religious belief system.

Pages 1437-1449
Maarten Timmers*, Soraia Barão*, Bianca Van Broeck, Ina Tesseur, John Slemmon, Katja De Waepenaert, Jennifer Bogert, Leslie M Shaw, Sebastiaan Engelborghs, Dieder Moechars, Marc Mercken, Luc Van Nueten, Luc Tritsmans, Bart de Strooper, Johannes Rolf Streffer (Handling Associate Editor: Henrik Zetterberg) *These authors contributed equally to this work.
BACE1 Dynamics Upon Inhibition with a BACE Inhibitor and Correlation to Downstream Alzheimer’s Disease Markers in Elderly Healthy Participants
Abstract: The β-site amyloid-β protein precursor (AβPP) cleaving enzyme-1 (BACE1) is the rate limiting enzyme in the generation of amyloid-β peptide (Aβ) from AβPP, one of the major pathways in Alzheimer’s disease (AD) pathology. Increased BACE1 levels and activity have been reported in the brain of patients with sporadic AD. Therefore, changes of BACE1 levels in the cerebrospinal fluid (CSF) have also been investigated as a possible biomarker of the disease. We analyzed BACE1 levels in CSF of elderly healthy participants before and after chronic treatment with a BACE inhibitor (BACEi) and evaluated the correlation between BACE1 levels and downstream AD markers. Overall, BACE1 CSF levels showed strong correlations to all downstream AD markers investigated. This is the first reported finding that shows BACE1 levels in CSF were well correlated to its end product Aβ1-42. As previously described, BACE1 levels were strongly correlated to total-tau and phosphorylated tau levels in CSF. Generally, chronic BACE inhibition did not influence BACE1 CSF protein levels. Follow-up studies including early-stage AD pathophysiology and prodromal AD patients will help to understand the importance of measuring BACE1 routinely in daily clinical practice and AD clinical trials.

Pages 1451-1457
Andrea Stoccoro, Pierpaola Tannorella, Maria Grazia Salluzzo, Raffaele Ferri, Corrado Romano, Benedetta Nacmias, Gabriele Siciliano, Lucia Migliore, Fabio Coppedè
The Methylenetetrahydrofolate Reductase C677T Polymorphism and Risk for Late-Onset Alzheimer’s disease: Further Evidence in an Italian Multicenter Study
Abstract: Background: A functional polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, namely C677T (rs1801133), results in increased Hcy levels and has been associated with risk of late-onset Alzheimer’s disease (LOAD). Many investigators reported association between rs1801133 and LOAD risk in Asian populations and in carriers of the apolipoprotein E (APOE) ε4 allele, but recent meta-analyses suggest a contribution also in other populations, including Caucasians and/or northern Africans. Objective: To further address this issue, we performed a relatively large case-control study, including 581 LOAD patients and 468 matched controls of Italian origin. APOE data were available for a subgroup of almost 600 subjects. Methods: Genotyping for rs1801133 was performed with PCR-RFLP techniques. Results: In the total population, the MTHFR 677T allele (OR = 1.20; 95% CI = 1.01–1.43) and carriers of the MTHFR 677T allele (CT + TT versus CC: OR = 1.34; 95% CI = 1.03–1.73) resulted in increased LOAD risk. Similarly, in APOE ε4 carriers, we observed an increased frequency of MTHFR 677CT carriers (CT versus CC: OR = 2.82; 95% CI = 1.25–6.32). Very interestingly, also in non-APOE ε4 carriers, both MTHFR 677T allele (OR = 1.38; 95% CI = 1.03–1.85) and MTHFR 677TT genotype (OR = 2.08; 95% CI = 1.11–3.90) were associated with LOAD. All these associations survived after corrections for age, gender, and multiple testing. Conclusions: The present results suggest that the MTHFR C677T polymorphism is likely a LOAD risk factor in our cohort, either in APOE ε4 or in non-APOE ε4 carriers.

Pages 1459-1468
Christian-Alexandre Castellano, Nancy Paquet, Isabelle J. Dionne, Hélène Imbeault, Francis Langlois, Etienne Croteau, Sébastien Tremblay, Mélanie Fortier, J. Jacques Matte, Guy Lacombe, Tamàs Fülöp, Christian Bocti, Stephen C. Cunnane (Handling Associate Editor: Steen Hasselbalch)
A 3-Month Aerobic Training Program Improves Brain Energy Metabolism in Mild Alzheimer’s Disease: Preliminary Results from a Neuroimaging Study
Abstract: Background: Aerobic training has some benefits for delaying the onset or progression of Alzheimer’s disease (AD). Little is known about the implication of the brain’s two main fuels, glucose and ketones (acetoacetate), associated with these benefits. Objective: To determine whether aerobic exercise training modifies brain energy metabolism in mild AD. Methods: In this uncontrolled study, ten patients with mild AD participated in a 3-month, individualized, moderate-intensity aerobic training on a treadmill (Walking). Quantitative measurement of brain uptake of glucose (CMRglu) and acetoacetate (CMRacac) using neuroimaging and cognitive testing were done before and after the Walking program. Results: Four men and six women with an average global cognitive score (MMSE) of 26/30 and an average age of 73 y completed the Walking program. Average total distance and treadmill speed were 8 km/week and 4 km/h, respectively. Compared to the Baseline, after Walking, CMRacac was three-fold higher (0.6 ± 0.4 versus 0.2 ± 0.1 µmol/100 g/min; p = 0.01). Plasma acetoacetate concentration and the blood-to-brain acetoacetate influx rate constant were also increased by 2-3-fold (all p ≤ 0.03). CMRglu was unchanged after Walking (28.0 ± 0.1 µmol/100 g/min; p = 0.96). There was a tendency toward improvement in the Stroop–color naming test (-10% completion time, p = 0.06). Performance on the Trail Making A&B tests was also directly related to plasma acetoacetate and CMRacac (all p ≤ 0.01). Conclusion: In mild AD, aerobic training improved brain energy metabolism by increasing ketone uptake and utilization while maintaining brain glucose uptake, and could potentially be associated with some cognitive improvement.

Pages 1469-1484
Yujiao Lu, Yan Dong, Donovan Tucker, Ruimin Wang, Mohammad Ejaz Ahmed, Darrell Brann, Quanguang Zhang
Treadmill Exercise Exerts Neuroprotection and Regulates Microglial Polarization and Oxidative Stress in a Streptozotocin-Induced Rat Model of Sporadic Alzheimer’s Disease
Abstract: Recent work has suggested that exercise may be beneficial in preventing or ameliorating symptoms of several neurological disorders, although the mechanism is not entirely understood. The current study was designed to examine the potential beneficial effect of treadmill exercise upon cognitive function in a streptozotocin (STZ)-induced rat model of Alzheimer’s disease (AD). Animals underwent treadmill exercise (30 min/day, 5 days/week) for 4 weeks after bilateral STZ intracerebroventricular injection (2.4 mg/kg). We demonstrated that treadmill exercise significantly attenuated STZ-induced neurodegeneration in the rat hippocampal CA1 region and strongly preserved hippocampal-dependent cognitive functioning. Further mechanistic investigation displayed a marked suppression of STZ-induced amyloid-β accumulation and tau phosphorylation. Intriguingly, treadmill exercise remarkably inhibited reactive gliosis following STZ insult and effectively shifted activated microglia from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype, which was correlated with a significantly reduced expression of pro-inflammatory mediators and a corresponding enhancement of anti-inflammatory cytokine expression in the hippocampus. Furthermore, treadmill exercise caused a robust suppression of oxidative damage as evidenced by significantly reduced peroxynitrite production, lipid peroxidation, and oxidized DNA damage. Finally, treadmill exercise strongly attenuated STZ-induced mitochondrial dysfunction manifested by a dramatically elevated intra-mitochondrial cytochrome c oxidase activity and ATP synthesis, and markedly inhibited neuronal apoptosis in the hippocampus. These findings demonstrate that treadmill exercise has a multifactorial effect to attenuate many of the pathological processes that play a key role in AD, and provide further support for the beneficial role of exercise as a potential therapeutic option in AD treatment.

Pages 1485-1493
Lei Yu, Robert S. Wilson, Julie A. Schneider, David A. Bennett, Patricia A. Boyle
Financial and Health Literacy Predict Incident Alzheimer’s Disease Dementia and Pathology
Abstract: Background: Domain specific literacy is a multidimensional construct that requires multiple resources including cognitive and non-cognitive factors. Objective: We test the hypothesis that domain specific literacy is associated with Alzheimer’s disease (AD) dementia and AD pathology after controlling for cognition. Methods: Participants were community-based older persons who completed a baseline literacy assessment, underwent annual clinical evaluations for up to 8 years, and agreed to organ donation after death. Financial and health literacy was measured using 32 questions and cognition was measured using 19 tests. Annual diagnosis of AD dementia followed standard criteria. AD pathology was examined postmortem by quantifying plaques and tangles. Cox models examined the association of literacy with incident AD dementia. Performance of model prediction for incident AD dementia was assessed using indices for integrated discrimination improvement and continuous net reclassification improvement. Linear regression models examined the independent association of literacy with AD pathology in autopsied participants. Results: All 805 participants were free of dementia at baseline and 102 (12.7%) developed AD dementia during the follow-up. Lower literacy was associated with higher risk for incident AD dementia (p<0.001), and the association persisted after controlling for cognition (hazard ratio=1.50, p=0.004). The model including the literacy measure had better predictive performance than the one with demographics and cognition only. Lower literacy also was associated with higher burden of AD pathology after controlling for cognition (β=0.07, p=0.035). Conclusion: Literacy predicts incident AD dementia and AD pathology in community-dwelling older persons, and the association is independent of traditional measures of cognition.

Pages 1495-1504
Jianping Jia, Cuibai Wei, Longfei Jia, Yi Tang, Junhua Liang, Aihong Zhou, Fangyu Li, Lu Shi, Rachelle S. Doody
Efficacy and Safety of Donepezil in Chinese Patients with Severe Alzheimer’s Disease: A Randomized Controlled Trial
Abstract: Background: Donepezil has been used worldwide for the treatment of severe Alzheimer’s disease (AD). Whether it is also appropriate for severe AD in Chinese patients remains unknown. Objective: To determine whether donepezil is effective and tolerable for Chinese patients with severe AD. Methods: The present study was a 24-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group study conducted at 38 investigational hospitals in China. Patients with severe AD were enrolled in this trail. Patients were randomly assigned in a 1:1 ratio to receive either donepezil or placebo (5 mg for 6 weeks and10 mg for the remaining 18 weeks). The efficacy for donepezil were evaluated by the SIB, the Clinician’s Interview-Based Impression of Change-Plus caregiver input (CIBIC-plus) and the MMSE. Safety parameters were monitored throughout. Results: A total of 313 patients included the donepezil (n = 157) and the placebo groups (n = 156). Donepezil group improved more in SIB scores (least squares [LS] mean difference: 4.8, 95% CI 1.56 to 8.08, p = 0.004) and CIBIC-plus scores (drug-placebo difference: -0.4, 95% CI -0.66 to 0.03, p = 0.04) than placebo groups at Week 24. The MMSE scores between drug and placebo groups did not differ significantly. Twenty-nine patients with serious adverse events (SAEs) were reported in donepezil (n=11) and placebo groups (n=18) (p = 0.08). Most SAEs were not considered drug-related. Conclusion: Donepezil for 24 weeks was more effective than placebo and showed good safety and tolerability in Chinese patients with severe AD. This study supports utility of the drug in severe stages of AD in the Chinese population.

Pages 1505-1518
Francesca Gelfo, Debora Cutuli, Annalisa Nobili, Paola De Bartolo, Marcello D’Amelio, Laura Petrosini, Carlo Caltagirone (Handling Associate Editor: Sigfrido Scarpa)
Chronic Lithium Treatment in a Rat Model of Basal Forebrain Cholinergic Depletion: Effects on Memory Impairment and Neurodegeneration
Abstract: Alzheimer’s disease (AD) is an age-related neurodegenerative disorder with multifactorial etiopathogenesis, characterized by progressive loss of memory and other cognitive functions. A fundamental neuropathological feature of AD is the early and severe brain cholinergic neurodegeneration. Lithium is a monovalent cation classically utilized in the treatment of mood disorders, but recent evidence also advances a beneficial potentiality of this compound in neurodegeneration. Interestingly, lithium acts on several processes whose alterations characterize the brain cholinergic impairment at short and long term. On this basis, the aim of the present research was to evaluate the potential beneficial effects of a chronic lithium treatment in preventing the damage that a basal forebrain cholinergic neurodegeneration provokes, by investigating memory functions and neurodegeneration correlates. Adult male rats were lesioned by bilateral injections of the immunotoxin 192 IgG-Saporin into the basal forebrain. Starting 7 days before the surgery, the animals were exposed to a 30-day lithium treatment, consisting of a 0.24% Li2CO3 diet. Memory functions were investigated by the open field test with objects, the sociability and preference for social novelty test, and the Morris water maze. Hippocampal and neocortical choline acetyltransferase (ChAT) levels and caspase-3 activity were determined. Cholinergic depletion significantly impaired spatial and social recognition memory, decreased hippocampal and neocortical ChAT levels and increased caspase-3 activity. The chronic lithium treatment significantly rescued memory performances but did not modulate ChAT availability and caspase-3 activity. The present findings support the lithium protective effects against the cognitive impairment that characterizes the brain cholinergic depletion.

Pages 1519-1524
Louis Jacob, Jens Bohlken, Karel Kostev
Prevalence of Use of Cardiovascular Drugs in Dementia Patients Treated in General Practices in Germany
Abstract: Background: Dementia is a chronic disease associated with numerous cardiovascular disorders. Objective: To analyze the prevalence of cardiovascular drug use in dementia patients treated in general practices in Germany. Methods: The present study included patients who were diagnosed with dementia (Alzheimer’s disease, vascular dementia, or unspecified dementia) in 2015. The main outcome measure was the proportion of patients using cardiovascular drugs. Demographical and clinical variables included age, sex, dementia type, and cardiovascular co-diagnoses. A multivariate logistic regression model was used to analyze the association between cardiovascular drug use and these variables. Results: We identified 7,987 and 1,268 dementia patients with and without prescriptions for cardiovascular drugs, respectively. The share of individuals who received cardiovascular treatments was 86.3%. Diuretics (20.9%), beta blocking agents (20.0%), and ACE inhibitors (17.4%) were the three most commonly prescribed types of medications. Patients between the ages of 71-80 (OR=1.59), 81-90 (OR=1.61), and over 90 years (OR=1.48) were more likely to receive cardiovascular drugs than patients under the age of 70 years. Moreover, compared to those with unspecified dementia, individuals with Alzheimer’s disease had a lower chance while those with vascular dementia had a higher chance of being prescribed these drugs (ORs equal to 0.81 and 1.22, respectively). Finally, we found a positive association between the use of cardiovascular drugs and all co-diagnoses (ORs ranging from 1.23 to 7.12). Conclusion: The prevalence of cardiovascular drug use in dementia patients was around 86%. This use was significantly associated with such factors as age, type of dementia, and co-diagnoses.

Pages 1525-1539
Qian Wang*, Wen-Xing Li*, Shao-Xing Dai, Yi-Cheng Guo, Fei-Fei Han, Jun-Juan Zheng, Gong-Hua Li, Jing-Fei Huang *These authors contributed equally to this work.
Meta-Analysis of Parkinson’s Disease and Alzheimer’s Disease Revealed Commonly Impaired Pathways and Dysregulation of NRF2-Dependent Genes
Abstract: Many lines of evidence suggest that Parkinson's disease (PD) and Alzheimer's disease (AD) have common characteristics, such as mitochondrial dysfunction and oxidative stress. As the underlying molecular mechanisms are unclear, we perform a meta-analysis with 9 microarray datasets of PD studies and 7 of AD studies to explore it. Functional enrichment analysis revealed that PD and AD both showed dysfunction in the synaptic vesicle cycle, GABAergic synapses, phagosomes, oxidative phosphorylation, and TCA cycle pathways, and AD had more enriched genes. Comparing the differentially expressed genes between AD and PD, we identified 54 common genes shared by more than six tissues. Among them, 31 downregulated genes contained the antioxidant response element (ARE) consensus sequence bound by NRF2. NRF2 is a transcription factor, which protects cells against oxidative stress through coordinated upregulation of ARE-driven genes. To our surprise, although NRF2 was upregulated, its target genes were all downregulated. Further exploration found that MAFF was upregulated in all tissues and significantly negatively correlated with the 31 NRF2-dependent genes in diseased conditions. Previous studies have demonstrated over-expressed small MAFs can form homodimers and act as transcriptional repressors. Therefore, MAFF might play an important role in dysfunction of NRF2 regulatory network in PD and AD.