Volume 52, Number 1, 2016

Pages 1-15

Qing Ye, Feng Bai, Zhijun Zhang
Shared Genetic Risk Factors for Late-Life Depression and Alzheimer’s Disease
Abstract: Background: Considerable evidence has been reported for the comorbidity between late-life depression (LLD) and Alzheimer’s disease (AD), both of which are very common in the general elderly population and represent a large burden on the health of the elderly. The pathophysiological mechanisms underlying the link between LLD and AD are poorly understood. Because both LLD and AD can be heritable and are influenced by multiple risk genes, shared genetic risk factors between LLD and AD may exist. Objective: The objective is to review the existing evidence for genetic risk factors that are common to LLD and AD and to outline the biological substrates proposed to mediate this association. Methods: A literature review was performed. Results: Genetic polymorphisms of brain-derived neurotrophic factor, Apolipoprotein E, interleukin 1-beta, and methylenetetrahydrofolate reductase have been demonstrated to confer increased risk to both LLD and AD by studies examining either LLD or AD patients. These results contribute to the understanding of pathophysiological mechanisms that are common to both of these disorders, including deficits in nerve growth factors, inflammatory changes, and dysregulation mechanisms involving lipoprotein and folate. Other conflicting results have also been reviewed, and few studies have investigated the effects of the described polymorphisms on both LLD and AD. Conclusion: The findings suggest that common genetic pathways may underlie LLD and AD comorbidity. Studies to evaluate the genetic relationship between LLD and AD may provide insights into the molecular mechanisms that trigger disease progression as the population ages.

Pages 17-24
Ethics Review

Jennifer H. Lingler, Meryl A. Butters, Amanda L. Gentry, Lu Hu, Amanda E. Hunsaker, William E. Klunk, Meghan K. Mattos, Lisa A. Parker, J. Scott Roberts, Richard Schulz (Handling Associate Editor: Allyson Rosen)
Development of a Standardized Approach to Disclosing Amyloid Imaging Research Results in Mild Cognitive Impairment
Abstract: The increased use of PET amyloid imaging in clinical research has sparked numerous concerns about whether and how to return such research test results to study participants. Chief among these is the question of how best to disclose amyloid imaging research results to individuals who have cognitive symptoms that could impede comprehension of the information conveyed. We systematically developed and evaluated informational materials for use in pre-test counseling and post-test disclosures of amyloid imaging research results in mild cognitive impairment (MCI). Using simulated sessions, persons with MCI and their family care partners (N=10 dyads) received fictitious but realistic information regarding brain amyloid status, followed by an explanation of how results impact Alzheimer’s disease risk. Satisfaction surveys, comprehension assessments, and focus group data were analyzed to evaluate the materials developed. The majority of persons with MCI and their care partners comprehended and were highly satisfied with the information presented. Focus group data reinforced findings of high satisfaction and included 6 recommendations for practice: 1) offer pre-test counseling, 2) use clear graphics, 3) review participants’ own brain images during disclosures, 4) offer take-home materials, 5) call participants post-disclosure to address emerging questions, and 6) communicate seamlessly with primary care providers. Further analysis of focus group data revealed that participants understood the limitations of amyloid imaging, but nevertheless viewed the prospect of learning one’s amyloid status as valuable and empowering.

Pages 25-31
Short Communication

Estrella Gómez-Tortosa, Cristina Prieto-Jurczynska, Soledad Serrano, Emilio Franco-Macías, Laura Olivié, Jesús Gallego, Rosa Guerrero-López, María José Trujillo-Tiebas, Carmen Ayuso, Pedro García Ruiz, Julián Pérez-Pérez, María José Sainz (Handling Associate Editor: Teodoro del Ser)
Diversity of Cognitive Phenotypes associated with C9ORF72 Hexanucleotide Expansion
Abstract: For diagnostic purposes, we screened for the C9ORF72 mutation in a) 162 FTLD cases, and b) 145 cases with other diagnoses but with some frontotemporal features or manifestations previously reported in C9 carriers. Ten cases (onset 50 to 75 years) harbored the expansion: seven had FTLD syndromes (4.3% of total, 11% of familial cases), and three (2%) had a different diagnosis. All positive cases had family history of dementia, psychiatric disease, or ALS, but only 20% of families with mixed FTLD/ALS phenotypes carried the expansion. Language impairment was the most common symptom, followed by behavioral changes, memory deficits, and parkinsonism. C9ORF72 mutation has a low frequency in our dementia series and very diverse clinical manifestations.

Pages 33-42
Chelsea Sanders, Stephanie Behrens, Sarah Schwartzb, Heidi Wengreen, Chris D. Corcoran, Constantine G. Lyketsos, JoAnn T. Tschanz (Handling Associate Editor: M. Cristina Polidori)
Nutritional Status is associated with Faster Cognitive Decline and Worse Functional Impairment in the Progression of Dementia: The Cache County Dementia Progression Study
Abstract: Nutritional status may be a modifiable factor in the progression of dementia. We examined the association of nutritional status and rate of cognitive and functional decline in a U.S. population-based sample. Study design was an observational longitudinal study with annual follow-ups up to 6 years of 292 persons with dementia (72% Alzheimer’s disease, 56% female) in Cache County, UT using the Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-sb), and modified Mini Nutritional Assessment (mMNA). mMNA scores declined by approximately 0.50 points/year, suggesting increasing risk for malnutrition. Lower mMNA score predicted faster rate of decline on the MMSE at earlier follow-up times, but slower decline at later follow-up times, whereas higher mMNA scores had the opposite pattern (mMNA by time β = 0.22, p = 0.017; mMNA by time2 β = -0.04, p = 0.04). Lower mMNA score was associated with greater impairment on the CDR-sb over the course of dementia (β = 0.35, p < 0.001). Assessment of malnutrition may be useful in predicting rates of progression in dementia and may provide a target for clinical intervention.

Pages 43-50
Chen-Chen Tan*, Yu Wan*, Meng-Shan Tan, Wei Zhang, Zi-Xuan Wang, Fu-Rong Sun, Dan Miao, Lan Tan, Jin-Tai Yu (Handling Associate Editor: Daniela Galimberti) *These authors contributed equally to this work.
Association of Frontotemporal Dementia GWAS Loci with Late-Onset Alzheimer’s Disease in a Northern Han Chinese Population
Abstract: Background: Both Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are a class of neurodegenerative diseases. Strong similarities in cerebrospinal fluid biomarker, imaging markers, and disease progression profiles suggest that some or most of the pathophysiology is shared between AD and FTD. A recent large genome-wide association study reported several single nucleotide polymorphisms (SNPs) at the RAB38, RAB38/CTSC, HLA-DRA/HLA-DRB5, and BTNL2 in association with FTD. Objective: To explore whether these SNPs are associated with AD risk. Methods: We conducted a case-control study to investigate the association of FTD-associated loci in 2338 Han Chinese subjects. Results: We observed significant differences in genotype distributions of rs302668 (pc=0.025), rs9268877 (pc=0.025), rs9268856 (p<0.001), and rs1980493 (pc=0.045) between cases and controls. The SNPs rs16913634 for RAB38/CTSC was unrelated to LOAD risk (p=0.088). Conclusion: The SNPs rs302668 in RAB38, rs9268877 and rs9268856 polymorphism in HLA-DRA/HLA-DRB5, and rs1980493 polymorphism in BTNL2 might play a role in the susceptibility to late-onset AD in the Han Chinese population.

Pages 51-64
Natalia Lelental, Sebastian Brandner, Olga Kofanova, Kaj Blennow, Henrik Zetterberg, Ulf Andreasson, Sebastiaan Engelborghs, Barbara Mroczko, Tomasz Gabryelewicz, Charlotte Teunisse, Brit Mollenhauer, Lucilla Parnetti, Davide Chiasserini, Jose Luis Molinuevo, Armand Perret-Liaudet, Marcel M. Verbeek, Niels Andreasen, Frederic Brosseron, Justyna M.C. Bahl, Sanna-Kaisa Herukka, Lucrezia Hausner, Lutz Frölich, Anne Labonte, Judes Poirier, Anne-Marie Miller, Norbert Zilka, Branislav Kovacech, Andrea Urbani, Silvia Suardi, Catarina Oliveira, Ines Baldeiras, Bruno Dubois, Uros Rot, Sylvain Lehmann, Anders Skinningsrud, Fay Betsou, Jens Wiltfang, Olymbia Gkatzima, Bengt Winblad, Michael Buchfelder, Johannes Kornhuber, Piotr Lewczuk (Handling Associate Editor: Daniela Galimberti)
Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics
Abstract: Background: Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples. Objective: To prepare and test alternative matrices for QC samples that could facilitate intra- and inter-laboratory QC of the NDD biomarkers. Methods: Three matrices were validated in this study: (A) human pooled CSF, (B) Aβ peptides spiked into human prediluted plasma, and (C) Aβ peptides spiked into solution of bovine serum albumin in phosphate-buffered saline. All matrices were tested also after supplementation with an antibacterial agent (sodium azide). We analyzed short- and long-term stability of the biomarkers with ELISA and chemiluminescence (Fujirebio Europe, MSD, IBL International), and performed an inter-laboratory variability study. Results: NDD biomarkers turned out to be stable in almost all samples stored at the tested conditions for up to 14 days as well as in samples stored deep-frozen (at -80°C) for up to one year. Sodium azide did not influence biomarker stability. Inter-center variability of the samples sent at room temperature (pooled CSF, freeze-dried CSF, and four artificial matrices) was comparable to the results obtained on deep-frozen samples in other large-scale projects. Conclusion: Our results suggest that it is possible to replace self-made, CSF-based QC samples with large-scale volumes of QC materials prepared with artificial peptides and matrices. This would greatly facilitate intra- and inter-laboratory QC schedules for NDD measurements.

Pages 65-75
Agostino Palmeri, Leonardo Mammana, Maria Rosaria Tropea, Walter Gulisano, Daniela Puzzo (Handling Associate Editor: Ottavio Arancio)
Salidroside, a Bioactive Compound of Rhodiola Rosea, Ameliorates Memory and Emotional Behavior in Adult Mice
Abstract: Rhodiola Rosea (R. Rosea) is a plant used in traditional popular medicine to enhance cognition and physical performance. R. Rosea medicinal properties have been related to its capability to act as an adaptogen, i.e., a substance able to increase the organism’s resistance to a variety of chemical, biological, and physical stressors in a non-specific way. These adaptogen properties have been mainly attributed to the glycoside salidroside, one of the bioactive compounds present in the standardized extracts of R. Rosea. Here, we aimed to investigate whether a single dose of salidroside is able to affect memory and emotional behavior in wild type adult mice. We performed fear conditioning to assess cued and contextual memory, elevated plus maze and open field to evaluate anxiety, and tail suspension test to evaluate depression. Our results showed that a single i.p. administration of salidroside was able to enhance fear memory and exerted an anxiolytic and antidepressant effect. These data confirmed the adaptogenic effect of R. Rosea bioactive compounds in animal models and suggest that salidroside might represent an interesting pharmacological tool to ameliorate cognition and counteract mood disorders.

Pages 77-90
Samantha L. Allison, Anne M. Fagan, John C. Morris, Denise Head
Spatial Navigation in Preclinical Alzheimer’s Disease
Abstract: Although several previous studies have demonstrated navigational deficits in early-stage symptomatic Alzheimer’s disease (AD), navigational abilities in preclinical AD have not been examined. The present investigation examined the effects of preclinical AD and early-stage symptomatic AD on spatial navigation performance. Performance on tasks of wayfinding and route learning in a virtual reality environment were examined. Comparisons were made across the following three groups: clinically normal without preclinical AD (n=42), clinically normal with preclinical AD (n=13), and early-stage symptomatic AD (n=16) groups. Preclinical AD was defined based on cerebrospinal fluid Aβ42 levels below 500 pg/ml. Preclinical AD was associated with deficits in the use of a wayfinding strategy, but not a route learning strategy. Moreover, post-hoc analyses indicated that wayfinding performance had moderate sensitivity and specificity. Results also confirmed early-stage symptomatic AD-related deficits in the use of both wayfinding and route learning strategies. The results of this study suggest that aspects of spatial navigation may be particularly sensitive at detecting the earliest cognitive deficits of AD.

Pages 91-99
Bora Yoon, Dong-Won Yang, Yun Jeong Hong, Seong Hye Choi, Sun Ah Park, Hee-Kyung Park, Yong-Duk Kim, Yong S. Shim (Handling Associate Editor: Sang Won Seo)
Differences in Depressive Patterns According to Disease Severity in Early-Onset Alzheimer’s Disease
Abstract: Background: Depression frequently combines with dementia, including early-onset Alzheimer’s disease (EOAD). Objective: We investigated differences in prevalence and characteristics of depressive symptoms according to dementia severity in EOAD patients. Methods: The 15-item Korean version of the Geriatric Depression Scale (GDS-15) was administered to 412 EOAD patients. Factor analysis was used to assess GDS-15 factor structure. We subdivided participants into three groups by disease severity, then compared the frequencies and scores of individual GDS-15 items and performed logistic regression analysis to assess associations between depressive symptoms and EOAD stage. Results: Factor analysis yielded three factor categories: 1) “hopelessness and ominousness” (symptoms no. 6, 8, 12, 14, 15); 2) “unhappiness and dissatisfaction” (no. 1, 3, 5, 7, 11); and 3) “monotony and lack of energy” (no. 2, 4, 9, 10, 13). Factor 2 depressive symptoms (no. 1, 5, 11) were less common in moderate EOAD. The risk of Factor 1 symptoms no. 12 (OR, 2.04; 95% CI, 1.19–3.50; p = 0.010) and 14 (OR, 1.84; 95% CI, 1.07–3.16; p = 0.028) was higher in mild than very mild EOAD. The risk of Factor 2 symptoms no. 9 (OR, 2.69; 95% CI, 1.08–6.71; p = 0.033) and 13 (OR, 2.12; 95% CI, 1.02–4.40; p = 0.043) was higher in moderate than mild EOAD. Conclusion: We confirmed that depressive symptoms differ according to EOAD severity. When assessing depressive symptoms related to dementia progression, we recommend focusing on “hopelessness and ominousness” in very mild EOAD and “unhappiness and dissatisfaction” in mild EOAD.

Pages 101-111
Ximeng Zhang, Xiaoying Cai, Xiaolei Shi, Zhenyang Zheng, Aiwu Zhang, Junliang Guo, Yannan Fang
Chronic Obstructive Pulmonary Disease as a Risk Factor for Cognitive Dysfunction: A Meta-Analysis of Current Studies
Abstract: Cognitive dysfunction has been shown to be associated with many risk factors, such as smoking, diabetes, and body mass index. Chronic obstructive pulmonary disease (COPD), a common disease within the elderly population, has also been found to be related to cognitive decline. However, whether COPD is a risk factor of cognitive dysfunction is not well established. The purpose of this meta-analysis is to investigate the role COPD plays in cognitive dysfunction. PubMed, Cochrane library and Web of Science databases were searched. Three cohort studies and eleven cross-sectional studies were found to be eligible. According to our results, COPD patients had a higher risk of cognitive dysfunction than controls (OR [odds ratio]: 1.72; 95% CI, 1.12-2.65; p=0.01). The exacerbation of COPD was strongly correlated with cognitive decline. COPD patients performed worse than controls on the Mini–Mental State Examination test, but the results were not statistically significant (OR: -0.79; 95% CI, [-1.78, 0.19]; p=0.11). Thus, more attention should be given to the occurrence of cognitive decline in COPD patients. The prevention and control of COPD exacerbation are critical.

Pages 113-126
Jingwei Shang, Toru Yamashita, Yun Zhai, Yumiko Nakano, Ryuta Morihara, Yusuke Fukui, Nozomi Hishikawa,Yasuyuki Ohta, Koji Abe
Strong Impact of Chronic Cerebral Hypoperfusion on Neurovascular Unit, Cerebrovascular Remodeling, and Neurovascular Trophic Coupling in Alzheimer’s Disease Model Mouse
Abstract: Although chronic cerebral hypoperfusion (CCH) may affect Alzheimer’s disease (AD) pathogenesis, the mechanism remains elusive. In the present study, we investigated the role of CCH on AD model mice in neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of galantamine. Alzheimer’s disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral hypoperfusion. CCH exacerbated neuronal loss and decrease of α7 subunit of nicotinic acetylcholine receptors (α7-nAChRs) expression in hippocampus and thalamus at 12 months. Meanwhile, CCH greatly induced advanced glycation end products expression, and blood-brain barrier leakage through observing IgG and MMP9 expressions. Furthermore, a significant number of dramatic enlarged cerebral vessels with remodeling, BDNF/TrkB decreased in neurovascular trophic coupling. The present study demonstrated that CCH strongly enhanced primary AD pathology including neurodegeneration, neurovascular unit disruption, cerebrovascular remodeling and neurovascular trophic coupling damage in AD mice, and that galantamine treatment greatly ameliorated such neuropathologic abnormalities.

Pages 127-132
Miia Tiihonen, Heidi Taipale, Antti Tanskanen, Jari Tiihonen, Sirpa Hartikainen (Handling Associate Editor: Diana Wucherer)
Incidence and Duration of Cumulative Bisphosphonate Use among Community-Dwelling Persons with or without Alzheimer’s Disease
Abstract: We studied the incidence and duration of cumulative bisphosphonate use among older Finnish women and men with or without Alzheimer’s disease (AD). The MEDALZ-2005 cohort is a nationwide sample of all persons with clinically diagnosed AD on 31 December 2005 and their age-, gender-, and region of residence-matched control persons without AD. Information on bisphosphonate use by persons with an AD diagnosis and their controls without AD during 2002–2009 was obtained from the prescription register database containing reimbursed medications. A total of 6,041 (11.8%) persons used bisphosphonates during the 8-year follow-up. Bisphosphonates were more commonly used among persons without AD (n = 3121, 12.3%) than among persons with AD (n = 2,920, 11.2%) (p = 0.001). The median duration of bisphosphonate use was 743 days (IQR). Among persons with AD, the median duration of use was 777 days (IQR) and among persons without AD, 701 days (IQR) (p = 0.011). People without AD more often used bisphosphonate combination preparations including vitamin D than did people with AD (p < 0.0001). Bisphosphonate use was more common among people without AD who had comorbidities, asthma/COPD, or rheumatoid arthritis compared with users with AD. Short-term users were more likely to be male, at least 80 years old, and not having AD. Although the incidence of bisphosphonate use was slightly higher among persons without AD, the cumulative duration of bisphosphonate use was longer in persons with AD. Short-term use was associated with male gender, older age, and not having AD.

Pages 133-143
María Eugenia López, Agustín Turrero, Pablo Cuesta, David López-Sanz, Ricardo Bruña, Alberto Marcos, Pedro Gil, Miguel Yus, Ana Barabash, José Antonio Cabranes, Fernando Maestú, Alberto Fernández
Searching for Primary Predictors of Conversion from Mild Cognitive Impairment to Alzheimer’s Disease: A Multivariate Follow-Up Study
Abstract: Recent proposals of diagnostic criteria within the healthy aging-Alzheimer’s disease (AD) continuum stressed the role of biomarker information. More importantly, such information might be critical to predict those mild cognitive impairment (MCI) patients at a higher risk of conversion to AD. Usually, follow-up studies utilize a reduced number of potential markers although the conversion phenomenon may be deemed as multifactorial in essence. In addition, not only biological but also cognitive markers may play an important role. Considering this background, we investigated the role of cognitive reserve, cognitive performance in neuropsychological testing, hippocampal volumes, APOE genotype, and magnetoencephalography power sources to predict the conversion to AD in a sample of 33 MCI patients. MCIs were followed up during a 2-year period and divided into two subgroups according to their outcome: The “stable” MCI group (sMCI, 21 subjects) and the “progressive” MCI group (pMCI, 12 subjects). Baseline multifactorial information was submitted to a hierarchical logistic regression analysis to build a predictive model of conversion to AD. Results indicated that the combination of left hippocampal volume, occipital cortex theta power, and clock drawing copy subtest scores predicted conversion to AD with a 100% of sensitivity and 94.7% of specificity. According to these results it might be suggested that anatomical, cognitive, and neurophysiological markers may be considered as “first order” predictors of progression to AD, while APOE or cognitive reserve proxies might play a more secondary role.

Pages 145-159
Geon-Ho Jahng, Janghoon Oh, Do-Wan Lee, Hyug-Gi Kim, Hak Young Rhee, Wonchul Shin, Jong-Woo Paik, Kyung Mi Lee, Soonchan Park, Bo-Young Choe, Chang-Woo Ryu (Handling Associate Editor: Yu Zhang)
Glutamine and Glutamate Complex, as Measured by Functional Magnetic Resonance Spectroscopy, Alters During Face-Name Association Task in Patients with Mild Cognitive Impairment and Alzheimer’s Disease
Abstract: Background: The metabolite response during a memory task in Alzheimer’s disease (AD) patients is unknown. Objective: To investigate the metabolite changes in subjects with AD, amnestic mild cognitive impairment (aMCI), and cognitively normal (CN) elderly during a memory task using functional magnetic resonance spectroscopy (fMRS). Methods: This study involved 23 young normal controls (YC), 24 CN elderly, 24 aMCI, and 24 mild and probable AD individuals. fMRS data were acquired at the precuneus and posterior cingulate brain regions during a face-name association task. Statistical analyses of quantified metabolites were performed to evaluate differences of the metabolite values between the stimulation conditions and among the four subject groups. Receiver operating curve analysis was performed to evaluate whether the metabolic changes after functional activations can differentiate the subject groups. Results: Glutamine and glutamate complex (Glx) was statistically significantly different between the fixation and repeat conditions in aMCI (p=0.0492) as well as between the fixation and the novel conditions in the AD (p=0.0412) group. The total N-acetylaspartate (tNAA) was statistically significantly different among the four subject groups in the fixation condition (DF=3, F=7.673, p<0.001), the novel condition (DF=3, F=6.945, p<0.001), and the repeat condition (DF=3, F=7.127, p<0.001). tNAA, tCr, and mIns could be used to differentiate CN from aMCI. Furthermore, tNAA, tCr, Glx, and Glu could also differentiate CN from AD, and aMCI from AD. Conclusion: Glx was altered during a stimulation that may be used to evaluate neuronal dysfunction in a demented patient. tNAA and tCr were reduced in patients with AD.

Pages 161-169
Benjamin Roeben, Walter Maetzler, Eugeen Vanmechelen, Claudia Schulte, Sebastian Heinzel, Konstantinos Stellos, Jana Godau, Heiko Huber, Kathrin Brockmann, Isabel Wurster, Alexandra Gaenslen, Eva Grüner, Raphael Niebler, Gerhard W. Eschweiler, Daniela Berg and the TREND study team
Association of Plasma Aβ40 Peptides, but not Aβ42, with Coronary Artery Disease and Diabetes Mellitus
Abstract: Background/Objective: Plasma levels of amyloid-beta (Aβ) 1-40 peptide have been proposed to be associated with cardiovascular mortality in patients with coronary artery disease (CAD). Therefore, we aimed to investigate the association of plasma Aβ levels with CAD, cardiovascular risk factors (CVRF), and APOE genotype in non-demented elderly individuals. Methods: Plasma Aβ1-40 and Aβ1-42 levels of 526 individuals (mean age of 63.0 ± 7.3 years) were quantified with the INNO-BIA plasma Aβ forms assay based on multiplex™ technique. APOE genotype was determined with an established protocol. Presence of CAD and CVRFs were ascertained using a questionnaire and/or medical records. Results: Plasma Aβ1-40 levels were significantly higher in individuals with CAD (p = 0.043) and, independently, in individuals with diabetes mellitus (DM) type 2 (p = 0.001) while accounting for age- and gender-effects. Plasma Aβ1-42 levels were higher in APOE ε4 carriers (p = 0.004), but were neither relevantly associated with CAD nor with any CVRF. Plasma Aβ1-40 showed no association with APOE genotype. Discussion: Our findings argue for an association of circulating plasma Aβ1-40 peptides with incident CAD and DM. Further investigations are needed to entangle the role of Aβ1-40 role in the pathophysiology of cardiovascular disease independent of its known role in Alzheimer’s disease.

Pages 171-178
Li Xiong, Sigurros Davidsdottir, Yael D. Reijmer, Ashkan Shoamanesh, Duangnapa Roongpiboonsopit, Sekh Thanprasertsuk, Sergi Martinez-Ramirez, Andreas Charidimou, Alison M. Ayres, Panagiotis Fotiadis, Edip Gurol, Deborah L. Blacker, Steven M. Greenberg, Anand Viswanathan
Cognitive Profile and its Association with Neuroimaging Markers of Non-Demented Cerebral Amyloid Angiopathy Patients in a Stroke Unit
Abstract: Background: Cerebral amyloid angiopathy (CAA) is increasingly recognized as a cause of cognitive impairment in the elderly, but the cognitive profile in patients with the disease has not been well characterized. Objective: To characterize the neuropsychological profile of CAA patients without dementia and to determine the association between cognitive performance in different domains and neuroimaging lesions characteristic of CAA. Methods: Fifty-eight non-demented CAA patients were compared to 138 cognitively normal subjects using a standard neuropsychological test battery. Total brain volume (TBV), white matter hyperintensities, number of lobar cerebral microbleeds, hippocampal volume, and cortical superficial siderosis in all CAA patients were assessed. The association between these neuroimaging markers and neuropsychological performance in different cognitive domains in the CAA group were analyzed. Results: Patients with CAA had significantly worse performance on all individual neuropsychological domains tested, when compared to the cognitive normal group. The cognitive decline of CAA patients was most noticeable in tests for processing speed with a Z score of -1.92±1.56 (mean±SD), then followed by executive function (-0.93±1.01), episodic memory (-0.87±1.29), semantic fluency (-0.73±1.06), and attention (-0.42±0.98). TBV of the CAA patients was correlated with processing speed (β=0.335, p=0.03) and executive function (β=0.394, p=0.01). Conclusions: Non-demented patients with CAA had cognitive deficits in multiple areas. Lower TBV was related to slower processing speed and worse executive function.

Pages 179-190
Hui-Fu Wang, Yu Wan, Xiao-Ke Hao, Lei Cao, Xi-Chen Zhu, Teng Jiang, Meng-Shan Tan, Lin Tan, Dao-Qiang Zhang, Lan Tan, Jin-Tai Yu, Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Daniela Galimberti)
Bridging Integrator 1 (BIN1) Genotypes Mediate Alzheimer’s Disease Risk by Altering Neuronal Degeneration
Abstract: Background: Bridging integrator 1 (BIN1) has been identified as one of the most associated loci for Alzheimer’s disease (AD), and recently was reported to modulate tau pathology to mediate AD in vitro. However, the effects of BIN1 on the AD related biomarkers in AD continuum were not specifically assessed. Objective: We explored the effects of BIN1 loci on AD specific biomarkers (CSF proteins, brain structures, glucose and amyloid-β (Aβ) metabolisms) to investigate the role BIN1 in AD pathogenesis. Methods: We calculated the associations of BIN1 loci with these markers at baseline and follow-up in multiple linear models in 812 ADNI subjects. Results: BIN1 loci were significantly associated with the levels of T-tau (rs744373: pc=0.047, rs13031703: pc=0.042) and P-tau (rs744373: pc=0.044, rs13031703: pc=0.019), but not with Aβ in CSF test. BIN1 genotypes were strongly related to atrophy of hippocampus (rs7561528: pc=0.011), CA1 (rs1469980: pc=0.029) and parahippocampus (rs72838284, pc=0.017) on MRI, and to glucose metabolism on FDG-PET, but not to Aβ deposition on AV45-PET imaging. Furthermore, haplotype and subgroup analysis confirmed these significant findings. In addition, the loci associated with these markers were also identified to influence the risk for AD in the meta-analysis of 74 046 European individuals. Conclusion: This study supported that BIN1 contributes to the risk of AD by altering neural degeneration (abnormal tau, brain atrophy and glucose metabolism) but not Aβ pathology.

Pages 191-203
Brian Downer, Sreenivas P. Veeranki, Rebeca Wong (Handling Associate Editor: Kaarin Anstey)
A Late Life Risk Index for Severe Cognitive Impairment in Mexico
Abstract: Background: Several dementia risk indices have been developed for older adults in high-income countries. However, no index has been developed for populations in low- or middle-income countries. Objective: To create a risk index for predicting severe cognitive impairment among adults aged ≥60 in Mexico and to compare the accuracy of this index to the Dementia Screening Indicator (DSI). Methods: This study included 3,002 participants from the Mexican Health and Aging Study (MHAS) interviewed in 2001 and 2012. The MHAS risk index included sociodemographic, health, and functional characteristics collected in 2001. A point value based on the beta coefficients from a multivariable logistic regression model was assigned to each risk factor and the total score was calculated. Results: The MHAS risk index (AUC=0.74 95% CI=0.70-0.77) and DSI (AUC=0.72 95% CI=0.69-0.77) had similar accuracy for discriminating between participants who developed severe cognitive impairment from those who did not. A score of ≥16 on the MHAS risk index had a sensitivity of 0.69 (95% CI=0.64-0.70) and specificity of 0.67 (95% CI=0.66-0.69). A score of ≥23 on the DSI had a sensitivity of 0.56 (95% CI=0.50-0.63) and specificity of 0.78 (95% CI=0.76-0.79). Discussion: The MHAS risk index and DSI have moderate accuracy for predicting severe cognitive impairment among older adults in Mexico. This provides evidence that existing dementia risk indices may be applicable in low- and middle-income countries such as Mexico. Future research should seek to identify additional risk factors that can improve the accuracy of the MHAS risk index.

Pages 205-211
Mami Takemoto, Kota Sato, Noriko Hatanaka, Toru Yamashita, Yasuyuki Ohta, Nozomi Hishikawa, Koji Abe
Different Clinical and Neuroimaging Characteristics in Early Stage Parkinson’s Disease with Dementia and Dementia with Lewy Bodies
Abstract: Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) both commonly exhibit brain Lewy body pathology and similar end-stage symptoms, but early symptoms differ. To clarify these differences, we compared the demographic characteristics, symptoms, cognitive and affective functioning, activities of daily life, and neuroimaging results between PDD (n = 52) and DLB (n = 46) patients. In measures of cognitive functioning, PDD patients had worse Hasegawa dementia scale-revised (HDS-R) scores (11.2 ± 4.8) and better frontal assessment battery (FAB) scores (11.3 ± 4.1) compared with DLB (17.0 ± 6.4, p = 0.013 and 8.6 ± 4.7, p = 0.039, respectively). DLB patients performed worse than PDD patients in “orientation to place” tasks. In affective functions, DLB patients had worse GDS (7.6 ± 3.4) and ABS (9.9 ± 5.3) scores than PDD patients (5.1 ± 4.1 and 4.8 ± 3.0, respectively). 99mTc-ECD images showed greater CBF in the whole cingulate gyrus and a lower CBF in the precuneus area in DLB than in PDD. These results suggest that PDD patients’ lower average scores for “repetition” (MMSE), “recent memory” (HDS-R), and “lexical fluency” (FAB) were related to lower CBF in the cingulate gyrus than in DLB. Furthermore, DLB patients’ poorer average subscale scores of “orientation to place” (MMSE) and “similarities”, “conflicting instructions”, and “go-no go” (FAB) tasks may be related to the lower CBF in the precuneus area in DLB than PDD.

Pages 213-222
Clément Pimouguet, Debora Rizzuto, Johan Fastbom, Mårten Lagergren, Laura Fratiglioni, Weili Xu
Influence of Incipient Dementia on Hospitalization for Primary Care Sensitive Conditions: A Population-Based Cohort Study
Abstract: Background: Studies have reported that moderate/severe stages of dementia are linked to increased hospitalization rates, but little is known about the influence of incipient dementia on hospitalizations for primary care sensitive conditions (PCSCs). Objective: To examine the associations between incipient dementia and hospitalization outcomes, including all-cause and PCSC hospitalization. Methods: A total of 2,268 dementia-free participants in the Swedish National study on Aging and Care-Kungsholmen were interviewed and clinically examined at baseline. Participants aged ≥78 years were followed for 3 years, and those aged 60-72 years, for 6 years. Number of hospitalizations was retrieved from the National Patient Register. Dementia was diagnosed in accordance with Diagnostic and Statistical Manual of Mental Disorders-IV criteria. Hospitalization outcomes were compared in participants who did and did not develop dementia. Zero-inflated Poisson regressions and logistic regressions were used in data analysis. Results: During the follow-up, 175 participants developed dementia. The unadjusted PCSC admission rate was 88.2 per 1000 person-years in those who developed dementia and 25.6 per 1000 person-years in those who did not. In the fully adjusted logistic regression model, incipient dementia was associated with an increased risk of hospitalization for PCSCs (OR=2.3, 95% CI 1.3−3.9) but not with the number of hospitalizations or with all-cause hospitalization. Risks for hospitalization for diabetes, congestive heart failure, and pyelonephritis were higher in those who developed dementia than those who did not. About 10% participants had a PCSC hospitalization attributable to incipient dementia. Conclusion: People with incipient dementia are more prone to hospitalization for PCSCs but not to all-cause hospitalization.

Pages 223-242
Patricia R. Spilman*, Veronique Corset*, Olivia Gorostiza, Karen S. Poksay, Veronica Galvan, Junli Zhang, Rammohan Rao, Clare Peters-Libeu, Jon Vincelette, Andrew McGeehan, Melita Dvorak-Ewell, Janine Beyer, Jesus Campagna, Krystof Bankiewicz, Patrick Mehlen, Varghese John**, Dale E. Bredesen** *These two authors contributed equally to this work. **These two authors share senior authorship.
Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer’s Disease
Abstract: Recent studies have shown that inoculation of susceptible mice with amyloid-β (Aβ) peptides accelerates Aβ deposition in the brain, supporting the idea that Aβ may be self-amplifying; however, the exact mechanism is not understood. Here we provide evidence that Aβ may self-amplify, in part, by inhibiting α-secretase ADAM10 (a disintegrin and metalloprotease) cleavage of full-length Aβ precursor protein (FL AβPP) and therefore allow greater β-secretase processing, and that Aβ itself is a substrate for ADAM10. Exposure of primary neuronal cultures from PDAβPP mice to exogenous rat Aβ1-40 resulted in increased de novo human Aβ1-42 production and exposure of cells to Aβ decreased production of ADAM10 cleavage product soluble AβPPα (sAβPPα). In a cell-free assay, Aβ decreased ADAM10 cleavage of the chimeric substrate MBP-AβPPC125 and Aβ itself was apparently cleaved by the enzyme. The axonal guidance and trophic factor netrin-1, however, reduced the Aβ1-40-induced Aβ1-42 increase, increased sAβPPα, and reversed the Aβ-induced sAβPPα decrease in vitro. In vivo, induction of netrin-1 expression in PDAβPPSwe/Ind transgenic mice resulted in reductions in both Aβ1-42 and Aβ1-40, and ICV delivery of netrin-1 to PDAβPPSwe/Ind mice increased sAβPPα, decreased Aβ, and improved working memory. Finally, to support further study of netrin-1’s potential as a therapeutic for Alzheimer’s disease, pilot gene therapy studies were performed and a netrin mimetic peptide synthesized and tested that, like netrin, can increase sAβPPα and decrease Aβ1-42 in vitro. Taken together, these data provide mechanistic insights into Aβ self-amplification and the ability of netrin-1 to disrupt it.

Pages 243-269
Miguel Ángel Ontiveros-Torres, María Luisa Labra-Barrios, Sofía Díaz-Cintra, Azucena Vázquez-Aguilar, Samadhi Moreno-Campuzano, Paola Flores-Rodríguez, Claudia Luna-Herrera, Raúl Mena, George Perry, Benjamín Florán-Garduño, José Luna-Muñoz, Juan Pedro Luna-Arias (Handling Editor: Jesus Avila)
Fibrillar Amyloid-β Accumulation Triggers an Inflammatory Mechanism Leading to Hyperphosphorylation of the Carboxyl-Terminal End of Tau Polypeptide in the Hippocampal Formation of the 3×Tg-AD Transgenic Mouse
Abstract: Alzheimer’s disease (AD) is a degenerative and irreversible disorder whose progressiveness is dependent on age. It is histopathologically characterized by the massive accumulation of insoluble forms of tau and amyloid-β (Aβ) as neurofibrillary tangles and neuritic plaques, respectively. Many studies have documented that these two polypeptides suffer several posttranslational modifications employing postmortem tissue sections from brains of patients with AD. In order to elucidate the molecular mechanisms underlying the posttranslational modifications of key players in this disease, including Aβ and tau, several transgenic mouse models have been developed. One of these models is the 3×Tg-AD transgenic mouse, carrying three transgenes encoding APPSWE, S1M146V, and TauP301L proteins. To further characterize this transgenic mouse, we determined the accumulation of fibrillar Aβ as a function of age in relation to the hyperphosphorylation patterns of TauP301L at both its N- and C-terminus in the hippocampal formation by immunofluorescence and confocal microscopy. Moreover, we searched for the expression of activated protein kinases and mediators of inflammation by western blot of whole protein extracts from hippocampal tissue sections since 3 to 28 months as well. Our results indicate that the presence of fibrillar Aβ deposits correlates with a significant activation of astrocytes and microglia in subiculum and CA1 regions of hippocampus. Accordingly, we also observed a significant increase in the expression of TNF-α associated to neuritic plaques and glial cells. Importantly, there is an overexpression of the stress activated protein kinases SAPK/JNK and Cdk-5 in pyramidal neurons, which might phosphorylate several residues at the C-terminus of TauP301L. Therefore, the accumulation of Aβ oligomers results in an inflammatory environment that upregulates kinases involved in hyperphosphorylation of TauP301L polypeptide.

Pages 271-281
Miguel A. Fernández-Blázquez, Marina Ávila-Villanueva, Fernando Maestú*, Miguel Medina* *These authors contributed equally to this work.
Specific Features of Subjective Cognitive Decline Predict Faster Conversion to Mild Cognitive Impairment
Abstract: Background: Alzheimer’s disease (AD) is a silent disorder that needs the earliest possible intervention in order to reduce its high economic and social impact. It has been recently suggested that subjective cognitive decline (SCD) appears at preclinical stages many years before the onset of AD. Therefore, SCD could become an ideal target for early therapeutic intervention. Objective: The goal of this study was to evaluate the clinical significance of SCD on the conversion from a cognitively healthy stage to a mild cognitive impairment (MCI) in one-year follow-up. Methods: A total of 608 cognitively intact individuals from the Vallecas Project’s cohort, a community-based prospective study to identify early markers of AD, were enrolled in this study. Participants were classified in three groups: i) No Complaints (NCg), ii) Subjects with complaints in one or more cognitive domains (SCDg), and iii) Subjects who, besides complaints, fulfilled the features of SCD Plus proposed by the International Working Group of SCD (SCD-Pg). Results: Individuals were followed up for a mean of 13.1 months (range 10.7-22.4). During this time, 41 volunteers developed MCI (6.7% of total sample). The conversion rate for SCD-Pg (18.9%) was significantly higher than SCDg (5.6%) and NCg (4.9%). Conclusion: Specific features associated with SCD may help to identify individuals at high risk of fast conversion to MCI. These results highlight the importance of a close follow-up of subjects with SCD-P and include them in early intervention programs because of their increased risk for the development of MCI.

Pages 283-293
Nina Gramunt, Gonzalo Sánchez-Benavides, Herman Buschke, Faustino Diéguez-Vide, Jordi Peña-Casanova, Xavier Masramon, Karine Fauria, Juan D. Gispert, José L. Molinuevo
The Memory Binding Test: Development of Two Alternate Forms into Spanish and Catalan
Abstract: Background: The Memory Binding Test (MBT) is emerging as a promising tool for the detection of subtle memory impairment suggestive of Alzheimer’s disease (AD). For such a test to be widely accessed and used, the availability of both alternate forms and language adaptations is required. Objectives: To develop a thorough methodology for obtaining alternate forms (A and B) of the MBT in Spanish and Catalan and to assess their equivalence. Method: According to the original development of the test, frequency was taken as the lexical variable of reference for the Spanish and Catalan adaptations. A crossed design protocol by form and language was used to compare the MBT results in a sample of 290 cognitively normal middle-aged participants. Pairwise Intraclass Correlation Coefficients (ICCs) were calculated among the six possible combinations. Results: The Spanish and Catalan lists of words for the MBT A and B resulting from the adaptation process as well as the original lists in English are presented. ICC indices for the comparisons between forms and languages ranged from 0.56 to 0.82. Conclusion: The MBT A and B in Spanish and Catalan showed similar outcomes and can be considered equivalent. Moreover, the thorough methodology presented here for the transcultural adaptation and equivalence study, could serve as a model for future adaptations of the MBT and other similar tests.

Pages 295-302
Andrew F. Teich, Mikako Sakurai, Mitesh Patel, Cameron Holman, Faisal Saeed, Jole Fiorito, Ottavio Arancio (Handling Associate Editor: Rada Koldamova)
PDE5 Exists in Human Neurons and is a Viable Therapeutic Target for Neurologic Disease
Abstract: Phosphodiesterase 5 (PDE5) is a critical component of the cGMP-PKG axis of cellular signaling in neurons, and inhibition of PDE5 has been shown to be therapeutic in a wide range of neurologic conditions in animal models. However, enthusiasm for PDE5 inhibitors in humans is limited by data suggesting that PDE5 may not exist in human neurons. Here, we first show that past attempts to quantify PDE5 mRNA were flawed due to the use of incorrect primers, and that when correct primers are used, PDE5 mRNA is detectable in human brain tissue. We then show that PDE5 protein exists in human brain by western blot and ELISA. Most importantly, we performed immunohistochemistry and demonstrate that PDE5 is present in human neurons. We hope that this work will trigger a renewed interest in the development of PDE5 inhibitors for neurologic disease.

Pages 303-315
Alba Sánchez, Ana Maseda, M. Pilar Marante-Moar, Carmen de Labra, Laura Lorenzo-López, José Carlos Millán-Calenti
Comparing the Effects of Multisensory Stimulation and Individualized Music Sessions on Elderly People with Severe Dementia: A Randomized Controlled Trial
Abstract: The objective of this study was to compare the effects of a multisensory stimulation environment (MSSE) and individualized music sessions on agitation, emotional and cognitive status, and dementia severity in a sample of institutionalized patients with severe dementia. Twenty-two participants with a diagnosis of severe or very severe dementia were randomly assigned to two groups: MSSE and individualized music sessions. Both groups participated in two 30-min weekly sessions over 16 weeks. Outcomes were agitation (Cohen-Mansfield Agitation Inventory, CMAI), mood (Cornell Scale for Depression in Dementia, CSDD), anxiety (Rating Anxiety in Dementia, RAID), cognitive function (Severe Mini-Mental State Examination, SMMSE), and the overall severity of dementia (Bedford Alzheimer Nursing Severity Scale, BANS-S). They were assessed at baseline (pre-trial), in the middle (mid-trial), at the end of the intervention (post-trial), and 8 weeks after the intervention (follow-up). Patients in the MSSE group showed significant improvement in their RAID and BANS-S scores compared with the individualized music group post- versus pre-trial. With regard to agitation, there was improvement during the intervention in both the MSSE and individualized music groups in the CMAI total score after 16 weeks of intervention, with no significant differences between the groups. The results suggest that MSSE could have better effects on anxiety symptoms and dementia severity in comparison with individualized music sessions in elderly patients with severe dementia.

Pages 317-331
Silke Matura, David Prvulovic, Daniel Hartmann, Monika Scheibe, Beate Sepanski, Marius Butz, Viola Oertel-Knöchel, Christian Knöchel, Tarik Karakaya, Fabian Fußer, Elke Hattingen, Johannes Pantel (Handling Associate Editor: Christina Wierenga)
Age-Related Effects of the Apolipoprotein E Gene on Brain Function
Abstract: The apolipoprotein E (ApoE) ε4 allele is a well-established genetic risk factor for sporadic Alzheimer’s disease. Some evidence suggests a negative role of the ApoE ε4 allele for cognitive performance in late life, while beneficial effects on cognition have been shown in young age. We investigated age-related effects of the ApoE gene on brain function by assessing cognitive performance, as well as functional activation patterns during retrieval of Face-Name pairs in a group of young (n = 50; age 26.4 ± 4.6 years, 25 ε4 carriers) and old (n = 40; age 66.1 ± 7.0 years, 20 ε4 carriers) participants. A cross-sectional factorial design was used to examine the effects of age, ApoE genotype, and their interaction on both cognitive performance and the blood oxygenation level dependent (BOLD) brain response during retrieval of Face-Name pairs. While there were no genotype-related differences in cognitive performance, we found a significant interaction of age and ApoE genotype on task-related activation bilaterally in anterior cingulate gyrus and superior frontal gyrus, as well as left and right insula. Old age was associated with increased activity in ε4 carriers. The increased BOLD response in old ε4 carriers during retrieval could indicate a neurocognitive disadvantage associated with the ε4 allele with increasing age. Furthermore, recruitment of neuronal resources resulted in enhanced memory performance in young ε4 carriers, pointing to a better neurofunctional capacity associated with the ApoE4 genotype in young age.

Pages 333-343
Arturo G. Isla*, Francisco Gabriel Vazquez-Cuevas*, José Fernando Peña-Ortega (Handling Associate Editor: Slavica Krantic) *These authors contributed equally to this work.
Exercise Prevents Amyloid-β-Induced Hippocampal Network Disruption by Inhibiting GSK3β Activation
Abstract: Exercise is becoming a promising therapeutic approach to prevent alterations both in Alzheimer’s disease (AD) patients and in transgenic models of AD. This neuroprotection has been associated with changes in hippocampal structure and function, as well as with the reduction of amyloid-β (Aβ) production and accumulation. However, whether exercise produces lasting changes in hippocampal population activity and renders it resistant to Aβ-induced network dysfunction is still unknown. Thus, we tested whether voluntary exercise changes hippocampal population activity and prevents its alteration in the presence of Aβ, which has been associated to glycogen synthase kinase-3β (GSK3β) activation. We found that the hippocampal population recorded in slices obtained from mice that exercised voluntarily (with free access to a running wheel for 21 days) exhibits higher power and a faster frequency composition than in slices obtained from sedentary animals. Moreover, the hippocampal network of mice that exercised becomes insensitive to Aβ-induced inhibition of spontaneous population activity. This protective effect correlates with the inability of Aβ to activate GSK3β, is mimicked by GSK3β inhibition with SB126763 (in slices obtained from sedentary mice), and is abolished by the inhibition of PI3K with LY294002 (in slices obtained from mice that exercised). We conclude that voluntary exercise produces a lasting protective state in the hippocampus, maintained in hippocampal slices by a PI3K-dependent mechanism that precludes its functional disruption in the presence of Aβ by avoiding GSK3β activation.

Pages 345-357
Akira Homma, Hirotsugu Atarashi, Naoki Kubota, Kenya Nakai, Takao Takase
Efficacy and Safety of Sustained Release Donepezil High Dose versus Immediate Release Donepezil Standard Dose in Japanese Patients with Severe Alzheimer’s Disease: A Randomized, Double-Blind Trial
Abstract: Background: Donepezil is an established treatment for mild, moderate, and severe Alzheimer’s disease (AD). An international study demonstrated superior efficacy of sustained release (SR) 23 mg/day donepezil over immediate release (IR) 10 mg/day donepezil for cognitive function, but not global function in moderate-to-severe AD. Objective: To demonstrate the superiority of SR 23 mg/day donepezil over IR 10 mg/day donepezil in Japanese patients with severe AD (SAD). Methods: In this multicenter, randomized, double-blind, parallel-group study, Japanese outpatients with SAD were randomly assigned to continue IR 10 mg/day or switch to SR 23 mg/day for 24 weeks. Endpoints included the Severe Impairment Battery (SIB), Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus), and safety. Results: Overall, 166 and 185 patients were randomized to receive IR 10 mg/day and SR 23 mg/day, respectively. SR 23 mg/day was not statistically superior to IR 10 mg/day by SIB (least squares mean difference [LSMD]: 0.0; 95% confidence interval [CI]: −1.7, 1.8; p=0.981) or CIBIC-plus (LSMD: 0.2; 95% CI: 0.0, 0.4; p=0.080). Common adverse events in the SR 23 mg group were decreased appetite, vomiting, diarrhea, and contusion. Safety findings were consistent with known safety profiles of donepezil. Conclusion: SR 23 mg/day donepezil was non-superior to IR 10 mg/day donepezil regarding the efficacy endpoints for Japanese SAD. Considering that a 10 mg/day dose is approved for SAD in Japan, the present findings suggest that IR 10 mg/day donepezil is the optimal dosage for Japanese patients with SAD.

Pages 359-371
Antonella Tramutola*, Gilda Pupo*, Fabio Di Domenico, Eugenio Barone, Andrea Arena, Chiara Lanzillotta, Diede Broekaart, Carla Blarzino, Elizabeth Head, D. Allan Butterfield, Marzia Perluigi (Handling Associate Editor: Tommaso Cassano) *These authors contributed equally to this work.
Activation of p53 in Down Syndrome and in the Ts65Dn Mouse Brain is Associated with a Pro-Apoptotic Phenotype
Abstract: Down syndrome (DS) is the most common genetic cause of intellectual disability, resulting from trisomy of chromosome 21. The main feature of DS neuropathology includes early onset of Alzheimer’s disease (AD), with deposition of senile plaques and tangles. We hypothesized that apoptosis may be activated in the presence of AD neuropathology in DS, thus we measured proteins associated with upstream and downstream pathways of p53 in the frontal cortex from DS cases with and without AD pathology and from Ts65Dn mice, at different ages. We observed increased acetylation and phosphorylation of p53, coupled to reduced MDM2/p53 complex level and lower levels of SIRT1. Activation of p53 was associated with a number of targets (BAX, PARP1, caspase-3, p21, heat shock proteins, and PGC1α) that were modulated in both DS and DS/AD compared with age-matched controls. In particular, the most relevant changes (increased p-p53 and acetyl-p53 and reduced formation of MDM2/p53 complex) were found to be modified only in the presence of AD pathology in DS. In addition, a similar pattern of alterations in the p53 pathway was found in Ts65Dn mice. These results suggest that p53 may integrate different signals, which can result in a pro-apoptotic-phenotype contributing to AD neuropathology in people with DS.

Pages 373-383
Kwangsik Nho, Andrew J. Saykin, Alzheimer’s Disease Neuroimaging Initiative, Peter T. Nelson
Hippocampal Sclerosis of Aging, a Common Alzheimer’s Disease ‘Mimic’: Risk Genotypes are Associated with Brain Atrophy Outside the Temporal Lobe
Abstract: Hippocampal sclerosis of aging (HS-Aging) is a common brain disease in older adults with a clinical course that is similar to Alzheimer’s disease. Four single-nucleotide polymorphisms (SNPs) have previously shown association with HS-Aging. The present study investigated structural brain changes associated with these SNPs using surface-based analysis. Participants from the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n=1,239), with both MRI scans and genotype data, were used to assess the association between brain atrophy and previously identified HS-Aging risk SNPs in the following genes: GRN, TMEM106B, ABCC9, and KCNMB2 (minor allele frequency for each is > 30%). A fifth SNP (near the ABCC9 gene) was evaluated in post-hoc analysis. The GRN risk SNP (rs5848_T) was associated with a pattern of atrophy in the dorsomedial frontal lobes bilaterally, remarkable since GRN is a risk factor for frontotemporal dementia. The ABCC9 risk SNP (rs704180_A) was associated with multifocal atrophy whereas a SNP (rs7488080_A) nearby (~50kb upstream) ABCC9 was associated with atrophy in the right entorhinal cortex. Neither TMEM106B (rs1990622_T), KCNMB2 (rs9637454_A), nor any of the non-risk alleles were associated with brain atrophy. When all four previously identified HS-Aging risk SNPs were summed into a polygenic risk score, there was a pattern of associated multifocal brain atrophy in a predominately frontal pattern. We conclude that common SNPs previously linked to HS-Aging pathology were associated with a distinct pattern of anterior cortical atrophy. Genetic variation associated with HS-Aging pathology may represent a non-Alzheimer’s disease contribution to atrophy outside of the hippocampus in older adults.