Volume 60, Number 2, 2017

Pages 335-340
Short Communication

Lucio Tremolizzo, Elisa Bianchi, Emanuela Susani, Elisabetta Pupillo, Paolo Messina, Angelo Aliprandi, Andrea Salmaggi, Maura Cosseddu, Andrea Pilotto, Barbara Borroni, Alessandro Padovani, Cristina Bonomini, Orazio Zanetti, Ildebrando Appollonio, Ettore Beghi, Carlo Ferrarese
Voluptuary Habits and Risk of Frontotemporal Dementia: A Case Control Retrospective Study
Abstract: Alcohol, coffee, and tobacco consumption was assessed on 151 FTD outpatients and 151 matched controls in a multicenter retrospective case-control design. No association was found for smoking and coffee intake. The risk of FTD was decreased by alcohol consumption (adj. OR 0.30, 95% CI 0.14-0.63); risk reduction was significant in current alcohol consumers (adj. OR 0.22, 95% CI 0.10-0.51). The risk of FTD inversely correlated with the duration of exposure (adj. OR 0.88, 95% CI 0.81-0.95, for every 5 years of exposure increase). Retrospective information and the unknown amount of consumed alcohol are limits of the present work.

Pages 341-347
Short Communication

Jun Ku Chung, Eric Plitman, Shinichiro Nakajima, Fernando Caravaggio, Shunichiro Shinagawa, Yusuke Iwata, Philip Gerretsen, Julia Kim, Hiroyoshi Takeuchi, Raihaan Patel, M. Mallar Chakravarty, Antonio Strafella, Ariel Graff-Guerrero, for the Alzheimer’s Disease Neuroimaging Initiative
The Effects of Cortical Hypometabolism and Hippocampal Atrophy on Clinical Trajectories in Mild Cognitive Impairment with Suspected Non-Alzheimer’s Pathology: A Brief Report
Abstract: The clinical and structural trajectories of suspected non-Alzheimer’ pathology (SNAP) remain elusive due to its heterogeneous etiology. Baseline and longitudinal clinical (global cognition, daily functioning, symptoms of dementia, and learning memory) and hippocampal volume trajectories over two years were compared between patients with amnestic mild cognitive impairment (aMCI) with SNAP with reduced hippocampal volumes (SNAP+HIPPO) and aMCI patients with SNAP without reduced hippocampal volumes. SNAP+HIPPO showed overall worse baseline cognitive functions. Longitudinally, SNAP+HIPPO showed faster deterioration of clinical symptoms of dementia. Having both hippocampal atrophy and cortical hypometabolism without amyloid pathology may exacerbate symptoms of dementia in aMCI.

Pages 349-358
Amanda J. Cross, Johnson George, Michael C. Woodward, David Ames, Henry Brodaty, Rory Wolfe, Michael H. Connors, Rohan A. Elliott (Handling Associate Editor: Carmel Hughes)
Potentially Inappropriate Medication, Anticholinergic Burden, and Mortality in People Attending Memory Clinics
Abstract: Background: There is limited evidence regarding the association between potentially inappropriate medications (PIM) and mortality in older people with cognitive impairment. Objective: To examine whether use of medications considered to be potentially inappropriate in older people with cognitive impairment (PIMcog) and anticholinergic cognitive burden (ACB) were associated with mortality in people who attended memory clinics. Methods: Cross-sectional and longitudinal analyses of data from the Prospective Research In MEmory clinics (PRIME) study. Participants were community-dwelling people who attended nine memory clinics and had a diagnosis of mild cognitive impairment or dementia. PIMcog was defined as any medication considered potentially inappropriate for a person with cognitive impairment according to Beers or STOPP criteria. Anticholinergic burden was calculated using the ACB scale. Time-dependent Cox-proportional hazards regression was used to analyze associations between PIMcog use/ACB score and all-cause mortality over a three-year follow-up period. The regression model included the baseline variables: age, gender, education, cognitive diagnoses, total number of medications, disease-burden, cognition, physical function, and neuropsychiatric symptoms. Results: Of 964 participants, 360 (37.3%) used one or more PIMcog at some time during the study; most commonly anticholinergics and sedatives. 624 (64.7%) participants used a medication with potential or definite anticholinergic properties (ACB>0) at some point during the study. Both PIMcog use (adjusted hazard ratio: 1.42 95% CI: 1.12-1.80) and ACB score (adjusted hazard ratio: 1.18 95% CI: 1.06-1.32) were associated with mortality. Conclusion: Use of PIMcogs and medications with anticholinergic properties was common among memory clinic patients and both were associated with mortality.

Pages 359-369
Farheen Rokad, Ryan Moseley, Rowan S. Hardy, Sasanka Chukkapalli, StJohn Crean, Lakshmyya Kesavalu, Sim K. Singhrao
Cerebral Oxidative Stress and Microvasculature Defects in TNF-α Expressing Transgenic and Porphyromonas gingivalis-Infected ApoE-/- Mice
Abstract: The polymicrobial dysbiotic subgingival biofilm microbes associated with periodontal disease appear to contribute to developing pathologies in distal body sites, including the brain. This study examined oxidative stress, in the form of increased protein carbonylation and oxidative protein damage, in the tumor necrosis factor-α (TNF-α) transgenic mouse that models inflammatory TNF-α excess during bacterial infection; and in the apolipoprotein knockout (ApoE-/-) mouse brains, following Porphyromonas gingivalis gingival monoinfection. Following 2,4-dinitrophenylhydrazine derivatization, carbonyl groups were detected in frontal lobe brain tissue lysates by immunoblotting and immunohistochemical analysis of fixed tissue sections from the frontotemporal lobe and the hippocampus. Immunoblot analysis confirmed the presence of variable carbonyl content and oxidative protein damage in all lysates, with TNF-α transgenic blots exhibiting increased protein carbonyl content, with consistently prominent bands at 25 kDa (p = 0.0001), 43 kDa, and 68 kDa, over wild-type mice. Compared to sham-infected ApoE-/- mouse blots, P. gingivalis-infected brain tissue blots demonstrated the greatest detectable protein carbonyl content overall, with numerous prominent bands at 25 kDa (p = 0.001) and 43 kDa (p = 0.0001) and an exclusive band to this group between 30-43 kDa* (p = 0.0001). In addition, marked immunostaining was detected exclusively in the microvasculature in P. gingivalis-infected hippocampal tissue sections, compared to sham-infected, wild-type, and TNF-α transgenic mice. This study revealed that the hippocampal microvascular structure of P. gingivalis-infected ApoE-/- mice possesses elevated oxidative stress levels, resulting in the associated tight junction proteins being susceptible to increased oxidative/proteolytic degradation, leading to a loss of functional integrity.

Pages 371-388
Lixiao Hao, Xiaoni Wang, Ling Zhang, Yue Xing, Qihao Guo, Xiaochen Hu, Bin Mu, Yili Chen, Guanqun Chen, Jing Cao, Xiaodong Zhi, Jiaojiao Liu, Xuanyu Li, Liu Yang, Jiachen Li, Wenying Du, Yu Sun, Ting Wang, Zhen Liu, Zheng Liu, Xuexue Zhao, Hongyan Li, Yang Yu, Xue Wang, Jianguo Jia, Ying Han (Handling Associate Editor: Ling-Qiang Zhu)
Prevalence, Risk Factors, and Complaints Screening Tool Exploration of Subjective Cognitive Decline in a Large Cohort of the Chinese Population
Abstract: Background: Substantial studies have reported the prevalence and the affecting factors of subjective cognitive decline (SCD). The complaints screening scale has also been used for probing. However, little is known in China. Objective: To investigate the prevalence and risk factors of SCD, and explore an SCD complaints screening scale in China. Methods: Stratified cluster random sampling was conducted. 2,689 residents aged 60-80 years completed questionnaire 1. 814 residents were included for clinical and neuropsychological evaluations. Two standards were used to make the diagnosis of mild cognitive impairment (MCI) and SCD, and a preliminary screening rate comparison was carried out. Finally, we assessed the risk factors of SCD and the correlation between the SCD-questionnaire 9 (SCD-Q9) and the Auditory Verbal Learning Test-Long Delay Free Recall (AVLT-LR). Results: 1) Standard 1 (ADNI2): the prevalence of SCD was 18.8% (95%CI=14.7-22.9%) and zero conformed to six criteria (SCD plus). 2) Standard 2 (Jak/Bondi): the prevalence of SCD was 14.4% (95%CI=10.7-18.1%). 3) Standard 1 had a relatively higher “false” positive rate, whereas Standard 2 had higher “false” negative rate. 4) Age, low education, fewer close friends, and daily drinking were independent risk factors for SCD progressing to MCI. 5) Total points of SCD-Q9 were negatively correlated to the value of AVLT-LR. Conclusions: The prevalence of SCD is high in the ShunYi District in Beijing, China. Age, low education, less social support, and daily drinking are independent risk factors. The brief SCD-Q9 can be used as a reference.

Pages 389-400
Jing Tao, Jiao Liu, Weilin Liu, Jia Huang, Xiehua Xue, Xiangli Chen, Jinsong Wu, Guohua Zheng, Bai Chen, Ming Li, Sharon Sun, Kristen Jorgenson, Courtney Lang, Kun Hu, Shanjia Chen, Lidian Chen, Jian Kong
Tai Chi Chuan and Baduanjin Increase Grey Matter Volume in Older Adults: A Brain Imaging Study
Abstract: The aim of this study is to investigate and compare how 12-weeks of Tai Chi Chuan and Baduanjin exercise can modulate brain structure and memory function in older adults. Magnetic resonance imaging and memory function measurements (Wechsler Memory Scale-Chinese revised, WMS-CR) were applied at both the beginning and end of the study. Results showed that both Tai Chi Chuan and Baduanjin could significantly increase grey matter volume (GMV) in the insula, medial temporal lobe, and putamen after 12-weeks of exercise. No significant differences were observed in GMV between the Tai Chi Chuan and Baduanjin groups. We also found that compared to healthy controls, Tai Chi Chuan and Baduanjin significantly improved visual reproduction subscores on the WMS-CR. Baduanjin also improved mental control, recognition, touch, and comprehension memory subscores of the WMS-CR compared to the control group. Memory quotient and visual reproduction subscores were both associated with GMV increases in the putamen and hippocampus. Our results demonstrate the potential of Tai Chi Chuan and Baduanjin exercise for the prevention of memory deficits in older adults.

Pages 401-425
Taro Kishi*, Shinji Matsunaga*, Kazuto Oya, Ikuo Nomura, Toshikazu Ikuta, Nakao Iwata *These authors contributed equally to this work.
Memantine for Alzheimer’s Disease: An Updated Systematic Review and Meta-analysis
Abstract: Background: The clinical benefit of memantine for Alzheimer’s disease (AD) remains inconclusive. Objective: We performed an updated systematic review and meta-analysis of the efficacy/safety of memantine in AD. Methods: We included randomized trials of memantine for AD patients. Cognitive function scores (CF), behavioral disturbances scores (BD), and all-cause discontinuation were used as primary measures. Effect size based on a random-effects model was evaluated in the meta-analyses. Results: Thirty studies (n=7,567; memantine versus placebo: N=11, n=3,298; memantine+cholinesterase inhibitors (M+ChEIs) versus ChEIs: N=17, n=4,175) were identified. Memantine showed a significant improvement in CF [standardized mean difference (SMD)=−0.24, 95% confidence intervals (95%CIs)=−0.34, −0.15, p<0.00001, I2=35%] and BD (SMD=−0.16, 95%CIs=−0.29, −0.04, p=0.01, I2=52%) compared with placebo. In the sensitivity analysis including only patients with moderate−severe AD, memantine was superior to the placebo in reducing BD without considerable heterogeneity (SMD=−0.20, 95%CIs=−0.34, −0.07, p=0.003, I2=36%). Compared with ChEIs, M+ChEIs showed a greater reduction in BD (SMD=−0.20, 95%CIs=−0.36, −0.03, p=0.02, I2=77%) and a trend of CF improvement (SMD=−0.11, 95%CIs=−0.22, 0.01, p=0.06, I2=56%). However, in the sensitivity analysis of double-blind, placebo-controlled studies only, M+ChEIs showed a significant reduction in BD compared with ChEIs without considerable heterogeneity (SMD=−0.11, 95%CIs=−0.21, −0.01, p=0.04, I2=40%). When performing the sensitivity analysis of donepezil studies only, M+ChEIs was superior to ChEIs in improving CF without considerable heterogeneity (SMD=−0.18, 95%CIs=−0.31, −0.05, p=0.006, I2=49%). No differences were detected in all-cause discontinuation between the groups. Conclusions: The meta-analyses suggest the credible efficacy and safety of memantine in treating AD when used alone or in combination with ChEIs.

Pages 427-437
Clara Li, Judith Neugroschl, Xiaodong Luo, Carolyn Zhu, Paul Aisen, Steven Ferris, Mary Sano
The Utility of the Cognitive Function Instrument (CFI) to Detect Cognitive Decline in Non-Demented Older Adults
Abstract: Background: Subjective cognitive complaint is a sensitive marker of decline. Objective: This study aimed to (1) examine reliability of subjective cognitive complaint using the Cognitive Function Instrument (CFI), and (2) assess the utility of the CFI to detect cognitive decline in non-demented elders. Methods: Data from a four-year longitudinal study at multiple Alzheimer’s Disease Cooperative Study (ADCS) sites were extracted (n=644). Of these, 497 had Clinical Dementia Rating (CDR) global scores of 0 and 147 had a CDR of 0.5. Mean age and education were 79.5±3.6 and 15.0±3.1 years, respectively. All participants and their study partners completed the subject and study partner CFI yearly. Modified Mini-Mental State Exam (mMMSE) and Free and Cued Selective Reminding Test (FCSRT) were administered. Scores below the predetermined cut-off scores on either measure at annual visit were triggers for a full diagnostic evaluation. Cognitive decline was defined by the absence/presence of the trigger. Results: Three-month test retest reliability showed that inter-class coefficients for subject and study partner CFI were 0.76 and 0.78, respectively. Generalized estimating equation method revealed that both subject and study partner CFI change scores and scores from previous year were sensitive to cognitive decline in the CDR 0 group (p < 0.05). In the CDR 0.5 group, only the study partner CFI change score predicted cognitive decline (p < 0.05). Conclusion: Cognitive decline was predicted differentially by CDR level with subject CFI scores providing the best prediction for those with CDR 0 while study partner CFI predicted best for those at CDR 0.5.

Pages 439-450
Michael S. Rafii, Ana S. Lukic, Randolph D. Andrews, James Brewer, Robert A. Rissman, Stephen C. Strother, Miles N. Wernick, Craig Pennington, William C. Mobley, Seth Ness, Dawn C. Matthews for the Down Syndrome Biomarker Initiative and the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Sid O'Bryant)
PET Imaging of Tau Pathology and Relationship to Amyloid, Longitudinal MRI, and Cognitive Change in Down Syndrome: Results from the Down Syndrome Biomarker Initiative (DSBI)
Abstract: Background: Adults with Down syndrome (DS) represent an enriched population for the development of Alzheimer’s disease (AD), which could aid the study of therapeutic interventions, and in turn, could benefit from discoveries made in other AD populations. Objectives: 1) Understand the relationship between tau pathology and age, amyloid deposition, neurodegeneration (MRI and FDG PET), and cognitive and functional performance; 2) detect and differentiate AD-specific changes from DS-specific brain changes in longitudinal MRI. Methods: Twelve non-demented adults, ages 30 to 60, with DS were enrolled in the Down Syndrome Biomarker Initiative (DSBI), a 3-year, observational, cohort study to demonstrate the feasibility of conducting AD intervention/prevention trials in adults with DS. We collected imaging data with 18F-AV-1451 tau PET, AV-45 amyloid PET, FDG PET, and volumetric MRI, as well as cognitive and functional measures and additional laboratory measures. Results: All amyloid negative subjects imaged were tau-negative. Among the amyloid positive subjects, three had tau in regions associated with Braak stage VI, two at stage V, and one at stage II. Amyloid and tau burden correlated with age. The MRI analysis produced two distinct volumetric patterns. The first differentiated DS from normal (NL) and AD, did not correlate with age or amyloid, and was longitudinally stable. The second pattern reflected AD-like atrophy and differentiated NL from AD. Tau PET and MRI atrophy correlated with several cognitive and functional measures. Conclusions: Tau accumulation is associated with amyloid positivity and age, as well as with progressive neurodegeneration measurable using FDG and MRI. Tau correlates with cognitive decline, as do AD-specific hypometabolism and atrophy.

Pages 451-460
Inelia Morales, Cristóbal Cerda-Troncoso, Víctor Andrade, Ricardo B. Maccioni
The Natural Product Curcumin as a Potential Coadjuvant in Alzheimer’s Treatment
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a progressive cognitive impairment of patients, affecting around 12% of people older than 65 years old. WHO estimated that over 48.6 million all over the world suffer this disease. On the basis of cumulative results on our research, we have postulated the neuroimmunomodulation hypothesis that appears to provide a reasonable explanation of both the preclinical and clinical observations. In this context, the long-term activation of the innate immune system triggers an anomalous cascade of molecular signals, finally leading to tau oligomerization in the pathway to neuronal degeneration. In the present scenario of the failure of many anti-AD drugs, nutraceutical compounds provide an avenue for AD prevention and possibly as coadjuvants in the treatment of this disease. Recent discoveries point to the relevance of curcumin, a natural anti-inflammatory agent, in controlling oxidative stress and improving cholinergic function in the brain, even though the mechanisms underlying these actions are unknown. We investigated the effects of curcumin in cultures of neuronal cells. For this study, we exposed cells to prooxidant conditions, both in the presence and absence of curcumin. Our data reveal that curcumin exert a strong neuroprotective effect in N2a cells, thus preventing toxicity by oxidative agents H2O2 and Fe+3. This is supported by results that indicate that curcumin control the neurodegenerative effects of both oxidative agents, relieving cells from the loss of neuritogenic processes induced by prooxidants. In addition, curcumin was able to slow down the tau aggregation curve and disassemble tau pathological oligomeric structures. Data suggest that curcumin could be a potential compound for prevention of cognitive disorders associated with AD.

Pages 461-481
Monica Javidnia, Michaeline L. Hebron, Yue Xin, Nikolas G. Kinney, Charbel E-H. Moussa
Pazopanib Reduces Phosphorylated Tau Levels and Alters Astrocytes in a Mouse Model of Tauopathy
Abstract: Hyperphosphorylation and aggregation of tau protein is a critical factor in many neurodegenerative diseases. These diseases are increasing in prevalence, and there are currently no cures. Previous work from our group and others has shown that tyrosine kinase inhibitors (TKIs) can stimulate autophagy, decrease pathological proteins, and improve symptoms in models of neurodegeneration. Here we examined the role of pazopanib in mouse models that express either human mutant P301L tau (TauP301L) or triple mutant amyloid precursor protein (3x-AβPP). The TauP301L mouse expresses P301L tau under the control of a prion promoter in both neurons and astrocytes, reminiscent of some human tauopathies. Pazopanib crosses the blood-brain barrier with no detectable peripheral off-side effects, and decreases p-tau in TauP301L mice. Pazopanib reaches a brain concentration sufficient for inhibition of several tyrosine kinases, including vascular endothelial growth factor receptors (VEGFRs). Further, pazopanib does not affect microglia but reduces astrocyte levels toward nontransgenic controls in TauP301L mice. Pazopanib does not alter amyloid beta levels or astrocytes in 3x-AβPP mice but modulates a number of inflammatory markers (IP-10, MIP-1α, MIP-1β, and RANTES). These data suggest that pazopanib may be involved in p-tau clearance and modulation of astrocytic activity in models of tauopathies.

Pages 483-493
Stéphane P. Poulin, David Bergeron, Bradford C. Dickerson for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Jeannie-Marie Leoutsakos)
Risk Factors, Neuroanatomical Correlates, and Outcome of Neuropsychiatric Symptoms in Alzheimer’s Disease
Abstract: Background: An integrative model of neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) is lacking. Objective: In this study, we aimed investigated the risk factors, anatomy, biology, and outcomes of NPS in AD. Methods: 181 subjects were included from the Alzheimer’s Disease Neuroimaging Study (ADNI). NPS were assessed with the Neuropsychiatric Inventory Questionnaire at baseline and 6 months. NPI>3 was used as a threshold for NPS positivity. Three NPS courses were characterized: 1) minimal/absent (negative at 0 and 6 months, n=77); 2) fluctuating (positive only at one time point, n=53); 3) persistent (positive at both time points, n=51). We examined the association between NPS course and family history of dementia, personal history of psychiatric disorders, cerebrospinal fluid biomarkers, atrophy patterns, as well as longitudinal cognitive and functional measures at 12 and 24 months (MMSE, CDR-SOB, FAQ). Results: AD subjects with absent, fluctuating, or persistent NPS had similar CSF amyloid-β and tau levels. AD subjects with minimal/absent NPS had less personal history of psychiatric disorders (35%) than those with fluctuating (57%; p=0.015) or persistent NPS (47%, not significant). At 24 months, AD subjects with persistent NPS had worse cognitive (MMSE; p=0.05) and functional (CDR-SOB; p=0.016) outcomes. Dorsolateral prefrontal atrophy was seen in persistent NPS, but not in fluctuating NPS. Conclusions: Our results suggest that individuals with personal history of psychiatric disorders might be more vulnerable to develop NPS throughout the course of AD. The worst cognitive and functional outcomes associated with NPS in AD underscores the importance of monitoring NPS early in the disease course.

Pages 495-504
Lasse Melvaer Giil, Øivind Midttun, Helga Refsum, Arve Ulvik, Rajiv Advani, A. David Smith, Per Magne Ueland
Kynurenine Pathway Metabolites in Alzheimer’s Disease
Abstract: Background: Metabolites of tryptophan, produced via the kynurenine pathway (kynurenines), have been linked to Alzheimer’s disease (AD) in small cohorts with conflicting results. Objective: To compare differences in plasma kynurenine levels between AD and controls and identify potential associations with cognition. Methods: The study included 65 histopathologically-confirmed AD patients and 65 cognitively-screened controls from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. Cognition was assessed using the Cambridge Cognitive Examination (CamCog). Tryptophan, kynurenines, neopterin, and vitamin B6 forms were measured in plasma by liquid chromatography-tandem mass spectrometry. Non-parametric statistics, logistic regression and standardized robust regressions were applied with a false discovery rate of 0.05. Results: Tryptophan, xanthurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid were lower in AD (Odds ratios (ORs) 0.24 – 0.47; p-values < 0.001 – 0.01). Pyridoxal 5’phosphate did not differ between AD and controls. Kynurenine, anthranilic acid, quinolinic acid, and markers of immune activation (neopterin, kynurenine/tryptophan ratio, and the PAr index (Pyridoxic acid/(Pyridoxal 5’phosphate + Pyridoxal)) increased with age (β 0.31 – 0.51; p-values < 0.001 – 0.006). Xanthurenic acid decreased with age (β: -0.42, p < 0.001). Elderly AD patients with high quinolinic acid performed worse on the CamCog test, indicated by a significant age*quinolinic acid interaction (β 0.21, p < 0.001). Conclusion: Plasma concentrations of several kynurenines were lower in patients with AD compared to controls. Low xanthurenic acid occurred in both AD and with aging. Inflammation-related markers were associated with age, but not AD. However, elevated QA was associated with poor cognition in older AD patients.

Pages 505-510
Louis Jacob, Leonie Adam-Schnepf, Karel Kostev
Persistence with Antihypertensive Drugs in Patients with Hypertension and Dementia in Germany
Abstract: Background: Hypertension, a chronic disease resulting from aging and its related physiopathological dysregulations, is often associated with dementia. Objective: The goal was to analyze the persistence with antihypertensive drugs in patients affected by both hypertension and dementia in Germany. Methods: This study included hypertension patients who were initially treated with antihypertensive drugs in 1,262 general practices in Germany between January 2013 and December 2015 (index date). Patients with hypertension and comorbid dementia were matched (1:1) to patients without dementia by age, gender, type of residence (nursing home versus home-care setting), physician, and initial antihypertensive therapy, using a propensity score method. The primary outcome was the rate of patients without treatment discontinuation with antihypertensive drugs in cases and controls in the 12 months following the index date. Cox regressions were used to determine the impact of dementia on persistence with antihypertensive treatment. Results: This study included 2,191 patients with hypertension and comorbid dementia and 2,191 patients with hypertension but without dementia. The mean age was 79.3 years (SD=10.3 years) in both groups. Twelve months after initiation of antihypertensive therapy, 73.5% of cases and 69.5% of controls were persistent (p<0.001). Dementia was associated with a significant decrease in the risk of non-persistence with antihypertensive drugs in the entire population (HR=0.86, 95% CI: 0.79-0.93). This finding was corroborated in five different subgroups (age ≤60 years, age 61-70 years, men, women, and patients living in home-care settings). Conclusions: Dementia was found to be a protective factor for persistence with antihypertensive drugs in Germany.

Pages 511-524
Katarina Willén, Agnieszka Sroka, Reisuke H. Takahashi, Gunnar K. Gouras (Handling Associate Editor: P. Hemachandra Reddy)
Heterogeneous Association of Alzheimer’s Disease-Linked Amyloid-β and Amyloid-β Protein Precursor with Synapses
Abstract: Alzheimer’s disease (AD) is increasingly viewed as a disease of synapses. Loss of synapses correlates better with cognitive decline than amyloid plaques and neurofibrillary tangles, the hallmark neuropathological lesions of AD. Soluble forms of amyloid-β (Aβ) have emerged as mediators of synapse dysfunction. Aβ binds to, accumulates, and aggregates in synapses. However, the anatomical and neurotransmitter specificity of Aβ and the amyloid-β protein precursor (AβPP) in AD remain poorly understood. In addition, the relative roles of Aβ and AβPP in the development of AD, at pre- versus post-synaptic compartments and axons versus dendrites, respectively, remain unclear. Here we use immunogold electron microscopy and confocal microscopy to provide evidence for heterogeneity in the localization of Aβ/AβPP. We demonstrate that Aβ binds to a subset of synapses in cultured neurons, with preferential binding to glutamatergic compared to GABAergic neurons. We also highlight the challenge of defining pre- versus post-synaptic localization of this binding by confocal microscopy. Further, endogenous Aβ42 accumulates in both glutamatergic and GABAergic AβPP/PS1 transgenic primary neurons, but at varying levels. Moreover, upon knock-out of presenilin 1 or inhibition of γ-secretase AβPP C-terminal fragments accumulate both pre- and post-synaptically; however earlier pre-synaptically, consistent with a higher rate of AβPP processing in axons. A better understanding of the synaptic and anatomical selectivity of Aβ/AβPP in AD can be important for the development of more effective new therapies for this major disease of aging.

Pages 525-536
João A. Amorim, Paula M. Canas, Angelo R. Tomé, Anabela P. Rolo, Paula Agostinho, Carlos M. Palmeira, Rodrigo A. Cunha
Mitochondria in Excitatory and Inhibitory Synapses have Similar Susceptibility to Amyloid-β Peptides Modeling Alzheimer’s Disease
Abstract: Mitochondrial dysfunction is proposed to trigger memory deficits and synaptic damage at the onset of Alzheimer’s disease (AD). However, it is unknown how mitochondria dysfunction might trigger synaptotoxicity and if a differential susceptibility of mitochondria located in synapses underlies the greater glutamatergic than GABAergic synaptotoxicity in early AD. Hippocampal synaptosomes (purified synapses) of a rat model of early AD, typified by selective memory deficits two weeks after intracerebroventricular injection of amyloid-β peptides (Aβ1-42, 2 nmol), simultaneously displayed three mitochondria-associated deleterious alterations: 1) hampered metabolism (decreased MTT reduction); 2) increased oxygen radical production (increased hydrogen peroxide production); 3) increased caspase-3 activity. The direct exposure of hippocampal synaptosomes to Aβ1-42 (500 nM) similarly decreased mitochondrial membrane potential (TMRM+ fluorescence) and increased mitochondria-derived oxygen radicals (MitoTraker®red-CM-H2Xros fluorescence) in individual glutamatergic (vesicular glutamate transporter-immunopositive) and GABAergic (vesicular GABA transporter-immunopositive) synaptosomes. However, significantly more glutamatergic than GABAergic synaptosomes were endowed with mitochondria (Tom20-immunopositive). These results indicate that dysfunctional mitochondria located in synapses can trigger synaptotoxicity through multifaceted mechanisms and that it is not the susceptibility of mitochondria to A but more likely a different impact of dysfunctional mitochondria that underlies the greater sensitivity to synaptotoxicity of glutamatergic than GABA synapses in early AD.

Pages 537-547
Adam Gerstenecker, David A. Hoagey, Daniel C. Marson, Kristen M. Kennedy
White Matter Degradation is Associated with Reduced Financial Capacity in Mild Cognitive Impairment and Alzheimer’s Disease
Abstract: Financial capacity (FC) is a cognitively complex activity of daily living that declines in mild cognitive impairment (MCI) and Alzheimer’s disease (AD), limiting an individual’s ability to manage one’s finances and function independently. The neural underpinnings of this decline in function are poorly understood but likely involve age-related and disease-related degradation across structural networks. The purpose of the current study was to determine if altered white matter integrity is associated with declining FC in persons with MCI and AD compared to older controls. Individuals with MCI due to AD (n=31), mild dementia (n=39), and cognitively healthy older adults (n=60) were administered a neuropsychological battery including the FC Instrument, a performance-based measure of FC. All 130 participants also underwent diffusion tensor imaging (DTI) upon which tract-based spatial statistics were performed. Both FC and white matter integrity decreased in accordance with disease severity with little to no effect in healthy, significant effects in MCI, and greater effects in AD. Regional white matter degradation (increased diffusivities and decreased fractional anisotropy) was associated with reduced FC in both MCI and AD groups even after controlling for age, education, and gender. Specifically, in MCI, decreased fractional anisotropy, but not increased diffusivities, was associated with poorer FC in widespread cingulo-parietal-frontal and temporo-occipital areas. In AD, rather than anisotropy, increased mean and axial diffusivities in anterior cingulate, callosum, and frontal areas associated with poorer FC. These findings suggest a severity gradient of white matter degradation across DTI metrics and AD stages that predict declining financial skill and knowledge.

Pages 549-560
Stuart D. Portbury, Dominic J. Hare, Charlotte Sgambelloni, Kali Perronnes, Ashley J. Portbury, David I. Finkelstein, Paul A. Adlard (Handling Associate Editor: Robert Rissman)
Trehalose Improves Cognition in the Transgenic Tg2576 Mouse Model of Alzheimer’s Disease
Abstract: This study assessed the therapeutic utility of the autophagy enhancing stable disaccharide trehalose in the Tg2576 transgenic mouse model of Alzheimer’s disease (AD) via an oral gavage of a 2% trehalose solution for 31 days. Furthermore, as AD is a neurodegenerative condition in which the transition metals, iron, copper, and zinc, are understood to be intricately involved in the cellular cascades leading to the defining pathologies of the disease, we sought to determine any parallel impact of trehalose treatment on metal levels. Trehalose treatment significantly improved performance in the Morris water maze, consistent with enhanced learning and memory. The improvement was not associated with significant modulation of full length amyloid-β protein precursor or other amyloid-β fragments. Trehalose had no effect on autophagy as assessed by western blot of the LC3-1 to LC3-2 protein ratio, and no alteration in biometals that might account for the improved cognition was observed. Biochemical analysis revealed a significant increase in the hippocampus of both synaptophysin, a synaptic vesicle protein and surrogate marker of synapses, and doublecortin, a reliable marker of neurogenesis. The growth factor progranulin was also significantly increased in the hippocampus and cortex with trehalose treatment. This study suggests that trehalose might invoke a suite of neuroprotective mechanisms that can contribute to improved cognitive performance in AD that are independent of more classical trehalose-mediated pathways, such as A reduction and activation of autophagy. Thus, trehalose may have utility as a potential AD therapeutic, with conceivable implications for the treatment of other neurodegenerative disorders.

Pages 561-576
Ellis Niemantsverdriet, Julie Ottoy, Charisse Somers, Ellen De Roeck, Hanne Struyfs, Femke Soetewey, Jeroen Verhaeghe, Tobi Van den Bossche, Sara Van Mossevelde, Johan Goeman, Peter Paul De Deyn, Peter Mariën, Jan Versijpt, Kristel Sleegers, Christine Van Broeckhoven, Leonie wyffels, Adrien Albert, Sarah Ceyssens, Sigrid Stroobants, Steven Staelens, Maria Bjerke*, Sebastiaan Engelborghs* *Joint last authors
The Cerebrospinal Fluid Aβ1-42/Aβ1-40 Ratio Improves Concordance with Amyloid-PET for Diagnosing Alzheimer’s Disease in a Clinical Setting
Abstract: Background: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-β (Aβ) increases when the CSF Aβ1-42/Aβ1-40 ratio is used as compared to CSF Aβ1-42 levels alone. Objective: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer’s disease (AD) in a clinical setting. Methods: Seventy-eight subjects (AD dementia (n=17), mild cognitive impairment (MCI, n=48), and cognitively healthy controls (n=13)) underwent a [18F]Florbetapir ([18F]AV45) PET scan, [18F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n=67), a lumbar puncture was performed and AD biomarkers were analyzed (Aβ1-42, Aβ1-40, T-tau, P-tau181). Results: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [18F]AV45 PET measures when the CSF Aβ1-42/Aβ1-40 was applied compared to Aβ1-42 alone. CSF biomarkers were stronger associated to [18F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matter. Conclusion: The concordance between CSF Aβ and [18F]AV45 PET increases when the CSF Aβ1-42/Aβ1-40 ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.

Pages 577-583
Marcel Levy Nogueira, Dalila Samri, Stéphane Epelbaum, Simone Lista, Per Suppa, Lothar Spies, Harald Hampel, Bruno Dubois, Marc Teichmann
Alzheimer’s Disease Diagnosis Relies on a Twofold Clinical-Biological Algorithm: Three Memory Clinic Case Reports
Abstract: The International Working Group recently provided revised criteria of Alzheimer’s disease (AD) proposing that the diagnosis of typical amnesic AD should be established by a clinical-biological signature, defined by the phenotype of an “amnesic syndrome of the hippocampal type” (ASHT) combined with positive in vivo evidence of AD pathophysiology in the cerebrospinal fluid (CSF) or on amyloid PET imaging. The application and clinical value of this refined diagnostic algorithm, initially intended for research purposes, is explored in three memory clinic cases presenting with different cognitive profiles including an ASHT, hippocampal atrophy, and CSF AD-biomarker data. The case reports highlight that the isolated occurrence of one of the two proposed AD criteria, ASHT or positive pathophysiological markers, does not provide a reliable diagnosis of typical AD. It is proposed that the twofold diagnostic IWG algorithm can be applied and operationalized in memory clinic settings to improve the diagnostic accuracy of typical amnesic AD in clinical practice.

Pages 585-592
Callixte Kuate-Tegueu, José-Alberto Avila-Funes, Nadine Simo, Mélanie Le Goff, Hélène Amiéva, Jean-François Dartigues, Maturin Tabue-Teguo
Association of Gait Speed, Psychomotor Speed, and Dementia
Abstract: Background: Gait speed (GS) and psychomotor speed (PS) could be considered as two different dimensions of age-related slowness and both measures are associated with higher risk of adverse health-related outcomes among elderly people. Objective: To determine the association between GS, PS, and incident dementia among community-dwelling older adults. Methods: Twelve-year longitudinal study of 1,265 participants in the Bordeaux Three-City Study, a French prospective to determine the risk of dementia and cognitive impairment attributable to cardiovascular risk factors. Participants completed a battery of cognitive tests, including time to complete the Trail Making Test A, and a walking speed test. The incidence of dementia was determined over the 12-year follow-up period. Cox proportional hazards models with delayed entry were used to estimate the cumulative risk of dementia and were adjusted for sex, education, and ApoE4 genotype. Results: Mean age of participants was 74.0 years (SD 4.8). Over the 12-year follow-up, 203 participants developed dementia. GS and PS were both independent predictors of incident all-cause dementia after 12 years of follow-up. For a one SD increase of either GS or PS, the hazard ratio (HR) for Alzheimer’s disease was 1.2 (95% CI=1.02-1.32) and 1.4 (95% CI=1.2-1.61), respectively; whereas for incident vascular dementia, the HR was 1.3 (95% CI=1.05-1.71) and 1.5 (95% CI=1.16-2.08), respectively. No significant interaction between GS and PS was observed. Conclusions: In older French people aged 65+, our findings showed that both low GS and PS were independently associated with risk of incident of Alzheimer’s disease and vascular dementia.

Pages 593-604
Panagiota Mavroeidi, Olga Mavrofrydi, Elpiniki Pappa, Myrto Panopoulou, Panagiota Papazafiri, Sylva Ηaralambous, Spiros Efthimiopoulos
Oxygen and Glucose Deprivation Alter Synaptic Distribution of Tau Protein: The Role of Phosphorylation
Abstract: Alterations in tau synaptic distribution are considered to underlie synaptic dysfunction observed in Alzheimer's disease (AD). In the present study, brain blood hypoperfusion was simulated in mouse brain slices, and tau levels and phosphorylation were investigated in total extracts, as well as in postsynaptic density fractions (PSDs) and non-PSDs obtained through differential extraction and centrifugation. Oxygen deprivation (OD) resulted in tau dephosphorylation at several AD-related residues and activation of GSK3β and phosphatase PP2A. On the contrary, glucose deprivation (GD) did not affect total levels of cellular tau or its phosphorylation despite inactivation of GSK3β. However, tau distribution in PSD and non-PSD fractions and the pattern of tau phosphorylation in these compartments is highly complex. In PSDs, tau was increased under GD conditions and decreased under OD conditions. GD resulted in tau dephosphorylation at Ser199, Ser262, and Ser396 while OD resulted in tau hyperphosphorylation at Ser199 and Ser404. In the non-PSD fraction, GD or OD resulted in lower levels of tau, but the phosphorylation status of tau was differentially affected. In GD conditions, tau was found dephosphorylated at Ser199, Thr205, and Ser404 and hyperphosphorylated at Ser262. However, in OD conditions tau was found hyperphosphorylated at Thr205, SerSer356, Ser396, and Ser404. Combined OD and GD resulted in degradation of cellular tau and dephosphorylation of PSD tau at Ser396 and Ser404. These results indicate that oxygen deprivation causes dephosphorylation of tau, while GD and OD differentially affect distribution of total tau and tau phosphorylation variants in neuronal compartments by activating different mechanisms.

Pages 605-614
Daniel G. Amen, Manuel Trujillo, David Keator, Derek V. Taylor, Kristen Willeumier, Somayeh Meysami, Cyrus A. Raji
Gender-Based Cerebral Perfusion Differences in 46,034 Functional Neuroimaging Scans
Abstract: Background: Studies have reported that females have widespread increases in regional cerebral blood flow, but the studies were relatively small and inconsistent. Objective: Here we analyzed a healthy and very large psychiatric population to determine the effect of gender, using single photon emission computed tomography (SPECT). Methods: Whole brain and region of interest (ROI) gender differences were analyzed in a total of 46,034 SPECT scans at baseline and concentration. The sample included 119 healthy subjects and 26,683 patients; a subset of 11,587 patients had complete diagnostic information. A total of 128 regions were analyzed according to the AAL Atlas, using ROI Extract and SPSS statistical software programs, controlling for age, diagnoses, and correcting for multiple comparisons. Results: Compared to males, healthy females showed significant whole brain (p<0.01) and ROI increases in 65 baseline and 48 concentration regions (p<0.01 corrected). Healthy males showed non-significant increases in 9 and 22 regions, respectively. In the clinical group, there were widespread significant increases in females, especially in the prefrontal and limbic regions, and specific increases in males in the inferior occipital lobes, inferior temporal lobes, and lobule 7 and Crus 2 of the cerebellum. These findings were replicated in the subset of 11,587 patients with the effect of diagnoses removed. Conclusions: Our results demonstrated significant gender differences in a healthy and clinical population. Understanding these differences is crucial in evaluating functional neuroimaging and may be useful in understanding the epidemiological gender differences among psychiatric disorders.

Pages 615-624
Leonardo Pantoni, Anna Poggesi, Stefano Diciotti, Raffaella Valenti, Stefano Orsolini, Eleonora Della Rocca, Domenico Inzitari, Mario Mascalchi, Emilia Salvadori (Handling Associate Editor: Daniela Galimberti)
Effect of Attention Training in Mild Cognitive Impairment Patients with Subcortical Vascular Changes: The RehAtt Study
Abstract: Background and Objective: Mild cognitive impairment (MCI) patients with small vessel disease (SVD) are at high dementia risk. We tested the effects of cognitive rehabilitation in these patients using the Attention Process Training-II (APT-II) program in a single-blinded, randomized clinical trial. Methods: Patients were randomized to APT-II or standard care and evaluated at baseline, 6, and 12 months with functional, quality of life, cognitive tests, and resting state functional MRI (rsfMRI). Results: Forty-six patients were enrolled and 43 (mean ± SD age 75.1 ± 6.8) completed the study. No change was seen in functionality and quality of life between treated and non-treated patients. However, the Rey Auditory-Verbal Learning Test immediate recall showed a significant improvement in treated compared to non-treated group (change score 6 versus 12 months: 1.8 ± 4.9 and -1.4 ± 3.8, p=0.021; baseline versus 12 months: 3.8 ± 6.1 and 0.2 ± 4.4, p=0.032). A higher proportion of treated patients had stable/better evaluation compared to non-treated group on Visual search test (6 versus 12 months: 95% versus 71%, p=0.038) and Rey–Osterrieth Complex Figure copy (6 versus 12 months: 95% versus 67%, p=0.027). RsfMRI, performed in a subsample, showed that the difference between follow-up and baseline in synchronization of activity in cerebellar areas was significantly greater in treated than in non-treated patients. Conclusion: We were unable to show a significant effect in quality of life or functional status in treated patients with MCI and SVD. However, APT-II produces some beneficial effects in focused attention and working memory and seems to increase activity in brain circuits involved in cognitive processes.

Pages 625-632
Chih-Ping Chung, Hsiang-Ying Lee, Po-Chen Lin, Pei-Ning Wang (Handling Associate Editor: Sergio Salmerón)
Cerebral Artery Pulsatility is Associated with Cognitive Impairment and Predicts Dementia in Individuals with Subjective Memory Decline or Mild Cognitive Impairment
Abstract: The concept that excess pulsation in cerebral arteries might be involved at the early stage of dementia is based on the results of studies on aorta stiffness. In these studies, aorta stiffness is cross-sectionally associated with cognitive impairment and longitudinally related to cognitive decline in non-demented subjects. However, a direct measure of cerebral artery pulsatility is absent in the literature. We aimed to investigate the associations between cerebral artery pulsatility and (1) different cognitive-domains and (2) conversion to dementia in non-demented individuals at the prodromal-stage of Alzheimer’s disease (AD). Non-demented individuals with subjective memory decline or mild cognitive impairment were included. Neuropsychological tests at baseline and cognitive status at 6 years were evaluated. Cerebral pulsatility was assessed in the middle cerebral artery (MCA) and posterior cerebral artery by transcranial color-coded sonography. Multivariate-analyses of 79 subjects with robust acoustic windows showed that increased pulsatility in cerebral arteries was significantly associated with impairment in corresponding cognitive domains. Analyses in 54 subjects who completed 6-year follow up revealed that high left MCA pulsation (pulsatility index≥1.1) independently predicted conversion to AD with an odds-ratio of 11:2. Our results demonstrate the spatio-temporal relationship between increased cerebral artery pulsation and cognitive impairment and suggest that increased cerebrovascular pulsation might be involved in the early pathogenesis of AD. Cerebrovascular pulsation may be a therapeutic target to prevent/delay AD onset. Future studies with other AD biomarkers and animal/cell models of increased vascular-pulsation are needed to elucidate the mechanisms by which cerebrovascular pulsatile injury initiates or precipitates neurodegeneration in AD.

Pages 633-649
Susana Cid-Fernández, Mónica Lindín, Fernando Díaz (Handling Associate Editor: Ioulietta Lazarou)
Neurocognitive and Behavioral Indexes for Identifying the Amnestic Subtypes of Mild Cognitive Impairment
Abstract: Early identification of amnestic mild cognitive impairment (aMCI) subtypes is important for early diagnosis and prognosis of Alzheimer’s disease. Healthy, single-domain (sdaMCI) and multiple-domain aMCI (mdaMCI) participants performed an auditory-visual distraction-attention task. Event-related brain potentials (ERPs) were recorded while the participants performed the task to evaluate Go/NoGo N2 and P3 ERP components. The results showed the expected behavioral and cognitive decline in mdaMCI participants relative to controls (fewer hits, longer reaction times [RTs], slightly smaller Go-N2 and NoGo-N2 amplitudes), while sdaMCI participants showed some decline (slightly longer RTs, smaller Go- and NoGo-N2 amplitudes) along with some unexpected results (a late positive slow wave, PSW) and good levels of execution. In addition, some of these parameters proved to be useful markers. Thus, the number of hits was the best marker for diagnosing mdaMCI participants (distinguishing them from controls, from sdaMCI participants, and from both groups together), while the PSW amplitude was the best marker for diagnosing sdaMCI participants (distinguishing them from controls, and from control & mdaMCI participants).

Pages 651-661
Alejandro Antón-Fernández, Jesús Merchán-Rubira, Jesús Avila, Félix Hernández, Javier DeFelipe, Alberto Muñoz
Phospho-Tau Accumulation and Structural Alterations of the Golgi Apparatus of Cortical Pyramidal Neurons in the P301S Tauopathy Mouse Model
Abstract: The Golgi apparatus (GA) is a highly dynamic organelle involved in the processing and sorting of cellular proteins. In Alzheimer's disease (AD), it has been shown to decrease in size and become fragmented in neocortical and hippocampal neuronal subpopulations. This fragmentation and decrease in size of the GA in AD has been related to the accumulation of hyperphosphorylated tau. However, the involvement of other pathological factors associated with the course of the disease, such as the extracellular accumulation of amyloid-β (Aβ) aggregates, cannot be ruled out, since both pathologies are present in AD patients. Here we use the P301S tauopathy mouse model to examine possible alterations of the GA in neurons that overexpress human tau (P301S mutated gene) in neocortical and hippocampal neurons, using double immunofluorescence techniques and confocal microscopy. Quantitative analysis revealed that neurofibrillary tangle (NFT)-bearing neurons had important morphological alterations and reductions in the surface area and volume of the GA compared with NFT-free neurons. Since in this mouse model there are no Aβ aggregates typical of AD, the present findings support the idea that the progressive accumulation of phospho-tau is associated with structural alterations of the GA, and that these changes may occur in the absence of Aβ pathology.

Pages 663-677
Elodie Pongan, Barbara Tillmann, Yohana Leveque, Béatrice Trombert, Jean Claude Getenet, Nicolas Auguste, Virginie Dauphinot, Hanane El Haouari, Malou Navez, Jean-Michel Dorey, Pierre Krolak-Salmon, Bernard Laurent, Isabelle Rouch and the LACMé group
Can Musical or Painting Interventions Improve Chronic Pain, Mood, Quality of Life, and Cognition in Patients with Mild Alzheimer’s Disease? Evidence from a Randomized Controlled Trial
Abstract: Background: Among non-pharmacological therapies, musical intervention is often used for patients with Alzheimer’s disease (AD) and patients presenting with chronic pain. However, their efficacy is still under debate. Objective: Our aim was to determine the efficacy of choral singing versus painting sessions on chronic pain, mood, quality of life, and cognition in AD patients. Methods: In this multicenter randomized controlled trial, 59 mild AD patients were randomized to a 12-week singing (SG; n=31) or painting group (PG; n=28). Chronic pain, anxiety, depression, and quality of life were assessed before, after, and 1 month after the sessions. Cognitive abilities were assessed before and after interventions. The evolution of these different measures was assessed with mixed linear models. The primary data analysis was by intention-to-treat, and completed by a ‘per protocol’ approach. Results: Both singing and painting interventions led to significant pain reduction (Time effect: F=4.71; p=0.01), reduced anxiety (Time effect: F=10.74; p < 0.0001), improved Quality of Life (Time effect: F=6.79; p=0.002), improved digit span (F=12.93; p=0.001), and inhibitory processes (Time effect: F=4.93; p=0.03). Depression was reduced over time in PG only (Time x Group effect: F=4.53; p=0.01). Verbal Memory performance remained stable over time in SG, but decreased in PG (Time x group effect: F= 9.29; p=0.004). Conclusion: Findings suggest that singing and painting interventions may reduce pain and improve mood, quality of life, and cognition in patients with mild AD, with differential effects of painting for depression and singing for memory performance.

Pages 679-690
Wuhai Tao*, Xin Li*, Junying Zhang, Yaojing Chen, Chao Ma, Zhen Liu, Caishui Yang, Wenxiao Wang, Kewei Chen, Jun Wang, Zhanjun Zhang *These authors contributed to the work equally.
Inflection Point in Course of Mild Cognitive Impairment: Increased Functional Connectivity of Default Mode Network
Abstract: The alteration of the default mode network (DMN) functional connectivity (FC) has been reported in patients with amnestic mild cognitive impairment (aMCI) as a predictor of Alzheimer’s disease (AD). However, no studies exist that examined stage-dependent DMN FC changes throughout the course of aMCI. The present study aims to characterize patterns of DMN FC over three aMCI stages as first defined. Utilizing the extreme groups approach on the performance of memory tasks, aMCI subjects were divided into mild, moderate, and severe stages. Independent component analysis was used to assess DMN for individual patients in each of the three cross-sectionally defined stages. Instead of finding that continued monotonic decline was the case for the hippocampus volume, which we also investigated in this study, we observed an increase in DMN functional connectivity from mild aMCI to moderate aMCI and a decrease to severe aMCI, mainly in the left precuneus and superior parietal lobe. Moreover, the FC was significantly associated with cognitive performance. Though a longitudinal study is needed to confirm these results, our cross-sectional finding is that non-linear FC changes in DMN could be a characteristic of prodromal early disease development.

Pages 691-698
Susanna C. Larsson, Matthew Traylor, Stephen Burgess, Hugh S. Markus
Genetically-Predicted Adult Height and Alzheimer’s Disease
Abstract: Background: Observational studies have linked increased adult height with better cognitive performance and reduced risk of Alzheimer’s disease (AD). It is unclear whether the associations are due to shared biological processes that influence height and AD or due to confounding by early life exposures or environmental factors. Objective: To use a genetic approach to investigate the association between adult height and AD. Methods: We selected 682 single nucleotide polymorphisms (SNPs) associated with height at genome-wide significance (p < 5 10-8) in the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Summary statistics for each of these SNPs on AD were obtained from the International Genomics of Alzheimer's Project (IGAP) of 17,008 individuals with AD and 37,154 controls. The estimate of the association between genetically predicted height and AD was calculated using the inverse-variance weighted method. Results: The odds ratio of AD was 0.91 (95% confidence interval, 0.86–0.95; p = 9.8 10-5) per one standard deviation increase (about 6.5 cm) in genetically predicted height based on 682 SNPs, which were clustered in 419 loci. In an analysis restricted to one SNP from each height-associated locus (n = 419 SNPs), the corresponding OR was 0.92 (95% confidence interval, 0.86–0.97; p = 4.8 10-3). Conclusion: This finding suggests that biological processes that influence adult height may have a role in the etiology of AD.

Pages 699-706
Alexandra M. Kueider, Yang An, Toshiko Tanaka, Melissa H. Kitner-Triolo, Stephanie Studenski, Luigi Ferrucci, Madhav Thambisetty (Handling Associate Editor: Alan Lerner)
Sex-Dependent Associations of Serum Uric Acid with Brain Function During Aging
Abstract: Serum uric acid (SUA) is an abundant natural antioxidant capable of reducing cellular oxidation, a major cause of neurodegenerative disease. In line with this, SUA levels are lower in Alzheimer’s disease; however, the association between SUA and cognition remains unclear. Results from studies examining the effects of SUA on cognition may be difficult to interpret in the context of normal versus pathological aging. This study examined sex-specific associations of baseline SUA with cognition during aging. Data from dementia-free participants initially aged 26-99 (N=1,451) recruited for the Baltimore Longitudinal Study of Aging (BLSA), were used in the current analyses. SUA was assessed using blood samples collected during research visits. Cognition was measured using five composite scores (verbal memory, attention, executive function, language, and visuospatial ability). At the first study visit, compared with women, men were older, more likely to be White, had more years of education, higher baseline SUA levels, and higher cardiovascular risk scores. Higher baseline SUA was associated with attenuated declines in attention (β=0.006; p=0.03) and visuospatial abilities (β=0.007; p=0.01) in men. There was a trend to suggest higher baseline SUA in men was associated with attenuated declines in language, but this finding did not reach statistical significance (p=0.09). There were no significant findings with SUA and cognition in women. In this sample of cognitively healthy, community-dwelling adults, we found that higher SUA levels at baseline were associated with attenuated declines in attention and visuospatial abilities in men. SUA was not associated with cognition or change in cognition over time in women.

Pages 707-719
Gali H. Weissberger, Rebecca J. Melrose, Candace M. Fanale, Joseph V. Veliz, David L. Sultzer (Handling Associate Editor: Gilles Chopard)
Cortical Metabolic and Cognitive Correlates of Disorientation in Alzheimer’s Disease
Abstract: Orientation to time, date, and place is commonly utilized in clinical settings to aid in diagnosis, staging, and monitoring of Alzheimer’s disease (AD). This study aimed to identify the cerebral metabolic correlates of orientation in patients with AD, and the degree to which regions associated with orientation overlap with memory-related structures. Eighty-five patients with a diagnosis of probable AD underwent fluorodeoxyglucose positron emission tomography (FDG-PET) and neuropsychological testing. Orientation items from the Dementia Rating Scale and recognition performance from the Consortium to Establish a Registry for AD (CERAD) Word List Learning test were correlated with cerebral glucose metabolism. Post-hoc analyses examined neuropsychological predictors of orientation. Better orientation performance related to greater cerebral metabolism in the bilateral middle-inferior temporal lobes, bilateral middle-posterior cingulate, left angular gyrus, and left middle occipital gyrus. In comparison, higher CERAD recognition discriminability score was associated with greater metabolic activity in left medial temporal lobe regions including the hippocampal and parahippocampal gyri, and the left fusiform gyrus. Post-hoc behavioral analyses revealed multiple cognitive functions to be related to orientation, including list learning, recognition memory, visuospatial functioning, attention, and language. Findings from the present study suggest that disorientation in AD results from dysfunction of a network of structures and cognitive abilities commonly found to be implicated in AD. The study supports the notion that memory is necessary but not sufficient for successful orientation.

Pages 721-731
Reagon Karki, Alpha Tom Kodamullil, Martin Hofmann-Apitius
Comorbidity Analysis between Alzheimer’s Disease and Type 2 Diabetes Mellitus (T2DM) Based on Shared Pathways and the Role of T2DM Drugs
Abstract: Background: Various studies suggest a comorbid association between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) indicating that there could be shared underlying pathophysiological mechanisms. Objective: This study aims to systematically model relevant knowledge at the molecular level to find a mechanistic rationale explaining the existing comorbid association between AD and T2DM. Method: We have used a knowledge-based modeling approach to build two network models for AD and T2DM using Biological Expression Language (BEL), which is capable of capturing and representing causal and correlative relationships at both molecular and clinical levels from various knowledge resources. Results: Using comparative analysis, we have identified several putative “shared pathways”. We demonstrate, at a mechanistic level, how the insulin signaling pathway is related to other significant AD pathways such as the neurotrophin signaling pathway, PI3K/AKT signaling, MTOR signaling, and MAPK signaling and how these pathways do cross-talk with each other both in AD and T2DM. In addition, we present a mechanistic hypothesis that explains both favorable and adverse effects of the anti-diabetic drug metformin in AD. Conclusion: The two computable models introduced here provide a powerful framework to identify plausible mechanistic links shared between AD and T2DM and thereby identify targeted pathways for new therapeutics. Our approach can also be used to provide mechanistic answers to the question of why some T2DM treatments seem to increase the risk of AD.

Pages 733-746
Li Zhang, Caixian Sun, Yaxi Jin, Kai Gao, Xudong Shi, Wenying Qiu, Chao Ma, Lianfeng Zhang (Handling Associate Editor: J. Wesson Ashford)
Dickkopf 3 (Dkk3) Improves Amyloid-β Pathology, Cognitive Dysfunction, and Cerebral Glucose Metabolism in a Transgenic Mouse Model of Alzheimer’s Disease
Abstract: Dysfunctional Wnt signaling is associated with Alzheimer’s disease (AD), and activation of the Wnt signaling pathway inhibits AD development. Dickkopf 3 (Dkk3) is a modulator of the Wnt signaling pathway and is physiologically expressed in the brain. The role of Dkk3 in the pathogenesis of AD has not been evaluated. In the present study, we determined that Dkk3 expression was significantly decreased in brain tissue from AD patients and the AD transgenic mouse model APPswe/PS1dE9 (AD mice). Transgenic mice with brain tissue-specific Dkk3 expression were generated or crossed with AD mice to study the effects of Dkk3 on AD. In AD mice, transgenic expression of Dkk3 improved abnormalities in learning, memory, and locomotor activity, reduced the accumulation of amyloid-β, and ameliorated glucose uptake deficits. Furthermore, we determined that Dkk3 downregulated GSK-3β, a central negative regulator in canonical Wnt signaling, and upregulated PKCβ1, a factor implicated in noncanonical Wnt signaling. This indicates that increased activation of GSK-3β and the inhibition of PKCβ1 in AD patients may be responsible for the dysfunctional Wnt signaling in AD. In summary, our data suggest that Dkk3 is an agonist of Wnt signaling, and the ability of transgenic expression of Dkk3 to compensate for the decrease in Dkk3 expression in AD mice, reverse dysfunctional Wnt signaling, and partially inhibit the pathological development of AD suggests that Dkk3 could serve as a therapeutic target for the treatment of AD.