Pages 333-338
Short Communication
Antigoni Manousopoulou, Satoshi Saito, Yumi Yamamoto, Nasser M. Al-Daghri, Masafumi Ihara, Roxana O. Carare, Spiros D. Garbis
Hemisphere Asymmetry of Response to Pharmacologic Treatment in an Alzheimer’s Disease Mouse Model
Abstract: The aim of this study was to examine hemisphere asymmetry of response to pharmacologic treatment in an Alzheimer’s disease mouse model using cilostazol as a chemical stimulus. Eight-month-old mice were assigned to vehicle or cilostazol treatment for three months and hemispheres were analyzed using quantitative proteomics. Bioinformatics interpretation showed that following treatment, aggregation of blood platelets significantly decreased in the right hemisphere whereas neurodegeneration significantly decreased and synaptic transmission increased in the left hemisphere only. Our study provides novel evidence on cerebral laterality of pharmacologic activity, with important implications in deciphering regional pharmacodynamic effects of existing drugs thus uncovering novel hemisphere-specific therapeutic targets.
Pages 339-343
Short Communication
Ruben Smith, Moa Wibom, Tomas Olsson, Douglas Hägerström, Jonas Jögi, Gil D. Rabinovici, Oskar Hansson (Handling Associate Editor: Flavio Nobili)
Posterior Accumulation of Tau and Concordant Hypometabolism in an Early-Onset Alzheimer’s Disease Patient with Presenilin-1 Mutation
Abstract: It is unclear whether the distribution of tau pathology differs between cases with early-onset familial Alzheimer's disease (AD) and sporadic AD. We present positron emission tomography (PET) data from a young patient with a presenilin-1 mutation (Thr116Asn). 18F-flutemetamol PET showed a distribution of amyloid-β fibrils similar to sporadic AD. However, the pattern of tau pathology, revealed using 18F-AV1451 PET, showed higher uptake in posterior cingulate, precuneus, parietal and occipital cortices compared to late-onset sporadic AD. Further, the tau pathology, but not amyloid pathology, exhibited a very clear inverse relationship with 18F-fluorodeoxyglucose-metabolism, indicating neuronal hypometabolism in regions affected by tau aggregates.
Pages 345-356
Brittany N. Dugger, Charisse M. Whiteside, Chera L. Maarouf, Douglas G. Walker, Thomas G. Beach, Lucia I. Sue, Angelica Garcia, Travis Dunckley, Bessie Meechoovet, Eric M. Reiman, Alex E. Roher
The Presence of Select Tau Species in Human Peripheral Tissues and Their Relation to Alzheimer’s Disease
Abstract: Tau becomes excessively phosphorylated in Alzheimer’s disease (AD) and is widely studied within the brain. Further examination of the extent and types of tau present in peripheral tissues and their relation to AD is warranted given recent publications on pathologic spreading. Cases were selected based on the presence of pathological tau spinal cord deposits (n=18). Tissue samples from sigmoid colon, scalp, abdominal skin, liver, and submandibular gland were analyzed by western blot and enzyme-linked immunosorbent assays (ELISAs) for certain tau species; frontal cortex gray matter was used for comparison. ELISAs revealed brain to have the highest total tau levels, followed by submandibular gland, sigmoid colon, liver, scalp, and abdominal skin. Western blots with antibodies recognizing tau phosphorylated at threonine 231(pT231), serine 396 and 404 (PHF-1), and an unmodified total human tau between residues 159 and 163 (HT7) revealed multiple banding patterns, some of which predominated in peripheral tissues. As submandibular gland had the highest levels of peripheral tau, a second set of submandibular gland samples were analyzed (n=36; 19 AD, 17 non-demented controls). ELISAs revealed significantly lower levels of pS396 (p=0.009) and pT231 (p=0.005) in AD cases but not total tau (p=0.18). Furthermore, pT231 levels in submandibular gland inversely correlated with Braak neurofibrillary tangle stage (p=0.04), after adjusting for age at death, gender, and postmortem interval. These results provide evidence that certain tau species are present in peripheral tissues. Of potential importance, submandibular gland pT231 is progressively less abundant with increasing Braak neurofibrillary tangle stage.
Pages 357-366
Oriol Turró-Garriga, Josep Garre-Olmo, Laia Calvó-Perxas, Ramón Reñé-Ramírez, Jordi Gascón-Bayarri, Josep Lluís Conde-Sala (Handling Associate Editor: Marcia Dourado)
Course and Determinants of Anosognosia in Alzheimer’s Disease: A 12-Month Follow-Up
Abstract: Anosognosia in Alzheimer’s disease (AD) has been associated with greater cognitive impairment and more behavioural and psychological symptoms of dementia (BPSD). This study examines the incidence, persistence, and remission rates of anosognosia over a 12-month period, as well as the related risk factors. This was an observational 12-month prospective study. The longitudinal sample comprised 177 patients with mild or moderate AD, and their respective caregivers. Anosognosia was assessed using the Anosognosia Questionnaire in Dementia, and we also evaluated cognitive status (Mini-Mental State Examination), functional disability (Disability Assessment in Dementia), and the presence of BPSD (Neuropsychiatric Inventory). Multinomial logistic regression was used to determine the variables associated with the incidence, persistence and remission of anosognosia. The prevalence of anosognosia was 39.5% (95% CI = 32.1-47.1) at baseline. At 12 months, incidence was 38.3% (95% CI = 28.6-48.0), persistence was 80.0% (95% CI = 69.9-90.1) and remission was 20.0% (95% CI = 9.9-30.1). The regression model identified lower age, more education, and the presence of delusions as variables associated with incidence, and more education, lower instrumental DAD score, and disinhibition as variables associated with persistence. No variables were associated with remission (n = 14). The presence of anosognosia in AD patients is high. Education and certain neuropsychiatric symptoms may explain a greater and earlier incidence of anosognosia. However, anosognosia also increases with greater cognitive impairment and disease severity.
Pages 367-376
Siddharth Ramanan, Emma Flanagan, Cristian E. Leyton, Victor L. Villemagne, Christopher C. Rowe, John R. Hodges, Michael Hornberger (Handling Associate Editor: Sharon Naismith)
Non-Verbal Episodic Memory Deficits in Primary Progressive Aphasias are Highly Predictive of Underlying Amyloid Pathology
Abstract: Diagnostic distinction of primary progressive aphasias (PPA) remains challenging, in particular for the logopenic (lvPPA) and nonfluent/agrammatic (naPPA) variants. Recent findings highlight that episodic memory deficits appear to discriminate these PPA variants from each other, as only lvPPA perform poorly on these tasks while having underlying amyloid pathology similar to that seen in amnestic dementias like Alzheimer’s disease (AD). Most memory tests are, however, language based and thus potentially confounded by the prevalent language deficits in PPA. The current study investigated this issue across PPA variants by contrasting verbal and non-verbal episodic memory measures while controlling for their performance on a language subtest of a general cognitive screen. A total of 203 participants were included (25 lvPPA; 29 naPPA; 59 AD; 90 controls) and underwent extensive verbal and non-verbal episodic memory testing, with a subset of patients (n=45) with confirmed amyloid profiles as assessed by Pittsburgh Compound B and PET. The most powerful discriminator between naPPA and lvPPA patients was a non-verbal recall measure (Rey Complex Figure delayed recall), with 81% of PPA patients classified correctly at presentation. Importantly, AD and lvPPA patients performed comparably on this measure, further highlighting the importance of underlying amyloid pathology in episodic memory profiles. The findings demonstrate that non-verbal recall emerges as the best discriminator of lvPPA and naPPA when controlling for language deficits in high load amyloid PPA cases.
Pages 377-389
Laura Serra, Mara Cercignani, Chiara Mastropasqua, Mario Torso, Barbara Spanò, Elena Makovac, Vanda Viola, Giovanni Giulietti, Camillo Marra, Carlo Caltagirone, Marco Bozzali (Handling Associate Editor: Daniela Galimberti)
Longitudinal Changes in Functional Brain Connectivity Predicts Conversion to Alzheimer’s Disease
Abstract: This longitudinal study investigates the modifications in structure and function occurring to typical Alzheimer’s disease (AD) brains over a 2-year follow-up, from pre-dementia stages of disease, with the aim of identifying biomarkers of prognostic value. Thirty-one patients with amnestic mild cognitive impairment were recruited and followed-up with clinical, neuropsychological, and MRI assessments. Patients were retrospectively classified as AD Converters or Non-Converters, and the data compared between groups. Cross-sectional MRI data at baseline, assessing volume and functional connectivity abnormalities, confirmed previous findings, showing a more severe pattern of regional grey matter atrophy and default-mode network disconnection in Converters than in Non-Converters. Longitudinally, Converters showed more grey matter atrophy in the frontotemporal areas, accompanied by increased connectivity in the precuneus. Discriminant analysis revealed that functional connectivity of the precuneus within the default mode network at baseline is the only parameter able to correctly classify patients in Converters and Non-Converters with high sensitivity, specificity, and accuracy.
Pages 391-403
Nora E. Gray, Jonathan A. Zweig, Colleen Kawamoto, Joseph F. Quinn, Philip F. Copenhaver (Handling Associate Editor: Stavros Baloyannis)
STX, a Novel Membrane Estrogen Receptor Ligand, Protects Against Amyloid-β Toxicity
Abstract: Because STX is a selective ligand for membrane estrogen receptors, it may be able to confer the beneficial effects of estrogen without eliciting the deleterious side effects associated with activation of the nuclear estrogen receptors. This study evaluates the neuroprotective properties of STX in the context of amyloid-β (Aβ) exposure. MC65 and SH-SY5Y neuroblastoma cell lines, as well as primary hippocampal neurons from wild type (WT) and Tg2576 mice, were used to investigate the ability of STX to attenuate cell death, mitochondrial dysfunction, dendritic simplification, and synaptic loss induced by Aβ. STX prevented Aβ-induced cell death in both neuroblastoma cell lines; it also normalized the decrease in ATP and mitochondrial gene expression caused by Aβ in these cells. Notably, STX also increased ATP content and mitochondrial gene expression in control neuroblastoma cells (in the absence of Aβ). Likewise in primary neurons, STX increased ATP levels and mitochondrial gene expression in both genotypes. In addition, STX treatment enhanced dendritic arborization and spine densities in WT neurons and prevented the diminished outgrowth of dendrites caused by Aβ exposure in Tg2576 neurons. These data suggest that STX can act as an effective neuroprotective agent in the context of Aβ toxicity, improving mitochondrial function as well as dendritic growth and synaptic differentiation. In addition, since STX also improved these endpoints in the absence of Aβ, this compound may have broader therapeutic value beyond Alzheimer’s disease.
Pages 405-415
Jiro Kida, Kiyotaka Nemoto, Chiaki Ikejima, Shogyoku Bun, Tatsuyuki Kakuma, Katsuyoshi Mizukami, Takashi Asada (Handling Associate Editor: Meryl Butters)
Impact of Depressive Symptoms on Conversion from Mild Cognitive Impairment Subtypes to Alzheimer’s Disease: A Community-Based Longitudinal Study
Abstract: Background: While longitudinal studies have investigated the relationships between mild cognitive impairment (MCI) subtypes and dementia subtypes, the results have been controversial. In addition, some research show that depression accompanied by MCI might increase the risk of Alzheimer’s disease (AD). Objective: The aim of this study is to longitudinally investigate the relationships between MCI subtypes and dementia subtypes, with special attention to the effect of comorbid depressive symptoms in a Japanese rural community. Methods: Non-demented participants (n=802) completed a baseline and follow-up study. Outcomes were conversion to dementia especially AD, MCI, or no conversion. A complementary log-log analysis was conducted to investigate the risk of dementia and AD in amnestic MCI (aMCI) compared to nonamnestic MCI (naMCI) groups. The impact of depressive symptoms on the transition from MCI to AD and from cognitively normal to MCI or AD were also analyzed. Results: The risk of developing dementia, in particular AD, for the aMCI group was significantly higher than that for the naMCI group. In the aMCI group, the presence of depressive symptoms increased the risk of developing AD, but depressive symptoms in the naMCI group did not. In the cognitively normal group, the presence of depressive symptoms increased the risk of aMCI but not naMCI. Conclusion: MCI subtyping could be useful in finding a prodrome for dementia and in particular for AD. The differing impacts of depressive symptoms on the development of AD suggest that the relationship between depressive symptoms and cognitive impairment could differ in aMCI and naMCI patients.
Pages 417-425
Wen-Xing Li*, Shao-Xing Dai*, Jia-Qian Liu, Qian Wang, Gong-Hua Li, Jing-Fei Huang *These authors contributed equally to this work.
Integrated Analysis of Alzheimer's Disease and Schizophrenia Dataset Revealed Different Expression Pattern in Learning and Memory
Abstract: Alzheimer’s disease (AD) and schizophrenia (SZ) are both accompanied by impaired learning and memory functions. This study aims to explore the expression profiles of learning or memory genes between AD and SZ. We downloaded 10 AD and 10 SZ datasets from GEO-NCBI for integrated analysis. These datasets were processed using RMA algorithm and a global renormalization for all studies. Then Empirical Bayes algorithm was used to find the differentially expressed genes between patients and controls. The results showed that most of the differentially expressed genes were related to AD whereas the gene expression profile was little affected in the SZ. Furthermore, in the aspects of the number of differentially expressed genes, the fold change and the brain region, there was a great difference in the expression of learning or memory related genes between AD and SZ. In AD, the CALB1, GABRA5, and TAC1 were significantly downregulated in whole brain, frontal lobe, temporal lobe, and hippocampus. However, in SZ, only two genes CRHBP and CX3CR1 were downregulated in hippocampus, and other brain regions were not affected. The effect of these genes on learning or memory impairment has been widely studied. It was suggested that these genes may play a crucial role in AD or SZ pathogenesis. The different gene expression patterns between AD and SZ on learning and memory functions in different brain regions revealed in our study may help to understand the different mechanism between two diseases.
Pages 427-437
Grazia D’Onofrio, Francesco Panza, Daniele Sancarlo, Francesco F. Paris, Leandro Cascavilla, Antonio Mangiacotti, Michele Lauriola, Giulia H. Paroni, Davide Seripa, Antonio Greco (Handling Associate Editor: Patrick Kehoe)
Delusions in Patients with Alzheimer’s Disease: A Multidimensional Approach
Abstract: In Alzheimer’s disease (AD) patients with delusions, clinical outcomes and mortality result from a combination of psychological, biological, functional, and environmental factors. We determined the effect of delusions on mortality risk, clinical outcomes linked to comprehensive geriatric assessment (CGA), cognitive, depressive, and neuropsychiatric symptoms (NPS) in 380 consecutive AD patients with Mini-Mental State Examination, Clinical Dementia Rating scale, 15-item Geriatric Depression Scale, and Neuropsychiatric Inventory (NPI), assessing one-year mortality risk using the Multidimensional Prognostic Index (MPI). We included 121 AD patients with delusions (AD-D) and 259 AD patients without delusions (AD-noD). AD-D patients were significantly older, with higher age at onset and cognitive impairment, a more severe stage of dementia, and more depressive symptoms than AD-noD patients. Disease duration was slightly higher in AD-D patients than in those without delusions, although this difference was not statistically significant. At CGA, AD-D patients showed a higher grade of disability in basic and instrumental activities of daily living, and an increased risk of malnutrition and bedsores. The two groups of patients significantly differed in MPI score (AD-D: 0.65 versus AD-noD: 0.51, p<0.0001) and MPI grade. AD-D patients showed also a significant higher score in NPI of the following NPS than AD-noD patients: hallucinations, agitation/aggression, depression mood, apathy, irritability/lability, aberrant motor activity, sleep disturbances, and eating disorders. Therefore, AD-D patients showed higher dementia severity, and higher impairment in cognitive and depressive symptoms, and several neuropsychiatric domains than AD-noD patients, and this appeared to be associated with higher multidimensional impairment and increased risk of mortality.
Pages 439-449
Edimansyah Abdin*, Mythily Subramaniam*, Evanthia Achilla, Siow Ann Chong, Janhavi Ajit Vaingankar, Louisa Picco, Rajeswari Sambasivam, Shirlene Pang, Boon Yiang Chua, Li Ling Ng, Hong Choon Chua, Derrick Heng, Martin Prince, Paul McCrone *These authors contributed equally to this work.
The Societal Cost of Dementia in Singapore: Results from the WiSE Study
Abstract: Background: There is currently limited evidence on the economic burden that dementia exerts on multi-ethnic Asian populations. Objective: The present study aimed to estimate the economic cost of dementia in Singapore. Methods: We used data from the Well-being of the Singapore Elderly study, a nationally representative survey of the older Singapore Resident population aged 60 years and above. Generalized linear modeling was used to estimate factors associated with costs. Results: The total cost of dementia in 2013 was estimated at S$532 million (95% CI, S$361 million to S$701 million) while the annual cost per person was estimated at S$10,245 per year (95% CI, S$6,954 to S$12,495). Apart from dementia, higher total societal cost were also significantly associated with older age, Indian ethnicity, and those who were diagnosed with heart problems, stroke, diabetes or depression, whereas being divorced/separated, lower education, and those who were diagnosed with hypertension were significantly associated with lower total societal cost. Conclusion: The study provides a rich body of information on healthcare utilization and cost of dementia, which is essential for future planning of services for the elderly population.
Pages 451-461
Ioannis Karakis, Matthew P. Pase, Alexa Beiser, Sarah L. Booth, Paul F. Jacques, Gail Rogers, Charles DeCarli, Ramachandran S. Vasan, Thomas J. Wang, Jayandra J. Himali, Cedric Annweiler, Sudha Seshadri (Handling Associate Editor: Thomas Shea)
Association of Serum Vitamin D with the Risk of Incident Dementia and Subclinical Indices of Brain Aging: The Framingham Heart Study
Abstract: Background: Identifying nutrition- and lifestyle-based risk factors for cognitive impairment and dementia may aid future primary prevention efforts. Objective: We aimed to examine the association of serum vitamin D levels with incident all-cause dementia, clinically characterized Alzheimer’s disease (AD), MRI markers of brain aging, and neuropsychological function. Methods: Framingham Heart Study participants had baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations measured between 1986 and 2001. Vitamin D status was considered both as a continuous variable and dichotomized as deficient (<10 ng/mL), or at the cohort-specific 20th and 80th percentiles. Vitamin D was related to the 9-year risk of incident dementia (n=1663), multiple neuropsychological tests (n=1291) and MRI markers of brain volume, white matter hyperintensities and silent cerebral infarcts (n=1139). Results: In adjusted models, participants with vitamin D deficiency (n=104, 8% of the cognitive sample) displayed poorer performance on Trail Making B-A (β= -0.03 to -0.05 ± 0.02) and the Hooper Visual Organization Test (β = -0.09 to -0.12 ± 0.05), indicating poorer executive function, processing speed, and visuo-perceptual skills. These associations remained when vitamin D was examined as a continuous variable or dichotomized at the cohort specific 20th percentile. Vitamin D deficiency was also associated with lower hippocampal volumes (β= -0.01 ± 0.01) but not total brain volume, white matter hyperintensities, or silent brain infarcts. No association was found between vitamin D deficiency and incident all-cause dementia or clinically characterized AD. Conclusions: In this large community-based sample, low 25(OH)D concentrations were associated with smaller hippocampal volume and poorer neuropsychological function.
Pages 463-470
Matthew T. White, Leslie M. Shaw, Sharon X. Xie4; for the Alzheimer's Disease Neuroimaging Initiative and the National Alzheimer's Coordinating Center (Handling Associate Editor: Michelle Mielke)
Evaluation of Cerebrospinal Fluid Assay Variability in Alzheimer's Disease
Abstract: Studies of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have indicated that much of the variability observed in the biomarkers may be due to measurement error. Biomarkers are often obtained with measurement error, which may make the diagnostic biomarker appear less effective than it truly is. In the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, technical replicates of CSF biomarkers are available; the National Alzheimer's Coordinating Center database contains longitudinal replicates of CSF biomarkers. We focus on the area under the receiver operating characteristic curve (AUC) as the measure of diagnostic effectiveness for differentiating AD from normal cognition using CSF biomarkers and compare AUC estimates obtained by a more standard, naïve method (which uses a single observation per subject and ignores measurement error) to a maximum likelihood (ML) based method (which uses all replicates per subject and adjusts for measurement error). The choice of analysis method depends upon the noise to signal ratio (i.e., the magnitude of the measurement error variability relative to the true biomarker variability); moderate to high ratios may significantly bias the naïve AUC estimate, and the ML-based method would be preferred. The noise to signal ratios were low for the ADNI biomarkers but high for the tTau and pTau biomarkers in NACC. Correspondingly, the naïve and ML-based AUC estimates were nearly identical in the ADNI data but dissimilar for the tTau and pTau biomarkers in the NACC data. Therefore, using the naïve method is adequate for analysis of CSF biomarkers in the ADNI study, but the ML method is recommended for the NACC data.
Pages 471-487
He Xu, Victoria M. Perreau, Krista A. Dent, Ashley I. Bush, David I. Finkelstein*, Paul A. Adlard* *These authors contributed equally to this work.
Iron Regulates Apolipoprotein E Expression and Secretion in Neurons and Astrocytes
Abstract: Background: There is strong evidence that iron homeostasis is impaired in the aging and Alzheimer’s disease (AD) brain and that this contributes to neurodegeneration. Apolipoprotein E (APOE) has been identified as the strongest genetic risk factor for AD. However, the interaction between the two has yet to be fully explored. Objective: This study aimed to investigate the relationship between exogenous iron levels and ApoE in neurons and astrocytes. Methods: Our study used primary cultured cortical neurons and astrocytes to investigate the changes in ApoE caused by iron. Western blot and RT-PCR were used to measure ApoE. Results: We observed that iron upregulated intracellular ApoE levels in both neurons and astrocytes at the post-transcriptional and transcriptional level, respectively. However, there was less full-length ApoE secreted by neurons and astrocytes after iron treatment. We speculate that this might impair brain lipid metabolism and amyloid-β clearance. In terms of ApoE receptors, we observed that neuronal LRP-1 levels were increased by the addition of exogenous iron, which could contribute to AβPP endocytosis in neurons. However, there were no significant changes in neuronal LDLR, astrocyte LDLR, or astrocyte LRP-1. Conclusion: Our study reveals that iron may contribute to the pathogenesis of AD by affecting ApoE and its receptors and supports the notion that iron chelation should be investigated as a therapeutic strategy for AD.
Pages 489-500
Ester Aso, Pol Andrés-Benito, Margarita Carmona, Rafael Maldonado, Isidre Ferrer (Handling Associate Editor: Tommaso Cassano)
Cannabinoid Receptor 2 Participates in Amyloid-β Processing in a Mouse Model of Alzheimer’s Disease but Plays a Minor Role in the Therapeutic Properties of a Cannabis-Based Medicine
Abstract: The endogenous cannabinoid system represents a promising therapeutic target to modify neurodegenerative pathways linked to Alzheimer’s disease (AD). The aim of the present study was to evaluate the specific contribution of CB2 receptor to the progression of AD-like pathology and its role in the positive effect of a cannabis-based medicine (1:1 combination of D9-tetrahidrocannabinol and cannabidiol) previously demonstrated to be beneficial in the AβPP/PS1 transgenic model of the disease. A new mouse strain was generated by crossing AβPP/PS1 transgenic mice with CB2 knockout mice. Results show that lack of CB2 exacerbates cortical Aβ deposition and increases the levels of soluble Aβ40. However, CB2 receptor deficiency does not affect the viability of AβPP/PS1 mice, does not accelerate their memory impairment, does not modify tau hyperphosphorylation in dystrophic neurites associated to Aβ plaques, and does not attenuate the positive cognitive effect induced by the cannabis-based medicine in these animals. These findings suggest a minor role for the CB2 receptor in the therapeutic effect of the cannabis-based medicine in AβPP/PS1 mice, but also constitute evidence of a link between CB2 receptor and Aβ processing.
Pages 501-514
José A. Luchsinger, Thania Perez, Helena Chang, Pankaj Mehta, Jason Steffener, Gnanavalli Pradabhan, Masanori Ichise, Jennifer Manly, Devangere P. Devanand, Emilia Bagiela
Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial
Abstract: Diabetes and hyperinsulinemia may be risk factors for Alzheimer’s disease (AD). We conducted a pilot study of metformin, a medication efficacious in treating and preventing diabetes while reducing hyperinsulinemia, among persons with amnestic mild cognitive impairment (aMCI) with the goal of collecting preliminary data on feasibility, safety, and efficacy. Participants were 80 men and women aged 55 to 90 years with aMCI, overweight or obese, without treated diabetes. We randomized participants to metformin 1000 mg twice a day or matching placebo for 12 months. The co-primary clinical outcomes were changes from baseline to 12 months in total recall of the Selective Reminding Test (SRT) and the score of the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcome was change in relative glucose uptake in the posterior cingulate-precuneus in brain fluorodeoxyglucose positron emission tomography. Change in plasma Aβ42 was an exploratory outcome. The mean age of participants was 65 years. Fifty percent of participants were women. The only baseline variable that was different between the arms was the ADAS-Cog. Metformin could not be tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose. There were no serious adverse events related to metformin. The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms. After adjusting for baseline ADAS-cog, changes in total recall of the SRT favored the metformin group (9.7 ± 8.5 versus 5.3 ± 8.5; p = 0.02). Differences for other outcomes were not significant. A larger trial seems warranted to evaluate the efficacy and cognitive safety of metformin in prodromal AD.
Pages 515-523
Huei-Yang Chen, Peter K. Panegyres
The Role of Ethnicity in Alzheimer’s Disease: Findings from the C-PATH Online Data Repository
Abstract: Background: Ethnic minorities seem to be at an increased risk of Alzheimer’s disease (AD). However, little is known about ethnic differences and the risks of early onset AD (EOAD). Objective: Cognitive function changes over time and odds of EOAD by ethnicity were analyzed by the mixed model and the logistic regression. Methods: Information on demographics, self-reported co-morbidities, cognitive functions (MMSE and ADAS-COG), and ApoE genotypes were collected for 6,500 subjects with AD obtained from the placebo arm of clinical trials; this data was examined by ethnicities: Caucasian, Asian, African American, Hispanic, and other minorities—including Native Alaskans, Americans, and Hawaiians. Results: Of the total subjects, Caucasians accounted for 89.0%, followed by 4.7% Asians, 2.7% African Americans, 2.4% Hispanics, and 1.2% Native Americans, Alaskans, and Hawaiians. Age, gender, EOAD status, co-morbidities, family history of AD, and ApoE genotypes were significantly different by ethnicity. ApoE ε2 allele is possibly overrepresented in the Native Americans, Africans, Hawaiians, and African Americans. A significant interaction with time, ethnicity, and cognitive performance was found, indicating more cognitive deterioration in other minorities than Caucasians for mini-mental state (p<0.01). After adjusting for co-morbidities and gender, the odds of EOAD among African Americans (OR: 1.6, 95%CI: 1.1-2.4) and Native Alaskans, Americans, and Hispanics (OR: 2.1, 95%CI: 1.2-3.5) were significantly higher, compared with Caucasians. Conclusions: Ethnicity may impact AD through age of onset, co-morbidities, family history, ApoE gene status, and cognitive change over time. The greater odds of EOAD among African Americans, Alaskans, and Hawaiians suggest that some ethnicities may be at risk of AD at a younger age.
Pages 525-532
Shuguang Chu*, Feijia Xu*, Ya Su, Hong Chen, Xin Cheng (Handling Associate Editor: Jintai Yu) *These authors contributed equally to this work.
Cerebral Amyloid Angiopathy (CAA)-Related Inflammation: Comparison of Inflammatory CAA and Amyloid-β-Related Angiitis
Abstract: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a relatively rare syndrome of reversible encephalopathy and could be divided into two subtypes of inflammatory CAA (ICAA) and amyloid-β-related angiitis (ABRA) according to histopathology. We present a case of pathologically proved ABRA with partial seizures and headache, and a focal lesion in the right temporal lobes on magnetic resonance imaging. Summarized from previous 139 ABRA and ICAA cases, ABRA is preferred when the lesion is enhanced on MRI and requires combination drug therapy, while ICAA is highly suspected with ApoE genotype of ε4/ε4. More clinical markers for diagnosis of CAA-ri warrant further researches.
Pages 533-544
Julián Benito-León, Israel Contador, Alex J. Mitchell, Ángela Domingo-Santos, Félix Bermejo-Pareja (Handling Associate Editor: Ignacio Casado Naranjo)
Performance on Specific Cognitive Domains and Cause of Death: A Prospective Population-Based Study in Non-Demented Older Adults (NEDICES)>
Abstract: Evidence regarding the relationship between performance on specific cognitive domains and cause of death is scarce. We assessed whether specific cognitive domains predicted mortality and the presence of any association with specific causes of death in a population-dwelling sample of non-demented older adults. In this population-based, prospective study (NEDICES), 2,390 non-demented subjects ≥65 years completed a brief neuropsychological battery. Cox's proportional hazards models, adjusted by sociodemographic and comorbidity factors, global cognitive performance, educational level, and premorbid intelligence were used to assess the risk of death. Participants were followed for a median of 9.2 years (range 0.01–10.7), after which the death certificates of those who died were examined. 880 (36.8%) of 2,390 participants died over a median follow-up of 5.5 years (range 0.01–10.5). Using adjusted Cox regression models, we found that hazard ratios for mortality in participants within the lowest tertiles (worse performance) were 1.31 (speed of cognitive processing, p=0.03); 1.22 (semantic fluency, p=0.04), 1.32 (delayed free recall, p=0.003), and 1.23 (delayed logical memory, p=0.03). Poor performance on delayed recall and speed of cognitive processing tests were associated with dementia and cerebrovascular disease mortality, respectively. Further, poor performance on semantic fluency was associated with decreased cancer mortality. In this study of community dwelling non-demented older adults, worse neuropsychological performance was associated with increased risk of mortality. Performance on specific cognitive domains were related to different causes of death. Of particular note there appears to be an inverse association between poor semantic fluency and cancer mortality.
Pages 545-561
Philipp Heßmann, Greta Seeberg, Jens Peter Reese, Judith Dams, Erika Baum, Matthias J. Müller, Richard Dodel, Monika Balzer-Geldsetzer (Handling Associate Editor: Julián Benito-León)
Health-Related Quality of Life in Patients with Alzheimer's Disease in Different German Health Care Settings
Abstract: The purpose of this study is to evaluate the health-related quality of life (HrQoL) of patients with Alzheimer’s disease (AD) in different care settings (institutionalized versus community-dwelling) across all severity stages of dementia. Patients were consecutively recruited with their primary caregivers (123 inpatients and 272 outpatients), and the impact of patient-related parameters such as behavioral and psychological symptoms of dementia (BPSD) (Geriatric Depression Scale [GDS] and Neuropsychiatric Inventory [NPI]) and functional capacity (Alzheimer’s Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]) on HrQoL was analyzed. Patients’ HrQoL was assessed using self-reported and caregiver-rated generic (EuroQoL Instrument) and dementia-specific (Quality of Life-Alzheimer’s Disease [Qol-AD]) scales. Patients reported a considerably higher HrQoL than their caregivers on the QoL-AD, EQ-5D, and EQ VAS (p < 0.001). Different dementia severity groups showed significantly worse results in HrQoL for patients with lower MMSE scores. The mean self-reported QoL-AD decreased from 32.3 ± 5.7 in the group with the highest MMSE scores to 27.1 ± 5.5 in patients with the lowest MMSE scores (p < 0.001). A considerably lower HrQoL was shown for institutionalized patients versus participants in outpatient settings (proxy-rated QoL-AD 19.7 ± 4.6 versus 26.0 ± 7.1, p < 0.001). Depressive symptoms (GDS), BPSD (NPI), and reduced functional capacity (ADCS-ADL) were evaluated for their impact on patients’ HrQoL. Multivariate models explained between 22% and 54% of the variance in patients’ HrQoL. To analyze the causative direction of the reported associations, further longitudinal studies should be conducted.
Pages 563-570
Andrea Pilotto, Rosanna Turrone, Inga Liepelt-Scarfone, Marta Bianchi, Loris Poli, Barbara Borroni, Antonella Alberici, Enrico Premi, Anna Formenti, Barbara Bigni, Maura Cosseddu, Elisabetta Cottini, Daniela Berg, Alessandro Padovani (Handling Associate Editor: Francesco Panza)
Vascular Risk Factors and Cognition in Parkinson’s Disease
Abstract: Vascular risk factors have been associated with cognitive deficits and incident dementia in the general population, but their role on cognitive dysfunction in Parkinson’s disease (PD) is still unclear. The present study addresses the single and cumulative effect of vascular risk factors on cognition in PD patients, taking clinical confounders into account. Standardized neuropsychological assessment was performed in 238 consecutive PD patients. We evaluated the association of single and cumulative vascular risk factors (smoking, diabetes, hypercholesterolemia, hypertension, and heart disease), with the diagnosis of PD normal cognition (PDNC, n=94), mild cognitive impairment (PD-MCI, n=111), and dementia (PDD, n=33). The association between single neuropsychological tests and vascular risk factors was evaluated with covariance analyses adjusted for age at onset, educational levels, gender, disease duration, and motor performance. Age, educational levels, disease duration, and motor function were significantly different between PDNC, PD-MCI, and PDD. Heart disease was the only vascular factor significantly more prevalent in PDD compared with PDNC in adjusted analyses. Performance of tests assessing executive and attention functions were significantly worse in patients with hypertension, heart disease, and/or diabetes (p<0.05). Heart disease is associated with dementia in PD, suggesting a potential window of intervention. Vascular risk factors act especially on attention and executive functions in PD. Vascular risk stratification may be useful in order to identify PD patients with a greater risk of developing dementia. These findings need to be verified in longitudinal studies.
Pages 571-580
Du Fang*, Zhihua Zhang*, Hang Li, Qing Yu, Justin T. Douglas, Anna Bratasz, Periannan Kuppusamy, Shirley ShiDu Yan (Handling Associate Editor: Hemachandra Reddy) *These authors contributed equally to this work.
Increased Electron Paramagnetic Resonance Signal Correlates with Mitochondrial Dysfunction and Oxidative Stress in an Alzheimer’s Disease Mouse Brain
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized clinically by cognitive decline and memory loss. The pathological features are amyloid-β peptide (Aβ) plaques and intracellular neurofibrillary tangles. Many studies have suggested that oxidative damage induced by reactive oxygen species (ROS) is an important mechanism for AD progression. Our recent study demonstrated that oxidative stress could further impair mitochondrial function. In the present study, we adopted a transgenic mouse model of AD (mAPP, overexpressing AβPP/Aβ in neurons) and performed redox measurements using in vivo electron paramagnetic resonance (EPR) imaging with methoxycarbamyl-proxyl (MCP) as a redox-sensitive probe for studying oxidative stress in early stage of transgenic AD mouse model. Through assessing oxidative stress, mitochondrial function and cognitive behaviors of mAPP mice at the age of 8-9 months, we found that oxidative stress and mitochondrial dysfunction appeared in the early onset of AD. Increased ROS levels were associated with defects of mitochondrial and cognitive dysfunction. Notably, the in vivo EPR method offers a unique way of assessing tissue oxidative stress in living animals under noninvasive conditions, and thus holds a potential for early diagnosis and monitoring the progression of AD.
Pages 581-590
Eva Louwersheimer, M. Antoinette Keulen, Martijn D. Steenwijk, Mike P. Wattjes, Lize C. Jiskoot, Hugo Vrenken, Charlotte E. Teunissen, Bart N.M. van Berckel, Wiesje M. van der Flier, Philip Scheltens, John C. van Swieten, Yolande A.L. Pijnenburg (Handling Associate Editor: Cristian Leyton)
Heterogeneous Language Profiles in Patients with Primary Progressive Aphasia due to Alzheimer’s Disease
Abstract: Background: The logopenic variant of Primary Progressive Aphasia (lvPPA) is associated with underlying Alzheimer’s disease (AD) pathology and characterized by impaired single word retrieval and repetition of phrases and sentences. Objective: We set out to study whether logopenic aphasia is indeed the prototypic language profile in PPA patients with biomarker evidence of underlying AD pathology and to correlate language profiles with cortical atrophy patterns on MRI. Methods: Inclusion criteria: (I) clinical diagnosis of PPA; (II) CSF profile and/or PiB-PET scan indicative for amyloid pathology; (III) availability of expert language evaluation. Based on language evaluation, patients were classified as lvPPA (fulfilling lvPPA core criteria), lvPPA extended (fulfilling core criteria plus other language disturbances), or PPA unclassifiable (not fulfilling lvPPA core criteria). Cortical atrophy patterns on MRI were visually rated and quantitative measurements of cortical thickness were performed using FreeSurfer. Results: We included 22 patients (age 67±7 years, 50% female, MMSE 21±6). 41% were classified as lvPPA, 36% as lvPPA extended with additional deficits in language comprehension and/or confrontation naming, and 23% as PPA unclassifiable. By both qualitative and quantitative measurements, patients with lvPPA showed mild global cortical atrophy on MRI, whereas patients with lvPPA extended showed more focal cortical atrophy, predominantly at the left tempo-parietal side. For PPA unclassifiable, qualitative measurements revealed a heterogeneous atrophy pattern. Conclusion: Although most patients fulfilled the lvPPA criteria, we found that their language profiles were heterogeneous. The clinical and radiological spectrum of PPA due to underlying AD pathology is broader than pure lvPPA.
Pages 591-604
Jung Min Song*, You Me Sung*, Jin Han Nam*, Hyejin Yoon, Andrew Chung, Emily Moffat, Mira Jung, Daniel T. S. Pak, Jungsu Kim, Hyang-Sook Hoe *These authors contributed equally to this work.
A Mercaptoacetamide-Based Class II Histone Deacetylase Inhibitor Increases Dendritic Spine Density via RasGRF1/ERK Pathway
Abstract: Background: The accumulation of amyloid-β (Aβ) leads to the loss of dendritic spines and synapses, which is hypothesized to cause cognitive impairments in Alzheimer’s disease (AD) patients. In our previous study, we demonstrated that a novel mercaptoacetamide-based class II histone deacetylase inhibitor (HDACI), known as W2, decreased Aβ levels and improved learning and memory in mice. However, the underlying mechanism of this effect is unknown. Objective: Because dendritic spine formation is associated with cognitive performance, here we investigated whether HDACI W2 regulates dendritic spine density and its molecular mechanism of action. Methods: To examine the effect of HDACI W2 on dendritic spine density, we conducted morphological analysis of dendritic spines using GFP transfection and Golgi staining. In addition, to determine the molecular mechanism of W2 effects on spines, we measured the levels of mRNAs and proteins involved in the Ras signaling pathway using quantitative real-time PCR, immunocytochemistry, and western analysis. Results: We found that HDACI W2 altered dendritic spine density and morphology in vitro and in vivo. Additionally, W2 increased the mRNA or protein levels of Ras GRF1 and phospho-ERK. Moreover, knockdown of RasGRF1 and inhibition of ERK activity prevented the W2-mediated spinogenesis in primary hippocampal neurons. Conclusion: Our Class II-selective HDACI W2 promotes the formation and growth of dendritic spines in a RasGRF1 and ERK dependent manner in primary hippocampal neurons.
Pages 605-617
Xiao-Ping Hong*, Tao Chen*, Ni-Na Yin, Yong-Ming Han, Fang Yuan, Yan-Jun Duan, Feng Shen, Yan-Hong Zhang, Ze-Bin Chen *These authors contributed equally to this work.
Puerarin Ameliorates D-Galactose Induced Enhanced Hippocampal Neurogenesis and Tau Hyperphosphorylation in Rat Brain
Abstract: Enhanced neurogenesis has been reported in the hippocampus of patients with Alzheimer’s disease (AD), the most common neurodegenerative disorder characterized with amyloid-β (Aβ) aggregation, tau hyperphosphorylation, and progressive neuronal loss. Previously we reported that tau phosphorylation played an essential role in adult hippocampal neurogenesis, and activation of glycogen synthase kinase (GSK-3), a crucial tau kinase, could induce increased hippocampal neurogenesis. In the present study, we found that treatment of D-galactose rats with Puerarin could significantly improve behavioral performance and ameliorate the enhanced neurogenesis and microtubule-associated protein tau hyperphosphorylation in the hippocampus of D-galactose rat brains. FGF-2/GSK-3 signaling pathway might be involved in the effects of Puerarin on hippocampal neurogenesis and tau hyperphosphorylation. Our finding provides primary in vivo evidence that Puerarin can attenuate AD-like enhanced hippocampal neurogenesis and tau hyperphosphorylation. Our finding also suggests Puerarin can be served as a treatment for age-related neurodegenerative disorders, such as AD.
Pages 619-629
Rónán O’Caoimh, Suzanne Timmons, D. William Molloy
Screening for Mild Cognitive Impairment: Comparison of “MCI Specific” Screening Instruments
Abstract: Background: Sensitive and specific instruments are required to screen for cognitive impairment (CI) in busy clinical practice. The Montreal Cognitive Assessment (MoCA) is widely validated but few studies compare it to tests designed specifically to detect mild cognitive impairment (MCI). Objective: Comparison of two “MCI specific” screens: the Quick Mild Cognitive Impairment screen (Qmci) and MoCA. Methods: Patients with subjective memory complaints (SMC; n=73), MCI (n=103), or dementia (n=274), and were referred to a university hospital memory clinic, underwent comprehensive assessment. Caregivers, without cognitive symptoms, were recruited as normal controls (n =101). Results: The Qmci was more accurate than the MoCA in differentiating MCI from controls, area under the curve (AUC) of 0.90 versus 0.80, p=0.009. The Qmci had greater (AUC 0.81), albeit non-significant, accuracy than the MoCA (AUC 0.73) in separating MCI from SMC, p=0.09. At its recommended cut-off (<62/100), the Qmci had a sensitivity of 90% and specificity of 87% for CI (MCI/dementia). Raising the cut-off to <65 optimized sensitivity (94%), reducing specificity (80%). At <26/30 the MoCA had better sensitivity (96%) but poor specificity (58%). A MoCA cut-off of <24 provided the optimal balance. Median Qmci administration time was 4.5 (± 1.3) minutes compared with 9.5 (± 2.8) for the MoCA. Conclusions: Although both tests distinguish MCI from dementia, the Qmci is particularly accurate in separating MCI from normal cognition and has shorter administration times, suggesting it is more useful in busy hospital clinics. This study reaffirms the high sensitivity of the MoCA but suggests a lower cut-off (<24) in this setting.
