Volume 33, Number 3, January 2013

Pages 547-658
Wolfgang Froestl, Andreas Muhs, Andrea Pfeifer
Cognitive Enhancers (Nootropics). Part 2: Drugs interacting with Enzymes
Abstract: Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer’s disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. This review covers the evolution of research in this field over the last 25 years.

Pages 659-674
Cedric Annweiler, David J Llewellyn, Olivier Beauchet (Handling Associate Editor: William Grant)
Low Serum Vitamin D Concentrations in Alzheimer’s Disease: A Systematic Review and Meta-Analysis
Abstract: Vitamin D has been investigated in association with cognitive function in older adults. It is unclear whether hypovitaminosis D could be associated with Alzheimer’s disease (AD). Our objective was to systematically review and quantitatively synthesize the association of low serum 25-hydroxyvitamin D (25OHD) concentrations with AD in adults. A Medline and PsycINFO® search was conducted on May 2012, with no limit of date, using the MeSH terms "Vitamin D" OR "Hydroxycholecalciferols" combined with the MeSH terms "Alzheimer disease" OR "Dementia" OR "Cognition" OR "Cognition disorders" OR "Memory" OR "Memory Disorders" OR "Executive Function" OR "Attention" OR "Neuropsychological Tests". Of the 284 selected studies, 10 observational studies (including 9 case-controls and 1 cohort study) met the selection criteria. All were of good quality. The number of AD cases ranged from 20 to 211 (40%-100% female). Finally, 7 case-control studies were eligible for fixed and random-effects meta-analyses of bias-corrected effect size of the difference in serum 25OHD concentrations between AD cases and controls using an inverse-variance method. The pooled effect size in random-effects meta-analysis was 1.40 (95%CI: 0.26;2.54), a ‘large’ effect size that indicates that serum 25OHD concentrations were 1.4 standard deviation units lower in AD cases compared to cognitively healthy controls (p=0.016). In conclusion, AD cases had lower serum vitamin D concentrations than matched controls. This reinforces the conceptualization of vitamin D as a ‘neurosteroid hormone’ and as a potential biomarker of AD.

Pages 675-679
Short Communication
Yen Ying Lim, Robert H. Pietrzak, Kathryn A. Ellis, Judith Jaeger, Karra Harrington, Tim Ashwood, Cassandra Szoeke, Ralph N. Martins, Ashley I. Bush, Colin L. Masters, Christopher C. Rowe, Victor L. Villemagne, David Ames, David Darby, Paul Maruff
Rapid Decline in Episodic Memory in Healthy Older Adults with High Amyloid-β
Abstract: High levels of amyloid-β (Aβ) have been associated with greater rates of decline in episodic memory over 18 months in healthy older adults. Serial assessments over shorter time intervals may facilitate earlier detection of Aβ-related memory decline in healthy older adults. In forty-four healthy older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Rate of Change Sub-Study, we compared rates of change in cognition over six months in healthy older adults with high and low levels of Aβ. High Aβ was associated with greater decline in episodic memory measures over 6 months in healthy older adults.

Supplementary Data for Lim et al. article (PDF)

Pages 681-698
Katherine E. Davis, Alex Easton, Madeline J. Eacott, John Gigg
Episodic-Like Memory for What-Where-Which Occasion is Selectively Impaired in the 3xTgAD Mouse Model of Alzheimer’s Disease
Abstract: Episodic memory loss is a defining feature of early-stage Alzheimer’s disease (AD). A test of episodic-like memory for the rat, the What-Where-Which occasion task (WWWhich), requires the association of object, location, and contextual information to form an integrated memory for an event. The WWWhich task cannot be solved by use of non-episodic information such as object familiarity and is dependent on hippocampal integrity. Thus, it provides an ideal tool with which to test capacity for episodic-like memory in the 3xTg murine model for AD. As this model captures much of the human AD phenotype, we hypothesized that these mice would show a deficit in the WWWhich episodic-like memory task. To test the specificity of any episodic-like deficit, we also examined whether mice could perform components of the WWWhich task that do not require episodic-like memory. These included object (Novel Object Recognition), location (Object Location Task, What-Where task), and contextual (What-Which) memory, as well as another three-component task that can be solved without reliance on episodic recall (What-Where-When; WWWhen). The results demonstrate for the first time that control 129sv/c57bl6 mice could form WWWhich episodic-like memories, wherea, 3xTgAD mice at 6 months of age were impaired. Importantly, while 3xTgAD mice showed some deficit on spatial component tasks, they were unimpaired in the more complex WWWhen combination task (which includes a spatial component and is open to non-episodic solutions). These results strongly suggest that AD pathology centered on the hippocampal formation mediates a specific deficit for WWWhich episodic-like memory in the 3xTgAD model.

Pages 699-713
Gucci Jijuan Gu, Di Wu, Harald Lund, Dan Sunnemark, Alexander Kvist, Roy Milner, Sonia Eckersley, Lars Nilsson, Karin Agerman, Ulf Landegren, Masood Kamali-Moghaddam
Elevated MARK2-Dependent Phosphorylation of Tau in Alzheimer’s Disease, Analyzed via Proximity Ligation
Abstract: The appearance of neurofibrillary tangles (NFT), one of the major hallmarks of Alzheimer’s disease (AD), is most likely caused by inappropriate phosphorylation and/or dephosphorylation of tau, eventually leading to the accumulation of NFTs. Enhanced phosphorylation of tau on Ser262 is detected early in the course of the disease and may have a role in the formation of tangles. Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser262 in vitro. In this study, we took advantage of the in situ proximity ligation assay (in situ proximity ligation assay) to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser262 in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser262. Furthermore, we observed elevated interactions between MARK2 and tau in postmortem human AD brains, compared to samples from non-demented elderly controls. Our results from transfected cells demonstrate specific interaction between MARK2 and tau, as well as MARK2-dependent phosphorylation of tau at Ser262. Furthermore, the elevated interactions between MARK2 and tau in AD brain sections suggests that MARK2 may play an important role in early phosphorylation of tau in AD, possibly qualifying as a therapeutic target for intervention to prevent disease progression.

Supplementary Data for Gu et al. article (PDF)

Pages 715-721
Carmen Echávarri, Saartje Burgmans, Harry Uylings, Manuel J. Cuesta, Victor Peralta, Wouter Kamphorst, Annemieke J.M. Rozemuller, Frans R.J. Verhey
Neuropsychiatric Symptoms in Alzheimer’s Disease and Vascular Dementia
Abstract: Neuropsychiatric symptoms (NPSs) have a large impact on the quality of life of patients with dementia. A few studies have compared neuropsychiatric disturbances between dementia subtypes, but the results were conflicting. In the present study, we investigated whether the prevalence of NPSs differs between Alzheimer’s disease (AD) and vascular dementia (VaD). The merit of our study is that we used clinical as well as histopathological information to differentiate between dementia subtypes. This retrospective descriptive study comprised 80 brains obtained from donors to the Netherlands Brain Bank between 1984 and 2010. These donors were diagnosed postmortem with AD (n = 40) or VaD (n = 40). We assessed the presence of NPSs by reviewing the information found in the patients’ medical files. The most prevalent symptom in the sample as a whole was agitation (45 cases, 57.0%), followed by depression (33, 41.2%) and anxiety (28, 35.4%). Our study tried to contribute to the discussion by including, for the first time in the literature, a sample of AD and VaD patients with neuropathologically confirmed diagnoses. Since no significant differences were found between AD and VaD patients, we suggest that the prevalence of NPSs cannot be predicted from the diagnosis of AD or VaD.

Pages 723-736
Per Selnes, Dag Aarsland, Atle Bjørnerud, Leif Gjerstad, Anders Wallin, Erik Hessen, Ivar Reinvang, Ramune Grambaite, Eirik Auning, Veslemøy Krohn Kjærvik, Paulina Due-Tønnessen, Vidar Stenset, Tormod Fladby
Diffusion Tensor Imaging Surpasses Cerebrospinal Fluid as Predictor of Cognitive Decline and Medial Temporal Lobe Atrophy in Subjective Cognitive Impairment and Mild Cognitive Impairment
Abstract: Neuropathological correlates of Alzheimer’s disease (AD) emerge years before dementia. Biomarkers preceding cognitive decline and reflecting the causative processes can potentially aid early intervention and diagnosis. Diffusion tensor imaging (DTI) indirectly reflects tissue microstructure. To answer whether DTI is an early biomarker for AD and to explore the relationship between DTI and the established biomarkers of medial temporal lobe atrophy and cerebrospinal fluid (CSF) Aβ42, T-tau, and P-tau, we longitudinally studied normal controls and patients with subjective (SCI) or mild (MCI) cognitive impairment. 21 controls and 64 SCI or MCI cases recruited from a university-hospital based memory clinic were re-examined after two to three years. FreeSurfer was used for longitudinal processing of morphometric data, and DTI derived fractional anisotropy, radial diffusivity, and mean diffusivity were analyzed in Tract-Based Spatial Statistics. Using regression models, we explored and compared the predictive powers of DTI and CSF biomarkers in regard to cognitive change and atrophy of the medial temporal lobe. Both DTI and CSF biomarkers significantly predicted cognitive decline and atrophy in the medial temporal lobe. In this population, however, DTI was a better predictor of dementia and AD-specific medial temporal lobe atrophy than the CSF biomarkers. The case for DTI as an early biomarker for AD is strengthened, but further studies are needed to confirm these results.

Pages 737-753
Katie Lunnon*, Martina Sattlecker*, Simon J. Furney*, Giovanni Coppola, Andrew Simmons, Petroula Proitsi, Michelle K. Lupton, Anbarasu Lourdusamy, Caroline Johnston, Hilkka Soininen, Iwona Kłoszewska, Patrizia Mecocci, Magda Tsolaki, Bruno Vellas, Daniel Geschwind, Simon Lovestone, Richard Dobson±, Angela Hodges± on behalf of the AddNeuroMed Consortium *,± These authors contributed equally.
A Blood Gene Expression Marker of Early Alzheimer’s Disease
Abstract: A marker of Alzheimer’s disease (AD) that can accurately diagnose disease at the earliest stage would significantly support efforts to develop treatments for early intervention. We have sought to determine the sensitivity and specificity of peripheral blood gene expression as a diagnostic marker of AD using data generated on HT-12v3 BeadChips. We first developed an AD diagnostic classifier in a training cohort of 78 AD and 78 control blood samples and then tested its performance in a validation group of 26 AD and 26 control and 118 mild cognitive impairment (MCI) subjects who were likely to have an AD-endpoint. A 48 gene classifier achieved an accuracy of 75% in the AD and control validation group. Comparisons were made with a classifier developed using structural MRI measures, where both measures were available in the same individuals. In AD and control subjects, the gene expression classifier achieved an accuracy of 70% compared to 85% using MRI. Bootstrapping validation produced expression and MRI classifiers with mean accuracies of 76% and 82%, respectively, demonstrating better concordance between these two classifiers than achieved in a single validation population. We conclude there is potential for blood expression to be a marker for AD. The classifier also predicts a large number of people with MCI, who are likely to develop AD, are more AD-like than normal with 76% of subjects classified as AD rather than control. Many of these people do not have overt brain atrophy, which is known to emerge around the time of AD diagnosis, suggesting the expression classifier may detect AD earlier in the prodromal phase. However, we accept these results could also represent a marker of diseases sharing common etiology.

Supplementary Data for Lunnon et al. article (PDF)

Pages 755-766
Latha Velayudhan, Petroula Proitsi, Eric Westman, J-Sebastian Muehlboeck, Patrizia Mecocci, Bruno Vellas, Magda Tsolaki, Iwona Kłoszewska, Hilkka Soininen, Christian Spenger, Angela Hodges, John Powell, Simon Lovestone, Andrew Simmons for the AddNeuroMed consortium
Entorhinal Cortex Thickness Predicts Cognitive Decline in Alzheimer’s Disease
Abstract: Biomarkers for Alzheimer's disease (AD) based on non-invasive methods are highly desirable for diagnosis, disease progression, and monitoring therapeutics. We aimed to study the use of hippocampal volume, entorhinal cortex (ERC) thickness, and whole brain volume (WBV) as predictors of cognitive change in patients with AD. 120 AD subjects, 106 mild cognitive impairment (MCI), and 99 non demented controls (NDC) from the multi-center pan-European AddNeuroMed study underwent MRI scanning at baseline and clinical evaluations at quarterly follow-up up to 1 year. The rate of cognitive decline was estimated using cognitive outcomes, Mini-Mental State Examination (MMSE) and Alzheimer disease assessment scale-cognitive (ADAS-cog) by fitting a random intercept and slope model. AD subjects had smaller ERC thickness and hippocampal and WBV volumes compared to MCI and NDC subjects. Within the AD group, ERC>WBV was significantly associated with baseline cognition (MMSE, ADAS-cog) and disease severity (Clinical dementia rating). Baseline ERC thickness was associated with both longitudinal MMSE and ADAS-cog score changes and WBV with ADAS-cog decline. These data indicates AD subjects with thinner ERC had lower baseline cognitive scores, higher disease severity, and predicted greater subsequent cognitive decline at one year follow up. ERC is a region known to be affected early in the disease. Therefore, the rate of atrophy in this structure is expected to be higher since neurodegeneration begins earlier. Focusing on structural analyses that predict decline can identify those individuals at greatest risk for future cognitive loss. This may have potential for increasing the efficacy of early intervention.

Pages 767-773
Maria Luisa Rocco, Andrea Pristerà, Luana Pistillo, Luigi Aloe, Nadia Canu, Luigi Manni
Brain Cholinergic Markers and Tau Phosphorylation are Altered in Experimental Type 1 Diabetes: Normalization by Electroacupuncture
Abstract: Diabetes often correlates with tau phosphorylation and the development of Alzheimer’s disease. Both are associated with brain cholinergic dysfunction that could benefit from nerve growth factor (NGF)-based therapies. Electroacupuncture (EA) improves brain NGF availability and action. Here we assessed the variations of NGF and tau phosphorylation in the cortex and hippocampus, as well as the expression of choline acetyltransferase in the basal forebrain following diabetes induction and EA in adult rats. We found that EA counteracts diabetes-associated tau hyperphosphorylation and decreases in NGF and choline acetyltransferase, suggesting a possible beneficial effect of EA on brain cholinergic system in diabetes.

Supplementary Data for Rocco et al. article (PDF)

Pages 775-780
Emilie Beaufils*, Diane Dufour-Rainfray*, Caroline Hommet, Florence Brault, Jean-Philippe Cottier, Maria Joao Ribeiro, Karl Mondon, Denis Guilloteau *These authors contributed equally.
Confirmation of the Amyloidogenic Process in Posterior Cortical Atrophy: Value of the Aβ42/Aβ40 Ratio
Abstract: Posterior cortical atrophy (PCA) is characterized by progressive higher-order visuo-perceptual dysfunction and praxis declines. This syndrome is related to several underlying diseases, including Alzheimer’s disease (AD), sometimes involving an amyloidogenic process. The aims of the study were to 1) define cerebrospinal fluid (CSF) biomarker profiles in PCA patients compared to AD patients and 2) explore the amyloidogenic process through the Aβ42/Aβ40 ratio in PCA patients to elucidate the underlying disease in vivo. CSF biomarker analysis (t-tau, p-tau, Aβ42, and Aβ42/Aβ40 ratio) and neuropsychological examination were performed in 22 PCA patients and compared with those of age-matched AD patients. Associated clinical neurological signs were investigated (e.g., extrapyramidal motor signs, myoclonus). CSF biomarker profiles did not differ significantly between the PCA and AD groups; 82% of patients with PCA fulfilled the biological criteria for typical AD with abnormal levels of the three markers and 18% of PCA patients presented atypical CSF profiles. All PCA patients with associated clinical neurological signs presented typical AD CSF profiles. The clinical presentations of these patients were similar to other PCA subjects. The Aβ42/Aβ40 ratio for all PCA patients, including those with atypical CSF profiles, was decreased. Most PCA syndromes were associated with CSF biomarkers suggestive of AD, even in cases with associated clinical neurological signs. The amyloidogenic process was confirmed by the decreased Aβ42/Aβ40 ratio for all patients. This analysis avoids misdiagnosis in the presence of physiologically high or low amyloid peptide production rates and provides information in vivo to improve understanding of the underlying disease in PCA.

Pages 781-796
Stéphane D. Girard, Kévin Baranger, Cyrielle Gauthier, Marlyse Jacquet, Anne Bernard, Guy Escoffier, Evelyne Marchetti, Michel Khrestchatisky, Santiago Rivera, François S. Roman (Handling Associate Editor: Gemma Casadesus)
Evidence for Early Cognitive Impairment Related to Frontal Cortex in the 5XFAD Mouse Model of Alzheimer's Disease
Abstract: The frontal cortex is a brain structure that plays an important role in cognition and is known to be affected in Alzheimer’s disease (AD) in humans. Over the past years, transgenic mouse models have been generated to recapitulate the main features of this disease, including cognitive impairments. This study investigates frontal cortex dependent learning abilities in one of the most early-onset transgenic murine model of AD, the 5XFAD mice. We compared frontal performance of 2-, 4-, and 6-month-old 5XFAD mice with their wild-type littermates using a newly developed automated device, the olfactory H-maze, in which mice have to discover three different rules consecutively according to the delayed reaction paradigm. We report early cognitive deficits related to frontal cortex appearing in 4-month-old 5XFAD mice before hippocampal-dependent learning and memory impairment, in relation with neuropathologic processes such as strong gliosis and emerging amyloid plaques. The present results demonstrate that the olfactory H-maze is a very sensitive and simple experimental paradigm that allows assessment of frontal functions in transgenic mice and should be useful to test pre-clinical therapeutic approaches to alter the course of AD.

Pages 797-805
Cara J. Westmark, Pamela R. Westmark, James S. Malter
Soy-Based Diet Exacerbates Seizures in Mouse Models of Neurological Disease
Abstract: Seizures are a common phenotype in many neurological disorders including Alzheimer’s disease, Down syndrome, and fragile X syndrome. Mouse models of these disorders overexpress amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) and are highly susceptible to audiogenic-induced seizures (AGS). We observed decreased AGS in these mice fed a casein-based, purified diet (D07030301) as opposed to a standard soy protein-containing, non-purified diet (Purina 5015). Our objective in this manuscript was to determine if soy protein, and in particular soy isoflavones, in the Purina 5015 were contributing to the seizure phenotype. Wild running, AGS, and death rates were assessed in juvenile mice fed Purina 5015, D07030301, D07030301 containing soy protein, or D07030301 supplemented with individual isoflavones (750 mg/kg daidzein or genistein). A short treatment (3 days) with Purina 5015 induced wild running and AGS in Alzheimer’s disease mice. A 3-day treatment with daidzein-supplemented diet, but not genistein, induced wild running in wild type mice. To understand the mechanism underlying daidzein activity, we assessed dendritic AβPP expression in primary, cultured, wild type neurons treated with daidzein or genistein. In vitro, daidzein significantly increased dendritic AβPP. Thus, the soy isoflavone daidzein recapitulated seizure induction in vivo and altered AβPP expression in vitro. These results have important implications for individuals on soy-based diets as well as for rodent model research.

Supplementary Data for Westmark et al. article (PDF)

Pages 807-822
Nathalie Le Bastard, Laetitia Aerts, Kristel Sleegers, Jean-Jacques Martin, Christine Van Broeckhoven, Peter Paul De Deyn*, Sebastiaan Engelborghs* (Handling Associate Editor: Piotr Lewczuk) *Joint last authors
Longitudinal Stability of Cerebrospinal Fluid Biomarker Levels: Fulfilled Requirement for Pharmacodynamic Markers in Alzheimer’s Disease
Abstract: The current treatment for Alzheimer’s disease (AD) is purely symptomatic, but medications interfering with underlying pathophysiological processes are being developed. To evaluate a possible disease-modifying effect, cerebrospinal fluid (CSF) biomarkers with a direct link to the underlying pathophysiology, such as amyloid-β1-42 (Aβ1-42), total tau protein (T-tau), and hyperphosphorylated tau (P-tau181P), may play an important role. If intra-individual fluctuations in biomarker levels are small, the difference between two samples could serve as a pharmacodynamic measure. The aim of this study was to evaluate the longitudinal stability of CSF Aβ1-42, T-tau, and P-tau181P levels in AD patients and control subjects. Serial CSF samples of 28 AD patients and 23 controls with a minimum time interval of 30 days were included in this study. Serial CSF samples from 10 progressive patients (7 mild cognitive impairment (MCI) patients and 3 controls progressing to MCI or AD) were also analyzed. Intra-individual CSF Aβ1-42 and P-tau181P levels were stable in AD and controls. Intra-individual CSF T-tau levels differed significantly in AD patients, but not in controls. Change in biomarker concentrations per time unit was also significant between groups, but not within groups. The difference in biomarker levels in samples from progressive patients was not significant. In conclusion, CSF levels of Aβ1-42, T-tau, and P-tau181P are relatively stable over time. Only T-tau increased in AD patients in comparison to controls, which does not preclude its use as a diagnostic marker, nor as a potential pharmacodynamic marker.

Pages 823-829
Natividad López, Consuelo Tormo, Isabel De Blas, Isabel Llinares, Jordi Alom
Oxidative Stress in Alzheimer’s Disease and Mild Cognitive Impairment with High Sensitivity and Specificity
Abstract: Some studies have determined that oxidative stress is a decisive factor in Alzheimer’s disease (AD) and even suggested that it is present in the initial phase of mild cognitive impairment (MCI). The aim of our study was to investigate the process of oxidative stress by measuring the level of malondialdehyde (MDA), the specific activity of two peripheral antioxidant defenses (superoxide dismutase (SOD) and ceruloplasmin), and the level of copper in AD and MCI patients and compare those results with healthy subjects. The sample group consisted of 36 patients with AD, 18 patients with MCI, and 33 healthy aged subjects. Blood samples were obtained from each subject. A significantly higher copper level was found in patients with AD and MCI compared to the control group. The levels of MDA showed a similar trend and were higher in patients from the AD and MCI groups than in the control group. It was found that both studied parameters had positive correlation in the whole studied population (r=0.340; p=0.001). A stepwise logistic regression analysis was used to identify an optimal combination of these biomarkers. The optimal biomarker combinations were MDA and SOD with area under the curve of 0.803 (0.691-0.915, CI 95%, p<0.001) for the diagnosis of AD. The optimal cutpoint yielded 88.0% Sensitivity and 70.0% Specificity. The biomarker combinations predicted AD and were markedly superior to individual biomarkers. Our findings support the hypothesis that oxidative stress might represent a sign of AD pathology and could be an early event in the progression of MCI to AD.

Pages 831-840
Joseph B. Dubé, Christopher T. Johansen, John F. Robinson, Joan Lindsay, Vladimir Hachinski, Robert A. Hegele (Handling Associate Editor: Francesco Lescai)
Genetic Determinants of “Cognitive Impairment, No Dementia”
Abstract: Dementia is a heritable condition with devastating effects on both patients and their caregivers. Studies have identified genetic variants associated with increased susceptibility to late-onset Alzheimer disease (AD)-related dementia; however, no studies have assessed whether genetic variation is associated with the early stages of cognitive decline. Given that cerebrovascular disease is an established mechanism in which chronic ischemia increases susceptibility to dementia, we assessed whether genetic variation associated with either cardio-metabolic or AD-related traits is associated with an early stage of cognitive decline called “cognitive impairment, no dementia” (CIND). We studied 484 CIND patients and 459 cognitively healthy controls selected from the Canadian Study of Health and Aging. We tested for association between ~200,000 genetic variants selected from genes associated with cardio-metabolic traits and CIND status using the Cardio-MetaboChip. We also assessed whether AD-related variants and APOE alleles were associated with CIND status, either individually or as part of a composite genetic risk score. We identified a potential association between the ZNF608/GRAMD3 locus, specifically the rs1439568 polymorphism and CIND status (major allele odds ratio [OR]=1.51; p=8.4x10-6). AD-related variants were not associated with CIND status,however APOE E4 allele frequency was significantly higher in CIND patients versus healthy controls (OR=1.35; p=0.044). We identified a potential association between the ZNF608/GRAMD3 locus and CIND status, although AD-related variants were not associated with CIND. Additional replication of this association signal is invited.

Supplementary Data for Dubé et al. article (PDF)

Pages 841-851
Ruiqing Ni, Amelia Marutle, Agneta Nordberg (Handling Associate Editor: Shun Shimohama)
Modulation of α7 Nicotinic Acetylcholine Receptor and Fibrillar Amyloid-β Interactions in Alzheimer’s Disease Brain
Abstract: The nicotinic receptors (nAChRs), which play a critical role in cognitive function, are impaired early in the course of Alzheimer’s disease (AD). We have previously demonstrated that amyloid-β (Aβ) assemblies bind to α7 nAChRs and form complexes in AD brain, suggesting that this cooperative process may contribute to disruption of synaptic function in AD. In the current study, we further characterized the interaction between different nAChR subtypes and fibrillar Aβ by binding assays in postmortem brain from AD and control cases using a wide range of drugs with different molecular targets, including selective nAChR subtype agonists, and the amyloid ligand Pittsburgh compound B (PIB) that binds with high (nanomolar) affinity to fibrillar Aβ. The α7 nAChR agonists varenicline and JN403, but not the α4β2 nAChR agonist cytisine, increased the 3H-PIB binding in autopsy tissue homogenates from AD and control frontal cortex. This effect was blocked in the presence of the α7 nAChR antagonists methyllycaconitine, α-bungarotoxin, and mecamylamine, but not by the α4β2 nAChR antagonist dihydro-β-erythroidine. Increases in 3H-PIB binding evoked by varenicline and JN403 were also prevented by pre-incubation with another amyloid ligand, BF-227. The acetylcholinesterase inhibitor and allosteric nAChR modulator galantamine as well as the N-methyl-d-aspartate receptor blocker memantine did not significantly alter 3H-PIB binding levels in AD brain. The present findings further support a specific interaction between fibrillar Aβ and α7 nAChRs in the brain, suggesting that treatment with α7 nAChR stimulatory drugs can modulate Aβ/α7 nAChR pathogenic signaling mechanisms in AD brain.

Pages 853-862
Ggotpin Kim*, Hyesook Kim*, Ki Nam Kim, Jung In Son, Seong Yoon Kim, Tsunenobu Tamura, Namsoo Chang *These authors contributed equally to this work.
Relationship of Cognitive Function with B Vitamin Status, Homocysteine, and Tissue Factor Pathway Inhibitor in Cognitively Impaired Elderly: A Cross-Sectional Survey
Abstract: Elevated homocysteine (Hcy) levels have been associated with an increased risk of cognitive impairment and Alzheimer’s disease (AD). Tissue factor pathway inhibitor (TFPI) has recently emerged as a candidate marker of endothelial damage in AD. We investigated the relationship between plasma levels of folate, vitamin B12, Hcy, and TFPI, as well as cognitive function in 321 [100 each with mild cognitive impairment (MCI) and AD, 121 normal subjects] Korean elderly (mean age 74.8 ± 7.2 years). Plasma folate and vitamin B12 concentrations were analyzed by radioimmunoassay, Hcy by the HPLC-fluorescence method, and TFPI by enzyme-linked immunosorbent assay. Plasma Hcy levels were higher in patients with AD and MCI than those in normal subjects (p < 0.001). The AD group had higher proportions of hyperhomocysteinemic (>15 μM) and folate deficient (<3.0 ng/mL) (p = 0.026) subjects. A multiple regression analysis after adjusting for covariates revealed positive relationships between plasma folate and the MMSE-KC and Boston Naming Test, and between plasma vitamin B12 and the Word List Memory Test in the AD group, but negative associations between plasma Hcy and the Word List Memory and Constructional Recall Tests and between plasma TFPI and the Boston Naming, Word List Recall, and Constructional Recall Tests. In contrast, only plasma folate level was positively associated with the MMSE-KC and Boston Naming Test in the MCI group. No associations were observed in the normal group. These results suggest that plasma folate, vitamin B12, Hcy, and TFPI are associated with cognitive function in cognitively impaired (AD and MCI) elderly and that the association was stronger in patients with AD.

Pages 863-880
Gang Wei*, Chen Yunbo*, Dong-Feng Chen, Xiao-Ping Lai, Dong-Hui Liu, Ru-Dong Deng, Jian-Hong Zhou, Sai-Xia Zhang, Yi-Wei Li, Hui Li, Liu-Fang Liu *These authors contributed equally to this work.
β-Asarone Inhibits Neuronal Apoptosis via the CaMKII/CREB/Bcl-2 Signaling Pathway in an in vitro Model and AβPP/PS1 Mice
Abstract: β-asarone, an active component of the Acori graminei rhizome that has been used as traditional Chinese herb, has been reported to be capable of inhibiting neuronal apoptosis. However, the signaling mechanism underlying the inhibitory effect of β-asarone has remained elusive. This study was aimed to investigate whether the CaMKII signaling pathway is involved in the β-asarone mediated neuroprotection. Using PC12 cells and primary cultures of cortical neurons treated with amyloid-β (Aβ)1-40 or Aβ1-42 peptide, we demonstrated that β-asarone can protect PC12 cells and cortical neurons and inhibit neuronal apoptosis by activating the CaMKII-α/p-CREB/Bcl-2 pathway. Moreover, CaMKII-α overexpression enhanced the β-asarone-induced p-CREB-Bcl-2 expression and anti-apoptotic effects. Interestingly, suppression of CaMKII-α by siRNA or a specific inhibitor can significantly reduce the β-asarone-induced p-CREB and Bcl-2 expression and Aβ1-40 induced neuronal apoptosis in PC12 cells. AβPP/PS1 mice at the age of 3 months and age-matched wild-type mice were intragastrically administered β-asarone (7 mg/kg/day, 21 mg/kg/day) or a vehicle daily for 4 months. β-asarone improved cognitive function of the AβPP/PS1 mice and reduced neuronal apoptosis in the cortex of the AβPP/PS1 mice. A significant increase in CaMKII/CREB/Bcl-2 expression was observed in the cortex of the AβPP/PS1 mice treated with β-asarone. In summary, our observations demonstrated that β-asarone can inhibit neuronal apoptosis via the CaMKII/CREB/Bcl-2 signaling pathway in in vitro models and in AβPP/PS1 mice. Therefore, β-asarone can be used as a potential therapeutic agent in the long-term treatment of Alzheimer’s disease.

Pages 881-888
Thomas Wisniewski, Kia Newman, Norman B. Javitt
Alzheimer’s Disease: Brain Desmosterol Levels
Abstract: Desmosterol is a C27 sterol intermediate in cholesterol synthesis generated during the metabolic pathway that transforms lanosterol into cholesterol. It has become of particular interest in the pathogenesis of Alzheimer’s disease (AD) because of the report that the activity of the gene coding for the enzyme DHCR24, which metabolizes desmosterol to cholesterol, is selectively reduced in the affected areas of the brain. Any change in the pattern of C27 sterol intermediates in cholesterol synthesis merits investigation with respect to the pathogenesis of AD, since neurosteroids such as progesterone can modulate the tissue levels. We therefore analyzed the C27 sterol composition using a metabolomics approach that preserves the proportion of the different sterol intermediates. In AD, the proportion of desmosterol was found to be less than that of age-matched controls. The findings do not directly support the focus on Seladin-1, although they could reflect different stages of a slowly progressive disease.