Volume 20, Number 2, June 2010

Pages 355-367
Review Article
Mak Adam Daulatzai
Early Stages of Pathogenesis in Memory Impairment during Normal Senescence and Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a progressive, neurodegenerative brain disease of the elderly characterized by memory loss, cognition, and behavioral abnormalities. Aging is the single most important risk factor and there is no proven therapy. Aging invariably decreases sensory stimuli and impacts on the thalamocortical system and its connectivity to key brain regions. Memory dysfunction in senescence and early AD, a function of acetylcholine decrease, is accompanied with dysfunctional basal forebrain, parietal, prefrontal, and entorhinal cortices, and indeed hippocampus. Cholinergic neurotransmission protects neurons from amyloid-β production and its toxicity, while cholinergic depletion enhances both. Available data on sleep disordered breathing and genioglossus dysfunction throw light on possible pathogenetic events leading to hypoxemia. Memory disturbances in normal elderly and early AD patients are intimately related to hypoxia, a reduction in blood supply, and glucose hypometabolism in the hippocampus and a number of key brain areas. The current hypothesis on memory impairment in the elderly and Alzheimer’s dementia, therefore, underscores age-related sensory losses, functional disconnection between strategic brain regions in conjunction with hypoxemia and hypometabolism. On the basis of available data, it is emphasized that (A) decreases in thalamocortical function decreases cholinergic activity and cerebral blood flow, while nocturnally, (B) repeated hypoxic events affect respiratory cholinergic mechanism and respiratory regulation. Consequently, the hypotrophy/atrophy of nucleus solitarius and nucleus ambiguus in pontomedullary junction affect hypoglossal nucleus, genioglossus function, upper airway patency, hypoxia, and cerebral oxygenation. These alterations may cause amyloid-β deposition extracellularly, and neurofibrillary cytopathology in cholinergic and other neurons intracellularly.

Pages 369-393
Review Article
D. Allan Butterfield, Sarita S. Hardas, Miranda L. Bader Lange (Handling Associate Editor: Ralph Martins)
Oxidatively Modified Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) and Alzheimer’s Disease: Many Pathways to Neurodegeneration
Abstract: Recently, the oxidoreductase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), has become a subject of interest as more and more studies reveal a surfeit of diverse GAPDH functions, extending beyond traditional aerobic metabolism of glucose. As a result of multiple isoforms and cellular locales, GAPDH is able to come in contact with a variety of small molecules, proteins, membranes, etc., that play important roles in normal and pathologic cell function. Specifically, GAPDH has been shown to interact with neurodegenerative disease-associated proteins, including the amyloid-β protein precursor (AβPP). Studies from our laboratory have shown significant inhibition of GAPDH dehydrogenase activity in Alzheimer’s disease (AD) brain due to oxidative modification. Although oxidative stress and damage is a common phenomenon in the AD brain, it would seem that inhibition of glycolytic enzyme activity is merely one avenue in which AD pathology affects neuronal cell development and survival, as oxidative modification can also impart a toxic gain-of-function to many proteins, including GAPDH. In this review, we examine the many functions of GAPDH with respect to AD brain; in particular, the apparent role(s) GAPDH in AD-related apoptotic cell death is emphasized.

Pages 395-408
Review Article
Miguel A. Lopez-Toledano, Mohammad Ali Faghihi, Nikunj S. Patel and Claes Wahlestedt
Adult Neurogenesis: A Potential Tool for Early Diagnosis in Alzheimer’s Disease?
Abstract: Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder characterized by progressive impairment of cognition and short-term memory loss. The deposition of amyloid-β (Aβ) 1-42 into senile plaques is an established feature of AD neuropathology. Controversy still exists about the amyloid pathway as the initiating mechanism or a mere consequence of the events leading to AD. Nevertheless, Aβ toxicity has been probed in vitro and in vivo and increased production or decreased clearance of Aβ peptides are reported to play a major role in the development of AD. Treatment of neural stem cells with Aβ in vitro induces neuronal differentiation. Increased neurogenesis has been also described in AD patients as well as in amyloid-β protein precursor (AβPP) transgenic mice. Adult neurogenesis is greatly enhanced in young AβPP transgenic mice, before other AD-liked pathologies, and reduced in older animals. This increased neurogenesis at young ages might be the first pathology related to AD, which is detectable long before other harmful manifestation of the disease. Therefore, understanding the mechanisms of Aβ-induced neurogenesis will reveal insights into the pathogenesis of AD and may prove useful as an early AD biomarker.

Pages 409-413
Perspective
John Hardy, Katrina Gwinn
Protected to Death
Abstract: Despite progress in human gene discovery, we believe that regulations regarding subject protections have not fully kept pace. We believe that weaknesses in the current regulatory system include variations in the understanding of genetic principles and in the application of regulations. We discuss what our thoughts regarding steps needed to create an environment where information is gathered from all parties involved, including via research into many of the remaining questions, in order to ensure that research participant protection is adequate, appropriate and is an evolving process which will allow it to keep pace with the rapid advances in human genetics.

Pages 415-416
Commentary on Hardy and Gwinn
   Peter J. Whitehouse and Daniel George
   Protecting Life and Lives: Putting Gene Research in Context

Pages 417-421
Short Communication
Nobuto Shibata, Bolati Kuerban, Miwa Komatsu, Tohru Ohnuma, Hajime Baba, Heii Arai
Genetic Association Between CALHM1, 2, and 3 Polymorphisms and Alzheimer's Disease in a Japanese Population
Abstract: A recent paper reported that a variant (rs2986017) of the calcium homeostasis modulator 1 (CALHM1) gene affects risk for late-onset Alzheimer’s disease (AD). This study aims to investigate whether single nucleotide polymorphisms (SNPs) of the CALHM1 gene are associated with AD. SNPs in the genes of two other CALHM subtypes, CALHM2 and CALHM3, were also studied. Our study failed to detect any association between the SNPs of the three genes and AD. Although rs729211 showed marginal association in the APOE4 negative group, the linkage disequilibrium analysis results suggest this to be a false positive.

Pages 423-426
Short Communication
Kristina E. Froud, Tina Wardhaugh, Duncan Banks, M. Jill Saffrey, Michael G. Stewart
ColostrininTM Alleviates Amyloid-β Induced Toxicity in Rat Primary Hippocampal Cultures
Abstract: ColostrininTM (CLN), a complex mixture of proline-rich polypeptides derived from colostrums, can alleviate cognitive decline in early Alzheimer’s disease patients. The molecular basis of the action of CLN has been studied in vitro using human neuroblastoma cell lines. The aim of the present study was to use quantitative immunocytochemistry and immunoblotting to investigate the ability of CLN to relieve amyloid-β (Aβ)-induced cytotoxicity in rat primary hippocampal neuronal cells. Our data confirm that CLN alleviates the effect of Aβ-induced cytotoxicity and causes a significant reduction in the elevated levels of the antioxidant enzyme SOD1.

Pages 427-439
Hideo Hara, Seiko Kataoka, Mayumi Anan, Akihiro Ueda, Tatsuro Mutoh, Takeshi Tabira
The Therapeutic Effects of the Herbal Medicine, Juzen-taiho-to, on Amyloid-β Burden in a Mouse Model of Alzheimer’s Disease
Abstract: Innate immunity, especially that involving macrophage function, reportedly diminishes with advancing age and in patients with Alzheimer’s disease (AD). In this study, we tried to elicit the non-specific activation of peripheral macrophages by oral administration of the herbal medicine Juzen-taiho-to (JTT), to assess its effect as a possible treatment for AD patients. Amyloid-β protein precursor transgenic mice were used as a model of AD to clarify the effect of JTT. Activated macrophages derived from bone marrow cross the blood-brain barrier, and then develop into microglia, which phagocytose aggregated amyloid-β (Aβ) in senile plaques. Here we show that orally administered JTT increased the number of CD11b-positive ramified microglia in the mouse brain. The immunohistochemical examination of brain sections stained with polyclonal anti-Aβ antibody showed reduced Aβ burden, and Aβ levels were also decreased in the insoluble fractions of brain homogenates, as determined by ELISA. Thus, the activation of peripheral macrophages by JTT might be a potential new therapeutic strategy for AD.

Pages 441-443
Commentary on Hara et al.
   Colin Combs
   Manipulating Phagocyte Activity in Alzheimer’s Disease

Pages 445-452
Nicolaas A. Verwey, Maartje I. Kester, Wiesje M. van der Flier, Robert Veerhuis, Hans Berkhof, Harry Twaalfhoven, Marinus A. Blankenstein, Philip Scheltens, Yolande A.L. Pijnenburg (Handling Associate Editor: Sanna-Kaisa Herukka)
Additional Value of CSF Amyloid-β40 Levels in the Differentiation between FTLD and Control Subjects
Abstract: To determine the additional value of cerebrospinal fluid (CSF) amyloid-β1-40 (Aβ40) next to amyloid-β1-42 (Aβ42), total tau (Tau), and tau phosphorylated at threonine-181 (pTau) to distinguish patients with frontotemporal lobar degeneration (FTLD), Alzheimer’s disease (AD), and controls, we measured CSF levels of Aβ40, Aβ42, pTau, and Tau in 55 patients with FTLD, 60 with AD, and 40 control subjects. Logistic regression was used to identify biomarkers that best distinguished the groups. Additionally, a decision tree (cost = test method; Matlab 7.7) was used to predict diagnosis selecting the best set of biomarkers with the optimal cut-off. Logistic regression showed that Aβ42 and pTau CSF levels provided optimal distinction between AD and FTLD. A combination of Aβ42, Tau, and Aβ40 optimally discriminated FTLD from controls and AD from controls. The decision tree used Aβ42 (cut-off 578 pg/ml) to identify AD (positive predictive value (PPV) 97%), followed by Tau (cut-off 336 pg/ml) to identify FTLD (PPV 67%), and in the last step, Aβ40 (cut-off 10 ng/ml) was used to differentiate controls (PPV 68%). Applying CSF Aβ40 levels in the model, the PPV of diagnosis increased to 75% as opposed to 70% when only Aβ42 and Tau were used. CSF Aβ40 levels added to the conventional CSF biomarkers increases the potential to discriminate subjects with dementia from controls. Our findings favor the implementation of CSF Aβ40 in differential diagnosis between FTLD, AD, and control subjects.

Pages 453-463
Ophélia Godin, Christophe Tzourio, Olivier Rouaud, Yicheng Zhu, Pauline Maillard, Florence Pasquier, Fabrice Crivello, Annick Alpérovitch, Bernard Mazoyer, Carole Dufouil (Handling Associate Editor: Sudha Seshadri)
Joint Effect of White Matter Lesions and Hippocampal Volumes on Severity of Cognitive Decline: The 3C-Dijon MRI Study
Abstract: Several brain magnetic resonance imaging (MRI) changes are observed in older individuals including white matter lesions (WML), silent brain infarcts (SBI), and cerebral atrophy. Few studies, however, have assessed the combined association of these changes on the severity of future cognitive decline. In the prospective population-based 3C-Dijon MRI study, 1701 non-demented participants aged 65 to 80 years at entry, had a brain MRI. Information on WML, hippocampal volumes, SBI presence, and brain parenchymal fraction were obtained. At 4-year follow-up, participants were screened for cognitive decline and dementia. Severity of cognitive decline was defined as none, moderate, or severe calculated from neuropsychological test performance change. The relation between brain MRI markers and longitudinal change in cognition was studied using polytomous logistic regression and multiple linear regression models controlling for potential confounders. Two-by-two interactions were tested including with the apolipoprotein E genotype. At follow-up, 46 participants showed severe cognitive deterioration and 224 participants showed moderate cognitive deterioration. In multivariable analyses, risk of severe cognitive deterioration as well as the cognitive decline rate were significantly increased in participants with higher WML volume (p<0.01) and smaller hippocampal volume (p<0.01). The results suggested that WML and hippocampal volumes had a cumulative effect on the future level of cognitive decline. The APOE genotype was found to be an effect modifier of this association. Vascular brain changes and degenerative processes coexist in normal older individuals. The co-occurrence of degenerative and non-degenerative pathologies could strongly affect the course of dementia expression.

Pages 465-475
Manuel D. Gahete, Alicia Rubio, Mario Durán-Prado, Jesús Avila, Raúl M. Luque, Justo P. Castaño
Expression of Somatostatin, Cortistatin, and Their Receptors, as well as Dopamine Receptors, but not of Neprilysin, are Reduced in the Temporal Lobe of Alzheimer’s Disease Patients
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive deficit, wherein the impairment of episodic memory is the major hallmark. AD patients exhibit augmented accumulation of amyloid-β (Aβ) and hyperphosphorylated tau protein in specific brain regions. In addition, several neuropeptides/neurotransmitter axes clearly associated with cognitive processes, Aβ turnover, and tau phosphorylation have also been found to be impaired in AD, such as somatostatin (SST)/cortistatin (CST) and dopamine (DA) systems. However, to date there is no precise quantitative data on the expression of these systems in the human brain of AD and normal patients. Here we measured by quantitative real-time PCR the mRNA levels of SST/CST, DA, and their receptors (sst1-5 and drd1-5, respectively) in addition to neprilysin (a SST-regulated enzyme involved in Aβ degradation) in three regions of the temporal lobe, one of the cortical regions most severely affected by AD. Our results reveal that some components of SST/CST- and DA-axes are divergently altered in the three areas of AD patients. Despite this region-specific regulation, an overall, common reduction of these systems was observed in the temporal lobe of AD patients. Conversely, neprilysin expression was not altered in AD, suggesting that Aβ accumulation observed in AD is due to a lack of neprilysin activation by SST rather than to a reduction of its expression. Collectively, our results define a comprehensive scenario wherein reduction of ssts, drds, and sst ligands SST and CST, could be involved, at least in part, in some of the more important defects observed in AD.

Pages 477-490
Uwe Friese, Thomas Meindl, Sabine C. Herpertz, Maximilian F. Reiser, Harald Hampel, Stefan J. Teipel
Diagnostic Utility of Novel MRI-Based Biomarkers for Alzheimer’s Disease: Diffusion Tensor Imaging and Deformation-Based Morphometry
Abstract: We report evidence that multivariate analyses of deformation-based morphometry and diffusion tensor imaging (DTI) data can be used to discriminate between healthy participants and patients with Alzheimer’s disease (AD) with comparable diagnostic accuracy. In contrast to other studies on MRI-based biomarkers which usually only focus on a single modality, we derived deformation maps from high-dimensional normalization of T1-weighted images, as well as mean diffusivity maps and fractional anisotropy maps from DTI of the same group of 21 patients with AD and 20 healthy controls. Using an automated multivariate analysis of the entire brain volume, widespread decreased white matter integrity and atrophy effects were found in cortical and subcortical regions of AD patients. Mean diffusivity maps and deformation maps were equally effective in discriminating between AD patients and controls (AUC = 0.88 vs. AUC = 0.85) while fractional anisotropy maps performed slightly inferior. Combining the maps from different modalities in a logistic regression model resulted in a classification accuracy of AUC = 0.86 after leave-one-out cross-validation. It remains to be shown if this automated multivariate analysis of DTI-measures can improve early diagnosis of AD in predementia stages.

Pages 491-500
Jing Li, Meng Zhang, Zhi-Qiang Xu, Chang-Yue Gao, Chuan-Qin Fang, Juan Deng, Jia-Chuan Yan, Yan-Jiang Wang, Hua-Dong Zhou
Vascular Risk Aggravates the Progression of Alzheimer’s Disease in a Chinese Cohort
Abstract: To investigate whether vascular risk affects the progression of Alzheimer’s disease (AD), 415 AD patients aged 65 years old and over without cerebrovascular diseases were enrolled and administered with a structured interview to assess demography, vascular risk factors, and cognitive and functional status at baseline, and 324 AD patients were followed up annually for 5 years. A mixed random effects regression model was used to identify the association between vascular risk, individual vascular risk factors, and the progression of AD. After adjusting for confounding factors, AD patients with vascular risk had faster cognitive and functional decline rates than the subjects without, and the individual vascular risk factors including hypertension and diabetes mellitus, transient ischemic attack and cerebrovascular accident during the follow-up were independently associated with the progression of AD. Our findings suggest that vascular risk aggravates the progression of AD and may be involved in the etiologic process of AD. Control of vascular risk may slow down the progression of AD.

Pages 501-507
Claudia Cacciari, Marta Moraschi, Margherita Di Paola, Andrea Cherubini, Maria Donata Orfei, Federico Giove, Bruno Maraviglia, Carlo Caltagirone, Gianfranco Spalletta
White Matter Microstructure and Apathy Level in Amnestic Mild Cognitive Impairment
Abstract: We aimed to assess white matter microstructural deficit correlates of apathy level in 20 patients with amnestic mild cognitive impairment by means of diffusion tensor imaging. Mean diffusivity correlated positively with apathy level in the right temporal portion of the uncinate, middle longitudinal and inferior longitudinal fascicule and in the parathalamic white matter, the fornix and the posterior cingulum of the right hemisphere. Fractional anisotropy results confirmed evidence of disconnection associated with apathy in all white matter areas except the middle longitudinal fasciculus. These results support the view that alterations in the neural mechanisms underlying apathy level occur in the early phase of degenerative dementias.

Pages 509-516
Noel G. Faux, Craig W. Ritchie, Adam Gunn, Alan Rembach, Andrew Tsatsanis, Justin Bedo, John Harrison, Lars Lannfelt, Kaj Blennow, Henrik Zetterberg, Martin Ingelsson, Colin L. Masters, Rudolph E. Tanzi, Jeffrey L. Cummings, Caroline M. Herd, Ashley I. Bush
PBT2 Rapidly Improves Cognition in Alzheimer’s Disease: Additional Phase II Analyses
Abstract: PBT2 is a copper/zinc ionophore that rapidly restores cognition in mouse models of Alzheimer’s disease (AD). A recent Phase IIa double-blind, randomized, placebo-controlled trial found that the 250 mg dose of PBT2 was well-tolerated, significantly lowered cerebrospinal fluid (CSF) levels of amyloid-β42, and significantly improved executive function on a Neuro-psychological Test Battery (NTB) within 12 weeks of treatment in patients with AD. In the post-hoc analysis reported here, the cognitive, blood marker, and CSF neurochemistry outcomes from the trial were subjected to further analysis. Ranking the responses to treatment after 12 weeks with placebo, PBT2 50 mg, and PBT2 250 mg revealed that the proportions of patients showing improvement on NTB Composite or Executive Factor z-scores were significantly greater in the PBT2 250 mg group than in the placebo group. Receiver-operator characteristic analyses revealed that the probability of an improver at any level coming from the PBT2 250 mg group was significantly greater, compared to placebo, for Composite z-scores (Area Under the Curve [AUC] = 0.76, p = 0.0007), Executive Factor z-scores (AUC = 0.93, p = 1.3x10-9), and near-significant for the ADAS-cog (AUC = 0.72, p = 0.056). There were no correlations between changes in CSF amyloid-β or tau species and cognitive changes. These findings further encourage larger-scale testing of PBT2 for AD.

Supplementary Data for Faux et al. article (PDF)

Pages 517-526
Andrew B. Newberg, Nancy Wintering, Dharma S. Khalsa, Hannah Roggenkamp, Mark R. Waldman
Meditation Effects on Cognitive Function and Cerebral Blood Flow In Subjects with Memory Loss: A Preliminary Study
Abstract: This preliminary study determined if subjects with memory loss problems demonstrate changes in memory and cerebral blood flow (CBF) after a simple 8-week meditation program. Fourteen subjects with memory problems had an IV inserted and were injected with 250MBq of Tc-99m ECD while listening to a neutral stimulus CD. They then underwent a pre-program baseline SPECT scan. Then subjects were guided through their first meditation session with a CD, during which they received an injection of 925MBq ECD, and underwent a pre-program meditation scan. Subjects completed an 8-week meditation program and underwent the same scanning protocol resulting in a post-program baseline and meditation scan. A region of interest (ROI) template obtained counts in each ROI normalized to whole brain to provide a CBF ratio. Baseline and meditation scans and neuropsychological testing were compared before and after the program. The meditation program resulted in significant increases (p<0.05) in baseline CBF ratios in the prefrontal, superior frontal, and superior parietal cortices. Scores on neuropsychological tests of verbal fluency, Trails B, and logical memory showed improvements after training. This preliminary study evaluated whether an 8-week meditation program resulted in improvements in neuropsychological function and differences in CBF in subjects with memory loss. While the findings are encouraging, there are a number of limitations that can be addressed in future studies with more participants and more detailed analyses.

Pages 527-546
Simona Capsoni, Cecilia Tiveron, Gianluca Amato, Domenico Vignone, Antonino Cattaneo
Peripheral Neutralization of Nerve Growth Factor Induces Immunosympathectomy and Central Neurodegeneration in Transgenic Mice
Abstract: We previously showed that anti-nerve growth factor (NGF) antibodies expressed in transgenic mice (AD11) determine a progressive neurodegeneration, comprising the triad of Alzheimer’s disease (AD) hallmarks: cholinergic loss, tau hyperphosphorylation, and amyloid-β peptide formation. However, since anti-NGF antibodies are produced both in the brain and in peripheral tissues of AD11 mice, the contribution of peripheral neutralization of NGF to the onset of brain neurodegeneration was still unexplored. To address this question, we characterized a line of transgenic mice (AD10) in which anti-NGF antibodies are obligatorily produced only in lymphocytes, being initially found in blood. In AD10 mice, peripheral NGF neutralization determines shrinkage of superior cervical ganglia (immunosympathectomy) and, as a consequence of this, peripheral anti-NGF antibodies cross the blood brain barrier (BBB) and reach the brain, determining an NGF-dependent neurodegeneration, largely superimposable to that observed in AD11 mice. This demonstrates that peripherally originated anti-NGF antibodies can determine a neurodegeneration in the central nervous system of an animal model. Consistently, peripherally-delivered NGF is effective in preventing the onset of the central cholinergic deficit. These findings could have a direct relevance for some human sporadic AD cases, highlighting the role of the BBB disruption and suggesting a causally relevant role of circulating antibodies in AD pathology.

Pages 547-560
Christine Bastin, Nacer Kerrouche, Françoise Lekeu, Stéphane Adam, Bénédicte Guillaume, Christian Lemaire, Joël Aerts, Géry d’Ydewalle, Fabienne Collette, Eric Salmon
Controlled Memory Processes in Questionable Alzheimer’s Disease: A View from Neuroimaging Research
Abstract: Alzheimer’s disease (AD) is characterized by a progressive loss of controlled cognitive processes, and neuroimaging studies at early stages of AD provide an opportunity to tease out the neural correlates of controlled processes. Accordingly, controlled and automatic memory performance was assessed with the Process Dissociation Procedure in 50 patients diagnosed with questionable Alzheimer’s disease (QAD). The patients’ brain glucose metabolism was measured using FDG-PET. After a follow-up period of 36 months, 27 patients had converted to AD, while 23 remained stable. Both groups showed a similar decrease in controlled memory processes but preserved automatic processes at entry into the study. Voxel-based cognitive and metabolic correlations showed that a decrease in controlled memory processes was preferentially correlated with lower activity in the dorsomedial prefrontal and posterior cingulate cortices in very early AD patients. In stable QAD patients, reduced controlled performance in verbal memory correlated with impaired activity in the left anterior hippocampal structure. The results demonstrated the central role of a medial frontal-posterior cingulate network for controlled processing of episodic memory in the early stages of AD.

Pages 561-567
Fiona Middle*, Antonia L. Pritchard*, Herlina Handoko, Sayeed Haque, Roger Holder, Peter Bentham, Corinne L. Lendon *These authors contributed equally to this work.
No Association Between Neuregulin 1 and Psychotic Symptoms in Alzheimer’s Disease Patients
Abstract: Alzheimer’s disease (AD) patients commonly suffer from behavioral and psychological symptoms of dementia (BPSD). Variants within the neuregulin-1 (NRG1) gene have been investigated both in early onset psychiatric disorders, such as schizophrenia and recently in AD patients with psychosis. In this study, we analyzed NRG1 variants in AD patients with and without psychosis. Our large cohort of 399 probable AD patients had longitudinal information on the BPSD, which was used to dichotomize patients into whether they had ever suffered from psychotic symptoms within the study period. The NRG1 single nucleotide polymorphisms rs3924999, rs35753505 (SNP8NRG221533) and the microsatellites 478B14-848 and 420M9-1395 were investigated for association with psychosis using genotype, allele, and haplotype analyses. No associations were found between any of these variants or haplotypic combinations with delusions, hallucinations, psychosis, or elation/mania in our cohort. Positive associations with polymorphisms and haplotype combinations of NRG1 have been reported in psychiatric disorders. One previous study found an association with psychosis in AD, with a SNP outside the haplotype block first reported for association with schizophrenia. We found no association with any of these variants in our cohort. Further investigations of this region on chromosome 8 are clearly required, with replication in different large longitudinal cohorts.

Pages 569-576
Jia-Min Zhuo, Warren D. Kruger, Domenico Praticò (Handling Associate Editor: Patrizia Mecocci)
The Herp Protein Pathway is Not Involved in the Pro-Amyloidotic Effect of Hyperhomocysteinemia
Abstract: Diet-induced high circulating levels of homocysteine, also known as hyper-homocysteinemia (HHcy), is associated with an acceleration of Alzheimer’s disease-like amyloidosis. Herp is a homocysteine-responsive stress protein, which has been shown to increases the formation of amyloid-β (Aβ) via interaction with presenilins in vitro. The aim of our paper was to investigate the functional role that Herp plays in HHcy-induced amyloidosis. Amyloidosis secondary to diet-induced HHcy in Tg2576 mice is associated with an increase of Herp protein and mRNA levels. By contrast, no other stress-related proteins are altered by the same diet regimen. Compared to wild type animals, brains from a genetically induced HHcy mouse model did not manifest any significant change in Herp levels. Cells stably over-expressing human AβPP Swedish mutant incubated with high levels of homocysteine had an increase in Aβ formation, but no change in Herp level. Finally, over-expression of Herp did not result in any significant modification of Aβ levels. We conclude that the Herp protein pathway is unlikely to be directly involved in the pro-amyloidotic effect of HHcy.

Pages 577-586
Ana M García, Nieves Ramón-Bou, Miquel Porta
Isolated and Joint Effects of Tobacco and Alcohol Consumption on Risk of Alzheimer’s Disease
Abstract: The roles of smoking and alcohol on the development of Alzheimer’s disease (AD) remain unclear. We performed a case-control study on the effects of both exposures before the age of onset of the disease in the cases (and same reference age for their age-matched controls) on disease risk. Interviews were conducted with population controls (n=246) and relatives of cases (n=176) identified through local Alzheimer’s Disease Associations. Logistic regression models were built adjusting by gender, age, residence, education, economic situation, employment, and history of dementia in close relatives. Risk of AD was unaffected by any measure of tobacco consumption. Alcohol consumers showed a lower risk of AD than never consumers (adjusted odds ratio, aOR=0.53, 95% CI 0.32, 0.88), with differences by gender (women aOR=0.48, 95% CI 0.27, 0.84; men aOR=0.80, 95% CI 0.23, 2.80). Mean daily total consumption of alcohol and time consuming alcohol showed increasingly protective dose-response relationships in women. Lower AD risk was observed in alcohol drinkers of both genders who never smoked (aOR=0.37, 95% CI 0.21, 0.65). All these associations were independent of the presence of apolipoprotein E4 allele(s) in the cases. Although the sample was small for some analyses addressing these interactions, our results suggest a protective effect of alcohol consumption, mostly in non-smokers, and the need to consider interactions between tobacco and alcohol consumption, as well as interactions with gender, when assessing the effects of smoking and/or drinking on the risk of AD.

Pages 587-598
Manja Lehmann, Jonathan D. Rohrer, Matthew J. Clarkson, Gerard R. Ridgway, Rachael I. Scahill, Marc Modat, Jason D. Warren, Sebastien Ourselin, Josephine Barnes, Martin N. Rossor, Nick C. Fox
Reduced Cortical Thickness in the Posterior Cingulate Gyrus is Characteristic of Both Typical and Atypical Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) can be difficult to differentiate clinically due to overlapping symptoms. Subject classification in research studies is often based on clinical rather than pathological criteria which may mean some subjects are misdiagnosed and misclassified. Recently, methods measuring cortical thickness using magnetic resonance imaging have been suggested to be effective in differentiating between clinically-defined AD and frontotemporal dementia (FTD) in addition to showing disease-related patterns of atrophy. In this study we used FreeSurfer, a freely-available and automated software tool, to measure cortical thickness in 28 pathologically-confirmed AD patients, of which 11 had a typical amnestic presentation and 17 an atypical presentation during life, 23 pathologically-confirmed FTLD subjects, and 25 healthy controls. Patients with AD pathology, irrespective of clinical diagnosis, showed reduced cortical thickness bilaterally in the medial temporal lobe, posterior cingulate gyrus, precuneus, posterior parietal lobe, and frontal pole compared with controls. We further showed that lower cortical thickness in the posterior cingulate gyrus, parietal lobe, and frontal pole is suggestive of AD pathology in patients with behavioral or language deficits. In contrast, lower cortical thickness in the anterior temporal lobe and frontal lobe is indicative of the presence of FTLD pathology in patients with a clinical presentation of FTD. Reduced cortical thickness in the posterior cingulate gyrus is characteristic of AD pathology in patients with typical and atypical clinical presentations of AD, and may assist a clinical distinction of AD pathology from FTLD pathology.

Pages 599-606
Fredrik Söderqvist, Lennart Hardell, Michael Carlberg, Kjell Hansson Mild
Radiofrequency Fields, Transthyretin, and Alzheimer’s Disease
Abstract: Radiofrequency field (RF) exposure provided cognitive benefits in an animal study. In Alzheimer’s disease (AD) mice, exposure reduced brain amyloid-β (Aβ) deposition through decreased aggregation of Aβ and increase in soluble Aβ levels. Based on our studies on humans on RF from wireless phones, we propose that transthyretin (TTR) might explain the findings. In a cross-sectional study on 313 subjects, we used serum TTR as a marker of cerebrospinal fluid TTR. We found a statistically significantly positive β coefficient for TTR for time since first use of mobile phones and desktop cordless phones combined (P=0.03). The electromagnetic field parameters were similar for the phone types. In a provocation study on 41 persons exposed during 30 min to an 890-MHz GSM signal with specific absorption rate of 1.0 Watt/kg to the temporal area of the brain, we found statistically significantly increased serum TTR 60 min after ending of exposure. In our cross-sectional study, use of oral snuff yielded statistically significantly increased serum TTR concentrations and nicotine has been associated with decreased risk for AD and to upregulate the TTR gene in choroid plexus but not in the liver, another source of serum TTR. TTR sequesters Aβ, thereby preventing the formation of Aβ plaques in the brain. Studies have shown that patients with AD have lowered TTR concentrations in the cerebrospinal fluid and have attributed the onset of AD to insufficient sequestering of Aβ by TTR. We propose that TTR might be involved in the findings of RF exposure benefit in AD mice.

Pages 607-615
Ta-Fu Chen, Rwei-Fen S. Huang, Sey-En Lin, Jyh-Feng Lu, Ming-Chi Tang, Ming-Jang Chiu
Folic Acid Potentiates the Effect of Memantine on Spatial Learning and Neuronal Protection in an Alzheimer’s Disease Transgenic Model
Abstract: Folic acid deficiency and hyperhomocysteinemia potentiate amyloid-β (Aβ) neuron toxicity. Memantine, an NMDA antagonist used in moderate to severe AD, is considered to be neuroprotective. We propose that folic acid might have a synergistic effect for memantine in protecting neurons from Aβ accumulation. We treated 8-month-old Tg2576 transgenic mice with memantine (30 mg/kg/day) with or without folic acid (8 mg/kg/day) for 4 months. Escape latencies of Morris water maze were significantly shorter in the folic acid-memantine treatment group Tg(+)_M+F compared to both the non-treatment transgenic controls Tg(+) and the memantine-treatment group Tg(+)_M (both p < 0.05). Analysis of Aβ40 and Aβ42 showed lower brain loading in both treatment groups but did not reach statistic significance. Histopathology analysis showed that Tg(+)_M+F had lower ratios of neuronal damage than Tg(+) (p < 0.001) and Tg(+)_M (p < 0.005). DNA analysis revealed that in the Tg(+)_M+F group, transcription was upregulated in 72 brain genes involved in neurogenesis, neural differentiation, memory, and neurotransmission compared to the Tg(+)_M group. In conclusion, we found that folic acid may potentiate the effect of memantine on spatial learning and neuronal protection. The benefit of combination therapy may be through co-action on the methylation-controlled Aβ production, and modification of brain gene expression.

Pages 617-623
Elizabeth A. Milward, David G. Bruce, Matthew W. Knuiman, Mark L. Divitini, Michelle Cole, Charles A. Inderjeeth, Roger M. Clarnette, Graham Maier, Assen Jablensky, John K. Olynyk (Handling Associate Editor: Craig S. Atwood)
A Cross-Sectional Community Study of Serum Iron Measures and Cognitive Status in Older Adults
Abstract: The relationship of iron status with cognition and dementia risk in older people is contentious. We have examined the longitudinal relationship between serum ferritin and cognition in 800 community-dwelling Australians 60 years or older. Iron studies (serum iron, transferrin saturation, serum ferritin) were performed in 1994/5 and 2003/4 and clinical and cognitive assessments were conducted in 2003/4 for 800 participants of the Busselton Health Study. All participants completed the Cambridge Cognitive test (CAMCOG). Those with CAMCOG scores <84 underwent expert clinical review for cognitive disorders, including the Clinical Dementia Rating scale. Mean serum iron (18.3 μmol/l) and transferrin saturation (28.5%) in 2003/4 did not differ significantly from 1994/5 whereas mean serum ferritin decreased from 162 μg/l in 1994/5 to 123 μg/l in 2003/4, possibly reflecting aging or dietary changes. No relationships were observed between serum iron or transferrin saturation and presence or absence of dementia (p>0.05). In participants without dementia (n=749), neither serum ferritin in 1994/5 or 2003/4 nor change in serum ferritin between these times was related to total CAMCOG or executive function scores, with or without adjustment for gender, age, National Adult reading test, or stroke history (all p>0.05). No relationships were observed between ferritin and cognition for participants with possible or probable dementia (n=51). All participants identified as HFE C282Y homozygous or with serum ferritin >1,000 ng/ml had normal CAMCOG scores. We conclude abnormal body iron stores (low or high) are unlikely to have clinically significant effects on cognition or dementia risk in community-dwelling older people.

Pages 625-636
Rui O. Costa*, Elisabete Ferreiro*, Sandra M. Cardoso, Catarina R. Oliveira and Cláudia M.F. Pereira *contributed equally to this work
ER Stress-Mediated Apoptotic Pathway Induced by Amyloid-β1-40 Peptide Requires the Presence of Functional Mitochondria
Abstract: Amyloid-β (Aβ) peptide plays a significant role in the pathogenesis of Alzheimer’s disease (AD). Previously we found that Aβ induces both mitochondrial and endoplasmic reticulum (ER) dysfunction leading to apoptosis, and now we address the relevance of ER-mitochondria crosstalk in apoptotic cell death triggered by this peptide. Using mitochondrial DNA-depleted ρ0 cells derived from the human NT2 teratocarcinoma cell line, characterized by the absence of functional mitochondria, and the parental ρ+ cells, we report here that treatment with the synthetic Aβ1-40 peptide, or the classical ER stressors thapsigargin or brefeldin A, increases GRP78 expression levels and caspase-4 activity, two ER stress markers, and also depletes ER calcium stores. Significantly, we show that the presence of functional mitochondria is required for ER stress-mediated apoptotic cell death triggered by toxic insults such as Aβ. We found that the increase in the levels of the pro-apoptotic transcription factor Gadd153/CHOP, which mediates ER stress-induced cell death, as well as caspase-9 and -3 activation and increased number of TUNEL-positive cells, occurs in treated parental ρ+ cells but is abolished in ρ0 cells. Our results strongly support the close communication between ER and mitochondria during apoptotic cell death induced by the Aβ peptide and provide insights into the molecular cascade of cell death in AD.

Pages 637-646
Elizabeth Head, Viorela Pop, Floyd Sarsoza, Rakez Kayed, Tina L. Beckett, Christa M. Studzinski, Jennifer L. Tomic, Charles G. Glabe, M. Paul Murphy (Handling Associate Editor: Peter Nelson)
Amyloid-β Peptide and Oligomers in the Brain and Cerebrospinal Fluid of Aged Canines
Abstract: The study of Alzheimer’s disease (AD) pathogenesis requires the use of animal models that develop some amount of amyloid pathology in the brain. Aged canines (beagles) naturally accumulate human-type amyloid-β peptide (Aβ) and develop parallel declines in cognitive function. However, the type and quantity of biochemically extracted Aβ in brain and cerebrospinal fluid (CSF), its link to aging, and similarity to human aging has not been examined systematically. Thirty beagles, aged 4.5-15.7 years, were studied. Aβ40 and Aβ42 were measured in CSF by ELISA, and from SDS and formic acid extracted prefrontal cortex. A sample of the contralateral hemisphere, used to assess immunohistochemical amyloid load, was used for comparison. In the brain, increases in Aβ42 were detected at a younger age, prior to increases in Aβ40, and were correlated with an increased amyloid load. In the CSF, Aβ42 decreased with age while Aβ40 levels remained constant. The CSF Aβ42/40 ratio was also a good predictor of the amount of Aβ in the brain. The amount of soluble oligomers in CSF was inversely related to brain extractable Aβ, whereas oligomers in the brain were correlated with SDS soluble Aβ42. These findings indicate that the Aβ in the brain of the aged canine exhibits patterns that mirror Aβ deposited in the human brain. These parallels support the idea that the aged canine is a useful intermediate between transgenic mice and humans for studying the development of amyloid pathology and is a potentially useful model for the refinement of therapeutic interventions.

Pages 647-657
Brian R. Ott, Ronald A. Cohen, Assawin Gongvatana, Ozioma C. Okonkwo, Conrad E. Johanson, Edward G. Stopa, John E. Donahue, Gerald D. Silverberg, the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Suzanne de la Monte)
Brain Ventricular Volume and Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease
Abstract: The frequent co-occurrence of Alzheimer’s disease (AD) pathology in patients with normal pressure hydrocephalus suggests a possible link between ventricular dilation and AD. If enlarging ventricles serve as a marker of faulty cerebrospinal fluid (CSF) clearance mechanisms, then a relationship may be demonstrable between increasing ventricular volume and decreasing levels of amyloid-β peptide (Aβ) in CSF in preclinical and early AD. CSF biomarker data (Aβ, tau, and phosphorylated tau) as well as direct measurements of whole brain and ventricular volumes were obtained from the Alzheimer’s Disease Neuroimaging Initiative dataset. The ratio of ventricular volume to whole brain volume was derived as a secondary independent measure. Baseline data were used for the group analyses of 288 subjects classified as being either normal (n=87), having the syndrome of mild cognitive impairment (n=136), or mild AD (n=65). Linear regression models were derived for each biomarker as the dependent variable, using the MRI volume measures and age as independent variables. For controls, ventricular volume was negatively associated with CSF Aβ in APOE ε4 positive subjects. A different pattern was seen in AD subjects, in whom ventricular volume was negatively associated with tau, but not Aβ in ε4 positive subjects. Increased ventricular volume may be associated with decreased levels of CSF Aβ in preclinical AD. The basis for the apparent effect of APOE ε4 genotype on the relationship of ventricular volume to Aβ and tau levels is unknown, but could involve altered CSF-blood-brain barrier function during the course of disease.

Pages 659-668
Bárbara Aisa, Francisco J. Gil-Bea, Maite Solas, Mónica García-Alloza, Christopher P. Chen, Mitchell K. Lai, Paul T. Francis, María Javier Ramírez (Handling Associate Editor: Christoph Laske)
Altered NCAM Expression Associated with the Cholinergic System in Alzheimer’s Disease
Abstract: Neurotransmitter system dysfunction and synapse loss have been recognized as hallmarks of Alzheimer’s disease (AD). Our hypothesis is that specific neurochemical populations of neurons might be more vulnerable to degeneration in AD due to particular deficits in synaptic plasticity. We have studied, in postmortem brain tissue, the relationship between levels of synaptic markers (NCAM and BDNF), neurochemical measurements (cholinacetyltransferase activity, serotonin, dopamine, GABA, and glutamate levels), and clinical data (cognitive status measured as MMSE score). NCAM levels in frontal and temporal cortex from AD patients were significantly lower than control patients. Interestingly, these reductions in NCAM levels were associated to an ApoE4 genotype. Levels of BDNF were also significantly reduced in both frontal and temporal regions in AD patients. The ratio between plasticity markers and neurochemical measurements was used to study which of the neurochemical populations was particularly associated to plasticity changes. In both the frontal and temporal cortex, there was a significant reduction in the ChAT/NCAM ratio in AD samples compared to controls. None of the ratios to BDNF were different between control and AD samples. Furthermore, Pearson’s product moment showed a significant positive correlation between MMSE score and the ChAT/NCAM ratio in frontal cortex (n = 19; r = 0.526*; p = 0.037) as well as in temporal cortex (n = 19; r = 0.601*; p = 0.018) in AD patients. Altogether, these data suggest a potential involvement of NCAM expressing neurons in the cognitive deficits in AD.

Pages 669-672
Meeting Report
Jesús Avila, George Perry, Pablo Martínez-Martín
Prospects on the origin of Alzheimer's disease

Pages 673-679
Meeting Report from the Alzheimer Research Forum
The Society for Neuroscience 2009 Meeting Report, Part 4

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