Volume 30, Number 4, June 2012

Pages 737-744
Petra Popovics, Alan J. Stewart
Phospholipase C-η activity may contribute to Alzheimer’s disease-associated calciumopathy
Abstract: Alzheimer’s disease (AD) is associated with altered neuronal Ca2+ homeostasis. Ca2+ is known to accumulate in AD-affected neurons leading to deficits in neurological activity that are characteristic of the disease. This has led to the coinage of the term “calciumopathy”. However, the mechanisms of how and why Ca2+ levels are increased in the AD-affected brain remain unknown. Identifying these mechanisms is crucial for our ability to treat and understand the disease processes that are occurring. Recent work has revealed the existence of a novel signaling pathway that may contribute toward this calciumopathy. Phospholipase C-η enzymes have recently been implicated in the modulation and amplification of Ca2+ signals and are known to be expressed in neuronal regions of the brain associated with cognition and memory. In this article their potential impact on neuronal Ca2+ signaling and AD pathogenesis is discussed.

Pages 745-749
Short Communication
Diego Albani*, Filippo Martinelli Boneschi*, Gloria Biella, Giacomo Giacalone, Sara Lupoli, Francesca Clerici, Luisa Benussi, Roberta Ghidoni, Daniela Galimberti, Rosanna Squitti, Stefania Mariani, Annamaria Confaloni, Giuseppe Bruno, Claudio Mariani, Elio Scarpini, Giuliano Binetti, Giuseppe Magnani, Massimo Franceschi, Gianluigi Forloni (Handling Associate Editor: Patrizia Mecocci) *These authors contributed equally to the work.
Replication Study to Confirm the Role of CYP2D6 Polymorphism rs1080985 on Donepezil Efficacy in Alzheimer’s Disease Patients
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder often treated with donepezil, an acetylcholinesterase inhibitor. Response to donepezil is variable, probably based on patients’ genetic background in donepezil metabolizing enzymes, including cytochrome 2D6 (CYP2D6). We evaluated the association between clinical response to donepezil and a common variant (rs1080985) of CYP2D6, previously reported to be associated with poor response to the drug. In a sample of 415 AD cases, we found evidence of association between rs1080985 and response to donepezil after 6 months of therapy (OR [95%CI]: 1.74 [1.01-3.00], p=0.04). Rs1080985 might be useful as predictor of poor response to short-term donepezil treatment.

Pages 751-756
Christian Schmidt, Stephane Haïk, Katsuya Satoh, Alberto Rábano, Pablo Martinez-Martin, Sigrun Roeber, Jean-Philippe Brandel, Miguel Calero-Lara, Jesús de Pedro-Cuesta, Jean-Louis Laplanche, Jean-Jaques Hauw, Hans Kretzschmar, Inga Zerr (Handling Associate Editor: Sandrine Andrieu)
Rapidly Progressive Alzheimer’s Disease: A Multicenter Update
Abstract: The objective was to characterize a rapidly progressive subtype of Alzheimer’s disease (rpAD). Multicenter (France, Germany, Japan, Spain) retrospective analyses of neuropathologically confirmed rpAD cases initially classified as prion disease due to their clinical phenotype were performed. Genetic properties, cerebrospinal fluid biomarkers, neuropathology, and clinical features were examined. Eighty-nine patients were included (median survival 10 months). APOE and PRNP codon 129 genotype distribution paralleled a healthy control group. APOE ε4 homozygosity was absent. Cerebrospinal fluid biomarkers were abnormal, but within a range as expected for classic AD, except for proteins 14-3-3, which were detectable in 42%. Thus, evidence of the existence of rpAD is accumulating. The APOE profile is intriguing, suggesting that this very rapid disease form might represent a distinct subtype of Alzheimer’s disease.

Pages 757-766
James A. Mortimer, Ding Ding, Amy R. Borenstein, Charles DeCarli, Qihao Guo, Yougui Wu, Qianhua Zhao, Shugang Chu (Handling Associate Editor: Jeff Burns)
Changes in Brain Volume and Cognition in a Randomized Trial of Exercise and Social Interaction in a Community-Based Sample of Non-Demented Chinese Elders
Abstract: Physical exercise has been shown to increase brain volume and improve cognition in randomized trials of non-demented elderly. Although greater social engagement was found to reduce dementia risk in observational studies, randomized trials of social interventions have not been reported. A representative sample of 120 elderly from Shanghai, China was randomized to four groups (Tai Chi, Walking, Social Interaction, No Intervention) for 40 weeks. Two MRIs were obtained, one before the intervention period, the other after. A neuropsychological battery was administered at baseline, 20 weeks, and 40 weeks. Comparison of changes in brain volumes in intervention groups with the No Intervention group were assessed by t-tests. Time-intervention group interactions for neuropsychological measures were evaluated with repeated-measures mixed models. Compared to the No Intervention group, significant increases in brain volume were seen in the Tai Chi and Social Intervention groups (p<0.05). Improvements also were observed in several neuropsychological measures in the Tai Chi group, including the Mattis Dementia Rating Scale score (p=0.004), the Trailmaking Test A (p=0.002) and B (p=0.0002), the Auditory Verbal Learning Test (p=0.009), and verbal fluency for animals (p=0.01). The Social Interaction group showed improvement on some, but fewer neuropsychological indices. No differences were observed between the Walking and No Intervention groups. The findings differ from previous clinical trials in showing increases in brain volume and improvements in cognition with a largely non-aerobic exercise (Tai Chi). In addition, intellectual stimulation through social interaction was associated with increases in brain volume as well as with some cognitive improvements.

Pages 767-778
Niklas Mattsson, Erik Portelius, Sindre Rolstad, Mikael Gustavsson, Ulf Andreasson, Mats Stridsberg, Anders Wallin, Kaj Blennow, Henrik Zetterberg (Handling Associate Editor: Lucilla Parnetti)
Longitudinal Cerebrospinal Fluid Biomarkers over Four Years in Mild Cognitive Impairment
Abstract: Cerebrospinal fluid (CSF) measurements of amyloid-β42 (Aβ42), total-tau (T-tau), and phosphorylated tau (P-tau) may be used to predict future Alzheimer’s disease (AD) dementia in patients with mild cognitive impairment (MCI). The precise temporal development of these biomarkers in relation to clinical progression is unclear. Earlier studies have been hampered by short follow-up. In an MCI cohort, we selected 15 patients who developed AD (MCI-AD) and 15 who remained cognitively stable during 4 years of follow-up. CSF was sampled at three serial occasions from each patient and analyzed for Aβ peptides, the soluble amyloid-β protein precursor protein fragments sAβPPα and sAβPPβ, T-tau, P-tau, and chromogranin B, which is a protein linked to regulated neuronal secretion. We also measured, for the first time in MCI patients, an extended panel of Aβ peptides by matrix-assisted-laser-desorption/ionization time-of-flight mass spectrometry (MS). Most biomarkers were surprisingly stable over the four years with coefficients of variation below or close to 10%. However, MCI-AD patients decreased in CSF AβX-40 and chromogranin B concentrations, which may indicate a reduced number of functional neurons or synapses with disease progression. The MS Aβ peptide panel was more useful than any single Aβ peptide to identify MCI-AD patients already at baseline. Knowledge on these biomarkers and their trajectories may facilitate early diagnosis of AD and be useful in future clinical trials to track effects of disease modifying drugs.

Supplementary Data for Mattsson et al. article (PDF)

Pages 779-790
Fernando Guzman-Sanchez, Fernando Valdivieso, Javier S. Burgos (Handling Associate Editor: Federico Licastro)
Aging-Related Neurostructural, Neuropathological, and Behavioral Changes Associated with Herpes Simplex Virus Type 1 Brain Infection in Mice
Abstract: To date, the main advances in understanding Alzheimer's disease (AD) have revolved around the genetic variants associated with the familial form of the disease, yet the majority of cases are sporadic. The main risk factor for AD is aging, followed by production of the E4 isoform of apolipoprotein E (APOE). Female gender also increases the risk of developing AD. Herpes simplex virus type 1 (HSV-1) has been epidemiologically and experimentally associated with AD, although no studies on its effects over aging have been undertaken. To assess the potential aging-related consequences of HSV-1 brain infection, 2 month-old wild-type and apoE-deficient mice were infected with the virus, and over the next 16 months analyses made of cerebral viral load, neuropathological, morphological, and metabolic changes in the brain, and cognitive performance. Viral load in the central nervous system (CNS) increased with age. The viral load in the brains of aged apoE+/+ female mice was 43 times that seen in apoE-/- male mice. No MRI-detectable morphological differences nor any clear neuropathological differences were seen between 18 month-old infected and mock-infected mice, although differences were seen in younger animals. Neuroinfection was associated with memory deficit and a reduction in metabolic indicators of CNS health.

Pages 791-803
Daniel M. Johnstone, Ross M. Graham, Debbie Trinder, Carlos Riveros, John K. Olynyk, Rodney J. Scott, Pablo Moscato, Elizabeth A. Milward
Changes in Brain Transcripts Related to Alzheimer’s Disease in a Model of HFE Hemochromatosis are not Consistent with Increased Alzheimer’s Disease Risk
Abstract: Iron abnormalities are observed in the brains of Alzheimer’s disease (AD) patients, but it is unclear whether common disorders of systemic iron overload such as hemochromatosis alter risks of AD. We used microarrays and real-time reverse transcription-PCR to investigate changes in the brain transcriptome of adult Hfe-/- mice, a model of hemochromatosis, relative to age- and gender-matched wildtype controls. Classification by functional pathway analysis revealed transcript changes for various genes important in AD. There were decreases of up to 9-fold in transcripts for amyloid-β protein precursor, tau, apolipoprotein E, presenilin 1, and various other γ-secretase components, as well as Notch signaling pathway molecules. This included decreased transcripts for ‘hairy and enhancer of split’ Hes1 and Hes5, downstream targets of Notch canonical signaling. The reductions in Hes1 and Hes5 transcripts provide evidence that the changes in levels of transcript for γ-secretase components and Notch signaling genes have functional consequences. The effects appeared relatively specific for AD in that few genes pertaining to other important neurodegenerative diseases, notably Parkinson’s disease and Huntington’s disease, or to inflammation, oxidative stress, or apoptosis, showed altered transcript levels. The observed effects on AD-related gene transcripts do not appear to be consistent with increased AD risk in HFE hemochromatosis and might, if anything, be predicted to protect against AD to some extent. As Hfe-/- mice did not have higher brain iron levels than wildtype controls, these studies highlight the need for further research in models of more severe hemochromatosis with brain iron loading.

Supplementary Data for Johnstone et al. article (PDF)
Supplementary File 1 for Johnstone et al. (xls)

Pages 805-813
Erik D. Gommer, Esther G.H.J. Martens, Pauline Aalten, Eri Shijaku, Frans R.J. Verhey, Werner H. Mess, Inez H.G.B. Ramakers, Jos P.H. Reulen (Handling Associate Editor: Jurgen Claassen)
Dynamic Cerebral Autoregulation in Subjects with Alzheimer´┐Żs Disease, Mild Cognitive Impairment, and Controls: Evidence for Increased Peripheral Vascular Resistance with Possible Predictive Value
Abstract: Cerebrovascular dysfunction plays a role not only in vascular causes of cognitive impairment but also in Alzheimer’s disease (AD). We hypothesized that cerebral autoregulation is impaired in patients with AD compared to subjects with mild cognitive impairment (MCI) and controls. Dynamic cerebral autoregulation (dCA) was investigated in 17 AD patients, 19 MCI subjects, and 20 controls (C). Groups were matched for age, gender, and level of education. Electrocardiogram and non-invasive finger arterial blood pressure were measured and transcranial doppler ultrasonography was used to measure cerebral blood flow velocity in right and left middle cerebral artery (MCA). Cerebrovascular resistance index (CVRi) was also computed. dCA in supine position was quantified based on spontaneous blood pressure variations by computation of the linear transfer function between arterial blood pressure and MCA cerebral blood flow velocity. dCA gain and phase were evaluated for different frequency bands. Results were also evaluated using a 3-parameter windkessel model (WKM). CVRi was significantly higher in AD (2.9±0.2) compared to both MCI (2.3±0.1, p=0.02) and C (2.1±0.1 mmHgs/cm, p=0.002). Five MCI patients who converted to AD during the course of the study also had higher CVRi compared to non-converters (2.8±0.6 versus 2.1±0.5 mmHgs/cm, p<0.05). No significant differences in dCA gain and phase were found. In terms of the WKM approach, in the order C→MCI→AD groups showed about equal arterial resistance and peripheral compliance, but increased peripheral vasculature resistance (26±2 versus 36±3 mmHgs/ml in C resp. AD, p=0.004). In conclusion, AD patients compared to MCI patients and controls have increased CVRi, whereas dCA parameters do not seem to differentiate AD patients. For MCI patients, CVRi might have predictive value in developing AD.

Pages 815-831
Soraya Santana, Maria Jesús Bullido, Maria Recuero, Fernando Valdivieso, Jesus Aldudo (Handling Associate Editor: Federico Licastro)
Herpes Simplex Virus Type I Induces an Incomplete Autophagic Response in Human Neuroblastoma Cells
Abstract: Autophagy is a homeostatic process involved in the turnover or elimination of cytoplasmic components, damaged organelles, and protein aggregates via a lysosomal degradation mechanism. Autophagy also provides a mechanism of innate immunity, known as xenophagy, designed to protect cells from intracellular pathogens, but it may unfortunately be subverted to act as a pro-viral pathway facilitating the replication of certain viruses. Herpes simplex virus type I (HSV-1) is a neurotropic virus that remains latent in host neurons; it is the most common cause of sporadic viral encephalitis. Moreover, HSV-1 has been related to the pathogenesis of Alzheimer’s disease. HSV-1 can modulate the autophagic process through a mechanism mediated by the viral protein ICP34.5. Here we report that HSV-1 induces a strong increase in GFP-LC3 and endogenous LC3 lipidation, and triggers the accumulation of intracellular autophagic compartments (mainly autophagosomes) without enhancing autophagic long-lived protein degradation in the late stages of infection. Autophagy inhibition mediated by ATG5 gene silencing had no effect on viral growth. The present results suggest that HSV-1 infection activates the host autophagic machinery and strongly controls the autophagic process, blocking the fusion of autophagosomes with lysosomes. These events might be important in the neurodegenerative process associated with HSV-1 infection.

Supplementary Data for Santana et al. article (PDF)

Pages 833-845
Adeline Rollin-Sillaire, Stéphanie Bombois, Vincent Deramecourt, Aline Steinert-Emptaz, Julia Salleron, Julie Morvan, Claude-Alain Maurage, Marc Steinling Florence Pasquier
Contribution of Single Photon Emission Computed Tomography to the Differential Diagnosis of Dementia in a Memory Clinic
Abstract: To evaluate the contribution of single photon emission computed tomography (SPECT) to the differential diagnosis of dementia, we studied 48 consecutive patients (median age: 63) with a degenerative or vascular dementia, a 99mTc-HMPAO SPECT imaging, and a diagnostic confirmation (autopsy or genetic mutation). The SPECT scans were visually rated by two nuclear medicine physicians (first blinded to the clinical data, then with the data). Comparisons between clinical diagnoses and/or SPECT imaging and neuropathology were performed. At the time of SPECT was performed, the clinical diagnosis of Alzheimer’s disease (AD) sensitivity was 83%, specificity was 76%, and diagnostic accuracy was 79%. The blinded SPECT sensitivity was 57%, specificity 92%, and diagnostic accuracy 75%. The SPECT associated with clinical data sensitivity was 65%, specificity 84%, and accuracy 75%. The clinical diagnosis of frontotemporal-lobar degeneration (FTLD), progressive supranuclear palsy (PSP), and corticobasal degeneration syndrome (CBDs) sensitivity was 83%, specificity 87%, and accuracy 85%. The blinded SPECT sensitivity was 50%, specificity 97%, and accuracy 79%. The SPECT associated with clinical data sensitivity was 61%, specificity was 93%, and accuracy 81%. Whenever the blinded SPECT interpretation agreed with the clinical diagnosis of AD and FTLD/PSP/CBDs, the condition was confirmed by neuropathological assessment in all cases. Compared with clinical diagnosis alone, SPECT imaging improved the specificity of the etiological diagnosis in degenerative dementia, although its sensitivity was not as good as that of clinical diagnosis. For AD and FTLD/PSP/CBDs, agreement between the clinical and SPECT-based diagnoses was always confirmed by neuropathological assessment.

Pages 847-856
David Wallon, Stéphane Rousseau, Anne Rovelet-Lecrux, Muriel Quillard-Muraine, Lucie Guyant-Maréchal, Olivier Martinaud, Jérémie Pariente, Michèle Puel, Adeline Rollin-Sillaire, Florence Pasquier, Isabelle Le Ber, Marie Sarazin, Bernard Croisile, Claire Boutoleau-Bretonnière, Catherine Thomas-Antérion, Claire Paquet, Olivier Moreaud, Audrey Gabelle, François Sellal, Mathilde Sauvée, Annie Laquerrière, Charles Duyckaerts, Marie-Bernadette Delisle, Nathalie Streichenberger, Béatrice Lannes, Didier Hannequin, Dominique Campion, and the collaborators of the GMAJ project (Handling Associate Editor: Sylvain Lehmann)
The French Series of Autosomal Dominant Early Onset Alzheimer’s Disease Cases: Mutation Spectrum and Cerebrospinal Fluid Biomarkers
Abstract: We describe 56 novel autosomal dominant early-onset Alzheimer families (ADEOAD) with PSEN1, PSEN2, and AβPP mutations or duplications, raising the total of families with mutations on known genes to 111 (74 PSEN1, 8 PSEN2, 16 AβPP, and 13 AβPP duplications) in the French series. In 33 additional families (23% of the series), the genetic determinism remained uncharacterized after this screening. Cerebrospinal fluid (CSF) biomarker levels were obtained for patients of 58 families (42 with known mutations and 16 without genetic characterization). CSF biomarkers profile was consistent with an AD diagnosis in 90% of families carrying mutations on known genes. In families without genetic cause identified, CSF biomarkers were consistent with AD diagnosis in 14/16 cases. Overall, these results support further genetic heterogeneity in the determinism of ADEOAD and suggest that other major genes remain to be characterized.

Supplementary Data for Wallon et al. article (PDF)

Pages 857-874
Päivi Hartikainen, Janne Räsänen, Valtteri Julkunen, Eini Niskanen, Merja Hallikainen, Miia Kivipelto, RitvaVanninen, Anne M.Remes, Hilkka Soininen
Cortical Thickness in Frontotemporal Dementia, Mild Cognitive Impairment, and Alzheimer’s Disease
Abstract: Cortical thickness analysis has been proposed as a potential diagnostic measure in memory disorders. In this retrospective study, we compared the cortical thickness values of 24 patients with frontotemporal dementia (FTD) to those of 25 healthy controls, 45 symptomatic subjects with stable mild cognitive impairment (S-MCI), 15 subjects with progressive mild cognitive impairment (P-MCI), and 36 patients with Alzheimer’s disease (AD). The patterns of regions of thinning in FTD when compared to controls and also S-MCI patients showed similar trends; thinning of the bilateral frontal poles and bilateral medial temporal lobe structures, especially the anterior part of the gingulum, the uncus, and parahippocampal gyri. Cortical thinning was found on the boundary regions of parietal and occipital lobes. In the P-MCI group compared to FTD, the trend of thinning in small distinct areas of the parietal and occipital lobes was observed. The FTD and AD groups did not differ statistically, but we found trends toward thinning in FTD of the left cingulate gyrus, and the left occipitotemporal gyri, and in AD of the inferior parietal, occipitoparietal, and the pericalcarine regions, more in the right hemisphere. In FTD, increased slowness in the executive test (Trail-Making A) correlated with the thinner cortex, whereas the language tests showed the lower scores, the thinner cortex in the left hemisphere. Cortical thickness might be a tool for detecting subtle changes in brain atrophy in screening of dementia prior to the development of diffuse or lobar atrophies.

Pages 875-887
Ivan Borbon, John Totenhage, Maria Teresa Fiorenza, Sonia Canterini, Wangjing Ke, Theodore Trouard, Robert P. Erickson (Handling Associate Editor: Sigfrido Scarpa)
Niemann-Pick C1 Mice, a Model of “Juvenile Alzheimer’s Disease”, with Normal Gene Expression in Neurons and Fibrillary Astrocytes Show Long Term Survival and Delayed Neurodegeneration
Abstract: Niemann-Pick C1 (NPC) disease, also known as “juvenile Alzheimer’s disease”, is a disease in which alterations in intracellular cholesterol trafficking occur. The contribution of various CNS cell types to the neurodegeneration has been of much interest. We have previously shown that expression of the normal gene only in fibrillary astrocytes could extend survival of Npc1-/- mice over 3-fold (Zhang et al, 2008). We have now studied expression only in neurons or in both neurons and fibrillary astrocytes. Neuron-only expression resulted in survivals of over a year (>5-fold) but motor symptoms started at about 6 months. As reflected in weight gain, this especially affected females who weighed less than wild-type starting at about 10 weeks while male differences in weight are delayed. Expression in both cell types led to a nearly normal phenotype with motor symptoms developing at about ten months and increased survival times. Purkinje cell loss was slowed, but severe, in both NSE- and NSE-GFAP-Npc1, transgenic Npc1-/- mice. MRI studies showed that myelination of the long tracts was significantly improved in NSE-Npc1 transgenics, perhaps less than in GFAP-Npc1 transgenics, and not differently than in the double transgenics. Memory was improved in both single and double transgenics. Somatic disease had not been ameliorated and lungs were massively infiltrated with foamy macrophages at 10 months. Our results suggest that neuron-only expression does not completely prevent neurodegeneration and that the addition of astrocyte expression decreases the rate/degree of decline.

Pages 889-898
Alexandre P. Muller*, Eduardo Rigon Zimmer*, Eduardo Kalinine, Clarissa B. Haas, Jean Pierre Oses, Adriano Martimbianco de Assis, Antonio Galina, Diogo O. Souza, Luis Valmor Portela *These authors contributed equally to this work.
Physical Exercise Exacerbates Memory Deficits Induced by Intracerebroventricular STZ but Improves Insulin Regulation of H2O2 Production in Mice Synaptosomes
Abstract: Insulin brain resistant state is associated with cognitive deficits and Alzheimer’s disease by mechanisms that may involve mitochondrial damage and oxidative stress. Conversely, physical exercise improves cognitive function and brain insulin signaling. The intracerebroventricular (i.c.v.) administration of streptozotocin (STZ) in rodents is an established model of insulin-resistant brain state. This study evaluates the effects of physical exercise on memory performance of i.c.v. STZ-treated mice (1 and 3 mg/kg) and whether insulin (50 and 100 ng/ml) modulates mitochondrial H2O2 generation in synaptosomes. S100B levels and SOD and CAT activities were assessed as markers of brain damage caused by STZ. Sedentary and exercise vehicle-treated mice demonstrated similar performance in object recognition memory task. In the water maze test, exercise vehicle-treated mice showed improvement performance in the acquisition and retrieval phases. The administration of STZ (1 mg/kg) before thirty days of voluntary physical exercise protocol impaired recognition and spatial memory only in exercised mice, whereas STZ (3 mg/kg) impaired the performance of sedentary and exercise groups. Moreover, STZ (3 mg/kg) increased hippocampal S100B levels in both groups and SOD/CAT ratio in the sedentary animals. Insulin decreased synaptosomal H2O2 production in exercised compared to sedentary mice; however, both STZ doses abolished this effect. Normal brain insulin signaling is mechanistically involved in the improvement of cognitive function induced by exercise through the regulation of mitochondrial H2O2 production. However, a prior blockade of brain insulin signaling with STZ abolished the benefits of exercise on memory performance and mitochondrial H2O2 regulation.

Pages 899-908
Annadora J. Bruce-Keller, Robert M. Brouillette, Catrine Tudor-Locke, Heather C. Foil, William P. Gahan, Danielle M. Nye, Leslie Guillory, Jeffrey N. Keller (Handling Associate Editor: Jeff Burns)
Relationship Between Cognitive Domains, Physical Performance, and Gait in Elderly and Demented Subjects
Abstract: Cognitive function declines with age, with studies linking decreases in cognitive function to increased fall risk. The association between declines in specific cognitive domains and the development of gait and physical performance deficits has not been established. The current cross-sectional study was designed to address these issues using well characterized control subjects (n=50), and individuals with early stage dementia (n=50) tightly matched for age, gender, and education. All participants received detailed cognitive assessments for global cognitive function, as well as for processing speed, verbal fluency, and executive function. Additionally, participants were administered single- and dual-task gait assessments (GAITRite) and Short Physical Performance Battery (SPPB) measures of physical performance (gait, balance, chair stands). Data show that all measures of cognitive function correlated significantly with measures of gait and physical performance when analyzed in all subjects or just subjects with dementia. However, data also reveal that measures of processing speed and verbal fluency correlated significantly with multiple aspects of motor performance in non-demented, control subjects, even when corrected for age. There was no correlation between global cognitive function and motor performance, and only limited relationship between executive function and motor performance in non-demented, control subjects. These studies reveal the complex interactions between cognitive function and gait/physical performance in the context of aging and dementia, and suggest that impairments in specific cognitive domains might undermine gait and physical performance and thus exacerbate fall risk in the elderly.

Pages 909-917
Carmen Echávarri, Saartje Burgmans, Maria Cristina Caballero, Federico García-Bragado, Frans R.J. Verhey, Harry B.M. Uylings
Co-occurrence of Different Pathologies in Dementia: Implications for Dementia Diagnosis
Abstract: The standard for differentiating between dementia subtypes is currently based on neuropathological changes and follows traditional nosological classifications. However, the high incidence of comorbid neuropathologies complicates the differentiation between dementia diagnoses in the clinic. The aim of this study was to investigate the grades of agreement between clinical and neuropathological diagnoses in neurodegenerative disorders, to compare them with rates found in previous studies, and to propose implications for dementia diagnostics. Patients, who donated their brains to the Brain Bank of Navarre (Pamplona, Spain), had been diagnosed with a neurodegenerative disorder during life (clinical diagnosis) and postmortem (neuropathological diagnosis). We studied a sample of patients with a short average time interval between the last clinical assessment and death (4.6 months). Overall, there was a mean grade of agreement of 44.0% between the clinical diagnosis and the pure neuropathological diagnosis (i.e., without co-morbid neuropathological disorders). This grade of agreement differed between dementia subtypes: e.g., 85 % for prion disease, 49% for Alzheimer’s disease, and 0% for Lewy body dementia. Our data confirm that co-occurrence of multiple neuropathological disorders is very common in individuals with dementia, and that the underlying neuropathology often differs from the neuropathology implied by the clinical diagnosis. These findings support a multidimensional approach to diagnosing dementia, in which dementia syndromes are not categorized into diagnostic subtypes, but are seen as syndromes characterized by a combination of various neuropathological dimensions.

Supplementary Data for Echavarri et al. article (PDF)

Pages 919-934
Cheng Zhang, Ching-Chang Kuo, Alan W.L. Chiu, June Feng (Handling Associate Editor: Xuemin Xu)
Prediction of S-glutathionylated Proteins Progression in Alzheimer’s Transgenic Mouse Model using Principle Component Analysis
Abstract: To date, prediction of Alzheimer’s disease (AD) is mainly based on clinical criteria because no well-established biochemical biomarkers for routine clinical diagnosis of AD currently exist. We developed an approach to aid in the early diagnosis of AD by using principal component analysis (PCA)-based spectral analysis of oxidized protein electrophoretic profiling. We found the combination of capillary electrophoresis based-S-glutathionylation distribution characterization. The comparison of leave-one-out AD versus non-AD gives the sensitivity of 100% and 93.33% in brain tissues and blood samples, respectively, while the specificity of 100% in brain and 90.0% in blood samples. Our findings demonstrate that PCA of S-glutathionylation electrophoretic profiling detects AD pathology features, and that the molecular weight based electrophoretic profiling of blood and brain S-glutathionylated proteins are sensitive to change, even at the early stage of the disease. Our results offer a previously unexplored diagnostic approach by using electrophoretic characteristics of oxidized proteins to serve as a predictor of AD progression and early stage screening.

Supplementary Data for Zhang et al. article (PDF)

Pages 935-942
David Bunce, Kaarin J Anstey, Nicolas Cherbuin, Prapti Gautam, Perminder Sachdev, Simon Easteal (Handling Associate Editor: Ralph Martins)
APOE Genotype and Entorhinal Cortex Volume in Non-Demented Community-Dwelling Adults in Midlife and Early Old Age
Abstract: The apolipoprotein E (APOE) ɛ4 allele is a risk factor for the neuropathological decline accompanying Alzheimer’s disease (AD) while, conversely, the ɛ2 allele offers protection. One of the brain structures exhibiting the earliest changes associated with the disease is the entorhinal cortex. We therefore investigated the volumes of the entorhinal cortex and other structures in the medial temporal lobe including the parahippocampal gyrus, temporal pole, and inferior, middle, and superior temporal cortices, in relation to APOE genotype. Our main objectives were to determine if (a) volumes systematically varied according to allele in a stepwise fashion, ɛ2>ɛ3>ɛ4, and (b) associations varied according to age. We investigate this association in 627 non-demented community-dwelling adults in middle age (44 to 48 years; n = 314) and older age (64 to 68 years; n = 313) who underwent structural MRI scans. We found no evidence of APOE-related variation in brain volumes in the age groups examined. We conclude that if a ɛ2>ɛ3>ɛ4 pattern in brain volumes does emerge in non-demented adults living in the community in old age, it is not until after the age of 68 years.

Pages 943-961
James L. Searcy*, Jeremiah T. Phelps*, Tristano Pancani, Inga Kadish, Jelena Popovic, Katie L. Anderson, Tina L. Beckett, Michael P. Murphy, Kuey-Chu Chen, Eric M. Blalock, Philip W. Landfield, Nada M. Porter, Olivier Thibault (Handling Associate Editor: Stennis Watson) *These authors contributed equally to the project.
Long-Term Pioglitazone Treatment Improves Learning and Attenuates Pathological Markers in a Mouse Model of Alzheimer’s Disease
Abstract; Thiazolidinediones (TZDs) are agonists at peroxisome proliferator-activated gamma-type (PPAR-g) receptors and are used clinically for the treatment of type 2 diabetes where they have been shown to reestablish insulin sensitivity, improve lipids profile, and reduce inflammation. Recent work also suggests that TZDs may be beneficial in Alzheimer’s disease (AD), ameliorating cognitive decline early in the disease process. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. Starting at 10 months of age, the triple transgenic mouse model of AD (3xTg-AD) with accelerated amyloid-β (Aβ) deposition and tau pathology was treated with the TZD pioglitazone (PIO-ActosÒ) at 18 mg/Kg body weight/day. After four months, PIO-treated animals showed multiple beneficial effects, including improved learning on the active avoidance task, reduced serum cholesterol, decreased hippocampal amyloid-β and tau deposits, and enhanced short- and long-term plasticity. Electrophysiological membrane properties and post-treatment blood glucose levels were unchanged by PIO. Gene microarray analyses of hippocampal tissue identified predicted transcriptional responses following TZD treatment as well as potentially novel targets of TZDs, including facilitation of estrogenic processes and decreases in glutamatergic and lipid metabolic/cholesterol dependent processes. Taken together, these results confirm prior animal studies showing that TZDs can ameliorate cognitive deficits associated with AD-related pathology, but also extend these findings by pointing to novel molecular targets in the brain.

Supplementary Data for Searcy et al. article (xlsx)

Pages 963-979
Arne Herring*, Anja Donath*, Katharina M. Steiner, Manuel P. Widera, Samira Hamzehian, Dimitrios Kanakis, Konrad Kölble, Ayman ElAli, Dirk M. Hermann, Werner Paulus, Kathy Keyvani (Handling Associate Editor: Antonia Gutiérrez) *These authors contributed equally to this work.
Reelin Depletion is an Early Phenomenon of Alzheimer’s Pathology
Abstract: Alterations in the expression of Reelin (RELN) have been implicated in the pathology of Alzheimer's disease (AD). However, whether these changes are cause or consequence of AD remains to be resolved. To better understand the role of RELN pathway in the development of AD, we examined the expression profile of RELN and its downstream signaling members APOER2, VLDLR, and DAB1 in AD-vulnerable regions of transgenic and wildtype mice as well as in AD patients and controls across disease stages and/or aging. We show that both AD pathology and aging are associated with perturbation of the RELN pathway in a species-, region-, and molecule-specific manner. Further, we show that depletion of RELN, but not its downstream signaling molecules, is detectable long before the onset of amyloid-β pathology in the murine hippocampus and in a pre-clinical AD stage in the human frontal cortex. This early event hints at a possible causative role of RELN decline in the precipitation of AD pathology and supports RELN’s potential as a pre-clinical marker for AD.

Pages 981-984

Mariacarla Ventriglia, Serena Bucossi, Valentina Panetta, Rosanna Squitti
Copper in Alzheimer’s Disease: A Meta-Analysis of Serum, Plasma, and Cerebrospinal Fluid Studies
Abstract: This contribution reviews and corrects data from our previous meta-analysis, which appeared in the Journal of Alzheimer’s Disease in 2011 concerning the role of copper in Alzheimer’s disease. We repeated the meta-analysis after excluding four of the five studies from our laboratory to avoid possible bias in the result. In addition, we included two studies on serum copper levels in Alzheimer’s disease not previously considered. The results indicate higher levels of copper in Alzheimer’s disease patients than in controls, confirming our previous conclusion.