Journal of Alzheimer's Disease - Volume 30, issue 4

Authors: Perry, George

Article Type: Editorial

DOI: 10.3233/JAD-2012-129909

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 735-735, 2012

Authors: Popovics, Petra | Stewart, Alan J.

Article Type: Research Article

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. Show more

Keywords: Calcium, dementia, inositol 1, 4, 5-triphosphate, phospholipases, signal amplification

DOI: 10.3233/JAD-2012-120241

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 737-744, 2012

Authors: Albani, Diego | Boneschi, Filippo Martinelli | Biella, Gloria | Giacalone, Giacomo | Lupoli, Sara | Clerici, Francesca | Benussi, Luisa | Ghidoni, Roberta | Galimberti, Daniela | Squitti, Rosanna | Mariani, Stefania | Confaloni, Annamaria | Bruno, Giuseppe | Mariani, Claudio | Scarpini, Elio | Binetti, Giuliano | Magnani, Giuseppe | Franceschi, Massimo | Forloni, Gianluigi

Article Type: Short Communication

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. Show more

Keywords: Alzheimer's disease, apolipoprotein E, CYP2D6, donepezil, pharmacogenetics, rs1080985

DOI: 10.3233/JAD-2012-112123

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 745-749, 2012

Authors: Schmidt, Christian | Haïk, Stephane | Satoh, Katsuya | Rábano, Alberto | Martinez-Martin, Pablo | Roeber, Sigrun | Brandel, Jean-Philippe | Calero-Lara, Miguel | de Pedro-Cuesta, Jesús | Laplanche, Jean-Louis | Hauw, Jean-Jaques | Kretzschmar, Hans | Zerr, Inga

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, heterogeneity, rapid decline

DOI: 10.3233/JAD-2012-120007

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 751-756, 2012

Authors: Mortimer, James A. | Ding, Ding | Borenstein, Amy R. | DeCarli, Charles | Guo, Qihao | Wu, Yougui | Zhao, Qianhua | Chu, Shugang

Article Type: Research Article

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. Show more

Keywords: Cognition, exercise, intervention studies, magnetic resonance imaging, pilot study, Tai Chi

DOI: 10.3233/JAD-2012-120079

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 757-766, 2012

Authors: Mattsson, Niklas | Portelius, Erik | Rolstad, Sindre | Gustavsson, Mikael | Andreasson, Ulf | Stridsberg, Mats | Wallin, Anders | Blennow, Kaj | Zetterberg, Henrik

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarkers, cerebrospinal fluid, chromogranin, mild cognitive impairment, tau

DOI: 10.3233/JAD-2012-120019

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 767-778, 2012

Authors: Guzman-Sanchez, Fernando | Valdivieso, Fernando | Burgos, Javier S.

Article Type: Research Article

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. Show more

Keywords: Aging, apolipoprotein E, brain, HSV-1 infection, gender, mouse, MRI

DOI: 10.3233/JAD-2012-120070

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 779-790, 2012

Authors: Johnstone, Daniel M. | Graham, Ross M. | Trinder, Debbie | Riveros, Carlos | Olynyk, John K. | Scott, Rodney J. | Moscato, Pablo | Milward, Elizabeth A.

Article Type: Research Article

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 transcripts 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. Show more

Keywords: Amyloid-β protein precursor, γ-secretase, hemochromatosis, HFE, iron, notch signaling

DOI: 10.3233/JAD-2012-112183

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 791-803, 2012

Authors: Gommer, Erik D. | Martens, Esther G.H.J. | Aalten, Pauline | Shijaku, Eri | Verhey, Frans R.J. | Mess, Werner H. | Ramakers, Inez H.G.B. | Reulen, Jos P.H.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, autoregulation, cerebral blood flow, mild cognitive impairment, transcranial doppler ultrasonography, transfer function analysis, windkessel model

DOI: 10.3233/JAD-2012-111628

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 805-813, 2012

Authors: Santana, Soraya | Bullido, Maria Jesús | Recuero, Maria | Valdivieso, Fernando | Aldudo, Jesus

Article Type: Research Article

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. Show more

Keywords: ATG5, autophagy, HSV-1, LC3, lysosome, neurodegeneration

DOI: 10.3233/JAD-2012-112000

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 815-831, 2012

Authors: Rollin-Sillaire, Adeline | Bombois, Stéphanie | Deramecourt, Vincent | Steinert-Emptaz, Aline | Salleron, Julia | Morvan, Julie | Maurage, Claude-Alain | Steinling, Marc | Pasquier, Florence

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, dementia, frontotemporal lobar degeneration, SPECT

DOI: 10.3233/JAD-2012-111067

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 833-845, 2012

Authors: Wallon, David | Rousseau, Stéphane | Rovelet-Lecrux, Anne | Quillard-Muraine, Muriel | Guyant-Maréchal, Lucie | Martinaud, Olivier | Pariente, Jérémie | Puel, Michèle | Rollin-Sillaire, Adeline | Pasquier, Florence | Le Ber, Isabelle | Sarazin, Marie | Croisile, Bernard | Boutoleau-Bretonnière, Claire | Thomas-Antérion, Catherine | Paquet, Claire | Moreaud, Olivier | Gabelle, Audrey | Sellal, François | Sauvée, Mathilde | Laquerrière, Annie | Duyckaerts, Charles | Delisle, Marie-Bernadette | Streichenberger, Nathalie | Lannes, Béatrice | Frebourg, Thierry | Hannequin, Didier | Campion, Dominique | The collaborators of the GMAJ project

Article Type: Research Article

Abstract: We describe 56 novel autosomal dominant early-onset Alzheimer disease (ADEOAD) families 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 mutation, 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. Show more

Keywords: Alzheimer's disease, AβPP, CSF biomarkers, early-onset, genetics, PSEN1, PSEN2

DOI: 10.3233/JAD-2012-120172

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 847-856, 2012

Authors: Hartikainen, Päivi | Räsänen, Janne | Julkunen, Valtteri | Niskanen, Eini | Hallikainen, Merja | Kivipelto, Miia | Vanninen, Ritva | Remes, Anne M. | Soininen, Hilkka

Article Type: Research Article

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 in FTD was also 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. Show more

Keywords: Alzheimer's disease, cortical thickness analysis, frontotemporal dementia, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-2012-112060

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 857-874, 2012

Authors: Borbon, Ivan | Totenhagen, John | Fiorenza, Maria Teresa | Canterini, Sonia | Ke, Wangjing | Trouard, Theodore | Erickson, Robert P.

Article Type: Research Article

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 [13]). 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. Show more

Keywords: Astrocyte-specific gene expression, cell autonomy, intracellular cholesterol transport, neurodegeneration, neuron-specific gene expression

DOI: 10.3233/JAD-2012-120199

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 875-887, 2012

Authors: Muller, Alexandre P. | Zimmer, Eduardo Rigon | Kalinine, Eduardo | Haas, Clarissa B. | Oses, Jean Pierre | Martimbianco de Assis, Adriano | Galina, Antonio | Souza, Diogo O. | Portela, Luis Valmor

Article Type: Research Article

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 H2 O2 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 H2 O2 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 H2 O2 production. However, a prior blockade of brain insulin signaling with STZ abolished the benefits of exercise on memory performance and mitochondrial H2 O2 regulation. Show more

Keywords: Alzheimer's disease, cognitive performance, insulin, insulin-resistant brain state, mitochondria, physical exercise

DOI: 10.3233/JAD-2012-112066

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 889-898, 2012

Authors: Bruce-Keller, Annadora J. | Brouillette, Robert M. | Tudor-Locke, Catrine | Foil, Heather C. | Gahan, William P. | Nye, Danielle M. | Guillory, Leslie | Keller, Jeffrey N.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, executive function, falls, physical performance, walking

DOI: 10.3233/JAD-2012-120025

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 899-908, 2012

Authors: Echávarri, Carmen | Burgmans, Saartje | Caballero, Maria Cristina | García-Bragado, Federico | Verhey, Frans R.J. | Uylings, Harry B.M.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, frontotemporal lobe degeneration, Lewy body dementia, neuropathology, vascular dementia

DOI: 10.3233/JAD-2012-111400

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 909-917, 2012

Authors: Zhang, Cheng | Kuo, Ching-Chang | Chiu, Alan W.L. | Feng, June

Article Type: Research Article

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 that the combination of capillary electrophoresis and PCA analysis of S-glutathionylation distribution characterization can be used in the sample classification and molecular weight (Mw) prediction. 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. Show more

Keywords: Alzheimer's disease prediction, capillary gel electrophoresis with laser induced fluorescence detection (CGE-LIF), principle component analysis (PCA), S-glutathionylated proteins (Pr-SSG)

DOI: 10.3233/JAD-2012-120028

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 919-934, 2012

Authors: Bunce, David | Anstey, Kaarin J. | Cherbuin, Nicolas | Gautam, Prapti | Sachdev, Perminder | Easteal, Simon

Article Type: Research Article

Abstract: The apolipoprotein E (APOE) ε4 allele is a risk factor for the neuropathological decline accompanying Alzheimer's disease (AD) while, conversely, the ε2 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, ε2 > ε3 > ε4, …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 ε2 > ε3 > ε4 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. Show more

Keywords: Age, Alzheimer's disease, APOE, entorhinal cortex

DOI: 10.3233/JAD-2012-112126

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 935-942, 2012

Authors: Searcy, James L. | Phelps, Jeremiah T. | Pancani, Tristano | Kadish, Inga | Popovic, Jelena | Anderson, Katie L. | Beckett, Tina L. | Murphy, Michael P. | Chen, Kuey-Chu | Blalock, Eric M. | Landfield, Philip W. | Porter, Nada M. | Thibault, Olivier

Article Type: Research Article

Abstract: Thiazolidinediones (TZDs) are agonists at peroxisome proliferator-activated gamma-type (PPAR-γ) receptors and are used clinically for the treatment of type 2 diabetes where they have been shown to reestablish insulin sensitivity, improve lipid profiles, 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-Actos® ) 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. Show more

Keywords: 3xTg-AD, aging, hippocampus, long-term potentiation, microarray analysis, pioglitazone, PPAR, T2DM

DOI: 10.3233/JAD-2012-111661

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 943-961, 2012

Authors: Herring, Arne | Donath, Anja | Steiner, Katharina M. | Widera, Manuel P. | Hamzehian, Samira | Kanakis, Dimitrios | Kölble, Konrad | ElAli, Ayman | Hermann, Dirk M. | Paulus, Werner | Keyvani, Kathy

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, APOER2, DAB1, human, reelin, TgCRND8, VLDLR

DOI: 10.3233/JAD-2012-112069

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 963-979, 2012

Authors: Ventriglia, Mariacarla | Bucossi, Serena | Panetta, Valentina | Squitti, Rosanna

Article Type: Correction

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.

Keywords: Alzheimer's disease, copper, meta-analysis, serum

DOI: 10.3233/JAD-2012-120244

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 981-984, 2012

Article Type: Other

DOI: 10.3233/JAD-2012-120245

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 985-987, 2012

Article Type: Other

DOI: 10.3233/JAD-2012-30424

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 989-998, 2012