Journal of Alzheimer's Disease - Volume 30, issue 3

Authors: Nation, Daniel A. | Delano-Wood, Lisa | Bangen, Katherine J. | Wierenga, Christina E. | Jak, Amy J. | Hansen, Lawrence A. | Galasko, Douglas R. | Salmon, David P. | Bondi, Mark W.

Article Type: Research Article

Abstract: Elevated pulse pressure (PP) is associated with cognitive decline and increased risk of Alzheimer's disease (AD) in older adults, although the mechanisms behind these associations remain unclear. To address this question, we examined whether antemortem late-life PP elevation predicted vascular or AD pathology in autopsy-confirmed AD patients. Sixty-five elderly patients (mean age 74.2 years) clinically diagnosed with possible or probable AD underwent neuropsychological testing and blood pressure examinations. Postmortem histopathological measures of cerebrovascular disease (CVD) and AD neuropathology were later obtained on these same patients. We expected that antemortem PP elevation, but not standard blood pressure measures such as systolic …or diastolic blood pressure, would predict the autopsy-based presence of CVD, and possibly AD pathology, in elderly AD patients. Results demonstrated that antemortem PP elevation was associated with the presence and severity of CVD at autopsy. For every 5 mmHg increase in antemortem PP there was an estimated 36% increase in the odds of having CVD at autopsy. Additionally, PP accounted for 12% of variance in CVD severity. No significant associations were present for cerebral amyloid angiopathy or Braak and Braak staging of the severity of AD pathology. Other standard blood pressure measures also did not significantly predict neuropathology. The association between antemortem PP and CVD at autopsy suggests that in older adults with AD, PP elevation may increase the risk of CVD. These findings may have treatment implications since some antihypertensive medications specifically address the pulsatile component of blood pressure (e.g., renin-angiotensin system inhibitors, calcium channel blockers). Show more

Keywords: Alzheimer's disease, blood pressure, cerebrovascular disease, pulse pressure

DOI: 10.3233/JAD-2012-111697

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 595-603, 2012

Authors: Balasa, Mircea | Vidal-Piñeiro, Didac | Lladó, Albert | Antonell, Anna | Bosch, Beatriz | Castellanos, Fernando | Bargalló, Nuria | Bartres-Faz, David | Molinuevo, José-Luis | Sánchez-Valle, Raquel

Article Type: Research Article

Abstract: Most cases of early-onset Alzheimer's disease (EOAD) are sporadic. A minority of EOAD are caused by specific genetic defects in PSEN1, PSEN2, or AβPP genes. Magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarker comparisons between sporadic and monogenic EOAD are practically inexistent. CSF and MRI data from 14 amnestic-onset sporadic EOAD (sEOAD) subjects were compared with data from 8 symptomatic PSEN1 mutation carriers (PSEN1) and 14 age-matched cognitively-preserved controls. CSF concentrations of amyloid-β (Aβ)42 , total tau (t-tau), and phosphorylated tau (p-tau) were determined. Cortical thickness (CTh) and grey matter loss were compared between groups and correlated with CSF …biomarkers. PSEN1 had significantly lower CSF Aβ42 levels compared to sEOAD (mean 244.8 pg/ml versus 381.4 pg/ml; p = 0.006), but no differences in t-tau or p-tau. Both sEOAD and PSEN1 showed widespread CTh loss in AD target areas when compared with controls. No differences were found in the direct comparison between sEOAD and PSEN1 CTh after adjusting for age and Mini-Mental Status Examination scores. Neither was a correlation found between Aβ42 levels and CTh. CTh in the left superior parietal and caudal middle frontal areas was negatively correlated with t-tau values. In conclusion, PSEN1 had lower Aβ42 CSF levels compared with sEOAD, suggesting a greater cerebral deposition of Aβ42 . These differences in Aβ42 deposition were not significantly reflected in the brain structure, and CTh was only correlated with total tau. The lack of significant differences in relation to t-tau and p-tau levels and to the severity of CTh or grey matter loss suggests a similar level of neuronal injury despite higher Aβ42 load in PSEN1. Show more

Keywords: Aβ42 levels, Alzheimer's disease, cerebrospinal fluid biomarkers, early onset, PSEN1 mutation

DOI: 10.3233/JAD-2012-111949

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 605-616, 2012

Authors: Mathew, Alex | Lindsley, Tara A. | Sheridan, Anna | Bhoiwala, Devang L. | Hushmendy, Shazaan F. | Yager, Eric J. | Ruggiero, Elizabeth A. | Crawford, Dana R.

Article Type: Research Article

Abstract: We previously showed a preferential degradation and down-regulation of mitochondrial DNA and RNA in hamster fibroblasts in response to hydrogen peroxide. Subsequent studies by others demonstrated that mitochondrial DNA can stimulate immune cells as a DAMP (damage associated molecular patterns) family member. However, the actual physical structure of this mitochondrial DNA DAMP and its importance in non-immune cell types are poorly understood. Here we report that transfected oxidant-initiated degraded mitochondrial polynucleotides, which we term “DeMPs”, strongly induce the proinflammatory cytokines interleukin 6, monocyte chemotactic protein-1, and tumor necrosis factor α in mouse primary astrocytes. Additionally, proinflammatory IL1β was induced, implicating …DeMPs in inflammasome activation. Furthermore, human cerebrospinal fluid (CSF) and plasma were found to contain detectable DeMP signal. Finally, significant degradation of mitochondrial DNA was observed in response to either a bolus or steady state hydrogen peroxide. Combined, these studies demonstrate, all for the first time, that a pathophysiologically relevant form of mitochondrial DNA (degraded) can elicit a proinflammatory cytokine induction; that a brain cell type (astrocytes) elicits a proinflammatory cytokine induction in response to these DeMPs; that this induction includes the inflammasome; that astrocytes are capable of inflammasome activation by DeMPs; that DeMPs are detectable in CSF and plasma; and that hydrogen peroxide can stimulate an early stage cellular degradation of mitochondrial DNA. These results provide new insights and are supportive of our hypothesis that DeMPs are a newly identified trigger of neurodegenerative diseases such as Alzheimer's disease, which are known to be associated with early stage inflammation and oxidation. Show more

Keywords: Astrocytes, damage associated molecular patterns (DAMPs), degraded mitochondrial polynucleotides (DeMPs), hydrogen peroxide, inflammasome, mitochondria, oxidative stress, proinflammatory cytokine

DOI: 10.3233/JAD-2012-120145

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 617-627, 2012

Authors: Ancelin, Marie-Laure | Carrière, Isabelle | Barberger-Gateau, Pascale | Auriacombe, Sophie | Rouaud, Olivier | Fourlanos, Spiros | Berr, Claudine | Dupuy, Anne-Marie | Ritchie, Karen

Article Type: Research Article

Abstract: The aim of this prospective cohort study was to evaluate the effects of lipid lowering agent (LLA) intake on cognitive function in 6,830 community-dwelling elderly persons. Cognitive performance (global cognitive functioning, visual memory, verbal fluency, psychomotor speed, and executive function), clinical diagnosis of dementia, and fibrate and statin use, were evaluated at baseline, and 2, 4, and 7 year follow-up. Multivariate Cox models were stratified by gender and adjusted for sociodemographic characteristics, mental and physical health including vascular risk factors, and genetic vulnerability (apolipoprotein E and cholesteryl ester transfer protein). For women but not men, fibrate use was specifically associated …with an increased risk over 7 years of decline in visual memory only (HR = 1.29, 95% CI = 1.09–1.54, p = 0.004), and did not increase risk for incident dementia. This association was independent of genetic vulnerability related to apolipoprotein E and cholesteryl exchange transfer protein polymorphisms and occurred only in women with higher low density lipoprotein (LDL)-cholesterol levels and treated with fibrate (HR = 1.39, 95% CI = 1.08–1.79, p = 0.01) and not in those with lower LDL-cholesterol levels irrespective of fibrate treatment. For both genders, no significant associations were found between statins (irrespective of their lipophilicity) and either cognitive decline or dementia incidence. This prospective study, adjusting for multiple confounders, found no evidence that LLA given in late life reduced the risk of cognitive decline and dementia, but did raise the possibility that women with treatment-resistant high LDL-cholesterol may be at increased risk of decline in visual memory. Show more

Keywords: Alzheimer's disease, apolipoprotein E, cholesteryl exchange transfer protein, cognitive aging, elderly, fibrate, prospective cohort, statin

DOI: 10.3233/JAD-2012-120064

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 629-637, 2012

Authors: Royall, Donald R. | Palmer, Raymond F. | O'Bryant, Sid E. | for the Texas Alzheimer's Research and Care Consortium

Article Type: Research Article

Abstract: The cognitive correlates of functional status are essential to dementia case-finding. Nevertheless, cognitive performance is a generally weak predictor of functional outcomes. We have employed structural equation models to explicitly distinguish functional status, and therefore “dementia-relevant” variance in cognitive task performance (i.e., δ) from the variance that is unrelated to a dementing process (i.e., g'). Together, g' + δ encompass Spearman's g. Although δ represents only a small fraction of the total variance in cognitive task performance, it is more strongly associated with dementia status than is g'. In this study, we validate δ in a well characterized Alzheimer's disease …cohort, the Texas Alzheimer's Research and Care Consortium. Our approach results in “error free” continuous variables. This suggests that δ can serve as a dementia specific endophenotype. As a result, future studies may be able to associate δ with inflammatory and genetic biomarkers. Show more

Keywords: Aging, cognition, dementia, functional status, g

DOI: 10.3233/JAD-2012-120055

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 639-649, 2012

Authors: Schmidt, Anke | Pahnke, Jens

Article Type: Research Article

Abstract: The development of early diagnostic and prognostic tools for the visualization of amyloid-β (Aβ) deposits is one important focus of current imaging research. In patients with Alzheimer's disease (AD), non-invasive and efficient detection of soluble and aggregated Aβ is important to determine the immediate success of intervention trails. The novel near infrared-fluorescence (NIRF) probe THK-265 efficiently penetrates the blood-brain barrier and has a strong and efficient binding to cerebral Aβ. Ex vivo microscopy of i) THK-265-labeling of plaques in paraffin-embedded tissue and ii) cerebral cryo-sections after intravenous injection of THK-265 confirmed a systematic increase of the NIRF signal corresponding to …Aβ plaque number and size during disease progression. Furthermore, we investigated different stages of plaque formation in amyloid-β protein precursor transgenic mice in vivo after intravenous application of THK-265 to evaluate different aggregation levels with NIRF signals. The intensity of the NIRF signal correlated well with the plaque burden, indicating its utility for direct monitoring of Aβ aggregation progression. In summary, our results support the use of the NIRF probe THK-265 for the diagnosis and direct visualization of amyloid deposits and open the possibility for efficient, pre-symptomatic monitoring of Aβ deposition in the aging brain. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid imaging, in vivo imaging, near-infrared

DOI: 10.3233/JAD-2012-112168

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 651-664, 2012

Authors: Wang, Xiaonan | Takata, Toshihiro | Bai, Xiaojuan | Ou, Fengrong | Yokono, Koichi | Sakurai, Takashi

Article Type: Research Article

Abstract: Amyloid-β (Aβ) oligomers are derived from proteolytic cleavage of amyloid-β protein precursor and can impair memory and hippocampal long-term potentiation (LTP) in vivo and in vitro. They are recognized as the primary neurotoxic agents in Alzheimer's disease. Pyruvate has a protective effect against Aβ-induced neuronal cell death in hippocampal slice cultures. However, whether pyruvate also has a protective effect against the inhibition of neuronal plasticity induced by Aβ remains to be elucidated. This study examined the effect of pyruvate on the Aβ-induced inhibition of LTP in the rat hippocampus. We found that pyruvate prevented the Aβ-induced inhibition of LTP as …strong as fostriecin, a specific protein phosphatase 2A (PP2A) inhibitor. Pyruvate prevented the Aβ block of Ca2+ /calmodulin dependent protein kinase 2 (CaMK2) autophosphorylation and the Aβ-induced PP2A activation. Pyruvate, but not lactate, decreased reactive oxygen species levels in CA1 slices exposed to Aβ. We propose that pyruvate could prevent the Aβ-induced inhibition of LTP by the re-autophosphorylation of CaMK2 through PP2A inactivation. The reduction of reactive oxygen species production is considered to be the upstream mechanism of this observed pyruvate protection. Show more

Keywords: Amyloid-β oligomer, calmodulin dependent protein kinase 2, long-term potentiation, protein phosphatase 2A, pyruvate, reactive oxygen species

DOI: 10.3233/JAD-2012-101869

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 665-673, 2012

Authors: Chakravarthy, Balu | Ménard, Michel | Ito, Shingo | Gaudet, Chantal | Dal Prà, Ilaria | Armato, Ubaldo | Whitfield, James

Article Type: Research Article

Abstract: The pan-specific p75 neurotrophin receptor (p75NTR ) is believed to play an important role in the pathogenesis of Alzheimer's disease (AD). It is involved in mediating amyloid-β (Aβ) toxicity and stimulating amyloidogenesis. In addition, we have recently shown that stimulating cultured SH-SY5Y human neuroblastoma cells with Aβ42 increases the level of membrane-associated p75NTR and that Aβ42 -accumation in two strains of transgenic AD model mice is accompanied by an increased level of hippocampal membrane-associated p75NTR (Chakravarthy et al. J Alzheimers Dis 19, 915-925, 2010). This raised an important question whether accumulating Aβ42 in human AD is …also accompanied by an increased hippocampal membrane-associated p75NTR . In this study, using polyclonal and monoclonal antibodies against the p75NTR receptor's intra- and extracellular domains, we show that indeed the mean level of membrane-associated p75NTR in the hippocampal formation is significantly higher (~two-fold, p < 0.03) in human AD brains than in identical samples of hippocampal formation in age-matched non-AD human brains. The possible relation of this elevated hippocampal p75NTR to AD cognitive decline is discussed. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, hippocampus, p75 neurotrophin receptor, SH-SY5Y human neuroblastoma

DOI: 10.3233/JAD-2012-120115

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 675-684, 2012

Authors: Lunnon, Katie | Ibrahim, Zina | Proitsi, Petroula | Lourdusamy, Anbarasu | Newhouse, Stephen | Sattlecker, Martina | Furney, Simon | Saleem, Muzamil | Soininen, Hilkka | Kłoszewska, Iwona | Mecocci, Patrizia | Tsolaki, Magda | Vellas, Bruno | Coppola, Giovanni | Geschwind, Daniel | Simmons, Andrew | Lovestone, Simon | Dobson, Richard | Hodges, Angela | on behalf of the AddNeuroMed Consortium

Article Type: Research Article

Abstract: Alzheimer's disease (AD), like other dementias, is characterized by progressive neuronal loss and neuroinflammation in the brain. The peripheral leukocyte response occurring alongside these brain changes has not been extensively studied, but might inform therapeutic approaches and provide relevant disease biomarkers. Using microarrays, we assessed blood gene expression alterations occurring in people with AD and those with mild cognitive changes at increased risk of developing AD. Of the 2,908 differentially expressed probes identified between the three groups (p < 0.01), a quarter were altered in blood from mild cognitive impairment (MCI) and AD subjects, relative to controls, suggesting a peripheral …response to pathology may occur very early. There was strong evidence for mitochondrial dysfunction with decreased expression of many of the respiratory complex I-V genes and subunits of the core mitochondrial ribosome complex. This mirrors changes previously observed in AD brain. A number of genes encoding cell adhesion molecules were increased, along with other immune-related genes. These changes are consistent with leukocyte activation and their increased the transition from circulation into the brain. In addition to expression changes, we also found increased numbers of basophils in people with MCI and AD, and increased monocytes in people with an AD diagnosis. Taken together this study provides both an insight into the functional response of circulating leukocytes during neurodegeneration and also identifies potential targets such as the respiratory chain for designing and monitoring future therapeutic interventions using blood. Show more

Keywords: Alzheimer's disease, blood, gene expression pattern analysis, inflammation, late onset, mild cognitive impairment, mitochondria

DOI: 10.3233/JAD-2012-111592

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 685-710, 2012

Authors: Sabbagh, Marwan N. | Messis, Chris | Friedland, Robert P. | Geula, Changiz

Article Type: Meeting Report

Abstract: Alzheimer's disease is growing in prevalence worldwide. Though many Western countries have developed programs of surveillance and care around Alzheimer's disease and dementia, certain regions of the world are beginning to recognize the magnitude of the disease burden in the general population. In the Middle East, there is growing awareness of the burden of Alzheimer's disease and how it impacts health economics, care delivery, and research. Here we summarize the proceedings of the 5th International Conference on Alzheimer's Disease in the Middle East. We had speakers from 20 countries updating the audience on progress toward improving healthcare and research related …to AD in this region of the world. Show more

Keywords: Alzheimer's disease, apolipoprotein E-4, Arab, Israeli, Middle East, pathogenesis

DOI: 10.3233/JAD-2012-120116

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 711-727, 2012