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  JOURNAL OF ALZHEIMER'S DISEASE

an IOS Press publication

CONTENTS/ABSTRACTS

 PDFs of all articles are available from IOS Press. 

F O R   A U T H O R S

VOLUMES 1-18

VOLUME 19

VOLUME 20

VOLUME 21

VOLUME 22

VOLUME 23

VOLUME 24

VOLUME 25

VOLUME 26

VOLUME 27

VOLUME 28

VOLUME 29

VOLUME 30

VOLUME 31

VOLUME 32

VOLUME 33

VOLUME 34

VOLUME 35

VOLUME 36

The Journal of Alzheimer's Disease is published by IOS Press. 1998-2012 Journal of Alzheimer's Disease

JAD - Volume 30, Number 3

Volume 30, Number 3, June 2012

Pages 467-474
Anthony Klugman, Declan P Naughton, Mokhtar Isaac, Iltaf Shah, Andrea Petroczi, Naji Tabet
Antioxidant Enzymatic Activities in Alzheimer’s Disease: The Relationship to Acetylcholinesterase Inhibitors
Abstract: The mode of action of acetylcholinesterase inhibitors (AChEIs) in Alzheimer’s disease (AD) is mainly by potentiating neuronal transmission. Animal studies have also consistently described a role for AChEIs in enhancement of antioxidants and attenuation of oxidative stress. The influence of AChEIs on blood antioxidants in AD patients has not been established before. Furthermore, AChEI treatment, or lack of it, may have contributed to the inconsistent antioxidant data reported by other studies so far. Here we sought to investigate the potential modulation effect of AChEIs on blood antioxidants in AD patients. Catalase (CAT) and glutathione reductase (GR) activities were analyzed in 25 drug naïve patients (Group A), 43 patients receiving AChEIs (Group B) and 34 cognitively unimpaired controls (Group C). A statistically significant difference for CAT and GR was observed between the two AD groups (A and B) when compared to the control group C (KW-H = 36.530, p < 0.001; post hoc tests p < 0.001 and KW-H = 37.814, p < 0.001; post hoc tests p < 0.001, respectively). In contrast, CAT and GR activities did not differ significantly between the two AD groups, and were not influenced by AChEI treatment. Hence, these results do not replicate the extensively reported data from animal studies and question whether AChEI efficacy in AD is mediated by processes beyond neuron to neuron enhancement of transmission. Studies assessing a wider range of oxidative/inflammatory markers taking into account type, dosage, and treatment duration of the various acetylcholinesterase inhibitors are now needed.

Pages 475-487
Peipeng Liang*, Zhiqun Wang*, Yanhui Yang, Kuncheng Li *These authors contributed equally.
Three Subsystems of the Inferior Parietal Cortex are Differently Affected in Mild Cognitive Impairment
Abstract: Inferior parietal cortex (IPC), including the intraparietal sulcus (IPS), angular gyrus (AG), and supramarginal gyrus (SG), plays an important role in episodic memory, and is considered to be one of the specific neuroimaging markers in predicting the conversion of mild cognitive impairment (MCI) to Alzheimer’s disease (AD). However, it is still unclear whether the connectivity of the IPC is impaired in MCI patients. In the present study, resting state fMRI was applied to examine the functional connectivity of the three subdivisions of the IPC in MCI patients after controlling the impact of regional grey matter atrophy. It was found that, using IPS, AG, and SG as seeds of functional connectivity, three canonical functional networks could be correspondingly traced, i.e., executive control network (ECN), default mode network (DMN), and salience network (SN), and the three networks are differently altered in MCI patients. In contrast to the healthy controls, it was found that in MCI patients: 1) AG connectivity was significantly reduced within the DMN; 2) IPS showed decreased connectivity with the right inferior frontal gyrus while increased connectivity with the left frontal regions within the ECN; and 3) SG displayed decreased connectivity with a distribution of regions including the frontal and parietal regions, with increased connectivity with some sub-cortical areas within the SN. Moreover, the connectivity within the three networks was correlated with episodic memory and general cognitive impairment in MCI patients. These results extend well beyond the DMN, and further suggest that MCI is associated with alteration of large-scale functional brain networks.

Pages 489-503
Julien Saint-Pol, Elodie Vandenhaute, Marie-Christine Boucau, Pietra Candela, Lucie Dehouck, Roméo Cecchelli, Marie-Pierre Dehouck, Laurence Fenart, Fabien Gosselet (Handling Associate Editor: Othman Ghribi)
Brain Pericytes ABCA1 Expression Mediates Cholesterol Efflux but not Cellular Amyloid-β Peptide Accumulation
Abstract: In brain, excess cholesterol is metabolized into 24S-hydroxycholesterol (24S-OH-chol) and eliminated into the circulation across the blood-brain barrier. 24S-OH-chol is a natural agonist of the nuclear liver X receptors (LXRs) involved in peripheral cholesterol homeostasis. The effects of this oxysterol on the pericytes embedded in the basal lamina of this barrier (close to the brain compartment) have not been previously studied. We used primary cultures of brain pericytes to demonstrate that the latter express LXR nuclear receptors and their target gene ATP-binding cassette, sub-family A, member 1 (ABCA1), known to be one of the major transporters involved in peripheral lipid homeostasis. Treatment with 24S-OH-chol caused an increase in ABCA1 expression that correlated with a reverse cholesterol transfer to apolipoprotein E, apolipoprotein A-I, and high density lipoprotein particles. Inhibition of ABCA1 decreased this efflux. As pericytes are able to internalize the amyloid-β peptides which accumulate in brain of Alzheimer’s disease patients, we then investigated the effects of 24S-OH-chol on this process. We found that the cellular accumulation process was not modified by 24S-OH-chol treatment. Overall, our results highlight the importance of the LXR/ABCA1 system in brain pericytes and suggest a new role for these cells in brain cholesterol homeostasis.

Supplementary Data for Saint-Pol et al. article (PDF)

Pages 505-522
Alfonso Diaz, Daniel Limon, Raúl Chávez, Edgar Zenteno, Jorge Guevara (Handling Associate Editor: Fabien Gosselet)
Aβ25-35 Injection into the Temporal Cortex Induces Chronic Inflammation that Contributes to Neurodegeneration and Spatial Memory Impairment in Rats
Abstract: Amyloid-β (Aβ)25-35 is able to cause memory impairment and neurodegenerative events. Recent evidence has shown that the injection of Aβ25-35 into the temporal cortex (TCx) of rats increases the inflammatory response; however, it is unclear how the inflammatory process could be involved in the progression of Aβ25-35 toxicity. In this study we investigated the role of inflammation in the neuronal damage and spatial memory impairment generated by Aβ25-35 in rat TCx using immunohistochemistry, ELISA, and a behavioral test in the radial maze. Our findings show that Aβ25-35 -injection into the TCx induced a reactive gliosis (GFAP and CD11b-reactivity) and an increase of pro-inflammatory cytokines (IL-1β, IL-6, IL-17, and TNF-α) in the TCx and the hippocampus at 5, 15, and 30 days after injection. Thirty days after Aβ25-35 injection, we observed that the inflammatory reaction probably contributed to increase the immunoreactivity of inducible nitric oxide synthase and nitrite levels, as well as to the loss of neurons in TCx and hippocampus. Behavioral performance showed that the neurodegeneration evoked by Aβ25-35 delayed acquisition of learning and impaired spatial memory, because the Aβ25-35-treated animals showed a greater number of errors during the task than the control group. Previous administration of an interleukin receptor antagonist (IL-1ra) (10 and 20 μg /μL, into TCx), an anti-inflammatory agent, suppressed the Aβ25-35-induced inflammatory response and neurodegeneration, as well as memory dysfunction. This study suggests that the chronic inflammatory reaction could contribute to the progression of Aβ25-35 toxicity and cause cognitive impairment.

Pages 523-530
Li Wan, Guangjun Nie, Jie Zhang, Baolu Zhao
Overexpression of Human Wild-Type Amyloid-β Protein Precursor Decreases the Iron Content and Increases the Oxidative Stress of Neuroblastoma SH-SY5Y Cells
Abstract: The accumulation of amyloid-β protein precursor (AβPP) is related to the pathogenesis of Alzheimer’s disease (AD); however, the underlying mechanism is still unclear. The abnormal interactions of AβPP with metal ions such as iron are implicated in the process of oxidative stress in AD brains. In this study, we found that the overexpression of wild-type human AβPP695 decreased the iron content and increased the oxidative stress in neuroblastoma SH-SY5Y cells. The catalase activity of stably transfected cells overexpressing wild-type AβPP695 (AβPP cells) was significantly lower than that of the control cells. Intracellular reactive oxygen species (ROS) generation and calcium levels significantly increased in AβPP cells compared to control cells. The mitochondrial membrane potential of AβPP cells was significantly lower than that of the control cells. Moreover, iron treatment decreased ROS and calcium levels and increased cell viability of AβPP cells. The iron deficiency in AβPP cells may contribute to the pathogenesis of AD.

Pages 531-543
LiFei Wei, Hui Yang, ZhaoHong Xie, ShaoNan Yang, HongNa Yang, CuiPing Zhao, Ping Wang, ShunLiang Xu, JunYing Miao, BaoXiang Zhao, JianZhong Bi
A Butyrolactone Derivative 3BDO Alleviates Memory Deficits and Reduces Amyloid-β Deposition in an AβPP/PS1 Transgenic Mouse Model
Abstract: Excessive extracellular deposition of amyloid- peptide (Aβ) in the brain is the pathological hallmark of Alzheimer’s disease (AD). Cumulative evidence indicates that autophagy is involved in the metabolism of Aβ and pathogenesis of AD. However, the molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. We recently found that long-term treatment with a butyrolactone derivative 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran- 2(3H)-one (3BDO) increased levels of insulin-degrading enzyme and neprilysin, suppressed autophagy via an mTOR pathway, lowered levels of Aβ, and prevented AD-like cognitive deficits in the AβPP/PS1 double transgenic mouse model. Therefore, our findings suggest that 3BDO may be beneficial in the prevention and treatment of AD.

Pages 545-558
Jiangang Long, Ping He, Yong Shen, Rena Li
New Evidence of Mitochondria Dysfunction in the Female Alzheimer’s Disease Brain: Deficiency of Estrogen Receptor-β
Abstract: Accumulating evidence suggests that mitochondria are important targets for the actions of estrogens and studies indicated that localization of estrogen receptor β (ERβ) in neuronal mitochondrial ERβ (mtERβ) might directly affect neuronal mitochondrial function in vitro. However, it is unknown what expression levels and how important mtERβ is in the human brain, particularly in a brain with Alzheimer’s disease (AD). In the present study, using rapidly autopsied human brain tissue, we found that the frontal cortices of female AD patients exhibited significantly reduced mtERβ, along with reduced mitochondrial cytochrome C oxidase activity, and increased protein carbonylation compared to that in normal controls. The correlation between mtERβ expression and mitochondrial cytochrome C oxidase activity in the female human brain is significant. To understand the possible mechanisms of mtERβ in AD-related mitochondrial dysfunction, using ERβKO mice as a model, we found that lack of ERβ enhanced brain reactive oxygen species generation and reduced mitochondrial membrane potential under Aβ peptide insult compared to brain mitochondria from wild-type control mice. Our studies, for the first time, demonstrated neuronal mtERβ expression in the human brain and the deficiency of mtERβ in the female AD brain is associated with the dysfunction of mitochondria. Our results from ERβKO mice demonstrated that ERβ depletion-induced mitochondrial dysfunction is mediated through increasing reactive oxygen generation and reduction of mitochondria membrane potential. These results indicate that ERβ depletion has the ability to impair mitochondrial function in mice, and reduction of brain mtERβ may significantly contribute to the mitochondrial dysfunction involved in AD pathogenesis in women.

Pages 559-572
Chuanhai Cao, David A. Loewenstein, Xiaoyang Lin, Chi Zhang, Li Wang, Ranjan Duara, Yougui Wu, Alessandra Giannini, Ge Bai, Jianfeng Cai, Maria Greig, Elizabeth Schofield, Raj Ashok, Brent Small, Huntington Potter, Gary W. Arendash
High Blood Caffeine Levels in MCI Linked to Lack of Progression to Dementia
Abstract: Although both human epidemiologic and animal model studies have suggested that caffeine/coffee protects against Alzheimer’s disease, direct human evidence for this premise has been lacking. In the present case-control study, two separate cohorts consisting of 124 total individuals (65-88 years old) were cognitively assessed and a blood sample taken for caffeine/biomarker analysis. Subjects were then monitored for cognitive status over the ensuing 2-4 year period to determine the extent to which initial plasma caffeine/biomarkers levels would be predictive of changes in cognitive status. Plasma caffeine levels at study onset were substantially lower (-51%) in mild cognitive impairment (MCI) subjects who later progressed to dementia (MCI→DEM) compared to levels in stable MCI subjects (MCI→MCI). Moreover, none of the MCI→DEM subjects had initial blood caffeine levels that were above a critical level of 1200 ng/ml, while half of stable MCI→MCI subjects had blood caffeine levels higher than that critical level. Thus, plasma caffeine levels greater than 1200 ng/ml (≈ 6 μM) in MCI subjects were associated with no conversion to dementia during the ensuing 2-4 year follow-up period. Among the 11 cytokines measured in plasma, three of them (GCSF, IL-10, and IL-6) were decreased in MCI→DEM subjects, but not in stable MCI→MCI subjects with high plasma caffeine levels. Coffee would appear to be the major or perhaps only source of caffeine for such stable MCI patients. This case-control study provides the first direct evidence that caffeine/coffee intake is associated with a reduced risk of dementia or delayed onset, particularly for those who already have MCI.

Supplementary Data for Cao et al. article (PDF)

Pages 573-583
Gemma Casadesús, Javier Gutierrez-Cuesta, Hyoung-gon Lee, Andrés Jiménez, Marta Tajes, Daniel Ortuño-Sahagún, Antoni Camins, Mark A. Smith, Mercè Pallàs
Neuronal Cell Cycle Re-Entry Markers are Altered in the Senescence Accelerated Mouse P8 (SAMP8)
Abstract: Senescence-accelerated mice 8 (SAMP8), a model of aging, display many established pathological features of Alzheimer’s disease (AD); however, whether cell cycle alterations exist in these animals remains unknown. Given that these animals present changes such as tau phosphorylation and redox imbalance, both associated with cell cycle alterations, we determined whether changes in cell cycle markers were present in SAMP8 and SAMR1 (control strain) at 3, 6, and 9 months-old brains. As expected, an increase in tau hyperphosphorylation and its associated machinery, i.e., cdk5 and GSK3β, was observed both between strains and also with aging. Particularly, significant differences in cyclin A, cyclin D1, cyclin E, Cdk2, cyclin B, pR, and E2F1 were found when comparing SAMP8 to SAMR1. More interestingly, a partial correlation with several cell cycle markers described in AD brain is found in SAMP8, indicating that some specific hallmarks of AD are also present in this strain, which has been postulated as an early switch model of the disease.

Pages 585-594
Ning-Ning Chen*, Dan-Ju Luo*, Xiu-Qing Yao, Cong Yu, Yi Wang, Qun Wang, Jian-Zhi Wang, Gong-Ping Liu *These authors contributed equally.
Pesticides Induce Spatial Memory Deficits with Synaptic Impairments and an Imbalanced Tau Phosphorylation in Rats
Abstract: Pesticides are widely used in agriculture, and epidemiological studies suggest that pesticide exposure is a risk factor for Alzheimer’s disease (AD), but the mechanisms are elusive. Here, we studied the effects of pesticide exposure on the cognitive ability and the underlying mechanisms in rats. Deltamethrin and carbofuran were administered respectively into the rats once a day for 28 days by gavage. We found that pesticide exposure induced spatial learning and memory deficits with a simultaneous decrease of N-methyl-D-aspartate receptor 1, synaptophysin, and synapsin I, all of which are memory-related synaptic proteins. Pesticide exposure also induced tau hyperphosphorylation at multiple AD-related phosphorylation sites with activation of glycogen synthase kinase-3β and inhibition of protein phosphatase-2A. Additionally, neuron loss in the hippocampus and cortex was observed upon administration of the pesticides. These results indicate that the pesticides exposure could induce AD-like pathology and cognitive abnormality in rats.

Pages 595-603
Daniel A. Nation, Lisa Delano-Wood, Katherine J. Bangen, Christina E. Wierenga, Amy J. Jak, Lawrence A. Hansen, Douglas R. Galasko, David P. Salmon, Mark W. Bondi (Handling Associate Editor: David Knopman)
Antemortem Pulse Pressure Elevation Predicts Cerebrovascular Disease in Autopsy-Confirmed Alzheimer’s Disease
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).

Pages 605-616
Mircea Balasa, Didac Vidal-Piñeiro, Albert Lladó, Anna Antonell, Beatriz Bosch, Fernando Castellanos, Nuria Bargalló, David Bartres-Faz, José-Luis Molinuevo, Raquel Sánchez-Valle (Handling Associate Editor: Estrella Gómez-Tortosa)
PSEN1 Mutation Carriers Present Lower Cerebrospinal Fluid Amyoid-β42 Levels than Sporadic Early-Onset Alzheimer’s Disease Patients but no Differences in Neuronal Injury Biomarkers
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.

Supplementary Data for Balasa et al. article (PDF)

Pages 617-627
Alex Mathew, Tara A. Lindsley, Anna Sheridan, Devang L. Bhoiwala, Shazaan F. Hushmendya, Eric J. Yager, Elizabeth A. Ruggiero, Dana R. Crawford (Handling Associate Editor: M. Flint Beal)
Degraded Mitochondrial DNA is a Newly Identified Subtype of the Damage Associated Molecular Pattern (DAMP) Family and Possible Trigger of Neurodegeneration
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.

Pages 629-637
Marie-Laure Ancelin*, Isabelle Carrière*, Pascale Barberger-Gateau, Sophie Auriacombe, Olivier Rouaud, Spiros Fourlanos, Claudine Berr, Anne-Marie Dupuy, Karen Ritchie *These authors contributed equally.
Lipid Lowering Agents, Cognitive Decline, and Dementia: The Three-City Study
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 (hazards ratio=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.

Pages 639-649
Donald R. Royall, Raymond F. Palmer, Sid E. O’Bryant, for the Texas Alzheimer’s Research and Care Consortium
Validation of a Latent Variable Representing the Dementing Process
Abstract: The cognitive correlates of functional status are essential to dementia case-finding. Never the less, 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., d) from the variance that is unrelated to a dementing process (i.e., g’). Together, g’ + d encompass Spearman’s g. Although d 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 d 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 d can serve as a dementia specific endophenotype. As a result, future studies may be able to associate d with inflammatory and genetic biomarkers.

Pages 651-664
Anke Schmidt, Jens Pahnke (Handling Associate Editor: Eric Westman)
Efficient Near-Infrared in vivo Imaging of Amyoid-β Deposits in Alzheimer’s Disease Mouse Models
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.

Pages 665-673
Xiaonan Wang, Toshihiro Takata, Xiaojuan Bai, Fengrong Ou, Koichi Yokono, Takashi Sakurai
Pyruvate Prevents the Inhibition of the Long-term Potentiation Induced by Amyloid-β through Protein Phosphatase 2A Inactivation
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.

Pages 675-684
Balu Chakravarthy, Michel Ménard, Shingo Ito, Chantal Gaudet, Ilaria Dal Prà, Ubaldo Armato, James Whitfield
Hippocampal Membrane-Associated p75NTR Levels are Increased in Alzheimer’s Disease
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.

Pages 685-710
Katie Lunnon*, Zina Ibrahim*, Petroula Proitsi, Anbarasu Lourdusamy, Stephen Newhouse, Martina Sattlecker, Simon Furney, Muzamil Saleem, Hilkka Soininen, Iwona Kłoszewska, Patrizia Mecocci, Magda Tsolaki, Bruno Vellas, Giovanni Coppola, Daniel Geschwind, Andrew Simmons, Simon Lovestone, Richard Dobson†, Angela Hodges† on behalf of the AddNeuroMed Consortium *,†These authors contributed equally to the work.
Mitochondrial Dysfunction and Immune Activation are Detectable in Early Alzheimer’s Disease Blood
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 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.

Supplementary Data for Lunnon et al. article (PDF)
Supplementary Table 1 (PDF)
Supplementary Table 2 (PDF)

Supplementary Table 3 (PDF)
Supplementary Table 4 (PDF)

Supplementary Table 5 (PDF)
Supplementary Table 6 (PDF)
Supplementary Table 7 (PDF)
Supplementary Table 8 (PDF)
Supplementary Table 9 (PDF)
Supplementary Table 10 (PDF)

Pages 711-727
Meeting Report
Marwan N. Sabbagh, Chris Messis, Robert P. Friedland, Changiz Geula
The 5th International Conference on Alzheimer’s Disease and Related Disorders in the Middle East, 15-17 May 2009, Limassol Cyprus

Pages 729-730
Book Review: Whole Person Dementia Assessment by Benjamin T. Mast, PhD, HPP [Health Professions Press], Baltimore, Maryland, 2011, 271 pp. Reviewed by Robert P. Friedland and Shivani Nandi.

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