Neurobiology of Aging RSS feed: Current Issue. Neurobiology of Aging publishes the results of studies in behavior, biochemistry, cell biology, endocrinology, molecular biology, morphology, neurology, neuropathology, pharmacology, physiology and protein chemistry in which the primary emphasis involves mechanisms of nervous system changes with age or diseases associated with age. Reviews and primary research articles are included, occasionally accompanied by open peer commentary. Letters to the Editor and brief communications are also acceptable. Brief reports of highly time-sensitive material are usually treated as rapid communications in which case editorial review is completed within six weeks and publication scheduled for the next available issue. The accepted abbreviation for Neurobiology of Aging for bibliographic citation is Neurobiol.Aging http://www.neurobiologyofaging.org/?rss=yesElsevier Inc.en © 2012 Published by Elsevier Inc. All rights reserved. Neurobiology of Aging0197-4580333March 2012 © 2012 Published by Elsevier Inc. All rights reserved. healthpermissions@elsevier.comhttp://www.neurobiologyofaging.org/article/PIIS0197458011005264/abstract?rss=yesEditorial Advisory Board10.1016/S0197-4580(11)00526-4Neurobiology of Aging 33, 3 (2012)2012-03-01Neurobiology of Aging2012-03-01333S0197-4580(11)X0015-5IFCIFChttp://www.neurobiologyofaging.org/article/PIIS0197458010002204/abstract?rss=yesAbstract: Alzheimer's disease (AD) is a complex disorder with a clear genetic component. Three genes have been identified as the cause of early onset familial AD (EOAD). The most common form of the disease, late onset Alzheimer's disease (LOAD), is, however, a sporadic one presenting itself in later stages of life. The genetic component of this late onset form of AD has been the target of a large number of studies, because only one genetic risk factor (APOE4) has been consistently associated with the disease. However, technological advances allow new approaches in the study of complex disorders. In this review, we discuss the new results produced by genome wide association studies, in light of the current knowledge of the complexity of AD genetics. The genetic architecture of Alzheimer's disease: beyond APP, PSENs and APOERita J. Guerreiro, Deborah R. Gustafson, John Hardy10.1016/j.neurobiolaging.2010.03.025Neurobiology of Aging 33, 3 (2012)2010-07-01Neurobiology of Aging2010-07-01333S0197-4580(11)X0015-5Regular Papers437456http://www.neurobiologyofaging.org/article/PIIS0197458010001831/abstract?rss=yesAbstract: Replications of the association between APOE-ε4 allele load and regional brain atrophy in Alzheimer's disease (AD) patients hold promise for future studies testing relationships between other disease risk gene variants and brain structure. A polymorphism, rs10868366, in the Golgi phosphoprotein 2 gene, GOLM1, was recently identified as an AD risk factor in a genome-wide association study. In a subset of the same AD cohort, we used voxel-based morphometry to test for association between the disease risk genotype and reduced regional gray matter (GM) volume in AD patients (n = 72). A mean 14% reduction in GM volume was observed in the left frontal gyrus with the higher risk GG genotype. A similar association was observed in an independent, dataset of nondemented subjects (n = 278), although with a smaller effect (1%). This replicated association with GM structural variation suggests that GOLM1 polymorphisms may be related to cognitive phenotypes. The greater effect size in AD patients also suggests that the GG genotype could be a risk factor for the expression of cognitive deficits in AD. Genetic variation in GOLM1 and prefrontal cortical volume in Alzheimer's diseaseBecky Inkster, Anil W. Rao, Khanum Ridler, Nicola Filippini, Brandon Whitcher, Thomas E. Nichols, Sally Wetten, Rachel A. Gibson, Michael Borrie, Andrew Kertesz, Danilo A. Guzman, Inge Loy-English, Julie Williams, Philipp G. Saemann, Dorothee P. Auer, Florian Holsboer, Federica Tozzi, Pierandrea Muglia, Emilio Merlo-Pich, Paul M. Matthews10.1016/j.neurobiolaging.2010.04.018Neurobiology of Aging 33, 3 (2012)2010-06-07Neurobiology of Aging2010-06-07333S0197-4580(11)X0015-5Regular Papers457465http://www.neurobiologyofaging.org/article/PIIS0197458010001788/abstract?rss=yesAbstract: Functional magnetic resonance imaging (fMRI) of default mode network (DMN) brain activity during resting is recently gaining attention as a potential noninvasive biomarker to diagnose incipient Alzheimer's disease. The aim of this study was to determine which method of data processing provides highest diagnostic power and to define metrics to further optimize the diagnostic value. fMRI was acquired in 21 healthy subjects, 17 subjects with mild cognitive impairment and 15 patients with Alzheimer's disease (AD) and data evaluated both with volumes of interest (VOI)-based signal time course evaluations and independent component analyses (ICA). The first approach determines the amount of DMN region interconnectivity (as expressed with correlation coefficients); the second method determines the magnitude of DMN coactivation. Apolipoprotein E (ApoE) genotyping was available in 41 of the subjects examined. Diagnostic power (expressed as accuracy) of data of a single DMN region in independent component analyses was 64%, that of a single correlation of time courses between 2 DMN regions was 71%, respectively. With multivariate analyses combining both methods of analysis and data from various regions, accuracy could be increased to 97% (sensitivity 100%, specificity 95%). In nondemented subjects, no significant differences in activity within DMN could be detected comparing ApoE ε4 allele carriers and ApoE ε4 allele noncarriers. However, there were some indications that fMRI might yield useful information given a larger sample. Time course correlation analyses seem to outperform independent component analyses in the identification of patients with Alzheimer's disease. However, multivariate analyses combining both methods of analysis by considering the activity of various parts of the DMN as well as the interconnectivity between these regions are required to achieve optimal and clinically acceptable diagnostic power. Diagnostic power of default mode network resting state fMRI in the detection of Alzheimer's diseaseWalter Koch, Stephan Teipel, Sophia Mueller, Jens Benninghoff, Maxmilian Wagner, Arun L.W. Bokde, Harald Hampel, Ute Coates, Maximilian Reiser, Thomas Meindl10.1016/j.neurobiolaging.2010.04.013Neurobiology of Aging 33, 3 (2012)2010-06-14Neurobiology of Aging2010-06-14333S0197-4580(11)X0015-5Regular Papers466478http://www.neurobiologyofaging.org/article/PIIS0197458010001557/abstract?rss=yesAbstract: In patients with Alzheimer's disease (AD), postmortem and imaging studies have revealed early and prominent reductions in cerebral serotonin 2A (5-HT2A) receptors. To establish if this was due to a selective disease process of the serotonin system, we investigated the cerebral 5-HT2A receptor and the serotonin transporter binding, the latter as a measure of serotonergic projections and neurons. Twelve patients with AD (average Mini Mental State Examination [MMSE]: 24) and 11 healthy age-matched subjects underwent positron emission tomography (PET) scanning with [18F]altanserin and [11C]N,N-Dimethyl-2-(2-amino-4-cyanopheylthio)benzylamine ([11C]DASB). Overall [18F]altanserin binding was markedly reduced in AD by 28%–39% (p = 0.02), whereas the reductions in [11C]DASB binding were less prominent and mostly insignificant, except for a marked reduction of 33% in mesial temporal cortex (p = .0005). No change in [11C]DASB binding was found in the midbrain. We conclude that the prominent reduction in neocortical 5-HT2A receptor binding in early AD is not caused by a primary loss of serotonergic neurons or their projections. Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer's disease: a combined [11C]DASB and [18F]altanserin-PET studyLisbeth Marner, Vibe G. Frokjaer, Jan Kalbitzer, Szabolcs Lehel, Karine Madsen, William F.C. Baaré, Gitte M. Knudsen, Steen G. Hasselbalch10.1016/j.neurobiolaging.2010.03.023Neurobiology of Aging 33, 3 (2012)2010-05-31Neurobiology of Aging2010-05-31333S0197-4580(11)X0015-5Regular Papers479487http://www.neurobiologyofaging.org/article/PIIS0197458010002022/abstract?rss=yesAbstract: Diffusion tensor (DT) magnetic resonance imaging (MRI) tractography was used to investigate microstructural and volumetric abnormalities of the major brain white matter (WM) tracts with aging in 84 healthy subjects. Linear relationships were found between age and mean diffusivity (MD) increase and fractional anisotropy (FA) decrease in all WM tracts, except the right cingulum and bilateral uncinate, where a linear correlation with age was found for FA only. Quadratic model fitted better MD and FA values of several tracts, including the corpus callosum, limbic pathways, and bilateral association, and corticospinal tracts. Age-related MD and FA abnormalities were associated with radial diffusivity increase in all WM tracts, while axial diffusivity changes were characterized by a considerable variation from a tract to another. A linear negative relationship with age was found for the volumes of the left cingulum and fornix, while the quadratic model fitted better age-related volume loss of corpus callosum and right inferior fronto-occipital fasciculus. Diffusion tensor magnetic resonance imaging may shed light into the complex pathological substrates of WM changes with aging. Microstructural changes and atrophy in brain white matter tracts with agingStefania Sala, Federica Agosta, Elisabetta Pagani, Massimiliano Copetti, Giancarlo Comi, Massimo Filippi10.1016/j.neurobiolaging.2010.04.027Neurobiology of Aging 33, 3 (2012)2010-07-01Neurobiology of Aging2010-07-01333S0197-4580(11)X0015-5Regular Papers488498.e2http://www.neurobiologyofaging.org/article/PIIS0197458010002216/abstract?rss=yesAbstract: Accumulating evidence indicates that white matter degeneration contributes to the neural disconnections that underlie Alzheimer's disease pathophysiology. Although this white matter degeneration is partly attributable to axonopathy associated with neuronal degeneration, amyloid β (Aβ) protein-mediated damage to oligodendrocytes could be another mechanism. To test this hypothesis, we studied effects of soluble Aβ in oligomeric form on survival and differentiation of cells of the oligodendroglial lineage using highly purified oligodendroglial cultures from rats at different developmental stages. Aβ oligomer at 10 μM or higher reduced survival of mature oligodendrocytes, whereas oligodendroglial progenitor cells (OPCs) were relatively resistant to the Aβ oligomer-mediated cytotoxicity. Further study revealed that Aβ oligomer even at 1 μM accelerated 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) formazan exocytosis in mature oligodendrocytes, and, more significantly, inhibited myelin sheet formation after induction of in vitro differentiation of OPCs. These results imply a novel pathogenetic mechanism underlying Aβ oligomer-mediated white matter degeneration, which could impair myelin maintenance and remyelination by adult OPCs, resulting in accumulating damage to myelinating axons thereby contributing to neural disconnections. Amyloid β1–42 oligomer inhibits myelin sheet formation in vitroMakoto Horiuchi, Izumi Maezawa, Aki Itoh, Kouji Wakayama, Lee-Way Jin, Takayuki Itoh, Charles DeCarli10.1016/j.neurobiolaging.2010.05.007Neurobiology of Aging 33, 3 (2012)2010-07-01Neurobiology of Aging2010-07-01333S0197-4580(11)X0015-5Regular Papers499509http://www.neurobiologyofaging.org/article/PIIS0197458010002071/abstract?rss=yesAbstract: A novel analysis of magnetic resonance imaging (MRI) scans based on multispectral image fusion was used to quantify iron deposits in basal ganglia and microbleeds in 143 nondemented subjects of the generally healthy Lothian Birth Cohort, who were tested for general cognitive ability (intelligence) at mean ages of 11, 70, and 72 years. Possessing more iron deposits at age 72 was significantly associated with lower general cognitive ability at age 11, 70, and 72, explaining 4% to 9% of the variance. The relationships with old age general cognitive ability remained significant after controlling for childhood cognition, suggesting that iron deposits are related to lifetime cognitive decline. Most iron deposits were in the basal ganglia, with few microbleeds. While iron deposits in the general population have so far been dismissed in the literature, our results show substantial associations with cognitive functioning. The pattern of results suggests that iron deposits are not only a biomarker of general cognitive ability in old age and age-related cognitive decline, but that they are also related to the lifelong-stable trait of intelligence. Brain iron deposits are associated with general cognitive ability and cognitive agingLars Penke, Maria C. Valdés Hernandéz, Susana Muñoz Maniega, Alan J. Gow, Catherine Murray, John M. Starr, Mark E. Bastin, Ian J. Deary, Joanna M. Wardlaw10.1016/j.neurobiolaging.2010.04.032Neurobiology of Aging 33, 3 (2012)2010-06-09Neurobiology of Aging2010-06-09333S0197-4580(11)X0015-5Regular Papers510517.e2http://www.neurobiologyofaging.org/article/PIIS0197458010001806/abstract?rss=yesAbstract: Two recent large genome-wide association studies have reported significant associations in the CLU (APOJ), CR1, and PICALM genes with the risk of Alzheimer’s disease (AD). In order to replicate these findings, we examined 7 single nucleotide polymorphisms (SNPs) most significantly implicated by these studies in a large case-control sample comprising 2707 individuals. Principle components analysis revealed no population substructure in our sample. While no association was observed with CR1 SNPs (p = 0.30–0.457), a trend of association was seen with the PICALM (p = 0.071–0.086) and CLU (p = 0.148–0.258) SNPs. A meta-analysis of 3 studies revealed significant associations with all 3 genes. Our data from an independent and large case-control sample suggest that these gene regions should be followed up by comprehensive resequencing to find functional variants. Association of CLU and PICALM variants with Alzheimer's diseaseM. Ilyas Kamboh, Ryan L. Minster, F. Yesim Demirci, Mary Ganguli, Steven T. DeKosky, Oscar L. Lopez, M. Michael Barmada10.1016/j.neurobiolaging.2010.04.015Neurobiology of Aging 33, 3 (2012)2010-06-07Neurobiology of Aging2010-06-07333S0197-4580(11)X0015-5Brief Communication518521http://www.neurobiologyofaging.org/article/PIIS0197458010002095/abstract?rss=yesAbstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder mainly characterized by amyloid-beta (Aβ) deposition and neurofibrillary tangles (NFTs). The abnormal enrichment of amyloid protein precursor (APP) leads to a high risk of AD. One of the plausible age-associated AD animal models, senescence-accelerated mouse prone 8 (SAMP8), have age-related learning and memory deficits. We found APP protein significantly increased in the hippocampus of aged SAMP8 mice. The 20 to 25 nucleotide (nt) tiny regulators, known as micro ribonucleic acids (miRNAs), have been found to play crucial roles in neurodegenerative diseases. Here, we examined the post-transcriptional regulation mechanism of APP mediated by micro ribonucleic acids and found that miR-16 was one of the post-transcriptional regulators of APP in SAMP8 mice. Overexpression of miR-16, both in vitro and in vivo, led to reduced APP protein expression. Furthermore, miR-16 and APP displayed complementary expression patterns in SAMP8 mice and BALb/c mice embryos. Taken together, these findings demonstrate that APP is a target of miR-16 and the abnormally low expression of miR-16 could potentially lead to APP protein accumulation in AD mice. MicroRNA-16 targets amyloid precursor protein to potentially modulate Alzheimer's-associated pathogenesis in SAMP8 miceWei Liu, Chang Liu, Jingxi Zhu, Pengcheng Shu, Bin Yin, Yanhua Gong, Boqin Qiang, Jiangang Yuan, Xiaozhong Peng10.1016/j.neurobiolaging.2010.04.034Neurobiology of Aging 33, 3 (2012)2010-07-12Neurobiology of Aging2010-07-12333S0197-4580(11)X0015-5Regular Papers522534http://www.neurobiologyofaging.org/article/PIIS0197458010001818/abstract?rss=yesAbstract: Oxidative stress is a primary factor inducing brain dysfunction in aged animals. However, how oxidation affects brain function is not fully understood. Here we show that oxidation inhibits signaling pathways essential for synaptic plasticities in the cerebellum. We first revealed that nitric oxide (NO)-dependent plasticities at the parallel fiber-Purkinje cell synapse (PF synapse) were impaired in the cerebellar slices from aged mice, suggesting a possible inhibitory action of protein oxidation by endogenous reactive oxygen species. PF-synaptic plasticities were also blocked in the cerebellar slices from young mice preincubated with oxidizing agents or thiol blocker. Because the treatment of the slices with the oxidizing agent did not affect basic electrophysiological properties of excitatory postsynaptic current of PF (PF-EPSC) and did not occlude the synaptic plasticities, oxidation was revealed to specifically inhibit signaling pathways essential for PF-synaptic plasticities. Finally, biochemical analysis confirmed the idea that inhibitory action of protein oxidation on the PF-synaptic plasticities was mediated by impairment of nitric oxide-induced protein S-nitrosylation. Therefore, oxidation was revealed to inhibit the S-nitrosylation-dependent signaling pathway essential for synaptic plasticity in a “competitive” manner. Protein oxidation inhibits NO-mediated signaling pathway for synaptic plasticitySho Kakizawa, Masahiko Shibazaki, Nozomu Mori10.1016/j.neurobiolaging.2010.04.016Neurobiology of Aging 33, 3 (2012)2010-06-28Neurobiology of Aging2010-06-28333S0197-4580(11)X0015-5Regular Papers535545http://www.neurobiologyofaging.org/article/PIIS019745801000151X/abstract?rss=yesAbstract: The aged canine (dog) is an excellent model for investigating the neurobiological changes that underlie cognitive impairment and neurodegeneration in humans, as canines and humans undergo similar pathological and behavioral changes with aging. Recent evidence indicates that a combination of environmental enrichment and antioxidant-fortified diet can be used to reduce the rate of age-dependent neuropathology and cognitive decline in aged dogs, although the mechanisms underlying these changes have not been established. We examined the hypothesis that an increase in levels of brain-derived neurotrophic factor (BDNF) is one of the factors underlying improvements in learning and memory. Old, cognitively impaired animals that did not receive any treatment showed a significant decrease in BDNF mRNA in the temporal cortex when compared with the young group. Animals receiving either an antioxidant diet or environmental enrichment displayed intermediate levels of BDNF mRNA. However, dogs receiving both an antioxidant diet and environmental enrichment showed increased levels of BDNF mRNA when compared with untreated aged dogs, approaching levels measured in young animals. BDNF receptor TrkB mRNA levels did not differ between groups. BDNF mRNA levels were positively correlated with improved cognitive performance and inversely correlated with cortical Aβ(1–42) and Aβ(1–40) levels. These findings suggest that environmental enrichment and antioxidant diet interact to maintain brain levels of BDNF, which may lead to improved cognitive performance. This is the first demonstration in a higher animal that nonpharmacological changes in lifestyle in advanced age can upregulate BDNF to levels approaching those in the young brain. BDNF increases with behavioral enrichment and an antioxidant diet in the aged dogMargaret Fahnestock, Monica Marchese, Elizabeth Head, Viorela Pop, Bernadeta Michalski, William N. Milgram, Carl W. Cotman10.1016/j.neurobiolaging.2010.03.019Neurobiology of Aging 33, 3 (2012)2010-05-07Neurobiology of Aging2010-05-07333S0197-4580(11)X0015-5Regular Papers546554http://www.neurobiologyofaging.org/article/PIIS0197458010001600/abstract?rss=yesAbstract: The TgCRND8 mouse model of Alzheimer's disease exhibits progressive cortical and hippocampal β-amyloid accumulation, resulting in plaque pathology and spatial memory impairment by 3 months of age. We tested whether TgCRND8 cognitive function is disrupted prior to the appearance of macroscopic plaques in an object recognition task. We found profound deficits in 8-week-old mice. Animals this age were not impaired on the Morris water maze task. TgCRND8 and littermate controls did not differ in their duration of object exploration or optokinetic responses. Thus, visual and motor dysfunction did not confound the phenotype. Object memory deficits point to the frontal cortex and hippocampus as early targets of functional disruption. Indeed, we observed altered levels of brain-derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) in these brain regions of preplaque TgCRND8 mice. Our findings suggest that object recognition provides an early index of cognitive impairment associated with amyloid exposure and reduced brain-derived neurotrophic factor expression in the TgCRND8 mouse. Object recognition memory and BDNF expression are reduced in young TgCRND8 miceBeverly M. Francis, John Kim, Meredith E. Barakat, Stephan Fraenkl, Yeni H. Yücel, Shiyong Peng, Bernadeta Michalski, Margaret Fahnestock, JoAnne McLaurin, Howard T.J. Mount10.1016/j.neurobiolaging.2010.04.003Neurobiology of Aging 33, 3 (2012)2010-05-07Neurobiology of Aging2010-05-07333S0197-4580(11)X0015-5Regular Papers555563http://www.neurobiologyofaging.org/article/PIIS019745801000179X/abstract?rss=yesAbstract: It is well established that there are remarkable similarities between song learning in oscine birds and acquisition of speech in young children. Human speech shows marked changes with senescence, but few studies have evaluated how song changes with advanced age in songbirds. To investigate the effect of old age on song, we compared song of old Bengalese finches (Lonchura striata domestica) with that of middle-aged birds. The main observed difference was a decrease in the song tempo, largely due to an increased intersyllable duration. Aging also affected the acoustic characteristics of the song, causing a decrease in pitch and in the range of frequency modulations. Gross morphological measurements of selected vocal muscles did not show detectable changes over this age range, suggesting that song deterioration may be due to neural deterioration. The age-induced temporal and acoustic changes in song parallel the acoustic changes that occur in human speech, suggesting songbirds as a suitable model for aging studies on learned vocal behavior. Age-related changes in the Bengalese finch song motor programBrenton G. Cooper, Jorge M. Méndez, Sigal Saar, Addison G. Whetstone, Ron Meyers, Franz Goller10.1016/j.neurobiolaging.2010.04.014Neurobiology of Aging 33, 3 (2012)2010-06-07Neurobiology of Aging2010-06-07333S0197-4580(11)X0015-5Brief Communication564568http://www.neurobiologyofaging.org/article/PIIS0197458010001776/abstract?rss=yesAbstract: Amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) is a progressive debilitating neurodegenerative disease with no cure. We propose a novel molecular model for the pathogenesis of ALS that involves an adenosine triphosphate (ATP)-dependent muscle neuronal lactate shuttle (MNLS) at the neuromuscular junction (NMJ) to regulate the flow of lactate from muscle to neurons and vice versa. Failure of the MNLS due to respiratory chain dysfunction is proposed to result in lactate toxicity and degeneration of nerve endings at the NMJ leading to nerve terminus dysjunction from the muscle cell. At a critical threshold where denervation outpaces reinnervation, a vicious cycle is established where the remaining innervated muscle fibers are required to work harder to compensate for normal function, and in so doing produce toxic lactate concentrations which induces further denervation and neuronal death. This mechanism explains the exponential progression of ALS leading to paralysis. The molecular events leading to the dysregulation of the MNLS and the dismantling of NMJ are explained in the context of known ALS familial mutations and age-related endocrine dyscrasia. Combination drug therapies that inhibit lactate accumulation at the NMJ, enhance respiratory chain function, and/or promote reinnervation are predicted to be effective therapeutic strategies for ALS. Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosisSivan Vadakkadath Meethal, Craig S. Atwood10.1016/j.neurobiolaging.2010.04.012Neurobiology of Aging 33, 3 (2012)2010-06-14Neurobiology of Aging2010-06-14333S0197-4580(11)X0015-5Regular Papers569581http://www.neurobiologyofaging.org/article/PIIS0197458010001545/abstract?rss=yesAbstract: Decreases in GH secretion with age may contribute to cognitive changes associated with aging. We evaluated the relation between GH secretion and cognition in elderly males by assessing correlations between GH secretion and performance on cognitive tests in conjunction with recording of event-related potentials (ERPs) to assess underlying neurophysiological mechanisms. GH secretion of 17 elderly male participants was assessed by a GHRH-GHRP-6 test. Standardized neuropsychological tests were used to assess cognitive function. EEG/ERPs were recorded to assess on-line electrocortical correlates of sensory-cortical processing and selective attention. GH secretion was significantly correlated with target detections and speed of responding in the selection-potential task. Furthermore, GH peak was significantly correlated with the performance letter-digit span test. The present data confirm that cognitive performance in elderly males is associated with GH secretion, with respect to target detection and speed of responding in conditions of selective attention, short-term memory, and basic processing speed. Cognitive performance in older males is associated with growth hormone secretionE.H. Quik, E.B. Conemans, G.D. Valk, J.L. Kenemans, H.P.F. Koppeschaar, P.S. van Dam10.1016/j.neurobiolaging.2010.03.022Neurobiology of Aging 33, 3 (2012)2010-05-20Neurobiology of Aging2010-05-20333S0197-4580(11)X0015-5Regular Papers582587http://www.neurobiologyofaging.org/article/PIIS0197458010001570/abstract?rss=yesAbstract: Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSC) have a potential therapeutic role in the treatment of neurological disorders, but their current clinical usage and mechanism of action has yet to be ascertained in Alzheimer's disease (AD). Here we report that hUCB-MSC transplantation into amyloid precursor protein (APP) and presenilin1 (PS1) double-transgenic mice significantly improved spatial learning and memory decline. Furthermore, amyloid-β peptide (Aβ) deposition, β-secretase 1 (BACE-1) levels, and tau hyperphosphorylation were dramatically reduced in hUCB-MSC transplanted APP/PS1 mice. Interestingly, these effects were associated with reversal of disease-associated microglial neuroinflammation, as evidenced by decreased microglia-induced proinflammatory cytokines, elevated alternatively activated microglia, and increased anti-inflammatory cytokines. These findings lead us to suggest that hUCB-MSC produced their sustained neuroprotective effect by inducing a feed-forward loop involving alternative activation of microglial neuroinflammation, thereby ameliorating disease pathophysiology and reversing the cognitive decline associated with Aβ deposition in AD mice. Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer's disease mouse model through modulation of neuroinflammationHyun Ju Lee, Jong Kil Lee, Hyun Lee, Janet E. Carter, Jong Wook Chang, Wonil Oh, Yoon Sun Yang, Jun-Gyo Suh, Byoung-Hee Lee, Hee Kyung Jin, Jae-sung Bae10.1016/j.neurobiolaging.2010.03.024Neurobiology of Aging 33, 3 (2012)2010-05-17Neurobiology of Aging2010-05-17333S0197-4580(11)X0015-5Regular Papers588602http://www.neurobiologyofaging.org/article/PIIS0197458010001594/abstract?rss=yesAbstract: Delirium is an acute, severe neuropsychiatric syndrome, characterized by cognitive deficits, that is highly prevalent in aging and dementia and is frequently precipitated by peripheral infections. Delirium is poorly understood and the lack of biologically relevant animal models has limited basic research. Here we hypothesized that synaptic loss and accompanying microglial priming during chronic neurodegeneration in the ME7 mouse model of prion disease predisposes these animals to acute dysfunction in the region of prior pathology upon systemic inflammatory activation. Lipopolysaccharide (LPS; 100 μg/kg) induced acute and transient working memory deficits in ME7 animals on a novel T-maze task, but did not do so in normal animals. LPS-treated ME7 animals showed heightened and prolonged transcription of inflammatory mediators in the central nervous system (CNS), compared with LPS-treated normal animals, despite having equivalent levels of circulating cytokines. The demonstration that prior synaptic loss and microglial priming are predisposing factors for acute cognitive impairments induced by systemic inflammation suggests an important animal model with which to study aspects of delirium during dementia. Systemic inflammation induces acute working memory deficits in the primed brain: relevance for deliriumCarol Murray, David J. Sanderson, Chris Barkus, Robert M.J. Deacon, J. Nicholas P. Rawlins, David M. Bannerman, Colm Cunningham10.1016/j.neurobiolaging.2010.04.002Neurobiology of Aging 33, 3 (2012)2010-05-14Neurobiology of Aging2010-05-14333S0197-4580(11)X0015-5Regular Papers603616.e3http://www.neurobiologyofaging.org/article/PIIS0197458010003210/abstract?rss=yesAbstract: Normal aging is accompanied by global as well as regional structural changes. While these age-related changes in gray matter volume have been extensively studied, less has been done using newer morphological indexes, such as cortical thickness and surface area. To this end, we analyzed structural images of 216 healthy volunteers, ranging from 18 to 87 years of age, using a surface-based automated parcellation approach. Linear regressions of age revealed a concomitant global age-related reduction in cortical thickness, surface area and volume. Cortical thickness and volume collectively confirmed the vulnerability of the prefrontal cortex, whereas in other cortical regions, such as in the parietal cortex, thickness was the only measure sensitive to the pronounced age-related atrophy. No cortical regions showed more surface area reduction than the global average. The distinction between these morphological measures may provide valuable information to dissect age-related structural changes of the brain, with each of these indexes probably reflecting specific histological changes occurring during aging. Normal age-related brain morphometric changes: nonuniformity across cortical thickness, surface area and gray matter volume?Herve Lemaitre, Aaron L. Goldman, Fabio Sambataro, Beth A. Verchinski, Andreas Meyer-Lindenberg, Daniel R. Weinberger, Venkata S. Mattay10.1016/j.neurobiolaging.2010.07.013Neurobiology of Aging 33, 3 (2012)2010-08-26Neurobiology of Aging2010-08-26333S0197-4580(11)X0015-5Abstracts of Online Articles617.e1617.e9http://www.neurobiologyofaging.org/article/PIIS0197458010003222/abstract?rss=yesAbstract: Gonadal hormones may influence cognitive function. Postmenopausal midlife women in the population-based Melbourne Women's Midlife Health Project cohort were administered a comprehensive battery of neuropsychological tests on two occasions 2 years apart. Participants (n = 148, mean age 60 years) had undergone natural menopause and were not using hormone therapy. Estrone, total and free estradiol, and total and free testosterone levels were measured at time of the first testing. Principal-component analysis identified four cognitive factors. In multiple linear regression analyses, better semantic memory performance was associated with higher total (p = 0.02) and free (p = 0.03) estradiol levels and a lower ratio of testosterone to estradiol (p = 0.007). There were trends for associations between better verbal episodic memory and lower total testosterone (p = 0.08) and lower testosterone/estradiol ratio (p = 0.06). Lower free testosterone levels were associated with greater 2-year improvement on verbal episodic memory (p = 0.04); higher testosterone/estradiol predicted greater semantic memory improvement (p = 0.03). In postmenopausal midlife women, endogenous estradiol and testosterone levels and the testosterone/estradiol ratio are associated with semantic memory and verbal episodic memory abilities. Hormone levels and cognitive function in postmenopausal midlife womenJoanne Ryan, Frank Z. Stanczyk, Lorraine Dennerstein, Wendy J. Mack, Margaret S. Clark, Cassandra Szoeke, Daniel Kildea, Victor W. Henderson10.1016/j.neurobiolaging.2010.07.014Neurobiology of Aging 33, 3 (2012)2010-10-04Neurobiology of Aging2010-10-04333S0197-4580(11)X0015-5Abstracts of Online Articles617.e11617.e22http://www.neurobiologyofaging.org/article/PIIS0197458010004926/abstract?rss=yesAbstract: Possession of the APOE-ε4 allele is the best established genetic risk factor for sporadic Alzheimer's disease (AD), while the ε2 allele may confer protection against the disease. Previous functional magnetic resonance imaging (fMRI) studies have shown an effect of APOE genotype on brain function, typically by comparing only ε4 carriers with noncarriers. Here we included a wide range of genotype groups to determine how closely the effects of APOE on brain function are related to differences in relative risk for AD. We used functional magnetic resonance imaging (fMRI) to compare the pattern of activation during an episodic encoding task and during a counting Stroop task in 76 adults, aged 32 to 55, with different APOE genotypes (23 ε2/ε3, 20 ε3/ε3, 26 ε3/ε4, and 7 ε4/ε4). Strikingly, participants with an increased risk (ε4 carriers) and with a decreased risk (ε2 carriers) for AD both showed increased activation, relative to ε3 homozygotes, during both tasks. The increased activation was due to decreased deactivation or paradoxical activation of nontask-related regions of the brain, which suggests an intrinsic effect of APOE on the differentiation of functional cortical networks. These results question the often assumed link between APOE, the blood oxygenation level dependent (BOLD) response, and AD risk. The effects of APOE on brain activity do not simply reflect the risk of Alzheimer's diseaseAaron J. Trachtenberg, Nicola Filippini, Jane Cheeseman, Eugene P. Duff, Matt J. Neville, Klaus P. Ebmeier, Fredrik Karpe, Clare E. Mackay10.1016/j.neurobiolaging.2010.11.011Neurobiology of Aging 33, 3 (2012)2011-01-13Neurobiology of Aging2011-01-13333S0197-4580(11)X0015-5Abstracts of Online Articles618.e1618.e13http://www.neurobiologyofaging.org/article/PIIS0197458010004951/abstract?rss=yesAbstract: Previous studies have shown that messenger RNA (mRNA) of the dynamin-binding protein (DNMBP), a scaffold protein regulating actin cytoskeleton and synaptic vesicle pools, is lower in neuropathologically-confirmed Alzheimer's brains. Here we investigated whether a deficit in long term memory formation during physiological aging is also associated with lower DNMBP expression. Hippocampal DNMBP mRNA was quantified by quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR) following inhibitory avoidance task in aged (26- to 27-month-old) rats that, according to memory performance, were ranked as good responders (GR) and bad responders (BR), in adult (3-month-old), late-adult (19-month-old), and aged (26–27-month-old) naive animals. We found that DNMBP mRNA levels were significantly higher in naive adults versus late adult and aged naive rats, in GR versus BR, and in pooled GR and BR versus aged-matched controls. Our data provide the first evidence that hippocampal DNMBP mRNA expression is reduced during physiological aging, and suggest that the capability to increase the expression of this mRNA may be a requirement for preserving long term memory formation during aging. Dynamin binding protein gene expression and memory performance in aged ratsTiziana Casoli, Giuseppina Di Stefano, Patrizia Fattoretti, Belinda Giorgetti, Marta Balietti, Fabrizia Lattanzio, Giorgio Aicardi, Daniela Platano10.1016/j.neurobiolaging.2010.11.012Neurobiology of Aging 33, 3 (2012)2011-01-13Neurobiology of Aging2011-01-13333S0197-4580(11)X0015-5Abstracts of Online Articles618.e15618.e19http://www.neurobiologyofaging.org/article/PIIS0197458011000157/abstract?rss=yesAbstract: We investigated whether abrupt ethanol withdrawal (EW) age-specifically inhibits a key mitochondrial enzyme, cytochrome c oxidase (COX), and whether estrogen mitigates this problem. We also tested whether this possible effect of EW involves a substrate (cytochrome c) deficiency that is associated with proapoptotic Bcl2-associated X protein (BAX) and mitochondrial membrane swelling. Ovariectomized young, middle age, and older rats, with or without 17β-estradiol (E2) implantation, underwent repeated EW. Cerebelli were collected to measure COX activity and the mitochondrial membrane swelling using spectrophotometry and the mitochondrial levels of cytochrome c and BAX using an immunoblot method. The loss of COX activity and the mitochondrial membrane swelling occurred only in older rats under control diet conditions but occurred earlier, starting in the young rats under EW conditions. E2 treatment mitigated these EW effects. EW increased mitochondrial BAX particularly in middle age rats but did not alter cytochrome c. Collectively EW hastens but E2 delays the age-associated loss of COX activity. This EW effect is independent of cytochrome c but may involve the mitochondrial overload of BAX and membrane vulnerability. Ethanol withdrawal hastens the aging of cytochrome c oxidaseMarianna E. Jung, Xiaohua Ju, Daniel B. Metzger, James W. Simpkins10.1016/j.neurobiolaging.2011.02.002Neurobiology of Aging 33, 3 (2012)2011-03-25Neurobiology of Aging2011-03-25333S0197-4580(11)X0015-5Abstracts of Online Articles618.e21618.e32http://www.neurobiologyofaging.org/article/PIIS0197458011000170/abstract?rss=yesAbstract: The authors investigated whether cognitive function may be used as an endophenotype for longevity by assessing the cognitive performance of a family-based cohort consisting of 1380 individuals from 283 families recruited for exceptional survival in field centers in Boston, New York, Pittsburgh, and Denmark. Cognitive performance was assessed in the combined offspring of the Long Life Family Study (LLFS) probands and their LLFS siblings as compared with their spouses' cognitive performance. Our results indicate that the combined offspring of the LLFS probands and their siblings achieve significantly higher scores on both digit forward and backward tasks (p = 5 10-5 and p = 8 10-4 respectively) as well as on a verbal fluency task (p = 0.008) when compared with their spouse controls. No differences between groups were found for the other cognitive tests assessed. We conclude that LLFS family members in the offspring generation demonstrate significantly better performance on multiple tasks requiring attention, working memory, and semantic processing when compared with individuals without a family history of exceptional survival, suggesting that cognitive performance may serve as an important endophenotype for longevity. Cognitive function in families with exceptional survivalSandra Barral, Stephanie Cosentino, Rosann Costa, Amy Matteini, Kaare Christensen, Stacy L. Andersen, Nancy W. Glynn, Anne B. Newman, Richard Mayeux10.1016/j.neurobiolaging.2011.02.004Neurobiology of Aging 33, 3 (2012)2011-03-25Neurobiology of Aging2011-03-25333S0197-4580(11)X0015-5Abstracts of Online Articles619.e1619.e7http://www.neurobiologyofaging.org/article/PIIS0197458011000182/abstract?rss=yesAbstract: Studies of recovery from stroke mainly utilize rodent models and focus primarily on young subjects despite the increased prevalence of stroke with age and the fact that recovery of function is more limited in the aged brain. In the present study, a nonhuman primate model of cortical ischemia was developed to allow the comparison of impairments in young and middle-aged monkeys. Animals were pretrained on a fine motor task of the hand and digits and then underwent a surgical procedure to map and lesion the hand-digit representation in the dominant motor cortex. Animals were retested until performance returned to preoperative levels. To assess the recovery of grasp patterns, performance was videotaped and rated using a scale adapted from human occupational therapy. Results demonstrated that the impaired hand recovers to baseline in young animals in 65–80 days and in middle-aged animals in 130–150 days. However, analysis of grasp patterns revealed that neither group recover preoperative finger thumb grasp patterns, rather they develop compensatory movements. Recovery from ischemia in the middle-aged brain: a nonhuman primate modelTara L. Moore, Ronald J. Killiany, Monica A. Pessina, Mark B. Moss, Seth P. Finklestein, Douglas L. Rosene10.1016/j.neurobiolaging.2011.02.005Neurobiology of Aging 33, 3 (2012)2011-04-04Neurobiology of Aging2011-04-04333S0197-4580(11)X0015-5Abstracts of Online Articles619.e9619.e24http://www.neurobiologyofaging.org/article/PIIS0197458011000200/abstract?rss=yesAbstract: Mitochondrial dysfunction is likely a significant contributing factor to Alzheimer disease pathogenesis, and both amyloid peptide (Aβ) and pathological forms of tau may contribute to this impairment. Cleavage of tau at Asp421 occurs early in Alzheimer disease, and Asp421-cleaved tau likely negatively impacts neuronal function. Previously we showed that expression of Asp421-cleaved tau in a neuronal cell model resulted in mitochondrial impairment. To extend these findings we expressed either full length tau or Asp421-cleaved tau (truncated tau) in primary cortical neurons and measured different aspects of mitochondrial function with or without the addition of sublethal concentrations of Aβ. The expression of truncated tau alone induced significant mitochondrial fragmentation in neurons. When truncated tau expression was combined with Aβ at sublethal concentrations, increases in the stationary mitochondrial population and the levels of oxidative stress in cortical neurons were observed. Truncated tau expression also enhanced Aβ-induced mitochondrial potential loss in primary neurons. These new findings show that Asp421-cleaved tau and Aβ cooperate to impair mitochondria, which likely contributes to the neuronal dysfunction in Alzheimer disease. Truncated tau and Aβ cooperatively impair mitochondria in primary neuronsRodrigo A. Quintanilla, Philip J. Dolan, Youngnam N. Jin, Gail V.W. Johnson10.1016/j.neurobiolaging.2011.02.007Neurobiology of Aging 33, 3 (2012)2011-03-31Neurobiology of Aging2011-03-31333S0197-4580(11)X0015-5Abstracts of Online Articles619.e25619.e35http://www.neurobiologyofaging.org/article/PIIS0197458011000388/abstract?rss=yesAbstract: The type 1 cannabinoid receptor (CB1) is a crucial modulator of synaptic transmission in brain and has been proposed as a potential therapeutic target in Parkinson's disease (PD), especially for treatment of levodopa-induced dyskinesias (LID). Our aim was to measure CB1 levels in brains of PD patients in vivo and to investigate the relation between CB1 availability and LID. We studied 12 healthy controls and 29 PD patients (9 drug-naïve patients with early PD, 10 patients with advanced PD and LID, and 10 patients with advanced PD without LID). PD patients were examined using the Unified Parkinson's Disease Rating Scale (UPDRS) and the modified Abnormal Involuntary Movement Scale (mAIMS). All subjects underwent positron emission tomography (PET) with the CB1-selective radioligand [18F] MK-9470 and magnetic resonance imaging (MRI). PD patients showed an absolute decrease in CB1 availability in the substantia nigra. By contrast, CB1 availability was relatively increased in nigrostriatal, mesolimbic, and mesocortical dopaminergic projection areas. CB1 availability did not differ significantly between advanced PD patients with and without LID. Within the group of PD patients with LID, there was no significant correlation between CB1 availability and LID severity. These data demonstrate regional changes in CB1 availability in PD in vivo, but do not support a role for dysregulation of CB1 levels in the pathogenesis of LID. Regional changes in type 1 cannabinoid receptor availability in Parkinson's disease in vivoKoen Van Laere, Cindy Casteels, Sophie Lunskens, Karolien Goffin, Igor D. Grachev, Guy Bormans, Wim Vandenberghe10.1016/j.neurobiolaging.2011.02.009Neurobiology of Aging 33, 3 (2012)2011-04-04Neurobiology of Aging2011-04-04333S0197-4580(11)X0015-5Abstracts of Online Articles620.e1620.e8http://www.neurobiologyofaging.org/article/PIIS019745801100042X/abstract?rss=yesAbstract: It is unknown whether lifestyle, including mental stimulation, and appropriate training interventions, may directly improve spatial navigation performance and its underlying neural substrates. Here we report that healthy younger and older men performing a cognitively demanding spatial navigation task every other day over 4 months display navigation-related gains in performance and stable hippocampal volumes that were maintained 4 months after termination of training. In contrast, control groups displayed volume decrements consistent with longitudinal estimates of age-related decline. Hippocampal barrier density, as indicated by mean diffusivity estimated from diffusion tensor imaging, showed a quadratic shape of increased density after training followed by a return to baseline in the right hippocampus, but declined in the control groups and in the left hippocampus. We conclude that sustained experiential demands on spatial ability protect hippocampal integrity against age-related decline. These results provide the first longitudinal evidence indicating that spatial navigation experience modifies hippocampal volumes in humans, and confirm epidemiological results suggesting that mental stimulation may have direct effects on neural integrity. Spatial navigation training protects the hippocampus against age-related changes during early and late adulthoodMartin Lövdén, Sabine Schaefer, Hannes Noack, Nils Christian Bodammer, Simone Kühn, Hans-Jochen Heinze, Emrah Düzel, Lars Bäckman, Ulman Lindenberger10.1016/j.neurobiolaging.2011.02.013Neurobiology of Aging 33, 3 (2012)2011-04-18Neurobiology of Aging2011-04-18333S0197-4580(11)X0015-5Abstracts of Online Articles620.e9620.e22http://www.neurobiologyofaging.org/article/PIIS0197458011000431/abstract?rss=yesAbstract: Tauopathies are characterized by hyperphosphorylation of the microtubule-associated protein tau and its accumulation into fibrillar aggregates. Toxic effects of aggregated tau and/or dysfunction of soluble tau could both contribute to neural defects in these neurodegenerative diseases. We have generated a novel knockin mouse model of an inherited tauopathy, frontotemporal dementia with parkinsonism linked to tau mutations on chromosome 17 (FTDP-17T). We incorporated a single mutation, homologous to the common FTDP-17T P301L mutation, directly into the endogenous mouse gene, mimicking the human disease situation. These mice express P301L-equivalent mutant tau at normal physiological levels from the knockin allele. Importantly, in contrast to existing transgenic mouse models that overexpress human P301L mutant tau, no overt tau pathology developed during the normal lifespan of the knockin mice. In fact, overall phosphorylation of tau was reduced, perhaps due to reduced microtubule binding. However, homozygous knockin mice did display intriguing age-dependent changes in axonal transport of mitochondria, and increased spontaneous locomotor activity in old age. These could represent early consequences of the tau dysfunction that eventually precipitates pathogenesis in humans. Age-dependent axonal transport and locomotor changes and tau hypophosphorylation in a “P301L” tau knockin mouseJonathan Gilley, Anjan Seereeram, Kunie Ando, Suzanne Mosely, Simon Andrews, Martin Kerschensteiner, Thomas Misgeld, Jean-Pierre Brion, Brian Anderton, Diane P. Hanger, Michael P. Coleman10.1016/j.neurobiolaging.2011.02.014Neurobiology of Aging 33, 3 (2012)2011-04-14Neurobiology of Aging2011-04-14333S0197-4580(11)X0015-5Abstracts of Online Articles621.e1621.e15http://www.neurobiologyofaging.org/article/PIIS0197458011000443/abstract?rss=yesAbstract: In Huntington's disease (HD), mutated huntingtin (mhtt) causes striatal neurodegeneration which is paralleled by elevated microglia cell numbers. In vitro corticostriatal slice and primary neuronal culture models, in which neuronal expression of mhtt fragments drives HD-like neurotoxicity, were employed to examine wild type microglia during both the initiation and progression of neuronal pathology. As neuronal pathology progressed, microglia initially localized in the vicinity of neurons expressing mhtt fragments increased in number, demonstrated morphological evidence of activation, and expressed the proliferation marker, Ki67. These microglia were positioned along irregular neurites, but did not localize with mhtt inclusions nor exacerbate mhtt fragment-induced neurotoxicity. Prior to neuronal pathology, microglia upregulated ionized calcium binding adaptor molecule 1 (Iba1), signaling a functional shift. With neurodegeneration, interleukin-6 and complement component 1q were increased. The results suggest a stimulatory, proliferative signal for microglia present at the onset of mhtt fragment-induced neurodegeneration. Thus, microglia effect a localized inflammatory response to neuronal mhtt expression that may serve to direct microglial removal of dysfunctional neurites or aberrant synapses, as is required for reparative actions in vivo. Activated microglia proliferate at neurites of mutant huntingtin-expressing neuronsAndrew D. Kraft, Linda S. Kaltenbach, Donald C. Lo, G. Jean Harry10.1016/j.neurobiolaging.2011.02.015Neurobiology of Aging 33, 3 (2012)2011-04-13Neurobiology of Aging2011-04-13333S0197-4580(11)X0015-5Abstracts of Online Articles621.e17621.e33http://www.neurobiologyofaging.org/article/PIIS0197458011000479/abstract?rss=yesAbstract: The National Institute on Aging Preclinical Alzheimer's disease Workgroup (PADW) has issued a preliminary report with recommendations for classifying preclinical Alzheimer's disease (pAD) according to 3 early disease stages. Here we examine the PADW recommendations in relation to neuropathological features in a large, consecutive series of cognitively intact elderly persons, autopsied within a year after cognitive testing (n = 126 cognitively intact patients with mean age 83.7 years at death). Subjects were grouped based on a hypothetical construct correlating pathological features with PADW stages. Many cognitively intact individuals were classifiable as pAD (53/126 or 43%), as expected based on epidemiological and biomarker studies. Of these, most (48%) were in “stage 3”, which corresponds to amyloid pathology with early neurodegeneration. As with prior studies, our data indicate that the development of neocortical neurofibrillary tangles is the key pathological event that is not observed in pAD cases: Braak stages III or IV pathology are hence not truly a substrate for “intermediate likelihood” that cognitive impairment is due to Alzheimer's disease (AD). We also stress the importance of comorbid non-Alzheimer's disease brain pathologies (hippocampal sclerosis, neocortical alpha-synucleinopathy, cerebrovascular disease, and brains with hippocampal neurofibrillary tangles but no cortical amyloid plaques) that can contribute to the development of cognitive impairment, or which may serve as confounds in the application of the PADW recommendations. While the final recommendations from the PADW working group have not yet been released, this preliminary analysis provides a perspective on those recommendations from a neuropathological point of view. Preclinical AD Workgroup staging: pathological correlates and potential challengesGregory A. Jicha, Erin L. Abner, Frederick A. Schmitt, Richard J. Kryscio, Kathryn P. Riley, Gregory E. Cooper, Nancy Stiles, Marta S. Mendiondo, Charles D. Smith, Linda J. Van Eldik, Peter T. Nelson10.1016/j.neurobiolaging.2011.02.018Neurobiology of Aging 33, 3 (2012)2011-04-21Neurobiology of Aging2011-04-21333S0197-4580(11)X0015-5Abstracts of Online Articles622.e1622.e16http://www.neurobiologyofaging.org/article/PIIS0197458011000480/abstract?rss=yesAbstract: We examined the associations between extracerebral markers of cholesterol homeostasis and cognitive decline over 6 years of follow-up, and studied the modifying effect of apolipoprotein E (ApoE) e4. Data were collected in the Longitudinal Aging Study Amsterdam (n = 967, with longitudinal data on cognition, ages ≥ 65 years) and analyzed using linear mixed models. General cognition (Mini-Mental State Examination; MMSE), memory (Auditory Verbal Learning Test), and information processing speed (Coding task) were measured. The results show that ApoE e4 was a significant effect modifier. Significant associations were found only in ApoE e4 noncarriers (n = 718). We found a nonlinear negative association between the ratio of lanosterol to cholesterol (≤ 189.96 ng/mg), a marker for cholesterol synthesis, and general cognition. Lower cholesterol absorption, i.e., lower ratios of campesterol and sitosterol to cholesterol, as well as a higher rate of cholesterol synthesis relative to absorption were associated with lower information processing speed. In ApoE e4 carriers, the negative association between the ratio of campesterol to cholesterol and memory reached borderline significance. Future research should focus on the interaction between (disturbed) cholesterol homeostasis and ApoE e4 status with respect to dementia. The role of extracerebral cholesterol homeostasis and ApoE e4 in cognitive declineTessa N. van den Kommer, Miranda G. Dik, Hannie C. Comijs, Dieter Lütjohann, Paul Lips, Cees Jonker, Dorly J.H. Deeg10.1016/j.neurobiolaging.2011.02.019Neurobiology of Aging 33, 3 (2012)2011-04-13Neurobiology of Aging2011-04-13333S0197-4580(11)X0015-5Abstracts of Online Articles622.e17622.e28http://www.neurobiologyofaging.org/article/PIIS0197458011000492/abstract?rss=yesAbstract: Physical exercise and fitness have been proposed as potential factors that promote healthy cognitive aging. Support for this hypothesis has come from cross sectional, longitudinal, and intervention studies. In the present review, we discuss several methodological problems that limit the conclusions of many studies. The lack of consensus on how to retrospectively measure exercise intensity is a major difficulty for all studies that attempt to estimate lifelong impact of exercise on cognitive performance in older adults. Intervention studies have a much better capacity to establish causality, but still suffer from difficulties arising from inadequate control groups and the choice and modality of administration of cognitive measures. We argue that, while the association between exercise and preserved cognition during aging is clearly demonstrated, the specific hypothesis that physical exercise is a cause of healthy cognitive aging has yet to be validated. A number of factors could mediate the exercise-cognition association, including depression, and social or cognitive stimulation. The complex interactions among these 3 factors and the potential impact of exercise on cognition remain to be systematically studied. At this time, the best prescription for lifestyle interventions for healthy cognitive aging would be sustained physical, social, and mental activities. What remains unknown is which type of activity might be most useful, and whether everyone benefits similarly from the same interventions. Measuring the impact of exercise on cognitive aging: methodological issuesDelyana I. Miller, Vanessa Taler, Patrick S.R. Davidson, Claude Messier10.1016/j.neurobiolaging.2011.02.020Neurobiology of Aging 33, 3 (2012)2011-04-25Neurobiology of Aging2011-04-25333S0197-4580(11)X0015-5Abstracts of Online Articles622.e29622.e43http://www.neurobiologyofaging.org/article/PIIS0197458011000509/abstract?rss=yesAbstract: Functional brain imaging studies of normal aging typically show age-related under- and overactivations during episodic memory tasks. Older individuals also undergo nonuniform gray matter volume (GMv) loss. Thus, age differences in functional brain activity could at least in part result from local atrophy. We conducted a series of voxel-based blood oxygen level-dependent (BOLD)-GMv analyses to highlight whether age-related under- and overrecruitment was accounted for by GMv changes. Occipital GMv loss accounted for underrecruitment at encoding. Efficiency reduction of sensory-perceptual mechanisms underpinned by these areas may partly be due to local atrophy. At retrieval, local GMv loss accounted for age-related overactivation of left dorsolateral prefrontal cortex, but not of left dorsomedial prefrontal cortex. Local atrophy also accounted for age-related overactivation in left lateral parietal cortex. Activity in these frontoparietal regions correlated with performance in the older group. Atrophy in the overrecruited regions was modest in comparison with other regions as shown by a between-group voxel-based morphometry comparison. Collectively, these findings link age-related structural differences to age-related functional under- as well as overrecruitment. Local brain atrophy accounts for functional activity differences in normal agingGrégoria Kalpouzos, Jonas Persson, Lars Nyberg10.1016/j.neurobiolaging.2011.02.021Neurobiology of Aging 33, 3 (2012)2011-04-25Neurobiology of Aging2011-04-25333S0197-4580(11)X0015-5Abstracts of Online Articles623.e1623.e13http://www.neurobiologyofaging.org/article/PIIS0197458011000595/abstract?rss=yesAbstract: Recent studies have linked dopamine to differences in behavior and brain activity in normal individuals. We explored these relationships in older and younger adults by investigating how functional connectivity between the striatum and prefrontal cortex is related to caudate dopamine and verbal working memory task performance. We studied 12 young and 18 older participants with functional magnetic resonance imaging (fMRI) during this task, and used positron emission tomography with the tracer 6-[18F]-fluoro-L-m-tyrosine (FMT) to assess dopamine synthesis capacity. Younger adults had a greater extent of frontal caudate functional connectivity during the load-dependent delay period of the working memory task than the older participants. Across all subjects, the extent of this functional connectivity was negatively correlated with dopamine synthesis capacity, such that participants with the greatest connectivity had the lowest caudate 6-[18F]-fluoro-L-m-tyrosine (FMT) signal. Additionally, the extent of functional connectivity was positively correlated with working memory performance. Overall these data suggest interdependencies exist between frontostriatal functional connectivity, dopamine, and working memory performance and that this system is functioning suboptimally in normal aging. Dopamine and frontostriatal networks in cognitive agingEllen C. Klostermann, Meredith N. Braskie, Susan M. Landau, James P. O'Neil, William J. Jagust10.1016/j.neurobiolaging.2011.03.002Neurobiology of Aging 33, 3 (2012)2011-04-22Neurobiology of Aging2011-04-22333S0197-4580(11)X0015-5Abstracts of Online Articles623.e15623.e24http://www.neurobiologyofaging.org/article/PIIS0197458011000601/abstract?rss=yesAbstract: Cognitively normal (NL) individuals with a maternal history of late-onset Alzheimer's disease (MH) show reduced brain glucose metabolism on FDG-PET as compared to those with a paternal history (PH) and those with negative family history (NH) of Alzheimer's disease (AD). This FDG-PET study investigates whether metabolic deficits in NL MH are associated with advancing maternal age at birth. Ninety-six NL individuals with FDG-PET were examined, including 36 MH, 24 PH, and 36 NH. Regional-to-whole brain gray matter standardized FDG uptake value ratios were examined for associations with parental age across groups using automated regions-of-interest and statistical parametric mapping. Groups were comparable for clinical and neuropsychological measures. Brain metabolism in AD-vulnerable regions was lower in MH compared to NH and PH, and negatively correlated with maternal age at birth only in MH. There were no associations between paternal age and metabolism in any group. Evidence for a maternally inherited, maternal age-related mechanism provides further insight on risk factors and genetic transmission in late-onset AD. Maternal age affects brain metabolism in adult children of mothers affected by Alzheimer's diseaseLisa Mosconi, Wai Tsui, John Murray, Pauline McHugh, Yi Li, Schantel Williams, Elizabeth Pirraglia, Lidia Glodzik, Susan De Santi, Shankar Vallabhajosula, Mony J. de Leon10.1016/j.neurobiolaging.2011.03.003Neurobiology of Aging 33, 3 (2012)2011-04-25Neurobiology of Aging2011-04-25333S0197-4580(11)X0015-5Abstracts of Online Articles624.e1624.e9http://www.neurobiologyofaging.org/article/PIIS0197458011000613/abstract?rss=yesAbstract: The interaction between PD1 on T lymphocytes and PD-L1 on antigen presenting cells (APC) modulates the balance between inflammation and tolerance by inducing IL-10 production and apoptosis of antigen-specific cells. We analyzed the PD1/PD-L1 pathway, annexin V (AV)-expression, and proliferation in amyloid-beta (Aβ)-stimulated PBMC of patients with Alzheimer's disease (AD) (N = 35) or mild cognitive impairment (MCI) (N = 30) and of age-matched healthy controls (HC; N = 30). Results showed that PD1-expressing CD4+ T cells, density of PD-L1 on CD14+ APC, IL-10 production, and PD-L1-expressing/IL-10-producing CD14+ APC were significantly reduced in AD and MCI patients compared to HC. Aβ-stimulated PD1/AV-expressing (apoptotic) CD4+ T cells were also diminished, whereas proliferation was augmented in AD and MCI patients compared to controls. Finally, incubation of cells with PD-L1-neutralizing antibodies significantly decreased apoptosis of Aβ-specific CD4+ T lymphocytes. An impairment of the PD-L1/PD1 pathway is present in AD and MCI. Such alteration results in reduced IL-10 production and diminished apoptosis of Aβ-specific CD4+ T lymphocytes; these phenomena could play a role in the neuroinflammation accompanying AD. A potential role for the PD1/PD-L1 pathway in the neuroinflammation of Alzheimer's diseaseMarina Saresella, Elena Calabrese, Ivana Marventano, Federica Piancone, Andrea Gatti, Elisabetta Farina, Margherita Alberoni, Mario Clerici10.1016/j.neurobiolaging.2011.03.004Neurobiology of Aging 33, 3 (2012)2011-04-25Neurobiology of Aging2011-04-25333S0197-4580(11)X0015-5Abstracts of Online Articles624.e11624.e22http://www.neurobiologyofaging.org/article/PIIS0197458011000789/abstract?rss=yesAbstract: Pathological hyperphosphorylation and aggregation of the tau protein is associated with dementia and can be the central cause of neurodegeneration. Here, we examined potential alterations in the level of the cholinergic enzyme acetylcholinesterase (AChE) in the brain of transgenic mice (Tg-VLW) expressing human tau mutations. Overexpression of mutant hyperphosphorylated tau (P-tau) led to an increase in the activity of AChE in the brain of Tg-VLW mice, paralleled by an increase in AChE protein and transcripts; whereas the levels of the enzyme choline acetyltransferase remained unaffected. VLW tau overexpression in SH-SY5Y cells also increased AChE activity levels. All major molecular forms of AChE were increased in the Tg-VLW mice, including tetrameric AChE, which is the major species involved in hydrolysis of acetylcholine in the brain. Colocalization of human P-tau and AChE supports the conclusion that P-tau can act to increase AChE. This study is the first direct evidence of a modulatory effect of P-tau on brain AChE expression. Altered expression of brain acetylcholinesterase in FTDP-17 human tau transgenic miceMaría-Ximena Silveyra, María-Salud García-Ayllón, Elena Gómez de Barreda, David H. Small, Salvador Martínez, Jesús Avila, Javier Sáez-Valero10.1016/j.neurobiolaging.2011.03.006Neurobiology of Aging 33, 3 (2012)2011-04-29Neurobiology of Aging2011-04-29333S0197-4580(11)X0015-5Abstracts of Online Articles624.e23624.e34http://www.neurobiologyofaging.org/article/PIIS0197458011000923/abstract?rss=yesAbstract: Lipofuscin accumulation is a characteristic feature of senescent postmitotic neuronal cells but estrogen may have protecting effects by inhibiting its formation. In the present ultrastructural study, lipofuscin accumulation was studied in 2 estrogen-α-receptive brainstem areas: nucleus pararetroambiguus (NPRA) and the commissural part of the solitary tract nucleus/A2 catecholaminergic group (NTScom/A2) and compared with the estrogen-insensitive medial tegmental field (mtf), in young (23 weeks) and aged (95 weeks) female hamsters. In the aged animals, extensive intracytoplasmic lipofuscin accumulation was observed. A total number of 6450 neurons were classified in 4 categories. Levels were significantly elevated in each of the brain areas studied. Lipofuscin accumulation was strongest in the mtf, less in NPRA, and remarkably less in the area of NTScom/A2. In conclusion, the observed differences in lipofuscin accumulation suggest: (1) considerable regional differences in the degree of neuronal vulnerability; and (2) a possible neuroprotective role for estrogen, because the degree of accumulation is inversely related to the density of the estrogen receptors, varying from nonreceptive (mtf) to NPRA and NTScom/A2 (most receptive). Regional differences in age-related lipofuscin accumulation in the female hamster brainstemPeter O. Gerrits, Rudie Kortekaas, Henk de Weerd, Jan G. Veening, Johannes J.L. van der Want10.1016/j.neurobiolaging.2011.03.015Neurobiology of Aging 33, 3 (2012)2011-05-09Neurobiology of Aging2011-05-09333S0197-4580(11)X0015-5Abstracts of Online Articles625.e1625.e9http://www.neurobiologyofaging.org/article/PIIS0197458011000959/abstract?rss=yesAbstract: Aging is associated with a deterioration of cognitive performance and with increased risk of neurodegenerative disorders. In the present study we tested whether the specific phosphodiesterase 5 inhibitor sildenafil could ameliorate the age-dependent cognitive impairments shown by the senescence-accelerated mouse prone-8 (SAMP8). Sildenafil administration (7.5 mg/kg for 4 weeks) to 5-month-old SAMP8 mice attenuated spatial learning and memory impairments shown by these mice in the Morris Water Maze. Tau hyperphosphorylation (AT8 but not PHF-1 epitope) shown by SAMP8 mice at this age was also decreased in the hippocampus of sildenafil-treated mice, an effect probably related to a decrease in cyclin-dependent kinase 5 protein expression and activity (p25/p35 ratio). Interestingly, sildenafil also phosphorylated Akt, which was associated with an increase of glycogen synthase kinase-3β phosphorylation, providing a plausible explanation for the reductions in tau hyperphosphorylation (AT8 and PHF-1 epitopes) and attenuation of cognitive deficits shown by 9-month-old SAMP8 mice. Overall, sildenafil might be beneficial in age-related brain dysfunction and could be an emerging candidate for the treatment of other neurodegenerative diseases. Sildenafil ameliorates cognitive deficits and tau pathology in a senescence-accelerated mouse modelLourdes Orejana, Lucía Barros-Miñones, Joaquín Jordán, Elena Puerta, Norberto Aguirre10.1016/j.neurobiolaging.2011.03.018Neurobiology of Aging 33, 3 (2012)2011-05-06Neurobiology of Aging2011-05-06333S0197-4580(11)X0015-5Abstracts of Online Articles625.e11625.e20http://www.neurobiologyofaging.org/article/PIIS0197458011000984/abstract?rss=yesAbstract: Physiological aging affects early sensory-perceptual processes. The aim of this experiment was to evaluate changes in auditory sensory memory in physiological aging using the Mismatch Negativity (MMN) paradigm as index. The MMN is a marker recorded through the electroencephalogram and is used to evaluate the integrity of the memory system. We adopted a new, faster paradigm to look for differences between 3 groups of subjects of different ages (young, middle age and older adults) as a function of short or long intervals between stimuli. We found that older adults did not show MMN at long interval condition and that the duration of MMN varied according to the participants' age. The current study provides electrophysiological evidence supporting the theory that the encoding of stimuli is preserved during normal aging, whereas the maintenance of sensory memory is impaired. Considering the advantage offered by the MMN paradigm used here, these data might be a useful reference point for the assessment of auditory sensory memory in pathological aging (e.g., in neurodegenerative diseases). Sensory memory during physiological aging indexed by mismatch negativity (MMN)Manuela Ruzzoli, Cornelia Pirulli, Debora Brignani, Claudio Maioli, Carlo Miniussi10.1016/j.neurobiolaging.2011.03.021Neurobiology of Aging 33, 3 (2012)2011-04-29Neurobiology of Aging2011-04-29333S0197-4580(11)X0015-5Abstracts of Online Articles625.e21625.e30http://www.neurobiologyofaging.org/article/PIIS019745801100114X/abstract?rss=yesAbstract: Oxidative stress is known to play a relevant role in Down syndrome (DS) and its effects are documented from embryonic life. Oxidative DNA damage has been shown to be significantly elevated in Down syndrome patients, and this has been indicated as an early event promoting neurodegeneration and Alzheimer type dementia. The aim of this study was to investigate the efficacy of coenzyme Q10 (CoQ10) in delaying the effect of oxidative damage in these patients. In our previous study we demonstrated a mild protective effect of CoQ10 on DNA, although the treatment was unable to modify the overall extent of oxidative damage at the patient level. Possible limitations of the previous study were: time of treatment (6 months) or spectrum of DNA lesions detected. In order to overcome these limitations we planned a continuation of the trial aimed at evaluating the effects of CoQ10 following a prolonged treatment. Our results highlight an age-specific reduction in the percentage of cells showing the highest amount of oxidized bases, indicating a potential role of CoQ10 in modulating DNA repair mechanisms. Prolonged coenzyme Q10 treatment in Down syndrome patients, effect on DNA oxidationLuca Tiano, Lucia Padella, Lucia Santoro, Paola Carnevali, Federica Principi, Francesca Brugè, Orazio Gabrielli, Gian Paolo Littarru10.1016/j.neurobiolaging.2011.03.025Neurobiology of Aging 33, 3 (2012)2011-05-25Neurobiology of Aging2011-05-25333S0197-4580(11)X0015-5Abstracts of Online Articles626.e1626.e8http://www.neurobiologyofaging.org/article/PIIS0197458011001151/abstract?rss=yesAbstract: Aging of olfactory function (discrimination and short-term memory) was studied in 2, 10, and 23-month-old mice. We also addressed the issue of the responsiveness of the aging system to olfactory experience-dependent plasticity by submitting mice of different ages to an enrichment paradigm, and assessed neurogenesis in the olfactory bulb and the status of the noradrenergic system, 2 effectors of enrichment. Discrimination ability and its response to enrichment were essentially preserved with aging. In contrast, memory and its improvement by enrichment were altered at 10 and 23 months. Regarding neurogenesis, we found less proliferation of progenitors at 10 months and then lower neuronal differentiation and survival at 23 months. Furthermore, enrichment did not improve neurogenesis beyond the age of 2 months. Noradrenergic markers and their response to enrichment were altered at 23 months in line with memory performance. Aging thus differentially affected olfactory discrimination and memory abilities and their responsiveness to enrichment. Bulbar neurogenesis was an early target of aging whose decline could contribute to age-dependent memory impairments. Behavioral and cellular markers of olfactory aging and their response to enrichmentNolwen L. Rey, Joëlle Sacquet, Alexandra Veyrac, François Jourdan, Anne Didier10.1016/j.neurobiolaging.2011.03.026Neurobiology of Aging 33, 3 (2012)2011-05-25Neurobiology of Aging2011-05-25333S0197-4580(11)X0015-5Abstracts of Online Articles626.e9626.e23http://www.neurobiologyofaging.org/article/PIIS0197458011001175/abstract?rss=yesAbstract: c-Ret has been shown to be crucial for neural development and survival. We have recently shown that complete impairment of tyrosine 1062 (Y1062)-phosphorylation in c-Ret causes congenital hearing loss with neurodegeneration of spiral ganglion neurons (SGNs) in homozygous c-Ret knockin mice (c-Ret-KIY1062F/Y1062F-mice). However, there is no information to link c-Ret and age-related hearing loss. Here we show that partial impairment of Y1062-phosphorylation in c-Ret accelerates age-related hearing loss in heterozygous c-Ret Y1062F knockin mice (c-Ret-KIY1062F/+-mice). In contrast, complete impairment of serine 697 (S697)-phosphorylation in c-Ret did not affect hearing levels in 10-month-old homozygous c-Ret S697A knockin mice (c-Ret-KIS697A/S697A-mice). The hearing loss involved late-onset neurodegeneration of spiral ganglion neurons in c-Ret-KIY1062F/+-mice. Morphological abnormalities in inner- and outer-hair cells and the stria vascularis in c-Ret-KIY1062F/+-mice were undetectable. The acceleration of age-related hearing loss in c-Ret-KIY1062F/+-mice was rescued by introducing constitutively activated RET. Thus, our results suggest that c-Ret is a novel age-related hearing loss-related molecule in mice. Our results suggest that these hearing losses partially share a common pathogenesis that is monogenetically caused by a single point mutation (Y1062F) in c-Ret. Partial impairment of c-Ret at tyrosine 1062 accelerates age-related hearing loss in miceNobutaka Ohgami, Michiru Ida-Eto, Naomi Sakashita, Michihiko Sone, Tsutomu Nakashima, Keiji Tabuchi, Tomofumi Hoshino, Atsuyoshi Shimada, Toyonori Tsuzuki, Masahiko Yamamoto, Gen Sobue, Mayumi Jijiwa, Naoya Asai, Akira Hara, Masahide Takahashi, Masashi Kato10.1016/j.neurobiolaging.2011.04.002Neurobiology of Aging 33, 3 (2012)2011-05-26Neurobiology of Aging2011-05-26333S0197-4580(11)X0015-5Abstracts of Online Articles626.e25626.e34http://www.neurobiologyofaging.org/article/PIIS0197458011001187/abstract?rss=yesAbstract: Medial temporal lobe atrophy (MTA) is a recognized marker of Alzheimer's disease (AD), however, it can be prominent in frontotemporal lobar degeneration (FTLD). There is an increasing awareness that posterior atrophy (PA) is important in AD and may aid the differentiation of AD from FTLD. Visual rating scales are a convenient way of assessing atrophy in a clinical setting. In this study, 2 visual rating scales measuring MTA and PA were used to compare atrophy patterns in 62 pathologically-confirmed AD and 40 FTLD patients. Anatomical correspondence of MTA and PA was assessed using manually-delineated regions of the hippocampus and posterior cingulate gyrus, respectively. Both MTA and PA scales showed good inter- and intrarater reliabilities (kappa > 0.8). MTA scores showed a good correspondence with manual hippocampal volumes. Thirty percent of the AD patients showed PA in the absence of MTA. Adding the PA to the MTA scale improved discrimination of AD from FTLD, and early-onset AD from normal aging. These results underline the importance of considering PA in AD diagnosis, particularly in younger patients where medial temporal atrophy may be less conspicuous. Posterior cerebral atrophy in the absence of medial temporal lobe atrophy in pathologically-confirmed Alzheimer's diseaseManja Lehmann, Esther L.G.E. Koedam, Josephine Barnes, Jonathan W. Bartlett, Natalie S. Ryan, Yolande A.L. Pijnenburg, Frederik Barkhof, Mike P. Wattjes, Philip Scheltens, Nick C. Fox10.1016/j.neurobiolaging.2011.04.003Neurobiology of Aging 33, 3 (2012)2011-05-19Neurobiology of Aging2011-05-19333S0197-4580(11)X0015-5Abstracts of Online Articles627.e1627.e12http://www.neurobiologyofaging.org/article/PIIS0197458011001205/abstract?rss=yesAbstract: SAMP8 mice represent a suitable model of accelerated senescence as compared with SAMR1 animals presenting normal aging. Five-month-old SAMP8 mice presented reflex eyelid responses like those of SAMR1 controls, but were incapable of acquiring classically-conditioned eye blink responses in a trace (230 milliseconds [ms] of interstimulus interval) paradigm. Although SAMP8 mice presented a normal paired-pulse facilitation of the hippocampal CA1-medial prefrontal synapse, an input/output curve study revealed smaller field excitatory postsynaptic potentials (fEPSPs) in response to strong stimulations of the CA1-prefrontal pathway. Moreover, SAMP8 mice did not show any activity-dependent potentiation of the CA1-prefrontal synapse across the successive conditioning sessions shown by SAMR1 animals. In addition, SAMP8 mice presented a functional deficit during an object recognition test, continuing to explore the familiar object when controls moved to the novel one. Alert behaving SAMP8 mice presented a significant deficit in long-term potentiation (LTP) at the CA1-medial prefrontal synapse. According to the present results, SAMP8 mice present noticeable functional deficits in hippocampal and prefrontal cortical circuits directly related with the acquisition and storage of new motor and cognitive abilities. Learning capabilities and CA1-prefrontal synaptic plasticity in a mice model of accelerated senescenceJuan Carlos López-Ramos, María Teresa Jurado-Parras, Coral Sanfeliu, Darío Acuña-Castroviejo, José M. Delgado-García10.1016/j.neurobiolaging.2011.04.005Neurobiology of Aging 33, 3 (2012)2011-06-10Neurobiology of Aging2011-06-10333S0197-4580(11)X0015-5Abstracts of Online Articles627.e13627.e26http://www.neurobiologyofaging.org/article/PIIS0197458011001217/abstract?rss=yesAbstract: We have previously identified presenilin-1 (PS1), the active component of the γ-secretase complex, as an interacting protein of the amyloid-associated enzyme acetylcholinesterase (AChE). In this study, we have explored the consequences of AChE-PS1 interactions. Treatment of SH-SY5Y cells with the AChE-inhibitor tacrine decreased PS1 levels, in parallel with increase in the secretion of amyloid precursor protein APPα, whereas the cholinergic agonist carbachol had no effect on PS1. AChE knockdown with siRNA also decreased PS1 levels, while AChE overexpression exerted opposing effect. AChE-deficient also had decreased PS1. Mice administered with tacrine or donepezil displayed lower levels of brain PS1. However, sustained AChE inhibition failed to exert long-term effect on PS1. This limited duration of response may be due to AChE upregulation caused by chronic inhibition. Finally, we exposed SH-SY5Y cells to β-amyloid (Aβ)42 which triggered elevation of both AChE and PS1 levels. The Aβ42-induced PS1 increase was abolished by siRNA AChE pretreatment, suggesting that AChE may participate in the pathological feedback loop between PS1 and Aβ. Our results provide insight into AChE-amyloid interrelationships. Changes in acetylcholinesterase expression are associated with altered presenilin-1 levelsMaría-Ximena Silveyra, María-Salud García-Ayllón, Carol Serra-Basante, Valeria Mazzoni, María-Salud García-Gutierrez, Jorge Manzanares, Janetta G. Culvenor, Javier Sáez-Valero10.1016/j.neurobiolaging.2011.04.006Neurobiology of Aging 33, 3 (2012)2011-05-30Neurobiology of Aging2011-05-30333S0197-4580(11)X0015-5Abstracts of Online Articles627.e27627.e37http://www.neurobiologyofaging.org/article/PIIS0197458011001515/abstract?rss=yesAbstract: Inheritance of the ε4 allele of apolipoprotein E (ApoE) is the only confirmed and consistently replicated risk factor for late onset Alzheimer's disease (AD). ApoE is also a key ligand for low-density lipoprotein (LDL) receptor-related protein (LRP), a major neuronal low-density lipoprotein receptor. Despite the considerable converging evidence that implicates ApoE and LRP in the pathogenesis of AD, the precise mechanism by which ApoE and LRP modulate the risk for AD remains elusive. Moreover, studies investigating expression of ApoE and LRP in AD brain have reported variable and contradictory results. To overcome these inconsistencies, we studied the mRNA expression of ApoE and LRP in the postmortem brain of persons who died at different stages of dementia and AD-associated neuropathology relative to controls by quantitative polymerase chain reaction (qPCR) and Western blotting analyses. Clinical dementia rating scores were used as a measure of dementia severity, whereas, Braak neuropathological staging and neuritic plaque density were used as indexes of the neuropathological progression of AD. ApoE and LRP mRNA expression was significantly elevated in the postmortem inferior temporal gyrus (area 20) and the hippocampus from individuals with dementia compared with those with intact cognition. In addition to their strong association with the progression of cognitive dysfunction, LRP and ApoE mRNA levels were also positively correlated with increasing neuropathological hallmarks of AD. Additionally, Western blot analysis of ApoE protein expression in the hippocampus showed that the differential expression observed at the transcriptional level is also reflected at the protein level. Given the critical role played by LRP and ApoE in amyloid beta (Aβ) and cholesterol trafficking, increased expression of LRP and ApoE may not only disrupt cholesterol homeostasis but may also contribute to some of the neurobiological features of AD, including plaque deposition. Association of ApoE and LRP mRNA levels with dementia and AD neuropathologyAfia Akram, James Schmeidler, Pavel Katsel, Patrick R. Hof, Vahram Haroutunian10.1016/j.neurobiolaging.2011.04.010Neurobiology of Aging 33, 3 (2012)2011-06-16Neurobiology of Aging2011-06-16333S0197-4580(11)X0015-5Abstracts of Online Articles628.e1628.e14http://www.neurobiologyofaging.org/article/PIIS0197458011004064/abstract?rss=yesAbstract: The arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene has been associated with stroke. The majority of the reported ALOX5AP associations have considered non-radiologically confirmed infarcts as the stroke phenotype. We assessed the association of genetic variants in ALOX5AP with stroke defined by the presence of infarcts on brain magnetic resonance imaging (MRI). We studied 202 persons with MRI-defined brain infarcts and 487 healthy individuals of Caribbean Hispanic ancestry. Another sample of European ancestry comprised 1823 persons with MRI-defined brain infarct and 7578 control subjects. Subjects were genotyped for the 4 single nucleotide polymorphisms (SNPs) that define ALOX5AP HapA haplotype. No association was found between SNPs and MRI-defined brain infarcts. Our data do not support the hypothesis that variants in ALOX5AP are associated with risk of MRI-defined brain infarcts. No association of ALOX5AP polymorphisms with risk of MRI-defined brain infarctsSandra Barral, Israel Fernández-Cadenas, Joshua C. Bis, Joan Montaner, Arfan M. Ikram, Lenore J. Launer, Myriam Fornage, Helena Schmidt, Adam M. Brickman, Sudha Seshadri, Richard Mayeux10.1016/j.neurobiolaging.2011.10.010Neurobiology of Aging 33, 3 (2012)2011-11-11Neurobiology of Aging2011-11-11333S0197-4580(11)X0015-5Genetic Reports Abstracts629.e1629.e3http://www.neurobiologyofaging.org/article/PIIS0197458011004301/abstract?rss=yesAbstract: Based on the substantial overlap in clinical and pathological characteristics of dementia with Lewy bodies (DLB) and Parkinson disease with dementia (PDD) with Alzheimer disease (AD) and Parkinson disease (PD) we hypothesized that these disorders might share underlying genetic factors. The contribution of both sequence and copy number variants (CNVs) in known AD and PD genes to the genetic etiology of DLB and PDD however is currently unclear. Therefore, we performed a gene-based mutation analysis of all major AD and PD genes in 99 DLB and 75 PDD patients, including familial and sporadic forms, from Flanders, Belgium. Also, copy number variants in APP, SNCA, and PARK2 were determined. In the AD genes we detected proven pathogenic missense mutations in PSEN1 and PSEN2, and 2 novel missense variants in PSEN2 and MAPT. In the PD genes we identified 1 SNCA duplication, the LRRK2 R1441C founder mutation and 4 novel heterozygous missense variants with unknown pathogenicity. Our results suggest a contribution of established AD and PD genes to the genetic etiology of DLB and PDD though to a limited extent. They do support the hypothesis of a genetic overlap between members of the Lewy body disease spectrum, but additional genes still have to exist. DLB and PDD: a role for mutations in dementia and Parkinson disease genes?Bram Meeus, Aline Verstraeten, David Crosiers, Sebastiaan Engelborghs, Marleen Van den Broeck, Maria Mattheijssens, Karin Peeters, Ellen Corsmit, Ellen Elinck, Barbara Pickut, Rik Vandenberghe, Patrick Cras, Peter Paul De Deyn, Christine Van Broeckhoven, Jessie Theuns10.1016/j.neurobiolaging.2011.10.014Neurobiology of Aging 33, 3 (2012)2011-11-28Neurobiology of Aging2011-11-28333S0197-4580(11)X0015-5Genetic Reports Abstracts629.e5629.e18http://www.neurobiologyofaging.org/article/PIIS0197458011004568/abstract?rss=yesAbstract: Mutations in valosin-containing protein (VCP) gene, already known to be associated with the multisystemic disorder, inclusion body myopathy with Paget's disease and frontotemporal dementia (IBMPFD), have been recently found also in familial cases of amyotrophic lateral sclerosis (ALS). To further define the frequency of VCP mutations in ALS Italian population, we screened a cohort of 166 familial ALS and 14 ALS-frontotemporal dementia (FTD) individuals. We identified a previously reported synonymous mutation (c.2093A>C; p.Q568Q), 2 intronic variants (c.1749-14C>T; c.2085-3C>T), and 1 nucleotide change (c.2814G>T) in the 3′ untranslated region (UTR). Bioinformatical analyses predicted no changes in splicing process or microRNA binding sites. Our results do not confirm a main contribution of VCP gene to familial ALS in the Italian population. Mutational analysis of VCP gene in familial amyotrophic lateral sclerosisCinzia Tiloca, Antonia Ratti, Viviana Pensato, Alessia Castucci, Gianni Sorarù, Roberto Del Bo, Lucia Corrado, Cristina Cereda, Carla D'Ascenzo, Giacomo P. Comi, Letizia Mazzini, Barbara Castellotti, Nicola Ticozzi, Cinzia Gellera, Vincenzo Silani, SLAGEN Consortium10.1016/j.neurobiolaging.2011.10.025Neurobiology of Aging 33, 3 (2012)2011-12-05Neurobiology of Aging2011-12-05333S0197-4580(11)X0015-5Genetic Reports Abstracts630.e1630.e2http://www.neurobiologyofaging.org/article/PIIS019745801100460X/abstract?rss=yesAbstract: A large genome-wide screen in patients with sporadic amyotrophic lateral sclerosis (ALS) showed that the common variant rs12608932 in gene UNC13A was associated with disease susceptibility. UNC13A regulates the release of neurotransmitters, including glutamate. Genetic risk factors that, in addition, modify survival, provide promising therapeutic targets in ALS, a disease whose etiology remains largely elusive. We examined whether UNC13A was associated with survival of ALS patients in a cohort of 450 sporadic ALS patients and 524 unaffected controls from a population-based study of ALS in The Netherlands. Additionally, survival data were collected from individuals of Dutch, Belgian, or Swedish descent (1767 cases, 1817 controls) who had participated in a previously published genome-wide association study of ALS. We related survival to rs12608932 genotype. In both cohorts, the minor allele of rs12608932 in UNC13A was not only associated with susceptibility but also with shorter survival of ALS patients. Our results further corroborate the role of UNC13A in ALS pathogenesis. UNC13A is a modifier of survival in amyotrophic lateral sclerosisFrank P. Diekstra, Paul W.J. van Vught, Wouter van Rheenen, Max Koppers, R. Jeroen Pasterkamp, Michael A. van Es, Helenius J. Schelhaas, Marianne de Visser, Wim Robberecht, Philip Van Damme, Peter M. Andersen, Leonard H. van den Berg, Jan H. Veldink10.1016/j.neurobiolaging.2011.10.029Neurobiology of Aging 33, 3 (2012)2011-11-28Neurobiology of Aging2011-11-28333S0197-4580(11)X0015-5Genetic Reports Abstracts630.e3630.e8http://www.neurobiologyofaging.org/article/PIIS0197458011005392/abstract?rss=yesContents10.1016/S0197-4580(11)00539-2Neurobiology of Aging 33, 3 (2012)2012-03-01Neurobiology of Aging2012-03-01333S0197-4580(11)X0015-5632634http://www.neurobiologyofaging.org/article/PIIS0197458011005306/abstract?rss=yesContents10.1016/S0197-4580(11)00530-6Neurobiology of Aging 33, 3 (2012)2012-03-01Neurobiology of Aging2012-03-01333S0197-4580(11)X0015-5OBCOBC