Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume: preliminary implications for serotonin-related function in mood and anxiety disorders

Background: Early life stress (ELS) is cited as a risk for mood and anxiety disorders, potentially through altered serotonin neurotransmission. We examined the effects of ELS, utilizing the variable foraging demand (VFD) macaque model, on adolescent monoamine metabolites. We sought to replicate an increase in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) observed in two previous VFD cohorts. We hypothesized that elevated cisternal 5-HIAA was associated with reduced neurotrophic effects, conceivably due to excessive negative feedback at somatodendritic 5-HT1A autoreceptors. A putatively decreased serotonin neurotransmission would be reflected by reductions in hippocampal volume and white matter (WM) fractional anisotropy (FA).Methods: When infants were 2-6 months of age, bonnet macaque mothers were exposed to VFD. We employed cisternal CSF taps to measure monoamine metabolites in VFD (N = 22) and non-VFD (N = 14) offspring (mean age = 2.61 years). Metabolites were correlated with hippocampal volume obtained by MRI and WM FA by diffusion tensor imaging in young adulthood in 17 males [10 VFD (mean age = 4.57 years)].Results: VFD subjects exhibited increased CSF 5-HIAA compared to non-VFD controls. An inverse correlation between right hippocampal volume and 5-HIAA was noted in VFD- but not controls. CSF HVA and MHPG correlated inversely with hippocampal volume only in VFD. CSF 5-HIAA correlated inversely with FA of the VVM tracts of the anterior limb of the internal capsule (ALIC) only in VFD.Conclusions: Elevated cisternal 5-HIAA in VFD may reflect increased dorsal raphe serotonin, potentially inducing excessive autoreceptor activation, inducing a putative serotonin deficit in terminal fields. Resultant reductions in neurotrophic activity are reflected by smaller right hippocampal volume. Convergent evidence of reduced neurotrophic activity in association with high CSF 5-HIAA in VFD was reflected by reduced FA of the ALIC.NIMHSuny Downstate Med Ctr, Nonhuman Primate Lab, Dept Psychiat & Behav Sci, Brooklyn, NY 11203 USANew York State Psychiat Inst & Hosp, New York, NY 10032 USASuny Downstate Med Ctr, Coll Med, Brooklyn, NY 11203 USAUniversidade Federal de São Paulo, Dept Psychiat & Neuroradiol, São Paulo, BrazilFranklin Beha Hlh Consultants, Bronx, NY USANew York State Psychiat Inst & Hosp, Dept Mol Imaging & Neuropathol, New York, NY 10032 USAIcahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USAIcahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USAIcahn Sch Med Mt Sinai, Dept Radiol, New York, NY 10029 USAIcahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USAIcahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USAYale Univ, Sch Med, Dept Psychiat, New Haven, CT USAMichael E Debakey VA Med Ctr, Mental Hlth Care Line, Houston, TX USABaylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USAYale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USAUniversidade Federal de São Paulo, Dept Psychiat & Neuroradiol, São Paulo, BrazilNIMH: R21MH066748NIMH: R01 MH059990Web of Scienc

A fibril-specific, conformation-dependent antibody recognizes a subset of Aβ plaques in Alzheimer disease, Down syndrome and Tg2576 transgenic mouse brain

Beta-amyloid (Aβ) is thought to be a key contributor to the pathogenesis of Alzheimer disease (AD) in the general population and in adults with Down syndrome (DS). Different assembly states of Aβ have been identified that may be neurotoxic. Aβ oligomers can assemble into soluble prefibrillar oligomers, soluble fibrillar oligomers and insoluble fibrils. Using a novel antibody, OC, recognizing fibrils and soluble fibrillar oligomers, we characterized fibrillar Aβ deposits in AD and DS cases. We further compared human specimens to those obtained from the Tg2576 mouse model of AD. Our results show that accumulation of fibrillar immunoreactivity is significantly increased in AD relative to nondemented aged subjects and those with select cognitive impairments (p < 0.0001). Further, there was a significant correlation between the extent of frontal cortex fibrillar deposit accumulation and dementia severity (MMSE r = −0.72). In DS, we observe an early age of onset and age-dependent accumulation of fibrillar OC immunoreactivity with little pathology in similarly aged non-DS individuals. Tg2576 mice show fibrillar accumulation that can be detected as young as 6 months. Interestingly, fibril-specific immunoreactivity was observed in diffuse, thioflavine S-negative Aβ deposits in addition to more mature neuritic plaques. These results suggest that fibrillar deposits are associated with disease in both AD and in adults with DS and their distribution within early Aβ pathology associated with diffuse plaques and correlation with MMSE suggest that these deposits may not be as benign as previously thought

Intracranial V. cholerae Sialidase Protects against Excitotoxic Neurodegeneration

Converging evidence shows that GD3 ganglioside is a critical effector in a number of apoptotic pathways, and GM1 ganglioside has neuroprotective and noötropic properties. Targeted deletion of GD3 synthase (GD3S) eliminates GD3 and increases GM1 levels. Primary neurons from GD3S−/− mice are resistant to neurotoxicity induced by amyloid-β or hyperhomocysteinemia, and when GD3S is eliminated in the APP/PSEN1 double-transgenic model of Alzheimer's disease the plaque-associated oxidative stress and inflammatory response are absent. To date, no small-molecule inhibitor of GD3S exists. In the present study we used sialidase from Vibrio cholerae (VCS) to produce a brain ganglioside profile that approximates that of GD3S deletion. VCS hydrolyzes GD1a and complex b-series gangliosides to GM1, and the apoptogenic GD3 is degraded. VCS was infused by osmotic minipump into the dorsal third ventricle in mice over a 4-week period. Sensorimotor behaviors, anxiety, and cognition were unaffected in VCS-treated mice. To determine whether VCS was neuroprotective in vivo, we injected kainic acid on the 25th day of infusion to induce status epilepticus. Kainic acid induced a robust lesion of the CA3 hippocampal subfield in aCSF-treated controls. In contrast, all hippocampal regions in VCS-treated mice were largely intact. VCS did not protect against seizures. These results demonstrate that strategic degradation of complex gangliosides and GD3 can be used to achieve neuroprotection without adversely affecting behavior

Observation of long-range, near-side angular correlations in proton-proton collisions at the LHC

This is the pre-print version of the Published Article, which can be accessed from the link below - Copyright @ 2010 Springer VerlagResults on two-particle angular correlations for charged particles emitted in proton-proton collisions at center-of-mass energies of 0.9, 2.36, and 7 TeV are presented, using data collected with the CMS detector over a broad range of pseudorapidity (eta) and azimuthal angle (phi). Short-range correlations in Delta(eta), which are studied in minimum bias events, are characterized using a simple "independent cluster" parametrization in order to quantify their strength (cluster size) and their extent in eta (cluster decay width). Long-range azimuthal correlations are studied differentially as a function of charged particle multiplicity and particle transverse momentum using a 980 inverse nb data set at 7 TeV. In high multiplicity events, a pronounced structure emerges in the two-dimensional correlation function for particle pairs with intermediate transverse momentum of 1-3 GeV/c, 2.0< |Delta(eta)| <4.8 and Delta(phi) near 0. This is the first observation of such a long-range, near-side feature in two-particle correlation functions in pp or p p-bar collisions

Observation of long-range, near-side angular correlations in proton-proton collisions at the LHC

Results on two-particle angular correlations for charged particles emitted in proton-proton collisions at center-of-mass energies of 0.9, 2.36, and 7TeV are presented, using data collected with the CMS detector over a broad range of pseudorapidity (eta) and azimuthal angle (phi). Short-range correlations in Delta(eta), which are studied in minimum bias events, are characterized using a simple "independent cluster" parametrization in order to quantify their strength (cluster size) and their extent in eta (cluster decay width). Long-range azimuthal correlations are studied differentially as a function of charged particle multiplicity and particle transverse momentum using a 980 nb(-1) data set at 7TeV. In high multiplicity events, a pronounced structure emerges in the two-dimensional correlation function for particle pairs with intermediate p(T) of 1-3 GeV/c, 2.

Aging-related tau astrogliopathy (ARTAG):harmonized evaluation strategy

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators