rLOAD: does sex mediate the effect of acute antiplatelet loading on stroke outcome.

BackgroundBiologic sex can influence response to pharmacologic therapy. The purpose of this proof-of-concept study was to evaluate the medicating effects of estrogen in the efficacy of acute antiplatelet loading therapy on stroke outcome in the rabbit small clot embolic model.MethodsFemale and male (20/group) New Zealand White rabbits were embolized to produce embolic stroke by injecting small blood clots into the middle cerebral artery via an internal carotid artery catheter. Two hours after embolization, rabbits were treated with standard dose antiplatelet loading (aspirin 10 mg/kg plus clopidogrel 10 mg/kg). Primary outcome measures were platelet inhibition, behavioral outcome P 50 (the weight of microclots (mg) that produces neurologic dysfunction in 50% of a group of animals), and effect of endogenous estrogen on outcome.ResultsFor the first time in a non-rodent model of stroke, it was found that higher endogenous estrogen levels resulted in significantly better behavioral outcome in female subjects (r s -0.70, p < 0.011). Platelet inhibition in response to collagen, arachidonic acid, and adenosine diphosphate (ADP) was not significantly different in females with higher vs. lower estrogen levels.ConclusionsBehavioral outcomes are improved with females with higher endogenous estrogen levels treated with standard dose antiplatelet loading. This is the first non-rodent study to demonstrate that higher endogenous estrogen levels in female rabbits appear to be neuroprotective in ischemic stroke. This research supports the further study of the effect of endogenous estrogen levels on outcome with standard dose antiplatelet loading in stroke patients not eligible for revascularization therapies

Plasma methionine sulfoxide in persons with familial Alzheimer’s disease mutations

The final, published version of this article is available at http://www.karger.com/?doi=10.1159/000338546.BACKGROUND: Convergent evidence suggests that oxidative stress plays a central role in the pathology of Alzheimer’s disease (AD). We asked if consequently, oxidation of methionine residues to methionine sulfoxide (MetO) increased in plasma proteins of persons carrying familial AD (FAD) mutations. METHODS: Plasma was collected from 31 persons from families harboring PSEN1 or APP mutations. Using Western blot analysis with a novel anti-MetO polyclonal antibody, MetO levels were measured and compared between FAD mutation carriers (MCs) and non-mutation carrying (NCs) kin. RESULTS: A MetO-positive 120 kDa gel band distinguished FAD MCs and NCs (mean 11.4 ± 2.8 vs. 4.0 ± 3.1, p = 0.02). In a subset of subjects for whom both measurements were available, MetO levels correlated well with plasma F2-isoprostane (r = 0.81, p < 0.001) and superoxide dismutase 1 (r = 0.52, p = 0.004) levels. CONCLUSIONS: Our data provide evidence for elevated MetO levels in persons carrying FAD mutations that correlate with other indices of oxidative stress and suggest that plasma oxidative stress markers may be useful for diagnosis of AD

Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease.

Altered brain metabolism is associated with progression of Alzheimer's Disease (AD). Mitochondria respond to bioenergetic changes by continuous fission and fusion. To account for three dimensional architecture of the brain tissue and organelles, we applied 3-dimensional electron microscopy (3D EM) reconstruction to visualize mitochondrial structure in the brain tissue from patients and mouse models of AD. We identified a previously unknown mitochondrial fission arrest phenotype that results in elongated interconnected organelles, "mitochondria-on-a-string" (MOAS). Our data suggest that MOAS formation may occur at the final stages of fission process and was not associated with altered translocation of activated dynamin related protein 1 (Drp1) to mitochondria but with reduced GTPase activity. Since MOAS formation was also observed in the brain tissue of wild-type mice in response to hypoxia or during chronological aging, fission arrest may represent fundamental compensatory adaptation to bioenergetic stress providing protection against mitophagy that may preserve residual mitochondrial function. The discovery of novel mitochondrial phenotype that occurs in the brain tissue in response to energetic stress accurately detected only using 3D EM reconstruction argues for a major role of mitochondrial dynamics in regulating neuronal survival

Smoking Enhances Risk for New External Genital Warts in Men

Repeat episodes of HPV-related external genital warts reflect recurring or new infections. No study before has been sufficiently powered to delineate how tobacco use, prior history of EGWs and HIV infection affect the risk for new EGWs. Behavioral, laboratory and examination data for 2,835 Multicenter AIDS Cohort Study participants examined at 21,519 semi-annual visits were evaluated. Fourteen percent (391/2835) of men reported or were diagnosed with EGWs at 3% (675/21,519) of study visits. Multivariate analyses showed smoking, prior episodes of EGWs, HIV infection and CD4+ T-lymphocyte count among the infected, each differentially influenced the risk for new EGWs

Neuronal pentraxin 1: A synaptic-derived plasma biomarker in Alzheimer's disease

Synaptic neurodegeneration is thought to be an early event initiated by soluble β-amyloid (Aβ) aggregates that closely correlates with cognitive decline in Alzheimer disease (AD). Apolipoprotein ε4 (APOE4) is the most common genetic risk factor for both familial AD (FAD) and sporadic AD; it accelerates Aβ aggregation and selectively impairs glutamate receptor function and synaptic plasticity. However, its molecular mechanisms remain elusive and these synaptic deficits are difficult to monitor. AD- and APOE4-dependent plasma biomarkers have been proposed, but synapse-related plasma biomarkers are lacking. We evaluated neuronal pentraxin 1 (NP1), a potential CNS-derived plasma biomarker of excitatory synaptic pathology. NP1 is preferentially expressed in brain and involved in glutamate receptor internalization. NP1 is secreted presynaptically induced by Aβ oligomers, and implicated in excitatory synaptic and mitochondrial deficits. Levels of NP1 and its fragments were increased in a correlated fashion in both brain and plasma of 7–8 month-old E4FAD mice relative to E3FAD mice. NP1 was also found in exosome preparations and reduced by dietary DHA supplementation. Plasma NP1 was higher in E4FAD+ (APOE4+/+/FAD+/−) relative to E4FAD- (non-carrier; APOE4+/+/FAD−/−) mice, suggesting NP1 is modulated by Aβ expression. Finally, relative to normal elderly, plasma NP1 was also elevated in patients with mild cognitive impairment (MCI) and elevated further in the subset who progressed to early-stage AD. In those patients, there was a trend towards increased NP1 levels in APOE4 carriers relative to non-carriers. These findings indicate that NP1 may represent a potential synapse-derived plasma biomarker relevant to early alterations in excitatory synapses in MCI and early-stage AD

Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study

Introduction: Curcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD. Methods: We performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex® with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured. Results: Mean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex® was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL). Conclusions: Curcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex® in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound. Trial registration ClinicalTrials.gov Identifier: NCT00099710

Tau Spread, Apolipoprotein E, Inflammation, and More: Rapidly Evolving Basic Science in Alzheimer Disease.

To date, Alzheimer disease drug candidates have produced negative results in human trials, and progress in moving new targets out of the laboratory and into trials has been slow. However, based on 3 decades of previous work, there is reason to hope that amyloid-based and other novel therapies will move at a faster pace toward successful clinical trials. This article highlights selected preclinical research topics that are rapidly advancing in the laboratory

rLOAD: does sex mediate the effect of acute antiplatelet loading on stroke outcome.

BackgroundBiologic sex can influence response to pharmacologic therapy. The purpose of this proof-of-concept study was to evaluate the medicating effects of estrogen in the efficacy of acute antiplatelet loading therapy on stroke outcome in the rabbit small clot embolic model.MethodsFemale and male (20/group) New Zealand White rabbits were embolized to produce embolic stroke by injecting small blood clots into the middle cerebral artery via an internal carotid artery catheter. Two hours after embolization, rabbits were treated with standard dose antiplatelet loading (aspirin 10&nbsp;mg/kg plus clopidogrel 10&nbsp;mg/kg). Primary outcome measures were platelet inhibition, behavioral outcome P 50 (the weight of microclots (mg) that produces neurologic dysfunction in 50% of a group of animals), and effect of endogenous estrogen on outcome.ResultsFor the first time in a non-rodent model of stroke, it was found that higher endogenous estrogen levels resulted in significantly better behavioral outcome in female subjects (r s -0.70, p &lt; 0.011). Platelet inhibition in response to collagen, arachidonic acid, and adenosine diphosphate (ADP) was not significantly different in females with higher vs. lower estrogen levels.ConclusionsBehavioral outcomes are improved with females with higher endogenous estrogen levels treated with standard dose antiplatelet loading. This is the first non-rodent study to demonstrate that higher endogenous estrogen levels in female rabbits appear to be neuroprotective in ischemic stroke. This research supports the further study of the effect of endogenous estrogen levels on outcome with standard dose antiplatelet loading in stroke patients not eligible for revascularization therapies

Parallel age-associated changes in brain and plasma neuronal pentraxin receptor levels in a transgenic APP/PS1 rat model of Alzheimer's disease.

Neuronal pentraxin receptor (NPR) is a synaptic protein implicated in AMPA receptor trafficking at excitatory synapses. Since glutamate neurotransmission is disrupted in Alzheimer's disease (AD), NPR levels measured from plasma represent a potential biomarker for synaptic dysfunction associated with AD. We sought to determine the relationship between AD pathology and brain and plasma NPR levels by examining age-associated NPR levels in these compartments in a transgenic APP/PS1 rat model of AD. NPR levels in cortical homogenate were similar in wild-type (Wt) and APP/PS1 rats at 3 months of age (prior to Aβ plaque deposition), but significantly increased in APP/PS1 rats by 9 and 18-20 months of age (after the onset of plaque deposition). These age-dependent differences were driven by proportional increases in NPR in membrane-associated cortical fractions. Genotype-related differences in NPR expression were also seen in the hippocampus, which exhibits significant Aβ pathology, but not in the cerebellum, which does not. Plasma analyses revealed increased levels of a 26 kDa NPR fragment in APP/PS1 rats relative to Wt rats by 18-20 months of age, which correlated with the levels of full-length NPR in cortex. Our findings indicate that cerebral accumulation of NPR and Aβ occurs with similar temporal and regional patterns in the APP/PS1 model, and suggest that a 26 kDa plasma NPR fragment may represent a peripheral biomarker of this process