AF710B, an M1/sigma-1 receptor agonist with long-lasting disease-modifying properties in a transgenic rat model of Alzheimer's disease.

INTRODUCTION: AF710B (aka ANAVEX 3-71) is a novel selective allosteric M1 muscarinic and sigma-1 receptor agonist. In 3×Tg-AD mice, AF710B attenuates cognitive deficits and decreases Alzheimer-like hallmarks. We now report on the long-lasting disease-modifying properties of AF710B in McGill-R-Thy1-APP transgenic (Tg) rats. METHODS: Chronic treatment with AF710B (10 µg/kg) was initiated in postplaque 13-month-old Tg rats. Drug or vehicle was administered orally daily for 4.5 months and interrupted 5 weeks before behavioral testing. RESULTS: AF710B long-term treatment reverted the cognitive deficits associated with advanced Alzheimer-like amyloid neuropathology in Tg rats. These effects were accompanied by reductions in amyloid pathology and markers of neuroinflammation and increases in amyloid cerebrospinal fluid clearance and levels of a synaptic marker. Importantly, these effects were maintained following a 5-week interruption of the treatment. DISCUSSION: With M1/sigma-1 activity and long-lasting disease-modifying properties at low dose, AF710B is a promising novel therapeutic agent for treating Alzheimer's disease.

An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: Relation to cognitive decline and longitudinal evaluation.

INTRODUCTION: Given that Alzheimer's pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need. METHODS: We investigated the plasma levels of Aß, proNGF, tPA, neuroserpin, metallo-proteases and inflammatory molecules in 31 individuals with DS (with and without dementia) and in 31 healthy controls. We examined associations between biomarkers and cognitive decline. RESULTS: Aß40 and Aß42 were elevated in DS plasma compared to controls, even in DS individuals without dementia. Plasma Aß correlated with the rate of cognitive decline across 2 years. ProNGF, MMP-1, MMP-3, MMP-9 activity, TNF-α, IL-6, and IL-10 were higher in DS plasma, even at AD-asymptomatic stages. Declining plasma Aß42 and increasing proNGF levels correlated with cognitive decline. A combined measure of Aß and inflammatory molecules was a strong predictor of prospective cognitive deterioration. CONCLUSIONS: Our findings support the combination of plasma and cognitive assessments for the identification of DS individuals at risk of dementia.

Number of motile spermatozoa inseminated and pregnancy outcomes in intrauterine insemination.

PURPOSE: To determine whether age modifies the effect of the number of motile spermatozoa inseminated (NMSI) as a predictor of success in Intrauterine Insemination (IUI). METHODS: This retrospective cohort study included all patients who underwent IUI at an academic infertility center between October 2004 and June 2018. The primary outcome was clinical pregnancy (CP; a gestational sac and fetal heartbeat on ultrasound). Results were analyzed by patient factors including age, NMSI, duration of infertility, and cause of infertility, along with treatment factors such as number of follicles and ovulation induction protocol. Factors associated with the odds of achieving a clinical pregnancy were analyzed using binary logistic generalized estimating equations to control for clustering effects by couple. Female age was categorized as <35 years vs. ≥35 years. RESULTS: Seven hundred thirty-seven couples that underwent 2062 IUI cycles for heterogeneous indications were included. The overall CP rate was 15.1% per cycle, and the cumulative CP rate per couple was 35.9%. For females < 35 years, the odds of CP per cycle were reduced for NMSI categories (× 106) of < 5.0 vs. ≥10.0 (OR = 0.49; 95% CI 0.29-0.83); the odds of CP per cycle did not differ for NMSI 5.0-9.9 vs. ≥10.0 (OR = 0.66; 0.37-1.18). For those ≥35 years, no difference was seen in the odds of CP per cycle for NMSI categories < 5.0 vs. ≥10.0 (OR = 1.55; 95% CI 0.72-3.31) or 5.0-9.9 vs. ≥10.0 (OR = 1.04; 95% CI 0.48-2.27). CONCLUSIONS: These results suggest that the NMSI can be used as a predictor of success in IUI in couples with women who are < 35 years of age; these patients should be counselled about their lower pregnancy rates when the NMSI is < 5.0 × 106. In patients ≥35 years, the NMSI does not appear to be a useful predictor of success. Further studies with larger sample size should be conducted.

Identification and Preliminary Validation of a Plasma Profile Associated with Cognitive Decline in Dementia and At-Risk Individuals: A Retrospective Cohort Analysis.

Biomarker discovery is a major need for earlier dementia diagnosis. We evaluated a plasma signature of amyloid, metallo-proteinases (MMPs), and inflammatory markers in a cohort of at-risk individuals and individuals clinically diagnosed with probable Alzheimer's disease (pAD). Using multiplex arrays, we measured Aß40, Aß42, MMP-1, MMP-3, MMP-9, IFN-γ, TNF-α, IL-6, IL-8, and IL-10 in plasma from 107 individuals followed every 6 months for 3 years. Final diagnoses included: pAD (n = 28), mild cognitive impairment (MCI, n = 30), subjective memory impairment (SMI, n = 30), and asymptomatic (NCI, n = 19). Blood was drawn at final follow-up. We used linear and logistic regressions to examine biomarker associations with prior known decline on the Montreal Cognitive Assessment (MoCA) and the Cambridge Cognitive Examination (CAMCOG); as well disease progression by the time of blood-draw. We derived a biomarker composite from the individual markers, and tested its association with a clinical diagnosis of pAD. Lower Aß40 and Aß42 and higher IL-8, IL-10, and TNF-α were associated with greater cognitive decline per the MoCA and CAMCOG. MMP-3 was higher in SMI, MCI, and pAD than NCI. Whereas the other investigative molecules did not differ between groups, composite scores-created using MoCA/CAMCOG-based trends in Aß40, Aß42, MMP-1, MMP-3, IL-8, IL-10, and TNF-α- were associated with a final diagnosis of pAD (c-statistic 0.732 versus 0.602 for age-sex alone). Thus, plasma amyloid, MMP, and inflammatory biomarkers demonstrated differences in individuals with cognitive deterioration and/or progression to MCI/pAD. Our findings support studying these markers earlier in the continuum of probable AD as well as in specific dementias.