👤 Lynne Krohn

Postpartum depression (PPD) is linked to neuroimmune dysregulation. Brexanolone, an intravenous formulation of the neurosteroid allopregnanolone and the first FDA-approved treatment for PPD, produces rapid and sustained antidepressant effects. However, its long-term mechanisms of action remain unclear. This study evaluated brexanolone's prolonged impact on two groups of biomarkers in whole blood: inflammatory mediators and growth/differentiation/neurotrophic factors. Whole blood was also maintained in culture (4 h) and subjected to lipopolysaccharide (LPS) stimulation of the TLR4 inflammatory pathway. Ten individuals with moderate-to-severe PPD received brexanolone and were assessed before, and at 6 h, ~7, and ~30 days post-infusion. BDNF significantly increased and remained elevated through 30 days, representing a sustained neurotrophic response. In contrast, inflammatory mediators CCL11, IL-6, TNF-α, and IL-18 showed rapid reductions by 6 h. TNF-α suppression lasted up to 7 days, while CCL11 and IL-6 remained suppressed through 30 days. These changes were associated with reductions in Hamilton Depression Rating Scale (HAM-D) scores over time. LPS-stimulated whole blood cultures revealed suppression of TLR4-induced CCL11, IL-1β, IL-6, IL-8, IL-18, TNF-α, HMGB1, and MIP-1β at 6 h. IL-8, IL-18, and TNF-α remained suppressed through 7 days, while IL-1β and CCL11 remained suppressed through 30 days, aligning with sustained HAM-D score improvements. Biomarker × time interactions suggested dynamic regulation of inflammatory and neurotrophic pathways. Given the small sample size, these findings should be interpreted as a pilot study, but they indicate that brexanolone promotes both rapid and sustained anti-inflammatory and neurotrophic effects supporting lasting symptom remission in PPD. Show less

There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD). To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD. Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests. We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls. Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society. Show less

Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)). Show less