Early postnatal allergic airway inflammation induces dystrophic microglia leading to excitatory postsynaptic surplus and autism-like behavior.

Microglia play key roles in synaptic pruning, which primarily occurs from the postnatal period to adolescence. Synaptic pruning is essential for normal brain development and its impairment is implicated in neuropsychiatric developmental diseases such as autism spectrum disorders (ASD). Recent epidemiological surveys reported a strong link between ASD and atopic/allergic diseases. However, few studies have experimentally investigated the relationship between allergy and ASD-like manifestations, particularly in the early postnatal period, when allergic disorders occur frequently. Therefore, we aimed to characterize how allergic inflammation in the early postnatal period influences microglia and behavior using mouse models of short- and long-term airway allergy. Male mice were immunized by an intraperitoneal injection of aluminum hydroxide and ovalbumin (OVA) or phosphate-buffered saline (control) on postnatal days (P) 3, 7, and 11, followed by intranasal challenge with OVA or phosphate-buffered saline solution twice a week until P30 or P70. In the hippocampus, Iba-1-positive areas, the size of Iba-1-positive microglial cell bodies, and the ramification index of microglia by Sholl analysis were significantly smaller in the OVA group than in the control group on P30 and P70, although Iba-1-positive microglia numbers did not differ significantly between the two groups. In Iba-1-positive cells, postsynaptic density protein 95 (PSD95)-occupied areas and CD68-occupied areas were significantly decreased on P30 and P70, respectively, in the OVA group compared with the control group. Immunoblotting using hippocampal tissues demonstrated that amounts of PSD95, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor 2, and N-methyl-D-aspartate (NMDA) receptor 2B were significantly increased in the OVA group compared with the control group on P70, and a similar increasing trend for PSD95 was observed on P30. Neurogenesis was not significantly different between the two groups on P30 or P70 by doublecortin immunohistochemistry. The social preference index was significantly lower in the three chamber test and the number of buried marbles was significantly higher in the OVA group than in the control group on P70 but not on P30, whereas locomotion and anxiety were not different between the two groups. Compared with the control group, serum basal corticosterone levels were significantly elevated and hippocampal glucocorticoid receptor (GR) amounts and nuclear GR translocation in microglia, but not in neurons or astrocytes, were significantly decreased in the OVA group on P70 but not on P30. Gene set enrichment analysis of isolated microglia revealed that genes related to immune responses including Toll-like receptor signaling and chemokine signaling pathways, senescence, and glucocorticoid signaling were significantly upregulated in the OVA group compared with the control group on P30 and P70. These findings suggest that early postnatal allergic airway inflammation induces dystrophic microglia that exhibit defective synaptic pruning upon short- and long-term allergen exposure. Furthermore, long-term allergen exposure induced excitatory postsynaptic surplus and ASD-like behavior. Hypothalamo-pituitary-adrenal axis activation and the compensatory downregulation of microglial GR during long-term allergic airway inflammation may also facilitate these changes.

Distinct retinal reflectance spectra from retinal hyperspectral imaging in Parkinson's disease.

BACKGROUND: Recent developments in the retinal hyperspectral imaging method have indicated its potential in addressing challenges posed by neurodegenerative disorders, such as Alzheimer's disease. This human clinical study is the first to assess reflectance spectra obtained from this imaging as a tool for diagnosing patients with Parkinson's disease (PD). METHODS: Retinal hyperspectral imaging was conducted on a total of 40 participants, including 20 patients with PD and 20 controls. Following preprocessing, retinal reflectance spectra were computed for the macular retina defined by four rectangular regions. Linear discriminant analysis classifiers underwent training to discern patients with PD from control participants. To assess the performance of the selected features, nested leave-one-out cross-validation was employed using machine learning. The indicated values include the area under the curve (AUC) and the corresponding 95% confidence interval (CI). RESULTS: Retinal reflectance spectra of PD patients exhibited variations in the spectral regions, particularly at shorter wavelengths (superonasal retina, wavelength < 490 nm; inferonasal retina, wavelength < 510 nm) when compared to those of controls. Retinal reflectance spectra yielded an AUC of 0.60 (95% CI: 0.43-0.78) and 0.60 (95% CI: 0.43-0.78) for the superonasal and inferonasal retina, respectively, distinguishing individuals with and without PD. CONCLUSION: Reflectance spectra obtained from retinal hyperspectral imaging tended to decrease at shorter wavelengths across a broad spectral range in PD patients. Further investigations building upon these preliminary findings are imperative to focus on the retinal spectral signatures associated with PD pathological hallmarks, including α-synuclein.

Effect of smoking on disease activity in multiple sclerosis patients treated with dimethyl fumarate or fingolimod.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), smoking is a known risk factor for disease susceptibility and disability progression. However, its impact on the efficacy of oral disease-modifying drugs (DMDs) is unclear. Therefore, we initiated a single-center, retrospective, observational study to investigate the relationship between smoking and disease activity in RRMS patients under oral DMDs. METHODS: We retrospectively enrolled RRMS patients who initiated oral DMDs (fingolimod or dimethyl fumarate) at our hospital between January 2012 and December 2019. Clinical data and smoking status at oral DMD initiation were collected up to December 2020. We conducted survival analyses for relapse and any disease activity, defined as relapse or MRI disease activity, among patients with distinct smoking statuses. RESULTS: We enrolled 103 RRMS patients under oral DMDs including 19 (18.4%) current smokers at baseline. Proportions of relapses and any disease activity during follow-up were higher in current smokers (relapse: p = 0.040, any disease activity: p = 0.004) and time from initiating oral DMDs to relapse was shorter in current smokers (log-rank test: p = 0.011; Cox proportional hazard analysis: hazard ratio (HR) 2.72 [95% confidence interval (CI) 1.22-6.09], p = 0.015) than in non-smokers. Time from initiating oral DMDs to any disease activity was also shorter in current smokers (log-rank test: p = 0.016; Cox proportional hazard analysis: HR 2.18 [95% CI 1.14-4.19], p = 0.019) than in non-smokers. The survival curves for relapse and any disease activity were not different between the former smoker and never-smoker groups. Multivariate survival analysis showed current smoking was an independent risk factor for relapse or any disease activity after adjusting for covariates (relapse: HR 2.54 [95% CI 1.06-6.10], p = 0.037; any disease activity: HR 3.47 [95% CI 1.27-9.50], p = 0.015). CONCLUSION: Smoking was a risk factor for disease activity in RRMS patients under oral DMD treatment. RRMS patients should be advised to stop smoking even after the initiation of DMDs.