Consistent abnormal activity in the putamen by dopamine modulation in Parkinson's disease: A resting-state neuroimaging meta-analysis.

OBJECTIVE: This study aimed to elucidate brain areas mediated by oral anti-parkinsonian medicine that consistently show abnormal resting-state activation in PD and to reveal their functional connectivity profiles using meta-analytic approaches. METHODS: Searches of the PubMed, Web of Science databases identified 78 neuroimaging studies including PD OFF state (PD-OFF) versus (vs.) PD ON state (PD-ON) or PD-ON versus healthy controls (HCs) or PD-OFF versus HCs data. Coordinate-based meta-analysis and functional meta-analytic connectivity modeling (MACM) were performed using the activation likelihood estimation algorithm. RESULTS: Brain activation in PD-OFF vs. PD-ON was significantly changed in the right putamen and left inferior parietal lobule (IPL). Contrast analysis indicated that PD-OFF vs. HCs had more consistent activation in the right paracentral lobule, right middle frontal gyrus, right thalamus, left superior parietal lobule and right putamen, whereas PD-ON vs. HCs elicited more consistent activation in the bilateral middle temporal gyrus, left occipital gyrus, right inferior frontal gyrus and right caudate. MACM revealed coactivation of the right putamen in the direct contrast of PD-OFF vs. PD-ON. Subtraction analysis of significant coactivation clusters for PD-OFF vs. PD-ON with the medium of HCs showed effects in the sensorimotor, top-down control, and visual networks. By overlapping the MACM maps of the two analytical strategies, we demonstrated that the coactivated brain region focused on the right putamen. CONCLUSIONS: The convergence of local brain regions and co-activation neural networks are involved the putamen, suggesting its potential as a specific imaging biomarker to monitor treatment efficacy. SYSTEMATIC REVIEW REGISTRATION: [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD CRD42022304150].

Monitoring Substantia Nigra Degeneration Using Free Water Imaging across Prodromal and Clinical Parkinson's Disease.

BACKGROUND: Substantia nigra (SN) free water has been suggested as a good surrogate marker in Parkinson's disease (PD). However, its usefulness for diagnosing prodromal PD (pPD) and monitoring disease progression warrants further validation. OBJECTIVE: The aim was to investigate SN free water values across prodromal and clinical stages of PD. METHODS: Four groups were enrolled in this study: 48 healthy controls (HC), 43 pPD patients, 50 de novo PD (dnPD) patients, and 49 medicated PD (mPD) patients. Based on diffusion tensor images, free water maps were calculated, and SN free water values were extracted from the anterior SN (ASN) and posterior SN (PSN). The SN free water values were compared among the four groups, and associations between free water and clinical symptoms were explored. The distinguishing power of PSN free water was evaluated using the receiver operating characteristic curve analysis. Follow-up was performed for 14 pPD patients. RESULTS: PSN free water in the pPD group was significantly higher than that in the HC group and significantly lower than that in the dnPD group. Surprisingly, the mPD group showed decreased PSN free water compared to the dnPD group. There was a positive correlation between motor symptoms and PSN free water in the pPD and dnPD groups. Longitudinal analysis showed a significant increase in PSN free water in pPD patients over time. CONCLUSIONS: The PSN free water increased from prodromal to early clinical stages, but the trend might be reversed in late disease stages. This biphasic trend should be considered when applying this marker in future studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Forkhead transcription factor FOXO3a mediates interferon-γ-induced MHC II transcription in macrophages.

Macrophages are professional antigen-presenting cells relying on the expression of class II major histocompatibility complex (MHC II) genes. Interferon-γ (IFN-γ) activates MHC II transcription via the assembly of an enhanceosome centred on class II trans-activator (CIITA). In the present study, we investigated the role of the forkhead transcription factor FOXO3a in IFN- γ-induced MHC II transcription in macrophages. Knockdown of FOXO3a, but not FOXO1 or FOXO4, diminished IFN-γ-induced MHC II expression in RAW cells. On the contrary, over-expression of FOXO3a, but neither FOXO1 nor FOXO4, enhanced CIITA-mediated trans-activation of the MHC II promoter. IFN-γ treatment promoted the recruitment of FOXO3a to the MHC II promoter. Co-immunoprecipitation and RE-ChIP assays showed that FOXO3a was a component of the MHC II enhanceosome forming interactions with CIITA, RFX5, RFXB and RFXAP. FOXO3a contributed to MHC II transcription by altering histone modifications surrounding the MHC II promoter. Of interest, FOXO3a was recruited to the type IV CIITA promoter and directly activated CIITA transcription by interacting with signal transducer of activation and transcription 1 in response to IFN-γ stimulation. In conclusion, our data unveil a novel role for FOXO3a in the regulation of MHC II transcription in macrophages.