Association of Gene Expression and Tremor Network Structure.

BACKGROUND: Transcriptomic changes in the essential tremor (ET)-associated cerebello-thalamo-cortical "tremor network" and their association to brain structure have not been investigated. OBJECTIVE: The aim was to characterize molecular changes associated with network-level imaging-derived phenotypes (IDP) found in ET. METHODS: We performed an imaging-transcriptomic study in British adults using imaging-genome-wide association study summary statistics (UK Biobank "BIG40" cohort; n = 33,224, aged 40-69 years). We imputed imaging-transcriptomic associations for 184 IDPs and analyzed functional enrichment of gene modules and aggregate network-level phenotypes. Validation was performed in cerebellar-tissue RNA-sequencing data from ET patients and controls (n = 55). RESULTS: Among 237,896 individual predicted gene expression levels for 6063 unique genes/transcripts, we detected 2269 genome-wide significant associations (Bonferroni P < 2.102e-7, 0.95%). These were concentrated in intracellular volume fraction measures of white matter pathways and in genes with putative links to tremor (MAPT, ARL17A, KANSL1, SPPL2C, LRRC37A4P, PLEKHM1, and FMNL1). Whole-tremor-network cortical thickness was associated with a gene module linked to mitochondrial organization and protein quality control (r = 0.91, P = 2e-70), whereas white-gray T1-weighted magnetic resonance imaging (MRI) contrast in the tremor network was associated with a gene module linked to sphingolipid synthesis and ethanolamine metabolism (r = -0.90, P = 2e-68). Imputed association effect sizes and RNA-sequencing log-fold change in the validation dataset were significantly correlated for cerebellar peduncular diffusion MRI phenotypes, and there was a close overlap of significant associations between both datasets for gray matter phenotypes (χ2 = 6.40, P = 0.006). CONCLUSIONS: The identified genes and processes are potential treatment targets for ET, and our results help characterize molecular changes that could in future be used for patient treatment selection or prognosis prediction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Autophagy and Exocytosis of Lipofuscin Into the Basolateral Extracellular Space of Human Retinal Pigment Epithelium From Fetal Development to Adolescence.

Purpose: To undertake the first ultrastructural characterization of human retinal pigment epithelial (RPE) differentiation from fetal development to adolescence. Methods: Ten fetal eyes and three eyes aged six, nine, and 17 years were examined in the temporal retina adjacent to the optic nerve head by transmission electron microscopy. The area, number, and distribution of RPE organelles were quantified and interpreted within the context of adjacent photoreceptors, Bruch's membrane, and choriocapillaris maturation. Results: Between eight to 12 weeks' gestation (WG), pseudostratified columnar epithelia with apical tight junctions differentiate to a simple cuboidal epithelium with random distribution of melanosomes and mitochondria. Between 12 to 26 WG, cells enlarge and show long apical microvilli and apicolateral junctional complexes. Coinciding with eye opening at 26 WG, melanosomes migrate apically whereas mitochondria distribute to perinuclear regions, with the first appearance of phagosomes, complex granules, and basolateral extracellular space (BES) formation. Significantly, autophagy and heterophagy, as evidenced by organelle recycling, and the gold standard of ultrastructural evidence for autophagy of double-membrane autophagosomes and mitophagosomes were evident from 32 WG, followed by basal infoldings of RPE cell membrane at 36 WG. Lipofuscin formation and deposition into the BES evident at six years increased at 17 years. Conclusions: We provide compelling ultrastructural evidence that heterophagy and autophagy begins in the third trimester of human fetal development and that deposition of cellular byproducts into the extracellular space of RPE takes place via exocytosis. Transplanted RPE cells must also demonstrate the capacity to subserve autophagic and heterophagic functions for effective disease mitigation.

Parkinson's Disease Risk Variant rs9638616 is Non-Specifically Associated with Altered Brain Structure and Function.

Background: A genome-wide association study (GWAS) variant associated with Parkinson's disease (PD) risk in Asians, rs9638616, was recently reported, and maps to WBSCR17/GALNT17, which is involved in synaptic transmission and neurite development. Objective: To test the association of the rs9638616 T allele with imaging-derived measures of brain microstructure and function. Methods: We analyzed 3-Tesla MRI and genotyping data from 116 early PD patients (aged 66.8±9.0 years; 39% female; disease duration 1.25±0.71 years) and 57 controls (aged 68.7±7.4 years; 54% female), of Chinese ethnicity. We performed voxelwise analyses for imaging-genetic association of rs9638616 T allele with white matter tract fractional anisotropy (FA), grey matter volume and resting-state network functional connectivity. Results: The rs9638616 T allele was associated with widespread lower white matter FA (t = -1.75, p = 0.042) and lower functional connectivity of the supplementary motor area (SMA) (t = -5.05, p = 0.001), in both PD and control groups. Interaction analysis comparing the association of rs9638616 and FA between PD and controls was non-significant. These imaging-derived phenotypes mediated the association of rs9638616 to digit span (indirect effect: ß= -0.21 [-0.42,-0.05], p = 0.031) and motor severity (indirect effect: ß= 0.15 [0.04,0.26], p = 0.045). Conclusions: We have shown that a novel GWAS variant which is biologically linked to synaptic transmission is associated with white matter tract and functional connectivity dysfunction in the SMA, supported by changes in clinical motor scores. This provides pathophysiologic clues linking rs9638616 to PD risk and might contribute to future risk stratification models.

Clinical effect of modified forsus appliance to children with mandibular retrusion / 华西口腔医学杂志

<p><b>OBJECTIVE</b>To evaluate the effects of modified Forsus appliance in the treatment of Class II mandibular retrusion.</p><p><b>METHODS</b>18 children with mandibular retrusion were selected and treated with modified Forsus appliance. Cephalometric radiographs were taken and analyzed at pre-treatment and post-treatment. Students' t-test was used to determine if there were significant differences between pre-treatment and post-treatment.</p><p><b>RESULTS</b>After 6-8 months of therapy, profiles were obviously improved. B moved forward (2.9+/-3.1) mm. ANB decreased (2.5+/-1.2) degrees. The overjet decreased (5.0+2.8) mm. The molar relationship was corrected to Class I from Class II. SN-OL increased (4.3+2.2) degrees. There was significant difference between pre-treatment and post-treatment.</p><p><b>CONCLUSION</b>Combined with straight wire appliance, modified Forsus appliance can effectively stimulate the mandibular growth, balance the jaw relationship, and correct mandibular retrusion.</p>

Assessment of left ventricular ejection fraction: comparison of two dimensional echocardiography, cardiac magnetic resonance imaging and 64-row multi-detector computed tomography / 老年心脏病学杂志（英文版）

Objectives To compare left ventricular ejection fraction (LVEF) determined from 64-row multi-detector computed tomography (64-row MDCT) with those determined from two dimensional echocardiography (2D echo) and cardiac magnetic resonance imaging (CMR). Methods Thirty-two patients with coronary artery disease underwent trans-thoracic 2D echo, CMR and contrast-enhanced 64-row MDCT for assessment of LVEF within 48 hours of each other. 64-row MDCT LVEF was derived using the Syngo Circulation software; CMR LVEF was by Area Length Ejection Fraction (ALEF) and Simpson method and 2D echo LVEF by Simpson method.Results The LVEF was 49.13 ± 15.91% by 2D echo, 50.72 ± 16.55% (ALEF method) and 47.65 ± 16.58%(Simpson method) by CMR and 50.00 ± 15.93% by 64-row MDCT. LVEF measurements by 64-row MDCT correlated well with LVEF measured with CMR using either the ALEF method (Pearson correlation r = 0.94, P ＜0.01) or Simpson method (r = 0.92, P＜0.01). It also correlated well with LVEF measured using 2D echo (r = 0.80, P ＜ 0.01). Conclusion LVEF measurements by 64-row MDCT correlated well with LVEF measured by CMR and 2D echo. The correlation between 64-row MDCT and CMR was better than the correlation between 2D echo with CMR. Standard data set from a 64-row MDCT coronary study can be reliably used to calculate the LVEF.