TFG regulates secretory and endosomal sorting pathways in neurons to promote their activity and maintenance.

Molecular pathways that intrinsically regulate neuronal maintenance are poorly understood, but rare pathogenic mutations that underlie neurodegenerative disease can offer important insights into the mechanisms that facilitate lifelong neuronal function. Here, we leverage a rat model to demonstrate directly that the TFG p.R106C variant implicated previously in complicated forms of hereditary spastic paraplegia (HSP) underlies progressive spastic paraparesis with accompanying ventriculomegaly and thinning of the corpus callosum, consistent with disease phenotypes identified in adolescent patients. Analyses of primary cortical neurons obtained from CRISPR-Cas9-edited animals reveal a kinetic delay in biosynthetic secretory protein transport from the endoplasmic reticulum (ER), in agreement with prior induced pluripotent stem cell-based studies. Moreover, we identify an unexpected role for TFG in the trafficking of Rab4A-positive recycling endosomes specifically within axons and dendrites. Impaired TFG function compromises the transport of at least a subset of endosomal cargoes, which we show results in down-regulated inhibitory receptor signaling that may contribute to excitation-inhibition imbalances. In contrast, the morphology and trafficking of other organelles, including mitochondria and lysosomes, are unaffected by the TFG p.R106C mutation. Our findings demonstrate a multifaceted role for TFG in secretory and endosomal protein sorting that is unique to cells of the central nervous system and highlight the importance of these pathways to maintenance of corticospinal tract motor neurons.

Left dural carotid cavernous fistula mimicking an inflammatory process: A case report.

A female in her 70s presented with altered mental status, left eye pain, ophthalmalgia, and diplopia following a fall. Brain MRI demonstrated contrast-enhancing left peri-insular T2 hyperintense changes that was read as possible herpes simplex encephalitis by neuroradiology. Cerebral angiogram revealed a Barrow Type D left sided carotid cavernous fistula. The patient was subsequently treated with endovascular transvenous coil embolization of the left cavernous sinus resulting in complete occlusion of the fistula. The goal of this case is to present a unique case of a carotid cavernous fistula radiologically mimicking herpes simplex encephalitis. Early recognition of carotid cavernous fistula on neuroimaging is important for prompt treatment of symptoms.

Readmission to an Acute Care Hospital During Inpatient Rehabilitation After Stroke.

OBJECTIVE: The aim of the study was to identify causes for readmission to acute care of patients admitted to inpatient rehabilitation facility after stroke. DESIGN: The institutional Uniform Data System for Medical Rehabilitation database was used to identify stroke patients who experienced readmission to acute care and an equal number of age-/sex-matched group of patients who successfully completed their inpatient rehabilitation facility stay during 2005-2018. Retrospective chart review was used to extract clinical data. The two study groups were compared using univariate and multivariate analyses. RESULTS: The rate of readmission to acute care was 4.7% (n = 89; age = 65 ± 14 yrs; 37% female; 65% White; 73% ischemic stroke). The most common indications for transfer were neurological (31%) and cardiovascular (28%). Compared with control group, the readmission to acute care group had statistically higher rates of comorbid conditions, lower median (interquartile range) Functional Independence Measure score on inpatient rehabilitation facility admission (55 [37-65] vs. 64 [51-78], P < 0.001), and a higher rate of sedative/hypnotic prescription (82% vs. 23%, P < 0.001). CONCLUSIONS: Readmission to acute care is not common in our cohort. Patients who experienced readmission to acute care had higher medical complexity and were prescribed more sedative/hypnotic medications than the control group. Practitioners should be vigilant in patients who meet these criteria.