Cell-Specific Dysregulation of Iron and Oxygen Homeostasis as a Novel Pathophysiology in PSP.

OBJECTIVE: Progressive supranuclear palsy (PSP) is a 4R-tauopathy showing heterogeneous tau cytopathology commencing in the globus pallidus (GP) and the substantia nigra (SN), regions also associated with age-related iron accumulation. Abnormal iron levels have been extensively associated with tau pathology in neurodegenerative brains, however, its role in PSP pathogenesis remains yet unknown. We perform the first cell type-specific evaluation of PSP iron homeostasis and the closely related oxygen homeostasis, in relation to tau pathology in human postmortem PSP brains. METHODS: In brain regions vulnerable to PSP pathology (GP, SN, and putamen), we visualized iron deposition in tau-affected and unaffected neurons, astroglia, oligodendrocytes, and microglia, using a combination of iron staining with immunolabelling. To further explore molecular pathways underlying our observations, we examined the expression of key iron and oxygen homeostasis mRNA transcripts and proteins. RESULTS: We found astrocytes as the major cell type accumulating iron in the early affected regions of PSP, highly associated with cellular tau pathology. The same regions are affected by dysregulated expression of alpha and beta hemoglobin and neuroglobin showing contrasting patterns. We discovered changes in iron and oxygen homeostasis-related gene expression associated with aging of the brain, and identified dysregulated expression of rare neurodegeneration with brain iron accumulation (NBIA) genes associated with tau pathology to distinguish PSP from the healthy aging brain. INTERPRETATION: We present novel aspects of PSP pathophysiology highlighting an overlap with NBIA pathways. Our findings reveal potential novel targets for therapy development and have implications beyond PSP for other iron-associated neurodegenerative diseases. ANN NEUROL 2023;93:431-445.

Muscle biopsy technical safety and quality using a self-contained, vacuum-assisted biopsy technique.

Muscle sampling via percutaneous biopsy has been shown to be safe and effective using a Bergström needle; however, the use of a single-operator, self-contained, vacuum-assisted biopsy technique has not been explored. We performed a retrospective chart review of muscle biopsy samples obtained using the Vacora® self-contained vacuum-assisted biopsy system between 2013 and 2016, at the Toronto General Hospital. During this period, 102 single-operator muscle biopsies were performed using the Vacora® system. 54/102 showed normal or non-specific findings, while 39/102 were suggestive or diagnostic of a neuromuscular condition. 8 samples did not provide sufficient muscle tissue for diagnosis, and complications (intramuscular hematoma) occurred in 3/102 cases. Mean sample weight was 0.19 grams, which exceeded reported mean sample weights using the suction-modified Bergström technique (0.125 grams). We therefore conclude that the Vacora® vacuum-assisted biopsy system provides a safe and effective method to obtain diagnostic muscle biopsy samples; although complication rates are slightly higher than reported using the Bergström technique, possibly related to more vigorous suction or a sharp needle tip.