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Gadolinium contrast administration, usually with magnetic resonance imaging, is an important diagnostic modality in the investigation of neurological pathologies. There is little evidence in the literature suggesting repeated exposure to intrathecal gadolinium results in symptoms mimicking post-concussive syndrome (PCS). We studied one patient who received intrathecal gadolinium to investigate a pain pump malfunction and presented with encephalopathic symptoms of confusion and aphasia with imaging consistent with intracranial gadolinium extravasation. The patient was followed up regularly with repeat imaging, reassessment of persistent symptoms, and specialist evaluations; however, symptoms remained refractory and resembled PCS. Our findings indicate a need to further investigate potential associations between intrathecal gadolinium exposure and a clinical presentation consistent with PCS, irrespective of histopathological changes.

Objective: Hyperleptinemia, hallmark of obesity, is a putative pathophysiologic trigger for atherosclerosis. We previously reported a stimulatory effect of leptin on TSP-1 (thrombospondin-1) expression, a proatherogenic matricellular protein implicated in atherogenesis. However, a causal role of TSP-1 in leptin-driven atherosclerosis remains unknown. Approach and Results: Seventeen-weeks-old ApoE −/− and TSP-1 −/− /ApoE −/− double knockout mice, on normocholesterolemic diet, were treated with or without murine recombinant leptin (5 µg/g bwt, IP) once daily for 3 weeks. Using aortic root morphometry and en face lesion assay, we found that TSP-1 deletion abrogated leptin-stimulated lipid-filled lesion burden, plaque area, and collagen accumulation in aortic roots of ApoE −/− mice, shown via Oil red O, hematoxylin and eosin, and Masson trichrome staining, respectively. Immunofluorescence microscopy of aortic roots showed that TSP-1 deficiency blocked leptin-induced inflammatory and smooth muscle cell abundance as well as cellular proliferation in ApoE −/− mice. Moreover, these effects were concomitant to changes in VLDL (very low-density lipoprotein)-triglyceride and HDL (high-density lipoprotein)-cholesterol levels. Immunoblotting further revealed reduced vimentin and pCREB (phospho-cyclic AMP response element-binding protein) accompanied with augmented smooth muscle-myosin heavy chain expression in aortic vessels of leptin-treated double knockout versus leptin-treated ApoE −/− ; also confirmed in aortic smooth muscle cells from the mice genotypes, incubated ± leptin in vitro. Finally, TSP-1 deletion impeded plaque burden in leptin-treated ApoE −/− on western diet, independent of plasma lipid alterations. Conclusions: The present study provides evidence for a protective effect of TSP-1 deletion on leptin-stimulated atherogenesis. Our findings suggest a regulatory role of TSP-1 on leptin-induced vascular smooth muscle cell phenotypic transition and inflammatory lesion invasion. Collectively, these results underscore TSP-1 as a potential target of leptin-induced vasculopathy.

OBJECTIVE –: Hyperleptinemia, hallmark of obesity, is a putative pathophysiologic trigger for atherosclerosis. We previously reported a stimulatory effect of leptin on thrombospondin-1 (TSP-1) expression, a proatherogenic matricellular protein implicated in atherogenesis. However, a causal role of TSP-1 in leptin-driven atherosclerosis remains unknown. APPROACH AND RESULTS –: 17-wks-old ApoE(−/−) and TSP-1(−/−)/ApoE(−/−) double knockout (dKO) mice, on normocholesterolemic diet, were treated with or without murine recombinant leptin (5µg/g bwt, IP) once daily for three weeks. Using aortic root morphometry and en-face lesion assay, we found that TSP-1 deletion abrogated leptin-stimulated lipid-filled lesion burden, plaque area and collagen accumulation in aortic roots of ApoE(−/−) mice, shown via Oil red O, H & E and Masson’s trichrome staining, respectively. Immunofluorescence microscopy of aortic roots showed that TSP-1 deficiency blocked leptin-induced inflammatory and smooth muscle cell abundance as well as cellular proliferation in ApoE(−/−) mice. Moreover, these effects were concomitant to changes in VLDL-triglyceride and HDL-cholesterol levels. Immunoblotting further revealed reduced vimentin and pCREB accompanied with augmented SM-MHC expression in aortic vessels of leptin-treated dKO vs. leptin-treated ApoE(−/−); also confirmed in aortic SMCs from the mice genotypes, incubated ± leptin in vitro. Finally, TSP-1 deletion impeded plaque burden in leptin-treated ApoE(−/−) on western diet, independent of plasma lipid alterations. CONCLUSIONS –: The present study provides evidence for a protective effect of TSP-1 deletion on leptin-stimulated atherogenesis. Our findings suggest a regulatory role of TSP-1 on leptin-induced VSMC phenotypic transition and inflammatory lesion invasion. Collectively, these results underscore TSP-1 as a potential target of leptin-induced vasculopathy.