Abstract
BACKGROUND: Niemann-Pick Disease Type C (NPC) is an ultra-rare disorder characterized by progressive psychiatric and neurologic manifestations, with late infantile, juvenile, and adolescent/adult presentations. We examined morphological properties of the choroid plexus, a protective blood-cerebrospinal fluid barrier, in NPC, and their relationship with neurodegeneration, clinical status, and circulatory markers. This study also determined whether choroid plexus morphology differentiates between NPC and more prevalent illnesses, schizophrenia (SZ) and bipolar disorder (BD), which have overlapping psychiatric symptoms with adolescent and adult-onset NPC and are associated with misdiagnosis. METHODS: Patients with NPC were assessed using neuroimaging, clinical instruments, and plasma protein quantification focusing on inflammatory markers. Morphological properties (i.e., choroid plexus volumes) were compared between patients with NPC (n = 17), SZ (n = 20), BD (n = 24), and healthy controls (HCs, n = 106). RESULTS: Choroid plexus enlargement (p < 0.05) and reduced thalamic volumes (p < 0.05) were observed in NPC patients versus HCs and SZ or BD patients. A logistic regression model with choroid plexus and thalamic volumes as predictors yielded high prediction accuracy for NPC vs. HCs, NPC vs. SZ, and NPC vs. BD (area under the receiver operating characteristics curve [AUROC] of 1). Choroid plexus volumes were negatively correlated with left (p = 0.009-0.012) and right (p = 0.007-0.025) thalamic volumes, left (r = -0.69, p = 0.003) and right (r = -0.71, p = 0.002) crus I of the cerebellum, and greater severity on the NPC-Suspicion Index psychiatric subscale (ρ = 0.72, p = 0.042). Targeted protein expression quantification revealed differential expression of TGFA, HLA-DRA, TNFSF12, EGF, INFG, and IL-18 in NPC patients vs. HCs (p < 0.05), with higher choroid plexus volumes correlating with IL-18 levels (ρ = 0.71, p = 0.047). CONCLUSION: The choroid plexus may play a critical role in NPC neuropathogenesis and serve as a novel biomarker for monitoring neurodegenerative and inflammatory processes in NPC.