Implications of the choroid plexus in Niemann-Pick disease Type C neuropathogenesis

Raquel van Gool; Mariesa Cay; Boyu Ren; Kailey Brodeur; Emma Golden; Benjamin Goodlett; Edward Yang; Tom Reilly; Caroline Hastings; Elizabeth M Berry-Kravis; Pui Y Lee; Maria Di Biase; Vanessa Cropley; Christos Pantelis; Dennis Velakoulis; Ann K Shinn; Walla Al-Hertani; Mark Walterfang; Jaymin Upadhyay

doi:10.1016/j.bbi.2024.12.024

Implications of the choroid plexus in Niemann-Pick disease Type C neuropathogenesis

Brain Behav Immun. 2024 Dec 15:124:376-384. doi: 10.1016/j.bbi.2024.12.024. Online ahead of print.

Authors

Raquel van Gool¹, Mariesa Cay², Boyu Ren³, Kailey Brodeur⁴, Emma Golden², Benjamin Goodlett⁵, Edward Yang⁶, Tom Reilly⁷, Caroline Hastings⁸, Elizabeth M Berry-Kravis⁹, Pui Y Lee⁴, Maria Di Biase¹⁰, Vanessa Cropley¹¹, Christos Pantelis¹², Dennis Velakoulis¹³, Ann K Shinn¹⁴, Walla Al-Hertani⁵, Mark Walterfang¹³, Jaymin Upadhyay¹⁵

Affiliations

¹ Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Neurology, Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, Limburg, the Netherlands.
² Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
³ Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
⁴ Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Neuropsychiatry Centre, Royal Melbourne Hospital, Melbourne, VIC, Australia.
⁸ Department of Pediatric Hematology and Oncology, UCSF Benioff Children's Hospital Oakland (Children Hospital and Research Center Oakland), Oakland, CA.
⁹ Department of Pediatrics, Neurological Sciences and Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, USA.
¹⁰ Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia.
¹¹ Centre for Youth Mental Health, The University of Melbourne, Vic, Australia Orygen, Parkville, Vic, Australia.
¹² Neuropsychiatry Centre, Royal Melbourne Hospital, Melbourne, VIC, Australia; Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia; Monash Institute of Pharmaceutical Sciences (MIPS), Monash University, Parkville, Vic, Australia.
¹³ Neuropsychiatry Centre, Royal Melbourne Hospital, Melbourne, VIC, Australia; Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia.
¹⁴ Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA; Schizophrenia and Bipolar Disorder Program, Psychotic Disorders Division, McLean Hospital, Belmont, MA, USA.
¹⁵ Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA. Electronic address: [email protected].

PMID: 39689839
DOI: 10.1016/j.bbi.2024.12.024

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.

Keywords: Bipolar Disorder; Blood Plasma; Choroid Plexus; Magnetic Resonance Imaging; Neuropsychiatric Symptoms; Niemann Pick Disease Type C; Schizophrenia; Thalamus.