title: Central cholinergic dysfunction in the adult form of Niemann Pick disease type C: a further link with Alzheimer's disease?
abstract: Adult patients with Niemann-Pick disease type C (NPC) usually develop cognitive impairment progressing to dementia, whose pathophysiology remains still unclear. Noteworthy parallels exist in cognitive impairment and cellular pathology of NPC and Alzheimer's disease (AD). In particular, alterations of cholinergic system, which represent one of the pathological hallmarks and contribute to cognitive deterioration in AD, have recently been demonstrated in a human brain autopsy and in an experimental model of NPC. This finding raised the issue that central cholinergic circuits dysfunction may contribute to pathophysiology of cognitive impairment in NPC as well, and prompted us to evaluate the cholinergic functional involvement in NPC patients by applying a neurophysiologic technique, named short-latency afferent inhibition (SAI). We describe clinical, biochemical, molecular and neuropsychological features, and SAI findings in three patients affected by NPC. Diagnosis of NPC was assessed by molecular analysis of the NPC1 gene in all patients. In two of them, biochemical analysis of intracellular accumulation of unesterified cholesterol was also performed. The main clinical features were cerebellar ataxia, vertical supranuclear gaze palsy and a variable degree of cognitive impairment ranging from only memory impairment to severe dementia. Electrophysiological evaluation revealed a reduced SAI in all three patients. Our SAI findings provide evidence of cholinergic dysfunction in patients with the adult form of NPC, supporting that cholinergic alterations may play a role in cognitive impairment in NPC, and strengthening the similarities between NPC and AD.
authors.affiliation: Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II of Naples, Via Sergio Pansini, 5, 80131, Naples, Italy.
authors.forename: Fiore
authors.initials: F
authors.lastname: Manganelli
authors.forename: Raffaele
authors.initials: R
authors.lastname: Dubbioso
authors.forename: Rosa
authors.initials: R
authors.lastname: Iodice
authors.forename: Antonietta
authors.initials: A
authors.lastname: Topa
authors.forename: Andrea
authors.initials: A
authors.lastname: Dardis
authors.forename: Cinzia Valeria
authors.initials: CV
authors.lastname: Russo
authors.forename: Lucia
authors.initials: L
authors.lastname: Ruggiero
authors.forename: Stefano
authors.initials: S
authors.lastname: Tozza
authors.forename: Alessandro
authors.initials: A
authors.lastname: Filla
authors.forename: Lucio
authors.initials: L
authors.lastname: Santoro
mesh_terms: D000328:Adult; D000344:Afferent Pathways / Q000503:physiopathology; D000544:Alzheimer Disease / Q000150:complications* / Q000523:psychology; D001342:Autonomic Nervous System Diseases / Q000150:complications* / Q000175:diagnosis / Q000523:psychology; D002352:Carrier Proteins / Q000235:genetics; D003072:Cognition Disorders / Q000209:etiology / Q000523:psychology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008279:Magnetic Resonance Imaging; D008562:Membrane Glycoproteins / Q000235:genetics; D009460:Neurologic Examination; D009483:Neuropsychological Tests; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000150:complications* / Q000523:psychology; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein