ORIGINAL COMMUNICATION Central cholinergic dysfunction in the adult form of Niemann Pick disease type C: a further link with Alzheimer’s disease? Fiore Manganelli • Raffaele Dubbioso • Rosa Iodice • Antonietta Topa • Andrea Dardis • Cinzia Valeria Russo • Lucia Ruggiero • Stefano Tozza • Alessandro Filla • Lucio Santoro Received: 23 December 2013 / Revised: 7 February 2014 / Accepted: 10 February 2014 Ó Springer-Verlag Berlin Heidelberg 2014 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 experi- mental 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 neurophysio- logic 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 accu- mulation 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 pro- vide evidence of cholinergic dysfunction in patients with the adult form of NPC, supporting that cholinergic altera- tions may play a role in cognitive impairment in NPC, and strengthening the similarities between NPC and AD. Keywords Niemann-Pick disease type C Á Dementia Á Cognitive impairment Á Short-latency afferent inhibition Á SAI Á Alzheimer’s disease Introduction Niemann-Pick disease type C (NPC) is a rare neurode- generative disorder that develops from a failure of cho- lesterol trafficking within the endosomal–lysosomal pathway. It is inherited in an autosomal-recessive fashion, and is caused by mutation of either the NPC1 (95 %) or NPC2 gene. The clinical spectrum of the disease ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. In adult forms of NPC, the main clinical features are cerebellar ataxia, vertical supranuclear gaze palsy, dysar- thria, cognitive impairment, movement disorders, viscero- megaly, psychiatric disorders and dysphagia [1]. Cognitive dysfunction is highly variable from patients with mild cognitive impairment to severely demented patients in later stage of disease [2, 3]. Interestingly, NPC has been proposed as a model of ‘‘juvenile Alzheimer’s disease’’ [4]. In fact, intriguing similarities exist in the cellular pathology of NPC and Alzheimer’s disease (AD), including neurofibrillary tangle formation, prominent lysosome system dysfunction, F. Manganelli and R. Dubbioso equally contributed to this work. F. Manganelli Á R. Dubbioso Á R. Iodice Á A. Topa Á C. V. Russo Á L. Ruggiero Á S. Tozza Á A. Filla Á L. Santoro (&) Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II of Naples, Via Sergio Pansini, 5, 80131 Naples, Italy e-mail: lusantor@unina.it A. Dardis Regional Coordinator Centre for Rare Diseases, University Hospital ‘‘Santa Maria della Misericordia’’, Udine, Italy 123 J Neurol DOI 10.1007/s00415-014-7282-2