Preliminary Results on Long-Term Potentiation-Like Cortical Plasticity and Cholinergic Dysfunction After Miglustat Treatment in Niemann-Pick Disease Type C

  • Alberto Benussi
  • Maria Sofia Cotelli
  • Maura Cosseddu
  • Valeria Bertasi
  • Marinella Turla
  • Ettore Salsano
  • Andrea Dardis
  • Alessandro Padovani
  • Barbara BorroniEmail author
Research Report
Part of the JIMD Reports book series (JIMD, volume 36)


Niemann-Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder, which manifests clinically with a wide range of neurological signs and symptoms. We assessed multiple neurological, neuropsychological and neurophysiological biomarkers using a transcranial magnetic stimulation (TMS) multi-paradigm approach in two patients with NPC carrying a homozygous mutation in the NPC1 gene, and in two heterozygous family members.

We assessed short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), long-interval intracortical inhibition (LICI), short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity with a paired associative stimulation (PAS) protocol.

Baseline SAI and LTP-like plasticity were impaired in both patients with NPC and in the symptomatic heterozygous NPC1 gene mutation carrier. Only a limited decrease in SICI and ICF was observed, while LICI was within normal range in all subjects at baseline. After 12 months of treatment with miglustat, a considerable improvement in SAI and LTP-like plasticity was observed in both patients with NPC. In conclusion, these biomarkers could help to confirm the diagnosis of NPC, and may give an indication of prognostic outcomes in pharmacological trials.


Long-term potentiation-like cortical plasticity Miglustat Niemann-Pick disease type C Short latency afferent inhibition Transcranial magnetic stimulation 

Supplementary material

459230_1_En_33_MOESM1_ESM.pdf (200 kb)
Supplementary Figure. SAI and LTP-like cortical plasticity in patients and HCs. (a) SAI at different ISIs. Data are plotted as a ratio to the unconditioned MEP amplitude. (b) PAS effect on corticospinal excitability, as measured by change in 1 mV MEP amplitude at various time points. HC healthy controls, ISI inter-stimulus interval, MEP motor evoked potential, P1/2/3/4 Patient 1/2/3/4, PAS paired associative stimulation, Pre pre-PAS baseline, SAI short-latency afferent inhibition (PDF 200 kb)


  1. Auer IA, Schmidt ML, Lee VMY et al (1995) Paired helical filament tau (PHFtau) in Niemann-Pick type C disease is similar to PHFtau in Alzheimer’s disease. Acta Neuropathol 90:547–551. doi: 10.1007/BF00318566 CrossRefPubMedGoogle Scholar
  2. Benussi A, Alberici A, Premi E et al (2015a) Phenotypic heterogeneity of Niemann-Pick disease type C in monozygotic twins. J Neurol 262:642–647. doi: 10.1007/s00415-014-7619-x CrossRefPubMedGoogle Scholar
  3. Benussi A, Padovani A, Borroni B (2015b) Transcranial magnetic stimulation in Alzheimer’s disease and cortical dementias. J Alzheimers Dis Parkinsonism 5:1–7. doi: 10.4172/2161-0460.1000197 Google Scholar
  4. Benussi A, Cosseddu M, Filareto I et al (2016) Impaired long-term potentiation-like cortical plasticity in presymptomatic genetic frontotemporal dementia. Ann Neurol 80:472–476. doi: 10.1002/ana.24731 CrossRefPubMedGoogle Scholar
  5. Bodovitz S, Klein WL (1996) Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J Biol Chem 271:4436–4440. doi: 10.1126/science.307.5714.1371o CrossRefPubMedGoogle Scholar
  6. Byun K, Kim J, Cho S-Y et al (2006) Alteration of the glutamate and GABA transporters in the hippocampus of the Niemann-Pick disease, type C mouse using proteomic analysis. Proteomics 6:1230–1236. doi: 10.1002/pmic.200500412 CrossRefPubMedGoogle Scholar
  7. Carstea ED, Morris JA, Coleman KG et al (1997) Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277:228–231CrossRefPubMedGoogle Scholar
  8. Chiba Y, Komori H, Takei S et al (2014) Niemann-Pick disease type C1 predominantly involving the frontotemporal region, with cortical and brainstem Lewy bodies: an autopsy case. Neuropathology 34:49–57. doi: 10.1111/neup.12047 CrossRefPubMedGoogle Scholar
  9. Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923CrossRefPubMedGoogle Scholar
  10. D’Arcangelo G, Grossi D, Racaniello M et al (2016) Miglustat reverts the impairment of synaptic plasticity in a mouse model of NPC disease. Neural Plast 2016:1–9. doi: 10.1155/2016/3830424 CrossRefGoogle Scholar
  11. Di Lazzaro V, Oliviero A, Pilato F et al (2005) Neurophysiological predictors of long term response to AChE inhibitors in AD patients. J Neurol Neurosurg Psychiatry 76:1064–1069. doi: 10.1136/jnnp.2004.051334 CrossRefPubMedGoogle Scholar
  12. Di Lorenzo F, Ponzo V, Bonnì S et al (2016) Long-term potentiation-like cortical plasticity is disrupted in Alzheimer’s disease patients independently from age of onset. Ann Neurol 80:202–210. doi: 10.1002/ana.24695 CrossRefPubMedGoogle Scholar
  13. Fu R, Yanjanin NM, Elrick MJ et al (2012) Apolipoprotein E genotype and neurological disease onset in Niemann-Pick disease, type C1. Am J Med Genet A 158A:2775–2780. doi: 10.1002/ajmg.a.35395 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Gibson JR, Bartley AF, Hays SA, Huber KM (2008) Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome. J Neurophysiol 100:2615–2626. doi: 10.1152/jn.90752.2008 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Hung YH, Walterfang M, Churilov L et al (2016) Neurological dysfunction in early maturity of a model for Niemann-Pick C1 carrier status. Neurotherapeutics. doi: 10.1007/s13311-016-0427-5 PubMedPubMedCentralGoogle Scholar
  16. Josephs KA, Matsumoto JY, Lindor NM (2004) Heterozygous Niemann-Pick disease type C presenting with tremor. Neurology 63:2189–2190. doi: 10.1212/01.wnl.0000145710.25588.2f CrossRefPubMedGoogle Scholar
  17. Kluenemann HH, Nutt JG, Davis MY, Bird TD (2013) Parkinsonism syndrome in heterozygotes for Niemann-Pick C1. J Neurol Sci 335:219–220. doi: 10.1016/j.jns.2013.08.033 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Liscum L, Ruggiero RM, Faust JR (1989) The intracellular transport of low density lipoprotein-derived cholesterol is defective in Niemann-Pick type C fibroblasts. J Cell Biol 108:1625–1636. doi: 10.1083/jcb.108.5.1625 CrossRefPubMedGoogle Scholar
  19. Liu C-C, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9:106–118. doi: 10.1038/nrneurol.2012.263 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Love S, Bridges LR, Case CP (1995) Neurofibrillary tangles in Niemann-Pick disease type C. Brain 118:119–129. doi: 10.1093/brain/118.1.119 CrossRefPubMedGoogle Scholar
  21. Manganelli F, Dubbioso R, Iodice R et al (2014) Central cholinergic dysfunction in the adult form of Niemann-Pick disease type C: a further link with Alzheimer’s disease? J Neurol 261:804–808. doi: 10.1007/s00415-014-7282-2 CrossRefPubMedGoogle Scholar
  22. Mattsson N, Olsson M, Gustavsson MK et al (2012) Amyloid-β metabolism in Niemann-Pick C disease models and patients. Metab Brain Dis 27:573–585. doi: 10.1007/s11011-012-9332-8 CrossRefPubMedGoogle Scholar
  23. Naureckiene S, Sleat DE, Lackland H et al (2000) Identification of HE1 as the second gene of Niemann-Pick C disease. Science 290:2298–2301. doi: 10.1126/science.290.5500.2298 CrossRefPubMedGoogle Scholar
  24. Palop JJ, Mucke L (2010) Amyloid-β–induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Rev Neurol 13(7):812–818. doi: 10.1038/nn.2583 Google Scholar
  25. Pentchev PG, Comly ME, Kruth HS et al (1985) A defect in cholesterol esterification in Niemann-Pick disease (type C) patients. Proc Natl Acad Sci U S A 82:8247–8251. doi: 10.1073/pnas.82.23.8247 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Porter FD, Scherrer DE, Lanier MH et al (2010) Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci Transl Med 2:56ra81. doi: 10.1126/scitranslmed.3001417 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Simons M, Keller P, De Strooper B et al (1998) Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A 95:6460–6464CrossRefPubMedPubMedCentralGoogle Scholar
  28. Vanier MT (2010) Niemann-Pick disease type C. Orphanet J Rare Dis 5:16. doi: 10.1186/1750-1172-5-16 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Walterfang MSMA, Abegg M, Lanyon LJ et al (2011) White and gray matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study. Neurology 76:201–202. doi: 10.1212/WNL.0b013e3181fe7341 CrossRefGoogle Scholar
  30. Walterfang M, Patenaude B, Abel LA et al (2013) Subcortical volumetric reductions in adult Niemann-Pick disease type C: a cross-sectional study. AJNR Am J Neuroradiol 34:1334–1340. doi: 10.3174/ajnr.A3356 CrossRefPubMedGoogle Scholar
  31. Wassif CA, Cross JL, Iben J et al (2015) High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets. Genet Med 18:41–48. doi: 10.1038/gim.2015.25 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Wolters A (2003) A temporally asymmetric hebbian rule governing plasticity in the human motor cortex. J Neurophysiol 89:2339–2345. doi: 10.1152/jn.00900.2002 CrossRefPubMedGoogle Scholar
  33. Yamazaki T, Chang TY, Haass C, Ihara Y (2001) Accumulation and aggregation of amyloid beta-protein in late endosomes of Niemann-pick type C cells. J Biol Chem 276:4454–4460. doi: 10.1074/jbc.M009598200 CrossRefPubMedGoogle Scholar
  34. Ziemann U, Reis J, Schwenkreis P et al (2015) TMS and drugs revisited 2014. Clin Neurophysiol 126:1847–1868. doi: 10.1016/j.clinph.2014.08.028 CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Alberto Benussi
    • 1
  • Maria Sofia Cotelli
    • 2
  • Maura Cosseddu
    • 1
  • Valeria Bertasi
    • 2
  • Marinella Turla
    • 2
  • Ettore Salsano
    • 3
  • Andrea Dardis
    • 4
  • Alessandro Padovani
    • 1
  • Barbara Borroni
    • 1
    Email author
  1. 1.Centre for Ageing Brain and Neurodegenerative Disorders, Neurology UnitUniversity of BresciaBresciaItaly
  2. 2.Neurology UnitValle Camonica HospitalBresciaItaly
  3. 3.Department of Clinical NeurosciencesFondazione IRCCS Istituto Neurologico “Carlo Besta”MilanItaly
  4. 4.University Hospital “Santa Maria della Misericordia”UdineItaly

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