Abstract
Introduction: Niemann–Pick disease type C (NPC) is a lysosomal storage disorder that leads to progressive neurodegeneration. The glucosylceramide synthase blocker miglustat is being used to treat NPC, but monitoring of disease progression and treatment response is difficult. NPC patients have elevated cerebrospinal fluid (CSF) levels of total-tau (T-tau) indicating axonal degeneration, and increased CSF amyloid β (Aβ) indicating abnormal brain amyloid metabolism, but it is unknown if start of miglustat treatment affects these biomarker levels.
Methods: Biomarkers were measured in serial CSF samples from NPC patients who started miglustat between samplings (N=5), were untreated at both samplings (N=5) or received treatment during the whole study (N=6) (median time between samplings 309 days [range 175–644]). CSF was analyzed for Aβ38, Aβ40, Aβ42, α-cleaved soluble APP, β-cleaved soluble APP, T-tau and phospho-tau.
Results: T-tau levels decreased in patients who started miglustat treatment (median 955 [range 338–1,271]ng/L at baseline vs. 382 [187–736]ng/L at follow-up, p=0.043). Untreated patients and continuously treated patients had stable levels (p>0.05). No changes were seen in the other biomarkers.
Conclusion: Reduced CSF T-tau suggests that miglustat treatment might affect axonal degeneration in NPC. However, the results must be interpreted with caution and verified in future studies, since this pilot study was small, treatment was not randomized, and patients starting treatment had higher baseline CSF T-tau than untreated patients.
Competing interests: None declared.
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Acknowledgments
We thank Åsa Källén, Monica Christiansson, Sara Hullberg and Dzemila Secic for excellent technical assistance. We are grateful to Mrs. Chris Hempel for her support of this study. We wish to thank the caretakers and patients for their participation.
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Communicated by: Robert Steiner.
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Synopsis
Cerebrospinal fluid levels of the axonal degeneration marker tau may decrease after start of miglustat treatment in Niemann–Pick type C.
Disclosures
This study was funded with grants from the Swedish Research Council (projects 14002, 2006–6227, 2006–2740 and 2006–3505), the Alzheimer’s Association (NIRG-08-90356), cNEUPRO, the Royal Swedish Academy of Sciences, Sahlgrenska University Hospital, the Söderberg Foundation, the Lundbeck Foundation, the Gothenburg Medical Society, the Swedish Medical Society, Swedish Brain Power, Stiftelsen Gamla Tjänarinnor, Gun och Bertil Stohnes stiftelse, Åhlén-stiftelsen, Alzheimer Foundation, Sweden, The Dementia Association, Sweden, a Bench to Bedside grant from the NIH Office of Rare Diseases, Therapeutics for Rare and Neglected Diseases program, and the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Dr Henrik Zetterberg has participated in an advisory board for GlaxoSmithKline.
Nicole M Yanjanin’s position has been supported by the Ara Parseghian Medical Research Foundation and Dana’s Angels Research Trust.
Dr Kaj Blennow has participated in an advisory board for Innogenetics.
Dr Niklas Mattsson has participated in an advisory board for Actelion Inc.
Dr Simona Bianconi reports no disclosures.
Dr Jan-Eric Månsson reports no disclosures.
Rao Fu reports no disclosures.
Dr Forbes D. Porter reports no disclosures.
Author Contributions
NM, KB, HZ and FP designed the study. SB, NY and FP established the clinical protocol, managed patients and collected samples. RF performed genotyping. NM analyzed the data and performed the statistical analysis. All authors participated in the interpretation of the data. NM drafted the manuscript and all other authors revised the manuscript.
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Mattsson, N. et al. (2011). Miglustat Treatment May Reduce Cerebrospinal Fluid Levels of the Axonal Degeneration Marker Tau in Niemann–Pick Type C. In: JIMD Reports - Case and Research Reports, 2011/3. JIMD Reports, vol 3. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2011_47
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DOI: https://doi.org/10.1007/8904_2011_47
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