Miglustat treatment may reduce cerebrospinal fluid levels of the axonal degeneration marker tau in niemann-pick type C

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 Aβ(38), Aβ(40), Aβ(42), 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.

Figures

Fig. 1

CSF T-tau and miglustat treatment. Follow-up sample was the next collected consecutive sample after basal sample. At baseline, patients starting treatment (a) had higher T-tau than patients without treatment (b) (p = 0.047) and patients with continuous treatment (c) (p = 0.018), but there was no significant difference between patients without treatment and patients on continuous treatment

Fig. 2

CSF P-tau and miglustat treatment. Follow-up sample was the next collected consecutive sample after basal sample

Fig. 3

Correlation of CSF amyloid markers at baseline and follow-up. The Spearman correlation coefficient was used for analyses of correlations. Follow-up sample was the next collected consecutive sample after basal sample. Patients starting miglustat treatment (circles), patients on continuous treatment (triangles), and untreated patients (boxes). As previously reported, NPC patients treated with miglustat had lower CSF Aβ1-42, sAPP-α and sAPP-β, (Mattsson et al. 2011), but no effects of treatment start could be seen in this study