Riluzole protects Huntington disease patients from brain glucose hypometabolism and grey matter volume loss and increases production of neurotrophins

  • Ferdinando Squitieri
  • Sara Orobello
  • Milena Cannella
  • Tiziana Martino
  • Pantaleo Romanelli
  • Giampiero Giovacchini
  • Luigi Frati
  • Luigi Mansi
  • Andrea Ciarmiello
Original Article

Abstract

Purpose

Huntington disease (HD) mutation increases gain-of-toxic functions contributing to glutamate-mediated excitotoxicity. Riluzole interferes with glutamatergic neurotransmission, thereby reducing excitotoxicity, enhancing neurite formation in damaged motoneurons and increasing serum concentrations of BDNF, a brain cortex neurotrophin protecting striatal neurons from degeneration.

Methods

We investigated metabolic and volumetric differences in distinct brain areas between 11 riluzole-treated and 12 placebo-treated patients by MRI and 18F-fluoro-2-deoxy-d-glucose (FDG) PET scanning, according to fully automated protocols. We also investigated the influence of riluzole on peripheral growth factor blood levels.

Results

Placebo-treated patients showed significantly greater proportional volume loss of grey matter and decrease in metabolic FDG uptake than patients treated with riluzole in all cortical areas (p<0.05). The decreased rate of metabolic FDG uptake correlated with worsening clinical scores in placebo-treated patients, compared to those who were treated with riluzole. The progressive decrease in metabolic FDG uptake observed in the frontal, parietal and occipital cortex correlated linearly with the severity of motor scores calculated by Unified Huntington Disease Rating Scale (UHDRS-I) in placebo-treated patients. Similarly, the rate of metabolic changes in the frontal and temporal areas of the brain cortex correlated linearly with worsening behavioural scores calculated by UHDRS-III in the placebo-treated patients. Finally, BDNF and transforming growth factor beta-1 serum levels were significantly higher in patients treated with riluzole.

Conclusion

The linear correlation between decreased metabolic FDG uptake and worsening clinical scores in the placebo-treated patients suggests that FDG-PET may be a valuable procedure to assess brain markers of HD.

Keywords

FDG-PET scan Volumetric MRI Neurotrophins Brain-derived neurotrophic factor Transforming growth factor 

Notes

Acknowledgments

We thank Dr. Jenny Sassone for providing help in setting up the ELISA analysis of patients’ serum. We also thank the European Huntington’s Disease (EURO-HD) Network, the patients’ family association ‘Associazione Italiana Corea di Huntington-Neuromed’, the Italian Society of Hospital Neurologists (S.N.O., ‘lascito Gobessi’) and the Italian Health Ministry (COFIN 2006; finalizzato ex art.56 2007), for their support to F.S. The financial support of Telethon-Italy to F.S. (grant no. GGP06181) is gratefully acknowledged.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Ferdinando Squitieri
    • 1
  • Sara Orobello
    • 1
  • Milena Cannella
    • 1
  • Tiziana Martino
    • 1
  • Pantaleo Romanelli
    • 2
  • Giampiero Giovacchini
    • 3
  • Luigi Frati
    • 4
  • Luigi Mansi
    • 5
  • Andrea Ciarmiello
    • 3
  1. 1.Neurogenetics Unit & Centre for Rare DiseaseIRCCS NeuromedPozzilliItaly
  2. 2.Department of NeurosurgeryIRCCS NeuromedPozzilliItaly
  3. 3.Unit of Nuclear MedicineS. Andrea HospitalLa SpeziaItaly
  4. 4.Department of Experimental MedicineUniversity “Sapienza”RomeItaly
  5. 5.Department of Nuclear MedicineSecond University of NaplesNaplesItaly

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