Experimental Brain Research

, Volume 184, Issue 4, pp 469–478 | Cite as

Locomotor response to levodopa in fluctuating Parkinson’s disease

  • Steven T. Moore
  • Hamish G. MacDougall
  • Jean-Michel Gracies
  • William G. Ondo
Research Article

Abstract

The aim of this study was to quantify the dynamic response of locomotion to the first oral levodopa administration of the day in patients with fluctuating Parkinson’s disease (PD). Stride length, walking speed, cadence and gait variability were measured with an ambulatory gait monitor in 13 PD patients (8 males) with a clinical history of motor fluctuations. The Unified Parkinson’s Disease Rating Scale (UPDRS) gait score (part 29) was also determined by a movement disorders specialist from video recordings. Subjects arrived in the morning in an ‘off’ state (no PD medication) and walked for a maximum length of 100 m. They then took their usual morning dose of oral levodopa and repeated the walking task at 13 min intervals (on average) over a 90 min period. Changes in stride length over time were fit with a Hill (Emax) function. Latency (time until stride length increased 15% of the difference between baseline and maximum response) and the Hill coefficient (shape of the ‘off–on’ transition) were determined from the fitted curve. Latency varied from 4.7 to 53.3 min post-administration [23.31 min (SD 14.9)], and was inversely correlated with age at onset of PD (R = −0.83; P = 0.0004). The Hill coefficient (H) ranged from a smooth hyperbolic curve (0.9) to an abrupt ‘off–on’ transition (16.9), with a mean of 8.1 (SD 4.9). H correlated with disease duration (R = 0.67; P = 0.01) and latency (R = 0.67; P = 0.01), and increased with Hoehn & Yahr stage in the ‘off’ state (P = 0.02) from 5.7 (SD 3.5) (H&Y III) to 11.9 (SD 4.7) (H&Y IV). Walking speed correlated with changes in mean stride length, whereas cadence and gait variability did not. UPDRS gait score also reflected improving gait in the majority of subjects (8), providing clinical confirmation of the objective measures of the locomotor response to levodopa. Increasing abruptness (H) of the ‘off–on’ transition with disease duration is consistent with results from finger-tapping studies, and may reflect reduced buffering capacity of pre-synaptic nigrostriatal dopaminergic neurons. Ambulatory monitoring of gait objectively measures the dynamic locomotor response to levodopa, and this information could be used to improve daily management of motor fluctuations.

Keywords

Stride length Walking speed Cadence Gait variability Young onset 

References

  1. Blin O, Ferrandez AM, Pailhous J, Serratrice G (1991) Dopa-sensitive and dopa-resistant gait parameters in Parkinson’s disease. J Neurol Sci 103:51–54PubMedCrossRefGoogle Scholar
  2. Bloem BR, Hausdorff JM, Visser JE, Giladi N (2004) Falls and freezing of gait in Parkinson’s disease: a review of two interconnected, episodic phenomena. Mov Disord 19:871–884PubMedCrossRefGoogle Scholar
  3. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134PubMedCrossRefGoogle Scholar
  4. Chana P, Kuntsmann C, Reyes-Parada M, Saez-Briones P (2004) Delayed early morning turn “ON” in response to a single dose of levodopa in advanced Parkinson’s disease: pharmacokinetics should be considered. J Neurol Neurosurg Psychiatry 75:1782–1783PubMedCrossRefGoogle Scholar
  5. Contin M, Riva R, Martinelli P, Triggs EJ, Albani F, Baruzzi A (1996) Rate of motor response to oral levodopa and the clinical progression of Parkinson’s disease. Neurology 46:1055–1058PubMedGoogle Scholar
  6. Contin M, Riva R, Martinelli P, Albani F, Avoni P, Baruzzi A (2001) Levodopa therapy monitoring in patients with Parkinson disease: a kinetic-dynamic approach. Ther Drug Monit 23:621–629PubMedCrossRefGoogle Scholar
  7. Czaja SJ, Sharit J (2003) Practically relevant research: capturing real world tasks, environments, and outcomes. Gerontologist 43(Spec No 1):9–18PubMedGoogle Scholar
  8. de la Fuente-Fernandez R, Pal PK, Vingerhoets FJ, Kishore A, Schulzer M, Mak EK, Ruth TJ, Snow BJ, Calne DB, Stoessl AJ (2000) Evidence for impaired presynaptic dopamine function in parkinsonian patients with motor fluctuations. J Neural Transm 107:49–57PubMedCrossRefGoogle Scholar
  9. de la Fuente-Fernandez R, Lu JQ, Sossi V, Jivan S, Schulzer M, Holden JE, Lee CS, Ruth TJ, Calne DB, Stoessl AJ (2001) Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson’s disease: PET evidence of increased dopamine turnover. Ann Neurol 49:298–303PubMedCrossRefGoogle Scholar
  10. Dunn W, Brown C, McGuigan A (1994) The ecology of human performance: a framework for considering the effect of context. Am J Occup Ther 48:595–607PubMedGoogle Scholar
  11. Fahn S, Elton RL, Members of the UPDRS Program (1987) Unified Parkinson’s disease rating scale. In: Fahn S, Marsden CD, Goldstein M, Calne DB (eds) Recent developments in Parkinson’s disease, vol 2. Macmillan Healthcare Information, Florham Park, pp 153–163Google Scholar
  12. Hanakawa T, Fukuyama H, Katsumi Y, Honda M, Shibasaki H (1999) Enhanced lateral premotor activity during paradoxical gait in Parkinson’s disease. Ann Neurol 45:329–336PubMedCrossRefGoogle Scholar
  13. Hausdorff JM, Cudkowicz ME, Firtion R, Wei JY, Goldberger AL (1998) Gait variability and basal ganglia disorders: stride-to-stride variations of gait cycle timing in Parkinson’s disease and Huntington’s disease. Mov Disord 13:428–437PubMedCrossRefGoogle Scholar
  14. Hausdorff JM, Schaafsma JD, Balash Y, Bartels AL, Gurevich T, Giladi N (2003a) Impaired regulation of stride variability in Parkinson’s disease subjects with freezing of gait. Exp Brain Res 149:187–194PubMedGoogle Scholar
  15. Hausdorff JM, Balash J, Giladi N (2003b) Effects of cognitive challenge on gait variability in patients with Parkinson’s disease. J Geriatr Psychiatry Neurol 16:53–58PubMedGoogle Scholar
  16. Hirasaki E, Moore ST, Raphan T, Cohen B (1999) Effects of walking velocity on vertical head and body movements during locomotion. Exp Brain Res 127:117–130PubMedCrossRefGoogle Scholar
  17. Holford NH, Sheiner LB (1981) Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 6:429–453PubMedCrossRefGoogle Scholar
  18. Kerrigan DC, Todd MK, Della Croce U, Lipsitz LA, Collins JJ (1998) Biomechanical gait alterations independent of speed in the healthy elderly: evidence for specific limiting impairments. Arch Phys Med Rehabil 79:317–322PubMedCrossRefGoogle Scholar
  19. MacDougall HG, Moore ST (2005) Marching to the beat of the same drummer: the spontaneous tempo of human locomotion. J Appl Physiol 99:1164–1173PubMedCrossRefGoogle Scholar
  20. MacKay-Lyons M (1998) Variability in spatiotemporal gait characteristics over the course of the l-dopa cycle in people with advanced Parkinson disease. Phys Ther 78:1083–1094PubMedGoogle Scholar
  21. McColl CD, Reardon KA, Shiff M, Kempster PA (2002) Motor response to levodopa and the evolution of motor fluctuations in the first decade of treatment of Parkinson’s disease. Mov Disord 17:1227–1234PubMedCrossRefGoogle Scholar
  22. Mitchell SL, Harper DW, Lau A, Bhalla R (2000) Patterns of outcome measurement in Parkinson’s disease clinical trials. Neuroepidemiology 19:100–108PubMedCrossRefGoogle Scholar
  23. Moore ST, MacDougall HG, Gracies J-M, Cohen H, Ondo WG (2007) Long-term monitoring of gait in Parkinson’s disease. Gait Posture 26:200–207PubMedCrossRefGoogle Scholar
  24. Morris ME, Matyas TA, Iansek R, Summers JJ (1996) Temporal stability of gait in Parkinson’s disease. Phys Ther 76:763–777 (discussion 778–780)PubMedGoogle Scholar
  25. Morris ME, Huxham F, McGinley J, Dodd K, Iansek R (2001) The biomechanics and motor control of gait in Parkinson disease. Clin Biomech (Bristol, Avon) 16:459–470CrossRefGoogle Scholar
  26. Muller T, Erdmann C, Bremen D, Schmidt WE, Muhlack S, Woitalla D, Goetze O (2006) Impact of gastric emptying on levodopa pharmacokinetics in Parkinson disease patients. Clin Neuropharmacol 29:61–67PubMedCrossRefGoogle Scholar
  27. Nutt JG (1987) Off–on phenomenon: relation to levodopa pharmacokinetics and pharmacodynamics. Ann Neurol 22:535–540PubMedCrossRefGoogle Scholar
  28. Nutt JG, Woodward WR, Hammerstad JP, Carter JH, Anderson JL (1984) The “off–on” phenomenon in Parkinson’s disease. Relation to levodopa absorption and transport. N Engl J Med 310:483–488PubMedCrossRefGoogle Scholar
  29. Ondo W (2003) Investigational pharmacological treatments for Parkinson’s diesease. In: Pahwa R, Lyons K, Koller W (eds) Handbook of Parkinson’s disease. Marcel Dekker, New YorkGoogle Scholar
  30. Ostrosky KM, VanSwearingen JM, Burdett RG, Gee Z (1994) A comparison of gait characteristics in young and old subjects. Phys Ther 74:637–644 (discussion 644–636)PubMedGoogle Scholar
  31. O’Sullivan JD, Said CM, Dillon LC, Hoffman M, Hughes AJ (1998) Gait analysis in patients with Parkinson’s disease and motor fluctuations: influence of levodopa and comparison with other measures of motor function. Mov Disord 13:900–906PubMedCrossRefGoogle Scholar
  32. Quinn N, Critchley P, Marsden CD (1987) Young onset Parkinson’s disease. Mov Disord 2:73–91PubMedCrossRefGoogle Scholar
  33. Schaafsma JD, Giladi N, Balash Y, Bartels AL, Gurevich T, Hausdorff JM (2003) Gait dynamics in Parkinson’s disease: relationship to Parkinsonian features, falls and response to levodopa. J Neurol Sci 212:47–53PubMedCrossRefGoogle Scholar
  34. Schrag A, Ben-Shlomo Y, Brown R, Marsden CD, Quinn N (1998) Young-onset Parkinson’s disease revisited—clinical features, natural history, and mortality. Mov Disord 13:885–894PubMedCrossRefGoogle Scholar
  35. Shannon KM (2004) Rating scales. In: Ebaidi M, Pfeiffer RF (eds) Parkinson’s disease. CRC Press, Boca Raton, pp 663–675Google Scholar
  36. Siegel KL, Metman LV (2000) Effects of bilateral posteroventral pallidotomy on gait of subjects with Parkinson disease. Arch Neurol 57:198–204PubMedCrossRefGoogle Scholar
  37. Sossi V, de la Fuente-Fernandez R, Holden JE, Schulzer M, Ruth TJ, Stoessl J (2004) Changes of dopamine turnover in the progression of Parkinson’s disease as measured by positron emission tomography: their relation to disease-compensatory mechanisms. J Cereb Blood Flow Metab 24:869–876PubMedCrossRefGoogle Scholar
  38. Sossi V, de la Fuente-Fernandez R, Schulzer M, Adams J, Stoessl J (2006) Age-related differences in levodopa dynamics in Parkinson’s: implications for motor complications. Brain 129:1050–1058PubMedCrossRefGoogle Scholar
  39. Teasdale N, Stelmach GE (1988) Movement disorders: the importance of the movement context. J Mot Behav 20:186–191PubMedGoogle Scholar
  40. Vokaer M, Azar NA, de Beyl DZ (2003) Effects of levodopa on upper limb mobility and gait in Parkinson’s disease. J Neurol Neurosurg Psychiatry 74:1304–1307PubMedCrossRefGoogle Scholar
  41. Yekutiel MP (1993) Patients’ fall records as an aid in designing and assessing therapy in Parkinsonism. Disabil Rehabil 15:189–193PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Steven T. Moore
    • 1
  • Hamish G. MacDougall
    • 1
    • 2
  • Jean-Michel Gracies
    • 1
  • William G. Ondo
    • 3
  1. 1.Department of NeurologyMount Sinai School of MedicineNew YorkUSA
  2. 2.School of PsychologyUniversity of SydneySydneyAustralia
  3. 3.Department of NeurologyBaylor College of MedicineHoustonUSA

Personalised recommendations