Assessment of locomotor response to levodopain fluctuating Parkinson’s disease

Steven T. Moore1, Hamish G. MacDougall1, Jean-Michel Gracies1 & William G. Ondo2

Neurology Departments; 1Mt Sinai School of Medicine, New York, NY, USA; 2Baylor College of Medicine, Houston TX.

Many laboratory and clinical studies have demonstrated the ability of levodopa to increase stride length and walking speed, typically evaluating gait over short distances (<10 m) prior to administration ('off') and at the peak dose ('on') of the levodopa medication cycle (see Morris(1) for review). However, the temporal dynamics of the locomotor response to levodopa, necessary for objective assessment of motor fluctuations, have not been successfully elucidated. A laboratory study (2) periodically assessed gait on a fixed 7-m walkway over the levodopa cycle but found no consistent changes in stride length, likely due to the contrived nature of the laboratory walking task that can temporarily enhance performance in PD patients (3). In contrast, the fine-motor dynamic response to a standardized dose of levodopa (100 mg) has been assessed using finger-tapping at 15-min intervals post-administration (4). The drug effect-time curve (taps/min versus time-since-administration) followed a hyperbolic profile in early stages of the disease, with a sharper sigmoidal 'off-on' transition in advanced PD. However, it is unclear whether finger-tapping accurately reflects the locomotor response to levodopa. A recent study has shown no correlation between the off-on variation in tapping and gait (5), suggesting a dissociation in the effects of levodopa on upper limb movements and locomotor function. In the current study we investigated whether a new ambulatory system for monitoring of gait (6) could be used to objectively assess locomotor fluctuations in PD.

1. Morris ME, Huxham F, McGinley J, Dodd K, Iansek R. The biomechanics and motor control of gait in Parkinson disease. Clin Biomech (Bristol, Avon) 2001;16(6):459-470.2. MacKay-Lyons M. Variability in spatiotemporal gait characteristics over the course of the L-dopa cycle in people with advanced Parkinson disease. Phys Ther 1998;78(10):1083-1094.3. Yekutiel MP. Patients' fall records as an aid in designing and assessing therapy in Parkinsonism. Disabil Rehabil 1993;15(4):189-193.4. Contin M, Riva R, Martinelli P, Triggs EJ, Albani F, Baruzzi A. Rate of motor response to oral levodopa and the clinical progression of Parkinson's disease. Neurology 1996;46(4):1055-1058.5. Vokaer M, Azar NA, de Beyl DZ. Effects of levodopa on upper limb mobility and gait in Parkinson's disease. J Neurol Neurosurg Psychiatry 2003;74(9):1304-1307.6. Moore ST, MacDougall H, Gracies J-M, Cohen H, Ondo W. Long-term monitoring of gait in Parkinson's Disease. Gait Posture 2006;doi:10.1016/j.gaitpost.2006.09.011.7. Holford NH, Sheiner LB. Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 1981;6(6):429-453.8. Levenberg K. A Method for the Solution of Certain Problems in Least Squares. Quart. Appl. Math. 1944;2:164-168.9. Marquardt D. An Algorithm for Least-Squares Estimation of Nonlinear Parameters. SIAM J. Appl. Math. 1963;11:431-441.10. Contin M, Riva R, Martinelli P, Albani F, Avoni P, Baruzzi A. Levodopa therapy monitoring in patients with Parkinson disease: a kinetic-dynamic approach. Ther Drug Monit 2001;23(6):621-629.

P498P498

METHODSTen participants diagnosed with idiopathic PD (8 males and 2 females) were enrolled in this study (Table 1). Age ranged from 45 to 72 years (62.3 [SD 8.2]), age at onset of PD from 20 to 60 years (43.2 [SD 11.4]), and time since onset from 6 to 28 years (19.1 [SD 8.0]). All participants were prescribed oral levodopa as the primary component in pharmacological management of PD, and had a clinical history of motor fluctuations. Participants arrived 8:00 am at the Movement Disorders clinic within the Department of Neurology at Baylor, without having taken their usual morning medication, in a clinically-defined 'off' state. Participants walked without assistance at a self-determined pace about a series of corridors of maximum length 100 m within the hospital complex immediately prior to usual morning

During the walking task the length of every stride was measured with an accuracy of 5 cm using a novel ambulatory device developed by the authors (6). An Inertial Measurement Unit, 9V battery and Bluetooth serial transmitter were mounted around the shank (just above the ankle) using an elasticized strap and Velcro. The device weighed less than 130 grams and did not interfere with locomotion. Vertical linear acceleration and sagittal angular velocity of the leg were transmitted wirelessly to a Pocket PC carried by an investigator, who typically walked a few meters behind the participant. After each walking trial leg movement data was processed using custom analysis software to provide stride length (6).A drug effect-time curve for the locomotor response to levodopa was determined by fitting all stride length values for each participant (total number of strides ranged from 284 to 682; mean 431 [SD 111]) with a sigmoid Emax (Hill) function (4, 7) using the Levenberg-Marquardt technique (8, 9). The latency of the locomotor response to levodopa was calculated as the time taken from administration until stride length increased 15% of the difference between baseline and maximum response following levodopa administration. The Hill coefficient, N, a dimensionless value which describes the abruptness of the stride length transition from 'off' to 'on', was also determined from the fit. A regression analysis was performed to determine the relationship of latency and the Hill coefficient to patient age, age at onset of PD, time since diagnosis, the morning and total daily levodopa dose, and changes in stride length (baseline, final, and delta). Correlations were considered significant for p < 0.05.

Subject ID

Age (yrs)

Onset (yrs)

Time since Dx

(yrs)

LD (morning)

mg

LD (total) mg Other PD meds

3 66 40 26 110 565 pramipexole 6 65 42 23 100 800 tolcapone 7 45 20 25 100 600 tolcapone 9 65 37 28 100 1250 -

10 65 54 11 250 1900 pramipexole 11 72 50 22 450 2350 pramipexole 12 68 52 16 150 1750 pramipexole 13 66 60 6 150 600 pramipexole 14 51 42 9 250 1250 entacapone, ropinirole 15 60 35 25 200 1600 ropinirole, deprenyl, amantadine

16.9 23.3 min

S11

0.97.3 min S13

6.026.0 min

S14

S15

9.930.9 min

Time (min)900 10 20 30 40 50 60 70 80

0.5 m

14.430.1 min

S3

S15 S85

Stri

de

Len

gth

(m)

2.32.37.0 min7.0 min

S10

4.915.6 min

S9

Stri

de

Len

gth

(m)

0.5 m

11.247.5 minS7

Stri

de

Len

gth

(m)

S6

0.5 m

11.125.0 min25.0 min

Stri

de

Len

gth

(m)

4.417.9 min

S12

0.5 m

Time (min)900 10 20 30 40 50 60 70 80

Latency Hill Coefficient

Individual stridesMean strideLatency

SL15 to SL85

Sigmoidal fit

Hill Coefficient Latency R p R p

0.029 0.94 0.67* 0.035* Age at onset of PD 0.45 0.19 0.88* 0.0007* Time since Dx 0.68* 0.031* 0.58** 0.077** LD (morning dose) 0.32 0.36 0.16 0.66 LD (total daily dose) 0.053 0.88 0.32 0.37 Initial SL (mean) 0.12 0.73 0.25 0.48 Final SL (mean) 0.24 0.50 0.13 0.73

SL (%) 0.10 0.79 0.23 0.52 0.66* 0.037* X X Latency

∆

Age

BACKGROUND

Consistent with previous studies of the dynamic response of finger-tapping to levodopa (4, 10), the locomotor transition from 'off' to 'on', represented by the Hill coefficient, was correlated with disease duration. A novel result was the latency to drug effect, i.e., increased stride length, was inversely related to age at onset of PD. In addition, the Hill coefficient was correlated with latency; the longer the delay until stride length increase the sharper the transition from 'off' to 'on'.

CONCLUSIONS

dopaminergic medication administration (see Table 1). Participants repeated the walking task approximately every 15 min over a 90 min period post-administration. Distance walked was dependent on patient ability, ranging from 1 to 90 m (51 m [SD 27]) when 'off' and from 30 to 94 m (60 m [SD 21]) in the 'on' state.

RESULTSS t r i d e d a t a f r o m a l l 1 0 part ic ipants were wel l f i t by an Emax (Hill) function (Fig. 1). The latency to increased stride length varied from 7.0 to 47.5 min (23.1 m i n [ S D 1 2 . 1 ] ) . T h e d y n a m i c locomotor response to levodopa, represented by the Hill coefficient, ranged from a smooth hyperbolic curve (N = 0.9) to an abrupt 'off/on' transition (N = 16.9), with a mean of 8.2 (SD 5.3).Despi te the re la t ive ly smal l n u m b e r o f p a r t i c i p a n t s s o m e statistically significant relationships were observed (Table 2). The Hill coefficient was positively correlated wi th both t ime s ince d iagnosis (p=0.031) and latency (p=0.037). Latency was strongly correlated with age at onset of PD (p= 0.0007). Not surprisingly, latency was also correlated with age (p= 0.035) as patients with young onset tended to be the younger subjects, and vice versa. However, a multivariable regression analysis adjusting for a g e a n d a g e a t o n s e t a s independent variables revealed that age at onset remained a significant pred ic tor o f la tency (p=0.013) whereas age d id not (p=0.80) . There was also a trend evident (p=0.077) in the relat ionship of latency to time since diagnosis. The Hill coefficient and latency showed no evidence of a relationship to the levodopa dose (morning or total), the mean stride length in the 'off' or 'on' state, and the relative change in stride length from 'off' to 'on' (Table 2).

Fig. 1. Stride length data from 10 PD patients f o l l o w i n g u s u a l m o r n i n g l e v o d o p a administration. The data were fit with an Emax (H i l l ) f unc t i on (b lue l i nes ) . The steepness of the 'off ' to 'on' transition is represented by the Hil l Coeff icient. The latency to an observable effect of levodopa on s t r ide length is shown as the green shaded regions.

Table 2. Regression analyses for the Hill Coefficient and Latency of t h e l o c o m o t o r r e s p o n s e t o levodopa.

Table 1. Patient Characteristics.