Levodopa ONOFF-state freezing of gait: Defining the gait and non-motor phenotype.

BACKGROUND: Freezing in the levodopa-medicated-state (ON-state) is a debilitating feature of Parkinson's disease without treatment options. Studies detailing the distinguishing features between people with freezing of gait that improves with levodopa and those whose freezing continues even on levodopa are lacking. OBJECTIVE: To characterize the gross motor, gait, and non-motor features of this phenotype. METHODS: Instrumented continuous gait was collected in the levodopa-medicated-state in 105 patients: 43 non-freezers (no-FOG), 36 with freezing only OFF-levodopa (OFF-FOG) and 26 with freezing both ON- and OFF-levodopa (ONOFF-FOG). Evaluation of motor and non-motor disease features was undertaken using validated scales. A linear mixed model with age, sex, disease duration, and motor UPDRS scores as covariates was used to determine differences in spatiotemporal gait and non-motor disease features among the groups. RESULTS: Compared to OFF-FOG, the ONOFF-FOG group had greater disease severity (on the Unified Parkinson's disease Rating Scale) and worse cognition (on the Montreal Cognitive Assessment, Frontal Assessment Battery and Scales for Outcome in Parkinson's disease-Cognition scales) and quality of life (on the PDQ-39), but similar mood (on the Hamilton depression and anxiety scales) and sleep quality (on Epworth sleepiness scale and RBD questionnaire). For several gait features, differences between the ONOFF-OFF groups were at least as large and in the opposite direction as differences between OFF-no groups, controlling for disease severity. Variability in ONOFF-FOG was greater than in other groups. Using results from our study and others, a power analysis for a potential future study reveals sample sizes of at least 80 ONOFF and 80 OFF-FOG patients would be needed to detect clinically meaningful differences. CONCLUSIONS: Intra-patient variability in spatiotemporal gait features was much greater in ONOFF-FOG than in the other two groups. Our results suggest that multifactorial deficits may lead to ONOFF-FOG development.

Differential Gait Decline in Parkinson's Disease Enhances Discrimination of Gait Freezers from Non-Freezers.

BACKGROUND: Freezing of gait (FOG) is a debilitating feature of Parkinson's disease (PD) for which treatments are limited. To develop neuroprotective strategies, determining whether disease progression is different in phenotypic variants of PD is essential. OBJECTIVE: To determine if freezers have a faster decline in spatiotemporal gait parameters. METHODS: Subjects were enrolled in a longitudinal study and assessed every 3- 6 months. Continuous gait in the levodopa ON-state was collected using a gait mat (Protokinetics). The slope of change/year in spatiotemporal gait parameters was calculated. RESULTS: 26 freezers, 31 non-freezers, and 25 controls completed an average of 6 visits over 28 months. Freezers had a faster decline in mean stride-length, stride-velocity, swing-%, single-support-%, and variability in single-support-% compared to non-freezers (p < 0.05). Gait decline was not correlated with initial levodopa dose, duration of levodopa therapy, change in levodopa dose or change in Montreal Cognitive Assessment scores (p > 0.25). Gait progression parameters were required to obtain 95% accuracy in categorizing freezers and non-freezers groups in a forward step-wise binary regression model. Change in mean stride-length, mean stride-width, and swing-% variability along with initial foot-length variability, mean swing-% and apathy scores were significant variables in the model. CONCLUSION: Freezers had a faster temporal decline in objectively quantified gait, and inclusion of longitudinal gait changes in a binary regression model greatly increased categorization accuracy. Levodopa dosing, cognitive decline and disease severity were not significant in our model. Early detection of this differential decline may help define freezing prone groups for testing putative treatments.

Increased foot strike variability in Parkinson's disease patients with freezing of gait.

INTRODUCTION: Freezing of gait (FOG) is a debilitating, late motor complication of Parkinson's disease (PD) that occurs in 50-80% of patients. Gait freezing significantly worsens quality of life by decreasing mobility and increasing falls. Studies have shown that patients with episodic freezing episodes also have deficits in continuous gait. We evaluated whether there was an objective gait correlate to the increased stumbling reported by many patients with gait freezing. METHODS: PD subjects and healthy controls (HC) were enrolled after IRB approval. Subjects with more than 1 fall/day or a Montreal Cognitive Assessment score <10 were excluded. Subjects walked at their normal pace, 8 lengths of a 20 × 4 foot pressure-sensor mat. Data was collected and analyzed using PKMAS software (Protokinetics) and statistical analysis performed using SPSS 22 (IBM). RESULTS: 72 age matched subjects (22 PD FOG, 27 PD no-FOG, and 23 HC) were enrolled. Disease duration and Hoehn & Yahr scores were not significantly different between the PD groups. Mean dimensions of foot strike were not significantly different between groups, but PD FOG subjects had increased step-to-step variability in foot strike as measured by the percent coefficient of variation (%CV) in foot strike length compared to PD no-FOG and HC, independent of stride velocity. In PD no-FOG subjects, fallers also had higher variability in foot strike length compared to non-fallers. CONCLUSION: PD subjects with FOG had increased variability in foot strike suggesting that in addition to stride length variability, foot strike variability could contribute to imbalance leading to falls.