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Gait and Motor Symptoms in Healthy Asymptomatic Relatives of Patients with PD Who Are Carriers of Mutations in the LRRK2 Gene

Gait disturbances play a major role in the motor manifestation of Parkinson's disease (PD). We aim to explore the possibility that subtle gait alterations are also present in the pre-diagnostic phase of PD and in populations at risk for developing PD. Therefore this study will investigate gait changes in patients and family members of carriers of genetic mutations in the LRRK2 gene.

Project Description:
Subjects will be invited to a gait evaluation in one of the centres participating in the study. All subjects will undergo a detailed neurological and general exam. In addition, performance based measures will be used to assess balance and mobility. Subjects will then be fitted with wearable sensors placed on the proximal wrists and lower back. Subjects will be asked to walk in a well-lit corridor, under 4 different walking conditions while the sensors quantify information on gait and arm swing during the different walks. Outcome measures will include gait speed, gait variability, step length, and magnitude and symmetry of arm swing during usual-walking and the effects of challenging walks on these gait features.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The evaluations of gait in a population at higher risk of developing PD, such as relatives of patients carrying LRRK2 mutations, may assist in understanding the pathophysiology of the disease, provide insight into the role of mutations in the LRRK2 gene in the development of PD, and perhaps solidify the intriguing possibility that gait dynamics during challenging conditions may serve as a new, sensitive biological marker of pre-symptomatic PD.

Anticipated Outcome:
We anticipate that healthy asymptomatic carriers of the LRRK2 mutation will demonstrate changes in gait performance during challenging tasks that will not be present in non carriers. These findings may reflect early pre-clinical motor alterations and if validated in this project may be used in the future as sensitive biomarkers in PD. 


Final Outcome

Gait disturbances play a major role in the motor manifestation of PD. Changes in gait speed and variability can already be detected in recently diagnosed, de novo patients, even before any visible or symptomatic gait disturbances are reported.  PD is known for its long pre-diagnostic phase. Therefore, our aim was to assess whether changes in gait and motor function could be detected in populations at risk even before the disease is diagnosed and to evaluate the relation of these measures to mutations in the LRRK2 gene.

394 subjects participated in this study from 7 clinical sites (155 asymptomatic relatives, 109 patients with PD and 130 control subjects with no family history of PD). Initial analysis revealed that patients with PD carriers of the G2019S mutation had higher gait variability and reduced arm swing and axial rotation as compared to patients who did not carry the mutation regardless of disease severity. Interestingly, asymptomatic carriers had higher gait variability then non-manifesting non-carriers and demonstrated increased arm swing asymmetry. The study demonstrates for the first time that motor measures are related to LRRK2. Quantitative evaluation may have utility for identifying early motor changes even in prodromal PD.



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