LRRK2 Mutation and Parkinson's Disease
LRRK2 Mutation and Parkinson's Disease
The Leucine-Rich Repeat Kinase 2 (LRRK2) is implicated in autosomal dominant Parkinson's
 disease (PKD). An inhibitor for the leucine-rich repeat kinase 2 (LRRK2) is in pre-clinical
 development for potential use in treating Parkinson's disease. Patients with PKD have
 cognitive impairments which develop alongside the typical motor symptoms but a full
 characterisation of the neurocognitive phenotype of PKD patients with LRRK2 mutation is
 currently lacking. This observational study conducted on a single visit will assess the
 phenotypic neurocognitive abnormalities of PKD patients with the LRRK2 mutation with the aim
 of identifying potential PD endpoints related to the LRRK2 mutation for future Phase I or II
 clinical trials of LRRK2 inhibitors.
The Leucine-Rich Repeat Kinase 2 (LRRK2) is implicated in autosomal dominant Parkinson's
 disease (PKD). An inhibitor for the leucine-rich repeat kinase 2 (LRRK2) is in pre-clinical
 development for potential use in treating Parkinson's disease. Patients with PKD have
 cognitive impairments which develop alongside the typical motor symptoms but a full
 characterisation of the neurocognitive phenotype of PKD patients with LRRK2 mutation is
 currently lacking. This observational study conducted on a single visit will assess the
 phenotypic neurocognitive abnormalities of PKD patients with the LRRK2 mutation with the aim
 of identifying potential PD endpoints related to the LRRK2 mutation for future Phase I or II
 clinical trials of LRRK2 inhibitors.

 Approximately 20 subjects with PKD bearing one of the known LRRK2 mutations will be
 investigated. Approximately 20 healthy subjects without the LRRK2 mutation who are matched
 with PKD patients will also be evaluated.

 Healthy subjects are not expected to be taking medications for PKD. Subjects with PKD may
 continue their medications for PKD treatment throughout the study, Testing will take place
 within 30 days of screening, depending on the subject's availability.
Any Subject:

 Inclusion Criteria:

 -  Male or female, age: >18 years.

 -  Capable of giving written informed consent, which includes compliance with the
 requirements and restrictions listed in the consent form.

 -  Sufficiently fluent in English that they are able to understand written and spoken
 instructions in the opinion of the investigator.

 Exclusion Criteria:

 -  Subjects with previous or current drug or alcohol dependence within 2 years of
 screening.

 -  Subjects who are unable to tolerate study procedures including MRI, or who are unable
 to perform the study procedures (e.g. due to severe musculoskeletal disease).

 -  Use of other prescription or non-prescription centrally acting drugs, including herbal
 (eg khat) and dietary supplements within 7 days or 5 half-lives (whichever is longer)
 prior to the procedures of Day 1, unless in the opinion of the Investigator and GSK
 Medical Monitor the medication will not interfere with the study procedures or
 compromise subject safety.

 -  Pregnant females as determined by positive serum or urine hCG test at screening.

 -  Lactating females.

 -  Unwillingness or inability to follow the procedures outlined in the protocol.

 -  Subject is mentally or legally incapacitated.

 -  Subject meets any of the MRI exclusion criteria.

 -  Subject is left-handed.

 PKD Patients:

 Inclusion Criteria:

 -  Diagnosis of Parkinson's disease according to the following criteria derived from the
 UKPD Society brain bank diagnostic criteria for PD (Hughes AJ et al., 1992):

 a) Bradykinesia must be present b) At least one of the following: muscular rigidity
 Resting tremor postural instability not caused by primary visual, vestibular,
 cerebellar or proprioceptive dysfunction c) Supportive prospective positive criteria
 for Parkinson's Disease (three of the following required for definite diagnosis):
 Resting tremor unilateral onset progressive disorder in first 5 years following onset,
 persistent asymmetry affecting side on which symptoms first appeared excellent
 response (70-100%) to levodopa in the clinical judgement of the investigator, based on
 the medical notes or during standard care d) None of the following clinical features
 which suggest a diagnosis other than Parkinson's disease: History of repeated strokes
 with stepwise symptom progression History of repeated head injury History of definite
 encephalitis Neuroleptic treatment at symptom onset Sustained remission Strictly
 unilateral features after 3 years Supranuclear gaze palsy Cerebellar signs In first
 five years following onset, early severe autonomic involvement such as orthostatic
 hypotension, impotence and bladder dysfunction Early (within 2 years on symptom onset)
 severe dementia with disturbed memory, language, praxis Babinski sign CT/MRI scan
 evidence of tumour or hydrocephalus Negative response to 1000mg of levodopa daily in
 divided doses.

 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure

 -  Parkinson's disease in Hoehn & Yahr criteria Stages I-III.

 -  Confirmed ascertainment as having the G2019S mutation in the LRRK2 gene.

 Exclusion Criteria:

 -  Subjects with clinically significant condition(s) other than Parkinson's disease
 which, in the opinion of the investigator, would render the subject unsuitable for the
 study (e.g. psychiatric, haematological, renal, hepatic, endocrinology, neurological
 [other than Parkinson's disease], cardiovascular, or active malignancy [other than
 benign skin malignancies]).

 -  Subjects with prior or current major psychosis (e.g. schizophrenia or psychotic
 depression) as assessed by the MINI neuropsychiatric interview.

 -  Subjects with severe clinical dementia as measured by UPDRS.

 -  Patients who are on centrally acting anti-cholinergic medication that is likely to
 impair cognitive function.

 -  Patients with positive drug screen results may still be included at the discretion of
 the investigator following a discussion of the result with the subject, and following
 a discussion with the sponsor.

 Healthy Subjects (Controls):

 Inclusion Criteria:

 -  Matched to patients with LRRK2 mutation for age, gender, premorbid reading IQ,
 handedness and smoking status (number of cigarettes smoked per day (0-10, 11-20, 21-30
 or 30+)).

 -  None of the clinical symptoms or signs of Parkinson's disease listed in section
 5.2.2.1.

 -  No family history of more than one first-degree relative with Parkinson's disease to
 suggest that the subject may be a carrier of one of the genetic mutations of
 Parkinson's disease.

 -  Confirmed ascertainment as not having LRRK2 mutation.

 -  Subject is not a genetically-related family member of a subject with LRRK2 mutation
 recruited into this study as per criteria above.

 -  Subject is healthy as determined by a responsible and experienced physician, based on
 a medical evaluation including medical history, physical examination, laboratory tests
 and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters
 outside the reference range for the population being studied may be included only if
 the Investigator and the GSK Medical Monitor agree that the finding is unlikely to
 introduce additional risk factors and will not interfere with the study procedures.

 -  No current or past history of Axis I psychiatric disorders as determined by MINI
 interview.

 Exclusion Criteria:

 -  A positive pre-study drug/alcohol screen.

 -  Currently taking any prescription medication, in particular medication with a central
 mechanism of action, unless in the opinion of the Investigator and GSK Medical Monitor
 the medication will not interfere with the study procedures or compromise subject
 safety.