Biomarker Study of REM sleep Behavior Disorder
|Principal Investigator: DavidShprecher|
|Keywords: Parkinson's Disease , REM Sleep Behavior Disorder , Dream enactment , Neurodegenerative Disease , Dementia with Lewy bodies , RBD||Department: Neurology|
|IRB Number: 00045164||Co Investigator:|
|Specialty: Neurology, Neurology, Neurology, Neurology, Neurology|
|Sub Specialties: Dementia, Movement Disorders, Parkinson's Disease, Sleep Disorders, Neurodegenerative Disorders|
Study Design and Purpose:
For unclear reasons, the rate of Parkinson disease (PD) in Utah is 30% higher than the national average. 1 As rate of Alzheimer disease is actually 10% lower than national average, longevity is not an adequate explanation for this finding. 80% of PD patients will eventually develop dementia. Dementia with Lewy bodies (DLB) and PD dementia, collectively known as Lewy body dementia (LBD), are the second leading cause of age-associated neurodegenerative dementia. 2,3 With a growing geriatric population, there is an urgent need to develop early detection and prevention strategies for LBD. This protocol is designed to clarify prevalence of risk factors for LBD, determine which risk factors and biomarkers are associated with diagnosis of LBD over time, and establish a cohort at-risk for LBD to allow rapid recruitment into future neuroprotection trials.
It has three components:
- Survey study- to obtain a representative sample of the local geriatric population.
- Cohort- enrolling a subset of at-risk and control participants (recruited primarily from the survey.)
- Biorepository- enrolling cohort and affected PD/atypical parkinsonism subjects.
- Determine the proportion of the Utah population aged 50 and over with iRBD and other risk factors (anosmia, constipation, mild cognitive impairment (MCI), psychosis, environmental exposures, family history) for LBD. This will be done using a survey in our geriatrics and primary care clinics.
- Determine relationship between history of sleep walking, as well as putative LBD risk factors, for presence of iRBD.
- Establish a cohort of “at risk” and control participants in a prospective study of LBD risk (with annual cognitive, motor, olfactory, color vision assessments). “At risk” will include those with iRBD, two or more first degree relatives affected, MCI, psychosis, anosmia, impaired color vision, or constipation.
- Measure baseline and annual symptom severity using the Hong Kong RBD self-report, 20 and explore relationship with risk of neurodegenerative disease, in our at-risk cohort.
- Determine how clinical characteristics of our cohort change over time. Baseline and annual assessments will include neurological exam (focused on possible motor symptoms of a parkinsonian disorder), neuropsychological assessment, olfactory and color vision testing.
- Determine rates of neurodegenerative disease in our cohort over time. This will be done using standard clinical criteria for diagnosis of dementing and parkinsonian disorders at each annual follow up exam.
- Determine contribution of baseline clinical characteristics to risk of neurodegenerative disease diagnosis.
- Create a biological sample bank containing “at risk”, control, and related neurodegenerative disease (PD, atypical parkinsonism) subject samples compatible with specific hypothesis generating (gene expression, metabolomic profiling, proteomic) and genetic techniques. Samples will be collected at each annual visit from cohort participants, but only once from subjects enrolled with a diagnosis of manifest parkinsonian disorder.
- Measure saliva alpha synuclein levels in all participants (where feasible), and annually in our cohort study participants. Hypotheses: 1) saliva alpha-synuclein levels will be elevated in subjects with alpha-synucleinopathy (PD, DLB, MSA) relative to controls or other disorders; 2) saliva alpha-synuclein level will correlate with imminent risk of alpha-synucleinopathy in the cohort study.
- Measure metabolomic profile of iRBD, newly diagnosed (untreated) PD, treated PD, diagnosed atypical parkinsonism, and control subjects. This will be done using peripheral blood as the tissue source. Hypotheses: 1) Analysis of metabolomic profiles will show clear differentiation between iRBD and control groups; 2) metabolomic profiles connoting risk of RBD will show overlap with those of manifest early (de novo) PD, treated PD, and or DLB; 3) metabolites related to cellular respiration will be linked to risk of neurodegenerative disease in iRBD subjects.
- Measure gene expression profile of iRBD, newly diagnosed (untreated) PD, treated PD, diagnosed atypical parkinsonism, and control subjects. This will be done using peripheral blood as the tissue source.
Hypotheses: 1) Analysis of gene expression profiles will show clear differentiation between iRBD and control groups; 2) gene expression profiles connoting risk of RBD will show overlap with those of manifest early (de novo) PD, treated PD, and/or DLB.
12. Measure impact of initial Parkinson disease medication therapy on selected biomarkers (metabolomics, gene expression). This will be done by measuring biomarker profiles before, and 6 weeks after, PD subjects starting first antiparkinsonian drug.
Survey Study: All patients aged 50 and over who have a scheduled appointment at a University of Utah Healthcare primary care clinic will be eligible to participate in the survey.
Cohort Study: Individuals can be self referred, referred by their clinician, recruited from our existing IRB approved study "Parkinson's genetic risk study", or recruited from the survey arm of this protocol. All survey respondents giving consent and accurate contact information for future contact, respondents to our study ad, or participants referred directly to the study, will be considered according to the following eligibility criteria:
All survey respondents will be eligible if they are: aged 50 and over, able to consider travel to study center for in-person assessment, (no chronic neurological conditions other than migraine, idiopathic neuropathy, or iRBD) and meet at least one of the following inclusion criteria. One exception is that individuals with definite iRBD (confirmed by a polysomnogram) do not need to be aged 50 or over; those aged 18+ will also be enrolled. This addresses a serious deficiency in prospective iRBD research so far, where no individuals under the age of 50 were enrolled (yet we know from clinical experience that iRBD can be prodromal in patients with onset of PD symptoms even before the age of 40.)
1. Screen positive for definite or probable RBD.
Idiopathic RBD (iRBD) subjects will be enrolled and classified according to degree of diagnostic confidence. Participating iRBD subjects cannot have history within past 6 months of taking medication with known activity in the central nervous system, or any neurodegenerative disease, narcolepsy or other potential secondary cause of RBD. They will be enrolled as “definite iRBD” if they meet the criteria outlined in the International Classification of Sleep Disorders, 2nd Ed. (ICSD) 21 These include presence of REM sleep without atonia on polysomnography as well as sleep related, injurious (or potentially injurious) dream enactment behavior documented by history or during polysomnogram. RBD subjects must not have epileptiform activity during the polysomnogram or an alternative explanation for the sleep disorder. Subjects will be enrolled as “probable iRBD” if they have a positive answer to REM sleep behavior disorder single question screen (RBD1Q), and PI or co-investigator interview reveals no alternative medical cause for sleep behavior/potential secondary cause for RBD. This instrument has been shown to have 93.8% sensitivity and 87.2% specificity for identification of patients who (upon completion of gold-standard polysomnography) will meet ICSD criteria for definite RBD after polysomnography.22
2. Have strong family history of PD (at least 2 first degree relatives affected).
3. Have both constipation and anosmia. Constipation will be defined by an average of less than one bowel movement daily. Anosmia will be defined by severe microsmia or anosmia using the brief smell identification test (B-SIT).
Controls will be identified from the survey study, and from a list of healthy individuals willing to be contacted about participating in neurology research. Patients of the movement disorder clinic, and each subject participating in this clinical study, will be asked to refer one non-genetically related individual to participate as a control. Controls must be of same gender, and within 2 years of age of enrolled subjects. They must also lack history of any chronic neurological disease, other than migraine or peripheral neuropathy. Referring patients, subjects, or their family members will be asked to refer potential controls. No contact will be extended until a direct call/email/letter is received from the potential control subject first, or unless the potential control has otherwise given direct consent, verbal or otherwise, to be contacted about this type of research.
Matching of iRBD subjects under the age of 50 will be done by identifying controls from spouses, in-laws or friends of participants.
All cohort participants will be asked to participate. In addition, all consenting individuals with PD or atypical parkinsonism from the Movement Disorder clinic (or those referred for the biorepository study) will participate. PD and each of the atypical disorders will be diagnosed according to established consensus criteria.
De novo (clinically possible) Parkinson disease will be defined as follows. De novo subjects must have been diagnosed within the past year and meet UK Brain Bank Criteria for diagnosis of idiopathic Parkinson disease.23 They must not have been exposed to any dopamine receptor blocking/depleting drugs in the past year, not have been exposed to any antiparkinsonian drugs, high dose (300+ mg/day) coenzyme Q10, or creatine monohydrate. Patient must meet previously published criteria for clinically possible early PD,24 which have also been utilized in the previously cited metabolomic studies of PD. These include presence of 2 out of 3 cardinal motor features (tremor, rigidity, bradykinesia), less than 5 years’ duration of motor symptoms, and lack of ‘red flags’ to suggest an alternative cause of parkinsonism.
Patients identified from chart review of existing Movement Disorder Clinic patients, and who meet diagnostic criteria for disorders classified as atypical parkinsonism, i.e. dementia with Lewy bodies, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), vascular parkinsonism (VP) or corticobasal degeneration (CBD), will also be asked to enroll as participants, but will not be matched to iRBD patients. They will, however be matched with control subjects for comparison of metabolomic and gene expression profiles. Clinically probable DLB will be diagnosed according to established consensus criteria.25 In summary, patients must have dementia (progressive cognitive decline leading to impairment of social or vocational activities), 2 out of 3 core features (cognitive fluctuations, recurrent visual hallucinations, parkinsonism), or 1 core feature plus one suggestive feature (RBD or severe neuroleptic sensitivity.)
In addition to inclusion/exclusion criteria detailed above:
Individuals cannot participate in cohort or biorepository as controls if they have chronic neurological conditions besides migraine or idiopathic neuropathy.
Individuals who are not felt by PI to be able to give informed consent directly cannot participate if they do not have an appropriate individual identified to partcipate on the potential subject's behalf in the informed consent process.