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Study Description

There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis and monitoring disease progression. In this study we evaluated cerebrospinal fluid (CSF) proteins, which are known to be critically involved in PD or identified in our preliminary profiling studies, aptamers, and RNAs as potential PD biomarkers. Access to subjects for this study was via the Pacific Northwest Udall Center (PANUC) and the Alzheimer's Disease Research Center (ADRC) at the University of Washington and Oregon Health and Sciences University (OHSU). Using CSF samples from 30 well-characterized patients with PD and 30 age-, sex-matched healthy controls, we prepared RNA seq libraries and performed deep sequencing of all RNA species, including small and long RNA, mRNAs, noncoding RNAs and differentially spliced transcripts. We then tried several methods for RNAseq data analysis to optimize our analysis pipeline. We identified a total of 3381 transcripts corresponding to 182 long intergenic RNAs (LincRNAs), 11 microRNAs (miRNAs), 2861 protein-coding transcripts, 200 pseudogenes and 127 antisense RNAs; some of them were differentially expressed between PD and control groups. Selected differentially expressed RNAs have been validated in the same set of CSF samples using real-time PCR (RT-PCR). Further validations in independent, larger cohorts of samples are still ongoing. Our results obtained so far suggested that CSF proteins and RNAs could be used as good indexes for PD diagnosis and disease severity/progression. This study is a part of the NIDDS-funded Parkinson's Disease Biomarkers Program (PDBP).

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Study Inclusion/Exclusion Criteria

Parkinson Disease (PD): All patients meet UK PD Society Brain Bank clinical diagnostic criteria for PD (Gibb et al., 1988) except that having "more than one affected relative" is not considered an exclusion criterion. In order to exclude dementia disorders other than PD with dementia (PD-D), a multi-tiered strategy was used: First, subjects with dementia with Lewy Bodies (DLB) have been excluded based on the diagnostic definition; in order to be diagnosed with PD or PD-D, subjects must present with motor symptoms AT LEAST ONE YEAR prior to the onset of dementia. This criterion excludes those with DLB, in which dementia is present at diagnosis. To exclude subjects with Alzheimer disease (AD)-like pathology, we test the cerebrospinal fluid (CSF) samples collected for all subjects for Aß and tau proteins, levels of which are sensitive biomarkers for AD. Subjects whose levels do not meet the cutoffs determined by our lab and others (Montine et al., 2010; Li et al., 2007; Fagan et al., 2007) are excluded. To limit inclusion of subjects with vascular dementia, we have excluded from our cohort patients with history of known stroke or other vascular diseases. Additionally, we determine Hachinski scores of all subjects, and exclude subjects based on established cutoffs (Moroney et al., 1997); the score may also be included as a covariate in the analysis to limit influence of vascular symptoms.

Controls: Control subjects are either spouses of patients in the PD or AD cohorts or community volunteers recruited from several sources (e.g., Veterans Service Organizations, the VA Voluntary Service Program, and local senior centers). This has allowed us to generate a control cohort that is well matched with our PD/AD cohorts in terms of demographic characteristics including age, sex, and education. All control volunteers undergo motor and cognitive evaluation by a trained clinician. They have no signs or symptoms suggesting cognitive impairment or neurological disease. Subjects with Montreal Cognitive Assessment (MoCA) scores less than 26 are excluded. Subjects with motor Unified Parkinson Disease Rating Scale (UPDRS) scores greater than 5 will be referred to a movement disorder specialist for detailed evaluation, and excluded if there are further concerns. Finally, it should be emphasized that although pathological confirmation has not been obtained in most subjects, all of them have been followed for 12 months or longer (median of 3 years) without demonstrating any symptoms or signs of neurological disorders, including mild cognitive impairment. It should also be noted that we have used these controls for many of our previous publications cited in the proposal, i.e., rich clinical data is available for this well-characterized cohort.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
RNA Sequencing Illumina HiSeq 2000 N/A N/A
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Diseases/Traits Related to Study (MESH terms)
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