Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program.
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ABSTRACT:
SUBMITTER: Gwinn K
PROVIDER: S-EPMC5619098 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundNeuroprotection for Parkinson's disease (PD) remains elusive. Biomarkers hold the promise of removing roadblocks to therapy development. The National Institute of Neurological Disorders and Stroke has therefore established the Parkinson's Disease Biomarkers Program to promote discovery of PD biomarkers for use in phase II and III clinical trials.MethodsUsing a novel consortium design, the Parkinson's Disease Biomarker Program is focused on the development of clinical and laboratory-based biomarkers for PD diagnosis, progression, and prognosis. Standardized operating procedures and pooled reference samples were created to allow cross-project comparisons and assessment of batch effects. A web-based Data Management Resource facilitates rapid sharing of data and biosamples across the research community for additional biomarker projects.ResultsEleven consortium projects are ongoing, seven of which recruit participants and obtain biosamples. As of October 2014, 1,082 participants have enrolled (620 PD, 101 with other causes of parkinsonism, 23 essential tremor, and 338 controls), 1,040 of whom have at least one biosample. Six thousand eight hundred ninety-eight total biosamples are available from baseline, 6-, 12-, and 18-month visits: 1,006 DNA, 1,661 RNA, 1,419 whole blood, 1,382 plasma, 1,200 serum, and 230 cerebrospinal fluid (CSF). Quality control analysis of plasma, serum, and CSF samples indicates that almost all samples are high quality (24 of 2,812 samples exceed acceptable hemoglobin levels).ConclusionsBy making samples and data widely available, using stringent operating procedures based on existing standards, hypothesis testing for biomarker discovery, and providing a resource that complements existing programs, the Parkinson's Disease Biomarker Program will accelerate the pace of PD biomarker research. © 2015 International Parkinson and Movement Disorder Society.
| S-EPMC4824671 | biostudies-literature
Project description:There is a high misdiagnosis rate between Parkinson's disease (PD) and atypical parkinsonian disorders (APD), such as progressive supranuclear palsy (PSP), the second most common parkinsonian syndrome. In our earlier studies, we identified and replicated RNA blood biomarkers in several independent cohorts, however, replication in a cohort that includes PSP patients has not yet been performed. To this end, we evaluated the diagnostic potential of nine previously identified RNA biomarkers using quantitative PCR assays in 138 blood samples at baseline from PD, PSP and healthy controls (HCs) nested in the PD Biomarkers Program. Linear discriminant analysis showed that COPZ1 and PTPN1 distinguished PD from PSP patients with 62.5% accuracy. Five biomarkers, PTPN1, COPZ1, FAXDC2, SLC14A1s and NAMPT were useful for distinguishing PSP from controls with 69% accuracy. Several biomarkers correlated with clinical features in PD patients. SLC14A1-s correlated with Unified Parkinson's Disease Rating Scale total and part III scores. In addition, COPZ1, PTPN1 and MLST8, correlated with Montreal Cognitive Assessment (MoCA). Interestingly, COPZ1, EFTUD2 and PTPN1 were downregulated in cognitively impaired (CI) compared to normal subjects. Linear discriminant analysis showed that age, PTPN1, COPZ1, FAXDC2, EFTUD2 and MLST8 distinguished CI from normal subjects with 65.9% accuracy. These results suggest that COPZ1 and PTPN1 are useful for distinguishing PD from PSP patients. In addition, the combination of PTPN1, COPZ1, FAXDC2, EFTUD2 and MLST8 is a useful signature for cognitive impairment. Evaluation of these biomarkers in a larger study will be a key to advancing these biomarkers into the clinic.
| S-EPMC5986959 | biostudies-literature
Project description:Background/objectiveTo synchronize data collection, the National Institute of Neurological Disorders and Stroke (NINDS) recommended Common Data Elements (CDEs) for use in Parkinson's disease (PD) research. This study delineated the progression patterns of these CDEs in a cohort of PD patients.MethodsOne hundred-twenty-five PD patients participated in the PD Biomarker Program (PDBP) at Penn State. CDEs, including MDS-Unified PD Rating Scale (UPDRS)-total, questionnaire-based non-motor (-I) and motor (-II), and rater-based motor (-III) subscales; Montreal Cognitive Assessment (MoCA); Hamilton Depression Rating Scale (HDRS); University of Pennsylvania Smell Identification Test (UPSIT); and PD Questionnaire (PDQ-39) were obtained at baseline and three annual follow-ups. Annual change was delineated for PD or subgroups [early = PDE, disease duration (DD) <1 y; middle = PDM, DD = 1-5 y; and late = PDL, DD > 5 y] using mixed effects model analyses.ResultsUPDRS-total, -II, and PDQ-39 scores increased significantly, and UPSIT decreased, whereas UPDRS-I, -III, MoCA, and HDRS did not change, over 36 months in the overall PD cohort. In the PDE subgroup, UPDRS-II increased and UPSIT decreased significantly, whereas MoCA and UPSIT decreased significantly in the PDM subgroup. In the PDL subgroup, UPDRS-II and PDQ-39 increased significantly. Other metrics within each individual subgroup did not change. Sensitivity analyses using subjects with complete data confirmed these findings.ConclusionAmong CDEs, UPDRS-total, -II, PDQ-39, and UPSIT all are sensitive metrics to track PD progression. Subgroup analyses revealed that these CDEs have distinct stage-dependent sensitivities, with UPSIT for DD < 5 y, PDQ-39 for DD > 5 y, UPDRS-II for early (DD < 1) or later stages (DD > 5).
| S-EPMC8177750 | biostudies-literature
Project description:Parkinson's disease (PD) is one of the common progressive neurodegenerative disorders with several motor and non-motor symptoms. Most of the motor symptoms may appear at a late stage where most of the dopaminergic neurons have been already damaged. In order to provide better clinical intervention and treatment at the onset of disease, it is imperative to find accurate biomarkers for early diagnosis, including prodromal diagnosis and preclinical diagnosis. At the same time, these reliable biomarkers can also be utilized to monitor the progress of the disease. In this review article, we will discuss recent advances in the development of PD biomarkers from different aspects, including clinical, biochemical, neuroimaging and genetic aspects. Although various biomarkers for PD have been developed so far, their specificity and sensitivity are not ideal when applied individually. So, the combination of multimodal biomarkers will greatly improve the diagnostic accuracy and facilitate the implementation of personalized medicine.
| S-EPMC6193101 | biostudies-other
Project description:There is a pressing need for biomarkers to diagnose Parkinson's disease (PD), assess disease severity, and prognosticate course. Various types of biologic specimens are potential candidates for identifying biomarkers--defined here as surrogate indicators of physiological or pathophysiological states--but blood has the advantage of being minimally invasive to obtain. There are, however, several challenges to identifying biomarkers in blood. Several candidate biomarkers identified in other diseases or in other types of biological fluids are being pursued as blood-based biomarkers in PD. In addition, unbiased discovery is underway using techniques including metabolomics, proteomics, and gene expression profiling. In this review, we summarize these techniques and discuss the challenges and successes of blood-based biomarker discovery in PD. Blood-based biomarkers that are discussed include ?-synuclein, DJ-1, uric acid, epidermal growth factor, apolipoprotein-A1, and peripheral inflammatory markers.
| S-EPMC4070332 | biostudies-literature
Project description:Parkinson's disease (PD) is one of the most common neurodegenerative movement disorder characterized by preferential loss of dopaminergic neurons of the substantia nigra pars compacta and the presence of Lewy bodies containing α-synuclein. Although the cause of PD remains elusive, remarkable advances have been made in understanding the possible causative mechanisms of PD pathogenesis. An explosion of discoveries during the past two decades has led to the identification of several autosomal dominant and recessive genes that cause familial forms of PD. The investigations of these familial PD gene products have shed considerable insights into the molecular pathogenesis of the more common sporadic PD. A growing body of evidence suggests that the etiology of PD is multifactorial and involves a complex interplay between genetic and environmental factors. Substantial evidence from human tissues, genetic and toxin-induced animal and cellular models indicates that mitochondrial dysfunction plays a central role in the pathophysiology of PD. Deficits in mitochondrial functions due to bioenergetics defects, alterations in the mitochondrial DNA, generation of reactive oxygen species, aberrant calcium homeostasis, and anomalies in mitochondrial dynamics and quality control are implicated in the underlying mechanisms of neuronal cell death in PD. In this review, we discuss how familial PD-linked genes and environmental factors interface the pathways regulating mitochondrial functions and thereby potentially converge both familial and sporadic PD at the level of mitochondrial integrity. We also provide an overview of the status of therapeutic strategies targeting mitochondrial dysfunction in PD. Unraveling potential pathways that influence mitochondrial homeostasis in PD may hold the key to therapeutic intervention for this debilitating neurodegenerative movement disorder.
| S-EPMC6027640 | biostudies-literature
Project description:Human serum samples from early-stage Parkinson's disease and non-diseased controls were probed onto human protein microarrays in order to identify differentially expressed autoantibody biomarkers that could be used as diagnostic indicators. Other neurodegenerative and non-neurodegenerative diseases were also used to help measure the specificity of the selected biomarkers.
2015-09-30 | GSE62283 | GEO
Project description:Many therapeutic strategies aimed at relieving symptoms of Parkinson's disease (PD) are currently used for treatment of this disease. With a hallmark of progressive degeneration of dopaminergic neurons, the absence of properly operational dopaminergic circuitry becomes a therapeutic target. Following diagnosis, dopamine replacement can be given in the form of L-DOPA (L-3,4-dihydroxyphenylalanine). Even though it is recognized as standard of care, this treatment strategy does not prevent the affected neurons from degenerating. Therefore, studies have been performed using gene therapy (GT) to make dopamine (DA) available from within the brain using an artificial DA circuitry. One approach is to administer a GT aimed at delivering the key enzymes for DA synthesis using a lentiviral vector system (Palfi et al., 2014). A similar approach has been investigated with adeno-associated virus (AAV) expressing aromatic L-amino acid decarboxylase, tyrosine hydroxylase, and GTP-cyclohydrolase I (Bankiewicz et al., 2000), which are downregulated in PD. Another GT approach to mitigate symptoms of PD used AAV-mediated delivery of GAD-67 (glutamate decarboxylase) (Kaplitt et al., 2007). This approach mimics the inhibitory effect of DA neurons on their targets, in reducing motor abnormalities. Finally, disease modifying strategies have been undertaken using neurotrophic factors such as neurturin (NTN) (Marks et al., 2008; Bartus et al., 2013a) or are ongoing with the closely related Glial cell line-derived neurotrophic factor. Those approaches are aiming at rescuing the degenerating neurons. All of the above mentioned strategies have their own merits, but also some disadvantages. So far, none of clinical applied GT studies has resulted in significant clinical benefit, although some clinical studies are ongoing and results are expected over the next few years.
| S-EPMC5220060 | biostudies-literature
Project description:BackgroundParkinson's disease (PD) is a disease of ⍺-synuclein aggregation-mediated dopaminergic neuronal loss in the substantia nigra pars compacta, which leads to motor and non-motor symptoms. Through the last two decades of research, there has been growing consensus that inflammation-mediated oxidative stress, mitochondrial dysfunction, and cytokine-induced toxicity are mainly involved in neuronal damage and loss associated with PD. However, it remains unclear how these mechanisms relate to sporadic PD, a more common form of PD. Both enteric and central nervous systems have been implicated in the pathogenesis of sporadic PD, thus highlighting the crosstalk between the gut and brain.Aimof Review: In this review, we summarize how alterations in the gut microbiome can affect PD pathogenesis. We highlight various mechanisms increasing/decreasing the risk of PD development. Based on the previous supporting evidence, we suggest how early interventions could protect against PD development and how controlling specific factors, including our diet, could modify our perspective on disease mechanisms and therapeutics. We explain the strong relationship between the gut microbiota and the brain in PD subjects, by delineating the multiple mechanisms involved inneuroinflammation and oxidative stress. We conclude that the neurodetrimental effects of western diet (WD) and the neuroprotective effects of Mediterranean diets should be further exploredin humans through clinical trials. Key Scientific Concepts of Review: Alterations in the gut microbiome and associated metabolites may contribute to pathogenesis in PD. In some studies, probiotics have been shown to exert anti-oxidative effects in PD via improved mitochondrial dynamics and homeostasis, thus reducing PD-related consequences. However, there is a significant unmet need for randomized clinical trials to investigate the effectiveness of microbial products, probiotic-based supplementation, and dietary intervention in reversing gut microbial dysbiosis in PD.
| S-EPMC10403695 | biostudies-literature