Peripheral Biomarkers of Parkinson's Disease Progression and Pioglitazone Effects.
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ABSTRACT:
SUBMITTER: Simon DK
PROVIDER: S-EPMC5061495 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
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Peripheral Biomarkers of Parkinson's Disease Progression and Pioglitazone Effects.
Simon David K DK Simuni Tanya T Elm Jordan J Clark-Matott Joanne J Graebner Allison K AK Baker Liana L Dunlop Susan R SR Emborg Marina M Kamp Cornelia C Morgan John C JC Ross G Webster GW Sharma Saloni S Ravina Bernard B
Journal of Parkinson's disease 20150101 4
Pioglitazone, an oral hypoglycemic agent, recently failed to show promise as a disease-modifying agent in a 44-week phase 2 placebo-controlled study in 210 Parkinson's disease (PD) subjects. We analyzed peripheral biomarkers, including leukocyte PGC-1α and target gene expression, plasma interleukin 6 (IL-6) as a marker of inflammation, and urine 8-hydroxydeoxyguanosine (8OHdG) as a marker of oxidative DNA damage. Baseline or changes from baseline in biomarker levels were not associated with the ...[more]
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Project description:BackgroundUsing surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true disease-modifying effects. A systematic review was undertaken to determine what biomarkers for disease progression in Parkinson's disease (PD) exist.MethodsMEDLINE and EMBASE (1950-2010) were searched using five search strategies. Abstracts were assessed to identify papers meriting review in full. Studies of participants with idiopathic PD diagnosed by formal criteria or clearly described clinical means were included. We made no restriction on age, disease duration, drug treatment, or study design. We included studies which attempted to draw associations between any tests used to investigate disease progression and any clinical measures of disease progression. The electronic search was validated by hand-searching the two journals from which most included articles came.Results183 studies were included: 163 (89%) cross-sectional, 20 (11%) longitudinal. The electronic search strategy had a sensitivity of 71.4% (95% CI 51.1-86.0) and a specificity of 97.1% (95% CI 96.5-97.7). In longitudinal studies median follow-up was 2.0 years (IQR 1.1-3.5). Included studies were generally poor quality--cross-sectional with small numbers of participants, applying excessive inclusion/exclusion criteria, with flawed methodologies and simplistic statistical analyses.ConclusionWe found insufficient evidence to recommend the use of any biomarker for disease progression in PD clinical trials, which may simply reflect the poor quality of research in this area. We therefore present a provisional 'roadmap' for conducting future disease progression biomarker studies, and recommend new quality criteria by which future studies may be judged.
| S-EPMC3637496 | biostudies-literature
Project description:BackgroundThe pathogenesis of PD has not been fully elucidated, but recent studies have shown that the adaptive immune system may play a role in the pathology of PD. However, there is a lack of longitudinal studies exploring the relationship between peripheral adaptive immune indicators and the rate of disease progression in PD.MethodsWe included early PD patients with disease duration < 3 years and assessed the severity of clinical symptoms and peripheral adaptive immune system indicators (CD3+, CD4+, CD8+ T lymphocyte subsets, CD4+:CD8+ ratio, IgG, IgM, IgA, C3, C4) at baseline. Clinical symptoms were followed up every year. We used the Unified Parkinson's Disease Rating Scale (UPDRS) to assess the disease severity and the Montreal Cognitive Assessment (MoCA) to assess global cognitive function.ResultA total of 152 PD patients were eventually included. The linear mixed model showed no significant association between baseline peripheral blood adaptive immune indicators and baseline MoCA scores or UPDRS part III scores. A higher baseline CD3+ lymphocyte percentage was associated with a slower rate of decline in MoCA scores. Baseline immune indicators were not associated with the rate of change of the UPDRS part III scores.ConclusionThe subset of peripheral T lymphocytes was related to the rate of cognitive decline in early PD patients, suggesting that the peripheral adaptive immune system may be involved in the process of cognitive decline in early PD.
| S-EPMC10243250 | biostudies-literature
Project description:The development of biomarkers to predict the progression of Parkinson's disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson's Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (?-syn), amyloid-beta1-42 (A?1-42), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF ?-syn, t-tau and p-tau levels, but not A?1-42, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of ?-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest A?1-42, or highest t-tau/A?1-42 and t-tau/?-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower ?-syn was significantly associated with worse cognitive test performance. APOE ?4 genotype was associated with lower levels of A?1-42, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance.
| S-EPMC5031365 | biostudies-literature
Project description:Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) cohorts to foster identification of the earliest markers of disease onset.
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Project description:BackgroundOur understanding of the etiology, pathophysiology, phenotypic diversity, and progression of Parkinson's disease has stagnated. Consequently, patients do not receive the best care, leading to unnecessary disability, and to mounting costs for society. The Personalized Parkinson Project (PPP) proposes an unbiased approach to biomarker development with multiple biomarkers measured longitudinally. Our main aims are: (a) to perform a set of hypothesis-driven analyses on the comprehensive dataset, correlating established and novel biomarkers to the rate of disease progression and to treatment response; and (b) to create a widely accessible dataset for discovery of novel biomarkers and new targets for therapeutic interventions in Parkinson's disease.Methods/designThis is a prospective, longitudinal, single-center cohort study. The cohort will comprise 650 persons with Parkinson's disease. The inclusion criteria are purposely broad: age ≥ 18 years; and disease duration ≤5 years. Participants are followed for 2 years, with three annual assessments at the study center. Outcomes include a clinical assessment (including motor and neuro-psychological tests), collection of biospecimens (stool, whole blood, and cerebrospinal fluid), magnetic resonance imaging (both structural and functional), and ECG recordings (both 12-lead and Holter). Additionally, collection of physiological and environmental data in daily life over 2 years will be enabled through the Verily Study Watch. All data are stored with polymorphic encryptions and pseudonyms, to guarantee the participants' privacy on the one hand, and to enable data sharing on the other. The data and biospecimens will become available for scientists to address Parkinson's disease-related research questions.DiscussionThe PPP has several distinguishing elements: all assessments are done in a single center; inclusion of "real life" subjects; deep and repeated multi-dimensional phenotyping; and continuous monitoring with a wearable device for 2 years. Also, the PPP is powered by privacy and security by design, allowing for data sharing with scientists worldwide respecting participants' privacy. The data are expected to open the way for important new insights, including identification of biomarkers to predict differences in prognosis and treatment response between patients. Our long-term aim is to improve existing treatments, develop new therapeutic approaches, and offer Parkinson's disease patients a more personalized disease management approach.Trial registrationClinical Trials NCT03364894 . Registered December 6, 2017 (retrospectively registered).
| S-EPMC6636112 | biostudies-literature
Project description:BackgroundInflammation contributes substantially to the pathogenesis of Parkinson's disease (PD). Plasma extracellular vesicle (EV)-derived cytokines are emerging biomarkers of inflammation. We conducted a longitudinal study of the plasma EV-derived cytokine profiles of people with PD (PwP).MethodsA total of 101 people with mild to moderate PD and 45 healthy controls (HCs) were recruited, and they completed motor assessments (Unified Parkinson Disease Rating Scale [UPDRS]) and cognitive tests at baseline and 1-year follow-up. We isolated the participants' plasma EVs and analyzed their levels of cytokines, including interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β.ResultsWe noted no significant changes in the plasma EV-derived cytokine profiles of the PwPs and HCs between baseline and the 1-year follow-up. Among the PwP, changes in plasma EV-derived IL-1β, TNF-α and IL-6 levels were significantly associated with changes in the severity of postural instability and gait disturbance (PIGD) and cognition. Baseline plasma EV-derived IL-1β, TNF-α, IL-6, and IL-10 levels were significantly associated with the severity of PIGD and cognitive symptoms at follow-up, and PwP with elevated IL-1β and IL-6 levels exhibited significant progression of PIGD over the study period.ConclusionThese results suggested the role of inflammation in PD progression. In addition, baseline levels of plasma EV-derived proinflammatory cytokines can be used to predict the progression of PIGD, the most severe motor symptom of PD. Additional studies with longer follow-up periods are necessary, and plasma EV-derived cytokines may serve as effective biomarkers of PD progression.
| S-EPMC10042681 | biostudies-literature
Project description:This research investigates the peripheral mechanisms of acupuncture in treating Parkinson's disease (PD), a progressive neurodegenerative disorder marked by motor impairments. While the central mechanisms of acupuncture have been extensively studied, our focus lies in the peripheral mechanisms at the acupoints, the sites of acupuncture signal initiation. Employing a PD model, we analyzed the local responses to acupuncture stimulation at these points. Our key finding was a significant elevation in both the number and activity of mast cells (MCs) in the peripheral tissues following acupuncture. Intriguingly, pre-treatment with an MC stabilizer diminished the acupuncture's therapeutic effects on PD symptoms. Similarly, local anesthesia with lidocaine at the acupoints attenuated the symptom improvement typically observed with acupuncture. Meanwhile, the augmentation of MC activity induced by acupuncture was significantly impeded by cromolyn, an MC stabilizer, but remained unaffected by lidocaine. This finding suggests that MC activity is a more upstream regulator of acupuncture effects compared to nerve conduction. This study provides groundbreaking insights into the initiation and transmission of acupuncture signals, highlighting the significant role of peripheral MC modulation in PD treatment.
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Project description:We investigate the gene expression signature of peripheral blood monocytes during the progression of Alzheimer's disease. We profiled gene expression in the mouse cortex using data obtained from RNA-seq of three individuals at 6-months old and three individuals at 24-months old.
2022-11-03 | GSE216918 | GEO
Project description:ObjectivesMany researchers have expected pioglitazone to serve as an effective neuroprotective agent against Parkinson's disease (PD). Therefore, we conducted this cohort study to investigate the association between pioglitazone use and PD by using a large Asian population-based dataset in Taiwan.DesignRetrospective cohort study.SettingTaiwan.Participants7906 patients with diabetes who had received pioglitazone were defined as the study cohort, and 7906 matched patients with diabetes who had not received pioglitazone were defined as the comparison cohort.Primary and secondary outcome measuresWe tracked each patient individually over a 5-year follow-up period to identify those diagnosed as having PD during this period. We performed Cox proportional hazard regression analyses to evaluate the HRs for PD between the study and comparison cohorts.ResultsThe findings indicated that among the sampled patients, PD occurred in 257 (1.63%): 119 (1.51%) pioglitazone users and 138 (1.75%) non-users. The adjusted HR for PD within the follow-up period was 0.90 (95% CI: 0.68 to 1.18) in the patients who had received pioglitazone compared with the matched patients who had not received pioglitazone. Moreover, this study revealed that pioglitazone use was not associated with PD incidence in men (HR: 1.06, 95% CI: 0.71 to 1.59) or women (HR: 0.84, 95% CI: 0.61 to 1.15).ConclusionsThis study did not find the relationship between pioglitazone use and PD incidence, regardless of sex, among an Asian population of patients with diabetes.
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Project description:The prognosis of neurodegenerative disorders is clinically challenging due to the inexistence of established biomarkers for predicting disease progression. Here, we performed an exploratory cross-sectional, case-control study aimed at determining whether gene expression differences in peripheral blood may be used as a signature of Parkinson's disease (PD) progression, thereby shedding light into potential molecular mechanisms underlying disease development. We compared transcriptional profiles in the blood from 34 PD patients who developed postural instability within ten years with those of 33 patients who did not develop postural instability within this time frame. Our study identified >200 differentially expressed genes between the two groups. The expression of several of the genes identified was previously found deregulated in animal models of PD and in PD patients. Relevant genes were selected for validation by real-time PCR in a subset of patients. The genes validated were linked to nucleic acid metabolism, mitochondria, immune response and intracellular-transport. Interestingly, we also found deregulation of these genes in a dopaminergic cell model of PD, a simple paradigm that can now be used to further dissect the role of these molecular players on dopaminergic cell loss. Altogether, our study provides preliminary evidence that expression changes in specific groups of genes and pathways, detected in peripheral blood samples, may be correlated with differential PD progression. Our exploratory study suggests that peripheral gene expression profiling may prove valuable for assisting in prediction of PD prognosis, and identifies novel culprits possibly involved in dopaminergic cell death. Given the exploratory nature of our study, further investigations using independent, well-characterized cohorts will be essential in order to validate our candidates as predictors of PD prognosis and to definitively confirm the value of gene expression analysis in aiding patient stratification and therapeutic intervention.
| S-EPMC4913914 | biostudies-literature