Imaging prodromal Parkinson disease: the Parkinson Associated Risk Syndrome Study.
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ABSTRACT:
SUBMITTER: Jennings D
PROVIDER: S-EPMC4239830 | biostudies-literature | 2014 Nov
REPOSITORIES: biostudies-literature
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Imaging prodromal Parkinson disease: the Parkinson Associated Risk Syndrome Study.
Jennings Danna D Siderowf Andrew A Stern Matthew M Seibyl John J Eberly Shirley S Oakes David D Marek Kenneth K
Neurology 20141008 19
<h4>Objectives</h4>The purpose of this study is to evaluate the relative risk of abnormal dopamine transporter (DAT) imaging for subjects with and without hyposmia and the feasibility of acquiring a large, community-based, 2-tiered biomarker assessment strategy to detect prodromal Parkinson disease (PD).<h4>Methods</h4>In this observational study, individuals without a diagnosis of PD, recruited through 16 movement disorder clinics, underwent tier 1 assessments (olfactory testing, questionnaires ...[more]
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Project description:To test the association between impaired olfaction and other prodromal features of PD in the Parkinson At-Risk Syndrome Study. The onset of olfactory dysfunction in PD typically precedes motor features, suggesting that olfactory testing could be used as a screening test. A combined strategy that uses other prodromal nonmotor features, along with olfactory testing, may be more efficient than hyposmia alone for detecting the risk of PD. Individuals with no neurological diagnosis completed a mail survey, including the 40-item University of Pennsylvania Smell Identification Test, and questions on prodromal features of PD. The frequency of reported nonmotor features was compared across individuals with and without hyposmia. A total of 4,999 subjects completed and returned the survey and smell test. Of these, 669 were at or below the 15th percentile based on age and gender, indicating hyposmia. Hyposmics were significantly more likely to endorse nonmotor features, including anxiety and depression, constipation, and rapid eye movement sleep behavior disorder symptoms, and to report changes in motor function. Twenty-six percent of subjects with combinations of four or more nonmotor features were hyposmic, compared to 12% for those reporting three or fewer nonmotor features (P < 0.0001). Hyposmia is associated with other nonmotor features of PD in undiagnosed individuals. Further assessment of hyposmic subjects using more specific markers for degeneration, such as dopamine transporter imaging, will evaluate whether combining hyposmia and other nonmotor features is useful in assessing the risk of future neurodegeneration.
| S-EPMC6342466 | biostudies-literature
Project description:A prodromal phase of Parkinson's disease (PD) may precede motor manifestations by decades. PD patients' siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had <1% probability of having prodromal PD; 100 between 1 and 10%, 26 siblings between 10 and 80%, one fulfilled the criteria for prodromal PD. According to the current analysis, we cannot confirm the increased risk of PD siblings for prodromal PD. Siblings showed a heterogeneous distribution of prodromal PD markers and probability. Additional parameters, including strong disease markers, should be investigated to verify if these results depend on validity and sensitivity of prodromal PD criteria, or if siblings' risk is not elevated.
| S-EPMC8423761 | biostudies-literature
Project description:ImportanceThe prodromal phase of Parkinson disease (PD) may last for more than 10 years. Recognition of the spectrum and occurrence of risk factors, comorbidities, and prodromal features of PD can increase understanding of the causes and development of the disease and help identify individuals at risk.ObjectiveTo identify the association of a subsequent diagnosis of PD with a range of risk factors and prodromal features, including lifestyle factors, comorbidities, and potential extracerebral manifestations of PD.Design, setting, and participantsThis was a case-control study using insurance claims of outpatient consultations of patients with German statutory health insurance between January 1, 2011, and December 31, 2020. Included were patients with incident diagnosis of PD without a previous diagnosis of parkinsonism or dementia and controls matched 1:2 for age, sex, region, and earliest year of outpatient encounter.ExposuresExposures were selected based on previous systematic reviews, case-control and cohort studies reporting on risk factors, comorbidities, and prodromal features of PD.Main outcomes and measuresPreviously postulated risk factors and prodromal features of PD, using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) coding.ResultsA total of 138 345 patients with incident PD (mean [SD] age, 75.1 [9.8] years; 73 720 male [53.3%]) and 276 690 matched controls (mean [SD] age, 75.1 (9.8) years; 147 440 male [53.3%]) were identified. Study participants were followed up for a mean (SD) of 6.0 (2.0) years. Consistent with previous reports, risk factors and prodromal features associated with PD included traumatic brain injury, odds ratio (OR), 1.62; 95% CI, 1.36-1.92; alcohol misuse, OR, 1.32; 95% CI, 1.21-1.44; hypertension, OR, 1.29; 95% CI, 1.26-1.31; anosmia, OR, 2.16; 95% CI, 1.59-2.93; and parasomnias (including RBD), OR, 1.62; 95% CI, 1.42-1.84. In addition, there were associations with restless legs syndrome (OR, 4.19; 95% CI, 3.91-4.50), sleep apnea (OR, 1.45; 95% CI, 1.37-1.54), epilepsy (OR, 2.26; 95% CI, 2.07-2.46), migraine (OR, 1.21; 95% CI, 1.12-1.29), bipolar disorder (OR, 3.81; 95% CI, 3.11-4.67), and schizophrenia (OR, 4.48; 95% CI, 3.82-5.25). The following diagnoses were also found to be associated with PD: sensory impairments beyond anosmia, such as hearing loss (OR, 1.14; 95% CI, 1.09-1.20) and changes of skin sensation (OR, 1.31; 95% CI, 1.21-1.43). There were also positive associations with skin disorders (eg, seborrheic dermatitis, OR, 1.30; 95% CI, 1.15-1.46; psoriasis, OR, 1.13; 95% CI, 1.05-1.21), gastrointestinal disorders (eg, gastroesophageal reflux, OR, 1.29; 95% CI, 1.25-1.33; gastritis, OR, 1.28; 95% CI, 1.24-1.33), conditions with a potential inflammatory component (eg, seronegative osteoarthritis, OR, 1.21; 95% CI, 1.03-1.43), and diabetes types 1 (OR, 1.32; 95% CI, 1.21-1.43) and 2 (OR, 1.24; 95% CI, 1.20-1.27). Associations even 5 to 10 years before diagnosis included tremor (odds ratio [OR], 4.49; 95% CI, 3.98-5.06), restless legs syndrome (OR, 3.73; 95% CI, 3.39-4.09), bipolar disorder (OR, 3.80; 95% CI, 2.82-5.14), and schizophrenia (OR, 4.00; 95% CI, 3.31-4.85).Conclusions and relevanceResults of this case-control study suggest that the associations found between PD and certain risk factors, comorbidities, and prodromal symptoms in a representative population may reflect possible early extrastriatal and extracerebral pathology of PD. This may be due to shared genetic risk with PD, medication exposure, or direct causation, or represent pathophysiologically relevant factors contributing to the pathogenesis of PD.
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Project description:BACKGROUND:The association of metabolic syndrome (MetS) with the development of Parkinson disease (PD) is currently unclear. We sought to determine whether MetS and its components are associated with the risk of incident PD using large-scale cohort data for the whole South Korean population. METHODS AND FINDINGS:Health checkup data of 17,163,560 individuals aged ≥40 years provided by the National Health Insurance Service (NHIS) of South Korea between January 1, 2009, and December 31, 2012, were included, and participants were followed up until December 31, 2015. The mean follow-up duration was 5.3 years. The hazard ratio (HR) and 95% confidence interval (CI) of PD were estimated using a Cox proportional hazards model adjusted for potential confounders. We identified 44,205 incident PD cases during follow-up. Individuals with MetS (n = 5,848,508) showed an increased risk of PD development compared with individuals without MetS (n = 11,315,052), even after adjusting for potential confounders including age, sex, smoking, alcohol consumption, physical activity, income, body mass index, estimated glomerular filtration rate, and history of stroke (model 3; HR, 95% CI: 1.24, 1.21-1.27). Each MetS component was positively associated with PD risk (HR, 95% CI: 1.13, 1.10-1.16 for abdominal obesity; 1.13, 1.10-1.15 for hypertriglyceridemia; 1.23, 1.20-1.25 for low high-density lipoprotein cholesterol; 1.05, 1.03-1.08 for high blood pressure; 1.21, 1.18-1.23 for hyperglycemia). PD incidence positively correlated with the number of MetS components (log-rank p < 0.001), and we observed a gradual increase in the HR for incident PD with increasing number of components (p < 0.001). A significant interaction between age and MetS on the risk of incident PD was observed (p for interaction < 0.001), and people aged ≥65 years old with MetS showed the highest HR of incident PD of all subgroups compared to those <65 years old without MetS (reference subgroup). Limitations of this study include the possibilities of misdiagnosis of PD and reverse causality. CONCLUSIONS:Our population-based large-scale cohort study suggests that MetS and its components may be risk factors of PD development.
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Project description:ObjectivesThe Parkinson Associated Risk Syndrome Study identified a cohort of healthy adults with hyposmia and dopamine transporter binding reduction to characterize individuals at risk for Parkinson's disease (PD). We describe the cognitive profile of this cohort.MethodsIndividuals older than 50 y without PD were recruited. Two hundred twenty-five completed cognitive testing and were included in the final analysis. A neuropsychological test battery was administered and normative scores created for global cognition, memory, executive function/working memory, processing speed/attention, visuospatial abilities, and language domains. Other non-motor symptoms (constipation, depression, anxiety, and rapid eye movement sleep behavior disorder) were assessed through questionnaires.ResultsIndividuals with both hyposmia and reduced dopamine transporter binding (n = 38) had lower mean scores for global cognition, executive function/working memory, and memory compared with all other participants (n = 187). In separate multivariate logistic regression models, lower global cognition (odds ratio, 1.97, P = 0.004), and specifically executive function/working memory (odds ratio, 1.84, P = 0.004) scores were associated with membership in the hyposmia with dopamine transporter reduction group. Combining hyposmia with relative impairment on specific cognitive domains increased the odds of dopamine transporter binding reduction compared with hyposmia alone, with the greatest increase in odds for hyposmia plus executive function/working memory relative impairment (68% increase in odds from 4.14 to 6.96).ConclusionChanges in global cognitive abilities, and specifically executive function/working memory, are present in individuals at risk for PD. Combining non-motor features, including cognition, improves prediction of dopamine transporter binding reduction.
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Project description:Identifying people with Parkinson disease during the prodromal period, including via algorithms in administrative claims data, is an important research and clinical priority. We sought to improve upon an existing penalized logistic regression model, based on diagnosis and procedure codes, by adding prescription medication data or using machine learning. Using Medicare Part D beneficiaries age 66-90 from a population-based case-control study of incident Parkinson disease, we fit a penalized logistic regression both with and without Part D data. We also built a predictive algorithm using a random forest classifier for comparison. In a combined approach, we introduced the probability of Parkinson disease from the random forest, as a predictor in the penalized regression model. We calculated the receiver operator characteristic area under the curve (AUC) for each model. All models performed well, with AUCs ranging from 0.824 (simplest model) to 0.835 (combined approach). We conclude that medication data and random forests improve Parkinson disease prediction, but are not essential.
| S-EPMC8389479 | biostudies-literature
Project description:There is disagreement in the literature whether olfaction may show specific impairments in Parkinson Disease (PD) and if olfactory tests comprised of selected odors could be more specific for diagnosis. We sought to validate previously proposed subsets of the University of Pennsylvania Smell Identification Test (UPSIT) odors for predicting conversion to PD in an independent, prodromal cohort. Conversion to PD was assessed in 229 participants in the Parkinson At Risk Study who completed baseline olfactory testing with the UPSIT and up to 12 years of clinical and imaging evaluations. No commercially available or proposed subset performed better than the full 40-item UPSIT. The proposed "PD-specific" subsets also did not perform better than expected by chance. We did not find evidence for selective olfactory impairment in Parkinson disease. Shorter odor identification tests, including commercially available 10-12 item tests, may have utility for ease of use and cost, but not for superior predictive value.
| S-EPMC10310835 | biostudies-literature
Project description:Numerically, the most important genetic risk factor for the development of Parkinson disease (PD) is the presence of a glucocerebrosidase gene (GBA) mutation.To evaluate longitudinally and clinically a GBA mutation-positive cohort and the evolution of the prodromal features of PD.Participants in a study of the etiology and prodrome of PD were reevaluated in this clinic-based 2-year follow-up report. Patients with type 1 Gaucher disease (GD) and heterozygous GBA mutation carriers were recruited in 2010 from the Lysosomal Storage Disorder Unit at the Royal Free Hospital, London, England. Thirty patients who previously received a diagnosis of type 1 GD, 28 heterozygous GBA mutation carriers, and 26 genetically unrelated controls were included. Exclusion criteria included a diagnosis of PD or dementia for both the patients with GD and the GBA mutation carriers and any existing neurological disease for the controls.Assessment was performed for clinical markers using standardized scales for hyposmia, rapid eye movement sleep behavior disorder, depression, autonomic dysfunction, cognitive function, and parkinsonian motor signs (using the Unified Parkinson's Disease Rating Scale motor subscale [UPDRS part III]).Over 2 years, depression scores were significantly worse for heterozygous carriers (mean baseline, 0.65; mean follow-up, 2.88; P?=?.01), rapid eye movement sleep behavior disorder scores were significantly worse for patients with GD (mean baseline, 0.93; mean follow-up, 2.93; P?<?.001) and heterozygotes (mean baseline, 0.10; mean follow-up, 2.30; P?<?.001), and UPDRS part III scores were significantly worse for patients with GD (mean baseline, 4.29; mean follow-up, 7.82; P?<?.001) and heterozygotes (mean baseline, 1.97; mean follow-up, 4.50; P?<?.001). For controls, there was a small but significant deterioration in the UPDRS part II (activities of daily living) score (mean baseline, 0.00; mean follow-up, 0.58; P?=?.006). At 2 years, olfactory and cognitive assessment scores were lower in patients with GD and heterozygotes compared with controls, but they did not differ significantly from baseline. When the results from the patients with GD and the heterozygotes were combined, a significant deterioration from baseline was observed, as reflected in the Rapid Eye Movement Sleep Behaviour Disorder Questionnaire (mean baseline, 0.51; mean follow-up, 2.63; P?<?.001), Beck Depression Inventory (mean baseline, 1.72; mean follow-up, 4.44; P?=?.002), and UPDRS part II (mean baseline, 0.88; mean follow-up, 2.01; P?<?.001) and part III scores (mean baseline, 3.09; mean follow-up, 6.10; P?<?.001) (all P?<?.01), and at 2 years, significant differences in University of Pennsylvania Smell Identification Test, Unified Multiple System Atrophy Rating Scale, Mini-Mental State Examination, Montreal Cognitive Assessment, and UPDRS part II and part III scores were observed between patients with GD/heterozygotes and controls (all P?<?.05).This study indicates that, as a group, GBA mutation-positive individuals show a deterioration in clinical markers consistent with the prodrome of PD. Within this group of individual, 10% appear to be evolving at a more rapid rate.
| S-EPMC4326672 | biostudies-literature
Project description:ImportanceDetecting individuals at risk for Parkinson disease (PD) during the prodromal phase could clarify disease mechanisms and allow for treatment earlier in the disease process to possibly slow or prevent the onset of motor PD.ObjectiveTo determine if the combination of smell identification testing followed by dopamine transporter (DAT) imaging can accurately and efficiently identify individuals from the general population at risk for conversion to a clinical diagnosis of PD.Design, setting, and participantsParticipants were identified from the community by olfactory testing assessed longitudinally with DAT imaging 2 and 4 years after baseline and by annual clinical follow-up to determine whether they had clinical evidence to establish a PD diagnosis. Participants were contacted by mail and completed olfactory testing at home. Longitudinal follow-up of clinical measures and DAT imaging occurred at specialty centers. There were 203 hyposmic and 100 normosmic participants. A total of 185 hyposmic and 95 normosmic individuals had at least 1 follow-up visit, and 152 hyposmic participants (82.2%) were either observed for 4 years or converted to PD during follow-up.Main outcomes and measuresPercentage of individuals with hyposmia and a DAT deficit that converted to PD and the change in PD clinical scale scores (Unified Parkinson's Disease Rating Scale) and DAT imaging during 4-year follow-up.ResultsOf 280 total participants, 140 (50.0%) were male, and the mean (SD) age of the cohort was 63 (8.7) years. Among 21 participants with hyposmia and a DAT deficit (65% or less of age-expected lowest putamen binding ratio) at baseline, 14 (67%) converted to PD at 4 years compared with 2 of 22 participants (9%) with a DAT in an indeterminate range (greater than 65%-80%) and 3 of 109 participants (2.8%) with no DAT deficit (greater than 80%) at baseline. Individuals with a baseline DAT deficit experienced a 4-year decline in DAT binding of 20.23% (SD, 15.04%) compared with 3.68% (SD, 18.36%) and 5.45% (SD, 13.58%) for participants with an indeterminate and no DAT deficit, respectively (P = .002). The relative risk of conversion to a diagnosis of PD in hyposmic individuals with a DAT deficit was 17.47 (95% CI, 7.02-43.45) compared with individuals with either indeterminate or no DAT deficit.Conclusions and relevanceThe combination of hyposmia and DAT deficit was highly predictive of conversion to PD within 4 years of clinical follow-up. Individuals with hyposmia and a DAT deficit had a 5% reduction in DAT binding annually, similar to early PD. These results provide a framework for planning disease prevention studies in PD.
| S-EPMC5710321 | biostudies-literature
Project description:ObjectiveThe objective of this study was to identify genetic variants on the X-chromosome associated with Parkinson disease (PD) risk.MethodsWe performed an X-chromosome-wide association study (XWAS) of PD risk by meta-analyzing results from sex-stratified analyses. To avoid spurious associations, we designed a specific harmonization pipeline for the X-chromosome and focused on a European ancestry sample. We included 11,142 cases, 280,164 controls, and 5,379 proxy cases, based on parental history of PD. Additionally, we tested the association of significant variants with (1) PD risk in an independent replication with 1,561 cases and 2,465 controls and (2) putamen volume in 33,360 individuals from the UK Biobank.ResultsIn the discovery meta-analysis, we identified rs7066890 (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 1.06-1.14, p = 2.2 × 10-9 ), intron of GPM6B, and rs28602900 (OR = 1.10, 95% CI = 1.07-1.14, p = 1.6 × 10-8 ) in a high gene density region including RPL10, ATP6A1, FAM50A, and PLXNA3. The rs28602900 association with PD was replicated (OR = 1.16, 95% CI = 1.03-1.30, p = 0.016) and shown to colocalize with a significant expression quantitative locus (eQTL) regulating RPL10 expression in the putamen and other brain tissues in the Genotype-Tissue Expression Project. Additionally, the rs28602900 locus was found to be associated with reduced brain putamen volume. No results reached genome-wide significance in the sex-stratified analyses.InterpretationWe report the first XWAS of PD and identify 2 genome-wide significant loci. The rs28602900 association was replicated in an independent PD dataset and showed concordant effects in its association with putamen volume. Critically, rs26802900 is a significant eQTL of RPL10. These results support a role for ribosomal proteins in PD pathogenesis and show that the X-chromosome contributes to PD genetic risk. ANN NEUROL 2021;90:22-34.
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