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AIM: To investigate motor, non-motor and cognitive progression in early Parkinson's disease (PD) patients with Mild Cognitive Impairment (MCI). METHODS: PD patients were recruited within 1 year of diagnosis and were classified into PD-MCI group and PD with normal cognition (PD-NC) group. H&Y staging scale, MDS-UPDRS part III were used to assess disease severity and motor progression. Non-motor symptom scale (NMSS) was used to evaluate the NMS progression. Cognitive progression was assessed from 5 cognitive domains. Annual progression changes in the longitudinal outcomes were examined via linear mixed model with random intercept effect. False discovery rate (FDR) method was performed to control for multiple testing comparison and q-value was calculated. We set the threshold of q-values as 0.1. RESULT: A total of 205 PD patients, including 107 PD-MCI and 98 PD-NC patients were assessed prospectively over a 5-year period. PD-MCI patients, compared to PD-NC group, had a significantly higher progression rate in H&Y score (0.11 vs. 0.06, p=0.03, q=0.08), MDS-UPDRS motor score (3.11 vs. 1.90 p<0.001, q=0.06) and postural instability gait difficulty (PIGD) score (0.40 vs. 0.20, p=0.02, q=0.07). PD-MCI group also exhibited significantly faster deterioration in NMSS perceptual domain (PD-MCI vs. PD-NC: 0.38 vs. -0.04, p=0.01, q=0.06) and cognitive visuospatial domain (PD-MCI vs. PD-NC: 0.13 vs. -0.06, p=0.048, q=0.09) after adjustment for confounders and multiple comparisons. CONCLUSIONS: PD-MCI patients had faster decline in motor functions, visuo-perceptual and visuospatial performance. These findings provide a more comprehensive prognosis of PD-MCI, which could be helpful for clinician to manage PD-MCI patients.
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Disfunción Cognitiva , Progresión de la Enfermedad , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/psicología , Disfunción Cognitiva/fisiopatología , Masculino , Femenino , Estudios Longitudinales , Anciano , Persona de Mediana Edad , Singapur/epidemiología , Índice de Severidad de la EnfermedadRESUMEN
Background: The detailed trajectory of data-driven subtypes in Parkinson's disease (PD) within Asian cohorts remains undisclosed. Objective: To evaluate the motor, non-motor symptom (NMS) progression among the data-driven PD clusters. Methods: In this 5-year longitudinal study, NMS scale (NMSS), Hospital Anxiety Depression Scale (HADS), and Epworth sleepiness scale (ESS) were carried out annually to monitor NMS progression. H& Y staging scale, MDS-UPDRS part III motor score, and postural instability gait difficulty (PIGD) score were assessed annually to evaluate disease severity and motor progression. Five cognitive standardized scores were used to assess detailed cognitive progression. Linear mixed model was performed to assess the annual progression rates of the longitudinal outcomes. Results: Two hundred and six early PD patients, consisting of 43 patients in cluster A, 98 patients in cluster B and 65 subjects in cluster C. Cluster A (severe subtype) had significantly faster progression slope in NMSS Domain 3 (mood/apathy) score (pâ=â0.01), NMSS Domain 4 (perceptual problems) score (pâ=â0.02), NMSS Domain 7 (urinary) score (pâ=â0.03), and ESS Total Score (pâ=â0.04) than the other two clusters. Cluster A also progressed significantly in PIGD score (pâ=â0.04). For cognitive outcomes, cluster A deteriorated significantly in visuospatial domain (pâ=â0.002), while cluster C (mild subtype) deteriorated significantly in executive domain (pâ=â0.04). Conclusions: The severe cluster had significantly faster progression, particularly in mood and perceptual NMS domains, visuospatial cognitive performances, and postural instability gait scores. Our findings will be helpful for clinicians to stratify and pre-emptively manage PD patients by developing intervention strategies to counter the progression of these domains.
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Progresión de la Enfermedad , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/fisiopatología , Masculino , Femenino , Estudios Longitudinales , Persona de Mediana Edad , Singapur/epidemiología , Anciano , Índice de Severidad de la Enfermedad , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/diagnósticoRESUMEN
INTRODUCTION: The decision to offer deep brain stimulation (DBS) to elderly patients with Parkinson's disease (PD) presents challenges due to higher perceived risks and uncertain long-term benefits. Here, we aimed to compare the outcomes after DBS for elderly versus non-elderly patients with PD. METHODS: We analyzed data from our institutional cohort and retrieved publicly available data through a systematic review. The exposure was age at DBS electrode insertion, which was defined as elderly (≥70 years old) and non-elderly (<70 years old). The outcomes examined were changes in the Movement Disorders Society-Parkinson's Disease Rating Scale (MDS-UPDRS) or UPDRS part III total score, levodopa-equivalent daily dose (LEDD), and adverse events. RESULTS: The included studies and our cohort comprised a total of 527 patients, with 111 (21.1 %) classified as elderly. There was no statistically significant difference in the change in MDS-UPDRS or UPDRS part III total score and generally no statistically significant difference in the change in LEDD between the elderly and non-elderly patients. Elderly patients had a higher incidence of wound infection (elderly 5.4 % vs non-elderly 1.9 %; p = 0.087) and inadequate wound healing (elderly 3.6 % vs non-elderly 1.4 %; p = 0.230), but this difference was not statistically significant. There was no significant difference in the incidence of mortality (elderly 0 % vs non-elderly 0 %; p = 1.000), stroke (elderly 0 % vs non-elderly 0.2 %; p = 1.000), and cognitive decline between the age groups. CONCLUSIONS: Notwithstanding the trend towards a higher risk of wound infection and inadequate wound healing, elderly patients have similar motor outcomes and levels of PD medication reduction as non-elderly patients after DBS for PD. Hence, age should not be used as the sole criterion for determining eligibility for DBS, and the decision to offer DBS to elderly patients should be personalized and made in a multidisciplinary setting, taking into consideration patient- and disease-related factors.
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Estimulación Encefálica Profunda , Enfermedad de Parkinson , Humanos , Estimulación Encefálica Profunda/métodos , Enfermedad de Parkinson/terapia , Anciano , Resultado del Tratamiento , Factores de Edad , Persona de Mediana Edad , Masculino , Femenino , Estudios de Cohortes , Anciano de 80 o más AñosRESUMEN
Background: Caffeine intake reduces risk of Parkinson's disease (PD), but the interaction with genes is unclear. The interaction of caffeine with genetic variants in those at high PD risk has healthcare importance. We investigate interactions of caffeine intake with risk variants found in Asians, and determine PD risk estimates in caffeine-drinkers carrying these variants. Methods: PD patients and controls without neurological disorders were included. Caffeine intake was assessed using a validated evaluation tool. Leucine rich repeat kinase 2 (LRRK2) risk variants were genotyped. Statistical analysis was conducted with logistic regression models. Gene-caffeine interactions were quantified using attributable proportion (AP) due to interaction (positive interaction defined as AP >0). Findings: 5100 subjects were screened and 4488 subjects (1790 PD, 2698 controls) with genetic data of at least one LRRK2 variant were included. Risk-variant-carriers who were non-caffeine-drinkers had increased PD odds compared to wildtype carriers who were caffeine-drinkers for G2385R [OR 8.6 (2.6-28.1) p < 0.001; AP = 0.71], R1628P [OR 4.6 (1.6-12.8) p = 0.004; AP = 0.50] and S1647T [OR 4.0 (2.0-8.1) p < 0.001; AP = 0.55] variants. Interpretation: Caffeine intake interacts with LRRK2 risk variants across three different groups of gene carriers. Asymptomatic risk-variant-carriers who are non-caffeine-drinkers have four to eight times greater PD risk compared to wildtype-caffeine-drinkers. Lifestyle modifications to mitigate PD risk in asymptomatic healthy risk variant carriers have potential roles in our Asian cohort. Funding: This study was supported by the National Medical Research Council (STaR and PD OF LCG 000207 grants) and Duke-NUS Medical School.
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BACKGROUND AND PURPOSE: A genome-wide association study-linked variant (PARK16 rs6679073) modulates the risk of Parkinson's disease (PD). We postulate that there may be differences in clinical characteristics between PARK16 rs6679073 carriers and noncarriers. In a prospective study, we investigate the clinical characteristics between PARK16 rs6679073 A allele carriers and noncarriers over 4 years. METHODS: A total of 204 PD patients, comprising 158 PARK16 rs6679073 A allele carriers and 46 noncarriers, were recruited. All patients underwent motor and nonmotor symptom and cognitive assessments yearly over 4 years. RESULTS: PARK16 rs6679073 carriers were less likely to have mild cognitive impairment (MCI) compared to noncarriers at both baseline (48.1% vs. 67.4%, p = 0.027) and 4-year follow-up (29.3% vs. 58.6%, p = 0.007). CONCLUSIONS: PD PARK16 rs6679073 carriers had significantly lower frequency of MCI in a 4-year follow-up study, suggesting that the variant may have a neuroprotective effect on cognitive functions.
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Disfunción Cognitiva , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Estudio de Asociación del Genoma Completo , Estudios Prospectivos , Estudios de Seguimiento , Disfunción Cognitiva/genética , Disfunción Cognitiva/complicacionesRESUMEN
BACKGROUND AND PURPOSE: A broad list of variables associated with mild cognitive impairment (MCI) in Parkinson disease (PD) have been investigated separately. However, there is as yet no study including all of them to assess variable importance. Shapley variable importance cloud (ShapleyVIC) can robustly assess variable importance while accounting for correlation between variables. Objectives of this study were (i) to prioritize the important variables associated with PD-MCI and (ii) to explore new blood biomarkers related to PD-MCI. METHODS: ShapleyVIC-assisted variable selection was used to identify a subset of variables from 41 variables potentially associated with PD-MCI in a cross-sectional study. Backward selection was used to further identify the variables associated with PD-MCI. Relative risk was used to quantify the association of final associated variables and PD-MCI in the final multivariable log-binomial regression model. RESULTS: Among 41 variables analysed, 22 variables were identified as significantly important variables associated with PD-MCI and eight variables were subsequently selected in the final model, indicating fewer years of education, shorter history of hypertension, higher Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor score, higher levels of triglyceride (TG) and apolipoprotein A1 (ApoA1), and SNCA rs6826785 noncarrier status were associated with increased risk of PD-MCI (p < 0.05). CONCLUSIONS: Our study highlighted the strong association between TG, ApoA1, SNCA rs6826785, and PD-MCI by machine learning approach. Screening and management of high TG and ApoA1 levels might help prevent cognitive impairment in early PD patients. SNCA rs6826785 could be a novel therapeutic target for PD-MCI. ShapleyVIC-assisted variable selection is a novel and robust alternative to traditional approaches for future clinical study to prioritize the variables of interest.
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Disfunción Cognitiva , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/psicología , Estudios Transversales , Pruebas Neuropsicológicas , Disfunción Cognitiva/psicología , Pruebas de Estado Mental y DemenciaRESUMEN
Background: Sleep disorders are common in Parkinson's disease (PD). However, the longitudinal relationship between sleep quality and the other non-motor symptoms of PD has not been well characterized, especially in early PD. Objective: To explore the value of baseline sleep quality in predicting the progression of other non-motor symptoms in early PD. Methods: 109 early PD patients were recruited to the study. Patients were stratified into good and poor sleepers using the Pittsburgh Sleep Quality Index (PSQI). Assessments performed at baseline and 1 year follow-up included the Epworth Sleepiness Scale, Fatigue Severity Scale, Non-Motor Symptom Scale, Geriatric Depression Scale, Hospital Anxiety and Depression Scale, Apathy Scale, Montreal Cognitive Assessment and detailed neuropsychological assessments. Multivariable linear regression was performed at baseline to investigate differences in clinical scores between poor and good sleepers, while multivariable regression models were used to investigate associations between sleep quality and progression of test scores at 1 year follow-up. Results: 59 poor sleepers and 50 good sleepers were identified. At baseline, poor sleepers had greater HADS anxiety scores (p = 0.013) [2.99 (95% CI 2.26, 3.73)] than good sleepers [1.59 (95% CI 0.75, 2.42)]. After 1 year, poor sleepers had greater fatigue (FSS scores +3.60 as compared to -2.93 in good sleepers, p = 0.007) and depression (GDS scores +0.42 as compared to -0.70, p = 0.006). Conclusion: This study shows a longitudinal association between sleep quality, fatigue, and depression in early PD patients, independent of medication effect and disease severity, this may support the hypothesis that a common serotonergic pathway is implicated in these non-motor symptoms.
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BACKGROUND: Neurofilament light is a marker of axonal degeneration, whose measurement from peripheral blood was recently made possible by new assays. OBJECTIVE: We aimed to determine whether plasma neurofilament light chain (NfL) concentration reflects brain white matter integrity in patients with early Parkinson's disease (PD). METHODS: 137 early PD patients and 51 healthy controls were included. Plasma NfL levels were measured using ultrasensitive single molecule array. 3T MRI including diffusion tensor imaging was acquired for voxelwise analysis of association between NfL and both fractional anisotropy (FA) and mean diffusivity (MD) in white matter tracts and subcortical nuclei. RESULTS: A pattern of brain microstructural changes consistent with neurodegeneration was associated with increased plasma NfL in most of the frontal lobe and right internal capsule, with decreased FA and increased MD. The same clusters were also associated with poorer global cognition. A significant cluster in the left putamen was associated with increased NfL, with a significantly greater effect in PD than controls. CONCLUSION: Plasma NfL may be associated with brain microstructure, as measured using diffusion tensor imaging, in patients with early PD. Higher plasma NfL was associated with a frontal pattern of neurodegeneration that also correlates with cognitive performance in our cohort. This may support a future role for plasma NfL as an accessible biomarker for neurodegeneration and cognitive dysfunction in PD.
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Imagen de Difusión Tensora , Enfermedad de Parkinson , Biomarcadores , Imagen de Difusión Tensora/métodos , Humanos , Filamentos Intermedios , Imagen por Resonancia Magnética , Proteínas de Neurofilamentos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagenRESUMEN
The biological underpinnings of the PD clusters remain unknown as the existing PD clusters lacks biomarker characterization. We try to identify clinical subtypes of Parkinson Disease (PD) in an Asian cohort and characterize them by comparing clinical assessments, genetic status and blood biochemical markers. A total of 206 PD patients were included from a multi-centre Asian cohort. Hierarchical clustering was performed to generate PD subtypes. Clinical and biological characterization of the subtypes were performed by comparing clinical assessments, allelic distributions of Asian related PD gene (SNCA, LRRK2, Park16, ITPKB, SV2C) and blood biochemical markers. Hierarchical clustering method identified three clusters: cluster A (severe subtype in motor, non-motor and cognitive domains), cluster B (intermediate subtype with cognitive impairment and mild non-motor symptoms) and cluster C (mild subtype and young age of onset). The three clusters had significantly different allele frequencies in two SNPs (Park16 rs6679073 A allele carriers in cluster A B C: 67%, 74%, 89%, p = 0.015; SV2C rs246814 T allele distribution: 7%, 12%, 25%, p = 0.026). Serum homocysteine (Hcy) and C-reactive protein (CRP) levels were also significantly different among three clusters (Mean levels of Hcy and CRP among cluster A B C were: 19.4 ± 4.2, 18.4 ± 5.7, 15.6 ± 5.6, adjusted p = 0.005; 2.5 ± 5.0, 1.5 ± 2.4, 0.9 ± 2.1, adjusted p < 0.0001, respectively). Of the 3 subtypes identified amongst early PD patients, the severe subtype was associated with significantly lower frequency of Park16 and SV2C alleles and higher levels of Hcy and CRP. These biomarkers may be useful to stratify PD subtypes and identify more severe subtypes.
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BACKGROUND: Lipid biomarkers have potential neuroprotective effects in Parkinson's disease (PD) and there is limited evidence in the field. OBJECTIVE: This study aims to investigate the association between comprehensive blood lipid biomarkers and PD. METHODS: A total of 205 PD patients and 102 non-PD subjects were included from Early Parkinson's disease Longitudinal Singapore (PALS) cohort. We investigated 6 serum lipid biomarkers including total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo A1), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B). PD patients were further classified into mild cognitive impairment (MCI) and normal cognition (NC) subgroups. We conducted a cross-sectionals study to examine the association between lipids and PD and further explored the relationship between lipids and PD-MCI. RESULTS: PD patients had significantly lower level of lipid panel including TC, TG, HDL-C, Apo A1, LDL-C, and Apo B (all pâ<â0.05). TC, TG, Apo A1, and Apo B levels were independent protective factors (pâ<â0.05) for PD in the logistic regression model. PD-MCI group had significantly higher mean TC, TG, and Apo A1 levels compared to PD-NC group. Higher TC, TG, and Apo A1 levels were independent risk factors (pâ<â0.05) for PD-MCI. CONCLUSION: We demonstrated that PD patients had significantly lower levels of lipid biomarkers while PD-MCI patients had higher levels of TC, TG, and Apo A1. TC, TG, and Apo A1 may be useful biomarkers for PD-MCI.
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Disfunción Cognitiva , Enfermedad de Parkinson , Apolipoproteína A-I , Apolipoproteínas B , Biomarcadores , HDL-Colesterol , LDL-Colesterol , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Humanos , Lípidos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , TriglicéridosRESUMEN
BACKGROUND: There is currently insufficient long-term data on costs of treatment in patients with Parkinson's disease (PD), which is chronic and progressive, and associated with substantial healthcare costs. Identifying patterns in healthcare utilization and cost may illuminate further discussion on early intervention. OBJECTIVE: To characterize long-term healthcare utilization and costs of PD in newly diagnosed patients managed by movement disorder specialists. METHODS: Using a longitudinal matched-cohort study of linked data from the National Neuroscience Institute Parkinson's disease and Movement Disorder and healthcare administrative databases in Singapore from 2008-2017, we compared healthcare utilization and costs between patients and controls matched on age, sex, race, and Charlson Comorbidity Index score. RESULTS: 1,162 patients met study inclusion criteria and 1,157 matched controls were identified. The total mean annual healthcare cost (at 2017 costs) was significantly increased in patients compared to controls from years 1-9 post-diagnosis. The increased cost was observed 2 years before diagnosis (USD2322 vs. 2052; pâ<â0.001). Mean annual cost attributable to PD increased from USD1854 at 1-year post-diagnosis to USD2652 at 9 years. Over 9 years, average costs were significantly higher across all domains of healthcare utilization except primary care-cost of intermediate and long-term care was increased by a factor of 2.5, specialist care by 2.3, emergency department visits by 1.6, and hospital admissions by 1.3. CONCLUSION: PD results in higher healthcare utilization and costs. Pre-diagnosis increase in healthcare utilization observed in patients supports the presence of prodromal PD symptoms and may present an opportunity for early diagnosis.
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Enfermedad de Parkinson , Estudios de Cohortes , Atención a la Salud , Costos de la Atención en Salud , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/terapia , Aceptación de la Atención de Salud , Estudios RetrospectivosRESUMEN
The alpha-synuclein gene promoter (SNCA-Rep1) is associated with Parkinson's disease (PD), but its relationship with performance across individual cognitive domains in early PD is unknown. This study aims to investigate Rep1 polymorphism and longitudinal change in cognition in early PD. In this longitudinal study, Rep1 allele lengths ("long" and "short") were determined in 204 early PD patients. All participants underwent annual neuropsychological assessments and followed up for 3 years. Linear-mixed model was performed to investigate the association of Rep1 status and longitudinal change in individual cognitive domains. At 3 years, significant decline in executive function was observed in long Rep1 allele carriers vs short allele carriers, controlling for potential confounders. This is the first longitudinal study demonstrating that long Rep1 allele carriers are at higher risk for executive dysfunction in early PD.
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Enfermedad de Parkinson , alfa-Sinucleína , Función Ejecutiva , Predisposición Genética a la Enfermedad , Humanos , Estudios Longitudinales , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/genética , Polimorfismo Genético , alfa-Sinucleína/genéticaRESUMEN
Background: Various classifications have been proposed to subtype Parkinson's disease (PD) based on their motor phenotypes. However, the stability of these subtypes has not been properly evaluated. Objective: The goal of this study was to understand the distribution of PD motor subtypes, their stability over time, and baseline factors that predicted subtype stability. Methods: Participants (n = 170) from two prospective cohorts were included: the Early PD Longitudinal Singapore (PALS) study and the National Neuroscience Institute Movement Disorders Database. Early PD patients were classified into tremor-dominant (TD), postural instability and gait difficulty (PIGD), and indeterminate subtypes according to the Movement Disorder Society's Unified PD Rating Scale (MDS-UPDRS) criteria and clinically evaluated for three consecutive years. Results: At baseline, 60.6% patients were TD, 12.4% patients were indeterminate, and 27.1% patients were PIGD subtypes (p < 0.05). After 3 years, only 62% of patients in TD and 50% of patients in PIGD subtypes remained stable. The mean levodopa equivalent daily dose (LEDD) was higher in the PIGD subtype (276.92 ± 232.91 mg; p = 0.01). Lower LEDD [p < 0.05, odds ratio (OR) 0.99, 95% confidence interval (CI): 0.98-0.99] and higher TD/PIGD ratios (p < 0.05, OR 1.77, 95% CI: 1.29-2.43) were independent predictors of stability of TD subtype with an area under the curve (AUC) of 0.787 (95%CI: 0.669-0.876), sensitivity = 57.8%, and specificity = 89.7%. Conclusion: Only 50-62% of PD motor subtypes as defined by MDS-UPDRS remained stable over 3 years. TD/PIGD ratio and baseline LEDD were independent predictors for TD subtype stability over 3 years.
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INTRODUCTION: Subjective cognitive complaints (SCC) and affective symptoms are highly prevalent in Parkinson's Disease (PD). In early PD, SCC prevalence and its affective correlates, using recommended Movement Disorders Society (MDS) Level II Criteria to define the underlying cognitive impairment, has not been previously explored. METHODS: We recruited 121 participants with early PD from two tertiary hospitals in Singapore. The presence of SCC was defined using a Non-Motor Symptoms Scale Domain-5 Score ≥1. Comprehensive neuropsychological testing was conducted with Mild Cognitive Impairment (PD-MCI) defined using recommended MDS Level II Criteria. Affective symptoms were assessed using the Hospital Anxiety Depression Scale (HADS), Geriatric Depression Scale (GDS) and Apathy Scale (AS). Analysis using multivariable linear regression model was performed. RESULTS: In our early PD cohort, SCC prevalence independent of underlying cognitive status was 38.8%. Prevalence of SCC in cognitively impaired and cognitively normal participants was 10.7% and 28.1% respectively (Ñ = 0.241). In cognitively normal PD participants, multivariable linear regression analysis revealed that SCC was significantly associated with anxiety (ß = 0.28, 95% CI = 0.09-0.79, p = 0.014), depression (ß = 0.31, 95% CI = 0.10-0.59, p = 0.006) and apathy (ß = 0.32, 95% CI = 1.15-5.98, p = 0.004). Such an association was not found in cognitively impaired PD participants. CONCLUSION: SCC is highly prevalent even in early PD. Its implications in early PD differ depending on underlying cognitive status. SCC in cognitively impaired participants underestimates the true prevalence of PD-MCI. In contrast, SCC in cognitively normal participants is suggestive of an underlying affective disorder.
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Síntomas Afectivos/fisiopatología , Disfunción Cognitiva/fisiopatología , Autoevaluación Diagnóstica , Enfermedad de Parkinson/fisiopatología , Síntomas Afectivos/epidemiología , Síntomas Afectivos/etiología , Anciano , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/epidemiologíaRESUMEN
Long alpha-synuclein gene (SNCA) promoter (Rep1) allele-carriers are linked to higher risk for Parkinson's disease (PD) and faster motor progression. Non-motor symptoms including autonomic, neuropsychiatric, and sleep disorders are common in PD. However, the relationship between SNCA Rep1 microsatellite lengths and non-motor symptoms in early PD remains to be elucidated. 171 consecutive early PD patients were recruited from tertiary clinics and genotyped for Rep1. Multivariable regression analyses were performed to examine associations between Rep1 alleles and non-motor outcome scores. Longer Rep1 alleles significantly associated with higher total Non-Motor Symptom Scale (NMSS) scores (p=.006) and Hospital Anxiety and Depression Scale (HADS) depression subscale scores (p=.002), after adjusting for covariates and Bonferroni correction. We demonstrated that SNCA Rep1 allele length influences overall non-motor symptom burden and depression in early PD patients. Further functional studies to evaluate the role of Rep1 in non-dopaminergic systems may unravel new therapeutic targets for non-motor symptoms in PD.
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Repeticiones de Microsatélite/genética , Enfermedad de Parkinson/genética , alfa-Sinucleína/genética , Anciano , Estudios Transversales , Depresión/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Factores de TiempoRESUMEN
BACKGROUND: The main motor subtypes of Parkinson's disease (PD) include tremor-dominant (TD) and postural instability gait disorder (PIGD), with varying disease course that warrant the development of biomarkers capable of predicting progression according to motor subtype. The PIGD subtype is associated with a poorer prognosis, hence identification of a biomarker associated with PIGD is clinically relevant. Neurofilament light (NfL) chain is a potential biomarker of disease severity in neurological disorders including PD. However, no study has investigated NfL and PD motor subtypes. Here, we aimed to investigate the diagnostic and prognostic utility of plasma NfL for PD motor subtypes in early Parkinson's disease. Given the higher risk for cognitive and motor decline in PIGD, we hypothesized that plasma NfL is a potential biomarker for PIGD. METHODS: Plasma NfL was measured in 199 participants (149 PD and 50 healthy controls, HC) using an ultrasensitive single molecule array. Patients were classified into TD or PIGD based on MDS-UPDRS components. After 2 years, 115 patients were reassessed. Association between NfL and clinical measures in PIGD and TD at baseline and at 2-year follow-up were analysed. RESULTS: At baseline, plasma NfL levels were higher in PD than HC (8.8 ± 3.4 vs 16.2 ± 7.6 pg/ml, p < 0.0001), and differentiated PD from HC with a good diagnostic accuracy (AUC = 0.833, p < 0.001). At 2 years, NfL was higher in PIGD than TD (18.4 ± 14.5 vs 12.6 ± 4.4 pg/ml, p = 0.039). Within the PIGD group, higher NfL associated significantly with worse global cognition and UPDRS motor scores at baseline, and was able to predict motor and cognitive decline at a mean follow-up duration of 1.9 years, controlled for age, sex and disease duration. CONCLUSIONS: In this longitudinal study, we demonstrated for the first time the potential utility of plasma NfL as a diagnostic and prognostic biomarker in PIGD even at early stages of PD. These important novel findings will require further confirmation in larger, longitudinal PD cohorts.
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Biomarcadores/sangre , Trastornos Neurológicos de la Marcha/diagnóstico , Marcha/fisiología , Filamentos Intermedios/metabolismo , Enfermedad de Parkinson/diagnóstico , Cognición/fisiología , Progresión de la Enfermedad , Femenino , Trastornos Neurológicos de la Marcha/complicaciones , Trastornos Neurológicos de la Marcha/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Pronóstico , Temblor/complicacionesRESUMEN
Parkinson's disease (PD) is a chronic neurodegenerative disease with complex motor and non-motor symptoms often leading to significant caregiver burden. An integrated, multidisciplinary care setup involving different healthcare professionals is the mainstay in the holistic management of PD. Many challenges in delivering multidisciplinary team (MDT) care exist, such as insufficient expertise among different healthcare professionals, poor interdisciplinary collaboration, and communication. The need to attend different clinics, incurring additional traveling and waiting time for allied health therapies can also make MDT care more burdensome. By shifting MDT care to local community settings and into patients' homes, patient-centered care can be achieved. In Singapore, the National Neuroscience Institute created the Community Care Partners Programme in 2007 to bring the allied MDT team to the community and nurse-led Integrated Community Care Programme for Parkinson's Disease in 2012 to provide care in community and at patient's home. However, attaining MDT care in the community setting is difficult to achieve where there is a shortage of PD-trained professionals. As such, interdisciplinary and transdisciplinary management would be other best practice options to deliver patient-centric care in PD. Telemedicine could be another viable option to bring the MDT closer to the patient.
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OBJECTIVE: The aim of this study is to compare Parkinson's disease (PD) treatment practices by movement disorder (MD) specialists across a decade, and to determine the factors that influence drug choice for the motor symptoms of PD in newly diagnosed drug-naïve patients. METHODS: This prospective temporal analysis included patients seen at the National Neuroscience Institute in Singapore and diagnosed with PD by MD specialists in the years 2007 and 2017. Primary outcomes were use of specific PD drugs and changes in drug-prescribing patterns. Descriptive analyses and multivariable logistic regression models determined the extent to which patient characteristics were associated with type of PD treatment. RESULTS: Of 230 patients with PD (mean (SD) age, 66.7 (10.3) years), 131 (57.0%) were male. From 2007 to 2017, the use of ergot dopamine agonists and anticholinergics decreased from 19.3% to 2.0% (P < 0.001) and from 12.0% to 2.7% (P = 0.004), respectively. The use of monoamine oxidase B inhibitors (MAOBI) increased from 13.3% to 25.2% (P = 0.033). The use of levodopa (LD)-sparing strategies decreased nonsignificantly from 33.7% to 24.5% (P = 0.133). Overall, 196 (85.2%) patients were initiated on symptomatic monotherapy, with LD being the most commonly prescribed. MAOBI was the most common drug used in combination therapy. Age ≤70 (adjusted OR, 11.9; 95% CI, 4.5-31.5) and Hoehn and Yahr (HY) stage <2 (adjusted OR, 3.4; 95% CI, 1.5-7.7) were independent factors for LD-sparing strategies. Non-LD prescriptions (13 of 92; 14.1%) were more likely to be discontinued compared to LD ones (6 of 149; 4.0%) (P = 0.005). CONCLUSIONS: Drug-prescribing patterns in PD have changed significantly through the last decade, influenced by emerging evidence and reports of adverse drug effects. Choosing drugs based on the patient's age and disease severity remain sound guiding principles across the years. It is important that international and national guidelines for pharmacotherapy in PD be updated consistently throughout different socioeconomic settings to optimize care.
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Importance: Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian). Objectives: To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts. Design Setting, and Participants: Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31â¯575 individuals passing quality control of 35â¯994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1â¯926â¯361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson's Disease Society Brain Bank Criteria. Main Outcomes and Measures: Genotypes of common variants, association with disease status, and polygenic risk scores. Results: Of 31â¯575 samples identified, 6724 PD cases (mean [SD] age, 64.3 [10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24â¯851 controls (age, 59.4 [11.4] years; 11â¯030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10-10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P = 3.40 × 10-3 for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P = 6.81 × 10-12). Conclusions and Relevance: This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta-genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.