Accuracy of routinely collected hospital administrative discharge data and death certificate ICD-10 diagnostic coding in progressive supranuclear palsy and corticobasal syndrome: a systematic review and validation study.

BACKGROUND: We conducted a systematic review to identify existing ICD-10 coding validation studies in progressive supranuclear palsy and corticobasal syndrome [PSP/CBS]) and, in a new study, evaluated the accuracy of ICD-10 diagnostic codes for PSP/CBS in Scottish hospital inpatient and death certificate data. METHODS: Original studies that assessed the accuracy of specific ICD-10 diagnostic codes in PSP/CBS were sought. Separately, we estimated the positive predictive value (PPV) of specific codes for PSP/CBS in inpatient hospital data (SMR01, SMR04) compared to clinical diagnosis in four regions. Sensitivity was assessed in one region due to a concurrent prevalence study. For PSP, the consistency of the G23.1 code in inpatient and death certificate coding was evaluated across Scotland. RESULTS: No previous ICD-10 validation studies were identified. 14,767 records (SMR01) and 1497 records (SMR04) were assigned the candidate ICD-10 diagnostic codes between February 2011 and July 2019. The best PPV was achieved with G23.1 (1.00, 95% CI 0.93-1.00) in PSP and G23.9 in CBS (0.20, 95% CI 0.04-0.62). The sensitivity of G23.1 for PSP was 0.52 (95% CI 0.33-0.70) and G31.8 for CBS was 0.17 (95% CI 0.05-0.45). Only 38.1% of deceased G23.1 hospital-coded cases also had this coding on their death certificate: the majority (49.0%) erroneously assigned the G12.2 code. DISCUSSION: The high G23.1 PPV in inpatient data shows it is a useful tool for PSP case ascertainment, but death certificate coding is inaccurate. The PPV and sensitivity of existing ICD-10 codes for CBS are poor due to a lack of a specific code.

Total Patient Delay: A Comparison of Patient and Clinician/Health System Delays in the Diagnosis of Progressive Supranuclear Palsy and Corticobasal Syndrome.

BACKGROUND: Early diagnosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) is important for clinical care and key to developing successful disease-modifying agents. The patient-dependent phases of decision-making made before contact with a healthcare professional have been inadequately studied. OBJECTIVES: To evaluate the patient-dependent phases of decision-making from symptom onset, comparing this to clinician and/or health system delays within the overall diagnostic pathway. METHODS: Using the Anderson General Model of Total Patient Delay and a mixed-methods approach in participants with PSP/CBS and their caregivers recruited to the Scottish PSP and CBS cohort, we quantified and evaluated the determinants of "appraisal", "illness," and "behavioral" delay, comparing this to the clinician and/or health system delays ("treatment" delay) within the overall time from symptom onset to diagnosis. RESULTS: The time from index symptom onset to diagnosis was 3.26 (interquartile range [IQR] = 2.42, 4.75) years in PSP and 2.58 (IQR = 1.69, 4.08) years in CBS. Patient appraisal delay was 24 (IQR = 6, 60) weeks in PSP and 8 (IQR = 5, 24) weeks in CBS, illness delay 0 (IQR = -14, 0) weeks in PSP and 0 (IQR = -4, 0) weeks in CBS, with little perceived behavioral delay. Determinants of delay included the non-specificity of symptoms, normalization of symptoms within the context of age or normal physiological variability, and the extent of insight into new somatic symptoms. CONCLUSIONS: Although patient appraisal delay contributes to overall diagnostic delay in PSP/CBS, the greater proportion of overall diagnostic delay arises after contact with a healthcare professional (treatment delay).

Incidence and risk factors of institutionalisation in Parkinson's disease and atypical parkinsonism.

INTRODUCTION: The basic epidemiology of institutionalisation (the need for long-term care in an institution) in parkinsonism is unclear. We aimed to identify the incidence of, and risk factors for, institutionalisation in Parkinson's disease (PD) and atypical parkinsonism (AP). METHODS: We analysed data from a prospective population-based incidence cohort of parkinsonism in North-East Scotland (the PINE study). 556 newly-diagnosed participants (PD, N = 200; AP, N = 98; controls, N = 258), recruited between 2002 and 2009, were prospectively followed life-long with data collection on place of residence. We determined the incidence and baseline predictors of institutionalisation using Cox regression. RESULTS: The median follow-up time was 9.3, 4.4, and 10.8 years in PD, AP, and controls respectively. 70 (35 %) PD, 53 (54 %) AP, and 43 (16 %) controls became institutionalised. The incidence rates of institutionalisation in PD, AP, and controls were 5.1, 20.8, and 1.8 per 100 person-years respectively. The median time to institutionalisation was 11.8 years in PD and 3.5 years in AP. Multivariable Cox regression showed that AP (HR versus PD = 3.05 [95 % CI 1.90,4.91]), increasing age (HR for 10-year increase = 1.82 [95 % CI 1.40,2.36]), poorer cognition (HR for MMSE<24 versus MMSE>27 = 2.62 [95 % CI 1.45, 4.73]), more-severe parkinsonian impairment (UPDRS part 3) (HR for 10-point increase = 1.25 [95 % CI 1.05, 1.48]) were independently associated with higher hazards of institutionalisation. Sex, co-morbidity, smoking history, and living alone were not associated with institutionalisation. CONCLUSION: Institutionalisation is much more frequent in parkinsonism, particularly in AP, than in controls. AP, older age, severe parkinsonian impairment, and poorer cognition were independent baseline predictors of institutionalisation.

Progressive multifocal leukoencephalopathy associated with carbamazepine-induced immune dysfunction and recovery after carbamazepine cessation.

A patient with epilepsy on carbamazepine developed a rapidly progressive cerebellar syndrome. Serial MRI showed progressive posterior fossa T2/fluid attenuated inversion recovery hyperintensity with gadolinium enhancement. Standard cerebrospinal fluid (CSF) analysis was normal. Detection of John Cunningham virus DNA in the CSF confirmed progressive multifocal leukoencephalopathy (PML). The only evidence of immune disfunction was hypogammaglobulinaemia and longstanding lymphopenia. After cessation of carbamazepine, the lymphocyte count and immunoglobulin levels returned to normal and the PML resolved, with good clinical recovery. No specific treatments for PML were given. We hypothesise that PML in this case was due to carbamazepine-induced prolonged mild immunosuppression with reconstitution of the immune system after carbamazepine cessation, resulting in recovery from PML. Effects of anticonvulsants on immune function and infection risk may contribute to epilepsy-related morbidity and mortality. Further investigation is needed to determine the frequency of immune dysfunction and infections in patients treated with anticonvulsants such as carbamazepine and whether interventions could reduce infection risk.

Cognitive and Motor Decline in Dementia with Lewy Bodies and Parkinson's Disease Dementia.

Background: There is a need to better understand the rate of cognitive and motor decline of Dementia with Lewy bodies (DLB) and Parkinson's disease Dementia (PDD). Objectives: To compare the rate of cognitive and motor decline in patients with DLB and PDD from the E-DLB Consortium and the Parkinson's Incidence Cohorts Collaboration (PICC) Cohorts. Methods: The annual change in MMSE and MDS-UPDRS part III was estimated using linear mixed regression models in patients with at least one follow-up (DLB n = 837 and PDD n = 157). Results: When adjusting for confounders, we found no difference in the annual change in MMSE between DLB and PDD (-1.8 [95% CI -2.3, -1.3] vs. -1.9 [95% CI -2.6, -1.2] [P = 0.74]). MDS-UPDRS part III showed nearly identical annual changes (DLB 4.8 [95% CI 2.1, 7.5]) (PDD 4.8 [95% CI 2.7, 6.9], [P = 0.98]). Conclusions: DLB and PDD showed similar rates of cognitive and motor decline. This is relevant for future clinical trial designs.

The evolution of diagnosis from symptom onset to death in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) compared to Parkinson's disease (PD).

BACKGROUND: Misdiagnosis and delayed diagnosis in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are common. Few studies have systematically evaluated the diagnostic process from symptom onset to death in representative cohorts. METHODS: All PSP/CBD cases (n = 28/2) and age-sex matched Parkinson's disease (PD) cases (n = 30) were identified from a UK prospective incident Parkinsonism cohort. Medical and research records were reviewed to compare median times from first index symptom to key diagnostic milestones and the nature/timing of secondary care referral and review. RESULTS: Index symptoms were similar apart from more tremor in PD (p < 0.001) and more impaired balance (p = 0.008) and falls (p = 0.004) in PSP/CBD. PD was diagnosed a median 0.96 years after index symptom. In PSP/CBD the median times from index symptom to identifying parkinsonism and then including PSP/CBD in the differential diagnosis and the final diagnosis were 1.88, 3.41 and 4.03 years, respectively (all p < 0.001). Survival from symptom onset in PSP/CBD and PD was not significantly different (5.98 vs 6.85 years, p = 0.72). More diagnoses (p < 0.001) were considered in PSP/CBD. Prior to diagnosis, PSP/CBD patients had more recurrent emergency attendances (33.3% vs 10.0%, p = 0.01) and were referred to more specialities than PD (median 5 vs 2). Time to any outpatient referral (0.70 vs 0.03 years, p = 0.025) and to specialist movement disorder review (1.96 vs 0.57 years, p = 0.002) was longer in PSP/CBD. CONCLUSIONS: The duration and complexity of the diagnostic journey were greater in PSP/CBD than age-sex matched PD but can be improved. In this older cohort, there was little difference in survival from symptom onset in PSP/CBD and age-sex matched PD.

Achieving proportionate governance review in Scotland: Threats and solutions.

The effectiveness of any healthcare-related research governance system is dependent on its ability to identify, challenge and change practices that compromise its ability to deliver timely, proportionate review. We present a case study outlining our experience of obtaining research ethics committee (REC) and Public Benefit and Privacy Panel (PBPP) for Health and Social Care approval to conduct a study which aimed to collect data on diagnostic and care pathways and determine the national prevalence of two rare diseases in Scotland. We discuss the threats posed to low-risk observational epidemiological research by disproportionate governance practices and propose practical solutions. In the context of increasing investment, the ever-increasing barriers to doing high-quality, low-risk epidemiological research using patient-identifiable information is concerning. Information governance committees, guided by clinical researchers, must step up as leaders in this area, making use of flexibilities and opportunities within the law.

Systematic Review of Prevalence Studies of Progressive Supranuclear Palsy and Corticobasal Syndrome.

Background: High-quality prevalence studies are important in estimating the burden of disease in a population, thus informing priority setting, resource allocation, delivery, and use of health services. Objectives: This study was undertaken to systematically review the methods and results of previous prevalence studies of progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) and make recommendations for future studies. Methods: A total of 2 authors independently identified original articles that described the prevalence of PSP or CBS using several comprehensive and overlapping search strategies, assessed study quality, and extracted relevant data. Descriptive and pooled analyses were performed as appropriate. Results: A total of 16 studies were identified in PSP and 9 studies in CBS, with highly heterogeneous methods of case definition, identification, and verification in identified studies. Few studies were deemed of necessary quality or methodological homogeneity to justify a full meta-analysis. In addition, few studies reported age- and sex-stratified results. The best 3 prevalence studies in PSP gave a pooled rate of 7.1 per 100,000 per year, whereas the pooled rate in 2 CBS studies was roughly 3 times lower at 2.3 per 100,000 per year. Based on crude rates, there was little evidence to suggest clear sex differences in the prevalence of PSP or CBS or that the prevalence of PSP had increased over time, but some evidence to suggest that prevalence may increase with increasing age. Conclusion: Given the paucity of prevalence studies in PSP and CBS, further high-quality prevalence studies are necessary.

Prevalence of Progressive Supranuclear Palsy and Corticobasal Syndrome in Scotland.

INTRODUCTION: We estimated the point prevalence of progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) at regional and national levels in Scotland, UK, as there are few high-quality prevalence studies of these conditions. METHODS: Nationally, multiple methods of case ascertainment were used including clinician and nurse specialist referral, searches of ICD-10 diagnostic coding in routinely collected electronic health data (Scottish Morbidity Record), and patient self-referral. In one region, we also searched GP databases and unselected hospital correspondence. Cases were verified by clinical examination or medical record review. National and regional total and age-sex-stratified crude prevalence rates on December 31, 2018, were calculated. RESULTS: The regional crude point prevalence was 4.28 per 100,000 (95% CI 2.90, 6.31) for PSP and 2.05 per 100,000 (95% CI 1.17, 3.59) for CBS. The national crude prevalence rates were lower due to the greater reliance on passive case ascertainment. There were no clear sex differences. At a national level, the peak crude prevalence rate for both PSP and CBS was in the 70-79 age group. DISCUSSION: The prevalence rates of PSP and CBS were similar to previous estimates with little change over the past 20 years.

GBA and APOE Impact Cognitive Decline in Parkinson's Disease: A 10-Year Population-Based Study.

BACKGROUND: Common genetic variance in apolipoprotein E (APOE), ß-glucocerebrosidase (GBA), microtubule-associated protein tau (MAPT), and α-synuclein (SNCA) has been linked to cognitive decline in Parkinson's disease (PD), although studies have yielded mixed results. OBJECTIVES: To evaluate the effect of genetic variants in APOE, GBA, MAPT, and SNCA on cognitive decline and risk of dementia in a pooled analysis of six longitudinal, non-selective, population-based cohorts of newly diagnosed PD patients. METHODS: 1002 PD patients, followed for up to 10 years (median 7.2 years), were genotyped for at least one of APOE-ε4, GBA mutations, MAPT H1/H2, or SNCA rs356219. We evaluated the effect of genotype on the rate of cognitive decline (Mini-Mental State Examanation, MMSE) using linear mixed models and the development of dementia (diagnosed using standardized criteria) using Cox regression; multiple comparisons were accounted for using Benjamini-Hochberg corrections. RESULTS: Carriers of APOE-ε4 (n = 281, 29.7%) and GBA mutations (n = 100, 10.3%) had faster cognitive decline and were at higher risk of progression to dementia (APOE-ε4, HR 3.57, P < 0.001; GBA mutations, HR 1.76, P = 0.001) than non-carriers. The risk of cognitive decline and dementia (HR 5.19, P < 0.001) was further increased in carriers of both risk genotypes (n = 23). No significant effects were observed for MAPT or SNCA rs356219. CONCLUSIONS: GBA and APOE genotyping could improve the prediction of cognitive decline in PD, which is important to inform the clinical trial selection and potentially to enable personalized treatment © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

First delirium episode in Parkinson's disease and parkinsonism: incidence, predictors, and outcomes.

To define the incidence, predictors and prognosis of the first hospital delirium episode in Parkinson's disease (PD) and atypical parkinsonism (AP), we identified the first hospital episode of delirium after diagnosis in the Parkinsonism Incidence in North-East Scotland (PINE) study, a prospective community-based incidence cohort of parkinsonism, using chart-based criteria to define delirium. Of 296 patients (189=PD, 107=AP [dementia with Lewy bodies, progressive supranuclear palsy, multiple system atrophy, vascular parkinsonism]), 152 developed delirium (PD = 98, AP = 54). Incidence of first hospital delirium episode per 100 person years was 8.1 (95% confidence interval [CI] 6.6-9.9) in PD and 18.5 (95% CI 13.9-24.7) in AP. Independent predictors of delirium were atypical parkinsonism (Hazard ratio [HR] vs PD = 2.83 [95% CI 1.60-5.03], age in PD but not in AP (HR for 10-year increase 2.29 [95% CI 1.74-3.02]), baseline MMSE (HR = 0.94 [95% CI 0.89-0.99]), APOE ε4 in PD (HR 2.16 [95% CI 1.15-4.08]), and MAPT H1/H1 in PD (HR 2.08 [95% CI 1.08-4.00]). Hazards of dementia and death after delirium vs before delirium were increased (dementia: HR = 6.93 [95% CI 4.18-11.48] in parkinsonism; death: HR = 3.76 [95% CI 2.65-5.35] in PD, 1.59 [95% CI 1.04-2.42] in AP). Delirium is a common non-motor feature of PD and AP and is associated with increased hazards of dementia and mortality. Whether interventions for early identification and treatment improve outcomes requires investigation.

Lack of Association Between GBA Mutations and Motor Complications in European and American Parkinson's Disease Cohorts.

BACKGROUND: Motor complications are a consequence of the chronic dopaminergic treatment of Parkinson's disease (PD) and include levodopa-induced dyskinesia (LIDs) and motor fluctuations (MF). Currently, evidence is on lacking whether patients with GBA-associated PD differ in their risk of developing motor complications compared to the general PD population. OBJECTIVE: To evaluate the association of GBA carrier status with the development of LIDS and MFs from early PD. METHODS: Motor complications were recorded prospectively in 884 patients with PD from four longitudinal cohorts using part IV of the UPDRS or MDS-UPDRS. Subjects were followed for up to 11 years and the associations of GBA mutations with the development of motor complications were assessed using parametric accelerated failure time models. RESULTS: In 439 patients from Europe, GBA mutations were detected in 53 (12.1%) patients and a total of 168 cases of LIDs and 258 cases of MF were observed. GBA carrier status was not associated with the time to develop LIDs (HR 0.78, 95%CI 0.47 to 1.26, p = 0.30) or MF (HR 1.19, 95%CI 0.84 to 1.70, p = 0.33). In the American cohorts, GBA mutations were detected in 36 (8.1%) patients and GBA carrier status was also not associated with the progression to LIDs (HR 1.08, 95%CI 0.55 to 2.14, p = 0.82) or MF (HR 1.22, 95%CI 0.74 to 2.04, p = 0.43). CONCLUSION: This study does not provide evidence that GBA-carrier status is associated with a higher risk of developing motor complications. Publication of studies with null results is vital to develop an accurate summary of the clinical features that impact patients with GBA-associated PD.

Association of GBA Genotype With Motor and Functional Decline in Patients With Newly Diagnosed Parkinson Disease.

OBJECTIVE: To establish the significance of glucocerebrosidase gene (GBA) carrier status on motor impairment in a large cohort of patients with incident Parkinson disease (PD). METHODS: Three European population-based studies followed 528 patients with PD from diagnosis. A total of 440 with genomic DNA from baseline were assessed for GBA variants. We evaluated motor and functional impairment annually using the Unified Parkinson's Disease Rating Scale (UPDRS) motor and activities of daily living (ADL) sections. Differential effects of classes of GBA variants on disease progression were evaluated using mixed random and fixed effects models. RESULTS: A total of 387 patients with idiopathic disease (age at baseline 70.3 ± 9.5 years; 60.2% male) and 53 GBA carriers (age at baseline 66.8 ± 10.1 years; 64.2% male) were included. The motor profile of the groups was clinically indistinguishable at diagnosis. GBA carriers showed faster annual increase in UPDRS scores measuring ADL (1.5 point per year, 95% confidence interval [CI] 1.1-2.0) and motor symptoms (2.2 points per year, 95% CI 1.3-3.1) compared to noncarriers (ADL, 1.0 point per year, 95% CI 0.9-1.1, p = 0.003; motor, 1.3 point per year, 95% CI 1.1-1.6, p = 0.007). Simulations of clinical trial designs showed that recruiting only GBA carriers can reduce trial size by up to 65% compared to a trial recruiting all patients with PD. CONCLUSION: GBA variants are linked to a more aggressive motor disease course over 7 years from diagnosis in patients with PD. A better understanding of PD progression in genetic subpopulations may improve disease management and has direct implications for improving the design of clinical trials.

Validation of a UPDRS-/MDS-UPDRS-based definition of functional dependency for Parkinson's disease.

INTRODUCTION: Functional dependency in basic activities of daily living (ADLs) is a key outcome in Parkinson's disease (PD). We aimed to define dependency in PD, using the original and MDS versions of the Unified Parkinson's Disease Rating Scale (UPDRS). METHODS: We developed two algorithms to define dependency from items of UPDRS Part 2 and MDS-UPDRS Part 2 relating to basic ADLs (feeding, dressing, hygiene and walking, and getting out of a chair). We validated both algorithms using data from 1110 patients from six community-based PD incidence cohorts, testing concurrent validity, convergent validity, and predictive validity. RESULTS: Our optimal algorithm showed high specificity and moderate to high sensitivity versus Schwab & England <80% (specificity 95% [95% confidence interval (CI) 93-97] and sensitivity 65% [95% CI 55-73] at baseline; 88% [95% CI 85-91] and 85% [95% CI 79-97] respectively at five-years follow-up). Convergent validity was demonstrated by strong associations between dependency defined by the algorithm and cognition (MMSE), quality of life (PDQ39), and impairment (UPDRS part 3) (all p < 0.001). Algorithm-defined dependency status also predicted mortality: HR for mortality in those dependent vs independent at baseline was 1.6 (95%CI 1.2-2.1) and in those dependent vs independent at five-years' follow-up was 2.2 (1.6-3.0). DISCUSSION: We have demonstrated the concurrent validity, convergent validity, and predictive validity of a UPDRS-/MDS-UPDRS-based algorithm to define functional dependency in PD. This can be used for studying dependency in any study where UPDRS or MDS-UPDRS part 2 data have been collected.

Treatment Responsiveness of Motor Features in Parkinson's Disease: A Matched Case-Control Analysis.

BACKGROUND: Treatment response in PD is important clinically and for research diagnostic criteria, but few objective data show treatment-responsiveness of PD motor features. OBJECTIVES: To evaluate the treatment response of motor features to moderate treatment doses in a "real-world" PD cohort. METHODS: We analyzed data from a community-based incident cohort of PD in North-East Scotland (PINE study). We assessed change in the UPDRS motor scale and its individual items over a period of up to 13 months comparing (1) patients with an increase of at least 300 mg of levodopa-equivalent dose (LED) and (2) patients without treatment change, matched for age, sex, and disease duration. RESULTS: We identified 101 matched pairs of patients with and without a treatment increase. LED increases were mostly 300 to 375 mg/day. Forty-two percent with treatment increase had ≥30% improvement in overall UPDRS motor score, a further 35% had substantial subjective improvement, but only 1 had an objective excellent (>70%) treatment response. Women responded better than men by 5.4 points (95% confidence interval [CI]: 2.7-8.1). All motor features improved with treatment, but after adjustment for age, sex, and initial score, only rest tremor (P < 0.001), rigidity (P = 0.01), bradykinesia (<0.001), posture (P = 0.01), and gait (P = 0.03) had significant improvements, compared to those with no treatment change. Dopa-less-responsive motor items, taken together, had small statistically significant relative improvements (1.1-point difference [95% CI: 0.4-1.8]; P = 0.004). CONCLUSIONS: Motor items sometimes previously considered dopa unresponsive have small improvements with moderate LED increases. Women respond better than men. Excellent treatment responses are uncommon. These data can inform clinical decisions about treatment.

Association of SNCA Parkinson's Disease Risk Polymorphisms With Disease Progression in Newly Diagnosed Patients.

Objectives: To evaluate the impact of SNCA polymorphisms originally identified as risk factors for Parkinson's disease (PD) on the clinical presentation and progression of the disease in a large cohort of population-based patients with incident PD. Methods: Four hundred thirty-three patients and 417 controls from three longitudinal cohorts were included in the study. Disease progression was recorded annually for up to 9 years using the Unified Parkinson's Disease Rating Scale (UPDRS) or Mini-Mental State Examination. Genotypes for five variants within the SNCA locus (rs2870004, rs356182, rs5019538, rs356219, and rs763443) were determined. We studied the association between each variant and disease progression using linear mixed-effects regression models. Results: The clinical profile of the patients with PD at the point of diagnosis was highly uniform between genotype groups. The rs356219-GG genotype was associated with a higher UPDRS II score than A-allele carriers (ß = 1.52; 95% confidence interval 0.10-2.95; p = 0.036), but no differences were observed in the rate of progression of the UPDRS II scores. rs356219-GG was also associated with a faster annual change in Mini-Mental State Examination score compared with A-carriers (ß = 0.03; 95% confidence interval 0.00-0.06; p = 0.043). Conclusions: We show that the known PD-risk variant rs356219 has a minor effect on modifying disease progression, whereas no differences were associated with rs2870004, rs356182, rs5019538, and rs763443. These findings suggest that SNCA variants associated with PD risk may not be major driving factors to the clinical heterogeneity observed for PD.

Age-related selection bias in Parkinson's disease research: are we recruiting the right participants?

OBJECTIVE: To describe, and explore heterogeneity in, age at onset/diagnosis in Parkinson's disease (PD) and compare mean age at onset/diagnosis in incidence studies with that in general PD research studies. METHODS: We systematically reviewed studies of PD incidence. We meta-analysed mean age at onset/diagnosis and age-stratum-specific incidence rates. We compared age-specific incidence rates in screening studies in the elderly with whole-population studies. We collated mean ages at onset/diagnosis in clinical studies of PD in five journals July-December 2016. RESULTS: In 17 studies reporting sufficient data to pool, mean age at onset/diagnosis was 69.6 years (95% CI 68.2-71.1), but heterogeneity was high (I2 = 96%). In ten of these studies reporting age at diagnosis specifically, the pooled mean age at diagnosis was slightly higher (71.6 [95% CI 70.6-72.6]) with lower, but still high, heterogeneity (I2 = 84%). In twelve whole-population studies reporting age-specific incidence rates, these peaked in age 70-79 (pooled incidence rate per 100,000 = 93.8 [95% CI 80.3-107.4]). Heterogeneity increased with each increase in age stratum (0% in youngest to 88% in oldest age stratum). Pooled age-specific incidence rates in five population-based screening studies of older age groups were several-fold higher than in whole-population studies. The mean of the reported mean ages at onset/diagnosis in recently published research studies was 60.8 (SD 5.6). CONCLUSION: The mean age of onset/diagnosis PD is about 70, although this may be an underestimate due to under-diagnosis in the elderly. Many published studies use age-unrepresentative subjects: the effect of this selection bias deserves further study.

Association of glucocerebrosidase polymorphisms and mutations with dementia in incident Parkinson's disease.

INTRODUCTION: Both polymorphisms and mutations in glucocerebrosidase (GBA) may influence the development of dementia in patients with Parkinson's disease. METHODS: Four hundred forty-two patients and 419 controls were followed for 7 years. Dementia was diagnosed using established criteria. Participants were analyzed for GBA genetic variants, including E326K, T369M, and L444P. Associations between GBA carrier status and dementia were assessed with Cox survival analysis. RESULTS: A total of 12.0% of patients with Parkinson's disease carried a GBA variant, and nearly half (22/53) of them progressed to dementia during follow-up. Carriers of deleterious GBA mutations (adjusted hazard ratio 3.81, 95% confidence interval 1.35 to 10.72; P = .011) or polymorphisms (adjusted hazard ratio 1.79; 95% confidence interval 1.07 to 3.00; P = .028) progressed to dementia more rapidly than noncarriers. DISCUSSION: GBA variants are of great clinical relevance for the development of dementia in Parkinson's disease, especially due to the relatively higher frequency of these alleles compared with other risk alleles.

Development and validation of prognostic survival models in newly diagnosed Parkinson's disease.

OBJECTIVE: The objective of this study was to develop valid prognostic models to predict mortality, dependency, and "death or dependency" for use in newly diagnosed Parkinson's disease (PD). METHODS: The models were developed in the Parkinsonism Incidence in North-East Scotland study (UK, 198 patients) and validated in the ParkWest study (Norway, 192 patients), cohorts that attempted to identify and follow-up all new PD cases in the study area. Dependency was defined using the Schwab & England scale. We selected variables measured at time of diagnosis to include in the models. Internal validation and external validation were performed by calculating C-statistics (discrimination) and plotting observed versus predicted risk in quantiles of predicted risk (calibration). RESULTS: Older age, male sex, increased severity of axial features, and Charlson comorbidity index were independent prognostic factors in the mortality model. Increasing age, higher smoking history, increased severity of axial features, and lower MMSE score were independent predictors in the models of dependency and "death or dependency." Each model had very good internal calibration and very good or good discrimination (internal and external C-statistics for the models were 0.73-0.75 and 0.68-0.78, respectively). Although each model clearly separated patients into groups according to risk, they tended to overestimate risk in ParkWest. The models were recalibrated to the baseline risk in the ParkWest study and then calibrated well in this cohort. CONCLUSIONS: We have developed prognostic models for predicting medium-term risk of important clinical outcomes in newly diagnosed PD. These models have validity for use for stratification of randomization, confounder adjustment, and case-mix correction, but they are inadequate for individualized prognostication. © 2017. The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.