Background: Subjective cognitive complaints (SCCs), which are associated with a higher risk of cognitive decline, are widespread in the patients with Parkinson's disease (PD). The previous studies have reported inconsistent factors related to SCCs in the patients with late-onset PD (LOPD), and there is limited information on SCCs in the patients with early-onset PD (EOPD).Objective: We aimed to investigate the factors associated with SCCs in the drug-naïve patients with EOPD and LOPD without cognitive impairment.Methods: This cross-sectional study included 332 drug-naïve patients with PD, among whom 134 were EOPD and 198 were LOPD. Motor and non-motor symptoms, such as global objective cognitive status, depression, anxiety, apathy, fatigue, sleep, rapid eye movement sleep behavior disorder, orthostatic hypotension, and excessive daytime sleepiness, were assessed.Results: Twenty-five (18.66%) patients with EOPD and 49 (24.74%) patients with LOPD reported SCCs. A multivariate binary logistic regression analysis revealed that older age at onset [odds ratio (OR) = 1.24, P = 0.002], higher apathy score (OR = 1.13, P = 0.003), and lower scores in the visuospatial/executive abilities (OR = 0.25, P < 0.001) and memory (OR = 0.50, P = 0.024) domains of the Montreal Cognitive Assessment were associated with a higher risk of SCCs in the EOPD group. Higher apathy (OR = 1.06, P = 0.011) and anxiety (OR = 1.14, P < 0.001) scores were associated with SCCs in the LOPD group.Conclusion: Subjective cognitive complaints are only associated with mood disorders in patients with LOPD. In addition, SCCs may reflect subthreshold cognitive impairment in the patients with EOPD.

Background Age at onset (AAO) is an essential feature of Parkinson's disease (PD) and can help predict disease progression and mortality. Identification of genetic variants influencing AAO of PD could lead to a better understanding of the disease's biological mechanism and provide clinical guidance. However, genetic determinants for AAO of PD remain mostly unknown, especially in the Asian population. Objectives To identify genetic determinants for AAO of PD in the Asian population. Methods We performed a genome‐wide association meta‐analysis on AAO of PD in 5166 Chinese patients with PD (Ndiscovery = 3628, Nreplication = 1538). We then conducted a further cross‐ethnic meta‐analysis using our results and summary statistics for the AAO of PD from the European population. Results The total heritability of AAO of PD was around 0.10 ~ 0.14, similar to that (~0.11) estimated in populations of European ancestry. One novel significant intergenic locus rs9783733 (NDN; PWRN4) was identified (P = 3.14E‐09, beta = 2.30, SE = 0.39). Remarkably, this variant could delay AAO of PD by ~2.43 years, with a more considerable effect on males (~3.18 years) than females (~1.45 years). The variant was suggestively significant in the cross‐ethnic meta‐analysis and suggested a positive selection in the East Asian population. Additionally, cross‐ethnic meta‐analysis identified a significant locus rs356203 in SNCA (P = 2.35E‐11, beta = −0.71, SE = 0.01). Conclusions These findings improve the current understanding of the genetic etiology of AAO of PD in different ethnic groups, and provide a new target for further research on PD pathogenesis and potential therapeutic options. © 2021 International Parkinson and Movement Disorder Society

Objective To evaluate whether the control status of type 2 diabetes mellitus (DM) influences the progression of Parkinson’s disease (PD). Methods We conducted a prospective cohort study from March 2009 to August 2020. Patients at baseline were categorized into DM and non‐DM groups, and those with DM were further classified into the well and poorly controlled DM groups based on the 7.0% of glycated hemoglobin (HbA1C) levels. Multivariate Cox proportional hazards regression models were used to explore the predictors for PD‐related outcomes by hazard ratios (HRs) and 95% confidence intervals (CIs). Results Of the 379 patients enrolled, 49 (12.9%) had DM, and 22 of DM (44.9%) were poorly controlled. The adjusted HRs were 2.060 (95% CI 1.165‐3.641) for United Rating Scale (UPDRS) III score increased ≥14 in the poorly controlled‐DM group, and 1.066 (95% CI 0.572‐1.986) in the well‐controlled DM group, relative to the non‐DM group (p trend = 0.025), after adjusting for sex, age, age of onset, body mass index, and UPDRS III and Montreal Cognitive Assessment (MoCA) scores at baseline. The adjusted HRs were 2.079 (95% CI 1.212‐3.566) for reaching Hoehn & Yahr stage ≥3 in the poorly controlled DM group, and 0.879 (95% CI 0.413‐1.871) in the well‐controlled DM group, compared with the non‐DM group (p trend = 0.021). Time to death or time to MoCA 3‐point decrease were not significantly different among the three groups. Interpretation Poorly controlled DM is an independent risk factor contributing to motor progression in PD. Our study highlights the importance of adequate control of diabetes in PD.

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A BS TRACT: Background: Defects in the α-synuclein, leucine-rich repeat kinase 2, or glucocerebrosidase genes have been regarded as essential contributors to PD. However, genetic variability of these genes with respect to early-onset PD remains poorly defined for the Chinese demographic. Objectives: We aim to systematically characterize the clinical and genetic architecture of α-synuclein, leucinerich repeat kinase 2, and glucocerebrosidase in Chinese early-onset PD patients. Methods: Whole-exome sequencing and Sanger sequencing were used to identify variants of α-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase in 662 Chinese early-onset PD patients. Haplotype and burden analyses were conducted to investigate the role of rare variants of these three genes in early-onset PD. Results: Sixty rare variants, including 23 novel variants, were identified in 73 patients (11.0%). Frequencies of patients with rare pathogenic/likely pathogenic variants of α-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase were 0.6%, 3.0%, and 5.4%, respectively. Evidences of two founder events exclusive to Asians were identified in 2 patients with leucine-rich repeat kinase 2 p.R1441C and 3 patients with α-synuclein p.A53V. Gene-based burden analysis supported glucocerebrosidase as a strong risk factor for early-onset PD, but argued against over-representation of rare variants in α-synuclein or leucine-rich repeat kinase 2 in early-onset PD. Clinically, no differences in motor or nonmotor symptoms were found between glucocerebrosidase variants carriers, and noncarriers or between leucine-rich repeat kinase 2 carriers and noncarriers. Patients with α-synuclein variants showed both rapid progression and worse cognitive impairment. Conclusion: Our study provides a better understanding of the clinical and genetic correlations of α-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase in early-onset PD, which may be beneficial for drafting genetic scanning strategies and evaluating disease progression.