High-depth whole-genome sequencing identifies structure variants, copy number variants and short tandem repeats associated with Parkinson's disease.

While numerous single nucleotide variants and small indels have been identified in Parkinson's disease (PD), the contribution of structural variants (SVs), copy number variants (CNVs), and short tandem repeats (STRs) remains poorly understood. Here we investigated the association using the high-depth whole-genome sequencing data from 466 Chinese PD patients and 513 controls. Totally, we identified 29,561 SVs, 32,153 CNVs, and 174,905 STRs, and found that CNV deletions were significantly enriched in the end-proportion of autosomal chromosomes in PD. After genome-wide association analysis and replication in an external cohort of 352 cases and 547 controls, we validated that the 1.6 kb-deletion neighboring MUC19, 12.4kb-deletion near RXFP1 and GGGAAA repeats in SLC2A13 were significantly associated with PD. Moreover, the MUC19 deletion and the SLC2A13 5-copy repeat reduced the penetrance of the LRRK2 G2385R variant. Moreover, genes with these variants were dosage-sensitive. These data provided novel insights into the genetic architecture of PD.

Gait Analysis with Wearable Sensors in Isolated REM Sleep Behavior Disorder Associated with Phenoconversion: An Explorative Study.

Background: Gait disturbance is a vital characteristic of motor manifestation in α- synucleinopathies, especially Parkinson's disease. Subtle gait alterations are present in isolated rapid eye movement sleep behavior disorder (iRBD) patients before phenoconversion; it is yet unclear, if gait analysis may predict phenoconversion. Objective: To investigate subtle gait alterations and explore whether gait analysis using wearable sensors is associated with phenoconversion of iRBD to α-synucleinopathies. Methods: Thirty-one polysomnography-confirmed iRBD patients and 33 healthy controls (HCs) were enrolled at baseline. All participants walked for a minute while wearing 6 inertial sensors on bilateral wrists, ankles, and the trunk (sternal and lumbar region). Three conditions were tested: (i) normal walking, (ii) fast walking, and (iii) dual-task walking. Results: Decreased arm range of motion and increased gait variation (stride length, stride time and stride velocity) discriminate converters from HCs at baseline. After an average of 5.40 years of follow-up, 10 patients converted to neurodegenerative diseases (converters). Cox regression analysis showed higher value of stride length asymmetry under normal walking condition to be associated with an early conversion of iRBD to α- synucleinopathies (adjusted HR 4.468, 95% CI 1.088- 18.349, p = 0.038). Conclusions: Stride length asymmetry is associated with progression to α- synucleinopathies in patients with iRBD. Gait analysis with wearable sensors may be useful for screening, monitoring, and risk stratification for disease-modifying therapy trials in patients with iRBD.

Association between postural tremor and risk of disability in community-dwelling older people.

BACKGROUND: The prevalence of postural tremor increases with age and the tremor has been found to be associated with aging-related physiological decline. However, whether postural tremor in older adults is associated with adverse outcomes such as disability is unclear. This study investigated the association between postural tremor and the risk of disability in activities of daily living (ADL) among community-dwelling older people. METHODS: Data were derived from a population-based study of Chinese adults aged ≥55 years. Postural tremor was assessed at baseline using a two-step method (i.e., tremor screening followed by examination of positive cases). ADL disability was determined using an 8-item questionnaire, which covered the mobility and self-care domains of ADL. Participants free of ADL disability at baseline were followed for up to 4 years. RESULTS: The prospective analyses included 5868 participants. Participants with postural tremor were at greater risk of incident ADL disability, particularly disability in the mobility domain of ADL. After multivariate adjustment, postural tremor was not significantly associated with incident ADL disability (multivariate-adjusted relative risk [RR] = 1.05, 95% confidence interval [CI] = 0.77-1.43), and was marginally associated with incident disability in the mobility domain of ADL (multivariate-adjusted RR = 1.36, 95% CI = 0.98-1.88). The risk of mobility-related ADL disability was significantly increased among men, but not women, with postural tremor (multivariate-adjusted RR = 1.84, 95% CI = 1.11-3.05). Older age and an increased number of chronic comorbidities mainly explained the higher risk of ADL disability in older people with postural tremor. CONCLUSIONS: Postural tremor in older adults is associated with greater incidence of ADL disability, particularly mobility-related ADL disability. The association is largely due to older age and a higher prevalence of chronic comorbidities in older people with postural tremor. Postural tremor is not a strong independent predictor of ADL disability in older people.

Structural and functional brain alterations in patients with idiopathic rapid eye movement sleep behavior disorder.

OBJECTIVE: To investigate structural and functional alterations in patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) compared with healthy controls. METHODS: Twenty-seven patients with polysomnography-confirmed iRBD and 33 healthy subjects were recruited. All subjects underwent a 3-tesla structural and resting-state functional magnetic resonance imaging (fMRI) examination. Voxel-based morphometry (VBM) analysis was performed to assess grey matter alterations between groups. The amplitude of low-frequency fluctuations (ALFF) was calculated and then compared to measure differences in spontaneous brain activity. Correlations were performed to explore associations between imaging metrics and clinical characteristics in iRBD patients. RESULTS: Compared with healthy controls, patients with iRBD had decreased grey matter volume in the frontal, temporal, parietal, occipital cortices as well as increased grey matter volume in cerebellum posterior lobe, putamen, and thalamus. Patients with iRBD also exhibited increased ALFF values in the right parahippocampal gyrus. Olfaction correlated with ALFF value changes in occipital cortices. CONCLUSIONS: Patients with iRBD had widespread decreases of grey matter volume. Increases of grey matter volume in cerebellum, putamen, and thalamus may suggest a compensatory effect, while the altered ALFF values in parahippocampal gyrus and occipital cortices may play a role in the underlying process of neurodegeneration in this disorder.

Detection of Motor Dysfunction With Wearable Sensors in Patients With Idiopathic Rapid Eye Movement Disorder.

Patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) are at high risk for conversion to synucleinopathy and Parkinson disease (PD). This can potentially be monitored by measuring gait characteristics of iRBD patients, although quantitative data are scarce and previous studies have reported inconsistent findings. This study investigated subclinical gait changes in polysomnography-proven iRBD patients compared to healthy controls (HCs) during 3 different walking conditions using wearable motor sensors in order to determine whether gait changes can be detected in iRBD patients that could reflect early symptoms of movement disorder. A total 31 iRBD patients and 20 HCs were asked to walk in a 10-m corridor at their usual pace, their fastest pace, and a normal pace while performing an arithmetic operation (dual-task condition) for 1 min each while using a wearable gait analysis system. General gait measurements including stride length, stride velocity, stride time, gait length asymmetry, and gait variability did not differ between iRBD patients and HCs; however, the patients showed decreases in range of motion (P = 0.004) and peak angular velocity of the trunk (P = 0.001) that were significant in all 3 walking conditions. iRBD patients also had a longer step time before turning compared to HCs (P = 0.035), and the difference between groups remained significant after adjusting for age, sex, and height. The decreased trunk motion while walking and increased step time before turning observed in iRBD may be early manifestations of body rigidity and freezing of gait and are possible prodromal symptoms of PD.

Musculoskeletal Pain in Parkinson's Disease.

BACKGROUND: Musculoskeletal pain is commonly experienced in patients with Parkinson's disease (PD). Few studies have investigated the clinical characteristics and risk factors associated with musculoskeletal pain. OBJECTIVES: To investigate the distribution, clinical characteristics, and factors associated with musculoskeletal pain in a large sample of patients with PD. METHODS: We enrolled 452 patients from two clinics and used a standardized questionnaire to collect demographic and clinical information. Musculoskeletal pain was diagnosed based on the Ford Classification System, and pain severity was assessed with the numeric rating scale (NRS). Multivariate regression models explored the association between clinical features of PD and quality of life and pain. RESULTS: Two hundred and six patients (45.58%) reported musculoskeletal pain, typically in their lower limbs and backs. Levodopa resulted in a ≥30% reduction in pain intensity scores in 170 subjects. Female sex (odds ratio [OR], 1.57; 95% CI, 1.07-2.29) and Levodopa-equivalent daily doses (LEDDs; OR, 3.35; 95% CI, 1.63-6.59) were associated with an increased risk for musculoskeletal pain. Pain duration (p = 0.017), motor symptoms (p < 0.001), and depression (p < 0.001) were significantly associated with quality of life. CONCLUSIONS: The lower limbs and back are common sites of musculoskeletal pain in patients with PD, and up to 82.52% of patients were responsive to Levodopa. Female sex and LEDDs are associated with musculoskeletal pain, suggesting that dopamine deficiencies, and not the motor and non-motor impairment, might be the most critical baseline risk factor of musculoskeletal pain.

Risk factors for possible REM sleep behavior disorders: A community-based study in Beijing.

OBJECTIVE: To explore the risk factors for idiopathic REM sleep behavior disorder (RBD) in a community population in Beijing. METHODS: Participants aged 55 years and above were recruited from the Beijing Longitudinal Study on Aging II cohort. We identified individuals with possible RBD (pRBD) using the validated RBD Questionnaire-Hong Kong in 2010. A series of environmental, lifestyle, and other potential risk factors were assessed via standardized questionnaires in 2009. Multivariable logistic regression analysis was performed to investigate the association between the studied factors and pRBD. RESULTS: Of 7,225 participants who were free of parkinsonism and dementia, 219 (3.0%) individuals were considered as having pRBD. Participants with pRBD reported more nonmotor and motor symptoms of Parkinson disease (PD) with adjusted odds ratios (ORs) ranging from 1.10 to 4.40. Participants with pRBD were more likely to report a family history of parkinsonism or dementia (OR 3.03, 95% confidence interval [CI] 1.23-7.46). There was a significant association between pRBD and self-reported hyperlipidemia (OR 1.51, 95% CI 1.09-2.10), ever smoking (OR 1.79, 95% CI 1.20-2.65), prior carbon monoxide (CO) poisoning (OR 2.30, 95% CI 1.39-3.83), and nonoccupational exposure to pesticides (OR 2.21, 95% CI 1.40-3.50). CONCLUSION: Our study replicated previously reported associations between pRBD and hyperlipidemia, smoking, pesticide exposure, and several prodromal PD symptoms. We also found previously unreported links with a positive family history of parkinsonism or dementia and CO poisoning. Risk factor profiles for pRBD partially resemble those defined for PD, but also differ in distinct ways.

Validation of a new olfactory test for Chinese Parkinson's disease patients.

INTRODUCTION: Hyposmia is a common non-motor symptom in Parkinson's disease (PD) and has been used to assist PD diagnosis and early screening of prodromal patients. Although the Brief Smell Identification Test (B-SIT) is the most commonly used olfactory test, its utility was limited by the culture difference in recognition of the smells included in the test. We have developed a new modified B-SIT test for Chinese (B-SITC), and validated and compare it with B-SIT in Chinese PD patients. METHODS: From 2015 to 2018, PD patients were recruited from the Movement Disorder Clinic of Xuanwu Hospital and healthy controls were recruited from the Beijing Longitudinal Study on Aging Cohort II. The two olfactory tests were used in healthy volunteers and PD patients. RESULTS: A total of 428 subjects participated in the study: 211 healthy controls and 217 PD patients. The average B-SIT and B-SITC scores were significantly different between control and PD groups (B-SIT, 9.18 ± 1.94 vs. 6.90 ± 2.44, P = 0.0001; B-SITC, 8.60 ± 1.93 vs. 5.91 ± 2.21, P = 0.0001). The B-SITC had good sensitivity (73.1%), specificity (76.8%), positive predictive value (76.8%), and negative predictive value (73.1%) for the diagnosis of Chinese PD, and the area under the curve (AUC) value was greater for the B-SITC than for the B-SIT (0.838 vs. 0.761). CONCLUSIONS: The B-SITC is useful for the clinical assessment of olfactory function in Chinese PD patients.

Education Moderates the Association of Probable REM Sleep Behavior Disorder With Cognitive and Motor Impairments in Community-Dwelling Older People.

Objectives: To investigate the relationship between probable rapid eye movement (REM) sleep behavior disorder (pRBD) and cognitive/motor impairments in a community-dwelling population and explore the moderating effects of education. Methods: In this cross-sectional study of the Beijing Longitudinal Study of Aging II (BLSA II), 4,477 subjects (≥55 years) fulfilled the inclusion criteria. pRBD was determined by the RBD Questionnaire-Hong Kong (RBDQ-HK). Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to test the global cognitive performance. Walking speed was used to measure motor function. Logistic regression was performed to assess the relationship between pRBD and cognitive/motor impairments and the moderating effects of education. Results: There were 147 participants (3.3%) with pRBD. Participants with pRBD showed increased risks for cognitive impairment [odds ratio (OR) = 1.88, 95% CI 1.24-2.85, p = 0.003], decreased gait speed (OR = 1.43, 95% CI 1.02-2.01, p = 0.03), but not for mild cognitive impairment (MCI) (measured by MoCA: OR = 1.01, 95% CI 0.68-1.50, p = 0.95; measured by MMSE: OR = 0.90, 95% CI 0.59-1.37, p = 0.62). Education modified the effect of pRBD on MCI (measured by MoCA: p < 0.001; measured by MMSE: p = 0.061) and gait speed (p = 0.008). Conclusions: Our findings suggest that pRBD increases the risk of cognitive/motor impairments for a community-dwelling older population, and education could alleviate the negative effects. These findings implicate that education may have beneficial effects on delaying the onset of cognitive/motor decline in pRBD subjects.

Decreased Penetrance of Parkinson's Disease in Elderly Carriers of Glucocerebrosidase Gene L444P/R Mutations: A Community-Based 10-Year Longitudinal Study.

BACKGROUND: Heterozygous mutations in the glucocerebrosidase gene (GBA) have been shown to be an important genetic risk factor for Parkinson's disease (PD) worldwide. However, the penetrance of GBA heterozygote for L444P, the common mutation for Asian population, is not known in older Chinese people. OBJECTIVES: To assess the conversion rate to PD in identified carriers of GBA L444P/R mutations in Chinese community-dwelling older adults. METHODS: The GBA gene was sequenced for mutations at position 444 in 8405 people older than 55 years who participated in the Beijing Longitudinal Study on Aging II cohort. Nine subjects were identified as heterozygous carriers of GBA L444P or L444R mutations at baseline and clinically followed up from 2009 to 2019 to investigate their PD conversion, motor and nonmotor symptoms, and change of vesicular monoamine transporter type 2 using tracer of [18 F]9-fluoropropyl-(+)-dihydrotetrabenazine (18 F-DTBZ, also known as 18 F-AV-133). RESULTS: Eight heterozygous GBA L444P and 1 L444R mutation carriers were identified without PD at baseline, and none of them developed clinical parkinsonism after a 10-year follow-up. CONCLUSIONS: Although GBA mutations may lead to an earlier onset PD, the majority of GBA L444P heterozygotes in older adults may not convert to PD. Further studies are warranted to identify factors that modify the risk of conversion. © 2020 International Parkinson and Movement Disorder Society.

Cervical dystonia incidence and diagnostic delay in a multiethnic population.

BACKGROUND: Current cervical dystonia (CD) incidence estimates are based on small numbers in relatively ethnically homogenous populations. The frequency and consequences of delayed CD diagnosis is poorly characterized. OBJECTIVES: To determine CD incidence and characterize CD diagnostic delay within a large, multiethnic integrated health maintenance organization. METHODS: We identified incident CD cases using electronic medical records and multistage screening of more than 3 million Kaiser Permanente Northern California members from January 1, 2003, to December 31, 2007. A final diagnosis was made by movement disorders specialist consensus. Diagnostic delay was measured by questionnaire and health utilization data. Incidence rates were estimated assuming a Poisson distribution of cases and directly standardized to the 2000 U.S. census. Multivariate logistic regression models were employed to assess diagnoses and behaviors preceding CD compared with matched controls, adjusting for age, sex, and membership duration. RESULTS: CD incidence was 1.18/100,000 person-years (95% confidence interval [CI], 0.35-2.0; women, 1.81; men, 0.52) based on 200 cases over 15.4 million person-years. Incidence increased with age. Half of the CD patients interviewed reported diagnostic delay. Diagnoses more common in CD patients before the index date included essential tremor (odds ratio [OR] 68.1; 95% CI, 28.2-164.5), cervical disc disease (OR 3.83; 95% CI, 2.8-5.2), neck sprain/strain (OR 2.77; 95% CI, 1.99-3.62), anxiety (OR 2.24; 95% CI, 1.63-3.11) and depression (OR 1.94; 95% CI, 1.4-2.68). CONCLUSIONS: CD incidence is greater in women and increases with age. Diagnostic delay is common and associated with adverse effects. © 2019 International Parkinson and Movement Disorder Society.

Visual dysfunction in patients with idiopathic rapid eye movement sleep behavior disorder.

OBJECTIVE: Visual dysfunction is a common feature in α-synucleiopathies but rarely assessed in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD). The current study is set to investigate the comprehensive visual function in iRBD as compared to patients of Parkinson's disease (PD) with RBD. METHODS: Eighty-three iRBD subjects diagnosed with polysomnograph (PSG), 52 early PD patients (Hoehn-Yahr stages<3) with RBD symptom prior to onset of motor symptoms and 79 healthy controls without RBD diagnosed based on RBD Questionnaire-Hong Kong (RBDQ-HK) were enrolled in this study. Visual function including color discrimination, stereopsis function, visual illusion (VI) or hallucination (VH) were assessed in addition to UPDRS, Purdue Pegboard test (PPT) and cognitive tests. RESULTS: Abnormal color discrimination and stereopsis were presented significantly higher in both iRBD and PD patients as compared to controls and more severe in PD than in iRBD. Color discrimination was decreased in all four color in PD patients but not green color in iRBD subjects. Stereopsis test was abnormal in both iRBD and PD, but the proportion of subjects with abnormal stereopsis was significantly higher in PD patients (69.6% vs 42%). Similar number of subjects with iRBD and PD were presented with illusion but only PD patients reported more hallucination. Changes of visual function were associated with age and cognition in both iRBD and PD subjects but was also affected independently by disease duration and clinical stage or fine motor function in PD. In addition, decreased fine motor function demonstrated by PPT was also observed in some iRBD subjects. CONCLUSION: Our results demonstrated comprehensively that visual dysfunction was present in iRBD subjects similar but in a less degree of severity to PD patients, and associated with age, cognition and motor deficit. Whether or not it can be useful in predicting iRBD conversion to PD warrants further investigation.

Postural Tremor Is Associated with Gait and Balance Impairments in Community-Dwelling Older People.

OBJECTIVES: We sought to assess associations of postural tremor with gait and balance impairments among community-dwelling older people in both cross-sectional and longitudinal analyses. DESIGN: A prospective cohort study. SETTING: Communities in Beijing, China. PARTICIPANTS: This study included 7075 individuals aged 55 years or older. MEASUREMENTS: Postural tremor was assessed using a two-step method (tremor screening followed by a confirmation examination of positive cases) at baseline. Gait and balance performances were measured with the Tinetti Mobility Test at baseline and 1 year later. RESULTS: At baseline, 45 (24.7%) of 182 tremor cases vs 663 (9.6%) of 6893 controls had gait and balance impairments. At 1-year follow-up, 19 (21.1%) of 90 tremor cases vs 416 (9.8%) of 4262 controls experienced a rapid decline in gait and balance performance. After controlling for potential confounders, postural tremor was associated with gait and balance impairments at baseline (odds ratio [OR] = 1.77; 95% confidence interval [CI] = 1.20-2.62; p = .004) and a rapid decline in gait and balance performance at 1-year follow-up (OR = 1.99; 95% CI = 1.17-3.39; p = .01). CONCLUSION: In this population-based cohort study, we found postural tremor was associated with gait and balance impairments among community-dwelling older people in both cross-sectional and longitudinal analyses. Our findings suggest that motor function should be routinely evaluated and monitored in older people with postural tremor. J Am Geriatr Soc 67:799-803, 2019.

Validation of the utility of the Brief Smell Identification Test in Chinese patients with Parkinson's disease.

INTRODUCTION: Hyposmia is a common non-motor symptom occurring in Parkinson's disease (PD), and has been included in the diagnostic criteria. Although a version of the Brief Smell Identification Test (B-SIT) has been developed specifically for Chinese populations, there have been no reports of the utility of this test in the diagnosis of PD in China. OBJECTIVE: Considering the influence of cultural factors on olfactory test findings, we sought to investigate the utility and efficiency of the B-SIT in Chinese PD patients. METHODS: PD patients were recruited from the Movement Disorder Clinic of Xuanwu Hospital, and healthy controls were recruited from the Beijing Longitudinal Study on Aging Cohort II, between 2015 and 2016. The B-SIT was used for olfactory function testing in all subjects, and the familiarity of 59 odors questionnaire was performed for the investigation of familiarity of odors. RESULTS: A sample of 275 subjects participated in the study, including 112 healthy controls and 163 PD patients. The sensitivity (64.1%), specificity (83.9%), positive predictive value (83.5%) and negative predictive value (64.8%) for identifying PD were measured with the B-SIT. The consistency values between the results of self-reported smell loss and hyposmia identified by B-SIT in control and PD groups were 74.8% and 64.2%, respectively. Most of the odors in the B-SIT were familiar to people in the Chinese population, based on a survey of 3356 subjects using a familiarity questionnaire. CONCLUSIONS: It is recommended to use the B-SIT olfactory test instead of self-reported smell loss for PD diagnosis for Chinese.

Prevalence of pre-diagnostic symptoms did not differ between LRRK2-related, GBA-related and idiopathic patients with Parkinson's disease.

INTRODUCTION: Glucocerebrosidase (GBA) mutations and leucine-rich repeat kinase 2 (LRRK2) variants are the most common genetic risk factors for late-onset Parkinson's disease (PD). In this study, we aimed to investigate the differences in pre-diagnostic symptoms of PD associated with the variants. METHODS: The participants were recruited from 24 centers across China and genotyped for LRRK2 G2385R and R1628P variants and GBA L444P mutation. Participants were surveyed with structural questionnaires for history of environmental exposure and living habits and interviewed to collect the time at onset of each symptoms before diagnosis. We compared the cumulative prevalence and manifestation pattern of symptoms between groups using multiple logistic regression, adjusting age and gender. RESULTS: Total 1799 PD patients were recruited, including 226 patients with LRRK2 G2385R or R1628P variant, 44 with GBA L444P mutation, three with both LRRK2 and GBA mutation, and 1526 idiopathic patients. The cumulative prevalence of non-motor and typical motor symptoms did not differ between groups before diagnosis (P > 0.05). The manifestation sequences of non-motor symptoms were indistinguishable between the LRRK2-carriers, GBA-carriers, and idiopathic PD subjects, and followed the sequence of constipation, hyposmia, sleep disorders, anxiety and depression, sexual dysfunction, urinary incontinency, dizziness and cognition. Slightly higher prevalence of hypomimia and micrographia were detected in the GBA-carriers. CONCLUSIONS: The prevalence of pre-diagnostic symptoms is almost indistinguishable between the LRRK2-carriers, GBA-carriers, and idiopathic PD before diagnosis; the sequence of the manifestation of non-motor symptoms largely conforms to the Braak stage for both genetic-related and idiopathic late-onset PD.

Olfactory Dysfunction in Parkinson's Disease Patients with the LRRK2 G2385R Variant.

Olfactory dysfunction has been reported in Parkinson's disease (PD) patients carrying the LRRK2 G2019S variant in Caucasians but rarely in those with the LRRK2 G2385R variant. In this study, we performed genotyping for the LRRK2 G2385R variant in PD patients recruited from the Movement Disorder Clinic of Xuanwu Hospital in Beijing and in healthy controls randomly selected from the Beijing Longitudinal Study on Aging cohort. The "five-odor olfactory detection array", an olfactory threshold test, was used to assess olfactory function. One hundred and eighty-six participants were enrolled, comprising 43 PD patients without (iPD) and 25 with (LRRK2-PD) the LRRK2 G2385R variant, and 118 healthy controls. Our results showed that the threshold of olfactory identification was significantly worse in PD patients than in controls, but not significantly different between the iPD and LRRK2-PD groups. These findings suggested that although olfactory function in LRRK2-PD patients is impaired, it is similar to that in iPD patients.

Association between common genetic risk variants and depression in Parkinson's disease: A dPD study in Chinese.

INTRODUCTION: Prediction of depression in patients with Parkinson's disease (PD) remains challenging. We investigated whether the common susceptible genetic variants for PD are associated with the risk and improves prediction of development of depression in PD (dPD). METHODS: 1134 individuals with a primary diagnosis of PD were recruited. Demographic information, Unified Parkinson's Disease Rating Scale (UPDRS), and 17-item Hamilton Rating Scale for Depression (HAMD) were obtained. Nine variants located in six susceptible genes for PD were determined in all subjects. Logistic regression analyses were used to identify the study genetic variants that individually and collectively best predicted the presence of depressive disorder (HAMD ≥14). RESULTS: Depression occurred in 19.8% of patients with PD. The GBA L444P variant was associated with an increased risk of depression (odds ratio [OR] = 2.69, 95% confidence interval [CI] = 1.31-5.53, P = 0.007) and SNCA-Rep1 (CA)12/12 showed a decreased risk for the presence of depression (OR = 0.54, 95% CI = 0.29-0.99, P = 0.049) in the PD population after adjusted for demographic and clinical factors. Stepwise logistic regression model found that female sex, UPDRS part II score, motor fluctuation, GBA L1444P and SNCA Rep-1 variants collectively best predict depression in PD. CONCLUSIONS: Besides non PD-specific and PD-specific clinical correlates, we showed that GBA L444P and SNCA Rep-1 were also associated with dPD. Our findings highlight the crucial role of genetic variants for the prediction of dPD in clinical practice and may shed light on the future development of better therapeutic targets for dPD.

Clinical Manifestation of Parkinson's Disease in Association with Rapid Eye Movement Sleep Behavior Disorder Onset.

AIMS: To confirm whether the presence and/or timing of rapid eye movement sleep behavior disorder (RBD) onset were associated with differences in clinical features of Parkinson's disease (PD), clinical characteristics of PD patients with RBD occurring before and after PD diagnosis were investigated. METHODS: Consecutive PD patients were enrolled between July 2011 and February 2012. RBD questionnaire Hong Kong and clinical interviews were used to identify RBD symptoms and onsets. All patients underwent evaluations to collect clinical and treatment information. RESULTS: Of all 79 PD patients, 21 (26.6%) and 22 (27.8%) patients had RBD prior to (RBD-PD) and after PD diagnosis (PD-RBD), respectively. Thirty-six (45.6%) PD patients reported no RBD at the time of study (PD-NRBD). PD-RBD had similar clinical features as PD-NRBD did except that Epworth sleepiness scale score was significantly higher in PD-RBD (p = 0.04). Compared to PD-RBD and PD-NRBD, RBD-PD had a higher frequency of reporting excessive daytime sleepiness (p = 0.019, p = 0.008, respectively) and constipation (p = 0.046, p = 0.032, respectively). CONCLUSION: Our preliminary results suggest that RBD-PD might be clinically different from PD-RBD, which appears to share similar characteristics with PD-NRBD, regarding only non-motor functions.

Association of ARNTL and PER1 genes with Parkinson's disease: a case-control study of Han Chinese.

Circadian disruptions may result in sleep problems, oxidative stress and an altered inflammatory response. These symptoms may contribute to PD pathogenesis, despite a lack of direct experimental evidence supporting this relationship. Clock genes are essential to drive and maintain circadian rhythm. To elucidate the possible role of circadian disruptions in PD, we investigated 132 tag variants in eight clock genes. We genotyped these tags within 1,394 Chinese cases and 1,342 controls using Illumina GoldenGate chips. We discovered that SNPs in ARNTL (rs900147, P = 3.33 × 10(-5), OR = 0.80) and PER1 (rs2253820, P = 5.30 × 10(-6), OR = 1.31) genes are significantly associated with PD risk. Moreover, the positive association of the ARNTL rs900147 variant was more robust in tremor dominant (TD) (P = 3.44 × 10(-4)) than postural instability and gait difficulty (PIGD) cases (P = 6.06 × 10(-2)). The association of the PER1 rs2253820 variant was more robust in PIGD (P = 5.42 × 10(-5)) than TD cases (P = 4.2 × 10(-2)). Haplotype analysis also showed that ARNTL and PER1 were associated with PD. Imputation analysis identified more SNPs within ARNTL and PER1 associated with PD, some of which may affect gene expression through altering the transcription factor binding site. In summary, our findings suggest that genetic polymorphisms in ARNTL and PER1 genes, as well as circadian disruptions, may contribute to PD pathogenesis.

Heterogeneity among patients with Parkinson's disease: cluster analysis and genetic association.

The clinical heterogeneity of Parkinson's disease (PD) reveals the presence of several PD subtypes. The objectives of this study were to identify PD subtypes using cluster analysis (CA) and to determine the association between the subtypes and the polymorphisms in LRRK2 (G2385R and R1628P) and GBA (L444P) genes. A k-means CA of demographics, disease progression, motor and non-motor symptoms was performed from 1,510 Chinese PD patients from the Chinese National Consortium on Neurodegenerative Diseases. Pearson correlation analysis was performed to eliminate uninformative characteristics. Blood samples from 852 patients were obtained for genetic analysis of LRRK2 and GBA. Genotypic associations between various subtypes and genetic variants were examined using chi-square test. We identified four different subtypes: subtype 1 was non-tremor dominant (NTD, n=469; 31.1%); subtype 2 had a rapid disease progression with late onset (RDP-LO, n=67; 4.4%); subtype 3 had benign pure motor characteristics (BPM, n=778; 51.5%) without non-motor disturbances; and subtype 4 was tremor dominant with slow disease progression (TD-SP, n=196; 13.0%). Subtypes 1, 2, and 4 had similar mean age of onset. No associations were identified between polymorphisms in LRRK2 (R1628P) and GBA (L444P) genes and the four subtypes (P>0.05).