Association of choroid plexus volume with motor symptoms and dopaminergic degeneration in Parkinson's disease.

BACKGROUND: The choroid plexus (CP) is involved in the clearance of harmful metabolites from the brain, as a part of the glymphatic system. This study aimed to investigate the association between CP volume (CPV), nigrostriatal dopaminergic degeneration and motor outcomes in Parkinson's disease (PD). METHODS: We retrospectively searched drug-naïve patients with early-stage PD who underwent dopamine transporter (DAT) scanning and MRI. Automatic CP segmentation was performed, and the CPV was calculated. The relationship between CPV, DAT availability and Unified PD Rating Scale Part III (UPDRS-III) scores was assessed using multivariate linear regression. We performed longitudinal analyses to assess motor outcomes according to CPV. RESULTS: CPV was negatively associated with DAT availability in each striatal subregion (anterior caudate, ß=-0.134, p=0.012; posterior caudate, ß=-0.162, p=0.002; anterior putamen, ß=-0.133, p=0.024; posterior putamen, ß=-0.125, p=0.039; ventral putamen, ß=-0.125, p=0.035), except for the ventral striatum. CPV was positively associated with the UPDRS-III score even after adjusting for DAT availability in the posterior putamen (ß=0.121; p=0.035). A larger CPV was associated with the future development of freezing of gait in the Cox regression model (HR 1.539, p=0.027) and a more rapid increase in dopaminergic medication in the linear mixed model (CPV×time, p=0.037), but was not associated with the risk of developing levodopa-induced dyskinesia or wearing off. CONCLUSION: These findings suggest that CPV has the potential to serve as a biomarker for baseline and longitudinal motor disabilities in PD.

Association between choroid plexus volume and cognition in Parkinson disease.

BACKGROUND AND PURPOSE: The choroid plexus (CP) clears harmful metabolites from the central nervous system as part of the glymphatic system. We investigated the association of CP volume (CPV) with baseline and longitudinal cognitive decline in patients with Parkinson disease (PD). METHODS: We retrospectively reviewed the medical records of 240 patients with newly diagnosed PD who had undergone detailed neuropsychological tests and high-resolution T1-weighted structural magnetic resonance imaging during the initial assessment. The CPV of each patient was automatically segmented, and the intracranial volume ratio was used in subsequent analyses. The relationship between CPV and baseline composite scores of each cognitive domain was assessed using multivariate linear regression analyses. A Cox proportional hazards model was used to compare the risk of dementia conversion with CPV. RESULTS: CPV negatively correlated with composite scores of the frontal/executive function domain (ß = -0.375, p = 0.002) after adjusting for age, sex, years of education, and parkinsonian symptom duration. The Cox regression model revealed that a larger CPV was associated with a higher risk of dementia conversion (hazard ratio [HR] = 1.509, p = 0.038), which was no longer significant after adjusting for the composite scores of the frontal/executive function domain. A mediation analysis demonstrated that the effect of CPV on the risk of dementia conversion was completely mediated by frontal/executive function (direct effect: HR = 1.203, p = 0.396; indirect effect: HR = 1.400, p = 0.015). CONCLUSIONS: Baseline CPV is associated with baseline frontal/executive function, which subsequently influences dementia conversion risk in patients with PD.

Serial changes of I-123 FP-CIT SPECT binding asymmetry in Parkinson's disease: Analysis of the PPMI data.

Background: Dopaminergic denervation and motor symptoms are usually asymmetric at the onset of Parkinson's disease (PD). In this study, we estimated the asymmetry of specific binding ratio (SBR) of I-123 FP-CIT SPECT images during 4-years of follow up, to demonstrate the pattern of serial changes of asymmetry. Methods: Clinical and I-123 FP-CIT SPECT image data of 301 PD patients and 141 normal controls were reviewed from the Parkinson's Progression Markers Initiative cohort. I-123 FP-CIT SPECT images were taken at baseline, 1-, 2-, and 4-year follow up periods for PD patients, and at baseline for normal controls. Asymmetry index were calculated by two methods. Method 1, by using the ratio of absolute difference of right and left SBRs to the average SBR. Method 2, by using the ratio of absolute difference of right and left SBRs to the SBR values of age-matched normal controls. Results: Asymmetry index by method 2 revealed a more significant decrease during the 4-year follow up period, compared with method 1. The baseline asymmetry index of the putamen by method 2 showed significant correlation with the non-dominant putamen SBRs. However, there were no significant correlation with the baseline asymmetry index by method 2 and motor symptoms, cognition, nor autonomic symptoms. Conclusion: We suggest a novel asymmetry index in association to age-matched normal SBR values. This novel index could be adopted in predicting and evaluating the natural course of PD.

Factors associated with motor severity in vascular parkinsonism with normal dopamine transporter imaging.

INTRODUCTION: To delineate the determinants of motor severity in vascular parkinsonism (VaP), we investigated the impact of regional white matter intensity (WMH) burden and co-morbidities on the motor score in the patients with VaP and normal dopamine transporter (DAT) imaging. METHODS: In this multicenter, retrospective study, we reviewed the records of 63 patients diagnosed with VaP and normal DAT imaging on 18F-FP-CIT PET. Signal hyperintensities in deep white matter (DWMH), periventricular (PVH), basal ganglia (BG) regions, and infratentorial foci (ITF) were rated according to Scheltens scale, a semi-quantitative visual rating system. Motor severity was assessed with Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Regional hyperintensity scores, patients' demographics, and co-morbidities such as type 2 diabetes, hypertension, dyslipidemia, and previous stroke history were used as starting variables, and stepwise regression analysis was performed to select independent predictors of motor severity. RESULTS: PVH (R = 0.33, p = 0.008) and DWMH score (R = 0.31, p = 0.015) correlated with the motor severity, while BG and ITF scores did not. Diabetic patients had significantly higher motor scores compared with non-diabetics (34.7 (13.0) vs. 27.5 (12.4), p = 0.008). Other factors such as sex, BMI, hypertension, dyslipidemia, and previous history of stroke did not impact motor severity. In multivariate analysis, PVH scores and diabetes significantly correlated with motor severity. CONCLUSION: PVH burden and diabetes were independent factors associated with motor severity in VaP with normal DAT imaging. Our results suggest that diabetes, along with white matter hyperintensities, may have a significant role in the development of motor symptoms in VaP.

Irritable bowel syndrome and subsequent risk of Parkinson's disease: a nationwide population-based matched-cohort study.

BACKGROUND: Gastrointestinal dysfunction (GI) is the most prevalent non-motor symptom of Parkinson's disease (PD), and its role in the risk of PD has been studied. In this study, we tried to evaluate whether irritable bowel syndrome (IBS) increased the risk of PD development stratified by sex, age, and IBS duration using a large nationwide cohort in Korea. METHODS: Patients aged ≥ 20 years with a primary diagnosis of IBS (ICD-10 codes: G56) more than three times were selected. A randomly matched cohort without IBS was enrolled by exact matching patients for sex, age, socioeconomic status, comorbidities, and year of enrollment to the IBS group with a ratio of 1:3. Cause-specific Cox regression models were used to identify hazards associated with PD development depending on the presence of IBS during the 11-year follow-up period. RESULTS: In total, 285,064 patients were enrolled in the study: 71,806 in the IBS cohort and 213,258 in the comparison cohort. Cause-specific Cox regression model showed a hazard ratio of 1.436 (95% CI, 1.226-1.682) for PD development in the IBS cohort, which is consistent in both male and female sexes. Subgroup analyses according to age groups showed that IBS increased PD risk only in individuals ≥ 65 years (HR = 1.449, 95% CI, 1.207-1.741). CONCLUSIONS: We found temporal relationship between IBS and PD at aged ≥ 65 years. There might be a possibility that IBS was an early manifestation of PD, and future studies for causal link between the two diseases to elucidate biomechanism are warranted.

Correlation of Dopaminergic Denervation and the Progression of Autonomic Dysfunctions in Different Clinical Subtypes of Parkinson's Disease.

BACKGROUND: Autonomic dysfunctions occur in the early stage of Parkinson's disease (PD) and impact the quality of life during the progression of the disease. In this study, we evaluated the serial progression of autonomic dysfunctions between different subtypes of a prospective PD cohort. MATERIALS AND METHODS: From the Parkinson's Progression Markers Initiative (PPMI) database, 325 PD patients (age: 61.2 ± 9.7, M : F = 215 : 110) were enrolled. Patients were subgrouped into tremor-dominant (TD), indeterminate, and postural instability and gait disorder (PIGD) subtypes. The progression of autonomic dysfunctions and dopaminergic denervation from I-123 FP-CIT SPECT images of each group were analyzed and compared at baseline, 12 months, 24 months, and 48 months of follow-up periods. RESULTS: The SCOPA-AUT score of the indeterminate subtype was significantly higher than that of the TD subtype (P < 0.05) at baseline and was significantly higher than that of both TD and PIGD subtypes (P < 0.05) at 48 months. The indeterminate subtype had the most significant correlation between the aggravation of dopaminergic denervation in I-123 FP-CIT SPECT images and the increase of SCOPA-AUT scores during 48 months of follow-up (r = 0.56, P < 0.01). CONCLUSIONS: Autonomic dysfunctions were most severe in the indeterminate subtype throughout the 48 months of the follow-up period, with a significant correlation with dopaminergic denervation. We suggest a positive relationship between dopaminergic denervation and autonomic dysfunctions of the indeterminate subtype, beginning from the early stage of PD.

Rapid drug increase and early onset of levodopa-induced dyskinesia in Parkinson's disease.

A higher levodopa dose is a strong risk factor for levodopa-induced dyskinesia (LID) in patients with Parkinson's disease (PD). However, levodopa dose can change during long-term medication. We explored the relationship between levodopa dose and time to onset of LID using longitudinal multicenter data. Medical records of 150 patients who were diagnosed with de novo PD and treated with levodopa until onset of LID were collected. Levodopa dose were assessed as the dose at 6 months from levodopa initiation and rate of dose increase between 6 months and onset of LID. The groups with earlier LID onset had higher levodopa and levodopa-equivalent dose at the first 6 months of treatment and rapid increase in both levodopa and levodopa-equivalent dose. Multivariable linear regression models revealed that female sex, severe motor symptom at levodopa initiation, and higher rate of increase in both levodopa and levodopa-equivalent dose were significantly associated with early onset of LID. The present results demonstrated that rapid increase in levodopa dose or levodopa-equivalent dose is associated with early onset of LID.

Areas of white matter hyperintensities and motor symptoms of Parkinson disease.

OBJECTIVE: To determine whether deep white matter and periventricular hyperintensities affect the motor symptoms of Parkinson disease (PD) differently, we analyzed MRI and dopamine transporter imaging. METHODS: We analyzed the medical records of patients with de novo PD who underwent dopamine transporter PET scanning and MRI at their first visit. Deep white matter and periventricular hyperintensities were scored with a visual rating scale, and motor symptoms were assessed by Unified Parkinson's Disease Rating Scale motor score and tremor, rigidity, bradykinesia, and axial symptom subscores. The influence of white matter hyperintensity on motor symptoms was explored using multivariable linear regression models. RESULTS: A total of 93 patients (mean age, 67.2 ± 9.9 years; 44 male) were included and the mean motor score was 25.0 ± 10.8. Subscores for bradykinesia and axial symptoms were correlated with both deep white matter and periventricular hyperintensities scores. Multivariable linear regression models revealed that deep white matter hyperintensities score was significantly associated with subscore for bradykinesia and periventricular hyperintensities score was associated with subscores for bradykinesia and axial symptoms after adjusting for putaminal dopamine transporter availability and clinical factors. CONCLUSIONS: These results demonstrate that deep white matter hyperintensities are associated with bradykinesia and periventricular hyperintensities are associated with bradykinesia and axial symptoms in patients with PD independently of the severity of dopaminergic depletion.

Uric acid level may not be reduced in essential tremor.

BACKGROUND: Essential tremor is very common, but characterization is difficult because of its heterogeneity. Neuropathology is important to elucidate the characteristics of neurological disorders. However, pathological findings in essential tremor have been inconsistent among studies. Uric acid is a strong antioxidant and might be a biomarker in neurodegenerative process. We hypothesized that uric acid level would be reduced if essential tremor is a neurodegenerative disease. Our aim was to compare uric acid level between essential tremor patients and healthy individuals. METHODS: This was a prospective, case-control, multicenter study with 92 essential tremor patients and 77 healthy subjects. For homogeneity, the essential tremor group was subdivided into two groups (hereditary and sporadic). Clinical and laboratory findings were compared among the essential tremor and healthy groups. RESULTS: The demographic characteristics were comparable among the groups. The uric acid level was lower in the essential tremor group than in healthy subjects, but the difference did not reach statistical significance. There was a negative correlation between uric acid level and disease duration in the hereditary group (p = .046) and between uric acid level and age at onset in the sporadic group (p = .012). The mean values of total cholesterol were significantly lower in the sporadic group than in the other groups (p = .011). Total cholesterol was positively correlated with age at onset in the hereditary essential tremor group (p = .010). CONCLUSIONS: We did not find any evidence that uric acid levels suggested essential tremor is a neurodegenerative disease. However, further research with more patients might be needed given the negative correlations of disease duration and age at onset with uric acid level.

The cholinergic contribution to the resting-state functional network in non-demented Parkinson's disease.

The cholinergic system arising from the basal forebrain plays an important role in cognitive performance in Parkinson's disease (PD). Here, we analyzed cholinergic status-dependent cortical and subcortical resting-state functional connectivity in PD. A total of 61 drug-naïve PD patients were divided into tertiles based on normalized substantia innominata (SI) volumes. We compared the resting-state network from seed region of interest in the caudate, posterior cingulate cortex (PCC), and SI between the lowest (PD-L) and highest tertile (PD-H) groups. Correlation analysis of the functional networks was also performed in all subjects. The functional network analysis showed that PD-L subjects displayed decreased striato-cortical functional connectivity compared with PD-H subjects. Selecting the PCC as a seed, the PD-L patients displayed decreased functional connectivity compared to PD-H patients. Meanwhile, PD-L subjects had significantly increased cortical functional connectivity with the SI compared with PD-H subjects. Correlation analysis revealed that SI volume had a positive correlation with functional connectivity from the right caudate and PCC. The present study demonstrated that PD patients exhibited unique functional connectivity from the caudate and the PCC that may be closely associated with cholinergic status, suggesting an important role for the cholinergic system in PD-associated cognition.

Subjective Cognitive Complaints and Objective Cognitive Impairment in Parkinson's Disease.

BACKGROUND AND PURPOSE: Subjective cognitive complaints (SCCs) are very common in patients with Parkinson's disease (PD). However, the relationship between SCCs and objective cognitive impairment is still unclear. This study aimed to determine whether SCCs are correlated with objective cognitive performance in patients with PD. METHODS: Totals of 148 cognitively normal patients, 71 patients with mild cognitive impairment (MCI), and 31 demented patients were recruited consecutively from a movement-disorders clinic. Their SCCs and cognitive performances were evaluated using the Cognitive Complaints Interview (CCI) and a comprehensive neuropsychological battery. RESULTS: The CCI score increased with age, duration of PD, and depression score, and was inversely correlated with cognitive performance. The association between CCI score and performance remained significant after adjustment for the depression score, age, and duration of PD. The CCI score could be used to discriminate patients with dementia from cognitively normal and MCI patients [area under the receiver operating characteristics curve (AUC) of 0.80], but not patients with MCI or dementia from cognitively normal patients (AUC of 0.67). CONCLUSIONS: SCCs as measured by the CCI are strongly correlated with objective cognitive performance in patients with PD. The CCI can also be used to screen for dementia in patients with PD.

Serial I-123-FP-CIT SPECT Image Findings of Parkinson's Disease Patients With Levodopa-Induced Dyskinesia.

Background: Levodopa-induced dyskinesia (LID) is a major complication of dopamine replacement drug usage in Parkinson's disease (PD) patients. Since the mechanism of LID is yet unclear, we analyzed serial [I-123] N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane (I-123 FP-CIT) single photon emission computed tomography (SPECT) images. We investigated the changes of dopaminergic innervation during the progression of PD in relation to the development of LID. Methods: Data were obtained from the Parkinson's Progression Markers Initiative (PPMI) database. Two hundred and ninety PD dopamine replacement drug-naïve patients (age 61.0 ± 9.7, M: F = 195: 95) were enrolled. I-123 FP-CIT SPECT images from baseline, 12, 24, and 48 months were analyzed among with clinical factors. specific binding ratios (SBRs) of the striatal regions from I-123 FP-CIT SPECT images were analyzed. We used independent tests and logistic regression for analysis of LID risk association. Results: Among 290 patients, 36 patients developed LID after 48 months follow-up. Baseline MDS-UPDRS Part II and III scores were significantly higher in the PD patients with LID, compared with the PD patients without LID. Striatal SBRs were significantly lower in the PD patients with LID at baseline, 24 and 48 months (p < 0.001). Multivariate analysis revealed MDS-UPDRS Part II and putaminal SBRs at baseline and 24 months to be significantly associated with the development of LID (p < 0.001). Also, patients who developed LID at 48 months had a higher decrease rate of putaminal SBR at the 24 months (p < 0.05), and 48 months (p < 0.01) period. Conclusion: In this study, we demonstrated the serial changes of the nigrostriatal dopaminergic innervation in relationship to LID development for the first time. The deterioration rate of dopaminergic innervation was significantly higher in the PD patients who developed LID, compared with the PD patients who did not develop LID. Serial follow up I-123 FP-CIT SPECT acquisition during the course of PD could be helpful in predicting the development of LID.

Validation of MoCA-MMSE Conversion Scales in Korean Patients with Cognitive Impairments.

BACKGROUND AND PURPOSE: Two conversion scales between the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) have been validated for Korean patients with Parkinson's disease. The aim of the present study was to validate these conversion scales for all patients with cognitive impairments regardless of dementia subtype. METHODS: Medical records of 323 subjects who completed both MMSE and MoCA on the same day were retrospectively reviewed. Mean, median, and root mean squared error (RMSE) of the difference between true and equivalent MMSE scores were calculated. Intraclass correlation coefficients (ICCs) between true and equivalent MMSE scores were also calculated. The validity of MoCA-MMSE conversion scales was evaluated according to educational level (low educated: ≤6 years; high educated: ≥7 years) and subtypes of cognitive impairment. RESULTS: The difference between true and equivalent MMSE scores had a median value of 0, a mean value of 0.19 according to the van Steenoven scale, a mean value of 0.57 according to the Lawton scale, RMSE value of 2.2 according to the van Steenoven scale, and RMSE value of 0.42 according to the Lawton scale. Additionally, ICCs between true and equivalent MMSE scores were 0.92 and 0.90 on van Steenovan and Lawton conversion scales, respectively. These results were maintained in subgroup analyses. CONCLUSIONS: Findings of the present study suggest that both van Steenovan and Lawton MoCA-MMSE conversion scales are applicable to transforming MoCA scores into MMSE scores in patients with cognitive impairments regardless of dementia subtype or educational level.

Sleepiness and Depression in Parkinson's Disease Patients Treated with Ropinirole and Levodopa.

OBJECTIVE: We aimed to investigate the effect of ropinirole on excessive daytime sleepiness (EDS) and depression in Parkinson's disease (PD) with a large population. METHODS: We conducted a cross-sectional observational study at nine hospitals in Korea between April 24, 2013, and April 22, 2015. We analyzed the demographic and clinical features, other medical history, history of antiparkinsonian medication within 6 months, Hoehn and Yahr stage (HY stage), Unified Parkinson's Disease Rating Scale (UPDRS) part II and III, Epworth Sleepiness Scale (ESS), and 30-item Geriatric Depression Scale (GDS-30). RESULTS: Four-hundred-thirteen patients with PD (mean age: 65.2 ± 9.0 years; men: 227 patients) were analyzed. Multivariate logistic regression analysis showed that age at examination, UPDRS II, and GDS-30 were independent risk factors for EDS and that sex, UPDRS II, and ESS were independent risk factors for depression. CONCLUSION: Our large group study did not find any significant associations of ropinirole with EDS and depression in Korean PD patients.

Repetitive Nerve Stimulation in MuSK-Antibody-Positive Myasthenia Gravis.

BACKGROUND AND PURPOSE: Responses to repetitive nerve stimulation (RNS) in patients with muscle-specific tyrosine kinase (MuSK) antibody (Ab)-positive myasthenia gravis (MG) vary depending on the muscles tested. We analyzed the RNS responses of limb and facial muscles in MuSK-Ab-positive and acetylcholine receptor (AChR)-Ab-negative MG (MuSK MG) and MuSK-Ab-negative and AChR-Ab-negative [double-seronegative (DSN)] MG patients. METHODS: We retrospectively compared RNS responses between 45 MuSK MG and 29 DSN MG. RNS was applied to the abductor digiti minimi, flexor carpi ulnaris, trapezius, orbicularis oculi, and nasalis muscles. RESULTS: Abnormal RNS responses in limb muscles were observed in 22.2 and 58.6% of MuSK MG and DSN MG patients, respectively, with abnormal facial responses observed in 77.8 and 65.5%, and abnormal responses observed in any of the five muscles in 86.7 and 72.4%. Abnormal RNS responses in the abductor digiti minimi or flexor carpi ulnaris were less frequent in MuSK MG (8.9 and 15.6%, respectively) than in DSN MG (37.9 and 55.2%), whereas the findings for other muscles were not significantly different between the groups. Abnormal facial responses but normal limb responses were independently associated with MuSK MG (odds ratio=5.224, 95% confidence interval=1.300-20.990). CONCLUSIONS: Abnormal RNS responses primarily in facial muscles without involvement of limb muscles were more pronounced in MuSK MG than in DSN MG. RNS of both facial and limb muscles in AChR-Ab-negative MG can increase the test sensitivity and aid in early suspicion of MuSK MG.

The MMSE and MoCA for Screening Cognitive Impairment in Less Educated Patients with Parkinson's Disease.

OBJECTIVE: To explore whether the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) can be used to screen for dementia or mild cognitive impairment (MCI) in less educated patients with Parkinson's disease (PD). METHODS: We reviewed the medical records of PD patients who had taken the Korean MMSE (K-MMSE), Korean MoCA (K-MoCA), and comprehensive neuropsychological tests. Predictive values of the K-MMSE and K-MoCA for dementia or MCI were analyzed in groups divided by educational level. RESULTS: The discriminative powers of the K-MMSE and K-MoCA were excellent [area under the curve (AUC) 0.86-0.97] for detecting dementia but not for detecting MCI (AUC 0.64-0.85). The optimal screening cutoff values of both tests increased with educational level for dementia (K-MMSE < 15 for illiterate, < 20 for 0.5-3 years of education, < 23 for 4-6 years, < 25 for 7-9 years, and < 26 for 10 years or more; K-MoCA < 7 for illiterate, < 13 for 0.5-3 years, < 16 for 4-6 years, < 19 for 7-9 years, < 20 for 10 years or more) and MCI (K-MMSE < 19 for illiterate, < 26 for 0.5-3 years, < 27 for 4-6 years, < 28 for 7-9 years, and < 29 for 10 years or more; K-MoCA < 13 for illiterate, < 21 for 0.5-3 years, < 23 for 4-6 years, < 25 for 7-9 years, < 26 for 10 years or more). CONCLUSION: Both MMSE and MoCA can be used to screen for dementia in patients with PD, regardless of educational level; however, neither test is sufficient to discriminate MCI from normal cognition without additional information.

Persistent Drug-Induced Parkinsonism in Patients with Normal Dopamine Transporter Imaging.

Functional neuroimaging for the dopamine transporter (DAT) is used to distinguish drug-induced parkinsonism (DIP) from subclinical Parkinson's disease (PD). Although DIP patients who show a normal DAT image are expected to recover completely, some do not. We investigated whether these patients showed changes in striatal DAT activity using semi-quantitative analysis of 18F-FP-CIT PET data. DIP patients with visually normal DAT images were selected from medical records. The subjects were classified as patients who recovered partially (PR) or completely within 12 months (CR). The 18F-FP-CIT uptake in each striatal subregion was compared between the CR and the PR groups. In total, 41 and 9 patients of the CR and PR groups were assessed, respectively. The two patient groups were comparable in terms of clinical characteristics including age, sex, and severity of parkinsonism. From semi-quantitative analysis of the PET image, the PR patients showed a relatively lower ligand uptake in the ventral striatum, the anterior putamen and the posterior putamen compared with the CR patients. This result suggests that persistent DIP in patients with visually normal DAT imaging may be associated with subtle decrement of DAT activity.