Symmetric and Profound Monoaminergic Degeneration in Parkinson's Disease with Premotor REM Sleep Behavior Disorder.

Background: Rapid eye movement sleep behavior disorder (RBD) may precede or follow motor symptoms in Parkinson's disease (PD). While over 70% of idiopathic RBD cases phenoconvert within a decade, a small subset develops PD after a more extended period or remains nonconverted. These heterogeneous manifestations of RBD in PD prompt subtype investigations. Premotor RBD may signify "body-first" PD with bottom-up, symmetric synucleinopathy propagation. Objective: Explore brainstem and nigrostriatal monoaminergic degeneration pattern differences based on premotor RBD presence and duration in de novo PD patients. Methods: In a cross-sectional analysis of de novo PD patients (n = 150) undergoing FP-CIT PET and RBD Single-Question Screen, the cohort was categorized into groups with and without premotor RBD (PDRBD +/-), with further classification of PDRBD + based on a 10-year duration of premotor RBD. Analysis of FP-CIT binding in the striatum and pons, striatal asymmetry, and striatum-to-pons ratios compared patterns of nigrostriatal and brainstem monoaminergic degeneration. Results: PDRBD + exhibited more severe and symmetrical striatal dopaminergic denervation compared to PDRBD-, with the difference in severity accentuated in the least-affected hemisphere. The PDRBD +<10Y subgroup displayed the most prominent striatal symmetry, supporting a more homogeneous "body-first" subtype. Pontine uptakes remained lower in PDRBD + even after adjusting for striatal uptake, suggesting early degeneration of pontine monoaminergic nuclei. Conclusions: Premotor RBD in PD is associated with severe, symmetrical nigrostriatal and brainstem monoaminergic degeneration, especially in cases with PD onset within 10 years of RBD. This supports the concept of a "widespread, bottom-up" pathophysiological mechanism associated with premotor RBD in PD.

The prevalence of non-troublesome dyskinesia in Parkinson's disease.

INTRODUCTION: Levodopa-induced dyskinesia is a common complication of long-term treatment of Parkinson's disease (PD), but its impact on daily activities is somewhat controversial. This study investigated the prevalence and severity of dyskinesia, particularly non-troublesome dyskinesia, to provide insights into its significance for long-term PD management. METHODS: We reviewed electronic medical records of 2571 PD patients, who had been followed up at Seoul National University Hospital and were seen between January 2016 and June 2017. Dyskinesia severity had been assessed during follow-up and was recorded with the highest score by considering its impact on functioning (0 = no dyskinesia, 1 = minimal with patient unaware, 2 = mild disability, 3 = moderate disability, 4 = severe disability). RESULTS: The prevalence of dyskinesia increased progressively with longer PD duration; 8.2% in the group with disease duration of 0-5 years, 40.7% for 6-10 years, 66.0% for 11-15 years, 74.6% for 16-20 years, and 83.2% for 21 years or more. The prevalence of dyskinesia scores ≥2 also increased with disease duration, with rates of 6.3% for 0-5 years, 31.9% for 6-10 years, 54.8% for 11-15 years, 62.9% for 16-20 years and 73.7% for 21 or more years. CONCLUSION: Despite the increasing prevalence and severity of dyskinesia with longer PD duration, the study found that less than non-troublesome dyskinesia remained at approximately 26.3% even after more than 21 years of disease duration. These findings suggest that dyskinesia may not be troublesome for many PD patients even in long-term.

Constipation is linked to accelerated cognitive and motor decline in isolated REM sleep behavior disorder.

INTRODUCTION: Constipation is associated with higher clinical severity and predicts cognitive decline in Parkinson's disease (PD). Whether the non-motor marker is associated with unfavorable motor and cognitive trajectories from the prodromal stage remains unclear. METHODS: In a longitudinal prospective cohort of subjects with isolated REM sleep behavior disorders (iRBD), subjects underwent repeated MDS-UPDRS and Mini-Mental Status Examination (MMSE) assessments. Generalized-estimating-equations (GEE) regression model was used to compare the time-dependent trajectories of MDS-UPDRS-III and MMSE scores between subjects with and without constipation at baseline. RESULTS: Twenty-nine subjects with constipation at baseline (iRBD+constipation) and 24 without (iRBD-constipation) were followed over 4.085 ± 2.645 years. The iRBD+constipation group presented faster decline of both MDS-UPDRS-III and MMSE scores, with additional estimated annual progression of +1.242 and -0.713 points, respectively, compared to the iRBD-constipation group (time*group p < 0.05). CONCLUSION: Constipation in isolated RBD is associated with accelerated progression of cognitive impairment and motor symptoms.

Prodromal dementia with Lewy bodies in REM sleep behavior disorder: A multicenter study.

INTRODUCTION: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia. METHODS: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed-effect models determined the annual progression of neuropsychological testing. RESULTS: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes. DISCUSSION: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion. HIGHLIGHTS: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. Decline in episodic memory best distinguished dementia-first from parkinsonism-first phenoconversion.

Caregiver Burden of Patients With Huntington's Disease in South Korea.

OBJECTIVE: This is the first prospective cohort study of Huntington's disease (HD) in Korea. This study aimed to investigate the caregiver burden in relation to the characteristics of patients and caregivers. METHODS: From August 2020 to February 2022, we enrolled patients with HD from 13 university hospitals in Korea. We used the 12-item Zarit Burden Interview (ZBI-12) to evaluate the caregiver burden. We evaluated the clinical associations of the ZBI-12 scores by linear regression analysis and investigated the differences between the low- and high-burden groups. RESULTS: Sixty-five patients with HD and 45 caregivers were enrolled in this cohort study. The average age at onset of motor symptoms was 49.3 ± 12.3 years, with an average cytosine-adenine-guanine (CAG)n of 42.9 ± 4.0 (38-65). The median ZBI-12 score among our caregivers was 17.6 ± 14.2. A higher caregiver burden was associated with a more severe Shoulson-Fahn stage (p = 0.038) of the patients. A higher ZBI-12 score was also associated with lower independence scale (B = -0.154, p = 0.006) and functional capacity (B = -1.082, p = 0.002) scores of patients. The caregiving duration was longer in the high- than in the low-burden group. Caregivers' demographics, blood relation, and marital and social status did not affect the burden significantly. CONCLUSION: HD patients' neurological status exerts an enormous impact on the caregiver burden regardless of the demographic or social status of the caregiver. This study emphasizes the need to establish an optimal support system for families dealing with HD in Korea. A future longitudinal analysis could help us understand how disease progression aggravates the caregiver burden throughout the entire disease course.

Clinical correlates of pareidolias and color discrimination deficits in idiopathic REM sleep behavior disorder and Parkinson's disease.

Visuoperceptual dysfunction is common in Parkinson's disease (PD) and is also reported in its prodromal phase, isolated REM sleep behavior disorder (iRBD). We aimed to investigate color discrimination ability and complex visual illusions known as pareidolias in patients with iRBD and PD compared to healthy controls, and their associating clinical factors. 46 iRBD, 43 PD, and 64 healthy controls performed the Farnsworth-Munsell 100 hue test and noise pareidolia tests. Any relationship between those two visual functions and associations with prodromal motor and non-motor manifestations were evaluated, including MDS-UPDRS part I to III, Cross-Cultural Smell Identification Test, sleep questionnaires, and comprehensive neuropsychological assessment. iRBD and PD patients both performed worse on the Farnsworth-Munsell 100 hue test and had greater number of pareidolias compared to healthy controls. No correlations were found between the extent of impaired color discrimination and pareidolia scores in either group. In iRBD patients, pareidolias were associated with frontal executive dysfunction, while impaired color discrimination was associated with visuospatial dysfunction, hyposmia, and higher MDS-UPDRS-III scores. Pareidolias in PD patients correlated with worse global cognition, whereas color discrimination deficits were associated with frontal executive dysfunction. Color discrimination deficits and pareidolias are frequent but does not correlate with each other from prodromal to clinically established stage of PD. The different pattern of clinical associates with the two visual symptoms suggests that evaluation of both color and pareidolias may aid in revealing the course of neurodegeneration in iRBD and PD patients.

Monoaminergic Degeneration and Ocular Motor Abnormalities in De Novo Parkinson's Disease.

BACKGROUND: Evaluating eye movements in Parkinson's disease (PD) provides valuable insights into the underlying pathophysiological changes. OBJECTIVE: The aim was to investigate the relationship between monoaminergic degeneration and ocular motor abnormalities in de novo PD. METHODS: Drug-naive PD patients who underwent N-(3-[18 F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane positron emission tomography scans and video-oculography at diagnosis were eligible. Measurements of saccadic accuracy, latency, and smooth pursuit gain and square wave jerk frequency were collected. Patients underwent Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and detailed cognitive tests. We investigated the associations between ocular motor measurements and specific tracer uptake ratios (SUR) in the caudate nucleus, anterior and posterior putamen, thalamus, and dorsal raphe nuclei, along with motor and cognitive symptoms. RESULTS: One-hundred twenty-four subjects were included in this study. Saccadic accuracy was positively associated with parkinsonian motor severity expressed as Hoehn and Yahr stages, MDS-UPDRS Part III scores, and subscores for bradykinesia and rigidity but not with tremor scores (PFDR < 0.05). Saccadic accuracy correlated with poor performances in the Rey-Complex-Figure copy, and latency with the Digit Symbol Coding and the Montreal Cognitive Assessment scores (PFDR < 0.05). Prolonged saccadic latency correlated with reduced thalamic SUR, whereas decreased saccadic accuracy correlated with reduced SUR in the anterior and posterior putamen (PFDR < 0.05). Reduced smooth pursuit gain showed associations with reduced SUR in the dorsal raphe, a serotonin-predominant region, but did not correlate with parkinsonism severity scores. CONCLUSION: Defective dopaminergic and nondopaminergic neural systems may discretely influence ocular motor function in de novo PD patients. © 2023 International Parkinson and Movement Disorder Society.

Brain olfactory-related atrophy in isolated rapid eye movement sleep behavior disorder.

OBJECTIVE: To investigate structural and functional connectivity changes in brain olfactory-related structures in a longitudinal prospective cohort of isolated REM sleep behavior disorder (iRBD) and their clinical correlations, longitudinal evolution, and predictive values for phenoconversion to overt synucleinopathies, especially Lewy body diseases. METHODS: The cohort included polysomnography-confirmed iRBD patients and controls. Participants underwent baseline assessments including olfactory tests, neuropsychological evaluations, the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, 3T brain MRI, and 18 F-FP-CIT PET scans. Voxel-based morphometry (VBM) was performed to identify regions of atrophy in iRBD, and volumes of relevant olfactory-related regions of interest (ROI) were estimated. Subgroups of patients underwent repeated volumetric MRI and resting-state functional MRI (fMRI) scans after four years. RESULTS: A total of 51 iRBD patients were included, with 20 of them converting to synucleinopathy (mean time to conversion 3.08 years). Baseline VBM analysis revealed atrophy in the right olfactory cortex and gyrus rectus in iRBD. Subsequent ROI comparisons with controls showed atrophy in the amygdala. These olfactory-related atrophies tended to be associated with worse depression, anxiety, and urinary problems in iRBD. Amygdala 18 F-FP-CIT uptake tended to be reduced in iRBD patients with hyposmia (nonsignificant after multiple comparison correction) and correlated with urinary problems. Resting-state fMRI of 23 patients and 32 controls revealed multiple clusters with aberrant olfactory-related functional connectivity. Hypoconnectivity between the putamen and olfactory cortex was associated with mild parkinsonian signs in iRBD. Longitudinal analysis of volumetric volumetric MRI in 22 iRBD patients demonstrated four-year progression of olfactory-related atrophy. Cox regression analysis revealed that this atrophy significantly predicted phenoconversion. INTERPRETATION: Progressive atrophy of central olfactory structures may be a potential indicator of Lewy body disease progression in iRBD.

Plasma neurofilament light-chain and phosphorylated tau as biomarkers of disease severity in Huntington's disease: Korean cohort data.

OBJECTIVE: To investigate neurofilament light chain (NfL), phosphorylated tau (p-Tau) and total tau (t-Tau) as plasma markers for clinical severity in Korean Huntington's disease (HD) cohort. METHODS: Genetically-confirmed 67 HD patients participated from 13 referral hospitals in South Korea. The subjects were evaluated with the Unified Huntington's Disease Rating Scale (UHDRS), total motor score (TMS) and total functional capacity (TFC), Mini-Mental Status Examination (K-MMSE), Montreal Cognitive Assessment (MoCA-K), and Beck's depression inventory (K-BDI). We measured plasma NfL, p-Tau and t-Tau concentrations using single-molecule array (SIMOA) assays. Stages of HD were classified based on UHDRS-TFC score and plasma markers were analyzed for correlation with clinical severity scales. RESULTS: Plasma NfL was elevated in both 6 premanifest and 61 full manifest HD patients compared to the reference value, which increased further from premanifest to manifest HD groups. The NfL level was not significantly correlated with UHDRS TMS or TFC scores in manifest HD patients. Plasma p-Tau was also elevated in HD patients (p = 0.038). The level was the highest in stage III-V HD (n = 30) group (post-hoc p < 0.05). The p-Tau was correlated with UHDRS TFC scores (adjusted p = 0.002). Plasma t-Tau neither differed among the groups nor associated with any clinical variables. CONCLUSIONS: This study supports plasma NfL being a biomarker for initial HD manifestation in Korean cohort, and a novel suggestion of plasma p-Tau as a potential biomarker reflecting the clinical severity in full-manifest HD.

Diet quality and prodromal Parkinson's disease probability in isolated REM sleep behavior disorder.

INTRODUCTION: It is reported that a diet that lowers oxidative stress reduces the prodromal Parkinson's disease (pPD) probability as well as the risk of Parkinson's disease (PD). In this study, we evaluated whether the diet quality of patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD) were associated with the pPD probability score, PD risk markers, or prodromal markers. METHODS: Polysomnography (PSG)-confirmed iRBD patients from the Neurology Department at Seoul National University Hospital were enrolled. We calculated the pPD probability using the "Web-based Medical Calculator for Prodromal Risk in Parkinsonism" Diet quality was assessed using the Recommended Food Score (RFS). RESULTS: We enrolled 101 patients with iRBD. The mean RFS score of patients with iRBD was 28.23 ± 9.29, which did not differ from the general population. Among patients with iRBD, the probability of pPD did not differ between the high and low RFS groups. In patients aged <70 years, although total RFS was not correlated with pPD probability (p = 0.529, Spearman rank correlation), legume consumption was negatively correlated with pPD probability (p = 0.032): furthermore, legume consumption was significantly higher in patients with fewer prodromal markers (p = 0.016). CONCLUSION: Diet quality assessed by RFS did not differ between the general population and patients with iRBD in Korea. Further studies are needed to confirm these protective effects of legume consumption on iRBD, which may have strong implications for the prevention and management of PD.

Inability to suppress head rotation during the saccade test as a clinical biomarker for cognitive dysfunction in Parkinson's disease.

BACKGROUND: There is a need for development of reliable and accessible clinical biomarker for detecting cognitive dysfunction in PD. This study aimed to investigate whether involuntary head rotation during the saccade test could serve as a potential biomarker for screening cognitive dysfunction in PD. METHODS: A total of 27 PD patients and nine age- and sex-matched healthy controls were prospectively enrolled in this study. A custom-designed gyroscope was attached to the forehead of each participant, and a saccade test consisting of 20 trials was conducted. The entire test was recorded on video, and two movement disorder experts independently rated the degree of head rotation, blinded to the patients' clinical information. The peak angular velocity of head rotation was derived from the gyroscope data. Participants underwent Montreal Cognitive Assessment (MoCA) as the cognitive evaluation. Correlation analysis was performed to assess the relationship between head rotation and MoCA scores. RESULTS: The mean peak angular velocity of head rotation significantly correlated with the MoCA scores (R = -0.52, p = 0.0023) including age, sex, disease duration, and education duration as cofactors. The optimal peak angular velocity thresholds for head rotation, which aligned with the manual ratings, were determined to be 5°/s and 10°/s for raters 1 and 2, respectively. The MoCA scores exhibited significant correlations with the number of head rotations, using both the 5°/s (R = -0.36, p = 0.042) and 10°/s (R = -0.49, p = 0.0048) thresholds. Furthermore, the mean angular velocity of the head demonstrated a 100% positive predictive value and specificity for the detection of cognitive impairment (MoCA < 26), based on the cut-offs of 5°/s and 10°/s. CONCLUSION: Inability to suppress head rotation during saccades may serve as a potential clinical biomarker for screening cognitive dysfunction in PD.

Progression of clinical markers in prodromal Parkinson's disease and dementia with Lewy bodies: a multicentre study.

The neurodegenerative synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson's disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson's disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson's disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.

The effect of continuous positive airway pressure (CPAP) on the quality of life in patients with multiple system atrophy.

PURPOSE: To evaluate the effect of continuous positive airway pressure (CPAP) on the quality of life (QoL) in patients with multiple system atrophy (MSA) and their caregivers. METHODS: We reviewed the electronic medical records of patients with MSA treated with CPAP (n = 15). After CPAP treatment, we checked the patient global impression of change (PGI-C) scale for sleep complaints and QoL for six patients who continued to use CPAP. QoL was also assessed for five caregivers of these patients. RESULTS: A total of 15 patients (6 women) were included. The mean age was 63.6 ± 8.1 years old and the mean disease duration was 4.9 years. The mean duration of CPAP treatment was 22.1 ± 10.6 months and the average compliance was 90%. Three patients died during CPAP treatment, and two patients discontinued CPAP after tracheostomy. For six patients who continued to use CPAP, sleep complaints minimally improved. Five patients reported an improved QoL, and all five caregivers reported improved caregivers' QoL. CONCLUSION: This study showed that the use of CPAP has a beneficial effect on sleep complaints and QoL of patients with MSA and their caregivers.

Laboratory prognostic factors for the long-term survival of multiple system atrophy.

To elucidate the biomarkers related to survival in multiple system atrophy(MSA), we analyzed the predictability of retrospectively collected blood markers for survival in 650 probable MSA. High absolute neutrophil count, red-cell distribution width, C-reactive protein, erythrocyte sedimentation rate, and low hemoglobin, protein, albumin, and creatinine were correlated with higher mortality in MSA. Systemic alteration in inflammation and nutritional status in the early stage are associated with higher mortality in MSA.

Measurement Issue in Antecollis.

Background: Antecollis is defined as an involuntary forward flexion of the neck. Previous reports have measured the neck flexion angles based on the line perpendicular to the ground. This led to an inflation of the neck flexion angles in patients who had combined forward truncal flexions, especially upper camptocormia. Methods: We examined the neck flexion angles and the upper camptocormia angle in the published photographs of antecollis. MEDLINE search was conducted using the following search terms: antecollis OR anterocollis. Lateral-view photographs of patients diagnosed with antecollis were collected. Neck flexion angles were measured with the classic 'perpendicular method' and the 'antecollis method' we developed. Results: Nine patient photographs were identified. While antecollis was the only described postural abnormality in eight cases, these patients exhibited upper camptocormia angles of 45° or larger. The mean neck flexion angle measured with the antecollis method was 49.7°, while the perpendicular method yielded 103.4°. Discussion: Upper camptocormia should be considered in the evaluation of antecollis. We propose a new method to measure neck flexion in relation to the torso, instead of the vertical line.

Long-Term Outcomes of Bilateral Subthalamic Nucleus Deep Brain Stimulation for Patients With Parkinson's Disease: 10 Years and Beyond.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) represents an effective treatment for severe Parkinson's disease (PD), but little is known about the long-term benefit. OBJECTIVE: To investigate the survival rate and long-term outcome of DBS. METHODS: We investigated all 81 patients including 37 males and 44 females who underwent bilateral STN DBS from March 2005 to March 2008 at a single institution. The current survival status of the patients was investigated. Preoperative and postoperative follow-up assessments were analyzed. RESULTS: The mean age at the time of surgery was 62 (range 27-82) years, and the median clinical follow-up duration was 145 months. Thirty-five patients (43%) died during the follow-up period. The mean duration from DBS surgery to death was 110.46 ± 40.8 (range 0-155) months. The cumulative survival rate is as follows: 98.8 ± 1.2% (1 year), 95.1 ± 2.4% (5 years), and 79.0 ± 4.5% (10 years). Of the 81 patients, 33 (40%) were ambulatory up to more than 11 years. The Unified Parkinson's Disease Rating Scale (UPDRS) score was significantly improved until 5 years after surgery although it showed a tendency to increase again after 10 years. The patient group with both electrodes located within the STN showed a higher rate of survival and maintained ambulation. CONCLUSION: STN DBS is a safe and effective treatment for patients with advanced PD. This study based on the long-term follow-up of large patient populations can be used to elucidate the long-term fate of patients who underwent bilateral STN DBS for PD.