Effects of physical exercise interventions on cognitive function in Parkinson's disease: An updated systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To determine whether physical exercise interventions can improve cognitive function, including overall performance and specific domains, in patients with Parkinson's disease (PD) and to provide potential evidence on how cognitive benefits can be optimized by exercise prescriptions. METHODS: Using PubMed, Web of Science, and Cochrane Library (from inception to August 2022), four independent reviewers screened the search results and extracted data from randomized controlled trials of physical exercise interventions in patients with PD with an outcome measure of cognitive function. Random-effects meta-analysis models were used to report standardized mean differences (SMDs) with 95 % confidence intervals (CIs). RESULTS: Twenty-one randomized controlled trials including 761 patients with PD were eligible for inclusion. Physical exercise interventions led to significant improvements in global cognitive function (SMD = 0.69; 95 % CI = 0.31 to 1.06; P < 0.001). With respect to cognitive domains, the significant effect of exercise was found on executive function (SMD = 0.94; 95 % CI = 0.05 to 1.83; P = 0.039), but not on attention/working memory, language, memory, and visuospatial function. In moderator variable analyses, the effect on global cognition was observed in combined exercise programs (SMD = 0.79; 95 % CI = 0.46 to 1.12; P < 0.001), whereas there were no significant positive effects in aerobic exercise programs, strength exercise programs, and flexibility exercise programs. In addition, exercise interventions of light-to-moderate intensity with at least 60 min in duration, and of any frequency or period, were beneficial to the global cognitive function. CONCLUSION: This updated systematic review and meta-analysis suggests that physical exercise interventions are effective in improving global cognitive function and, to a lesser extent, executive function in patients with PD. At least 60 min a day of combined exercise programs on as many days of the week as feasible may be recommended as the non-pharmacological therapeutic option to improve cognitive function.

Associations of Orthostatic Hypotension and Orthostatic Intolerance with Domain-Specific Cognitive Decline in Patients with Early Parkinson Disease: An 8-Year Follow-up.

OBJECTIVE: Although orthostatic hypotension (OH) and orthostatic intolerance (OI) are prevalent in patients with Parkinson disease (PD), it remains unclear how these conditions primarily affect the trajectory of decline in specific cognitive domains. This study aimed to explore the effects of OH and OI on longitudinal domain-specific cognitive changes in patients with PD. DESIGN: An 8-year follow-up of the Parkinson Progression Markers Initiative cohort study. SETTING AND PARTICIPANTS: A total of 403 patients with early, untreated PD and 195 matched healthy controls were included. They were classified into OH, OI, and normal groups. OH was defined according to the international consensus, and OI was defined as the presence of orthostatic symptoms without meeting the criteria for OH. METHODS: The patients underwent detailed neuropsychological testing annually for up to 8 years of follow-up. Linear mixed effects models were used to investigate the associations between OH, OI, and longitudinal cognitive changes. RESULTS: The prevalence of both OH and OI in patients with PD was significantly higher than that in controls (13.4% vs 7.2%, P = .002, for OH, and 29.3% vs 14.4%, P < .001, for OI). The OH group in patients with PD showed a faster decline in Letter-Number Sequencing (LNS) (ß = -0.11, 95% CI -0.20 to -0.02, t = -2.44, P = .015) and Semantic Fluency Test (SFT) (ß = -0.44, 95% CI -0.81 to -0.08, t = -2.42, P = .016) scores than the normal group. Similarly, the OI group showed a steeper decline in LNS (ß = -0.08, 95% CI -0.14 to -0.01, t = -2.20, P = .028) and SFT (ß = -0.36, 95% CI -0.63 to -0.08, t = -2.55, P = .011) scores compared to the normal group. There were no significant longitudinal changes in the other neuropsychological test scores between the groups. CONCLUSIONS AND IMPLICATIONS: Both OH and OI may be associated with a faster decline in executive function among cognitive domains of patients with PD. These findings may highlight the potential importance of orthostatic blood pressure control in PD patients with OH and even those with orthostatic symptoms without OH.

Effects of high-intensity interval training and moderate-intensity continuous training on sarcopenia-related parameters in participants with Parkinson's disease: A 24-week randomized pilot trial substudy.

OBJECTIVE: To evaluate the potential efficacy of two different supervised exercise regimens, namely high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT), on sarcopenia-related parameters in participants with Parkinson's disease (PD). METHODS: We analyzed data from a randomized controlled pilot trial (CRIS identifier: KCT0007130). An aerobic exercise intervention using a cycle ergometer (40-60 min) in combination with calisthenics (5 min) was performed in three sessions/week for 24 weeks for HIIT (60% maximum aerobic power for 30-50 s with 1-min rest intervals) and MICT (50% peak oxygen consumption) groups. Changes in sarcopenia-related parameters, including appendicular skeletal muscle mass (ASM), ASM index (ASM/height2), handgrip strength, 6-min walking distance, and 30-s chair-stand test (30CST) score, were compared among the HIIT (n = 9), MICT (n = 10), and usual care (n = 11) groups. RESULTS: The HIIT group showed greater increases in leg lean mass (p = 0.011), ASM (p = 0.035), and ASM index (p = 0.025), and greater improvements in 6-min walking distance (p = 0.024) and 30CST scores (p = 0.026) compared with the usual care group. However, among these parameters, only the 30CST score significantly improved in the MICT group compared to the usual care group (p = 0.002). Three of the four (75%) sarcopenic patients who underwent HIIT showed improved sarcopenia after the 24-week exercise intervention, whereas it did not improve in the sarcopenic patients included in the MICT (n = 2) and usual care (n = 2) groups. CONCLUSION: This study suggests that HIIT may be superior to MICT in improving sarcopenia in patients with PD. Further large-scale investigations are required to confirm our findings.

Prognostic significance of peripheral neutrophils and lymphocytes in early untreated Parkinson's disease: an 8-year follow-up study.

BACKGROUND: To explore whether peripheral blood neutrophils and lymphocytes are associated with longitudinal motor and cognitive decline in patients with early Parkinson's disease (PD) and, to uncover the disease-specific mechanisms underlying these associations. METHODS: Data were obtained from the Parkinson's Progression Markers Initiative cohort. We included 376 patients with recently diagnosed, drug-naïve PD and 178 matched healthy controls. The patients underwent annual assessments, including the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part 3 test to measure motor function and the Montreal Cognitive Assessment (MoCA) to measure cognitive function, for up to 8 years of follow-up. Dopamine transporter (DAT) imaging was performed at baseline and the 1-year, 2-year and 4-year follow-up visits. RESULTS: At baseline, patients with PD showed higher neutrophil and lower lymphocyte counts, resulting in a higher neutrophil-to-lymphocyte ratio (NLR) than that in healthy controls. Higher neutrophil counts were associated with a greater increase in MDS-UPDRS part 3 scores in patients with PD (estimate: 0.25, 95% CI: 0.12 to 0.37, p<0.001). Correspondingly, higher neutrophil levels were related to a greater reduction in DAT activity in the caudate (estimate: -0.007, 95% CI: -0.014 to -0.001, p=0.046) and putamen (estimate: -0.0039, 95% CI: -0.0077 to -0.0002, p=0.042). However, there were no significant effects of lymphocyte count and NLR on changes in the MDS-UPDRS part 3 and MoCA scores and striatal DAT uptake over time. CONCLUSION: Among the blood biomarkers, only a higher neutrophil count was associated with faster motor progression along with accelerated nigrostriatal dopaminergic degeneration in patients with PD. The impact of neutrophils and lymphocytes on longitudinal cognitive changes remains unclear. TRIAL REGISTRATION NUMBER: NCT01141023.

Peripheral blood inflammatory cytokines in prodromal and overt α-synucleinopathies: a review of current evidence.

While the pathomechanisms of α-synucleinopathies are not completely understood, accumulating evidence suggests a role of neuroinflammation in the development and progression of the diseases. In addition, emerging data provide insights into the potential role of central neuroinflammation in prodromal α-synucleinopathies. Given the considerable bidirectional crosstalk between peripheral and central inflammation, peripheral blood inflammatory cytokines may be a useful tool to understand immune responses in association with α-synucleinopathies. Indeed, the accessibility and practicality of using blood samples have facilitated multiple investigations evaluating peripheral blood inflammatory cytokines in overt α-synucleinopathies, whereas the associations between these biomarkers and prodromal α-synucleinopathies remain unclear. In this review, we provide an overview of the current evidence available for the role of peripheral blood inflammatory cytokines in prodromal and overt α-synucleinopathies.

Quantitative measurement of motor activity during sleep in isolated REM sleep behavior disorder patients using actigraphy before and after treatment with clonazepam.

STUDY OBJECTIVES: We conducted a prospective study to quantify motor activity during sleep measured by actigraphy before and after 3 months of treatment with clonazepam in patients with video-polysomnography (vPSG) confirmed isolated rapid eye movement (REM) sleep behavior disorder (iRBD). METHODS: The motor activity amount (MAA) and the motor activity block (MAB) during sleep were obtained from actigraphy. Then, we compared quantitative actigraphic measures with the results of the REM sleep behavior disorder questionnaire for the previous 3-month period (RBDQ-3M) and of the Clinical Global Impression-Improvement scale (CGI-I), and analyzed correlations between baseline vPSG measures and actigraphic measures. RESULTS: Twenty-three iRBD patients were included in the study. After medication treatment, large activity MAA dropped in 39% of patients, and the number of MABs decreased in 30% of patients when applying 50% reduction criteria. 52% of patients showed more than 50% improvement in either one. On the other hand, 43% of patients answered "much or very much improved" on the CGI-I, and RBDQ-3M was reduced by more than half in 35% of patients. However, there was no significant association between the subjective and objective measures. Phasic submental muscle activity during REM sleep was highly correlated with small activity MAA (Spearman's rho = 0.78, p < .001) while proximal and axial movements during REM sleep correlated with large activity MAA (rho = 0.47, p = .030 for proximal movements, rho = 0.47, p = .032 for axial movements). CONCLUSIONS: Our findings imply that quantifying motor activity during sleep using actigraphy can objectively assess therapeutic response in drug trials in patients with iRBD.

Change of iron content in brain regions after intravenous iron therapy in restless legs syndrome: quantitative susceptibility mapping study.

STUDY OBJECTIVES: The pathomechanism of restless legs syndrome (RLS) is related to brain iron deficiency and iron therapy is effective for RLS; however, the effect of iron therapy on human brain iron state has never been studied with magnetic resonance imaging. This study aimed to investigate the change of brain iron concentrations in patients with RLS after intravenous iron therapy using quantitative susceptibility mapping (QSM). METHODS: We enrolled 31 RLS patients and 20 healthy controls. All participants underwent initial baseline (t0) assessment using brain magnetic resonance imaging, serum iron status, and sleep questionnaires including international RLS Study Group rating scale (IRLS). RLS patients underwent follow-up tests at 6 and 24 weeks (t1 and t2) after receiving 1000 mg ferric carboxymaltose. Iron content of region-of-interest on QSM images was measured for 13 neural substrates using the fixed-shaped method. RESULTS: RLS symptoms evaluated using IRLS were significantly improved after iron treatment (t0: 29.7 ± 6.5, t1: 19.5 ± 8.5, t2: 21.3 ± 10.1; p < .001). There was no significant difference in susceptibility values between the controls and RLS patients at t0. In the caudate nucleus, putamen, and pulvinar thalamus of RLS patients, the QSM values differed significantly for three timepoints (p = .035, .048, and .032, respectively). The post-hoc analysis revealed that the QSM values increased at t1 in the caudate nucleus (66.8 ± 18.0 vs 76.4 ± 16.6, p = .037) and decreased from t1 to t2 in the putamen (69.4 ± 16.3 vs 62.5 ± 13.6, p = .025). Changes in the QSM values for the pulvinar and caudate nuclei at t1 were positively and negatively correlated with symptomatic improvement, respectively (r = 0.361 and -0.466, respectively). CONCLUSIONS: Intravenous iron treatment results in changes in brain iron content which correlate to reductions in RLS severity. This suggests a connection between symptom improvement and the associated specific brain regions constituting the sensorimotor network.

Association of Early Weight Change With Cognitive Decline in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVE: To examine whether early weight change is associated with subsequent deterioration in cognitive function, including overall performance and specific domains, in Parkinson disease (PD). METHODS: This observational study used data from the Parkinson Progression Markers Initiative cohort. The patients underwent annual nonmotor assessments covering neuropsychiatric, sleep-related, and autonomic symptoms for up to 8 years of follow-up. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) and detailed neuropsychological testing. Linear mixed-effects models were applied to investigate the association of early weight change with longitudinal evolution of cognitive and other nonmotor symptoms. RESULTS: A total of 358 patients with early PD were classified into weight loss (decrease of >3% body weight during the first year; n = 98), weight maintenance (within ±3%; n = 201), and weight gain (increase of >3%; n = 59) groups. The weight loss group showed a significantly faster decline in MoCA scores than the weight maintenance group (ß = -0.19, 95% CI -0.28 to -0.10). With respect to specific cognitive domains, the weight loss group showed a steeper decline in sematic fluency test scores (ß = -0.37, 95% CI -0.66 to -0.08) and MoCA phonemic fluency scores (ß = -0.18, 95% CI -0.31 to -0.05) and, to a lesser extent, Letter-Number Sequencing scores (ß = -0.07, 95% CI -0.14 to 0.01) compared with the weight maintenance group. Conversely, the weight gain group showed a slower decline in the Symbol Digit Modalities Test scores (ß = 0.34, 95% CI 0.05 to 0.63), although no association was found with longitudinal changes in MoCA scores. We did not find any significant effects of weight change on the progression of other nonmotor symptoms. DISCUSSION: Early weight loss was associated with a faster progression of decline in global cognitive function and executive function in patients with PD, whereas early weight gain was associated with a slower progression of decline in processing speed and attention. The impact of early weight change on nonmotor symptoms seemed to be specific to cognition.

Emotional and Environmental Factors Aggravating Dream Enactment Behaviors in Patients with Isolated REM Sleep Behavior Disorder.

Objective: To identify emotional and environmental factors that aggravate dream enactment behaviors (DEBs) in isolated rapid eye movement (REM) sleep behavior disorder (iRBD). Methods: In this cross-sectional study, a total of 96 polysomnography-confirmed iRBD patients (mean age, 68.5 years; men, 68%) and their caregivers completed questionnaires regarding potential aggravating factors related to DEBs, including emotion/feelings (stress, anger, anxiety, depressive mood, fatigue, pain), food (alcohol, caffeine, overeating in the evening, fasting/hunger), activities and sleep patterns (strenuous exercise, sex before bed, conflict/fighting, sleep deprivation, oversleeping, sleeping away from home, watching TV before bed), weather/environmental factors (cloudy or rainy weather, heat, cold, noise) and medication (skipping medication, taking hypnotics). Results: The patients reported that stress (61%) was the most aggravating factor for DEBs, followed by anxiety (56%), anger (51%), fatigue (49%), and watching TV before bed (46%). Similarly, the caregivers reported that these factors were most relevant to the aggravation of DEBs in the patients, although some factors were ranked differently. In the subgroup analyses, aggravating factors for DEBs did not differ by RBD symptom severity. Interestingly, the proportion of patients experiencing DEB aggravation by stress, anxiety and depressive mood was significantly higher in women than in men. Furthermore, depressed patients reported that stress and cloudy or rainy weather made DEBs worse than nondepressed patients. Conclusion: Our results suggest that DEBs in iRBD patients may be mainly aggravated by emotional factors. These negative effects appeared to be more prominent in female and depressed patients.

Association of Nucleus Basalis of Meynert Functional Connectivity and Cognition in Idiopathic Rapid-Eye-Movement Sleep Behavior Disorder.

BACKGROUND AND PURPOSE: Cognitive impairments are common in isolated rapid-eye-movement sleep behavior disorder (iRBD), in which the cholinergic system may play an important role. This study aimed to characterize the cortical cholinergic activity using resting-state functional connectivity (FC) of the nucleus basalis of Meynert (NBM) according to the cognitive status of iRBD patients. METHODS: In this cross-sectional study, 33 patients with polysomnography-confirmed iRBD and 20 controls underwent neuropsychological evaluations and resting-state functional magnetic resonance imaging. Thirteen of the iRBD patients had mild cognitive impairment (iRBD-MCI), and the others were age-matched patients with normal cognition (iRBD-NC). The seed-to-voxel NBM-cortical FC was compared among the patients with iRBD-MCI, patients with iRBD-NC, and controls. Correlations between average values of significant clusters and cognitive function scores were calculated in the patients with iRBD. RESULTS: There were group differences in the FC of the NBM with the left lateral occipital cortex and lingual gyrus (adjusted for age, sex, and education level). The strength of FC was lower in the iRBD-MCI group than in the iRBD-NC and control groups (each post-hoc p<0.001). The average NBM-lateral occipital cortex FC was positively correlated with the memory-domain score in iRBD patients. CONCLUSIONS: The results obtained in this study support that cortical cholinergic activity is impaired in iRBD patients with MCI. FC between NBM and posterior regions may play a central role in the cognitive function of these patients.

White matter tract-specific microstructural disruption is associated with depressive symptoms in isolated RBD.

OBJECTIVE: White matter (WM) tract-specific changes may precede gray matter loss in isolated rapid eye movement sleep behavior disorder (iRBD). We aimed to evaluate tract-specific WM changes using tract-specific statistical analysis (TSSA) and their correlation with clinical variables in iRBD patients. METHODS: This was a cross-sectional single-center study of 50 polysomnography-confirmed iRBD patients and 20 age- and sex-matched controls. We used TSSA to identify tract-specific fractional anisotropy (FA) and mean diffusivity (MD) in fourteen major fiber tracts and analyzed between-group differences in these values. Correlations between FA or MD values and clinical variables, including RBD symptom severity, depression and cognition, were evaluated. RESULTS: Patients with iRBD showed lower FA in the right anterior thalamic radiation (ATR) and higher MD in the bilateral ATR and right inferior fronto-occipital fasciculus (IF-OF) than controls after adjusting for age, sex, and years of education. MD values in the IF-OF positively correlated with scores on the Korean version of the Rapid Eye Movement Sleep Behavior Disorder Questionnaire-Hong Kong (RBDQ-KR, p = 0.042) and the Korean version of the geriatric depression scale (GDS-K, p = 0.002) in iRBD patients. Only GDS-K scores independently correlated with IF-OF MD values after adjusting for RBDQ-KR scores (adjusted p = 0.026). CONCLUSION: This study suggests WM microstructural disruption in the bilateral ATR and right IF-OF in patients with iRBD and that alterations in the IF-OF may contribute to depressive symptoms.

Alerting network alteration in isolated rapid eye movement sleep behavior disorder patients with mild cognitive impairment.

OBJECTIVE: Mild cognitive impairment (MCI) was found in 30-50% of the isolated REM sleep behavior disorder (iRBD) patients. Furthermore, it is known that patients with Parkinson's disease have attention network defects. Given that iRBD is known to be the prodromal disease of α-synucleinopathies, our aim was to investigate whether there are attention network dysfunctions in iRBD patients following the presence of MCI. METHODS: 14 healthy controls, 48 iRBD patients, 24 with MCI and 24 without MCI, were included in this study. Attention network task (ANT) was used to assess alerting, orienting, and executive control networks. Event-related potentials (ERPs) and behavioral performances were recorded during the ANT. Parietal N1 and P3 components were analyzed to find effects of the three attention networks. RESULTS: IRBD patients without MCI showed neuropsychological, behavioral, and ERP results similar to those of healthy controls. On the other hand, iRBD patients with MCI showed a general decline in cognitive domains with no alerting effect (controls, p = 0.043; iRBD-noMCI, p = 0.014; iRBD-MCI, p = 0.130) while preserving orienting and executive control effect. Furthermore, iRBD patients with MCI had impairments in executive function and verbal memory domains, compared to iRBD patients without MCI. CONCLUSIONS: Our findings indicate that when cognition is reduced to MCI levels in iRBD patients, the attention network, especially the alerting component, is impaired. The attention network and cognition, on the other hand, can be preserved in iRBD patients due to the compensatory mechanism.

Apolipoprotein E ε4 is not associated with cognitive impairment in patients with idiopathic REM sleep behavior disorder.

We analyzed 136 patients (age, 67.5 ± 6.9 years; men, 59.6%) with idiopathic rapid eye movement sleep behavior disorder (iRBD). The results of the neuropsychological tests were not significantly different between APOE ε4 carriers and noncarriers, suggesting that the APOE ε4 allele was not associated with cognitive impairment in iRBD.

Characteristics and prognosis of patients with cryptogenic stroke and suggestive of patent foramen ovale.

AIMS: The purpose of this study were to identify the usefulness of screening for PFO using agitated saline echocardiography (ASE) and characteristics and prognosis of patients with suggestive of patent foramen ovale (PFO). METHODS: Three hundred three patients (mean age, 53 ± 9 years; 199 [66%] men) admitted with acute stroke or suspicion of stroke were included. Patients were classified into those with and without right-to-left shunt (RLS) according to the ASE results (positive ASE [n = 92] vs. negative ASE [n = 211]). Fifty-one out of ninety-two patients with positive ASE and twenty-one out of two hundred eleven patients with negative ASE underwent TEE with ASE to confirm PFO. RESULTS: Ninety-two were positive for ASE and thirty-six of the fifty-one patients who underwent TEE were confirmed as having PFO. Of the patients with RLS grade 1, 50% were diagnosed with PFO and all patients with RLS grade ≥ 2 were diagnosed with PFO. All patients with negative ASE had no PFO (sensitivity of 100% and specificity of 58%). Patients with positive ASE were younger, had a lower body mass, and a lower prevalence of hypertension. The positive ASE patients had a higher mean S' velocity and better diastolic function. Four of ninety-one patients with positive ASE and thirteen of one hundred seventy-seven showed recurrence of stroke and suspicion of stroke. CONCLUSION: Transthoracic ASE is a good method to screen for PFO. Patients with suggestive of PFO had lower risk factors, less atherosclerosis, and better cardiac performance.

A new rapid titration protocol for lamotrigine that reduces the risk of skin rash.

OBJECTIVE: Lamotrigine is one of the most widely used antiepileptic drugs, but it has a critical issue of a skin rash if the starting dose is too high or the escalation rate is too rapid. We investigated the efficacy and safety of a novel and rapid titration protocol for lamotrigine that takes only 11 days to reach a daily dose of 200 mg. METHODS: We prospectively enrolled 33 adult patients (age 18-85) who were diagnosed with epilepsy and started lamotrigine administration for the first time at a single tertiary hospital. Our new protocol starts with a subthreshold dose of the drug and then administers a stepwise-incremental dose until reaching the full therapeutic dose within 11 days. RESULTS: Of 29 patients analyzed, only two (6.9%) experienced idiosyncratic skin rash before the first follow-up visit at 2 weeks (±3 days). In addition, a therapeutic concentration was reached in more than 75% of studied patients after 2 weeks of lamotrigine administration. SIGNIFICANCE: These findings demonstrate the value of the novel tolerance induction protocol for lamotrigine, which could widen the available application of lamotrigine in various situations. However, this study is a preliminary study limited by a small number of patients and its nonrandomized and open-label design, so the current protocol needs more rigorous clinical evaluations before the application to the real clinical setting.

Association of Physical Activity and APOE Genotype With Longitudinal Cognitive Change in Early Parkinson Disease.

OBJECTIVE: To determine whether greater physical activity could modify the negative association of APOE ε4 with longitudinal cognitive changes in early Parkinson disease (PD) and to uncover the disease-specific mechanism for explaining such benefits of physical activity. METHODS: We used data from the Parkinson's Progression Markers Initiative cohort. Because self-reported physical activity, measured by the Physical Activity Scale of the Elderly, was initiated at 2 years after enrollment, this longitudinal analysis was based on assessments performed at years 2, 3, and 4. Cognitive function was measured annually with the Montreal Cognitive Assessment (MoCA). Dopamine transporter (DAT) imaging was performed at years 2 and 4. We assessed the interactive associations between physical activity and the APOE ε4 allele on the longitudinal changes in MoCA scores and striatal DAT activities. RESULTS: A total of 173 patients with early PD (age 63.3 ± 10.0 years, 27% APOE ε4 carriers) were included. The APOE ε4 allele showed a steeper rate of cognitive decline than the non-APOE ε4 allele (estimate -1.33, 95% confidence interval [CI] -2.12 to -0.47, p = 0.002). However, there was a significant interaction between physical activity and APOE ε4 such that higher physical activity was related to slower APOE ε4-related cognitive decline (estimate 0.007, 95% CI 0.003-0.011, p = 0.001). No significant interaction was found between physical activity and the APOE ε4 allele regarding the change in striatal DAT activities. CONCLUSION: Increased physical activity attenuated APOE ε4-related vulnerability to early cognitive decline in patients with PD. This protective effect did not appear to be mediated by striatal dopaminergic function. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT01141023. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that increased physical activity was associated with decreased APOE ε4-related early cognitive decline in patients with PD.

Content Analysis of Korean Videos Regarding Restless Legs Syndrome on YouTube.

OBJECTIVE: To evaluate the accuracy and quality of Korean videos associated with restless legs syndrome (RLS) on YouTube. METHODS: A YouTube search was performed on April 1, 2020 using the term "restless legs syndrome" in the Korean language. Two reviewers coded the source, content, and demographics of the included videos. Video quality was assessed using the modified DISCERN (mDISCERN) instrument. RESULTS: Among the 80 videos analyzed, 44 (55.0%) were reliable, and 36 (45.0%) were misleading. There was a trend toward a higher number of mean daily views in the misleading videos than in the reliable videos. Most of the misleading videos (72.2%) advocated complementary and alternative medicine as a primary treatment for RLS. Although the reliable videos had higher mDISCERN scores than the misleading videos, the overall quality of the reliable videos was low. CONCLUSION: Many Korean videos regarding RLS on YouTube involve a risk of exposure to misinformation and are of unsatisfactory quality.

Impact of the apolipoprotein E ε4 allele on early Parkinson's disease progression.

OBJECTIVE: Emerging evidence shows that apolipoprotein E (APOE) ε4 exacerbates alpha-synuclein pathology. We aimed to investigate whether the APOE ε4 allele contributes to early Parkinson's disease (PD) progression. METHODS: This cohort study included 361 early PD patients who were classified as APOE ε4 carriers (n = 90) and noncarriers (n = 271). The patients underwent yearly motor and nonmotor assessments covering neuropsychiatric, sleep-related, and autonomic symptoms over 5 years of follow-up. Dopamine transporter (DAT) imaging was conducted at baseline and the 1-, 2-, and 4-year follow-up visits. RESULTS: The APOE ε4 carriers had steeper declines in the Montreal Cognitive Assessment score (p=0.005) and the semantic fluency test score (p=0.012) than the noncarriers. No significant between-group differences in the longitudinal changes in motor, other nonmotor, and DAT imaging variables were observed. CONCLUSIONS: Our exploratory analyses show that only cognitive performance was negatively affected by the APOE ε4 allele in the progression of early PD. More specifically, this allele was associated with poorer performance in semantic verbal fluency among cognitive domains.