Extra-Basal Ganglia Brain Structures Are Related to Motor Reserve in Parkinson's Disease.

BACKGROUND: The "motor reserve" is an emerging concept based on the discrepancy between the severity of parkinsonism and dopaminergic degeneration; however, the related brain structures have not yet been elucidated. OBJECTIVE: We investigated brain structures relevant to the motor reserve in Parkinson's disease (PD) in this study. METHODS: Patients with drug-naïve, early PD were enrolled, who then underwent dopamine transporter (DAT) scan and diffusion tensor imaging (DTI). The severity of motor symptoms was evaluated with the Unified Parkinson's Disease Rating Scale score of bradykinesia and rigidity on the more affected side and dopaminergic degeneration of DAT uptake of the more affected putamen. Individual motor reserve estimate (MRE) was evaluated based on the discrepancy between the severity of motor symptoms and dopaminergic degeneration. Using DTI and the Brainnetome atlas, brain structures correlated with MRE were identified. RESULTS: We enrolled 193 patients with drug-naïve PD (mean disease duration of 15.6±13.2 months), and the MRE successfully predicted the increase of levodopa equivalent dose after two years. In the DTI analysis, fractional anisotropy values of medial, inferior frontal, and temporal lobes, limbic structures, nucleus accumbens, and thalamus were positively correlated with the MRE, while no brain structures were correlated with mean diffusivity. Additionally, degree centrality derived from the structural connectivity of the frontal and temporal lobes and limbic structures was positively correlated with the MRE. CONCLUSION: Our results show empirical evidence for MR in PD and brain structures relevant to MR, particularly, the extra-basal ganglia system including the limbic and frontal structures.

Daily Exercise Patterns and Their Differences between Parkinson's Disease Patients with and without Postural Instability.

Background: Due to the clinical impact of exercise in patients with Parkinson's disease (PD), management should include personalized and effective exercises according to patient's PD stage. We investigated the detailed exercise behaviors of patients with mild to advanced PD and compared their patterns between PD with and without postural instability (PI). Methods: We enrolled PD patients from September to December 2019. Clinical data on parkinsonism, exercise behaviors, and Physical Activity Scale of the Elderly (PASE) scores were collected and compared between mild PD without PI (Hoehn-Yahr (HY) stages 1 and 2) and advanced PD with PI (HY stages 3 and 4). Results: In total, 263 PD patients were recruited. The mean exercise frequency was 4.7 ± 2.1 times/week, and the average duration was 7.8 ± 6.7 hours/week. The most common exercise was an aerobic exercise (71.9%) of mild-to-moderate intensity, with active walking being the most common (49.0%). The mild PD patients demonstrated a higher duration and intensity of exercise and more physical activity than the advanced PD patients. However, the frequency of exercise was not significantly different between the two groups. The PASE score was significantly higher in mild PD patients than in advanced PD patients (p < 0.001). Conclusion: PD patients focused mostly on aerobic exercises, especially active walking. With the disease progression, the amount and intensity of exercise decreased while frequency remained. Higher intensity of exercise is needed in the mild PD group, while the advanced PD group requires the increment of duration for each exercise session.

Motor and Non-motor Symptoms Associated With Exercise Behavior in Parkinson's Disease Patients: Factors Differ Between Patients With and Without Postural Instability.

Background: Exercise is an important treatment for Parkinson's disease (PD). Therefore, recognizing determinants of exercise behavior for PD based on disease stage is essential. We sought to find whether the determinants differ based on presence of postural instability (PI), which is indicative of disease stage in PD. Methods: We enrolled patients at Samsung Medical Center from September 2019 to November 2020, who had the ability to perform exercise [modified Hoehn and Yahr (HY) stage ≤ 3]. All the motor and non-motor symptoms were investigated. The exercise of the PD patients was evaluated using the Physical Activity Scale of the Elderly (PASE)-leisure score. We classified patients into PD without PI (HY stage 1 - 2) and PD with PI (HY stage 2.5 - 3) groups. Multivariate linear regression was performed using backward elimination in each group to determine factors associated with PASE-leisure score. Results: A total of 233 patients were enrolled. In the PD without PI group (n = 177), the positive determinant of exercise was Activities-Specific Balance Confidence (ABC) score (ß = 0.142, p = 0.032), and the negative determinants were fatigue score (ß = -0.228, p = 0.018), female (ß = -6.900, p = 0.016) and currently employed status (ß = -6.072, p = 0.046). In the PD with PI group (n = 56), the positive determinant was non-motor symptom scale (NMSS) score (ß = 0.221, p = 0.017) and disease duration (ß = 1.001, p = 0.036), while the negative determinants were UPDRS part 3 score (ß = -0.974, p < 0.001), UPDRS part 4 score (ß = -2.192, p = 0.002), and age (ß = -1.052, p < 0.001). Conclusion: Different motor and non-motor symptoms were associated with the exercise in PD patients with and without PI. When encouraging PD patients to exercise, personalized and different strategies should be applied based on the presence of PI.

Extra-basal ganglia iron content and non-motor symptoms in drug-naïve, early Parkinson's disease.

BACKGROUND: Although iron dyshomeostasis is associated with Parkinson's disease (PD) pathogenesis, the relationship between iron deposition and non-motor involvement in PD is not fully understood. In this study, we investigated basal ganglia and extra-basal ganglia system iron contents and their correlation with non-motor symptoms in drug-naïve, early-stage PD patients. METHODS: We enrolled 14 drug-naïve, early-stage PD patients and 12 age/sex-matched normal controls. All participants underwent brain magnetic resonance imaging to obtain the effective transverse relaxation rate (R2*) and quantitative susceptibility mapping (QSM). Deep brain structures, including the nucleus accumbens, caudate nucleus, putamen, globus pallidus, thalamus, hippocampus, and amygdala, were delineated using the FSL-FIRST; the substantia nigra, red nucleus, and dentate nucleus were segmented manually. Inter-group differences in R2* and QSM values, as well as their association with clinical parameters of PD, were investigated. RESULTS: Substantia nigra and putamen R2* values were significantly higher in PD patients than in normal controls, despite no significant difference in QSM values. Regarding the non-motor symptom scales, PD sleep scale score negatively correlated with R2* values in the red nucleus and right amygdala, Scales for Outcomes in Parkinson's disease-Autonomic scores were positively correlated with R2* values in the right amygdala and left hippocampus, and cardiovascular sub-score of Non-Motor Symptoms Scale for PD was positively associated with the QSM value in the left hippocampus. CONCLUSION: In this study, iron content in the extra-basal ganglia system was significantly correlated with non-motor symptoms, especially sleep problems and dysautonomia, even in early-stage PD.

Extracerebellar Signs and Symptoms in 117 Korean Patients with Early-Stage Spinocerebellar Ataxia.

BACKGROUND AND PURPOSE: Spinocerebellar ataxias (SCAs) are the most common form of hereditary ataxias. Extracerebellar signs have been well described and are helpful in differentiating the SCA subtypes. However, there are few reports on the early-stage extracerebellar signs in various SCA subtypes. This study explored the clinical and magnetic resonance imaging (MRI) characteristics of early-stage SCAs in the Korean population. METHODS: We retrospectively reviewed the medical records of genetically confirmed SCA patients with a disease duration of <5 years. Data on baseline characteristics, extracerebellar signs, and initial MRI findings were organized based on SCA subtypes. RESULTS: This study included 117 SCA patients with a median age at onset of 40.6 years. The family history was positive in 71.8% of the patients, and the median disease duration and the score on the Scale for the Assessment and Rating of Ataxia at the initial visit were 2.6 years and 5.0, respectively. SCA3 was the most prevalent subtype, and oculomotor abnormalities were the most frequent extracerebellar signs in early-stage SCAs. Saccadic slowing was characteristic of SCA2 and SCA7, and gaze-evoked nystagmus was prominent in SCA6. Parkinsonism was relatively frequent in SCA8 and SCA3. Decreased visual acuity was specific for SCA7. Dementia was not an early manifestation of SCAs. Brain MRI revealed a pattern of pontocerebellar atrophy in SCA2 and SCA7, while SCA6 demonstrated only cerebellar cortical atrophy. CONCLUSIONS: SCA patients exhibited diverse extracerebellar signs even in the early stage. Specific extracerebellar signs were characteristic of specific subtypes, which could facilitate differential diagnoses of early-stage SCAs.

The changes of exercise pattern and clinical symptoms in patients with Parkinson's disease in the era of COVID-19 pandemic.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has disrupted everyday life of Parkinson's disease (PD) patients, but its clinical impact has not been illustrated. In this study, we investigated the change in physical activity and subsequently clinical symptoms of PD during the COVID-19 pandemic. METHODS: We enrolled PD patients who were able to ambulate independently and had visited our clinic at Samsung Medical Centre from December 2019 to January 2020 (baseline) and in May 2020 (follow-up during the COVID-19 crisis), and divided them into either 'the sustained exercise group' or 'the reduced exercise group'. Then, we assessed the change in the exercise and clinical features between these two groups over the study period. RESULTS: A total of 100 subjects were recruited. During the COVID-19 pandemic, the amount, duration and frequency of exercise were reduced. There was decrease in number of patients who do indoor-solo exercise and increase in that of patients who do not exercise. One third reported subjective worsening of both motor and non-motor features, although Unified PD Rating Scale (UPDRS) part 3 score was similar. Additionally, the reduced exercise group reported more motor and non-motor aggravation than the sustained exercise group, despite lack of significant difference in the UPDRS part 3 score. CONCLUSION: The COVID-19 pandemic had a clear impact on exercise and subjective symptoms in PD patients, with reduced exercise being related to a subjective increase in both motor and non-motor symptoms of PD. Maintaining exercise should therefore be emphasized even in situations like the COVID-19 pandemic.

Clarification of undiagnosed ataxia using whole-exome sequencing with clinical implications.

BACKGROUND: Hereditary cerebellar ataxias exhibit heterogeneous phenotypes and genotypes. To date, advancement of next-generation sequencing technologies have identified many causative genes for ataxia in various population. In this study, whole-exome sequencing (WES) was utilized to explore the genetic cause of ataxia among Korean patients who remained undiagnosed following routine investigation. METHODS: Patients with ataxia were enrolled in this study. We excluded patients with acquired, degenerative, and trinucleotide repeat ataxias, such as spinocerebellar ataxia 1 (SCA1), SCA2, SCA3, SCA6, SCA7, SCA8, SCA17, Dentatorubral-pallidoluysian atrophy, and Friedreich ataxia. WES was performed. After basic filtering based on population databases, we then performed primary filtering to screen for known ataxia-associated genes, followed by expanded filtering customized for individual patients. RESULTS: We enrolled 77 ataxia patients from 68 families. Eighteen families had pathogenic or likely pathogenic variants in 14 different genes, including NEU1, APTX, SPG7, HTRA1, POLG2, SYNE1, CACNA1G, CACNA1A, ITPR1, AHI1, SPG11, ANO10, ATM, and C5orf42, resulting in a diagnostic yield of 26.5%. Hereditary spastic paraplegia was the most common diagnosis. Adult-onset ataxias and those without family history were frequently encountered. Variants of unknown significance were found in 14 (20.6%) families, some of which were highly probable from the clinical perspective. CONCLUSION: Using WES, we explored the molecular etiology of ataxia in patients whom were not diagnosed through routine clinical investigation. This study revealed unexpected rare disorders as well as the known ataxia-associated genes in a Korean population.

The Dysfunctional Autonomic Function and "Dysfunctional" Fatigue in Drug Naïve Parkinson's Disease.

BACKGROUND: Fatigue is a common and disabling non-motor symptom in Parkinson's disease (PD). Autonomic dysfunction is suggested as the possible pathophysiology of fatigue, but it has not been investigated in drug-naïve PD patients. OBJECTIVE: In the present study, the relationship between fatigue and autonomic dysfunction in drug-naïve PD patients was investigated. METHODS: In the present study, 89 drug-naïve PD patients were analyzed. The Parkinson's disease fatigue scale (PFS) was used to divide the patients into fatigue (mean PFS≥3.3) and non-fatigue groups (mean PFS < 3.3). The autonomic function test (AFT), Scale for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT), Unified Parkinson's Disease Rating Scale (UPDRS)-I, -II, -III, modified Hoehn and Yahr (H&Y) scale, Montreal Cognitive Assessment (MoCA), Parkinson's Disease Questionnaire-39 (PDQ-39), Parkinson's Disease Sleep Scale (PDSS), and Beck Depress Index (BDI) were performed in all the participants. The AFT results and clinical scales were compared using multiple logistic regression analysis. RESULTS: The prevalence of fatigue was 23.6% (n = 21) in drug-naïve PD patients. Total SCOPA-AUT score was higher in the fatigue group than in the non-fatigue group. The fatigue group had lower inspiratory:expiratory (I:E) ratio and Valsalva ratio. The prevalence of abnormal sympathetic skin response and orthostatic hypotension (OH) was 19% and 38.1%, respectively, in the fatigue group. Regression model analysis revealed that SCOPA-AUT and OH were the most related factor of fatigue in drug-naïve PD patients. CONCLUSION: Autonomic dysfunction in drug-naïve PD patients was investigated using a subjective scale as well as objective tests. The results indicated that fatigue is associated with autonomic dysfunction, especially OH, in drug-naïve PD patients.

Successful Pallidal Stimulation in a Patient with KMT2B-Related Dystonia.

Although the KMT2B gene was identified as a causative gene for early-onset generalized dystonia, the efficacy of deep brain stimulation (DBS) in KMT2B-related dystonia has not been clearly elucidated. Here, we describe a 28-year-old woman who developed generalized dystonia with developmental delay, microcephaly, short stature, and cognitive decline. She was diagnosed with KMT2B- related dystonia using whole-exome sequencing with a heterozygous frameshift insertion of c.515dupC (p.T172fs) in the KMT2B gene. Oral medications and botulinum toxin injection were not effective. The dystonia markedly improved with bilateral pallidal DBS (the Burke-Fahn-Marsden Dystonia Rating Scale score was reduced from 30 to 5 on the dystonia movement scale and from 11 to 1 on the disability scale), and she could walk independently. From this case, we suggest that bilateral globus pallidus internus DBS can be an effective treatment option for patients with KMT2B-related generalized dystonia.

Sleep and libido in men with obstructive sleep apnea syndrome.

OBJECTIVES: The objectives of this study were to investigate the relationship between a low libido and objective sleep parameters as well as mood disturbances in patients with obstructive sleep apnea syndrome (OSA). METHODS: We enrolled 436 untreated patients who were newly diagnosed with OSA (all male, mean age 42.8 years). Patients completed the Symptom checklist-90-Revised (SCL-90-R), Epworth Sleepiness Scale (ESS), Beck Depression Inventory-II (BDI), and Beck Anxiety Inventory (BAI). Patients were divided into low-libido and normal-libido groups according to their response to the statement "Loss of sexual interest or pleasure" on the SCL-90-R. RESULTS: Approximately 23% of patients reported a low libido. Patients with a low libido were older (47.5 ± 9.0 vs. 41.4 ± 11.1 years; p < 0.001), had more nocturia (33.3% vs. 16.6%; p < 0.001), higher BDI (9.0 (5.0-14.0) vs. 5.0 (2.0-9.0); p < 0.001) and BAI score (11.0 (6.3-16.8) vs. 5.0 (2.0-10.0); p < 0.001). These patients had a lower non-REM sleep stage 3 (N3) % (0.1 (0-4.0) vs. 2.3 (0.1-7.9); p < 0.001). Multivariate analysis revealed that older age and higher BDI score were independent factors associated with a low libido. CONCLUSIONS: Men with untreated OSA suffered from a low libido. Older age and depressed mood were the most important factors of low libido in middle-aged men with OSA.

Weight Change Is a Characteristic Non-Motor Symptom in Drug-Naïve Parkinson's Disease Patients with Non-Tremor Dominant Subtype: A Nation-Wide Observational Study.

Despite the clinical impact of non-motor symptoms (NMS) in Parkinson's disease (PD), the characteristic NMS in relation to the motor subtypes of PD is not well elucidated. In this study, we enrolled drug-naïve PD patients and compared NMS between PD subtypes. We enrolled 136 drug-naïve, early PD patients and 50 normal controls. All the enrolled PD patients were divided into tremor dominant (TD) and non-tremor dominant (NTD) subtypes. The Non-Motor Symptom Scale and scales for each NMS were completed. We compared NMS and the relationship of NMS with quality of life between normal controls and PD patients, and between the PD subtypes. Comparing with normal controls, PD patients complained of more NMS, especially mood/cognitive symptoms, gastrointestinal symptoms, unexplained pain, weight change, and change in taste or smell. Between the PD subtypes, the NTD subtype showed higher total NMS scale score and sub-score about weight change. Weight change was the characteristic NMS related to NTD subtype even after controlled other variables with logistic regression analysis. Even from the early stage, PD patients suffer from various NMS regardless of dopaminergic medication. Among the various NMS, weight change is the characteristic NMS associated with NTD subtype in PD patients.

Characteristic lesion pattern and echocardiographic findings in extra-cardiac shunt-related stroke.

Among embolic strokes of undetermined source, under-recognized etiology such as extra-cardiac shunt could be a potential risk factor. We sought to characterize infarction patterns on diffusion-weighted imaging (DWI) and transesophageal echocardiography (TEE) findings in extra-cardiac shunt-related stroke. We enrolled 96 consecutive patients with cryptogenic stroke who had an extra- or intra-cardiac shunt. Diagnosis of the shunt was performed using TEE with agitated saline contrast and pulmonary vein isolation. Infarction patterns on DWI and total lesion volume were analyzed. Bubble amounts through the shunt were classified via the International Consensus Criteria (ICC). Short-term prognosis, patterns and size of DWI lesions, and involved vascular territories were not significantly different between two groups. Multivariate analysis revealed that extra-cardiac shunt group has a smaller total infarct volume (odds ratio [OR]=0.427, 95% confidence interval [95% CI] 0.228-0.799, p=0.008), and significantly higher bubble grade during resting state and lower grade during the Valsalva maneuver (OR= 0.539, 95% CI 0.438-0.663, p<0.001). Stroke related to an extra-cardiac shunt presented smaller infarct volume, favorable clinical outcomes and characteristic finding on TEE with agitated saline contrast. Further study is needed to confirm whether the extra-cardiac shunt is an independent risk factor.

Mesial Temporal Lobe Epilepsy in Congenital Toxoplasmosis: A Case Report.

Toxoplasmosis is a rare disease caused by intracellular protozoan parasite, Toxoplasma gondii. Though most patients with toxoplasmosis are asymptomatic, congenital toxoplasmosis in the fetus can cause ocular involvement such as chorioretinitis and central nervous system disease including intracerebral calcification, nystagmus, hydrocephalus and microcephaly. Also, these brain lesions can cause seizure secondarily. Our patient was diagnosed with congenital toxoplasmosis, based on toxoplasma-specific serologic test with typical clinical symptoms, including chorioretinitis, nystagmus, hydrocephalus and cerebral palsy. Her brain imaging findings revealed not only the multifocal encephalomalacia, but also multifocal cerebral calcification including intracerebral calcification in left perihippocampal region. Her epileptogenic zone was defined as mesial temporal lobe including hippocampus on left side by seizure semiology, electroencephalogram and neuroimaging including single photon emission computed tomography and 18F-Fluorodeoxyglucose positron-emission tomography. Her seizures were refractory to multiple anti-epileptic drugs. We report a patient with congenital toxoplasmosis who showed intractable mesial temporal lobe epilepsy.

Surgical treatment of mesial temporal lobe epilepsy in a patient with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is the most common neurocutaneous disease. Main neurologic manifestations are represented by neoplasms such as optic gliomas, but epilepsy can occur by CNS lesions in less than 10%. Our patient was diagnosed, based on café-au-lait spots and axillary freckles. Her brain MRI did not show only multiple CNS lesions, like hamartomas, but also mesial temporal lesions. On brain-MRI the mesial temporal lesions had increased high signal intensities and suspiciously increased volume. Moreover scalp lesions could be confirmed by thin-slice, fat suppression, enhanced lesions on skin and subcutaneous areas, indicating neurofibromas. The seizure onset zone was confirmed by presurgical evaluation including electrophysiology and neuroimaging. Her seizures were refractory to multiple antiepileptic drugs, but became free after anteromesial temporal resection. We report a patient with the NF1 in mesial temporal lobe epilepsy. Epilepsy surgery was also effective in this case.