Clonal dynamics in early human embryogenesis inferred from somatic mutation.

Cellular dynamics and fate decision in early human embryogenesis remain largely unknown owing to the challenges of performing studies in human embryos1. Here, we explored whole-genomes of 334 single-cell colonies and targeted deep sequences of 379 bulk tissues obtained from various anatomical locations of seven recently deceased adult human donors. Using somatic mutations as an intrinsic barcode, we reconstructed early cellular phylogenies that demonstrate (1) an endogenous mutational rate that is higher in the first cell division but decreases to approximately one per cell per cell division later in life; (2) universal unequal contribution of early cells to embryo proper, resulting from early cellular bottlenecks that stochastically set aside epiblast cells within the embryo; (3) examples of varying degrees of early clonal imbalances between tissues on the left and right sides of the body, different germ layers and specific anatomical parts and organs; (4) emergence of a few ancestral cells that will substantially contribute to adult cell pools in blood and liver; and (5) presence of mitochondrial DNA heteroplasmy in the fertilized egg. Our approach also provides insights into the age-related mutational processes and loss of sex chromosomes in normal somatic cells. In sum, this study provides a foundation for future studies to complete cellular phylogenies in human embryogenesis.

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.

Validation of the REM behaviour disorder phenoconversion-related pattern in an independent cohort.

BACKGROUND: A brain glucose metabolism pattern related to phenoconversion in patients with idiopathic/isolated REM sleep behaviour disorder (iRBDconvRP) was recently identified. However, the validation of the iRBDconvRP in an external, independent group of iRBD patients is needed to verify the reproducibility of such pattern, so to increase its importance in clinical and research settings. The aim of this work was to validate the iRBDconvRP in an independent group of iRBD patients. METHODS: Forty iRBD patients (70 ± 5.59 years, 19 females) underwent brain [18F]FDG-PET in Seoul National University. Thirteen patients phenoconverted at follow-up (7 Parkinson disease, 5 Dementia with Lewy bodies, 1 Multiple system atrophy; follow-up time 35 ± 20.56 months) and 27 patients were still free from parkinsonism/dementia after 62 ± 29.49 months from baseline. We applied the previously identified iRBDconvRP to validate its phenoconversion prediction power. RESULTS: The iRBDconvRP significantly discriminated converters from non-converters iRBD patients (p = 0.016; Area under the Curve 0.74, Sensitivity 0.69, Specificity 0.78), and it significantly predicted phenoconversion (Hazard ratio 4.26, C.I.95%: 1.18-15.39). CONCLUSIONS: The iRBDconvRP confirmed its robustness in predicting phenoconversion in an independent group of iRBD patients, suggesting its potential role as a stratification biomarker for disease-modifying trials.

Longitudinal intravital imaging of cerebral microinfarction reveals a dynamic astrocyte reaction leading to glial scar formation.

Cerebral microinfarct increases the risk of dementia. But how microscopic cerebrovascular disruption affects the brain tissue in cellular-level are mostly unknown. Herein, with a longitudinal intravital imaging, we serially visualized in vivo dynamic cellular-level changes in astrocyte, pericyte and neuron as well as microvascular integrity after the induction of cerebral microinfarction for 1 month in mice. At day 2-3, it revealed a localized edema with acute astrocyte loss, neuronal death, impaired pericyte-vessel coverage and extravascular leakage of 3 kDa dextran (but not 2 MDa dextran) indicating microinfarction-related blood-brain barrier (BBB) dysfunction for small molecules. At day 5, the local edema disappeared with the partial restoration of microcirculation and recovery of pericyte-vessel coverage and BBB integrity. But brain tissue continued to shrink with persisted loss of astrocyte and neuron in microinfarct until 30 days, resulting in a collagen-rich fibrous scar surrounding the microinfarct. Notably, reactive astrocytes expressing glial fibrillary acidic protein (GFAP) appeared at the peri-infarct area early at day 2 and thereafter accumulated in the peri-infarct until 30 days, inducing glial scar formation in cerebral cortex. Our longitudinal intravital imaging of serial microscopic neurovascular pathophysiology in cerebral microinfarction newly revealed that astrocytes are critically susceptible to the acute microinfarction and their reactive response leads to the fibrous glial scar formation.

Serum Inflammatory Markers and Progression of Nonmotor Symptoms in Early Parkinson's Disease.

BACKGROUND: The influence of peripheral inflammation on nonmotor symptoms (NMSs) in Parkinson's disease (PD) remains unclear. OBJECTIVE: The aim of this study was to explore whether serum inflammatory marker profiles are associated with the progression of NMSs in early PD. METHODS: We included 45 patients with early PD and 20 healthy control subjects. Six inflammatory markers, including interleukin (IL)-1ß, IL-2, IL-6, IL-10, tumor necrosis factor-α, and high-sensitivity C-reactive protein, were measured. NMSs were assessed using the Non-Motor Symptoms Scale, Montreal Cognitive Assessment, and Composite Autonomic Symptom Score-31 at baseline and after 3 years. RESULTS: Principal component (PC) analysis showed that only PC3 scores, mainly loaded by IL-2 and IL-6, were significantly elevated in the PD group compared with the control group. Higher PC3 scores in the PD group were associated with faster progression of Non-Motor Symptoms Scale total and mood/apathy domain scores. There were no significant associations of PC scores with Montreal Cognitive Assessment and Composite Autonomic Symptom Score-31 score changes. CONCLUSIONS: Peripheral inflammation may be related to the evolution of NMSs, particularly mood symptoms, in the early stages of PD. © 2022 International Parkinson and Movement Disorder Society.

Brain Metabolic Correlates of Dopaminergic Denervation in Prodromal and Early Parkinson's Disease.

BACKGROUND: It remains unclear how brain metabolic activities transform in response to dopamine deficiency in the prodromal and early phases of Parkinson's disease (PD). OBJECTIVE: To investigate the relationship between nigrostriatal dopaminergic denervation and brain glucose metabolism in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and early PD. METHODS: This cohort study included 28 patients with polysomnography-confirmed iRBD, 24 patients with de novo PD with probable rapid eye movement sleep behavior disorder (denovo PD), and 28 healthy controls (HCs) who underwent two positron emission tomography scans with 18 F-fluorodeoxyglucose (all participants) and 18 F-N-3-fluoropropyl-2ß-carboxymethoxy-3ß-(4-iodophenyl)-nortropane (except for one denovo PD patient and 15 HCs). We analyzed striatal and voxel-wise whole-brain glucose metabolism in relation to nigrostriatal dopaminergic integrity and comparatively investigated the whole-brain metabolic connectivity among the groups. We also assessed longitudinal metabolic changes against progressive dopaminergic denervation over 4 years in the iRBD group. RESULTS: From HCs to iRBD and finally to the denovo PD, dopaminergic integrity positively correlated with metabolic activity in the caudate, whereas a negative correlation was observed in the posterior putamen. In the iRBD group, there was a metabolic increase in the inferior orbitofrontal cortex against putaminal dopaminergic denervation at baseline, but negative correlations were newly observed in the superior orbitofrontal cortex and superior frontal gyrus at the 4-year follow-up. The denovo PD group showed negative correlations in the cerebellum and fusiform gyrus. Intra- and inter-regional metabolic connectivities in the parieto-occipital cortices were enhanced in the iRBD group compared with the denovo PD and HC groups. In the iRBD group, overall metabolic connectivity was strengthened along with enhanced basal ganglia-frontal connection by advancing dopaminergic denervation. CONCLUSIONS: Our findings suggest diverse trajectories of metabolic responses associated with dopaminergic denervation between individual brain areas in the prodromal and early PD stages. © 2022 International Parkinson and Movement Disorder Society.

ASSOCIATION BETWEEN EPIRETINAL MEMBRANE, EPIRETINAL PROLIFERATION, AND PROGNOSIS OF FULL-THICKNESS MACULAR HOLE CLOSURE.

PURPOSE: To demonstrate the effects of epiretinal membrane (ERM) and epiretinal proliferation on surgical outcomes for full-thickness macular hole. METHODS: Nested case-control study with propensity score matching. Patients operated on for full-thickness macular hole between January 2011 and March 2020 were enrolled. The primary outcome was failure of the macular hole closure, and the secondary outcome was unfavorable hole closure (V or λ type closure) at 6 months after the surgery. RESULTS: Five hundred and thirty-four eyes of 534 patients met the inclusion criteria. After 1:1 propensity score matching (127 pairs), patients demonstrating ERM were more likely to have a failure of hole closure (adjusted odds ratio, 2.71; 95% confidence interval, 1.19-6.14) and unfavorable hole closure (adjusted odds ratio, 2.07; 95% confidence interval, 1.16-3.71). Epiretinal membrane spanning the hole margin (hole marginal ERM) greatly increased the likelihood of unfavorable hole closure (adjusted odds ratio, 2.13; 95% confidence interval, 1.12-4.07). Patients with hole marginal-ERM + epiretinal proliferation were more likely to have a failure of hole closure (38.4%) compared with those with no ERM (11.8%). CONCLUSION: Patients with ERM had a higher risk for adverse surgical outcomes for full-thickness macular hole closure. The location of the ERM relative to the macular hole and the presence of epiretinal proliferation might affect the surgical outcomes for full-thickness macular hole closure.

Longitudinal Changes in Isolated Rapid Eye Movement Sleep Behavior Disorder-Related Metabolic Pattern Expression.

BACKGROUND: It remains unclear whether and how the isolated rapid eye movement (REM) sleep behavior disorder (iRBD)-related metabolic pattern (RBDRP) changes with disease progression in iRBD. OBJECTIVE: To examine longitudinal changes in RBDRP expression in iRBD patients and to explore trajectories of relative metabolic activities of individual brain regions constituting RBDRP. METHODS: In this cohort study, 25 iRBD patients (mean age [±standard deviation], 69.2 ± 5.3 years; 12 [48%] patients were men) and 24 age-matched healthy controls were included. The patients underwent at least two 18 F-fluorodeoxyglucose positron emission tomography scans at baseline and at the 2-year and/or 4-year follow-ups. We measured the RBDRP expression of the patients and controls which was validated by reproduction in a separate iRBD cohort (n = 13). RESULTS: At baseline, the RBDRP expression discriminated iRBD patients from healthy controls. However, the RBDRP expression z scores tended to decrease over time in the patients, especially with longer follow-ups, and this tendency was observed even in patients with high-risk of phenoconversion. Furthermore, the degree of RBDRP expression at baseline did not predict the disease conversion. The RBDRP breakdown was mainly provoked by the attenuation of relative hypermetabolism in the frontal cortex including premotor areas and relative hypometabolism in the occipital cortex. The putaminal metabolic activity increased steadily with the disease progression. CONCLUSIONS: The RBDRP expression in iRBD patients was altered significantly over time. Some of the brain metabolic changes seem to represent attempted functional compensation against ongoing neurodegeneration. The RBDRP expression measurement at one time point may not be a reliable biomarker for predicting disease conversion. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Late-life falling and depressive symptoms associated with the risk of Parkinson's disease: a nationwide cohort data analysis.

BACKGROUND: This study aimed to evaluate the relationship between the history of late-life falling and the development of Parkinson's disease (PD) and investigate whether depressive symptoms interact with falling to increase PD risk. METHODS: We identified 1,223,726 subjects without PD who underwent the National Screening Program for Transitional Age at 66 years between 2009 and 2013 using the National Health Cohort database. In this program, every participant was assessed whether they experienced falling for the past six months. Depressive symptoms were evaluated with a three-item questionnaire extracted from the Geriatric Depression Scale. Incident PD was traced for a mean 4.23 ± 1.50 years. Cox proportional hazard regression models were used to assess the risk of PD by falling history with and without depressive symptoms after adjusting for other confounding variables. RESULTS: In this cohort, the PD incidence rate was 1.30 and 1.03 cases per 1000 person-years in groups with and without falling and 1.34 and 1.00 cases per 1000 person-years in groups with and without depressive symptoms. The predictive risk of PD was increased by either a history of falling (HR = 1.24; 95% CI 1.11-1.40) or the presence of depressive symptoms (HR = 1.31; 95% CI 1.21-1.42) after adjusting for possible confounding variables. For individuals with both falling and depressive symptoms, PD risk increased further (HR = 1.66; 95% CI 1.40-1.97), but with sex-differences. The two factors increased PD risk in a sub-additive manner in men, whereas synergistically in women. CONCLUSIONS: This national cohort database shows that late-life depressive symptoms accompanied by a falling event pose an increase in the risk of PD in older adults.

Tocilizumab treatment for new onset refractory status epilepticus.

We investigated the therapeutic potential of the interleukin-6 receptor inhibitor tocilizumab in 7 patients with new onset refractory status epilepticus (NORSE) who remained refractory to conventional immunotherapy with rituximab (n = 5) or without rituximab (n = 2). Status epilepticus (SE) was terminated after 1 or 2 doses of tocilizumab in 6 patients with a median interval of 3 days from the initiation. They had no recurrence of SE during the observation. However, 2 patients experienced severe adverse events related to infection during the tocilizumab therapy. Further prospective controlled studies are warranted to validate the efficacy and safety of tocilizumab in patients with NORSE. Ann Neurol 2018;84:940-945.

Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors.

BACKGROUND: We aimed to compare intra- and extracranial responses to immune checkpoint inhibitors (ICIs) in lung cancer with brain metastases (BM), and to explore tumor microenvironments of the brain and lungs focusing on the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway. METHODS: Two cohorts of lung cancer patients with BM were analyzed. Cohort 1 included 18 patients treated with nivolumab or pembrolizumab, and intra- and extracranial responses were assessed. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy. Specimens from cohort 2 were subjected to immunohistochemical analysis for the following markers: CD3, CD4, CD8, FOXP3, and PD-1 on tumor infiltrating lymphocytes (TIL) and PD-L1 on tumor cells. RESULTS: Seven patients (38.9%) in cohort 1 showed progressive disease in both primary and intracranial lesions. Although the other 11 patients exhibited a partial response or stable disease in the primary lesion, eight showed a progression in BM. Interestingly, PD-1+ TILs were significantly decreased in BM (P = 0.034). For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP3+ (P = 0.016), and PD-1+ (P = 0.016) TILs. CONCLUSIONS: There may be discordant responses to an ICI of lung cancer between primary lung lesion and BM based on discrepancies in the tumor microenvironment. The diminished infiltration of PD-1+ TILs in tumor tissue within the brain may be one of the major factors that hinder the response to anti-PD-1 antibody in BM.

Peripheral Blood Inflammatory Cytokines in Idiopathic REM Sleep Behavior Disorder.

BACKGROUND: Although previous research provides insight into the role of neuroinflammation in idiopathic REM sleep behavior disorder, the association of this disorder with peripheral blood inflammatory markers remains unclear. OBJECTIVE: To investigate inflammatory cytokines in plasma samples in patients with idiopathic rapid eye movement sleep behavior disorder and to explore whether these markers are associated with prodromal symptoms of α-synucleinopathies. METHODS: We collected plasma from patients with polysomnographically confirmed idiopathic rapid eye movement sleep behavior disorder without parkinsonism or dementia (n = 54) and from healthy controls (n = 56). The following cytokines were measured: interleukin-1ß, interleukin-2, interleukin-6, interleukin-10, and tumor necrosis factor-α. The idiopathic REM sleep behavior disorder patients underwent sleep, motor, cognitive, olfactory, and autonomic testing. RESULTS: The anti-inflammatory cytokine, interleukin-10, levels in the idiopathic rapid eye movement sleep behavior disorder group were significantly upregulated compared to the control group (P = 0.022), but this difference did not withstand Bonferroni correction. The other proinflammatory cytokine levels did not differ between the groups. No correlation was found between the cytokine levels and any clinical variable. CONCLUSIONS: Our data do not provide evidence supporting the role of peripheral inflammation in idiopathic rapid eye movement sleep behavior disorder. However, considering the limited statistical power because of the small sample size, further large-scale longitudinal studies with a broader spectrum of cytokines are needed to clarify this issue. © 2019 International Parkinson and Movement Disorder Society.

Determinants of Functional Independence or Its Loss following Subthalamic Nucleus Stimulation in Parkinson's Disease.

OBJECTIVE: This study aimed to describe the change in functional status following bilateral subthalamic nucleus stimulation (STN-DBS) in Parkinson's disease (PD) and to identify predictors of postoperative functional dependence. METHODS: We included PD patients with bilateral STN-DBS who had complete Schwab & England Activities of Daily Living (S&E ADL) Scale data at baseline and 6 months after surgery from our prospective registry. Functional dependence was defined as an S&E ADL score of less than 80%. All data were collected from the on-medication state and on-stimulation state (after surgery). Logistic regression analyses were performed to determine the factors predictive of functional dependence after surgery. RESULTS: A total of 196 patients were included. At baseline, 41 patients were functionally dependent and the other 155 were functionally independent. Among the patients with preoperative dependence, 32 (78%) became functionally independent after surgery, and this conversion was associated with a lower baseline axial score (p = 0.012). Among the patients with preoperative independence, 21 (14%) developed postoperative dependence, and this conversion was associated with a higher baseline axial score (p = 0.013) and its smaller improvement (p < 0.001). Female sex (odds ratio [OR] 3.214; 95% confidence interval [CI] 1.210-8.542; p = 0.019) and a higher baseline axial score (OR 1.184; 95% CI 1.056-1.327; p = 0.004) significantly predicted the risk of postoperative functional dependence. CONCLUSIONS: We found that functional status following bilateral STN-DBS is closely related to preoperative axial symptoms. When loss of independence is a potential target for STN-DBS, clinicians should take into consideration the severity of axial impairment before surgery.

Temporal trajectory of quality of life and its predictors in recipients of hematopoietic stem cell transplantation.

This prospective longitudinal study evaluated the temporal trajectory of health-related quality of life (HRQOL) and its associated factors in patients who received hematopoietic stem cell transplantation (SCT) 6 months after transplantation. Eighty-nine adult patients who were admitted to Seoul National University Hospital for SCT were consecutively included in the study. The participants completed three standardized questionnaires: Insomnia Severity Index, Hospital Anxiety and Depression Scale, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. The participants completed the study questionnaires at three time points: before SCT (T1), immediately after SCT (T1), and 6 months after SCT (T3). Immediately after SCT, HRQOL decreased significantly (p < 0.001), followed by recovery over 6 months. The conditioning regimen for SCT showed no correlation with HRQOL at T2 (p = 0.283) or T3 (p = 0.799), with no significant difference in HRQOL between allogeneic and autologous SCT recipients at T2 (p = 0.829) or T3 (p = 0.824). Depression (p = 0.042), pain (p = 0.023), and appetite loss (p = 0.004) negatively influenced HRQOL at T1, whereas only pain (p = 0.048) remained an important factor at T2. Six months after SCT, the two most frequent symptoms, fatigue and financial problems, became major factors (p = 0.004 and p = 0.005, respectively). Depression began to play an important role in HRQOL again at T3 (p = 0.040). These findings demonstrate that SCT recipients need both psychological and medical support to achieve a better HRQOL after SCT.

Expanding the Spectrum of Dopa-Responsive Dystonia (DRD) and Proposal for New Definition: DRD, DRD-plus, and DRD Look-alike.

Previously, we defined DRD as a syndrome of selective nigrostriatal dopamine deficiency caused by genetic defects in the dopamine synthetic pathway without nigral cell loss. DRD-plus also has the same etiologic background with DRD, but DRD-plus patients have more severe features that are not seen in DRD because of the severity of the genetic defect. However, there have been many reports of dystonia responsive to dopaminergic drugs that do not fit into DRD or DRD-plus (genetic defects in the dopamine synthetic pathway without nigral cell loss). We reframed the concept of DRD/DRD-plus and proposed the concept of DRD look-alike to include the additional cases described above. Examples of dystonia that is responsive to dopaminergic drugs include the following: transportopathies (dopamine transporter deficiency; vesicular monoamine transporter 2 deficiency); SOX6 mutation resulting in a developmentally decreased number of nigral cells; degenerative disorders with progressive loss of nigral cells (juvenile Parkinson's disease; pallidopyramidal syndrome; spinocerebellar ataxia type 3), and disorders that are not known to affect the nigrostriatal dopaminergic system (DYT1; GLUT1 deficiency; myoclonus-dystonia; ataxia telangiectasia). This classification will help with an etiologic diagnosis as well as planning the work up and guiding the therapy.

Predictive and prognostic value of PET/CT imaging post-chemoradiotherapy and clinical decision-making consequences in locally advanced head & neck squamous cell carcinoma: a retrospective study.

BACKGROUND: The accuracy of (18)F-fluorodeoxygluocose positron emission tomography/computed tomography (PET/CT) in predicting immediate failure after radical chemoradiotherapy (CRT) for HNSCC is poorly characterized at present. The purpose of this study was to examine PET/CT as a predictive and prognostic gauge of immediate failure after CRT and determine the impact of these studies on clinical decision making in terms of salvage surgery. METHODS: Medical records of 78 consecutive patients receiving radical CRT for locally advanced HNSCC were reviewed, analyzing PET/CTs done before and 3 months after CRT. Immediate failure was defined as residual disease or locoregional and/or systemic relapse within 6 months after CRT. RESULTS: Maximum standard uptake value (SUV) of post CRT PET/CT (postSUVmax) was found optimal for predicting immediate failure at a cutpoint of 4.4. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were 90.0%, 83.8%, 98.3%, and 45.0%, respectively. Of 78 patients studied, postSUVmax ≥ 4.4 prevailed in 20 (25.6%), with postSUVmax <4.4 in 58 (74.4%). At postSUVmax ≥ 4.4 (vs. postSUVmax <4.4) OS was poorer by comparison (3-year OS: 56.9 vs. 87.7%; P = 0.005), as was progression-free survival (3-year PFS: 42.9 vs. 81.1%; P < 0.001). At postSUVmax ≥ 4.4, OS with and without immediate salvage surgery did not differ significantly (3-year OS: 60.0 vs. 55.6%; Log-rank P = 0.913). CONCLUSION: Post CRT PET/CT imaging has prognostic value in terms of OS and PFS and is useful in predicting immediate therapeutic failure, given its high NPV. However, OS was not significantly altered by early salvage surgery done on the basis of post CRT PET/CT findings.

Oculomotor nerve tumors masquerading as recurrent painful ophthalmoplegic neuropathy: report of two cases and review of the literature.

BACKGROUND: In recurrent painful ophthalmoplegic neuropathy (RPON) that was previously termed as ophthalmoplegic migraine, enhancement of the ocular motor cranial nerves could be seen in the cisternal segment during the acute phase. However, various tumors involving the oculomotor nerve may mimic RPON. METHODS: We report two patients with MRI findings of oculomotor nerve schwannoma who initially presented with RPON, and found through the literature review five more patients with oculomotor nerve tumors that masqueraded as RPON. RESULTS: All patients showed an involvement of the oculomotor nerve. The radiological or pathological diagnosis included schwannoma in five, venous angioma in one, and neuromuscular harmatoma in another one. MRIs with gadolinium documented an enhancing nodule involving the cisternal portion of the oculomotor nerve in six of them, which was also observed on follow-up MRIs without an interval change. CONCLUSIONS: It should be recognized that an incomplete recovery may occur during future attacks in patients with otherwise uncomplicated RPON. Follow-up MRIs are required to detect tumors involving the ocular motor cranial nerves, especially in patients with suspected RPON when the recovery is incomplete.

Clinical usefulness of the SARC-F questionnaire to assess sarcopenia in patients with Parkinson's disease.

OBJECTIVE: To investigate the accuracy of the SARC-F questionnaire to identify sarcopenia in patients with Parkinson's disease (PD). METHODS: We prospectively recruited patients with PD who had a score of 3 or lower on the Hoehn and Yahr (H&Y) scale. Appendicular skeletal muscle mass (ASM), hand grip strength, and the SARC-F were used to assess sarcopenia. The cutoffs for the ASM index and hand grip strength to diagnose sarcopenia were based on the Asian Working Group for Sarcopenia 2019 consensus. A score ≥4 on the SARC-F was considered at risk for sarcopenia. RESULTS: A total of 365 patients with PD were included (mean age, 71.1 years; men, 53.2 %), and 73 (20.0 %) were diagnosed with sarcopenia. The area under the receiver operating characteristic curve of the SARC-F was 0.702 (95 % confidence interval, 0.634-0.770). Using the recommended cutoff score of ≥4, the SARC-F showed a sensitivity of 38.4 %, specificity of 85.6 %, positive predictive value (PPV) of 40.0 %, and negative predictive value (NPV) of 84.7 %. The Youden's index was the highest at a cutoff score of ≥2, in which the SARC-F showed a sensitivity of 67.1 %, specificity of 65.4 %, PPV of 32.7 %, and NPV of 88.8 %. These predictive values were similar to those obtained using a cutoff score of ≥2.5 or 3 on the H&Y scale. CONCLUSION: The application of the SARC-F to the mild-to moderate PD population is not appropriate as a first-step screening tool to diagnose sarcopenia. Given the comparable predictive values of the SARC-F and H&Y scale, this questionnaire may be considered only for ruling out sarcopenia in patients with similar disease severity.

Role of exercise in modulating prefrontal cortical activation for improved gait and cognition in Parkinson's disease patients.

PURPOSE: This narrative review evaluated the impact of exercise on gait and cognitive functions in patients with Parkinson's disease (PD), focusing on prefrontal cortical (PFC) activation assessed using near-infrared spectroscopy (NIRS). METHODS: A literature search was conducted in the PubMed and Web of Science databases using keywords such as "Parkinson's disease," "gait," "cognitive functions," "exercise," and "NIRS," focusing on publications from the last decade. Studies measuring PFC activity using NIRS during gait tasks in patients with PD were selected. RESULTS: The review indicated that patients with PD demonstrate increased PFC activity during gait tasks compared to healthy controls, suggesting a greater cognitive demand for movement control. Exercise has been shown to enhance neural efficiency, thus improving gait and cognitive functions. CONCLUSION: Exercise is crucial for improving gait and cognitive functions in patients with PD through increased PFC activation. This emphasizes the importance of incorporating exercise into PD management plans and highlights the need for further studies on its long-term effects and the neurobiological mechanisms underlying its benefits, with the aim of optimizing therapeutic strategies and improving patients' quality of life.