Morphometric analysis of spinal motor neuron degeneration in sporadic amyotrophic lateral sclerosis.

OBJECTIVES: This study aimed to clarify the relationship between 43-kDa TAR DNA-binding protein (TDP-43) pathology and spinal cord anterior horn motor neuron (AHMN) atrophy in sporadic amyotrophic lateral sclerosis (SALS). METHODS: Eight patients with SALS and 12 controls were included in this study. Formalin-fixed specimens of lumbar spinal cord samples were paraffin-embedded and sectioned at the level of the fourth lumbar spinal cord with a 4 µm thickness. Using a microscope, the long diameters of the neurons with nucleoli were measured in spinal AHMNs stained with an anti-SMI-32 antibody. AHMNs were divided into medial and lateral nuclei for statistical analysis. We also used previously reported data to measure the long diameter of AHMNs with initial TDP-43 pathology, in which TDP-43 was present both in the nucleus and cytoplasm. RESULTS: The long diameter of the lumbar spinal AHMNs in patients with SALS was smaller in the medial nucleus (42.54 ± 9.33 µm, n = 24) and the lateral nucleus (49.41 ± 13.86 µm, n = 129) than in controls (medial nucleus: 55.84 ± 13.49 µm, n = 85, p < 0.001; lateral nucleus: 62.39 ± 13.29 µm, n = 756, p < 0.001, Mann-Whitney U test). All 21 motor neurons with initial TDP-43 pathology were in the lateral nucleus, and their long diameter (67.60 ± 18.3 µm, p = 0.352) was not significantly different from that of controls. CONCLUSION: Motor neuron atrophy in SALS does not occur during the initial stages of TDP-43 pathology, and TDP-43 pathology is already advanced in the atrophied motor neurons.

The speed of completion of the decremental responses on repetitive nerve stimulation.

Objective: It is generally believed that the decremental response in repetitive nerve stimulation (RNS) stabilizes at the fourth or fifth response. We have a preliminary impression that the decremental response approaches a plateau earlier in proximal muscles than in distal muscles. We investigated the speed of the completion of the decremental response in different muscles. Methods: The "decrement completion ratio (DCR)" in the second or third response (DCR2 or DCR3) was defined as the ratio of the decremental percentage of the second or third response to that of the fourth response. Patients showing more than 10% decremental response both in the abductor pollicis (APB) and deltoid muscles were retrospectively extracted from our EMG database. The DCR2 and DCR3 were compared between two muscles in patients with myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS). Results: Identified subjects consisted of 11patients with MG and 11 patients with ALS. Multiple regression analysis revealed that only the difference of muscle influenced on DCR2 and DCR3, with no contribution from the different disorder (MG or ALS) or the initial amplitude of the compound muscle action potential (CMAP). Both DCR2 and DCR3 were significantly higher in deltoid than in APB. In ALS, the normalized CMAP amplitude was not different between APB and deltoid whereas the decremental percentage was significantly higher in deltoid, suggesting a lower safety factor of the neuromuscular transmission in proximal muscles. Conclusions: The decremental response completed more rapidly in deltoid than in APB which may be related to the lower safety factor also documented by this study. Significance: Unexpected early completion of the decrement such as at the second response in RNS is not a technical error but may be an extreme of the rapid completion in deltoid, a proximal muscle.

Negative features of sporadic amyotrophic lateral sclerosis: Motor neurons of Onuf's nucleus survive in ADAR2-conditional knockout mice.

Patients with amyotrophic lateral sclerosis (ALS) do not develop oculomotor disturbances and vesicorectal dysfunction until end-stage disease owing to the survival of certain motor neurons (MNs), including oculomotor neurons and MNs within Onuf's nucleus. In sporadic ALS, adenosine deaminase acting on RNA 2 (ADAR2)-mediated editing of GluA2 mRNA at the Q/R site is compromised in lower MNs. We previously developed genetically modified mice with a conditional knockout of ADAR2 in cholinergic neurons (ADAR2flox/flox/VAChT-Cre, Fast; AR2). These mice displayed slow and progressive lower motor neuron death with TAR DNA-binding protein 43 (TDP-43) pathology, attributable to insufficient editing at the GluA2 Q/R site due to ADAR2 deficiency. MN death was more common in fast-fatigable MNs owing to differential vulnerability under conditions of ADAR2 deficiency. Although facial and hypoglossal nerves were impaired in AR2 mice, cell death did not occur within the oculomotor nerve nucleus, as observed in patients with sporadic ALS. Since the basis for avoiding cystorectal damage in ALS is unknown, we compared the features of Onuf's nucleus MNs in 12-month-old AR2 mice with those in age-matched wild-type mice. Although the number of MNs was not significantly lower in AR2 mice, the neurons exhibited a shrunken morphology and TDP-43 pathology. Onuf's nucleus MNs could survive in an ADAR2-deficient state and mainly included fast fatigue-resistant (FR) and slow (S) MNs. In summary, FR and S MNs show increased resilience to ADAR2 deficiency, potentially participating in an important neuronal death avoidance mechanism in ALS.

A Cerebral Embolism Caused by a Malignant Peripheral Nerve Sheath Tumor in a Patient with Neurofibromatosis Type 1.

A 31-year-old man with neurofibromatosis type 1 (NF-1) had undergone resection of a malignant peripheral nerve sheath tumor (MPNST) on the buttock 3 months previously. He subsequently underwent mechanical thrombectomy for a hyperacute left middle cerebral artery embolism. Histopathologically, the emboli comprised neurofilament-positive pleomorphic tumor cells with geographic necrosis and conspicuous mitosis and were identified as MPNST. The patient died of respiratory failure due to lung MPNST metastasis on day 15 of hospitalization. To our knowledge, this is the first report of a spontaneous cerebral embolism due to MPNST in a NF-1 patient.

Impact of Istradefylline on Levodopa Dose Escalation in Parkinson's Disease: ISTRA ADJUST PD Study, a Multicenter, Open-Label, Randomized, Parallel-Group Controlled Study.

INTRODUCTION: A higher levodopa dose is a risk factor for motor complications in Parkinson's disease (PD). Istradefylline (IST) is used as adjunctive treatment to levodopa in PD patients with off episodes, but its impact on levodopa dose titration remains unclear. The objective of this study was to investigate the effect of IST on levodopa dose escalation in PD patients with wearing-off. METHODS: This was a multicenter, open-label, randomized, parallel-group controlled study (ISTRA ADJUST PD) in which PD patients experiencing wearing-off (n = 114) who were receiving levodopa 300-400 mg/day were randomized to receive IST or no IST (control). Levodopa dose was escalated according to clinical severity. The primary endpoint was cumulative additional levodopa dose, and secondary endpoints were changes in symptom rating scales, motor activity determined by a wearable device, and safety outcomes. RESULTS: The cumulative additional levodopa dose throughout 37 weeks and dose increase over 36 weeks were significantly lower in the IST group than in the control group (both p < 0.0001). The Movement Disorder Society Unified Parkinson's Disease Rating Scale Part I and device-evaluated motor activities improved significantly from baseline to 36 weeks in the IST group only (all p < 0.05). Other secondary endpoints were comparable between the groups. Adverse drug reactions (ADRs) occurred in 28.8% and 13.2% of patients in the IST and control groups, respectively, with no serious ADRs in either group. CONCLUSION: IST treatment reduced levodopa dose escalation in PD patients, resulting in less cumulative levodopa use. Adjunctive IST may improve motor function more objectively than increased levodopa dose in patients with PD. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180248.

Non-traumatic Rectus Sheath Hematoma During Direct Oral Anticoagulation.

We report a case of anticoagulation therapy complicated by a non-traumatic rectus sheath hematoma (RSH). RSH is a relatively rare occurrence caused by bleeding into the rectus sheath following the rupture of the superior and inferior epigastric vessels combined with a primary tear of the rectus muscle fibers. Herein, we report a rare presentation of RSH in a 73-year-old man taking the direct oral anticoagulant (DOAC) apixaban orally. The patient presented with sudden right abdominal pain after a severe cough, which worsened with cough and movement. The Fothergill and Carnett signs were positive. The platelet count, renal function test, and the prothrombin time/international normalized ratio were within the normal range. The activated partial thromboplastin time was 40.0 s, slightly longer than normal. Computed tomography (CT) of the abdomen and pelvis showed RSH, and DOAC therapy was temporarily discontinued. Subsequently, RSH resolution was confirmed via CT four weeks after the onset. DOACs are safer and more efficacious than warfarin for patients with non-valvular atrial fibrillation. However, RSH is a potential complication of anticoagulant therapy. This case report demonstrates that RSH should be considered in the differential diagnosis of sudden-onset abdominal pain and mass in patients on DOACs.

[Foot drop and cyclic sensory disturbance of the right lower limb due to endometriosis].

We report the case of a 40-year-old woman, with endometriosis, who presented with a history of foot drop and cyclic sensory disturbance of the right lower limb. She was initially diagnosed with lumbar disc herniation. Neurological examination revealed muscle weakness and sensory disturbance associated with the right sciatic nerve. Nerve conduction studies revealed a low amplitude sensory nerve action potential in the right superficial fibular and sural nerves. Pelvic magnetic resonance imaging revealed an endometriotic cyst in the right ovary, and an endometriotic lesion extending from the right ovary, pelvis, and the right sciatic nerve. Though her symptoms moderately improved with hormonal therapy, the foot drop remained. Our case and previous reports suggest that endometriosis with sciatic neuropathy shows cyclic neurological symptoms during menstruation, with a higher incidence on the right extremity. This case highlights that endometriosis should be considered as a potential differential diagnosis in women of reproductive age with sciatic nerve dysfunction. Its cyclic neurological manifestations should be investigated.

Characteristics of sagittal spinopelvic alignment in patients with Parkinson's disease presenting with dropped head syndrome: a case series study.

BACKGROUND: Dropped head syndrome (DHS) is a rare specific abnormal posture known to develop in Parkinson's disease (PD). This case series study aimed to characterize DHS by analyzing the characteristics of sagittal spinopelvic alignment in patients with PD/DHS. METHODS: The study included eight patients with PD/DHS (men = 3, women = 5; mean age, 68.1 ± 6.4 years). Sagittal spinopelvic alignment was evaluated using 10 parameters on whole-spine lateral radiographs. RESULTS: The time from the onset of PD to that of DHS varied among the patients from 0 to 15.3 years. In three patients, DHS appeared before the diagnosis of PD. The severity of motor symptoms at DHS onset varied from modified Hoehn and Yahr stage 1 to 4 among the patients. Although the spinopelvic parameters differed among PD/DHS individuals, all patients exhibited cervical kyphosis (cervical lordosis < 0˚). In patients with a larger T1 slope and greater thoracic kyphosis, anterocollis tended to be more severe. According to the assessment of the sagittal vertical axis (SVA), half of the patients showed a positive SVA (SVA ≥ 0 mm), whereas the other half showed a negative SVA (SVA < 0 mm). CONCLUSION: DHS appeared regardless of the duration or severity of PD. Although all patients with PD/DHS exhibited cervical kyphosis, the C7 plumb line was shifted anteriorly in half of the patients and posteriorly in the other half.

Effect of Serum Perampanel Concentration on Sporadic Amyotrophic Lateral Sclerosis Progression.

BACKGROUND AND PURPOSE: To clarify the effect of perampanel (PER) on sporadic amyotrophic lateral sclerosis (sALS) progression, the relationship between the changes in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores and serum PER concentrations was investigated. METHODS: 12 patients with sALS from our hospital who agreed to participate and completed the PER for sALS randomized phase 2 study were included. After completing the study, we retrospectively obtained serum PER concentration data from the patients. Based on their mean PER concentrations, we divided the patients who had been taking PER into two groups: four patients with a mean PER concentration of ≥400 ng/mL were assigned to the H group, and three with a mean PER concentration of <400 ng/mL were assigned to the L group. The control group consisted of five patients who had been taking a placebo. We obtained the ALSFRS-R scores of each patient at 36 and 48 weeks after randomization. The differences in ALSFRS-R scores at baseline (0 weeks) and each subsequent week were used in the analysis. RESULTS: At 48 weeks, there were no differences in the degree of deterioration of the bulbar, upper and lower limb, and respiratory ALSFRS-R subscores and total ALSFRS-R score. However, at 36 weeks, the bulbar subscore was significantly lower in the H group than in the control group (p=0.032). CONCLUSIONS: Because high PER concentrations may exacerbate bulbar symptoms in patients with sALS, serum PER measurements may be beneficial when patients with sALS are taking PER.

Pathological features of glial cells and motor neurons in the anterior horn of the spinal cord in sporadic ALS using ADAR2 conditional knockout mice.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective degeneration of motor neurons (MNs). In the MNs of patients with ALS, adenosine deaminase acting on RNA 2 (ADAR2)-mediated RNA editing of GluA2 mRNA at the Q/R site is profoundly deficient. In genetically modified mice (ADAR2flox/flox/VAChT-Cre.Fast; AR2), the selective knockout of ADAR2 in cholinergic neurons induced progressive loss of lower MNs. MNs exhibiting an age-related increase in abnormal TDP-43 localization and reduced ADAR2 immunoreactivity are localized in the lateral areas of the anterior horns (AHs) in aged wild-type mice. However, the patterns in the AHs of AR2 mice remain unknown. In this study, we investigated whether similar degeneration is observed in AR2 mice. We compared the number of astrocytes and MNs in the lateral and medial AHs of the lumbar spinal cord of 12-month-old AR2 mice with age-matched wild-type mice. The number of MNs significantly decreased in both the lateral and medial areas in AR2 mice AHs, particularly in the former. The number of reactive astrocytes increased significantly in the lateral areas of the AHs of AR2 mice. In conclusion, stronger activation of astrocytes with reduction of MNs in the ADAR2 deficiency-related lateral area increases in AR2 mice AHs. Fast fatigable MNs are expected to be present in the lateral area of the AHs. We found that MN death is more common in the lateral area of AHs associated with FF MNs due to differences in vulnerability to MN under ADAR2 deficiency.

Detection of Major Depressive Disorder Based on a Combination of Voice Features: An Exploratory Approach.

In general, it is common knowledge that people's feelings are reflected in their voice and facial expressions. This research work focuses on developing techniques for diagnosing depression based on acoustic properties of the voice. In this study, we developed a composite index of vocal acoustic properties that can be used for depression detection. Voice recordings were collected from patients undergoing outpatient treatment for major depressive disorder at a hospital or clinic following a physician's diagnosis. Numerous features were extracted from the collected audio data using openSMILE software. Furthermore, qualitatively similar features were combined using principal component analysis. The resulting components were incorporated as parameters in a logistic regression based classifier, which achieved a diagnostic accuracy of ~90% on the training set and ~80% on the test set. Lastly, the proposed metric could serve as a new measure for evaluation of major depressive disorder.

Clinical Features of Parkinson's Disease in Patients with Early-Onset Freezing of Gait.

Background: Freezing of gait (FOG) is an important symptom that can impair activities of daily living in patients with Parkinson's disease (PD). However, its pathogenic mechanism is largely unknown. The aim of the present study was to elucidate the clinical characteristics of newly diagnosed and levodopa-naïve patients with PD who present with FOG. Methods: A total of 53 patients with untreated PD (29 men and 24 women) within 2 years of disease onset were included in the study. Using item 3 of the Freezing of Gait Questionnaire (FOG-Q), patients were classified as "freezers" and "nonfreezers" and compared for cognitive function, depressive symptoms, apathy, olfactory function, motor severity, gait parameters, and daily physical activity. We also assessed the relationship between FOG severity (total score of items 3-6 on the FOG-Q) and various clinical parameters. Results: The FOG was reported by 8 (15%) patients with PD. The Apathy Scale score (p=0.018), Modified Hoehn and Yahr stage (p < 0.001), Unified Parkinson's Disease Rating Scale part III score (p < 0.001), and postural instability and gait disorder score (p < 0.001) were significantly higher, and the mean gait acceleration amplitude (p=0.006) was significantly lower in freezers compared to that in nonfreezers. However, there was no significant correlation between FOG severity and these clinical parameters. There was also no significant difference in cognitive function, depressive symptoms, and olfactory function between the two groups. Daily physical activity was significantly lower in freezers than that in nonfreezers. Conclusions: Since FOG develops soon after PD onset, the study findings suggest that the FOG might be associated with the severity of apathy, motor symptoms, and in particular, gait disturbance.

Evaluating the impact of adjunctive istradefylline on the cumulative dose of levodopa-containing medications in Parkinson's disease: study protocol for the ISTRA ADJUST PD randomized, controlled study.

BACKGROUND: Levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD) more than 50 years after its clinical introduction. However, the onset of motor complications can limit pharmacological intervention with levodopa, which can be a challenge when treating PD patients. Clinical data suggest using the lowest possible levodopa dose to balance the risk/benefit. Istradefylline, an adenosine A2A receptor antagonist indicated as an adjunctive treatment to levodopa-containing preparations in PD patients experiencing wearing off, is currently available in Japan and the US. Preclinical and preliminary clinical data suggested that adjunctive istradefylline may provide sustained antiparkinsonian benefits without a levodopa dose increase; however, available data on the impact of istradefylline on levodopa dose titration are limited. The ISTRA ADJUST PD study will evaluate the effect of adjunctive istradefylline on levodopa dosage titration in PD patients. METHODS: This 37-week, multicenter, randomized, open-label, parallel-group controlled study in PD patients aged 30-84 years who are experiencing the wearing-off phenomenon despite receiving levodopa-containing medications ≥ 3 times daily (daily dose 300-400 mg) began in February 2019 and will continue until February 2022. Enrollment is planned to attain 100 evaluable patients for the efficacy analyses. Patients will receive adjunctive istradefylline (20 mg/day, increasing to 40 mg/day) or the control in a 1:1 ratio, stratified by age, levodopa equivalent dose, and presence/absence of dyskinesia. During the study, the levodopa dose will be increased according to symptom severity. The primary study endpoint is the comparison of the cumulative additional dose of levodopa-containing medications during the treatment period between the adjunctive istradefylline and control groups. Secondary endpoints include changes in efficacy rating scales and safety outcomes. DISCUSSION: This study aims to clarify whether adjunctive istradefylline can reduce the cumulative additional dose of levodopa-containing medications in PD patients experiencing the wearing-off phenomenon, and lower the risk of levodopa-associated complications. It is anticipated that data from ISTRA ADJUST PD will help inform future clinical decision-making for patients with PD in the real-world setting. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031180248 ; registered 12 March 2019.

Characteristics of sagittal spinopelvic alignment in patients with Parkinson's disease.

INTRODUCTION: The aim of this study was to characterize the associations between sagittal spinopelvic alignment and motor symptoms in patients with Parkinson's disease (PD). METHODS: The study included patients with idiopathic PD (aged <80 years and with abnormal posture). All patients underwent whole-spine lateral and coronal radiography. Sagittal spinopelvic alignment was evaluated using nine parameters. Motor symptoms were evaluated using the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score-with bradykinesia and axial motor sub-scores. Multivariate analysis was used to analyze associations between motor symptoms and sagittal spinopelvic alignment in PD patients according to sex. RESULTS: The study subjects were 79 PD patients (39 men, 40 women; median age, 70 years). Clear sex-related differences were noted. In male patients, the MDS-UPDRS part III score correlated significantly with cervical sagittal vertical axis (SVA), and bradykinesia and axial motor scores correlated significantly with SVA, cervical SVA, and T1 slope. In female patients, the MDS-UPDRS part III score correlated significantly with thoracic kyphosis, bradykinesia score correlated significantly with cervical SVA and thoracic kyphosis, and the axial motor score correlated significantly with SVA, cervical SVA, T1 slope, sacral slope, and pelvic tilt. CONCLUSION: Our results showed clear correlations among various motor symptoms and sagittal global alignment in PD patients and that these correlations are different in female PD patients and their male counterparts.

Correlation between Cerebrospinal Fluid IL-12 Levels and Severity of Encephalopathy in Children.

The roles of cytokines in the cerebrospinal fluid (CSF) of patients with acute encephalopathy remain unclear and controversial. In this study, the profiles of 26 cytokines and others were determined in 17 children with infection-associated neurological complications. Interleukin (IL)-12 levels were found to be high in a few of the patients. A comparison of the IL-12 levels in the CSF of patients demonstrated that IL-12 (p70) is almost always increased in those with encephalopathy. Levels of IL-12 in the CSF were highly correlated with the levels of PDGF-bb and IL-RA. IL-12 levels were found to be weakly correlated with IFN-γ levels, and strongly correlated with VEGF levels. These results demonstrate that IL-12 levels may affect the clinical symptoms of pediatric patients with encephalopathy.

Persistent Hemichorea as a Preceding Symptom of Cerebral Infarction Due to Middle Cerebral Artery Stenosis.

We herein report an 84-year-old woman with right middle cerebral artery (MCA) stenosis who presented with persistent left hemichorea preceding cerebral infarction. She visited our hospital on day 9 after the hemichorea onset. Magnetic resonance imaging (MRI) showed no acute cerebral infarction. Magnetic resonance angiography revealed right MCA stenosis. Her hemichorea persisted for 19 days and subsequently disappeared. On day 21, she developed left hemiplegia. Repeat MRI revealed a cerebral infarction in the right putamen. MCA stenosis can present with persistent hemichorea, even in the absence of cerebral infarction. Persistent hemichorea with MCA stenosis may presage cerebral infarction.

Relationship between 123I-FP-CIT-SPECT and motor severity in drug-naive patients with Parkinson's disease.

INTRODUCTION: Although functional imaging is useful for the diagnosis and pathophysiological evaluation of Parkinson's disease (PD), little is known about the relationship between functional imaging findings and PD clinical features. The objective of this study was to determine the relationship between 123I-FP-CIT-SPECT findings and motor symptoms, in particular gait disturbance. METHODS: The study included 46 drug-naive patients with early-stage PD. The specific binding ratios (SBRs) in the striatum and its subregions, namely anterior/posterior putamen and caudate nucleus, were calculated in patients who underwent 123I-FP-CIT-SPECT. Motor symptoms were evaluated using the modified Hoehn and Yahr (HY) stage and the Unified Parkinson's Disease Rating Scale (UPDRS) part III. Gait disturbance was evaluated by the mean gait cycle duration and the mean gait acceleration amplitude measured with a wearable sensor. RESULTS: The mean SBRs of the striatum and anterior putamen were significantly associated with the modified HY stage and UPDRS part III score. The mean SBR of the caudate nucleus was significantly associated with the UPDRS part III score. The mean striatal SBR was also significantly associated with the mean gait cycle duration and mean gait acceleration amplitude. CONCLUSION: The mean striatal SBR, as determined by 123I-FP-CIT-SPECT, was significantly associated with motor severity and gait severity in drug-naive patients with PD.