The SYNGAP1 3'UTR Variant in ALS Patients Causes Aberrant SYNGAP1 Splicing and Dendritic Spine Loss by Recruiting HNRNPK.

Fused in sarcoma (FUS) is a pathogenic RNA-binding protein in amyotrophic lateral sclerosis (ALS). We previously reported that FUS stabilizes Synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3' untranslated region (UTR) and maintains spine maturation. To elucidate the pathologic roles of this mechanism in ALS patients, we identified the SYNGAP1 3'UTR variant rs149438267 in seven (four males and three females) out of 807 ALS patients at the FUS binding site from a multicenter cohort in Japan. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, increased isoform α1 levels, and decreased isoform γ levels, which caused dendritic spine loss. Moreover, the SYNGAP1 variant excessively recruited FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK), and antisense oligonucleotides (ASOs) blocking HNRNPK altered aberrant splicing and ameliorated dendritic spine loss. These data suggest that excessive recruitment of RNA-binding proteins, especially HNRNPK, as well as changes in SYNGAP1 isoforms, are crucial for spine formation in motor neurons.SIGNIFICANCE STATEMENT It is not yet known which RNAs cause the pathogenesis of amyotrophic lateral sclerosis (ALS). We previously reported that Fused in sarcoma (FUS), a pathogenic RNA-binding protein in ALS, stabilizes synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3' untranslated region (UTR) and maintains dendritic spine maturation. To elucidate whether this mechanism is crucial for ALS, we identified the SYNGAP1 3'UTR variant rs149438267 at the FUS binding site. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, which caused dendritic spine loss along with excessive recruitment of FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK). Our findings that dendritic spine loss is because of excess recruitment of RNA-binding proteins provide a basis for the future exploration of ALS-related RNA-binding proteins.

Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients.

BACKGROUND: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS. METHODS: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS. RESULTS: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10-8). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression. CONCLUSIONS: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.

Associations between the ALSFRS-R score and urate levels during 12 months of edaravone treatment for amyotrophic lateral sclerosis: Post hoc analysis of ALSFRS-R scores in clinical studies MCI186-16, MCI186-17, and MCI186-19.

INTRODUCTION/AIMS: In this study we examined the relationship between urate levels at baseline and functional change measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score after edaravone treatment. METHODS: Data from the edaravone trials MCI186-16, MCI186-17, and MCI186-19 were analyzed, including the following treatment sequence groups: edaravone-edaravone (EE, n = 113); edaravone-placebo (EP, n = 45); and placebo-edaravone (PE, n = 146). Subgroups were defined as low baseline urate (below the median value of 4.8 mg/dL) and high baseline urate (≥4.8 mg/dL). The differences in ALSFRS-R total score change and urate change were evaluated using the mixed model for repeated measurement for overall population, by urate-level subgroup, and by trial. RESULTS: Compared with the PE group, the EE group showed a slower decline in ALSFRS-R score, regardless of the urate baseline level, and a slower decline in urate level in the higher baseline urate subgroup. Smaller changes in ALSFRS-R score and urate were observed in patients diagnosed with "probable, laboratory-supported ALS." There was a positive correlation between changes from baseline to cycle 12 in urate levels and ALSFRS-R score. DISCUSSION: Edaravone treatment in ALS patients diagnosed with "definite ALS" or "probable ALS" showed slowing of disease progression, regardless of baseline urate level. In addition, because edaravone treatment was associated with a slower decline in urate level in the higher baseline urate subgroup and urate-level changes were associated with changes in ALSFRS-R score, urate level, and/or change may be one indicator in predicting disease progression after edaravone administration.

Associations between urate levels and amyotrophic lateral sclerosis functional score with edaravone treatment: Post hoc analysis of studies MCI186-16, MCI186-17, and MCI186-19.

INTRODUCTION/AIMS: Edaravone in amyotrophic lateral sclerosis (ALS) was analyzed in two phase 3 studies (MCI186-16 and MCI186-19). Those trials enrolled patients with Japanese ALS severity grades 1 and 2 (less severe ALS), but many patients progressed to grades 3 and 4 during the double-blind treatment period. The placebo patients who initiated edaravone treatment in the open-label periods provided an opportunity to assess the effects of edaravone in more severe ALS. This study also assessed the association between ALS Functional Rating Scale-Revised (ALSFRS-R) slope and biomarker changes after open-label edaravone initiation. METHODS: Change in ALSFRS-R slope in placebo patients before and after initiating edaravone treatment was assessed using the random coefficient model. The association of ALSFRS-R change and blood marker changes was explored by the least absolute shrinkage and selection operator (LASSO) method of machine learning. RESULTS: Twenty-four percent of patients (35/146) in the placebo-edaravone group showed ≥25% slowing of decline in the ALSFRS-R slope. Within the 25% slower-decline group, 60% (21/35) had Japanese ALS severity grades 3 or 4 at the start of edaravone treatment. The LASSO model identified serum urate as associated with the percentage change in ALSFRS-R slope. The rate of decrease in urate was smaller in the 25% slower-decline group than in the non-25% slower-decline group during edaravone treatment. DISCUSSION: This post hoc analysis indicated that ALS patients, including those with advanced ALS severity grades, may receive benefit in the group of patients whose urate levels are stable during the course of the edaravone treatment.

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.

Prognosis of amyotrophic lateral sclerosis patients undergoing tracheostomy invasive ventilation therapy in Japan.

OBJECTIVE: The aim of this study is to describe and clarify the factors affecting the prognosis of Japanese patients with amyotrophic lateral sclerosis (ALS) undergoing tracheostomy invasive ventilation (TIV) therapy. METHODS: We conducted a prospective longitudinal observational case-control study using a multicentre registry. ALS patients who started TIV therapy after registration (TIV group) and those who did not receive TIV (non-TIV group) were included. We compared the survival time between the TIV group and the non-TIV group using a propensity score matching analysis and evaluated the prognostic factors in the TIV group. RESULTS: From February 2006 to January 2018, 190 patients in the TIV group and 1093 patients in the non-TIV group were included in this study. The mean age of disease onset and usage rate of gastrostomy and non-invasive ventilation therapy differed between the groups. In the propensity score matching analysis using known prognostic factors, the median overall survival time of the TIV group was significantly greater than that of the non-TIV group (11.33 years vs 4.61 years; p<0.001). Analysis using the Cox proportional hazard model suggested that older age of onset and respiratory onset was an independent factor for poor prognosis after starting TIV therapy. CONCLUSION: We showed that there was a significant difference of approximately 7 years in life expectancy between Japanese ALS patients who did and did not receive TIV therapy.

Coronary spastic angina after the administration of intravenous immunoglobulin in myasthenia gravis: a case report.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease caused by antibodies that block or destroy nicotinic acetylcholine receptors at the neuromuscular junction. Most of MG patients need immunosuppression agents in addition to treatments that alleviate the symptoms. Intravenous immunoglobulin (IVIg) and plasma exchange are specific treatments given to patients with severe MG and myasthenia gravis crisis. IVIg therapy can cause an increase in serum viscosity; therefore, the risk for thromboembolic events, such as stroke, myocardial infarction, and pulmonary embolism, are reported after IVIg therapy. CASE PRESENTATION: An MG patient was treated with pyridostigmine bromide and prednisolone. The patient's symptoms worsened 26 days after the commencement of treatment and was presented with head drop and dyspnea. The patient was diagnosed with MG crisis and IVIg was initiated. However, the patient reported chest pain and dyspnea 3 days after IVIg had started. An electrocardiogram (ECG) revealed ST elevations in leads II, III, and aVF. A cardiac catheterization was performed and stenosis, obstruction, and sclerosis were ruled out. Glyceryl trinitrate relieved the patient's symptoms, suggesting coronary spastic angina (CSA). CONCLUSIONS: We report the first case of CSA after IVIg. Practitioners should be aware of the potential risks of CSA when administering IVIg for MG patients, in particular in old patients with vascular risk factors.

Kikuchi-Fujimoto disease (histiocytic necrotizing lymphadenitis) with atypical encephalitis and painful testitis: a case report.

BACKGROUND: Kikuchi-Fujimoto disease is a self-limited clinicopathologic entity that is increasingly recognized worldwide. Kikuchi-Fujimoto disease is characterized by cervical lymphadenopathy occurring in young adults. Neurologic involvement is rare, and testitis directly caused by Kikuchi-Fujimoto disease has not yet been reported. CASE PRESENTATION: A 19-year-old man was brought to our clinic with complaints of fever, headache, fatigue, and left lower quadrant pain that had persisted for 3 weeks. On physical examination, painful cervical lymphadenopathies were observed. Meningitis was suspected based on a cerebrospinal fluid examination, and left-sided orchitis was diagnosed based on findings from magnetic resonance imaging and ultrasonography. However, neither antibiotics nor antiviral drugs were effective in treating the patient's symptoms. On the 20th day of hospitalization, the patient experienced a loss of consciousness, and brain T2-weighted magnetic resonance imaging showed asymmetrical, high-signal intensities in both basal nuclei and the left temporal lobe. Encephalitis was suspected, and the patient was treated with intravenous prednisolone pulse therapy (1 g/day) for 3 days and intravenous immunoglobulin therapy for 5 days. A left cervical lymph node biopsy showed apoptotic necrosis in paracortical and cortical areas with an abundance of macrophages and large lymphoid cells, which had irregular nuclei suggestive of Kikuchi-Fujimoto disease; the pathological findings from a brain biopsy were the same as those of the cervical lymph node biopsy. The encephalitis and cervical lymphadenopathies followed a benign course, as did the testitis. CONCLUSIONS: This is the first report of Kikuchi-Fujimoto disease involving painful testitis and pathologically proven asymmetrical brain regions. Kikuchi-Fujimoto disease should be included in the differential diagnosis when a patient presents with encephalitis, testitis, and fever of unknown origin.

Treatment with telmisartan, a long-acting angiotensin II receptor blocker, prevents migraine attacks in Japanese non-responders to lomerizine.

Lomerizine, calcium channel blocker, is the most used medication for migraine prophylaxis in Japan. The effectiveness of this drug is reported as 50-75%. Telmisartan is angiotensin II receptor blockers which plasma half-life is 24 h. We examined whether telmisartan has preventative benefits in lomerizine non-responsive migraineurs. Lomerizine non-responders received telmisartan (20 mg/day) for 3 months after the investigation period of 3 months. Blood pressure, frequency of headache days/month, headache severity, and doses of triptans and analgesics were analyzed by Wilcoxon signed rank test. Thirty-three migraineurs (25 women and 8 men) participated in this study. Seven patients had migraine with aura and 26 patients had migraine without aura. Mean age (SD) was 46.6 (10.3) years. Mean duration (SD) of migraine was 20.4 (12.5) years. Headache severity exhibited mild degree in 5 patients, moderate degree in 9 patients and severe degree in 19 patients. Mean frequency (SD) of headache days was 10.9 (8.5) days/month. Mean usage (SD) of triptans was 4.8 (5.1) tablets/month and that of analgesics was 15.2 (22.2) tablets/month. Five patients (15%) had hypertension. Telmisartan administration had benefits in 30 patients (90%). This medication significantly decreased frequency of headache days (P < 0.01) and headache severity (P < 0.01). Doses of triptans were reduced at one-third (P < 0.05) and those of analgesia at one-fifth after telmisartan treatment (P < 0.01). After telmisartan, mean (SD) of systolic blood pressure was significantly decreased (P < 0.05). The present study supported that telmisartan treatment had preventive effects in 90% of lomerizine non-responders. Telmisartan non-responders (10%) exhibited chronic migraine and long migraine duration.

Clinical Profile and Changes of Serum Lipid Levels in Epileptic Patients after Cerebral Infarction.

BACKGROUND: Antiepileptic drugs (AEDs) may increase development of dyslipidemia and cerebrovascular disease (CVD). We examined the clinical profile and changes of serum lipid levels after AED monotherapy in patients with poststroke epilepsy (PSE) after cerebral infarction (CI). SUBJECTS AND METHODS: Medical records were reviewed in consecutive 2144 CI patients. Monotherapy of valproate, carbamazepine (CBZ), phenytoin (PHT), zonisamide, levetiracetam, or lamotrigine was performed in PSE patients. Serum lipid levels were measured before and at 3 months after AED treatment. RESULTS: The prevalence of PSE was 7.0% in CI patients. The TOAST etiology disclosed large-artery atherosclerosis in 68 patients (45%), cardioembolism in 63 patients (42%), and undetermined cause in 19 patients (13%). CVD risk profile showed obesity of 18 patients (12%), current smoker of 30 patients (20%), hypertension of 75 patients (50%), diabetes mellitus of 32 patients (21%), dyslipidemia of 15 patients (10%), and atrial fibrillation of 63 patients (42%). CBZ or PHT administration increased serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels significantly compared to baseline and AED-untreated controls. Those levels were not increased significantly in other AED and control groups. Serum high-density lipoprotein-cholesterol and triglyceride levels did not differ statistically in all groups. CONCLUSIONS: The prevalence of post-CI epilepsy was 7.0%. The pathogenesis contributed to atherothrombosis and cardioembolism. CBZ or PHT administration increased serum TC and LDL-C significantly. Thus, we should pay more attention to serum lipid levels in patients receiving cytochrome P450 (CYP)-induced AEDs, and might considerer switching to non-CYP-induced AEDs in patients with unfavorable serum lipid changes.

A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN.

OBJECTIVE: To classify the patterns of functional decline in patients with sporadic amyotrophic lateral sclerosis (ALS) and explore the genetic backgrounds that modified these patterns. METHODS: We included 465 patients with sporadic ALS in the analysis and clustered the longitudinal functional scores in the registered patients, using a mixture approach of a non-linear mixed-effects model. We conducted a genome-wide analysis of 572 983 single nucleotide polymorphisms (SNPs). We then assessed the association between the clusters of longitudinal functional scores and SNPs. RESULTS: We identified the following four clusters of longitudinal functional decline in the cases: a rapid decline cluster, an intermediate decline cluster, a sigmoidal decline cluster and a moderate decline cluster. We identified seven SNPs associated with the rapid decline cluster, using a recessive model (p=3.47-8.34×10(-8)). The OR for the probabilities of the rapid decline cluster ranged from 5.5 to 5.84. Homozygosity for the minor alleles in the seven SNPs, which constituted a linkage disequilibrium (LD) block, was associated with decreased expression of TTN (encoding Titin, a large sarcomere protein) in the expression quantitative trait loci database of a large-scale Japanese genetic variation database (p=8.6×10(-10)-1.1×10(-7)). TTN expression in immortalised lymphocyte lines was decreased in patients who were homozygous for the minor alleles compared with those who were homozygous for the major alleles (n=19 in each group, p=0.002). CONCLUSIONS: We detected an LD block associated with a rapid functional decline in patients with sporadic ALS, which is linked to decreased expression of TTN.

Late-onset spinal form xanthomatosis without brain lesion: a case report.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive sterol storage disease caused by a mutated sterol 27-hydroxylase (CYP27A1) gene. Patients with typical CTX show neurological dysfunction including bilateral cataracts, paresis, cerebral ataxia, dementia, and psychiatric disorders, and magnetic resonance imaging (MRI) has revealed symmetrical lesions in the cerebellar white matter. CASE PRESENTATION: We report the case of a patient with late-onset spinal form CTX without brain lesion. He showed pyramidal tract signs, and impaired joint position and vibration sensation in the lower limbs. Cervical sagittal MRI demonstrated a longitudinally extensive white matter abnormality in the dorsal column of the C2-C7 spinal cord; however, a brain MRI revealed an absence of lesions, including in the cerebellar white matter. Genetic analysis of CYP27A1 revealed that the patient was compound heterozygous for p.Gln85Arg in exon 1, a novel mutation, and p.Arg405Gln in exon 7, a previously reported mutation. CONCLUSION: This is the first report of late-onset spinal form CTX without typical neurological symptoms, and the first report of p.Gln85Arg in CYP27A1. We speculate that spinal form CTX without brain lesion is a clinically and radiologically rare variation of CTX. Therefore, spinal xanthomatosis should be included in the differential diagnosis of chronic myelopathy even with late-onset and/or no other typical neurological findings.

A case of sinus arrest and post-hiccup cough syncope in medullary infarction.

We describe asymptomatic sinus arrest and post-hiccup cough syncope in a patient with medullary infarction. A 78-year-old woman developed arrhythmia, hiccup, and cough syncope attacks. Neurological examination was not remarkable. Cough syncope occurs after hiccup attacks. Bradycardia and decreased blood pressure were also present after the beginning cough. Holter 24-hour electrocardiography monitor exhibited 65 episodes of asymptomatic sinus arrest more than 3 seconds. Magnetic resonance imaging disclosed acute infarction in the bilateral medial regions and the right tegmentum of the upper and middle medulla oblongata. Cerebral angiography showed severe atherosclerotic changes in the vertebral arteries. These clinicoradiological findings suggested that a distinct topography of medullary lesions could cause a series of cardiovascular and respiratory dysfunction. Thus, physicians should pay more attention to the medullary lesion in patients with arrhythmia and syncope.

Emergency Revascularization for Acute Vertebral Artery Occlusion Accompanied by Systemic Lupus Erythematosus: A Case Report.

The efficacy of mechanical thrombectomy (MT) for acute ischemic stroke has been established, but there are few reports on the effectiveness of MT for stroke patients with collagen disease. We report the case of a systemic lupus erythematosus (SLE) patient with cerebral infarction who underwent MT. A 48-year-old woman had been diagnosed with SLE for 30 years. She visited our hospital because of dizziness from the day before, but when she arrived at the hospital parking lot, she developed vomiting and impaired consciousness. An MRI revealed increased cerebellar hemisphere infarction and magnetic resonance angiography (MRA) did not visualize the right vertebral artery or basilar artery. Urgent cerebral angiography was performed, and angiography of the right vertebral artery revealed occlusion of the V4 segment of the vertebral artery. In addition to these angiographic findings, the patient also had impaired consciousness and was judged to be in need of emergency revascularization treatment. We performed an MT using a stent retriever. Immediately after the angiography examination, reperfusion to the basilar artery and severe stenosis of the right vertebral artery were noted. Therefore, percutaneous transluminal angioplasty (PTA) and stent placement for vertebral artery stenosis were done. This procedure successfully maintained the patency of the vertebral artery and blood flow to the basilar artery. Her consciousness improved; she only had mild nausea and no remarkable neurological findings.

Emergency Mechanical Thrombectomy for Acute Middle Cerebral Artery Occlusion Accompanied by Adult-Onset Still's Disease.

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory condition of an unknown etiology. Stroke is a rare complication associated with AOSD; most of these are cerebral infarctions due to the occlusion of small blood vessels. Here, we report the first case of mechanical thrombectomy in a patient with cerebral infarction due to a large vessel occlusion associated with AOSD. A 60-year-old man with no underlying disease was diagnosed with AOSD. Sixteen days after admission, he suddenly lost consciousness and was found to have right hemiplegia and aphasia. Head CT showed early signs of ischemic infarction in the left insular cortex, and head CT angiography demonstrated occlusion in a part of the left middle cerebral artery (MCA). Therefore, we decided that mechanical thrombectomy was an indication of revascularization. We performed mechanical thrombectomy using a Trevo NXT 4 × 28 mm (Stryker, Kalamazoo, USA) and obtained reperfusion of the MCA. The results of the cerebral angiography were indicative of an embolic cerebral infarction, and we investigated the source of the embolism including an insertable cardiac monitor (ICM) (Reveal LINQ, Medtronic, Minneapolis, USA). However, no disease other than AOSD that could be a source of embolism was observed. Therefore, AOSD was assumed to be associated with embolisms. AOSD may cause embolic cerebral infarction and may be indicated for mechanical thrombectomy.

Isolated prosopagnosia caused by damage to the right inferior longitudinal fasciculus: a case report.

Prosopagnosia is a cognitive disorder in which facial recognition is severely impaired despite normal vision and intelligence. Prosopagnosia was first reported in the 1800s, but its cause remains unclear. Although other neurological symptoms are often present, some patients have pure prosopagnosia. The bilateral occipital lobes are believed to be associated with symptoms. Recent brain imaging techniques have identified the right fusiform gyrus (rFG), located at the junction of the right occipital temporal lobe, as the affected region. In this report, we present a case of associative prosopagnosia with no concomitant symptoms in a 76-year-old man. Brain magnetic resonance imaging detected a subcortical hemorrhage in the right temporal lobe. Using tractography based on diffusion tensor imaging, we visualized atrophy of the right inferior longitudinal fasciculus (ILF). This is the first time tractography has been used to show a clear association between associative prosopagnosia and ILF damage projecting from the rFG.

Surface-based Analyses of Diffusional Kurtosis Imaging in Amyotrophic Lateral Sclerosis: Relationship with Onset Subtypes.

PURPOSE: Here, we aimed to characterize the cortical and subcortical microstructural alterations in the brains of patients with amyotrophic lateral sclerosis (ALS). In particular, we compared these features between bulbar-onset ALS (b-ALS) and limb-onset ALS (l-ALS). METHODS: Diffusion MRI data (b = 0, 700, 2000 ms/mm2, 1.7-mm isotropic voxel) from 28 patients with ALS (9 b-ALS and 19 l-ALS) and 17 healthy control subjects (HCs) were analyzed. Diffusional kurtosis imaging (DKI) metrics were sampled at the mid-cortical and subcortical surfaces. We used permutation testing with a nonparametric combination of mean diffusivity (MD), fractional anisotropy (FA), and mean kurtosis (MK) to assess intergroup differences over the cerebrum. We also carried out an atlas-based analysis focusing on Brodmann Area 4 and 6 (primary motor and premotor areas) and investigated the correlation between MRI metrics and clinical parameters. RESULTS: At both the mid-cortical and subcortical surfaces, b-ALS was associated with significantly greater MD, smaller FA, and smaller MK in the motor and premotor areas than HC. In contrast, the patients with l-ALS showed relatively moderate differences relative to HCs. The ALS Functional Rating Scale-Revised bulbar subscore was significantly correlated with the diffusion metrics in Brodmann Area 4. CONCLUSION: The distribution of abnormalities over the cerebral hemispheres and the more severe microstructural alteration in b-ALS compared to l-ALS were in good agreement with findings from postmortem histology. Our results suggest the feasibility of surface-based DKI analyses for exploring brain microstructural pathologies in ALS. The observed differences between b-ALS and l-ALS and their correlations with functional bulbar impairment support the clinical relevance of DKI measurement in the cortical and juxtacortical regions of patients with ALS.

Clinical characteristics of patients with Parkinson's disease with reduced 123I-metaiodobenzylguanidine uptake in the major salivary glands and heart.

BACKGROUND: Parkinson's disease (PD) shows cardiac sympathetic denervation (SD) in 123I-metaiodobezylguanidine (MIBG) scintigraphy. Recently, SD in the major salivary glands (MSG-SD) was introduced as a possible radiological feature of PD. OBJECTIVE: To identify the clinical characteristics of patients with PD with reduced MSG and cardiac MIBG uptake (dual-SD) compared with those with reduced MSG or cardiac MIBG uptake only (single-SD). METHODS: We recruited 90 patients with PD and 30 controls and evaluated their non-motor (e.g., hyposmia, autonomic dysfunction) and motor (e.g., Movement Disorder Society-Unified Parkinson's Disease Rating Scale) features. We also assessed MIBG uptake in the MSG and heart using a quantitative semi-automatic method, and compared MIBG uptakes between PD and controls. We set cut-off values for optimal sensitivity and specificity, and compared the clinical characteristics of patients with PD between dual- and single-SD groups. RESULTS: MSG and cardiac MIBG uptakes were significantly reduced in PD. Sixty-one patients had dual-SD, 25 had single-SD, and four had non-SD. In patients with PD with normal cardiac SD, 76.5% (13/17) of whom showed abnormalities only in MSG-SD. When clinical characteristics were compared between the dual-SD and single-/non-SD groups, patients in the dual-SD group were older and had more severe hyposmia and autonomic dysfunction, except motor features. Multiple logistic regression analysis identified age as an important confounder. CONCLUSIONS: Patients with PD with dual-SD have more severe non-motor features than other patients. Autonomic dysfunction might progress independently from dopaminergic degeneration. Furthermore, our findings indicate that aging is a crucial factor in PD progression.

The clinical practice guideline for the management of amyotrophic lateral sclerosis in Japan-update 2023.

Amyotrophic lateral sclerosis (ALS) is an adult-onset intractable motor neuron disease characterized by selective degeneration of cortical neurons in the frontotemporal lobe and motor neurons in the brainstem and spinal cord. Impairment of these neural networks causes progressive muscle atrophy and weakness that spreads throughout the body, resulting in life-threatening bulbar palsy and respiratory muscle paralysis. However, no therapeutic strategy has yet been established to halt ALS progression. Although evidence for clinical practice in ALS remains insufficient, novel research findings have steadily accumulated in recent years. To provide updated evidence-based or expert consensus recommendations for the diagnosis and management of ALS, the ALS Clinical Practice Guideline Development Committee, approved by the Japanese Society of Neurology, revised and published the Japanese clinical practice guidelines for the management of ALS in 2023. In this guideline, disease-modifying therapies that have accumulated evidence from randomized controlled trials were defined as "Clinical Questions," in which the level of evidence was determined by systematic reviews. In contrast, "Questions and Answers" were defined as issues of clinically important but insufficient evidence, according to reports of a small number of cases, observational studies, and expert opinions. Based on a literature search performed in February 2022, recommendations were reached by consensus, determined by an independent panel, reviewed by external reviewers, and submitted for public comments by Japanese Society of Neurology members before publication. In this article, we summarize the revised Japanese guidelines for ALS, highlighting the regional and cultural diversity of care processes and decision-making. The guidelines cover a broad range of essential topics such as etiology, diagnostic criteria, disease monitoring and treatments, management of symptoms, respiration, rehabilitation, nutrition, metabolism, patient instructions, and various types of care support. We believe that this summary will help improve the daily clinical practice for individuals living with ALS and their caregivers.

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.