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To clarify the immunogenetic background of patients with immunoglobulin G (IgG)4 anti-neurofascin 155 (NF155) antibody-positive chronic inflammatory demyelinating polyneuropathy (CIDP), we genotyped the extended human leukocyte antigen (HLA) haplotypes in 22 Japanese patients with this disorder and compared them with those of healthy Japanese controls. All IgG4 anti-NF155 antibody-positive CIDP patients exclusively carried either HLA-DRB1*15:01-DRB5*01:01-DQA1*01:02-DQB1*06:02 or -(A*24:02)-B*52:01-C*12:02-DRB1*15:02-DRB5*01:02-DQA1*01:03-DQB1*06:01, resulting in significantly increased HLA-DRB1*15, -DRB1*15:01, -DQB1*06:01/06:02, -DQB1*06:02, and -DRB1*15:01-DQB1*06:02 frequencies compared with healthy Japanese controls. These findings indicate the involvement of specific HLA class II molecules in the pathomechanisms of IgG4 anti-NF155 antibody-positive CIDP.

To determine the usefulness of MRI measurements in patients with pure akinesia with gait freezing (PAGF), Richardson’s syndrome, and Parkinson’s disease for diagnosis. We obtained MRI measurements for patients with PAGF, Richardson’s syndrome, or Parkinson’s disease: 9 patients with PAGF, 26 with Richardson’s syndrome, and 93 with Parkinson’s disease. We measured the area of the pons and midbrain on midsagittal MRIs and the midbrain width on axial MRIs. We also calculated the mean values of the superior cerebellar peduncle, middle cerebellar peduncle, and cerebral crus width; the pons area-to-midbrain area ratio; the middle cerebellar peduncle width-to-superior cerebellar peduncle width ratio; and the magnetic resonance (MR) Parkinsonism index. The Richardson’s syndrome group had the highest pons area-to-midbrain area ratio and MR Parkinsonism index; the Parkinson’s disease group had the lowest values. The Parkinson’s disease group also had the highest midbrain width and cerebral crus width, with the lowest values being seen in the Richardson’s syndrome group. The PAGF group had the intermediate values of the pons area-to-midbrain area ratio and MR Parkinsonism index between the Richardson’s syndrome group and the Parkinson’s disease group, whereas significant differences were found only in the pons area-to-midbrain area ratio. Results from receiver operating characteristic curve analyses showed that the pons area-to-midbrain area ratio has a higher sensitivity, specificity, and accuracy than the MR Parkinsonism index. The pons area-to-midbrain area ratio is more useful to distinguish PAGF from Richardson’s syndrome and Parkinson’s disease than the MR Parkinsonism index.

Intracellular aberrant protein aggregation is linked to the mechanism of Parkinson’s disease (PD). Autonomic dysfunction is commonly found because α-synuclein aggregate in autonomic nerves in patie...

Little is known in mechanism and clinical features of transient focal neurological episodes (TFNEs) in patients with both hereditary transthyretin (ATTR) type and Aβ-type cerebral amyloid angiopath...

Insulin-derived amyloidosis is a complication of insulin therapy. The amyloid fibril protein is derived from the injected insulin and forms an amyloid deposit at the injection site [1,2]. The clini...

Transthyretin familial amyloid polyneuropathy (ATTR-FAP) is a fatal hereditary amyloidosis characterized by extracellular deposition of amyloid fibrils composed of transthyretin (TTR) [1,2]. Tafami...

Although there is growing evidence suggesting the involvement of oxidative stress in neurological disorders [1], evidence of oxygen-mediated damage in neuropathy due to ATTR-PN remains to be discus...

Alport syndrome (AS) is a rare hereditary disease that presents with chronic kidney disease and sensorineural hearing loss, and is diagnosed by its clinical features, pathological features on renal tissue, and mode of inheritance. We report a woman in her 20 s who exhibited persistent haematuria with normal renal function and sensorineural hearing loss. Her family members exhibited the same clinical findings among three generations and were suspected of having autosomal dominant AS (ADAS). Renal biopsy showed minor glomerular abnormalities on light microscopy and extensive thinning of the glomerular basement membrane on electron microscopy. Whole-exome analysis revealed a known COL4A4 (type IV collagen α4) mutation (c. 2510 G > C: p. Gly837Ala). Two pedigrees with the same variant have been reported previously, one as ADAS and the other as autosomal recessive AS. However, these two cases exhibited no sensorineural hearing loss. The analysis in the present case revealed another missense variant in ESPN (Espin), an actin-bundling protein, which is a causative gene for sensorineural hearing loss. Although the pathophysiological significance of this novel missense variant needs to be clarified, computational analysis predicted that the variant creates a new phosphorylation site for protein kinase C. Our case suggests a possible association of hereditary sensorineural hearing loss with ADAS. Whole-exome analysis should be considered to diagnose hereditary and multiple-organ disorders.

We report the clinical features of a patient with hereditary transthyretin (ATTR) amyloidosis associated with a novel mutation (Y114S, p.Y134S). A 65-year-old Japanese man was admitted to our hospital after a 3-year history of progressive dyspnea on exertion. Five years previously, he presented dysesthesia in both hands caused by carpal tunnel syndrome. A genetic analysis revealed a base pair substitution of adenine to cytosine in the second codon of exon 4, residue 114, in the TTR gene (c.401A>C). The clinical characteristics were progressive cardiomyopathy with a poor vital prognosis, late onset, sporadic case, bilateral carpal tunnel syndrome, hypothyroidism, and small fiber neuropathy.

Transthyretin (TTR) is a major amyloidogenic protein associated with hereditary (ATTRm) and nonhereditary (ATTRwt) intractable systemic transthyretin amyloidosis. The pathological mechanisms of ATTR-associated amyloid fibril formation are incompletely understood, and there is a need for identifying compounds that target ATTR. C-terminal TTR fragments are often present in amyloid-laden tissues of most patients with ATTR amyloidosis, and on the basis of in vitro studies, these fragments have been proposed to play important roles in amyloid formation. Here, we found that experimentally-formed aggregates of full-length TTR are cleaved into C-terminal fragments, which were also identified in patients' amyloid-laden tissues and in SH-SY5Y neuronal and U87MG glial cells. We observed that a 5-kDa C-terminal fragment of TTR, TTR81–127, is highly amyloidogenic in vitro, even at neutral pH. This fragment formed amyloid deposits and induced apoptosis and inflammatory gene expression also in cultured cells. Using the highly amyloidogenic TTR81–127 fragment, we developed a cell-based high-throughput screening method to discover compounds that disrupt TTR amyloid fibrils. Screening a library of 1280 off-patent drugs, we identified two candidate repositioning drugs, pyrvinium pamoate and apomorphine hydrochloride. Both drugs disrupted patient-derived TTR amyloid fibrils ex vivo, and pyrvinium pamoate also stabilized the tetrameric structure of TTR ex vivo in patient plasma. We conclude that our TTR81–127–based screening method is very useful for discovering therapeutic drugs that directly disrupt amyloid fibrils. We propose that repositioning pyrvinium pamoate and apomorphine hydrochloride as TTR amyloid-disrupting agents may enable evaluation of their clinical utility for managing ATTR amyloidosis.

Background Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is characterized by adult onset, a slowly progressive course and autosomal dominant inheritance. It remains unclear whether myopathic changes occur histopathologically. Methods We encountered 2 patients in a family with a heterozygous p.P285L mutation in TRK-fused gene (TFG), which is known to cause HMSN-P. The affected individuals developed proximal-dominant muscle weakness in their 40s, which slowly progressed to a motor neuron disease-like phenotype. Results Muscle biopsy showed myopathic pathology including fiber size variability, increased internal nuclei, fiber splitting, and core-like structures, associated with neurogenic changes: large groups of atrophic fibers and fiber type-grouping. Immunohistochemistry revealed sarcoplasmic aggregates of TFG, TDP-43, and p62 without congophilic material. Conclusions The present study demonstrates myopathic changes in HMSN-P. Although the mechanisms underlying the skeletal muscle involvement remain to be elucidated, immunohistochemistry suggests that abnormal protein aggregation may be involved in the myopathic pathology.

Background Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is caused by a variant transthyretin (TTR), which is a serum protein secreted by the liver. Mass spectrometry (MS) is a useful tool that can detect variant TTRs in serum samples from patients with ATTRv amyloidosis. We previously reported several mass spectrometric methods to detect variant TTRs in serum samples. Those methods require cumbersome immunoprecipitation with anti-TTR antibodies and significant time to analyze the variant TTRs. In our study here, we developed a new simple and quick method to detect variant TTRs in serum samples by means of matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) MS without immunoprecipitation (direct MALDI). Methods By using direct MALDI, we analyzed 288 serum samples obtained from patients who were clinically suspected having amyloidosis to investigate the usefulness of this direct MALDI method to detect variant TTRs in serum samples. Results The method completed the process within 30 min. We successfully identified variant TTRs in serum samples from patients, except for a few patients with TTR Glu61Lys and Glu89Gln mutations because of the small mass shift of those variant TTRs from wild-type TTR. We also found that the mass shifts of variant TTRs measured by direct MALDI corresponded to theoretical mass changes. Conclusion Our results suggest that the direct MALDI method is useful for the screening of ATTRv amyloidosis.

PURPOSE: To explore the usefulness of myocardial late iodine enhancement (LIE) and extracellular volume (ECV) quantification by using dual-energy cardiac CT. MATERIALS AND METHODS: In this single-center retrospective study, a total of 40 patients were evaluated with LIE CT by using a dual-layer spectral detector CT system. Among these, 21 also underwent cardiac MRI. Paired image sets were created by using standard imaging at 120 kVp, virtual monochromatic imaging (VMI) at 50 keV, and iodine density imaging. The contrast-to-noise ratio and image quality were then compared. Two observers assessed the presence of LIE and calculated the interobserver agreements. Agreement between CT and cardiac MRI when detecting late-enhancing lesions and calculating the ECV was also assessed. RESULTS: The contrast-to-noise ratio was significantly higher by using VMI than by using standard 120-kVp imaging, and the mean visual image quality score was significantly higher by using VMI than by using either standard or iodine density imaging. For interobserver agreement of visual detection of LIE, the agreement for VMI was excellent and the κ value (κ, 0.87) was higher than that for the standard 120-kVp (κ, 0.70) and iodine density (κ, 0.83) imaging. For detecting late-enhancing lesions, agreement with cardiac MRI was excellent by using VMI (κ, 0.90) and iodine density imaging (κ, 0.87) but was only good by using standard 120-kVp imaging (κ, 0.66). Quantitative comparisons of the ECV calculations by using CT and cardiac MRI showed excellent correlation (r(2) = 0.94). CONCLUSION: Dual-energy cardiac CT can assess myocardial LIE and quantify ECV, with results comparable to those obtained by using cardiac MRI. © RSNA, 2019 See also the commentary by Litt in this issue.

Background After previous earthquakes, a high prevalence of deep vein thrombosis (DVT) has been reported. We examined DVT prevalence and risk factors in evacuees of the Kumamoto earthquakes by performing mobile DVT screening at various evacuation centers around the epicenter. Methods and Results: For 1 month after the Kumamoto earthquake on 14 April 2016, mobile DVT screening using portable ultrasonography (US) was performed at 80 evacuation centers. Questionnaires, physical examination, and US of the lower limb were carried out, and simple D-dimer measurements were undertaken for DVT-positive examinees. The total number of examinees was 1,673, of whom 178 (10.6%) had DVT. The prevalence of DVT seemed to be gradually decreasing in the screening period, but age, use of sleep medication, prevalence of hypertension, dyslipidemia, leg edema, and lower leg varix were significantly higher in the DVT positive group than in the negative group. On multivariable logistic regression analysis, high age (≥70 years old), use of sleep medication, lower leg edema, and lower leg varix were significant predictors of DVT. In examinees with these 4 predictors, the DVT positive rate was 71.4%. Conclusions In the first month after the Kumamoto earthquakes, DVT prevalence and severity, evaluated on D-dimer level, decreased with the passage of time. Mobile DVT screening indicated significant factors stratifying DVT risk in the evacuees.

We investigated the efficacy of a combined approach with stent retriever-assisted aspiration catheter for distal intracranial vessel occlusion (distal combined technique [DCT]).We evaluated consecutive patients with acute ischemic stroke with distal occlusion in anterior circulation, including occlusions of the M2/M3 or A2/A3 segments, who received endovascular therapy (EVT) in a single center. Modified Thrombolysis in Cerebral Infraction (mTICI) score including TICI 2C category, processing time from puncture to reperfusion, proportion of a favorable clinical outcome at discharge (modified Rankin Scale [mRS] score ≤2), and incidence of symptomatic intracranial hemorrhage (sICH) were compared between the DCT and single device approach technique (non-DCT) groups.Of 65 patients, 28 were treated with EVT using the DCT and 37 were treated with EVT with a single device approach (non-DCT). In the DCT group, a higher reperfusion rate at the first pass (mTICI score ≥2B, 92% vs. 54%; P = 0.0008; mTICI score ≥2C, 71% vs. 16%; P0.0001; mTICI score 3, 57% vs. 14%; P = 0.0004) and shorter time from puncture to successful reperfusion (median, 31 vs. 43 minutes; P = 0.0006) were achieved, respectively. The final successful reperfusion rate was also higher in the DCT group than in the non-DCT group (mTICI score ≥2C, 85% vs. 51%; P = 0.004; mTICI score 3, 75% vs. 43%; P = 0.012), respectively. sICH occurred in 2 patients in the non-DCT group. Patients with mRS score ≤2 at discharge were more prevalent in the DCT than in the non-DCT group (57% vs. 27%, respectively; P = 0.021).This retrospective analysis indicated that the DCT is a useful and safe strategy for patients with distal anterior intracranial vessel occlusion.

The diagnosis of wild-type transthyretin cardiac amyloidosis (ATTRwt) is frequently missed or delayed because of the limited specificity of manifestations. We investigated the utility of combined assessment of high-sensitivity cardiac troponin T (hs-cTnT) measurement andWe divided 39 consecutive ATTRwt patients into two groups depending on whether serum hs-cTnT measurement andDiagnostic yield was higher in group B than in group A (1.2 vs. 5.4 ATTRwt patients per 1000 hospitalized patients, p0.01). Group B patients presented broad clinical features that were different from group A patients with classical characteristics. Atrial fibrillation was more frequent (12.5% vs. 58.1%, p=0.044) and inter-ventricular septum (IVS) thickness and relative wall thickness (RWT) were smaller in group B patients than in group A patients (IVS thickness: 16.1±2.4mm vs. 13.6±2.8mm, p=0.023; RWT: 0.71±0.11mm vs. 0.58±0.13mm, p=0.014). Furthermore, left ventricular hypertrophy (LVH) (IVS thickness ≥15mm) was more frequent in patients in group A than in patients in group B (87.5% vs. 33.3%, p=0.013). No significant difference was observed in the mean value of left ventricular ejection fraction (LVEF), whereas the dispersion of LVEF was high in group B (interquartile range: 47-58% vs. 39-57%).An integrated approach consisting of hs-cTnT measurement and

Background: When considering weekend effect or off-hour effect, time period from admission to regular hospital working hours might affect stroke prognosis more strongly than the timing of admission. We investigated whether admission time until working hours affects clinical prognosis using a regional multicenter stroke registry. Methods: We recruited data from the stroke registry ‘K-PLUS,’ between 2013 and 2017. Acute stroke patients admitted within 24 hours from the last time to be well were included. Patients with premorbid modified Rankin Scale (mRS) score of 3 or more were excluded. Working hours were defined as 9:00-17:00 on weekdays. Patients were divided into those admitted during working hours (WH group) and two other groups according to the time from admission to working hours: within 24 hours (short-wait group), over 24 hours (long-wait group). In-hospital complications and the mRS score at discharge were compared among the groups. Results: Out of 4,729 participants, 2,912 (62%) were admitted outside working hours. Although in-hospital pneumonia after stroke occurred more frequently in the long-wait group (10%) than in the other groups (7%), mortality was not different among the 3 groups. The proportion of patients with mRS score 0-1 at discharge showed a decreasing trend with the time period before working hours: 37% in the WH group, 34% in the short-wait group, and 31% in the long-wait group (p< 0.001). When the WH group was used as a reference, the odds ratio for mRS score 0-1 was 0.86 (95% confidence interval, 0.73-0.93) in the short-wait group and 0.78 (0.65-0.93) in the long-wait group, respectively, after adjusting for other factors including age, stroke severity, and thrombolytic therapy. Conclusion: Our regional multicenter stroke registry demonstrated the evidence that acute stroke patients admitted before 24 hours or more until the regular hospital working hours have poor prognosis.

The highly sulfated domains of heparan sulfate (HS), alias HS S-domains, are made up of repeated trisulfated disaccharide units [iduronic acid (2S)-glucosamine (NS, 6S)] and are selectively remodeled by extracellular endoglucosamine 6-sulfatases (Sulfs). Although HS S-domains are critical for signal transduction of several growth factors, their roles in amyloidoses are not yet fully understood. Herein, we found HS S-domains in the kidney of a patient with transthyretin amyloidosis. In in vitro assays with cells stably expressing human Sulfs, heparin, a structural analog of HS S-domains, promoted aggregation of transthyretin in an HS S-domain–dependent manner. Interactions of cells with transthyretin fibrils and cytotoxicity of these fibrils also depended on HS S-domains at the cell surface. Furthermore, glypican-5, encoded by the susceptibility gene for nephrotic syndrome GPC5, was found to be accumulated in the transthyretin amyloidosis kidney. Our study, thus, provides a novel insight into the pathologic roles of HS S-domains in amyloidoses, and we propose that enzymatic remodeling of HS chains by Sulfs may offer an effective approach to inhibiting formation and cytotoxicity of amyloid fibrils. 189;2

Background: In acute ischemic stroke patients with distal intracranial vessel occlusion, efficacy of endovascular therapy remains debatable. A combined approach of stent retriever-assisted aspiration catheter for distal intracranial vessel occlusion (Distal combined technique; DCT) has potential for better recanalization rate than traditional techniques. The aim of this study was to investigate the efficacy of DCT. Methods: We evaluated consecutive acute ischemic stroke patients with distal anterior circulation artery occlusions including M2/M3 or A2/A3 segment, who underwent endovascular therapy from January, 2016 to June, 2018 in our center. Angiographical findings (modified Thrombolysis in Cerebral Ischemic [mTICI] score, including TICI 2c category), number of procedures, the processing time from puncture to reperfusion, favorable clinical outcome at 90-day (modified Rankin Scale [mRS] ≤ 2), and any symptomatic intracranial hemorrhage were compared between the DCT group and the non-DCT group. Results: Of 49 patients (mean aged 76 ± 11 years; 25 (51%) women; median NIHSS score at baseline 15), 17 (35%) were treated with DCT. Occlusion site was M2 in 25 patients, M2-3 in 18, and A2/A3 in 6. In the DCT group, higher reperfusion rates at the first pass (mTICI ≥ 2b, 94% vs. 53%, p = 0.003; mTICI ≥ 2c, 76% vs. 15%, p < 0.001; mTICI3 52% vs. 12%, p = 0.005), less number of procedures (median 1 vs. 2, p < 0.001), and shorter time from puncture to successful reperfusion (mean 33 min. vs. 53 min., p = 0.002) were observed. After all the endovascular procedures, the final successful reperfusion rate was also higher in the DCT group than in the non-DCT group (mTICI ≥ 2b, 100% vs. 84%, p = 0.148; mTICI ≥ 2c, 88% vs. 53% p = 0.025; mTICI3, 70% vs. 43%, p = 0.131). Symptomatic intracranial hemorrhage occurred in 1 patient in each group. A higher trend was observed in the rate of mRS ≤ 2 at 90 days in the DCT group (83% vs. 52% p = 0.083) compared to the non-DCT group. Conclusions: In patients with distal intracranial vessel occlusion, combined approach of stent retriever-assisted aspiration catheter is safe and efficacious; possibly leading to favorable long-term outcome.

Introduction: Relationship between the selection of oral anticoagulants after acute stroke as secondary prevention and clinical outcome is not elucidated. Our aim is to compare clinical outcome in patients receiving direct oral anticoagulants (DOACs) versus warfarin after their stroke. Methods: In the regional stroke registry, K-PLUS, 1,019 consecutive patients with cardioembolic stroke who were prescribed anticoagulants were retrospectively enrolled from April 2011 to May 2016. Patients with premorbid modified Rankin Scale score of 3 or more and those with incomplete clinical data were excluded. The residual 323 patients were divided into 2 groups by their receiving anticoagulants after their stroke: the warfarin group and the DOACs group. Clinical characteristics, length of hospital stay, Functional Independence Measure (FIM) scores on admission and at discharge of rehabilitation hospital, and mean daily FIM gain were compared between the 2 groups. Results: In the 323 patients, median age was 79 (interquartile range: 73-85) years and 176 (54.5%) were men. A total of 146 patients (46.2%) was prescribed DOACs (dabigatran in 15, rivaroxaban in 46, apixaban in 72, and edoxaban in 13). Median age (81 vs. 79 in median, p = .03) and NIHSS score on acute hospital admission (10 in DOACs vs. 17 in warfarin, p < .01) were lower, and length of acute hospital stay was shorter (13 vs. 17 days, p < .01) in the DOACs group than the warfarin group. In rehabilitation hospitals, both FIM score on admission (86 vs. 32, p < .01) and daily FIM gain (0.22 vs. 0.10, p < .01) was significantly higher in the DOACs group. On multivariate analysis, DOACs prescription (odds ratio 1.79; 95% CI, 1.10-2.93) and NIHSS on acute hospital admission (1.04 per 1 point; 1.01-1.08) were correlated with daily FIM gain ≥ 0.15, independent of other factors including age, length of acute hospital stay, and FIM on admission of rehabilitation hospital. Conclusion: Patients receiving DOACs after their cardioembolic stroke might achieve better clinical outcome than those with warfarin.

Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the common type of hereditary small vessel disease. The clinical presentation of CADASIL has been reported as varies, and there may exist the racial gap between Asian and Caucasian people. However, the clinical features of CADASIL in Japan is still unclear. This study aimed to elucidate the epidemiological and clinical features of CADASIL based on the nationwide survey in Japan. Methods: Target subjects were patients with CADASIL who had visited the certified hospitals (totally 1, 448 hospitals) by Japanese Society of Neurology and/or Japan Stroke Society in 2016. This study consisted of two steps surveys; patients with CADASIL were identified genetically by the first questionnaire, and their clinical features were assessed by the second questionnaire. Selected 6 hospitals registered the data of patients with CADASIL to REDCap system. Results: Based on the Japanese criteria (Mizuta et al. 2017), 88 patients (50 males and 38 females) with definite CADASIL were reported. Mean age at symptom onset was 49.4 years. Late onset (> 60 years) patients were 15 (17.0%), episode of migraine was detected in 26 patients (29.5%), and patients who had vascular risk factor(s) were 33 (37.5%). Stroke-like episodes with neurological signs were detected in 59 patients (67%), cognitive impairment in 31 patients (35.2%), pyramidal sign in 41 patients (46.6%), and pseudobulbar palsy in 20 patients (22.7%). Abnormal deep white matter lesions (WMLs) were detected in 85 patients (96.6%), WMLs extending to anterior temporal pole in 73 patients (83.0%), and cerebral microbleeds in 41 patients (46.6%). Conclusions: Although, CADASIL is characterized by early onset of stroke and without vascular risk, there were more than a few CADASIL patients with late onset and vascular risk factors in Japan.

Amyloidosis is one of the most well-known protein-misfolding diseases caused by the deposition of insolu- ble amyloid fibrils in extracellular spaces. At least 31 amyloid fibril proteins have been identified. To elu- cidate the pathogenesis and diagnose the type of amyloidosis, mass spectrometric techniques, including liquid chromatography/tandem mass spectrometry and matrix-assisted laser desorption/ionization time of flight mass spectrometry, have been widely used for the analysis of biological samples, such as serum, urine, and tissues. We review new insights into the diagnosis and pathogenesis of amyloidosis using several mass spectrometric methods. [Review].

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid-β (Aβ) deposition, which leads to lobar hemorrhage and dementia. Biological molecules affecting the development of CAA have not been fully characterized. In this study, we performed proteome analysis of biopsied leptomeningeal and cortical vessels obtained from 6 CAA patients and 5 non-CAA patients who underwent surgery for large lobar hemorrhages. We found that 6 proteins, including Aβ, apolipoprotein E (apoE), clusterin (CLU), albumin, complement C4 and vitronectin were significantly upregulated in the vessels of CAA patients as compared to non-CAA patients. ApoE and CLU were found in all CAA patients. We next examined the effects of apoE and CLU on the early phase of Aβ aggregation, using a simple yet powerful in vitro model of CAA, which recapitulates the intramural periarterial drainage pathway model. We found that physiological concentrations of apoE and CLU delayed the initiation time of amyloid growth kinetics in a concentration-dependent manner. These data indicate that apoE and CLU may act as extracellular chaperones to inhibit Aβ amyloid deposition in CAA.

Cardiac amyloidosis is emerging as an underdiagnosed cause of heart failure and mortality. Growing literature suggests that a noninvasive diagnosis of cardiac amyloidosis is now feasible. However, the diagnostic criteria and utilization of imaging in cardiac amyloidosis are not standardized. In this paper, Part 2 of a series, a panel of international experts from multiple societies define the diagnostic criteria for cardiac amyloidosis and appropriate utilization of echocardiography, cardiovascular magnetic resonance imaging, and radionuclide imaging in the evaluation of patients with known or suspected cardiac amyloidosis.

Familial amyloid polyneuropathy is a hereditary systemic amyloidosis caused by a mutation in the transthyretin (TTR) gene. Amyloid deposits in tissues of patients contain not only full-length TTR but also C-terminal TTR fragments. However, in vivo models to evaluate the pathogenicity of TTR fragments have not yet been developed. Here, we generated transgenic Caenorhabditis elegans strains expressing several types of TTR fragments or full-length TTR fused to enhanced green fluorescent protein in the body wall muscle cells and analyzed the phenotypes of the worms. The transgenic strain expressing residues 81–127 of TTR, which included the β-strands F and H, formed aggregates and caused defective worm motility and a significantly shortened lifespan compared with other strains. These findings suggest that the C-terminal fragments of TTR may contribute to cytotoxicity of TTR amyloidosis in vivo. By using this C. elegans model system, we found that (−)-epigallocatechin-3-gallate, a major polyphenol in green tea, significantly inhibited the formation of aggregates, the defective motility, and the shortened lifespan caused by residues 81–127 of TTR. These results suggest that our newly developed C. elegans model system will be useful for in vivo pathological analyses of TTR amyloidosis as well as drug screening.

HASPIN is a serine/threonine kinase that regulates mitosis by phosphorylating histone H3 at threonine 3. The expression levels of HASPIN in various cancers are associated with tumor malignancy and poor survival, suggesting that HASPIN inhibition may suppress cancer growth. As HASPIN mRNA levels are elevated in human breast cancer tissues compared with adjacent normal tissues, we examined the growth-suppressive effects of CHR-6494, a potent HASPIN inhibitor, in breast cancer cell lines in vitro and in vivo. We found that HASPIN was expressed in breast cancer cells of all molecular subtypes, as well as in immortalized mammary epithelial cells. HASPIN expression levels appeared to be correlated with the cell growth rate but not the molecular subtype of breast cancer. CHR-6494 exhibited potent antiproliferative effects against breast cancer cell lines and immortalized mammary epithelial cells in vitro, but failed to inhibit the growth of MDA-MB-231 xenografted tumors under conditions that have significant effects in a colorectal cancer model. These results imply that CHR-6494 does have antiproliferative effects in some situations, and further drug screening efforts are anticipated to identify more potent and selective HASPIN inhibition for use as an anticancer agent in breast cancer patients.

Since autonomic dysfunction is closely associated with autoimmune encephalitis (AE), the objective of this study was to determine the autonomic symptoms and the prevalence of anti-α3 subunit of the ganglionic-type nicotinic acetylcholine receptor (gAChRα3) antibodies in the patients with AE. We reviewed the clinical features of 19 AE patients, and specifically analyzed sera for anti-gAChRα3 antibodies using the luciferase immunoprecipitation system (LIPS) assay. Cardiovascular autonomic symptoms were found to be common in patients with AE, and hypersalivation was seen only in patients with NMDAR encephalitis. LIPS detected anti-gAChRα3 antibodies in the sera from patients with AE (5/29, 26%). This study is the first to demonstrate that clinical characteristics including autonomic symptoms of AE patients with seropositivity for gAChR autoantibodies. It will be important to verify the role of gAChR antibodies in autonomic dysfunction and brain symptoms to clarify the pathogenesis of AE.

Myotonia congenita is a non-dystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction caused by a mutation in the gene encoding skeletal muscle chloride channel-1 (CLCN1). We encountered a case of Thomsen disease with ptosis. A short tau inversion recovery MR imaging demonstrated high-intensity lesions in the levator palpebrae superioris muscles. Molecular genetic testing revealed a heterozygosity for the c.1439C>A (p.P480H) mutation in the CLCN1 gene. The expression level of ClC-1 was significantly reduced on the sarcolemma of the biceps brachii muscle from the patient, compared with that from healthy volunteer. Functional analysis of the p.P480H mutation is required for further elucidating the pathogenesis of Thomsen disease.

Objective:To examine the morphology of Schwann cells and endoneurial microvessels with electron microscopy.Methods:Sural nerve biopsy specimens from 49 patients with familial amyloid polyneuropathy (FAP) with transthyretin Val30Met mutation were assessed. Patients included 11 early-onset cases from endemic foci and 38 late-onset cases from nonendemic areas.Results:Loss of nerve fibers with or without neighboring amyloid deposition was a common feature. The amount of amyloid deposition was greater relative to the extent of nerve fiber loss in early-onset cases than in late-onset cases. The atrophy of Schwann cells, particularly nonmyelinating Schwann cells, that were apposed to amyloid fibrils was more conspicuous in early-onset cases than in late-onset cases. The numbers of endothelial cell nuclei, endothelial cell profiles, and occluded microvessels were significantly increased in the patients with FAP compared with 37 patients with nutritional/alcoholic neuropathies (p < 0.05, 0.01, and 0.01, respectively). Findings suggestive of the disruption of blood-nerve barriers such as the loss of tight junctions and the fenestration of endothelial cells were also found more frequently in the patients with FAP (p < 0.001), regardless of the presence or absence of amyloid deposition.Conclusions:These findings suggest that direct insult of amyloid fibrils causes Schwann cell damage, resulting in the predominant loss of small-fiber axons characteristic of early-onset cases. In addition, vasculopathy may participate in the pathogenesis of neuropathy, particularly in late-onset cases.

The available clinical data are limited in a rare glomerular disease, renal amyloidosis. We aimed to clarify the clinical features of renal amyloidosis from database of the Japan Renal Biopsy Registry (J-RBR). We performed a cross-sectional study with database of the J-RBR of the Japanese Society of Nephrology. We identified 281 cases of renal amyloidosis from 20,997 cases enrolled into the J-RBR from 2007 to 2014. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were compared among the levels of ages, amount of urine protein excretion (AUPE) or CKD G stages. The prevalence of renal amyloidosis was 1.3 % (281/20,997). DBP significantly decreased in higher age quartiles (P = 0.034). SBP and DBP did not increase in the progression of AUPE levels and CKD G stages. In multiple regression analysis, eGFR was a significant independent factor for SBP in all cases and a subgroup without hypertensive agents. There was a reverse significant relationship between SBP and eGFR. Blood pressure did not significantly increase in elderly and much proteinuric condition in renal amyloidosis. The progression of CKD and decrease of eGFR did not produce the higher SBP. The mechanism underlying these results remains unclear; however, they are unique features of renal amyloidosis. The couple of hypotensive and hypertensive conditions might produce no relationship between blood pressure and CKD stages.

Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival.

Although a wide range of strategies have been established to improve intravenous tissue plasminogen activator (IV-tPA) treatment rates, international benchmarking has not been regularly used as a systems improvement tool. We compared acute stroke codes (ASC) between two hospitals in Australia and Japan to study the activation process and potentially improve the implementation of thrombolysis. Consecutive patients who were admitted to each hospital via ASC were prospectively collected. We compared IV-tPA rates, factors contributing to exclusion from IV-tPA, and pre- and in-hospital process of care. IV-tPA treatment rates were significantly higher in the Australian hospital than in the Japanese (41% versus 25% of acute ischaemic stroke patients, p=0.0016). In both hospitals, reasons for exclusion from IV-tPA treatment were intracerebral haemorrhage, mild symptoms, and stroke mimic. Patients with baseline National Institutes of Health Stroke Scale score⩽5 were more likely to be excluded from IV-tPA in the Japanese hospital. Of patients treated with IV-tPA, the door-to-needle time (median, 63 versus 54minutes, p=0.0355) and imaging-to-needle time (34 versus 27minutes, p=0.0220) were longer in the Australian hospital. Through international benchmarking using cohorts captured under ASC, significant differences were noted in rates of IV-tPA treatment and workflow speed. This variation highlights opportunity to improve and areas to focus targeted practice improvement strategies.

Domino liver transplantation (DLT) with liver grafts from patients with hereditary transthyretin (TTR) amyloidosis has been performed throughout the world because of a severe liver graft shortage. Reports of acquired systemic TTR amyloidosis in domino liver recipients have been increasing; however, the precise pathogenesis and clinical course of acquired TTR amyloidosis remains unclear. We analyzed the relationship between the occurrence of acquired amyloidosis and clinical features in 22 consecutive domino liver donors with hereditary TTR amyloidosis (10 males and 12 females; mean age at DLT: 37.2 years; TTR mutations: V30M [n = 19], Y114C [n = 1], L55P [n = 1], and S50I [n = 1]) and 22 liver recipients (16 males and 6 females; mean age at DLT, 46.2 years). The mean times from DLT to amyloid first appearance and transplant recipient symptom onset were 8.2 years and 9.9 years, respectively. Kaplan-Meier analysis and quantification of the amyloid deposition revealed aging of recipients correlated with early de novo amyloid deposition. The sex of donors and recipients and the age, disease duration, and disease severity of donors had no significant effect on the latency of de novo amyloid deposition. In conclusion, our results demonstrate that recipient aging is associated with the early onset de novo amyloidosis. Because acquired amyloidosis will likely increase, careful follow-up for early amyloidosis detection and new treatments, including TTR stabilizers and gene-silencing therapies, are required. Liver Transplantation 22 656-664 2016 AASLD.

A 37-year-old man was hospitalized for an evaluation of acute bilateral multiple subcortical infarcts. There were no specific signal abnormalities in the temporal pole or external capsule. An abdominal skin biopsy showed granular, electron-dense, osmiophilic material (GOM) in the smooth muscle cells on electron microscopy. A direct sequencing analysis of NOTCH3 revealed a heterozygous c.986G>A substitution in exon 6, resulting in a Cys329Tyr amino acid replacement. According to these findings, the patient was diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencehalopathy (CADASIL). Thus, early phases of CADASIL can present as acute bilateral multiple subcortical infarcts without a characteristic temporal pole or any external capsule lesions.

Many claim that they do not have enough neurologists in Japan, but supply and demand of neurologists remains to be analyzed. To investigate the recruitment for the Japanese Society of Neurology (JSN), the subcommittee of JSN for education performed a questionnaire-based survey in 80 medical universities and 271 board-certified education facilities throughout Japan. The response rate to the questionnaire was 77.5% in medical universities and 42.4% in education facilities. It was shown that each department of neurology in university recruits average 2.2 doctors, while they supposed that more than 4 doctors to be recruited every year. The questionnaire survey included what measures JSN should take in order to promote recruitment for JSN.

A 70-year-old woman with Charcot-Marie-Tooth disease (CMT) suffered from nephrotic syndrome and a renal biopsy revealed non-AA amyloid depositions that contained immunoglobulin light chain λ. Her serum λ free LC was elevated to 80.8 mg/L and she was diagnosed with primary amyloid light-chain (AL) amyloidosis. She was subsequently treated with lenalidomide, cyclophosphamide, and dexamethasone (RCD). After 14 cycles of RCD, she achieved complete remission. Her serum albumin levels gradually normalized to 3.1 g/dL. No exacerbation of neurologic symptoms related to CMT was observed. Thus, RCD may be a well-tolerated and effective regimen for treating AL amyloidosis in patients with CMT disease.

A 76-year-old woman was admitted to our hospital because of transthyretin-related familial amyloid polyneuropathy (TTR-FAP). She had developed bilateral vitreous opacity at the age of 58 and paroxysmal atrial fibrillation at the age of 62. She suffered gait disturbance and dysesthesia of the limbs at the age of 68 and was diagnosed with FAP involving a homozygous Val30Met mutation in the amyloidogenic transthyretin (ATTR) gene after a genetic test. Her parents were cousins, and her aunt's medical history included pacemaker implantation and polyneuropathy. At the age of 74, the patient developed gait disturbance and dysesthesia of her extremities. A neurological examination revealed visual loss, hearing impairment, distal muscle weakness, dysesthesia, and decreased sensation in all modalities in her extremities. She could neither walk nor remain standing without support. Brain magnetic resonance imaging (MRI) revealed a low intensity lesion on the surface of the cerebellum on T2*-weighted images and susceptibility-weighted images. A low intensity pattern that was indicative of the classical type of superficial siderosis was detected. At the age of 76, when she was admitted to our hospital because of the deterioration of her gait disturbance and dysesthesia, brain MRI showed that the patient's cerebellar atrophy and hemosiderin deposition had worsened. Some reports suggest that FAP patients that are homozygous for the ATTR Val30Met mutation are more likely to develop central nervous involvement than those that are heterozygous for the mutation. Superficial siderosis may be responsible for the central nervous involvement.

Amyloidosis is a protein conformational disorder in which amyloid fibrils accumulate in the extracellular space and induce organ dysfunction. Recently, two different amyloidogenic proteins, transthyretin (TTR) and apolipoprotein A-I (Apo A-I), were identified in amyloid deposits in knee joints in patients with knee osteoarthritis (OA). However, clinicopathological differences related to those two kinds of amyloid deposits in the knee joint remain to be clarified. Here, we investigated the clinicopathological features related to these knee amyloid deposits associated with knee OA and the biochemical characteristics of the amyloid deposits. We found that all of our patients with knee OA had amyloid deposits in the knee joints, especially in the meniscus, and those deposits were primarily derived from TTR and/or Apo A-I. Some patients with knee OA, however, had unclassified amyloid deposits. One of our interesting observations concerned the different effects of aging on each type of amyloid formed. The frequency of formation of ATTR deposits clearly increased with age, but that of AApo A-I deposits decreased. Furthermore, we found that ∼16% of patients with knee OA developed ATTR/AApo A-I double deposits in the meniscus. Amyloid deposition may therefore be a common histopathological feature associated with knee OA. Also, aging may induce ATTR formation in the knee joint in elderly patients with knee OA, whereas AApo A-I formation may be inversely correlated with age.

A nationwide survey on systemic wild-type ATTR (ATTRwt) amyloidosis was conducted to elucidate the frequency, clinical picture and possible diagnostic issues of ATTRwt amyloidosis in Japan.A questionnaire was sent to 4629 clinical departments across Japan. A total of 2341 (50.6%) responses were returned completed for further analysis.Fifty-one patients with ATTRwt amyloidosis (82% male) were identified between January 2012 and December 2014. The study subjects were identified in 11 departments at 10 institutes. The mean age of onset and diagnosis were 71.6 and 73.6 years, respectively. The main clinical findings were cardiac failure (76%), cardiac conduction defects/arrhythmia (59%), renal dysfunction (49%), carpal tunnel syndrome (45%) and spinal canal stenosis (22%).ATTRwt amyloidosis is diagnosed in a limited number of institutes in Japan and is therefore considered to be underdiagnosed.

Purpose There is scant data related to prehospital delay in cases of acute ischemic stroke from multicenter studies conducted after change of the therapeutic window of intravenous tissue plasminogen activator (iv-tPA) administration to within 4.5 h of onset. We investigated factors causing prehospital delay and their associations with clinical outcomes using data from a regional multicenter stroke registry. Methods Data from the multicenter regional stroke registry were analyzed. Patients admitted within 24 h of the last known well time were categorized according to whether their admission was early (≤ 4 h; n = 2350) or delayed (> 4 h; n = 2752). We then compared patients’ backgrounds and outcomes between the two groups. Results Five-thousand, one-hundred two patients presented at hospitals within 24 h of onset. On multivariate analysis, atrial fibrillation, higher NIHSS score on admission, anterior circulation stroke, detection of symptoms immediately after onset, and emergency system use were positively associated with early admission, whereas modified Rankin Scale (mRS) score before onset, onset at home, diabetes, current smoking, dementia and symptom detection between 00:00 and 06:00 h were negatively associated. Early admission was associated with mRS scores of 0–2 at discharge independent of backgrounds, stroke severity, and thrombolytic therapy (odds ratio, 1.56; 95% confidence interval, 1.32–1.84). Conclusions Certain patient factors relating to prehospital delay, such as lack of awareness of onset or non-cardioembolic etiology, are crucial but often inevitable. However, earlier admission was associated mRS scores of 0–2 independent of other factors. This study may help to plan educational activities to general population or public awareness campaigns.

To detect vascular Notch3 extracellular domain aggregates in CADASIL, we developed a novel dot-blot assay with both autopsy and biopsy skin samples. We obtained samples from 11 patients with CADASIL and 12 control patients, and we performed dot-blot analyses by using sequential biochemical tissue extractions with three different antibodies against specific regions of the Notch3 extracellular domain. We also analyzed clinical features and vascular accumulations of Notch3 by immunohistochemistry. Via the dot-blot assay with the antibody against the C-terminal region of the Notch3 extracellular domain, we successfully detected Notch3 extracellular domain aggregates in skin tissue homogenates obtained from patients with CADASIL. Our novel method may therefore aid the diagnosis of CADASIL.