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Background and aims Patients with transthyretin amyloid polyneuropathy (ATTR-PN) show decreased motor and sensory nerve amplitudes and conduction. Electrophysiological changes over time may be sensitive indicators of progression. This analysis from the Transthyretin Amyloidosis Outcomes Survey (THAOS) assessed longitudinal changes in nerve conduction as signals of neurologic disease progression in patients with hereditary ATTR (ATTRv) amyloidosis. Methods Patients with ATTRv in THAOS with recorded nerve conduction values were included (data cut-off: January 06, 2020); changes in nerve amplitude and velocity over time were assessed. Results Patients (n=1389) were 45.0% male; 80.4% were the Val30Met (p.Val50Met) genotype. Mean (SD) age at enrollment was 43.6 (14.5) years; duration of symptoms was 9.3 (6.4) years. Median (10th, 90th percentile) sural nerve amplitude and velocity was 18.0 (4.9, 35.0) μV and 50.7 (41.0, 57.9) m/s; peroneal conduction was 13.0 (4.4, 27.0) μV and 51.0 (41.7, 59.7) m/s, respectively. Median (10th, 90th percentile) percentage change from baseline in sural nerve amplitude was variable, but generally decreased over time from -7.4 (-43.2, 52.4) at year 1 to -14.4 (-76.9, 46.7) at year 8. Percent change from baseline in sural nerve velocity declined similarly: -0.1 (-14.5, 15.3) at year 1 and -6.4 (-21.3, 10.5) at year 8. The decline was more pronounced in patients with greater disability at baseline. Similar patterns were observed for the peroneal nerve. Interpretation These data show an association between nerve amplitudes and velocities and disease severity, suggesting progressive deterioration in nerve conduction may be an indicator of ATTRv amyloidosis disease progression.

Introduction AKCEA-TTR-LRx is a ligand-conjugated antisense (LICA) drug in development for the treatment of hereditary transthyretin amyloidosis (hATTR), a fatal disease caused by mutations in the transthyretin (TTR) gene. AKCEA-TTR-LRx shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-LRx is conjugated to a triantennary N-acetylgalactosamine moiety that supports receptor-mediated uptake by hepatocytes, the primary source of circulating TTR. This advanced design increases drug potency to allow for lower and less frequent dosing. The NEURO-TTRansform study will investigate whether AKCEA-TTR-LRx is safe and efficacious, with the aim of improving neurologic function and quality of life in hATTR-PN patients. Methods/Design Approximately 140 adults with stage 1 (independent ambulation) or 2 (requires ambulatory support) hATTR-PN are anticipated to enroll in this multicenter, open-label, randomized, phase 3 study. Patients will be assigned 6:1 to AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks or inotersen 300 mg once weekly until the prespecified week 35 interim efficacy analysis, after which patients receiving inotersen will receive AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-LRx through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-LRx arm with the historical placebo arm from the phase 3 trial of inotersen (NEURO-TTR). The primary outcome measures are between-group differences in the change from baseline in serum TTR, modified Neuropathy Impairment Score + 7, and Norfolk Quality of Life—Diabetic Neuropathy questionnaire. Conclusion NEURO-TTRansform is designed to determine whether targeted delivery of AKCEA-TTR-LRx to hepatocytes with lower and less frequent doses will translate into clinical and quality-of-life benefits for patients with hATTR-PN. Trial Registration The study is registered at ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10). Supplementary Information The online version contains supplementary material available at 10.1007/s40120-021-00235-6., Plain Language Summary Hereditary transthyretin amyloidosis with peripheral neuropathy (hATTR-PN for short) is a rare inherited condition.In hATTR-PN, a protein called transthyretin (TTR for short) builds up and damages nerves throughout the body.This neuropathy causes symptoms such as weakness, loss of sensation, and pain.Currently available medicines can slow disease progression, but researchers are looking for more effective treatments with fewer side effects.AKCEA-TTR-LRx is an investigational treatment for hATTR-PN.AKCEA-TTR-LRx prevents the liver from making TTR, reducing the amount that causes disease progression.It is similar to an existing treatment called inotersen, but designed for better delivery to the liver and is more potent.This article describes the NEURO-TTRansform study that will evaluate how effective AKCEA-TTR-LRx is for treating hATTR-PN.Around 140 adults with hATTR-PN from the USA, Canada, and Europe will be able to take part in this study.The study treatment period will be 85 weeks long. People will receive injections underneath the skin of either:AKCEA-TTR-LRx every 4 weeks, orInotersen once a week for 35 weeks, followed by a switch to AKCEA-TTR-LRx every 4 weeks.People may continue to receive AKCEA-TTR-LRx after the study treatment period ends.In this study, researchers will compare results from people who received AKCEA-TTR-LRx to results from people who received no active ingredients (called placebo) in a similar study (called NEURO-TTR).Researchers will measure the differences in peoples’:Neuropathy symptoms.Quality of life.TTR protein levels in the blood. Supplementary Information The online version contains supplementary material available at 10.1007/s40120-021-00235-6.

Aims Hereditary transthyretin (ATTRv) amyloidosis is the most frequent and representative form of autosomal dominant hereditary systemic amyloidosis. Disease‐modifying treatments of the disease are more effective during the early stages, and we require biomarkers to detect early pathological changes for prompt diagnosis. This study aimed to investigate whether plasma growth differentiation factor 15 (GDF‐15) levels could aid detection of early pathological changes in ATTRv amyloidosis. Methods and results We retrospectively studied 32 patients with ATTRv amyloidosis, eight asymptomatic TTR mutation carriers, and eight healthy volunteers. We evaluated plasma GDF‐15 levels in these subjects as related to levels of brain natriuretic peptide and high‐sensitivity troponin T, echocardiographic features, 99mTc‐pyrophosphate (PYP) scans, and cardiac magnetic resonance imaging findings. Plasma GDF‐15 levels significantly increased even in asymptomatic TTR mutation carriers compared with healthy volunteers (P

Background: Using transthoracic echocardiography, including 2D speckle tracking imaging (STI), this study examined cardiac function after domino liver transplantation (DLT) with liver grafts explanted from patients with hereditary amyloidogenic transthyretin amyloidosis. Methods and Results: In all, 14 patients who underwent DLT at Kumamoto University Hospital and for whom 2D STI information was available were enrolled in the study; time-dependent echocardiographic changes were evaluated in 7. Although left ventricular (LV) systolic and diastolic function did not differ between the pre- and post-DLT periods (mean [±SD] 5.4±1.0 years after DLT), there were significant (P−14%) than preserved basal LS (57.2±3.5 vs. 39.6±16.0 years; P−14%; odds ratio 28.39, 95% confidence interval 1.89–427.45, P

BACKGROUND We previously reported that a high score (2 or 3 points) according to the Kumamoto criteria, a combination of high-sensitivity cardiac troponin T (hs-cTnT) ≥0.308 ng/mL, the length of QRS ≥ 120 ms in electrocardiogram, and left ventricular (LV) posterior wall thickness ≥ 13.6 mm, increases the pretest probability of 99m Tc-labeled pyrophosphate (99m Tc-PYP) scintigraphy in patients with suspected transthyretin amyloid cardiomyopathy (ATTR-CM). However, some patients with a low score (0 or 1 point) show positive findings on 99m Tc-PYP scintigraphy. Therefore, we evaluated the usefulness of additional examinations, including echocardiographic assessment of myocardial strain, to raise the pretest probability of 99m Tc-PYP scintigraphy for these patients. METHODS AND RESULTS We examined 109 consecutive patients aged ≥70 years with low scores according to the Kumamoto criteria who underwent 99m Tc-PYP scintigraphy. Nineteen patients (17%) had positive 99m Tc-PYP scintigraphy findings. The relative apical longitudinal strain (LS) index (apical LS/ basal LS + mid LS) (RapLSI) was significantly higher in patients with positive than negative 99m Tc-PYP scintigraphy findings (1.04 ± 0.37 vs 0.70 ± 0.28, P

The molecular pathogenesis of human amyloidosis has been elucidated greatly during the last 20 years. Based on the understanding of the molecular mechanisms of amyloid fibril formation and deposition, various kinds of new drugs and therapeutics have been emerging to improve the prognosis of amyloidosis and even cure this disease. In this review article, we first summarize the pathogenesis and state-of-the-art therapeutics of representative types of systemic human amyloidosis, that is, immunoglobulin light chain-related, transthyretin-related, amyloid A-associated and β2 -microglobulin-related amyloidosis. Next, we describe the essential roles of pathological diagnosis, especially the typing diagnosis of amyloidosis to appropriately guide type-specific therapies of amyloidosis patients. Finally, we introduce the activities of the government-funded group for surveys and research of amyloidosis in Japan, especially the nation-wide pathology consultation system of amyloidosis, which started in April 2018. The nation-wide improvement of the typing diagnosis of amyloidosis is essential for the appropriate treatment and care of amyloidosis patients in Japan.

Amyloid transthyretin (ATTR) amyloidosis with polyneuropathy (PN) is a progressive, debilitating, systemic disease wherein transthyretin protein misfolds to form amyloid, which is deposited in the endoneurium. ATTR amyloidosis with PN is the most serious hereditary polyneuropathy of adult onset. It arises from a hereditary mutation in the TTR gene and may involve the heart as well as other organs. It is critical to identify and diagnose the disease earlier because treatments are available to help slow the progression of neuropathy. Early diagnosis is complicated, however, because presentation may vary and family history is not always known. Symptoms may be mistakenly attributed to other diseases such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), idiopathic axonal polyneuropathy, lumbar spinal stenosis, and, more rarely, diabetic neuropathy and AL amyloidosis. In endemic countries (e.g., Portugal, Japan, Sweden, Brazil), ATTR amyloidosis with PN should be suspected in any patient who has length-dependent small-fiber PN with autonomic dysfunction and a family history of ATTR amyloidosis, unexplained weight loss, heart rhythm disorders, vitreous opacities, or renal abnormalities. In nonendemic countries, the disease may present as idiopathic rapidly progressive sensory motor axonal neuropathy or atypical CIDP with any of the above symptoms or with bilateral carpal tunnel syndrome, gait disorders, or cardiac hypertrophy. Diagnosis should include DNA testing, biopsy, and amyloid typing. Patients should be followed up every 6–12 months, depending on the severity of the disease and response to therapy. This review outlines detailed recommendations to improve the diagnosis of ATTR amyloidosis with PN.

Background 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 and 99mTc-pyrophosphate (99mTc-PYP) scintigraphy as diagnostic modalities in ATTRwt. Methods We divided 39 consecutive ATTRwt patients into two groups depending on whether serum hs-cTnT measurement and 99mTc-PYP scintigraphy were adopted as diagnostic tools: group A patients (n = 8) who were diagnosed before the introduction of these two tools and group B patients (n = 31) who were diagnosed after the introduction of the two tools. We retrospectively evaluated the two groups. Results Diagnostic yield was higher in group B than in group A (1.2 vs. 5.4 ATTRwt patients per 1000 hospitalized patients, p Conclusions An integrated approach consisting of hs-cTnT measurement and 99mTc-PYP scintigraphy significantly increases the diagnostic rate of ATTRwt and has a high potential to identify ATTRwt patients with a variety of clinical phenotypes.

To date, almost all case reports of insulin‐derived amyloidosis described the presence of a subcutaneous mass that was observable on physical examination. This report presents two cases of insulin‐derived amyloidosis without palpable masses at insulin injection sites. In both cases, blood glucose concentrations improved, and the insulin dose could be reduced by an average of 45% after changing the insulin injection sites. The insulin absorption at the site was reduced to at most 40% of that at a normal site in one case. Magnetic resonance imaging and ultrasonography were useful to screen and differentiate insulin‐derived amyloidosis without a palpable mass. This report showed that insulin‐derived amyloidosis without a palpable mass can be present at the insulin injection site, and has similar clinical effects to insulin‐derived amyloidosis with palpable masses., This report showed that insulin‐derived amyloidosis without a palpable mass can be present at the insulin injection site and has similar clinical effects to insulin‐derived amyloidosis with palpable masses. Magnetic resonance imaging and ultrasonography were useful to screen and differentiate insulin‐derived amyloidosis without a palpable mass.

Highlights • We describe the first case of binasal hemianopia due to bilateral optic perineuritis. • Bilateral optic perineuritis should be considered as a causative disease of binasal hemianopia. • Early diagnosis of optic perineuritis is crucial to avoid irreversible visual impairment.

A cross-sectional study was conducted to clarify the adverse events of COVID-19 vaccines in Japanese young population.The proportion of participants with adverse events at the vaccination site (immediately or within 30 minutes after vaccination) was 0.5%, and anaphylaxis occurred in one female student (0.03%).We analyzed 1,877 data obtained from a questionnaire survey of 1,993 vaccinated individuals. Eighty-two percent of participants complained of local adverse events. Injection site pain was the most common local adverse event (71%). Systemic adverse events occurred in 48% of participants. The most common adverse event was myalgia (34%).A multivariable logistic regression model was used to determine risk factors.Local adverse events were associated with sex (female) and allergy history, with odds ratios (ORs) (95% confidence interval [CI]) of 2.15 (1.69-2.73) and 1.73 (1.10-2.74), respectively. Systemic adverse events were associated with sex (female), age (The results of this study clarified for the first time that age less than 20 years is a risk factor for systemic adverse events from the COVID-19 Vaccine Moderna Intramuscular Injection. This information will give impacts on considering adverse events and its mechanisms in mRNA vaccination.

Cerebral small vessel disease (SVD) is associated with white matter hyperintensities (WMHs), thereby contributing to vascular dementia and movement disorder. However, the pathomechanisms responsible for WMH-related small vessel degeneration remain poorly understood due to the technical limitations of current methods. The aim of this study was to clarify the 2- and 3-dimensional (2D and 3D) pathological features of small vessels and white matter (WM) in the brains of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), HTRA1-autosomal dominant disease (HTRA1-AD) and sporadic SVD (sSVD). From a cohort of 86 consecutive autopsied patients with SVDs, we retrieved those with genetically confirmed CADASIL and HTRA1-AD (three and three, respectively), and four with sSVD. We quantitatively evaluated WM and vascular changes in the frontal portion of the centrum semiovale and temporal lobe using conventional 2D and chemically cleared 3D analytical methods with light-sheet fluorescence microscopy. Quantitatively, the WM pathology, including the density of myelin, axons and gliosis, was most severe in CADASIL, but unexpectedly sSVD was second in order of severity, followed by HTRA1-AD. The density of clasmatodendrocytes, known to be irreversibly injured astrocytes, was considerably highest in HTRA1-AD. The vascular pathology, including arteriole and capillary sclerosis and the extent of the perivascular space, was most severe in CADASIL, whereas the density of smooth muscle actin (SMA) positivity was most decreased in HTRA1-AD. 3D immunohistochemistry for SMA demonstrated two distinct patterns of SMA loss within the vessels: (1) CADASIL and sSVD: diffuse loss, being prominent in small branches, (2) HTRA1-AD: selective loss in main branches. Overall, the extent of WM and vascular degeneration is most severe in CADASIL, whereas SMA loss is most evident in HTRA1-AD. These differences in the size and distribution of affected vessels may be related to the heterogeneous WM pathology and underlying pathomechanisms of SVD.

Objective To characterize the CSF cytokine profile in chronic inflammatory demyelinating polyneuropathy (CIDP) patients with IgG4 anti‐neurofascin 155 (NF155) antibodies (NF155+ CIDP) or those lacking anti‐NF155 antibodies (NF155− CIDP). Methods Twenty‐eight CSF cytokines/chemokines/growth factors were measured by multiplexed fluorescent immunoassay in 35 patients with NF155+ CIDP, 36 with NF155− CIDP, and 28 with non‐inflammatory neurological disease (NIND). Results CSF CXCL8/IL‐8, IL‐13, TNF‐α, CCL11/eotaxin, CCL2/MCP‐1, and IFN‐γ were significantly higher, while IL‐1β, IL‐1ra, and G‐CSF were lower, in NF155+ CIDP than in NIND. Compared with NF155− CIDP, CXCL8/IL‐8 and IL‐13 were significantly higher, and IL‐1β, IL‐1ra, and IL‐6 were lower, in NF155+ CIDP. CXCL8/IL‐8, IL‐13, CCL11/eotaxin, CXCL10/IP‐10, CCL3/MIP‐1α, CCL4/MIP‐1β, and TNF‐α levels were positively correlated with markedly elevated CSF protein, while IL‐13, CCL11/eotaxin, and IL‐17 levels were positively correlated with increased CSF cell counts. IL‐13, CXCL8/IL‐8, CCL4/MIP‐1β, CCL3/MIP‐1α, and CCL5/RANTES were decreased by combined immunotherapies in nine NF155+ CIDP patients examined longitudinally. By contrast, NF155− CIDP had significantly increased IFN‐γ compared with NIND, and exhibited positive correlations of IFN‐γ, CXCL10/IP‐10, and CXCL8/IL‐8 with CSF protein. Canonical discriminant analysis of cytokines/chemokines revealed that NF155+ and NF155− CIDP were separable, and that IL‐4, IL‐10, and IL‐13 were the three most significant discriminators. Interpretation Intrathecal upregulation of type 2 helper T (Th2) cell cytokines is characteristic of IgG4 NF155+ CIDP, while type 1 helper T cell cytokines are increased in CIDP regardless of the presence or absence of anti‐NF155 antibodies, suggesting that overproduction of Th2 cell cytokines is unique to NF155+ CIDP.

ObjectiveTo elucidate the clinical characteristics of acquired ATTR amyloidosis after domino liver transplantation (DLT) with liver grafts explanted from patients with hereditary variant ATTR (ATTRv) amyloidosis.MethodsWe evaluated the presence of amyloid deposits and clinical symptoms in 30 recipients of domino liver transplants (24 men and 6 women) who underwent DLT with liver grafts explanted from patients with ATTRv amyloidosis. We analyzed symptoms and measures of 7 cases of symptomatic acquired ATTR amyloidosis and compared those with 30 patients with ATTRv amyloidosis who were the domino liver donors. We also reviewed the literature on case studies of acquired ATTR amyloidosis.ResultsWe found amyloid deposition in 13 of our 30 domino liver recipients. A Kaplan-Meier analysis estimated that the median time from DLT to the first detection of amyloid was 8.5 years. In the literature review, the mean time was 7.3 years, with a wide range of 0.5–13 years. Our 7 symptomatic cases and the literature cases with acquired ATTR amyloidosis presented with clinical features that differed from patients with ATTRv amyloidosis who were the domino liver donors. Patients with acquired ATTR amyloidosis showed markedly milder autonomic disturbance, which is one of the main symptoms of ATTRv amyloidosis.ConclusionsCareful monitoring is required for DLT recipients of ATTRv liver grafts because the time from DLT to disease onset has a wide range and the clinical picture of these DLT recipients is distinct from that of liver donors.

BACKGROUND A recent study revealed a high prevalence of transthyretin (TTR) cardiac amyloidosis (CA) in elderly patients. 99 mTc-labeled pyrophosphate (99 mTc-PYP) scintigraphy is a remarkably sensitive and specific modality for TTR-CA, but is only available in specialist centres; thus, it is important to raise the pretest probability. The aim of this study was to evaluate the characteristics of patients with 99 mTc-PYP positivity and make recommendations about patient selection for 99 mTc-PYP scintigraphy.Methods and Results:We examined 181 consecutive patients aged ≥70 years who underwent 99 mTc-PYP scintigraphy at Kumamoto University Hospital between January 2012 and December 2018. Logistic regression analyses showed that high-sensitivity cardiac troponin T (hs-cTnT) ≥0.0308 ng/mL, left ventricular posterior wall thickness ≥13.6 mm, and wide QRS (QRS ≥120 ms) were strongly associated with 99 mTc-PYP positivity. We developed a new index for predicting 99 mTc-PYP positivity by adding 1 point for each of the 3 factors. The 99 mTc-PYP positive rate increased by a factor of 4.57 for each 1-point increase (P

Background and purpose A nationwide survey was conducted to understand the epidemiology of cerebral amyloid angiopathy-related intracerebral hemorrhage (CAA-related ICH) and cerebral amyloid angiopathy-related inflammation/vasculitis (CAA-ri) in Japan. Methods To estimate the total number and clinical features of patients with CAA-related ICH and CAA-ri between January 2012 and December 2014 and to analyze their clinical features, questionnaires were sent to randomly selected hospitals in Japan. Results In the first survey, 2348 of 4657 departments responded to the questionnaire (response rate 50.4%). The total numbers of reported patients with CAA-related ICH and CAA-ri were 1338 and 61, respectively, and their total numbers in Japan were estimated to be 5900 [95% confidence interval (CI) 4800-7100] and 170 (95% CI 110-220), respectively. The crude prevalence rates were 4.64 and 0.13 per 100 000 population, respectively. The clinical information of 474 patients with CAA-related ICH obtained in the second survey was as follows: (i) the average age of onset was 78.4 years; (ii) the prevalence increased with age; (iii) the disease was common in women; and (iv) hematoma most frequently occurred in the frontal lobe. Sixteen patients with CAA-ri for whom data were collected in the second survey had the following characteristics: (i) median age of onset was 75 years; (ii) cognitive impairment and headache were the most frequent initial manifestations; and (iii) focal neurological signs, such as motor paresis and visual disturbance, were frequently observed during the clinical course. Conclusions The numbers of patients with CAA-related ICH and CAA-ri in Japan were estimated.

TO THE EDITOR: Diagnosis of amyloidosis, with the possible exception of cardiac transthyretin amyloidosis (ATTR) in patients without monoclonal components,[1][1] requires demonstration of tissue amyloid deposits and identification of the amyloidogenic protein.[2][2],[3][3] The gold standard for

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid beta (Aβ) deposits and causes cerebral hemorrhages and dementia in elderly people. Memantine is used in Alzheimer's disease to inhibit the glutamatergic system by blocking N-methyl-D-aspartate receptors. Its therapeutic effects in CAA are unclear, however. Here, we used APP23 transgenic mice (CAA model) to investigate whether memantine has direct therapeutic effects on cerebrovascular Aβ deposits. We treated APP23 mice and age-matched wild-type littermates with memantine at ages 6-18 months. We counted the numbers of vessels with Aβ and hemosiderin deposits. We measured soluble and insoluble Aβ40 and Aβ42 levels and levels of amyloid precursor protein (APP), APP-processing enzymes (α-, β-, γ-secretase), and Aβ-degrading enzymes (insulin-degrading enzyme [IDE], neprilysin). Memantine reduced cerebrovascular Aβ and hemosiderin deposits in APP23 mice. Compared with controls, memantine-treated APP23 mice had reduced Aβ40 levels and increased levels of hippocampal and vascular IDE. Our results suggest that memantine reduces cerebrovascular Aβ deposits by enhancing Aβ-cleaving IDE expression. The clinical availability of memantine may allow its use as a novel therapeutic agent in CAA.

Mutations in the Matrin 3 (MATR3) gene have been identified as a cause of amyotrophic lateral sclerosis (ALS) or vocal cord and pharyngeal weakness with distal myopathy (VCPDM). This study investigated the mechanism by which mutant MATR3 causes multisystem proteinopathy (MSP) including ALS and VCPDM. We first analyzed the muscle pathology of C57BL/6 mice injected with adeno-associated viruses expressing human WT or mutant (S85C) MATR3. We next generated transgenic mice that overexpress mutant (S85C) MATR3, driven by the CMV early enhancer/chicken β-actin promoter, and evaluated their clinicopathological features. Intramuscular injection of viruses expressing WT and mutant MATR3 induced similar myogenic changes, including smaller myofibers with internal nuclei, and upregulated p62 and LC3-II. Mutant MATR3 transgenic mice showed decreased body weight and lower motor activity. Muscle histology demonstrated myopathic changes including fiber-size variation, internal nuclei and rimmed vacuoles. Spinal cord histology showed a reduced number of motor neurons, and activation of microglia and astrocytes. Comprehensive proteomic analyses of muscle demonstrated upregulation of proteins related to chaperones, stress response, protein degradation, and nuclear function. Overexpression of WT and mutant MATR3 similarly caused myotoxicity, recapitulating the clinicopathological features of MSP. These models will be helpful for analyzing MSP pathogenesis and for understanding the function of MATR3. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Background Insulin-derived amyloidosis is a skin-related complication of insulin therapy that interferes with insulin therapy. Although toxicities of in vitro-formed insulin amyloid fibrils have been well studied, the toxicity of insulin-derived amyloidosis remains to be clarified. Case presentation A 58-year-old man with type 2 diabetes mellitus underwent a lower limb amputation due to diabetic gangrene. Several antibiotics including minocycline were administered for infection and sepsis. A hard mass at the insulin injection sites in the lower abdomen was discovered by chance four months later. Although no abnormal findings in the surface skin of the mass were observed, necrotic tissue was seen around the mass when a biopsy was performed. Histological and toxicity studies were performed for this patient and four other patients with abdominal masses at insulin injection sites. Histological and immunohistochemical studies showed that the masses had typical characteristics of amyloid deposits in all cases, whereas necrotic findings were seen adjacent to the amyloid deposit only in the case presented. Toxicity studies indicated that the amyloid tissue from the present case had significant cell toxicity compared to the control skin tissue or the amyloid tissues from the other four cases. Conclusions This report showed that toxic insulin-derived amyloidosis can occur. In addition, this report suggested that toxic insulin-derived amyloidosis may cause necrosis in the surrounding tissue. Although the toxic amyloid deposit of insulin-derived amyloidosis was found in only one patient, no structural differences between toxic and non-toxic deposits were seen on histological and immunohistochemical studies. Electronic supplementary material The online version of this article (10.1186/s12902-019-0385-0) contains supplementary material, which is available to authorized users.

In April of 2016, major earthquakes occurred in Kumamoto, Japan. There is limited information on how major earthquakes affect patients with Parkinson's disease (PD). This study investigates the effect of major earthquakes on patients with PD. The participants were outpatients with PD from hospitals located in areas heavily damaged by the earthquakes. We performed an anonymous survey at nine medical institutions to investigate the condition of these patients during the month following the earthquakes. We collected questionnaires from 335 patients with PD. The mean age was 72.6, and the mean disease duration was 7.4 years. Regarding physical conditions, 29.3% of the patients worsened, 1.5% improved, and 68.1% had no change. The mental health of 35.2% of the patients worsened, 2.4% improved, and 57.9% had no change. The most frequently exacerbated neurologic symptoms included bradykinesia (56.1%), gait disturbance (51.0%), freezing of gait (40.8%), extension of "off" time (38.8%), and constipation (38.8%). The worsening mental conditions included fear of an aftershock (77.1%), anxiety (49.2%), insomnia (47.5%), melancholy feelings (45.8%), and fatigability (38.1%). Patients forced to evacuate reported significantly more physical and mental health symptoms (p 0.01). The influences of major earthquakes on patients with PD were identified. After major earthquakes, we should consider the care required for patients' physical and mental health especially for those who experienced evacuation.

The purposes of the present study were to identify anti-striational antibodies in myasthenia gravis (MG) patients with myositis and/or myocarditis using a combination of cell-based assays and flow cytometry (cytometric cell-based assays) and to describe the main clinical implications. Among 2,609 stored samples collected from all over Japan between 2003 and 2016, we had serum samples from 30 MG patients with myositis and/or myocarditis. Cytometric cell-based assays with titin, ryanodine receptor, and voltage-gated Kv1.4 were performed. Autoantibodies were determined by differences in phycoerythin fluorescence between the 293F cells and titin-transfected cells. MG patients with myositis and/or myocarditis as well as late-onset and thymoma-associated MG had anti-titin, anti-ryanodine receptor, and anti-Kv1.4 antibodies. In contrast, patients with early-onset MG, those with other myopathies and healthy controls did not have anti-titin or anti-Kv1.4 antibodies with some exceptions, but they possessed anti-ryanodine receptor antibodies. Thirty MG patients with myositis and/or myocarditis showed a severe generalized form, and 21 of them had thymoma. Anti-titin and anti-Kv1.4 antibodies were found in 28 (93%) and 15 (50%) patients, respectively, and all patients had at least one of these antibodies. Cytometric cell-based assays thus demonstrated that anti-striational antibodies are biomarkers of MG with myositis and/or myocarditis.

A survey was conducted with neurologists regarding their attitudes toward cannabis. Comparison was made between respondents who had previously been exposed to information about cannabis (31 neurologists), hereafter referred to as the "informed group," and those who had not (81 neurologists), hereafter referred to as the "non-informed group." While more than half of the respondents in both groups showed some acceptance toward the usage of cannabis for research purposes, there was a stronger tendency to accept the use of cannabis for medical purposes in the informed group. Since this acceptance was more often displayed by respondents who had adequate knowledge of the medical use of cannabis, this suggests that providing information on cannabis is useful in promoting acceptance. The result of the survey indicated that a portion of neurologists acknowledges the usefulness of cannabis, and that one's receptivity toward cannabis can be improved if adequate information is provided about cannabis.

We divided acute ischemic stroke patients into an oldest old group (≥90 years, n = 414) and an elderly group (75-89 years, n = 1,927), and compared the clinical characteristics between the two groups. Female sex, early admission, severe stroke on admission, atrial fibrillation, and cardioembolic stoke were significantly more frequent in the oldest-old group. On the other hand, risk factors associated with atherosclerosis were less frequent in the oldest-old group. There were no differences in hyper-acute recanalization therapy between the two groups, whereas antithrombotic therapy for secondary prevention at discharge was introduced less frequently in the oldest-old group than in the elderly group. Death prior to discharge from the acute care hospital , and death at 3 months were significantly more frequent in the oldest-old group. Moreover, in the oldest old group, severe stroke and atrial fibrillation were independent predictors for both death prior to discharge from the acute care hospital and at 3 months after onset. Oldest-old stroke patients had poor outcome, although they had received aggressive treatment as same as elderly patients. Therefore, as the number of oldest-old stroke patients is increasing, the demand for cooperation in the healthcare system is likely to grow, including acute care hospitals.

Most intractable tissue-degenerative disorders share a common pathogenic condition, so-called proteinopathy. Amyloid-related disorders are the most common proteinopathies and are characterized by amyloid fibril deposits in the brain or other organs. Aging is generally associated with the development of these amyloid-related disorders, but we still do not fully understand how functional proteins become pathogenic amyloid deposits during the human aging process. We identified a novel amyloidogenic protein, named epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1), in massive venous amyloid deposits in specimens that we obtained from an autopsied patient who died of gastrointestinal bleeding. Our postmortem analyses of additional patients indicate that EFEMP1 amyloid deposits frequently developed in systemic venous walls of elderly people. EFEMP1 was highly expressed in veins, and aging enhanced venous EFEMP1 expression. In addition, biochemical analyses indicated that these venous amyloid deposits consisted of C-terminal regions of EFEMP1. In vitro studies showed that C-terminal regions formed amyloid fibrils, which inhibited venous tube formation and cell viability. EFEMP1 thus caused a novel age-related venous amyloid-related disorder frequently found in the elderly population. Understanding EFEMP1 amyloid formation provides new insights into amyloid-related disorders occurring during the aging process. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

BACKGROUND AND PURPOSE Neuromyelitis optica spectrum disorder (NMOSD) often presents in the elderly with an insidious onset of symptoms and aggressive progression. There have been anecdotal cases of very late onset (VLO)-NMOSD, but case series reports are rare. The aim of this retrospective study was to clarify the clinical features of VLO-NMOSD. METHODS According to the age at onset, we classified patients with NMOSD into three subgroups: ≤49 years, early onset NMOSD (EO-NMOSD); 50-69 years, late onset NMOSD (LO-NMOSD); and ≥70 years, VLO-NMOSD. We evaluated the clinical characteristics, magnetic resonance imaging (MRI) findings, laboratory data, and immunotherapies of the groups. RESULTS Overall, 12 men and 64 women with a median (interquartile range) age at onset and duration of disease of 42.0 (29.0-55.8) years and 70.0 (16.3-143.0) months, respectively, were included. Eight (11%) patients had VLO-NMOSD, 22 (29%) had LO-NMOSD, and 46 (61%) had EO-NMOSD. Patients with EO-NMOSD had a significantly longer interval between episodes as well as time between the first symptom and diagnosis of NMOSD than did those with VLO-NMOSD and LO-NMOSD (p = 0.046). Optic neuritis and nerve lesions on MRI were significantly less frequent in patients with VLO-NMOSD than in those with LO-NMOSD and EO-NMOSD (p = 0.002 and p = 0.028, respectively). In contrast, patients with VLO-NMOSD had higher nadir Expanded Disability Status Scale and Nurick scale scores and a significantly longer spinal lesion length than did those with LO-NMOSD and EO-NMOSD (p = 0.029, p = 0.049, and p = 0.032, respectively). CONCLUSIONS Patients with VLO-NMOSD tend to develop severe myelitis with long cord lesions but not optic neuritis.

Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid β (Aβ) in walls of leptomeningeal vessels and cortical capillaries in the brain. The loss of integrity of these vessels caused by cerebrovascular Aβ deposits results in fragile vessels and lobar intracerebral hemorrhages. CAA also manifests with progressive cognitive impairment or transient focal neurological symptoms. Although development of therapeutics for CAA is urgently needed, the pathogenesis of CAA remains to be fully elucidated. In this review, we summarize the epidemiology, pathology, clinical and radiological features, and perspectives for future research directions in CAA therapeutics. Recent advances in mass spectrometric methodology combined with vascular isolation techniques have aided understanding of the cerebrovascular proteome. In this paper, we describe several potential key CAA-associated molecules that have been identified by proteomic analyses (apolipoprotein E, clusterin, SRPX1 (sushi repeat-containing protein X-linked 1), TIMP3 (tissue inhibitor of metalloproteinases 3), and HTRA1 (HtrA serine peptidase 1)), and their pivotal roles in Aβ cytotoxicity, Aβ fibril formation, and vessel wall remodeling. Understanding the interactions between cerebrovascular Aβ deposits and molecules that accumulate with Aβ may lead to discovery of effective CAA therapeutics and to the identification of biomarkers for early diagnosis.

A 64-year-old Japanese man with recurrent cerebral ischemic events and cognitive impairment was suspected of having cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) because of a family history and brain magnetic resonance imaging findings of cerebral white matter hyperintensities. The cysteine-sparing variation p.Val237Met was identified in NOTCH3. An intensive skin biopsy showed negative results (no granular osmiophilic material or positive NOTCH3 immunostaining), suggesting that the patient's definite diagnosis and pathogenicity of p.Val237Met were uncertain. We additionally reviewed previous reports of two Japanese families with p.Val237Met.