Publications by authors named "Yukio Ando"

459 Publications

Preceding direct oral anticoagulant administration reduces the severity of stroke in patients with atrial fibrillation - K-PLUS registry.

J Clin Neurosci 2021 Jul 6;89:106-112. Epub 2021 May 6.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Amyloidosis, Nagasaki International University, Sasebo, Japan. Electronic address:

Background: Stroke severity can be mitigated by preceding anticoagulant administration in acute ischemic stroke patients with atrial fibrillation (AF). We investigated if such mitigative effects are different between warfarin and direct oral anticoagulants (DOACs).

Material And Methods: We collected data from a regional multicenter stroke registry. Ischemic stroke or transient ischemic attack patients with AF were included. Background characteristics, National Institutes of Health Stroke Scale (NIHSS) score on admission, lesion characteristics, and in-hospital death were analyzed according to preceding antithrombotic agents at onset.

Results: A total of 2173 patients had AF; 628 were prescribed warfarin, 272 DOACs, 429 antiplatelets alone, and 844 no antithrombotics. The NIHSS score on admission was lowest in the DOACs group compared to the other groups. In neuroimaging analysis, small ischemic lesions were observed more frequently in the DOACs group, while large ischemic lesions were less frequent in this group. When the no antithrombotics group was used as a reference, the adjusted odds ratio for moderate to severe stroke was 0.56 (95% confidence interval, 0.40-0.78) in the DOACs group, while it was 0.98 (0.77-1.24) in the warfarin group and 0.94 (0.72-1.22) in the antiplatelets group. In-hospital mortality was lowest in the DOACs group compared to the other groups.

Conclusion: Preceding DOAC administration might mitigate the severity of stroke in AF patients more strongly than other antithrombotics, possibly leading to a better outcome in patients with stroke.
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http://dx.doi.org/10.1016/j.jocn.2021.04.027DOI Listing
July 2021

Age-related amyloidosis outside the brain: A state-of-the-art review.

Ageing Res Rev 2021 Jun 8;70:101388. Epub 2021 Jun 8.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address:

Inside and outside the brain, accumulation of amyloid fibrils plays key roles in the pathogenesis of fatal age-related diseases such as Alzheimer's and Parkinson's diseases and wild-type transthyretin amyloidosis. Although the incidence of all amyloidoses increases with age, for some types of amyloidosis aging is known as the main direct risk factor, and these types are typically diseases of elderly people. More than 10 different precursor proteins are known to cause age-associated amyloidosis; these proteins include amyloid β protein, α-synuclein, transthyretin, islet amyloid polypeptide, atrial natriuretic factor, and the newly discovered epidermal growth factor-containing fibulin-like extracellular matrix protein 1. Except for intracerebral amyloidoses, most age-related amyloidoses have been little studied. Indeed, in view of the increasing life expectancy in our societies, understanding how aging is involved in the process of amyloid fibril accumulation and the effects of amyloid deposits on the aging body is extremely important. In this review, we summarize current knowledge about the nature of amyloid precursor proteins, the prevalence, clinical manifestations, and pathogenesis of amyloidosis, and recent advances in our understanding of age-related amyloidoses outside the brain.
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http://dx.doi.org/10.1016/j.arr.2021.101388DOI Listing
June 2021

Characteristics of Patients with Late- vs. Early-Onset Val30Met Transthyretin Amyloidosis from the Transthyretin Amyloidosis Outcomes Survey (THAOS).

Neurol Ther 2021 May 22. Epub 2021 May 22.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Introduction: Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is a clinically heterogeneous disease caused by mutations in the transthyretin (TTR) gene. The most common mutation, Val30Met, can manifest as an early- or late-onset disease.

Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease and asymptomatic patients with TTR mutations. This is a descriptive analysis of symptomatic patients with ATTRv Val30Met amyloidosis with late- (age at least 50 years) vs. early-onset (age less than 50 years) disease in THAOS (data cutoff August 1, 2019).

Results: Of 1389 patients with ATTRv Val30Met amyloidosis, 491 (35.3%) had late-onset disease. Compared with early-onset, patients with late-onset were more likely to be male (66.2% vs. 53.6%) and have a longer mean (standard deviation [SD]) time from onset to diagnosis (3.8 [3.4] vs. 2.7 [4.1] years). Late-onset disease was associated with more severe neurological impairment at enrollment (median [10th, 90th percentile] derived Neuropathy Impairment Score in the Lower Limbs, 25.0 [4.0, 69.3] vs. 8.0 [0, 54.8]; Neurologic Composite Score, 42.0 [2.0, 155.0] vs. 21.0 [0, 102.0]). Cardiac findings were more prominent in late-onset disease. An overall interpretation of electrocardiogram as abnormal was reported in 72.1% of late-onset patients (vs. 44.3% early-onset). A left-ventricular septal thickness of at least 12 mm was reported in 69.7% of late-onset patients (vs. 14.6% early-onset). All differences were statistically significant (p < 0.001).

Conclusion: In THAOS, late-onset ATTRv Val30Met amyloidosis is common, presenting with more severe neurologic and cardiac findings at enrollment. Heterogeneity of disease may make it more difficult to diagnose. Increased recognition of late-onset ATTRv Val30Met amyloidosis could lead to more timely diagnosis and improve patient outcomes.

Trial Registration: ClinicalTrials.gov NCT00628745.
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http://dx.doi.org/10.1007/s40120-021-00258-zDOI Listing
May 2021

Anti-NXP2 antibody-positive dermatomyositis with aortic thrombus in normal aortic wall.

Rheumatology (Oxford) 2021 05;60(5):e159-e161

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto.

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http://dx.doi.org/10.1093/rheumatology/keaa713DOI Listing
May 2021

Very late onset neuromyelitis optica spectrum disorders.

Eur J Neurol 2021 May 7. Epub 2021 May 7.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

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.
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http://dx.doi.org/10.1111/ene.14901DOI Listing
May 2021

Current Management and Therapeutic Strategies for Cerebral Amyloid Angiopathy.

Int J Mol Sci 2021 Apr 8;22(8). Epub 2021 Apr 8.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

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.
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http://dx.doi.org/10.3390/ijms22083869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068954PMC
April 2021

Evaluation of the antiproliferative effects of the HASPIN inhibitor CHR-6494 in breast cancer cell lines.

PLoS One 2021 14;16(4):e0249912. Epub 2021 Apr 14.

Faculty of Pharmaceutical Sciences, Nagasaki International University, Sasebo, Nagasaki, Japan.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249912PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046223PMC
April 2021

Feasibility of assessing progression of transthyretin amyloid polyneuropathy using nerve conduction studies: Findings from the Transthyretin Amyloidosis Outcomes Survey (THAOS).

J Peripher Nerv Syst 2021 Jun 7;26(2):160-166. Epub 2021 May 7.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.

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. Patients with ATTRv in THAOS with recorded nerve conduction values were included (data cut-off: January 6, 2020); changes in nerve amplitude and velocity over time were assessed. 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. 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.
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http://dx.doi.org/10.1111/jns.12444DOI Listing
June 2021

Carpal tunnel syndrome as an early red-flag sign of ATTRwt amyloidosis.

J Nucl Cardiol 2021 Apr 6. Epub 2021 Apr 6.

Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.

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http://dx.doi.org/10.1007/s12350-021-02584-zDOI Listing
April 2021

Temporal Change in Longitudinal Strain After Domino Liver Transplantation With Liver Grafts Explanted From Patients With Hereditary Amyloidogenic Transthyretin Amyloidosis.

Circ Rep 2020 Nov 10;2(12):730-738. Epub 2020 Nov 10.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University Kumamoto Japan.

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. 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<0.05 for all) increases in the post- vs. pre-DLT period in basal longitudinal strain (LS; -13.4±2.3 vs. -19.3±4.4), relative apical LS index (=apical LS/[basal LS+mid LS]; 0.75±0.20 vs. 0.58±0.08), and LV ejection fraction/global LS (3.91±0.58 vs. 3.06±0.44). Age at the time of DLT was significantly higher in the group with impaired (>-14%) than preserved basal LS (57.2±3.5 vs. 39.6±16.0 years; P<0.05). When control subjects (n=14) were added to the enrolled DLT recipients, multivariable logistic regression analysis revealed that a history of DLT was significantly associated with impaired basal LS (>-14%; odds ratio 28.39, 95% confidence interval 1.89-427.45, P<0.05). LV systolic and diastolic function was preserved in the long term after DLT. However, 2D STI revealed subtle cardiac dysfunction in DLT recipients, which may be an early manifestation of cardiac amyloidosis.
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http://dx.doi.org/10.1253/circrep.CR-20-0106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937528PMC
November 2020

Heterozygous Cysteine-sparing NOTCH3 Variant p.Val237Met in a Japanese Patient with Suspected Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: A Case Report.

Intern Med 2021 Mar 8. Epub 2021 Mar 8.

Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan.

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.
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http://dx.doi.org/10.2169/internalmedicine.6096-20DOI Listing
March 2021

Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-L (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy.

Neurol Ther 2021 Jun 26;10(1):375-389. Epub 2021 Feb 26.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Introduction: AKCEA-TTR-L 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-L shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-L 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-L 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-L 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-L 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-L through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-L 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-L 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).
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http://dx.doi.org/10.1007/s40120-021-00235-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140170PMC
June 2021

Efficacy of salbutamol monotherapy in slow-channel congenital myasthenic syndrome caused by a novel mutation in CHRND.

Muscle Nerve 2021 04 26;63(4):E30-E32. Epub 2021 Jan 26.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

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http://dx.doi.org/10.1002/mus.27166DOI Listing
April 2021

Effect of phosphatidic acid on antiganglioside antibody reactivity in the isolated facial diplegia variant of Guillain-Barré syndrome: a case report.

Acta Neurol Belg 2021 Jan 8. Epub 2021 Jan 8.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.

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http://dx.doi.org/10.1007/s13760-020-01592-zDOI Listing
January 2021

Clarification on the definition of complete haematologic response in light-chain (AL) amyloidosis.

Amyloid 2021 Mar 7;28(1):1-2. Epub 2021 Jan 7.

Amyloidosis Research and Treatment Center, Foundation "Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo", Department of Molecular Medicine, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1080/13506129.2020.1868810DOI Listing
March 2021

Plasma growth differentiation factor 15: a novel tool to detect early changes of hereditary transthyretin amyloidosis.

ESC Heart Fail 2021 Apr 30;8(2):1178-1185. Epub 2020 Dec 30.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-0811, Japan.

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, Tc-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 < 0.01). Plasma GDF-15 levels were significantly correlated with plasma brain natriuretic peptide values (P < 0.01), serum high-sensitivity troponin T values (P < 0.05), and interventricular septal thickness at end-diastole (P < 0.01) in patients with ATTRv amyloidosis. Plasma GDF-15 levels in patients with PYP-positive ATTRv amyloidosis were significantly higher than those in patients with PYP-negative ATTRv amyloidosis (P < 0.01). Plasma GDF-15 levels in patients with late gadolinium enhancement-positive ATTRv amyloidosis were significantly higher than those in patients with late gadolinium enhancement-negative ATTRv amyloidosis (P < 0.01). Groups of patients with different TTR genotypes manifested different plasma GDF-15 levels.

Conclusions: Growth differentiation factor 15 may reflect early pathological changes of ATTRv amyloidosis.
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http://dx.doi.org/10.1002/ehf2.13176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006664PMC
April 2021

Amyloid fibril formation is suppressed in microgravity.

Biochem Biophys Rep 2021 Mar 17;25:100875. Epub 2020 Dec 17.

Department of Amyloidosis Research, Faculty of Pharmaceutical Sciences, Nagasaki International University, 2825-7 Huis Ten Bosch Sasebo, Nagasaki, 859-3298, Japan.

In the future, humans may live in space because of global pollution and weather fluctuations. In microgravity, convection does not occur, which may change the amyloidogenicity of proteins. However, the effect of gravity on amyloid fibril formation is unclear and remains to be elucidated. Here, we analyzed the effect of microgravity on amyloid fibril formation of amyloidogenic proteins including insulin, amyloid β (Aβ), and transthyretin (TTR). We produced microgravity (10 ) by using the gravity controller Gravite. Human insulin, Aβ, and human wild-type TTR (TTRwt) were incubated at pH 3.0, 7.0, and 3.5 at 37 °C, respectively, in 1  on the ground or in microgravity. We measured amyloidogenicity via the thioflavin T (ThT) method and cell-based 1-fluoro-2,5-bis[()-3-carboxy-4-hydroxystyryl]benzene (FSB) assay. ThT fluorescence intensity and cell-based FSB assay results for human insulin samples were decreased in microgravity compared with results in 1 . Aβ samples did not differ in ThT fluorescence intensity in microgravity and in 1  on the ground. However, in the cell-based FSB assay, the staining intensity was reduced in microgravity compared with that on 1 . Human TTRwt tended to form fewer amyloid fibrils in ThT fluorescence intensity and cell-based FSB assays in microgravity than in 1 . Human insulin and Aβ showed decreased amyloid fibril formation in microgravity compared with that in 1 . Human TTRwt tended to form fewer amyloid fibrils in microgravity. Our experiments suggest that the earth's gravity may be an accelerating factor for amyloid fibril formation.
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http://dx.doi.org/10.1016/j.bbrep.2020.100875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750487PMC
March 2021

Apolipoprotein AI amyloid deposits in the ligamentum flavum in patients with lumbar spinal canal stenosis.

Amyloid 2021 Jun 11;28(2):107-112. Epub 2020 Dec 11.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Amyloidosis is a protein-misfolding disease characterised by insoluble amyloid deposits in the extracellular space of various organs and tissues, such as the brain, heart, kidneys, and ligaments. We previously reported the frequent occurrence of amyloid deposits in the ligament flavum in the presence of lumbar spinal canal stenosis (LSCS), which is a common spinal disorder in older individuals. Our earlier clinicopathological studies revealed that amyloid deposits derived from transthyretin (TTR) were involved in the pathogenesis of LSCS. ATTR amyloid was the most common form in the ligamentum flavum, but amyloid deposits that were not identified still existed in more than 50% of patients with LSCS. In this study, we found apolipoprotein AI (AApoAI) amyloid deposits in the ligamentum flavum of patients with LSCS. The deposits occurred in 12% of patients with LSCS. Biochemical studies revealed that the amyloid deposits consisted mainly of full-length ApoAI. As a notable finding, the lumbar ligamentum flavum of patients who had LSCS with double-positive amyloid deposits-positive for both ATTR and AApoAI-was significantly thicker than that of patients who had LSCS with single-positive-that is, positive for either ATTR or AApoAI-amyloid deposits. We thus suggest that lumbar AApoAI amyloid formation may enhance the pathological changes of lumbar ATTR amyloidosis in patients with LSCS.
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http://dx.doi.org/10.1080/13506129.2020.1858404DOI Listing
June 2021

Usefulness of relative apical longitudinal strain index to predict positive Tc-labeled pyrophosphate scintigraphy findings in advanced-age patients with suspected transthyretin amyloid cardiomyopathy.

Echocardiography 2020 11 4;37(11):1774-1783. Epub 2020 Nov 4.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

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 Tc-labeled pyrophosphate ( 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 Tc-PYP scintigraphy. Therefore, we evaluated the usefulness of additional examinations, including echocardiographic assessment of myocardial strain, to raise the pretest probability of 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 Tc-PYP scintigraphy. Nineteen patients (17%) had positive 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 Tc-PYP scintigraphy findings (1.04 ± 0.37 vs 0.70 ± 0.28, P < .01). Multivariable logistic regression analysis revealed that a high RapLSI (≥1.04) was significantly associated with Tc-PYP positivity (odds ratio, 14.14; 95% confidence interval, 3.36-59.47; P < .01). The sensitivity, specificity, and accuracy of the diagnostic model using the RapLSI for identification of Tc-PYP positivity were 53%, 94%, and 87%, respectively.

Conclusions: A high RapLSI can raise the pretest probability of Tc-PYP scintigraphy in patients with a low score according to the Kumamoto criteria. The RapLSI can assist clinicians in determining strategies for these patients.
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http://dx.doi.org/10.1111/echo.14892DOI Listing
November 2020

Pre-Hospital Delay in Patients with Acute Ischemic Stroke in a Multicenter Stroke Registry: K-PLUS.

J Stroke Cerebrovasc Dis 2020 Nov 7;29(11):105284. Epub 2020 Sep 7.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto 860-8556, Japan; Department of Amyloidosis Research, Nagasaki International University, Sasebo, Japan.

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.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105284DOI Listing
November 2020

Antibodies to the α3 subunit of the ganglionic-type nicotinic acetylcholine receptors in patients with autoimmune encephalitis.

J Neuroimmunol 2020 12 21;349:577399. Epub 2020 Sep 21.

Department of Molecular Neurology and Therapeutics, Kumamoto University Hospital, Kumamoto, Japan. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577399DOI Listing
December 2020

Avoiding misdiagnosis: expert consensus recommendations for the suspicion and diagnosis of transthyretin amyloidosis for the general practitioner.

BMC Fam Pract 2020 09 23;21(1):198. Epub 2020 Sep 23.

Amyloidosis Research and Treatment Center Foundation, IRCCS Policlinico San Matteo, San Matteo, Italy.

Background: Transthyretin amyloidosis (also known as ATTR amyloidosis) is a systemic, life-threatening disease characterized by transthyretin (TTR) fibril deposition in organs and tissue. A definitive diagnosis of ATTR amyloidosis is often a challenge, in large part because of its heterogeneous presentation. Although ATTR amyloidosis was previously considered untreatable, disease-modifying therapies for the treatment of this disease have recently become available. This article aims to raise awareness of the initial symptoms of ATTR amyloidosis among general practitioners to facilitate identification of a patient with suspicious signs and symptoms.

Methods: These consensus recommendations for the suspicion and diagnosis of ATTR amyloidosis were developed through a series of development and review cycles by an international working group comprising key amyloidosis specialists. This working group met to discuss the barriers to early and accurate diagnosis of ATTR amyloidosis and develop a consensus recommendation through a thorough search of the literature performed using PubMed Central.

Results: The cardiac and peripheral nervous systems are most frequently involved in ATTR amyloidosis; however, many patients often also experience gastrointestinal and other systemic manifestations. Given the multisystemic nature of symptoms, ATTR amyloidosis is often misdiagnosed as a more common disorder, leading to significant delays in the initiation of treatment. Although histologic evaluation has been the gold standard to confirm ATTR amyloidosis, a range of tools are available that can facilitate early and accurate diagnosis. Of importance, genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy.

Conclusions: A diagnostic algorithm based on initial red flag symptoms and manifestations of cardiac or neurologic involvement will facilitate identification by the general practitioner of a patient with clinically suspicious symptoms, enabling subsequent referral of the patient to a multidisciplinary specialized medical center.
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http://dx.doi.org/10.1186/s12875-020-01252-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513485PMC
September 2020

Characteristics of Patients with Hereditary Transthyretin Amyloidosis and an Evaluation of the Safety of Tafamidis Meglumine in Japan: An Interim Analysis of an All-case Postmarketing Surveillance.

Clin Ther 2020 09 12;42(9):1728-1737.e6. Epub 2020 Aug 12.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Pharmacy, Nagasaki International University, Nagasaki, Japan.

Purpose: An all-case, single-arm, observational, postmarketing surveillance is underway to assess the safety of tafamidis in patients with hereditary transthyretin (ATTRv) amyloidosis with peripheral polyneuropathy, also called transthyretin-type familial amyloid polyneuropathy, in Japan. Results from an interim analysis (data cutoff date, May 15, 2018) are presented in this preliminary report.

Methods: Patients were registered and treated with tafamidis meglumine 20 mg/d in routine clinical practice (observation period, 156 weeks). Data on patient demographic and clinical characteristics and adverse drug reactions (ADRs) were captured using case-report forms.

Findings: Of 219 patients included (mean age, 59.7 years; patients with age at disease onset ≥50 years, 61.2%; mean treatment duration, 95.5 weeks), 143 (65.3%) were male, 126 (57.5%) had a family history of ATTRv amyloidosis, and 149 (68.0%) originated from nonendemic areas. The most common ADRs were diarrhea (1.4%) and hematuria (0.9%). Six serious ADRs (pneumonia, bacteremia, malignant melanoma, pancreatic carcinoma, hematuria, and hereditary neuropathic amyloidosis [primary disease exacerbation]) were reported; no ADRs leading to death were recorded.

Implications: This interim analysis successfully provided comprehensive, nationwide epidemiologic data from 219 Japanese patients with ATTRv amyloidosis. The safety profile of tafamidis was largely consistent with that obtained from previous research. No new safety concerns were identified to date. Data presented in this interim analysis are subject to change following completion of the study, and we will continue to assess the safety and effectiveness of tafamidis throughout the study. ClinicalTrials.gov identifier: NCT02146378.
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http://dx.doi.org/10.1016/j.clinthera.2020.07.001DOI Listing
September 2020

A Nationwide Survey and Multicenter Registry-Based Database of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Japan.

Front Aging Neurosci 2020 14;12:216. Epub 2020 Jul 14.

Department of Neurology, Mie University Graduate School of Medicine, Tsu, Japan.

Objectives: Clinical characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) include migraine, recurrent stroke, white matter lesions, and vascular dementia. CADASIL is one of the most common hereditary cerebral small vessel diseases. Clinical presentation of CADASIL varies and a racial gap may exist between the Asian and Caucasian populations. This is the first nationwide epidemiological survey which aimed to elucidate the clinical features of CADASIL in Japan. Moreover, the registration database of CADASIL was constructed.

Methods: Subjects included CADASIL patients who visited the hospitals (totally 1,448 hospitals) certified by the Japanese Society of Neurology and/or Japan Stroke Society in 2016. This study consisted of a two-step survey; 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 all CADASIL patients using a Research Electronic Data Capture (REDCap) system for the second questionnaire.

Results: Based on the criteria, 88 patients (50 male and 38 female) with CADASIL were enrolled. The mean age of symptom onset was 49.5 years. Sixteen (18.2%) patients had an elderly onset (>60 years). Thirteen patients (13.6%) had history of migraine with aura and 33 patients (37.5%) had vascular risk factor(s). From among the 86 patients who were examined using magnetic resonance imaging, abnormal deep white matter lesions were detected in 85 patients (98.8%), WMLs extending to anterior temporal pole in 73 patients (84.9%), and cerebral microbleeds in 41 patients (47.7%). Anti-platelet therapy was received by 65 patients (73.9%). Thirty-eight patients (43.2%) underwent treatment with lomerizine hydrochloride. Thirty-four different mutations of were found in exons 2, 3, 4, 5, 6, 8, 11, 14, and 19. Most of the mutations existed in exon 4 ( = 44, 60.3%). The prevalence rate of CADASIL was 1.20 to 3.58 per 100,000 adults in Japan.

Conclusion: This questionnaire-based study revealed clinical features and treatment status in Japanese CADASIL patient, although it may not be an exhaustive search. We have constructed the REDCap database for these CADASIL patients.
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http://dx.doi.org/10.3389/fnagi.2020.00216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381163PMC
July 2020

Novel dot-blot assay for detection of vascular Notch3 aggregates in patients with CADASIL.

J Neurol Sci 2020 08 21;415:116931. Epub 2020 May 21.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; Department of Amyloidosis Research, Nagasaki International University, Sasebo 859-3298, Japan.

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.
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http://dx.doi.org/10.1016/j.jns.2020.116931DOI Listing
August 2020

Trends in Diagnostic Imaging of Cardiac Amyloidosis: Emerging Knowledge and Concepts.

Radiographics 2020 Jul-Aug;40(4):961-981. Epub 2020 May 22.

From the Departments of Diagnostic Radiology (S.O., M.K., Y.N., Y.Y.), Cardiovascular Medicine (S.T., H.U., K.T.), Molecular Laboratory Medicine (H.U.), and Neurology (M.U., T.Y., Y.A.), Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjyo, Chuo-ku, Kumamoto 860-8556, Japan.

Cardiac amyloidosis (CA) has long been recognized as a rare disease. However, recent advances in cardiac imaging have led to increased identification of hidden CA in patients diagnosed with heart failure. This shift suggests that the actual incidence of CA is underestimated. The prognosis of CA is generally poor, especially in patients with advanced heart failure. However, recent developments in therapeutic interventions have improved the survival of patients with CA. An early diagnosis and interventions involving effective therapies are essential contributors to improved prognoses. Recent noninvasive diagnostic imaging modalities such as echocardiography, cardiac MRI, and nuclear imaging have facilitated the precise and early diagnosis of CA and enabled the initiation of appropriate management. The authors present an updated review of the clinical features of CA, including a discussion of current trends in noninvasive diagnostic imaging. RSNA, 2020.
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http://dx.doi.org/10.1148/rg.2020190069DOI Listing
May 2020

Monitoring of asymptomatic family members at risk of hereditary transthyretin amyloidosis for early intervention with disease-modifying therapies.

J Neurol Sci 2020 Jul 2;414:116813. Epub 2020 Apr 2.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto-shi, Kumamoto 860-8556, Japan; Department of Amyloidosis Research, Nagasaki International University, Japan. Electronic address:

Background: Hereditary transthyretin (ATTRv) amyloidosis is an adult-onset, systemic disorder caused by mutations in the transthyretin (TTR) gene. As ATTRv amyloidosis is inherited in an autosomal dominant manner, family members of the patients are at risk of developing the disease.

Methods: With an objective of discussing recommendations on monitoring of family members for early diagnosis of ATTRv amyloidosis, we held a medical advisory board meeting in Tokyo, Japan, in October 2017.

Results: Our recommendations are summarized as follows: periodic follow-up genetic counseling should be offered to asymptomatic gene mutation carriers; follow-up assessments should be started when the carriers are still asymptomatic to test for amyloidosis onset, irrespective of TTR genotype and age at onset in the particular family. We suggest annual routine assessments and in-depth assessments every 3-5 years, with the frequency of these increased as required. Periodical monitoring of asymptomatic gene mutation carriers is crucial for attending physicians to detect early signs or symptoms of the disease and start disease-modifying therapy (DMT).

Conclusions: The monitoring strategy for asymptomatic TTR gene mutation carriers should progress toward rapid diagnosis and early intervention with DMT. This approach may be more appropriate for countries with more resources.
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http://dx.doi.org/10.1016/j.jns.2020.116813DOI Listing
July 2020

Ganglionic Acetylcholine Receptor Antibodies and Autonomic Dysfunction in Autoimmune Rheumatic Diseases.

Int J Mol Sci 2020 Feb 16;21(4). Epub 2020 Feb 16.

Department of Molecular Neurology and Therapeutics, Kumamoto University Hospital, Kumamoto 860-8556, Japan.

Autonomic neuropathy has been reported in autoimmune rheumatic diseases (ARD) including Sjögren's syndrome, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. However, the pathophysiological mechanism underlying autonomic dysfunction remains unknown to researchers. On the other hand, autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder, which causes dysautonomia that is mediated by autoantibodies against ganglionic acetylcholine receptors (gAChRs). The purpose of this review was to describe the characteristics of autonomic disturbance through previous case reports and the functional tests used in these studies and address the importance of anti-gAChR antibodies. We have established luciferase immunoprecipitation systems to detect antibodies against gAChR in the past and determined the prevalence of gAChR antibodies in various autoimmune diseases including AAG and rheumatic diseases. Autonomic dysfunction, which affects lower parasympathetic and higher sympathetic activity, is usually observed in ARD. The anti-gAChR antibodies may play a crucial role in autonomic dysfunction observed in ARD. Further studies are necessary to determine whether anti-gAChR antibody levels are correlated with the severity of autonomic dysfunction in ARD.
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http://dx.doi.org/10.3390/ijms21041332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073227PMC
February 2020