Disease-Modifying Drugs Extend Survival in Hereditary Transthyretin Amyloid Polyneuropathy.

Hereditary transthyretin (ATTRv) amyloidosis is a rare, fatal systemic disease, associated with polyneuropathy and cardiomyopathy, that is caused by mutant transthyretin (TTR). In addition to liver transplantation, several groundbreaking disease-modifying drugs (DMDs) such as tetrameric TTR stabilizers and TTR gene-silencing therapies have been developed for ATTRv amyloid polyneuropathy. They were based on a working hypothesis of the mechanisms of ATTRv amyloid formation. In this retrospective cohort study, we investigated survival of all 201 consecutive patients with ATTRv amyloidosis in our center. The effects of DMDs on survival improvements were significant not only in early-onset patients but also in late-onset patients. ANN NEUROL 2024;95:230-236.

Silencing of ocular transthyretin, a gene responsible for hereditary transthyretin amyloidosis, by intravitreal injection of an siRNA conjugate into rabbit eyes.

The first small interfering RNA (siRNA) therapeutic received approval for hereditary transthyretin (ATTRv) amyloidosis, and the patients' lifespan extension by specific inhibition of hepatic synthesis of transthyretin (TTR) is expected. However, ocular amyloidosis in these patients has been a crucial issue. This study aims to evaluate the efficacy and safety of intravitreal TTR siRNA conjugate injection into rabbit eyes. Rabbit (r) TTR siRNA is a screened TTR siRNA conjugate from 53 candidates. The intraocular pressure (IOP) immediately after injection was high despite the 65.9 % decrease of aqueous humor TTR protein levels in the rTTR siRNA group compared with those in the Control siRNA group 2 weeks after the 50 µL siRNA injection. The IOP spike was milder after the 30 µL siRNA injection, and aqueous humor TTR levels decreased by ∼50 % in the rTTR siRNA group, which is consistent with the mRNA levels in the retina. The parameters of dark-adapted, light-adapted, and light-adapted 30 Hz electroretinogram and the thickness of each retinal layer in histological analysis demonstrated no significant differences between the groups. In conclusion, we developed TTR siRNA conjugates for rabbit eyes, and the results indicate that intravitreal TTR siRNA conjugate injection could be a therapeutic option for ocular amyloidosis caused by ATTRv amyloidosis.

Long-term course of a case with a novel homozygous kyphoscoliosis peptidase variant.

We herein report a case with a novel homozygous variant in the kyphoscoliosis peptidase (KY) gene. A 58-year-old Japanese female was referred to our hospital with a gait disturbance that gradually worsened after the age of 50. She had bilateral equinus foot deformity since early childhood. Neurological examination revealed moderate weakness of the neck, trunk, femoral, and brachial muscles, mild respiratory failure, and areflexia. Whole-exome sequencing revealed a novel homozygous frameshift variant of the KY gene, NM_178554.6:c.824del p.(Glu275Glyfs*53). Our case demonstrated that KY-associated neuromuscular disease can present with extremely slow progressive muscle weakness and respiratory failure over a long natural course.

Correlation between a commercial electrophysiological test of sudomotor function and intraepidermal nerve fiber density in hereditary transthyretin amyloidosis.

INTRODUCTION/AIMS: In the early stage, hereditary transthyretin (ATTRv) amyloidosis predominantly affects small nerve fibers, resulting in autonomic dysfunction and impaired sensation of pain and temperature. Evaluation of small fiber neuropathy (SFN) is therefore important for early diagnosis and treatment of ATTRv amyloidosis. Herein, we aimed to investigate the accuracy of a quick and non-invasive commercial sudomotor function test (SFT) for the assessment of SFN in ATTRv amyloidosis. METHODS: We performed the SFT in 39 Japanese adults with ATTRv amyloidosis, and we analyzed the correlations between electrochemical skin conductance (ESC) values obtained via the SFT and the parameters of other neuropathy assessment methods. RESULTS: ESC in the feet demonstrated significant, moderate correlations with intraepidermal nerve fiber density (IENFD) results (Spearman's rank correlation coefficient [rs ], 0.58; p < .002) and other neuropathy assessment methods including the sensory nerve action potential amplitude in the nerve conduction studies (rs , 0.52; p < .001), the Neuropathy Impairment Score (rs , -0.45; p < .01), the heat-pain detection threshold (rs , -0.62; p < .0001), and the autonomic section of the Kumamoto ATTRv clinical score (rs , -0.53; p < .0001). DISCUSSION: In this study, we found that ESC values in the feet via the SFT demonstrated significant, moderate correlations with IENFD and other SFN assessment methods in patients with ATTRv amyloidosis, suggesting that the SFT appears to be an appropriate method for assessment of SFN in this disease.

Myocardial extracellular volume quantification in cardiac amyloidosis: a comparative study between cardiac computed tomography and magnetic resonance imaging.

OBJECTIVES: Myocardial extracellular volume (ECV) on computed tomography (CT), an alternative to cardiac magnetic resonance (CMR), has significant practical clinical advantages. However, the consistency between ECVs quantified via CT and CMR in cardiac amyloidosis (CA) has not been investigated sufficiently. Therefore, the current study investigated the application of CT-ECV in CA with CMR-ECV as the reference standard. METHODS: We retrospectively evaluated 31 patients with CA who underwent cardiac CT and CMR. Pearson correlation analysis was performed to investigate correlations between CT-ECV and CMR-ECV at each segment. Further, correlations between ECV and clinical parameters were assessed. RESULTS: There were no significant differences in the mean global ECVs between CT scan and CMR (51.3% ± 10.2% vs 50.0% ± 10.5%). CT-ECV was correlated with CMR-ECV at the septal (r = 0.88), lateral (r = 0.80), inferior (r = 0.79), anterior (r = 0.77) segments, and global (r = 0.87). In both CT and CMR, the ECV had a weak to strong correlation with high-sensitivity cardiac troponin T level, a moderate correlation with global longitudinal strain, and an inverse correlation with left ventricular ejection fraction. Further, the septal ECV and global ECV had a slightly higher correlation with the clinical parameters. CONCLUSIONS: Cardiac CT can quantify myocardial ECV and yield results comparable to CMR in patients with CA. Moreover, a significant correlation between CT-ECV and clinical parameters was observed. Thus, CT-ECV can be an imaging biomarker and alternative to CMR-ECV. CLINICAL RELEVANCE STATEMENT: Cardiac CT can quantify myocardial ECV and yield results comparable to CMR in patients with CA, and CT-ECV can be used clinically as an imaging biomarker and alternative to CMR-ECV. KEY POINTS: • A significant correlation was found between CT myocardial extracellular volume and cardiac MR myocardial extracellular volume in patients with cardiac amyloidosis. • In CT and cardiac MR, the myocardial extracellular volume correlated well with high-sensitivity cardiac troponin T level, global longitudinal strain, and left ventricular ejection fraction. • CT myocardial extracellular volume can be an imaging biomarker and alternative to cardiac MR myocardial extracellular volume.

Efficacy of Computed Tomography-Based Evaluation of Myocardial Extracellular Volume Combined With Red Flags for Early Screening of Concealed Cardiac Amyloidosis in Patients With Atrial Fibrillation.

BACKGROUND: The prevalence of transthyretin amyloid cardiomyopathy (ATTR-CM) in atrial fibrillation (AF) patients remains unclear. We explored the efficacy of computed tomography-based myocardial extracellular volume (CT-ECV) combined with red flags for the early screening of concealed ATTR-CM in AF patients undergoing catheter ablation.Methods and Results: Patients referred for AF ablation at Oita University Hospital were prescreened using the red-flag signs defined by echocardiographic or electrocardiographic findings, medical history, symptoms, and blood biochemical findings. Myocardial CT-ECV was quantified in red flag-positive patients using routine pre-AF ablation planning cardiac CT with the addition of delayed-phase cardiac CT scans. Patients with high (>35%) ECV were evaluated using technetium pyrophosphate (99 mTc-PYP) scintigraphy. A cardiac biopsy was performed during the planned AF ablation procedure if 99 mTc-PYP scintigraphy was positive. Between June 2022 and June 2023, 342 patients were referred for AF ablation. Sixty-seven (19.6%) patients had at least one of the red-flag signs. Myocardial CT-ECV was evaluated in 57 patients because of contraindications to contrast media, revealing that 16 patients had high CT-ECV. Of these, 6 patients showed a positive 99 mTc-PYP study, and 6 patients were subsequently diagnosed with wild-type ATTR-CM via cardiac biopsy and genetic testing. CONCLUSIONS: CT-ECV combined with red flags could contribute to the systematic early screening of concealed ATTR-CM in AF patients undergoing catheter ablation.

Exploring the impact of super-resolution deep learning on MR angiography image quality.

PURPOSE: The aim of this study is to assess the effect of super-resolution deep learning-based reconstruction (SR-DLR), which uses k-space properties, on image quality of intracranial time-of-flight (TOF) magnetic resonance angiography (MRA) at 3 T. METHODS: This retrospective study involved 35 patients who underwent intracranial TOF-MRA using a 3-T MRI system with SR-DLR based on k-space properties in October and November 2022. We reconstructed MRA with SR-DLR (matrix = 1008 × 1008) and MRA without SR-DLR (matrix = 336 × 336). We measured the signal-to-noise ratio (SNR), contrast, and contrast-to-noise ratio (CNR) in the basilar artery (BA) and the anterior cerebral artery (ACA) and the sharpness of the posterior cerebral artery (PCA) using the slope of the signal intensity profile curve at the half-peak points. Two radiologists evaluated image noise, artifacts, contrast, sharpness, and overall image quality of the two image types using a 4-point scale. We compared quantitative and qualitative scores between images with and without SR-DLR using the Wilcoxon signed-rank test. RESULTS: The SNRs, contrasts, and CNRs were all significantly higher in images with SR-DLR than those without SR-DLR (p < 0.001). The slope was significantly greater in images with SR-DLR than those without SR-DLR (p < 0.001). The qualitative scores in MRAs with SR-DLR were all significantly higher than MRAs without SR-DLR (p < 0.001). CONCLUSION: SR-DLR with k-space properties can offer the benefits of increased spatial resolution without the associated drawbacks of longer scan times and reduced SNR and CNR in intracranial MRA.

Epidemiological study of the subtype frequency of systemic amyloidosis listed in the Annual of the Pathological Autopsy Cases in Japan.

Clinical presentation of systemic amyloidosis differs among subtypes, and accurate subtype classification is important for choosing the treatment. Amyloid transthyretin (ATTR) amyloidosis was the predominant among the recently consulted amyloidosis cases in Japan. To reveal the latest subtype frequency of systemic amyloidosis among autopsy cases in Japan. We analyzed systemic amyloidosis cases autopsied from January 2017 to December 2018, that were listed in the Annuals of the Pathological Autopsy Cases in Japan, Volumes 60 and 61. When the subtype was unclear, we performed a questionnaire survey, immunohistochemistry with in-house rabbit polyclonal anti-κ116 - 133 , anti-λ118 -134 , and anti-transthyretin115 -124 antibodies, and proteomic analysis. Out of 481 systemic amyloidosis cases listed in the Annuals, 411 cases were available for analysis (85.4%). We classified 399 of these systemic amyloidosis cases. ATTR was the most common subtype (44.4%, n = 177), followed by amyloid immunoglobulin light chain (AL) (38.8%, n = 155). Amyloid A and amyloid ß2 -microglobulin were 9.3% (n = 37) and 6.0% (n = 24), respectively. Double deposition of amyloid was identified in 1.6% (n = 6). In 168 cases (42.1%), systemic amyloidosis was the main cause of death. Of these cases, AL was the most common subtype (47.6%, n = 80), followed by ATTR (41.1%, n = 69). ATTR is the most predominant subtype among the current autopsy cases in Japan.

Optimizing High-Resolution MR Angiography: The Synergistic Effects of 3D Wheel Sampling and Deep Learning-Based Reconstruction.

OBJECTIVE: The aim of this study was to assess the utility of the combined use of 3D wheel sampling and deep learning-based reconstruction (DLR) for intracranial high-resolution (HR)-time-of-flight (TOF)-magnetic resonance angiography (MRA) at 3 T. METHODS: This prospective study enrolled 20 patients who underwent head MRI at 3 T, including TOF-MRA. We used 3D wheel sampling called "fast 3D" and DLR for HR-TOF-MRA (spatial resolution, 0.39 × 0.59 × 0.5 mm3) in addition to conventional MRA (spatial resolution, 0.39 × 0.89 × 1 mm3). We compared contrast and contrast-to-noise ratio between the blood vessels (basilar artery and anterior cerebral artery) and brain parenchyma, full width at half maximum in the P3 segment of the posterior cerebral artery among 3 protocols. Two board-certified radiologists evaluated noise, contrast, sharpness, artifact, and overall image quality of 3 protocols. RESULTS: The contrast and contrast-to-noise ratio of fast 3D-HR-MRA with DLR are comparable or higher than those of conventional MRA and fast 3D-HR-MRA without DLR. The full width at half maximum was significantly lower in fast 3D-MRA with and without DLR than in conventional MRA (P = 0.006, P < 0.001). In qualitative evaluation, fast 3D-MRA with DLR had significantly higher sharpness and overall image quality than conventional MRA and fast 3D-MRA without DLR (sharpness: P = 0.021, P = 0.001; overall image quality: P = 0.029, P < 0.001). CONCLUSIONS: The combination of 3D wheel sampling and DLR can improve visualization of arteries in intracranial TOF-MRA.

Number of Passes of Endovascular Therapy for Stroke With a Large Ischemic Core: Secondary Analysis of RESCUE-Japan LIMIT.

BACKGROUND: The increased risk of intracranial hemorrhage with multiple passes in endovascular therapy (EVT) for large vessel occlusion with a large ischemic core is a concern. We explored the effect of the number of EVT passes on patients in a randomized clinical trial. METHODS: This post hoc study was the secondary analysis of RESCUE-Japan LIMIT, which was a randomized clinical trial comparing EVT and medical treatment alone for large vessel occlusion with large ischemic core. We grouped patients according to the number of passes with successful reperfusion (modified Thrombolysis in Cerebral Infarction score, ≥2b) in 1, 2, and 3 to 7 passes and failed reperfusion (modified Thrombolysis in Cerebral Infarction score, 0-2a) after any pass in the EVT group, and these groups were compared with medical treatment group. The primary outcome was modified Rankin Scale score of 0 to 3 at 90 days. Secondary outcomes were improvement in National Institutes of Health Stroke Scale score of ≥8 at 48 hours, mortality at 90 days, symptomatic intracranial hemorrhage, and any intracranial hemorrhage within 48 hours. RESULTS: The number of patients who received EVT with successful reperfusion after 1, 2, and 3 to 7 passes and failed reperfusion were 44, 23, 19, and 14, respectively, and 102 received medical treatment alone. The adjusted odds ratios (95% CIs) for the primary outcome relative to medical treatment were 5.52 (2.23-14.28) after 1 pass, 6.45 (2.22-19.30) after 2 passes, 1.03 (0.15-4.48) after 3 to 7 passes, and 1.17 (0.16-5.37) if reperfusion failed. The adjusted odds ratios (95% CIs) for any intracranial hemorrhage within 48 hours relative to medical treatment were 1.88 (0.90-3.93) after 1 pass, 5.14 (1.97-14.72) after 2 passes, 3.00 (1.09-8.58) after 3 to 7 passes, and 6.16 (1.87-24.27) if reperfusion failed. CONCLUSIONS: The successful reperfusion within 2 passes was associated with better clinical outcomes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03702413.

CT Extracellular Volume Fraction versus Myocardium-to-Lumen Signal Ratio for Cardiac Amyloidosis.

Background Large studies on the diagnostic performance of CT-derived myocardial extracellular volume fraction (ECV) for detecting cardiac amyloidosis are lacking. A simple and practical index as a surrogate for CT ECV would be clinically useful. Purpose To compare the diagnostic performances between CT-derived myocardial ECV and myocardium-to-lumen signal ratio for the detection of cardiac amyloidosis in a large patient sample. Materials and Methods This retrospective study included patients who underwent CT ECV analysis because of suspected heart failure or cardiomyopathy between January 2018 and July 2021. CT ECV was quantified using routine pre-transcatheter aortic valve replacement planning cardiac CT, pre-atrial fibrillation ablation planning cardiac CT, or coronary CT angiography with the addition of unenhanced and delayed phase cardiac CT scans. The diagnostic performances of CT ECV and myocardium-to-lumen signal ratio in delayed phase cardiac CT (a simplified index not requiring unenhanced CT and hematocrit) for detecting cardiac amyloidosis were evaluated using the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Results Of 552 patients (mean age, 69 years ± 14 [SD]; 295 men), 41 had cardiac amyloidosis. The sensitivity of CT ECV for amyloidosis was 90% (37 of 41 patients [95% CI: 77, 97]), with a specificity of 92% (472 of 511 patients [95% CI: 90, 95]) and optimal ECV cutoff value of 37% (AUC, 0.97 [95% CI: 0.96, 0.99]). The sensitivity of myocardium-to-lumen signal ratio was 88% (36 of 41 patients [95% CI: 74, 96]), with a specificity of 92% (469 of 511 patients [95% CI: 89, 94]) and optimal myocardium-to-lumen signal ratio cutoff value of 0.87 (AUC, 0.96 [95% CI: 0.94, 0.97]; P = .27 for comparison with ECV). Conclusion CT-derived myocardial extracellular volume fraction and myocardium-to-lumen signal ratio showed comparable and excellent diagnostic performance in detecting cardiac amyloidosis in a large patient sample. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Williams in this issue.

Deep learning-based reconstruction can improve the image quality of low radiation dose head CT.

OBJECTIVES: To evaluate the image quality of deep learning-based reconstruction (DLR), model-based (MBIR), and hybrid iterative reconstruction (HIR) algorithms for lower-dose (LD) unenhanced head CT and compare it with those of standard-dose (STD) HIR images. METHODS: This retrospective study included 114 patients who underwent unenhanced head CT using the STD (n = 57) or LD (n = 57) protocol on a 320-row CT. STD images were reconstructed with HIR; LD images were reconstructed with HIR (LD-HIR), MBIR (LD-MBIR), and DLR (LD-DLR). The image noise, gray and white matter (GM-WM) contrast, and contrast-to-noise ratio (CNR) at the basal ganglia and posterior fossa levels were quantified. The noise magnitude, noise texture, GM-WM contrast, image sharpness, streak artifact, and subjective acceptability were independently scored by three radiologists (1 = worst, 5 = best). The lesion conspicuity of LD-HIR, LD-MBIR, and LD-DLR was ranked through side-by-side assessments (1 = worst, 3 = best). Reconstruction times of three algorithms were measured. RESULTS: The effective dose of LD was 25% lower than that of STD. Lower image noise, higher GM-WM contrast, and higher CNR were observed in LD-DLR and LD-MBIR than those in STD (all, p ≤ 0.035). Compared with STD, the noise texture, image sharpness, and subjective acceptability were inferior for LD-MBIR and superior for LD-DLR (all, p < 0.001). The lesion conspicuity of LD-DLR (2.9 ± 0.2) was higher than that of HIR (1.2 ± 0.3) and MBIR (1.8 ± 0.4) (all, p < 0.001). Reconstruction times of HIR, MBIR, and DLR were 11 ± 1, 319 ± 17, and 24 ± 1 s, respectively. CONCLUSION: DLR can enhance the image quality of head CT while preserving low radiation dose level and short reconstruction time. KEY POINTS: • For unenhanced head CT, DLR reduced the image noise and improved the GM-WM contrast and lesion delineation without sacrificing the natural noise texture and image sharpness relative to HIR. • The subjective and objective image quality of DLR was better than that of HIR even at 25% reduced dose without considerably increasing the image reconstruction times (24 s vs. 11 s). • Despite the strong noise reduction and improved GM-WM contrast performance, MBIR degraded the noise texture, sharpness, and subjective acceptance with prolonged reconstruction times relative to HIR, potentially hampering its feasibility.

Prevalence of Cardiac Amyloidosis in Patients Undergoing Carpal Tunnel Release With Amyloid Deposition.

BACKGROUND: Carpal tunnel syndrome (CTS) is considered an early sign of cardiac amyloidosis (CA) because amyloid deposition is often confirmed in the tenosynovium removed during carpal tunnel release (CTR); however, the prevalence of concomitant CA is unclear.Methods and Results: We prospectively examined 700 patients who underwent CTR and evaluated amyloid deposition after tenosynovium removal. Amyloid deposition was observed in 261 (37%) patients, who were significantly older and predominantly male (P<0.05). Of them, 120 agreed to cardiac screening. We performed 99 mTc-labeled pyrophosphate (99 mTc-PYP) scintigraphy in 12 patients who met either of the following criteria: (1) interventricular septal diameter (IVSd) ≥14 mm or (2) 12 mm ≤ IVSd < 14 mm with above-normal limits in high-sensitivity cardiac troponin T (hs-cTnT). Six patients (50%) had positive findings on 99 mTc-PYP scintigraphy and were diagnosed with wild-type transthyretin CA. Concomitant CA was observed in 6/120 (5%) CTR patients with amyloid deposition and 50% (6/12) in patients with left ventricular hypertrophy (≥12 mm) with increased hs-cTnT levels. CONCLUSIONS: Amyloid deposition was frequently observed in the removed tenosynovium of elderly men with CTS. Cardiac screening may be useful for early diagnosis of CA in patients undergoing CTR with amyloid deposition.

Feasibility study of super-resolution deep learning-based reconstruction using k-space data in brain diffusion-weighted images.

PURPOSE: The purpose of this study is to evaluate the influence of super-resolution deep learning-based reconstruction (SR-DLR), which utilizes k-space data, on the quality of images and the quantitation of the apparent diffusion coefficient (ADC) for diffusion-weighted images (DWI) in brain magnetic resonance imaging (MRI). METHODS: A retrospective analysis was performed on 34 patients who had undergone DWI using a 3 T MRI system with SR-DLR reconstruction based on k-space data in August 2022. DWI was reconstructed with SR-DLR (Matrix = 684 × 684) and without SR-DLR (Matrix = 228 × 228). Measurements were made of the signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) in white matter (WM) and grey matter (GM), and the full width at half maximum (FWHM) of the septum pellucidum. Two radiologists assessed image noise, contrast, artifacts, blur, and the overall quality of three image types using a four-point scale. Quantitative and qualitative scores between images with and without SR-DLR were compared using the Wilcoxon signed-rank test. RESULTS: Images with SR-DLR showed significantly higher SNRs and CNRs than those without SR-DLR (p < 0.001). No statistically significant variances were found in the apparent diffusion coefficients (ADCs) in WM and GM between images with and without SR-DLR (ADC in WM, p = 0.945; ADC in GM, p = 0.235). Moreover, the FWHM without SR-DLR was notably lower compared to that with SR-DLR (p < 0.001). CONCLUSION: SR-DLR has the potential to augment the quality of DWI in DL MRI scans without significantly impacting ADC quantitation.

α-Enolase reduces cerebrovascular Aß deposits by protecting Aß amyloid formation.

Cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid ß (Aß) deposits and causes dementia and cerebral hemorrhage. Although α-enolase (ENO1) was shown to possess multifunctional roles, its exact functions in CAA pathogenesis have not been determined. In this study, we focused on ENO1, a well-known glycolytic enzyme, which was previously identified via a proteomic approach as an upregulated protein in brain samples from patients with Alzheimer's disease (AD). We utilized the thioflavin T fluorescence assay and transmission electron microscopy to monitor the effects of ENO1 on amyloid formation by Aß peptides. We also cultured murine primary cerebrovascular smooth muscle cells to determine the effects of ENO1 on Aß cytotoxicity. To investigate the effects of ENO1 in vivo, we infused ENO1 or a vehicle control into the brains of APP23 mice, a transgenic model of AD/CAA, using a continuous infusion system, followed by a cognitive test and pathological and biochemical analyses. We found that novel functions of ENO1 included interacting with Aß and inhibiting its fibril formation, disrupting Aß fibrils, and weakening the cytotoxic effects of these fibrils via proteolytic degradation of Aß peptide. We also demonstrated that infusion of ENO1 into APP23 mouse brains reduced cerebrovascular Aß deposits and improved cognitive impairment. In addition, we found that enzymatically inactivated ENO1 failed to inhibit Aß fibril formation and fibril disruption. The proteolytic activity of ENO1 may thus underlie the enzyme's cytoprotective effect and clearance of Aß from the brain, and ENO1 may be a therapeutic target in CAA.

Myopathic changes caused by protein aggregates in adult-onset spinal muscular atrophy.

Spinal muscular atrophy (SMA), an autosomal-recessive lower motor neuron disease, causes progressive proximal muscle waste and weakness. It remains unclear whether myopathic changes are involved in pathogenesis. We encountered a patient with adult-onset SMA caused by a homozygous deletion in exon 7 of the survival motor neuron 1 (SMN1) gene who had had four copies of SMN2 exon 7. Muscle biopsy showed neurogenic features of groups of atrophic fibers, fiber-type grouping, and pyknotic nuclear clumps associated with fibers with rimmed vacuoles. Immunohistochemistry revealed sarcoplasmic aggregates of phosphorylated TDP-43 and p62 but not SMN. This study demonstrated myopathic changes with the accumulation of phosphorylated p62 and TDP-43 in the muscles of a patient with SMA, suggesting that abnormal protein aggregation may be involved in myopathic pathology.

Underdosed Direct Oral Anticoagulants in Atrial Fibrillation Patients Reduce Stroke Severity and Improve Outcome.

BACKGROUND AND PURPOSE: Anticoagulant drugs, including vitamin K antagonist (VKA) and direct oral anticoagulants (DOACs), can reduce stroke severity and are associated with good functional outcomes. Some patients are prescribed lower-than-recommended doses of DOACs; whether these have similar effects has not been clarified. METHODS: We retrospectively evaluated 1,139 consecutive ischemic stroke and transient ischemic attack patients with atrial fibrillation. Patients were divided into 5 groups according to their preceding anticoagulant drug therapies: no anticoagulant therapy (ACn), undercontrolling VKA doses (VKAuc), recommended, controlling VKA doses (VKArec), prescribed underdoses of DOAC (DOACud), and recommended doses of DOAC (DOACrec). We investigated the associations between these anticoagulant drug therapies and patients' initial stroke severity and 3-month outcomes. RESULTS: Median National Institutes of Health Stroke Scale scores at admission were as follows: ACn: 16, VKAuc: 15, VKArec: 9, DOACud: 5, and DOACrec: 7. When the ACn group was used as a reference, regression analysis showed that VKArec (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.01-2.21), DOACud (OR 2.84, 95% CI: 1.47-5.66), and DOACrec (OR 1.83, 95% CI: 1.23-2.74) were associated with milder stroke severity, while VKAuc was not. Median 3-month modified Rankin Scale scores were 2 in the DOACud and DOACrec groups and 4 in all other groups. After adjusting for confounding factors, DOACud (OR 3.14, 95% CI: 1.50-6.57) and DOACrec (OR 1.67, 95% CI: 1.05-2.64) were associated with good 3-month outcomes while VKAuc and VKArec were not. CONCLUSIONS: In patients with atrial fibrillation, recommended doses and underdoses of DOACs reduced stroke severity on admission and were associated with good 3-month outcomes.

Amyloid deposit corresponds to technetium-99m-pyrophosphate accumulation in abdominal fat of patients with transthyretin cardiac amyloidosis.

BACKGROUND: Radionuclide imaging using bone-avid tracers plays a critical role in diagnosing transthyretin cardiac amyloidosis (ATTR-CA), but technetium-99m-pyrophosphate (PYP) rarely allows the detection of extracardiac amyloid infiltration. We retrospectively investigated the frequency of PYP uptake in the subcutaneous abdominal fat of patients with ATTR-CA and its relevance to the results of fine-needle aspiration biopsy (FNAB) of this tissue. METHODS: Chest-centered images of PYP scintigraphy were obtained 2 h after the intravenous injection of the tracer (20 mCi), and the frequency of PYP uptake in the subcutaneous abdominal fat was evaluated. Amyloid deposits of fat smears taken by subcutaneous abdominal fat FNAB were assessed by Congo red staining. RESULTS: Twenty-four patients with ATTR-CA were included. Ten (41.7%) patients showed some PYP uptake in the subcutaneous abdominal fat (positive PYP group), and 14 patients did not (negative PYP group). Amyloid deposits were detected by subcutaneous abdominal fat FNAB in 7/10 patients (70.0%) of the positive PYP group versus 0/14 patients (0%) of the negative PYP group, and the difference was significant. CONCLUSIONS: In patients with ATTR-CA, abnormal PYP uptake in the subcutaneous abdominal fat could reflect the regional amyloid deposition confirmed by FNAB of this tissue.

Extracardiac Biopsy Sensitivity in Transthyretin Amyloidosis Cardiomyopathy Patients With Positive 99 mTc-Labeled Pyrophosphate Scintigraphy Findings.

BACKGROUND: The accurate sensitivity of amyloid deposition in extracardiac tissue (subcutaneous tissue and gastrointestinal tract) has not been evaluated in transthyretin amyloidosis cardiomyopathy (ATTR-CM) patients. This study aimed to evaluate the sensitivity of amyloid deposition in obtained endomyocardial and extracardiac biopsies.Methods and Results: This study retrospectively evaluated 175 consecutive ATTR-CM patients (wild-type [ATTRwt]: 134, hereditary [ATTRv]: 41) who had positive findings on 99 mTc-labeled pyrophosphate (99 mTc-PYP) scintigraphy and underwent tissue biopsy of at least one organ (subcutaneous tissue, gastrointestinal tract, and endomyocardium). Amyloid deposition was observed in the subcutaneous tissue of 57/150 patients (38%), gastrointestinal tract of 80/131 patients (61%), and endomyocardium of 108/109 patients (99%). Compared to patients with ATTRv, ATTRwt had significantly lower sensitivity in subcutaneous tissue (73% vs. 25%, P<0.01) and tended to be lower in the gastrointestinal tract (74% vs. 57%, P=0.08) biopsies. Among 124 patients who underwent both subcutaneous tissue and gastrointestinal tract biopsies, amyloid was detected in at least 1 specimen in 91 (73%) patients. The sensitivity of the combination of extracardiac biopsies was 66% and 94% in ATTRwt-CM and ATTRv-CM, respectively. Multivariate analysis reveals that ATTRv was the only significant predictor of amyloid deposition in the subcutaneous tissue. CONCLUSIONS: Subcutaneous tissue and gastrointestinal tract biopsy sensitivity are inadequate, especially in patients with ATTRwt; however, the combination of these extracardiac biopsies contributes to increased sensitivity in patients with positive 99 mTc-PYP scintigraphy findings.

Feasibility Study of Dendrimer-Based TTR-CRISPR pDNA Polyplex for Ocular Amyloidosis in Vitro.

Hereditary amyloidgenic transthyretin (ATTR) amyloidosis is caused by a genetic point-mutated transthyretin such as TTR Val30Met (TTR V30M), since it forms protein aggregates called amyloid resulting in the tissue accumulation and functional disorders. In particular, ATTR produced by retinal pigment epithelial cells often causes ATTR ocular amyloidosis, which elicits deterioration of ocular function and ultimately blindness. Therefore, development of novel therapeutic agents is urgently needed. Genome-editing technology using Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated proteins (CRISPR-Cas9) system is expected to be a therapeutic approach to treat genetic diseases, such as ATTR amyloidosis caused by a point mutation in TTR gene. Previously, we reported that glucuronylglucosyl-ß-cyclodextrin conjugated with a polyamidoamine dendrimer (CDE) had excellent gene transfer ability and that underlying dendrimer inhibited TTR aggregation. Conversely, folate receptors are known to be highly expressed in retina; thus, folate has potential as a retinal target ligand. In this study, we prepared a novel folate-modified CDE (FP-CDE) and investigated its potential as a carrier for the retinal delivery of TTR-CRISPR plasmid DNA (pDNA). The results suggested that FP-CDE/TTR-CRISPR pDNA could be taken up by retinal pigment epithelial cells via folate receptors, exhibited TTR V30M amyloid inhibitory effect, and suppressed TTR production via the genome editing effect (knockout of TTR gene). Thus, FP-CDE may be useful as a novel therapeutic TTR-CRISPR pDNA carrier in the treatment of ATTR ocular amyloidosis.