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.

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.

Bilateral Hilar and Mediastinal Lymphadenopathy as an Initial Manifestation of Amyloidosis.

A 75-year-old male visited our hospital with bilateral hilar lymph node swelling detected on chest radiography during an annual medical checkup. Chest computed tomography revealed swelling of multiple hilar mediastinal lymph nodes. Histopathological and immunohistochemical examinations of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) specimens from the hilar lymph nodes revealed amyloid deposition. Bilateral hilar and mediastinal lymphadenopathies can be the first manifestations of amyloidosis diagnosed using EBUS-TBNA.

Characterization of heterozygous ATTR Tyr114Cys amyloidosis-specific induced pluripotent stem cells.

Hereditary transthyretin (TTR) amyloidosis (ATTRv amyloidosis) is autosomal dominant and caused by mutation of TTR gene. Heterozygous ATTR Tyr114Cys (p.Tyr134Cys) amyloidosis is a lethal disease with a life expectancy of about 10 years after onset of the disease. However, the molecular pathogenesis of ATTR Tyr114Cys amyloidosis is still largely unknown. In this study, we took advantage of disease-specific induced pluripotent stem (iPS) cells and generated & characterized the heterozygous ATTR Tyr114Cys amyloidosis-specific iPS cells (Y114C iPS cells), to determine whether Y114C iPS cells could be useful for elucidating the pathogenesis of ATTR Tyr114Cys amyloidosis. We successfully differentiated heterozygous Y114C iPS cells into hepatocyte like cells (HLCs) mainly producing TTR protein. On day 27 after differentiation, the expression of hepatocyte maker albumin was detected, and TTR expression was significantly increased in HLCs differentiated from Y114C iPS cells. LC-MS/MS analysis showed that both WT TTR & ATTR Y114C protein were indeed expressed in the HLCs differentiated from Y114C iPS cells. Notably, the number of detected peptides derived from ATTR Y114C protein was lower than that of WT TTR protein, indeed indicating the clinical phenotype of ATTR Tyr114Cys amyloidosis. Taken together, we first reported the heterozygous Y114C iPS cells generated from patient with ATTR Tyr114Cys amyloidosis, and suggested that Y114C iPS cells could be a potential pathological tool, which may contribute to elucidating the molecular pathogenesis of heterozygous ATTR Tyr114Cys amyloidosis.

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.

Origin of Transthyretin in Cerebral Amyloid Angiopathy.

This case series evaluates the correlation between transthyretin and cerebral amyloid angiopathy progression in individuals with hereditary transthyretin amyloidosis.

A new staging system using right atrial strain in patients with immunoglobulin light-chain cardiac amyloidosis.

AIMS: There are minimal data on the prognostic impact of right atrial strain during the reservoir phase (RASr) in patients with immunoglobulin light-chain (AL) cardiac amyloidosis. METHODS AND RESULTS: Among 78 patients who were diagnosed with AL cardiac amyloidosis at Kumamoto University Hospital from 2007 to 2022, 72 patients with sufficient two-dimensional speckle tracking imaging data without chemotherapy before the diagnosis were retrospectively analysed. During a median follow-up of 403 days, 31 deaths occurred. Age and the rate of male sex were not significantly different between the all-cause death group and the survival group (age, 70.4 ± 8.8 years vs. 67.0 ± 10.0 years, P = 0.14, male sex, 65% vs. 66%, P = 0.91). The estimated glomerular filtration rate (eGFR) was significantly lower, and B-type natriuretic peptide (BNP) and high sensitivity cardiac troponin T (hs-cTnT) were significantly higher, in the all-cause death group versus the survival group (eGFR, 48.2 ± 21.0 mL/min/1.73 m2 vs. 59.4 ± 24.4 mL/min/1.73 m2 , P < 0.05, BNP, 725 [360-1312] pg/mL vs. 123 [81-310] pg/mL, P < 0.01, hs-cTnT, 0.12 [0.07-0.18] ng/mL vs. 0.05 [0.03-0.08] ng/mL, P < 0.01). Left ventricular (LV) global longitudinal strain (GLS) (LV-GLS), left atrial strain during the reservoir phase (LASr), right ventricular GLS (RV-GLS), and RASr were significantly lower in the all-cause death group versus the survival group (LV-GLS, 8.5 ± 4.3% vs. 11.8 ± 3.8%, P < 0.01, LASr, 8.8 ± 7.1% vs. 14.3 ± 8.1%, P < 0.01, RV-GLS, 11.6 ± 5.1% vs. 16.4 ± 3.9%, P < 0.01, RASr, 10.2 ± 7.3% vs. 20.7 ± 9.5%, P < 0.01). RASr was significantly associated with all-cause death after adjusting for RV-GLS, LV-GLS and LASr (hazard ratio [HR]: 0.91, 95% confidence interval [95% CI]: 0.83-0.99, P < 0.05). RASr and log-transformed BNP were significantly associated with all-cause death after adjusting for log-transformed troponin T and eGFR (RASr, HR: 0.93, 95% CI: 0.87-1.00, P < 0.05; log-transformed BNP, HR: 2.10, 95% CI: 1.17-3.79, P < 0.05). The optimal cut-off values were RASr: 16.4% (sensitivity: 66%, specificity: 84%, area under curve [AUC]: 0.81) and BNP: 311.2 pg/mL (sensitivity: 83%, specificity: 78%, AUC: 0.82) to predict all-cause mortality using ROC analysis. Kaplan-Meier analysis revealed that patients with low RASr (<16.4%) or high BNP (>311.2 pg/mL) had a significantly high probability of all-cause death (both, P < 0.01). We devised a new staging score by adding 1 point if RASr decreased or BNP levels increased more than each cut-off value. The HR for all-cause death using score 0 as a reference was 5.95 (95% CI: 1.19-29.79; P < 0.05) for score 1 and 23.29 (95% CI: 5.37-100.98; P < 0.01) for score 2. CONCLUSIONS: The new staging system using RASr and BNP predicted prognosis in patients with AL cardiac amyloidosis.

A Novel Mutation of VPS13D-related Disorders with Parkinsonism.

We herein report a case of VPS13D-related disorder with a novel homogeneous variant. A 58-year-old Japanese woman was referred to our hospital with slowly progressive gait disturbance and cognitive impairment. A neurological examination revealed decreased spontaneity, recent memory impairment, Parkinsonism, cerebellar ataxia, pyramidal signs, and autonomic dysfunction. Dopamine transporter single-photon-emission computed tomography showed a markedly reduced uptake in the striatum bilaterally. Whole-exome sequencing revealed a novel homozygous missense variant of the VPS13D gene (Arg3267Pro). Our case suggests that mutations in VPS13D may cause parkinsonism, in addition to the previously reported cerebellar ataxia and spastic paraplegia.

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.

Technetium-99m-pyrophosphate imaging-based computed tomography-guided core-needle biopsy of internal oblique muscle in wild-type transthyretin cardiac amyloidosis.

BACKGROUND: Technetium-99m-pyrophosphate (99mTc-PYP) uptake in the internal oblique muscle (IOM), which is often observed in patients with wild-type transthyretin cardiac amyloidosis (ATTR-CA), indicates amyloid transthyretin (ATTR) deposition. OBJECTIVE: This study aimed to assess the safety and efficacy of 99mTc-PYP imaging-based computed tomography (CT)-guided core-needle biopsy of the IOM as a new extracardiac screening biopsy for confirming the presence of ATTR deposits. METHODS: Patients with suspected ATTR-CA in whom myocardial tracer uptake was detected on chest- and abdomen-centered images of 99mTc-PYP scintigraphy underwent CT-guided core-needle biopsy at the site with the highest tracer uptake in the IOM between September 2021 and November 2022. RESULTS: All 18 consecutive patients (mean age, 86.3 years ± 6.5; 61.1% male) enrolled in the study showed 99mTc-PYP uptake into the IOM. Adequate tissue samples were obtained from all patients except one without serious complications. Immunohistochemical analysis confirmed ATTR deposits in 16/18 (88.9%) patients. In the remaining two patients, ATTR deposits were observed via endomyocardial biopsy. All patients were diagnosed with wild-type ATTR-CA based on transthyretin gene sequence testing results. CONCLUSION: In wild-type ATTR-CA, 99mTc-PYP imaging-based CT-guided core-needle biopsy of the IOM could be used as an extracardiac screening biopsy to confirm the presence of ATTR deposits.

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.

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.

Treatment response and neurofilament light chain levels with long-term patisiran in hereditary transthyretin-mediated amyloidosis with polyneuropathy: 24-month results of an open-label extension study.

BACKGROUND: Longitudinal changes in neurofilament light chain (NfL) levels were evaluated alongside prespecified clinical assessments 24 months into the patisiran Global open-label extension (OLE) study in patients with ATTRv amyloidosis with polyneuropathy. METHODS: All patients enrolled in the Global OLE, from phase III APOLLO and phase II OLE parent studies, received patisiran. Assessments included measures of polyneuropathy (modified Neuropathy Impairment Score+7 (mNIS+7)), quality of life (QOL; Norfolk QOL-Diabetic Neuropathy questionnaire (Norfolk QOL-DN)), and plasma NfL. RESULTS: Patients receiving patisiran in the parent study (APOLLO-patisiran, n = 137; phase II OLE-patisiran, n = 25) demonstrated sustained improvements in mNIS+7 (mean change from parent study baseline (95% confidence interval): APOLLO-patisiran -4.8 (-8.9, -0.6); phase II OLE-patisiran -5.8 (-10.5, -1.2)) and Norfolk QOL-DN (APOLLO-patisiran -2.4 (-7.2, 2.3)), and maintained reduced NfL levels at Global OLE 24 months. After initiating patisiran in the Global OLE, APOLLO-placebo patients (n = 49) demonstrated stabilized mNIS+7, improved Norfolk QOL-DN, and significantly reduced NfL levels. Patisiran continued to demonstrate an acceptable safety profile. Earlier patisiran initiation was associated with a lower exposure-adjusted mortality rate. CONCLUSIONS: Long-term patisiran treatment led to sustained improvements in neuropathy and QOL, with NfL demonstrating potential as a biomarker for disease progression and treatment response in ATTRv amyloidosis with polyneuropathy.

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.

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.

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.

Effects of tafamidis on the left ventricular and left atrial strain in patients with wild-type transthyretin cardiac amyloidosis.

AIMS: Although tafamidis is used in patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA), its specific effect on cardiac function is unclear. Thus, this study aimed to investigate the effect of tafamidis on left atrial and ventricular function using speckle-tracking echocardiography for 1 year of treatment in patients with ATTRwt-CA. METHODS AND RESULTS: We included 23 patients (mean age, 76 years) with ATTRwt-CA confirmed via biopsy. We analyzed the left ventricular and left atrial (LA) strain using two-dimensional speckled tracking echocardiography and compared these parameters before and 1 year after starting treatment with tafamidis between 16 patients with sinus rhythm (SR) and 7 patients with atrial fibrillation (AF). In ATTRwt-CA patients with SR, LA reservoir strain significantly improved by 1-year tafamidis treatment (10.5±5.0% to 11.9±5.3%, P=0.0307) although global longitudinal strain (GLS) did not (-10.6±3.1% to -11.3±3.0%, P=0.0608). In contrast, LA reservoir strain was not significantly changed (5.4±2.9% to 4.9±1.7%, P=0.4571), and GLS deteriorated (-8.4±2.3% to -6.8±1.4%, P=0.0267) in ATTRwt CA patients with AF. CONCLUSION: Left atrial function improved with tafamidis treatment in ATTRwt-CA patients with SR, but not left ventricular function. However, these cardiac functions did not improve with tafamidis treatment in ATTRwt-CA patients with AF.

Transthyretin amyloid deposition in ligamentum flavum (LF) is significantly correlated with LF and epidural fat hypertrophy in patients with lumbar spinal stenosis.

Lumbar spinal stenosis (LSS) is a degenerative disease characterized by intermittent claudication and numbness in the lower extremities. These symptoms are caused by the compression of nerve tissue in the lumbar spinal canal. Ligamentum flavum (LF) hypertrophy and spinal epidural lipomatosis in the spinal canal are known to contribute to stenosis of the spinal canal: however, detailed mechanisms underlying LSS are still not fully understood. Here, we show that surgically harvested LFs from LSS patients exhibited significantly increased thickness when transthyretin (TTR), the protein responsible for amyloidosis, was deposited in LFs, compared to those without TTR deposition. Multiple regression analysis, which considered age and BMI, revealed a significant association between LF hypertrophy and TTR deposition in LFs. Moreover, TTR deposition in LF was also significantly correlated with epidural fat (EF) thickness based on multiple regression analyses. Mesenchymal cell differentiation into adipocytes was significantly stimulated by TTR in vitro. These results suggest that TTR deposition in LFs is significantly associated with increased LF hypertrophy and EF thickness, and that TTR promotes adipogenesis of mesenchymal cells. Therapeutic agents to prevent TTR deposition in tissues are currently available or under development, and targeting TTR could be a potential therapeutic approach to inhibit LSS development and progression.

A Gluteus Medius Muscle Biopsy to Confirm Amyloid Transthyretin Deposition in Wild-type Transthyretin Cardiac Amyloidosis: A Report of Two Cases.

In patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA), the uptake of the tracer on technetium-99m-labeled pyrophosphate (99mTc-PYP) scintigraphy, which indicates amyloid transthyretin (ATTR) per se, is often observed in skeletal muscles, such as the abdominal oblique and gluteal muscles. Among extracardiac biopsies for confirming ATTR deposition in ATTRwt-CA, a 99mTc-PYP imaging-based computed tomography (CT)-guided core needle biopsy of the internal oblique muscle has relatively high sensitivity. In some patients, the 99mTc-PYP uptake is more pronounced in the gluteal muscles than in oblique muscles. We herein report two cases of ATTRwt-CA in which a CT-guided biopsy of the gluteus medius muscle with 99mTc-PYP uptake confirmed the presence of ATTR deposits.