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.

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.

Development of Benziodarone Analogues with Enhanced Potency for Selective Binding to Transthyretin in Human Plasma.

Transthyretin amyloidosis is a fatal disorder caused by transthyretin amyloid aggregation. Stabilizing the native structure of transthyretin is an effective approach to inhibit amyloid aggregation. To develop kinetic stabilizers of transthyretin, it is crucial to explore compounds that selectively bind to transthyretin in plasma. Our recent findings demonstrated that the uricosuric agent benziodarone selectively binds to transthyretin in plasma. Here, we report the development of benziodarone analogues with enhanced potency for selective binding to transthyretin in plasma compared to benziodarone. These analogues featured substituents of chlorine, bromine, iodine, a methyl group, or a trifluoromethyl group, at the 4-position of the benzofuran ring. X-ray crystal structure analysis revealed that CH···O hydrogen bonds and a halogen bond are important for the binding of the compounds to the thyroxine-binding sites. The bioavailability of benziodarone analogues with 4-Br, 4-Cl, or 4-CH3 was comparable to that of tafamidis, a current therapeutic agent for transthyretin amyloidosis.

Binding of serum-derived amyloid-associated proteins to amyloid fibrils.

BACKGROUND: Amyloid signature proteins such as serum amyloid P component, apolipoprotein E (ApoE), and ApoA-IV generally co-localise with amyloid, regardless of the types of amyloid precursor protein or the organs. Most of these proteins derive from serum and have reportedly been involved in amyloid fibril formation and stabilisation, as well as in excretion and degradation of amyloid precursor proteins. However, the processes and mechanisms by which these specific proteins deposit together with amyloid fibrils have not been clarified. METHODS: We analysed the binding of serum proteins to amyloid fibrils derived from amyloid ß and insulin in vitro by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Specific serum proteins including ApoA-I, ApoE, ApoA-IV, ApoC-III and vitronectin adhered to amyloid fibrils at high concentrations in vitro. In addition, the profile of these proteins commonly occurred in both amyloid ß and insulin amyloid fibrils and was mostly consistent with the composition of amyloid signature proteins. We also showed that high concentrations of serum proteins can adhere to amyloid fibrils in a short time. CONCLUSIONS: Our in vitro results suggest that amyloid signature proteins coexist with amyloid primarily dependent on the binding of each serum protein, in the extracellular fluid, to amyloid fibrils.

Effectiveness of active occupational therapy in patients with acute stroke: A propensity score-weighted retrospective study.

Background and purpose: The effects of therapy and patient characteristics on rehabilitation outcomes in patients with acute stroke are unclear. We investigated the effects of intensive occupational therapy (OT) on patients with acute stroke. Methods: We performed a retrospective cohort study using the 2005-2016 Japan Rehabilitation Database, from which we identified patients with stroke (n = 10,270) who were admitted to acute care hospitals (n = 37). We defined active OT (AOT) and non-AOT as OT intervention times (total intervention time/length of hospital stay) longer or shorter than the daily physical therapy intervention time, respectively. The outcomes assessed were the Functional Independence Measure (FIM) and National Institutes of Health Stroke Scale (NIHSS) scores, duration of hospitalization, and rate of discharge. Propensity scores and inverse probability of treatment weighting analyses adjusted for patient characteristics were performed to investigate the effects of AOT on patient outcomes. Results: We enrolled 3,501 patients (1,938 and 1,563 patients in the AOT and non-AOT groups, respectively) in the study. After inverse probability of treatment weighting, the AOT group had a shorter length of hospitalization (95% confidence interval: -3.7, -1.3, p < 0.001), and the FIM (95% confidence interval: 2.0, 5.7, p < 0.001) and NIHSS (95% confidence interval; 0.3, 1.1, p < 0.001) scores improved significantly. Subgroup analysis showed that lower NHISS scores for aphasia, gaze, and neglect and lower overall NIHSS and FIM scores on admission led to a greater increase in FIM scores in the AOT group. Conclusions: AOT improved the limitations in performing activities of daily living (ADL) and physical function in patients with acute stroke and reduced the length of hospitalization. Additionally, subgroup analysis suggested that the increase in FIM score was greater in patients with severe limitations in performing ADLs and worse cognitive impairment, such as neglect, on admission.

[A case of antepartum reversible cerebral vasoconstriction syndrome].

A 35-year-old pregnant woman with mild migraine experienced thunderclap headache at 37 weeks of gestation. Her cerebral MRA showed arterial segmental narrowing of right middle cerebral artery and bilateral posterior cerebral artery. When admitted, she had no sign of eclampsia/preeclampsia. After 4 days, she had premature rupture of the membrane and gave birth by caesarean section. Caesarean section immediately resolved the headache. The postpartum course of the patient and her baby was uneventfull. One month after her onset, her cerebral MRA showed improvement in arterial segmental narrowing of cerebral artery. We diagnosed reversible cerebral vasoconstriction syndrome (RCVS) assoiated with pregnancy. Pregnancy-related RCVS develops primarily during the puerperal period, but our case was a rare case that developed just before delivery and was successful with aggressive intervention. When antepartum RCVS develops, early cesarean section with epidural anesthesia in parallel with active treatment for headache may lead to good outcomes for both mother and child.

Immune checkpoint inhibitors in the onset of myasthenia gravis with hyperCKemia.

Immune checkpoint inhibitors sometimes cause neuromuscular adverse events. Although a few cases of myasthenia gravis with hyperCKemia triggered by immune checkpoint inhibitors have been described, conclusive evidence remains limited. We conducted a systematic review of published cases of myasthenia gravis with hyperCKemia related to immune checkpoint inhibitors. Moreover, we tested anti-striational antibodies in the case of myasthenia gravis with myositis after nivolumab administration. We located 17 published case reports. Anti-striational antibodies were tested in six cases and five cases were positive. Our systematic analyses revealed poor prognosis in myasthenia gravis combined hyperCKemia with immune checkpoint inhibitors.

Claspin recruits Cdc7 kinase for initiation of DNA replication in human cells.

Claspin transmits replication stress signal from ATR to Chk1 effector kinase as a mediator. It also plays a role in efficient replication fork progression during normal growth. Here we have generated conditional knockout of Claspin and show that Claspin knockout mice are dead by E12.5 and Claspin knockout mouse embryonic fibroblast (MEF) cells show defect in S phase. Using the mutant cell lines, we report the crucial roles of the acidic patch (AP) near the C terminus of Claspin in initiation of DNA replication. Cdc7 kinase binds to AP and this binding is required for phosphorylation of Mcm. AP is involved also in intramolecular interaction with a N-terminal segment, masking the DNA-binding domain and a newly identified PIP motif, and Cdc7-mediated phosphorylation reduces the intramolecular interaction. Our results suggest a new role of Claspin in initiation of DNA replication during normal S phase through the recruitment of Cdc7 that facilitates phosphorylation of Mcm proteins.