Increase of HCN current in SOD1-associated amyotrophic lateral sclerosis.

The clinical manifestations of sporadic amyotrophic lateral sclerosis (ALS) vary widely. However, the current classification of ALS is mainly based on clinical presentations, while the roles of electrophysiological and biomedical biomarkers remain limited. Herein, we investigated a group of patients with sporadic ALS and an ALS mouse model with superoxide dismutase 1 (SOD1)/G93A transgenes using nerve excitability tests (NET) to investigate axonal membrane properties and chemical precipitation, followed by enzyme-linked immunosorbent assay analysis to measure plasma misfolded protein levels. Six of 19 patients (31.6%) with sporadic ALS had elevated plasma misfolded SOD1 protein levels. In sporadic ALS patients, only those with elevated misfolded SOD1 protein levels showed an increased inward rectification in the current-threshold (I/V) curve and an increased threshold reduction in the hyperpolarizing threshold electrotonus (TE) in the NET study. Two familial ALS patients with SOD1 mutations also exhibited similar electrophysiological patterns of NET. For patients with sporadic ALS showing significantly increased inward rectification in the I/V curve, we noted an elevation in plasma misfolded SOD1 level, but not in total SOD1, misfolded C9orf72, or misfolded phosphorylated TDP43 levels. Computer simulations demonstrated that the aforementioned axonal excitability changes are likely associated with an increase in hyperpolarization-activated cyclic nucleotide-gated (HCN) current. In SOD1/G93A mice, NET also showed an increased inward rectification in the I/V curve, which could be reversed by a single injection of the HCN channel blocker, ZD7288. Daily treatment of SOD1/G93A mice with ZD7288 partially prevented the early motor function decline and spinal motor neuron death. In summary, sporadic ALS patients with elevated plasma misfolded SOD1 exhibited similar patterns of motor axonal excitability changes as familial ALS patients and ALS mice with mutant SOD1 genes, suggesting the existence of SOD1-associated sporadic ALS. The observed NET pattern of increased inward rectification in the I/V curve was attributable to an elevation in the HCN current in SOD1-associated ALS.

Bilateral optic neuritis and encephalopathy as the atypical presentations of multiple sclerosis following severe acute respiratory syndrome coronavirus 2 infection.

Numerous evidence suggests coronavirus disease 2019 (COVID-19) potentially triggers demyelinating diseases, inclusive of multiple sclerosis (MS), and acute disseminated encephalomyelitis (ADEM), and various mechanisms have been proposed. We report a 42-year-old male presented with bilateral optic neuritis and encephalopathy, 2 weeks following COVID-19 infection. He denied any history or family history of neurological and ocular diseases. Severe bilateral visual impairment (only light perception) and pain with eye movement were reported. Fundoscopy revealed bilateral optic disc swelling. Magnetic resonance imaging showed tortuous bilateral optic nerves with optic nerve and nerve sheath enhancement. Multiple hyperintense nodules in bilateral cerebral white matter were noted on fluid-attenuated inversion recovery T2-weighted imaging without diffusion restriction or gadolinium contrast enhancement. Hypointense nodules in cerebral white matter were also noted on T1-weighted imaging, which implied some old lesions. Dissemination in space and time and cerebrospinal fluid-specific oligoclonal bands confirmed the diagnosis of MS. Both serum aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies were negative. He received pulse steroid therapy for 5 days, followed by slowly tapering oral prednisolone. His vision, ocular motion pain, and encephalopathy improved gradually. However, the visual outcome was still poor (bilateral 20/400), and optic atrophy was noticed during 1-year follow-up. To our knowledge, this is the first case of MS following severe acute respiratory syndrome coronavirus 2 infection presented with bilateral optic neuritis and encephalopathy. Since these manifestations are exceedingly rare in MS, we suspect acute immune reactions induced by COVID-19 could bring about the atypical ADEM-like presentations of MS.

Altered connectivity of central autonomic network: effects of dysautonomia in hereditary transthyretin amyloidosis with polyneuropathy.

BACKGROUND: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a progressive fatal disorder caused by deposition of mutant transthyretin (TTR) amyloids mainly in the nerves and heart. Autonomic dysfunction is a major disabling manifestation, affecting 90% of patients with late-onset ATTRv-PN. The current study aimed to investigate brain functional alterations associated with dysautonomia due to peripheral autonomic nerve degeneration in ATTRv-PN. METHODS: Resting-state functional MRI data were acquired from 43 ATTRv-PN patients predominantly of A97S (p.A117S) genotype, and the functional connectivity of central autonomic regions was assessed. RESULTS: Compared with age-matched healthy controls, the ATTRv-PN patients exhibited (1) reduced functional connectivity of the central autonomic regions such as hypothalamus, amygdala, anterior insula, and middle cingulate cortex with brain areas of the limbic, frontal, and somatosensory systems, and (2) correlations of reduced functional autonomic connectivity with the severity of autonomic dysfunction especially orthostatic intolerance, decreased heart rate variability, and greater clinical disability. CONCLUSIONS: Our findings provide evidence linking peripheral autonomic dysfunction with altered connectivity in the central autonomic network in ATTRv-PN.

Altered gut microbiota in Taiwanese A97S predominant transthyretin amyloidosis with polyneuropathy.

Increasing evidence suggests that gut microbiota alterations are related to development and phenotypes of many neuropsychiatric diseases. Here, we evaluated the fecal microbiota and its clinical correlates in patients with hereditary transthyretin amyloidosis (ATTRv) and polyneuropathy. Fecal microbiota from 38 ATTRv patients and 39 age-matched controls was analyzed by sequencing 16S V3-V4 ribosomal RNA, and its relationships with clinical characteristics of polyneuropathy and cardiomyopathy were explored. The familial amyloidotic polyneuropathy stage was stage I, II, and III in 13, 18, and 7 patients. 99mTc-PYP SPECT showed a visual score of 2 in 15 and 3 in 21 patients. The gut microbiota of ATTRv patients showed higher alpha diversity (ASV richness and Shannon effective numbers) and dissimilar beta diversity compared to controls. Relative abundance of microbiota was dominated by Firmicutes and decreased in Bacteroidetes in ATTRv patients than in controls. Patients with more myocardial amyloid deposition were associated with increased alpha diversity, and the abundance of Clostridia was significantly correlated with pathophysiology of polyneuropathy in ATTRv patients. These findings demonstrated alterations in the gut microbiota, especially Firmicutes, in ATTRv. The association between altered microbiota and phenotypes of cardiomyopathy and polyneuropathy might suggest potential contributions of gut microbiota to ATTRv pathogenesis.

Unique clinical and electrophysiological features in the peripheral nerve system in patients with sialidosis - a case series study.

BACKGROUND: To investigate the peripheral nervous system involvement in S sialidosis with typical features of myoclonus, seizure, and giant waves in somatosensory evoked potentials suggesting hyperexcitability in the central nervous system. METHODS: The clinical presentation of patients with genetically confirmed sialidosis was recorded. Neurophysiological studies, including nerve conduction studies (NCSs), F-wave studies, and needle electromyography (EMG), were performed on these patients. RESULTS: Six patients (M/F: 2:4) were recruited. In addition to the classical presentation, intermittent painful paresthesia was noted in four patients, and three of whom reported it as the earliest symptom. In the NCSs, one patient had reduced compound muscle action potential amplitudes in the right ulnar nerve, while another patient had prolonged distal motor latency in the bilateral tibial and peroneal nerves. Prolonged F-wave latency (83.3%), repeater F-waves (50%), and neurogenic polyphasic waves in EMG (in 2 out of 3 examined patients) were also noted. Interestingly, a very late response was noted in the F-wave study of all patients, probably indicating lesions involving the proximal peripheral nerve or spinal cord. CONCLUSION: In addition to the central nervous system, the peripheral nervous system is also involved in sialidosis, with corresponding clinical symptoms. Further study on these phenomena is indicated.

Tafamidis improves myocardial longitudinal strain in A97S transthyretin cardiac amyloidosis.

Background: Transthyretin cardiomyopathy (ATTR-CM) is a debilitating disease that has received much attention since the emergence of novel treatments. The Transthyretin Cardiomyopathy Clinical Trial showed that tafamidis, a transthyretin tetramer stabilizer, effectively reduced the declines in functional capacity and quality of life. However, Ala97Ser (A97S) hereditary ATTR-CM is underrepresented in major ATTR-CM tafamidis trials. Objectives: We aim to investigate the change in global longitudinal strain (GLS) of A97S ATTR-CM patients after 12 months of tafamidis treatment. Methods: We retrospectively analysed a prospective cohort of patients with A97S ATTR-CM who received tafamidis meglumine (61 mg/day) at the National Taiwan University Hospital. Echocardiography with speckle tracking strain analysis was performed at baseline and 12 months after treatment. Results: In all, 20 patients were included in the cohort. The baseline left ventricular ejection fraction (LVEF) and interventricular septum (IVS) thickness were 59.20 ± 13.23% and 15.10 ± 3.43 mm, respectively. After 12 months of tafamidis treatment, the LVEF and IVS were 61.83 ± 15.60% (p = 0.244) and 14.59 ± 3.03 mm (p = 0.623), respectively. GLS significantly improved from -12.70 ± 3.31% to -13.72 ± 3.17% (p = 0.048), and longitudinal strain (LS) in apical and middle segments significantly improved from -16.05 ± 4.82% to -17.95 ± 3.48% (p = 0.039) and -11.89 ± 4.38% to -13.58 ± 3.12% (p = 0.039), respectively. Subgroup analysis showed that patients with LVEF < 50% had a better treatment response and improvement in GLS. The patients with an IVS ⩾ 13 mm had an improvement in two-chamber LS from -10.92 ± 4.25% to -13.15 ± 3.87% (p = 0.042) and an improvement in apical left ventricular LS from -15.30 ± 5.35% to -17.82 ± 3.99% (p = 0.031). Conclusion: Tafamidis significantly improved GLS, and particularly apical and middle LS in A97S ATTR-CM patients.

Tafamidis improves myocardial longitudinal strain in A97S transthyretin cardiac amyloidosis Transthyretin cardiomyopathy (ATTR-CM) is a severe heart condition that has gained attention due to recent advancements in treatments. One of these treatments, called tafamidis, has been shown to be effective in maintaining heart function and quality of life. However, there has been limited research on a specific genetic variation of ATTR-CM: A97S. Our aim was to determine whether A97S ATTR-CM patients experienced improved heart function after one year of tafamidis treatment. We conducted this study at the National Taiwan University Hospital, where we enrolled 20 A97S ATTR-CM patients. We used echocardiography to evaluate their heart function, focusing on a parameter called global longitudinal strain. The results showed that after one year of tafamidis treatment, these patients experienced a significant improvement in their global longitudinal strain, particularly in the apical and middle regions of the heart. In conclusion, tafamidis appears to be beneficial for A97S ATTR-CM patients by enhancing their heart's global longitudinal strain, which is a positive sign for their cardiac health.

Diflunisal versus tafamidis on neuropathy and cardiomyopathy in hereditary transthyretin amyloidosis.

OBJECTIVES: Hereditary transthyretin (TTR) amyloidosis (ATTRv) is frequently complicated by polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTRv-CM). The long-term efficacy of diflunisal on both polyneuropathy and cardiomyopathy in ATTRv patients, especially those with non-V30M genotypes, has not been fully investigated and compared with that of tafamidis. METHODS: We compared the structural and biochemical characteristics of A97S-TTR complexed with tafamidis with those of diflunisal, and prospectively followed up and compared the progression of polyneuropathy and cardiomyopathy between ATTRv-PN patients taking diflunisal and those taking tafamidis. RESULTS: Both diflunisal and tafamidis effectively bind to the two thyroxine-binding sites at the A97S-TTR dimer-dimer interface and equally and almost sufficiently reduce amyloid fibril formation. Thirty-five ATTRv-PN patients receiving diflunisal and 22 patients receiving tafamidis were enrolled. Compared with no treatment, diflunisal treatment significantly delayed the transition of FAP Stage 1 to 2 and Stage 2 to 3 and decreased the deterioration in parameters of the ulnar nerve conduction study (NCS). The progression of FAP stage or NCS parameters did not differ between patients treated with diflunisal and those treated with tafamidis. Both diflunisal and tafamidis treatments significantly decreased radiotracer uptake on 99mTc-PYP SPECT and stabilized cardiac wall thickness and blood pro-B-type natriuretic peptide levels. No significant adverse events occurred during diflunisal or tafamidis treatment. INTERPRETATIONS: The binding patterns of both tafamidis and diflunisal to A97S-TTR closely resembled those observed in the wild type. Diflunisal can effectively delay the progression of polyneuropathy and cardiomyopathy with similar efficacy to tafamidis and may become a cost-effective alternative treatment for late-onset ATTRv-PN.

Use of Technetium-99m-Pyrophosphate Single-Photon Emission Computed Tomography/Computed Tomography in Monitoring Therapeutic Changes of Eplontersen in Patients With Hereditary Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Hereditary transthyretin amyloid cardiomyopathy (hATTR-CM) is a progressive and fatal disease. Recent evidence indicates that bone scintigraphy may serve as a tool to monitor the effectiveness of hATTR-CM treatment. The objective of this study was to examine how eplontersen therapy influences the semiquantitative uptake of technetium-99m-pyrophosphate in individuals diagnosed with hATTR-CM. METHODS AND RESULTS: We retrospectively analyzed a prospective cohort from the NEURO-TTRansform trial, including patients with hATTR-CM receiving eplontersen (45 mg/4 weeks). A control group comprised patients with hATTR-CM who had not received eplontersen, inotersen, tafamidis, or patisiran. Technetium-99m-pyrophosphate single-photon emission computed tomography/computed tomography was conducted at baseline and during follow-up. Thirteen patients with hATTR-CM were enrolled, with 6 receiving eplontersen and 7 serving as the control group. The median follow-up time was 544 days. The eplontersen group exhibited a significant decrease in volumetric heart and lung ratio (3.774 to 2.979, P=0.028), whereas the control group showed no significant change (4.079 to 3.915, P=0.237). Patients receiving eplontersen demonstrated a significantly greater reduction in volumetric heart and lung ratio compared with the control group (-20.7% versus -3.4%, P=0.007). CONCLUSIONS: The volumetric heart and lung ratio used to quantify technetium-99m-pyrophosphate uptake showed a significant reduction subsequent to eplontersen treatment in individuals diagnosed with hATTR-CM. These findings suggest the potential efficacy of eplontersen in treating hATTR-CM and highlight the value of technetium-99m-pyrophosphate single-photon emission computed tomography/computed tomography as a tool for monitoring therapeutic effectiveness.