Neck triangle nerve enlargement in hereditary transthyretin amyloidosis correlates with changes in the autonomic, cardiac, and gastrointestinal systems.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv) is a hereditary disease that affects multiple bodily systems. Although sonography generally reveals enlargement of nerves in the limbs, the brachial plexus, and vagus nerve, the clinical significance of these findings remains unclear. METHODS: We performed sonographic measurements of the median nerve, cervical spinal nerves at the C5-C7 level, and the vagus nerve in patients with ATTRv and healthy controls. Clinical profiles and cardiac and gastrointestinal examination results were also collected for linear regression analysis. RESULTS: We recruited 47 patients with ATTRv (males/females: 34/13, age: 65.6 ± 5.3 years). The sampled segments were all significantly larger than those of the controls. In the clinical profiles, the sum of the Z scores of the neck triangle nerves (cervical spinal nerves and vagus nerve) and of all nerves (cervical spinal nerves, vagus nerve, and median nerve at the wrist) significantly correlated with the familial amyloid polyneuropathy stage, onset of autonomic nervous system (ANS) symptoms, and autonomic symptom scores. On cardiac examinations, several ultrasonography and magnetic resonance imaging parameters (primarily those that reflect heart volume) were found to be significantly correlated with the sum of the Z scores of the cervical spinal nerves but not with the Z score of the vagus nerve. In gastrointestinal evaluation, the cross-sectional area of the vagus nerve was correlated with gastric emptying time parameters on scintigraphy. CONCLUSIONS: Neck triangle nerve enlargement on sonography correlated with parameters related to ANS dysfunction, indicating that nerve enlargement observed on ultrasonography may serve as a potential surrogate biomarker of ATTRv.

Limbic Connectivity Underlies Pain Treatment Response in Small-Fiber Neuropathy.

OBJECTIVE: Small-fiber neuropathy (SFN) is characterized by neuropathic pain due to degeneration of small-diameter nerves in the skin. Given that brain reorganization occurs following chronic neuropathic pain, this study investigated the structural and functional basis of pain-related brain changes after skin nerve degeneration. METHODS: Diffusion-weighted and resting-state functional MRI data were acquired from 53 pathologically confirmed SFN patients, and the structural and functional connectivity of the pain-related network was assessed using network-based statistic (NBS) analysis. RESULTS: Compared with age- and sex-matched controls, the SFN patients exhibited a robust and global reduction of functional connectivity, mainly across the limbic and somatosensory systems. Furthermore, lower functional connectivity was associated with skin nerve degeneration measured by reduced intraepidermal nerve fiber density and better therapeutic response to anti-neuralgia medications, particularly for the connectivity between the insula and the limbic areas including the anterior and middle cingulate cortices. Similar to the patterns of functional connectivity changes, the structural connectivity was robustly reduced among the limbic and somatosensory areas, and the cognition-integration areas including the inferior parietal lobule. There was shared reduction of structural and functional connectivity among the limbic, somatosensory, striatal, and cognition-integration systems: (1) between the middle cingulate cortex and inferior parietal lobule and (2) between the thalamus and putamen. These observations indicate the structural basis underlying altered functional connectivity in SFN. INTERPRETATION: Our findings provide imaging evidence linking structural and functional brain dysconnectivity to sensory deafferentation caused by peripheral nerve degeneration and therapeutic responses for neuropathic pain in SFN. ANN NEUROL 2023;93:655-667.

Inflammatory Neuropathy Consortium base (INCbase): a protocol of a global prospective observational cohort study for the development of a prediction model for treatment response in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: INCbase is an international, multicenter prospective observational study using a customizable web-based modular registry to study the clinical, biological and electrophysiological variation and boundaries of chronic inflammatory demyelinating polyneuropathy (CIDP). The primary objective of INCbase is to develop and validate a clinical prediction model for treatment response. METHODS: All patients meeting clinical criteria for CIDP can be included in INCbase. Collected data include demographics, clinical history, diagnostics and various domains of clinical outcomes. Data is collected at a minimum of every 6 months for two years, and more frequently at the discretion of the investigational site to allow for assessment of unexpected changes in treatment response or clinical status. Participants can be enrolled in various sub-studies designed to capture data relevant to specific groups of interest. Data is entered directly into the web-based data entry system by local investigators and/or participants. Collection and local storage of biomaterial is optional. To develop a clinical prediction model for treatment response, newly diagnosed patients with active disease warranting start of first-line treatment will be included. The study population will be split into a development and validation cohort. Univariate and multivariate logistic regression analysis will be used to identify and combine predictors at start of treatment for treatment response at six months. Model performance will be assessed through discrimination and calibration in an external validation cohort. The externally validated prediction model will be made available to researchers and clinicians on the INCbase website. DISCUSSION: With this study, we aim to create a clinically relevant and implementable prediction model for treatment response to first line treatments in CIDP. INCbase enrollment started in April 2021, with 29 centers across 8 countries and 303 patients participating to date. This collaborative effort between academia, patient advocacy organizations and pharmaceutical industry will deepen our understanding of how to diagnose and treat CIDP.

Patisiran, an RNAi therapeutic for hereditary transthyretin-mediated amyloidosis: Sub-analysis in Taiwanese patients from the APOLLO study.

BACKGROUND: To examine the efficacy and safety of patisiran, an RNA interference therapeutic, in patients from Taiwan with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy. METHODS: The APOLLO phase 3 trial included patients from Taiwan who received patisiran 0.3 mg/kg intravenously or placebo once every 3 weeks (q3w) for 18 months (18 M), followed by patisiran 0.3 mg/kg q3w in an ongoing global open-label extension (OLE) study. The primary endpoint was change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 18 M. RESULTS: Eighteen Taiwanese patients were enrolled in APOLLO (patisiran, n = 8; placebo, n = 10; all A97S gene variant) and 14 continued in the global OLE. In this Taiwanese sub-population, beneficial treatment effects at 18 M were observed in mNIS+7 (least squares mean difference in change from baseline [patisiran-placebo], -26.5 points; 95% confidence interval: -45.5, -7.5). Patients who switched from placebo to patisiran demonstrated slowing of polyneuropathy progression at month 12 in the global OLE, while those who received patisiran in APOLLO maintained the beneficial treatment effects. Patisiran had an acceptable safety profile in the Taiwanese sub-population. CONCLUSION: This analysis suggests that patisiran is well tolerated and may provide a substantial clinical benefit for Taiwanese patients with hATTR amyloidosis with polyneuropathy. TRIAL REGISTRATION INFORMATION: The studies were registered on the ClinicalTrials.gov. The APOLLO study ClinicalTrials.gov identifier is NCT01960348 (https://clinicaltrials.gov/ct2/show/NCT01960348), with the registration date of October 10, 2013, and the first patient was enrolled on December 13, 2013. For the global OLE, the ClinicalTrials.gov identifier is NCT02510261 (https://clinicaltrials.gov/ct2/show/NCT02510261) with the registration date of July 29, 2015, and the first patient was enrolled on July 13, 2015. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that treatment with patisiran is safe and efficacious in Taiwanese patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy.

Application of Robotic Stereotactic Assistance (ROSA) for spontaneous intracerebral hematoma aspiration and thrombolytic catheter placement.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) accounts for up to 20% of all strokes and results in 40% mortality at 30 days. Although conservative medical management is still the standard treatment for ICH patients with small hematoma, patients with residual hematoma ≤15 mL after surgery are associated with better functional outcomes and survival rates. This study reported our clinical experience with using Robotic Stereotactic Assistance (ROSA) as a safe and effective approach for stereotactic ICH aspiration and intra-clot catheter placement. METHODS: A retrospective analysis was conducted of patients with spontaneous ICH who underwent ROSA-guided ICH aspiration surgery. ROSA-guided ICH surgical techniques, an aspiration and intra-clot catheter placement protocol, and a specific operative workflow (pre-operative protocol, intraoperative procedure and postoperative management) were employed to aspirate ICH using the ROSA One Brain, and appropriate follow-up care was provided. RESULTS: From September 14, 2021 to May 4, 2022, a total of 7 patients were included in the study. Based on our workflow design, ROSA-guided stereotactic ICH aspiration effectively aspirated more than 50% of hematoma volume (or more than 30 mL for massive hematomas), thereby reducing the residual hematoma to less than 15 mL. The mean operative time of entire surgical procedure was 1.3 ± 0.3 h, with very little perioperative blood loss and no perioperative complications. No patients required catheter replacement and all patients' functional status improved. CONCLUSIONS: Within our clinical practice ROSA-guided ICH aspiration, using our established protocol and workflow, was safe and effective for reducing hematoma volume, with positive functional outcomes.

Use of technetium-99m-pyrophosphate single-photon emission computed tomography/computed tomography in monitoring therapeutic changes of RNA interference therapeutics in patients with hereditary transthyretin amyloid cardiomyopathy.

BACKGROUND: RNA interference therapeutics reduce transthyretin production; however, their effect on hereditary transthyretin amyloid cardiomyopathy (ATTR-CA) remains unclear. We aimed to investigate alterations in technetium-99 m (99mTc)-pyrophosphate (PYP) single-photon emission computed tomography/computed tomography (SPECT/CT) outcomes in patients receiving patisiran or vutrisiran. METHODS: We retrospectively identified individuals with hereditary ATTR-CA who received patisiran or vutrisiran. First and second 99mTc-PYP SPECT/CT data, including visual grading, planar heart to contralateral lung (H/CL) ratio, and volumetric heart to lung (H/L) ratio were assessed. RESULTS: Eight patients with hereditary ATTR-CA were enrolled. Cohort A included four patients who underwent their first 99mTc-PYP SPECT/CT imaging at the initiation of small interfering RNA (siRNA) treatment, while cohort B comprised four patients who had been receiving siRNA treatment before their first 99mTc-PYP SPECT/CT imaging (median duration 1281 days). Overall, there were numerical reductions in planar H/CL ratio (1.7 ± 0.2 to 1.6 ± 0.1, p = 0.050) and a significant improvement in volumetric H/L ratio (4.0 ± 0.9 to 3.5 ± 0.4, p = 0.035). Although without significance, subgroup analysis showed more pronounced changes in cohort A for both planar H/CL ratio and volumetric H/L ratio (-20.1 ± 12.6% and -17.1 ± 11.4%) compared to cohort B (-3.3 ± 11.2% and -4.3 ± 12.7%). CONCLUSION: Our results demonstrated a significant decrease in volumetric H/L ratio in hereditary ATTR-CA patients receiving RNA interference therapeutics.

Nonpermissive Skin Environment Impairs Nerve Regeneration in Diabetes via Sec31a.

OBJECTIVE: Although the microenvironment for peripheral nerve regeneration is permissive, such a mechanism is defective in diabetes, and the molecular mediators remain elusive. [Correction added on May 11, 2022, after first online publication: In the preceding sentence, "is ok" was changed to "is defective".] This study aimed to (1) investigate the relationship between skin innervation and collagen pathology in diabetic neuropathy and to (2) clarify the molecular alterations that occur in response to hyperglycemia and their effects on axon regeneration. METHODS: We addressed this issue using two complementary systems: (1) human skin from patients with diabetic neuropathy and to (2) a coculture model of human dermal fibroblasts (HDFs) with rat dorsal root ganglia neurons in the context of intrinsic neuronal factor and extrinsic microenvironmental collagen and its biosynthetic pathways. RESULTS: In diabetic neuropathy, the skin innervation of intraepidermal nerve fiber density (IENFd), a measure of sensory nerve degeneration, was reduced with similar expression of a growth associated protein 43, a marker of nerve regeneration. In contrast, the content and packing of collagen in the diabetic skin became more rigid than the control skin. Sec31a, a protein that regulates the collagen biosynthetic pathway, was upregulated and inversely correlated with IENFd. In the cell model, activated HDFs exposed to high-glucose medium enhanced the expression of Sec31a and collagen I through the activation of transforming growth factor ß, a profibrotic molecule. Sec31a upregulation impaired neurite outgrowth. This effect was reversed by silencing Sec31a expression and neurite outgrowth was resumed. INTERPRETATION: The current study provides evidence that Sec31a plays a key role in inhibiting nerve regeneration in diabetic neuropathy. ANN NEUROL 2022;91:821-833.

RU-Net: skull stripping in rat brain MR images after ischemic stroke with rat U-Net.

BACKGROUND: Experimental ischemic stroke models play a fundamental role in interpreting the mechanism of cerebral ischemia and appraising the development of pathological extent. An accurate and automatic skull stripping tool for rat brain image volumes with magnetic resonance imaging (MRI) are crucial in experimental stroke analysis. Due to the deficiency of reliable rat brain segmentation methods and motivated by the demand for preclinical studies, this paper develops a new skull stripping algorithm to extract the rat brain region in MR images after stroke, which is named Rat U-Net (RU-Net). METHODS: Based on a U-shape like deep learning architecture, the proposed framework integrates batch normalization with the residual network to achieve efficient end-to-end segmentation. A pooling index transmission mechanism between the encoder and decoder is exploited to reinforce the spatial correlation. Two different modalities of diffusion-weighted imaging (DWI) and T2-weighted MRI (T2WI) corresponding to two in-house datasets with each consisting of 55 subjects were employed to evaluate the performance of the proposed RU-Net. RESULTS: Extensive experiments indicated great segmentation accuracy across diversified rat brain MR images. It was suggested that our rat skull stripping network outperformed several state-of-the-art methods and achieved the highest average Dice scores of 98.04% (p < 0.001) and 97.67% (p < 0.001) in the DWI and T2WI image datasets, respectively. CONCLUSION: The proposed RU-Net is believed to be potential for advancing preclinical stroke investigation and providing an efficient tool for pathological rat brain image extraction, where accurate segmentation of the rat brain region is fundamental.

Continuous lumbar drainage after aneurysmal subarachnoid hemorrhage decreased malondialdehyde in cerebrospinal fluid and improved outcome.

PURPOSE: The use of a continuous lumbar drain (LD) for the treatment of aneurysmal subarachnoid hemorrhage (aSAH), and malondialdehyde (MDA), a marker of oxidative stress, is correlated with clinical outcome. This study aimed to investigate the relationship between LD placement and MDA level after aSAH. METHODS: Patients with modified Fisher's grade III and IV aSAH who underwent early aneurysm obliteration were enrolled. Cerebrospinal fluid (CSF) was obtained on day 7 after aSAH in non-LD group. In LD group, the LD was inserted on day 3 after aSAH for continuous CSF drainage. The levels of intrathecal hemoglobin, total bilirubin, ferritin, and MDA were measured. RESULTS: There were 41 patients in non-LD group (age: 58.7 ± 13.7 years; female: 61.0%) and 48 patients in LD group (age: 58.3 ± 10.4 years; female: 79.2%). There were more favorable outcomes (Glasgow Outcome Scale ≥4) at 3 months after aSAH in LD group (p = 0.0042). The intrathecal hemoglobin, total bilirubin, ferritin, and MDA levels at day 7 after aSAH were all significantly lower in LD group. An older age (>60 years) (p = 0.0293), higher MDA level in the CSF (p = 0.0208), and delayed ischemic neurological deficit (p = 0.0451) were independent factors associated with unfavorable outcomes. LD placement was associated with a decreased intrathecal MDA level on day 7 after aSAH (p < 0.001). CONCLUSION: The intrathecal MDA level at day 7 after aSAH can be an effective outcome indicator in modified Fisher's grade III/IV aSAH. Continuous CSF drainage via a LD can decrease the intrathecal MDA level and improve the functional outcome.

Efficacy of Tafamidis in Patients with Ala97Ser Hereditary Transthyretin Cardiac Amyloidosis: A Six-Month Follow-Up Study.

Background: Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease. A97S (p.Ala117Ser) is the most common transthyretin genetic mutation in Taiwan. Tafamidis is a transthyretin stabilizer, and it has been shown to improve outcomes. However, its effect on A97S ATTR-CM subtypes remains unknown. Objectives: This study aimed to investigate the efficacy of tafamidis in patients with hereditary A97S ATTR-CM after 6 months of treatment. Methods: We retrospectively analyzed ATTR-CM patients who received tafamidis (61 mg/day) treatment at National Taiwan University Hospital. Functional status, biochemistry and echocardiography were measured at baseline and after 6 months of tafamidis treatment. The outcome measure was to compare the N-terminal pro-brain natriuretic peptide (NT-proBNP) level at baseline and after 6 months of tafamidis treatment. Results: Twenty patients were enrolled in this study. Their mean age was 63.0 ± 5.8 years and 75% were men. The baseline left ventricular (LV) mass index was 200.9 ± 63.9 g/m2, and the baseline LV ejection fraction was 58.9 ± 13.5%. After 6 months of treatment, the log NT-proBNP level significantly improved from 2.9 ± 0.6 to 2.7 ± 0.5 (p = 0.036). Subgroup analysis showed that the LV posterior wall thickness and left atrial diameter were significantly higher in the patients with improved NT-proBNP, suggesting the benefits of tafamidis for ATTR-CM patients with severe cardiac involvement. Conclusions: The patients with hereditary A97S ATTR-CM in this study had decreased levels of NT-proBNP after 6 months of tafamidis treatment, and this reduction was especially pronounced in those with more severe cardiac involvement.

Maladaptive motor cortical excitability and connectivity in polyneuropathy with neuropathic pain.

BACKGROUND AND PURPOSE: Sensory symptoms, especially neuropathic pain, are common in polyneuropathy. Conventional diagnostic tools can evaluate structural or functional impairment of nerves but cannot reveal mechanisms of neuropathic pain. Changes in the brain after polyneuropathy may play roles in the genesis of neuropathic pain. METHODS: This cross-sectional study investigated changes of cortical excitability within left primary motor cortex (M1) by measuring resting motor thresholds, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and afferent inhibition between polyneuropathy patients and controls, and investigated the correlates of these parameters with neuropathic pain and M1 structural and functional connectivity assessed by diffusion tractography imaging and functional magnetic resonance imaging. RESULTS: Thirty-three painful and 15 nonpainful neuropathic patients and 21 controls were enrolled. There were no differences in intraepidermal nerve fiber density, nerve conduction studies, thermal thresholds, or autonomic functional tests between patients with and without neuropathic pain. Compared to controls, neuropathic patients exhibited similar resting motor thresholds or afferent inhibition, but attenuated SICI and augmented ICF, especially in painful patients. Changes of intracortical excitability in neuropathic patients were correlated with intensities of neuropathic pain, and different presentations of SICI and ICF were noted between patients with and without thermal paresthesia. Additionally, short-latency afferent inhibition at an interstimulus interval of 20 ms was associated with structural connectivity of left M1 with brain areas associated with pain perception. CONCLUSIONS: Maladaptive cortical excitability with altered structural connectivity in left M1 developed after peripheral nerve degeneration and was associated with neuropathic pain and sensory symptoms in polyneuropathy.

Diabetic visceral neuropathy of gastroparesis: Gastric mucosal innervation and clinical significance.

BACKGROUND AND PURPOSE: The pathogenesis of diabetic gastroparesis due to visceral neuropathy involves multidimensional mechanisms with limited exploration of gastric mucosal innervation. This study aimed to examine quantitatively this topic and its relationship with gastroparesis symptoms and gastric emptying in diabetes. METHODS: We prospectively enrolled 22 patients with type 2 diabetes and gastroparesis symptoms and 25 age- and gender-matched healthy controls for comparison. The assessments included: (i) neuropathology with quantification of gastric mucosal innervation density (MID) on endoscopic biopsy; (ii) clinical manifestations based on the Gastroparesis Cardinal Symptom Index (GCSI) questionnaire; and (iii) functional tests of gastric emptying scintigraphy (GES). RESULTS: In patients with diabetes, stomach fullness, bloating and feeling excessively full after meals constituted the most common GCSI symptoms. Seven patients with diabetes (32%) had prolonged gastric emptying patterns. In diabetes, gastric MID was significantly lower in all the regions examined compared with the controls: antrum (294.8 ± 237.0 vs. 644.0 ± 222.0 mm/mm3 ; p < 0.001), body (292.2 ± 239.0 vs. 652.6 ± 260.9 mm/mm3 ; p < 0.001), and fundus (238.0 ± 109.1 vs. 657.2 ± 332.8 mm/mm3 ; p < 0.001). Gastric MID was negatively correlated with gastroparesis symptoms and total scores on the GCSI (p < 0.001). Furthermore, gastric MID in the fundus was negatively correlated with fasting glucose and glycated hemoglobin levels. Gastric emptying variables, including half emptying time and gastric retention, were prolonged in patients with diabetes, and gastric retention at 3 h was correlated with fasting glucose level. CONCLUSION: In diabetes, gastric MID was reduced and GES parameters were prolonged. Both were correlated with gastroparesis symptoms and glycemic control. These findings provide pathology and functional biomarkers for diabetic visceral neuropathy of gastroparesis and underlying pathophysiology.

Two separate functions of NME3 critical for cell survival underlie a neurodegenerative disorder.

We report a patient who presented with congenital hypotonia, hypoventilation, and cerebellar histopathological alterations. Exome analysis revealed a homozygous mutation in the initiation codon of the NME3 gene, which encodes an NDP kinase. The initiation-codon mutation leads to deficiency in NME3 protein expression. NME3 is a mitochondrial outer-membrane protein capable of interacting with MFN1/2, and its depletion causes dysfunction in mitochondrial dynamics. Consistently, the patient's fibroblasts were characterized by a slow rate of mitochondrial dynamics, which was reversed by expression of wild-type or catalytic-dead NME3. Moreover, glucose starvation caused mitochondrial fragmentation and cell death in the patient's cells. The expression of wild-type and catalytic-dead but not oligomerization-attenuated NME3 restored mitochondrial elongation. However, only wild-type NME3 sustained ATP production and viability. Thus, the separate functions of NME3 in mitochondrial fusion and NDP kinase cooperate in metabolic adaptation for cell survival in response to glucose starvation. Given the critical role of mitochondrial dynamics and energy requirements in neuronal development, the homozygous mutation in NME3 is linked to a fatal mitochondrial neurodegenerative disorder.

Candida albicans triggers NADPH oxidase-independent neutrophil extracellular traps through dectin-2.

Candida albicans is one of the top leading causes of healthcare-associated bloodstream infection. Neutrophil extracellular traps (NET) are known to capture and kill pathogens. It is reported that opsonized C. albicans-triggered NETosis is NADPH oxidase-dependent. We discovered a NADPH oxidase-independent NETosis pathway in neutrophil response to unopsonized C. albicans. While CR3 engagement with opsonized C. albicans triggered NET, dectin-2 recognized unopsonized C. albicans and mediated NET formation. Engagement of dectin-2 activated the downstream Syk-Ca2+-PKCδ-protein arginine deiminase 4 (PAD4) signaling pathway which modulated nuclear translocation of neutrophil elastase (NE), histone citrullination and NETosis. In a C. albicans peritonitis model we observed Ki67+Ly6G+ NETotic cells in the peritoneal exudate and mesenteric tissues within 3 h of infection. Treatment with PAD4 inhibitor GSK484 or dectin-2 deficiency reduced % Ki67+Ly6G+ cells and the intensity of Ki67 in peritoneal neutrophils. Employing DNA digestion enzyme micrococcal nuclease, GSK484 as well as dectin-2-deficient mice, we further showed that dectin-2-mediated PAD4-dependent NET formation in vivo restrained the spread of C. albicans from the peritoneal cavity to kidney. Taken together, this study reveals that unopsonized C. albicans evokes NADPH oxidase-independent NETosis through dectin-2 and its downstream signaling pathway and dectin-2-mediated NET helps restrain fungal dissemination.

Early changes of nerve integrity in preclinical carriers of hereditary transthyretin Ala117Ser amyloidosis with polyneuropathy.

BACKGROUND AND PURPOSE: Disease-modifying therapies provide new horizons for hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) to slow neuropathic progression. Initiating treatment at the earliest time requires biomarkers reflecting both small- and large-fiber degeneration in carriers. METHODS: This study included examinations of pathology (intraepidermal nerve fiber [IENF] density), physiology (nerve conduction studies, autonomic function test, and nerve excitability), and psychophysics (thermal thresholds) in carriers to compare to healthy controls and asymptomatic diabetic patients. RESULTS: There were 43 carriers (44.2 ± 11.4 years, p.Ala117Ser in 42 carriers), 43 controls (43.4 ± 12.7 years) including 26 noncarrier families, and 50 asymptomatic diabetic patients (58.1 ± 9.5 years). Carriers had lower IENF densities than controls and similar densities as diabetic patients. Median nerve conduction parameters, especially distal motor latency, were the most frequent neurophysiological abnormality in carriers, could differentiate carriers from controls and diabetic patients, were correlated with IENF densities in carriers but not in controls and diabetic patients, and were correlated with nerve excitability parameters in carriers but not in controls. Fifteen carriers (34.9%) with electrophysiological evidence of median nerve entrapment at the wrist had lower IENF densities and more abnormal conduction parameters than carriers without. We defined nerve dysfunction index-the ratio of median distal motor latency to IENF density-which differentiated carriers from controls. CONCLUSIONS: In late-onset ATTRv-PN carriers with predominant p.Ala117Ser, median conduction parameters were the most common neurophysiological abnormalities and served as surrogate signatures of small- and large-fiber impairment. Combination of median distal motor latency and IENF density can reflect early neuropathy in carriers.

Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy.

Parkinson's disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson's disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A>C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson's disease probands with autosomal-dominant Parkinson's disease and 1934 patients with sporadic Parkinson's disease revealed another two variants in UQCRC1 in the probands with familial Parkinson's disease, c.931A>C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G>A) and a frameshift insertion (c.73_74insG, p.Ala25Glyfs*27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson's disease.

Segmentation of Rat Brains and Cerebral Hemispheres in Triphenyltetrazolium Chloride-Stained Images after Stroke.

Ischemic stroke is one of the leading causes of death among the aged population in the world. Experimental stroke models with rodents play a fundamental role in the investigation of the mechanism and impairment of cerebral ischemia. For its celerity and veracity, the 2,3,5-triphenyltetrazolium chloride (TTC) staining of rat brains has been extensively adopted to visualize the infarction, which is subsequently photographed for further processing. Two important tasks are to segment the brain regions and to compute the midline that separates the brain. This paper investigates automatic brain extraction and hemisphere segmentation algorithms in camera-based TTC-stained rat images. For rat brain extraction, a saliency region detection scheme on a superpixel image is exploited to extract the brain regions from the raw complicated image. Subsequently, the initial brain slices are refined using a parametric deformable model associated with color image transformation. For rat hemisphere segmentation, open curve evolution guided by the gradient vector flow in a medial subimage is developed to compute the midline. A wide variety of TTC-stained rat brain images captured by a smartphone were produced and utilized to evaluate the proposed segmentation frameworks. Experimental results on the segmentation of rat brains and cerebral hemispheres indicated that the developed schemes achieved high accuracy with average Dice scores of 92.33% and 97.15%, respectively. The established segmentation algorithms are believed to be potential and beneficial to facilitate experimental stroke study with TTC-stained rat brain images.

Skin nerve pathology: Biomarkers of premanifest and manifest amyloid neuropathy.

OBJECTIVE: Small-fiber sensory and autonomic symptoms are early presentations of familial amyloid polyneuropathy (FAP) with transthyretin (TTR) mutations. This study aimed to explore the potential of skin nerve pathologies as early and disease-progression biomarkers and their relationship with skin amyloid deposits. METHODS: Skin biopsies were performed in patients and carriers to measure intraepidermal nerve fiber (IENF) density, sweat gland innervation index of structural protein gene product 9.5 (SGII[PGP9.5]) and peptidergic vasoactive intestinal peptide (SGII[VIP]), and cutaneous amyloid index. These skin pathologies were analyzed with clinical disability assessed by FAP stage score (stage 0-4) and compared to neurophysiological and psychophysical tests. RESULTS: There were 70 TTR-mutant subjects (22 carriers and 48 patients), and 66 cases were TTR-A97S. Skin nerve pathologies were distinct according to stage. In carriers, both skin denervation and peptidergic sudomotor denervation were evident: (1) IENF density was gradually reduced from stage 0 through 4, and (2) SGII(VIP) was markedly reduced from stage 1 to 2. In contrast, SGII(PGP9.5) was similar between carriers and controls, but it declined in patients from stage 2. Skin amyloids were absent in carriers and became detectable from stage 1. Cutaneous amyloid index was correlated with SGII(PGP9.5) and stage in a multivariate mixed-effect model. When all tests were compared, only IENF density, SGII(PGP9.5), and cutaneous amyloid index were correlated with stage, and IENF density had the highest abnormal rate in carriers. INTERPRETATION: Biomarkers of sensory and sudomotor innervation exhibited a stage-dependent progression pattern, with sensory nerve degeneration as the early skin nerve pathology. Ann Neurol 2019;85:560-573.

Cardiac manifestations and prognostic implications of hereditary transthyretin amyloidosis associated with transthyretin Ala97Ser.

BACKGROUND: The cardiac manifestations of late-onset hereditary transthyretin amyloidosis with p.A97S variant have not been extensively studied, and the prognostic factors remain unclear. METHODS: The clinical profile, echocardiography, and ECG of patients diagnosed with ATTR p.A97S polyneuropathy between 2000 and 2016 were retrospectively collected. 67 patients with ATTR p.A97S were collected. RESULTS: A total of 82% of patients met the criteria for left ventricular (LV) hypertrophy. Reduced global longitudinal strain (GLS) was noted in 42.1% of patients, and 14% of patients had a relative apical sparing pattern. A low voltage pattern in the ECG was observed in 31.3% of patients, while 64.2% presented with a pseudoinfarction pattern. End-systolic LV inner dimension (HR: 2.25 (95% CI: 1.01-5.01), p = 0.048), reduced GLS (HR: 5.26 (1.08-25.0), p = 0.039), relative apical longitudinal strain (RALS>1, HR: 8.57 (1.69-43.3), p = 0.009), increased E/A ratio (HR: 6.51 (1.17-36.4), p = 0.033), and increased QRS duration (HR: 1.02 (1.00-1.04), p = 0.05) were correlated with reduced survival in univariate analysis. Multivariate analysis revealed reduced RALS was significantly correlated with reduced survival (HR: 13.00 (1.81-93.45), p = 0.011). CONCLUSION: Our findings reveal that ATTR p.A97S is a cardiomyopathy as well as a polyneuropathic syndrome. Routine use of more contemporary echocardiographic techniques are recommended to identify cardiac amyloidosis and provide prognostic information.

Pathophysiology of Central Poststroke Pain: Motor Cortex Disinhibition and Its Clinical and Sensory Correlates.

Background and Purpose- Central poststroke pain (CPSP) is a disabling condition in stroke patients, and evidence suggests that altered corticospinal and motor intracortical excitability occurs in neuropathic pain. The objective of this study was to investigate changes in motor cortex excitability and sensorimotor interaction and their correlates with clinical manifestations and alterations in somatosensory systems in CPSP patients. Methods- Fourteen patients with CPSP but no motor weakness were compared with age- and sex-matched healthy controls for motor cortex excitability and sensorimotor interaction assessed by transcranial magnetic stimulation to measure resting motor thresholds, short-interval intracortical inhibition, intracortical facilitation, and afferent inhibitions. The sensory pathway was evaluated by quantitative sensory testing, contact heat evoked potential, and somatosensory evoked potentials. Clinical pain and quality of life were assessed with validated tools. Results- The duration of CPSP was 3.3±3.0 years (ranging 0.5-10 years), and pain significantly impaired quality of life. Compared with the unaffected hemisphere, the stroke hemisphere had higher thermal thresholds, lower contact heat evoked potential amplitudes, and prolonged cortical somatosensory evoked potential latencies. There was no difference in resting motor thresholds between the stroke and unaffected hemisphere or between patients and controls. CPSP patients had a reduction in short-interval intracortical inhibition in the stroke hemisphere compared with that in the unaffected hemispheres of patients and controls. No changes were noted in afferent inhibitions between the stroke and unaffected hemispheres. The short-interval intracortical inhibition of the stroke hemisphere was negatively correlated with self-rated health on a visual analog scale and positively correlated with cortical somatosensory evoked potential latencies. Conclusions- CPSP patients with intact corticospinal tracts showed reduced motor intracortical inhibition in the stroke hemisphere, suggesting defective gamma-aminobutyric acid-ergic inhibition. This disinhibition was associated with impaired quality of life and was related to dorsal column-medial lemniscus pathway dysfunction.