Cerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases.

Cerebrospinal fluid (CSF) biomarkers reflect brain pathophysiology and are used extensively in translational research as well as in clinical practice for diagnosis of neurological diseases, e.g., Alzheimer's disease (AD). However, CSF biomarker concentrations may be influenced by non-disease related inter-individual variability. Here we use a data-driven approach to demonstrate the existence of inter-individual variability in mean standardized CSF protein levels. We show that these non-disease related differences cause many commonly reported CSF biomarkers to be highly correlated, thereby producing misleading results if not accounted for. To adjust for this inter-individual variability, we identified and evaluated high-performing reference proteins which improved the diagnostic accuracy of key CSF AD biomarkers. Our reference protein method attenuates the risk for false positive findings, and improves the sensitivity and specificity of CSF biomarkers, with broad implications for both research and clinical practice.

Uraemic brainstem encephalopathy mimicking ocular myasthenia: a case report.

BACKGROUND: Uraemia causes a generalised encephalopathy as its most common neurological complication. Isolated brainstem uraemic encephalopathy is rare. We report a case of fatigable ptosis and complex ophthalmoplegia in brainstem uraemic encephalopathy. CASE PRESENTATION: A 22-year-old Sri Lankan man with end stage renal failure presented with acute onset diplopia and drooping of eyelids progressively worsening over one week. The patient had not complied with the prescribed renal replacement therapy which was planned to be initiated 5 months previously. On examination, his Glasgow coma scale score was 15/15, He had a fatigable asymmetrical bilateral ptosis. The ice-pack test was negative. There was a complex ophthalmoplegia with bilateral abduction failure and elevation failure of the right eye. The diplopia did not worsen with prolonged stare. The rest of the neurological examination was normal. Serum creatinine on admission was 21.81 mg/dl. The repetitive nerve stimulation did not show a decremental pattern. Magnetic resonance imaging (MRI) of the brain demonstrated diffuse midbrain and pontine oedema with T2 weighted/FLAIR hyperintensities. The patient was haemodialyzed on alternate days and his neurological deficits completely resolved by the end of the second week of dialysis. The follow up brain MRI done two weeks later demonstrated marked improvement of the brainstem oedema with residual T2 weighted/FLAIR hyperintensities in the midbrain. CONCLUSIONS: Uraemia may rarely cause an isolated brainstem encephalopathy mimicking ocular myasthenia, which resolves with correction of the uraemia.

Superoxide dismutase nanozymes: current status and future perspectives on brain disease treatment and diagnosis.

Superoxide dismutase (SOD) is an important metalloenzyme that catalyzes the dismutation of superoxide radicals (O2˙-) into hydrogen peroxide (H2O2) and oxygen (O2). However, the clinical application of SOD is severely limited due to its structural instability and high cost. Compared with natural enzymes, nanomaterials with enzyme-like activity, nanoenzymes, are more stable, economical and easy to modify and their activity can be adjusted. Certain nanozymes that exhibit SOD-like activity have been created and shown to help prevent illnesses brought about by oxidative stress. These SOD-like nanozymes offer an important solution to the problems associated with the clinical application of SOD. In this review, we briefly introduce neurodegenerative diseases, present the research progress of SOD-like nanoenzymes in the diagnosis and treatment of brain diseases, review their mechanism of action in the treatment and diagnosis of brain diseases, and discuss the shortcomings of the current research with a view to providing a reference for future research. We expect more highly active SOD-like nanoenzymes to be developed with a wide range of applications in the diagnosis and treatment of brain diseases.

[A case of COVID-associated encephalopathy in a patient with multiple sclerosis]. / Klinicheskii sluchai COVID-assotsiirovannoi entsefalopatii u patsienta s rasseyannym sklerozom.

A case of acute encephalopathy manifested with impaired consciousness, hemichorrhea, speech and cognitive impairment in a female patient with COVID-19 and multiple sclerosis is presented. In the literature, there are isolated reports of such a combination of diseases, and therefore difficulties arise in carrying out differential diagnosis and prescribing therapy. Given the limited knowledge about the long-term consequences of COVID-19, systematic analysis of such cases and follow-up of such patients is necessary.

GNB1 Encephalopathy: Clinical Case Report and Literature Review.

GNB1 encephalopathy is a rare genetic disease caused by pathogenic variants in the G Protein Subunit Beta 1 (GNB1) gene, with only around 68 cases documented worldwide. Although most cases had been caused by de novo germline mutations, in this case, the pathogenic variant was inherited from patient's mother, indicating an autosomal dominant inheritance pattern. The patient presented at 25 years of age with mild developmental delay and cognitive impairment, prominent generalized dystonia, and horizontal nystagmus which are all characterizing symptoms of GNB1 encephalopathy. Electroencephalography (EEG) showed no epileptiform patterns, and magnetic resonance imaging (MRI) revealed hypointensities in globus pallidus and dentate nucleus areas. The main theory for GNB1 encephalopathy pathogenesis is neuronal hyperexcitability caused by impaired ion channel regulation. Due to low specificity of symptoms, diagnosis relies on genetic testing. As there are no standardized GNB1 encephalopathy treatment guidelines, evaluation of different treatment options is based on anecdotal cases. Reviewing different treatment options, deep brain stimulation and intrathecal baclofen pump, as well as some other medications still in preclinical trials, seem to be the most promising.

Connectional-style-guided contextual representation learning for brain disease diagnosis.

Structural magnetic resonance imaging (sMRI) has shown great clinical value and has been widely used in deep learning (DL) based computer-aided brain disease diagnosis. Previous DL-based approaches focused on local shapes and textures in brain sMRI that may be significant only within a particular domain. The learned representations are likely to contain spurious information and have poor generalization ability in other diseases and datasets. To facilitate capturing meaningful and robust features, it is necessary to first comprehensively understand the intrinsic pattern of the brain that is not restricted within a single data/task domain. Considering that the brain is a complex connectome of interlinked neurons, the connectional properties in the brain have strong biological significance, which is shared across multiple domains and covers most pathological information. In this work, we propose a connectional style contextual representation learning model (CS-CRL) to capture the intrinsic pattern of the brain, used for multiple brain disease diagnosis. Specifically, it has a vision transformer (ViT) encoder and leverages mask reconstruction as the proxy task and Gram matrices to guide the representation of connectional information. It facilitates the capture of global context and the aggregation of features with biological plausibility. The results indicate that CS-CRL achieves superior accuracy in multiple brain disease diagnosis tasks across six datasets and three diseases and outperforms state-of-the-art models. Furthermore, we demonstrate that CS-CRL captures more brain-network-like properties, and better aggregates features, is easier to optimize, and is more robust to noise, which explains its superiority in theory.

Meta-analysis of evaluating neuron specific enolase as a serum biomarker for sepsis-associated encephalopathy.

INTRODUCTION: Brain dysfunction in sepsis is known as Sepsis-associated encephalopathy (SAE), which often results in severe cognitive and neurological sequelae and increases the risk of death. Neuron specific enolase (NSE) may serve as an important neurocritical biomarker for detection and longitudinal monitoring in SAE patients. Our Meta-analysis aimed to explore the diagnostic and prognostic value of serum NSE in SAE patients. Currently, no systematic Review and Meta-analysis have been assessed that NSE as a biomarker of SAE. METHODS: The study protocol was registered in the PROSPERO database (CRD42023398736) and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We conducted a systematic review and Meta-analysis to evaluate the serum NSE's diagnostic accuracy for SAE and prognostic strength for probability of death of septic patients. We systematic searched electronic bibliographic databases from PubMed, MEDLINE, Web of Science, Embase, Cochrane databases, CNKI, CQVIP, and WFSD. QUADAS-2 assessment tool was used to evaluate quality and risk of bias of the selected studies. Subgroup analyses, funnel plots, sensitivity analyses were also carried out. Review Manager version 5.4 and Stata16.0. was used for statistical analysis. RESULTS: This Meta-analysis included 22 studies with 1361 serum samples from SAE patients and 1580 serum samples from no-encephalopathy septic (NE) patients. The Meta-analysis showed that individuals with SAE had higher serum NSE level than NE controls (SMD 1.93 (95 % CI 1.51-2.35), P < 0.00001). In addition, there are 948 serum samples from survival septic patients and 446 serum samples from non-survival septic patients, septic patients with survival outcomes had lower serum NSE levels than those with death outcomes (SMD -1.87 (95 % CI -2.43 to -1.32), P < 0.00001). CONCLUSION: Our Meta-analysis reveals a significant association between elevated NSE concentrations and the increased likelihood of concomitant SAE and mortality during septic patients. This comprehensive analysis will equip ICU physicians with up-to-date insights to accurately identify patients at risk of SAE and implement appropriate intervention strategies to mitigate morbidity and improve neurological outcomes. However, it is important to note that the presence of substantial heterogeneity among studies poses challenges in determining the most effective discrimination cutoff values and optimal sampling collection time.

Interventionism and Intelligibility: Why Depression Is Not (Always) a Brain Disease.

Major depressive disorder (MDD) is a serious condition with a large disease burden. It is often claimed that MDD is a "brain disease." What would it mean for MDD to be a brain disease? I argue that the best interpretation of this claim is as offering a substantive empirical hypothesis about the causes of the syndrome of depression. This syndrome-causal conception of disease, combined with the idea that MDD is a disease of the brain, commits the brain disease conception of MDD to the claim that brain dysfunction causes the symptoms of MDD. I argue that this consequence of the brain disease conception of MDD is false. It incorrectly rules out genuine instances of content-sensitive causation between adverse conditions in the world and the characteristic symptoms of MDD. Empirical evidence shows that the major causes of depression are genuinely psychological causes of the symptoms of MDD. This rules out, in many cases, the "brute" causation required by the brain disease conception. The existence of cases of MDD with non-brute causes supports the reinstatement of the old nosological distinction between endogenous and exogenous depression.

Characterization of neurological morbidity associated with thyroid antibodies: Hashimoto's encephalopathy and beyond.

BACKGROUND: Hashimoto's Encephalopathy (HE) manifests with various neurologic symptoms associated with elevated thyroglobulin (TG) and/or thyroperoxidase (TPO) antibodies. Some patients with thyroid antibodies exhibit neurological presentations not consistent with HE. This study aims to characterize the spectrum of neurological morbidity in patients with thyroid antibodies. METHODS: We reviewed all patients tested for TG or TPO antibodies from 2010 to 2019. Patients tested for thyroid antibodies as part of a neurological workup for new symptoms were classified into the following categories: patients meeting full criteria for HE, patients with other neuroimmunological disorders, patients with unexplained neurological symptoms not fully meeting HE criteria, and patients with incidental non neuroimmunological disorders. RESULTS: There were 2717 patients with positive thyroid antibodies in the dataset including 227 patients (78% female, age 54 ± 19 years) who met inclusion criteria. Twelve patients (5%) met HE criteria, 30 (13%) had other neuroimmunological disorders, 32 (14%) had unexplained neurological symptoms, and 153 (67.4%) had incidental disorders. In addition to cognitive dysfunction, seizures, movement disorders, motor weakness, and psychosis, HE patients were also more likely to have cerebellar dysfunction, language impairment, and sensory deficits. They were more likely to carry a Hashimoto's thyroiditis diagnosis and had higher titers of thyroid antibodies. They all had a robust response to steroids. CONCLUSION: The neurological spectrum of HE may be wider than previously reported, including frequent cerebellar, sensory, and language dysfunction. A subgroup of thyroid antibody positive patients with unexplained neurological symptoms may represent further expansion of thyroid antibody-related neurological disorders.

Understanding immune microenvironment alterations in the brain to improve the diagnosis and treatment of diverse brain diseases.

Abnormal inflammatory states in the brain are associated with a variety of brain diseases. The dynamic changes in the number and function of immune cells in cerebrospinal fluid (CSF) are advantageous for the early prediction and diagnosis of immune diseases affecting the brain. The aggregated factors and cells in inflamed CSF may represent candidate targets for therapy. The physiological barriers in the brain, such as the blood‒brain barrier (BBB), establish a stable environment for the distribution of resident immune cells. However, the underlying mechanism by which peripheral immune cells migrate into the brain and their role in maintaining immune homeostasis in CSF are still unclear. To advance our understanding of the causal link between brain diseases and immune cell status, we investigated the characteristics of immune cell changes in CSF and the molecular mechanisms involved in common brain diseases. Furthermore, we summarized the diagnostic and treatment methods for brain diseases in which immune cells and related cytokines in CSF are used as targets. Further investigations of the new immune cell subtypes and their contributions to the development of brain diseases are needed to improve diagnostic specificity and therapy.

Clinical Characterization and Ancillary Tests in Susac Syndrome: A Systematic Review.

Susac syndrome (SuS) is an orphan microangiopathic disease characterized by a triad of encephalopathy, visual disturbances due to branch retinal artery occlusions, and sensorineuronal hearing loss. Our previous systematic review on all cases of SuS reported until 2012 allowed for a better understanding of clinical presentation and diagnostic findings. Based on these data, we suggested diagnostic criteria in 2016 to allow early diagnosis and treatment of SuS. In view of the accumulation of new SuS cases reported in the last 10 years and improved diagnostic tools, we here aimed at updating the demographic and clinical features of SuS and to review the updated ancillary tests being used for SuS diagnosis. Therefore, based on the 2016 criteria, we systematically collected and evaluated data on SuS published from January 2013 to March 2022.

Rapid exome sequencing for children with severe acute encephalopathy - A case series.

Increasingly, next-generation sequencing (NGS) is becoming an invaluable tool in the diagnosis of unexplained acute neurological disorders, such as acute encephalopathy/encephalitis. Here, we describe a brief series of pediatric patients who presented at the pediatric intensive care unit with severe acute encephalopathy, initially suspected as infectious or inflammatory but subsequently diagnosed with a monogenic disorder. Rapid exome sequencing was performed during the initial hospitalization of three unrelated patients, and results were delivered within 7-21 days. All patients were previously healthy, 1.5-3 years old, of Muslim Arab descent, with consanguineous parents. One patient presenting with acute necrotizing encephalopathy (ANEC). Her sister presented with ANEC one year prior. Exome sequencing was diagnostic in all three patients. All were homozygous for pathogenic and likely-pathogenic variants associated with recessive disorders; MOCS2, NDUFS8 and DBR1. Surprisingly, the initial workup was not suggestive of the final diagnosis. This case series demonstrates that the use of rapid exome sequencing is shifting the paradigm of diagnostics even in critical care situations and should be considered early on in children with acute encephalopathy. A timely diagnosis can direct initial treatment as well as inform decisions regarding long-term care.

c.202_204del in NUP214 causes late onset form of febrile encephalopathy.

Nucleoporins (NUPs) are a group of transporter proteins that maintain homeostasis of nucleocytoplasmic transport of proteins and ribonucleic acids under physiological conditions. Biallelic pathogenic variants in NUP214 are known to cause susceptibility to acute infection-induced encephalopathy-9 (IIAE9, MIM#618426), which is characterized by severe and early-onset febrile encephalopathy causing neuroregression, developmental delay, microcephaly, epilepsy, ataxia, brain atrophy, and early death. NUP214-related IIAE9 has been reported in eight individuals from four distinct families till date. We identified a novel in-frame deletion, c.202_204del p.(Leu68del), in NUP214 by exome sequencing in a 20-year-old male with episodic ataxia, seizures, and encephalopathy, precipitated by febrile illness. Neuroimaging revealed progressive cerebellar atrophy. In silico predictions show a change in the protein conformation that may alter the downstream protein interactions with the NUP214 N-terminal region, probably impacting the mRNA export. We report this novel deletion in NUP214 as a cause for a late onset and less severe form of IIAE9.

Newly discovered variants in unexplained neonatal encephalopathy.

BACKGROUND: The genetic background of neonatal encephalopathy (NE) is complicated and early diagnosis is beneficial to optimizing therapeutic strategy for patients. METHODS: NE Patients with unclear etiology received regular clinical tests including ammonia test, metabolic screening test, amplitude-integrated electroencephalographic (aEEG) monitoring, brain Magnetic Resonance Imaging (MRI) scanning, and genetic test. The protein structure change was predicted using Dynamut2 and RoseTTAFold. RESULTS: 15 out of a total of 113 NE Patients were detected with newly reported pathogenic variants. In this sub-cohort, (1) seizure was the primary initial symptoms; (2) four patients had abnormal metabolic screening results, and two of them were also diagnosed with excessive blood ammonia concentration; (3) the brain MRI results were irregular in three infants and the brain waves were of moderate-severe abnormality in about a half of the patients. The novel pathogenic variants discovered in this study belonged to 12 genes, and seven of them were predicted to introduce a premature translation termination. In-silicon predictions showed that four variants were destructive to the protein structure of KCNQ2. CONCLUSION: Our study expands the mutation spectrum of genes associated with NE and introduces new evidence for molecular diagnosis in this newborn illness.