Neurofilament light chain in the assessment of patients with multiple sclerosis / Neurofilamento de cadeia leve na avaliação de pacientes com esclerose múltipla

ABSTRACT Multiple sclerosis (MS) is an autoimmune, inflammatory, and degenerative disease of the central nervous system. Axonal degeneration is triggered by inflammation and is the pathological substrate of progressive disability in patients with MS. Therapeutic interventions can reduce inflammatory activity, thus delaying neurodegeneration and the progression of disability. Disease activity and neurodegeneration are assessed mainly through clinical evaluation and magnetic resonance imaging. These measures lack sensitivity and accuracy, so new biomarkers are necessary. Several markers have been studied and to date the most promising is neurofilament light (NfL), a component of the axonal cytoskeleton, which is released into cerebrospinal fluid (CSF) following axonal damage. In the present study, we review the current knowledge about CSF NfL determination in MS, clinically isolated syndrome, and radiologically isolated syndrome, and critically discuss how CSF NfL measurement may contribute to therapeutic decision-making in these patients.

RESUMO A esclerose múltipla (EM) é uma doença autoimune, inflamatória e degenerativa do sistema nervoso central. A degeneração axonal é deflagrada pelo processo inflamatório e é o substrato patológico da incapacidade na EM. As intervenções terapêuticas reduzem a inflamação retardando a neurodegeneração e a progressão da incapacidade. A neurodegeneração é avaliada pelo quadro clínico e pela ressonância magnética. Estas mensurações não suficientemente acuradas, havendo necessidade de novos biomarcadores. Diversos biomarcadores têm sido estudados e, até o presente, o mais promissor é o neurofilamento de cadeia leve (NfL). O mesmo é um componente do citoesqueleto que é liberado no líquido cefalorraquidiano após injúria axonal. No presente estudo nós revisamos o conhecimento atual acerca do NfL na EM, síndrome clinica isolada e síndrome radiológica isolada, discutindo criticamente como a determinação deste biomarcador pode contribuir na tomada de decisões clínicas.

The cerebrospinal fluid in multiple sclerosis: far beyond the bands / O líquido cefalorraquidiano na esclerose múltipla: muito além das bandas

ABSTRACT The cerebrospinal fluid analysis has been employed for supporting multiple sclerosis diagnosis and ruling out the differential diagnoses. The most classical findings reflect the inflammatory nature of the disease, including mild pleocytosis, mild protein increase, intrathecal synthesis of immunoglobulin G, and, most typically, the presence of oligoclonal bands. In recent years, new biomarkers have emerged in the context of multiple sclerosis. The search for new biomarkers reflect the need of a better evaluation of disease activity, disease progression, and treatment efficiency. A more refined evaluation of disease and therapy status can contribute to better therapeutic choices, particularly in escalation of therapies. This is very relevant taking into account the availability of a greater number of drugs for multiple sclerosis treatment in recent years. In this review, we critically evaluate the current literature regarding the most important cerebrospinal fluid biomarkers in multiple sclerosis. The determination of biomarkers levels, such as chemokine ligand 13, fetuin A, and mainly light neurofilament has shown promising results in the evaluation of this disease, providing information that along with clinical and neuroimaging data may contribute to better therapeutic decisions.

RESUMO A análise do líquido cefalorraquidiano tem sido empregada para avaliação diagnóstica da esclerose múltipla e a exclusão dos diagnósticos diferenciais. Os achados clássicos refletem a natureza inflamatória da doença, incluindo discreta pleocitose, leve hiperproteinorraquia, aumento da síntese intratecal de imunoglobulina G e, mais tipicamente, a presença de bandas oligoclonais. Nos últimos anos, surgiram novos biomarcadores para esclerose múltipla, e esta busca por marcadores reflete a necessidade de melhor avaliar a atividade e a progressão da doença, bem como a eficácia terapêutica. Uma avaliação mais refinada da atividade da doença e da resposta aos medicamentos pode contribuir para melhores decisões terapêuticas, particularmente no que se refere à troca de medicação. Isto é muito importante nos dias de hoje, quando surgem novas opções medicamentosas. Neste artigo de revisão, avaliamos criticamente a literatura atual referente aos novos marcadores liquóricos na esclerose múltipla. A mensuração destes marcadores, como a quimiocina CXCL13, fetuína A e, principalmente, o neurofilamento de cadeia leve, demonstrou resultados promissores na avaliação da doença, provendo informações que, em conjunto com dados clínicos e de neuroimagem, podem contribuir para melhores decisões terapêuticas.

Significance of neurofilament light in the diagnosis and prognosis of neuromyelitis optica spectrum disorders / 中华神经科杂志

Objective To discover the significance of neurofilament light (NFL) chain of cerebrospinal fluid (CSF), an axonal injury biomarker, in diagnosis and prognosis prediction of neuromyelitis optica spectrum disorders(NMOSD).Methods Sixty-one NMOSD patients and 24 other patients such as neurosis, migraine and so on, with lumbar puncture were enrolled as NMOSD group and normal control (NC) group from in and out patients of Department of Neurology of Navy General Hospital from January 2014 to August 2016. The clinical and neuroimaging features of NMOSD group and CSF samples of both groups were collected,and the NFL levels of CSF were measured by enzyme linked immunosorbent assay. The CSF NFL levels in different subtypes of NMOSD patients were compared, and the influence factors of the NFL levels in CSF were calculated by multiple linear regression analysis. Results The NFL levels of CSF in NMOSD group (2 729.00(14 862.00) pg/ml) were significantly higher than that in NC group ((299.50(308.00) pg/ml, t=8.588, P=0.000;t test of NFL levels was performed after logarithmicly transforming based on 10). There were no statistically significant differences of CSF NFL levels among optic neuritis, longitudinally extensive transverse myelitis and neuromyelitis optica. In NMOSD group, age (b=0.017, P<0.01), Expanded Disability Status Scale score (b=0.078, P<0.05) and enhancement in gadolinium-magnetic resonance imaging (b=0.478, P<0.01) were correlated with the NFL levels of CSF, while gender, courses of diseases and aquaporin 4 antibody in serum were not related to the NFL levels. Conclusion The NFL levels of CSF are conducive to assess the severity and probable progress of NMOSD.

Value of Alzheimer-associated neuronal thread protein level in urine for diagnosing Alzheimer's disease / 中华老年医学杂志

Objective To investigate the value of Alzheimer-associated neuronal thread protein (AD7c-NTP) level in urine for diagnosing Alzheimer's disease (AD). Methods The urine samples of 450 subjects were collected from out-department of our hospital.There were 257 people with AD diseases (131 mild cases,126 moderate and severe cases) and 193 healthy control.ELISA was applied to test the level of AD7c-NTP in urine samples. Results The levels of AD7c-NTP were (1.94±0.74)μg/L,(3.92 ± 0.86 ) μg/L and (0.65 ± 0.80) μg/L in mild AD,moderate and severe AD,healthy control groups,respectively.There were differences among three groups(F=-13.520,P＜0.001),and between mild and moderate and severe AD(t =1.727,P＜ 0.001).The level of AD7c-NTP was negatively related with MMSE score in mild AD (r =- 0.23,P =0.006),while no correlation was found between AD7c-NTP and MMSE in moderate and severe AD(r=0.59,P =0.113).Using receiver operating characteristic curve(ROC curve),the optimal cutoff point of AD7cNTP in urine for diagnosis of AD was 1.50 μg/L,with 90.6％ sensitivity and 91.8％ specificity,area under the curve was 0.94(95％ CI:0.91-0.97). Conclusions The level of AD7c-NTP in urine may be one of parameters for diagnosing AD.

Influence of Scalp Point-through-point Acupuncture on 200 kDa Neurofilament Protein in Rats with Acute Cerebral Infarction / 针灸推拿医学（英文版）

Objective: To investigate the effect of scalp point-through-point acupuncture on 200 kDa neurofilament protein (NF-200) in rats with acute cerebral infarction and explore its mechanism on nerve plasticity in cerebral infarction rats. Methods: Healthy male Wistar rats were randomly allocated to sham operation (Group A), model (Group B) and acupuncture (Group C) groups. A rat middle cerebral artery occlusion (MCAO) model of cerebral ischemia was made. NF-200 mRNA was measured by reverse transcriptase polymerase chain reaction (RT-PCR) in each group on the 7th, 14th and 28th days. Results: The cerebral expression of NF-200 in group C was significantly different from those in groups A and B (P＜0.05); there was a significant difference between groups C and B or A at different time windows (P＜0.01),indicating that scalp point-through-point acupuncture could improve the cerebral expression of NF-200. Conclusion: Scalp point-through-point acupuncture can improve neural function,promote the recovery of limb function and increase the expression of NF-200 after cerebral ischemia, exerting a regulative effect on neuronal plasticity in the brain.

Neurofilament Protein Subtype Expression in Neuronal Migration Disorders

BACKGROUND: Neuronal migration disorder (NMD) is one of the causes of medically intractable epilepsy. As neurosurgical treatments for medically intractable epilepsy have expanded recently, precise histopathologic diagnosis is required. Histopathologic grading of NMD is important due to its association with neocortical development and expectation of prognosis. Many studies revealed abnormalities of neuronal cytoskeletal protein in abnormal neuronal cells of NMD. METHODS: We performed immunohistochemical staining for neurofilament protein (NF) subtypes, one of the neuronal cytoskeletal proteins, and investigated the staining pattern of specific cells in each grade of NMD. RESULTS: NF-L was more intensely labeled in perikarya, dendrites, and axons of normal or small sized dysplastic neurons, cytomegalic neurons, and balloon cells than of normal-looking neurons. Furthermore, positive reaction was more intense in high-grade lesion. NF-H and NF-M were mainly positive in the axons of gray and white matter and weakly positive in a few cytomegalic neurons and some balloon cells. CONCLUSION: NF-L is a better marker than NF-H and NF-M for the detection of normal or small sized dysplastic neurons, cytomegalic neurons, and balloon cells and for grading of NMD.

Cytoskeletal Changes in Cortical Dysplasia

Cortical dysplasia is a cause of intractable epilepsy and a candidate for surgical resection to control epileptic attacks. The neuronal cytomegaly and balloon cell change are the diagnostic hallmarks of cortical dysplasia. Little research has been performed about the normal-sized dysplastic neuron which has complex arborizing dendrites and lacks in its polarity. The aim of this study was to define the histopathologic characteristics of the neurons in cortical dysplasia. Twelve cases of cortical dysplasia who underwent partial lobectomy for intractable seizures were selected and immunohistochemical staining for NF-M/H, MAP2, tau, and ubiquitin was performed. The perikarya and dendrite of dysplastic neurons were more intensely labeled with antibodies for the high and medium molecular weight neurofilament proteins (NF-M/H) than normal neurons. Immunoreactivity with the MAP2 antibody expressed mainly within the somatodendritic regions was present in the dysplastic or normal neurons without any significant difference in intensity. The complex arborizing dendrites of dysplastic neurons were easily identified due to pronounced immunoreactivity within the somatodendritic regions. Immunoreactivity with the primary antibody against tau and ubiquitin was present in the normal-looking neurons as well as the dysplastic neurons. This study suggests that the dysplastic neurons in cortical dysplasia are accompanied by changes of cytoskeletal neurofilaments, and the immunohistochemical stains for NF-M/H, MAP2, tau, and ubiquigin are useful to detect them.

Acute stress affects the PRA and AngⅡ levels in plasma and the cytoskeletons in hippocampus in adult rats / 中国病理生理杂志

AIM:To observe the changes in plasma rennin activity(PRA)and angiotensin Ⅱ(AngⅡ)level and the cytoskeletons in dorsal hippocampus(DH)in male and female stressed rats.METHODS:The adult Sprague-Dawley male and femal rats were stressed for 6 h per day.Three days later,the levels of PRA and AngⅡin plasma were determined by radioimmunoassay,and the expression of nestin and NF200 in dentate gyrus(DG)and CA3 regions were observed with immunohistochemical staining.RESULTS:①The levels of PRA in plasma of male or female rats were decreased in stressed rats compared with control groups(P