Brain and Nerve最新文献

Considering its proven clinical usefulness and supportive evidence, intravenous immunoglobulin (IVIg) is used as first-line therapy for chronic inflammatory demyelinating polyneuropathy (CIDP) during the acute and chronic stages. However, the pathomechanism underlying IVIg administration for CIDP remains unclear. Autoantibodies, complement, inflammatory cytokines, chemokines, T cells, B cells, macrophages, and the blood-nerve barrier contribute to the onset and progress of CIDP. The mechanisms underlying the actions of IVIg in CIDP include the following: (1)neutralization of pathological autoantibodies by anti-idiotype antibodies, (2)inhibition of the neonatal Fc receptor (FcRn) with a consequent decrease in pathological autoantibodies, (3)neutralization of cytokines, chemokines, and complement, (4)activity modulation of T cells, B cells, and macrophages, and (5) recovery of blood-nerve barrier function. Compared with the management of typical CIDP, IVIg therapy is less effective for management of autoimmune nodopathy associated with anti-neurofascin-155 or contactin-1 IgG4 antibodies because (1)anti-idiotype antibodies associated with IVIg cannot effectively neutralize IgG4 owing to the strong antigen specificity of IgG4 autoantibodies, and (2)complement, T cells, and macrophages play an insignificant role in the pathomechanism of autoimmune nodopathy. Further understanding of the mechanisms underlying IVIg action and effectiveness of molecular targeted therapy, such as use of FcRn or complement inhibitors and the CD20 monoclonal antibody, is warranted to develop novel therapeutic strategies against CIDP.

B-cell therapy using anti-CD20 antibodies significantly suppresses relapse and is therefore an important treatment option for multiple sclerosis (MS). Based on the production of inflammatory cytokines and enhanced antigen-presenting capacity, B cells trigger MS relapses via activation of pathogenic T cells. Suppression of these abnormal actions of B cells is the primary mechanism underlying relapse prevention using B-cell therapies. Treatments that target B cells are also expected to suppress chronic progression of MS through modulation of B-cell activity within the central nervous system. B-cell therapies based on novel approaches are expected to improve the regulation of acute and chronic MS pathology.

Blood biomarkers are minimally invasive, are available at a relatively low cost, and are easily accessible; therefore, they are expected to play a pivotal role in the diagnosis of dementia. Measurement of the amyloid-β ratio and phosphorylated tau in plasma has shown high potential for accurate detection of brain pathology in patients with Alzheimer's disease. Studies have investigated blood biomarkers that reflect neurodegeneration and neuroinflammation in patients with dementia. Challenges associated with blood biomarker use include the lack of robustness of the test and the role of confounders that potentially prevent their immediate clinical application. Further real-world studies are warranted to validate the usefulness of blood biomarkers in dementia management. Appropriate recommendations for the use of blood biomarkers for dementia have been published for physicians and investigators, both in Japan and overseas. Considering the versatility of blood biomarkers, they should be cautiously introduced for clinical use.

The molecular pathogenesis of Alzheimer's disease (AD) has been elucidated through the biochemical analysis of senile plaques, neurofibrillary tangles, and pathological features of the brains of patients with AD. Genetic analysis, initiated with familial AD investigation, has revealed that Aβ aggregation and accumulation are crucial processes in AD pathogenesis. The success of lecanemab against aggregated Aβ is the result of these efforts. Meanwhile, research on tau as a causative molecule in AD and various other tauopathies is advancing gradually. Furthermore, genetic analysis has revealed that the inflammatory response of glial cells modifies AD pathophysiology; a novel therapeutic strategy for inflammation control is thus currently under consideration. This article summarizes the latest discoveries related to these new therapeutic strategies for AD.

Amyloid-related imaging abnormalities (ARIA) represent the most frequent adverse effect of lecanemab, a monoclonal antibody drug that targets amyloid beta. ARIA is observed in approximately 20% of patients who receive lecanemab. Most patients are asymptomatic; however, some develop serious neurological symptoms, and optimal management remains clinically challenging in such cases. In this review, I summarize the pathomechanism underlying ARIA and associated disorders, in addition to countermeasures for ARIA.

The launch of lecanemab (an anti-Aβ antibody) has introduced a new treatment for Alzheimer's disease. In contrast to conventional therapeutic approaches to dementia, this drug requires new concepts in diagnosis, evaluation, and adverse effects. Specifically, evaluation of the efficacy of lecanemab is extremely important because this drug does not prevent but only slows the rate of disease progression. In this report, I have discussed future issues, including my personal viewpoint and also described the guidelines for promotion of the optimal use of lecanemab issued by the Ministry of Health, Labour, and Welfare.

Tau positron emission tomography (PET) is a neuroimaging technique that visualizes tau deposition using PET tracers that selectively bind to tau aggregates. Studies have reported the diagnostic and prognostic value of tau PET in Alzheimer's disease and other tauopathies. However, the binding profiles of tau PET drugs vary widely across tauopathies; therefore, an accurate understanding of the disease-specific characteristics is essential for interpretation of tau PET findings. In this review, we discuss the properties of tau-PET agents and their applications in various diseases.

Alzheimer's disease (AD) is a common dementia disorder in the elderly individuals, accounting for approximately 60-70% of all dementia cases. Recently, significant progress has been made in developing and approving anti-amyloid antibody drugs as one of the disease-modifying therapies (DMT) that aim to slow the progression of AD by targeting amyloid-beta accumulation in the brain. Notable drugs such as aducanumab, lecanemab, and donanemab have shown potential in clinical trials, leading to the approval of aducanumab and lecanemab, and approval is also expected for donanemab. Other anti-amyloid drugs such as remternetug and trontinemab are also under development. However, challenges remain, including adverse effects like amyloid-related imaging abnormalities (ARIA) and the need for addressing healthcare preparedness to support their use. This paper outlines the current status of DMT for AD, including the clinical trial results and current applications of these drugs. It also discusses the existing challenges to improve the safety and accessibility of DMTs.

Neurodegenerative diseases represent the most common cause of dementia. Protein aggregation is upstream in the pathological mechanisms and is a therapeutic target in the development of disease-modifying drugs in this patient population. Notably, α-synuclein or DNA-binding protein of 43kDa (TDP-43) is commonly involved in the pathomechanisms that contribute to non-Alzheimer neurodegenerative diseases. Several immunotherapy clinical trials on α-synuclein have progressed to phase 2, and small-molecule therapeutics are ongoing. With regard to TDP-43, immunotherapies that target protein aggregates are currently being developed, and research is underway to investigate several drugs that target the associated causative gene. Further research is warranted for deeper insight into both disease-modifying drugs; biomarker tests need to be developed to determine their efficacy. However, both proteins aggregate and accumulate in the brain in many neurodegenerative diseases and dementia; therefore, they are therapeutically significant, and future progress is expected in research and development.

Conventionally, APOE genetic testing has not been recommended as a component of the standard diagnostic and management practices for Alzheimer's disease. However, recent research highlights the importance of this test, particularly for assessment of the safety profile of anti-amyloid-β therapies. Therefore, the current United States guidelines for the administration of lecanemab explicitly advise APOE genetic testing. However, integration of this testing into clinical practice is associated with many clinical, ethical, legal, and economic challenges. It is important to initiate comprehensive discussions to address these multifaceted issues in Japan.