Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system involving aquaporin–4 antibodies, and complement is strongly implicated in its pathogenesis. In other words, the presence of aquaporin–4 antibodies, disruption of the blood–brain barrier, and complement activation are all necessary for the development of NMOSD. Pathologically, the focus of inflammation is around blood vessels, and in addition to lymphocyte and macrophage infiltration, there is a common finding of complement and IgG deposition and loss of staining for aquaporin 4 and GFAP. As in other autoimmune diseases, B–cell depletion therapy and IL–6 receptor antibodies are effective in preventing relapses, and complement C5 inhibitors can almost completely suppress clinically severe relapses. In the past, oral glucocorticoids (GCs) were prescribed in almost all cases and unapproved oral immunosuppressants were used as adjuncts or substitutes, but the effect on relapse prevention was not sufficient and there were often problems with the side effects of GCs. With the approval of five expensive biologic agents, it is important to consider how to use them differently.

A definitive diagnosis of neurodegenerative diseases, including Alzheimer disease (AD) and Lewy body disease (LBD), requires a neuropathological examination. Each neurodegenerative disease affects specific vulnerable regions and is associated with system degeneration, characterized by the accumulation of abnormal proteins and the formation of distinctive morphological aggregates in the nerve and glial cells, called proteinopathy.

The neuropathological findings of AD are characterized by the appearance of neurofibrillary tangles (NFTs) and senile plaques. The likelihood of pathological AD is determined by a comprehensive assessment of the spread of amyloid β (Aβ), the density of senile plaques, and the distribution of NFTs. The pathological hallmark of AD is the presence of AD–related pathology beyond the physiological range. Appropriate evaluation should be performed according to standardized protocols for neuropathological diagnosis.

LBD refers to conditions in which Lewy bodies are pathologically recognized as a disease concept. Lewy bodies appear widely not only in the brain but also in the peripheral autonomic nervous system, making LBD a systemic disease. The extent and severity caused by Lewy body involvement vary by case, and the affected system corresponds to various clinical symptoms. The pathological diagnosis of dementia with Lewy bodies (DLB) is based on the international diagnostic criteria of the DLB Consortium. LBD pathology often coexists with AD pathology, and the likelihood of detecting pathological findings of both diseases increases with age.

To enhance the sensitivity of clinical diagnosis of AD and LBD and clarify their pathogeneses, comparing and examining the clinical findings and neuropathological observations in detail in each case is crucial.

Alzheimer disease (AD) is the most common dementia disease and is characterized by major pathological features in the brain, such as senile plaques composed of amyloid beta protein (Aβ), neurofibrillary tangles of tau protein, and neuronal cell death. In the pathophysiology of AD, the “amyloid hypothesis” has been proposed, which posits that abnormal aggregates of Aβ causes damage to neurons with phosphorylated tau. Recently, the pathological significance of not only insoluble Aβ fibrils that accumulate as amyloid in the brain, but also eraly and intermediate aggregates such as oligomers and protofibrils has been emphasized (oligomer hypothesis). In particular, the pathogenesis of Aβ protofibrils, the target molecule of lecanemab, has attracted attention following the positive results of a phase 3 clinical trial in early AD patients and its approval in the United States, Japan, and other countries. We mainly used high–speed atomic force microscopy to show that lecanemab not only binds to and surrounds protofibrils with high affinity, but also binds to spherical oligomers and inhibits the further aggregation process of Aβ, thereby reducing neurotoxicity. Donanemab is also an antibody that has been shown to be effective in phase 3 clinical trials. Donanemab is an antibody that targets N3pG Aβ (Aβ pyroglutamylated at the 3rd N–terminal residue) fibrils in Aβ plaques. In a phase 3 clinical trial targeting early AD patients, the mean change in the integrated Alzheimer Disease Rating Scale (iADRS) score, the primary endpoint, at 76 weeks was 35.1% lower in the donanemab group with mild to moderate tau deposition compared to the placebo group.

Although there are many issues such as ARIA (amyloid–related imaging abnormalities) to be resolved, and it should be noted that some countries are cautious about approving drugs, the development of disease–modifying therapies for AD, mainly anti–Aβ antibodies, is progressing steadily.

Tauopathy is a pathological condition characterized by the accumulation of tau with abnormal folding structures in the central nervous system. In this review, we discuss the normal functions of tau, the pathophysiology of tauopathy, the mechanisms of various anti–tau therapies, and future perspectives on anti–tau therapy. Although the function of tau in stabilizing microtubules is well known, it is also recognized to have other functions. In tauopathy, the gain of toxic function due to tau aggregation and loss of function are important. Anti–tau therapies generally involve immunotherapies, including anti–tau antibodies, post–translational modification modifiers, microtubule stabilizers, antisense oligonucleotides, and agents targeting neuroinflammation. However, the efficacy of these approaches remains unestablished, which requires further studies of more sophisticated treatments, as well as the pathophysiology of tauopathy and improved clinical trials.

With the advent of disease modifying therapies for Alzheimer disease (AD) being used in clinical practice, biomarkers that can accurately diagnose the neuropathology of AD and other dementing disorders have become essential. The definitive diagnosis of brain amyloid and tau pathologies is now possible through PET imaging, and there is a growing demand for blood–based biomarkers suitable for screening tests. In 2018, the ATN classification system was proposed and ATN biomarkers have been introduced for the diagnosis and staging for AD. However, all the ATN biomarkers proposed in 2018 were cerebrospinal fluid (CSF) biomarkers. Since 2018, considerable progress has been made in the field of research on biomarkers for AD. Under such circumstances, the “Revised Criteria for Diagnosis and Staging of AD” has been presented by the Alzheimer's Association Workgroup in 2024. The biggest difference of the biomarkers featured in 2024 criteria from those in 2018 is that CSF or plasma p–tau217 and 181 are not any more classified as the biomarkers for tau proteinopathy, but classified as the biomarkers for brain amyloid in the same category as Amyloid–PET. Therefore, we now need a fluid “T” biomarker that reflects brain tau burden without interference from brain amyloid. We thus developed a novel plasma T–BM, mid–p–tau, in QST and have shown that the plasma mid–p–tau levels showed linear correlations with the tau PET accumulation in the Braak 3&4 and 5&6 regions. We concluded that our novel plasma mid–pTau assay serves as a promising surrogate biomarker for AD–tau deposition, which facilitates efficient and accurate selection the patients suitable for anti–amyloid therapies. Furthermore, it will be necessary from now on to establish multiple biomarkers, including those beyond ATN, and apply them to clinical practice.

Parkinson disease (PD) belongs to a family of disorders called Lewy body disease (LBD), which is pathologically characterized by the appearance of intracellular inclusions (Lewy bodies ; LBs) in neurons that are composed mainly of misfolded α–synuclein (αS). Based on the concept of “proteinopathy”, which attributes the cause of a disease to a single molecule, LBD is included in the higher concept of “synucleinopathy”. Although αS is a small protein that does not have a distinct structure in its physiological state, it will aggregate and exert toxicity due to abnormal folding (misfolding) by gene mutation/duplication or a variety of physicochemical stress. For this reason, many of the disease–modifying therapies for LBD/synucleinopathies have been developed with a focus on reducing or removing abnormally aggregated αS. In this paper, I will explain the disease–modifying therapies targeting αS protein for synucleinopathies, focusing on immunotherapy and aggregation inhibitors, and discuss future issues.

α–Synucleinopathies, including Parkinson Disease (PD), Multiple System Atrophy (MSA), and Lewy Body Dementia (DLB), are characterized by the pathological accumulation of misfolded α–synuclein (α–syn) aggregates. Recent advancements in fluid biomarkers, particularly α–syn seed amplification assays (SAA), have opened new avenues for early and precise diagnosis. Real–Time Quaking–induced Conversion (RT–QuIC) and similar assays have demonstrated high sensitivity and specificity in detecting α–syn seeds in cerebrospinal fluid (CSF) and blood, correlating with clinical subtypes and progression stages. Additionally, efforts to integrate biomarkers such as α–syn SAA with imaging techniques and genetic markers are shaping a biological classification and staging framework for PD and related disorders. However, challenges persist, including variability in assay protocols, substrate preparation, and interference from biological matrices in blood–based assays. Emerging technologies, such as Nano–QuIC, aim to address these issues by enhancing detection sensitivity and specificity. The continued refinement of biomarker assays promises to revolutionize diagnostic accuracy, facilitate early therapeutic intervention, and provide critical insights into the molecular mechanisms underlying α–synucleinopathies.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of motor neurons. A prominent pathological hallmark of ALS is the aggregation of TAR DNA–binding protein 43 (TDP–43), an RNA/DNA–binding protein involved in various cellular processes, including RNA metabolism and stress granule dynamics. In sporadic ALS, cytoplasmic aggregation of TDP–43 and its depletion in the nucleus are widely recognized as pathological features. Although the precise mechanisms underlying TDP–43 pathology remain unclear, both gain–of–function and loss–of–function effects are believed to contribute to disease progression.

Recent research efforts have focused on developing therapeutic strategies targeting TDP–43 abnormalities. Among these, bosutinib, a Src/c–Abl inhibitor, and antisense oligonucleotides targeting ATXN2 have been identified as potential therapeutic agents, with clinical trials have been conducted. Furthermore, immunotherapy, including monoclonal antibodies (mAbs) and single–chain variable fragments (scFvs), has shown significant promise. These antibodies selectively bind to pathological TDP–43 aggregates, facilitating their clearance via proteasome– and autophagy–mediated pathways while sparing physiological TDP–43. Notable examples include VH7Vk9 scFv and 3B12A scFv, which have demonstrated preclinical efficacy in reducing TDP–43 aggregation, mitigating neuroinflammation, and improving motor and cognitive functions.

These therapeutic approaches aim to modulate TDP–43 dynamics, prevent its misfolding, and restore cellular proteostasis. However, the clinical translation of TDP–43–targeted therapies presents significant challenges, particularly in ensuring the safety and specificity of these interventions. The development of efficient delivery systems, such as viral vectors, is critical for their therapeutic success. Future research should focus on optimizing these strategies and evaluating their long–term effects in ALS and other TDP–43 proteinopathies.

This manuscript provides an overview of TDP–43 pathology and highlights recent advancements in molecular and antibody–based therapeutic interventions, offering insights into potential treatment avenues for ALS.

We reviewed management of restless–leg syndrome (RLS) and akathisia (AKA) with regard to psychiatric diseases. Both disorders comprise motor hyperactivity, numb sensation in the limbs and psychomotor agitation, the difference of occurrence being in the daytime in AKA while in the nighttime in RLS. The underlying mechanism of RLS and AKA remains still unknown ; however, it may include abnormalities not only in dopaminergic pathways but also emotional pathways in the brain. Management of the patients with RLS or AKA should start checking premorbid medications. If dopamine receptor antagonists (for ameliorating psychiatry or gastroenterology diseases) have been used, quit and change them, and it is recommended to start dopaminergic and/or GABAergic medications. Collaboration of neurologists and psychiatrists is recommended to maximize patients' quality of life.

We focused on globular–shaped amyloid β–protein (Aβ) oligomer (gAβO), a part of high–molecular–weight Aβ oligomers among the various fractions in amyloid aggregation, and examined the molecular interactions of gAβO extracted from size exclusion chromatography. Thioflavin T analysis and high–speed atomic force microscopy revealed that gAβO did not show fibril formation, but had a facilitating effect for Aβ aggregation, especially primary nucleation and fibril elongation in low–molecular–weight Aβ42. Furthermore, the promoting effect of gAβO was influenced by the coexistence of mature Aβ42 fibril seeds. Our results indicate that gAβO is a highly toxic fraction of Aβ aggregates that is deeply involved in the pathogenesis of Alzheimer disease, especially in the early stages of the disease.