Kanta Horie

Washington University in St. Louis | WUSTL , Wash U · Department of Neurology

Background Lecanemab is a humanized immunoglobulin G1 monoclonal antibody targeting neurotoxic Aβ protofibrils and Aβ plaques, which reduces markers of amyloid and significantly slows clinical decline on multiple cognition and function measures. Cerebrospinal fluid (CSF) microtubule‐binding region (MTBR) of tau containing the residue 243 (MTBR‐tau2...

A 10 mg/kg every 2 week (Q2W) dose of the humanized IgG1 monoclonal antibody lecanemab was approved after demonstrating significant clinical benefit in slowing cognitive decline in early Alzheimer’s disease (AD) in two clinical studies (the phase 2 Study 201 and phase 3 Clarity AD). A less frequent every 4 weeks lecanemab 10 mg/kg maintenance dosin...

Background Alzheimer’s disease (AD) blood tests that can identify and quantify amyloid plaques, tau tangles, and cognitive and clinical decline are needed in clinical practice, including primary care. However, these tests require validation in diverse groups and real‐world settings. The Study to Evaluate Amyloid in Blood and Imaging Related to Deme...

Background Fluid biomarkers represent an informative and cost‐effective way to detect and monitor Alzheimer’s disease (AD). However, as we recently showed, the overall proteome average in CSF exhibits a non‐disease related average signal (inter‐individual variability), which can reduce the precision of concentration based CSF AD biomarkers.¹ Now, w...

Background P‐tau217 has emerged as a compelling alternative to long‐established p‐tau181 to accurately measure tau modifications in biofluids in response to brain Abeta and tau deposition in Alzheimer’s disease (AD). Understanding the specificity and significance of p‐tau217 changes over AD stages is critical to interpret its potential response to...

BACKGROUND This study examines whether phosphorylated plasma Tau217 ratio (pTau217R) can predict tau accumulation in different brain regions, as measured by positron emission tomography (PET) standardized uptake value ratio (SUVR), for staging Alzheimer's disease (AD). METHODS Plasma pTau217R was measured using immunoprecipitation‐mass spectrometr...

INTRODUCTION Cerebrospinal fluid (CSF) tau phosphorylation at multiple sites is associated with cortical amyloid and other pathologic changes in Alzheimer's disease. These relationships can be non‐linear. We used an artificial neural network to assess the ability of 10 different CSF tau phosphorylation sites to predict continuous amyloid positron e...

Introduction Narcolepsy type 1 (NT1) is caused by orexin (hypocretin) deficiency with 85-95% loss of orexinergic neurons reported in the hypothalamus. Patients with NT1 have cerebrospinal fluid (CSF) orexin-A immunoreactivity deficiency ≤110 pg/ml, as detected using a polyclonal anti-orexin-A radioimmunoassay (RIA). Although some narcolepsy type 2...

Biological staging of individuals with Alzheimer’s disease (AD) may improve diagnostic and prognostic workup of dementia in clinical practice and the design of clinical trials. In this study, we used the Subtype and Stage Inference (SuStaIn) algorithm to establish a robust biological staging model for AD using cerebrospinal fluid (CSF) biomarkers....

Background Alzheimer disease (AD) is a slowly progressive neurodegenerative disorder characterized by the presence of amyloid plaques that can be measured in vivo with positron emission tomography (PET). PET quantifies the lifetime accumulation of amyloid plaques, while cerebrospinal fluid (CSF) biomarkers reflect the production and clearance of Aβ...

Background Staging Alzheimer’s disease (AD) allows for the identification of key milestones and inflection points in the disease course. However, most current in vivo disease staging methods rely on costly and low‐accessible measures such as PET. Our objective was to generate and evaluate a staging model based on multiple cerebrospinal fluid (CSF)...

Background As Alzheimer’s disease progresses, pathological tau spreads through the brain via synaptically connected pathways. Tau proteins containing the microtubule binding region (MTBR) may be essential to form extracellular ‘seeds’ that initiate and propagate pathology. To simulate this process preclinically, we have further characterised an AD...

Background E2814 is a human IgG1 antibody that binds to microtubule binding region of tau (MTBR‐tau), a critical domain for the seeding and spreading of tau pathology in Alzheimer’s Disease (AD). It is being developed for the treatment of AD by stopping tau propagation and slowing the associated cognitive decline. E2814 has been evaluated in health...

Background Staging Alzheimer’s disease (AD) allows for the identification of key milestones and inflection points in the disease course. However, most current in vivo disease staging methods rely on costly and low‐accessible measures such as PET. Our objective was to generate and evaluate a staging model based on multiple cerebrospinal fluid (CSF)...

Biological staging of individuals with Alzheimer's disease (AD) may improve diagnostic and prognostic work-up of dementia in clinical practice and the design of clinical trials. Here, we created a staging model using the Subtype and Stage Inference (SuStaIn) algorithm by evaluating cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau biomarkers in 426...

Aggregated insoluble tau is one of two defining features of Alzheimer’s disease. Because clinical symptoms are strongly correlated with tau aggregates, drug development and clinical diagnosis need cost-effective and accessible specific fluid biomarkers of tau aggregates; however, recent studies suggest that the fluid biomarkers currently available...

Cerebrospinal fluid (CSF) amyloid-β peptide (Aβ)42/Aβ40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer’s disease (AD). The present study used mass spectrometry to measure concentrations of nine phosphorylated and five nonphosphorylated tau species and phosphorylation occupancies (perc...

Objective: Identifying cerebrospinal fluid measures of the microtubule binding region of tau (MTBR-tau) species that reflect tau aggregation could provide fluid biomarkers that track Alzheimer disease related neurofibrillary tau pathological changes. We examined CSF MTBR-tau species in dominantly inherited Alzheimer disease (DIAD) mutation carrier...

Hyperphosphorylated tau isoforms (p‐tau) in cerebrospinal fluid (CSF) and plasma represent promising measures to monitor Alzheimer disease (AD) pathological changes. Brain amyloid deposition precedes tau aggregation and associated clinical decline by two decades. Several CSF and plasma p‐tau isoforms have been described as potential surrogates for...

Impaired proteostasis is associated with normal aging and is accelerated in neurodegeneration. This impairment may lead to the accumulation of protein, which can be toxic to cells and tissue. In a subset of frontotemporal lobar degeneration with tau pathology (FTLD-tau) cases, pathogenic mutations in the microtubule-associated protein tau ( MAPT )...

Brain tau aggregation is a pathological hallmark of Alzheimer’s disease (AD) and the tau microtubule binding region (MTBR) is the core of AD tau tangles. Recently, we identified the enrichment of some specific MTBR species in sporadic AD brain tangles. Corresponding soluble MTBR species in the CSF increased together with clinical progression and ta...

Despite recent advances in fluid biomarker research in Alzheimer’s disease (AD), there are no fluid biomarkers or imaging tracers with utility for diagnosis and/or theragnosis available for other tauopathies. Using immunoprecipitation and mass spectrometry, we show that 4 repeat (4R) isoform-specific tau species from microtubule-binding region (MTB...

CSF Aβ42/Aβ40 and tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer disease (AD). This study used mass spectrometry to measure concentrations of 9 phosphorylated and 5 non-phosphorylated species, and phosphorylation occupancies (phosphorylated/non-phosphorylated [%]) at 10 sites. In 750 individuals with a median...

Background: E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase9 (PDE9) being evaluated as a treatment for dementia with Lewy bodies. Methods: Phase 1, randomized, double-blind, single ascending dose (SAD, n=96) and multiple ascending dose (MAD, n=68) studies evaluated E2027 doses (5 to 1200 mg) in healthy subjects. The...

Tau is a microtubule-binding protein expressed in neurons, and the equal ratios between 4-repeat (4R) and 3-repeat (3R) isoforms are maintained in normal adult brain function. Dysregulation of 3R:4R ratio causes tauopathy, and human neurons that recapitulate tau isoforms in health and disease will provide a platform for elucidating pathogenic proce...

Background Hyperphosphorylation of tau leads to conformational changes that destabilize microtubules and hinder axonal transport in Alzheimer's disease (AD). However, it remains unknown whether white matter (WM) decline due to AD is associated with specific Tau phosphorylation site(s). Methods In autosomal dominant AD (ADAD) mutation carriers (MC)...

The protein tau and its isoforms are associated with several neurodegenerative diseases, many of which are characterized by greater deposition of the 4-repeat (4R) tau isoform; however, the role of 4R tau in disease pathogenesis remains unclear. We created antisense oligonucleotides (ASOs) that alter the ratio of 3R to 4R tau to investigate the rol...

Background Recent advances in the development of novel Alzheimer’s disease (AD) measures of amyloid, tau, and neurodegeneration in cerebrospinal fluid (CSF) and blood have enabled a better understanding of the links between amyloid‐beta (Aβ), tau species and neurodegeneration in the brain, CSF, and blood. The discoveries of novel tau species in CSF...

Background Recent analyses of tau phosphorylation in cerebrospinal fluid (CSF) from dominantly inherited Alzheimer disease (DIAD) patients have pinpointed early modification of phosphorylated tau (p‐tau) at 217 (pT217) occurring simultaneously with emergence of amyloid plaques. This has opened new perspective in diagnosing AD pathology at preclinic...

Background Accumulations of tau aggregates and amyloid plaques in brain are hallmarks of Alzheimer’s disease (AD). Recent studies in characterizing tau species, especially phosphorylated tau‐181 (p‐tau181) and p‐tau217 in AD brain and biofluids suggested that these species start increasing at preclinical stage, correlate with amyloid plaques, and i...

Neurofibrillary tangles (NFTs) composed of hyperphosphorylated and misfolded tau protein are a pathological hallmark of Alzheimer’s disease and other tauopathy conditions. Tau is predominantly an intraneuronal protein but is also secreted in physiological and pathological conditions. The extracellular tau has been implicated in the seeding and prop...

Tau is a microtubule associated protein in the brain that aggregates in Alzheimer’s disease to form pathological tangles and neurites. Insoluble tau aggregates composed of the microtubule binding region (MTBR) of tau are highly associated with the cognitive and clinical symptoms of Alzheimer’s disease. In contrast, levels of soluble forms of tau, s...

Background Brain tau aggregates are, together with amyloid plaques, hallmarks of Alzheimer Disease (AD). Structural characterization of tau aggregates in AD, Pick’s disease and Chronic Traumatic Encephalopathy demonstrate distinct folds leading to tau aggregation. However, initiation and propagation mechanisms involved are still unknown. One hypoth...

Background Understanding tau kinetics in the human central nervous system is critical for evaluating the effects of tau‐targeted therapies and designing clinical trials against tau in Alzheimer disease (AD) and other primary tauopathies. We hypothesized that tau production or clearance is altered in tauopathies and measured tau kinetics in AD and i...

Background Recent advances in understanding the links between amyloid‐beta (Aβ) and specific tau isoforms in brain, cerebrospinal fluid (CSF), and blood indicate that a cascade of events of Alzheimer’s disease (AD) pathophysiology begin with detection of altered CSF and blood Aβ 42/40 ratio, followed by increases in amyloid plaques by Positron Emis...

Background Tau deposition in brain is a pathological hallmark of some neurodegenerative disorders including Alzheimer’s disease (AD). Braak staging of post‐mortem tissue suggests pathological tau spreads through the brain via synaptically connected pathways, and specific tau isoforms containing the microtubule binding region (MTBR) are thought to b...

Herein, commercially available columns employed in hydrophilic interaction chromatography (HILIC) were characterized by determining their ability to selectively distinguish the minute structural differences between small molecules such as nucleosides and xanthines in complex sample matrices. Principal component analysis (PCA) was applied to the dat...

Abstract Alzheimer’s disease (AD) neuropathologic change is characterized by amyloid plaques and neurofibrillary tangles (NFTs) that consist of aggregated amyloid beta (Abeta) and hyperphosphorylated tau proteins (p-tau), respectively. Although the global relationship between Abeta and p-tau has been studied for decades, it is still unclear whether...

Highly sensitive and specific plasma biomarkers for Alzheimer's disease (AD) have the potential to improve diagnostic accuracy in the clinic and facilitate research studies including enrollment in prevention and treatment trials. We recently reported CSF tau hyperphosphorylation, especially on T217, is an accurate predictor of β-amyloidosis at asym...

Measurement of phosphorylated tau protein in blood plasma allows Alzheimer’s disease to be distinguished from other neurological diseases and may assist in disease detection during the prodromal stage.

Tau deposition in the brain is a pathological hallmark of many neurodegenerative disorders, including Alzheimer's disease (AD). During the course of these tauopathies, tau spreads throughout the brain via synaptically-connected pathways. Such propagation of pathology is thought to be mediated by tau species ("seeds") containing the microtubule bind...

Background: One of the current problems in the field of metabolomics is the difficulty in integrating data collected using different equipment at different facilities, because many metabolomic methods have been developed independently and are unique to each laboratory. Methods: In this study, we examined whether different analytical methods amon...

Mifepristone, which is an orally active synthetic steroid with antiprogesterone activity, is known as an ovarian toxicant. Because the available data regarding the histopathologic characteristics of ovarian toxicity in nonhuman primates are limited, the present study was undertaken in order to investigate detailed histopathologic changes accompanyi...

Multivariate curve resolution-alternating least squares (MCR-ALS) method was investigated for its potential to accelerate pharmaceutical research and development. The fast and efficient separation of complex mixtures consisting of multiple components, including impurities as well as major drug substances, remains a challenging application for liqui...

A meter-scale monolithic silica capillary column modified with urea-functional groups for hydrophilic interaction liquid chromatography (HILIC) was developed for highly efficient separation of biological compounds. We prepared a ureidopropylsilylated monolithic silica capillary column with a minimum plate height of 12 μm for nucleosides and a perme...

An estimation of the performance and optimization of gradient HPLC conditions using various columns for maximum total peak capacity was studied for "one-shot proteomics" which involves one-dimensional gradient HPLC, connected to an electrospray ionization (ESI)-mass spectrometry (MS), using a monolithic silica-C₁₈ capillary column (350 cm long and...

Anion-exchange (AEX) columns were prepared by on-column polymerization of acrylates and methacrylates containing tertiary amino or quaternary ammonium groups on monolithic silica in a fused silica capillary modified with anchor groups. The columns provided a plate height (H) of less than 10 microm at optimum linear velocity (u) with keeping their h...

Long monolithic silica-C18 capillary columns of 100 microm i.d. were prepared, and the efficiency was examined using reversed-phase HPLC under a pressure of up to 47 MPa. At linear velocities of 1-2 mm/s, 100,000-500,000 theoretical plates could be generated with a single column (90-440 cm in length) using an acetonitrile-water (80/20) mobile phase...

A polyacrylamide (PAAm)-modified monolithic silica capillary column of increased phase ratio, 200T-PAAm, for hydrophilic interaction liquid chromatography (HILIC) was prepared. The column showed high separation efficiency, with a theoretical plate height H = 7–20 μm at a linear velocity, u = 1–7 mm/s. From a kinetic plot analysis, it was expected t...

Hydrophilic interaction chromatography (HILIC) is important for the separation of highly polar substances including biologically active compounds, such as pharmaceutical drugs, neurotransmitters, nucleosides, nucleotides, amino acids, peptides, proteins, oligosaccharides, carbohydrates, etc. In the HILIC mode separation, aqueous organic solvents ar...

Monolithic silica capillary columns for hydrophilic interaction liquid chromatography (HILIC) were prepared by on-column polymerization of acrylic acid on monolithic silica in a fused silica capillary modified with anchor groups. The products maintained the high permeability (K=5 x 10(-14)m(2)) and provided a plate height (H) of less than 10 microm...

High efficiency and highly retentive monolithic silica capillary columns were obtained by polymerization of octadecyl methacrylate using alpha,alpha'-azobis-isobutyronitrile (AIBN) as a free radical initiator. Hybrid type monolithic silica columns (25 cm total length x 200 microm I.D.) prepared from a mixture of tetramethoxysilane and methyltrimeth...

Theoretical calculations are presented to optimize modulation period for maximum total peak capacity in comprehensive two-dimensional HPLC (2D-HPLC) taking into account the effect of modulation on the apparent peak capacity of the first-dimension (1D) separation. Results indicate that modulation periods are most favorable when they are adjusted to...

Weak cation-exchange (WCX) and HILIC modes columns were prepared by on-column polymerization of acrylic acid on monolithic silica capillary columns modified with N-(3-triethoxysilylpropyl)methacrylamide anchor groups. The polymer-coated columns could be used for HILIC mode separation of pyridylamino (PA)-sugars and peptides including a tryptic dige...

HILIC mode columns were prepared by an on-column polymerization of acrylamide on a monolithic silica capillary column modified with N-(3-trimethoxysilylpropyl)methacrylamide as the anchor group. The products showed HILIC mode retention characteristics with three times greater permeability and slightly higher column efficiency compared to a commerci...