Large-scale Deep Proteomic Analysis in Alzheimer's Disease Brain Regions Across Race and Ethnicity.

Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non-Hispanic White (NHW) population. Here we aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial and ethnic groups. Methods: Dorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) brain tissues were donated from multiple centers (Mayo Clinic, Emory University, Rush University, Mt. Sinai School of Medicine) and were harmonized through neuropathological evaluation, specifically adhering to the Braak staging and CERAD criteria. Among 1105 DLPFC tissue samples (998 unique individuals), 333 were from African American donors, 223 from Latino Americans, 529 from NHW donors, and the rest were from a mixed or unknown racial background. Among 280 STG tissue samples (244 unique individuals), 86 were African American, 76 Latino American, 116 NHW and the rest were mixed or unknown ethnicity. All tissues were uniformly homogenized and analyzed by tandem mass tag mass spectrometry (TMT-MS). Results: As a Quality control (QC) measure, proteins with more than 50% missing values were removed and iterative principal component analysis was conducted to remove outliers within brain regions. After QC, 9,180 and 9,734 proteins remained in the DLPC and STG proteome, respectively, of which approximately 9,000 proteins were shared between regions. Protein levels of microtubule-associated protein tau (MAPT) and amyloid-precursor protein (APP) demonstrated AD-related elevations in DLPFC tissues with a strong association with CERAD and Braak across racial groups. APOE4 protein levels in brain were highly concordant with APOE genotype of the individuals. Discussion: This comprehensive region resolved large-scale proteomic dataset provides a resource for the understanding of ethnoracial-specific protein differences in AD brain.

Proteomic changes in the human cerebrovasculature in Alzheimer's disease and related tauopathies linked to peripheral biomarkers in plasma and cerebrospinal fluid.

INTRODUCTION: Cerebrovascular dysfunction is a pathological hallmark of Alzheimer's disease (AD). Nevertheless, detecting cerebrovascular changes within bulk tissues has limited our ability to characterize proteomic alterations from less abundant cell types. METHODS: We conducted quantitative proteomics on bulk brain tissues and isolated cerebrovasculature from the same individuals, encompassing control (N = 28), progressive supranuclear palsy (PSP) (N = 18), and AD (N = 21) cases. RESULTS: Protein co-expression network analysis identified unique cerebrovascular modules significantly correlated with amyloid plaques, cerebrovascular amyloid angiopathy (CAA), and/or tau pathology. The protein products within AD genetic risk loci were concentrated within cerebrovascular modules. The overlap between differentially abundant proteins in AD cerebrospinal fluid (CSF) and plasma with cerebrovascular network highlighted a significant increase of matrisome proteins, SMOC1 and SMOC2, in CSF, plasma, and brain. DISCUSSION: These findings enhance our understanding of cerebrovascular deficits in AD, shedding light on potential biomarkers associated with CAA and vascular dysfunction in neurodegenerative diseases.

Mapping medically relevant RNA isoform diversity in the aged human frontal cortex with deep long-read RNA-seq.

Determining whether the RNA isoforms from medically relevant genes have distinct functions could facilitate direct targeting of RNA isoforms for disease treatment. Here, as a step toward this goal for neurological diseases, we sequenced 12 postmortem, aged human frontal cortices (6 Alzheimer disease cases and 6 controls; 50% female) using one Oxford Nanopore PromethION flow cell per sample. We identified 1,917 medically relevant genes expressing multiple isoforms in the frontal cortex where 1,018 had multiple isoforms with different protein-coding sequences. Of these 1,018 genes, 57 are implicated in brain-related diseases including major depression, schizophrenia, Parkinson's disease and Alzheimer disease. Our study also uncovered 53 new RNA isoforms in medically relevant genes, including several where the new isoform was one of the most highly expressed for that gene. We also reported on five mitochondrially encoded, spliced RNA isoforms. We found 99 differentially expressed RNA isoforms between cases with Alzheimer disease and controls.

Bridging the Gap: Multi-Omics Profiling of Brain Tissue in Alzheimer's Disease and Older Controls in Multi-Ethnic Populations.

INTRODUCTION: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked African Americans (AA) and Latin Americans (LA), who are disproportionately affected by AD. METHODS: To bridge this gap, Accelerating Medicines Partnership in AD (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTS: We generated multi-omics data and curated and harmonized phenotypic data from AA (n=306), LA (n=326), or AA and LA (n=4) brain donors plus Non-Hispanic White (n=252) and other (n=20) ethnic groups, to establish a foundational dataset enriched for AA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSION: Inclusion of traditionally underrepresented groups in multi-omics studies is essential to discover the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD.

Heparin-enriched plasma proteome is significantly altered in Alzheimer's Disease.

Introduction: Heparin binding proteins (HBPs) with roles in extracellular matrix assembly are strongly correlated to ß-amyloid (Aß) and tau pathology in Alzheimer's disease (AD) brain and cerebrospinal fluid (CSF). However, it remains challenging to detect these proteins in plasma using standard mass spectrometry-based proteomic approaches. Methods: We employed heparin affinity chromatography, followed by off-line fractionation and tandem mass tag mass spectrometry (TMT-MS), to capture and enrich HBPs in plasma obtained from AD (n=62) and control (n=47) samples. These profiles were then correlated to a consensus AD brain proteome, as well as with Aß, tau and phosphorylated tau (pTau) CSF biomarkers from the same individuals. We then leveraged published human postmortem brain proteome datasets to assess the overlap with the heparin-enriched plasma proteome. Results: Heparin-enrichment from plasma was highly reproducible, enriched well-known HBPs like APOE and thrombin, and depleted high-abundance proteins such as albumin. A total of 2865 proteins, spanning 10 orders of magnitude were detectable. Utilizing a consensus AD brain protein co-expression network, we observed that specific plasma HBPs exhibited consistent direction of change in both brain and plasma, whereas others displayed divergent changes highlighting the complex interplay between the two compartments. Elevated HBPs in AD plasma, when compared to controls, included members of the matrisome module in brain that accumulate within Aß deposits, such as SMOC1, SMOC2, SPON1, MDK, OLFML3, FRZB, GPNMB, and APOE. Additionally, heparin enriched plasma proteins demonstrated significant correlations with conventional AD CSF biomarkers, including Aß, total tau, pTau, and plasma pTau from the same individuals. Conclusion: These findings support the utility of a heparin-affinity approach for enriching amyloid-associated proteins, as well as a wide spectrum of plasma biomarkers that reflect pathological changes in the AD brain.

Proteomic Changes in the Human Cerebrovasculature in Alzheimer's Disease and Related Tauopathies Linked to Peripheral Biomarkers in Plasma and Cerebrospinal Fluid.

Dysfunction of the neurovascular unit stands as a significant pathological hallmark of Alzheimer's disease (AD) and age-related neurodegenerative diseases. Nevertheless, detecting vascular changes in the brain within bulk tissues has proven challenging, limiting our ability to characterize proteomic alterations from less abundant cell types. To address this challenge, we conducted quantitative proteomic analyses on both bulk brain tissues and cerebrovascular-enriched fractions from the same individuals, encompassing cognitively unimpaired control, progressive supranuclear palsy (PSP), and AD cases. Protein co-expression network analysis identified modules unique to the cerebrovascular fractions, specifically enriched with pericytes, endothelial cells, and smooth muscle cells. Many of these modules also exhibited significant correlations with amyloid plaques, cerebral amyloid angiopathy (CAA), and/or tau pathology in the brain. Notably, the protein products within AD genetic risk loci were found concentrated within modules unique to the vascular fractions, consistent with a role of cerebrovascular deficits in the etiology of AD. To prioritize peripheral AD biomarkers associated with vascular dysfunction, we assessed the overlap between differentially abundant proteins in AD cerebrospinal fluid (CSF) and plasma with a vascular-enriched network modules in the brain. This analysis highlighted matrisome proteins, SMOC1 and SMOC2, as being increased in CSF, plasma, and brain. Immunohistochemical analysis revealed SMOC1 deposition in both parenchymal plaques and CAA in the AD brain, whereas SMOC2 was predominantly localized to CAA. Collectively, these findings significantly enhance our understanding of the involvement of cerebrovascular abnormalities in AD, shedding light on potential biomarkers and molecular pathways associated with CAA and vascular dysfunction in neurodegenerative diseases.

Unveiling Resilience to Alzheimer's Disease: Insights From Brain Regional Proteomic Markers.

Studying proteomics data of the human brain could offer numerous insights into unraveling the signature of resilience to Alzheimer's disease. In our previous study with rigorous cohort selection criteria that excluded 4 common comorbidities, we harnessed multiple brain regions from 43 research participants with 12 of them displaying cognitive resilience to Alzheimer's disease. Based on the previous findings, this work focuses on 6 proteins out of the 33 differentially expressed proteins associated with resilience to Alzheimer's disease. These proteins are used to construct a decision tree classifier, enabling the differentiation of 3 groups: (i) healthy control, (ii) resilience to Alzheimer's disease, and (iii) Alzheimer's disease with dementia. Our analysis unveiled 2 important regional proteomic markers: Aß peptides in the hippocampus and PA1B3 in the inferior parietal lobule. These findings underscore the potential of using distinct regional proteomic markers as signatures in characterizing the resilience to Alzheimer's disease.

Using deep long-read RNAseq in Alzheimer's disease brain to assess medical relevance of RNA isoform diversity.

Due to alternative splicing, human protein-coding genes average over eight RNA isoforms, resulting in nearly four distinct protein coding sequences per gene. Long-read RNAseq (IsoSeq) enables more accurate quantification of isoforms, shedding light on their specific roles. To assess the medical relevance of measuring RNA isoform expression, we sequenced 12 aged human frontal cortices (6 Alzheimer's disease cases and 6 controls; 50% female) using one Oxford Nanopore PromethION flow cell per sample. Our study uncovered 53 new high-confidence RNA isoforms in medically relevant genes, including several where the new isoform was one of the most highly expressed for that gene. Specific examples include WDR4 (61%; microcephaly), MYL3 (44%; hypertrophic cardiomyopathy), and MTHFS (25%; major depression, schizophrenia, bipolar disorder). Other notable genes with new high-confidence isoforms include CPLX2 (10%; schizophrenia, epilepsy) and MAOB (9%; targeted for Parkinson's disease treatment). We identified 1,917 medically relevant genes expressing multiple isoforms in human frontal cortex, where 1,018 had multiple isoforms with different protein coding sequences, demonstrating the need to better understand how individual isoforms from a single gene body are involved in human health and disease, if at all. Exactly 98 of the 1,917 genes are implicated in brain-related diseases, including Alzheimer's disease genes such as APP (Aß precursor protein; five), MAPT (tau protein; four), and BIN1 (eight). As proof of concept, we also found 99 differentially expressed RNA isoforms between Alzheimer's cases and controls, despite the genes themselves not exhibiting differential expression. Our findings highlight the significant knowledge gaps in RNA isoform diversity and their medical relevance. Deep long-read RNA sequencing will be necessary going forward to fully comprehend the medical relevance of individual isoforms for a "single" gene.

Whole genome deconvolution unveils Alzheimer's resilient epigenetic signature.

Assay for Transposase Accessible Chromatin by sequencing (ATAC-seq) accurately depicts the chromatin regulatory state and altered mechanisms guiding gene expression in disease. However, bulk sequencing entangles information from different cell types and obscures cellular heterogeneity. To address this, we developed Cellformer, a deep learning method that deconvolutes bulk ATAC-seq into cell type-specific expression across the whole genome. Cellformer enables cost-effective cell type-specific open chromatin profiling in large cohorts. Applied to 191 bulk samples from 3 brain regions, Cellformer identifies cell type-specific gene regulatory mechanisms involved in resilience to Alzheimer's disease, an uncommon group of cognitively healthy individuals that harbor a high pathological load of Alzheimer's disease. Cell type-resolved chromatin profiling unveils cell type-specific pathways and nominates potential epigenetic mediators underlying resilience that may illuminate therapeutic opportunities to limit the cognitive impact of the disease. Cellformer is freely available to facilitate future investigations using high-throughput bulk ATAC-seq data.

Cross-species comparative analysis of single presynapses.

Comparing brain structure across species and regions enables key functional insights. Leveraging publicly available data from a novel mass cytometry-based method, synaptometry by time of flight (SynTOF), we applied an unsupervised machine learning approach to conduct a comparative study of presynapse molecular abundance across three species and three brain regions. We used neural networks and their attractive properties to model complex relationships among high dimensional data to develop a unified, unsupervised framework for comparing the profile of more than 4.5 million single presynapses among normal human, macaque, and mouse samples. An extensive validation showed the feasibility of performing cross-species comparison using SynTOF profiling. Integrative analysis of the abundance of 20 presynaptic proteins revealed near-complete separation between primates and mice involving synaptic pruning, cellular energy, lipid metabolism, and neurotransmission. In addition, our analysis revealed a strong overlap between the presynaptic composition of human and macaque in the cerebral cortex and neostriatum. Our unique approach illuminates species- and region-specific variation in presynapse molecular composition.

Brain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer's disease.

Resilience to Alzheimer's disease is an uncommon combination of high disease burden without dementia that offers valuable insights into limiting clinical impact. Here we assessed 43 research participants meeting stringent criteria, 11 healthy controls, 12 resilience to Alzheimer's disease and 20 Alzheimer's disease with dementia and analyzed matched isocortical regions, hippocampus, and caudate nucleus by mass spectrometry-based proteomics. Of 7115 differentially expressed soluble proteins, lower isocortical and hippocampal soluble Aß levels is a significant feature of resilience when compared to healthy control and Alzheimer's disease dementia groups. Protein co-expression analysis reveals 181 densely-interacting proteins significantly associated with resilience that were enriched for actin filament-based processes, cellular detoxification, and wound healing in isocortex and hippocampus, further supported by four validation cohorts. Our results suggest that lowering soluble Aß concentration may suppress severe cognitive impairment along the Alzheimer's disease continuum. The molecular basis of resilience likely holds important therapeutic insights.

Prediction of neuropathologic lesions from clinical data.

INTRODUCTION: Post-mortem analysis provides definitive diagnoses of neurodegenerative diseases; however, only a few can be diagnosed during life. METHODS: This study employed statistical tools and machine learning to predict 17 neuropathologic lesions from a cohort of 6518 individuals using 381 clinical features (Table S1). The multisite data allowed validation of the model's robustness by splitting train/test sets by clinical sites. A similar study was performed for predicting Alzheimer's disease (AD) neuropathologic change without specific comorbidities. RESULTS: Prediction results show high performance for certain lesions that match or exceed that of research annotation. Neurodegenerative comorbidities in addition to AD neuropathologic change resulted in compounded, but disproportionate, effects across cognitive domains as the comorbidity number increased. DISCUSSION: Certain clinical features could be strongly associated with multiple neurodegenerative diseases, others were lesion-specific, and some were divergent between lesions. Our approach could benefit clinical research, and genetic and biomarker research by enriching cohorts for desired lesions.

Parkinson's Progression Markers Initiative brain autopsy program.

We report on the initial 17 (11 male:6 female) brain autopsies from across Europe and the United States in the Parkinson's Progression Markers Initiative (PPMI). Clinical diagnoses were Parkinson's disease (n = 15), multiple system atrophy (n = 1), and Dementia with Lewy bodies (n = 1); average age of death = 72 ± 8 yr. Cognitive assessment at last evaluation was 5 with normal cognition, 7 with mild cognitive impairment, and 5 with dementia. Genetic assessment showed 4 participants were heterozygous or homozygous for GBA N370S and 3 were heterozygous carriers for LRRK2 R1441G or G2019S; 1 was an APOE ε2 carrier and 5 were APOE ε4 carriers. Longitudinal DAT neuroimaging as well as CSF and plasma biomarker data are summarized. Neuropathologic examination confirmed all clinical diagnoses and showed the expected frequencies of common comorbidities; no evidence of chronic traumatic encephalopathy was observed. Thus, brain autopsy data can provide confirmation, clarification, and new insights into the PD progression observed during life. As it grows, the PPMI brain autopsy program will provide a deeply-annotated research resource to the community of investigators focused on developing biomarkers for PD progression.

Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis: APLIOS, a randomized phase-2 study.

BACKGROUND: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS). OBJECTIVE: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion. METHODS: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUCτ) and maximum plasma concentration (Cmax) for Weeks 8-12. B-cell depletion and safety/tolerability were assessed. RESULTS: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUCτ, 487.7 vs 474.1 h × µg/mL (ratio 1.03); Cmax, 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated. CONCLUSION: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion.

Epidemiology of bone metastases.

BACKGROUND: This study evaluated the incidence of de novo bone metastasis across all primary cancer sites and their impact on survival by primary cancer site, age, race, and sex. QUESTIONS/PURPOSES: Our objectives were (I) characterize the epidemiology of de novo bone metastasis with respect to patient demographics, (II) characterize the incidence by primary site, age, and sex (2010-2015), and (III) compare survival of de novo metastatic cancer patients with and without bone metastasis. METHODS: This is a retrospective, population-based study using nationally representative data from the Surveillance, Epidemiology, and End Results program, 2010-2015. Incidence rates by year of diagnosis, annual percentage changes, Kaplan-Meier, univariate and multiple Cox regression models are included in the analysis. RESULTS: Of patients with cancer in the SEER database, 5.1% were diagnosed with metastasis to bone, equaling ~18.8 per 100,000 bone metastasis diagnoses in the US per year (2010-2015). For adults >25, lung cancer is the most common primary site (2015 rate: 8.7 per 100,000) with de novo bone metastases, then prostate and breast primaries (2015 rates: 3.19 and 2.38 per 100,000, respectively). For patients <20 years old, endocrine cancers and soft tissue sarcomas are the most common primaries. Incidence is increasing for prostate (Annual Percentage Change (APC) = 4.6%, P < 0.001) and stomach (APC = 5.0%, P = 0.001) cancers. The presence of de novo bone metastasis was associated with a limited reduction in overall survival (HR = 1.02, 95%, CI = [1.01-1.03], p < 0.001) when compared to patients with other non-bone metastases. CONCLUSION: The presence of bone metastasis versus metastasis to other sites has disease site-specific impact on survival. The incidence of de novo bone metastasis varies by age, sex, and primary disease site.

Single-synapse analyses of Alzheimer's disease implicate pathologic tau, DJ1, CD47, and ApoE.

Synaptic molecular characterization is limited for Alzheimer's disease (AD). Our newly invented mass cytometry­based method, synaptometry by time of flight (SynTOF), was used to measure 38 antibody probes in approximately 17 million single-synapse events from human brains without pathologic change or with pure AD or Lewy body disease (LBD), nonhuman primates (NHPs), and PS/APP mice. Synaptic molecular integrity in humans and NHP was similar. Although not detected in human synapses, Aß was in PS/APP mice single-synapse events. Clustering and pattern identification of human synapses showed expected disease-specific differences, like increased hippocampal pathologic tau in AD and reduced caudate dopamine transporter in LBD, and revealed previously unidentified findings including increased hippocampal CD47 and lowered DJ1 in AD and higher ApoE in AD with dementia. Our results were independently supported by multiplex ion beam imaging of intact tissue. This highlights the higher depth and breadth of insight on neurodegenerative diseases obtainable through SynTOF.

Resident Training and the Assessment of Orthopaedic Surgical Skills.

Medical knowledge and technical skills are foundations of surgical competency. The American Board of Orthopaedic Surgery (ABOS) and the Resident Review Committee for Orthopaedic Surgery recently mandated simulation training to improve surgical skills, listing 17 surgical skills modules to improve residents' technical skills. However, there is no established tool to measure the effectiveness of these modules. The Global Index for Technical Skills (GRITS) tool has been previously validated for evaluating general surgery residents. The aim of this study was to determine whether the GRITS tool is valid, practical, and reliable in evaluating the skills of orthopaedic residents in a simulation setting, whether the outcomes correlate to performance in the operating room, and to what extent these simulation modules are valued by residents. METHODS: Simulation performance was assessed longitudinally on 5 residents using the GRITS assessment through postgraduate years (PGY) 1 to 5 (n = 25 evaluations) in a simulated volar forearm approach using cadaveric specimens. An additional 20 PGY-1 residents were evaluated cross-sectionally in this same time frame. Written, open-ended feedback on the simulation experience was sought and analyzed via a thematic analysis. For correlative data, evaluations (n = 65 evaluations) of a variety of authentic surgical procedures were compiled on PGY-2 through PGY-5 orthopaedic residents and compared with the simulated experiences. RESULTS: GRITS scores were averaged for each group of residents, and validity and reliability were assessed using R-software. PGY-1 residents' mean GRITS evaluation score (expressed as a value from 1 to 5) was 3.4. Longitudinally, this mean score increased over the PGY years 2-5 to 4.4, 4.7, 4.9, and 4.8, respectively. Of the parameters measured by GRITS, the lowest average scores were "flow of operation" and "time and motion" across all levels, although these did improve over PGY years 2 to 5. Findings were consistent between simulation and "real-world" procedures. Open-ended responses evaluating the module were positive. CONCLUSIONS: Our study suggests that the GRITS tool shows promise as an effective and reliable method for assessing orthopaedic resident's technical skills based on an ABOS module system.

Working to Increase Stability through Exercise (WISE): screening, recruitment, and baseline characteristics.

BACKGROUND: The aim of this paper is to describe the utility of various recruitment modalities utilized in the Working to Increase Stability through Exercise (WISE) study. WISE is a pragmatic randomized trial that is testing the impact of a 3-year, multicomponent (strength, balance, aerobic) physical activity program led by trained volunteers or delivered via DVD on the rate of serious fall-related injuries among adults 65 and older with a past history of fragility fractures (e.g., vertebral, fall-related). The modified goal was to recruit 1130 participants over 2 years in three regions of Pennsylvania. METHODS: The at-risk population was identified primarily using letters mailed to patients of three health systems and those over 65 in each region, as well as using provider alerts in the health record, proactive recruitment phone calls, radio advertisements, and presentations at community meetings. RESULTS: Over 24 months of recruitment, 209,301 recruitment letters were mailed, resulting in 6818 telephone interviews. The two most productive recruitment methods were letters (72% of randomized participants) and the research registries at the University of Pittsburgh (11%). An average of 211 letters were required to be mailed for each participant enrolled. Of those interviewed, 2854 were ineligible, 2,825 declined to enroll and 1139 were enrolled and randomized. Most participants were female (84.4%), under age 75 (64.2%), and 50% took an osteoporosis medication. Not having a prior fragility fracture was the most common reason for not being eligible (87.5%). The most common reason provided for declining enrollment was not feeling healthy enough to participate (12.6%). CONCLUSIONS: The WISE study achieved its overall recruitment goal. Bulk mailing was the most productive method for recruiting community-dwelling older adults at risk of serious fall-related injury into this long-term physical activity intervention trial, and electronic registries are important sources and should be considered.

Clinical Perspectives on the Molecular and Pharmacological Attributes of Anti-CD20 Therapies for Multiple Sclerosis.

Anti-CD20 therapies have demonstrated considerable efficacy in the treatment of relapsing multiple sclerosis, constituting a high-efficacy treatment approach for reducing relapse risk and mitigating disability progression. These therapies have been shown to strongly deplete circulating B cells and small subsets of CD3+ CD4 and CD8 T cells that express low levels of CD20. While the clinical profiles of the various anti-CD20 monoclonal antibodies used in treating multiple sclerosis are well-described in the literature, greater understanding of the implications of their distinct molecular and pharmacological attributes is needed. In this review, we focus on four anti-CD20 monoclonal antibodies-rituximab, ocrelizumab, ofatumumab, and ublituximab-that are currently used, approved, or in late-stage clinical development for the treatment of multiple sclerosis. We provide clinical perspectives on the potential implications of differences in molecular structures, target epitopes, dosing regimens, mechanisms and impact on B-cell depletion and reconstitution, immunogenicity, administration-related reactions, and infection risks.