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Reliable biomarkers are needed to inform clinical management and trials in Charcot-Marie-Tooth disease (CMT), the most common inherited neuropathy. Peripherin and periaxin, biomarkers of peripheral nerve axonal damage and demyelination, respectively, have recently been validated in the inflammatory neuropathies. Here, we evaluate their potential utility in CMT, alongside neurofilament light chain (NfL) and existing outcome measures.We measured serum peripherin, periaxin, and NfL in patients with CMT1A (n=12),CMT2A (n=8) and CMTX (n=8), and compared levels to healthy controls (HC, n=20).Peripherin was higher in CMT1A, CMT2A, and CMTX compared to HC (all p<0.05). NfL was higher in all neuropathy groups versus HC (all p<0.01). Periaxin was elevated in two out of eight CMT2A patients, two out of eight CMTX patients, and below detection limit in CMT1A. Strong correlations were observed between peripherin and clinical tests: stair climb test CMT1A (rho = -0.912, p=0.0006) and 6-minute walk test in CMTX (rho = -1, p=0.0167).Fluid biomarkers show promise in CMT. We aim to selectively measure periaxin in patients with clinical evidence of disease progression, where elevated levels may indicate active demyelination. Larger cohorts are being tested to assess the individual and combined contributions of all three biomarkers to clinical evaluation.roberto.bellanti@nhs.net

Dr. Petersen will be a panelist.

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Dr. Sha will be a panelist.

Significance & Background: Drug hypersensitivity reactions (HSRs) impact patient cancer treatments and outcomes. These reactions can be defined by their clinical presentation (phenotypes), pathophysiology (endotype), and biomarkers. For patients undergoing rapid desensitization (RDD), biomarkers such as skin testing, serum tryptase, and serum lnterleukin (IL)-6 levels can be used to guide protocol selection (both initial and subsequent if continued reactions) and clinical outcomes. Purpose: To develop a RDD treatment algorithm based on the initial and breakthrough HSR phenotypes and associated biomarkers in patients referred to the Brigham and Women's Hospital Drug Desensitization Center. Methods: This study was a retrospective IRB-approved descriptive analysis of adult patients from January 2022 through August 2023. Data collected included symptom presentation, desensitization protocols/outcomes and the following associated biomarkers: skin test, tryptase, and IL-6 levels at the initial reaction and during breakthrough desensitization reactions (BTRs). Interventions: Patients were classified into 3 groups based on endophenotype (Type 1, Cytokine Release Reactions (CRR), and Mixed). Positive skin testing and/or elevated tryptase levels with only symptoms of Type 1 HSR were provided multiple bag desensitization protocols. Patients with an elevated IL-6 that only experienced CRR symptoms were provided a 1 bag protocol. Patients that experienced mixed reactions symptoms of both CRR and Type 1 and/or positive biomarkers received multiple bag protocols. Results: A total of 1,633 desensitization protocols were provided to 326 patients. Biomarkers obtained included skin testing (242 patients), initial reaction tryptase levels (185 patients), BTR tryptase levels (154 patients), initial reaction IL-6 levels (35 patients), and BTR IL-6 levels (142 patients). Based on biomarkers specific desensitization protocols were administered, 4 bag / 16 step (30), 3 bag / 12 step (835), 2 bag / 8 step (327), 1 bag /4-6 step (356) and 1 bag challenges (85). There were 87% protocols (1423) were completed without reactions and 13% with mild to moderate reactions, without deaths. Of the 228/1633 (14%) desensitization protocols completed in patients with an initial CRR phenotype, 208 (91.2%) were successfully completed without reactions. Discussion: Defining the pathogenic mechanism of HSRs helps select specific desensitization protocols (number of bags, steps, and premedication), which increases safety upon re-exposure. The application of biomarkers, although useful in understanding HSR phenotype and endotypes, may have an even greater impact when used to predict response or modify treatment in the setting of desensitization to targeted therpies.

Background AD is defined by cortical amyloid‐β (Aβ), tau neurofibrillary tangles, and neurodegeneration, pathological processes which may contribute to cognitive decline by altering large scale functional brain networks. To test this hypothesis, we examined whether plasma biomarkers of AD pathology (Aβ42/40, phosphorylated tau [pTau‐181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) related to longitudinal changes in resting‐state functional connectivity (rsFC) in cognitively unimpaired participants from the Baltimore Longitudinal Study of Aging. Method Baseline plasma biomarkers were measured with Quanterix SIMOA assays. Functional connectivity (3T resting‐state fMRI) was derived using a predefined cortical parcellation mask from which intra‐network connectivity from seven functional networks was extracted for each participant. Amyloid status (positive/negative) was defined using plasma Aβ42/40 (Figure 1). Linear mixed effects models adjusted for age, sex, race, education, gray matter volume, and time‐covariate interactions were used to determine whether 1) baseline plasma biomarkers predicted longitudinal changes in rsFC, 2) the magnitude of the biomarker‐related rsFC changes differed by amyloid status, and 3) rsFC predicted longitudinal changes in cognition. Result Longitudinal connectivity analyses (mean age±SD=65.49±16.17) included 490 participants (1190 visits; mean follow‐up time=4.31±1.68 years). Higher Aβ42/40, GFAP, and NfL were associated with faster declines in rsFC within several networks (P‐range=0.01‐0.04; Figure 2). Overall, plasma biomarker‐rsFC associations differed by amyloid status (P‐range=0.01‐0.045). Among amyloid‐positive participants, lower levels of Aβ42/40, and higher levels of GFAP, and NfL (Figure 2) were associated with faster declines in rsFC in the visual, dorsal and ventral attention, limbic, and frontoparietal networks (P range=<0.002‐0.04). There were no statistically significant associations between plasma biomarkers and rsFC change among amyloid‐negative participants. Among 760 participants with at least one rsFC scan (mean age±SD=67.21±14.93; 1550 visits, follow‐up time=3.94±1.60 years), we found that baseline rsFC in several networks predicted changes in cognition, e.g., working memory, verbal fluency, and visuospatial abilities (P range=0.02‐0.049; Figure 3). Conclusion Among cognitively normal individuals, plasma biomarkers of Aβ42/40, astrogliosis, and neuronal injury are associated with future intra‐network functional brain changes, particularly in the context of elevated amyloid. Hypo‐ and hyper‐ intra‐network connectivity may drive changes in cognitive performance.

Background Hyperphosphorylation of tau protein underlies the accumulation of neurofibrillary tangles (NFT) in the brain, a neuropathological hallmark of Alzheimer’s Disease (AD). Braak stages, which reflect the regional spread of NFTs, are defined by NFT presence in the entorhinal cortex (Stages I and II), limbic regions including the hippocampus (III and IV), and neocortex (V and VI). Diffusion weighted imaging (DWI) is a magnetic resonance imaging (MRI) technique that sensitizes the MRI signal to the random motion of water molecules and has shown promise for detecting AD‐related microstructural brain changes, including NFT presence. Since diffusion patterns may be disrupted in NFT formation, DWI metrics may be sensitive to NFT formation. In this study, we examine the relationships between DWI metrics of neurodegeneration and Braak stage progression determined by positron emission tomography (PET) imaging. Method 139 participants from the Wisconsin ADRC and Wisconsin Registry for Alzheimer’s Prevention on the AD continuum (Table 1) were imaged with multi‐shell DWI and MK‐6240 PET within 36 months of each other. Parameter maps of Neurite Density Index (NDI), Orientation Dispersion Index (ODI) and Isotropic Volume Fraction (ISO) were computed and average values of each were extracted from the hippocampus, anterior parahippocampal gyrus, and whole‐brain cortical gray matter. We used a linear mixed‐effects model to test DWI’s ability to predict PET‐based Braak Stage, with age, sex, clinical diagnosis, DWI protocol, and the interaction between age and each metric as covariates. Result Two significant relationships between Braak stage and NDI were found. As Braak stage increased, NDI significantly decreased in the hippocampus and whole‐brain cortical grey matter. Additionally, there was a significant interaction between cortical grey matter NDI and age. The results are uncorrected for multiple comparisons. Conclusion Our findings suggest that, as the extent of tau accumulation increases, there is a concurrent decline in neurite density in the hippocampus and cortical grey matter, and further, the association between NDI and Braak stage progression was more pronounced in older individuals. Therefore, NDI, a metric sensitive to axonal and dendritic loss, may track AD‐related pathology. Additional work is needed to determine the specificity of DWI metrics to tangle pathology.