Citations

Background/Objectives: Dizziness is a symptom of many disorders across a wide range of etiologies. If dizzy patients are seen for vestibular evaluation with an audiologist and no vestibular reason for the patient’s dizziness is found, the medical referral pathway can become convoluted. This can leave patients feeling discouraged and unable to manage their symptoms. Clinically symptomatic chronic respiratory alkalosis (CSCRA) is an acid–base disorder that typically presents with dizziness but is unfamiliar to practitioners in vestibular and balance care settings. Methods: In a retrospective chart review deemed exempt by the Mayo Clinic Institutional Review Board, 74 patients at Mayo Clinic Arizona were included. All had consultations with both Audiology and Aerospace Medicine to assess their dizzy symptoms. Results: After completing vestibular testing, arterial blood gas (ABG) testing, and a functional test developed at Mayo Clinic Arizona called the Capnic Challenge test, 40% of patients were found to have CSCRA contributing to their dizzy symptoms. Many of these patients also had common comorbidities of CSCRA, like postural orthostatic tachycardia syndrome (POTS), migraines, and sleep apnea. Fewer than one-fourth of these patients had measurable vestibulopathies causing their dizziness. Half of the patients referred by the vestibular audiologist to Aerospace Medicine had a diagnosis of CSCRA. Conclusions: Assessment for CSCRA should be considered as a next step for patients presenting with dizziness without a vestibular component. Being aware of the prevalence of CSCRA and its comorbidities may help balance providers offer quality interprofessional referrals and improve patient quality of life.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndrome, predominantly affecting women. Psychological distress is common pre- and post-SCAD, yet sex-specific patterns remain understudied. This cross-sectional study aimed to examine sex differences in the psychological distress of patients with SCAD. METHODS: Adult patients diagnosed with SCAD within the past 3 years, confirmed by coronary angiography, were recruited from 6 Canadian hospitals between April 2022 and January 2025. Participants completed questionnaires assessing sociodemographics and validated measures of psychological distress: Patient Health Questionnaire-9 for depression, Generalized Anxiety Disorder-7 for generalized anxiety, Cardiac Anxiety Questionnaire for cardiac-related anxiety, and PTSD Checklist-5 for posttraumatic stress symptoms. Sex differences were analyzed using t tests for continuous variables and χ 2 tests for categorical variables. Multivariable linear regression models assessed the association between sex and psychological distress, adjusting for age, pre-SCAD mental health diagnosis, and employment status. RESULTS: Among 326 patients (92.9% women; mean age=53.3±11.1 years), women reported higher rates of preexisting mental health conditions (29.2% versus 8.7%; P =0.035). Post-SCAD women reported higher mean scores than men on the Patient-Health-Questionnaire-9, Cardiac-Anxiety-Questionnaire, and PTSD Checklist-5 (all P <0.05). Female sex was associated with greater depressive (B=2.94; P =0.010), cardiac anxiety (B=7.09; P =0.008), and posttraumatic stress symptoms (B=5.94; P =0.048) after adjustment. Clinically significant symptoms were more common in women versus men: 25.1% versus 0% (depression), 21.5% versus 4.4% (anxiety), 54.8% versus 26.1% (cardiac anxiety), and 15.5% versus 0% (posttraumatic stress). CONCLUSIONS: Both women and men experience clinically significant cardiac anxiety following SCAD, but women report a greater psychological burden, including more preexisting mental health conditions and twice the distress after SCAD. These results underscore the importance of routine psychological screening and timely intervention to support mental health and recovery outcomes, particularly among women.

ABSTRACT Objective This study aims to identify both fluid and neuroimaging biomarkers for CSF1R‐RD that can inform the optimal timing of treatment administration to maximize therapeutic benefit, while also providing sensitive quantitative measurements to monitor disease progression. Methods Our study compared neuroimaging and fluid (plasma and cerebrospinal fluid (CSF)) biomarkers across three distinct populations: asymptomatic CSF1R pathogenic variant carriers ( N = 14), symptomatic CSF1R pathogenic variant carriers ( N = 17), and healthy controls ( N = 30). We evaluated biomarker correlations with both an established (Montreal Cognitive Assessment (MoCA)) and a novel (CSF1R Clinical Severity Score (CCSS)) clinical diagnostic scale to investigate potential clinical utility. Additionally, we tested the relationship between select biomarkers and cortical thickness using 3D T1‐weighted MPRAGE scans, providing a highly valuable physiological component to our analyses. Results Our results demonstrate that while plasma glial fibrillary acidic protein (GFAP) displays a high sensitivity for distinguishing early‐stage CSF1R‐RD patients from healthy controls, plasma neurofilament light chain (NfL) is more effective for tracking disease progression following the onset of symptoms. Interpretation Overall, our study provides evidence for plasma NfL and GFAP as valuable biomarkers of earliest symptom onset and disease progression for CSF1R‐RD.

Abstract Purpose: Combined mTOR and MEK inhibition, critical components of the RAS effector pathway underlying the pathogenesis of neurofibromatosis type 1 (NF1)–related tumors, caused regression in a malignant peripheral nerve sheath tumor (MPNST) transgenic mouse model. The primary objective was to determine the clinical benefit rate in patients with unresectable/metastatic MPNST. Patients and Methods: The study design was a multi-institutional, open-label, Simon two-stage, phase II study of the MEK inhibitor selumetinib and mTOR inhibitor sirolimus. Patients ≥12 years with histologically confirmed MPNST received selumetinib 50 mg twice daily and sirolimus 4 mg once daily, in continuous 28-day cycles. Correlative studies evaluated patient-reported pain, immune signature in peripheral blood, and cell-free DNA (cfDNA). Results: A total of 21 heavily pretreated patients [seven females; median age, 41 years (range, 16–72); and 14 with NF1] with advanced disease enrolled at five participating sites. Clinical benefit was observed in only one of seven in stage 1 and one of 14 patients in stage 2. The median number of cycles was two (range, 1–6). Most common adverse events (AE) were grade ≤2 gastrointestinal toxicity, acneiform rash, hypertriglyceridemia, mucositis, and transaminase elevation. Unlike the preclinical model, early 18F-fluorodeoxyglucose PET scan performed during cycle 1 demonstrated partial metabolic responses in five patients (24%), but these did not correlate with objective responses after cycle 2. cfDNA was able to detect MPNST with the potential to be a biomarker of response. Conclusions: The combination was safe, with manageable and expected AEs, but did not meet study parameters for further evaluation in MPNST. Correlative studies were informative and may guide future therapeutic trials of MPNST.

Abstract Background The number of cancer survivors aged older than 65 years is rising rapidly. Current evidence‐based exercise guidelines lack specific guidance for older cancer survivors as a result of insufficient evidence. An expert panel was convened to develop consensus‐based recommendations for exercise in older cancer survivors. Methods The development of recommendations was guided by the Grading of Recommendations Assessment, Development, and Evaluation Evidence‐to‐Decision framework for good practice statements. The panel drew from the available literature, a Delphi survey of exercise and health professionals, other exercise guidelines, clinical and research expertise, and interest‐holder input provided by a community advisory board of older cancer survivors and caregivers ( n = 11). Recommendations had to be deemed accessible (i.e., no added barriers) to older cancer survivors and feasible to implement. The panel voted on the strength of the recommendation for or against each statement, with consensus set at 85% agreement. Results Consensus was reached on 11 recommendations covering the following areas: medical evaluation/clearance for exercise, pre‐exercise assessment, exercise prescription, exercise tolerance and safety, exercise delivery, and behavioral support. The recommendations aimed to promote engagement in and uptake of appropriately prescribed exercise programming by older cancer survivors, while keeping barriers and risks as low as possible. Conclusions Older cancer survivors can benefit from appropriately prescribed exercise, which should be an essential component of their cancer care. Exercise and health professionals need to consider the unique needs of older cancer survivors to ensure that exercise is safe and effective for this population, while also reducing barriers to reach as many people as possible.

Erdheim-Chester disease (ECD) is a rare disease characterized by the accumulation of neoplastic histiocytes in various extra-nodal tissues. Tissue biopsies involved by ECD are difficult to distinguish from reactive inflammatory infiltrates given the bland appearance of the neoplastic histiocytes. Confirmation of the ECD diagnosis often relies on molecular studies to confirm BRAF V600E mutation or other activating mutations involving MAPK pathway genes. In this study, we examined the diagnostic utility of cyclin D1 and pERK as immunohistochemical markers of MAPK pathway activation in ECD compared with its histopathologic mimics. The cohort included 41 clinically confirmed ECD patients, most with known genetic alterations in MAPK pathway genes (n=38). In 3 cases no mutation was identified. 37 of 41 (90%) of ECD cases showed cyclin D1 overexpression, with frequent staining in the cytoplasm as well as the nucleus. pERK expression was observed in 32 of 39 (82%) cases. Cyclin D1 staining was negative in histopathologic mimics of ECD, apart from weak patchy staining in fat necrosis and uniform staining in a subset of cases of juvenile/adult xanthogranuloma. While not entirely sensitive or specific, in the proper clinical and radiologic context strong nuclear and cytoplasmic cyclin D1 expression within histiocytic infiltrates helps to support a diagnosis of ECD.

Abstract Variants in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene, which causes cystic fibrosis, have become increasingly well‐characterized in recent decades. However, clinicians remain challenged by CFTR variants that result in variable expressivity and reduced penetrance, including the variant R117H (c.350G>A) and the intron 9 poly‐thymidine (poly‐T) and poly‐thymidine‐guanosine (TG) tracts, highlighting a knowledge gap that impacts the delivery of accurate information to patients and families. To address this gap, we developed an educational resource that provides descriptive likelihoods of specific phenotypes that may result from genotypes including R117H and the poly‐T and TG tracts. Development of the resource was grounded in an extensive literature review, clinical expertise, and publicly available CFTR variant databases, with feedback incorporated from CF clinicians, genetic counselors, and CF content experts. Genotypes were determined to have very low, low, moderate, high, or very high likelihood of resulting in CF, CFTR‐related disorder (CFTR‐RD), no symptoms, or the designation of CFTR‐related metabolic syndrome/CF‐screen positive, inconclusive diagnosis (CRMS/CFSPID) following CF newborn screening. The resource described in this report is intended to help clinicians navigate the uncertainty surrounding potential diagnostic scenarios to present accurate assessments to patients and families, a critical component of CF genetic testing and counseling.

Abstract Background Apolipoprotein E (apoE) facilitates the fibrillization and deposition of amyloid β (Aβ) in Alzheimer's Disease (AD). Supported by robust literature from various groups, in our current study we have investigated the relative amyloidogenic properties of the three major human APOE alleles. Knowledge from such studies could provide insight into the role of ApoE protein in the deposition, evolution and maturation of parenchymal Aβ. Method We used hAbetaSAA (Jax Labs) mice crossed with human APOE targeted replacement mice to create hAbetaSAA mice homozygous for human APOE E2, E3 and E4 . Furthermore, APPsi mice (hAPPswe/indiana: Borchelt) expressing human APOE E3 or E4 were injected intracerebrally with AD brain lysates to examine the role of APOE genotype on Aβ seeding. Neuropathological examination was conducted via immunohistochemistry, immunofluorescence and immunoblotting. Result hAbetaSAA mice expressing human APOE E4 showed higher Aβ deposition relative to APOE E3 and APOE E2 by 5 months of age and progressing through 8 months and 13 months of age. In comparison, APP mice expressing humanized Aβ (Jax Labs) with human APOE E4 did not develop deposits in their lifetime. hAbetaSAA mice with endogenous mouse Apoe had the highest Aβ plaque deposition, with an approximately 60‐fold increase in Aβ burden compared to SAA APP mice expressing APOE E3 , especially in the earlier deposition phase. Removing mouse Apoe resulted in dose‐dependent reduction in Aβ deposition, consistent with previously published literature. Plaque morphology did not show any notable differences between APOE genotypes, and colocalization of apoE with Aβ were relatively equivalent across different APOE genotypes. Further, in the APPsi model seeded with AD‐derived seeds, we found that mice with APOE E4 or APOE E3 developed equal burdens of diffuse parenchymal Aβ, with no detectable changes in plaque morphology. Conclusion We conclude that apoE variants broadly influence the rate of amyloid deposition, but do not modify the morphology of the resulting deposits or colocalization with Aβ. Notably, when seeding with AD patient brain lysate, there was no significant difference in Aβ burden between APPsi mice expressing APOE E3 and E4 . Our study adds insights into the role of apoE isoforms in determining Aβ‐related phenotype.

Abstract Background Some cases of Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) feature the mislocalization of the normally nuclear TAR DNA binding protein (TDP‐43) to the cytoplasm where it is incorporated into inclusions in affected brain regions. TDP‐43 plays a crucial role in the suppression of cryptic exons in the mature RNA of many targets in both AD and FTD. One such target, Stathmin‐2 (STMN2), is misspliced in the absence of TDP‐43 leading to a reduction of STMN2 RNA and protein while the levels of the cryptic splice variant is increased. Cryptic exons are not conserved across species, meaning previous Tdp‐43 models did not capture Stmn2 processing defects and Stmn2 loss of function (LOF). We hypothesize that STMN2 LOF contributes to cognitive phenotypes observed in AD and FTD. Method We have generated a novel mouse that more accurately models human disease mechanisms by expressing short‐hairpin (shRNA) via adeno associated virus in the central nervous system of a recently described humanized Stmn2 mouse model in which Stmn2 splicing is dependent on Tdp‐43. In this mouse we will simultaneously model Tdp‐43 loss of function and aberrant Stmn2 splicing. Result Our preliminary experiments demonstrate that humanized Stmn2 mice expressing shRNA against Tardbp have a reduction of Tardbp RNA and TDP‐43 protein compared to mice expressing a non‐targeting shRNA. Tdp‐43 knock‐down is accompanied by cryptic splicing of endogenous mouse targets, Sortilin 1 and Translin . As anticipated, we also detected cryptic Stmn2 splicing, suggesting that correct Stmn2 splicing is dependent on Tdp‐43 in this model. We will further characterize motor and cognitive functions in addition to neurodegeneration and gliosis in these animals. Conclusion We anticipate this novel model, and our subsequent studies will identify relevant disease mechanisms and provide an invaluable tool with which to investigate therapies for AD and FTD.

Abstract Background The National Institute on Aging Alzheimer's Disease Family Based Study (NIA‐ AD FBS) is a multi‐site, longitudinal study aimed to be a data and bio sample resource for investigators worldwide. Since its inception in 2002 the FBS goal has been to promote greater cooperation and sharing of clinical and biological resources among researchers. Methods The focus of the Family Based Study (FBS) has been the recruitment of families with at least two affected individuals and a third first degree relative with or without dementia and willing to participate. Participants are from different ethnic backgrounds including Caucasian, African American and Hispanics. The FBS study is actively recruiting both late onset (LOAD) and early onset Alzheimer's Disease (EOAD) families as well as conducting follow up evaluations every two years, approximately. Uniform assessments are completed across all sites and include DNA, Plasma, PaXgene and PBMC samples collection and brain autopsies whenever possible. We conduct both in person and remote evaluations and use the services of a mobile phlebotomy company to collect bio samples. In addition, we’ve created a protocol for genetic testing on the proband for EOAD families where an additional sample is sent to a CLIA approved lab and after genetic counseling, the presence or not of AD related mutations is disclosed to the families. Results To date, this cohort has recruited 1,756 families and acquired data from 9,682 family members. Families are from Caucasian, African Americans and Hispanics ethnic groups. The cohort has longitudinal clinical data, cognitive assessment, family history and bio samples available for sharing. Genotype data includes APOE, GWAS, WES, WGS, brain methylation, RNA sequencing and biomarkers data. Conclusion The NIA‐LOAD FBS study is the largest collection of familial Alzheimer's Disease worldwide and many genetic studies of Alzheimer's disease (AD) have included cases and controls from this dataset. Over 140 publications have used data and/or samples from FBS to address the genetics of Alzheimer's Disease. The enriched resources provided by this cohort are invaluable to the scientific community.