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Abstract Background An intense search is underway for tau PET tracers with enhanced capability to visualize tau aggregates. Research indicates that [18F] AV1451 and [18F]MK 6240 exhibit comparable binding properties in terms of spatial distribution and severity of tau aggregates, as observed both in‐vivo and in‐vitro. This study focused on head‐to‐head pathological comparison of both the tracers binding specificity to tangle maturity levels (pretangles, mature tangles and ghost tangles) of tau aggregates as seen on autoradiography as compared to CP‐13 (early tangle maturity marker) and PHF‐1(middling tangle maturity marker) immunohistochemical (IHC) stains in Alzheimer's disease (AD) and non‐AD tauopathies. Method Study participants included included those with AD and non‐AD tauopathies. Analyses were performed on serial 5um formalin fixed paraffin embedded postmortem human brain sections acquired from Mayo clinic brain bank. Visual assessment of colocalization with IHC as well as quantitative analyses were used. IHC sections were incubated with antibodies CP‐13 (recognizing early tangle maturity) and PHF‐1 (recognizing middling tangle maturity). Result A total of 38 participants were examined. The participants included a spectrum from normal to AD, including mild cognitive impairment (MCI) and atypical AD. Participants with N279K (4R), P301L (4R), and R406W MAPT mutations (3R+4R) were included as well. Both the tracers showed strong binding to AD tau aggregates and no or minimal binding to non‐AD tauopathies. Generally, early tangle maturity tau accumulation participants had more tau demonstrated with CP‐13 than PHF‐1 and both the tracers [18F]MK 6240 and [18F]AV 1451 binding are well correlated with the PHF‐1 staining suggesting the preference for middling tangle level and minimal to early tangles. Conclusion The emergence and validation of these new tau PET tracers have opened new opportunities for the development of more accurate diagnostic and management tools for AD. In our study on post‐mortem sections, [ 18 F]MK‐6240 and [ 18 F]Flortaucipir showed similar binding profiles with preference to middling tangle maturity levels.

Abstract Background Primary progressive apraxia of speech (PPAOS) is a neurodegenerative disorder affecting speech motor planning/programming. Current interventions for PPAOS are limited and often adapted from treatments for nondegenerative AOS, which rely on intensive practice to maintain speech accuracy for practiced items. Systematic interventions for PPAOS are scarce, and no studies have explored differential effects across AOS subtypes. PPAOS subtypes include those with predominant phonetic (articulatory distortions and substitutions) or prosodic (slow speech rate, segmentation) speech changes. These subtypes likely differ in their neural underpinnings and may respond variably to intervention. Delayed auditory feedback (DAF), which introduces a slight delay in hearing one's speech, has shown promise in altering speech rate and fluency for stuttering and hypokinetic dysarthria, though its effects on stroke‐related AOS have been mixed. Recent studies suggest DAF can increase speech rate in patients with AOS in the context of nonfluent/agrammatic primary progressive aphasia. We hypothesized DAF would improve speech clarity and fluency in PPAOS, with subtype‐specific effects: phonetic PPAOS may see slower, more accurate speech, while prosodic PPAOS may produce faster, less segmented speech. Method Four PPAOS patients (3 prosodic, 1 phonetic) completed a web‐based speech battery with and without DAF. Feedback delay was calibrated individually using the DAF Pro app. Speech metrics were analyzed acoustically, and blinded perceptual ratings of deviant speech features were conducted. Results Key data are summarized in Table 1. Three out of four patients found the DAF helpful and two re‐recorded with DAF to allow for quantitative analysis. Patient 1 produced words faster with DAF but had slower total sentence production times; he did not find it helpful. Patient 2 spoke slower with DAF. Both patients produced AMRs faster with DAF, while SMRs were faster for Patient 1 and slower for Patient 2. Blinded perceptual judgments of speech clarity and prosody revealed mixed effects of DAF across participants. Conclusions Preliminary results suggest DAF may differentially benefit phonetic and prosodic PPAOS, particularly in sentences compared to word production. Further research is needed to assess clinical significance, refine DAF calibration, and explore patient‐perceived improvements with guided practice in a larger, more diverse sample.

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.

Hearing loss is a highly prevalent disease state affecting almost 1 in 5 individuals globally. Growing research shows that untreated or undertreated hearing loss carries significant long-term sequelae, including increased risk of social isolation, depression, and cognitive decline, among other ramifications. Limited awareness and common misperceptions among the general US adult population and primary care providers contribute to low rates of referral to hearing specialty clinics and underutilization of hearing aids, cochlear implants, and other rehabilitative devices. Comprised of diverse membership, the Hearing Health Collaborative (HHC) was formed in May 2021 to identify and overcome challenges impacting good health care practices and public policy on hearing care in connection with healthy aging. This editorial documents a recent outcome of the HHC derived from a structured A3 process. Specifically, initiative 2, a proposal to develop a simple, clinically anchored staging system primarily for use by frontline providers and patients, is presented. Unlike other common disorders that harbor long-term health sequelae, a corresponding pragmatic clinical staging system—leveraging precedent disease staging convention, based on clinically meaningful outcomes and prognosis for acquired hearing loss—does not exist. The development of this staging system will potentially allow for improved communication across providers and patients, facilitate referral pathways, and ultimately enable patient access to timely and appropriate care.

Background: Among the 1.5 million cases of cutaneous squamous cell carcinoma (cSCC) diagnosed annually in the United States, a subset of aggressive tumors recur or metastasize. Treatment options include total margin-controlled surgery, such as Mohs micrographic surgery or other forms of peripheral and deep en face margin assessment (MMS/PDEMA), and standard excision with postoperative vertical section margin assessment (SEVMA). NCCN Guidelines recommend MMS/PDEMA for the management of cSCC classified as very high risk based on NCCN risk stratification criteria. This study aims to validate the recommendation of MMS/PDEMA as the preferred surgical approach for NCCN very high-risk cSCCs, using data from a multicenter, multinational cohort. Methods: A multicenter cohort study was conducted across 12 sites, including 10 in the United States, 1 in Spain, and 1 in Brazil, comprising 2,752 primary NCCN very high-risk cSCCs treated with MMS/PDEMA or SEVMA. Propensity score–weighted analysis was used to balance baseline characteristics. Outcomes included local recurrence (LR), nodal metastasis (NM), distant metastasis (DM), and disease-specific death (DSD). Results: After balancing baseline characteristics, SEVMA was associated with a 2-fold higher rate of poor outcomes, including recurrence, metastasis, and DSD, compared with MMS/PDEMA. The 3-year cumulative incidence of poor outcomes was higher for SEVMA: LR (12.5% vs 5.9%), NM (11.6% vs 6.0%), DM (4.3% vs 1.9%), and DSD (6.2% vs 3.3%). Conclusions: This study supports the NCCN recommendation of MMS/PDEMA for NCCN very high-risk cSCC, showing reduced recurrence, metastasis, and cSCC-specific mortality compared with SEVMA.

Localized cutaneous squamous cell carcinoma (cSCC) has a favorable prognosis, unlike advanced disease, especially with clinical perineural invasion (PNI), which poses substantial management challenges due to aggressivity and higher recurrence, metastasis, and mortality risks. PNI, a high-risk staging feature, has worse outcomes, particularly when clinically evident rather than incidental. Clinical PNI (cPNI) is evident by clinical symptoms (such as pain, paresthesia, or motor deficits) or radiologic findings, whereas incidental PNI (iPNI) is identified only histologically without associated symptoms or radiologic evidence. PNI remains a novel area with varying practice patterns across institutions. Improving risk stratification and tailoring multidisciplinary approaches are critical for optimizing outcomes. Our review outlines clinical practice patterns at our institution, providing insights into managing cSCC with PNI, focusing on diagnosis, imaging, staging, and emerging immunotherapies. A structured search was conducted using the terms “perineural invasion,” “cutaneous squamous cell carcinoma,” and “immunotherapy.” cPNI has a poor prognosis and requires nuanced clinical decision-making. Surgery and radiation remain central to management. Adjuvant therapy offers substantial survival benefit in cSCC with PNI, with improved disease-free and overall survival compared with surgery alone, supporting its use in appropriately selected high-risk patients. Traditional systemic therapies, including cisplatin and cetuximab, remain foundational but have shown only moderate response rates and limited durability in advanced or neurotropic cSCC. In contrast, immunotherapy—now preferred for advanced or unresectable cases—has transformed management, with programmed cell death protein-1 (PD-1) inhibitors showing promising results (up to 69% response rate) and disease stabilization. Neoadjuvant immunotherapy may enable tumor downstaging, improve radiation planning, and reduce surgical morbidity. Imaging for squamous cell carcinoma (SCC) with PNI aids staging and surveillance, but symptoms remain key for detecting recurrence. Our multidisciplinary approach emphasizes personalized care. Larger trials are needed to define the optimal role and sequencing of immunotherapy in this high-risk patient population.

Abstract Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancy, can be effectively treated with allogeneic hematopoietic cell transplantation (HCT). Older age at HCT and mismatched donors are known to affect overall survival (OS). However, the influence of specific clinical manifestations or WAS variant class on OS and factors associated with event-free survival (EFS) remain incompletely defined. We analyzed outcomes of 308 patients with WAS who underwent HCT at 37 institutions of the Primary Immune Deficiency Treatment Consortium from 1990 to 2018. With a median follow-up of 5.3 years, the 5-year OS and EFS were 87.2% and 79.7%, respectively. Age ≥5 years, donor type, and a pre-HCT history of severe infection had a negative impact on OS and EFS, whereas pre-HCT autoimmunity had no impact. Reduced-intensity regimens were associated with lower T-cell and myeloid donor chimerism, particularly when non–busulfan-based regimens were used. Low myeloid donor chimerism was associated with lower platelet counts. Mixed chimerism was not consistently associated with post-HCT autoimmunity. Patients with class I (exon 1-2 missense and intron 5 hot spot variants) and class II variants (all others) had similar pre-HCT clinical symptom severity and no difference in OS, EFS, or platelet recovery post-HCT. In conclusion, our study showed excellent long-term OS and EFS after HCT for WAS, highlighting the importance of early HCT, before the development of severe infections. We confirmed that HCT using busulfan-based conditioning was associated with improved donor chimerism and platelet recovery. This trial was registered at www.clinicaltrials.gov as NCT02064933.

Abstract Background: The functional importance of bone marrow adipocytes (BMA) is frequently overlooked even though they are critical components of the BM (bone marrow) microenvironment. BMA have been proposed to play a supportive role within the hematopoietic niche and to directly sustain hematopoietic stem cell (HSC) survival as well as to preferentially support leukemia cell survival and proliferation (Sabbah Cell Commun Signal 2023). Although significant ex-vivo data implicates direct and indirect crosstalk between BMA and neoplastic HSCs (Venti Front Endocrinol 2022), the possible role of BMA in myeloproliferative neoplasms and their dynamics following therapy have yet to be characterized. Adiponectin, an anti- inflammatory adipokine that maintains metabolic homeostasis through regulation of insulin sensitivity, lipid metabolism and pro-inflammatory signaling is low in MPN patients and increases with IFN-α therapy (Avcu Int J Hematol. 2006). IFN-α has also been implicated in inhibiting adipogenesis via JAK-STAT1 signaling (Lee Biochim Biophys Act. 2016). A single institutional study of IFN-α in patients with essential thrombocythemia (ET) and polycythemia vera (PV) confirmed the potential for BM histopathologic responses and a correlation with molecular responses (Masarova Exp Hematol Oncol 2017). The aim of this analysis was to characterize the change in BM cellularity and fat composition with pegylated IFN α-2a (Pegasys; PEG) and the relationship with both hematologic and molecular response from tissue collected in prospective, global clinical trials of PEG in patients with ET/PV. Methods: A total of 24 subjects from the phase 2 MPN-RC 111 (Yacoub Blood 2019) salvage PEG study and 16 subjects from the MPN-RC 112 (Mascarenhas Blood 2022) phase 3 study comparing PEG to HU with available clinical, BM H&E slides, laboratory and molecular data were included in this retrospective analysis of prospective clinical trial data. We assigned a semi-quantitative score for changes in cellularity, fat distribution, and megakaryocyte (MK) histo-topography for changes from baseline, at 12, 24 and 36 months when available. Changes in BMA content and para-trabecular distribution were assessed on whole slide digital images with machine learning models. BMA content was quantified with a QuPath pixel classifier that distinguished adipocytes from other marrow components (Bankhead Scientific Reports 2017). Para-trabecular adipocyte distribution was assessed by leveraging UNI2-h, a self-supervised Vision Transformer (ViT-H/14) model and successor to UNI (Mahmood Nature 2024). UNI2-h was pre-trained on 200 million image tiles from over 300,000 H&E and IHC slides. In this study, UNI2-h was adapted to distinguish between high and low para-trabecular adiposity using image tiles centered on trabeculae. Trabeculae with a surrounding layer of adipocytes were labeled as ‘high’ adiposity, while ‘low’ para-trabecular fat distribution was defined by the direct contact of cellular marrow with trabeculae, lacking surrounding adipocytes. Results: A total of 40 PEG-treated ET (n=18) and PV (n=22) patients were included in this analysis with a median age of 64 years (26-85), 77% JAK2V617F+, 23% CALRmut+, and 40% treatment-naïve. The median JAK2V617F variant allele fraction (VAF) was 26% (range 3-96%). A complete hematologic response (CHR) was obtained with PEG in 58%, 61% attained >20% reduction in driver VAF and 48% attained a >50% reduction in VAF (MR) within 24 months of baseline. We observed an increase in BMA content and notable increase in para-trabecular distribution (confirmed by morphology and ML, independently) in 93% and 53% of PEG treated patients attaining a MR versus only 31% and 6% who did not attain MR, respectively (P Value=0.0004). There was more notable improvement towards normalization of MK histo-topography and orderly erythropoiesis in MR (86.6%) than in non-MR (31.2%) (P value=0.001). Increase in BMA content, BMA para-trabecular distribution, or improvement in MK histo-topography were not associated with achievement of CHR or changes in CALR VAF in this small cohort. Cytokine correlation with BMA dynamics is currently ongoing and will be reported at the meeting. Conclusion: Treatment of MPN patients with IFN-α resulted in reproducible changes in BM cellularity including MK histo-topography, erythropoiesis, BMA number and distribution. Changes in BMA were closely associated with reduction in JAK2V617F VAF following PEG treatment.