Citations

AbstractBackgroundTraumatic encephalopathy syndrome (TES) is the proposed clinical syndrome of chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impacts in contact/collision sports. A core clinical feature of TES is cognitive impairment, particularly in memory and executive functions. Cognitive intraindividual variability (IIV) is the extent of variability in neuropsychological test performance (i.e., dispersion of test scores) and is believed to be an indicator of disruption in executive control, linked to altered fronto‐subcortical circuits. Here, we examined cognitive IIV as a method to detect subtle executive dysfunction in TES that may not be captured by traditional neuropsychological measures.MethodThe sample included former American football players (120 professional, 60 college); participants were males, aged 45‐74. Participants completed a baseline neuropsychological test battery (n = 8 excluded for suboptimal performance validity). A multidisciplinary diagnostic consensus conference classified participants using the 2021 NINDS Consensus Diagnostic Criteria for TES (see Table‐1): (1) No‐TES (n = 62); (2) TES‐CTE Suggestive (n = 35); (3) TES‐CTE Possible (n = 21); (4) TES‐CTE Probable (n = 54). TES‐CTE Possible and Probable were combined. The coefficient of variation (CoV) was used to measure cognitive IIV (CoV = iSD/iOTBM, iOTBM = average T‐score across neuropsychological tests; iSD = standard deviation of iOTBM). A higher CoV indicates greater score dispersion. To avoid circularity, memory and executive tests used for classifying TES groups were intentionally excluded from the CoV calculation. Analysis of covariance compared the TES groups on CoV, controlling for age, education, and race.ResultResults showed a significant difference in CoV between TES groups, F(2, 165) = 8.20 p<.001, partial η2 = .09. The TES‐CTE Possible/Probable group had the highest CoV (M = .226, SE = .007), compared with the TES‐no (M = .192, SE = .008, p<.001) and TES‐CTE Suggestive groups (M = .178, SE = .011, p<.001). CoV did not significantly differ between the TES‐no and TES‐CTE suggestive groups (Mdiff = 0.014, SE = .013, p = .293).ConclusionThe TES‐CTE possible/probable group had the highest cognitive IIV with ∼23% dispersion (vs. ∼18‐19% in TES‐no and TES‐CTE suggestive groups), suggesting greater cognitive variability in those with the greatest likelihood for having underlying CTE (based on TES criteria). This finding emphasizes the potential utility of exploring cognitive IIV as a method for detecting nuanced executive dysfunction in TES.

AbstractBackgroundFew normative data for computerized measures administered in unsupervised remote environments are available. We aimed to determine what variables to include in normative models for remote self‐administered assessments, develop normative data for measures administered through Mayo Test Drive (MTD, a multi‐device remote cognitive assessment platform) and evaluate application of norms.Method1240 adults ages 33‐100 (96% White) from the Mayo Clinic Study of Aging and Mayo Alzheimer’s Disease Research Center met normative sample inclusion criteria that included a concordant Cognitively Unimpaired (CU) diagnosis (3 independent raters all diagnosed CU) and CDR = 0 (see Table 1 for sample characteristics). Raw test scores were converted to normalized scaled scores. We derived regression‐based normative data that adjusted for age, age2, sex and education (base model); alternative models are also provided (age+age2+sex; age+ age2). We evaluated whether additional model terms beyond the base model were needed using an a priori cut‐off of 1% variance improvement in adjusted R2 over and above the base model. We examined rates of low test performance defined as performance below ‐1 SD in independent validation samples (n = 167 concordant CU, n = 64 mild cognitive impairment (MCI), n = 14 dementia). Rates are considered significantly different than expected when 95% confidence intervals (CIs) do not include the expected 14.7% base rate frequency.ResultNo additional potential model terms met our a priori cut‐off for inclusion beyond the base model (see Table 2), including other quadratic and cubic terms or interactions, device type, response input type, potential session interference, and national area deprivation index (ADI available in subset; N = 776). Application of norms showed expected rates of low test performance among CU participants (95% CI includes expected base rate) and significantly greater than expected rates of low test performance for all variables in MCI (e.g., 62.5% for composite) and dementia (e.g., 71.4% for composite; see Table 3).ConclusionTypical normative models appear appropriate for remote self‐administered measures and are sensitive to cognitive impairment. Device type and response input did not explain enough variance to warrant inclusion in normative models but are important for individual level interpretation. Future work will improve representation of individuals from under‐represented groups.

Abstract Purpose: Around 10% to 15% of prostate cancers harbor recurrent aberrations in the Forkhead Box A1 gene, FOXA1, whereby the alteration type and the effect on the forkhead (FKH) domain affect protein function. We developed a FOXA1 classification system to inform clinical management. Experimental Design: A total of 5,014 prostate cancer samples were examined using whole-exome and -transcriptome sequencing from the Caris Life Sciences database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain. These were in the first part of the FKH domain [class 1A: amino acids (AA) 168–246], within the Wing2 region of FKH (class 1B: AA 247–269), or outside FKH (class 1C: AA 1–167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1–269 and class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims. Results: FOXA1 alterations did not influence survival when considered in aggregate but had distinct prognostic effects when stratified by class. In primary prostate samples, class 1A alterations were associated with overall improved survival (HR, 0.57; P = 0.03); a similar trend was seen in metastatic biopsies with class 1B (HR, 0.84; P = 0.09). Conversely, in primary specimens, class 1C exhibited worse survival upon second-generation androgen receptor signaling inhibitor treatment (HR, 1.93; P &lt; 0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR, 2.05; P &lt; 0.001) and worse outcomes to first-line androgen-deprivation therapies (HR, 2.5; P &lt; 0.001). Class 3A alterations indicated improved survival (HR, 0.70; P = 0.01), whereas class 3B alterations portended poor outcomes (HR, 1.50; P &lt; 0.001). Amplifications (class 4) indicated poor outcomes in metastatic samples (HR, 1.48; P = 0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European Americans, African Americans had increased class 1C alterations, whereas Asian/Pacific Islander patients had increased class 1B alterations. Conclusions: FOXA1 alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision-making for patients with prostate cancer and uncovers important racial differences.

Importance Molecular techniques, including next-generation sequencing, genomic copy number profiling, fusion transcript detection, and genomic DNA methylation arrays, are now indispensable tools for the workup of central nervous system (CNS) tumors. Yet there remains a great deal of heterogeneity in using such biomarker testing across institutions and hospital systems. This is in large part because there is a persistent reluctance among third-party payers to cover molecular testing. The objective of this Review is to describe why comprehensive molecular biomarker testing is now required for the accurate diagnosis and grading and prognostication of CNS tumors and, in so doing, to justify more widespread use by clinicians and coverage by third-party payers. Observations The 5th edition of the World Health Organization (WHO) classification system for CNS tumors incorporates specific molecular signatures into the essential diagnostic criteria for most tumor entities. Many CNS tumor types cannot be reliably diagnosed according to current WHO guidelines without molecular testing. The National Comprehensive Cancer Network also incorporates molecular testing into their guidelines for CNS tumors. Both sets of guidelines are maximally effective if they are implemented routinely for all patients with CNS tumors. Moreover, the cost of these tests is less than 5% of the overall average cost of caring for patients with CNS tumors and consistently improves management. This includes more accurate diagnosis and prognostication, clinical trial eligibility, and prediction of response to specific treatments. Each major group of CNS tumors in the WHO classification is evaluated and how molecular diagnostics enhances patient care is described. Conclusions and Relevance Routine advanced multidimensional molecular profiling is now required to provide optimal standard of care for patients with CNS tumors.

ObjectiveTo determine which ear environment risk factors impact ossiculoplasty hearing outcomes and to generate a statistically‐valid grading system for ossiculoplasty outcome reporting.Study TypeRetrospective case series.MethodsA multi‐institutional database was generated from cases performed between 2011 and 2019. Preoperative and postoperative hearing thresholds were recorded alongside potential ear environment risk factors. Multiple variable linear regression statistical analyses of risk factors were applied to determine independent association with postoperative pure tone average air‐bone gap (PTA‐ABG). Significant factors were used to generate a statistically‐weighted grading scale of Ear Environment Risk (EER).Results1679 cases had a mean follow‐up time of 33.6 months (SD 36.3) and a mean postoperative PTA‐ABG of 21.2 (SD 12.8). Multiple revision status (p < 0.001), presence of canal wall down mastoidectomy cavity (p = 0.020), absent malleus (p < 0.001), absent stapes superstructure (p = 0.016), frequent otorrhea (p = 0.008), pediatric age (p < 0.001), and blunted/lateralized tympanic membrane (p = 0.003) were independently correlated with PTA‐ABG. These factors were incorporated into an EER Scoring System with four distinct risk groups wherein each risk group was significantly correlated with PTA‐ABG, and this grading system was better correlated with PTA‐ABG (Kendall's τ = 0.193) than other existing published grading scales.ConclusionGrading environment risk according to a novel EER scoring system generates meaningful risk groupings that correlate with ossiculoplasty postoperative PTA‐ABG, and this holds potential to frame reporting of hearing outcomes for future ossiculoplasty research.Level of Evidence3 Laryngoscope, 135:S1–S11, 2025

Abstract US clinical practice guidelines for the diagnostic evaluation of cognitive impairment due to Alzheimer's disease (AD) or AD and related dementias (ADRD) are decades old and aimed at specialists. This evidence‐based guideline was developed to empower all—including primary care—clinicians to implement a structured approach for evaluating a patient with symptoms that may represent clinical AD/ADRD. Through a modified‐Delphi approach and guideline‐development process (7374 publications were reviewed; 133 met inclusion criteria) an expert workgroup developed recommendations as steps in a patient‐centered evaluation process. This summary focuses on recommendations, appropriate for any practice setting, forming core elements of a high‐quality, evidence‐supported evaluation process aimed at characterizing, diagnosing, and disclosing the patient's cognitive functional status, cognitive–behavioral syndrome, and likely underlying brain disease so that optimal care plans to maximize patient/care partner dyad quality of life can be developed; a companion article summarizes specialist recommendations. If clinicians use this guideline and health‐care systems provide adequate resources, outcomes should improve in most patients in most practice settings. Highlights US clinical practice guidelines for the diagnostic evaluation of cognitive impairment due to Alzheimer's disease (AD) or AD and related dementias (ADRD) are decades old and aimed at specialists. This evidence‐based guideline was developed to empower all—including primary care—clinicians to implement a structured approach for evaluating a patient with symptoms that may represent clinical AD/ADRD. This summary focuses on recommendations, appropriate for any practice setting, forming core elements of a high‐quality, evidence‐supported evaluation process aimed at characterizing, diagnosing, and disclosing the patient's cognitive functional status, cognitive–behavioral syndrome, and likely underlying brain disease so that optimal care plans to maximize patient/care partner dyad quality of life can be developed; a companion article summarizes specialist recommendations. If clinicians use this guideline and health‐care systems provide adequate resources, outcomes should improve in most patients in most practice settings.

Abstract US clinical practice guidelines for the diagnostic evaluation of cognitive impairment due to Alzheimer's disease (AD) or a related dementia (ADRD) are two decades old. This evidence‐based guideline was developed to empower all clinicians to implement a structured approach for evaluating a patient with symptoms that may represent clinical AD/ADRD. An expert workgroup conducted a review of 7374 publications (133 met inclusion criteria) and developed recommendations as steps in an evaluation process. This summary briefly reviews core recommendations and details specialist recommendations of a high‐quality, evidence‐supported evaluation process aimed at characterizing, diagnosing, and disclosing the patient's cognitive functional status, cognitive–behavioral syndrome, and likely underlying brain disease so that optimal care plans to maximize patient/care partner dyad quality of life can be developed; a companion article summarizes primary care recommendations. If clinicians use the recommendations in this guideline and health‐care systems provide adequate resources, outcomes should improve in most patients in most practice settings. Highlights US clinical practice guidelines for the diagnostic evaluation of cognitive impairment due to Alzheimer's disease (AD) or related dementias (ADRD) are decades old and aimed at specialists. This evidence‐based guideline was developed to empower all—including primary care—clinicians to implement a structured approach for evaluating a patient with symptoms that may represent clinical AD/ADRD. This summary focuses on recommendations appropriate for specialty practice settings, forming key elements of a high‐quality, evidence‐supported evaluation process aimed at characterizing, diagnosing, and disclosing the patient's cognitive functional status, cognitive–behavioral syndrome, and likely underlying brain disease so that optimal care plans to maximize patient/care partner dyad quality of life can be developed; a companion article summarizes primary care recommendations. If clinicians use this guideline and health‐care systems provide adequate resources, outcomes should improve in most patients in most practice settings.

Abstract US clinical practice guidelines for the diagnostic evaluation of cognitive impairment due to Alzheimer's Disease (AD) or AD and related dementias (ADRD) are decades old and aimed at specialists. This evidence‐based guideline was developed to empower all—including primary care—clinicians to implement a structured approach for evaluating a patient with symptoms that may represent clinical AD/ADRD. As part of the modified Delphi approach and guideline development process (7374 publications were reviewed; 133 met inclusion criteria) an expert workgroup developed recommendations as steps in a patient‐centered evaluation process. The workgroup provided a summary of validated instruments to measure symptoms in daily life (including cognition, mood and behavior, and daily function) and to test for signs of cognitive impairment in the office. This article distills this information to provide a resource to support clinicians in the implementation of this approach in clinical practice. The companion articles provide context for primary care and specialty clinicians with regard to how to fit these instruments into the workflow and actions to take when integration of performance on these instruments with clinical profile and clinician judgment support potential cognitive impairment.

Abstract Pituitary tumors require a diverse, multidisciplinary approach in their management. Stereotactic radiosurgery (single or hypofractionated) and fractionated radiotherapy are integral parts of the armamentarium. With the introduction of highly conformal, stereotactic ionizing radiation approaches, the reported tumor control rates and clinical outcomes have improved significantly. This review details the indications, risks, and outcomes of pituitary radiosurgery and radiation therapy, and presents in brief the differences in treatment approaches between stereotactic radiosurgery, fractionated radiation therapy, and proton therapy.