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Abstract Background Progressive apraxia of speech (PAOS) is characterized by difficulties with motor speech programming and planning. PAOS targets gray matter (GM) and white matter (WM) microstructure that can be assessed using diffusion tensor imaging (DTI) and multishell applications, such as neurite orientation dispersion and density imaging (NODDI). In this study, we aimed to apply DTI and NODDI to add further insight into PAOS tissue microstructure. Methods Twenty‐two PAOS patients and 26 age‐ and sex‐matched controls, recruited by the Neurodegenerative Research Group (NRG) at Mayo Clinic, underwent diffusion MRI on 3T MRI. Brain maps of fractional anisotropy (FA) and mean diffusivity (MD) from DTI and intracellular volume fraction (ICVF) and isotropic volume fraction (IsoVF) from NODDI were generated. Global WM and GM, and specific WM tracts were identified using tractography and lobar GM regions. Results Global WM differences between PAOS and controls were greatest for ICVF, and global GM differences were greatest for MD and IsoVF. Abnormalities in key WM tracts involved in PAOS, including the body of the corpus callosum and frontal aslant tract, were identified with FA, MD, and ICVF, with excellent differentiation of PAOS from controls (area under the receiver operating characteristic curves >.90). MD and ICVF identified abnormalities in arcuate fasciculus, thalamic radiations, and corticostriatal tracts. Significant correlations were identified between an index of articulatory errors and DTI and NODDI metrics from the arcuate fasciculus, frontal aslant tract, and inferior longitudinal fasciculus. Conclusions DTI and NODDI represent different aspects of brain tissue microstructure, increasing the number of potential biomarkers for PAOS.

Study Design Cadaveric study. Objectives The purpose of this study was to compare a novel, integrated 3D navigational system (NAV) and conventional fluoroscopy in the accuracy, efficiency, and radiation exposure of thoracolumbar percutaneous pedicle screw (PPS) placement. Methods Twelve skeletally mature cadaveric specimens were obtained for twelve individual surgeons. Each participant placed bilateral PS at 11 segments, from T8 to S1. Prior to insertion, surgeons were randomized to the sequence of techniques and the side (left or right). Following placement, a CT scan of the spine was obtained for each cadaver, and an independent reviewer assessed the accuracy of screw placement using the Gertzbein grading system. Outcome metrics of interest included a comparison of breach incidence/severity, screw placement time, total procedure time, and radiation exposure between the techniques. Bivariate statistics were employed to compare outcomes at each level. Results A total of 262 screws (131 using each technique) were placed. The incidence of cortical breaches was significantly lower with NAV compared to FG (9% vs 18%; P = .048). Of breaches with NAV, 25% were graded as moderate or severe compared to 39% in the FG subgroup ( P = .034). Median time for screw placement was significantly lower with NAV (2.7 vs 4.1 min/screw; P = .012), exclusive of registration time. Cumulative radiation exposure to the surgeon was significantly lower for NAV-guided placement (9.4 vs 134 μGy, P = .02). Conclusions The use of NAV significantly decreased the incidence of cortical breaches, the severity of screw breeches, screw placement time, and radiation exposure to the surgeon when compared to traditional FG.

ImportanceThere has been little consideration of genomic risk of recurrence by breast cancer subtype despite evidence of racial disparities in breast cancer outcomes.ObjectiveTo evaluate associations between clinical trial end points, namely pathologic complete response (pCR) and distant recurrence–free survival (DRFS), and race and examine whether gene expression signatures are associated with outcomes by race.Design, Setting, and ParticipantsThis retrospective cohort study used data from the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 (I-SPY 2) multicenter clinical trial of neoadjuvant chemotherapy with novel agents and combinations for patients with previously untreated stage II/III breast cancer. Analyses were conducted of associations between race and short- and long-term outcomes, overall and by receptor subtypes, and their association with 28 expression biomarkers. The trial enrolled 990 female patients between March 30, 2010, and November 5, 2016, with a primary tumor size of 2.5 cm or greater and clinical or molecular high risk based on MammaPrint or hormone receptor (HR)-negative/ERBB2 (formerly HER2 or HER2/neu)–positive subtyping across 9 arms. This data analysis was performed between June 10, 2021, and October 20, 2022.ExposureRace, tumor receptor subtypes, and genomic biomarker expression of early breast cancer.Main Outcomes and MeasuresThe primary outcomes were pCR and DRFS assessed by race, overall, and by tumor subtype using logistic regression and Cox proportional hazards regression models. The interaction between 28 expression biomarkers and race, considering pCR and DRFS overall and within subtypes, was also evaluated.ResultsThe analytic sample included 974 participants (excluding 16 self-reporting as American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or multiple races due to small sample sizes), including 68 Asian (7%), 120 Black (12%), and 786 White (81%) patients. Median (range) age at diagnosis was 47 (25-71) years for Asian, 49 (25-77) for Black, and 49 (23-73) years for White patients. The pCR rates were 32% (n = 22) for Asian, 30% for Black (n = 36), and 32% for White (n = 255) patients (P = .87). Black patients with HR-positive/ERBB2-negative tumors not achieving pCR had significantly worse DRFS than their White counterparts (hazard ratio, 2.28; 95% CI, 1.24-4.21; P = .01), with 5-year DRFS rates of 55% (n = 32) and 77% (n = 247), respectively. Black patients with HR-positive/ERBB2-negative tumors, compared with White patients, had higher expression of an interferon signature (mean [SD], 0.39 [0.87] and −0.10 [0.99]; P = .007) and, compared with Asian patients, had a higher mitotic score (mean [SD], 0.07 [1.08] and −0.69 [1.06]; P = .01) and lower estrogen receptor/progesterone receptor signature (mean [SD], 0.31 [0.90] and 1.08 [0.95]; P = .008). A transforming growth factor β signature had a significant association with race relative to pCR and DRFS, with a higher signature associated with lower pCR and worse DRFS outcomes among Black patients only.Conclusions and RelevanceThe findings show that women with early high-risk breast cancer who achieve pCR have similarly good outcomes regardless of race, but Black women with HR-positive/ERBB2-negative tumors without pCR may have worse DRFS than White women, highlighting the need to develop and test novel biomarker-informed therapies in diverse populations.

Objectives The aim of the study was to identify trends in postoperative management of persons undergoing surgery for Zenker diverticula (ZD) by evaluating length of stay (LOS), diet on discharge, and imaging with or without surgical complication. Methods Prospectively enrolled adult patients with cricopharyngeal muscle dysfunction with diverticula undergoing surgery from August 1, 2017 to February 1, 2023 were included. Data were extracted from a multi‐institutional REDCap database, summarizing means, medians, percentages, and frequencies. Fisher's exact or chi squared analyses were utilized, as appropriate, to compare subsets of data. Descriptive analysis assessed differences in clinical course and the relationship to postoperative management. Results There were 298 patients with a mean (standard deviation) age of 71.8 (11.2) years and 60% male. Endoscopic surgery was performed in 79.5% (237/298) of patients versus 20.5% (61/298) open surgery. Sixty patients (20.1%) received postoperative imaging, with four leaks identified. Complications were identified in 9.4% of cases ( n = 29 complications in 28 patients), more commonly in open surgery. Most (81.2%) patients were discharged within 23 h. About half of patients (49%) were discharged from the hospital on a pureed/liquid diet; 36% had been advanced to a soft diet. In patients without complications, LOS was significantly longer following open cases ( p = 0.002); postoperative diet was not different between open and endoscopic ( p = 0.26). Conclusions Overall, most patients are discharged within 23 h without imaging. However, LOS was affected by surgical approach. Postoperative complications are different in endoscopic versus open surgery. Complications with either approach were associated with prolonged LOS, need for imaging, and diet restriction. Level of Evidence Level III Laryngoscope , 134:2678–2683, 2024

AbstractBackgroundThere has been a rise in remote cognitive testing for neurodegenerative diseases. The ALLFTD Mobile App is designed to capture clinical features of frontotemporal dementia (FTD) through repeated remote assessment on smartphones. This is a departure from traditional neuropsychological practice in which a single examiner‐led assessment occurs in a controlled setting. When participants complete tasks on their own, those with greater disease severity may be more variable in their performance for a variety of reasons (e.g. greater distractibility, less engagement). Here we study whether intraindividual cognitive variability (IIV) is associated with older age and increasing disease severity.MethodParticipants were 279 (mean age = 54.9) healthy controls and participants with sporadic FTD or from familial FTD kindreds with a range of disease severities based on FTLD Clinical Dementia Rating scale (CDR®+NACC‐FTLD Global) scores: 0 (n = 132), 0.5 (n = 54), and ≥1 (n = 47). Participants completed three cognitive tasks at least two times across twelve days. Measures included an adaptive memory task and gamified versions of Flanker and Go/no‐go tasks. IIV was operationalized as the standard deviation in performance on each task. Regression analyses investigated the relationship of IIV with CDR®+NACC‐FTLD group, and with age in those without symptoms. Education and gender were included as covariates in all analyses.ResultGreater disease severity (CDR®+NACC‐FTLD) was associated with greater variability on Flanker (p<.001) and Go/No‐go (p = .02) tasks; a positive but non‐significant association was seen with memory testing (p = .16). Post‐hoc comparisons found that those with CDR®+NACC‐FTLD of 0.5 had significantly more IIV on the Flanker task (𝛃 = .39, p = .004) than those with CDR®+NACC‐FTLD’s of 0. Moreover, those with a CDR®+NACC‐FTLD ≥1 had significantly greater IIV on the Flanker (𝛃 = .85, p<.001) and Go/No‐go tasks (𝛃 = .51, p = .007) than those with a CDR®+NACC‐FTLD of 0. In those without symptoms (CDR®+NACC‐FTLD = 0), age was associated with increased IIV on the Flanker (𝛃 = .27, p<.001) and Go/no‐go (𝛃 = .23, p<.001) tasks.ConclusionIncreased IIV, particularly on processing speed/executive functioning tasks, was associated with greater age and greater functional impairment, even in the mildest stages. Future investigations exploring predictors of IIV and the prognostic value of IIV are warranted.

AbstractBackgroundFrontotemporal dementia (FTD) is a leading cause of dementia in individuals under age 65. Due to limitations in access to in‐person evaluations, there is an urgent need to examine remote, accessible, and low‐burden assessment techniques for FTD. Unobtrusive monitoring of at‐home computer use in older adults has shown that those with mild cognitive impairment (MCI) have significant declines in computer use over time. To extend these findings, we characterized daily trajectories in smartphone battery percentage, a proxy of smartphone use, and examined relationships with clinical indicators of disease severity in FTD.MethodParticipants included 250 adults enrolled in the ALLFTD Mobile App study (mean age = 53.9 [SD = 14.9]; 59% women; 94% White). To assess clinical disease severity, all participants completed the FTLD Clinical Dementia Rating scale (CDR®+NACC FTLD), a brief neuropsychological battery, the Neuropsychiatric Inventory Questionnaire (NPI‐Q), and brain MRI. The ALLFTD Mobile App was installed onto participants’ smartphones for remote, passive, continuous monitoring of smartphone use (average days of monitoring = 82 [range = 7‐541]). Battery percentage was collected every 15 minutes. Linear mixed effects models examined linear, quadratic, and cubic effects of time of day (i.e., hour; modeled as person‐specific random effects) and their interactions with each measure of disease severity on battery percentage. Models covaried for age.Result57% of participants were clinically normal, 21% had MCI, and 22% had dementia. CDR®+NACC FTLD Global score interacted with hour such that participants with MCI and dementia had flatter battery curves (i.e., less change in battery percentage throughout the day – a proxy of less smartphone use) than clinically normal participants (ps<0.001). Additional models showed that worse memory (hour3 x memory score: 𝛃 = 0.59, p<0.001) and executive functioning (hour3 x executive score: 𝛃 = 0.64, p<0.001), more neuropsychiatric symptoms (hour3 x NPI‐Q: 𝛃 = ‐0.22, p = 0.004), and smaller gray matter volumes (controlling for intracranial volume; hour3 x volume: 𝛃 = 0.49, p<0.001) were also statistically significantly related to less battery usage throughout the day.ConclusionThese findings are proof‐of‐concept that passively acquired smartphone data, specifically battery usage, can provide insights about disease progression in FTD. Results support future research focusing on the development of passively collected digital metrics sensitive to clinical declines in neurodegenerative disease.

AbstractBackgroundPatients with a yes‐no reversal verbally and non‐verbally respond “yes” when they mean “no” and vice versa. They are typically aware of the error and able to correct it given additional time. This symptom commonly, but not exclusively, occurs in patients with primary progressive apraxia of speech (PPAOS). PPAOS is a form of frontotemporal dementia associated with hypometabolism in the supplementary motor area (SMA; e.g., Utianski et al., 2018); as the disease progresses, a wider network of frontal and subcortical regions become implicated. Behaviorally, this symptom seems to reflect poor response inhibition, but the specific anatomical underpinning is not yet understood. Given the brain regions known to be involved in PPAOS, we hypothesized that yes‐no reversals emerge due to degeneration of regions near the SMA and/or frontostriatal regions.MethodWe conducted an exploratory retrospective study of 28 patients who presented with PPAOS and had an FDG‐PET scan; 14 (50%) endorsed yes‐no reversals (see Table 1 for group characteristics). Clinically, AOS severity was measured using clinician ratings (0 = absent, 4 = severe) and frontal dysfunction was captured by the Frontal Assessment Battery (FAB) and the Frontal Behavioral Inventory (FBI). We also measured median standardized uptake value ratios (SUVRs) in the SMA and pre‐SMA, as well as the head and body of the caudate with automated, in‐house software. The caudate ROI was selected based on visual comparison of the FDG‐PET scans between groups and the association between this region and inhibition during response interference (e.g., Schmidt et al., 2020).ResultNeither AOS severity nor hypometabolism in the pre‐SMA/SMA regions differed significantly between groups. In contrast, patients with a yes‐no reversal demonstrated significantly lower scores on the FAB and greater hypometabolism in the caudate body relative to patients without (see Figure 1).ConclusionResults suggest that yes‐no reversals relate to frontostriatal dysfunction rather than AOS severity or SMA activity in these patients. Further research is needed to address why a disproportionate number of patients with PPAOS develop this symptom.

AbstractBackgroundSmartphone‐based cognitive and motor tests enable frequent remote assessments in observational research studies and clinical trials, limiting travel burden and increasing access to research for underrepresented groups. One such smartphone tool is the ALLFTD Mobile App, which was designed to capture the clinical features of neurodegenerative diseases via a battery of cognitive, speech, and motor tasks. In this study, we focus on recruiting a demographically diverse normative sample. We have partnered with the UCSF Brain Health Registry (BHR) to recruit 1,000 cognitively healthy participants across the lifespan. Here we describe the study design and initial feasibility results.MethodsWe designed an automated workflow in which participants never interact with the study team except for troubleshooting. BHR participants without reported cognitive impairment were contacted by email to participate in this study (n = 668). Interested participants downloaded the app onto their smartphone and completed in‐app electronic consent. They were asked to complete three ∼30‐minute sessions of cognitive, motor and speech measures over two weeks. Adherence was determined by evaluating the completion rate of app tasks. In a subset who completed a user experience questionnaire (n = 116), responses were quantified using descriptive statistics.ResultsThe current enrollment rate is 23.20% (155/668) of contacted participants. Average age is 62 (SD = 8.2, range = 25‐84). Average adherence is 76%. Participants reported a range of perceived task difficulty: 38% indicated tasks were “very easy” or “somewhat easy”, 26% indicated they were “neutral,” 36% found the tasks “somewhat difficult,” and none reported them to be “very difficult.” The time commitment was reported to be acceptable by 97% of participants, and 20% were willing to complete additional tasks. Over half (59%) of participants indicated that they preferred using a smartphone to complete cognitive assessments over traditional pen‐and‐paper measures.ConclusionsOur preliminary results demonstrate the feasibility and acceptability of recruiting participants, including older adults, through a registry and conducting remote smartphone testing via a fully automated workflow that is highly scalable. Future analysis will study the effects of demographic factors on feasibility and investigate the reliability and validity of the app measures in this sample.

AbstractBackgroundThe spectrum of what is referred to as nonfluent/agrammatic primary progressive aphasia includes patients with isolated apraxia of speech (PPAOS), progressive agrammatic aphasia (PAA), or a combination thereof (AOS‐PAA). When AOS is present, there is typically an underlying 4R tauopathy (corticobasal degeneration; progressive supranuclear palsy); isolated PAA is more often associated with a 3R tauopathy (Pick’s disease). While pathological studies confirm the clinical syndrome is the sequela of these proteinopathies, beta‐amyloid (Aβ) deposition has also been observed. Given the growing number of treatment options, it is important to better understand the incidence of Alzheimer’s disease (AD) in PPAOS‐PAA spectrum disorders.Methods65 patients recruited by the Neurodegenerative Research Group at Mayo Clinic underwent Aβ‐PET imaging using Pittsburgh Compound B (PiB) and tau‐PET imaging with [18F]flortaucipir at the same visit (PPAOS = 23; PAA = 6; AOS‐PAA = 36). A global PiB SUVR (standardized uptake value ratio)≥1.48 and temporal lobe tau meta‐ROI SUVR≥1.25 were deemed Aβ and tau positive, respectively. The incidence of Aβ and tau positivity and clinical‐demographic profiles were compared among groups.ResultsThere was no difference in age, sex, APOE status, tau/Aβ positivity or PET SUVRs across clinical groups (Table 1). Patients differed on indices of aphasia and AOS severity, in concordance with group membership; there was no difference on a memory measure. Eight patients (12%) were both Aβ and tau positive (indicative of the presence of AD), with an additional 20 patients (31%) positive on only one biomarker (Table 1). Of the eight Aβ and tau positive patients, seven had AOS (six prosodic predominant AOS). Aβ more than tau SUVRs increased with age and were related to each other (Figure 1).ConclusionsAβ and tau positivity is not uncommon in AOS and/or PAA patients, particularly in older patients. Enrollment criteria for Aβ or tau targeted pharmacological trials should consider concordance of biological variables and clinical presentations, rather than simply biological biomarkers. Alternatively, if such patients are enrolled, the outcome measures should reflect the clinical impairments, as it is not yet known if or how concomitant AD influences the clinical presentation.

Objective To describe the incidence of injuries and illnesses among paediatric Team USA athletes competing in the Tokyo 2020 Olympic and Paralympic Games, and the 2022 Beijing Olympic and Paralympic Games. Methods An electronic medical record system documented all injuries and illnesses that occurred while competing in the four Games periods. Incidence (IR) with 95% CI per 1000 athlete days were calculated for both injuries and illnesses. Incidence rate ratios (IRR) were calculated to compare injury and illness rates based on age (paediatric vs non-paediatric) sex, Games period and sport type. Results Two hundred paediatric athletes (age range, 15–21 years) competed across the four Games periods, representing 16.1% of all Team USA athletes. The overall injury IR (95% CI) was 13.4 (9.8 to 18.1), and the overall illness IR was 5.5 (3.3 to 8.7). There were no differences in incidence between paediatric and non-paediatric athletes for either injury (IRR (95% CI): 0.9 (0.6 to 1.2)) or illness (IRR (95% CI): 0.9 (0.5 to 1.5)). Female paediatric athletes were more likely to sustain an injury compared with male paediatric athletes (IRR (95% CI): 2.4 (1.1 to 5.3)). The most common mechanism of injury was gradual onset (IR, 4.3 (2.3 to 7.2)), and injuries most commonly occurred during practices (IR, 7.0 (4.5 to 10.5)). Conclusion Paediatric athletes account for a substantial proportion of Team USA athletes. It is essential that paediatric sports medicine experts are included in the medical team given that paediatric Team USA athletes are just as likely as their adult teammates to sustain an injury or illness.