Citations

AbstractINTRODUCTIONWe used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early‐onset Alzheimer's disease (EOAD).METHODSWe included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non‐Alzheimer's disease (EOnonAD) participants from the Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel‐wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden.RESULTSEOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non‐carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non‐carriers also had greater gray matter atrophy than female ε4 carriers.DISCUSSIONThe effects of sex and APOE ε4 must be considered when studying these populations.HIGHLIGHTS Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE ε4) carrier status on neuroimaging biomarkers among early‐onset Alzheimer's disease (EOAD), early‐onset non‐AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.

Abstract INTRODUCTION We compared white matter hyperintensities (WMHs) in early‐onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early‐onset amyloid‐negative cognitively impaired (EOnonAD) groups in the Longitudinal Early‐Onset Alzheimer's Disease Study. METHODS We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t ‐tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden. RESULTS EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group. DISCUSSION EOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD. Highlights This study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early‐onset amyloid‐negative cognitively impaired (EOnonAD) groups across all brain regions.

AbstractIntroductionOne goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early‐onset Alzheimer's disease (EOAD).MethodsCerebrospinal fluid (CSF) concentrations of Aβ1‐40, Aβ1‐42, total tau (tTau), pTau181, VILIP‐1, SNAP‐25, neurogranin (Ng), neurofilament light chain (NfL), and YKL‐40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated.ResultsBiomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP‐25, and Ng in EOAD differed significantly from cognitively normal and early‐onset non‐AD dementia; NfL, YKL‐40, and VILIP‐1 did not. Across groups, all biomarkers except SNAP‐25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP‐25 were correlated with at least one cognitive measure.DiscussionThis study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.

Abstract Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)–like (N = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.

AbstractPurposeIdentifying predictive factors for all‐cause reoperation after anterior cruciate ligament reconstruction could inform clinical decision making and improve risk mitigation. The primary purposes of this study are to (1) determine the incidence of all‐cause reoperation after anterior cruciate ligament reconstruction, (2) identify predictors of reoperation after anterior cruciate ligament reconstruction using machine learning methodology, and (3) compare the predictive capacity of the machine learning methods to that of traditional logistic regression.MethodsA longitudinal geographical database was utilized to identify patients with a diagnosis of new anterior cruciate ligament injury. Eight machine learning models were appraised on their ability to predict all‐cause reoperation after anterior cruciate ligament reconstruction. Model performance was evaluated via area under the receiver operating characteristics curve. To explore modeling interpretability and radiomic feature influence on the predictions, we utilized a game‐theory‐based method through SHapley Additive exPlanations.ResultsA total of 1400 patients underwent anterior cruciate ligament reconstruction with a mean postoperative follow‐up of 9 years. Two‐hundred and eighteen (16%) patients experienced a reoperation after anterior cruciate ligament reconstruction, of which 6% of these were revision ACL reconstruction. SHapley Additive exPlanations plots identified the following risk factors as predictive for all‐cause reoperation: diagnosis of systemic inflammatory disease, distal tear location, concomitant medial collateral ligament repair, higher visual analog scale pain score prior to surgery, hamstring autograft, tibial fixation via radial expansion device, younger age at initial injury, and concomitant meniscal repair. Pertinent negatives, when compared to previous studies, included sex and timing of surgery. XGBoost was the best‐performing model (area under the receiver operating characteristics curve of 0.77) and outperformed logistic regression in this regard.ConclusionsAll‐cause reoperation after anterior cruciate ligament reconstruction occurred at a rate of 16%. Machine learning models outperformed traditional statistics and identified diagnosis of systemic inflammatory disease, distal tear location, concomitant medial collateral ligament repair, higher visual analog scale pain score prior to surgery, hamstring autograft, tibial fixation via radial expansion device, younger age at initial injury, and concomitant meniscal repair as predictive risk factors for reoperation. Pertinent negatives, when compared to previous studies, included sex and timing of surgery. These models will allow surgeons to tabulate individualized risk for future reoperation for patients undergoing anterior cruciate ligament reconstruction.Level of evidenceIII.

Importance Lensectomy with primary intraocular lens (IOL) implantation is often used in the management of nontraumatic pediatric cataract, but long-term data evaluating the association of age and IOL location with the incidence of complications are limited. Objective To describe the incidence of complications and additional eye surgeries through 5 years following pediatric lensectomy with primary IOL implantation and association with age at surgery and IOL location. Design, Setting, and Participants This prospective cohort study used Pediatric Eye Disease Investigator Group cataract registry data from 61 institution- and community-based practices over 3 years (June 2012 to July 2015). Participants were children younger than 13 years without baseline glaucoma who had primary IOL implantation (345 bilateral and 264 unilateral) for nontraumatic cataract. Data analysis was performed between September 2021 and January 2023. Exposures Lensectomy with primary IOL implantation. Main Outcome and Measures Five-year cumulative incidence of complications by age at surgery (<2 years, 2 to <4 years, 4 to <7 years, and 7 to <13 years) and by IOL location (sulcus vs capsular bag) were estimated using Cox proportional hazards models. Results The cohort included 609 eyes from 491 children (mean [SD] age, 5.6 [3.3] years; 261 [53%] male and 230 [47%] female). Following cataract extraction with primary IOL implantation, a frequent complication was surgery for visual axis opacification (VAO) (cumulative incidence, 32%; 95% CI, 27%-36%). Cumulative incidence was lower with anterior vitrectomy at the time of IOL placement (12%; 95% CI, 8%-16%) vs without (58%; 95% CI, 50%-65%), and the risk of undergoing surgery for VAO was associated with not performing anterior vitrectomy (hazard ratio [HR], 6.19; 95% CI, 3.70-10.34; P < .001). After adjusting for anterior vitrectomy at lens surgery, there were no differences in incidence of surgery for VAO by age at surgery (<2 years, HR, 1.35 [95% CI, 0.63-2.87], 2 to <4 years, HR, 0.86 [95% CI, 0.44-1.68], 4 to <7 years, HR, 1.06 [95% CI, 0.72-1.56]; P = .74) or by capsular bag vs sulcus IOL fixation (HR, 1.22; 95% CI, 0.36-4.17; P = .75). Cumulative incidence of glaucoma plus glaucoma suspect by 5 years was 7% (95% CI, 4%-9%), which did not differ by age after controlling for IOL location and laterality. Conclusions and Relevance In this cohort study, a frequent complication following pediatric lensectomy with primary IOL was surgery for VAO, which was associated with primary anterior vitrectomy not being performed but was not associated with age at surgery or IOL location. The risk of glaucoma development across all ages at surgery suggests a need for long-term monitoring.