Citations

Abstract Disclosure: S. Maraka: None. R. Owen: None. N.M. Singh Ospina: None. M. Knox: None. T. Dodds: None. H. Spencer: None. A. Albashaireh: None. A. Shah: None. S. Syed: None. S. Naqvi: None. H. Motahari: None. S. Thumma: None. E. Ambrogini: None. J.P. Brito: None. Objective: Levothyroxine (LT4) therapy has not been shown to improve quality of life (QoL), thyroid-related symptoms, cardiovascular events, or mortality for patients with subclinical hypothyroidism (SCH) in clinical trials. We conducted this pilot, double-blind, placebo-controlled clinical trial to evaluate the effects of LT4 discontinuation among adults with SCH. Methods: We aimed to randomize 50 adults 1:1 to continue receiving LT4 (25-75 mcg/day) for SCH or discontinue it (switch to placebo). The primary outcome was feasibility. Secondary outcomes included changes in QoL measures (Thyroid-specific QoL Patient-Reported Outcome [ThyPRO]-Hypothyroid Symptoms and Tiredness scores, EuroQoL 5-Dimension Self-Report Questionnaire [EQ-5D]) assessed at baseline and 6 months post-randomization, and incidence of adverse events (overt hypothyroidism, hyperthyroidism, atrial fibrillation, stroke, acute coronary syndrome, heart failure, fracture, mortality). Higher scores for ThyPRO indicate more symptoms and tiredness and for EQ-5D, better health state. Data are reported as mean (standard deviation). Analysis of covariance model adjusting for age and baseline measure of the variable was performed for the outcomes based on the intention-to-treat principle. Results: Fifty participants were enrolled (33% recruitment rate); 24 were randomized to the LT4 and 26 to the discontinuation group. Five patients were excluded post-randomization due to lack of ascertainment of SCH diagnosis (final N=45; 21 LT4, 24 discontinuation). There was no statistically significant difference at baseline between the discontinuation and LT4 groups in age [65.7 (10.6) vs. 71.0 (7.9) yrs], gender (male 75 vs. 86%), LT4 dose (25 mcg; 29.2 vs. 33.3%, 50 mcg; 54.2 vs. 47.6%, 75 mcg; 16.7 vs. 19.0%), TSH [3.1 (1.0) vs. 3.2 (1.4) mIU/L], TPOAb positivity (17 vs. 19%), ThyPRO-Hypothyroid Symptoms [27.1 (20.4) vs. 21.1 (18.4)] and Tiredness score [33.2 (23.7) vs. 31.1 (23.9)], and EQ-5D [0.746 (0.229) vs. 0.758 (0.193)]. A patient in the discontinuation group withdrew for personal reasons (98% completion rate). Two patients in the discontinuation group met study criteria to restart LT4 (TSH>10 mIU/L; n=1, fatigue; n=1). At final visit, 34.8% of patients in the discontinuation group had mild SCH compared to 9.5% of patients on LT4 (p=0.07). There was no statistically significant difference between the discontinuation and LT4 groups in ThyPRO-Hypothyroid Symptoms [28.3 (22.8) vs. 22.9 (19.5)], Tiredness [27.6 (22.8) vs. 32.8 (22.1)], and EQ-5D score [0.750 (0.232) vs. 0.741 (0.180)]. A patient suffered rib fracture (placebo); no other adverse event of interest was reported. Conclusion: This pilot clinical trial showed the feasibility and safety of discontinuing LT4 in patients with SCH. These findings support proceeding with a larger multi-site clinical trial to fully assess the effects of LT4 discontinuation. Presentation: Thursday, June 15, 2023

AbstractBackgroundPrevious studies have shown that magnetic susceptibility is increased in several subcortical regions in progressive supranuclear palsy (PSP). However, it is still unclear how subcortical and cortical susceptibilities vary across different PSP variants, Parkinson's disease (PD), and corticobasal syndrome (CBS).ObjectiveThis study aims to clarify the susceptibility profiles in the subcortical and cortical regions in different PSP variants, PD, and CBS.MethodsSixty‐four patients, 20 PSP‐Richardson syndrome (PSP‐RS), 9 PSP‐parkinsonism (PSP‐P), 7 PSP‐progressive gait freezing, 4 PSP‐postural instability, 11 PD, and 13 CBS, and 20 cognitively normal control subjects underwent a 3‐Tesla magnetic resonance imaging scan to reconstruct quantitative susceptibility maps. Region‐of‐interest analysis was performed to obtain susceptibility in several subcortical and cortical regions. Bayesian linear mixed effect models were used to estimate susceptibility within group and differences between groups.ResultsIn the subcortical regions, patients with PSP‐RS and PSP‐P showed greater susceptibility than control subjects in the pallidum, substantia nigra, red nucleus, and cerebellar dentate (P < 0.05). Patients with PSP‐RS also showed greater susceptibility than patients with PSP‐progressive gait freezing, PD, and CBS in the red nucleus and cerebellar dentate, and patients with PSP‐P showed greater susceptibility than PD in the red nucleus. Patients with PSP‐postural instability and CBS showed greater susceptibility than control subjects in the pallidum and substantia nigra. No significant differences were observed in any cortical region.ConclusionsThe PSP variants and CBS had different patterns of magnetic susceptibility in the subcortical regions. The findings will contribute to our understanding about iron profiles and pathophysiology of PSP and may provide a potential biomarker to differentiate PSP variants, PD, and CBS. © 2023 International Parkinson and Movement Disorder Society.

Abstract Background Blood-based biomarkers (BBBs) are a growing area of study for improving Alzheimer’s disease (AD) clinical evaluation. BBBs have been demonstrated to correlate with AD CSF biomarkers as well as neuroimaging results for assessment of amyloid pathology. Currently BBBs may be used as a screening tool for patient selection in clinical trials, and alongside more well characterized biomarkers like amyloid-PET and CSF markers for evaluation of individuals presenting with cognitive impairment. A comparative study of several AD BBBs assays was performed to assess bias between two platforms, as well as correlation to markers of amyloid pathology. Methods The study included 146 plasma samples from 112 cognitively normal (CN), and 34 mild cognitive impairment (MCI) or AD dementia individuals. Plasma Aβ42, Aβ40, and pTau181 concentrations were obtained using the Fujirebio Lumipulse and Quanterix Simoa immunoassays. Assay comparison between Fujirebio and Quanterix were performed for Aβ42, Aβ40, Aβ42/Aβ40 ratio, pTau181, and pTau181/Aβ42 ratio using Passing-Bablok regression and regression slopes were obtained. Amyloid-PET was performed using Pittsburg Compound B, and a standard uptake value ratio (SUVR) of 1.48 was used to classify amyloid status. In the CN group, 69 were amyloid negative, and 43 were amyloid positive. In the MCI/AD dementia group, 8 were amyloid negative and 26 were amyloid positive. Spearman’s rank correlation coefficient (rho) was used to determine correlation between assays and correlation of each with Amyloid-PET SUVRs. Results Between Fujirebio (y) and Quanterix (x) assays, measured Aβ42 and Aβ40 concentrations showed a large bias with y = 5.23x − 14.25, and y = 4.42x − 264.87, respectively. A moderate to strong correlation was observed between assays for Aβ42 and Aβ40 with rho values of 0.641 (P &lt; 0.0001), and 0.498 (P &lt; 0.0001), respectively. The ratio of Aβ42/Aβ40 corrected this bias with y = 0.96x + 0.03 and rho = 0.509 (P &lt; 0.0001). pTau181 showed little bias between methods with y = 0.92x + 0.48, and a rho = 0.592 (P &lt; 0.0001). However, the pTau181/Aβ42 ratio showed a large bias driven mostly by differences in the Aβ42 concentrations with y = 0.27x + 0.04 and rho = 0.574 (P &lt; 0.0001). Quanterix assay results correlated with amyloid-PET SUVR yielded rho coefficients of AB42/40 ratio = −0.219 (P = 0.079), pTau181 = 0.380 (P &lt; 0.0001), and pTau181/Aβ42 ratio = 0.466 (P &lt; 0.0001). Fujirebio assay results correlated with amyloid-PET SUVR showed AB42/40 ratio rho = −0.551 (P &lt; 0.0001), pTau181 rho = 0.370 (P &lt; 0.0001), and pTau181/Aβ42 ratio rho = 0.391 (P &lt; 0.0001). Conclusion This study demonstrates that some BBBs methods differ significantly between manufacturers. Little bias was observed between the Aβ42/Aβ40 and pTau181 determinations for the evaluated platforms; however, significant bias was observed in Aβ42, Aβ40, and the pTau181/Aβ42 ratio. The Fujirebio platform demonstrated stronger correlation of the Aβ42/Aβ40 ratio with amyloid-PET SUVR, while Quanterix showed better correlation of the pTau181/Aβ42 ratio. The pTau181 assays showed similar correlation to amyloid-PET SUVR. Bias between assays as well as clinical correlation differences may preclude the generalization of clinical performance of AD BBBs assays between platforms.

Abstract Background Neurofibromatosis type 2 (NF2)-related schwannomatosis is an autosomal dominant tumor-predisposition syndrome characterized by bilateral vestibular schwannomas (VS). In patients with VS associated with NF2, vascular endothelial growth factor A inhibitor, bevacizumab, is a systemic treatment option. The aim of this study is to retrospectively evaluate NF2 patient responses to bevacizumab on VS growth and symptom progression. Methods This is a retrospective analysis of patients seen at the Mayo Clinic Rochester Multidisciplinary NF2 Clinic. Results Out of 76 patients with NF2 evaluated between 2020 and 2022, we identified 19 that received treatment with bevacizumab. Thirteen of these patients discontinued bevacizumab after median treatment duration of 12.2 months. The remaining 6 patients are currently receiving bevacizumab treatment for a median duration of 9.4 months as of March, 2023. Fifteen patients had evaluable brain MRI data, which demonstrated partial responses in 5 patients, stable disease in 8, and progression in 2. Within 6 months of bevacizumab discontinuation, 5 patients had rebound growth of their VS greater than 20% from their previous tumor volume, while 3 did not. Three patients with rebound growth went on to have surgery or irradiation for VS management. Conclusions Our single-institution experience confirms prior studies that bevacizumab can control progression of VS and symptoms associated with VS growth. However, we note that there is the potential for rapid VS growth following bevacizumab discontinuation, for which we propose heightened surveillance imaging and symptom monitoring for at least 6 months upon stopping anti-VEGF therapy.

PURPOSE The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid–dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design. PATIENTS AND METHODS Patients with newly diagnosed O 6 -methylguanine–DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780 ). RESULTS Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit ( P > .05). CONCLUSION The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.

A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity—findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.

An inscription over the north entrance of what today is the Mayo Medical School Student Center reads “Non multa sed bona,” which translates to “Not many but good.” One might enjoy “a quickening of the homiletic pulse” while reflecting on the productive careers of surgeons William J. Mayo, Charles H. Mayo, Donald Guthrie, William L. Estes, Jr., and Harold L. Foss, their influences on each other and surgery in general, and the appropriateness of this Latin aphorism as a tribute to them and to what they as unique achievers accomplished in the practice of medicine—relatively few in numbers, but excellent.

See the Reply by Semla and Steinman in this issue.

AbstractThe Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to improve Alzheimer's disease (AD) clinical trials. Since 2006, ADNI has shared clinical, neuroimaging, and cognitive data, and biofluid samples. We used conventional search methods to identify 1459 publications from 2021 to 2022 using ADNI data/samples and reviewed 291 impactful studies. This review details how ADNI studies improved disease progression understanding and clinical trial efficiency. Advances in subject selection, detection of treatment effects, harmonization, and modeling improved clinical trials and plasma biomarkers like phosphorylated tau showed promise for clinical use. Biomarkers of amyloid beta, tau, neurodegeneration, inflammation, and others were prognostic with individualized prediction algorithms available online. Studies supported the amyloid cascade, emphasized the importance of neuroinflammation, and detailed widespread heterogeneity in disease, linked to genetic and vascular risk, co‐pathologies, sex, and resilience. Biological subtypes were consistently observed. Generalizability of ADNI results is limited by lack of cohort diversity, an issue ADNI‐4 aims to address by enrolling a diverse cohort.

Abstract INTRODUCTION We aimed to describe baseline amyloid‐beta (Aβ) and tau‐positron emission tomograrphy (PET) from Longitudinal Early‐onset Alzheimer's Disease Study (LEADS), a prospective multi‐site observational study of sporadic early‐onset Alzheimer's disease (EOAD). METHODS We analyzed baseline [18F]Florbetaben (Aβ) and [18F]Flortaucipir (tau)‐PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aβ+) from EOnonAD (Aβ−) based on the combination of visual read by expert reader and image quantification. RESULTS 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid‐PET; 231 (95.1%) of them were tau‐PET positive (A+T+). Tau‐PET signal was elevated across cortical regions with a parietal‐predominant pattern, and higher burden was observed in younger and female EOAD participants. DISCUSSION LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau‐PET binding at baseline might have implications for therapeutic strategies in patients with EOAD. HIGHLIGHTS 72% of patients with clinical EOAD were positive on both amyloid‐ and tau‐PET. Amyloid‐positive patients with EOAD had high tau‐PET signal across cortical regions. In EOAD, tau‐PET mediated the relationship between amyloid‐PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau‐PET.