Achenbach, Sara J.

Abstract Context Patients with adrenal hormone excess demonstrate increased cardiovascular (CV) risk and mortality. Objective We aimed to determine the effect of adrenal disorders on the inflammation marker glycoprotein acetylation (GlycA), total branched-chain amino acids (BCAAs), ketone bodies, and the gut microbiome-derived metabolites trimethylamine N-oxide (TMAO) and betaine. Methods We conducted a single-center cross-sectional study of patients with nonfunctioning adenomas (NFAs), mild autonomous cortisol secretion (MACS), primary aldosteronism (PA), Cushing syndrome (CS), pheochromocytoma/paragangliomas (PPGLs), other benign or malignant adrenal masses, and adrenocortical carcinoma (ACC) between January 2015 and July 2022 (n = 802). Referent individuals included participants in the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study (n = 5241). GlycA, BCAAs, ketone bodies, TMAO, and betaine were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted for age, sex, body mass index, smoking, hypertension, diabetes mellitus, and statin therapy. Results In age- and sex-adjusted comparison to referent individuals, increased GlycA was noted in all patient categories, increased BCAAs in NFA, MACS, CS, PA, and ACC, increased TMAO in patients with other malignant adrenal masses, increased betaine in NFA and MACS, and increased ketone bodies in NFA, CS, and ACC. Essentially similar findings were observed in fully adjusted analysis and after exclusion of participants with diabetes and CV disease. Conclusion Patients with functioning and nonfunctioning adrenal masses demonstrated increased GlycA and BCAAs, biomarkers associated with adverse cardiometabolic disorders and mortality. Patients with NFA demonstrated an adverse metabolic profile similar to patients with MACS and CS.

Abstract Chronic Lymphocytic Leukemia (CLL) exhibits a substantial familial risk that extends beyond CLL to other B-cell lymphomas (including follicular lymphoma and diffuse large B-cell lymphoma). Monoclonal B-cell Lymphocytosis (MBL), a precursor to CLL, is also associated with a significant risk for hematologic malignancies overall and for lymphoid malignancies, specifically. Moreover, previous research has shown an association between the CLL polygenic risk score (CLL-PRS) and common lymphoma subtypes. This study aims to further evaluate CLL-PRS associations with hematological cancer overall and by lineage while also considering MBL status a strong risk factor for lymphoid malignancies. Utilizing the Mayo Clinic Biobank, we selected individuals aged 40 years or older, residing in proximal counties, who had no prior hematologic malignancies, and with available biospecimens. MBL screening was done using 8-color flow cytometry, and MBL with CLL (CD5+/CD20dim) or atypical CLL (CD5+/CD20+) immunophenotype were included. CLL-PRS was calculated from 41 known susceptibility variants, with weights being the log of the odds ratios from the largest CLL genome-wide association study. Incident hematologic malignancies were ascertained through ICD codes and confirmed via medical record review. Hazard ratios (HR) and 95% confidence intervals (CIs) for associations with hematologic malignancies were estimated through Cox regression. Of 7,332 participants, 1,150 (16%) screened positive for MBL; median age was 67 years (range 40-101), and 37% male. Median follow-up was 2.9 years (range 0-13), and 56 hematologic cancers were identified. After adjusting for age and sex, the CLL-PRS was associated with increased risk of developing hematologic (HR=1.49, 95%CI=1.12-1.98, P=0.006) which was all attributable to lymphoid cancers (HR=1.79, 95%CI=1.26-2.56, P=0.001). When adjusting for baseline MBL status in the models, the CLL-PRS associations remained significant but were attenuated for hematological (HR=1.33, 95%CI=0.99-1.79, P=0.058) and lymphoid (HR=1.56, 95%CI=1.07-2.26, P=0.020) malignancies, while MBL status was also significantly associated with risk of hematologic (HR=2.76, 95%CI=1.55-4.91, P=0.001) and lymphoid (HR=3.61, 95%CI=1.78-3.32, P<0.001) malignancies. In this prospective cohort study of individuals screened for MBL, CLL-PRS was associated with an elevated risk of hematologic malignancies overall and within the lymphoid lineage, underscoring a shared genetic etiology across many B-cell lymphomas. However, the associations between CLL-PRS and hematologic malignancies were attenuated when accounting for MBL status or when analyzing among MBL-positive individuals, highlighting the role of MBL status in these associations. Further research with expanded cohorts is needed to unravel these complex genetic and clinical interactions. Citation Format: Raphael Mwangi, Dennis P. Robinson, Sara J. Achenbach, Geffen Kleinstern, Aaron D. Norman, Kari G. Rabe, Janet E. Olson, Neil E. Kay, Rosalie Griffin, Nicholas J. Boddicker, Esteban Braggio, Sameer A. Parikh, Curtis A. Hanson, Celine M. Vachon, James R. Cerhan, Tait D. Shanafelt, Susan L. Slager. Genetic associations with hematologic malignancies: An evaluation of CLL polygenic risk score and MBL status in the Mayo Clinic Biobank Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6152.

Objective To evaluate the incidence and outcomes of large artery (LA) involvement among patients with giant cell arteritis (GCA) and to compare LA involvement to non-GCA patients. Methods The study included Olmsted County, Minnesota, USA residents with incident GCA between 1950 and 2016 with follow-up through 31 December 2020, death or migration. A population-based age-matched/sex-matched comparator cohort without GCA was assembled. LA involvement included aortic aneurysm, dissection, stenosis in the aorta or its main branches diagnosed within 1 year prior to GCA or anytime afterwards. Cumulative incidence of LA involvement was estimated; Cox models were used. Results The GCA cohort included 289 patients (77% females, 81% temporal artery biopsy positive), 106 with LA involvement. Reported cumulative incidences of LA involvement in GCA at 15 years were 14.8%, 30.2% and 49.2% for 1950–1974, 1975–1999 and 2000–2016, respectively (HR 3.48, 95% CI 1.67 to 7.27 for 2000–2016 vs 1950–1974). GCA patients had higher risk for LA involvement compared with non-GCA (HR 3.22, 95% CI 1.83 to 5.68 adjusted for age, sex, comorbidities). Thoracic aortic aneurysms were increased in GCA versus non GCA (HR 13.46, 95% CI 1.78 to 101.98) but not abdominal (HR 1.08, 95% CI 0.33 to 3.55). All-cause mortality in GCA patients improved over time (HR 0.62, 95% CI 0.41 to 0.93 in 2000–2016 vs 1950–1974) but remained significantly elevated in those with LA involvement (HR 1.89, 95% CI 1.39 to 2.56). Conclusions LA involvement in GCA has increased over time. Patients with GCA have higher incidences of LA involvement compared with non-GCA including thoracic but not abdominal aneurysms. Mortality is increased in patients with GCA and LA involvement highlighting the need for continued surveillance.

Abstract Context Patients with nonfunctioning adrenal adenomas (NFA) and mild autonomous cortisol secretion (MACS) demonstrate an increased risk of chronic kidney disease (CKD); however, factors associated with CKD are unknown. Objective We aimed to identify the factors associated with CKD and assess the effect of adrenalectomy on kidney function in patients with NFA or MACS. Methods A single-center cohort study of patients with NFA and MACS, 1999 to 2020, was conducted. MACS was diagnosed based on post dexamethasone suppression test (DST) cortisol greater than or equal to 1.8 mcg/dL. Age, sex, dysglycemia, hypertension, therapy with statin, angiotensin-converting enzyme inhibitor, or angiotensin II receptor blocker were included in the multivariable analysis. Outcomes included estimated glomerular filtration rate (eGFR) at the time of diagnosis with MACS or NFA and postadrenalectomy delta eGFR. Results Of 972 patients, 429 (44%) had MACS and 543 (56%) had NFA. At the time of diagnosis, patients with MACS had lower eGFR (median 79.6 vs 83.8 mL/min/1.73 m2; P < .001) than patients with NFA. In a multivariable analysis, factors associated with lower eGFR were older age, hypertension, and higher DST. In 204 patients (MACS: 155, 76% and NFA: 49, 24%) treated with adrenalectomy, postadrenalectomy eGFR improved in both groups starting at 18 months up to 3.5 years of follow-up. Factors associated with increased eGFR were younger age, lower preadrenalectomy eGFR, and longer follow-up period. Conclusion DST cortisol is an independent risk factor for lower eGFR in patients with adrenal adenomas. Patients with both MACS and NFA demonstrate an increase in eGFR post adrenalectomy, especially younger patients with lower eGFR pre adrenalectomy.

Abstract Disclosure: M. Moazzami: Grant Recipient; Self; Rochester Epidemiology Project. S. Achenbach: None. E. Atkinson: None. I. Bancos: None. Background: Epidemiology of adrenal insufficiency (AI) is incompletely characterized with most data originating from referral centers and registries. We aimed to determine the incidence, morbidity index, risk of hospitalizations, and mortality in patients with AI living in Olmsted County, Minnesota. Methods: We assessed the standardized incidence rate, morbidity index, risk of hospitalizations and mortality of AI in residents (aged 18+) in Olmsted County, MN, USA, from Jan 1, 2005, to December 31, 2021. The data was collected using the Rochester Epidemiology Project (REP), a database of medical records for all Olmsted County residents since 1966. Incidence rates were standardized for age and sex according to the 2020 US white population. Sex- and age- matched referent subjects were selected from the REP. AI was defined based on presence of oral chronic glucocorticoid therapy (hydrocortisone, prednisone, prednisolone, or dexamethasone) defined as (1) any hydrocortisone use or (2) 6 months of consecutive use of prednisone, prednisolone, or dexamethasone or (3) two AI diagnosis codes 6+ months apart plus at least one glucocorticoid prescription within 1 year of the second diagnosis. Elixhauser morbidity index was used. Findings: Between 2005 and 2021, 5419 patients were diagnosed with AI (median age of 62 years, range 18-103), 56% women). Overall standardized incidence rates for AI increased from 206 (95% CI 174-238) in 2005 to 252 (223-280) per 100 000 person-years in 2021. At baseline, patients with AI had a higher morbidity index (median 3 vs median 1, p <0.001) and a higher history of hospitalizations within 5 years prior to baseline (57% vs 30%; p<0.001) when compared to referent subjects. When comparing patients with AI to referent subjects, and after adjusting for age, sex, morbidity index and prior history of hospitalizations, patients with AI were more likely to be hospitalized during follow-up (aHR 1.4, 95% CI 1.3-1.5). When comparing patients with AI to referent subjects, and after adjusting age, sex, and morbidity index, patients with AI had higher mortality (aHR 1.7, 95% CI 1.6-1.9). Patients with AI demonstrated a higher risk of dying from musculoskeletal disorders (aHR 4.9, 95% CI 2.2-10.8), respiratory disorders (aHR 4.7, 95% CI 3.3-6.6), neoplasms (aHR 2.4, 95% CI 2.0-2.9), and infectious disorders (aHR 2.3, 95% CI 1.2-4.3) than referent subjects. Interpretation: We demonstrate an increase in AI incidence between 2005 and 2021. Surprisingly, even after controlling for morbidity and prior hospitalizations, patients with AI were more likely to be hospitalized. In comparison to referent subjects, mortality was higher in patients with AI, even after adjustment for morbidity index. Presentation: Friday, June 16, 2023

Abstract Disclosure: R. Sandooja: None. A. Kittithaworn: None. P. Dogra: None. D. Gruppen: None. E. Atkinson: None. S. Achenbach: None. K. Yu: None. M. Connelly: None. V. Simha: None. R.P. Dullaart: None. I. Bancos: None. INTRODUCTION: Based on the spectrum of cortisol excess, adrenal adenomas are classified as adenomas with Cushing syndrome (CS), adenomas with mild autonomous cortisol secretion (MACS), and non-functioning adenomas (NFA). Patients with adrenal adenomas demonstrate a high prevalence of cardiovascular morbidity and mortality proportional to the degree of hypercortisolism. Evidence on whether dyslipidemia is a contributing cardiovascular risk factor in patients with NFA and MACS is discrepant. We aimed to characterize (apo) lipoprotein abnormalities across the spectrum of cortisol excess in patients with adenomas as compared to referent subjects. METHODS: Study Design: Single center cross sectional study between 01/2015 - 05/2021.Patients: Adults with NFA, MACS, or CS were consecutively enrolled. MACS was diagnosed based on post-dexamethasone cortisol >1.8 mcg/dL. Referent subjects were recruited from local population of patients with available abdominal imaging and no adrenal disorders. All subjects provided fasting ethylenediaminetetraacetic acid (EDTA) venous samples. Measurements: Nuclear magnetic resonance (NMR) spectroscopy measurements included total cholesterol (TC), low-density lipoprotein (LDL) and LDL particle concentrations, high-density lipoprotein (HDL) subclasses, apolipoprotein B (apo B), triglycerides (TG) and TG-rich lipoprotein concentrations. RESULTS: Participants included 101 patients with CS (median age 44 years, IQR 31-58, 85% women), 158 patients with MACS (median age 62 years, IQR 51-70, 62% women), 166 patients with NFA (median age 60 years, IQR 53--66, 63% women) and 136 referent subjects (median age 68 years, IQR 57-77, 52% women). Patients had higher BMI (32 vs 27 kg/m2), higher prevalence of hypertension (72% vs 46%) and diabetes mellitus (27% vs 9%) as compared to reference subjects. Statin therapy was used in 32% of patients and referent subjects. After adjusting for age, sex, BMI, smoking, diabetes, hypertension, and statin therapy, as compared to referent subjects, we found inconsistent increase in TC, LDL cholesterol and TG across CS, MACS and NFA and no consistent differences in LDL size, HDL variables, TG and TG-rich lipoproteins. However, when compared to referent subjects, LDL particle concentrations- CS(OR 1.78, 95% CI 1.33-2.39), MACS (OR 1.31, 95% CI 1.03-1.67), and NFA (OR 1.43, 95% CI 1.12-1.82) and Apo B levels were higher in all patient categories: CS (OR 2.26, 95% CI 1.57-3.24), MACS (OR 1.36 95% CI 1.00-1.85 ), and NFA (OR 1.54 95% CI 1.13-2.09). These differences were particularly evident in patients not on statin therapy. CONCLUSIONS: We found that LDL particle and Apo B concentrations were elevated in all patient groups, including those with MACS and NFA. In comparison to conventional lipid measurements, LDL particle and Apo B may serve as a better biomarker of the future cardiovascular risk in patients with adrenal adenomas. Presentation: Friday, June 16, 2023

Abstract Disclosure: J. Saini: None. R. Nathani: None. C. Zhang: None. M. Suresh: None. K. Thangamuthu: None. S. Singh: None. V. Fell: None. E.J. Atkinson: None. S. Achenbach: None. N.H. Stricker: None. I. Bancos: None. Background: Patients with mild autonomous cortisol secretion (MACS) have impaired cognition compared to patients with non-functioning adrenal adenomas. However, the impact of adrenalectomy on cognitive function in patients with MACS is unclear. Objective: To determine the impact of adrenalectomy on cognitive function in patients with MACS. Methods: Single-center prospective longitudinal study of adults with MACS. MACS was defined as serum cortisol >1.8 mcg/dL after the 1 mg dexamethasone suppression test (DST) in patients with adrenal adenomas without any overt features of hypercortisolism. Patients underwent cognitive evaluation using the standardized National Institute of Health (NIH) Toolbox Cognition Battery (7 tests of attention, episodic and working memory, language, executive function, cognitive flexibility, and processing speed) prior to adrenalectomy and at follow-up at least 10 months post-surgery. Fully corrected T-scores for age, sex, education, and race were compared using a paired t-test before and after adrenalectomy. A T-score of 50 is average performance (SD of 10). Total cognition is composite of fluid cognition (executive function, episodic memory, cognitive flexibility, working memory and processing speed) and crystallized cognition (language and vocabulary). Results: A total of 27 patients with MACS (median age 59.7 years, IQR 51.4-66.9, 17, 63% women) underwent cognitive evaluation prior to and at a median of 1.5 years (IQR, 1.1- 2.0) after adrenalectomy. Before surgery, median post-DST cortisol was 3.8 mcg/dL (IQR, 2.7-6.4) mcg/dL. Of the 27 patients, 21 (78%) patients developed post-operative adrenal insufficiency with 6 (21%) patients still requiring still requiring glucocorticoid replacement at the time of the last follow-up. At baseline, the mean total composite T-score was 50.7 (9.3), with fluid composite T-score of 49.9 (9.4) and crystallized composite T-score of 51.3 (8.7). Following adrenalectomy, all three composite T-scores improved compared to baseline. The crystallized composite T-score (composed of language and vocabulary) increased by a mean of 3.7 (5.5), P=0.001, the fluid composite T-score (composed of episodic, executive, working memory, cognitive flexibility, and processing speed) increased by a mean of 3.1 (8.3), P=0.068, and the total composite T-score improved by a mean of 3.9 (6.2), P=0.004. Conclusion: We showed that adrenalectomy in patients with MACS is associated with improvement in cognition. However, as test results may improve with practice (i.e., improvement due to taking the test the second time), to determine whether the improvements observed represent a reliable change in cognition, the next step is to evaluate for cognition score changes in referent subjects. Presentation: Friday, June 16, 2023

Abstract Disclosure: C.D. Zhang: None. S. Singh: None. J. Saini: None. M. Suresh: None. K. Thangamuthu: None. R. Nathani: None. A.L. Ebbehøj: None. V. Fell: None. S.J. Achenbach: None. E.J. Atkinson: None. S. Khosla: None. I. Bancos: None. Background: Patients with mild autonomous cortisol secretion (MACS) have higher rates of fractures compared to patients with non-functioning adrenal nodules, but bone mass is typically only modestly reduced. We hypothesized that chronic exposure to mild levels of cortisol excess may lead to a deterioration in bone quality. Objective: To characterize the effect of MACS on bone metabolism and bone microarchitecture, as measured by high-resolution peripheral quantitative computed tomography (HR-pQCT). Methods: In this cross-sectional single-center study, patients with MACS were matched by age, sex, and gonadal status to referent subjects without adrenal nodules. MACS was defined as serum cortisol concentration >1.8 mcg/dL after the 1 mg overnight dexamethasone suppression test (1-mg DST), in the absence of a classic Cushingoid phenotype. Those with other known secondary causes of osteoporosis and/or on pharmacologic treatment for low bone mass were excluded. All study participants underwent a bone health interview, blood draw for bone turnover markers, dual-energy x-ray absorptiometry (DXA) scan with trabecular bone score (TBS), and HR-pQCT of the non-dominant radius and tibia. Participants with a recent fracture within 12 months were excluded from the analysis of bone turnover markers. The Kruskal-Wallis test was used to compare measurements between groups. Results: A total of 82 patients with MACS and 82 referent subjects were prospectively enrolled between 1/2019 and 7/2022. The median age of study participants at the time of enrolment was 57 years (interquartile range [IQR], 47-65), and 57 (70%) were women. In the MACS cohort, the median cortisol following 1-mg DST was 3.2 mcg/dL (IQR, 2.3-6.5) with median ACTH of 8.7 pg/mL (IQR, 6.0-14.0) and median DHEA-S of 42.0 mcg/dL (IQR 23.0-68.0). While no differences in bone mineral density (BMD) were observed at any site (lumbar spine, total hip, femoral neck, or distal radius) between the two groups, patients with MACS had decreased TBS (1.374 vs 1.467, P <0.001) and lower osteocalcin concentrations (16.9 vs. 19.7 ng/mL, P = 0.005) than referent subjects without adrenal nodules. On HR-pQCT at the tibia, patients with MACS had significantly reduced trabecular volumetric BMD (151.6 vs 167.4 mg hydroxyapatite/cm3, P = 0.002), trabecular bone volume/tissue volume ratio (0.219 vs 0.237, P = 0.011), and number of trabeculae (1.428 vs 1.506 1/mm, P = 0.045), while trabecular separation (0.707 vs 0.656, P = 0.023) was increased compared to referent subjects. Conclusions: Patients with MACS have altered bone metabolism and microstructural deterioration that is not evident on routine DXA BMD testing. These changes may mediate their increased fracture risk and could serve as biomarkers of cortisol-induced changes in the bone. Presentation: Thursday, June 15, 2023

Abstract Disclosure: J. Saini: None. R. Nathani: None. S. Singh: None. V. Fell: None. E. Atkinson: None. S. Achenbach: None. S. Khosla: None. I. Bancos: None. Background: Previous studies reported that both cortisol secretion and bone metabolism biomarkers follow a circadian pattern of secretion. Patients with mild autonomous cortisol secretion (MACS) demonstrate an increased risk of fractures. As most patients with MACS do not have increased cortisol production, we hypothesized that abnormal circadian cortisol secretion is associated with impaired bone metabolism. Objective: To compare the circadian secretory pattern of bone metabolism biomarkers in relation to cortisol circadian secretion in patients with MACS versus referent subjects. Methods: We conducted a pilot cross-sectional study of patients with MACS and referent subjects. MACS was diagnosed in patients with adrenal adenomas based on an abnormal 1 mg dexamethasone suppression test (cortisol >1.8 mcg/dL). Referent subjects with available abdominal imaging within 5 years and adrenal disorder were recruited from the community. Participants were admitted to the clinical research unit for blood sampling every 2 hours over 24h period. Measurements included total and free cortisol, calcium, parathyroid hormone (PTH), osteocalcin, amino-terminal propeptide type 1 collagen (PINP), and carboxy-terminal telopeptide of type 1 collagen (CTX). Subjects with disorders or medication affecting bone metabolism were excluded. Time periods of blood draw were categorized into the morning (6 to 12 hours), afternoon (14-18 hours) and night (20-2 hours). Delta (morning measurements/afternoon measurements) was calculated. Results: Subjects included 12 patients with MACS (median age 57, IQR 48-67, 83% women) and 10 referent subjects (median age 57, IQR 50-63, 80% women). The 24-hour area under the curve for total (10342 vs 9090 mcg/dL, p=0.468) and free cortisol (437 vs 329 mcg/dL, p=0.086) was no different between patients with MACS and referent subjects. However, the mean night total (6.7 vs 4.3 mcg/dL, p=0.056) and free cortisol (0.2 vs 0.1 mcg/dL, p=0.035) was higher in MACS vs referent subjects. The area under the curve for calcium, phosphorus, CTX, osteocalcin and PINP were similar between patients and referent subjects, however, the area under the curve for PTH was higher in patients vs referent subjects (mean 64179 vs 42602 pg/mL, p=0.021). Both delta total cortisol (mean 8.6 vs 5.5, p=0.01) and delta PTH (mean -1.5 vs 4.2, p=0.051) was higher in referent subjects vs patients with MACS. Conclusion: When compared to referent subjects, patients with MACS have similar 24-hour cortisol production but demonstrate an increase in night-time cortisol secretion and a blunting of diurnal cortisol (lower morning/afternoon cortisol). Patients with MACS have higher PTH production overall, as well as an abnormal diurnal PTH secretion. Noted abnormalities in PTH may contribute to the MACS-associated impairment in bone health. Presentation: Thursday, June 15, 2023

Abstract Disclosure: J. Saini: None. R. Nathani: None. S. Singh: None. K. Thangamuthu: None. M. Suresh: None. C. Zhang: None. A.L. Ebbehøj: None. M. Thomas: None. V. Fell: None. E. Atkinson: None. S. Achenbach: None. N. Stricker: None. I. Bancos: None. Introduction: While patients with overt Cushing syndrome are reported to have impaired cognition, the impact of milder, long-standing hypercortisolism on cognition is incompletely characterized. Objective: To determine the impact of MACS on cognition as compared to age, sex, and education-matched referent subjects. Methods: We conducted a single-center cross-sectional study of adults with MACS and referent subjects. MACS was defined as serum cortisol>1.8 mcg/dL after 1 mg dexamethasone suppression test (DST) in patients with adrenal incidentalomas. Referent subjects were included if they had abdominal imaging and had no adrenal disorders. Exclusion criteria were malignancy and exogenous glucocorticoid use within 1 year. All participants underwent a cognitive evaluation using the NIH Toolbox Cognition Battery between 1/2019 to 7/2022. NIH Toolbox assesses 8 cognitive domains using 7 tests and yields 3 composite scores: fluid cognition (executive function, episodic memory, cognitive flexibility, working memory, and processing speed), crystallized cognition (language and vocabulary), and total composite cognition (composite of all). Results are given in fully corrected T scores (adjusted for age, sex, race, and education) with an average of 50 and a standard deviation (SD) of 10. A subgroup analysis was performed based on DST cortisol. The Kruskal-Wallis test was used to compare scores between groups. Results: A total of 94 patients with MACS (median age 57.2 years, IQR 47.8-66.5, 70% women) and 94 referent subjects (median age 58 years, IQR 49.1-66.4, 70% women) were included. The median post-DST cortisol in patients with MACS was 3.3 mcg/dL (IQR, 2.4-6.2). The mean (SD) total composite T-score was lower in patients with MACS vs referent subjects (51 (9.1) vs 56.3 (9.3), P<0.001). Patients with MACS demonstrated lower mean fluid composite T-score when compared to referent subjects (49.5 (10.4) vs 56.9 (9.7), P<0.001). However, mean crystallized composite T-scores were similar in patients with MACS and referent subjects (52.3 (8.1) vs 53.9 (9.6), P=0.342). A subgroup analysis of patients with post-DST cortisol <3 mcg/dL (n=40) vs patients with post-DST cortisol >3 mcg/dL (n=54) did not show any differences in the total, fluid, or crystalized composite scores. Conclusion: Patients with MACS demonstrate lower cognitive performances than a referent group suggesting MACS has a subtle impact on cognitive functioning. The pattern of cognitive impairment in patients with MACS is similar to that seen with normal cognitive aging: impaired fluid cognitions and unaffected crystallized cognition). Cognitive performance did not differ based on the degree of MACS suggesting that in the absence of overt features of hypercortisolism, the degree of MACS is less important than the presence of MACS. Presentation: Thursday, June 15, 2023