Citations

Abstract INTRODUCTION Plasma p‐tau217 and p‐tau217/Aβ42 reliably identify non‐Hispanic White individuals with symptomatic and pre‐clinical AD. However, performance across ethnoracially diverse groups remains unknown. METHODS Cognitively normal Black, Hispanic, and non‐Hispanic White participants completed cognitive evaluations, brain magnetic resonance imaging (MRI), amyloid and tau positron emission tomography (PET), and measures of kidney function. Plasma p‐tau217 and Aβ42 were measured using Fujirebio Lumipulse assays. Pre‐clinical AD detection was evaluated using symptomatic and cohort‐derived optimized cutoffs. RESULTS Among 191 participants (57 Black, 46 Hispanic White, 88 non‐Hispanic White), age‐adjusted plasma p‐tau217 and p‐tau217/Aβ42 performed similarly in detecting amyloid‐positive individuals (≥ 25 Centiloids), regardless of race/ethnicity. Both measures independently correlated with amyloid deposition, whereas estimated glomerular filtration rate (eGFR) correlated solely with p‐tau217. Pre‐clinical AD optimized cutoffs (p‐tau217 ≥ 0.132 pg/ml; p‐tau217/Aβ42 ≥ 0.0059) outperformed cutoffs established in symptomatic individuals (sensitivity: 83% vs. 57%; 77% vs. 63%; negative predictive value [NPV] > 93%). DISCUSSION Plasma biomarkers performed similarly across ethnoracially diverse cohorts. Optimized cutoffs may improve early detection and trial enrollment.

Abstract Background Tau‐PET neuroimaging is increasingly applied to diagnose and stage, track progression, and assess response to putative disease‐modifying treatments in individuals with Alzheimer disease. However, it remains to be seen whether findings established in predominantly non‐Hispanic White (nHW) cohorts will generalize to Black and Latino participants who are underrepresented in dementia research. Method Community‐dwelling Black ( n = 83) and Latino participants ( n = 27) completed MRI (with quantification of white matter hyperintensity volumes), and amyloid‐ (PiB or florbetapir) and tau‐ (flortaucipir) PET brain imaging as part of a longitudinal study of memory and aging at Mayo Clinic in Florida. Global and regional tau‐PET standardized uptake value ratios (normalized to the cerebellar crus) were determined in Black and Latino participants and compared with findings from an independent cohort of nHW participants ( n = 110), 1:1‐matched for age, sex, education, and global Clinical Dementia Rating®. Conditional logistic modeling compared 47 regions of interest, adjusted for false discovery rate. Relevant associations between flortaucipir retention and clinical outcomes were assessed using Spearman rank correlations. Result Eighty‐three Black (mean 72±10.8‐years‐old, 63% female, 33% cognitively impaired) and 27 Latino participants (mean 65.8‐years‐old, 56% female, 11% cognitively impaired) completed neuroimaging. Data were compared with findings in 110 matched nHW individuals. Global tau‐PET burden was similar between matched cohorts (Black and nHW participants, mean SUVR: 1.34±0.39 vs 1.36±0.37, p = 0.71; Latino and nHW participants, mean SUVR: 1.17±0.09 vs 1.20±0.11, p = 0.66). Lower flortaucipir uptake was noted in the caudate ( p = 0.005) and putamen ( p = 0.022) of Black/Latino participants (vs nHW), although differences attenuated following adjustment for white matter hyperintensity volume. Global flortaucipir retention increased with age (Black: Rho=0.31; Latino: Rho=0.46; nHW: Rho=0.27; p <0.05), amyloid Centiloids (Black: Rho=0.65; Latino: Rho=0.41; nHW: Rho=0.58; p <0.05), and cognitive impairment (i.e., Clinical Dementia Rating® Sum‐of‐Box scores, Black/Latino: Rho=0.31, p = 0.07; nHW: 0.76, p <0.001). Conclusion Tau‐PET patterns were similar across ethnoracial groups after adjusting for white matter hyperintensity volumes—a biomarker of small vessel disease. Flortaucipir retention increased with age, amyloid accumulation, and cognitive impairment across all cohorts. These findings affirm the clinical and research applications of tau PET in diverse cohorts. Acknowledgements : Flortaucipir precursor and technology was supported by Avid Radiopharmaceuticals.

Abstract Background Dementia with Lewy Bodies (DLB) has been overlooked or misdiagnosed as Alzheimer's disease (AD) dementia due to its frequent concomitant AD pathology with Lewy Body Disease (LBD) pathology. Although autopsy confirmation has been the gold standard for the precise diagnosis of DLB, time‐course 123 I‐FP‐CIT SPECT (DaT‐SPECT) findings in autopsy‐confirmed DLB are not well characterized. We previously reported that the DaTQUANT z‐score of the more affected side of the putamen has the best discriminatory power in detecting LBD pathology and nigrostriatal degeneration in dementia patients and demonstrated z‐score of −1 as the cutoff value. We sought to examine how DaT‐SPECT findings change over time in autopsy confirmed LBD patients in preparation for its use in LBD targeted clinical trials. Method Eight autopsy confirmed neocortical or limbic LBD patients who underwent two or more DaT‐SPECT were included. Nigrostriatal dopamine transporter (DaT) binding and age‐adjusted z‐scores were analyzed using the DaTQUANT 2.0 software (GE Healthcare). Result Six patients (75%) were male. The patients had 2.5±0.7 longitudinal DaT‐SPECT scans. Clinical diagnosis at initial scan was: DLB (75%), mild cognitive impairment (MCI) with REM sleep behavior disorder (RBD) (13%), and isolated RBD (iRBD) (13%). Clinical diagnosis at last scan was: DLB (88%) and iRBD (12%). All patients developed dementia during life. Mean age at initial scan/last scan/autopsy were 71.1±7.0/73.4±6.9/75.1±7.3 years old. Time from initial and last scan to autopsy were 4.0±1.9 and 1.8±1.9 years respectively. Seven patients (88%) had neocortical LBD and one (12%) had limbic LBD. Concomitant AD pathology was observed in four patients (two males (33%), two females (100%)). All patients had DaTQUANT putamen z‐score <‐1.0 at their initial scan including in MCI+RBD (‐1.76) and iRBD (‐1.53) patients. In the DLB patients at their initial scans, five (83%) had DaTQUANT putamen z‐score <‐2.0 and one (17%) had z‐score of ‐1.55. All patients (100%) showed DaTQUANT putamen z‐score <‐2.0 at their last scans. Conclusion DaTQUANT using cut‐off putamen z‐score of ‐1 was associated with underlying LBD pathology including at their iRBD and MCI stages. Nigrostriatal DaT binding tends to decline over time with DaTQUANT z‐score <‐2 at their last scans.

Abstract Background Bedside cognitive screening tools intend to reliably and efficiently detect cognitive impairment in research, clinical, and community settings. Black American (BA) and Hispanic/Latino (H/L) adults obtain lower performance on widely used screeners, largely driven by demographics and structural and social determinants of health (SSDoH). This study characterized the performance of the Montreal Cognitive Assessment (MoCA) performance in a cohort of cognitively normal ethnoracially diverse adults while considering cohort‐specific factors that contributed to misclassification of impairment. Method Cognitively normal BA and H/L participants completed a comprehensive neurological assessment, neuropsychological testing, and MRI and amyloid‐ and tau‐PET imaging as part of a longitudinal study of memory and aging at Mayo Clinic in Florida. Demographically adjusted MoCA cutoffs were applied to BA (MoCA ≤ 22) and WH/L (MoCA ≤ 24) subgroups. Hierarchical binary logistic regression assessed whether amyloid burden (Centiloid value) improved prediction of scoring below demographically adjusted MoCA cutoffs beyond demographic/SSDoH factors, including age, education, and Area Deprivation Index (ADI). Result Participants included 105 (47 WH/L, 58 BA/AA) cognitively normal adults (mean age = 64.71 years, SD = 8.91; 62.9% female) with average of 16.07 years of education (SD=2.35) and mild‐to‐moderate neighborhood disadvantage (mean ADI=47.60, SD=23.77). 40% of H/L participants (MoCA (≤ 24) and 17% of BA participants (MoCa ≤22) scored below demographically adjusted MoCA cut‐offs. For the H/L subgroup, the best fitting model included age, education, ADI, and amyloid burden ( R 2 = 0 .43, χ 2 = 10.98, p = 0.03). Age (OR=1.21, 95% CI: 0.986 – 1.487) and amyloid burden (OR = 0.83, 95% CI: 0.67 – 1.03) approached statistical significance as individual predictors ( p = 0.06, p = 0.09). In the BA/AA subgroup, the best fitting model included age, education and ADI only ( R 2 = 0.47, χ 2 = 9.06, p = 0.02), with education approaching significance as an individual predictor (OR=0.46, 95% CI: 0.21 – 1.01, p = 0.05). Conclusion Sociodemographic factors continued to drive low MoCA performance in cognitively normal individuals despite applying demographically adjusted cut‐off scores by subgroup. These factors differentially impacted performance among BA/AA and WH/L participants. Careful consideration of these factors is warranted to mitigate risk of overdiagnosing impairment based on cognitive screening across clinical and research settings.

Abstract Background Dementia with Lewy Bodies (DLB) has been overlooked or misdiagnosed as Alzheimer’s disease (AD) dementia due to its frequent concomitant AD pathology with Lewy Body Disease (LBD) pathology. Although autopsy confirmation has been the gold standard for the precise diagnosis of DLB, time‐course 123 I‐FP‐CIT SPECT (DaT‐SPECT) findings in autopsy‐confirmed DLB are not well characterized. We previously reported that the DaTQUANT z‐score of the more affected side of the putamen has the best discriminatory power in detecting LBD pathology and nigrostriatal degeneration in dementia patients and demonstrated z‐score of −1 as the cutoff value. We sought to examine how DaT‐SPECT findings change over time in autopsy confirmed LBD patients in preparation for its use in LBD targeted clinical trials. Method Eight autopsy confirmed neocortical or limbic LBD patients who underwent two or more DaT‐SPECT were included. Nigrostriatal dopamine transporter (DaT) binding and age‐adjusted z‐scores were analyzed using the DaTQUANT 2.0 software (GE Healthcare). Result Six patients (75%) were male. The patients had 2.5±0.7 longitudinal DaT‐SPECT scans. Clinical diagnosis at initial scan was: DLB (75%), mild cognitive impairment (MCI) with REM sleep behavior disorder (RBD) (13%), and isolated RBD (iRBD) (13%). Clinical diagnosis at last scan was: DLB (88%) and iRBD (12%). All patients developed dementia during life. Mean age at initial scan/last scan/autopsy were 71.1±7.0/73.4±6.9/75.1±7.3 years old. Time from initial and last scan to autopsy were 4.0±1.9 and 1.8±1.9 years respectively. Seven patients (88%) had neocortical LBD and one (12%) had limbic LBD. Concomitant AD pathology was observed in four patients (two males (33%), two females (100%)). All patients had DaTQUANT putamen z‐score <‐1.0 at their initial scan including in MCI+RBD (‐1.76) and iRBD (‐1.53) patients. In the DLB patients at their initial scans, five (83%) had DaTQUANT putamen z‐score <‐2.0 and one (17%) had z‐score of ‐1.55. All patients (100%) showed DaTQUANT putamen z‐score <‐2.0 at their last scans. Conclusion DaTQUANT using cut‐off putamen z‐score of ‐1 was associated with underlying LBD pathology including at their iRBD and MCI stages. Nigrostriatal DaT binding tends to decline over time with DaTQUANT z‐score <‐2 at their last scans.

Background: Carotid stenosis has been associated with stroke and cognitive impairment. It remains unclear if hypometablism, a marker for neurodegeneration, may be in the mechanistic pathway in the association between carotid stenosis and cognitive decline. This study aims to investigate whether patients with carotid stenosis exhibit reduced cerebral glucose metabolism, using 18-FDG PET imaging as a sensitive measure of brain’s glucose metabolism. Methods: We have identified 138 patients from one health care system who underwent 18-FDG PET imaging and had extracranial carotid imaging (doppler ultrasound/CT angiography/MR angiography) within 1 year of PET scan. Severity of carotid stenosis was defined using NASCET criteria as <50% (mild), 50-69% (moderate), >70% (high-grade). Cerebral glucose metabolism was quantified by measuring standardized uptake value ratio (SUVR) after normalizing to pons in 12 different regions of interest (ROI). Hypometabolism was defined using the cutoff of SUVR <1.41. SUVR and hypometabolism measures were compared across severity of carotid stenosis. Results: Of 138 patients identified, 54 were excluded due to indeterminant ipsilateral hemisphere status. Mild, moderate and severe stenosis was present in 86.9%, 4.8%, 8.3%, respectively. The analysis revealed a numerically reduced cerebral glucose metabolism in patients with moderate to severe carotid stenosis compared to control subjects (Table 1). The most pronounced decrease in FDG uptake was observed in regions supplied by the affected carotid artery, particularly the ipsilateral cortical areas. There was a numerically increased risk of hypometabolism with increasing carotid stenosis: Adjusted odds of hypometabolism ipsilateral to the carotid stenosis were 2.90, 5.56 across patients with moderate and high-grade carotid stenosis in sensorimotor cortex (trend-P=0.095). These findings were consistent across different regions supplied by the stenotic carotid artery but attenuated in territories supplied by unaffected posterior arteries (Table 2). Conclusions: FDG-PET imaging demonstrates reduced glucose metabolism in patients with carotid stenosis, suggesting that cerebral hypoperfusion may contribute to the metabolic disturbances observed in these patients. These results underscore the importance of early detection and management of carotid stenosis to mitigate potential cerebral metabolic deficits and the associated risk of dementia and ischemic stroke.