Abstract Background The A/T/N research framework for Alzheimer’s Disease calls for the importance of examining differences in these biomarkers across racial and ethnic groups. This study aims to address this need and examine the correlation and application between A/T/N plasma and neuroimaging biomarkers among a diverse cohort. Method Data were analyzed on Non‐Hispanic White (NHW) (n = 14 A+, n = 117 A‐; n = 4 T+, n = 83 T‐; n = 204 N+, 388 N‐) and Mexican American (MA) (n = 2 A+; n = 75 A‐; n = 3 T+, n = 27 T‐; n = 205 N+, n = 443 N‐) participants from the Health and Aging Brain Study‐ Health Disparities. Participants underwent a blood draw and neuroimaging (MRI, PET Amyloid and Tau). Plasma A/T/N biomarkers of Amyloid Beta (Aβ) 40, 42, Total Tau (T‐Tau), PTau‐181, and Neurofilament Light Chain (Nf‐L) were derived using Single Molecule Array (SIMOA) technology on HD‐X. Pearson correlations were conducted using plasma and neuroimaging A/T/N biomarkers. Due to the limited sample size of A+ and T+, support vector machine models were run in the total sample to examine the application of plasma biomarkers in predicting neuroimaging derived A+/T+/N+. Result In the total sample, Aβ 42 correlated with all PET amyloid ROIs. Ptau‐181 correlated with PET Tau SUVR in the Medial Temporal and Posterior Cingulate and clinical read of Tau +, same with T‐Tau. Nf‐L also correlated with MRI derived N+. Aβ 40 and 42 produced an AUC of 69% in detecting PET Amyloid + while T‐Tau and Ptau‐181 produced an AUC of 86% in detecting PET Tau +. Nf‐L alone produced an AUC of 66% in detecting MRI derived N+. Among MAs, Aβ 40 correlated with PET amyloid Frontal, Anterior Posterior Cingulate, Lateral Parietal, and Global SUVR while Ptau‐181 correlated with clinical read of Tau +. Nf‐L correlated with MRI derived N+ among MAs. Among NHWs, Aβ 40 and 42 correlated with clinical read of Amyloid +, while the later correlated with all PET amyloid ROIs. Neither T‐Tau, Ptau‐181 nor Nf‐L correlated with respective T or N neuroimaging biomarkers among NHWs. Conclusion This work supports prior findings and highlights ethnic specific differences in the interconnection between A/T/N plasma and neuroimaging biomarkers.
Introduction Resting state functional MRI (RS-fMRI) is currently used in numerous clinical and research settings. The localization of resting state networks (RSNs) has been utilized in applications ranging from group analysis of neurodegenerative diseases to individual network mapping for pre-surgical planning of tumor resections. Reproducibility of these results has been shown to require a substantial amount of high-quality data, which is not often available in clinical or research settings. Methods In this work, we report voxelwise mapping of a standard set of RSNs using a novel deep 3D convolutional neural network (3DCNN). The 3DCNN was trained on publicly available functional MRI data acquired in n = 2010 healthy participants. After training, maps that represent the probability of a voxel belonging to a particular RSN were generated for each participant, and then used to calculate mean and standard deviation (STD) probability maps, which are made publicly available. Further, we compared our results to previously published resting state and task-based functional mappings. Results Our results indicate this method can be applied in individual subjects and is highly resistant to both noisy data and fewer RS-fMRI time points than are typically acquired. Further, our results show core regions within each network that exhibit high average probability and low STD. Discussion The 3DCNN algorithm can generate individual RSN localization maps, which are necessary for clinical applications. The similarity between 3DCNN mapping results and task-based fMRI responses supports the association of specific functional tasks with RSNs.
In cognitively normal older adults, task-positive networks, such as the dorsal attention network (DAN), show greater neural recruitment in response to attention-demanding tasks than at rest, whereas the task-negative default mode network (DMN) shows the opposite pattern. The inverse relationship, or anticorrelation, between the two networks likely reflects efficient competition for cognitive resources. We hypothesized that if functional connectivity between the DAN and DMN is dysregulated in early Alzheimer's Disease (AD), then anticorrelations will be weaker and increased cognitive intraindividual variability (IIV), or increased inconsistencies in cognitive performance, will occur. Neuroimaging and cognitive measures from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used to assess within and between network functional connectivity and IIV in cognitively normal older adults and those with early AD. Analyses were then replicated using data from Washington University's Knight Alzheimer's Disease Research Center (ADRC) to ensure statistical validity. In the ADNI sample, cognitive IIV was greater in individuals with early AD compared to cognitively normal older adults. Furthermore, the relationship between cognitive IIV and the DAN-DMN anticorrelation was weaker for individuals with early AD than cognitively normal individuals. Preliminary analyses on data from the ADRC showed similar results. Collectively, the results from ADNI and ADRC support conclusions that in early stages of AD, overall cognitive functioning becomes less consistent, and that decreases in cognitive consistency are associated with a breakdown in functional network anticorrelations. This study provides insight into how alterations in the dynamics of functional networks give rise to behavioral changes in early AD.
Abstract Background Previous research suggests that African Americans are potentially at greater risk for developing Alzheimer disease (AD). Genetic, social, environmental, and cardiovascular factors may increase the risk of AD. The objectives of this project are as follows: (1) Assess neuroimaging biomarkers of amyloid (A), tau (T), and neurodegeneration (N) for potential racial differences. (2) Consider mediating effects of socioeconomic status (SES) and cardiovascular risk factors on observed race differences. Methods Imaging measures of AT(N) (amyloid and tau positron emission tomography (PET) structural magnetic resonance imaging, and resting state functional connectivity (rs‐fc)) were collected from African American (n=169) and Caucasian (n=935) participants. Cardiovascular (white matter hyperintensities on MRI, blood pressure, and body mass index) and area‐based socioeconomic status (SES) were assessed as possible mediating factors in a multiple mediation analysis. This analysis assumed nonlinear relationships between the mediation effects and allowed for all four mediators to be considered simultaneously. Results Compared to Caucasian participants, African American participants had lower amyloid PET burden but greater neurodegeneration, as measured by decreased cortical volumes and decreased AD global rs‐fc signature. African American participants were substantially more likely to be female (64%) compared to Caucasian participants (55% female). Female participants had greater tau burden and decreased AD cortical signature volume; but no significant race by sex interactions were observed. African Americans had lower area‐based SES and higher blood pressure, BMI, and white matter hyperintensity volumes. These proposed mediators significantly influenced associations between race and cortical amyloid PET accumulation, AD cortical signature volume, and AD global rs‐fc signature. Area‐level SES in particular was a significant mediating factor, and BMI had a significant effect on amyloid burden. Conclusion Observed racial differences in AD are not primarily due to immutable, genetic differences, but rather modifiable factors fueled by differences in social contexts and resources, particularly area‐level SES. Future studies should emphasize collection of relevant psychosocial factors in addition to the development of intentional diversity and inclusion efforts to improve the racial/ethnic and socioeconomic representativeness of AD studies.
Abstract Background Structural MRI can describe neurodegeneration associated with aging and Alzheimer Disease (AD). Brain age gap (BAG) quantifies the difference between chronological age and predicted “brain age” and can be estimated using many published algorithms. Higher BAG indicates accelerated brain aging. Regional estimates of volume and thickness detect structural differences in AD signature regions (e.g., hippocampus, tempo‐parietal regions). This project aimed to identify the structural MRI measure that had the best correspondence with Clinical Dementia Rating (CDR) in an ethno‐racially diverse sample. Method We compared structural MRI measures in the Health & Aging Brain Study–Health Disparities (691 non‐Hispanic Black (NHB), 1094 Mexican‐American (MA) and 1085 non‐Hispanic White (NHW) participants). We calculated BAG using DeepBrainNet (BAG DBN ) and BrainAgeR (BAG BAR ). We derived Freesurfer‐based cortical thickness (meta‐ROI) and hippocampal volume (normalized for intracranial volume). We applied ANOVA followed by post‐hoc Tukey tests to assess differences in the interaction of self‐identified race/ethnicity and CDR, correcting for age, gender, and scanner. We performed ordinal regression to predict CDR using the same covariates, except CDR. Result After correction for multiple comparisons, BAG DBN significantly differed between CDR 0 and CDR 0.5 in MA (p corrected =0.045) and NHB (p corrected =0.017) but not NHW (p corrected =0.110). The other measures significantly differed between CDR 0 and CDR 0.5 for NHW only (Figure 1). For individuals with a 1 Z‐score elevation in BAG DBN (6.1 years), NHW have 1.21 (95%CI: 1.18, 1.26) times the odds of being CDR 0.5, while NHB significantly greater risk (OR = 1.31, 95%CI: 1.27, 1.36). MA have 1.26 times the odds (95%CI: 1.22, 1.31). In contrast, for individuals with a 1 Z‐score decrease in cortical thickness, there is no difference in odds ratio by ethno‐racial group (NHW=1.21, 95%CI: 1.17, 1.27; NHB=1.30, 95%CI: 1.24, 1.37; MA=1.28, 95%CI: 1.24, 1.33) (Figure 2). Conclusion The neurodegeneration measures with the strongest correspondence to CDR varied by ethno‐racial group. BAG DBN may display greater sensitivity to the subtle changes that occur as individuals transition from CDR = 0 to 0.5 in underrepresented cohorts. Further work is needed to understand what features BAG DBN captures, but this suggests care should be taken when choosing neurodegeneration markers.
Abstract Background There are few assessments of possible racial differences in Alzheimer disease (AD) biomarkers because research cohorts typically are not diverse. Should differences exist, they may inform the understanding of AD pathogenesis as well as the role of social determinants of health (SDOH). Method We assessed a non‐clinic‐based cohort of 1255 community living persons, age 45 and older, who were enrolled in studies of aging and dementia at the Knight ADRC (St Louis, Missouri, USA). Participants completed at least one brain magnetic resonance imaging (MRI) study, and/or at least one amyloid positron emission tomography (PET) scan, and/or at least one lumbar puncture to obtain cerebrospinal fluid (CSF) for biomarker assays. The cohort included 1082 white participants and 173 participants who self‐identified as Black or African American (AA); 33% of participants in each group had early‐stage symptomatic AD and 67% in each group were cognitively normal. Result Both racial groups demonstrated expected biomarker changes as a function of clinical status (eg, lower hippocampal volumes in persons with symptomatic AD). Higher body mass index and HgA1c levels were noted in AAs, but there was no racial difference in the frequency of MRI‐confirmed cerebral infarcts. There also were no differences in the mean cortical standardized uptake value ratios for Pittsburgh Compound B or in amyloid‐beta 42 concentrations in CSF. However, mean CSF concentrations of tau and phosphorylated tau 181 were lower in AA participants, a finding that was evident primarily in carriers of the ε 4 allele of APOE . The CSF concentrations of soluble TREM2, a mediator of the inflammatory response to AD pathology, also were lower in AAs. Finally, decreased volumes in brain regions comprising the AD cortical signature were lower in AAs but this difference was mediated, at least in part, by SDOH. Conclusion There are racial differences in AD biomarkers between white and AA research participants, including for the AD cortical signature, a putative marker of neurodegeneration in the AT(N) framework. SDOH contribute to these differences, either independently or through interactions with biological factors.
Abstract Background Neurofilament light chain (NfL) is considered a biomarker of neuronal injury and degeneration and is increasingly used to evaluate disease progression across multiple neurological conditions including Alzheimer Disease (AD). Despite growing attention as an injury marker, little is known about how NfL relates to brain structure and what other factors may influence this relationship. The objective of this study was to determine whether NfL level in the cerebrospinal fluid (CSF) is more strongly associated with total gray, white, and/or white matter hyperintensity (WMH) volume and assess how this association changes as a function of age and amyloid status. Method CSF NfL was measured in 397 individuals who also underwent structural MRI and amyloid positron emission tomography (PET) using Pittsburgh Compound B (PiB). PiB positivity was defined as having a mean cortical standard uptake value ratio ≥1.42. Images underwent volumetric segmentation using FreeSurfer 5.3. Pearson’s r correlation analysis was used to determine the association between NfL and age. A multivariate regression model was used to determine whether NfL predicts total gray volume, white volume, and/or WMH volumes in PiB positive (PiB+) and negative (PiB‐) individuals. Correlation analyses also assessed the association between NfL and gray, white, and WMH volume. Additional regression models were used to determine region specific associations between NfL and white/gray matter volume. Age was accounted for in all models. Result NfL was significantly correlated with age, r=0.63, p <0.001 (Figure 1). Accounting for age, NfL predicted total gray, white, and WMH volume, regardless of PiB status ( p s<0.01; Figure 2 and 3). When including gray, white, and WMH volume in the same model, NfL was associated with total WMH volume (r= 0.43, p <0.001), but not gray or white matter volume ( p s>0.05) across individuals. Conclusion Collectively, these results suggest that NfL is a non‐specific marker of aging and white‐matter integrity with limited sensitivity to amyloid status. Given the association with WMH volume across individuals, it is likely that NfL reflects other processes such as cerebrovascular disease.
Abstract Background Ethno‐racial differences are observed in amyloid (A), tau (T), and neurodegeneration (N) plasma biomarkers of Alzheimer’s disease (AD). In neuroimaging studies, structural and social determinant of health (SSDOH) factors and associated health outcomes may mediate observed racial differences in neurodegeneration markers. However, little is known regarding the potential effects of SSDOH and downstream comorbidities on ethno‐racial differences in AT(N) plasma biomarkers. This study A) assessed potential differences in plasma A β 42, A β 40, A β 42/40, t‐tau, and NfL among Mexican Americans (MA), non‐Hispanic Blacks (NHB), and non‐Hispanic Whites (NHW); B) determined whether SSDOH and comorbidity factors mediate potential ethno‐racial differences in AD plasma biomarkers. Method Data were obtained from the diverse and well‐characterized Health and Aging Brain Study – Health Disparities (HABS‐HD) and included MAs (n = 931), NHBs (n = 258), and NHWs (n = 942). Group differences in AT(N) plasma biomarkers were assessed using analysis of covariance. Age, sex, and cognitive status (Clinical Dementia Rating Scale Sum of Boxes) were included as covariates. Two multiple mediation models were performed with SSDOH (acculturation, chronic stress, income, area deprivation index) and comorbidity factors (body mass index [BMI], blood pressure, diabetes history) as the potential mediators, respectively. Models accounted for age, sex, and cognitive status, assumed nonlinear relationships, and allowed for mediators to be considered simultaneously. Result Plasma A β 42 was significantly lower in MAs compared to NHWs ( p <0.05). Plasma NfL was significantly higher in MAs compared to NHBs ( p <0.01) and for NHWs compared to NHBs ( p <0.05). No other significant differences in plasma variables were observed ( p ’s>0.05). Group differences in plasma A β 42 were mediated by comorbidity factors (BMI and history of diabetes), but not SSDOH. MAs had greater BMIs and history of diabetes compared to NHWs, both of which were associated with lower plasma A β 42 levels. SSDOH and comorbidity factors did not mediate group differences in plasma NfL. Conclusion Using a large and diverse community‐based cohort, we demonstrate that ethno‐racial differences in AD‐specific plasma biomarkers are, in part, due to modifiable health and comorbidity factors. This work informs the conditions that give rise to ethno‐racial differences in plasma ATN biomarkers while highlighting potential ethno‐racial disparities in AD research.
