INTRODUCTION Disease‐modifying therapies (DMTs) for Alzheimer's disease (AD) will increase diagnostic demand. A non‐invasive blood‐based biomarker (BBBM) test for detection of amyloid‐β pathology may reduce diagnostic barriers and facilitate DMT initiation. OBJECTIVE To explore heterogeneity in AD care pathways and potential role of BBBM tests. METHODS Survey of 213 healthcare professionals/payers in US/China/UK/Germany/Spain/France and two advisory boards (US/Europe). RESULTS Current diagnostic pathways are heterogeneous, meaning many AD patients are missed while low‐risk patients undergo unnecessary procedures. Confirmatory amyloid testing (cerebrospinal fluid biomarkers/positron emission tomography) is utilized in few patients, resulting in diagnostic/treatment delays. A high negative‐predictive‐value test could streamline the diagnostic pathway by reducing unnecessary procedures in low‐risk patients; supporting confirmatory testing where needed. Imminent approval of DMTs will increase need for fast and reliable AD diagnostic tests. DISCUSSION An easy‐to‐use, accurate, non‐invasive BBBM test for amyloid pathology could guide diagnostic procedures or referral, streamlining early diagnosis and DMT initiation.

Purpose: For quantitative susceptibility mapping (QSM), the lack of ground-truth in clinical settings makes it challenging to determine suitable parameters for the dipole inversion. We propose a probabilistic Bayesian approach for QSM with built-in parameter estimation, and incorporate the nonlinear formulation of the dipole inversion to achieve a robust recovery of the susceptibility maps. Theory: From a Bayesian perspective, the image wavelet coefficients are approximately sparse and modelled by the Laplace distribution. The measurement noise is modelled by a Gaussian-mixture distribution with two components, where the second component is used to model the noise outliers. Through probabilistic inference, the susceptibility map and distribution parameters can be jointly recovered using approximate message passing (AMP). Methods: We compare our proposed AMP with built-in parameter estimation (AMP-PE) to the state-of-the-art L1-QSM, FANSI and MEDI approaches on the simulated and in vivo datasets, and perform experiments to explore the optimal settings of AMP-PE. Reproducible code is available at https://github.com/EmoryCN2L/QSM_AMP_PE Results: On the simulated Sim2Snr1 dataset, AMP-PE achieved the lowest NRMSE, DFCM and the highest SSIM, while MEDI achieved the lowest HFEN. On the in vivo datasets, AMP-PE is robust and successfully recovers the susceptibility maps using the estimated parameters, whereas L1-QSM, FANSI and MEDI typically require additional visual fine-tuning to select or double-check working parameters. Conclusion: AMP-PE provides automatic and adaptive parameter estimation for QSM and avoids the subjectivity from the visual fine-tuning step, making it an excellent choice for the clinical setting.

Alzheimer’s disease (AD) is currently defined at the research level by the aggregation of amyloid-β (Aβ) and tau proteins in brain. While biofluid biomarkers are available to measure Aβ and tau pathology, few biomarkers are available to measure the complex pathophysiology that is associated with these two cardinal neuropathologies. Here we describe the proteomic landscape of cerebrospinal fluid (CSF) changes associated with Aβ and tau pathology in 300 individuals as assessed by two different proteomic technologies—tandem mass tag (TMT) mass spectrometry and SomaScan. Harmonization and integration of both data types allowed for generation of a robust protein co-expression network consisting of 34 modules derived from 5242 protein measurements, including disease-relevant modules associated with autophagy, ubiquitination, endocytosis, and glycolysis. Three modules strongly associated with the apolipoprotein E ε4 (APOE ε4) AD risk genotype mapped to oxidant detoxification, mitogen associated protein kinase (MAPK) signaling, neddylation, and mitochondrial biology, and overlapped with a previously described lipoprotein module in serum. Neddylation and oxidant detoxification/MAPK signaling modules had a negative association with APOE ε4 whereas the mitochondrion module had a positive association with APOE ε4. The directions of association were consistent between CSF and blood in two independent longitudinal cohorts, and altered levels of all three modules in blood were associated with dementia over 20 years prior to diagnosis. Dual-proteomic platform analysis of CSF samples from an AD phase 2 clinical trial of atomoxetine (ATX) demonstrated that abnormal elevations in the glycolysis CSF module—the network module most strongly correlated to cognitive function—were reduced by ATX treatment. Individuals who had more severe glycolytic changes at baseline responded better to ATX. Clustering of individuals based on their CSF proteomic network profiles revealed ten groups that did not cleanly stratify by Aβ and tau status, underscoring the heterogeneity of pathological changes not fully reflected by Aβ and tau. AD biofluid proteomics holds promise for the development of biomarkers that reflect diverse pathologies for use in clinical trials and precision medicine.

Purpose: Undersampling is used to reduce the scan time for high-resolution 3D magnetic resonance imaging. In order to achieve better image quality and avoid manual parameter tuning, we propose a probabilistic Bayesian approach to recover 𝑅∗ 2 map and phase images for quantitative susceptibility mapping (QSM), while allowing automatic parameter estimation from undersampled data. Theory: Sparse prior on the wavelet coefficients of images is interpreted from a Bayesian perspective as sparsity-promoting distribution. A novel nonlinear approximate message passing (AMP) framework that incorporates a mono-exponential decay model is proposed. The parameters are treated as unknown variables and jointly estimated with image wavelet coefficients. Methods: Undersampling takes place in the y-z plane of k-space according to the Poisson-disk pattern. Retrospective undersampling is performed to evaluate the performances of different reconstruction approaches, prospective undersampling is performed to demonstrate the feasibility of undersampling in practice. Results: The proposed AMP with parameter estimation (AMP-PE) approach successfully recovers 𝑅∗ 2 maps and phase images for QSM across various undersampling rates. It is more computationally efficient, and performs better than the state-of-the-art 𝑙1-norm regularization (L1) approach in general, except a few cases where the L1 approach performs as well as AMP-PE. Conclusion: AMP-PE achieves better performance by drawing information from both the sparse prior and the mono-exponential decay model. It does not require parameter tuning, and works with a clinical, prospective undersampling scheme where parameter tuning is often impossible or difficult due to the lack of ground-truth image.

Inclusion of Black participants in clinical research is a national priority, particularly for diseases in which they face disproportionate risk. Currently, Black participants are significantly underrepresented within clinical trials and longitudinal research. In an effort to overcome logistical barriers that may limit research participation, this study examined the reliability and feasibility of two mobile smartphone application-based cognitive measures in a diverse middle aged and older adult sample. Black (n=44; Mage=59.93) and non-Hispanic white (NHW; n=50; Mage=61.06) participants completed traditional paper-based neuropsychological testing and two app-based measures, Arrows and Number Match. Arrows and Number Match are adaptations of traditional neuropsychological measures, the Flanker Task and Symbol Digit Modalities Test, respectively. Intraclass correlations demonstrated poor to moderate reliability (range: .417-.569) between performance on the app-based versions and performance on the traditional versions. There were no race related differences in performance on Arrows. Performance score differences by racial group were not statistically significant on Number Match, but trended toward significance, (t (81) = 1.91, p = .06). Both Black and NHW participants rated the applications as feasible and acceptable, though Black participants endorsed a stronger likelihood of future use (M=3.95, SD=0.94) than their NHW counterparts (M=3.50, SD=1.15), p = .04. These findings add to the growing literature on remote cognitive testing in response to the necessity of increased accessibility within research.

Objective: The Mayo Normative Studies (MNS) represents a robust dataset that provides demographically corrected norms for the Rey Auditory Verbal Learning Test. We report MNS application to an independent cohort to evaluate whether MNS norms accurately adjust for age, sex, and education differences in subjects from a different geographic region of the country. As secondary goals, we examined item-level patterns, recognition benefit compared to delayed free recall, and derived Auditory Verbal Learning Test (AVLT) confidence intervals (CIs) to facilitate clinical performance characterization. Method: Participants from the Emory Healthy Brain Study (463 women, 200 men) who were administered the AVLT were analyzed to demonstrate expected demographic group differences. AVLT scores were transformed using MNS normative correction to characterize the success of MNS demographic adjustment. Results: Expected demographic effects were observed across all primary raw AVLT scores. Depending on sample size, MNS normative adjustment either eliminated or minimized all observed statistically significant AVLT differences. Estimated CIs yielded broad CI ranges exceeding the standard deviation of each measure. The recognition performance benefit across age ranged from 2.7 words (SD = 2.3) in the 50–54-year-old group to 4.7 words (SD = 2.7) in the 70–75-year-old group. Conclusions: These findings demonstrate generalizability of MNS normative correction to an independent sample from a different geographic region, with demographic adjusted performance differences close to overall performance levels near the expected value of T = 50. A large recognition performance benefit is commonly observed in the normal aging process and by itself does not necessarily suggest a pathological retrieval deficit.

Background: Air pollution has been associated with cognitive function in the elderly. Previous studies have not evaluated the simultaneous effect of neighborhood-level socioeconomic status (N-SES), which can be an essential source of bias. Objectives: We explored N-SES as a confounder and effect modifier in a cross-sectional study of air pollution and subjective cognitive function. Methods: We included 12,058 participants age 50+ years from the Emory Healthy Aging Study in Metro Atlanta using the Cognitive Function Instrument (CFI) score as our outcome, with higher scores representing worse subjective cognitive function. We estimated 9-year average ambient carbon monoxide (CO), nitrogen oxides (NOx), and fine particulate matter (PM2.5) concentrations at residential addresses using a fusion of dispersion and chemical transport models. We collected census-tract level N-SES indicators and created two composite measures via principal component analysis and k-means clustering. Associations between pollutants and CFI and effect modification by N-SES were estimated via linear regression models adjusted for age, education, race and N-SES. Results: N-SES confounded the association between air pollution and CFI, independent of individual characteristics. We found significant effect modifications by N-SES for the association between air pollution and CFI (p-values<0.001) suggesting that effects of air pollution differ depending on N-SES. Participants living in areas with low N-SES were most vulnerable to air pollution. In the lowest N-SES urban areas, interquartile range (IQR) increases in CO, NOx, and PM2.5 were associated with 5.4% (95%-confidence interval, −0.2,11.3), 4.9% (−0.4,10.4), and 9.8% (2.2,18.0) changes in CFI, respectively. In lowest N-SES suburban areas, IQR increases in CO, NOx, and PM2.5 were associated with higher changes in CFI, namely 13.0% (0.9,26.5), 13.0% (−0.1,27.8), and 17.3% (2.5,34.2), respectively. Discussion: N-SES is an important confounder and effect modifier in our study. This finding could have implications for studying health effects of air pollution and identifying susceptible populations.

There is no gold standard for the diagnosis of Alzheimer’s disease (AD), except for autopsies, which motivates the use of unsupervised learning. A mixture of regressions is an unsupervised method that can simultaneously identify clusters from multiple biomarkers while learning within-cluster demographic effects. Cerebrospinal fluid (CSF) biomarkers for AD have detection limits, which create additional challenges. We apply a mixture of regressions with a multivariate truncated Gaussian distribution (also called a censored multivariate Gaussian mixture of regressions or a mixture of multivariate Tobit regressions) to over 3000 participants from the Emory Goizueta Alzheimer’s Disease Research Center and Emory Healthy Brain Study to examine amyloid-beta peptide 1–42 (Abeta42), total tau protein and phosphorylated tau protein in CSF with known detection limits. We address three gaps in the literature on the mixture of regressions with a truncated multivariate Gaussian distribution: software availability; inference; and clustering accuracy. We discovered three clusters that tend to align with an AD group, a normal control profile, and non-AD pathology. The CSF profiles differed by race, gender, and the genetic marker ApoE4, highlighting the importance of considering demographic factors in unsupervised learning with detection limits. Notably, African American participants in the AD-like group had significantly lower tau burden.

Integration of the omics data, including metabolomics and proteomics, provides a unique opportunity to search for new associations within metabolic disorders, including Alzheimer’s disease. Using metabolomics, we have previously profiled oxylipins, endocannabinoids, bile acids, and steroids in 293 CSF and 202 matched plasma samples from AD cases and healthy controls and identified both central and peripheral markers of AD pathology within inflammation-regulating cytochrome p450/soluble epoxide hydrolase pathway. Additionally, using proteomics, we have identified five cerebrospinal fluid protein panels, involved in the regulation of energy metabolism, vasculature, myelin/oligodendrocyte, glia/inflammation, and synapses/neurons, affected in AD, and reflective of AD-related changes in the brain. In the current manuscript, using metabolomics-proteomics data integration, we describe new associations between peripheral and central lipid mediators, with the above-described CSF protein panels. Particularly strong associations were observed between cytochrome p450/soluble epoxide hydrolase metabolites, bile acids, and proteins involved in glycolysis, blood coagulation, and vascular inflammation and the regulators of extracellular matrix. Those metabolic associations were not observed at the gene-co-expression level in the central nervous system. In summary, this manuscript provides new information regarding Alzheimer’s disease, linking both central and peripheral metabolism, and illustrates the necessity for the “omics” data integration to uncover associations beyond gene co-expression.

Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation of the amyloid-β (Aβ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)—are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aβ plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aβ plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aβ and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aβ and tau.