Risk of Alzheimer's disease is associated with longitudinal changes in plasma biomarkers in the multi-ethnic Washington Heights-Hamilton Heights-Inwood Columbia Aging Project (WHICAP) cohort.

BACKGROUND: Alzheimer's disease (AD) biomarkers can help differentiate cognitively unimpaired (CU) individuals from mild cognitive impairment (MCI) and dementia. The role of AD biomarkers in predicting cognitive impairment and AD needs examination. METHODS: In 628 CU individuals from a multi-ethnic cohort, amyloid beta (Aß)42, Aß40, phosphorylated tau-181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were measured in plasma. RESULTS: Higher baseline levels of p-tau181/Aß42 ratio were associated with an increased risk of incident dementia. A biomarker pattern (with elevated Aß42/Aß40 but low p-tau181/Aß42) was associated with decreased dementia risk. Compared to CU, participants who developed MCI or dementia had a rapid decrease in this protective biomarker pattern reflecting AD-specific pathological change. DISCUSSION: Elevated levels of AD biomarker p-tau181/Aß42, by itself or combined with a low Aß42/Aß40 level, predicts clinically diagnosed AD. Individuals with a rapid change in these biomarkers may need close monitoring for the potential downward trajectory of cognition. HIGHLIGHTS: We discuss a multi-ethnic, urban community study of elderly individuals. The study consisted of a longitudinal assessment over 6 years with repeated clinical assessments. The study used blood-based biomarkers as predictors of mild cognitive impairment and Alzheimer's disease.

Frontal-to-visual information flow explains predictive motion tracking.

Predictive tracking demonstrates our ability to maintain a line of vision on moving objects even when they temporarily disappear. Models of smooth pursuit eye movements posit that our brain achieves this ability by directly streamlining motor programming from continuously updated sensory motion information. To test this hypothesis, we obtained sensory motion representation from multivariate electroencephalogram activity while human participants covertly tracked a temporarily occluded moving stimulus with their eyes remaining stationary at the fixation point. The sensory motion representation of the occluded target evolves to its maximum strength at the expected timing of reappearance, suggesting a timely modulation of the internal model of the visual target. We further characterize the spatiotemporal dynamics of the task-relevant motion information by computing the phase gradients of slow oscillations. We discovered a predominant posterior-to-anterior phase gradient immediately after stimulus occlusion; however, at the expected timing of reappearance, the axis reverses the gradient, becoming anterior-to-posterior. The behavioral bias of smooth pursuit eye movements, which is a signature of the predictive process of the pursuit, was correlated with the posterior division of the gradient. These results suggest that the sensory motion area modulated by the prediction signal is involved in updating motor programming.

Neurofilament light chain: A potential biomarker for cerebrovascular disease in children with sickle cell anaemia.

Cerebrovascular injury frequently occurs in children with sickle cell anaemia (SCA). Limited access to magnetic resonance imaging and angiography (MRI-MRA) in sub-Saharan Africa impedes detection of clinically unapparent cerebrovascular injury. Blood-based brain biomarkers of cerebral infarcts have been identified in non-SCA adults. Using plasma samples from a well-characterized cross-sectional sample of Ugandan children with SCA, we explored relationships between biomarker levels and MRI-detected cerebral infarcts and transcranial Doppler (TCD) arterial velocity. Testing was performed using a 4-plex panel of brain injury biomarkers, including neurofilament light chain (NfL), a central nervous system neuron-specific protein. Mean biomarker levels from the SCA group (n = 81) were similar to those from non-SCA sibling controls (n = 54). Within the SCA group, NfL levels were significantly higher in those with MRI-detected infarcts compared to no infarcts, and higher with elevated TCD velocity versus normal velocity. Elevated NfL remained strongly associated with MRI-detected infarcts after adjusting for sex and age. All non-SCA controls and SCA participants lacking MRI-detected infarcts had low NfL levels. These data suggest potential utility of plasma-based NfL levels to identify children with SCA cerebrovascular injury. Replication and prospective studies are needed to confirm these novel findings and the clinical utility of NfL versus MRI imaging.

Neural representations of ensemble coding in the occipital and parietal cortices.

The human visual system is able to extract summary statistics from sets of similar items, but the underlying neural mechanism remains poorly understood. Using functional magnetic resonance imaging (fMRI) and an encoding model, we examined how the neural representation of ensemble coding is constructed by manipulating the task-relevance of ensemble features. We found a gradual increase in orientation-selective responses to the mean orientation of multiple stimuli along the visual hierarchy only when these orientations were task-relevant. Such responses to the ensemble orientation were present in the extrastriate area, V3, even when the mean orientation was not task-relevant, indicating that the ensemble representation can co-exist with the task-relevant individual feature representation. Ensemble orientations were also represented in frontal regions, but those representations were robust only when each mean orientation was linked to a motor response dimension. Together, our findings suggest that the neural representation of the ensemble percept is formed by pooling signals at multiple levels of the visual processing stream.

Elevated In Vitro Kinase Activity in Peripheral Blood Mononuclear Cells of Leucine-Rich Repeat Kinase 2 G2019S Carriers: A Novel Enzyme-Linked Immunosorbent Assay-Based Method.

BACKGROUND: Leucine-rich repeat kinase 2 kinase inhibitors are being vigorously pursued as potential therapeutic options; however, there is a critical need for sensitive and quantitative assays of leucine-rich repeat kinase 2 function and target engagement. OBJECTIVES: Our objective was to compare collection and storage protocols for peripheral blood mononuclear cells, and to determine the optimal conditions for downstream analyses of leucine-rich repeat kinase 2 in PD cohorts. METHODS: Here, we describe enzyme-linked immunosorbent assay-based assays capable of detecting multiple aspects of leucine-rich repeat kinase 2 function at endogenous levels in human tissues. RESULTS: In peripheral blood mononuclear cells from both healthy and affected carriers of the G2019S mutation in leucine-rich repeat kinase 2, we report, for the first time, significantly elevated in vitro kinase activity, while detecting a significant increase in pS935/leucine-rich repeat kinase 2 in idiopathic PD patients. CONCLUSIONS: Quantitative assays such as these described here could potentially uncover specific markers of leucine-rich repeat kinase 2 function that are predictive of disease progression, aid in patient stratification, and be a critical component of upcoming clinical trials. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Slow Temporal Dynamics of Motion-Induced Brightness Shift Reveals Impact of Adaptation.

Brightness of an object is determined by various factors including ambient illumination, surface reflectance of the object, and spatial and temporal relation between the object and its surrounding context. Recently, it has been demonstrated that the motion of an object alters its own and nearby object's appearance such as brightness and color. This study aims to unveil mechanisms of the motion-induced brightness shift by measuring its temporal dynamics. We found that the motion-induced brightness shift occurred instantaneously with the motion onset when the motion was introduced abruptly. However, the brightness of a stationary object was altered gradually by a nearby moving object in about 2 s time window when the stationary dot was introduced abruptly. Two distinct temporal dynamics (slow vs. fast) of the motion-induced brightness shift demonstrate that both slow neural adaptation and fast neural normalization processes determine the brightness shift induced by the object's motion.

Less Is More: Semantic Information Survives Interocular Suppression When Attention Is Diverted.

UNLABELLED: The extent of unconscious semantic processing has been debated. It is well established that semantic information is registered in the absence of awareness induced by inattention. However, it has been debated whether semantic information of invisible stimuli is processed during interocular suppression, a procedure that renders one eye's view invisible by presenting a dissimilar stimulus to the other eye. Inspired by recent evidence demonstrating that reduced attention attenuates interocular suppression, we tested a counterintuitive hypothesis that attention withdrawn from the suppressed target location facilitates semantic processing in the absence of awareness induced by interocular suppression. We obtained an electrophysiological marker of semantic processing (N400 component) while human participants' spatial attention was being manipulated with a cueing paradigm during interocular suppression. We found that N400 modulation was absent when participants' attention was directed to the target location, but present when diverted elsewhere. In addition, the correlation analysis across participants indicated that the N400 amplitude was reduced with more attention being directed to the target location. Together, these results indicate that inattention attenuates interocular suppression and thereby makes semantic processing available unconsciously, reconciling conflicting evidence in the literature. We discuss a tight link among interocular suppression, attention, and conscious awareness. SIGNIFICANCE STATEMENT: Interocular suppression offers a powerful means of studying the extent of unconscious processing by rendering a salient stimulus presented to one eye invisible. Here, we provide evidence that attention is a determining factor for unconscious semantic processing. An electrophysiological marker for semantic processing (N400 component) was present when attention was diverted away from the suppressed stimulus but absent when attention was directed to that stimulus, indicating that inattention facilitates unconscious semantic processing during the interocular suppression. Although contrary to the common sense assumption that attention facilitates information processing, this result is in accordance with recent studies showing that attention modulates interocular suppression but is not necessary for semantic processing. Our finding reconciles the conflicting evidence and advances theories of consciousness.

Distinct neural mechanisms for spatially lateralized and spatially global visual working memory representations.

Visual working memory (VWM) allows humans to actively maintain a limited amount of information. Whereas previous electrophysiological studies have found that lateralized event-related potentials (ERPs) track the maintenance of information in VWM, recent imaging experiments have shown that spatially global representations can be read out using the activity across the visual cortex. The goal of the present study was to determine whether both lateralized and spatially global electrophysiological signatures coexist. We first show that it is possible to simultaneously measure lateralized ERPs that track the number of items held in VWM from one visual hemfield and parietooccipital α (8-12 Hz) power over both hemispheres indexing spatially global VWM representations. Next, we replicated our findings and went on to show that this bilateral parietooccipital α power as well as the contralaterally biased ERP correlate of VWM carries a signal that can be used to decode the identity of the representations stored in VWM. Our findings not only unify observations across electrophysiology and imaging techniques but also suggest that ERPs and α-band oscillations index different neural mechanisms that map on to lateralized and spatially global representations, respectively.

Effect of Attention on the Initiation of Binocular Rivalry.

Recent studies suggest that attention is necessary for perceptual alternations in binocular rivalry. It has been shown that attention plays a role in not only accelerating but also even enabling perceptual fluctuation in ongoing phase of binocular rivalry. In this study, we tested whether attention also plays a role in suppressing a rival stimulus in its initial phases by measuring proportions of mixed dominance. We hypothesized that when attention is directed toward the location of rival stimuli prior to their presentation, the proportion of mixed dominance is lower than when attention is directed away from that location because of attentional facilitation. However, we found that the proportion of mixed dominance did not differ depending on the locus of attention, although we adopted well-established experimental paradigms for manipulating spatial attention. This result suggests that attention is not a determining factor in establishing initial perceptual dominance in binocular rivalry.

Retrieval-Induced Inhibition in Short-Term Memory.

We used a visual illusion called motion repulsion as a model system for investigating competition between two mental representations. Subjects were asked to remember two random-dot-motion displays presented in sequence and then to report the motion directions for each. Remembered motion directions were shifted away from the actual motion directions, an effect similar to the motion repulsion observed during perception. More important, the item retrieved second showed greater repulsion than the item retrieved first. This suggests that earlier retrieval exerted greater inhibition on the other item being held in short-term memory. This retrieval-induced motion repulsion could be explained neither by reduced cognitive resources for maintaining short-term memory nor by continued inhibition between short-term memory representations. These results indicate that retrieval of memory representations inhibits other representations in short-term memory. We discuss mechanisms of retrieval-induced inhibition and their implications for the structure of memory.

Modulation of lipid kinase PI4KIIα activity and lipid raft association of presenilin 1 underlies γ-secretase inhibition by ginsenoside (20S)-Rg3.

Amyloid ß-peptide (Aß) pathology is an invariant feature of Alzheimer disease, preceding any detectable clinical symptoms by more than a decade. To this end, we seek to identify agents that can reduce Aß levels in the brain via novel mechanisms. We found that (20S)-Rg3, a triterpene natural compound known as ginsenoside, reduced Aß levels in cultured primary neurons and in the brains of a mouse model of Alzheimer disease. The (20S)-Rg3 treatment induced a decrease in the association of presenilin 1 (PS1) fragments with lipid rafts where catalytic components of the γ-secretase complex are enriched. The Aß-lowering activity of (20S)-Rg3 directly correlated with increased activity of phosphatidylinositol 4-kinase IIα (PI4KIIα), a lipid kinase that mediates the rate-limiting step in phosphatidylinositol 4,5-bisphosphate synthesis. PI4KIIα overexpression recapitulated the effects of (20S)-Rg3, whereas reduced expression of PI4KIIα abolished the Aß-reducing activity of (20S)-Rg3 in neurons. Our results substantiate an important role for PI4KIIα and phosphoinositide modulation in γ-secretase activity and Aß biogenesis.

Data-Independent Acquisition and Label-Free Quantification for Quantitative Proteomics Analysis of Human Cerebrospinal Fluid.

This article presents a practical guide to mass spectrometry-based data-independent acquisition and label-free quantification for proteomics analysis applied to cerebrospinal fluid, offering a robust and scalable approach to probing the proteomic composition of the central nervous system. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Cerebrospinal fluid sample collection and preparation for mass spectrometry analysis Basic Protocol 2: Mass spectrometry sample analysis with data-independent acquisition Support Protocol: Data-dependent mass spectrometry and spectral library construction Basic Protocol 3: Analysis of mass spectrometry data.

Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression.

INTRODUCTION: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early AD pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify CSF biomarkers for AD-related CNS pathophysiologic changes using tissue and fluids with early pathology, free of post-mortem artifact. METHODS: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes. RESULTS: AD pathology on biopsy correlates with CSF ß-amyloid-40/42, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/ß-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights 7 core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data.. DISCUSSION: As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking.

Risk of Alzheimer's Disease is Associated with Longitudinal Changes in Plasma Biomarkers in the Multiethnic Washington Heights, Inwood Columbia Aging Project Cohort.

INTRODUCTION: Alzheimer's disease (AD) biomarkers can help differentiate cognitively unimpaired (CU) individuals from mild cognitive impairment (MCI) and dementia. The role of AD biomarkers in predicting cognitive impairment and AD needs examination. METHODS: In 628 CU individuals from a multi-ethnic cohort, Aß42, Aß40, phosphorylated tau-181 (P-tau181), glial fibrillary acid protein (GFAP), and neurofilament light chain (NfL) were measured in plasma. RESULTS: Higher baseline levels of P-tau181/Aß42 ratio were associated with increased risk of incident dementia. A biomarker pattern (with elevated Aß42/Aß40 but low P-tau181/Aß42) was associated with decreased dementia risk. Compared to CU, participants who developed MCI or dementia had a rapid decrease in the biomarker pattern reflecting AD-specific pathological change. DISCUSSION: Elevated levels of AD biomarker P-tau181/Aß42, by itself or combined with a low Aß42/Aß40 level, predicts clinically diagnosed AD. Individuals with a rapid change in these biomarkers may need close monitoring for the potential downward trajectory of cognition.

Evaluation of Plasma Biomarkers for A/T/N Classification of Alzheimer Disease Among Adults of Caribbean Hispanic Ethnicity.

Importance: Cerebrospinal fluid (CSF) and plasma biomarkers can detect biological evidence of Alzheimer disease (AD), but their use in low-resource environments and among minority ethnic groups is limited. Objective: To assess validated plasma biomarkers for AD among adults of Caribbean Hispanic ethnicity. Design, Setting, and Participants: In this decision analytical modeling study, adults were recruited between January 1, 2018, and April 30, 2022, and underwent detailed clinical assessments and venipuncture. A subsample of participants also consented to lumbar puncture. Established CSF cut points were used to define AD biomarker-positive status, allowing determination of optimal cut points for plasma biomarkers in the same individuals. The performance of a panel of 6 plasma biomarkers was then assessed with respect to the entire group. Data analysis was performed in January 2023. Main Outcomes and Measures: Main outcomes were the association of plasma biomarkers amyloid-ß 1-42 (Aß42), amyloid-ß 1-40 (Aß40), total tau (T-tau), phosphorylated tau181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) with AD diagnosis. These biomarkers allow assessment of amyloid (A), neurofibrillary degeneration (T), and neurodegeneration (N) aspects of AD. Statistical analyses performed included receiver operating characteristics, Pearson and Spearman correlations, t tests, and Wilcoxon rank-sum, chi-square, and Fisher exact tests. Exposures: Exposures included age, sex, education, country of residence, apolipoprotein-ε4 (APOE-ε4) allele number, serum creatinine, blood urea nitrogen, and body mass index. Results: This study included 746 adults. Participants had a mean (SD) age of 71.0 (7.8) years, 480 (64.3%) were women, and 154 (20.6%) met clinical criteria for AD. Associations were observed between CSF and plasma P-tau181 (r = .47 [95% CI, 0.32-0.60]), NfL (r = 0.57 [95% CI, 0.44-0.68]), and P-tau181/Aß42 (r = 0.44 [95% CI, 0.29-0.58]). For AD defined by CSF biomarkers, plasma P-tau181 and P-tau181/Aß42 provided biological evidence of AD. Among individuals judged to be clinically healthy without dementia, biomarker-positive status was determined by plasma P-tau181 for 133 (22.7%) and by plasma P-tau181/Aß42 for 104 (17.7%). Among individuals with clinically diagnosed AD, 69 (45.4%) had plasma P-tau181 levels and 89 (58.9%) had P-tau181/Aß42 levels that were inconsistent with AD. Individuals with biomarker-negative clinical AD status tended to have lower levels of education, were less likely to carry APOE-ε4 alleles, and had lower levels of GFAP and NfL than individuals with biomarker-positive clinical AD. Conclusions and Relevance: In this cross-sectional study, plasma P-tau181 and P-tau181/Aß42 measurements correctly classified Caribbean Hispanic individuals with and without AD. However, plasma biomarkers identified individuals without dementia with biological evidence of AD, and a portion of those with dementia whose AD biomarker profile was negative. These results suggest that plasma biomarkers can augment detection of preclinical AD among asymptomatic individuals and improve the specificity of AD diagnosis.

Semantic analysis does not occur in the absence of awareness induced by interocular suppression.

It has been intensely debated whether visual stimuli are processed to the point of semantic analysis in the absence of awareness. In the present study, we measured the extent to which the meaning of a stimulus was registered using the N400 component of human event-related potentials (ERPs), a highly sensitive index of the semantic mismatch between a stimulus and the context in which it is presented. Observers judged the semantic relatedness of a context and target word while ERPs were recorded under continuous flash suppression (Experiments 1 and 2) and binocular rivalry (Experiment 3). Finally, we parametrically manipulated the visibility of the target word by increasing the contrast between the target word and the suppressive stimulus presented to the other eye (Experiment 4). We found that the amplitude of the N400 was attenuated with increasing suppression depth and was absent whenever the observers could not discriminate the meaning of suppressed words. We discuss these findings in the context of single-process models of consciousness, which can account for a large body of empirical evidence obtained from visual masking, attentional manipulations, and, now, interocular suppression paradigms.

Event-related potentials elicited by errors during the stop-signal task. II: human effector-specific error responses.

Although previous research with human and nonhuman primates has examined the neural correlates of performance monitoring, discrepancies in methodology have limited our ability to make cross-species generalizations. One major obstacle arises from the use of different behavioral responses and tasks across different primate species. Specifically, it is unknown whether performance-monitoring mechanisms rely on different neural circuitry in tasks requiring oculomotor vs. skeletomotor responses. Here, we show that the human error-related negativity (ERN) elicited by a saccadic eye-movement response relative to a manual response differs in several critical ways. The human saccadic ERN exhibits a prolonged duration, a broader frontomedial voltage distribution, and different neural source estimates than the manual ERN in exactly the same stop-signal task. The human saccadic error positivity (Pe) exhibited a frontomedial voltage distribution with estimated electrical sources in supplementary motor area and rostral anterior cingulate cortex for saccadic responses, whereas the manual Pe showed a posterior scalp distribution and potential origins in the superior parietal lobule. These findings constrain models of the cognitive mechanisms indexed by the ERN/Pe complex. Moreover, by paralleling work with nonhuman primates performing the same saccadic stop-signal task (Godlove et al. 2011), we demonstrate a cross-species homology of error event-related potentials (ERPs) and lay the groundwork for definitively localizing the neural sources of performance-monitoring ERPs.

Blood-Based Biomarkers for Alzheimer's Disease in Older Adults with Posttraumatic Stress Disorder.

Background: Posttraumatic stress disorder (PTSD) is associated with cognitive decline and risk for dementia, but the neuropathology involved is unclear. Objective: The aim of this study was to determine whether PTSD is associated with increased levels of Alzheimer's disease (AD) blood-based biomarkers. Methods: Individuals aged 50 years and older with PTSD were compared to trauma-exposed healthy controls (TEHCs) at baseline on serum measures of amyloid-ß (Aß) 42 and 40 levels, the Aß 42/Aß 40 ratio, and total tau. Serum was analyzed using ultrasensitive Simoa Human Neurology 3-Plex A assay (N3PA). Linear regressions modeling each AD biomarker as a function of group were used to investigate between-group differences, controlling for age, sex, and educational attainment (years). Results: TEHC participants (N = 26) were 53.8% male with mean age 66.8±10.7, whereas PTSD participants (N = 44) were 47.7% male and aged 62.5±9.1 years. No between-group differences were noted on demographic characteristics or cognitive performance measured with the NIH Toolbox Cognition Battery. There were no significant between-group differences in serum Aß 40 (TEHC 105.8±51.6 versus PTSD 93.2±56.1, p = 0.46), Aß 42 (TEHC 8.1±4.6 versus PTSD 7.8±4.6, p = 0.63), Aß 42/Aß 40 (TEHC 0.08±0.03 versus PTSD 0.09±0.03, p = 0.27), or total tau (TEHC 0.5±0.3 versus PTSD 0.5±0.4, p = 0.77). Likewise, there were no significant interaction effects of amyloid or tau serum concentrations and PTSD group status on cognitive functioning. Conclusion: Findings from cognitive assessments and serum analyses do not support PTSD-induced neurodegeneration of the Alzheimer's type as a pathway linking PTSD to increased incidence of dementia in older adults.

Volumetric Variability of the Ventromedial Prefrontal Cortex Reflects the Propensity for Engaging in High-Stakes Gambling Behavior.

The human ventromedial prefrontal cortex (vmPFC) has been traditionally associated with decision-making under risk. Neuroimaging studies of such decision-making processes have largely focused on patients with vmPFC lesions or pathological gambling behavior, leading to a relative paucity of work focusing on the structural variability of the vmPFC in healthy individuals. To address this, we developed a decision-making task that allowed healthy players to choose to participate in either low stakes or high-stakes gambling on a trial-by-trial basis, and computed a metric that indexes the propensity for engaging in gambles with greater potential payoffs. We leveraged voxel-based morphometric analyses to examine the association between prefrontal gray matter volume and individual differences in the propensity for seeking high-risk/high-reward situations. Our analyses showed that vmPFC gray matter volume was inversely correlated with an increased tendency for engaging in high-stakes gambling. These results converge with findings from functional neuroimaging and brain lesion studies of vmPFC, and further extend them to show that normative variability in brain structure could also underpin risk-taking behavior.

Correlation of plasma and neuroimaging biomarkers in Alzheimer's disease.

Blood-based phosphorylated tau (Ptau) 181 and 217 biomarkers are sensitive and specific for Alzheimer's disease. In this racial/ethnically diverse cohort study, participants were classified as biomarker positive (Ptau+) or negative (Ptau-) based on Ptau 181 and 217 concentrations and as cognitively impaired (Sym) or unimpaired (Asym). The four groups, Ptau-/Asym, Ptau+/Asym, Ptau-/Sym, and Ptau+/Sym, differed by age, APOE-4 allele frequency, total tau, neurofilament light chain, and cortical thickness measured by MRI. Our results add to increasing evidence that plasma Ptau 181 and 217 concentrations are valid Alzheimer's disease biomarkers in diverse populations.