Music training is related to late ERP modulation and enhanced performance during Simon task but not Stroop task.

Increasing evidence suggests that music training correlates with better performance in tasks measuring executive function components including inhibitory control, working memory and selective attention. The Stroop and Simon tasks measure responses to congruent and incongruent information reflecting cognitive conflict resolution. However, there are more reports of a music-training advantage in the Simon than the Stroop task. Reports indicate that these tasks may differ in the timing of conflict resolution: the Stroop task might involve early sensory stage conflict resolution, while the Simon task may do so at a later motor output planning stage. We hypothesize that musical experience relates to conflict resolution at the late motor output stage rather than the early sensory stage. Behavioral responses, and event-related potentials (ERP) were measured in participants with varying musical experience during these tasks. It was hypothesized that musical experience correlates with better performance in the Simon but not the Stroop task, reflected in ERP components in the later stage of motor output processing in the Simon task. Participants were classified into high- and low-music training groups based on the Goldsmith Musical Sophistication Index. Electrical brain activity was recorded while they completed visual Stroop and Simon tasks. The high-music training group outperformed the low-music training group on the Simon, but not the Stroop task. Mean amplitude difference (incongruent-congruent trials) was greater for the high-music training group at N100 for midline central (Cz) and posterior (Pz) sites in the Simon task and midline central (Cz) and frontal (Fz) sites in the Stroop task, and at N450 at Cz and Pz in the Simon task. N450 difference peaks occurred earlier in the high-music training group at Pz. Differences between the groups at N100 indicate that music training may be related to better sensory discrimination. These differences were not related to better behavioral performance. Differences in N450 responses between the groups, particularly in regions encompassing the motor and parietal cortices, suggest a role of music training in action selection during response conflict situations. Overall, this supports the hypothesis that music training selectively enhances cognitive conflict resolution during late motor output planning stages.

CO2 cerebrovascular reactivity measured with CBF-MRI in older individuals: Association with cognition, physical function, amyloid, and tau proteins.

Vascular pathology is the second leading cause of cognitive impairment and represents a major contributing factor in mixed dementia. However, biomarkers for vascular cognitive impairment and dementia (VCID) are under-developed. Here we aimed to investigate the potential role of CO2 Cerebrovascular Reactivity (CVR) measured with phase-contrast quantitative flow MRI in cognitive impairment and dementia. Forty-five (69 ± 7 years) impaired (37 mild-cognitive-impairment and 8 mild-dementia by syndromic diagnosis) and 22 cognitively-healthy-control (HC) participants were recruited and scanned on a 3 T MRI. Biomarkers of AD pathology were measured in cerebrospinal fluid. We found that CBF-CVR was lower (p = 0.027) in the impaired (mean±SE, 3.70 ± 0.15%/mmHg) relative to HC (4.28 ± 0.21%/mmHg). After adjusting for AD pathological markers (Aß42/40, total tau, and Aß42/p-tau181), higher CBF-CVR was associated with better cognitive performance, including Montreal Cognitive Assessment, MoCA (p = 0.001), composite cognitive score (p = 0.047), and language (p = 0.004). Higher CBF-CVR was also associated with better physical function, including gait-speed (p = 0.006) and time for five chair-stands (p = 0.049). CBF-CVR was additionally related to the Clinical-Dementia-Rating, CDR, including global CDR (p = 0.026) and CDR Sum-of-Boxes (p = 0.015). CBF-CVR was inversely associated with hemoglobin A1C level (p = 0.017). In summary, CBF-CVR measured with phase-contrast MRI shows associations with cognitive performance, physical function, and disease-severity, independent of AD pathological markers.

Widespread theta coherence during spatial cognitive control.

Cognitive control allows humans to process relevant sensory information while minimizing distractions from irrelevant stimuli. The neural basis of cognitive control is known to involve frontal regions of the brain such as the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC), but the temporal dynamics of larger scale networks is unclear. Here we used EEG with source localization to identify how the neural oscillations localized to the mPFC and ACC coordinate with parietal, sensory, and motor areas during spatial cognitive control. Theta coherence (3-8 Hz) between the mPFC and ACC increased with task difficulty and predicted individual differences in reaction time. Individual differences in accuracy were predicted by earlier activation of ACC-motor coherence, highlighting the relationship between processing speed and task performance. Our results provide evidence that successful cognitive control requires dynamic coordination between a widespread network of brain regions. Long range theta coherence may be a key mechanism for efficient cognitive control across the neocortex.

Blood-Brain Barrier Breakdown in Relationship to Alzheimer and Vascular Disease.

OBJECTIVE: Blood-brain barrier (BBB) breakdown has been suggested to be an early biomarker in human cognitive impairment. However, the relationship between BBB breakdown and brain pathology, most commonly Alzheimer disease (AD) and vascular disease, is still poorly understood. The present study measured human BBB function in mild cognitive impairment (MCI) patients on 2 molecular scales, specifically BBB's permeability to water and albumin molecules. METHODS: Fifty-five elderly participants were enrolled, including 33 MCI patients and 22 controls. BBB permeability to water was measured with a new magnetic resonance imaging technique, water extraction with phase contrast arterial spin tagging. BBB permeability to albumin was determined using cerebrospinal fluid (CSF)/serum albumin ratio. Cognitive performance was assessed by domain-specific composite scores. AD pathology (including CSF Aß and ptau) and vascular risk factors were examined. RESULTS: Compared to cognitively normal subjects, BBB in MCI patients manifested an increased permeability to small molecules such as water but was no more permeable to large molecules such as albumin. BBB permeability to water was found to be related to AD markers of CSF Aß and ptau. On the other hand, BBB permeability to albumin was found to be related to vascular risk factors, especially hypercholesterolemia, but was not related to AD pathology. BBB permeability to small molecules, but not to large molecules, was found to be predictive of cognitive function. INTERPRETATION: These findings provide early evidence that BBB breakdown is related to both AD and vascular risks, but their effects can be differentiated by spatial scales. BBB permeability to small molecules has a greater impact on cognitive performance. ANN NEUROL 2021;90:227-238.

MarkVCID cerebral small vessel consortium: I. Enrollment, clinical, fluid protocols.

The concept of vascular contributions to cognitive impairment and dementia (VCID) derives from more than two decades of research indicating that (1) most older individuals with cognitive impairment have post mortem evidence of multiple contributing pathologies and (2) along with the preeminent role of Alzheimer's disease (AD) pathology, cerebrovascular disease accounts for a substantial proportion of this contribution. Contributing cerebrovascular processes include both overt strokes caused by etiologies such as large vessel occlusion, cardioembolism, and embolic infarcts of unknown source, and frequently asymptomatic brain injuries caused by diseases of the small cerebral vessels. Cerebral small vessel diseases such as arteriolosclerosis and cerebral amyloid angiopathy, when present at moderate or greater pathologic severity, are independently associated with worse cognitive performance and greater likelihood of dementia, particularly in combination with AD and other neurodegenerative pathologies. Based on this evidence, the US National Alzheimer's Project Act explicitly authorized accelerated research in vascular and mixed dementia along with frontotemporal and Lewy body dementia and AD itself. Biomarker development has been consistently identified as a key step toward translating scientific advances in VCID into effective prevention and treatment strategies. Validated biomarkers can serve a range of purposes in trials of candidate interventions, including (1) identifying individuals at increased VCID risk, (2) diagnosing the presence of cerebral small vessel disease or specific small vessel pathologies, (3) stratifying study participants according to their prognosis for VCID progression or treatment response, (4) demonstrating an intervention's target engagement or pharmacodynamic mechanism of action, and (5) monitoring disease progression during treatment. Effective biomarkers allow academic and industry investigators to advance promising interventions at early stages of development and discard interventions with low success likelihood. The MarkVCID consortium was formed in 2016 with the goal of developing and validating fluid- and imaging-based biomarkers for the cerebral small vessel diseases associated with VCID. MarkVCID consists of seven project sites and a central coordinating center, working with the National Institute of Neurologic Diseases and Stroke and National Institute on Aging under cooperative agreements. Through an internal selection process, MarkVCID has identified a panel of 11 candidate biomarker "kits" (consisting of the biomarker measure and the clinical and cognitive data used to validate it) and established a range of harmonized procedures and protocols for participant enrollment, clinical and cognitive evaluation, collection and handling of fluid samples, acquisition of neuroimaging studies, and biomarker validation. The overarching goal of these protocols is to generate rigorous validating data that could be used by investigators throughout the research community in selecting and applying biomarkers to multi-site VCID trials. Key features of MarkVCID participant enrollment, clinical/cognitive testing, and fluid biomarker procedures are summarized here, with full details in the following text, tables, and supplemental material, and a description of the MarkVCID imaging biomarker procedures in a companion paper, "MarkVCID Cerebral small vessel consortium: II. Neuroimaging protocols." The procedures described here address a range of challenges in MarkVCID's design, notably: (1) acquiring all data under informed consent and enrollment procedures that allow unlimited sharing and open-ended analyses without compromising participant privacy rights; (2) acquiring the data in a sufficiently wide range of study participants to allow assessment of candidate biomarkers across the various patient groups who might ultimately be targeted in VCID clinical trials; (3) defining a common dataset of clinical and cognitive elements that contains all the key outcome markers and covariates for VCID studies and is realistically obtainable during a practical study visit; (4) instituting best fluid-handling practices for minimizing avoidable sources of variability; and (5) establishing rigorous procedures for testing the reliability of candidate fluid-based biomarkers across replicates, assay runs, sites, and time intervals (collectively defined as the biomarker's instrumental validity). Participant Enrollment Project sites enroll diverse study cohorts using site-specific inclusion and exclusion criteria so as to provide generalizable validation data across a range of cognitive statuses, risk factor profiles, small vessel disease severities, and racial/ethnic characteristics representative of the diverse patient groups that might be enrolled in a future VCID trial. MarkVCID project sites include both prospectively enrolling centers and centers providing extant data and samples from preexisting community- and population-based studies. With approval of local institutional review boards, all sites incorporate MarkVCID consensus language into their study documents and informed consent agreements. The consensus language asks prospectively enrolled participants to consent to unrestricted access to their data and samples for research analysis within and outside MarkVCID. The data are transferred and stored as a de-identified dataset as defined by the Health Insurance Portability and Accountability Act Privacy Rule. Similar human subject protection and informed consent language serve as the basis for MarkVCID Research Agreements that act as contracts and data/biospecimen sharing agreements across the consortium. Clinical and Cognitive Data Clinical and cognitive data are collected across prospectively enrolling project sites using common MarkVCID instruments. The clinical data elements are modified from study protocols already in use such as the Alzheimer's Disease Center program Uniform Data Set Version 3 (UDS3), with additional focus on VCID-related items such as prior stroke and cardiovascular disease, vascular risk factors, focal neurologic findings, and blood testing for vascular risk markers and kidney function including hemoglobin A1c, cholesterol subtypes, triglycerides, and creatinine. Cognitive assessments and rating instruments include the Clinical Dementia Rating Scale, Geriatric Depression Scale, and most of the UDS3 neuropsychological battery. The cognitive testing requires ≈60 to 90 minutes. Study staff at the prospectively recruiting sites undergo formalized training in all measures and review of their first three UDS3 administrations by the coordinating center. Collection and Handling of Fluid Samples Fluid sample types collected for MarkVCID biomarker kits are serum, ethylenediaminetetraacetic acid-plasma, platelet-poor plasma, and cerebrospinal fluid (CSF) with additional collection of packed cells to allow future DNA extraction and analyses. MarkVCID fluid guidelines to minimize variability include fasting morning fluid collections, rapid processing, standardized handling and storage, and avoidance of CSF contact with polystyrene. Instrumental Validation for Fluid-Based Biomarkers Instrumental validation of MarkVCID fluid-based biomarkers is operationally defined as determination of intra-plate and inter-plate repeatability, inter-site reproducibility, and test-retest repeatability. MarkVCID study participants both with and without advanced small vessel disease are selected for these determinations to assess instrumental validity across the full biomarker assay range. Intra- and inter-plate repeatability is determined by repeat assays of single split fluid samples performed at individual sites. Inter-site reproducibility is determined by assays of split samples distributed to multiple sites. Test-retest repeatability is determined by assay of three samples acquired from the same individual, collected at least 5 days apart over a 30-day period and assayed on a single plate. The MarkVCID protocols are designed to allow direct translation of the biomarker validation results to multicenter trials. They also provide a template for outside groups to perform analyses using identical methods and therefore allow direct comparison of results across studies and centers. All MarkVCID protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the MarkVCID kits will undergo biological validation to determine whether the candidate biomarker measures important aspects of VCID such as cognitive function. Analytic methods and results of these validation studies for the 11 MarkVCID biomarker kits will be published separately. The results of this rigorous validation process will ultimately determine each kit's potential usefulness for multicenter interventional trials aimed at preventing or treating small vessel disease related VCID.

Association of cerebrovascular reactivity and Alzheimer pathologic markers with cognitive performance.

OBJECTIVE: To determine whether MRI-based cerebrovascular reactivity (CVR) can predict cognitive performance independently of Alzheimer pathologic markers, we studied the relationship between cognition, CVR, and CSF-derived ß-amyloid42 (Aß42) and tau in a group of elderly individuals with mixed Alzheimer and vascular cognitive impairment and dementia. METHODS: This was a cross-sectional study of 72 participants 69 ± 8 years of age consisting of individuals with normal cognition (n = 28) and cognitive impairment (n = 44) (including 36 with mild cognitive impairment [MCI] and 8 with mild dementia). CVR was measured with hypercapnia-MRI. Whole-brain CVR (percent blood oxygen level-dependent per 1 mm Hg Etco2) was used to estimate vasodilatory capacity. Montreal Cognitive Assessment (MoCA) scores, cognitive domains scores, and a global composite cognitive score were obtained. AD biomarkers included CSF assays of Aß42 and tau. RESULTS: Whole-brain CVR was lower in the impaired (mean ± SE, 0.132 ± 0.006%/mm Hg) compared to the normal (0.151 ± 0.007%/mm Hg) group (ß = -0.02%/mm Hg; 95% confidence interval [CI] -0.038 to -0.001). After adjustment for CSF Aß42 and tau, higher whole-brain CVR was associated with better performance on the MoCA (ß = 29.64, 95% CI 9.94-49.34) and with a global composite cognitive score (ß = 4.32, 95% CI 0.05-8.58). When the CVR marker was compared with the Fazekas score based on white matter hyperintensities and vascular risk-score in a single regression model predicting the MoCA score, only CVR revealed a significant effect (ß = 28.09, 95% CI 6.14-50.04), while the other 2 measures were not significant. CONCLUSIONS: CVR was significantly associated with cognitive performance independently of AD pathology. Whole-brain CVR may be a useful biomarker for evaluating cognitive impairment related to vascular disease in older individuals. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CVR was significantly associated with cognitive performance independent of AD pathology.

Brain Oxygen Extraction Is Differentially Altered by Alzheimer's and Vascular Diseases.

BACKGROUND: Alzheimer's disease and vascular cognitive impairment (VCI), as well as their concurrence, represent the most common types of cognitive dysfunction. Treatment strategies for these two conditions are quite different; however, there exists a considerable overlap in their clinical manifestations, and most biomarkers reveal similar abnormalities between these two conditions. PURPOSE: To evaluate the potential of cerebral oxygen extraction fraction (OEF) as a biomarker for differential diagnosis of Alzheimer's disease and VCI. We hypothesized that in Alzheimer's disease OEF will be reduced (decreased oxygen consumption due to decreased neural activity), while in vascular diseases OEF will be elevated (increased oxygen extraction due to abnormally decreased blood flow). STUDY TYPE: Prospective cross-sectional. POPULATION: Sixty-five subjects aged 52-89 years, including 33 mild cognitive impairment (MCI), 7 dementia, and 25 cognitively normal subjects. FIELD STRENGTH/SEQUENCE: 3T T2 -relaxation-under-spin-tagging (TRUST) and fluid-attenuated inversion recovery imaging (FLAIR). ASSESSMENT: OEF, consensus diagnoses of cognitive impairment, vascular risk factors (such as hypertension, hypercholesterolemia, diabetes, smoking, and obesity), cognitive assessments, and cerebrospinal fluid concentration of amyloid and tau were assessed. STATISTICAL TESTS: Multiple linear regression analyses of OEF with diagnostic category (normal, MCI, or dementia), vascular risks, cognitive performance, amyloid and tau pathology. RESULTS: When evaluating the entire group, OEF was found to be lower with more severe cognitive impairment (ß = -2.70 ± 1.15, T = -2.34, P = 0.02), but was higher with greater vascular risk factors (ß = 1.36 ± 0.55, T = 2.48, P = 0.02). Further investigation of the subgroup of participants with low vascular risks (N = 44) revealed that lower OEF was associated with worse cognitive performance (ß = 0.04 ± 0.01, T = 3.27, P = 0.002) and greater amyloid burden (ß = 92.12 ± 41.23, T = 2.23, P = 0.03). Among cognitively impaired individuals (N = 40), higher OEF was associated with greater vascular risk factors (ß = 2.19 ± 0.71, T = 3.08, P = 0.004). DATA CONCLUSION: These findings suggest that OEF is differentially affected by Alzheimer's disease and VCI pathology and may be useful in etiology-based diagnosis of cognitive impairment. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3 J. MAGN. RESON. IMAGING 2020;52:1829-1837.

Cerebrovascular reactivity mapping using intermittent breath modulation.

Cerebrovascular reactivity (CVR), an index of brain vessel's dilatory capacity, is typically measured using hypercapnic gas inhalation or breath-holding as a vasoactive challenge. However, these methods require considerable subject cooperation and could be challenging in clinical studies. More recently, there have been attempts to use resting-state BOLD data to map CVR by utilizing spontaneous changes in breathing pattern. However, in subjects who have small fluctuations in their spontaneous breathing pattern, the CVR results could be noisy and unreliable. In this study, we aim to develop a new method for CVR mapping that does not require gas-inhalation yet provides substantially higher sensitivity than resting-state CVR mapping. This new method is largely based on resting-state scan, but introduces intermittent modulation of breathing pattern in the subject to enhance fluctuations in their end-tidal CO2 (EtCO2) level. Here we examined the comfort level, sensitivity, and accuracy of this method in two studies. First, in 8 healthy young subjects, we developed the intermittent breath-modulation method using two different modulation frequencies, 6 â€‹s per breath and 12 â€‹s per breath, respectively, and compared the results to three existing CVR methods, specifically hypercapnic gas inhalation, breath-holding, and resting-state. Our results showed that the comfort level of the 6-s breath-modulation method was significantly higher than breath-holding (p â€‹= â€‹0.007) and CO2-inhalation (p â€‹= â€‹0.015) methods, while not different from the resting-state, i.e. free breathing method (p â€‹= â€‹0.52). When comparing the sensitivity of CVR methods, the breath-modulation methods revealed higher Z-statistics compared to the resting-state scan (p â€‹< â€‹0.008) and was comparable to breath-holding results. Next, we tested the feasibility of breath-modulation CVR mapping (6 â€‹s per breath) in 21 cognitively normal elderly participants and compared quantitative CVR values to that obtained with the CO2-inhalation method. Whole-brain CVR was found to be 0.150 â€‹± â€‹0.055 and 0.154 â€‹± â€‹0.032 %ΔBOLD/mmHg for the breath-modulation and CO2-inhalation method, respectively, with a significant correlation between them (y â€‹= â€‹0.97x, p â€‹= â€‹0.007). CVR mapping with intermittent breath modulation may be a useful method that combines the advantages of resting-state and CO2-inhalation based approaches.

Neural correlates of auditory sensory memory dynamics in the aging brain.

The auditory system allows us to monitor background environmental sound patterns and recognize deviations that may indicate opportunities or threats. The mismatch negativity and P3a potentials have generators in the auditory and inferior frontal cortex and index expected sound patterns (standards) and any aberrations (deviants). The mismatch negativity and P3a waveforms show increased positivity for consecutive standards and deviants preceded by more standards. We hypothesized attenuated repetition effects in older participants, potentially because of differences in prefrontal functions. Young (23 ± 5 years) and older (75 ± 5 years) adults were tested in 2 oddball paradigms with pitch or location deviants. Significant repetition effects were observed in the young standard and deviant waveforms at multiple time windows. Except the earliest time window (30-100 ms), repetition effects were absent in the older group. Repetition effects were significant at frontal but not temporal lobe sites and did not differ among pitch and location deviants. However, P3a repetition was evident in both ages. Findings suggest age differences in the dynamic updating of sensory memory for background sound patterns.

Normal variations in brain oxygen extraction fraction are partly attributed to differences in end-tidal CO2.

Cerebral oxygen extraction fraction is an important physiological index of the brain's oxygen consumption and supply and has been suggested to be a potential biomarker for a number of diseases such as stroke, Alzheimer's disease, multiple sclerosis, sickle cell disease, and metabolic disorders. However, in order for oxygen extraction fraction to be a sensitive biomarker for personalized disease diagnosis, inter-subject variations in normal subjects must be minimized or accounted for, which will otherwise obscure its interpretation. Therefore, it is essential to investigate the physiological underpinnings of normal differences in oxygen extraction fraction. This work used two studies, one discovery study and one verification study, to examine the extent to which an individual's end-tidal CO2 can explain variations in oxygen extraction fraction. It was found that, across normal subjects, oxygen extraction fraction is inversely correlated with end-tidal CO2. Approximately 50% of the inter-subject variations in oxygen extraction fraction can be attributed to end-tidal CO2 differences. In addition, oxygen extraction fraction was found to be positively associated with age and systolic blood pressure. By accounting for end-tidal CO2, age, and systolic blood pressure of the subjects, normal variations in oxygen extraction fraction can be reduced by 73%, which is expected to substantially enhance the utility of oxygen extraction fraction as a disease biomarker.

The association between BOLD-based cerebrovascular reactivity (CVR) and end-tidal CO2 in healthy subjects.

Cerebrovascular reactivity (CVR) mapping using CO2-inhalation can provide important insight into vascular health. At present, blood-oxygenation-level-dependent (BOLD) MRI acquisition is the most commonly used CVR method due to its high sensitivity, high spatial resolution, and relatively straightforward processing. However, large variations in CVR across subjects and across different sessions of the same subject are often observed, which can cloud the ability of this promising measure in detecting diseases or monitoring treatment responses. The present work aims to identify the physiological components underlying the observed variability in CVR data. When studying the association between CVR value and the subject's CO2 levels in a total of N = 253 healthy participants, we found that CVR was lower in individuals with a higher basal end-tidal CO2, EtCO2 (slope = -0.0036 ±â€¯0.0008%/mmHg2, p < 0.001), or with a greater EtCO2 change (ΔEtCO2) with hypercapnic condition (slope = -0.0072 ±â€¯0.0018%/mmHg2, p < 0.001). In a within-subject setting, when studying the CVR difference between two repeated scans (with repositioning) in relation to the corresponding differences in basal EtCO2 and ΔEtCO2 (n = 11), it was found that CVR values were lower if the basal EtCO2 or ΔEtCO2 during that particular scan session was greater. The present work suggests that basal physiological state and the level of hypercapnic stimulus intensity should be considered in application studies of CVR in order to reduce inter-subject and intra-subject variations in the data. Potential approaches to use these findings to reduce noise and augment sensitivity are proposed.

Brain Oxygen Extraction by Using MRI in Older Individuals: Relationship to Apolipoprotein E Genotype and Amyloid Burden.

Background Apolipoprotein E4 (APOE4) is a major genetic risk factor for late-onset Alzheimer disease. However, the mechanisms by which APOE4 affects the brain, underpinning this risk, have not been fully elucidated. Purpose To investigate the influence of APOE4 on global cerebral oxygen extraction fraction (OEF) and possible mediation through amyloid burden by using MRI-based brain oxygen extraction technique. Materials and Methods Participants were enrolled from a longitudinal prospective study, the Biomarkers for Older Controls at Risk for Dementia study (data collected from January 2015 to December 2017), of whom 35% (50 of 143 participants) were APOE4 carriers. OEF was measured by using a T2-relaxation-under-spin-tagging MRI technique with a 3.0-T MRI system. PET acquired with carbon 11-labeled Pittsburgh compound B tracer was available in 119 participants to measure amyloid burden. Cognitive performance was assessed by using domain-specific composite scores including executive function, episodic memory, visual-spatial processing, and language. Linear regression analysis was performed to investigate the relationship between APOE4, OEF, and amyloid burden. The association between OEF and cognitive function was studied for the entire study cohort and separately for the APOE4 carriers and noncarriers. Results A total of 143 cognitively healthy individuals (mean age 6 standard deviation, 69.1 years 6 8.2; 57 men and 86 women) were studied. APOE4 genetic status was associated with lower OEF (noncarriers, 41.1% 6 5.8; one E4 allele, 40.1% 6 4.9; two E4 alleles, 36.7% 6 4.5; P = .03). Furthermore, among APOE4 carriers, lower OEF correlated with lower executive function scores (b = 0.079 z score for each percent change in OEF; P = .03). Amyloid burden and OEF were independently associated with APOE4 but were not associated with one another, suggesting that the effect of APOE4 on OEF is not mediated by amyloid. Conclusion MRI-based brain oxygen extraction shows that cognitively healthy carriers of the apolipoprotein E4 gene manifest diminished brain oxygen extraction capacity independent of amyloid burden. ©RSNA, 2019 Online supplemental material is available for this article.

Arterial-spin-labeling (ASL) perfusion MRI predicts cognitive function in elderly individuals: A 4-year longitudinal study.

BACKGROUND: With the disappointing outcomes of clinical trials on patients with Alzheimer's disease or mild cognitive impairment (MCI), there is increasing attention to understanding cognitive decline in normal elderly individuals, with the goal of identifying subjects who are most susceptible to imminent cognitive impairment. PURPOSE/HYPOTHESIS: To evaluate the potential of cerebral blood flow (CBF) as a biomarker by investigating the relationship between CBF at baseline and cognition at follow-up. STUDY TYPE: Prospective longitudinal study with a 4-year time interval. POPULATION: 309 healthy subjects aged 20-89 years old. FIELD STRENGTH/SEQUENCE: 3T pseudo-continuous-arterial-spin-labeling MRI. ASSESSMENT: CBF at baseline and cognitive assessment at both baseline and follow-up. STATISTICAL TESTS: Linear regression analyses with age, systolic blood pressure, physical activity, and baseline cognition as covariates. RESULTS: Linear regression analyses revealed that whole-brain CBF at baseline was predictive of general fluid cognition at follow-up. This effect was observed in the older group (age ≥54 years, ß = 0.221, P = 0.004), but not in younger or entire sample (ß = 0.018, P = 0.867 and ß = 0.089, P = 0.098, respectively). Among major brain lobes, frontal CBF had the highest sensitivity in predicting future cognition, with a significant effect observed for fluid cognition (ß = 0.244 P = 0.001), episodic memory (ß = 0.294, P = 0.001), and reasoning (ß = 0.186, P = 0.027). These associations remained significant after accounting for baseline cognition. Voxelwise analysis revealed that medial frontal cortex and anterior cingulate cortex, part of the default mode network (DMN), are among the most important regions in predicting fluid cognition. DATA CONCLUSION: In a healthy aging cohort, CBF can predict general cognitive ability as well as specific domains of cognitive function. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. MAGN. RESON. IMAGING 2018;48:449-458.

Anosognosia for hemiplegia: The contributory role of right inferior frontal gyrus.

OBJECTIVE: Awareness of motor functioning is most likely a complex process that requires integration of sensory-motor feedback to constantly update the system on the functioning of the limb during motor behavior. Using lesion mapping procedures and behavioral measures, the current study aimed to evaluate neural correlates of anosognosia for hemiplegia (AHP) in the acute stage (first 48 hr) of right hemisphere stroke. METHOD: Thirty-five individuals with right hemisphere stroke who presented to an urban medical center within 24 hr of symptom onset were included in the study. All 35 individuals had hemiplegia, and 8 of these individuals exhibited AHP. RESULTS: Fisher's exact test statistical map of lesion-deficit association (range is between-log(p) 4 to 11) found maximal value of 10.9 located in pars orbitalis (Brodmann's Area 47; BA). In this selected location, 6 out of 8 patients with AHP had tissue abnormality, whereas none of the unaffected subjects had tissue abnormality in BA 47. Right BA 44/45 was also found to be lesioned more frequently in individuals with AHP (75%) than without AHP (11%). CONCLUSIONS: The current study findings provide preliminary support for unique involvement of the right inferior frontal gyrus (IFG), pars orbitalis (BA 47) in AHP. The current data suggest that frontal operculum may play a key role in awareness of limb functioning.

Functional recovery after moderate/severe traumatic brain injury: a role for cognitive reserve?

OBJECTIVE: To evaluate the hypothesis that educational attainment, a marker of cognitive reserve, is a predictor of disability-free recovery (DFR) after moderate to severe traumatic brain injury (TBI). METHODS: Retrospective study of the TBI Model Systems Database, a prospective multicenter cohort funded by the National Institute on Disability and Rehabilitation Research. Patients were included if they were admitted for rehabilitation after moderate to severe TBI, were aged 23 years or older, and had at least 1 year of follow-up. The main outcome measure was DFR 1 year postinjury, defined as a Disability Rating Scale score of zero. RESULTS: Of 769 patients included, 214 (27.8%) achieved DFR at 1 year. In total, 185 patients (24.1%) had <12 years of education, while 390 (50.7%) and 194 patients (25.2%) had 12 to 15 years and ≥16 years of education, respectively. DFR was achieved by 18 patients (9.7%) with <12 years, 120 (30.8%) with 12 to 15 years, and 76 (39.2%) with ≥16 years of education (p < 0.001). In a logistic regression model controlling for age, sex, and injury- and rehabilitation-specific factors, duration of education of ≥12 years was independently associated with DFR (odds ratio 4.74, 95% confidence interval 2.70-8.32 for 12-15 years; odds ratio 7.24, 95% confidence interval 3.96-13.23 for ≥16 years). CONCLUSION: Educational attainment was a robust independent predictor of 1-year DFR even when adjusting for other prognostic factors. A dose-response relationship was noted, with longer educational exposure associated with increased odds of DFR. This suggests that cognitive reserve could be a factor driving neural adaptation during recovery from TBI.