Pulse pressure and APOE ε4 dose interact to affect cerebral blood flow in older adults without dementia.

This study assessed whether the effect of vascular risk on cerebral blood flow (CBF) varies by gene dose of apolipoprotein (APOE) ε4 alleles. 144 older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative underwent arterial spin labeling and T1-weighted MRI, APOE genotyping, fluorodeoxyglucose positron emission tomography (FDG-PET), lumbar puncture, and blood pressure (BP) assessment. Vascular risk was assessed using pulse pressure (systolic BP - diastolic BP). CBF was examined in six AD-vulnerable regions: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. Linear regressions tested the interaction between APOE ε4 dose and pulse pressure on CBF in each region, adjusting for age, sex, cognitive classification, antihypertensive medication use, FDG-PET, reference CBF region, and AD biomarker positivity. There was a significant interaction between pulse pressure and APOE ɛ4 dose on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex, such that higher pulse pressure was associated with lower CBF only among ε4 homozygous participants. These findings demonstrate that the association between pulse pressure and regional CBF differs by APOE ε4 dose, suggesting that targeting modifiable vascular risk factors may be particularly important for those genetically at risk for AD.

Regional White Matter Hyperintensities Relate to Specific Cognitive Abilities in Older Adults Without Dementia.

INTRODUCTION: White matter hyperintensities (WMHs) are magnetic resonance imaging markers of small vessel cerebrovascular disease that are associated with cognitive decline and clinical Alzheimer disease. Previous studies have often focused on global or total WMH; less is known about associations of regional WMHs and cognitive abilities among older adults without dementia. METHODS: A total of 610 older adults with normal cognition (n=302) or mild cognitive impairment (n=308) from the Alzheimer's Disease Neuroimaging Initiative underwent neuropsychological testing and magnetic resonance imaging. Linear regression models examined associations between regional WMH volumes and cognition, adjusting for age, sex, education, apolipoprotein E ε4 allele frequency, and pulse pressure. RESULTS: Among all participants, greater regional WMH volume in all lobes was associated with poorer performance on memory and speed/executive functioning. Among participants with normal cognition, greater temporal and occipital WMH volumes were associated with poorer memory, whereas no regional WMH volumes were associated with speed/executive function. DISCUSSION: Results show that greater regional WMH volume relates to poorer cognitive functioning-even among those with normal cognition. Together with results from previous studies, our findings raise the possibility that WMH may be a useful therapeutic target and/or important effect modifier in treatment or prevention dementia trials.

White Matter Hyperintensity Volume and Amyloid-PET Synergistically Impact Memory Independent of Tau-PET in Older Adults Without Dementia.

BACKGROUND: Alzheimer's disease (AD) and cerebrovascular disease are common, co-existing pathologies in older adults. Whether the effects of cerebrovascular disease and AD biomarkers on cognition are additive or synergistic remains unclear. OBJECTIVE: To examine whether white matter hyperintensity (WMH) volume moderates the independent association between each AD biomarker and cognition. METHODS: In 586 older adults without dementia, linear regressions tested the interaction between amyloid-ß (Aß) positron emission tomography (PET) and WMH volume on cognition, independent of tau-PET. We also tested the interaction between tau-PET and WMH volume on cognition, independent of Aß-PET. RESULTS: Adjusting for tau-PET, the quadratic effect of WMH interacted with Aß-PET to impact memory. There was no interaction between either the linear or quadratic effect of WMH and Aß-PET on executive function. There was no interaction between WMH volume and tau-PET on either cognitive measure. CONCLUSION: Results suggest that cerebrovascular lesions act synergistically with Aß to affect memory, independent of tau, highlighting the importance of incorporating vascular pathology into biomarker assessment of AD.

Cognitive reserve moderates the association between cerebral blood flow and language performance in older adults with mild cognitive impairment.

Higher cognitive reserve (CR) may offer protection from cognitive changes associated with reduced cerebral blood flow (CBF). We investigated CR as a moderator of the effect of CBF on cognition in older adults with mild cognitive impairment (MCI; N = 46) and those who are cognitively unimpaired (CU; N = 101). Participants underwent arterial spin labeling MRI, which was used to quantify CBF in 4 a priori regions. Estimated verbal intelligence quotient (VIQ) served as a proxy for CR. Multiple linear regressions examined whether VIQ moderated associations between CBF and cognition and whether this differed by cognitive status. Outcomes included memory and language performance. There were 3-way interactions (CBF*VIQ*cognitive status) on category fluency when examining hippocampal, superior frontal, and inferior frontal CBF. Follow-up analyses revealed that, within the MCI but not CU group, there were CBF*VIQ interactions on fluency in all a priori regions examined, where there were stronger, positive associations between CBF and fluency at higher VIQ. Conclusion: In MCI, higher CR plays a role in strengthening CBF-fluency associations.

Brain Derived Neurotrophic Factor Interacts with White Matter Hyperintensities to Influence Processing Speed and Hippocampal Volume in Older Adults.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in regulating synaptic activity and plasticity. OBJECTIVE: Given that type-2 diabetes (T2DM) increases the risk of cognitive decline, and studies have suggested lower BDNF levels may be a risk factor of diabetic neurovascular complications, we sought to investigate total white matter hyperintensities (WMH) as a moderator of the effect of BDNF on hippocampal volume and cognition. METHODS: Older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative (N = 454 including 49 with T2DM and 405 without diabetes) underwent neuropsychological evaluation, magnetic resonance imaging to quantify hippocampal and WMH volumes, and blood draw to assess BDNF. RESULTS: Adjusting for age, sex, and APOE ɛ4 carrier status, there was a significant interaction between total WMH and BDNF on bilateral hippocampal volume in the non-T2DM group (t = 2.63, p = 0.009). Examination of main effect models with a dichotomous high/low BNDF group revealed a significant main effect for low BDNF (t = -4.98, p < 0.001), such that as WMH increased, bilateral hippocampal volume decreased. There was also a significant interaction between total WMH and BDNF on processing speed in the non-T2DM group (t = 2.91, p = 0.004). There was a significant main effect for low BDNF (t = -3.55, p < 0.001) such that as WMH increased, processing speed decreased. The interactions were not significant in the T2DM group. CONCLUSION: These results further elucidate the protective role that BDNF plays on cognition, as well as the cognitive effects of WMH.

Greater accelerometer-measured physical activity is associated with better cognition and cerebrovascular health in older adults.

OBJECTIVES: Physical activity (PA) may help maintain brain structure and function in aging. Since the intensity of PA needed to effect cognition and cerebrovascular health remains unknown, we examined associations between PA and cognition, regional white matter hyperintensities (WMH), and regional cerebral blood flow (CBF) in older adults. METHOD: Forty-three older adults without cognitive impairment underwent magnetic resonance imaging (MRI) and comprehensive neuropsychological assessment. Waist-worn accelerometers objectively measured PA for approximately one week. RESULTS: Higher time spent in moderate to vigorous PA (MVPA) was uniquely associated with better memory and executive functioning after adjusting for all light PA. Higher MVPA was also uniquely associated with lower frontal WMH volume although the finding was no longer significant after additionally adjusting for age and accelerometer wear time. MVPA was not associated with CBF. Higher time spent in all light PA was uniquely associated with higher CBF but not with cognitive performance or WMH volume. CONCLUSIONS: Engaging in PA may be beneficial for cerebrovascular health, and MVPA in particular may help preserve memory and executive function in otherwise cognitively healthy older adults. There may be differential effects of engaging in lighter PA and MVPA on MRI markers of cerebrovascular health although this needs to be confirmed in future studies with larger samples. Future randomized controlled trials that increase PA are needed to elucidate cause-effect associations between PA and cerebrovascular health.

Sex moderates the association between age and myelin water fraction in the cingulum and fornix among older adults without dementia.

Background: Decreasing white matter integrity in limbic pathways including the fornix and cingulum have been reported in Alzheimer's disease (AD), although underlying mechanisms and potential sex differences remain understudied. We therefore sought to explore sex as a moderator of the effect of age on myelin water fraction (MWF), a measure of myelin content, in older adults without dementia (N = 52). Methods: Participants underwent neuropsychological evaluation and 3 T MRI at two research sites. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) quantified MWF in 3 a priori regions including the fornix, hippocampal cingulum (CgH), and cingulate cingulum (CgC). The California Verbal Learning Test-Second Edition assessed learning and delayed recall. Multiple linear regressions assessed for (1) interactions between age and sex on regional MWF and (2) associations of regional MWF and memory. Results: (1) There was a significant age by sex interaction on MWF of the fornix (p = 0.002) and CgC (p = 0.005), but not the CgH (p = 0.192); as age increased, MWF decreased in women but not men. (2) Fornix MWF was associated with both learning and recall (ps < 0.01), but MWF of the two cingulum regions were not (p > 0.05). Results were unchanged when adjusting for hippocampal volume. Conclusion: The current work adds to the literature by illuminating sex differences in age-related myelin decline using a measure sensitive to myelin and may help facilitate detection of AD risk for women.

Longitudinal Intraindividual Cognitive Variability Is Associated With Reduction in Regional Cerebral Blood Flow Among Alzheimer's Disease Biomarker-Positive Older Adults.

Intraindividual variability (IIV) across neuropsychological measures within a single testing session is a promising marker predictive of cognitive decline and development of Alzheimer's disease (AD). We have previously shown that greater IIV is cross-sectionally associated with reduced cerebral blood flow (CBF), but not with cortical thickness or brain volume, in older adults without dementia who were amyloid beta (Aß) positive. However, there is little known about the association between change in IIV and CBF over time. Therefore, we examined 12-month longitudinal change in IIV and interactions of IIV and AD biomarker status on changes in regional CBF. Fifty-three non-demented Alzheimer's Disease Neuroimaging Initiative (ADNI) participants underwent lumbar puncture to obtain cerebrospinal fluid (CSF) at baseline and neuropsychological testing and magnetic resonance imaging (MRI) exams at baseline and 12-month follow-up evaluation. IIV was calculated as the intraindividual standard deviation across 6 demographically-corrected neuropsychological measures. Pulsed arterial spin labeling (ASL) MRI was acquired to quantify CBF and FreeSurfer-derived a priori CBF regions of interest (ROIs) were examined. AD biomarker positivity was determined using a published CSF p-tau/Aß ratio cut-score. Change scores were calculated for IIV, CBF, and mean neuropsychological performance from baseline to 12 months. Hierarchical linear regression models showed that after adjusting for age and gender, there was a significant interaction between IIV change and biomarker-positivity (p-tau/Aß+) for change in entorhinal and hippocampal CBF but not for the other ROIs. Specifically, increases in IIV were associated with reductions in entorhinal and hippocampal CBF among individuals who were biomarker-positive (n = 21). In contrast, there were no significant associations between change in IIV and CBF among those who were biomarker-negative (n = 32). Findings remained similar when analyses were performed adjusting for change in mean level of neuropsychological performance. Changes in IIV may be sensitive to changes in regional hypoperfusion in AD-vulnerable regions among AD biomarker-positive individuals, above and beyond demographics and mean neuropsychological performance. These findings provide further evidence supporting IIV as a potential marker of cerebrovascular brain changes in individuals at risk for dementia.

Race and ethnicity considerations in traumatic brain injury research: Incidence, reporting, and outcome.

PRIMARY OBJECTIVE: This study has three goals: to determine whether there is a higher rate of traumatic brain injury (TBI) for people of color (POC), whether TBI studies report racial/ethnic demographics, and whether there is a discrepancy in discharge destinations between Whites and POC. We examined whether 1) a higher percentage of POC would sustain head injuries than expected, 2) the majority of TBI studies examined (>50%) would not include racial/ethnic demographics, and 3) Whites would be discharged to further treatment over POC. RESEARCH DESIGN: Retrospective study and literature review. METHODS AND PROCEDURES: Data from the Pennsylvania Trauma System Foundation was used to determine the number of POC with TBI using X2 analysis, as well as where patients with TBI were being discharged using a configural frequency analysis. PubMed was used for the literature search to examine the frequency of reporting race/ethnicity in TBI literature. MAIN OUTCOMES AND RESULTS: Results demonstrated that Blacks sustain more TBIs than would be expected (p < .05), the majority of scientific studies (78%) do not report racial/ethnic demographic information, and Whites are discharged to further care more often than POC. CONCLUSIONS: These findings highlight differences in incidence and treatment of TBI between White individuals and POC, raising important considerations for providers and researchers.

Enhanced default mode connectivity predicts metacognitive accuracy in traumatic brain injury.

OBJECTIVE: To examine the role that intrinsic functional networks, specifically the default mode network, have on metacognitive accuracy for individuals with moderate to severe traumatic brain injury (TBI). METHOD: A sample of 44 individuals (TBI, n = 21; healthy controls [HCs], n = 23) were included in the study. All participants underwent an MRI scan and completed neuropsychological testing. Metacognitive accuracy was defined as participants' ability to correctly judge their item-by-item performance on an abstract reasoning task. Metacognitive values were calculated using the signal detection theory approach of area under the receiver operating characteristic curve. Large-scale subnetworks were created using Power's 264 Functional Atlas. The graph theory metric of network strength was calculated for six subsystem networks to measure functional connectivity. RESULTS: There were significant interactions between head injury status (TBI or HC) and internetwork connectivity between the anterior default mode network (DMN) and salience network on metacognitive accuracy (R2 = 0.13, p = .047) and between the posterior DMN and salience network on metacognitive accuracy (R2 = 0.15, p = .038). There was an interpretable interaction between head injury status and internetwork connectivity between the attention network and salience network on metacognitive accuracy (R2 = 0.13, p = .067). In all interactions, higher connectivity predicted better metacognitive accuracy in the TBI group, but this relationship was reversed for the HC group. CONCLUSION: Enhanced connectivity to both anterior and posterior regions within the DMN facilitates metacognitive accuracy postinjury. These findings are integrated into a larger literature examining network plasticity in TBI. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Prefrontal gray matter volume predicts metacognitive accuracy following traumatic brain injury.

OBJECTIVE: To examine metacognitive ability (MC) following moderate to severe traumatic brain injury (TBI) using an empirical assessment approach and to determine the relationship between alterations in gray matter volume (GMV) and MC. METHOD: A sample of 62 individuals (TBI n = 34; healthy control [HC] n = 28) were included in the study. Neuroimaging and neuropsychological data were collected for all participants during the same visit. MC was quantified using an approach borrowed from signal detection theory (Type II area under the receiver operating characteristic curve calculation) to evaluate judgments during a modified version of the 3rd edition of the Wechsler Adult Intelligence Scale's Matrix Reasoning subtest where half of the items were presented randomly and half were presented in the order of increasing difficulty. Retrospective confidence judgments were collected on an item-by-item basis. Brain volumetric analyses were conducted using FreeSurfer software. RESULTS: Analyses of the modified Matrix Reasoning task data demonstrated that HCs significantly outperformed TBIs (ordered: d = .63; random: d = .58). There was a significant difference between groups for MC for the randomly presented stimuli (d = .54) but not the ordered stimuli. There was an association between GMV and MC in the TBI group between the right orbital region and MC (R2 = .11). In the HC group, there were associations between the left posterior (R2 = .17), left orbital (R2 = .29), and left dorsolateral (R2 = .21) regions and MC. CONCLUSIONS: These results are consistent with those of previous research on MC in the cognitive neurosciences, but this study demonstrates that injury may moderate the regional contributions to MC. (PsycINFO Database Record

Diminished neural network dynamics in amnestic mild cognitive impairment.

Mild cognitive impairment (MCI) is widely regarded as an intermediate stage between typical aging and dementia, with nearly 50% of patients with amnestic MCI (aMCI) converting to Alzheimer's dementia (AD) within 30 months of follow-up (Fischer et al., 2007). The growing literature using resting-state functional magnetic resonance imaging reveals both increased and decreased connectivity in individuals with MCI and connectivity loss between the anterior and posterior components of the default mode network (DMN) throughout the course of the disease progression (Hillary et al., 2015; Sheline & Raichle, 2013; Tijms et al., 2013). In this paper, we use dynamic connectivity modeling and graph theory to identify unique brain "states," or temporal patterns of connectivity across distributed networks, to distinguish individuals with aMCI from healthy older adults (HOAs). We enrolled 44 individuals diagnosed with aMCI and 33 HOAs of comparable age and education. Our results indicated that individuals with aMCI spent significantly more time in one state in particular, whereas neural network analysis in the HOA sample revealed approximately equivalent representation across four distinct states. Among individuals with aMCI, spending a higher proportion of time in the dominant state relative to a state where participants exhibited high cost (a measure combining connectivity and distance), predicted better language performance and less perseveration. This is the first report to examine neural network dynamics in individuals with aMCI.

Corrigendum: Dedifferentiation Does Not Account for Hyperconnectivity after Traumatic Brain Injury.

[This corrects the article on p. 297 in vol. 8, PMID: 28769858.].

Dedifferentiation Does Not Account for Hyperconnectivity after Traumatic Brain Injury.

OBJECTIVE: Changes in functional network connectivity following traumatic brain injury (TBI) have received increasing attention in recent neuroimaging literature. This study sought to understand how disrupted systems adapt to injury during resting and goal-directed brain states. Hyperconnectivity has been a common finding, and dedifferentiation (or loss of segregation of networks) is one possible explanation for this finding. We hypothesized that individuals with TBI would show dedifferentiation of networks (as noted in other clinical populations) and these effects would be associated with cognitive dysfunction. METHODS: Graph theory was implemented to examine functional connectivity during periods of task and rest in 19 individuals with moderate/severe TBI and 14 healthy controls (HCs). Using a functional brain atlas derived from 83 functional imaging studies, graph theory was used to examine network dynamics and determine whether dedifferentiation accounts for changes in connectivity. Regions of interest were assigned to one of three groups: task-positive, default mode, or other networks. Relationships between these metrics were then compared with performance on neuropsychological tests. RESULTS: Hyperconnectivity in TBI was most commonly observed as increased within-network connectivity. Network strengths within networks that showed differences between TBI and HCs were correlated with performance on five neuropsychological tests typically sensitive to deficits commonly reported in TBI. Hyperconnectivity within the default mode network (DMN) during task was associated with better performance on Digit Span Backward, a measure of working memory [R2(18) = 0.28, p = 0.02]. In other words, increased differentiation of networks during task was associated with better working memory. Hyperconnectivity within the task-positive network during rest was not associated with behavior. Negative correlation weights were not associated with behavior. CONCLUSION: The primary hypothesis that hyperconnectivity occurs through dedifferentiation was not supported. [corrected]. Instead, enhanced connectivity post injury was observed within network. Results suggest that the relationship between increased connectivity and cognitive functioning may be both state (rest or task) and network dependent. High-cost network hubs were identical for both rest and task, and cost was negatively associated with performance on measures of psychomotor speed and set-shifting.