Interaction of APOE, cerebral blood flow, and cortical thickness in the entorhinal cortex predicts memory decline.

The ε4 allele of the apolipoprotein E (APOE) gene, a risk factor for cognitive decline, is associated with alterations in medial temporal lobe (MTL) structure and function, yet little research has been dedicated to understanding how these alterations might interact to negatively impact cognition. To bridge this gap, the present study employed linear regression models to determine the extent to which APOE genotype (ε4+, ε4-) modifies interactive effects of baseline arterial spin labeling MRI-measured cerebral blood flow (CBF) and FreeSurfer-derived cortical thickness/volume (CT/Vo) in two MTL regions of interest (entorhinal cortex, hippocampus) on memory change in 98 older adults who were cognitively normal at baseline. Baseline entorhinal CBF was positively associated with memory change, but only among ε4 carriers with lower entorhinal CT. Similarly, baseline entorhinal CT was positively associated with memory change, but only among ε4 carriers with lower entorhinal CBF. Findings suggest that APOE ε4 carriers may experience concomitant alterations in neurovascular function and morphology in the MTL that interact to negatively affect cognition prior to the onset of overt clinical symptoms. Results also suggest the presence of distinct multimodal neural signatures in the entorhinal cortex that may signal relative risk for cognitive decline among this group, perhaps reflecting different stages of cerebrovascular compensation (early effective vs. later ineffective).

Neurobehavioral symptom validity and performance validity in veterans: Evidence for distinct outcomes across data types.

Self-reported traumatic brain injury (TBI) is common in combat veterans, and identification of psychiatric and neuropsychological consequences following TBI has become a priority for veteran healthcare. Given the importance of accurately capturing symptoms potentially related to TBI in VA settings, validity metrics are frequently used to evaluate both neuropsychological testing validity and the validity of symptom self-reports. The Validity-10 of the Neurobehavioral Symptom Inventory is one such metric that was designed to evaluate symptom over-reporting and thus identify individuals who may produce inconclusive testing profiles. However, the Validity-10's ability to predict objective effort during neuropsychological testing has not been sufficiently explored in veterans. Clinical evaluation data were collected from 295 veterans seeking treatment in a VA TBI clinic. We examined whether the Validity-10 can predict invalid performance on a battery of neuropsychological tests. Validity-10 was a poor predictor of performance validity metrics. Results provide a conceptual replication of earlier work demonstrating that performance and symptom validity are divergent. As such, separate evaluation of these domains is warranted during evaluations conducted in veteran TBI populations.

Anterior Cingulate Structure and Perfusion is Associated with Cerebrospinal Fluid Tau among Cognitively Normal Older Adult APOEɛ4 Carriers.

Evidence suggests the ɛ4 allele of the apolipoprotein E (APOE) gene may accelerate an age-related process of cortical thickening and cerebral blood flow (CBF) reduction in the anterior cingulate cortex (ACC). Although the neural basis of this association remains unclear, evidence suggests it might reflect early neurodegenerative processes. However, to date, associations between cerebrospinal fluid (CSF) biomarkers of neurodegeneration, such as CSF tau, and APOE-related alterations in ACC cortical thickness (CTH) and CBF have yet to be explored. The current study explored the interaction of CSF tau and APOE genotype (ɛ4+, ɛ4-) on FreeSurfer-derived CTH and arterial spin labeling MRI-measured resting CBF in the ACC (caudal ACC [cACC] and rostral ACC [rACC]) among a sample of 45 cognitively normal older adults. Secondary analyses also examined associations between APOE, CTH/CBF, and cognitive performance. In the cACC, higher CSF tau was associated with higher CTH and lower CBF in ɛ4+, whereas these relationships were not evident in ɛ4-. In the rACC, higher CSF tau was associated with higher CTH for both ɛ4+ and ɛ4-, and with lower CBF only in ɛ4+. Significant interactions of CSF tau and APOE on CTH/CBF were not observed in two posterior reference regions implicated in Alzheimer's disease. Secondary analyses revealed a negative relationship between cACC CTH and executive functioning in ɛ4+ and a positive relationship in ɛ4-. Findings suggest the presence of an ɛ4-related pattern of increased CTH and reduced CBF in the ACC that is associated with biomarkers of neurodegeneration and subtle decrements in cognition.

APOE modifies the interaction of entorhinal cerebral blood flow and cortical thickness on memory function in cognitively normal older adults.

OBJECTIVE: The ε4 allele of the apolipoprotein E (APOE) gene increases risk for cognitive decline in normal and pathologic aging. However, precisely how APOE ε4 exerts its negative impact on cognition is poorly understood. The present study aimed to determine whether APOE genotype (ε4+ vs. ε4-) modifies the interaction of medial temporal lobe (MTL) resting cerebral blood flow (CBF) and brain structure (cortical thickness [CT], volume [Vo]) on verbal memory performance. METHODS: Multiple linear regression models were employed to investigate relationships between APOE genotype, arterial spin labeling MRI-measured CBF and FreeSurfer-based CT and Vo in four MTL regions of interest (left and right entorhinal cortex and hippocampus), and verbal memory performance among a sample of 117 cognitively normal older adults (41 ε4+, 76 ε4-) between the ages of 64 and 89 (mean age â€‹= â€‹73). RESULTS: Results indicated that APOE genotype modified the interaction of CBF and CT on memory in the left entorhinal cortex, such that the relationship between entorhinal CBF and memory was negative (lower CBF was associated with better memory) in non-carriers with higher entorhinal CT, positive (higher CBF was associated with better memory) in non-carriers with lower entorhinal CT, and negative (higher CBF was associated with worse memory) in ε4 carriers with lower entorhinal CT. CONCLUSIONS: Findings suggest that older adult APOE ε4 carriers may experience vascular dysregulation and concomitant morphological alterations in the MTL that interact to negatively affect memory even in the absence overt clinical symptoms, providing potential insight into the mechanistic link between APOE ε4 and detriments in cognition. Moreover, findings suggest a distinct multimodal neural signature in ε4 carriers (higher CBF and lower CT in the entorhinal cortex) that could aid in the identification of candidates for future clinical trials aimed at preventing or slowing cognitive decline. Differential findings with respect to ε4 carriers and non-carriers are discussed in the context of neurovascular compensation.

Dose-dependent association of accelerometer-measured physical activity and sedentary time with brain perfusion in aging.

INTRODUCTION: Age-related decreases in cerebral blood flow (CBF) may lead to cognitive decline, while physical activity (PA) can maintain CBF and cognition in aging. The intensity of PA needed to affect CBF in aging, and the independent effects of sedentary time on CBF are currently unknown. Moreover, research conducted in free-living environments with objective measures of PA (e.g., accelerometry) is lacking. METHODS: This cross-sectional study used accelerometry to objectively measure sedentary time, all light PA [AllLightPA], moderate-to-vigorous PA [MVPA], and total activity counts [TAC] in 52 cognitively healthy older adults. Robust linear regressions investigated the association of CBF (using arterial spin labeling magnetic resonance imaging) in frontal and medial temporal regions, with each PA intensity and sedentary time. RESULTS: Greater sedentary time was significantly associated with lower CBF in lateral and medial frontal regions after adjusting for MVPA, while higher AllLightPA (adjusted for MVPA), MVPA (adjusted for AllLightPA), and TAC were associated with greater CBF in lateral and medial frontal regions. DISCUSSION: Lighter activities, as well as MVPA, are beneficial to CBF in brain regions typically affected by the aging process and malleable to exercise interventions (i.e., the frontal lobes), whereas sedentary time is an independent risk factor for neurovascular dysregulation in normal aging.

Mild Traumatic Brain Injury Burden Moderates the Relationship Between Cognitive Functioning and Suicidality in Iraq/Afghanistan-Era Veterans.

OBJECTIVES: Suicidal ideation (SI) is highly prevalent in Iraq/Afghanistan-era veterans with a history of mild traumatic brain injury (mTBI), and multiple mTBIs impart even greater risk for poorer neuropsychological functioning and suicidality. However, little is known about the cognitive mechanisms that may confer increased risk of suicidality in this population. Thus, we examined relationships between neuropsychological functioning and suicidality and specifically whether lifetime mTBI burden would moderate relationships between cognitive functioning and suicidal ideation. METHODS: Iraq/Afghanistan-era Veterans with a history of mTBI seeking outpatient services (N = 282) completed a clinical neuropsychological assessment and psychiatric and postconcussive symptom questionnaires. RESULTS: Individuals who endorsed SI reported more severe post-traumatic stress disorder (PTSD), depression, and postconcussive symptoms and exhibited significantly worse memory performance compared to those who denied SI. Furthermore, mTBI burden interacted with both attention/processing speed and memory, such that poorer performance in these domains was associated with greater likelihood of SI in individuals with a history of three or more mTBIs. The pattern of results remained consistent when controlling for PTSD, depression, and postconcussive symptoms. CONCLUSIONS: Slowed processing speed and/or memory difficulties may make it challenging to access and use past experiences to solve current problems and imagine future outcomes, leading to increases in hopelessness and SI in veterans with three or more mTBIs. Results have the potential to better inform treatment decisions for veterans with history of multiple mTBIs. (JINS, 2019, 25, 79-89).

Neurocognition, psychiatric symptoms, and lifetime homelessness among veterans with a history of traumatic brain injury.

We retrospectively investigated archival clinical data, including correlates of lifetime homelessness, in 503 Veterans with a history of traumatic brain injuries (86.5% mild) who completed neuropsychological evaluations and passed performance validity tests. The 471 never-homeless and 32 ever-homeless Veterans were compared on demographic factors, TBI severity, psychiatric diagnosis, subjective symptoms, and neuropsychological functioning. Homelessness history was significantly associated with unemployment, lower disability income, more severe depressive, anxiety, posttraumatic stress disorder, and postconcussive symptoms, and lower performances on two of fifteen neurocognitive tests. In a multiple logistic regression model, current unemployment and substance use disorder remained significantly associated with lifetime homelessness.

The potential of calibrated fMRI in the understanding of stress in eating disorders.

Eating disorders (ED), including Anorexia Nervosa (AN), Bulimia Nervosa (BN), and Binge Eating Disorder (BED), are medically dangerous psychiatric disorders of unknown etiology. Accumulating evidence supports a biopsychosocial model that includes genetic heritability, neurobiological vulnerability, and psychosocial factors, such as stress, in the development and maintenance of ED. Notably, stress hormones influence appetite and eating, and dysfunction of the physiological stress response has been implicated in ED pathophysiology. Stress signals also appear associated with food reward neurocircuitry response in ED, providing a possible mechanism for the role of stress in appetite dysregulation. This paper provides a review of some of the interacting psychological, behavioral, physiological, and neurobiological mechanisms involved in the stress response among individuals with ED, and discusses novel neuroimaging techniques to address potential physiological confounds of studying neural correlates of stress in ED, such as calibrated fMRI.

Correlates of employment and postsecondary education enrolment in Afghanistan and Iraq veterans with traumatic brain injuries.

PRIMARY OBJECTIVE: About 20% of Iraq and Afghanistan Veterans have sustained a traumatic brain injury (TBI), which can result in postconcussive symptoms and difficulty transitioning from the military to civilian employment and postsecondary education. To better inform programs help Veterans transition back into civilian life, we evaluated correlates of employment and postsecondary education enrolment among treatment-seeking Veterans with a history of TBI. RESEARCH DESIGN: A cross-sectional design, using an archival database of VA medical records, was used to answer these research questions. METHODS AND PROCEDURES: We examined demographic, TBI-related, postconcussive, psychiatric, and neuropsychological factors in 390 Veterans (86% with mild TBI) to determine what factors were associated with employment or enrolment in postsecondary education. Bivariate correlations and multivariate regression were used. MAIN OUTCOMES AND RESULTS: age, minority status, and service connected disability ratings were significantly associated with employment and postsecondary education enrolment in a multivariate context, whereas TBI-related factors and neurocognitive, postconcussive, and psychiatric symptom severity were not associated with employment or postsecondary education outcomes. CONCLUSIONS: Further research is needed to confirm these findings and to evaluate the contribution of age, minority status, and disability on successful return to work and/or school for Veterans with a history of TBI.

Subjective Cognitive Decline Modifies the Relationship Between Cerebral Blood Flow and Memory Function in Cognitively Normal Older Adults.

OBJECTIVES: Subjective cognitive decline (SCD), or self-reported cognitive decline despite normal neuropsychological test performance, is a risk factor for objective cognitive decline and Alzheimer's disease (AD). While brain mechanisms contributing to SCD are not well defined, studies show associations with vascular risk factors and altered cerebral blood flow (CBF), raising the hypothesis that those with SCD might be experiencing vascular dysregulation, or a disruption in the normal relationship between CBF and cognition. We examined whether the association between CBF and verbal memory performance differs between those with SCD (SCD+) and those without SCD (SCD-). METHODS: Linear mixed-effects models were used to investigate whether the voxel-wise relationship between arterial spin labeling (ASL) MRI-measured CBF and verbal memory performance was modified by SCD among a group of 70 cognitively normal older adults (35 SCD+, 35 SCD-; mean age=72) matched on age, gender, and symptoms of depression. RESULTS: Results indicated that the SCD- group exhibited positive associations between verbal memory and CBF within the posterior cingulate cortex, middle temporal gyrus, and inferior frontal gyrus, whereas the SCD+ group displayed negative associations between verbal memory and CBF within the posterior cingulate cortex, middle temporal gyrus, hippocampus, fusiform gyrus, and inferior frontal gyrus. CONCLUSIONS: Findings suggest that, while higher CBF is supportive of memory function in those without SCD, higher CBF may no longer support memory function in those presenting with SCD, perhaps reflecting neurovascular dysregulation. (JINS, 2018, 24, 213-223).

Temporal gradient during famous face naming is associated with lower cerebral blood flow and gray matter volume in aging.

OBJECTIVE: Evidence suggests that famous face naming may be a cognitive ability especially sensitive to the early pathological processes of Alzheimer's disease (AD) and that those at risk for AD may demonstrate a Ribot temporal gradient (RTG), characterized by better performance for naming remote famous faces than for naming recent famous faces. Reductions in cerebral blood flow (CBF) and gray matter volume (GMV) have been implicated in the neuropathological cascade of AD and show utility as biomarkers of AD risk. We examined whether a RTG during famous face naming was associated with lower CBF and/or GMV among a group of cognitively normal older adults. METHODS: Voxel-wise independent samples t-tests were employed to contrast resting CBF values between those who exhibited a RTG (RTG+) during a famous face naming task and those who did not (RTG-) among a sample of 52 cognitively normal older adults (25 RTG-, 27 RTG+; mean age = 73). Groups were also compared on GMV using a voxel-wise general linear model. RESULTS: Significant group differences in CBF and GMV were found, whereby the RTG+ group demonstrated reduced CBF and GMV within medial temporal lobe regions (hippocampus, parahippocampal gyrus), relative to the RTG- group. CONCLUSIONS: This represents the first study to show that cognitively intact older adults who demonstrate a RTG during famous face naming exhibit vascular dysregulation and structural changes similar to that seen in AD risk. Findings suggest that famous face naming ability may be particularly sensitive to the very early brain changes associated with AD.

Postconcussive symptom overreporting in Iraq/Afghanistan Veterans with mild traumatic brain injury.

A comprehensive evaluation, including the assessment of neurobehavioral symptoms, has been instituted at the Department of Veterans Affairs (VA) healthcare system to address the large number of Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) Veterans returning with mild traumatic brain injuries (mTBIs). The Validity-10 is measure of symptom overreporting embedded within the Neurobehavioral Symptom Inventory, a component of the comprehensive evaluation that assesses postconcussive symptom severity. The Validity-10 is composed of 10 unlikely/low-frequency items and a validated cutoff score to identify postconcussive symptom overreporting. We examined the items and cutoff used in the initial development and validation study of the Validity-10 through retrospective chart reviews of 331 treatment-seeking Veterans who sustained an mTBI. The Validity-10 exhibited significant relationships with psychiatric variables, VA service connection, and neuropsychological performance validity (all p < 0.01), but nonsignificant relationships with demographic and injury variables (all p > 0.05). Furthermore, the Validity-10 modestly predicted neuropsychological performance validity test failure over and above psychiatric comorbidities and VA service connection. The present study supports the use of the Validity-10 to assess symptom validity in treatment-seeking OIF/OEF Veterans with a history of mTBI.

Multivariate assessment of subjective and objective measures of social and family satisfaction in Veterans with history of traumatic brain injury.

Approximately 20% of current-era Veterans have sustained a traumatic brain injury (TBI), which can result in persistent postconcussive symptoms. These symptoms may disrupt family and social functioning. We explored psychiatric, postconcussive, and cognitive factors as correlates of objective functioning and subjective satisfaction in family and social relationships. At entry into a supported employment study, 50 unemployed Veterans with a history of mild to moderate TBI and current cognitive impairment were administered baseline assessments. Multivariate stepwise regressions determined that higher levels of depressive symptomatology were strongly associated with less frequent social contact, as well as lower subjective satisfaction with family and social relationships. Worse verbal fluency predicted less frequent social contact, whereas worse processing speed and switching predicted higher levels of subjective satisfaction with family relationships. The pattern of results remained similar when examining those Veterans with only mild TBI. Depressive symptoms and cognitive functioning may impact Veterans' social contact and satisfaction with family and social relationships. Evidence-based interventions addressing depression and cognition may therefore aid in improving community reintegration and satisfaction with social and family relationships.

Higher Brain Perfusion May Not Support Memory Functions in Cognitively Normal Carriers of the ApoE ε4 Allele Compared to Non-Carriers.

Age-related changes in cerebral blood flow (CBF), which carries necessary nutrients to the brain, are associated with increased risk for mild cognitive impairment (MCI) and Alzheimer's disease (AD). Whether the association between CBF and cognition is moderated by apolipoprotein E (ApoE) ε4 genotype, a known risk factor for AD, remains understudied, with most research focusing on exploring brain regions in which there are diagnostic group differences in CBF (i.e., cognitively normal vs. MCI vs. AD). This study measured resting CBF via arterial spin labeling (ASL) magnetic resonance imaging (MRI) and verbal memory functions using a composite score in 59 older adults with normal cognition (38 ε3; 21 ε4). Linear mixed effect models were employed to investigate if the voxel-wise relationship between verbal memory performance and resting CBF was modified by ApoE genotype. Results indicated that carriers of the ApoE ε4 allele display negative associations between verbal memory functions and CBF in medial frontal cortex, medial and lateral temporal cortex, parietal regions, insula, and the basal ganglia. Contrarily, ε3 carriers exhibited positive associations between verbal memory functions and CBF in medial frontal cortex, thalamus, insula, and basal ganglia. Findings suggest that higher CBF was associated with worse verbal memory functions in cognitively normal ε4 carriers, perhaps reflecting dysregulation within the neurovascular unit, which is no longer supportive of cognition. Results are discussed within the context of the vascular theory of AD risk.

The Utility of Cerebral Blood Flow as a Biomarker of Preclinical Alzheimer's Disease.

There is accumulating evidence suggesting that changes in brain perfusion are present long before the clinical symptoms of Alzheimer's disease (AD), perhaps even before amyloid-ß accumulation or brain atrophy. This evidence, consistent with the vascular hypothesis of AD, implicates cerebral blood flow (CBF) in the pathogenesis of AD and suggests its utility as a biomarker of preclinical AD. The extended preclinical phase of AD holds particular significance for disease modification, as treatment would likely be most effective in this early asymptomatic stage of disease. This highlights the importance of identifying reliable and accurate biomarkers of AD that can differentiate normal aging from preclinical AD prior to clinical symptom manifestation. Cerebral perfusion, as measured by arterial spin labeling magnetic resonance imaging (ASL-MRI), has been shown to distinguish between normal controls and adults with AD. In addition to demonstrating diagnostic utility, CBF has shown usefulness as a tool for identifying those who are at risk for AD and for predicting subtle cognitive decline and conversion to mild cognitive impairment and AD. Taken together, this evidence not only implicates CBF as a useful biomarker for tracking disease severity and progression, but also suggests that ASL-measured CBF may be useful for identifying candidates for future AD treatment trials, especially in the preclinical, asymptomatic phases of the disease.

Cerebral blood flow measured by arterial spin labeling MRI as a preclinical marker of Alzheimer's disease.

There is growing recognition that cerebral hypoperfusion is related to the pathogenesis of Alzheimer's disease (AD), implicating the measurement of cerebral blood flow (CBF) as a possible biomarker of AD. The ability to identify the earliest and most reliable markers of incipient cognitive decline and clinical symptoms is critical to develop effective preventive strategies and interventions for AD. Arterial spin labeling (ASL) magnetic resonance imaging (MRI) measures CBF by magnetically labeling arterial water and using it as an endogenous tracer. Studies using ASL MRI in humans indicate that CBF changes are present several years before the development of the clinical symptoms of AD. Moreover, ASL-measured CBF has been shown to distinguish between cognitively normal individuals, adults at risk for AD, and persons diagnosed with AD. Some studies indicate that CBF may even be sensitive for predicting cognitive decline and conversion to mild cognitive impairment and AD over time. Taken together, evidence suggests that the current staging models of AD biomarker pathology should incorporate early changes in CBF as a useful biomarker, possibly present even earlier than amyloid-ß accumulation. Though still a research tool, ASL imaging is a promising non-invasive and reliable method with the potential to serve as a future clinical tool for the measurement of CBF in preclinical AD.