Dynamic association between perfusion and white matter integrity across time since injury in Veterans with history of TBI.

ObjectiveCerebral blood flow (CBF) plays a critical role in the maintenance of neuronal integrity, and CBF alterations have been linked to deleterious white matter changes. Although both CBF and white matter microstructural alterations have been observed within the context of traumatic brain injury (TBI), the degree to which these pathological changes relate to one another and whether this association is altered by time since injury have not been examined. The current study therefore sought to clarify associations between resting CBF and white matter microstructure post-TBI.Methods37 veterans with history of mild or moderate TBI (mmTBI) underwent neuroimaging and completed health and psychiatric symptom questionnaires. Resting CBF was measured with multiphase pseudocontinuous arterial spin labeling (MPPCASL), and white matter microstructural integrity was measured with diffusion tensor imaging (DTI). The cingulate cortex and cingulum bundle were selected as a priori regions of interest for the ASL and DTI data, respectively, given the known vulnerability of these regions to TBI.ResultsRegression analyses controlling for age, sex, and posttraumatic stress disorder (PTSD) symptoms revealed a significant time since injury × resting CBF interaction for the left cingulum (p < 0.005). Decreased CBF was significantly associated with reduced cingulum fractional anisotropy (FA) in the chronic phase; however, no such association was observed for participants with less remote TBI.ConclusionsOur results showed that reduced CBF was associated with poorer white matter integrity in those who were further removed from their brain injury. Findings provide preliminary evidence of a possible dynamic association between CBF and white matter microstructure that warrants additional consideration within the context of the negative long-term clinical outcomes frequently observed in those with history of TBI. Additional cross-disciplinary studies integrating multiple imaging modalities (e.g., DTI, ASL) and refined neuropsychiatric assessment are needed to better understand the nature, temporal course, and dynamic association between brain changes and clinical outcomes post-injury

Outcomes of Randomized Clinical Trials of Interventions to Enhance Social, Emotional, and Spiritual Components of Wisdom: A Systematic Review and Meta-analysis.

ImportanceWisdom is a neurobiological personality trait made up of specific components, including prosocial behaviors, emotional regulation, and spirituality. It is associated with greater well-being and happiness.ObjectiveTo evaluate the effectiveness of interventions to enhance individual components of wisdom.Data sourcesMEDLINE and PsycINFO databases were searched for articles published through December 31, 2018.Study eligibility criteriaRandomized clinical trials that sought to enhance a component of wisdom, used published measures to assess that component, were published in English, had a minimum sample size of 40 participants, and presented data that enabled computation of effect sizes were included in this meta-analysis.Data extraction and synthesisRandom-effect models were used to calculate pooled standardized mean differences (SMDs) for each wisdom component and random-effects meta-regression to assess heterogeneity of studies.Main outcomes and measuresImprovement in wisdom component using published measures.ResultsFifty-seven studies (N = 7096 participants) met review criteria: 29 for prosocial behaviors, 13 for emotional regulation, and 15 for spirituality. Study samples included people with psychiatric or physical illnesses and from the community. Of the studies, 27 (47%) reported significant improvement with medium to large effect sizes. Meta-analysis revealed significant pooled SMDs for prosocial behaviors (23 studies; pooled SMD, 0.43 [95% CI, 0.22-0.3]; P = .02), emotional regulation (12 studies; pooled SMD, 0.67 [95% CI, 0.21-1.12]; P = .004), and spirituality (12 studies; pooled SMD, 1.00 [95% CI, 0.41-1.60]; P = .001). Heterogeneity of studies was considerable for all wisdom components. Publication bias was present for prosocial behavior and emotional regulation studies; after adjusting for it, the pooled SMD for prosocial behavior remained significant (SMD, 0.4 [95% CI, 0.16-0.78]; P = .003). Meta-regression analysis found that effect sizes did not vary by wisdom component, although for trials on prosocial behaviors, large effect sizes were associated with older mean participant age (β, 0.08 [SE, 0.04]), and the reverse was true for spirituality trials (β, -0.13 [SE, 0.04]). For spirituality interventions, higher-quality trials had larger effect sizes (β, 4.17 [SE, 1.07]), although the reverse was true for prosocial behavior trials (β, -0.91 [SE 0.44]).Conclusions and relevanceInterventions to enhance spirituality, emotional regulation, and prosocial behaviors are effective in a proportion of people with mental or physical illnesses and from the community. The modern behavioral epidemics of loneliness, suicide, and opioid abuse point to a growing need for wisdom-enhancing interventions to promote individual and societal well-being

Interactive effects of vascular risk burden and advanced age on cerebral blood flow.

Vascular risk factors and cerebral blood flow (CBF) reduction have been linked to increased risk of cognitive impairment and Alzheimer's disease (AD); however the possible moderating effects of age and vascular risk burden on CBF in late life remain understudied. We examined the relationships among elevated vascular risk burden, age, CBF, and cognition. Seventy-one non-demented older adults completed an arterial spin labeling MR scan, neuropsychological assessment, and medical history interview. Relationships among vascular risk burden, age, and CBF were examined in a priori regions of interest (ROIs) previously implicated in aging and AD. Interaction effects indicated that, among older adults with elevated vascular risk burden (i.e., multiple vascular risk factors), advancing age was significantly associated with reduced cortical CBF whereas there was no such relationship for those with low vascular risk burden (i.e., no or one vascular risk factor). This pattern was observed in cortical ROIs including medial temporal (hippocampus, parahippocampal gyrus, uncus), inferior parietal (supramarginal gyrus, inferior parietal lobule, angular gyrus), and frontal (anterior cingulate, middle frontal gyrus, medial frontal gyrus) cortices. Furthermore, among those with elevated vascular risk, reduced CBF was associated with poorer cognitive performance. Such findings suggest that older adults with elevated vascular risk burden may be particularly vulnerable to cognitive change as a function of CBF reductions. Findings support the use of CBF as a potential biomarker in preclinical AD and suggest that vascular risk burden and regionally-specific CBF changes may contribute to differential age-related cognitive declines

Baseline White Matter Hyperintensities and Hippocampal Volume are Associated With Conversion From Normal Cognition to Mild Cognitive Impairment in the Framingham Offspring Study.

INTRODUCTION: We examined associations between magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration with mild cognitive impairment (MCI) diagnosis at baseline and conversion from normal cognition to MCI at follow-up. METHODS: Framingham Offspring participants underwent brain MRI and neuropsychological assessment at baseline (n=1049) and follow-up (n=561). Participants were classified at baseline and at follow-up as cognitively normal or MCI using sensitive neuropsychological criteria. White matter hyperintensity (WMH) volume, covert brain infarcts, hippocampal volume, and total cerebral brain volume were quantified. RESULTS: Baseline measures of WMH and hippocampal volume were associated with MCI status cross-sectionally and also with conversion from normal cognition to MCI at 6.5-year follow-up. Annualized change rates in total cerebral brain volume and hippocampal volume were associated with conversion from normal cognition to MCI to follow-up. DISCUSSION: Baseline WMH and hippocampal volume are markers that are both associated with conversion from normal cognition to MCI, highlighting the role of both vascular lesions and neurodegeneration in MCI

Assessing Working Memory in Mild Cognitive Impairment with Serial Order Recall.

BACKGROUND: Working memory (WM) is often assessed with serial order tests such as repeating digits backward. In prior dementia research using the Backward Digit Span Test (BDT), only aggregate test performance was examined. OBJECTIVE: The current research tallied primacy/recency effects, out-of-sequence transposition errors, perseverations, and omissions to assess WM deficits in patients with mild cognitive impairment (MCI). METHODS: Memory clinic patients (n = 66) were classified into three groups: single domain amnestic MCI (aMCI), combined mixed domain/dysexecutive MCI (mixed/dys MCI), and non-MCI where patients did not meet criteria for MCI. Serial order/WM ability was assessed by asking participants to repeat 7 trials of five digits backwards. Serial order position accuracy, transposition errors, perseverations, and omission errors were tallied. RESULTS: A 3 (group)×5 (serial position) repeated measures ANOVA yielded a significant group×trial interaction. Follow-up analyses found attenuation of the recency effect for mixed/dys MCI patients. Mixed/dys MCI patients scored lower than non-MCI patients for serial position 3 (p \u3c 0.003) serial position 4 (p \u3c 0.002); and lower than both group for serial position 5 (recency; p \u3c 0.002). Mixed/dys MCI patients also produced more transposition errors than both groups (p \u3c 0.010); and more omissions (p \u3c 0.020), and perseverations errors (p \u3c 0.018) than non-MCI patients. CONCLUSIONS: The attenuation of a recency effect using serial order parameters obtained from the BDT may provide a useful operational definition as well as additional diagnostic information regarding working memory deficits in MCI

Reduced Regional Cerebral Blood Flow Relates to Poorer Cognition in Older Adults With Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) increases risk for dementia, including Alzheimer’s disease (AD). Many previous studies of brain changes underlying cognitive impairment in T2DM have applied conventional structural magnetic resonance imaging (MRI) to detect macrostructural changes associated with cerebrovascular disease such as white matter hyperintensities or infarcts. However, such pathology likely reflects end-stage manifestations of chronic decrements in cerebral blood flow (CBF). MRI techniques that measure CBF may (1) elucidate mechanisms that precede irreversible parenchymal damage and (2) serve as a marker of risk for cognitive decline. CBF measured with arterial spin labeling (ASL) MRI may be a useful marker of perfusion deficits in T2DM and related conditions. We examined associations among T2DM, CBF, and cognition in a sample of 49 well-characterized nondemented older adults. Along with a standard T1-weighted scan, a pseudocontinuous ASL sequence optimized for older adults (by increasing post-labeling delays to allow more time for the blood to reach brain tissue) was obtained on a 3T GE scanner to measure regional CBF in FreeSurfer derived regions of interest. Participants also completed a neuropsychological assessment. Results showed no significant differences between individuals with and without T2DM in terms of cortical thickness or regional brain volume. However, adjusting for age, sex, comorbid vascular risk factors, and reference CBF (postcentral gyrus) older adults with T2DM demonstrated reduced CBF in the hippocampus, and inferior temporal, inferior parietal, and frontal cortices. Lower CBF was associated with poorer memory and executive function/processing speed. When adjusting for diabetes, the significant associations between lower regional CBF and poorer executive function/processing speed remained. Results demonstrate that CBF is reduced in older adults with T2DM, and suggest that CBF alterations likely precede volumetric changes. Notably, relative to nondiabetic control participants, those with T2DM showed lower CBF in predilection sites for AD pathology (medial temporal lobe and inferior parietal regions). Findings augment recent research suggesting that perfusion deficits may underlie cognitive decrements frequently observed among older adults with T2DM. Results also suggest that CBF measured with ASL MRI may reflect an early and important marker of risk of cognitive impairment in T2DM and related conditions

Blast-Exposed Veterans With Mild Traumatic Brain Injury Show Greater Frontal Cortical Thinning and Poorer Executive Functioning

Objective: Blast exposure (BE) and mild traumatic brain injury (mTBI) have been independently linked to pathological brain changes. However, the combined effects of BE and mTBI on brain structure have yet to be characterized. Therefore, we investigated whether regional differences in cortical thickness exist between mTBI Veterans with and without BE while on deployment. We also examined whether cortical thickness (CT) and cognitive performance differed among mTBI Veterans with low vs. high levels of cumulative BE.Methods: 80 Veterans with mTBI underwent neuroimaging and completed neuropsychological testing and self-report symptom rating scales. Analyses of covariance (ANCOVA) were used to compare blast-exposed Veterans (mTBI+BE, n = 51) to those without BE (mTBI-BE, n = 29) on CT of frontal and temporal a priori regions of interest (ROIs). Next, multiple regression analyses were used to examine whether CT and performance on an executive functions composite differed among mTBI Veterans with low (mTBI+BE Low, n = 22) vs. high (mTBI+BE High, n = 26) levels of cumulative BE.Results: Adjusting for age, numer of TBIs, and PTSD symptoms, the mTBI+BE group showed significant cortical thinning in frontal regions (i.e., left orbitofrontal cortex [p = 0.045], left middle frontal gyrus [p = 0.023], and right inferior frontal gyrus [p = 0.034]) compared to the mTBI-BE group. No significant group differences in CT were observed for temporal regions (p's > 0.05). Multiple regression analyses revealed a significant cumulative BE × CT interaction for the left orbitofrontal cortex (p = 0.001) and left middle frontal gyrus (p = 0.020); reduced CT was associated with worse cognitive performance in the mTBI+BE High group but not the mTBI+BE Low group.Conclusions: Findings show that Veterans with mTBI and BE may be at risk for cortical thinning post-deployment. Moreover, our results demonstrate that reductions in CT are associated with worse executive functioning among Veterans with high levels of cumulative BE. Future longitudinal studies are needed to determine whether BE exacerbates mTBI-related cortical thinning or independently negatively influences gray matter structure

Assessment of Alzheimer's disease risk with structural and functional magnetic resonance imaging : an arterial spin labeling study

BACKGROUND : There are several risk factors for the development of Alzheimer's disease (AD) including the apolipoprotein E (APOE) e4 allele, an important susceptibility gene for AD, and mild cognitive impairment (MCI). The literature to date generally indicates that nondemented older adults at risk for AD by virtue of their cognitive (i.e., MCI) and/or genetic (i.e., APOE) status demonstrate reduced medial temporal lobe (MTL) volumes and divergent brain response patterns during memory encoding relative to their counterparts not at risk. METHODS : We used arterial spin labeling (ASL) functional magnetic resonance imaging (FMRI) to examine the influence of AD risk on functional brain responses to memory encoding. Participants were 43 individuals aged 60 or older. Twenty- nine individuals were classified as cognitively normal and 14 met criteria for MCI. Twenty individuals were APOE e4 carriers whereas 23 were non-e4 carriers. The risk groups were equivalent in terms of mean age, mean years of education, gender distribution, vascular risk, or medial temporal lobe (MTL) volumes. RESULTS : Individuals at genetic risk for AD by virtue of the presence of at least one APOE e4 allele demonstrated increased MTL resting state CBF relative to their non-e4 counterparts. In contrast, individuals characterized as MCI showed decreased MTL resting state CBF relative to their cognitively normal peers. There was a trend toward a cognitive status by genotype interaction for percent change CBF. In the cognitively normal group there was no difference in percent change CBF based on APOE genotype. In contrast, in the MCI group, APOE e4 carriers demonstrated significantly greater activation relative to non-e4 carriers. CONCLUSIONS : Our findings provide support for the notion that individuals at risk for AD demonstrate changes in brain function in the preclinical period prior to the onset of dementia. Further, our results suggest that abnormal resting state CBF and FMRI response pattern to memory encoding may be early indicators of brain dysfunction in individuals at risk for developing AD and, therefore, ASL MRI may provide a sensitive technique for identifying individuals at risk, monitoring changes in neural activity due to developing AD neuropathology, and assessing effectiveness of disease- modifying treatment