Aging Affects Dopaminergic Neural Mechanisms of Cognitive Flexibility.

Aging is accompanied by profound changes in the brain's dopamine system that affect cognitive function. Evidence of powerful individual differences in cognitive aging has sharpened focus on identifying biological factors underlying relative preservation versus vulnerability to decline. Dopamine represents a key target in these efforts. Alterations of dopamine receptors and dopamine synthesis are seen in aging, with receptors generally showing reduction and synthesis demonstrating increases. Using the PET tracer 6-[18F]fluoro-l-m-tyrosine, we found strong support for upregulated striatal dopamine synthesis capacity in healthy older adult humans free of amyloid pathology, relative to young people. We next used fMRI to define the functional impact of elevated synthesis capacity on cognitive flexibility, a core component of executive function. We found clear evidence in young adults that low levels of synthesis capacity were suboptimal, associated with diminished cognitive flexibility and altered frontoparietal activation relative to young adults with highest synthesis values. Critically, these relationships between dopamine, performance, and activation were transformed in older adults with higher synthesis capacity. Variability in synthesis capacity was related to intrinsic frontoparietal functional connectivity across groups, suggesting that striatal dopamine synthesis influences the tuning of networks underlying cognitive flexibility. Together, these findings define striatal dopamine's association with cognitive flexibility and its neural underpinnings in young adults, and reveal the alteration in dopamine-related neural processes in aging. SIGNIFICANCE STATEMENT: Few studies have combined measurement of brain dopamine with examination of the neural basis of cognition in youth and aging to delineate the underlying mechanisms of these associations. Combining in vivo PET imaging of dopamine synthesis capacity, fMRI, and a sensitive measure of cognitive flexibility, we reveal three core findings. First, we find evidence supporting older adults' capacity to upregulate dopamine synthesis. Second, we define relationships between dopamine, cognition, and frontoparietal activity in young adults indicating high levels of synthesis capacity are optimal. Third, we demonstrate alteration of these relationships in older adults, suggesting neurochemical modulation of cognitive flexibility changes with age.

Utilizing a combined hospital and criminal justice database to identify risk factors for repeat firearm injury or violent-crime arrest among firearm victims.

Introduction: Identifying firearm victims with the greatest risk of repeat-firearm exposure and offering interventions has the potential to disrupt recurrent violence. This study explored risk factors associated with repeat violence among survivors of intentional firearm injury in a unique clinical and criminal justice (CJ) dataset. Methods: This study analyzed a retrospective cohort (n = 4058) of persons injured by nonfatal intentional firearm violence from 2013 to 2016 in one metropolitan area. Data were collected from a single level I trauma center, city police records, and state CJ databases from 1948 to 2019. The primary outcome of interest was another firearm injury or violent-crime arrest (defined as a violent or firearm felony offense). Results: Among 4058 nonfatal intentional firearm victims, 1202 (29.6%) individuals had a repeat-firearm injury or violent-crime arrest. In a bivariate analysis, history of mental, physical, and/or emotional abuse (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.40-1.86), mental health diagnosis (OR, 1.88; 95% CI, 1.51-2.35), or illegal substance use (OR, 2.87; 95% CI, 2.48-3.32) was associated with increased risk of repeat-firearm injury or violent-crime arrest. Prior felony arrest (OR, 3.68; 95% CI, 3.19-4.24), prior incarceration (OR, 3.72; 95% CI, 3.04-4.56), prior firearm charge (OR, 4.06; 95% CI, 3.33-4.96), and suspected gang membership (OR, 8.69; 95% CI, 6.14-12.32) demonstrated the greatest association with significant repeat violence. Conclusions: Thirty percent of those who experienced an intentional firearm injury were found to have a repeat-firearm injury or violent-crime arrest multi-disciplinary interventions that address the complex needs of a CJ-involved population are needed to mitigate significant repeat violence.

Subjective cognitive decline and ß-amyloid burden predict cognitive change in healthy elderly.

OBJECTIVE: To assess in a longitudinal study whether subjective cognitive decline (SCD) and brain ß-amyloid (Aß) contribute unique information to cognitive decline. METHODS: One hundred thirty-six healthy elderly from the Berkeley Aging Cohort Study were followed up for a mean of 4 years. SCD and affective measures were generated from the Geriatric Depression Scale (GDS) with factor analysis on data from a larger set of 347 healthy, nondepressed (GDS <11) elderly individuals. Cognition was summarized with previously validated factor scores. Pittsburgh compound B (PiB)-PET scans were acquired to determine the presence (PiB+) or absence (PiB-) of Aß pathology. Mixed models were used to assess the independent and interactive effects of SCD, affective features, PiB status, and time on cognition, with adjustment for demographic variables. RESULTS: SCD score demonstrated good construct validity compared to an existing measure of subjective memory and was partially explained by several lower-order measurements. Mixed models revealed that SCD interacted with PiB status to predict change in episodic memory and global cognition over time, with adjustment for affective features. PiB+ individuals with more severe SCD demonstrated the steepest cognitive decline. Worse SCD predicted faster decline in working memory independently of PiB status. No such effects were seen for affective scores when adjusted for SCD. CONCLUSIONS: PiB+ individuals with SCD are at greatest risk of cognitive decline. Evidence for amyloid alone is not sufficient to indicate risk of rapid cognitive decline in healthy elderly. Effects of GDS on cognitive decline in nondepressed cohorts may be driven by SCD rather than subsyndromal depression.

Impact of lifestyle dimensions on brain pathology and cognition.

Single lifestyle factors affect brain biomarkers and cognition. Here, we addressed the covariance of various lifestyle elements and investigated their impact on positron emission tomography-based ß-amyloid (Aß), hippocampal volume, and cognitive function in aged controls. Lower Aß burden was associated with a lifestyle comprising high cognitive engagement and low vascular risk, particularly in apolipoprotein E ε4 carriers. Although cognitive function was related to high lifetime cognitive engagement and low vascular risk, Aß load had no relation to current cognitive function. The covariance between high adult socioeconomic status, high education, and low smoking prevalence predicted better cognitive function and this was mediated by larger hippocampal volume. Our data show that lifestyle is a complex construct composed of associated variables, some of which reflect factors operating over the life span and others which may be developmental. These factors affect brain health via different pathways, which may reinforce one another. Our findings moreover support the importance of an intellectually enriched lifestyle accompanied by vascular health on both cognition and presumed cerebral mediators of cognitive function.

PET Imaging of Tau Deposition in the Aging Human Brain.

Tau pathology is a hallmark of Alzheimer's disease (AD) but also occurs in normal cognitive aging. Using the tau PET agent (18)F-AV-1451, we examined retention patterns in cognitively normal older people in relation to young controls and AD patients. Age and ß-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory performance. PET detection of tau in other isocortical regions required the presence of cortical ß-amyloid and was associated with decline in global cognition. Furthermore, patterns of tracer retention corresponded well with Braak staging of neurofibrillary tau pathology. The present study defined patterns of tau tracer retention in normal aging in relation to age, cognition, and ß-amyloid deposition.