The correlative triad among aging, dopamine, and cognition: current status and future prospects

The brain neuronal systems defined by the neurotransmitter dopamine (DA) have since long a recognized role in the regulation of motor functions. More recently, converging evidence from patient studies, animal research, pharmacological intervention, and molecular genetics indicates that DA is critically implicated also in higher-order cognitive functioning. Many cognitive functions and multiple markers of striatal and extrastriatal DA systems decline across adulthood and aging. Research examining the correlative triad among adult age, DA, and cognition has found strong support for the view that age-related DA losses are associated with age-related cognitive deficits. Future research strategies for examining the DA-cognitive aging link include assessing (a) the generality/specificity of the effects; (b) the relationship between neuromodulation and functional brain activation; and (c) the release of DA during actual task performance.     

Relations between aging sensory/sensorimotor and cognitive functions

Recent evidence is reviewed to examine relations among sensory, sensorimotor, and cognitive aging. Age-heterogeneous cross-sectional data sets show substantial covariation among sensory, sensorimotor and intellectual abilities, and an increase in covariation from adulthood to old and very old age. Recent longitudinal analyses suggest that changes in sensory and intellectual functioning are interrelated. Experimental studies investigate the interdependence between cognitive and sensory/sensorimotor aging by examining the effects of simulated sensory loss on cognitive performance, or the effects of cognitive load manipulations on sensory or motor performance. Generally, both types of manipulations hinder older adults' performance more than that of younger adults. Theoretically, the age-associated intensification of the links among sensory, sensorimotor and cognitive functions observed both correlationally and experimentally may point to (a). common causes influencing all three functions; (b). an increase in resource overlap, cross-domain resource competition, and compensatory tradeoffs; and (c). a combination of the two. Future research aiming at discerning the relative import of these possibilities would profit from an integration of experimental and correlational research strategies.     

Static and dynamic longitudinal structural analyses of cognitive changes in old age

BACKGROUND: Among the main data-analytical advances of recent decades are Latent Growth Models (LGM) and Multilevel Models (MLM) for the analysis of longitudinal data. OBJECTIVE: We discuss the relative advantages and disadvantages of the two analytical methods and offer some practical guidelines concerning the choice between LGM and MLM based on (a). completeness and balance of the data, (b). theoretical functional form of change examined, (c). examination of the error structure, (d). theoretical relations among differential level effects and differential change effects, and (e). role of time-invariant covariates. METHODS: To discuss LGM and MLM, we provide illustrations from applications to the Berlin Aging Study (BASE) and the Swiss Interdisciplinary Longitudinal Study on the Oldest Old (SWILSO-O). RESULTS: As predicted by two-component theories of lifespan cognition, performance on a vocabulary test (indicator of broad crystallized intelligence) did not decline over time, while scores on a digit letter test (indicator of broad fluid intelligence) decreased over 6 years. Differential level effects were obtained on both variables, while average and differential change effects were obtained only for the digit letter test. In a second set of analyses, we tested the error-free effect that a broad fluid intelligence indicator exerted on the latent yearly change in a broad crystallized intelligence indicator, and vice versa. In both data sets we obtained strong evidence for a more reliable effect of the fluid indicator on the change in the crystallized indicator. This evidence provided support for the dedifferentiation hypothesis of cognitive abilities in very old age. CONCLUSIONS: New insights into cognitive aging phenomena can be gained with proper applications of LGM and MLM. We posit that the choice between LGM and MLM and their specification rests on theoretical and empirical motives to be defined a priori.     

Bilateral testicular teratoma in infancy: report of a rare case treated by testis-sparing surgery.

Testicular tumors are rarely seen in childhood, with germ-cell tumors as the most common type. Teratoma is second only to yolk sac tumor in frequency. Bilateral testicular teratoma is extremely rare. Orchiectomy has been the standard treatment for most tumors of the testes in the past. However, in children, testis-sparing surgery has become the treatment of choice for benign lesions including teratoma. A 10-month-old infant with synchronous bilateral testicular teratomas, one of which was disclosed by ultrasonography, is presented here. While the larger teratoma required unilateral orchiectomy, the smaller tumor in the contralateral testicle was enucleated by testis-sparing surgery. The follow-up at three years was uneventful with normal development of the testis and the boy. Testicular teratoma may reside in both testicles without clinical symptoms. Ultrasound of both testes provides coherent preoperative diagnosis, allowing the surgeon to consider testicular-sparing procedures, thus preventing anorchia in these rare occurrences.     

Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma

Activating BRAF kinase mutations arise in approximately 7% of all human tumors, and preclinical studies have validated the RAF-mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase-ERK signaling cascade as a potentially important therapeutic target in this setting. Selective RAF kinase inhibitors are currently undergoing clinical development, and based on the experience with other kinase-targeted therapeutics, it is expected that clinical responses to these agents, if observed, will lead to the eventual emergence of drug resistance in most cases. Thus, it is important to establish molecular mechanisms underlying such resistance to develop effective therapeutic strategies to overcome or prevent drug resistance. To anticipate potential mechanisms of acquired resistance to RAF inhibitors during the course of treatment, we established drug-resistant clones from a human melanoma-derived cell line harboring the recurrent V600E activating BRAF mutation, which exhibits exquisite sensitivity to AZ628, a selective RAF kinase inhibitor. We determined that elevated CRAF protein levels account for the acquisition of resistance to AZ628 in these cells, associated with a switch from BRAF to CRAF dependency in tumor cells. We also found that elevated CRAF protein levels may similarly contribute to primary insensitivity to RAF inhibition in a subset of BRAF mutant tumor cells. Interestingly, AZ628-resistant cells demonstrating either primary drug insensitivity or acquired drug resistance exhibit exquisite sensitivity to the HSP90 inhibitor geldanamycin. Geldanamycin effectively promotes the degradation of CRAF, thereby revealing a potential therapeutic strategy to overcome resistance to RAF inhibition in a subset of BRAF mutant tumors.     

Reliability of quantitative multiparameter maps is high for magnetization transfer and proton density but attenuated for R1 and R2 * in healthy young adults

We investigate the reliability of individual differences of four quantities measured by magnetic resonance imaging‐based multiparameter mapping (MPM): magnetization transfer saturation (MT), proton density (PD), longitudinal relaxation rate (R₁), and effective transverse relaxation rate (R₂*). Four MPM datasets, two on each of two consecutive days, were acquired in healthy young adults. On Day 1, no repositioning occurred and on Day 2, participants were repositioned between MPM datasets. Using intraclass correlation effect decomposition (ICED), we assessed the contributions of session‐specific, day‐specific, and residual sources of measurement error. For whole‐brain gray and white matter, all four MPM parameters showed high reproducibility and high reliability, as indexed by the coefficient of variation (CoV) and the intraclass correlation (ICC). However, MT, PD, R₁, and R₂* differed markedly in the extent to which reliability varied across brain regions. MT and PD showed high reliability in almost all regions. In contrast, R₁ and R₂* showed low reliability in some regions outside the basal ganglia, such that the sum of the measurement error estimates in our structural equation model was higher than estimates of between‐person differences. In addition, in this sample of healthy young adults, the four MPM parameters showed very little variability over four measurements but differed in how well they could assess between‐person differences. We conclude that R₁ and R₂* might carry only limited person‐specific information in some regions of the brain in healthy young adults, and, by implication, might be of restricted utility for studying associations to between‐person differences in behavior in those regions.     

Lifespan changes in multi-tasking: concurrent walking and memory search in children, young, and older adults

We investigated dual-task performance of cognitive (semantic fluency) and sensorimotor tasks (walking) in 120 children and adults from four age groups (9-year olds, M=9.52 years; 11-year olds, M=11.51 years; young adults, M=25.34 years; older adults, M=64.28 years; N=30 per group). Distances walked during 90 s and numbers of category exemplars generated in the semantic fluency task showed an inverted U-shape function with age. In line with general resource models proportional dual-task costs in walking also showed a U-shaped relation as a function of age with pronounced decrements in the youngest and oldest groups. Only 9-year olds showed significant costs in the cognitive task. Individual differences in single-task performance accounted for more than half of the variance in dual-task performance. Reliable age-related residual variance implicated additional factors particularly in children's developing multi-tasking performances.     

Higher intraindividual variability is associated with more forgetting and dedifferentiated memory functions in old age

Intraindividual trial-to-trial reaction time (RT) variability is commonly found to be higher in clinical populations or life periods that are associated with impaired cognition. In the present study, higher within-person trial-to-trial RT variability in a perceptual speed task is related to more forgetting and dedifferentiation of memory functions in older adults (aged 60-71 years). More specifically, our study showed that individuals in a high-variability group (n = 175) forgot more memory scenes over a 1-week retention interval than individuals in the low-variability group (n = 174). In contrast, slower RT speed was associated with poorer episodic memory in general, but unrelated to the amount of forgetting. Moreover, results from multiple group latent factor analyses showed that episodic memory and working memory functions were more highly correlated in the high-variability (r = .63) than in the low-variability (r = .25) group. Given that deficits in dopamine (DA) modulation may underlie increases in RT variability, the present findings are in line with (i) recent animal studies implicating DA in long-term episodic memory consolidation and (ii) neurocomputational work linking DA modulation of performance variability to dedifferentiation of cognitive functions in old age.     

Motor-equivalent covariation stabilizes step parameters and center of mass position during treadmill walking

We investigated motor-equivalent stabilization of task-related variables (TRV) at times of heel strike in eight healthy young men (23–30 years) who walked on a motorized treadmill at self-selected and prescribed speeds within the normal walking speed range. The TRV consisted of step parameters (step length and width) and the center of mass (CoM) position relative to the support (back and front feet). Motor-equivalent stabilization of the TRV was assessed using a decorrelation technique, comparing empirical to decorrelated (covariation-free) variability. Analysis indicated reliable covariation for all TRV. In both the fore-aft and lateral directions, stabilization by covariation was highest for CoM position relative to the front foot, indicating a prioritization of equilibrium-related variables. Correlations among TRV revealed that the relation between CoM and step parameter control differed between the fore-aft and lateral directions. While stabilization of lateral foot position appears to be due to control of CoM relative to each foot, step length showed small, but reliable, stabilization beyond CoM stabilization, which may be related to spatiotemporal regularity of the step pattern.