Dedifferentiation of Functional Brain Activation Associated With Greater Visual Discrimination Accuracy in Middle-Aged and Older Adults.

Neural dedifferentiation refers to an age-related phenomenon whereby brain functions that are localized to specific, distinct, and differentiated brain areas in young adults become less so as people reach more advanced age. Older adults tend to exhibit greater spread of cortical activation on fMRI during cognitive processing compared to younger adults, with evidence that this occurs during visuoperceptual processing. Some age-related functional changes are considered compensatory, but whether dedifferentiation is compensatory is not clearly understood. The current study assessed dedifferentiation and visual discrimination performance during simultaneous match-to-sample tasks from the Visual Assessment Battery (VAB) among 40 healthy middle-aged and older adults using fMRI. Task-relevant regions of interest (ROIs) were created in the dorsal stream for discrimination of spatial location, the ventral stream for shape, and an area encompassing V5 for velocity. Dedifferentiation, or less specificity in functional activation, was associated with greater discrimination accuracy and more years of education. Secondary analyses showed that reduced functional activation in task-relevant ROIs was associated with faster discrimination speed. Age was unassociated with functional activation. Results suggest that dedifferentiation is compensatory. Lack of age effects suggest that other factors beyond age, such as cognitive or brain reserve, may better predict performance when considering cognitive skills that are relatively stable as adults age, such as visual discrimination.

Demographically-adjusted norms for the paced auditory serial addition test and letter number sequencing test in Spanish-speaking adults: Results from the neuropsychological norms for the U.S.-Mexico border region in Spanish (NP-NUMBRS) Project.

OBJECTIVE: The Paced Auditory Serial Addition Test (PASAT) and Wechsler Adult Intelligence Scale Letter Number Sequencing subtest (LNS) are two commonly used measures of working memory. Demographic variables (age, education, ethnicity, etc.) can impact performance on these measures, underscoring the need for demographically adjusted norms. We aimed to develop normative data for the PASAT and LNS for Spanish-speaking adults living in the U.S.-Mexico border region as part of a larger normative effort. METHOD: Participants were native Spanish-speakers from the Neuropsychological Norms for the U.S. Mexico Border Region in Spanish (NP-NUMBRS) project. Two hundred and forty-nine participants completed the PASAT and 202 participants completed LNS. Ages ranged from 19 to 60 and education from 0 to 20 years. RESULTS: Older age was associated with lower scores on LNS (p < .01) but not PASAT. Lower education was associated with lower scores on both tests (ps < .001). Women obtained lower raw scores than men on PASAT (ps < .003), and there were no significant main effects of gender on LNS raw scores. Raw-to-scaled score conversions were calculated, and fractional polynomial equations were developed to calculate demographically-adjusted T-scores accounting for age, education, and gender. Published norms for English-speaking non-Hispanic Whites substantially overestimated rates of impairment (defined as T-score < 40) on both the PASAT and LNS. CONCLUSIONS: The use of the population-specific normative data may improve detection of working memory dysfunction in U.S. Spanish-speaking adults and contribute to improved diagnostic accuracy and treatment planning in this population. Whether the norms generalize to U.S. Spanish-speakers from other countries remains to be determined.

An fMRI study of age-associated changes in basic visual discrimination.

Clinical neuropsychology lacks tests of basic visuoperceptual and spatial skills that have well-controlled administration and sophisticated measurement methods. Items from the Visual Assessment Battery (VAB), a simultaneous match-to-sample task, assessed visual discrimination in 40 healthy adults aged 51-91 during fMRI. The tasks were designed to isolate discrimination of either location, shape, or velocity, and they each had three levels of difficulty. The Location task uniquely activated the dorsal visual processing stream, the Shape task the ventral stream, and the Velocity task an area encompassing V5. Greater age was associated with greater neural recruitment, particularly in frontal areas. Behaviorally, greater age was associated with prolonged response times, but not reduced accuracy. Increased difficulty was associated with slower responses and reduced accuracy, regardless of age. Results validated the specialization of brain regions for spatial, perceptual, and movement discriminations and the use of the VAB to assess functioning localized to these regions. Visual discrimination ability does not change dramatically with age, but like many cognitive processes, performance slows. Anterior neural recruitment during visual discrimination increases with age.

Frontal Gamma-Aminobutyric Acid Concentrations Are Associated With Cognitive Performance in Older Adults.

BACKGROUND: Gamma-aminobutyric acid (GABA), the brain's principal inhibitory neurotransmitter, has been associated with perceptual and attentional functioning. Recent application of magnetic resonance spectroscopy (MRS) provides in vivo evidence for decreasing GABA concentrations during adulthood. It is unclear, however, how age-related decrements in cerebral GABA concentrations contribute to cognitive decline, or whether previously reported declines in cerebral GABA concentrations persist during healthy aging. We hypothesized that participants with higher GABA concentrations in the frontal cortex would exhibit superior cognitive function and that previously reported age-related decreases in cortical GABA concentrations continue into old age. METHODS: We measured GABA concentrations in frontal and posterior midline cerebral regions using a Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) 1H-MRS approach in 94 older adults without history or clinical evidence of mild cognitive impairment or dementia (mean age, 73 years). We administered the Montreal Cognitive Assessment to assess cognitive functioning. RESULTS: Greater frontal GABA concentrations were associated with superior cognitive performance. This relation remained significant after controlling for age, years of education, and brain atrophy. GABA concentrations in both frontal and posterior regions decreased as a function of age. CONCLUSIONS: These novel findings from a large, healthy, older population indicate that cognitive function is sensitive to cerebral GABA concentrations in the frontal cortex, and GABA concentration in frontal and posterior regions continue to decline in later age. These effects suggest that proton MRS may provide a clinically useful method for the assessment of normal and abnormal age-related cognitive changes and the associated physiological contributors.

The aging brain: Movement speed and spatial control.

BACKGROUND/OBJECTIVES: With aging, people commonly develop motor slowing (bradykinesia). Although this slowness with aging may be entirely related to degradation of the cerebral networks important in motor programing, it is possible that, at least in part, it may be a learned procedure for enhancing the accuracy and/or precision of movements. The goal of this study is to test these contradictory hypotheses. METHODS: Twenty-four healthy adults, 12 younger than age 26 and 12 older than age 65 were asked to make alternative marks with a pen between a card centered in front of them and a series of circles distributed across a page. Performance was timed, and participants were instructed to complete the task as quickly as possible while not sacrificing accuracy for speed. The circle sizes and hand used varied by trial. RESULTS: The older adults performed the task more slowly for all target circle diameters. As the circles decreased in size, the younger adults performed the task more rapidly than did the older participants, but the younger participants also had a greater decline in accuracy. CONCLUSIONS: During this aiming task, healthy older adults were less likely than younger adults to sacrifice accuracy for speed. Thus, at least in part, their slowing may be a learned adaptive strategy.

Current Heavy Alcohol Consumption is Associated with Greater Cognitive Impairment in Older Adults.

BACKGROUND: The acute consumption of excessive quantities of alcohol causes well-recognized neurophysiological and cognitive alterations. As people reach advanced age, they are more prone to cognitive decline. To date, the interaction of current heavy alcohol (ethanol [EtOH]) consumption and aging remains unclear. This study tested the hypothesis that negative consequences of current heavy alcohol consumption on neurocognitive function are worse with advanced age. Further, we evaluated the relations between lifetime history of alcohol dependence and neurocognitive function METHODS: Sixty-six participants underwent a comprehensive neurocognitive battery. Current heavy EtOH drinkers were classified using National Institute on Alcohol Abuse and Alcoholism criteria (EtOH heavy, n = 21) based on the Timeline follow-back and a structured clinical interview and compared to nondrinkers, and moderate drinkers (EtOH low, n = 45). Of the total population, 53.3% had a lifetime history of alcohol dependence. Neurocognitive data were grouped and analyzed relative to global and domain scores assessing: global cognitive function, attention/executive function, learning, memory, motor function, verbal function, and speed of processing. RESULTS: Heavy current EtOH consumption in older adults was associated with poorer global cognitive function, learning, memory, and motor function (ps < 0.05). Furthermore, lifetime history of alcohol dependence was associated with poorer function in the same neurocognitive domains, in addition to the attention/executive domain, irrespective of age (ps < 0.05). CONCLUSIONS: These data suggest that while heavy current alcohol consumption is associated with significant impairment in a number of neurocognitive domains, history of alcohol dependence, even in the absence of heavy current alcohol use, is associated with lasting negative consequences for neurocognitive function.

Cognitively Engaging Activity Is Associated with Greater Cortical and Subcortical Volumes.

As the population ages and dementia becomes a growing healthcare concern, it is increasingly important to identify targets for intervention to delay or attenuate cognitive decline. Research has shown that the most successful interventions aim at altering lifestyle factors. Thus, this study examined how involvement in physical, cognitive, and social activity is related to brain structure in older adults. Sixty-five adults (mean age = 71.4 years, standard deviation = 8.9) received the Community Healthy Activities Model Program for Seniors (CHAMPS), a questionnaire that polls everyday activities in which older adults may be involved, and also underwent structural magnetic resonance imaging. Stepwise regression with backward selection was used to predict weekly time spent in either social, cognitive, light physical, or heavy physical activity from the volume of one of the cortical or subcortical regions of interest (corrected by intracranial volume) as well as age, education, and gender as control variables. Regressions revealed that more time spent in cognitive activity was associated with greater volumes of all brain regions studied: total cortex (ß = 0.289, p = 0.014), frontal (ß = 0.276, p = 0.019), parietal (ß = 0.305, p = 0.009), temporal (ß = 0.275, p = 0.020), and occipital (ß = 0.256, p = 0.030) lobes, and thalamus (ß = 0.310, p = 0.010), caudate (ß = 0.233, p = 0.049), hippocampus (ß = 0.286, p = 0.017), and amygdala (ß = 0.336, p = 0.004). These effects remained even after accounting for the positive association between cognitive activity and education. No other activity variable was associated with brain volumes. Results indicate that time spent in cognitively engaging activity is associated with greater cortical and subcortical brain volume. Findings suggest that interventions aimed at increasing levels of cognitive activity may delay cognitive consequences of aging and decrease the risk of developing dementia.

Age exacerbates HIV-associated white matter abnormalities.

Both HIV disease and advanced age have been associated with alterations to cerebral white matter, as measured with white matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), and more recently with diffusion tensor imaging (DTI). This study investigates the combined effects of age and HIV serostatus on WMH and DTI measures, as well as the relationships between these white matter measures, in 88 HIV seropositive (HIV+) and 49 seronegative (HIV-) individuals aged 23-79 years. A whole-brain volumetric measure of WMH was quantified from FLAIR images using a semi-automated process, while fractional anisotropy (FA) was calculated for 15 regions of a whole-brain white matter skeleton generated using tract-based spatial statistics (TBSS). An age by HIV interaction was found indicating a significant association between WMH and older age in HIV+ participants only. Similarly, significant age by HIV interactions were found indicating stronger associations between older age and decreased FA in the posterior limbs of the internal capsules, cerebral peduncles, and anterior corona radiata in HIV+ vs. HIV- participants. The interactive effects of HIV and age were stronger with respect to whole-brain WMH than for any of the FA measures. Among HIV+ participants, greater WMH and lower anterior corona radiata FA were associated with active hepatitis C virus infection, a history of AIDS, and higher current CD4 cell count. Results indicate that age exacerbates HIV-associated abnormalities of whole-brain WMH and fronto-subcortical white matter integrity.

HIV effects on age-associated neurocognitive dysfunction: premature cognitive aging or neurodegenerative disease?

Marked improvements in survival and health outcome for people infected with HIV have occurred since the advent of combination antiretroviral therapy over a decade ago. Yet HIV-associated neurocognitive disorders continue to occur with an alarming prevalence. This may reflect the fact that infected people are now living longer with chronic infection. There is mounting evidence that HIV exacerbates age-associated cognitive decline. Many middle-aged HIV-infected people are experiencing cognitive decline similar that to that found among much older adults. An increased prevalence of vascular and metabolic comorbidities has also been observed and is greatest among older adults with HIV. Premature age-associated neurocognitive decline appears to be related to structural and functional brain changes on neuroimaging, and of particular concern is the fact that pathology indicative of neurodegenerative disease has been shown to occur in the brains of HIV-infected people. Yet notable differences also exist between the clinical presentation and brain disturbances occurring with HIV and those occurring in neurodegenerative conditions such as Alzheimer's disease. HIV interacts with the aging brain to affect neurological structure and function. However, whether this interaction directly affects neurodegenerative processes, accelerates normal cognitive aging, or contributes to a worsening of other comorbidities that affect the brain in older adults remains an open question. Evidence for and against each of these possibilities is reviewed.

The role of carotid intima-media thickness in predicting longitudinal cognitive function in an older adult cohort.

BACKGROUND AND PURPOSE: Carotid atherosclerosis is a risk factor for cerebrovascular disease in older adults. Although age-related cognitive decline has been associated with cerebrovascular disease, not much is known about the consequences of carotid atherosclerosis on longitudinal cognitive function. This study examines the longitudinal relationship between atherosclerosis and cognition in a sample of non-demented older subjects using baseline measurements of carotid intima media thickness (CIMT) and annual cognitive measures of executive function (EXEC) and verbal memory (MEM). METHODS: Baseline measurements included CIMT derived from B-mode carotid artery ultrasound, structural T1-weighted images of white matter hypointensities (WMH), white matter lesions (WML), and cerebral infarct. Hypertension, low-density lipoprotein (LDL), diabetes, and waist to hip ratios (WHR) were included as covariates in our models to control for cerebrovascular risks and central adiposity. Annual composite scores of EXEC and MEM functions were derived from item response theory. Linear mixed models were used to model longitudinal cognitive change. RESULTS: A significant inverse relationship was found between baseline CIMT and annual EXEC score, but not annual MEM score. Subjects included in the highest 4th quartile of CIMT showed a rate of annual decline in EXEC score that was significant relative to subjects in lower quartile groups (p<0.01). The relationship between the 4th quartile of CIMT and annual EXEC score remained significant after independently adjusting for imaging measures of white matter injury and cerebral infarct. CONCLUSIONS: Older adult subjects with the highest index of CIMT showed an annual decline in EXEC scores that was significant relative to subjects with lower quartile measurements of CIMT, independent of our measures of white matter injury and cerebral infarct. Our findings suggest that elevated measures of CIMT may mark an atherosclerotic state, resulting in a decline in executive function and not memory in non-demented older adults.

Verbal memory declines more rapidly with age in HIV infected versus uninfected adults.

OBJECTIVES: In the current era of effective antiretroviral treatment, the number of older adults living with HIV is rapidly increasing. This study investigated the combined influence of age and HIV infection on longitudinal changes in verbal and visuospatial learning and memory. METHOD: In this longitudinal, case-control design, 54 HIV seropositive and 30 seronegative individuals aged 40-74 years received neurocognitive assessments at baseline visits and again one year later. Assessment included tests of verbal and visuospatial learning and memory. Linear regression was used to predict baseline performance and longitudinal change on each test using HIV serostatus, age, and their interaction as predictors. Multivariate analysis of variance (MANOVA) was used to assess the effects of these predictors on overall baseline performance and overall longitudinal change. RESULTS: The interaction of HIV and age significantly predicted longitudinal change in verbal memory performance, as did HIV status, indicating that although the seropositive group declined more than the seronegative group overall, the rate of decline depended on age such that greater age was associated with a greater decline in this group. The regression models for visuospatial learning and memory were significant at baseline, but did not predict change over time. HIV status significantly predicted overall baseline performance and overall longitudinal change. CONCLUSIONS: This is the first longitudinal study focused on the effects of age and HIV on memory. Findings suggest that age and HIV interact to produce larger declines in verbal memory over time. Further research is needed to gain a greater understanding of the effects of HIV on the aging brain.