Christian Chicherio

Human aging magnifies genetic effects on executive functioning and working memory

We demonstrate that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. We assess two common Val/Met polymorphisms, one affecting the Catechol-O-Methyltransferase (COMT) enzyme, which degrades dopamine (DA) in prefrontal cortex (PFC), and the other influencing the brain-derived neurotrophic factor (BDNF) protein. In two tasks (Wisconsin Card Sorting and spatial working memory), we find that effects of COMT genotype on cognitive performance are magnified in old age and modulated by BDNF genotype. Older COMT Val homozygotes showed particularly low levels of performance if they were also BDNF Met carriers. The age-associated magnification of COMT gene effects provides novel information on the inverted U-shaped relation linking dopaminergic neuromodulation in PFC to cognitive performance. The modulation of COMT effects by BDNF extends recent evidence of close interactions between frontal and medial-temporal circuitries in executive functioning and working memory.

Age-related decline in brain resources modulates genetic effects on cognitive functioning

Individual differences in cognitive performance increase from early to late adulthood, likely reflecting influences of a multitude of factors. We hypothesize that losses in neurochemical and anatomical brain resources in normal aging modulate the effects of common genetic variations on cognitive functioning. Our hypothesis is based on the assumption that the function relating brain resources to cognition is nonlinear, so that genetic differences exert increasingly large effects on cognition as resources recede from high to medium levels in the course of aging. Direct empirical support for this hypothesis comes from a study by Nagel et al. (2008), who reported that the effects of the Catechol-O-Methyltransferase (COMT) gene on cognitive performance are magnified in old age and interacted with the Brain-Derived Neurotrophic Factor (BDNF) gene. We conclude that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. Extensions of the hypothesis to other polymorphisms are discussed. (150 of 150 words)

Ebbinghaus revisited: Influences of the bdnf val66met polymorphism on backward serial recall are modulated by human aging

The brain-derived neurotrophic factor (BDNF) plays an important role in activity-dependent synaptic plasticity, which underlies learning and memory. In a sample of 948 younger and older adults, we investigated whether a common Val66Met missense polymorphism (rs6265) in the BDNF gene affects the serial position curve—a fundamental phenomenon of associative memory identified by Hermann Ebbinghaus more than a century ago. We found a BDNF polymorphism effect for backward recall in older adults only, with Met-allele carriers (i.e., individuals with reduced BDNF signaling) recalling fewer items than Val homozygotes. This effect was specific to the primacy and middle portions of the serial position curve, where intralist interference and associative demands are especially high. The poorer performance of older Met-allele carriers reflected transposition errors, whereas no genetic effect was found for omissions. These findings indicate that effects of the BDNF polymorphism on episodic memory are most likely to be observed when the associative and executive demands are high. Furthermore, the findings are in line with the hypothesis that the magnitude of genetic effects on cognition is greater when brain resources are reduced, as is the case in old age.

Peak individual alpha frequency qualifies as a stable neurophysiological trait marker in healthy younger and older adults

The individual alpha frequency (IAF) of the human EEG reflects systemic properties of the brain, is highly heritable, and relates to cognitive functioning. Not much is known about the modifiability of IAF by cognitive interventions. We report analyses of resting EEG from a large-scale training study in which healthy younger (20-31 years, N = 30) and older (65-80 years, N = 28) adults practiced 12 cognitive tasks for ∼100 1-h sessions. EEG was recorded before and after the cognitive training intervention. In both age groups, IAF (and, in a control analysis, alpha amplitude) did not change, despite large gains in cognitive performance. As within-session reliability and test-retest stability were high for both age groups, imprecise measurements cannot account for the findings. In sum, IAF is highly stable in healthy adults up to 80 years, not easily modifiable by cognitive interventions alone, and thus qualifies as a stable neurophysiological trait marker.

Individual alpha peak frequency is related to latent factors of general cognitive abilities

Some eighty years after the discovery of the human electroencephalogram (EEG) and its dominant rhythm, alpha (~10Hz), the neurophysiological functions and behavioral correlates of alpha oscillations are still under debate. Similarly, the biological mechanisms contributing to the general factor of intelligence, or g, have been under scrutiny for decades. Individual alpha frequency (IAF), a trait-like parameter of the EEG, has been found to correlate with individual differences in cognitive performance and cognitive abilities. Informed by large-scale theories of neural organization emphasizing the general functional significance of oscillatory activity, the present study replicates and extends these findings by testing the hypothesis that IAF is related to intelligence at the level of g, rather than at the level of specific cognitive abilities. Structural equation modeling allowed us to statistically control for measurement error when estimating the association between IAF and intellectual functioning. In line with our hypothesis, we found a statistically reliable and substantial correlation between IAF and g (r=.40). The magnitude of this correlation did not differ significantly between younger and older adults, and captured all of the covariation between IAF and the cognitive abilities of reasoning, memory, and perceptual speed. The observed association between IAF and g provides a parsimonious explanation for the commonly observed diffuse pattern of correlations between IAF and cognitive performance. We conclude that IAF is a marker of global architectural and functional properties of the human brain.

Individual differences in cognitive plasticity: an investigation of training curves in younger and older adults

To date, cognitive intervention research has provided mixed but nevertheless promising evidence with respect to the effects of cognitive training on untrained tasks (transfer). However, the mechanisms behind learning, training effects and their predictors are not fully understood. Moreover, individual differences, which may constitute an important factor impacting training outcome, are usually neglected. We suggest investigating individual training performance across training sessions in order to gain finer-grained knowledge of training gains, on the one hand, and assessing the potential impact of predictors such as age and fluid intelligence on learning rate, on the other hand. To this aim, we propose to model individual learning curves to examine the intra-individual change in training as well as inter-individual differences in intra-individual change. We recommend introducing a latent growth curve model (LGCM) analysis, a method frequently applied to learning data but rarely used in cognitive training research. Such advanced analyses of the training phase allow identifying factors to be respected when designing effective tailor-made training interventions. To illustrate the proposed approach, a LGCM analysis using data of a 10-day working memory training study in younger and older adults is reported.

Brain energy metabolism in Alzheimer’s disease: 99mTc-HMPAO SPECT imaging during verbal fluency and role of astrocytes in the cellular mechanism of 99mTc-HMPAO retention ☆

The central hypothesis of the study which has been carried out as part of the NRP38 program, is that perturbations of brain energy metabolism are critically involved in the neurodegeneration occurring in Alzheimers disease (AD) and that they may correlate with early cognitive dysfunctioning. In the present multidisciplinary study we set out to monitor brain energy metabolism using FDG-PET and HMPAO-SPECT imaging in a cohort of individuals over 65 years of age, drawn from the general population. HMPAO-SPECT imaging, which is a simpler and more widely accessible imaging procedure than FDG-PET, was performed under basal conditions and during the performance of a cognitive task (verbal fluency test). Three groups were studied. Two groups (groups I and II) included individuals age 65 or more, with no cognitive impairment and carrying an APOE4 positive or APOE4 negative phenotype, respectively; a third group (group III) included patients with clinical signs of AD. Each subject entering the study underwent an FDG-PET, an HMPAO-SPECT and an extensive battery of neuropsychological tests which assess various aspects of cognitive functioning, with a strong emphasis on working memory, divided attention and executive functions. A total of 101 participants were submitted to brain imaging and neuropsychological testing. Among these, 60 participants received the same set of imaging and neuropsychological tasks 24-36 months after the first set (phase II). In this article, we present a preliminary analysis performed on ten subjects from groups I and II and nine subjects from group III: activation (verbal fluency task) induced a specific pattern of increase in HMPAO retention (including BA 9/10, BA 18 bilaterally and right BA 17). In contrast to controls, in nine AD subjects no significant differences in HMPAO retention were observed when comparing activation and basal conditions. The cellular and molecular mechanisms that underlie the retention of HMPAO, the tracer used for single photon emission computed tomography (SPECT) imaging, has been studied in vitro in purified preparations of neurons and astrocytes with the aim of investigating the contribution of different cell types to hexamethyl-propyleneamineoxime labeled with technetium-99m (99mTc-HMPAO) retention in vitro. Results show that 99mTc-HMPAO retention predominates in astrocytes over neurons by a factor of approximately 2.5. Diethyl maleate, ethacrynic acid and buthionine sulfoximine, three agents which significantly reduce glutathione levels, also decreased 99mTc-HMPAO retention in both astrocytes and in neurons. Decrease did not always correlate with glutathione levels however, thus suggesting that other factors could be involved. The data presented indicate that astrocytes might constitute a prominent site of 99mTc-HMPAO retention and most likely contribute significantly to the SPECT signal. In addition, they also suggest that specific alterations in glial cell metabolism could explain flow-independent changes in 99mTc-HMPAO retention in the brain as observed by SPECT in certain pathologies (including Alzheimers disease). In particular, these observations suggest a key role of astrocytes in the signal detected with the imaging procedure, which is altered in the Alzheimers cohort subjected to the verbal fluency activation task.

Negative neurofunctional effects of frequency, depth and environment in recreational scuba diving: the Geneva “memory dive” study

Objectives: To explore relationships between scuba diving activity, brain, and behaviour, and more specifically between global cerebral blood flow (CBF) or cognitive performance and total, annual, or last 6 months’ frequencies, for standard dives or dives performed below 40 m, in cold water or warm sea geographical environments. Methods: A prospective cohort study was used to examine divers from diving clubs around Lac Léman and Geneva University Hospital. The subjects were 215 healthy recreational divers (diving with self-contained underwater breathing apparatus). Main outcome measures were: measurement of global CBF by 133Xe SPECT (single photon emission computed tomography); psychometric and neuropsychological tests to assess perceptual-motor abilities, spatial discrimination, attentional resources, executive functioning, and memory; evaluation of scuba diving activity by questionnaire focusing on number and maximum depth of dives and geographical site of the diving activity (cold water v warm water); and body composition analyses (BMI). Results: (1) A negative influence of depth of dives on CBF and its combined effect with BMI and age was found. (2) A specific diving environment (more than 80% of dives in lakes) had a negative effect on CBF. (3) Depth and number of dives had a negative influence on cognitive performance (speed, flexibility and inhibition processing in attentional tasks). (4) A negative effect of a specific diving environment on cognitive performance (flexibility and inhibition components) was found. Conclusions: Scuba diving may have long-term negative neurofunctional effects when performed in extreme conditions, namely cold water, with more than 100 dives per year, and maximal depth below 40 m.

Increased intraindividual variability is a marker of ADHD but also of dyslexia: A study on handwriting

It has been suggested that intraindividual variability (IIV) in neuropsychological tasks may be a specific characteristic of Attention-Deficit Hyperactivity Disorder (ADHD), but previous research has not thoroughly examined whether IIV also concerns academic performance or other types of developmental disabilities. The present study investigates the role of IIV in 15 children with ADHD without reading difficulties, 15 children with dyslexia without associated symptoms of ADHD, and 15 typically developing children (TDC) in a simple response time (SRT) task and in a skill more directly related with school learning-handwriting. Results show that children with ADHD and those with dyslexia have a greater IIV than the TDC in both tasks. However, the pattern of the relationship between IIV in SRT and handwriting was different in children with ADHD and dyslexia: the IIV in the handwriting task was found to depend on IIV in the SRT task only in children with dyslexia. These findings support the crucial role of IIV not only in ADHD but also in other developmental disabilities, but suggest that in children with ADHD it may present specific aspects related with motor control.

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.