Goran Papenberg

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.

Aging magnifies the effects of dopamine transporter and D2 receptor genes on backward serial memory

Aging compromises dopamine transporter (DAT) and receptor mechanisms in the frontostriatal circuitry. In a sample of 1288 younger and older adults, we investigated (i) whether individual differences in genotypes of the DAT gene (i.e., SLC6A3, the DAT variable number of tandem repeat 9/9, 9/10, and 10/10) and in the D2 receptor (DRD2) gene (i.e., the C957T [rs6277] CC and any T) interactively contribute to phenotype variations in episodic memory performance; and (ii) whether these genetic effects are magnified in older adults, because of considerable declines in the dopamine functions. Our results showed that carrying genotypes associated with higher levels of striatal synaptic dopamine (DAT 9/9) and higher density of extrastriatal D2 receptors (C957T CC) were associated with better backward serial recall, an episodic memory task with high encoding and retrieval demands. Critically, the gene-gene interaction effect was reliably stronger in older than in younger adults. In line with the resource modulation hypothesis, our findings suggest that aging-related decline in brain phenotypes (e.g., dopamine functions) could alter the relations between genotypes and behavioral phenotypes (e.g., episodic memory).

Lower theta inter-trial phase coherence during performance monitoring is related to higher reaction time variability : A lifespan study

Trial-to-trial reaction time (RT) variability is consistently higher in children and older adults than in younger adults. Converging evidence also indicates that higher RT variability is (a) associated with lower behavioral performance on complex cognitive tasks, (b) distinguishes patients with neurological deficits from healthy individuals, and also (c) predicts longitudinal cognitive decline in older adults. However, so far the processes underlying increased RT variability are poorly understood. Previous evidence suggests that control signals in the medial frontal cortex (MFC) are reflected in theta band activity and may implicate the coordination of distinct brain areas during performance monitoring. We hypothesized that greater trial-to-trial variability in theta power during performance monitoring may be associated with greater behavioral variability in response latencies. We analyzed event-related theta oscillations assessed during a cued-Go/NoGo task in a lifespan sample covering the age range from middle childhood to old age. Our results show that theta inter-trial coherence during NoGo trials increases from childhood to early adulthood, and decreases from early adulthood to old age. Moreover, in all age groups, individuals with higher variability in medial frontal stimulus-locked theta oscillations showed higher trial-to-trial RT variability behaviorally. Importantly, this effect was strongest at high performance monitoring demands and independent of motor response execution as well as theta power. Taken together, our findings reveal that lower theta inter-trial coherence is related to greater behavioral variability within and across age groups. These results hint at the possibility that more variable MFC control may be associated with greater performance fluctuations.

Dopaminergic gene polymorphisms affect long-term forgetting in old age: Further support for the magnification hypothesis

Emerging evidence from animal studies suggests that suboptimal dopamine (DA) modulation may be associated with increased forgetting of episodic information. Extending these observations, we investigated the influence of DA-relevant genes on forgetting in samples of younger (n = 433, 20–31 years) and older (n = 690, 59–71 years) adults. The effects of single nucleotide polymorphisms of the DA D2 (DRD2) and D3 (DRD3) receptor genes as well as the DA transporter gene (DAT1; SLC6A3) were examined. Over the course of one week, older adults carrying two or three genotypes associated with higher DA signaling (i.e., higher availability of DA and DA receptors) forgot less pictorial information than older individuals carrying only one or no beneficial genotype. No such genetic effects were found in younger adults. The results are consistent with the view that genetic effects on cognition are magnified in old age. To the best of our knowledge, this is the first report to relate genotypes associated with suboptimal DA modulation to more long-term forgetting in humans. Independent replication studies in other populations are needed to confirm the observed association.

Aging-related magnification of genetic effects on cognitive and brain integrity

Heritability studies document substantial genetic influences on cognitive performance and decline in old age. Increasing evidence shows that effects of genetic variations on cognition, brain structure, and brain function become stronger as people age. Disproportionate impairments are typically observed for older individuals carrying disadvantageous genotypes of different candidate genes. These data support the resource-modulation hypothesis, which states that genetic effects are magnified in persons with constrained neural resources, such as older adults. However, given that findings are not unequivocal, we discuss the need to address several factors that may resolve inconsistencies in the extant literature (gene-gene and gene-environment interactions, study populations, gene-environment correlations, and epigenetic mechanisms).

Dopamine D2 receptor availability is linked to hippocampal–caudate functional connectivity and episodic memory

Significance Cognitive functioning depends in part on dopamine neurotransmission in the brain. Research implicates the dopamine D1 receptor family in cognitive functions linked to the prefrontal cortex, such as working memory. The dopamine D2 receptor family has also been linked to cognition, but it remains unclear to which cognitive functions it is specifically related. We examined the relation of D2 receptors to episodic memory, working memory, and speed of processing. D2 receptors in the caudate and hippocampus were related to episodic memory and modulated caudate–hippocampal functional connections. These findings link the dopamine D2 system to hippocampus-based cognitive functions. D1 and D2 dopamine receptors (D1DRs and D2DRs) may contribute differently to various aspects of memory and cognition. The D1DR system has been linked to functions supported by the prefrontal cortex. By contrast, the role of the D2DR system is less clear, although it has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions. Here we present results from 181 healthy adults between 64 and 68 y of age who underwent comprehensive assessment of episodic memory, working memory, and processing speed, along with MRI and D2DR assessment with [11C]raclopride and PET. Caudate D2DR availability was positively associated with episodic memory but not with working memory or speed. Whole-brain analyses further revealed a relation between hippocampal D2DR availability and episodic memory. Hippocampal and caudate D2DR availability were interrelated, and functional MRI-based resting-state functional connectivity between the ventral caudate and medial temporal cortex increased as a function of caudate D2DR availability. Collectively, these findings indicate that D2DRs make a specific contribution to hippocampus-based cognition by influencing striatal and hippocampal regions, and their interactions.

COMT polymorphism and memory dedifferentiation in old age

According to a neurocomputational theory of cognitive aging, senescent changes in dopaminergic modulation lead to noisier and less differentiated processing. The authors tested a corollary hypothesis of this theory, according to which genetic predispositions of individual differences in prefrontal dopamine (DA) signaling may affect associations between memory functions, particularly in old age. Latent correlations between factors of verbal episodic memory and spatial working memory were compared between individuals carrying different allelic variants of the Catechol-O-Methyltransferase (COMT) Val158Met polymorphism, which influences DA availability in prefrontal cortex. In younger adults (n = 973), correlations between memory functions did not differ significantly among the 3 COMT genotypes (r = .35); in older adults (n = 1333), however, the correlation was significantly higher in Val homozygotes (r = .70), whose prefrontal DA availability is supposedly the lowest of all groups examined, than in heterozygotes and Met homozygotes (both rs = .29). Latent means of the episodic memory and working memory factors did not differ by COMT status within age groups. However, when restricting the analysis to the low-performing tertile of older adults (n = 443), we found that Val homozygotes showed lower levels of performance in both episodic memory and working memory than heterozygotes and Met homozygotes. In line with the neurocomputational theory, the observed dedifferentiation of memory functions in older Val homozygotes suggests that suboptimal dopaminergic modulation may underlie multiple facets of memory declines during aging. Future longitudinal work needs to test this conjecture more directly.

MicroRNA-138 is a potential regulator of memory performance in humans

Genetic factors underlie a substantial proportion of individual differences in cognitive functions in humans, including processes related to episodic and working memory. While genetic association studies have proposed several candidate “memory genes,” these currently explain only a minor fraction of the phenotypic variance. Here, we performed genome-wide screening on 13 episodic and working memory phenotypes in 1318 participants of the Berlin Aging Study II aged 60 years or older. The analyses highlight a number of novel single nucleotide polymorphisms (SNPs) associated with memory performance, including one located in a putative regulatory region of microRNA (miRNA) hsa-mir-138-5p (rs9882688, P-value = 7.8 × 10−9). Expression quantitative trait locus analyses on next-generation RNA-sequencing data revealed that rs9882688 genotypes show a significant correlation with the expression levels of this miRNA in 309 human lymphoblastoid cell lines (P-value = 5 × 10−4). In silico modeling of other top-ranking GWAS signals identified an additional memory-associated SNP in the 3′ untranslated region (3′ UTR) of DCP1B, a gene encoding a core component of the mRNA decapping complex in humans, predicted to interfere with hsa-mir-138-5p binding. This prediction was confirmed in vitro by luciferase assays showing differential binding of hsa-mir-138-5p to 3′ UTR reporter constructs in two human cell lines (HEK293: P-value = 0.0470; SH-SY5Y: P-value = 0.0866). Finally, expression profiling of hsa-mir-138-5p and DCP1B mRNA in human post-mortem brain tissue revealed that both molecules are expressed simultaneously in frontal cortex and hippocampus, suggesting that the proposed interaction between hsa-mir-138-5p and DCP1B may also take place in vivo. In summary, by combining unbiased genome-wide screening with extensive in silico modeling, in vitro functional assays, and gene expression profiling, our study identified miRNA-138 as a potential molecular regulator of human memory function.

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.

Genetics and Functional Imaging: Effects of APOE, BDNF, COMT, and KIBRA in Aging

Increasing evidence from cross-sectional and longitudinal molecular-genetic studies suggests that effects of common genetic variations on cognitive functioning increase with aging. We review the influence of candidate genes on brain functioning in old age, focusing on four genetic variations that have been extensively investigated: APOE, BDNF, COMT, and KIBRA. Similar to the behavioral evidence, there are reports from age-comparative studies documenting stronger genetic effects on measures of brain functioning in older adults compared to younger adults. This pattern suggests disproportionate impairments of neural processing among older individuals carrying disadvantageous genotypes. We discuss various factors, including gene-gene interactions, study population characteristics, lifestyle factors, and diseases, that need to be considered in future studies and may help understand inconsistent findings in the extant literature.