Heart rate reactivity is associated with future cognitive ability and cognitive change in a large community sample

The relationship between cardiovascular reactions to acute mental challenge in the laboratory and cognitive ability has received scant attention. The present study examined the association between reactivity and future cognitive ability. Heart rate and blood pressure reactions to a mental stress task were measured in 1647 participants comprising three distinct age cohorts. Cognitive ability was assessed using the Alice Heim-4 test of general intelligence and choice reaction time 5 and 12 years later. High heart rate reactivity was related to higher general intelligence scores and faster choice reaction times at both follow-ups. High heart rate reactivity was also associated with a smaller decline in cognitive ability between assessments. These associations were still evident following adjustment for a wide range of potentially confounding variables. The present results are consistent with the notion that high reactivity may not always be a maladaptive response and that low or blunted reactivity may also have negative corollaries.     

Evolutionary conserved longevity genes and human cognitive abilities in elderly cohorts

Genetic influences have an important role in the ageing process. The genetic factors that influence success in bodily ageing may also contribute to the successful ageing of cognitive abilities. A comparative genomics approach found longevity genes conserved between yeast Saccharomyces cerevisiae and nematode Caenorhabditis elegans. We hypothesised that these longevity genes influence variance in cognitive ability and age-related cognitive decline in humans. Here, we investigated six of these genes that have human orthologs and show expression in the brain. We tested AFG3L2 (MIM: 604581, AFG3 ATPase family gene 3-like 2 (yeast)), FRAP1 (MIM: 601231, a FK506 binding protein 12-rapamycin associated protein), MAT1A, MAT2A (MIM: 610550 and 601468, methionine adenosyltransferases I alpha and II alpha, respectively), SYNJ1 and SYNJ2 (MIM: 604297 and 609410, synaptojanin-1 and synaptojanin-2, respectively) in approximately 1000 healthy older Scots: the Lothian Birth Cohort 1936 (LBC1936). They were tested on general cognitive ability at age 11 years. At a mean age of 70 years, they re-sat the same general cognitive ability test and underwent an additional battery of diverse cognitive tests. In all, 70 tag and functional SNPs in the six longevity genes were genotyped and tested for association with cognition and cognitive ageing in LBC1936. Suggestive associations were detected between SNPs in SYNJ2, MAT1A, AFG3L2 and SYNJ1 and a general memory factor and general cognitive ability at age 11 and 70 years. Replication studies for cognitive ability associations were performed in 2506 samples from the Cognitive Ageing Genetics in England and Scotland consortium. A meta-analysis replicated the SYNJ2 association with cognitive abilities (lowest P=0.00077). SYNJ2 is a novel gene in which variation is potentially associated with cognitive abilities.     

Brain white matter damage in aging and cognitive ability in youth and older age

Cerebral white matter hyperintensities (WMH) reflect accumulating white matter damage with aging and impair cognition. The role of childhood intelligence is rarely considered in associations between cognitive impairment and WMH. We studied community-dwelling older people all born in 1936, in whom IQ had been assessed at age 11 years. We assessed medical histories, current cognitive ability and quantified WMH on MR imaging. Among 634 participants, mean age 72.7 (SD 0.7), age 11 IQ was the strongest predictor of late life cognitive ability. After accounting for age 11 IQ, greater WMH load was significantly associated with lower late life general cognitive ability (β = ?0.14, p < 0.01) and processing speed (β = ?0.19, p < 0.001). WMH were also associated independently with lower age 11 IQ (β = ?0.08, p < 0.05) and hypertension. In conclusion, having more WMH is significantly associated with lower cognitive ability, after accounting for prior ability, age 11IQ. Early-life IQ also influenced WMH in later life. Determining how lower IQ in youth leads to increasing brain damage with aging is important for future successful cognitive aging.     

Impact of impaired glucose tolerance and type 2 diabetes on cognitive aging

Type 2 diabetes is becoming increasingly common in most Westernized countries and it now occurs at a younger age. There are pathologies associated with diabetes, mostly systemic ones. However, a growing number of studies is also showing that diabetes is associated with impaired cognitive processes in older adults and hasten the progression to dementia. The most common cognitive deficits are decreases in processing speed and verbal memory; these may extend to other aspects of cognition with increasing age. The link between diabetes and cognitive decline is obscured by depression, hypertension, as well as cardio- and cerebrovascular diseases, all of which occur to varying degrees in diabetic patients. A few studies indicate that controlling blood glucose with anti-diabetic treatments may help prevent the cognitive decline in diabetic patients before they are 70 years old. After that age, diabetes appears to produce faster cognitive decline and may increase the occurrence of pathological changes associated with vascular dementia or Alzheimer's disease.     

Unhappiness, health and cognitive ability in old age

BACKGROUND: To test whether scores on depression inventories on entry to a longitudinal study predict mental ability over the next 4-16 years. METHOD: Associations between scores on the Beck Depression Inventory and on tests of intelligence, vocabulary and memory were analysed in 5070 volunteers aged 49-93 years after differences in prescribed drug consumption, death and drop-out, sex, socio-economic advantage and recruitment cohort effects had also been considered. RESULTS: On all cognitive tasks Beck scores on entry, even in the range 0-7 indicating differences in above average contentment, affected overall levels of cognitive performance but not rates of age-related cognitive decline suggesting effects of differences in life satisfaction rather than in depression. CONCLUSIONS: A new finding is that, in old age, increments in life satisfaction are associated with better cognitive performance. Implications for interpreting associations between depression inventory scores and cognitive performance in elderly samples are discussed.     

The association between telomere length, physical health, cognitive ageing, and mortality in non-demented older people

Telomeres are nucleo-protein complexes that protect the ends of chromosomes. The telomeric DNA component shortens each time a somatic cell replicates, eventually leading to cell senescence. Telomere length has been associated with morbidity and mortality rates from age-related diseases. We tested the hypotheses that mean peripheral blood leukocyte telomere length, at age 79 years, is associated with physical health at age 79, cognitive ability at age 79, lifetime cognitive change, smoking, alcohol consumption, social class in adulthood, and mortality in a cohort of people without dementia (the Lothian Birth Cohort 1921: LBC1921). There was a small, significant association between telomere length and verbal fluency (a test of executive function) before (r=-0.16, p=0.027) and after (r=-0.17, p=0.022) adjustment for mental ability at age 11. This might be a type 1 error. Otherwise, we find that telomere length in old age does not have a significant association with age-related physical and cognitive decline or mortality.     

Education and age-related decline in cognitive performance: Systematic review and meta-analysis of longitudinal cohort studies

Central theories of cognitive aging propose that education is an important protective factor for decline in cognitive performance in older age. We conducted a systematic review and meta-analysis of reported estimates of an association between educational attainment and change in performance in six cognitive domains (episodic memory, processing speed, verbal fluency, crystallized intelligence, fluid intelligence, and global ability) in the general population of older individuals. The systematic search (11^th of October 2019) identified 92 eligible articles. The episodic memory domain had the highest number of estimates (37 estimates from 18 articles, n = 109,281) included in the meta-analysis. The fewest estimates (6 estimates from 6 articles, n = 5263) were included for fluid intelligence. Pooled mean estimates from an inverse-variance weighted random effects analysis were not statistically significant and indicated that any association between education and change in cognitive performance is likely of a negligible magnitude. The estimates for education’s role (one additional year) for change in cognitive performance ranged from -0.019 (95 % confidence interval, CI = -0.047, 0.010) to 0.004SD (CI = -0.003, 0.012) per decade. Even if the larger positive point estimates (i.e., protective effects) are selectively considered, the influence of education on change is still at least 12 times less important for the cognitive functioning of an older individual than the association between education and level of cognitive performance. Sensitivity analyses did not substantially alter these results. However, heterogeneity was substantial, and remained largely unexplained by mean age, mean educational attainment, Gini coefficient, GDP per capita, maximum follow-up period, and publication year. Overall, education is an important factor in aging due to its robust association with level of performance, but the current base of empirical evidence is not revealing a consistent and substantial association between educational attainment and changes in cognitive performance in the general population. Theories of cognitive aging must be updated to incorporate this pattern of findings.     

Presynaptic markers of cholinergic function in the rat brain: relationship with age and cognitive status

The nature of age-related changes in cholinergic function and their relationship to age-related behavioral decline were examined in the present study. Male Fischer-344 rats of four ages (four, 11, 17 and 23 months) were tested in a battery of cognitive tasks. Discrete microdissections of brain areas involved in cognitive function were performed, and activity of choline acetyltransferase and levels of hemicholinium-3 binding were determined to assess the integrity of cholinergic innervation. Age-related changes in cholinergic markers occurred predominantly in the medial septal area and its target areas (hippocampus and cingulate cortex), and were also present in the posterior caudate. However, most of the age-related changes in cholinergic markers were already present at ages at which behavioral impairment was not yet maximal. There were some consistent correlations between behavioral and neurochemical measures, independent of age, but these accounted for relatively small proportions of variance in behavioral performance. For most of these correlations, lower levels of presynaptic cholinergic markers were related to better behavioral performance. In brain areas in which correlations changed with age, lower levels of presynaptic cholinergic markers were associated with better performance in young rats, whereas higher levels were associated with better performance in aged rats. Recent lesion studies using a toxin selective for basal forebrain cholinergic neurons have suggested that these neurons do not play as central a role in learning and memory in young and aged animals as was previously thought. When considered in this context, the present results suggest that preserved cholinergic function in old age might act indirectly to sustain cognitive ability. Changes in cholinergic function may represent one of a number of age-related neurobiological events that underlie behavioral impairments, or may be a permissive factor for other age-related processes that are more directly responsible for cognitive impairments.     

Cytomegalovirus infection and cognitive abilities in old age

Cytomegalovirus infection has been implicated in cognitive impairment in studies using brief clinical assessments though findings are inconsistent. The association between cytomegalovirus infection, measured as serostatus or a semiquantitative assessment of antibody level, and cognitive abilities in a sample of older adults was examined. Cytomegalovirus status was assessed at a mean age of 70 years in 1061 participants of the Lothian Birth Cohort 1936. Cognitive ability scores were available for general cognitive ability, processing speed, memory, and vocabulary. Background demographic and environmental factors included father's social class, years of education, childhood cognitive ability, overcrowding in childhood, and access to indoor toilet facilities. Cytomegalovirus seropositive individuals had lower cognitive ability at age 70: mean IQ was 99.1 (SD, 15.1) versus 102.4 (SD, 13.1) in seronegative individuals (t = 3.65; p < 0.001). The likelihood of contracting cytomegalovirus infection by age 70 was predicted by a number of demographic and environmental factors and, after accounting for these, cytomegalovirus infection (considered as serostatus) was not cognitively detrimental. Within cytomegalovirus seropositive individuals, however, higher cytomegalovirus antibody levels were associated with lower general cognitive ability.     

Iron accumulation in the striatum predicts aging-related decline in motor function in rhesus monkeys

Changes in the nigrostriatal system may be involved with the motor abnormalities seen in aging. These perturbations include alterations in dopamine (DA) release, regulation and transport in the striatum and substantia nigra, striatal atrophy and elevated iron levels in the basal ganglia. However, the relative contribution of these changes to the motor deficits seen in aging is unclear. Thus, using the rhesus monkey as a model, the present study was designed to examine several of these key alterations in the basal ganglia in order to help elucidate the mechanisms contributing to age-related motor decline. First, 32 female rhesus monkeys ranging from 4 to 32 years old were evaluated for their motor capabilities using an automated hand-retrieval task. Second, non-invasive MRI methods were used to estimate brain composition and to indirectly measure relative iron content in the striatum and substantia nigra. Third, in vivo microdialysis was used to evaluate basal and stimulus-evoked levels of DA and its metabolites in the striatum and substantia nigra of the same monkeys. Our results demonstrated significant decreases in motor performance, decreases in striatal DA release, and increases in striatal iron levels in rhesus monkeys as they age from young adulthood. A comprehensive statistical analysis relating age, motor performance, DA release, and iron content indicated that the best predictor of decreases in motor ability, above and beyond levels of performance that could be explained by age alone, was iron accumulation in the striatum. This suggests that striatal iron levels may be a biomarker of motor dysfunction in aging; and as such, can be monitored non-invasively by longitudinal brain MRI scans. The results also suggest that treatments aimed at reducing accumulation of excess iron in the striatum during normal aging may have beneficial effects on age-related deterioration of motor performance.     

Estimated maximal and current brain volume predict cognitive ability in old age

Brain tissue deterioration is a significant contributor to lower cognitive ability in later life; however, few studies have appropriate data to establish how much influence prior brain volume and prior cognitive performance have on this association. We investigated the associations between structural brain imaging biomarkers, including an estimate of maximal brain volume, and detailed measures of cognitive ability at age 73 years in a large (N = 620), generally healthy, community-dwelling population. Cognitive ability data were available from age 11 years. We found positive associations (r) between general cognitive ability and estimated brain volume in youth (male, 0.28; females, 0.12), and in measured brain volume in later life (males, 0.27; females, 0.26). Our findings show that cognitive ability in youth is a strong predictor of estimated prior and measured current brain volume in old age but that these effects were the same for both white and gray matter. As 1 of the largest studies of associations between brain volume and cognitive ability with normal aging, this work contributes to the wider understanding of how some early-life factors influence cognitive aging.     

No association of CETP genotype with cognitive function or age-related cognitive change

A cholesteryl ester transfer protein (CETP) genotype (V/V homozygosity for I405V, NCBI dbSNP rs5882) has been associated with preservation of cognitive function in old age, in addition to its associations with exceptional longevity and cardiovascular disease. We tested the hypotheses that this polymorphism was associated with either level of cognitive function or lifetime cognitive change in 525 participants who took part in the Scottish Mental Survey of 1932. Participants took the same well-validated mental ability test at ages 11 and 79. Scores were also available for several other mental ability tests at age 79, and history of cardiovascular disease was available. Frequency of the V/I genotype was slightly greater than expected in the sample, possibly consistent with some role for the V polymorphism in longevity, and the V/V genotype was associated with a lower rate of cardiovascular disease history. There were, however, no significant associations of CETP genotype with either childhood IQ or current cognitive function in old age, or with lifetime change in cognitive function.     

Neuroprotective effects of cognitive enrichment

Cognitive enrichment early in life, as indicated by level of education, complexity of work environment or nature of leisure activities, appears to protect against the development of age-associated cognitive decline and also dementia. These effects are more robust for measures of crystallized intelligence than for measures of fluid intelligence and depend on the ability of the brain to compensate for pathological changes associated with aging. This compensatory ability is referred to as cognitive reserve. The cognitive reserve hypothesis suggests that cognitive enrichment promotes utilization of available functions. Alternatively, late life cognitive changes in cognition may be linked to a factor, such as cholinergic dysfunction, that is also present early in life and contributes to the reduced levels of early life cognitive enrichment. Beneficial effects of environmental enrichment early in life have also been observed in rodents and primates. Research with rodents indicates that these changes have structural correlates, which likely include increased synapses in specific brain regions. Dogs also show age-dependent cognitive decline, and both longitudinal and cross-sectional studies indicate that this decline can be attenuated by cognitive enrichment. Furthermore, cognitive enrichment has differential effects, improving some functions more than others. From a neurobiological perspective, behavioral enrichment in the dog may act to promote neurogenesis later in life. This can be distinguished from nutritional interventions with antioxidants, which appear to attenuate the development of neuropathology. These results suggest that a combination of behavioral and nutritional or pharmacological interventions may be optimal for reducing the rate of age-dependent cognitive decline.     

Clinical, imaging, lesion, and genetic approaches toward a model of cognitive control

The ability to suppress or override competing attentional and behavioral responses is a key component of cognitive processes. This ability continues to develop throughout childhood and appears to be disrupted in a number of childhood disorders (e.g., attention deficit/hyperactivity disorder and Tourette syndrome). At least two brain regions have been implicated repeatedly in these disorders--the frontal lobes and the basal ganglia. The common problem in cognitive control and overlap in implicated brain regions across disorders suggest a single underlying biological mechanism. At the same time, the distinct symptomatology observed across these disorders suggests multiple mechanisms are at play. This article presents converging evidence from clinical, neuroimaging, lesion, and genetic studies to provide a mechanistic model of cognitive control whereby the basal ganglia are involved in inhibition of competing actions and the frontal cortex is involved in representing the relevant thoughts and guiding the appropriate behaviors.     

Memory and cognitive function in normal aging

Memory and cognitive function are known to decline in normal aging. This impairment is due both to inevitable biologic attrition of brain function and to intercurrent disease processes. Memory storage, speed of response, channel capacity, and Performance IQ on the Wechsler Adult Intelligence Scale tend to be most impaired; Verbal IQ and previously learned skills (“crystallized intelligence”) tend to be preserved. Differences between individuals, independent of age, are often more significant than age‐related losses until very advanced age. The biases of cross‐sectional and longitudinal studies may exaggerate or minimize age‐related differences and should be recognized.     

Respiratory sinus arrhythmia and cognitive functioning in children

We examined associations between children's cognitive performance and both basal respiratory sinus arrhythmia (RSA) and RSA regulation to a reaction time task. Cognitive performance was examined in the lab via standardized tests of cognitive functioning (Woodcock–Johnson III) and a reaction time task. Results suggest that a higher level of basal RSA is predictive of better performance on WJ III scales examining fluid intelligence (e.g., working memory, cognitive efficiency). RSA reactivity was not significantly related to cognitive performance. Results build on and extend the literature by demonstrating that, in typically developing elementary school age children, RSA is related to well‐standardized measures of cognitive performance even after controlling for potential confounds. © 2008 Wiley Periodicals, Inc. Dev Psychobiol 51: 249–258, 2009     

Autoimmunity and age-associated cognitive decline

It is suggested that the immune system may play a role in the etiology of age-associated cognitive decline and/or Alzheimer's disease. The relationship between brain-reactive antibodies (BRA) and age-associated cognitive dysfunction is reviewed and discussed. A parallel relationship between BRA increases with age and decline of avoidance learning capacity is described in mouse models. Transfer of immunity from old to young mice was found to accelerate both age-related formation of brain-reactive antibodies and age-related decline of avoidance learning capacity. Short-lived mouse genotypes with accelerated autoimmunity were found to show accelerated age-related declines in their ability to acquire an avoidance response when compared with nonautoimmune mice. Overall, these findings suggest that the immune system could be an important target for development of intervention strategies aimed at extending the intellectually competent period of life. Mice in which autoimmunity is accelerated may be useful as models for the development of such interventions.     

Speed of information processing,health, and cognitive performance in older adults

We tested the hypothesis that reduction in information processing speed could serve as the primary factor underlying age‐related cognitive changes in a group of 55‐to 77‐year‐old adults. Information processing speed was measured using the P300 latency of auditory evoked potentials. Cognitive performance was measured using the Wisconsin Card Sorting Test (WCST) and the Benton Facial Recognition Test (BFRT), which were chosen on the basis of their demonstrated relationship to frontal versus more posterior neural systems, respectively. P300 latency made a significant contribution to the prediction of complex‐pattern‐matching ability (BFRT), but it did not contribute any unique variance to the prediction of cognitive flexibility (WCST). On the other hand, estimates of cardiovascular health accounted for 28% of unique variance in the WCST, but virtually no unique variance on the BFRT. These data are incompatible with a single‐factor model of age‐related cognitive decline.     

Microstructural white matter changes mediate age‐related cognitive decline on the Montreal Cognitive Assessment (MoCA)

Although the relationship between aging and cognitive decline is well established, there is substantial individual variability in the degree of cognitive decline in older adults. The present study investigates whether variability in cognitive performance in community‐dwelling older adults is related to the presence of whole brain or tract‐specific changes in white matter microstructure. Specifically, we examine whether age‐related decline in performance on the Montreal Cognitive Assessment (MoCA), a cognitive screening tool, is mediated by the white matter microstructural decline. We also examine if this relationship is driven by the presence of cardiovascular risk factors or variability in cerebral arterial pulsatility, an index of cardiovascular risk. Sixty‐nine participants (aged 43–87) completed behavioral and MRI testing including T1 structural, T2‐weighted FLAIR, and diffusion‐weighted imaging (DWI) sequences. Measures of white matter microstructure were calculated using diffusion tensor imaging analyses on the DWI sequence. Multiple linear regression revealed that MoCA scores were predicted by radial diffusivity (RaD) of white matter beyond age or other cerebral measures. While increasing age and arterial pulsatility were associated with increasing RaD, these factors did not mediate the relationship between total white matter RaD and MoCA. Further, the relationship between MoCA and RaD was specific to participants who reported at least one cardiovascular risk factor. These findings highlight the importance of cardiovascular risk factors in the presentation of cognitive decline in old age. Further work is needed to establish whether medical or lifestyle management of these risk factors can prevent or reverse cognitive decline in old age.     

Cerebral microbleeds are related to subjective cognitive failures: the RUN DMC study

Cerebral small vessel disease (SVD), including white matter lesions (WML) and lacunar infarcts, is related to objective cognitive impairment but also to subjective cognitive failures (SCF). SCF have reported to be an early predictor of dementia. Cerebral microbleeds (MB) are another manifestation of SVD and have been related to cognitive impairment, but the role of MB in SCF has never been studied. We therefore investigated whether MB are related to SCF among non-demented elderly individuals with SVD, independent of coexisting WML and lacunar infarcts. The RUN DMC study is a prospective cohort study among 503 older persons with cerebral SVD between 50 and 85 years of age. All participants underwent FLAIR and T2* scanning. SCF, subjective memory failures (SMF), and subjective executive failures (SEF) were assessed. The relation between SCF and the presence, number and location of MB was assessed by linear regression analyses adjusted for age, sex, education, depressive symptoms, cognitive function, total brain volume, normalized hippocampal volume, territorial infarcts, WML, and lacunar infarcts. MB were present in 11%. We found a relation between the presence, total number and lobar located MB, and SCF, SMF, and SEF and the reported progression of these failures, especially in participants with good objective cognitive function. In conclusion, MB are related to SCF independent of co-existing WML and lacunar infarcts, especially in those with good objective cognitive performance. These results suggest that MB are associated with the earliest manifestations of cognitive impairment. MB may help us to understand the role of the ever-expanding spectrum of SVD in cognitive impairment.