Air pollution, cognitive deficits and brain abnormalities: a pilot study with children and dogs

Exposure to air pollution is associated with neuroinflammation in healthy children and dogs in Mexico City. Comparative studies were carried out in healthy children and young dogs similarly exposed to ambient pollution in Mexico City. Children from Mexico City (n: 55) and a low polluted city (n:18) underwent psychometric testing and brain magnetic resonance imaging MRI. Seven healthy young dogs with similar exposure to Mexico City air pollution had brain MRI, measurement of mRNA abundance of two inflammatory genes cyclooxygenase-2, and interleukin 1 beta in target brain areas, and histopathological evaluation of brain tissue. Children with no known risk factors for neurological or cognitive disorders residing in a polluted urban environment exhibited significant deficits in a combination of fluid and crystallized cognition tasks. Fifty-six percent of Mexico City children tested showed prefrontal white matter hyperintense lesions and similar lesions were observed in dogs (57%). Exposed dogs had frontal lesions with vascular subcortical pathology associated with neuroinflammation, enlarged Virchow-Robin spaces, gliosis, and ultrafine particulate matter deposition. Based on the MRI findings, the prefrontal cortex was a target anatomical region in Mexico City children and its damage could have contributed to their cognitive dysfunction. The present work presents a groundbreaking, interdisciplinary methodology for addressing relationships between environmental pollution, structural brain alterations by MRI, and cognitive deficits/delays in healthy children.     

The role of white matter hyperintensities and medial temporal lobe atrophy in age-related executive dysfunctioning

Various studies support an association between white matter hyperintensities (WMH) and deficits in executive function in nondemented ageing. Studies examining executive functions and WMH have generally adopted executive function as a phrase including various functions such as flexibility, inhibition, and working memory. However, these functions include distinctive cognitive processes and not all may be affected as a result of WMH. Furthermore, atrophy of the medial temporal lobe (MTA) is frequently observed in ageing. Nevertheless, in previous studies of nondemented ageing MTA was not considered when examining a relationship between white matter and executive function. The goal of the present study was to examine how WMH and MTA relate to a variety of executive functions, including flexibility, fluency, inhibition, planning, set shifting, and working memory. Strong correlations were observed between WMH and MTA and most of the executive functions. However, only MTA was related to flexibility and set shifting performance. Regression analysis furthermore showed that MTA was the strongest predictor of working memory, after which no further significant association with WMH was noted. Alternatively, both MTA and periventricular hyperintensities independently predicted inhibition performance. These findings emphasize the importance of MTA when examining age-related decline in executive functioning.     

White Matter Hyperintensities and Working Memory: An Explorative Study

ABSTRACT

White matter hyperintensities (WMH) are commonly observed in elderly people and may have the most profound effect on executive functions, including working memory. Surprisingly, the Digit Span backward, a frequently employed working memory task, reveals no association with WMH. In the present study, it was investigated whether more detailed analyses of WMH variables and study sample selection are important when establishing a possible relationship between the Digit Span backward and WMH. To accomplish this, the Digit Span backward and additional working memory tests, WMH subscores, and cardiovascular risk factors were examined. The results revealed that performance on the Digit Span backward test is unrelated to WMH, whereas a relationship between other working memory tests and WMH was confirmed. Furthermore, a division between several white matter regions seems important; hyperintensities in the frontal deep white matter regions were the strongest predictor of working memory performance.     

Aging Effects on Recollection and Familiarity: The Role of White Matter Hyperintensities

ABSTRACT

Previous studies have indicated that aging is associated with declines in recollection whereas familiarity-based recognition is left largely unaffected. The brain changes underlying these recollection declines are yet not well understood. In the current study we examined the role of white matter integrity as measured by white matter hyperintensities (WMH) on age-related changes in recollection and familiarity. Recognition was measured using a remember/know procedure (Experiment 1) and a source-memory process-dissociation procedure (Experiment 2). Robust age related declines in recollection were observed, but there was no evidence that white matter damage was related to the observed memory declines. Although future studies with larger samples will be necessary to fully characterize the role of WMH in normal age-related declines in different types of memory, the results suggest that declines in recollection are not strongly related to the brain changes indexed by WMHs.     

Processing speed in normal aging: Effects of white matter hyperintensities and hippocampal volume loss

Changes in cognitive functioning are said to be part of normal aging. Quantitative MRI has made it possible to measure structural brain changes during aging which may underlie these decrements which include slowed information processing and memory loss. Much has been written on white matter hyperintensities (WMH), which are associated with cognitive deficits on tasks requiring processing speed and executive functioning, and hippocampal volume loss, which is associated with memory decline. Here we examine volumetric MRI measures of WMH and hippocampal volume loss together in relation to neuropsychological tests considered to be measures of executive functioning and processing speed in 81 non-demented elderly individuals, aged 75–90. Correlational analysis showed that when controlling for age, both greater WMH volume and smaller hippocampal volume were correlated with slower performances on most tests with the exception of a battery of continuous performance tests in which only WMH was correlated with slower reaction time (RT). We then performed a series of hierarchical multiple regression analyses to examine the independent contributions of greater WMH volume and reduced hippocampal volume to executive functioning and processing speed. The results showed that for the four measures requiring executive functioning and speed of processing, WMH volume and hippocampal volume combined predicted between 21.4% and 37% of the explained variance. These results suggest that WM integrity and hippocampal volume influence cognitive decline independently on tasks involving processing speed and executive function independent of age.     

The Relation of White Matter Hyperintensities to Cognitive Performance in the Normal Old: Education Matters

ABSTRACT

This study examined whether the severity of cerebral white matter abnormalities (evident on MR images as white matter hyperintensities (WMH)) was related to the cognitive performance of 141 high-functioning older adults. The elderly showed the typical age decrement on measures of processing speed, working memory, and inhibition; however WMH severity was significantly related only to processing speed. The strength of this relationship was, however, influenced by the educational level of the participants, such that processing speed was more associated with WMH severity in less-educated than in well-educated participants. This is consistent with recent concepts of cognitive reserve, but does raise a question as to the underlying source of the cognitive decrement found in the sort of well-educated elders typically used in cognitive-aging studies.     

The relation of white matter hyperintensities to cognitive performance in the normal old: education matters

This study examined whether the severity of cerebral white matter abnormalities (evident on MR images as white matter hyperintensities (WMH)) was related to the cognitive performance of 141 high-functioning older adults. The elderly showed the typical age decrement on measures of processing speed, working memory, and inhibition; however WMH severity was significantly related only to processing speed. The strength of this relationship was, however, influenced by the educational level of the participants, such that processing speed was more associated with WMH severity in less-educated than in well-educated participants. This is consistent with recent concepts of cognitive reserve, but does raise a question as to the underlying source of the cognitive decrement found in the sort of well-educated elders typically used in cognitive-aging studies.     

Microstructural integrity of the corpus callosum linked with neuropsychological performance in adolescents

Background: Diffusion tensor imaging (DTI) has revealed microstructural aspects of adolescent brain development, the cognitive correlates of which remain relatively uncharacterized. Methods: DTI was used to assess white matter microstructure in 18 typically developing adolescents (ages 16–18). Fractional anisotropy (FA) and mean diffusion (MD) were evaluated within the splenium and body of the corpus callosum in relation to cognitive performance. Results: Visuospatial construction abilities were associated with white matter integrity in both the splenium and body of the corpus callosum, while only splenium integrity was associated with language and psychomotor function. Conclusion: Results suggest that, for typically developing adolescents, white matter coherence positively relates to visuospatial, psychomotor, and language skills. These findings may have implications for the cognitive functioning of clinical populations in which typical white matter development is altered.     

Neurocognitive correlates of white matter quality in adolescent substance users

Background

Progressive myelination during adolescence implicates an increased vulnerability to neurotoxic substances and enduring neurocognitive consequences. This study examined the cognitive manifestations of altered white matter microstructure in chronic marijuana and alcohol-using (MJ + ALC) adolescents.

Methods

Thirty-six MJ + ALC adolescents (ages 16–19) and 36 demographically similar controls were evaluated with diffusion tensor imaging (Bava et al., 2009) and neurocognitive tests. Regions of group difference in fractional anisotropy (FA) and mean diffusivity (MD) were analyzed in relation to cognitive performance.

Results

In users, lower FA in temporal areas related to poorer performance on attention, working memory, and speeded processing tasks. Among regions where users had higher FA than controls, occipital FA was positively associated with working memory and complex visuomotor sequencing, whereas FA in anterior regions was negatively associated with verbal memory performance.

Conclusions

Findings suggest differential influences of white matter development on cognition in MJ + ALC using adolescents than in non-using peers. Neuroadaptation may reflect additive and subtractive responses to substance use that are complicated by competing maturational processes.     

White matter integrity and pictorial reasoning in high-functioning children with autism

The current study investigated the neurobiological role of white matter in visuospatial versus linguistic processing abilities in autism using diffusion tensor imaging. We examined differences in white matter integrity between high-functioning children with autism (HFA) and typically developing controls (CTRL), in relation to the groups’ response times (RT) on a pictorial reasoning task under three conditions: visuospatial, V, semantic, S, and V + S, a hybrid condition allowing language use to facilitate visuospatial transformations.     

White matter development during adolescence as shown by diffusion MRI

Previous volumetric developmental MRI studies of the brain have shown white matter development continuing through adolescence and into adulthood. This review presents current findings regarding white matter development and organization from diffusion MRI studies. The general trend during adolescence (age 12–18 years) is towards increasing fractional anisotropy (FA) with age and decreasing mean diffusivity (MD) with age, findings primarily due to decreasing radial diffusivity with age. However, results of studies vary as to the regional specificity of such age-related changes, likely due in part to methodological issues. Another general trend is for FA to positively correlate and MD to negatively correlate with cognitive function. This trend is however region-specific, task-specific, and population-specific; some studies have in fact found negative correlations of FA and positive correlations of MD in specific regions with specific measures of cognitive performance. There are also published reports of sexual dimorphism in white matter development, indicating differing developmental trajectories between males and females as well as differing relationships developmentally between white matter architecture and cognitive function. There is a need for more research to further elucidate the development of white matter and its relation to cognitive function during this critical developmental period.     

Correlation between gray/white matter volume and cognition in healthy elderly people

This study applied volumetric analysis and voxel-based morphometry (VBM) of brain magnetic resonance (MR) images to assess whether correlations exist between global and regional gray/white matter volume and the cognitive functions of semantic memory and short-term memory, which are relatively well preserved with aging, using MR image data from 109 community-dwelling healthy elderly individuals. We used the Information and Digit Span subtests of the Wechsler Adult Intelligent Scale-Revised as measures of semantic memory and short-term memory, respectively. We found significant positive correlations between the gray matter ratio, the percentage of gray matter volume in the intracranial volume, and performance on the Digit Span subtest, and between the regional gray matter volumes of the bilateral anterior temporal lobes and performance on the Information subtest. No significant correlations between performance on the cognitive tests and white matter volume were found. Our results suggest that individual variability in specific cognitive functions that are relatively well preserved with aging is accounted for by the variability of gray matter volume in healthy elderly subjects.     

Sex differences in brain volume are related to specific skills, not to general intelligence

It has been proposed that males would show higher mean scores than females in general intelligence (g) because (1) men have, on average, larger brains than women, and (2) brain volume correlates with g. Here we report a failure to support the conclusion derived from these premises. High resolution MRIs were acquired in a sample of one hundred healthy young participants for estimating total, gray, and white matter volumes. Participants also completed an intelligence battery - comprising tests measuring abstract, verbal, and spatial abilities - that allowed the extraction of g scores. Results showed consistent relations between sex differences in brain volumes and non-g spatial and verbal skills but not for g.     

Myelin breakdown mediates age-related slowing in cognitive processing speed in healthy elderly men

Background

To assess the hypothesis that in a sample of very healthy elderly men selected to minimize risk for Alzheimer’s disease (AD) and cerebrovascular disease, myelin breakdown in late-myelinating regions mediates age-related slowing in cognitive processing speed (CPS).

Materials and methods

The prefrontal lobe white matter and the genu of the corpus callosum myelinate later in brain development (late-myelinating white matter; LMWM) and are more vulnerable to breakdown due to the effects of normal aging. An in vivo MRI biomarker of myelin integrity (transverse relaxation rates; R₂) of LMWM was obtained for 38 very healthy elderly adult men (mean age = 66.3 years; SD = 6.0; range = 55–76). To evaluate regional specificity, we also assessed a contrasting early-myelinating region (splenium of the corpus callosum; SWM), which primarily contains axons involved in visual processing. CPS was assessed using the Trail Making Test.

Results

LMWM R₂ and CPS measures were significantly correlated (r = .515, p = .0009), but no significant association between R₂ and CPS was detected in the splenium (p = .409). LMWM R₂, but not SWM R₂, was a significant mediator of the relationship between age and CPS (p = .037).

Conclusions

In this very healthy elderly sample, age-related slowing in CPS is mediated by myelin breakdown in highly vulnerable late-myelinating regions but not in the splenium.     

Atrophy of the parietal lobe in preclinical dementia

Cortical grey matter atrophy patterns have been reported in healthy ageing and Alzheimer disease (AD), but less consistently in the parietal regions of the brain. We investigated cortical grey matter volume patterns in parietal areas. The grey matter of the somatosensory cortex, superior and inferior parietal lobule was measured in 75 older adults (38 cognitively stable and 37 individuals with cognitive decline after 3 years). Dementia screening 6 years after scanning resulted in nine AD cases from the cognitively stable (n=3) and cognitive decline group (n=6), who were assigned to a third group, the preclinical AD group. When regional differences in cortical volume in the parietal lobe areas were compared between groups, significant differences were found between either the cognitive decline or stable group on the one hand and preclinical AD individuals on the other hand in the inferior parietal lobule. Group membership was best predicted by the grey matter volume of the inferior parietal lobule, compared to the other parietal lobe areas. The parietal lobe was characterised by a differential atrophy pattern based on cognitive status, which is in agreement with the 'last-developed-first-atrophied' principle. Future studies should investigate the surplus value of the inferior parietal lobe as a potential marker for the diagnosis of AD compared to other brain regions, such as the medial temporal lobe and the prefrontal lobe.     

Neuroanatomical substrates of age-related cognitive decline

There are many reports of relations between age and cognitive variables and of relations between age and variables representing different aspects of brain structure and a few reports of relations between brain structure variables and cognitive variables. These findings have sometimes led to inferences that the age-related brain changes cause the age-related cognitive changes. Although this conclusion may well be true, it is widely recognized that simple correlations are not sufficient to warrant causal conclusions, and other types of correlational information, such as mediation and correlations between longitudinal brain changes and longitudinal cognitive changes, also have limitations with respect to causal inferences. These issues are discussed, and the existing results on relations of regional volume, white matter hyperintensities, and diffusion tensor imaging measures of white matter integrity to age and to measures of cognitive functioning are reviewed. It is concluded that at the current time the evidence that these aspects of brain structure are neuroanatomical substrates of age-related cognitive decline is weak. The final section contains several suggestions concerning measurement and methodology that may lead to stronger conclusions in the future.     

Finding the g-factor in brain structure using the method of correlated vectors

It is unclear whether brain mechanisms underlying human intelligence are distributed throughout the brain or mainly concentrated in the frontal lobes. Data are inconsistent possibly due, at least in part, to the different ways the construct of intelligence is measured. Here we apply the method of correlated vectors to determine how the general factor of intelligence (g) is related to regional gray matter and white matter volumes. This is a re-analysis of an earlier study showing regional gray matter and white matter volume is correlated to Full Scale IQ (FSIQ). However, it is well-known that FSIQ taps several cognitive abilities and skills in addition to g. The results now show that the g factor accounts for several but not all FSIQ/gray matter correlations distributed throughout the brain and these areas may differ for young and older adults.     

Verbal–spatial IQ discrepancies impact brain activation associated with the resolution of cognitive conflict in children and adolescents

Verbal–spatial discrepancies are common in healthy individuals and in those with neurodevelopmental disorders associated with cognitive control deficits including: Autism Spectrum Disorder, Non‐Verbal Learning Disability, Fragile X, 22q11 deletion, and Turner Syndrome. Previous data from healthy individuals suggest that the magnitude of the difference between verbal IQ (VIQ) and performance IQ (PIQ) scores (the VIQ>PIQ discrepancy) is associated with reduced thickness in frontal and parietal cortices (inferior frontal, anterior cingulate, inferior parietal lobule, and supramarginal gyrus) that support cognitive control. Unknown is whether the VIQ>PIQ discrepancy is associated with functional deficits in these areas in healthy or ill children and adolescents. We assessed the effects of the VIQ>PIQ discrepancy on fMRI BOLD response during the resolution of cognitive conflict in 55 healthy children and adolescents during performance of a Simon Spatial Incompatibility task. As the magnitude of the VIQ>PIQ discrepancy increased, activation of fronto‐striatal, limbic, and temporal regions decreased during conflict resolution (p < .05, corrected). In exploratory analyses, the VIQ>PIQ discrepancy was associated with reduced functional connectivity from right inferior frontal gyrus to right thalamus and increased functional connectivity to right supramarginal gyrus (ps < .03, uncorrected). The VIQ>PIQ discrepancy may be an important aspect of an individual's cognitive profile and likely contributes to, or is associated with, deficient cognitive control processes characteristic of many childhood disorders.     

DNA markers associated with general and specific cognitive abilities

Multivariate quantitative genetic research suggests a hierarchical model of cognitive abilities where genetic effects are largely general, cutting across most cognitive abilities. Some genetic effects, however, are specific to certain cognitive abilities. These results lead to a hypothesis for molecular genetic research: Although most genes associated with one cognitive ability will be related to other cognitive abilities, some genes will be specific to a particular cognitive ability. The current research explored this hypothesis in an analysis of data in specific cognitive abilities from 86 children from 6 to 12 years of age from a larger allelic association study of general cognitive ability. Eight DNA markers were entered simultaneously in separate multiple regression analyses predicting each of four specific cognitive ability factors (Verbal, Spatial, Perceptual Speed, Memory), as well as WISC-R subtest scores. Four marjers (CTGB33, EST00083, HLA, and SOD2) showed similar effects across the cognitive ability scales, suggesting that they are related to general cognitive ability (g). These associations became negligible when the effects of ‘g’ (WISC-R IQ) were removed. Three markers (ADH5, DM, and NGFB) continued to be significantly associated with specific cognitive ability scales after the effects of ‘g’ were removed. Although preliminary, these molecular genetic results support the hierarchical model predicted by quantitative genetic research.     

Inspection time and intelligence in 7-yr-old children: A follow-up

Remeasures of inspection time (IT) were obtained from 30 of the 47 children reported in Nettelbeck and Young (Personality and Individual Differences, 10, 605–614, 1989). Ages ranged from 7 yr–0 months to 7–11 and Full Scale IQ (WISC-R) ranged from 93 to 142 (mean = 116.5 SD = 12.2). Correlations between IT and the WISC-R subtests, scales and factors used in the earlier study were generally statistically significant: and similar to those found earlier. The correlation between IT and Full Scale IQ was — 0.49, with those children whose IQs were below the median score of 116 again contributing more to this outcome. Similarly, the IT-IQ correlation was higher among children showing less well-directed attention in the IT task. Once again IT correlated better with Verbal IQ, supporting the hypothesis that IT is better associated with more general intellectual functioning than with specific cognitive abilities. Cross-lagged panel correlations between IT and IQ were —0.40, whether predicting IQ from IT or the reverse. Thus, there was no evidence for a causal relationship between these variables, although both may reflect a common cognitive ability factor.