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.     

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.     

Cerebral White Matter Integrity and Cognitive Aging: Contributions from Diffusion Tensor Imaging

The integrity of cerebral white matter is critical for efficient cognitive functioning, but little is known regarding the role of white matter integrity in age-related differences in cognition. Diffusion tensor imaging (DTI) measures the directional displacement of molecular water and as a result can characterize the properties of white matter that combine to restrict diffusivity in a spatially coherent manner. This review considers DTI studies of aging and their implications for understanding adult age differences in cognitive performance. Decline in white matter integrity contributes to a disconnection among distributed neural systems, with a consistent effect on perceptual speed and executive functioning. The relation between white matter integrity and cognition varies across brain regions, with some evidence suggesting that age-related effects exhibit an anterior–posterior gradient. With continued improvements in spatial resolution and integration with functional brain imaging, DTI holds considerable promise, both for theories of cognitive aging and for translational application.     

Growth of white matter in the adolescent brain: Myelin or axon?

White matter occupies almost half of the human brain. It contains axons connecting spatially segregated modules and, as such, it is essential for the smooth flow of information in functional networks. Structural maturation of white matter continues during adolescence, as reflected in age-related changes in its volume, as well as in its microstructure. Here I review recent observations obtained with magnetic resonance imaging in typically developing adolescents and point out some of the known variations in structural properties of white matter vis-à-vis brain function in health and disease. I conclude by re-focusing the interpretations of MR-based studies of white matter from myelin to axon.     

Structural Imaging Measures of Brain Aging

During the course of normal aging, biological changes occur in the brain that are associated with changes in cognitive ability. This review presents data from neuroimaging studies of primarily “normal” or healthy brain aging. As such, we focus on research in unimpaired or nondemented older adults, but also include findings from lifespan studies that include younger and middle aged individuals as well as from populations with prodromal or clinically symptomatic disease such as cerebrovascular or Alzheimer’s disease. This review predominantly addresses structural MRI biomarkers, such as volumetric or thickness measures from anatomical images, and measures of white matter injury and integrity respectively from FLAIR or DTI, and includes complementary data from PET and cognitive or clinical testing as appropriate. The findings reveal highly consistent age-related differences in brain structure, particularly frontal lobe and medial temporal regions that are also accompanied by age-related differences in frontal and medial temporal lobe mediated cognitive abilities. Newer findings also suggest that degeneration of specific white matter tracts such as those passing through the genu and splenium of the corpus callosum may also be related to age-related differences in cognitive performance. Interpretation of these findings, however, must be tempered by the fact that comorbid diseases such as cerebrovascular and Alzheimer’s disease also increase in prevalence with advancing age. As such, this review discusses challenges related to interpretation of current theories of cognitive aging in light of the common occurrence of these later-life diseases. Understanding the differences between “Normal” and “Healthy” brain aging and identifying potential modifiable risk factors for brain aging is critical to inform potential treatments to stall or reverse the effects of brain aging and possibly extend cognitive health for our aging society.     

White Matter: Organization and Functional Relevance

Norman Geschwind’s landmark paper in 1965, “Disconnexion Syndromes in Animals and Man,” inspired a generation of investigators to consider the effects of focal brain lesions disrupting higher brain functions. Although Geschwind viewed disconnection as resulting from either white or gray matter lesions, his signature article drew upon the insights of 19th century neurologists and firmly established white matter within the vocabulary of behavioral neurology, neuropsychology, and cognitive neuroscience. This influence, and the advent of sensitive neuroimaging techniques later in the 20th century, led to white matter gradually gaining more attention as an essential component of distributed neural networks subserving cognition and emotion. Today, whereas focal white matter lesions remain central to the pathogenesis of classic neurobehavioral syndromes, diffuse white matter involvement is regarded as increasingly relevant to a wide variety of dementia syndromes and a host of neuropsychiatric disorders as well. In parallel, better understanding of the neurobiology of brain white matter at all ages has been achieved. While much remains to be explored, a general conceptual formulation is that white matter supports information transfer to complement the information processing carried out by gray matter. As knowledge of the organization and functional relevance of white matter continues to advance, improved understanding of the role of myelinated tracts in higher function can be anticipated, and with it many clinical benefits.     

Mapping brain maturation and cognitive development during adolescence

Non-invasive mapping of brain structure and function with magnetic resonance imaging (MRI) has opened up unprecedented opportunities for studying the neural substrates underlying cognitive development. There is an emerging consensus of a continuous increase throughout adolescence in the volume of white matter, both global and local. There is less agreement on the meaning of asynchronous age-related decreases in the volume of grey matter in different cortical regions; these might equally represent loss ("pruning") or gain (intra-cortical myelination) of tissue. Functional MRI studies have so far focused mostly on executive functions, such as working memory and behavioural inhibition, with very few addressing questions regarding the maturation of social cognition. Future directions for research in this area are discussed in the context of processing biological motion and matching perceptions and actions.     

Alcohol-related amnesia and dementia: animal models have revealed the contributions of different etiological factors on neuropathology, neurochemical dysfunction and cognitive impairment

Chronic alcoholism is associated with impaired cognitive functioning. Over 75% of autopsied chronic alcoholics have significant brain damage and over 50% of detoxified alcoholics display some degree of learning and memory impairment. However, the relative contributions of different etiological factors to the development of alcohol-related neuropathology and cognitive impairment are questioned. One reason for this quandary is that both alcohol toxicity and thiamine deficiency result in brain damage and cognitive problems. Two alcohol-related neurological disorders, alcohol-associated dementia and Wernicke-Korsakoff syndrome have been modeled in rodents. These pre-clinical models have elucidated the relative contributions of ethanol toxicity and thiamine deficiency to the development of dementia and amnesia. What is observed in these models--from repeated and chronic ethanol exposure to thiamine deficiency--is a progression of both neural and cognitive dysregulation. Repeated binge exposure to ethanol leads to changes in neural plasticity by reducing GABAergic inhibition and facilitating glutamatergic excitation, long-term chronic ethanol exposure results in hippocampal and cortical cell loss as well as reduced hippocampal neurotrophin protein content critical for neural survival, and thiamine deficiency results in gross pathological lesions in the diencephalon, reduced neurotrophic protein levels, and neurotransmitters levels in the hippocampus and cortex. Behaviorally, after recovery from repeated or chronic ethanol exposure there is impairment in working or episodic memory that can recover with prolonged abstinence. In contrast, after thiamine deficiency there is severe and persistent spatial memory impairments and increased perseverative behavior. The interaction between ethanol and thiamine deficiency does not produce more behavioral or neural pathology, with the exception of reduction of white matter, than long-term thiamine deficiency alone.     

A genetic analysis of brain volumes and IQ in children

In a population-based sample of 112 nine-year old twin pairs, we investigated the association among total brain volume, gray matter and white matter volume, intelligence as assessed by the Raven IQ test, verbal comprehension, perceptual organization and perceptual speed as assessed by the Wechsler Intelligence Scale for Children-III. Phenotypic correlations between the brain volumes and intelligence traits ranged between .20 and .33. Processing speed and brain volume did not correlate. The relation between brain volume and intelligence was entirely explained by a common set of genes influencing both sets of phenotypes.     

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.     

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.     

长期高策略性技能训练对运动员大脑白质结构的影响：一项DTI研究

目前关于运动员经验优势的脑机制还存在争议, 尤其对于涉及较多认知过程参与的高策略性技能项目运动员, 其大脑白质结构可塑性变化还需进一步探究。研究横向对比了乒乓球运动员和非运动员大脑白质纤维束的弥散张量成像数据。结果发现, 相比于非运动员, 乒乓球运动员在连接背侧和腹侧通路脑区的双侧皮质脊髓束、左侧上纵束、左侧下纵束和双侧额枕下束的各向异性值(FA)更大, 进一步分析发现, 部分腹侧通路白质纤维束FA增加的原因是径向扩散系数(RD)下降。研究结果支持了动作双通路模型。提示经过长期高策略性技能训练, 乒乓球运动员在背侧和腹侧通路上的白质纤维束结构完整性增强。     

White matter maturation supports the development of reasoning ability through its influence on processing speed

The structure of the human brain changes in several ways throughout childhood and adolescence. Perhaps the most salient of these changes is the strengthening of white matter tracts that enable distal brain regions to communicate with one another more quickly and efficiently. Here, we sought to understand whether and how white matter changes contribute to improved reasoning ability over development. In particular, we sought to understand whether previously reported relationships between white matter microstructure and reasoning are mediated by processing speed. To this end, we analyzed diffusion tensor imaging data as well as data from standard psychometric tests of cognitive abilities from 103 individuals between the ages of 6 and 18. We used structural equation modeling to investigate the network of relationships between brain and behavior variables. Our analyses provide support for the hypothesis that white matter maturation (as indexed either by microstructural organization or volume) supports improved processing speed, which, in turn, supports improved reasoning ability.     

Neuropsychological profile and neuroimaging in patients with 22Q11.2 Deletion Syndrome: a review.

22q11.2 Deletion Syndrome is associated with cognitive, behavioural, and psychiatric problems and is known to affect brain structure. Recently, 22q11.2 Deletion Syndrome has been proposed as a disease model for a genetic subtype of schizophrenia. In this paper we discuss the currently available literature on neurocognitive functioning and brain anatomy in patients with 22q11.2 Deletion Syndrome, and how this contributes to our understanding of the neurobiology of schizophrenia. Research on cognitive functioning in 22q11.2 Deletion Syndrome patients suggests a specific cognitive profile with impairments on arithmetical, visuo-spatial, and executive tasks and relatively preserved language skills. Prominent findings of neuroimaging studies in 22q11.2 Deletion Syndrome patients are: reduction of overall brain volume, midline defects, structural alterations of cerebellum and frontal lobe, white matter abnormalities, and decreased grey matter volumes in parietal and temporal areas. We describe how brain abnormalities in patients with 22q11.2 Deletion Syndrome may contribute to the understanding of the clinical syndrome including cognitive impairments, psychotic symptoms, and social and communication problems.     

Sex differences in the IQ-white matter microstructure relationship: A DTI study

Sex differences in the relationship between general intelligence and brain structure are a topic of increasing research interest. Early studies focused mainly on gray and white matter differences using voxel-based morphometry, while more recent studies investigated neural fiber tracts using diffusion tensor imaging (DTI) to analyze the white matter microstructure. In this study we used tract-based spatial statistics (TBSS) on DTI to test how intelligence is associated with brain diffusion indices and to see whether this relationship differs between men and women. 63 Men and women divided into groups of lower and higher intelligence were selected. Whole-brain DTI scans were analyzed using TBSS calculating maps of fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). The results reveal that the white matter microstructure differs between individuals as a function of intelligence and sex. In men, higher intelligence was related to higher FA and lower RD in the corpus callosum. In women, in contrast, intelligence was not related to the white matter microstructure. The higher values of FA and lower values of RD suggest that intelligence is associated with higher myelination and/or a higher number of axons particularly in men. This microstructural difference in the corpus callosum may increase cognitive functioning by reducing inter-hemispheric transfer time and thus account for more efficient brain functioning in men.     

Where cognitive development and aging meet: face learning ability peaks after age 30

Research on age-related cognitive change traditionally focuses on either development or aging, where development ends with adulthood and aging begins around 55 years. This approach ignores age-related changes during the 35 years in-between, implying that this period is uninformative. Here we investigated face recognition as an ability that may mature late relative to other abilities. Using data from over 60,000 participants, we traced the ability to learn new faces from pre-adolescence through middle age. In three separate experiments, we show that face learning ability improves until just after age 30 – even though other putatively related abilities (inverted face recognition and name recognition) stop showing age-related improvements years earlier. Our data provide the first behavioral evidence for late maturation of face processing and the dissociation of face recognition from other abilities over time demonstrates that studies on adult age development can provide insight into the organization and development of cognitive systems.     

Differential brain shrinkage over 6 months shows limited association with cognitive practice

The brain shrinks with age, but the timing of this process and the extent of its malleability are unclear. We measured changes in regional brain volumes in younger (age 20–31) and older (age 65–80) adults twice over a 6 months period, and examined the association between changes in volume, history of hypertension, and cognitive training. Between two MRI scans, 49 participants underwent intensive practice in three cognitive domains for 100 consecutive days, whereas 23 control group members performed no laboratory cognitive tasks. Regional volumes of seven brain structures were measured manually and adjusted for intracranial volume. We observed significant mean shrinkage in the lateral prefrontal cortex, the hippocampus, the caudate nucleus, and the cerebellum, but no reliable mean change of the prefrontal white matter, orbital-frontal cortex, and the primary visual cortex. Individual differences in change were reliable in all regions. History of hypertension was associated with greater cerebellar shrinkage. The cerebellum was the only region in which significantly reduced shrinkage was apparent in the experimental group after completion of cognitive training. Thus, in healthy adults, differential brain shrinkage can be observed in a narrow time window, vascular risk may aggravate it, and intensive cognitive activity may have a limited effect on it.     

Different early rearing experiences have long‐term effects on cortical organization in captive chimpanzees (Pan troglodytes)

Consequences of rearing history in chimpanzees (Pan troglodytes) have been explored in relation to behavioral abnormalities and cognition; however, little is known about the effects of rearing conditions on anatomical brain development. Human studies have revealed that experiences of maltreatment and neglect during infancy and childhood can have detrimental effects on brain development and cognition. In this study, we evaluated the effects of early rearing experience on brain morphology in 92 captive chimpanzees (ages 11–43) who were either reared by their mothers (n = 46) or in a nursery (n = 46) with age‐group peers. Magnetic resonance brain images were analyzed with a processing program (BrainVISA) that extracts cortical sulci. We obtained various measurements from 11 sulci located throughout the brain, as well as whole brain gyrification and white and grey matter volumes. We found that mother‐reared chimpanzees have greater global white‐to‐grey matter volume, more cortical folding and thinner grey matter within the cortical folds than nursery‐reared animals. The findings reported here are the first to demonstrate that differences in early rearing conditions have significant consequences on brain morphology in chimpanzees and suggests potential differences in the development of white matter expansion and myelination.     

DEVELOPMENTAL SEX DIFFERENCES IN THE RELATION OF NEUROANATOMICAL CONNECTIVITY TO INTELLIGENCE

Recent neuroimaging research has shown sex-related differences in the relationship between brain structure and cognitive function. Anatomical studies have shown a greater reliance for cognitive function on white matter structure in adult females, and a greater reliance on gray matter structure in adult males. Functional neuroimaging studies have also shown a greater correlation between brain connectivity and cognitive function in females. However, this relationship is not present in young childhood (5 years old) but appears during the developmental period. Here sex differences in structure–function relationships and their developmental trajectory are investigated using diffusion tensor imaging (DTI) on a large cohort of over 100 normal children ages 5–18. Significant sex–X–IQ interactions on fractional anisotropy (FA), a marker for white matter organization, were seen in the left frontal lobe, in fronto-parietal areas bilaterally, and in the arcuate fasciculus bilaterally, with girls showing positive correlations of FA with IQ, and boys showing a negative correlation. Significant sex–X–IQ–X–age interactions on FA were also seen in the left frontal lobe and in fronto-parietal areas bilaterally, showing a developmental effect. These results strongly corroborate previous findings regarding sex differences in structure–function relationships regarding intelligence. Results also indicate that a naïve interpretation of “more is better” with respect to FA may not be accurate, especially in adult males.