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Increased performance variability has been demonstrated in several groups and conditions, including aging and cognitive decline. Structural brain characteristics underlying this phenomenon have so far been elusive. However, there is reason to expect that disconnectivity in associative pathways, whether caused by immature or degraded white matter (WM) tracts, will increase performance variability by neural noise. The aim of this study was to test whether the quality of WM, measured by diffusion tensor imaging, is related to performance variability in healthy adults. Intraindividual standard deviation of the reaction time (sdRT) across trials and median reaction time (mRT) from 270 participants were obtained from a speeded continuous performance task (Eriksen flanker task) with two conditions (congruent, incongruent). Tract-based spatial statistics was used to test the relationship with diffusion characteristics [fractional anisotropy (FA), mean diffusion (MD), radial diffusion (RD), axial diffusion (AD)]. Robust relationships between sdRT and all diffusion measures were found in most WM areas, independently of mRT, age, and sex. The effects were anatomically more widespread in the congruent than the incongruent condition, covering almost 50% of the voxels for RD and MD, and >25% of the voxels for FA and AD. Partial betas were in the range 0.45-0.55, and the strength of the relationships increased significantly with age. For mRT, the effects were smaller and unstable across condition. We concluded that performance variability is a likely consequence of individual differences in WM integrity, and that it is a promising behavioral correlate of individual differences in WM microstructure.

Two distinctly different maturational processes - cortical thinning and white matter maturation - take place in the brain as we mature from late childhood to adulthood. To what extent does each contribute to the development of complex cognitive functions like working memory? The independent and joint contributions of cortical thickness of regions of the left fronto-parietal network and the diffusion characteristics of the connecting pathway of the left superior longitudinal fasciculus (SLF) in accounting for verbal working memory performance were investigated, using a predefined regions of interest-approach. 108 healthy participants aged 8-19 years underwent MRI, including anatomical and diffusion tensor imaging (DTI), as well as cognitive testing using a digit span task. Radial diffusivity of the SLF, as well as cortical thickness of supramarginal gyrus and rostral middle frontal cortex, were negatively related to digit span forwards performance, independently of age. Radial diffusivity of the SLF was also negatively related to digit span backwards. A multi-modal analysis showed that cortical thickness and SLF microstructure were complementary in explaining working memory span. Furthermore, SLF microstructure and cortical thickness had different impact on working memory performance during the developmental period, suggesting a complex developmental interplay. The results indicate that cortical and white matter maturation each play unique roles in the development of working memory., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Distributed brain areas support intellectual abilities in adults. How structural maturation of these areas in childhood enables development of intelligence is not established. Neuroimaging can be used to monitor brain development, but studies to date have typically considered single imaging modalities. To explore the impact of structural brain maturation on the development of intelligence, we used a combination of cortical thickness, white matter (WM) volume and WM microstructure in 168 healthy participants aged 8-30 years. Principal component analyses (PCAs) were conducted separately for cortical thickness, WM volume, fractional anisotropy (FA) and mean diffusivity (MD) in 64 different brain regions. For all four parameters, the PCAs revealed a general factor explaining between 40% and 53% of the variance across regions. When tested separately, negative age-independent relationships were found between intellectual abilities and cortical thickness and MD, respectively, while WM volume and FA were positively associated with intellectual abilities. The relationships between intellectual abilities and brain structure varied with age, with stronger relationships seen in children and adolescents than in young adults. Multiple regression analysis with the different imaging measures as simultaneous predictors, showed that cortical thickness, WM volume and MD all yielded unique information in explaining intellectual abilities in development. The present study demonstrates that different imaging modalities and measures give complementary information about the neural substrates of intellectual abilities in development, emphasizing the importance of multimodal imaging in investigations of neurocognitive development., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Early detection is vital in the quest to develop a cure for Alzheimer's disease (AD), and CSF biomarkers (Aβ42, t-tau, p-tau) and MRI morphometry distinguish AD from healthy controls. Aβ42 and neurodegenerative biomarkers may precede clinical symptoms, but it is not clear whether AD invariably follows and whether neuropsychological tests are as sensitive. Aβ42 is related to plaque burden, which was assumed to be the main cause of AD. Evidence is now pointing to other forms of Aβ, for example, soluble Aβ oligomers, and it is possible that plaques are secondary rather than causative to neuronal damage. This makes it less obvious that CSF Aβ42 necessarily is the most potent marker. Atrophy has been regarded as a downstream event, but novel MRI analysis techniques detect atrophy at a stage where the cognitive reductions are small and possibly reversible, and MRI is superior to CSF biomarkers in the prediction of cognitive decline. The impact of biomarkers may be dynamic; changed Aβ42 is seen in cognitively normal, while atrophy causes decrements later. In conclusion, CSF and MRI biomarkers are extremely important, but it is not known whether they can distinguish events that will lead to AD from events that will not before cognitive reductions are measurable.

Magnetic resonance imaging (MRI) is the principal method for studying structural age-related brain changes in vivo. However, previous research has yielded inconsistent results, precluding understanding of structural changes of the aging brain. This inconsistency is due to methodological differences and/or different aging patterns across samples. To overcome these problems, we tested age effects on 17 different neuroanatomical structures and total brain volume across five samples, of which one was split to further investigate consistency (883 participants). Widespread age-related volume differences were seen consistently across samples. In four of the five samples, all structures, except the brainstem, showed age-related volume differences. The strongest and most consistent effects were found for cerebral cortex, pallidum, putamen and accumbens volume. Total brain volume, cerebral white matter, caudate, hippocampus and the ventricles consistently showed non-linear age functions. Healthy aging appears associated with more widespread and consistent age-related neuroanatomical volume differences than previously believed., (Copyright © 2009 Elsevier Inc. All rights reserved.)

Context: Emotional, cognitive, and behavioral response patterns underlying temperament and personality are established early and remain stable from childhood. Anxiety-related traits are associated with psychiatric disease and represent predisposing factors for various affective disorders, including depression and anxiety. Emotional processing relies on the structural and functional integrity of distributed neuronal circuits. Therefore, anxiety-related personality traits and associated increased risk of psychiatric disease might be rooted in structural variability in large-scale neuronal networks., Objective: To test the hypothesis that individuals with high scores on the harm avoidance (HA) subscale of the Temperament and Character Inventory show reduced white matter (WM) structural integrity in distributed brain areas, including corticolimbic pathways involved in emotional processing and reappraisal., Design: Healthy participants completed the Temperament and Character Inventory and underwent diffusion tensor imaging. Tract-based spatial statistics were used to examine the associations between HA and WM integrity across the brain., Setting: Center for the Study of Human Cognition, Department of Psychology, University of Oslo, Oslo, Norway., Participants: A total of 263 healthy adults aged 20 to 85 years recruited through newspaper advertisements., Main Outcome Measure: Neuroimaging diffusivity indexes of brain WM microstructure, including fractional anisotropy, mean and radial diffusivity, and their associations with HA., Results: In line with our hypothesis, increased HA was associated with decreased fractional anisotropy and increased mean and radial diffusivity in major WM tracts, including pathways connecting critical hubs in a corticolimbic circuit. There was no evidence of modulating effects of sex, degree of subclinical depression, alcohol consumption, general intellectual abilities, or years of education., Conclusions: Increased HA is associated with decreased WM microstructure, implying that structural connectivity modulates anxiety-related aspects of personality. Decreased WM integrity reflects increased susceptibility to psychiatric disease and represents a promising biomarker that might ultimately facilitate targeted pharmacological and psychological interventions and treatment of disease.

Diffusion tensor imaging (DTI) and CSF biomarkers are useful diagnostic tools to differentiate patients with mild cognitive impairment (MCI) from normal controls, and may help predict conversion to dementia. Total Tau protein (T-tau) and DTI parameters are both markers for axonal damage, thus it is of interest to determine if DTI parameters are associated with elevated CSF T-tau levels in patients with cognitive impairment. For this purpose, patients with subjective cognitive impairment (SCI) and MCI were recruited from a university based memory clinic. Regions of interest were used to determine fractional anisotropy (FA), radial diffusivity (DR) and axial diffusivity (DA) in known white matter tracts in patients with MCI (n=39) and SCI (n=8) and 26 cognitively healthy controls. Significant lower FA and higher DR values were observed in patients with pathological vs. patients with normal CSF T-tau levels and vs. controls in left posterior cingulum fibers. T-tau values were negatively correlated with FA and positively correlated with DR values in the posterior cingulum fibers. Cingulum fiber diffusivity was related to T-tau pathology in SCI/MCI patients and altered DR may suggest that loss of myelin contributes to early white matter changes in patients at risk of developing Alzheimer's disease (AD)., (Copyright © 2009 Elsevier Inc. All rights reserved.)

Efficient attention is pivotal for cognitive functioning, and individual differences in attentional functions are likely related to variations in structural properties of the brain. Attention is supported by separate processes, and models of the relationship between attention and brain structure must take this into account. The Attention Network Test (ANT) yields behavioral measures of 3 independent attentional components: executive control (EC), alerting, and orienting. EC relates to resolving cognitive interference, alerting refers to continuous maintenance of a vigilant state, and orienting to selection of and orienting toward sensory information. Evidence from functional neuroimaging studies suggests that the ANT components recruit different cortical networks. However, the structural correlates are not established. Therefore, ANT scores were correlated with cortical thickness across the brain surface in 268 healthy adults spanning 20-84 years of age. Specific correlations were found between cortical thickness and EC and alerting in regions implicated by functional neuroimaging and lesion studies, including anterior cingulate, lateral prefrontal, and right inferior frontal gyri for EC and parietal areas for alerting. The brain-behavior correlations were relatively stable across adulthood, indicating that factors influencing cortical maturation rather than aging-related atrophy specifically were instrumental in shaping the structural foundation for visuospatial attention in adults.

Mild cognitive impairment (MCI), especially amnestic, often represents pre-dementia Alzheimer's disease, characterized by medial temporal lobe atrophy, while white matter (WM) alterations are insufficiently described. We analyze both cortical morphometric and WM diffusivity differences in amnestic versus non-amnestic subtypes and ask if memory and WM tract affection are related independently of cortical atrophy. Forty-nine patients from a university-hospital based memory clinic with a score of 3 on the Global Deterioration Scale aged 43-77 years (45% female) were included. Two neuropsychologists have classified cases as amnestic (aMCI), non-amnestic (naMCI), or less advanced (laMCI), not satisfying criteria for aMCI/naMCI. Diffusion tensor imaging (DTI) WM tract and morphometric data of the temporal-parietal memory network were compared among patient subtypes and related to story, word list, and visual memory. WM radial and mean diffusivity (DR and MD), underlying the entorhinal cortex, were higher in aMCI compared with laMCI. WM DR and MD, underlying the entorhinal, parahippocampal, and middle temporal cortex, explained unique variance in word list and story memory, and this was not due to secondary effects of cortical thinning. DTI may thus potentially aid diagnosis in early disease stages. ).

Purpose: To explore white matter (WM) and gray matter tissue integrity in the apparently unaffected hemisphere of patients with herpes simplex encephalitis (HSE) who have gross unilateral medial temporal lobe (MTL) lesions and both verbal and visuospatial memory deficits., Materials and Methods: This study had institutional ethics committee approval and included written informed consent. Magnetic resonance (MR) imaging was performed in five patients who had recovered from HSE (one woman, four men; median age, 32 years; interquartile range, 28.5-37 years) and 51 age-matched controls (30 women, 21 men; median age, 32 years; interquartile range, 28-37 years). As markers of microstructural WM integrity, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity (RD) derived from diffusion-tensor (DT) imaging were used. An automated regional brain segmentation approach yielded estimates of subcortical volumes, including hippocampus, and cortical thickness. Group differences were evaluated by using permutation tests., Results: Examination of standard MR images found unilateral lesions in all patients. The patients with HSE showed reduced FA and increased MD and RD in several WM tracts contralateral to lesions (P < .05, corrected for multiple comparisons). Affected tracts included connections between the MTLs and other parts of the brain. No significant group differences were observed in subcortical volume or cortical thickness., Conclusion: These results suggest that patients with HSE have reduced microstructural integrity of normal-appearing WM contralateral to grossly visible lesions. These subtle lesions, detectable at DT imaging, probably contribute to the memory impairment manifested by these patients., Supplemental Material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100179/-/DC1., (© RSNA, 2010)

Mapping the cerebral structural correlates of age-related cognitive decline is a growing area of research. The aim of the present study was to investigate the relationship between healthy elderly's perceived memory functioning in daily life, neuropsychological test performance on a standardized test on verbal memory, and cortical thickness and subcortical volumes in brain regions implicated in memory networks, including the medial temporal lobe (MTL). Eighty-three healthy and cognitively well-functioning volunteers aged 60-85 years underwent MRI scans, Everyday Memory Questionnaire (EMQ), and neuropsychological assessment. Both self-perceived memory in daily life related to attention and executive functions and an objective measure of verbal recall (CVLT) were, independently, associated with thickness of the left MTL. The two cognitive variables were uncorrelated, and including both measures in the model nearly doubled the amount of explained variance on MTL thickness. This suggests that measures of perceived everyday memory might substantially inform and supplement studies investigating the relationships between neuropsychological test performance and brain morphology. The results are consistent with a bigger-is-better relationship in the MTL and suggest that EMQ and neuropsychological test performance have detectable and comparable structural correlates in a region critically involved in memory functions in the well-functioning elderly.

Higher-order cognitive functions are supported by distributed networks of multiple interconnected cortical and subcortical regions. Efficient cognitive processing depends on fast communication between these regions, so the integrity of the connections between them is of great importance. It is known that white matter (WM) development is a slow process, continuing into adulthood. While the significance of cortical maturation for intellectual development is described, less is known about the relationships between cognitive functions and maturation of WM connectivity. In this cross-sectional study, we investigated the associations between intellectual abilities and development of diffusion tensor imaging (DTI) derived measures of WM microstructure in 168 right-handed participants aged 8-30 years. Independently of age and sex, both verbal and performance abilities were positively related to fractional anisotropy (FA) and negatively related to mean diffusivity (MD) and radial diffusivity (RD), predominantly in the left hemisphere. Further, verbal, but not performance abilities, were associated with developmental differences in DTI indices in widespread regions in both hemispheres. Regional analyses showed relations with both FA and RD bilaterally in the anterior thalamic radiation and the cortico-spinal tract and in the right superior longitudinal fasciculus. In these regions, our results suggest that participants with high verbal abilities may show accelerated WM development in late childhood and a subsequent earlier developmental plateau, in contrast to a steadier and prolonged development in participants with average verbal abilities. Longitudinal data are needed to validate these interpretations. The results provide insight into the neurobiological underpinnings of intellectual development., (© 2010 Wiley-Liss, Inc.)

The brain's ability to alter its functional and structural architecture in response to experience and learning has been extensively studied. Mental stimulation might serve as a reserve mechanism in brain aging, but macrostructural brain changes in response to cognitive training have been demonstrated in young participants only. We examined the short-term effects of an intensive memory training program on cognition and brain structure in middle-aged and elderly healthy volunteers. The memory trainers completed an 8-week training regimen aimed at improving verbal source memory utilizing the Method of Loci (MoL), while control participants did not receive any intervention. Both the memory trainers and the controls underwent magnetic resonance imaging (MRI) scans and memory testing pre and post 8 weeks of training or no training, respectively. Cortical thickness was automatically measured across the cortical mantle, and data processing and statistical analyses were optimized for reliable detection of longitudinal changes. The results showed that memory training improved source memory performance. Memory trainers also showed regional increases in cortical thickness compared with controls. Furthermore, thickness change in the right fusiform and lateral orbitofrontal cortex correlated positively with improvement in source memory performance, suggesting a possible functional significance of the structural changes. These findings demonstrate that systematic mental exercise may induce short-term structural changes in the aging human brain, indicating structural brain plasticity in elderly. The present study included short-term assessments, and follow-up studies are needed in order to assess whether such training indeed alters the long-term structural trajectories., (Copyright 2010 Elsevier Inc. All rights reserved.)

Reduced levels of beta-amyloid(1-42) (Abeta1-42) and increased levels of tau proteins in the cerebrospinal fluid (CSF) are found in Alzheimer's disease (AD), likely reflecting Abeta deposition in plaques and neuronal and axonal damage. It is not known whether these biomarkers are associated with brain atrophy also in healthy aging. We tested the relationship between CSF levels of Abeta1-42 and tau (total tau and tau phosphorylated at threonine 181) proteins and 1-year brain atrophy in 71 cognitively normal elderly individuals. Results showed that under a certain threshold value, levels of Abeta1-42 correlated highly with 1-year change in a wide range of brain areas. The strongest relationships were not found in the regions most vulnerable early in AD. Above the threshold level, Abeta1-42 was not related to brain changes, but significant volume reductions as well as ventricular expansion were still seen. It is concluded that Abeta1-42 correlates with brain atrophy and ventricular expansion in a subgroup of cognitively normal elderly individuals but that reductions independent of CSF levels of Abeta1-42 is common. Further research and follow-up examinations over several years are needed to test whether degenerative pathology will eventually develop in the group of cognitively normal elderly individuals with low levels of Abeta1-42.

Magnetic resonance imaging volumetry studies report inverted U-patterns with increasing white-matter (WM) volume into middle age suggesting protracted WM maturation compared with the cortical gray matter. Diffusion tensor imaging (DTI) is sensitive to degree and direction of water permeability in biological tissues, providing in vivo indices of WM microstructure. The aim of this cross-sectional study was to delineate age trajectories of WM volume and DTI indices in 430 healthy subjects ranging 8-85 years of age. We used automated regional brain volume segmentation and tract-based statistics of fractional anisotropy, mean, and radial diffusivity as markers of WM integrity. Nonparametric regressions were used to fit the age trajectories and to estimate the timing of maximum development and deterioration in aging. Although the volumetric data supported protracted growth into the sixth decade, DTI indices plateaued early in the fourth decade across all tested regions and then declined slowly into late adulthood followed by an accelerating decrease in senescence. Tractwise and voxel-based analyses yielded regional differences in development and aging but did not provide ample evidence in support of a simple last-in-first-out hypothesis of life-span changes.

Cortical thickness decreases from childhood throughout life, as estimated by magnetic resonance imaging (MRI). This monotone trajectory does not reflect the fundamentally different neurobiological processes underlying morphometric changes in development versus aging. We hypothesized that intracortical gray matter (GM) and subjacent white matter (WM) T1-weighted signal intensity would distinguish developmental and age-related changes in the cortex better than thickness. Intracortical GM and subjacent WM signal intensity and cortical thickness was measured across the brain surface in a healthy life span sample (n=429, 8-85 years). We also computed the relaxation rate of T2* (R2*) from multiecho sequences and mapped intracortical GM and subjacent WM values to the surface to delineate age-related variability in R2* and to adjust the T1 signal intensity for possible confounds of accumulated iron. While monotone age-related reductions in thickness were found, both intracortical GM and subcortical WM signal intensity showed inverted U patterns with peaks from eight to approximately 30 years of age. The spatial pattern of intracortical neurodevelopment followed a posterior-anterior gradient, with earliest maturation of occipital visual cortices and most protracted in superior frontal regions. From 50s and 60s, substantial signal reductions were observed in several regions, including the insula, cingulate, and inferior temporal gyrus. R2* showed similar patterns but peaked much later than the T1-weighted signal intensity measures. The results are presented as animations yielding detailed depictions of the dynamic regional variability in cortical neurodevelopment and aging and demonstrate that cortical thickness and T1-weighted signal intensity are sensitive to different cortical maturational and aging-related processes., (Copyright 2010 Elsevier Inc. All rights reserved.)

This study (n=161) related morphometric MR imaging, FDG-PET and APOE genotype to memory scores in normal controls (NC), mild cognitive impairment (MCI) and Alzheimer's disease (AD). Stepwise regression analyses focused on morphometric and metabolic characteristics of the episodic memory network: hippocampus, entorhinal, parahippocampal, retrosplenial, posterior cingulate, precuneus, inferior parietal, and lateral orbitofrontal cortices. In NC, hippocampal metabolism predicted learning; entorhinal metabolism predicted recognition; and hippocampal metabolism predicted recall. In MCI, thickness of the entorhinal and precuneus cortices predicted learning, while parahippocampal metabolism predicted recognition. In AD, posterior cingulate cortical thickness predicted learning, while APOE genotype predicted recognition. In the total sample, hippocampal volume and metabolism, cortical thickness of the precuneus, and inferior parietal metabolism predicted learning; hippocampal volume and metabolism, parahippocampal thickness and APOE genotype predicted recognition. Imaging methods appear complementary and differentially sensitive to memory in health and disease. Medial temporal and parietal metabolism and morphometry best explained memory variance. Medial temporal characteristics were related to learning, recall and recognition, while parietal structures only predicted learning., (Copyright 2008. Published by Elsevier Inc.)

A range of cognitive abilities improves in childhood and adolescence. It has been proposed that the protracted development of executive functions is related to the relatively late maturation of the prefrontal cortex. However, this has rarely been directly investigated. In this cross-sectional study, 98 healthy children and adolescents (8-19 years old) were tested with six tasks considered to index three frequently postulated executive functions; updating (Keep track and Letter memory), inhibition (Antisaccade and Stroop) and shifting (Plus minus and Trail making). Task performance was then related to magnetic resonance imaging (MRI) measures of cortical thickness. The behavioral results did not indicate any clear organization of the executive function measures in the domains updating, inhibition and shifting. Limitations associated with the use of speed-based scores from the tasks considered to index shifting ability were also indicated. Independently of the effects of age, performance on the Keep track task was associated with thinner cortex bilaterally in clusters encompassing parietal and frontal regions, including the left inferior frontal gyrus, while performance on the Antisaccade task was associated with thinner cortex bilaterally in occipital and parietal regions. Further, levels of performance on the Antisaccade and Stroop tasks were related to estimated rates of cortical maturation in posterior brain regions, but not in the prefrontal cortex. The results from the present study add to previous knowledge about the cortical correlates of executive functions by indicating an important role of posterior cerebral areas in executive development., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Many brain structures show a complex, non-linear pattern of maturation and age-related change. Often, quadratic models (beta(0) + beta(1)age + beta(2)age(2) + epsilon) are used to describe such relationships. Here, we demonstrate that the fitting of quadratic models is substantially affected by seemingly irrelevant factors, such as the age-range sampled. Hippocampal volume was measured in 434 healthy participants between 8 and 85 years of age, and quadratic models were fit to subsets of the sample with different age-ranges. It was found that as the bottom of the age-range increased, the age at which volumes appeared to peak was moved upwards and the estimated decline in the last part of the age-span became larger. Thus, whether children were included or not affected the estimated decline between 60 and 85 years. We conclude that caution should be exerted in inferring age-trajectories from global fit models, e.g. the quadratic model. A nonparametric local smoothing technique (the smoothing spline) was found to be more robust to the effects of different starting ages. The results were replicated in an independent sample of 309 participants., (2010 Elsevier Inc. All rights reserved.)

Background and Purpose: Prenatal drug exposure may influence the developing brain. Our aim was to study WM characteristics with DTI in children with prenatal opiate and polysubstance exposure and in controls. We assessed whether group differences in FA, DA, and DR could be found and related to cognitive function., Materials and Methods: The study was approved by a committee for medical research ethics. Parents signed an informed consent; children gave spoken consent. Our sample included 14 prenatally substance-exposed adopted children (5 girls; age range, 8.6-13.9 years; mean, 11.3 +/- 1.7 years) and 14 control children (7 girls; age range, 9.0-10.2 years; mean, 9.8 +/- 0.3 years). Tract-based spatial statistics were used to define a common WM skeleton for the sample, and FA was compared between groups throughout the skeleton, controlling for age and sex. Clusters of significant group differences >or=100 voxels (P <. 05) were identified. FA, DA, and DR within clusters were correlated with cognitive function., Results: Ten clusters of FA group differences, mostly in central, posterior, and inferior parts of the brain, were identified (P <. 05), showing lower FA in substance-exposed children. FA and DA correlated positively and DR, negatively with cognitive function across groups., Conclusions: Prenatally substance-exposed children exhibited lower FA in restricted areas of WM, mostly relatively central, inferior, and posterior, where myelination occurs early in development. Myelin in these areas may be particularly vulnerable to prenatal substance exposure. FA and DR related moderately to cognitive function. Potential confounding factors existed and were considered.

The development of cortical gray matter, white matter (WM) volume, and WM microstructure in adolescence is beginning to be fairly well characterized by structural magnetic resonance imaging (sMRI) and diffusion tensor imaging (DTI) studies. However, these aspects of brain development have rarely been investigated concurrently in the same sample and hence the relations between them are not understood. We delineated the age-related changes in cortical thickness, regional WM volume, and diffusion characteristics and investigated the relationships between these properties of brain development. One hundred and sixty-eight healthy participants aged 8-30 years underwent sMRI and DTI. The results showed regional age-related cortical thinning, WM volume increases, and changes in diffusion parameters. Cortical thickness was the most strongly age-related parameter. All classes of measures showed unique associations with age. The results indicate that cortical thinning in adolescence cannot be explained by WM maturation in underlying regions as measured by volumetry or DTI. Moderate associations between cortical thickness and both volume and diffusion parameters in underlying WM regions were also found, although the relationships were not strong. It is concluded that none of the measures are redundant and that the integration of the 3 will yield a more complete understanding of brain maturation.

Burgmans, van Boxtel, Vuurman, et al. (2009) published an interesting study titled "The Prevalence of Cortical Gray Matter Atrophy May Be Overestimated in the Healthy Aging Brain" on how subclinical cognitive disorders may affect correlations between age and cortical volume. Correlations between cortical gray matter volume and age were found in 30 elderly with cognitive decline after 6 years, but not in 28 elderly without cognitive decline. This study is important, and demonstrates that preclinical cognitive disorders may affect cortical brain volumes before being detectable by neuropsychological tests. However, we are not convinced by the conclusions: "... gray matter atrophy... is to a lesser extent associated with the healthy aging process, but more likely with brain processes underlying significant cognitive decline" (p. 547) and "... cortical gray matter atrophy in the aging brain may be overestimated in a large number of studies on healthy aging" (p. 547). We analyzed the cross-sectional MR data (n = 1,037) as well as longitudinal data from a sample of very well-screened elderly followed by cognitive testing for 2 years. In the cross-sectional data, the correlations between age and brain volumes were generally not much reduced when the upper age limit was lowered. This would not be expected if age-related incipient cognitive disorders caused the correlations given that the incidence of cognitive decline increased with age. Longitudinally, 1-year atrophy was identified in all tested regions. It is likely that cortical brain atrophy is manifested in cognitively normal elderly without subclinical cognitive disorders., (Copyright 2010 APA, all rights reserved)

Brain atrophy and altered CSF levels of amyloid beta (Abeta(42)) and the microtubule-associated protein tau are potent biomarkers of Alzheimer's disease (AD)-related pathology. However, the relationship between CSF biomarkers and brain morphometry is poorly understood. Thus, we addressed the following questions. (1) Can CSF biomarker levels explain the morphometric differences between normal controls (NC) and patients with mild cognitive impairment (MCI) or AD? (2) How are CSF biomarkers related to atrophy across the brain? (3) How closely are CSF biomarkers and morphometry related to clinical change [clinical dementia rating sum of boxes (CDR-sb)]? Three hundred seventy participants (105 NC, 175 MCI, 90 AD) from the Alzheimer's Disease Neuroimaging Initiative were studied, of whom 309 were followed for 1 year and 176 for 2 years. Analyses were performed across the entire cortical surface, as well as for 30 cortical and subcortical regions of interest. Results showed that CSF biomarker levels could not account for group differences in brain morphometry at baseline but that CSF biomarker levels showed moderate relationships to longitudinal atrophy rates in numerous brain areas, not restricted to medial temporal structures. Baseline morphometry was at least as predictive of atrophy as were CSF biomarkers. Even MCI patients with levels of Abeta(42) comparable with controls and of p-tau lower than controls showed more atrophy than the controls. Morphometry predicted change in CDR-sb better than did CSF biomarkers. These results indicate that morphometric changes in MCI and AD are not secondary to CSF biomarker changes and that the two types of biomarkers yield complementary information.

Background and Purpose: Different biomarkers for AD may potentially be complementary in diagnosis and prognosis of AD. Our aim was to combine MR imaging, FDG-PET, and CSF biomarkers in the diagnostic classification and 2-year prognosis of MCI and AD, by examining the following: 1) which measures are most sensitive to diagnostic status, 2) to what extent the methods provide unique information in diagnostic classification, and 3) which measures are most predictive of clinical decline., Materials and Methods: ADNI baseline MR imaging, FDG-PET, and CSF data from 42 controls, 73 patients with MCI, and 38 patients with AD; and 2-year clinical follow-up data for 36 controls, 51 patients with MCI, and 25 patients with AD were analyzed. The hippocampus and entorhinal, parahippocampal, retrosplenial, precuneus, inferior parietal, supramarginal, middle temporal, lateral, and medial orbitofrontal cortices were used as regions of interest. CSF variables included Abeta42, t-tau, p-tau, and ratios of t-tau/Abeta42 and p-tau/Abeta42. Regression analyses were performed to determine the sensitivity of measures to diagnostic status as well as 2-year change in CDR-SB, MMSE, and delayed logical memory in MCI., Results: Hippocampal volume, retrosplenial thickness, and t-tau/Abeta42 uniquely predicted diagnostic group. Change in CDR-SB was best predicted by retrosplenial thickness; MMSE, by retrosplenial metabolism and thickness; and delayed logical memory, by hippocampal volume., Conclusions: All biomarkers were sensitive to the diagnostic group. Combining MR imaging morphometry and CSF biomarkers improved diagnostic classification (controls versus AD). MR imaging morphometry and PET were largely overlapping in value for discrimination. Baseline MR imaging and PET measures were more predictive of clinical change in MCI than were CSF measures.

It is suggested that reductions in a medial temporo-parietal episodic memory network characterize Alzheimer's disease (AD), while changes in a fronto-striatal executive network characterize healthy aging. In the present study, magnetic resonance imaging (MRI) was used to test this directly. MRI scans of 372 participants from two samples were analyzed: Sample 1 consisted of 96 very mild to moderate AD patients, 93 healthy elderly (HE), and 137 young (HY), all with available MR scans, while Sample 2 consisted of 46 MCI patients, with available MR scans and measures of CSF biomarkers Abeta42 and tau protein. Substantial morphometric reductions of the medial temporo-parietal network were found in AD, while the fronto-striatal network was less affected. Both networks were affected by healthy aging, but the fronto-striatal to a greater degree than the medial temporo-parietal. Further exploratory analyses of 49 cortical and subcortical structures indicated no overlap between predictors of AD vs. HE and predictors of HE vs. HY. CSF biomarker pathology correlated with the medial temporo-parietal but not fronto-striatal network. Likewise, the AD-prone structures from the exploratory analyses were related to CSF biomarkers, while the aging-prone structures were not. It is concluded that the pattern of macrostructural brain changes in very mild to moderate AD can be clearly delineated from that of healthy aging.

The structure of the brain is constantly changing from birth throughout the lifetime, meaning that normal aging, free from dementia, is associated with structural brain changes. This paper reviews recent evidence from magnetic resonance imaging (MRI) studies about age-related changes in the brain. The main conclusions are that (1) the brain shrinks in volume and the ventricular system expands in healthy aging. However, the pattern of changes is highly heterogeneous, with the largest changes seen in the frontal and temporal cortex, and in the putamen, thalamus, and accumbens. With modern approaches to analysis of MRI data, changes in cortical thickness and subcortical volume can be tracked over periods as short as one year, with annual reductions of between 0.5% and 1.0% in most brain areas. (2) The volumetric brain reductions in healthy aging are likely only to a minor extent related to neuronal loss. Rather, shrinkage of neurons, reductions of synaptic spines, and lower numbers of synapses probably account for the reductions in grey matter. In addition, the length of myelinated axons is greatly reduced, up to almost 50%. (3) Reductions in specific cognitive abilities--for instance processing speed, executive functions, and episodic memory--are seen in healthy aging. Such reductions are to a substantial degree mediated by neuroanatomical changes, meaning that between 25% and 100% of the differences between young and old participants in selected cognitive functions can be explained by group differences in structural brain characteristics.

Subjective and mild cognitive impairment (SCI and MCI) are etiologically heterogeneous conditions. This poses problems for assessment of pathophysiological mechanisms and risk of conversion to dementia. Neuropsychological, imaging, and cerebrospinal fluid (CSF) findings serve to distinguish Alzheimer's disease (AD) and other etiological subgroups. Tau-molecules stabilize axonal microtubuli; high CSF total tau (T-tau) reflects ongoing axonal damage consistent with AD. Here, we stratify patients by CSF T-tau pathology to determine if memory network diffusion tensor imaging (DTI) predicts memory performance in the absence of elevated T-tau. We analyzed neuropsychological test results, hippocampus volume (HcV) and white matter diffusivity in 45 patients (35 with normal T-tau). The T-tau pathology group showed more hippocampus atrophy and memory impairment than the normal T-tau group. In the T-tau normal group: (1) memory was related with white matter diffusivity [fractional anisotropy (FA) and radial diffusivity (DR)], and (2) FA of the genu corpus callosum was a unique predictor of variance for verbal learning, and HcV did not contribute to this prediction. The smaller sample size in the T-tau pathology group precludes firm conclusions. In the normal T-tau group, white matter tract and memory changes may be associated with normal aging, or with non-tau related pathological mechanisms.

An accurate description of changes in the brain in healthy aging is needed to understand the basis of age-related changes in cognitive function. Cross-sectional magnetic resonance imaging (MRI) studies suggest thinning of the cerebral cortex, volumetric reductions of most subcortical structures, and ventricular expansion. However, there is a paucity of detailed longitudinal studies to support the cross-sectional findings. In the present study, 142 healthy elderly participants (60-91 years of age) were followed with repeated MRI, and were compared with 122 patients with mild to moderate Alzheimer's disease (AD). Volume changes were measured across the entire cortex and in 48 regions of interest. Cortical reductions in the healthy elderly were extensive after only 1 year, especially evident in temporal and prefrontal cortices, where annual decline was approximately 0.5%. All subcortical and ventricular regions except caudate nucleus and the fourth ventricle changed significantly over 1 year. Some of the atrophy occurred in areas vulnerable to AD, while other changes were observed in areas less characteristic of the disease in early stages. This suggests that the changes are not primarily driven by degenerative processes associated with AD, although it is likely that preclinical changes associated with AD are superposed on changes due to normal aging in some subjects, especially in the temporal lobes. Finally, atrophy was found to accelerate with increasing age, and this was especially prominent in areas vulnerable to AD. Thus, it is possible that the accelerating atrophy with increasing age is due to preclinical AD.

Instability in performance is a prominent feature of aging. In this study, 133 participants evenly distributed across the adult lifespan underwent a three-stimulus event-related potentials (ERPs) paradigm, and instability in P3a/P3b latency and reaction time (RT) were measured. P3a is related to alertness or reorientation of attention and it was elicited by distractor stimuli. P3b is related to controlled attentional processes and it was triggered by target stimuli. Maximum-likelihood estimation (MLE) was used to quantify the level of variability in latency across the single sweep ERPs. The results revealed increased variability in RT but not in P3a/P3b latency with age. Variability in P3a/P3b latency was related to executive functions, and variability in RT to speed. Generally, the relationships tended to increase with age. It can be concluded that increased variability in RT with age is caused by instability in processes related to response execution and possibly response selection, but not stimulus classification. Further, the results indicate that intraindividual variability is not a uniform concept, but has unique explanatory value at the neurophysiological and behavioral level.

MRI-based estimates of cerebral morphometric properties, e.g. cortical thickness, are pivotal to studies of normal and pathological brain changes. These measures are based on automated or manual segmentation procedures, which utilize the tissue contrast between gray and white matter on T(1)-weighted MR images. Tissue contrast is unlikely to remain a constant property across groups of different age and health. An important question is therefore how the sensitivity of cortical thickness estimates is influenced by variability in WM/GM contrast. The effect of adjusting for variability in WM/GM contrast on age sensitivity of cortical thickness was tested in 1189 healthy subjects from six different samples, enabling evaluation of consistency of effects within and between sites and scanners. Further, the influence of Alzheimer's disease (AD) diagnosis on cortical thickness with and without correction for contrast was tested in an additional sample of 96 patients. In healthy controls, regional increases in the sensitivity of the cortical thickness measure to age were found after correcting for contrast. Across samples, the strongest effects were observed in frontal, lateral temporal and parietal areas. Controlling for contrast variability also increased the cortical thickness estimates' sensitivity to AD, thus replicating the finding in an independent clinical sample. The results showed increased sensitivity of cortical estimates to AD in areas earlier reported to be compromised in AD, including medial temporal, inferior and superior parietal regions. In sum, the findings indicate that adjusting for contrast can increase the sensitivity of MR morphometry to variables of interest.

Brain development during late childhood and adolescence is characterized by decreases in gray matter (GM) and increases in white matter (WM) and ventricular volume. The dynamic nature of development across different structures is, however, not well understood, and the present magnetic resonance imaging study took advantage of a whole-brain segmentation approach to describe the developmental trajectories of 16 neuroanatomical volumes in the same sample of children, adolescents, and young adults (n = 171; range, 8-30 years). The cerebral cortex, cerebral WM, caudate, putamen, pallidum, accumbens area, hippocampus, amygdala, thalamus, brainstem, cerebellar GM, cerebellar WM, lateral ventricles, inferior lateral ventricles, third ventricle, and fourth ventricle were studied. The cerebral cortex was further analyzed in terms of lobar thickness and surface area. The results revealed substantial heterogeneity in developmental trajectories. GM decreased nonlinearly in the cerebral cortex and linearly in the caudate, putamen, pallidum, accumbens, and cerebellar GM, whereas the amygdala and hippocampus showed slight, nonlinear increases in GM volume. WM increased nonlinearly in both the cerebrum and cerebellum, with an earlier maturation in cerebellar WM. In addition to similarities in developmental trajectories within subcortical regions, our results also point to differences between structures within the same regions: among the basal ganglia, the caudate showed a weaker relationship with age than the putamen and pallidum, and in the cerebellum, differences were found between GM and WM development. These results emphasize the importance of studying a wide range of structural variables in the same sample, for a broader understanding of brain developmental principles.

Cross-sectional magnetic resonance imaging (MRI) studies of cortical thickness and volume have shown age effects on large areas, but there are substantial discrepancies across studies regarding the localization and magnitude of effects. These discrepancies hinder understanding of effects of aging on brain morphometry, and limit the potential usefulness of MR in research on healthy and pathological age-related brain changes. The present study was undertaken to overcome this problem by assessing the consistency of age effects on cortical thickness across 6 different samples with a total of 883 participants. A surface-based segmentation procedure (FreeSurfer) was used to calculate cortical thickness continuously across the brain surface. The results showed consistent age effects across samples in the superior, middle, and inferior frontal gyri, superior and middle temporal gyri, precuneus, inferior and superior parietal cortices, fusiform and lingual gyri, and the temporo-parietal junction. The strongest effects were seen in the superior and inferior frontal gyri, as well as superior parts of the temporal lobe. The inferior temporal lobe and anterior cingulate cortices were relatively less affected by age. The results are discussed in relation to leading theories of cognitive aging.

Age is associated with substantial macrostructural brain changes. While some recent magnetic resonance imaging studies have reported larger age effects in men than women, others find no sex differences. As brain morphometry is a potentially important tool in diagnosis and monitoring of age-related neurological diseases, e.g., Alzheimer's disease (AD), it is important to know whether sex influences brain aging. We analyzed cross-sectional magnetic resonance scans from 1143 healthy participants from seven subsamples provided by four independent research groups. In addition, 96 patients with mild AD were included. Estimates of cortical thickness continuously across the brain surface, as well as volume of 17 subcortical structures, were obtained by use of automated segmentation tools (FreeSurfer). In the healthy participants, no differences in aging slopes between women and men were found in any part of the cortex. Pallidum corrected for intracranial volume showed slightly higher age correlations for men. The analyses were repeated in each of the seven subsamples, and the lack of age x sex interactions was largely replicated. Analyses of the AD sample showed no interactions between sex and age for any brain region. We conclude that sex has negligible effects on the age slope of brain volumes both in healthy participants and in AD.

This study compared sensitivity of FDG-PET, MR morphometry, and diffusion tensor imaging (DTI) derived fractional anisotropy (FA) measures to diagnosis and memory function in mild cognitive impairment (MCI). Patients (n=44) and normal controls (NC, n=22) underwent FDG-PET and MRI scanning yielding measures of metabolism, morphometry and FA in nine temporal and parietal areas affected by Alzheimer's disease and involved in the episodic memory network. Patients also underwent memory testing (RAVLT). Logistic regression analysis yielded 100% diagnostic accuracy when all methods and ROIs were combined, but none of the variables then served as unique predictors. Within separate ROIs, diagnostic accuracy for the methods combined ranged from 65.6% (parahippocampal gyrus) to 73.4 (inferior parietal cortex). Morphometry predicted diagnostic group for most ROIs. PET and FA did not uniquely predict group, but a trend was seen for the precuneus metabolism. For the MCI group, stepwise regression analyses predicting memory scores were performed with the same methods and ROIs. Hippocampal volume and FA of the retrosplenial WM predicted learning, and hippocampal metabolism and parahippocampal cortical thickness predicted 5 minute recall. No variable predicted 30 minute recall independently of learning. In conclusion, higher diagnostic accuracy was achieved when multiple methods and ROIs were combined, but morphometry showed superior diagnostic sensitivity. Metabolism, morphometry and FA all uniquely explained memory performance, making a multi-modal approach superior. Memory variation in MCI is likely related to conversion risk, and the results indicate potential for improved predictive power by the use of multimodal imaging.

White matter (WM) is critical to cognitive function and brain activity. The objective of the present study was to test whether diffusion tensor imaging (DTI) derived WM measures are related to the cognitive event-related potential error-related negativity (ERN). Eighty-seven healthy middle-aged adults underwent DTI scanning and electrophysiological recordings while doing a version of the Eriksen flanker task. ERN was elicited in error trials. Fractional anisotropy (FA) was calculated based on the DTI scans. FA indexes degree of anisotropic diffusion in every voxel, and is assumed related to the integrity of myelinated fiber bundles. The principal neuronal generator for ERN is located in the anterior cingulate cortex (ACC). Hence, the relationship between FA in the cingulum bundle and ERN amplitude was tested. It was found that FA in the left posterior cingulate correlated with ERN. Eigenvalue analyses revealed that radial diffusivity was responsible for the FA effect. ERN amplitude predicted response accuracy in the Flanker task, suggesting that electrophysiological measures are intermediate explanatory variables connecting DTI indices of WM organization, synchronization of large cell assemblies, and behavior.

There is still limited knowledge about the relationship between different structural brain parameters, despite huge progress in analysis of neuroimaging data. The aim of the present study was to test the relationship between fractional anisotropy (FA) from diffusion tensor imaging (DTI) and regional white matter (WM) volume. As WM volume has been shown to develop until middle age, the focus was on changes in WM properties in the age range of 40 to 60 years. 100 participants were scanned with magnetic resonance imaging (MRI). Each hemisphere was parcellated into 35 WM regions, and volume, FA, axial, and radial diffusion in each region were calculated. The relationships between age and the regional measures of FA and WM volume were tested, and then FA and WM volume were correlated, corrected for intracranial volume, age, and sex. WM volume was weakly related to age, while FA correlated negatively with age in 26 of 70 regions, caused by a mix of reduced axial and increased radial diffusion with age. 23 relationships between FA and WM volume were found, with seven being positive and sixteen negative. The positive correlations were mainly caused by increased radial diffusion. It is concluded that FA is more sensitive than volume to changes in WM integrity during middle age, and that FA-age correlations probably are related to reduced amount of myelin with increasing age. Further, FA and WM volume are moderately to weakly related and to a large extent sensitive to different characteristics of WM integrity.

Studies of the event-related potentials (ERPs) P3a/P3b have given insights into age effects on cognitive processes in the brain, and it has been established that latency increases and amplitude decreases with age. However, if latency jitter, that is, variation in single trial latencies, is larger in elderly than in younger participants, this may create an artificial age-amplitude correlation. The aim of this article is to test whether correction for latency jitter affects the P3a/P3b age correlations. One hundred thirty-three healthy adults (20-88 years old) went through a 3-stimuli visual oddball paradigm. Latency jitter was corrected by use of a Maximum Likelihood Estimation method. The results showed that corrections for latency jitter did not significantly affect the correlations between P3a/P3b and age. It is concluded that previous reports of amplitude reduction as a function of age seem to be valid regardless of whether latency jitter correction has been applied.

Background and Purpose: Mild cognitive impairment (MCI) may affect several cognitive domains, including attention and reasoning, but is often first characterized by memory deficits. The purpose of this study was to ask these 2 questions: 1) Can levels of CSF tau proteins and amyloid beta 42 peptide explain thinning of the cerebral cortex in patients with MCI? 2) How are brain morphometry, CSF biomarkers, and apolipoprotein E (APOE) allelic variation related to episodic memory function in MCI?, Materials and Methods: Hippocampal volume and cortical thickness were estimated by MR imaging and compared for patients with MCI (n = 18) and healthy controls (n = 18). In addition, regions of interest (ROIs) were selected in areas where the MCI group had atrophy and which overlapped with the episodic memory network (temporal, entorhinal, inferior parietal, precuneus/posterior cingulate, and frontal). Relationships among morphometry, CSF biomarkers, APOE, and memory were tested. The analyses were repeated with an independent sample of patients with MCI (n = 19)., Results: Patients with MCI and pathologic CSF values had hippocampal atrophy. However, both patients with pathologic and patients with nonpathologic CSF had a thinner cortex outside the hippocampal area. CSF pathology was related to hippocampal volume, whereas relationships with cortical thickness were found mainly in one of the samples. Morphometry correlated robustly with memory performance across MCI samples, whereas less stable results were found for tau protein., Conclusion: The differences in hippocampal volume between the MCI and the healthy control groups were only found in patients with pathologic CSF biomarkers, whereas differences in cortical thickness were also found for patients without such pathologic features. Morphometry in areas in the episodic memory network was robustly correlated with memory performance. It is speculated that atrophy in these areas may be associated with the memory problems seen in MCI.

Effects of APOE genotype on age-related slopes of cortical thinning was estimated by measuring the thickness of the cerebral cortex on a point-by-point basis across the cortical mantle in 96 healthy non-demented volunteers aged 48-75 years. Fifty nine were APOE epsilon 4- (no epsilon 4 allele) and 37 were epsilon 4+ (1 or 2 epsilon 4 alleles). The genotype groups had similar age, sex and IQ. Two T(1)-weighted MP-RAGE sequences were averaged for each participant to yield images with high signal-to-noise ratio, and quantified using semi-automated analysis tools. epsilon 4 carriers had thicker cortex than non-carriers in several frontal and temporal areas in both hemispheres, but showed a steeper age-related decline in adjacent areas. Upon comparison of the epsilon 4-specific age-related thinning with previously published patterns of thinning in normal aging and Alzheimer's disease (AD), we conclude that APOE epsilon 4 may function to accelerate thinning in areas found to decline in aging (medial prefrontal and pericentral cortex), but also to initiate thinning in areas associated with AD and amyloid-beta aggregation (occipitotemporal and basal temporal cortex).

Morphological abnormalities of the cerebral cortex have been reported in a number of MRI-studies in schizophrenia. Uncertainty remains regarding cause, mechanism and progression of the alterations. It has been suggested that antipsychotic medication reduces total gray matter volumes, but results are inconsistent. In the present study differences in regional cortical thickness between 96 patients with a DSM-IV diagnosis of schizophrenia (n=81) or schizoaffective disorder (n=15) and 107 healthy subjects (mean age 42 years, range 17-57 years) were investigated using MRI and computer image analysis. Cortical thickness was estimated as the shortest distance between the gray/white matter border and the pial surface at numerous points across the entire cortical mantle. The influence of age and antipsychotic medication on variation in global and regional cortical thickness was explored. Thinner cortex among patients than controls was found in prefrontal and temporal regions of both hemispheres, while parietal and occipital regions were relatively spared. Some hemispheric specificity was noted, as regions of the prefrontal cortex were more affected in the right hemisphere, and regions of the temporal cortex in the left hemisphere. No significant interaction effect of age and diagnostic group on variation in cortical thickness was demonstrated. Among patients, dose or type of antipsychotic medication did not affect variation in cortical thickness. The results from this hitherto largest study on the topic show that prefrontal and temporal cortical thinning in patients with schizophrenia compared to controls is as pronounced in older as in younger subjects. The lack of significant influence from antipsychotic medication supports that regional cortical thinning is an inherent feature of the neurobiological disease process in schizophrenia.

The purpose of the study was to assess the relationship between the P3a/P3b brain potentials, cortical thickness, and cognitive function in aging. Thirty-five younger and 37 older healthy participants completed a visual three-stimuli oddball ERP (event-related potential)-paradigm, a battery of neuropsychological tests, and MRI scans. Groups with short vs. long latency, and low vs. high amplitude, were compared on a point by point basis across the entire cortical mantle. In the young, thickness was only weakly related to P3. In the elderly, P3a amplitude effects were found in parietal areas, the temporoparietal junction, and parts of the posterior cingulate cortex. P3b latency was especially related to cortical thickness in large frontal regions. Path models with the whole sample pooled together were constructed, demonstrating that cortical thickness in the temporoparietal cortex predicted P3a amplitude, which in turn predicted executive function, and that thickness in orbitofrontal cortex predicted P3b latency, which in turn predicted fluid function. When age was included in the model, the relationship between P3 and cognitive function vanished, while the relationship between regional cortical thickness and P3 remained. It is concluded that thickness in specific cortical areas correlates with scalp recorded P3a/P3b in elderly, and that these relationships differentially mediate higher cognitive function., (Copyright 2007 Wiley-Liss, Inc.)

Morphometric cerebral characteristics were studied in children with prenatal poly-substance exposure (n=14) compared to controls (n=14) without such exposure. Ten of the substance-exposed children were born to mothers who used opiates (heroin) throughout the pregnancy. Groups were compared across 16 brain measures: cortical gray matter, cerebral white matter, hippocampus, amygdala, thalamus, accumbens area, caudate, putamen, pallidum, brainstem, cerebellar cortex, cerebellar white matter, lateral ventricles, inferior lateral ventricles, and the 3rd and 4th ventricles. In addition, continuous measurement of thickness across the entire cortical mantle was performed. Volumetric characteristics were correlated with ability and questionnaire assessments 2 years prior to scan. Compared to controls, the substance-exposed children had smaller intracranial and brain volumes, including smaller cerebral cortex, amygdala, accumbens area, putamen, pallidum, brainstem, cerebellar cortex, cerebellar white matter, and inferior lateral ventricles, and thinner cortex of the right anterior cingulate and lateral orbitofrontal cortex. Pallidum and putamen appeared especially reduced in the subgroup exposed to opiates. Only volumes of the right anterior cingulate, the right lateral orbitofrontal cortex and the accumbens area, showed some association with ability and questionnaire measures. The sample studied is rare and hence small, so conclusions cannot be drawn with certainty. Morphometric group differences were observed, but associations with previous behavioral assessment were generally weak. Some of the volumetric differences, particularly thinner cortex in part of the right lateral orbitofrontal cortex, may be moderately involved in cognitive and behavioral difficulties more frequently experienced by opiate and poly-substance-exposed children.

Information processing speed is a central concept in cognitive psychology and neuropsychology. Previous studies have mostly focused on mean reaction time (RT), and largely ignored intra-individual differences (the standard deviation of the RT: sdRT). Still, intra-individual inconsistency across trials has been shown to correlate with age, neurological disorders, intelligence, and performance on cognitive tests. However, sdRT has not been correlated with neuroanatomical variables. Such knowledge is important to the understanding of the neurobiological foundation for intra-individual variability. In the present study, white matter (WM) and cortical gray matter (GM) volume obtained from the average of two MR scans of 71 healthy participants (aged 20-88 years) were correlated with sdRT and mean RT obtained from a 3-stimulus visual oddball task. Negative correlations were hypothesized between sdRT and WM and between mean RT and cortical GM volume. These hypotheses were confirmed. The correlation between sdRT and WM volume was significant also independently of effects of age, gender, and mean RT, while there was a trend towards a significant correlation (p=.085) between cortical GM volume and mean RT independently of age. A path model was constructed, showing that age and sdRT gave independent contributions to the variance in performance intelligence, and that WM volume predicted performance score through the influence of sdRT. Further, sdRT was a stronger predictor of performance intelligence than mean RT. It is concluded that sdRT and mean RT may have different neuroanatomical correlates, and that sdRT is related to WM characteristics of the brain.

The purpose of the study was to test whether trial-to-trial variation in amplitude of the brain potentials P3a and P3b is related to age, intelligence (verbal and performance abilities), and brain volumetry. One hundred and thirty-three participants underwent neuropsychological testing and an event-related potential task, whereas a subgroup (n=72) also had magnetic resonance scans. Trial-to-trial variation in P3a amplitude correlated positively with age, and negatively with verbal and performance intelligence. Trial-to-trial variation in amplitude also correlated negatively with thickness in the temporoparietal junction and the precentral gyrus of the cerebral cortex, but these relationships were dependent on the influence of age. The results indicate that intraindividual variability should be used as a variable in the study of central nervous system function.

Do person characteristics determine when novel, attention-grabbing stimuli loose their novelty? The aim of the present study was to investigate habituation of the visual event-related potentials (ERP) P3a and P3b in men that (1) were engaged in extreme sports, (2) had extremely high scores on the Impulsivity Sensation Seeking scale of the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ), yet were not engaged in extreme sports, or (3) had extremely low scores on ZKPQ. The results showed that P3a habituated significantly more in extreme sporters than in the other groups. The same was not found in comparison of the high and the low ZKPQ scorers. There were not differences between the groups in overall amplitude. It is concluded that ERP habituation may be more relevant than mere amplitude to the sensation seeking trait in extreme sporters, and that they differ from others in ERPs related to automatic alerting-related processes, not controlled cognitive processing.

The relationship of visual P3a and P3b to age and neuropsychological performance was investigated in 26 healthy children (6.8-15.8 years) and 129 adult volunteers (20.0-88.8 years). Within the sample of children, an effect of age on midline topography was observed, with higher frontal amplitudes in the youngest compared to the oldest children. Increasing age was associated with lower P3a and P3b amplitude and shorter P3b latency at Fz. Performance on neuropsychological tests (matrix reasoning from WASI, digit span from WAIS, word order and hand movement from Kaufman) was only weakly associated with measures of P3a and P3b. The analyses were then repeated with the full life-span sample (n = 155). It was found that for P3a, amplitude decreased and latency increased with age. For P3b, the pattern was more complex, with a nonlinear amplitude reduction and no latency change with age. It appears that the development of P3a in children represents the start of processes that later continue in the adult life-span, but that the automatic processes indexed by P3a seems to mature earlier than the controlled processes reflected by P3b. Finally, it was demonstrated that the relationships between neuropsychological test scores (matrix reasoning, digit span) and P3 parameters were complex, following a mix of linear and nonlinear patterns. It is suggested that the neuropsychological significance of the different P3a and P3b parameters may change from childhood to the adult life-span.

The aim of this study was to determine the role of regional cortical thickness in recall of verbal material over an extended time period. MRI scans of healthy adults of varying ages were obtained. Two scans were averaged per person to achieve high spatial resolution, and a semi-automated method for continuous measurement of thickness across the entire cortical mantle was employed. Verbal memory tests assessing recall after 5 min, 30 min, and a mean interval of 83 days were administered. A general linear model (GLM) of the effects of thickness at each vertex on the different memory indices was computed, controlling for gender, age, IQ, and intracranial volume. These analyses were repeated with hippocampal volume as an additional variable to be controlled for, to assess to which extent effects of cortical thickness were independent of hippocampal size. Minute effects of cortical thickness were observed with regard to shorter time intervals (5 and 30 min). However, even when controlling for the effects of hippocampal volume, higher recall across months was associated with thicker cortex of distinct areas including parts of the gyrus rectus, the middle frontal gyrus, the parieto-occipital sulcus and the lingual gyrus of both hemispheres. In addition, hemisphere-specific associations were found in parts of the right temporal and parietal lobe as well as parts of the left precuneus. This supports a unique and critical role of the thickness of distinct cortical areas in recall after months, more than after minutes.

There is a lack of studies mapping electrophysiological event-related potentials (ERPs) to structural neuroanatomical characteristics. The aim of the present study was to integrate electrophysiological memory-related activity with cortical and hippocampal volume, as well as psychometric memory performance, in a life-span sample. More specifically, we wanted to investigate the functional significance of the often-observed frontal shift of ERP amplitude with increasing age and whether neuroanatomical characteristics can explain this shift. Sixty six healthy participants (20-78 years) went through a neuropsychological examination, MRI scans, and a visual recognition ERP task with verbal stimuli. The results showed that ERPs elicited in the recognition memory task (the old/new effect) correlated significantly with cortical volume, but not with hippocampal volume. Large cortex predicted more differentiated ERP activity and not just larger amplitude in general, implying more distinct and efficient retrieval. Furthermore, ERP amplitude, cortical volume, and hippocampal volume all predicted scores on a composite memory scale. All these relationship were dependent upon the common influence of age. Finally, the participants with the most anterior distribution of activity showed the poorest recognition memory performance. Neither cortical nor hippocampal volume were related to this frontal shift. It is concluded that the distribution of activity along the anterior-posterior axis in a memory paradigm may have functional but not neuroanatomical volumetric correlates. The functional correlates need not be restricted to the older age groups.

In the present study, we investigated age-related changes in interactions between efficiency of neuronal repair mechanisms and efficiency of cholinergic neurotransmission in the context of attentional orienting. In addition, we explored white matter volume changes as possible neuronal underpinnings. A sample of 230 healthy middle-aged (53-64 years) and older (65-75 years) adults was genotyped for polymorphisms of APOE and CHRNA4, a nicotinic receptor subunit gene. Participants were administered a visuospatial attention task involving letter discrimination with location cues of varying validity. Genotype effects on white matter volume were also investigated in a subset of participants who received MRI scans. APOE interacted with CHRNA4, such that APOE-epsilon4 carriers who were also CHRNA4 TT homozygotes showed disproportionately slowed reaction time (RT) following invalid location cues. The interaction was stronger in the middle-aged participants than in the older participants. There was also a trend for individuals with combined APOE-epsilon4/CHRNA4 TT genotypes to show both lower white matter volume and slower overall RT on the attention task The interaction of a neurotransmission gene (CHRNA4) and a susceptibility gene (APOE) suggests that the efficiency of neuronal repair mechanisms may modulate the cholinergic system to influence attentional function.