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The locus coeruleus (LC) is one of the earliest sites of tau pathology, making it a key structure in early Alzheimer’s disease (AD) progression. As the primary source of norepinephrine for the brain, reduced LC integrity may have negative consequences for brain health, yet macrostructural brain measures (e.g. cortical thickness) may not be sensitive to early stages of neurodegeneration. We therefore examined whether LC integrity was associated with differences in cortical gray matter microstructure among 435 men (mean age = 67.5; range = 62–71.7). LC structural integrity was indexed by contrast-to-noise ratio (LCCNR) from a neuromelanin-sensitive MRI scan. Restriction spectrum imaging (RSI), an advanced multi-shell diffusion technique, was used to characterize cortical microstructure, modeling total diffusion in restricted, hindered, and free water compartments. Higher LCCNR (greater integrity) was associated with higher hindered and lower free water diffusion in multiple cortical regions. In contrast, no associations between LCCNR and cortical thickness survived correction. Results suggest lower LC integrity is associated with patterns of cortical microstructure that may reflect a reduction in cytoarchitectural barriers due to broader neurodegenerative processes. These findings highlight the potential utility for LC imaging and advanced diffusion measures of cortical microstructure in assessing brain health and early identification of neurodegenerative processes.

Objective Distal sensory polyneuropathy (DSP) is a disabling consequence of human immunodeficiency virus (HIV), leading to poor quality of life and more frequent falls in older age. Neuropathic pain and paresthesia are prevalent symptoms; however, there are currently no known curative treatments and the longitudinal course of pain in HIV-associated DSP is poorly characterized. Methods This was a prospective longitudinal study of 265 people with HIV (PWH) enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study with baseline and 12-year follow-up evaluations. Since pain and paresthesia are highly correlated, statistical decomposition was used to separate the two symptoms at baseline. Multivariable logistic regression analyses of decomposed variables were used to determine the effects of neuropathy symptoms at baseline on presence and worsening of distal neuropathic pain at 12-year follow-up, adjusted for covariates. Results Mean age was 56 ± 8 years, and 21% were female at follow-up. Nearly the entire cohort (96%) was on antiretroviral therapy (ART), and 82% had suppressed (≤50 copies/mL) plasma viral loads at follow-up. Of those with pain at follow-up (n = 100), 23% had paresthesia at the initial visit. Decomposed paresthesia at baseline increased the risk of pain at follow-up (odds ratio [OR] 1.56; 95% confidence interval [CI] 1.18, 2.07), and decomposed pain at baseline predicted a higher frequency of pain at follow-up (OR 1.96 [95% CI 1.51, 2.58]). Conclusions Paresthesias are a clinically significant predictor of incident pain at follow-up among aging PWH with DSP. Development of new therapies to encourage neuroregeneration might take advantage of this finding to choose individuals likely to benefit from treatment preventing incident pain.

Author(s): Elman, Jeremy A; Puckett, Olivia K; Beck, Asad; Fennema-Notestine, Christine; Cross, Latonya K; Dale, Anders M; Eglit, Graham ML; Eyler, Lisa T; Gillespie, Nathan A; Granholm, Eric L; Gustavson, Daniel E; Hagler, Donald J; Hatton, Sean N; Hauger, Richard; Jak, Amy J; Logue, Mark W; McEvoy, Linda K; McKenzie, Ruth E; Neale, Michael C; Panizzon, Matthew S; Reynolds, Chandra A; Sanderson-Cimino, Mark; Toomey, Rosemary; Tu, Xin M; Whitsel, Nathan; Williams, McKenna E; Xian, Hong; Lyons, Michael J; Franz, Carol E; Kremen, William S | Abstract: IntroductionThe locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep-wake cycle, modulating cognitive function, and AD progression.MethodsParticipants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (LCCNR ). We examined LCCNR , cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction.ResultsHeritability of LCCNR was .48. Participants with aMCI showed greater daytime dysfunction. Lower LCCNR was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction.DiscussionReduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep-related dysfunction, and risk for aMCI. These findings in late-middle-aged adults highlight the potential of MRI-based measures of LC integrity in early identification of AD risk.

How and when education improves cognitive capacity is an issue of profound societal importance. Education and later-life education-related factors, such as occupational complexity and engagement in cognitive-intellectual activities, are frequently considered indices of cognitive reserve, but whether their effects are truly causal remains unclear. In this study, after accounting for general cognitive ability (GCA) at an average age of 20 y, additional education, occupational complexity, or engagement in cognitive-intellectual activities accounted for little variance in late midlife cognitive functioning in men age 56–66 ( n = 1009). Age 20 GCA accounted for 40% of variance in the same measure in late midlife and approximately 10% of variance in each of seven cognitive domains. The other factors each accounted for n = 367). In our view, the most parsimonious explanation of our results, a meta-analysis of the impact of education, and epidemiologic studies of the Flynn effect is that intellectual capacity gains due to education plateau in late adolescence/early adulthood. Longitudinal studies with multiple cognitive assessments before completion of education would be needed to confirm this speculation. If cognitive gains reach an asymptote by early adulthood, then strengthening cognitive reserve and reducing later-life cognitive decline and dementia risk may really begin with improving educational quality and access in childhood and adolescence.

Individual differences in white matter tract microstructure, measured with diffusion tensor imaging (DTI), demonstrate substantial heritability. However, it is unclear to what extent this heritability reflects global genetic influences or tract-specific genetic influences. The goal of the current study was to quantify the proportion of genetic and environmental variance in white matter tracts attributable to global versus tract-specific influences. We assessed fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) across 11 tracts and 22 subdivisions of these tracts in 392 middle-aged male twins from the Vietnam Era Twin Study of Aging (VETSA). In principal component analyses of the 11 white matter tracts, the first component, which represents the global signal, explained 50.1% and 62.5% of the variance in FA and MD, respectively. Similarly, the first principal component of the 22 tract subdivisions explained 38.4% and 47.0% of the variance in FA and MD, respectively. Twin modeling revealed that DTI measures of all tracts and subdivisions were heritable, and that genetic influences on global FA and MD accounted for approximately half of the heritability in the tracts or tract subdivisions. Similar results were observed for the AD and RD diffusion metrics. These findings underscore the importance of controlling for DTI global signals when measuring associations between specific tracts and outcomes such as cognitive ability, neurological and psychiatric disorders, and brain aging.

Negative fateful life events (FLEs) such as interpersonal conflict, death in the family, financial hardship, and serious medical emergencies can act as allostatic stressors that accelerate biological aging. However, the relationship between FLEs and neuroanatomical aging is not well understood. We examined 359 men (mean age 62years) participating in the Vietnam Era twin study of aging (VETSA) to determine whether negative midlife FLEs are associated with advanced brain aging after controlling for physical, psychological, and lifestyle factors. At two different time points, participants were assessed for negative FLEs, health and well-being, general cognitive ability, socioeconomic status, depression, and ethnicity. Participants underwent a magnetic resonance imaging examination, and T1-weighted images were processed with FreeSurfer. Subsequent neuroanatomical measurements were entered into the Brain-Age Regression Analysis and Computation Utility software (BARACUS) to predict brain age. Having more midlife FLEs, particularly relating to interpersonal relationships, was associated with advanced predicted brain aging (i.e., higher predicted brain age relative to chronological age). This association remained after controlling for the significant covariates of alcohol consumption, cardiovascular risk, adult socioeconomic status, and ethnicity.

Two basic neuroimaging-based characterizations of white matter tracts are the magnitude of water diffusion along the principal tract orientation (axial diffusivity, AD) and water diffusion perpendicular to the principal orientation (radial diffusivity, RD). It is generally accepted that decreases in AD reflect disorganization, damage, or loss of axons, whereas increases in RD are indicative of disruptions to the myelin sheath. Previous reports have detailed the heritability of individual AD and RD measures, but have not examined the extent to which the same or different genetic or environmental factors influence these two phenotypes (except for corpus callosum). We implemented bivariate twin analyses to examine the shared and independent genetic influences on AD and RD. In the Vietnam Era Twin Study of Aging, 393 men (mean age = 61.8 years, SD = 2.6) underwent diffusion-weighted magnetic resonance imaging. We derived fractional anisotropy (FA), mean diffusivity (MD), AD, and RD estimates for 11 major bilateral white matter tracts and the mid-hemispheric corpus callosum, forceps major, and forceps minor. Separately, AD and RD were each highly heritable. In about three-quarters of the tracts, genetic correlations between AD and RD were >.50 (median = .67) and showed both unique and common variance. Genetic variance of FA and MD were predominately explained by RD over AD. These findings are important for informing genetic association studies of axonal coherence/damage and myelination/demyelination. Thus, genetic studies would benefit from examining the shared and unique contributions of AD and RD.

Heavy alcohol consumption is associated with deleterious changes in the brain but associations of moderate alcohol intake are not well understood. We examined the association of alcohol consumption with brain white matter health in 377 middle-aged men (56–66 years old; mean 61.8 ± 2.6 years) who were participants in the Vietnam Era Twin Study of Aging (VETSA). T1-, T2-, proton density-, and diffusion-weighted magnetic resonance images were obtained. Diffusion measures were quantified from 12 major white matter tracts. Global white matter lesion (WML) burden was also quantified. Mixed effects linear models examined differences in diffusivity and WMLs by amount of alcohol intake. Analyses adjusted for numerous demographic, health, and lifestyle variables. An inverted-U association was found between alcohol intake and fractional anisotropy (FA) in several tracts, including the inferior-frontal-occipital fasciculus, uncinate fasciculus, superior longitudinal fasciculus, the forceps minor and the anterior thalamic radiations. In these tracts, FA increased with increasing alcohol intake, peaking with moderate alcohol intake (9–28 drinks in 14 days), and declining with heavier intake. Associations remained significant after exclusion of individuals with diabetes or hypertension. There was a U-shaped association in WML burden with highest burden among never drinkers and heavy drinkers (>28 drinks in 14 days). This association was no longer significant after exclusion of individuals with hypertension, since WML burden among heavy drinkers no longer differed from that of other drinkers. This suggests that hypertension related to heavy alcohol intake may contribute to WML burden observed among heavy drinkers. Together, these correlational results suggest that among middle-aged men, moderate drinking may be associated with metrics of better white matter health, particularly microstructural measures, whereas drinking beyond recommended guidelines may be associated with both microstructural and macrostructural white matter damage., Highlights • In middle-aged men brain white matter metrics differed by amount of alcohol intake. • Fractional anisotropy (FA) was highest among moderate drinkers. • FA decreased with heavier drinking (>2 drinks/day, on average). • Never drinkers and heavy drinkers had highest white matter lesion burden. • Light to moderate drinking is associated with indices of better white matter health.

Pupillary responses during cognitive tasks are linked to functioning of the locus coeruleus (LC). The LC is an early site of abnormal tau deposition, which may contribute to key aspects of Alzheimer’s disease (AD) pathophysiology. We previously found attenuation of pupillary responses to increases in cognitive load in individuals with mild cognitive impairment (MCI), suggesting pupillary responses may provide a biomarker of early risk for AD associated with LC dysfunction. The LC modulates cortical activity through two modes of operation: tonic and phasic. Early LC damage has been predicted to result in a state of persistent high tonic LC activity that may disrupt task-related phasic activity. To further examine whether pupillary responses are associated with early LC dysfunction, we measured pupil dilation during a digit span task as a measure of phasic activity, and low frequency BOLD variance (LFBV) during resting-state fMRI in key nodes of the ventral attention network as a measure of cortical reactivity related to LC tonic activity in 358 middle-aged men. Individuals with greater LFBV in ventral attention network nodes, i.e., higher tonic brain activity at rest, showed a smaller increase in pupil dilation from low to moderate cognitive loads. Thus, higher tonic LFBV activity at rest was related to reduced task-appropriate phasic dilation increases. The results support predictions from prominent models of LC functioning in which early LC dysfunction leads to persistent high tonic rates of activity during rest and lower signal-to-noise of phasic responses during task performance. Taken together with previous findings of early AD pathophysiology in LC and reduced phasic dilation responses to increased cognitive load in individuals with MCI, the present results suggest that pupillary responses may index early LC dysfunction and should receive further study as a potential biomarker of risk for AD.

© 2016 Elsevier Inc. General cognitive ability (GCA) has substantial explanatory power for behavioral and health outcomes, but its cortical substrate is still not fully established. GCA is highly polygenic and research to date strongly suggests that its cortical substrate is highly polyregional. We show in map-based and region-of-interest-based analyses of adult twins that a complex cortical configuration underlies GCA. Having relatively greater surface area in evolutionary and developmentally high-expanded prefrontal, lateral temporal, and inferior parietal regions is positively correlated with GCA, whereas relatively greater surface area in low-expanded occipital, medial temporal, and motor cortices is negatively correlated with GCA. Essentially the opposite pattern holds for relative cortical thickness. The phenotypic positive-to-negative gradients in our cortical-GCA association maps were largely driven by a similar pattern of genetic associations. The patterns are consistent with regional cortical stretching whereby relatively greater surface area is related to relatively thinner cortex in high-expanded regions. Thus, the typical "bigger is better" view does not adequately capture cortical-GCA associations. Rather, cognitive ability is influenced by complex configurations of cortical development patterns that are strongly influenced by genetic factors. Optimal cognitive ability appears to be driven both by the absolute size and the polyregional configuration of the entire cortex rather than by small, circumscribed regions.

© 2015 Journal of NeuroVirology, Inc. A wide spectrum of neurocognitive deficits characterises HIV infection in adults. HIV infection is additionally associated with morphological brain abnormalities affecting neural substrates that subserve neurocognitive function. Early life stress (ELS) also has a direct influence on brain morphology. However, the combined impact of ELS and HIV on brain structure and neurocognitive function has not been examined in an all-female sample with advanced HIV disease. The present study examined the effects of HIV and childhood trauma on brain morphometry and neurocognitive function. Structural data were acquired using a 3T Magnetom MRI scanner, and a battery of neurocognitive tests was administered to 124 women: HIV-positive with ELS (n = 32), HIV-positive without ELS (n = 30), HIV-negative with ELS (n = 31) and HIV-negative without ELS (n = 31). Results revealed significant group volumetric differences for right anterior cingulate cortex (ACC), bilateral hippocampi, corpus callosum, left and right caudate and left and right putamen. Mean regional volumes were lowest in HIV-positive women with ELS compared to all other groups. Although causality cannot be inferred, findings also suggest that alterations in the left frontal lobe, right ACC, left hippocampus, corpus callosum, left and right amygdala and left caudate may be associated with poorer neurocognitive performance in the domains of processing speed, attention/working memory, abstraction/executive functions, motor skills, learning and language/fluency with these effects more pronounced in women living with both HIV and childhood trauma. This study highlights the potential contributory role of childhood trauma to brain alterations and neurocognitive decline in HIV-infected individuals.

© 2015, Springer Science+Business Media New York. Chronic cigarette use has been consistently associated with differences in the neuroanatomy of smokers relative to nonsmokers in case–control studies. However, the etiology underlying the relationships between brain structure and cigarette use is unclear. A community-based sample of male twin pairs ages 51–59 (110 monozygotic pairs, 92 dizygotic pairs) was used to determine the extent to which there are common genetic and environmental influences between brain structure and average lifetime cigarette use. Brain structure was measured by high-resolution structural magnetic resonance imaging, from which subcortical volume and cortical volume, thickness and surface area were derived. Bivariate genetic models were fitted between these measures and average lifetime cigarette use measured as cigarette pack-years. Widespread, negative phenotypic correlations were detected between cigarette pack-years and several cortical as well as subcortical structures. Shared genetic and unique environmental factors contributed to the phenotypic correlations shared between cigarette pack-years and subcortical volume as well as cortical volume and surface area. Brain structures involved in many of the correlations were previously reported to play a role in specific aspects of networks of smoking-related behaviors. These results provide evidence for conducting future research on the etiology of smoking-related behaviors using measures of brain morphology.

© 2014 Elsevier Inc. The phenotypic and genetic relationship between global cortical size and general cognitive ability (GCA) appears to be driven by surface area (SA) and not cortical thickness (CT). Gyrification (cortical folding) is an important property of the cortex that helps to increase SA within a finite space, and may also improve connectivity by reducing distance between regions. Hence, gyrification may be what underlies the SA-GCA relationship. In previous phenotypic studies, a 3-dimensional gyrification index (3DGI) has been positively associated with cognitive ability and negatively associated with mild cognitive impairment, Alzheimer's disease, and psychiatric disorders affecting cognition. However, the differential genetic associations of 3DGI and SA with GCA are still unclear. We examined the heritability of 3DGI, and the phenotypic, genetic, and environmental associations of 3DGI with SA and GCA in a large sample of adult male twins (N. = 512). Nearly 85% of the variance in 3DGI was due to genes, and 3DGI had a strong phenotypic and genetic association with SA. Both 3DGI and total SA had positive phenotypic correlations with GCA. However, the SA-GCA correlation remained significant after controlling for 3DGI, but not the other way around. There was also significant genetic covariance between SA and GCA, but not between 3DGI and GCA. Thus, despite the phenotypic and genetic associations between 3DGI and SA, our results do not support the hypothesis that gyrification underlies the association between SA and GCA.

While many studies have reported that individual differences in personality traits are genetically influenced, the neurobiological bases mediating these influences have not yet been well characterized. To advance understanding concerning the pathway from genetic variation to personality, here we examined whether measures of heritable variation in neuroanatomical size in candidate regions (amygdala and medial orbitofrontal cortex) were associated with heritable effects on personality. A sample of 486 middle-aged (mean=55 years) male twins (complete MZ pairs=120; complete DZ pairs=84) underwent structural brain scans and also completed measures of two core domains of personality: positive and negative emotionality. After adjusting for estimated intracranial volume, significant phenotypic (r(p)) and genetic (r(g)) correlations were observed between left amygdala volume and positive emotionality (r(p)=.16, p

Understanding the genetic and environmental contributions to measures of brain structure such as surface area and cortical thickness is important for a better understanding of the nature of brain-behavior relationships and changes due to development or disease. Continuous spatial maps of genetic influences on these structural features can contribute to our understanding of regional patterns of heritability, since it remains to be seen whether genetic contributions to brain structure respect the boundaries of any traditional parcellation approaches. Using data from magnetic resonance imaging scans collected on a large sample of monozygotic and dizygotic twins in the Vietnam Era Twin Study of Aging, we created maps of the heritability of areal expansion (a vertex-based area measure) and cortical thickness and examined the degree to which these maps were affected by adjustment for total surface area and mean cortical thickness. We also compared the approach of estimating regional heritability based on the average heritability of vertices within the region to the more traditional region-of-interest (ROI)-based approach. The results suggested high heritability across the cortex for areal expansion and, to a slightly lesser degree, for cortical thickness. There was a great deal of genetic overlap between global and regional measures for surface area, so maps of region-specific genetic influences on surface area revealed more modest heritabilities. There was greater inter-regional variability in heritabilities when calculated using the traditional ROI-based approach compared to summarizing vertex-by-vertex heritabilities within regions. Discrepancies between the approaches were greatest in small regions and tended to be larger for surface area than for cortical thickness measures. Implications regarding brain phenotypes for future genetic association studies are discussed. © The Authors 2012.

Self-esteem and well-being are important for successful aging, and some evidence suggests that self-esteem and well-being are associated with hippocampal volume, cognition and stress responsivity. Whereas most of this evidence is based on studies on older adults, we investigated self-esteem, well-being and hippocampal volume in 474 male middle-aged twins. Self-esteem was significantly positively correlated with hippocampal volume (0.09, P = 0.03 for left hippocampus, 0.10, P = 0.04 for right). Correlations for well-being were not significant (Ps > 0.05). There were strong phenotypic correlations between self-esteem and well-being (0.72, P < 0.001) and between left and right hippocampal volume (0.72, P < 0.001). In multivariate genetic analyses, a two-factor additive genetic and unique environmental (AE) model with well-being and self-esteem on one factor and left and right hippocampal volumes on the other factor fits the data better than Cholesky, independent pathway or common pathway models. The correlation between the two genetic factors was 0.12 (P = 0.03); the correlation between the environmental factors was 0.09 (P > 0.05). Our results indicate that largely different genetic and environmental factors underlie self-esteem and well-being on one hand and hippocampal volume on the other. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Methamphetamine (METH) dependence is frequently comorbid with HIV infection and both have been linked to alterations of brain structure and function. In a previous study, we showed that the brain volume loss characteristic of HIV infection contrasts with METH-related volume increases in striatum and parietal cortex, suggesting distinct neurobiological responses to HIV and METH (Jernigan et al., 2005). Functional magnetic resonance imaging (fMRI) has the potential to reveal functional interactions between the effects of HIV and METH. In the present study, 50 participants were studied in four groups: an HIV+ group, a recently METH-dependent group, a dually affected group, and a group of unaffected community comparison subjects. An fMRI paradigm consisting of motor sequencing tasks of varying levels of complexity was administered to examine blood oxygenation level dependent (BOLD) changes. Within all groups, activity increased significantly with increasing task complexity in large clusters within sensorimotor and parietal cortex, basal ganglia, cerebellum, and cingulate. The task complexity effect was regressed on HIV status, METH status, and the HIV. ×. METH interaction term in a simultaneous multiple regression. HIV was associated with less complexity-related activation in striatum, whereas METH was associated with less complexity-related activation in parietal regions. Significant interaction effects were observed in both cortical and subcortical regions; and, contrary to expectations, the complexity-related activation was less aberrant in dually affected than in single risk participants, in spite of comparable levels of neurocognitive impairment among the clinical groups. Thus, HIV and METH dependence, perhaps through their effects on dopaminergic systems, may have opposing functional effects on neural circuits involved in motor programming. © 2012 Elsevier Ireland Ltd.

The estimation of cortical thickness is in part dependent on the degree of contrast in T1 signal intensity between white matter and gray matter along the cortical mantle. The ratio of white matter to gray matter signal (WM/GM contrast) has been found to vary as a function of age and Alzheimer's disease status, suggesting a biological component to what might otherwise be labeled as a nuisance variable. The aim of the present study was to determine if measures of WM/GM contrast are genetically influenced, as well as the degree to which this phenotype may be related to the genetic and environment determinants of cortical thickness. Participants were 514 male twins (130 monozygotic, 97 dizygotic pairs, and 60 unpaired individuals) from the Vietnam Era Twin Study of Aging. Ages ranged from 51 to 59. years. Measures of WM/GM contrast and cortical thickness were derived for 66 cortical regions of interest (ROI) using FreeSurfer-based methods. Univariate and bivariate twin analyses were used in order to estimate the heritability of WM/GM contrast, as well as the degree of shared genetic and environmental variance between WM/GM contrast and cortical thickness. WM/GM contrast was found to be significantly heritable in the majority of ROIs. The average heritability across individual ROIs was highest in the occipital lobe (.50), and lowest in the cingulate cortex (.24). Significant phenotypic correlations between WM/GM contrast and cortical thickness were observed for most of the ROIs. The majority of the phenotypic correlations were negative, ranging from -.11 to -.54. Of the 66 associations, only 17 significant genetic correlations were found, ranging from -.16 to -.34, indicating small amounts of shared genetic variance. The majority of the phenotypic correlations were accounted for by small unique environmental effects common between WM/GM contrast and cortical thickness. These findings demonstrate that like cortical thickness, WM/GM contrast is a genetically influenced brain structure phenotype. The lack of significant genetic correlations with cortical thickness suggests that this measure potentially represents a unique source of genetic variance, one that has yet to be explored by the field of imaging genetics. © 2012 Elsevier Inc.

Building the Brain Brain connectivity is often described as a network of discrete independent cables analogous to a switchboard, but how is the physical structure of the brain constructed (see the Perspective by Zilles and Amunts )? Wedeen et al. (p. 1628 ) used high-resolution diffusion tensor imaging in humans and four species of nonhuman primates to identify and compare the geometric structure of large fiber tracts in the brain. Fiber tracts followed a highly constrained and regular geometry, which may provide an efficient solution for pathfinding during ontogenetic development. Much of development occurs through elaboration and assembly of semiautonomous building blocks. Chen et al. (p. 1634 ) applied statistical analysis to the form of the human cortex in brain-imaging studies that compared more than 400 di- and mono-zygotic twins. The findings suggest that the structure of the human cortex is defined by genetics.

The presence of an ApoE ε4 allele (ε4+) increases the risk of developing Alzheimer's disease (AD). Previous studies support an adverse relationship between ε4+ status and brain structure and function in mild cognitive impairment and AD; in contrast, the presence of an ε2 allele may be protective. Whether these findings reflect disease-related effects or pre-existing endophenotypes, however, remains unclear. The present study examined the influence of ApoE allele status on brain structure solely during middle-age in a large, national sample. Participants were 482 men, ages 51-59, from the Vietnam Era Twin Study of Aging (VETSA). T1-weighted images were used in volumetric segmentation and cortical surface reconstruction methods to measure regional volume and thickness. Primary linear mixed effects models predicted structural measures with ApoE status (ε3/3, ε2/3, ε3/4) and control variables for effects of site, non-independence of twin data, age, and average cranial vault or cortical thickness. Relative to the ε3/3 group, the ε3/4 group demonstrated significantly thinner cortex in superior frontal and left rostral and right caudal midfrontal regions; there were no significant effects of ε4 status on any temporal lobe measures. The ε2/3 group demonstrated significantly thicker right parahippocampal cortex relative to the ε3/3 group. The ApoE ε4 allele may influence cortical thickness in frontal areas, which are later developing regions thought to be more susceptible to the natural aging process. Previous conflicting findings for mesial temporal regions may be driven by the inclusion of older individuals, who may evidence preclinical manifestations of disease, and by unexamined moderators of ε4-related effects. The presence of the ε2 allele was related to thicker cortex, supporting a protective role. Ongoing follow-up of the VETSA sample may shed light on the potential for age-and disease-related mediation of the influence of ApoE allele status. © 2011 The authors and IOS Press. All rights reserved.

Animal data demonstrate that the development of distinct cortical areas is influenced by genes that exhibit highly regionalized expression patterns. In this paper, we show genetic patterning of cortical surface area derived from MRI data from 406 adult human twins. We mapped genetic correlations of areal expansion between selected seed regions and all other cortical locations, with the selection of seed points based on results from animal studies. " Marching seeds" and a data-driven, hypothesis-free, fuzzy-clustering approach provided convergent validation. The results reveal strong anterior-to-posterior graded, bilaterally symmetric patterns of regionalization, largely consistent with patterns previously reported in nonhuman mammalian models. Broad similarities in genetic patterning between rodents and humans might suggest a conservation of cortical patterning mechanisms, whereas dissimilarities might reflect the functionalities most essential to each species. © 2011 Elsevier Inc.

Due to the increasing need for subject privacy, the ability to deidentify structural MR images so that they do not provide full facial detail is desirable. A program was developed that uses models of nonbrain structures for removing potentially identifying facial features. When a novel image is presented, the optimal linear transform is computed for the input volume (Fischl et al. [2002]: Neuron 33:341-355; Fischl et al. [2004]: Neuroimage 23 (Suppl 1):S69-S84). A brain mask is constructed by forming the union of all voxels with nonzero probability of being brain and then morphologically dilated. All voxels outside the mask with a nonzero probability of being a facial feature are set to 0. The algorithm was applied to 342 datasets that included two different T1-weighted pulse sequences and four different diagnoses (depressed, Alzheimer's, and elderly and young control groups). Visual inspection showed none had brain tissue removed. In a detailed analysis of the impact of defacing on skull-stripping, 16 datasets were bias corrected with N3 (Sled et al. [1998]: IEEE Trans Med Imaging 17:87-97), defaced, and then skull-stripped using either a hybrid watershed algorithm (Ségonne et al. [2004]: Neuroimage 22:1060-1075, in FreeSurfer) or Brain Surface Extractor (Sandor and Leahy [1997]: IEEE Trans Med Imaging 16:41-54; Shattuck et al. [2001]: Neuroimage 13:856-876); defacing did not appreciably influence the outcome of skull-stripping. Results suggested that the automatic defacing algorithm is robust, efficiently removes nonbrain tissue, and does not unduly influence the outcome of the processing methods utilized; in some cases, skull-stripping was improved. Analyses support this algorithm as a viable method to allow data sharing with minimal data alteration within large-scale multisite projects. © 2007 Wiley-Liss, Inc.

The present study aimed to determine how older bilingual subjects' naming performance is affected by their knowledge of two languages. Twenty-nine aging (mean age = 74.0; SD = 7.1) Spanish-English bilinguals were asked to name all pictures in the Boston Naming Test (BNT) first in their dominant language and then in their less-dominant language. Bilinguals with similar naming scores in each language, or relatively balanced bilinguals, named more pictures correctly when credited for producing a correct name in either language. Balanced bilinguals also named fewer pictures in their dominant language than unbalanced bilinguals, and named more pictures correctly in both languages if the pictures had cognate names (e.g., dart is dardo in Spanish). Unbalanced bilinguals did not benefit from the alternative (either-language) scoring procedure and showed cognate effects only in their nondominant language. These findings may help to guide the interpretation of neuropsychological data for the purpose of determining cognitive status in older bilinguals and can be used to develop models of bilingual language processing. Bilinguals'ability to name pictures reflects their experience with word forms in both languages. © 2007 The International Neuropsychological Society.

Objective: The authors examined the separate and combined effects of methamphetamine dependence and HIV infection on brain morphology. Method: Morphometric measures obtained from magnetic resonance imaging of methamphetamine-dependent and/or HIV-positive participants and their appropriate age- and education-matched comparison groups were analyzed. Main effects of age, HIV infection, methamphetamine dependence, and the interactions of these factors were examined in analyses of cerebral gray matter structure volumes. Results: Independent of the effect of age, HIV infection was associated with reduced volumes of cortical, limbic, and striatal structures. There was also some evidence of an interaction between age and HIV infection such that older HIV-positive participants suffered disproportionate loss. Methamphetamine dependence was surprisingly associated with basal ganglia and parietal cortex volume increases, and in one of these structures-the nucleus accumbens-there appeared to be a larger effect in younger methamphetamine abusers. Neurocognitive impairment was associated with decreased cortical volumes in HIV-positive participants but with increased cortical volumes in methamphetamine-dependent participants. Conclusions: These results suggest significant brain structure alterations associated with both HIV infection and methamphetamine dependence. The regional patterns of the changes associated with these factors were distinct but overlapping, and the effects on brain volumes were opposing. Although the results of the present study provide little information about the specific mechanisms leading to the unexpected methamphetamine effects, they may be related to glial activation or neuritic growth, both of which have been associated with methamphetamine exposure in animal studies. These results have implications for the interpretation of brain morphological findings in methamphetamine-dependent, HIV-positive individuals, a group whose numbers are unfortunately increasing.

Poster Session P2: Diagnosis and Disease Progression - Neuroimaging R E G I O N A L MR BRAIN V O L U M E S IN THE PREDICTION OF COGNITIVE DECLINE IN AD Wes S. Houston* 1, Christine Fennema-Notestine 1'2 , Nikki R. Home 3, Mark W. Bondi L2, Sarah L. Archibald 1'2, Terry L. Jernigan 1'2, David P. Salmon 4. 1VA San Diego Healthcare System, San Diego, CA, USA; e University of California, San Diego, Department of Psychiatry, San Diego, CA, USA; S San Diego State University~University of California, San Diego Joint Doctoral Program in Clinical Psychology. San Diego, CA, USA. 4 University of California, San Diego, Department of Neurosciences, San Diego, CA, USA. Contact e-mail: whouston@ucsd.edu Background: The characteristic pattern of cognitive deterioration in Alzheimer's disease (AD) is a decline in episodic memory followed by a progressive worsening of other cognitive abilities including executive, language and visuomotor skills. Consistent and predictable neuropatho- logical changes have also been observed in AD. In its earliest stages, AD neuropathology originates in the mesial temporal areas including the hippocampus and entorhinal cortices followed by a spreading to cortical association areas (Braak & Braak, 1998). Objective: In an effort to predict annual rate of cognitive decline, we examined regional structural magnetic resonance (MR) brain volumes in mild-to-moderate AD. Given the pat- tern of progressive cortical atrophy, we expected cortical brain changes in mild-to-moderate AD patients to be more highly correlated with language and visuomotor abilities than with memory ahihties, given its primacy and prominence in the earliest stages of the disease. Methods: Thirty-one patients with mild-to-moderate AD were administered a measure of general cognitive abilities, Dementia Rating Scale (DRS, Mattis, 1973) both at the time of receiving a structural MR scan and approximately one year later. One-year change in general cognitive abilities was calculated by subtracting the baseline DRS total score from the DRS total the following year. Multiple regression and simple correlations were calculated between brain volumes of 8 cortical regions (i.e., left and right frontal, temporal, parietal and occipital areas). Results: The mean DRS decline was 8.29 points (SD = 12.37). A correlation matrix indicated that left and right occipital gray (r = 0.39; p = 0.02, r = 0.35; p = 0.03, respectively) and left parietal gray volumes (1 = 0.37; p = 0.02) had the strongest linear relation with a one-year decline in cognitive functioning. Multiple regression analysis revealed that only the left occipital cortical area was retained in the final model (R 2 = 0.15; p = 0.03). Conclusion: Cognitive decline in this sample of mild-to-moderate AD patients was best predicted by atrophy in regions other than the temporal lobes, consistent with the known pattern of neuropathologic spreading in this stage of AD. Support: NIH/NIA P50AG05131, AG12674, & AG04085, DVA Medical Research Service NEURAL CORRELATES OF IMPAIRED SEMANTIC MEMORY IN ALZHEIMER'S DISEASE Murray Grossman*, James Gee, Peachie Moore, Melissa Work, Phyllis Koenig. University of Pennsylvania, Philadelphia, PA, USA. Contact e-mail: mgrossma@mail.med.upenn.edu Background: Our model of semantic memory includes feature knowl- edge for categories, and processes such as categorization that use this knowledge to make semantic decisions. AD patients have impaired se- mantic memory that may involve degraded semantic feature knowledge and impaired categorization processes. Objective: Determine the basis for impaired semantic memory in AD. Methods: 123 mild-to-moderate AD patients performed a semantic category membership judgment task. Feature representations were assessed by examining judgments for natural vs manufactured stimuli. Semantic processes were examined by assessing judgments of foils: Errors discriminating between category members and related non-members (e.g. for the category VEGETABLE, a related foil is apple ) suggest a deficit using rule-based processes to distinguish between partially-overlapping stimuli; Errors discriminating between category mem- bers and unrelated non-members (e.g. for the category VEGETABLE, an unrelated foil is chair ) suggest a deficit with similarity-based processes used to distinguish between non-overlapping stimuli. Regression analyses related semantic performance to cortical volume in a subgroup of 12 AD patients using voxel-based morphometry analyses of spatially normalized and segmented structural MtlI images obtained at 1.5T (voxels 0.9 x 0.9 x 1.3 mm). Results: AD patients had significantly impaired overall category membership judgments. Individual patient analyses revealed a significant impairment in 24% of AD patients, according to z-scores relative to 25 matched controls. Judgments of the natural category were significantly less accurate than the manufactured category. Error analyses revealed a deficit in the rule-based categorization process needed to discriminate between category exemplars and partially-overlapping foils that are not category members. This categorization impairment was more evident in the natu- ral than the manufactured category. MRI correlations associated overall semantic judgment performance with dorsolateral prefrontal and inferior temporal cortex of the left hemisphere in AD. This overlapped with the MR/correlations for the rule-based categorization processing impairment, but not with correlations for the degraded natural category of knowledge. Conclusions: Category-specific semantic deficits in AD may be due in part to impaired categorization processes. Consistent with fMRI activation studies in healthy adults and AD patients, MRI correlations relate impaired semantic categorization to disease in a left hemisphere network involving multimodal frontal and temporal association cortex. AGE-RELATED CORTICAL GREY MATTER REDUCTIONS IN NONDEMENTED DOWN'S SYNDROME ADULTS DETERMINED BY MAGNETIC RESONANCE IMAGING W I T H VOXEL-BASED MORPHOMETRY Stefan J. Teipel* 1, Gene E. Alexander 2, Marc B. Schapiro 3 , Hans-Jtkgen M~511er 1 , Stanley I, Rapoport 4, Harald Hampel I . 1Alzheimer Memorial Center, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany; SNeuroimage Analysis Laboratory, Department of Psychology, Arizona State University, Tempe, AZ, USA; 3Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; 4Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. Contact e -mail: Stefan. Teipel@ reed. uni-muenchen.de Background: Aging in Down's syndrome (DS) is accompanied by amyloid and neurofibriUary pathology whose distribution replicates pathological features of Alzheimer's disease (AD). Based on these findings, DS has been proposed as a model to study the predementia stages of AD. Objective: To investigate age effects on regional cortical grey matter in predementia stages of DS. Methods: We applied the automated and objective technique of voxel-based morphometry, implemented in SPM 99 (Wellcome Department of Imaging Neuroscience, London, UK), to the analysis of structural MRI from 27 nondemented DS adults (mean age 41.1 years, 15 women). Results: Regional grey matter volume was decreased with advancing age in bilateral parietal cortex (mainly the precuneus and inferior parietal lobule), bilateral frontal cortex with left side predominance (mainly middle frontal gyms), left occipital cortex (mainly lingual cortex), fight precentral and left postcentral gyms, left transverse temporal gyms, and right parahippocampal gyms. The reductions were unrelated to gender, intracranial volume or general cognitive function. Grey matter volume was relatively preserved in subcortical nuclei, periventricular regions, the basal surface of the brain (bilateral orbitofrontal and anterior temporal), and the anterior cingnlate gyms, Conclusions: Our findings suggest grey matter reductions in allocortex and association neocortex in the predementia stage of DS. The most likely substrate of these changes is alterations or loss of allocortical and neocortical neurons due to AD type pathology.

Poster Session P3: Diagnosis and Disease Progression mechanism of contrast at 3 Tesla. T2 was measured with a whole-brain spin echo prepared 3D fast spin echo sequence using echo times of 16 and 76 ms. Thirteen subjects with AD (mean age 76, mean MMSE 19) and 11 age-matched control subjects (mean age 73) were studied. Images of the ratio of the short and long echo time were transformed to a standard space using SPM 99 software and compared for significant differences between patients and controls on a voxel by voxel basis. Results: Shortened T2 indicating elevated ferritin iron concentration was found in Alzheimer's patients in a bilateral distribution in the inferior putamen, globus pallidus and internal capsule. (Figure 1) Iron related changes were not seen in most of the cortex, perhaps due to masking from high T2 signal of CSF in areas of atrophy, though indications of shortened T2 were also seen in the posterior cingulate cortex. Conclusions: High field MRI can readily demonstrate differences in iron sensitive relaxation at high field strength in patients with Alzheimer's disease. High field MRI may be useful for longitudinal measurements to monitor the biochemical efficacy of metal chelation therapy. The spatial distribution of the iron related differences in AD encompasses the nucleus basalis of Meynert and may parallel the loss of cortical cholinergic enervation. A C O V A R I A N C E R E S T I N G P E T PATTERN THAT DISCRIMINATES BETWEEN HEALTHY ELDERLY AND EARLY AD PATIENTS CORRELATES WITH F U N C T I O N A L A N D C O G N I T I V E S E V E R I T Y IN SUBJECTS WITH C O G N I T I V E I M P A I R M E N T B U T NO DEMENTIA Nikolaos Scarmeas *1 , Christian G. Habeck I , Eric Zarahn 1, Karen E. Anderson 2, Aileen Park ~, John Hilton I, Gregory Pelton 1, Matthias H. Tabert 1 , Lawrence S. Honig 1, James R. Moeller 1, Davangere E Devanand 1 , Yaakov Stern I . 1Columbia University, New York, NY, USA; 2University of Baltimore, Baltimore, MD, USA. Contact e-mail: ns257@ columbia, edu Background: Multivariate techniques capture a different dimension of the imaging data (eovariance among brain regions) than voxel-based or ROI analyses, but have rarely been used to in detecting AD. Objective(s): We sought to identify a single covariance pattern of relative rest blood flow that would help in discriminating between AD patients and elderly controls, and would display meaningful associations with cognitive performance measures in subjects with minimal to mild cognitive impairment (CI) but not dementia. Methods: Non-quantitative H215 0 PET scans during rest were acquired in 16 probable AD subjects selected for mild severity (modified Mini Mental Status examination [mMMS] 46/57; sd 5.1) (CDR = 1), 16 cognitively intact elderly controls (mMMS 54/57; sd 2.5) (CDR = 0) and 23 CI subjects (mMMS 54/57; sd 2.6) (broadly defined, including subjects with CDR = 0 and CDR = 0.5). AD-Control discrimination was attempted via (i) voxel-wise comparisons, (ii) ROI analyses and (iii) multivariate voxel-wise regional covariance analysis. The covariance analysis derived pattern was then prospectively applied to the CI subjects. Results: There were no significant mean flow differences in either voxel-wise or ROI analyses. However, the mukivariate analyses identified a covariance pattern whose mean expression was significantly higher in the AD patients as compared to controls (p = 0.03) (sensitivity 76-94%; specificity 63-81%). Sites of increased concomitant flow included insuta, cuneus, pulvinar, lingual, fusiform, superior occipital and parahippocampal gyri, whereas decreased concomitant flow was found in cingulate, inferior parietal lobule, middle and inferior frontal, supramarginal and precentral gyri. When prospectively applied to the CI subjects, the covariance pattern discriminated well between subjects with CDR = 0 and CDR = 0.5 (p = 0.009). Expression of this pattern correlated inversely with Selective Reminding Test total recall (r = -0.401, p = 0.002), delayed recall (r = -0.351, p = 0.008) and mMMS scores (r = -0.401, p = 0.002) in all 3 groups combined, and in the CI group alone. Conclusions: Multivariate techniques may be of use in early AD diagnosis even when univariate methods fall. They also provide a sensitive tool for differentiating subjects with CI into those with higher and lower functional and cognitive abilities, and perhaps into those with greater probability of subsequent conversion to AD. •f• Neuroimaging MRI SIGNAL HYPERINTENSITIES PREDICT MORE RAPID C O G N I T I V E D E C L I N E IN ALZHEIMER'S DISEASE (AD) Lawrence S. Honig* 1, Nikolaos Scarmeas 1, Aliza Riba 1, Marilyn Albert 2, Jason Brandt 2, Yaakov Stern s . 1Columbia University College of Physicians & Surgeons, New York, NY, USA; 2Johns Hopkins University, Baltimore, MD, USA. Contact e-mail: lh456@columbia.edu Background: Cerebrovascular disease is common in the elderly, with or without AD. MRI frequently shows signal hyperintensities, of presumed microvascular origin, even in persons without clinical strokes. However, it is not established whether there is a relationship between onset, or course, of AD and these hyperintensities. Objective: Determine whether burden of MR[ T2-weighted signal hyperintensities relates to rapidity of cognitive de- cline in AD. Methods: We used data from a longitudinal, three-site study of patients with mild AD who were followed with neuropsychological testing including modified Mini-Mental State (mMMS; scale 0-57) every 6 months, for an average followup period of 2.3 years. Entry criteria excluded patients with cortical infarcts or lacunes > lcm. MRI films at baseline were available for 54 patients with mean age 75 yrs, education 14.9 yrs, and mMMS 43; this sample included 55% females, 56% apohpoproteinE4+, and 31% with hypertension, 12% diabetes, 18% hyperlipidemia, and 14% coronary heart disease. Each baseline FLAIR or T2-weighted MRI was rated, blind to clinical data, using the Scheltens scale (0-84 maximum) which includes assessment of periventricular, supratentorial, basal ganglionic, and infraten- torial signal hyperintensities. Results: Mean Scheltens total score was 8.3. Average decline in mMMS was 3.26 points/year. Using GEE analysis, we found a significant relationship (p = 0.04) between Scheltens MRI score and the rate of cognitive decline: 0.13 mMMS points/Scheltens point/year, or about 5% increased speed of decline per Scheltens point. This relationship remained significant, even with adjustments for baseline mMMS, age, sex, education, and apoE4. Examination of Scheltens component scores showed that supratentorial white matter lesions were most responsible for the ob- served association (p = 0.001). The effect of white matter abnormalities was not simply related to vascular risk factors (hypertension, diabetes, hyperlipidemia, or heart disease), since even after further adjustment for these variables, the association of cognitive decline and MR[ findings was preserved. Conclusions: Brain white matter signal change is associated with increased rapidity of cognitive decline in AD. This association does not appear to simply relate to underlying vascular risk factors, but may be due to white matter hyperintensifies providing a superimposed injurious factor on AD pathology, contributing to cognitive decline. REGIONAL DISTRIBUTION OF WHITE MATTER CHANGES IN ALZHEIMER'S DISEASE Christine Fennema-Notesfine .1,2 , Sarah L. Archibald 1,2, Anthony C. Gamst 3, Leon J. Thai 3, Terry L. Jernigan 1,2. 1UCSD Dept. of Psychiatry, La Jolla, CA, USA; 2VASDHS, San Diego, CA, USA; 3 UCSD Dept. of Neuroseience, La Jolla, CA, USA. Contact e-mail: fennema @ ucsd. edu Background: While previous work in Alzheimer's Disease (AD) has care- fully described gray matter changes, significant white matter (WM) volume loss and increases in abnormal signal in the WM have also been reported (e.g., Englund et al., 1987; Jemigan et al., 1991). Recent work has height- ened interest in better understanding WM changes in AD. Bartzokis (2004) proposed a model of AD-related neurodegeneration based on the normal pattern of myelination; later-myelinating regions (e.g., temporal and frontal cortices) may be affected first in AD, relative to early-myelinating regions (e.g., primary motor cortex). There is a clear need for more information on regional W M changes across the lifespan and in AD (Jernigan et aI., 2004). Objective: To systematically investigate the regional distribution of W M changes in AD with morphometric analyses of structural magnetic reso- nance imaging (MRI). Methods: Forty-eight AD and 44 elderly control (NC) participants were studied. Trained anatomists delineated frontal, parietal, occipital, temporal, and deep cerebral WM boundaries on tissue-segmented images. Regional WM volumes and amount of abnormal W M were mea

Background In the absence of significant opportunistic infection, the most common alterations on neuroimaging in the brains of patients with AIDS include enlarged cerebrospinal fluid spaces, white-matter loss, volume loss in striatal structures, and white-matter signal abnormalities. Although previous studies have linked brain viral levels to these alterations, other neuropathological mechanisms might also contribute to them. Objective To examine the relationship between findings on premortem magnetic resonance images and postmortem neuropathologic evidence of human immunodeficiency virus (HIV) encephalitis and neurodegeneration. Design Morphometric analysis of magnetic resonance imaging in seropositive cases with matched seronegative controls, and the correlation of these volumes to neuropathological measures in autopsied seropositive cases. Setting University of California, San Diego, HIV Neurobehavioral Research Center. Subjects Twenty-one seropositive subjects studied at autopsy and 19 seronegative cases. Main Outcome Measures In vivo structural magnetic resonance imaging data analyzed by quantitative methods, with comparison of volumes from magnetic resonance imaging and neuropathological data from autopsies. Results The HIV-seropositive subjects demonstrated cerebrospinal fluid increases relative to seronegative controls. These increases were associated with a significant decrease in the volumes of cerebral and cerebellar white matter, caudate nucleus, hippocampus, and, to a lesser extent, cerebral cortex. The volume of cerebral white-matter tissue with elevated signal was also increased. This signal elevation in white matter predicted the autopsy diagnosis of HIV encephalitis, as well as the extent of dendritic loss as assessed by analysis of microtubule-associated protein 2 immunoreactivity. Conclusions White-matter and cortical damage resulting from HIV disease are closely related. In vivo magnetic resonance imaging may be a valuable adjunct in the assessment of patients at risk for developing HIV encephalitis.

Neurobiology of Aging 25 (2004) 37–39 Commentary White matter mapping is needed T.L. Jernigan ∗ , Christine Fennema-Notestine University of California, San Diego and the VASDHS, 9500 Gilman Drive, La Jolla, CA 92093-0949, USA Received 23 May 2003; accepted 3 June 2003 1. Modern brain maps lack information about oligodendrocyte structure and function An intriguing hypothesis has been advanced regarding the role of ongoing processes of myelination in the patho- genesis of Alzheimers Disease (Bartzokis, this issue). The protracted course of myelin deposition in dorsal forebrain regions was described over three decades ago in the elegant studies by Yakovlev and Lecours [12]. However, modern imaging methods permit detailed investigation of these processes in living people for the first time, and studies with these techniques have served to emphasize the degree to which ongoing events formerly deemed “maturation” merge with alterations previously associated with involu- tion. For example, recent MRI studies of brain morphology in late childhood and early adulthood [5,7–9] confirm the earlier pathological evidence for continued “whitening” of the substance of the brain long past the point at which total cranial volume is at its peak. It is now clear that exuberant brain growth in the earliest stages of neurodevelopment gives way gradually to a more dynamic interplay between progressive changes, primarily proliferation of oligodendro- cytes and myelination (but also in limited cases associated with neurogenesis and neuritic branching), offset by regres- sive changes (i.e. apoptosis and loss of neuronal processes) that are also occurring from the very beginning of brain development. Thus, the years of life between the end of adolescence and extending through middle age are probably more accurately viewed, not as years of “stability” in brain development (as they have been previously), but as a period during which progressive and regressive changes happen to be in relative balance. The neurobiological implications of ongoing dynamics of brain development during this period are likely to be no less for that coincidence, and the trea- tise by Bartzokis should provide increased impetus for the needed work of defining these implications. It is particularly relevant for this discussion that most recent work in neuroimaging has focused on the brain’s Corresponding author. Tel.: +1-858-622-5882; fax: +1-858-622-5890. E-mail address: tjernigan@ucsd.edu (T.L. Jernigan). 0197-4580/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2003.06.002 gray matter structures, and, by implication, on neuronal cell populations. Relatively few studies have focused on white matter, and most of these have examined high-signal abnormalities that are well visualized with structural imag- ing methods. In Fig. 1A, data from our laboratory taken from separate previously published studies of brain devel- opment and aging [1,4,9] are presented together. These data were generated concurrently using standardized MR mor- phometric techniques. Volumes of the total white matter compartment of the cerebrum are plotted against the ages of normal volunteers of different ages ranging from 7 to 99 years. The volumes are expressed as proportions of vol- ume of the supratentorial cranial vault, the average value of which has been reported to change negligibly, if at all, over this age range. Thus, the function is likely to reflect primarily the volume of myelinated white matter. The data from adults 20 to 70 years of age are too sparse to define with any precision the shape of the underlying function, but they are certainly consistent with evidence reviewed by Bartzokis indicating substantial ongoing myelination in adults. Developmental studies have emphasized late myeli- nation in frontal and parietal lobe regions, but the function we observe in the temporal lobe, possibly more relevant to the pathology of early AD, shows a similar (if less striking) pattern, as shown in Fig. 1B. Surprisingly, the pattern is also present within a deep subcortical white matter region which includes the internal and external capsules and surrounds the diencephalon and basal ganglia (Fig. 1C). The model presented by Bartzokis relies upon evidence for what he refers to as “heterochronologic” development of human white matter. That the process of myelination has differing time courses in different regions is not in doubt; however, a map across the brain revealing the status of myeli- nation at each point during the lifespan does not exist, and, arguably, what does exist is inadequate to provide definitive evidence regarding the hypothesis. If myelination in some deep subcortical regions (as shown in Fig. 1C) continues as long as that in “cortico-cortical” association areas, how then does this relate to the distribution of lesions in AD? The point is not that the known “heterochronicity” of myelina- tion is inconsistent with the model presented by Bartzokis

The very high sensitivity and specificity of odor identification tasks in discriminating between Alzheimer's patients and normals suggests that they reflect the presence of underlying neuropathology. Significant neuropathological changes are seen in areas critical to processing olfactory information, even in the early stages of Alzheimer's disease (AD). The current study was designed to investigate whether performance on olfactory tasks (odor threshold and odor identification) was related to volumetric MRI measures of mesial temporal areas central to olfactory information processing and important in the neuropathology of AD. Participants were 8 male and 5 female patients with probable AD, and 10 male and 12 female normal age-matched controls, diagnosed at the UCSD Alzheimer's Disease Research Center. The study investigated correlations between volumetric measures of hippocampus, the parahippocampal gyrus and the amygdala, and the psychophysical measures of olfactory function. Robust relationships were observed between mesial temporal lobe volumes and olfactory functional measures. The finding of a strong relationship between left hippocampal volume and performance on the odor identification task (r = .85) is compatible with a left-hemisphere superiority for verbally mediated olfactory tasks. The findings suggest a neural substrate for the breakdown in functional performance on verbally mediated odor identification tasks in Alzheimer's disease and suggest the utility of quantitative MRI measures and psychophysical performance in the assessment of AD. These results support the potential clinical utility of inclusion of odor identification tests in diagnostic batteries for detecting AD. (JINS, 2003, 9, 459–471.)