Differential Effects of Aging on Regional Corpus Callosum Microstructure and the Modifying Influence of Pulse Pressure.

The corpus callosum is composed of several subregions, distinct in cellular and functional organization. This organization scheme may render these subregions differentially vulnerable to the aging process. Callosal integrity may be further compromised by cardiovascular risk factors, which negatively influence white matter health. Here, we test for heterochronicity of aging, hypothesizing an anteroposterior gradient of vulnerability to aging that may be altered by the effects of cardiovascular health. In 174 healthy adults across the adult lifespan (mean age = 53.56 ± 18.90; range, 20-94 years old, 58.62% women), pulse pressure (calculated as participant's systolic minus diastolic blood pressure) was assessed to determine cardiovascular risk. A deterministic tractography approach via diffusion-weighted imaging was utilized to extract fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) from each of five callosal subregions, serving as estimates of microstructural health. General linear models tested the effects of age, hypertension, and pulse pressure on these cross-sectional metrics. We observed no significant effect of hypertensive diagnosis on callosal microstructure. We found a significant main effect of age and an age-pulse pressure interaction whereby older age and elevated pulse pressure were associated with poorer FA, AD, and RD. Age effects revealed nonlinear components and occurred along an anteroposterior gradient of severity in the callosum. This gradient disappeared when pulse pressure was considered. These results indicate that age-related deterioration across the callosum is regionally variable and that pulse pressure, a proxy of arterial stiffness, exacerbates this aging pattern in a large lifespan cohort.

Geospatial environmental complexity, spatial brain volume, and spatial behavior across the Alzheimer's disease spectrum.

INTRODUCTION: Understanding impact of environmental properties on Alzheimer's disease (AD) is paramount. Spatial complexity of one's routinely navigated environment is an important but understudied factor. METHODS: A total of 660 older adults from National Alzheimer's Coordinating Center (NACC) dataset were geolocated and environmental complexity index derived from geospatial network landmarks and points-of-interest. Latent models tested mediation of spatial navigation-relevant brain volumes and diagnosis (cognitively-healthy, mild cognitive impairment [MCI], AD) on effect of environmental complexity on spatial behavior. RESULTS: Greater environmental complexity was selectively associated with larger allocentric (but not egocentric) navigation-related brain volumes, lesser diagnosis of MCI and AD, and better spatial behavioral performance, through indirect hierarchical mediation. DISCUSSION: Findings support hypothesis that spatially complex environments positively impact navigation neural circuitry and spatial behavior function. Given the vulnerability of these very circuits to AD pathology, residing in spatially complex environments may be one factor to help stave off the brain atrophy that accompanies spatial navigation deficits across the AD spectrum.

Longitudinal changes in gray matter correspond to changes in cognition across the lifespan: implications for theories of cognition.

The present study examines the association between gray matter volume and cognition. Studies that have examined this issue have focused primarily on older adults, whereas the present study examines the issue across the entire adult lifespan. A total of 463 adults, ages 20-88 at first assessment, were followed longitudinally across three assessments over 8-10years. Significant individual differences in a general cognition measure comprised of measures of speed of processing, working memory, and episodic memory were observed, as well as in measures of cortical and subcortical gray matter. Parallel process latent growth curve modeling showed a reliable relationship between decreases in cortical matter and cognitive decline across the entire adult lifespan, which persisted after controlling for age effects. Implications of these findings in relation to progression toward dementia, risk assessment, cognitive intervention, and environmental factors are discussed, as well as implications for theories of cognitive aging.

One-year aerobic exercise increases cerebral blood flow in cognitively normal older adults.

The impact of aerobic exercise training (AET) on cerebral blood flow (CBF) regulation remains inconclusive. This study investigated the effects of one-year progressive, moderate-to-vigorous AET on CBF, central arterial stiffness, and cognitive performance in cognitively normal older adults. Seventy-three older adults were randomly assigned to AET or stretching-and-toning (SAT, active control) intervention. CBF was measured with 2D duplex ultrasonography. Central arterial stiffness, measured by carotid ß-stiffness index, was assessed with the ultrasonography and applanation tonometry. Cerebrovascular resistance (CVR) was calculated as mean arterial pressure divided by CBF. A cognitive battery was administered with a focus on memory and executive function. Cardiorespiratory fitness was measured by peak oxygen consumption (V˙O2peak). One-year AET increased V˙O2peak and CBF and decreased CVR and carotid ß-stiffness index. In the AET group, improved V˙O2peak was correlated with increased CBF (r = 0.621, p = 0.001) and decreased CVR (r = -0.412, p = 0.037) and carotid ß-stiffness index (r = -0.478, p = 0.011). Further, increased Woodcock-Johnson recall score was associated with decreased CVR (r = -0.483, p = 0.012) and carotid ß-stiffness index (r = -0.498, p = 0.008) in AET group (not in SAT group). In conclusion, one-year progressive, moderate-to-vigorous aerobic exercise training increased CBF and decreased carotid arterial stiffness and CVR which were associated with improved memory function in cognitively normal older adults.

Aerobic exercise training and neurocognitive function in cognitively normal older adults: A one-year randomized controlled trial.

BACKGROUND: Current evidence is inconsistent on the benefits of aerobic exercise training for preventing or attenuating age-related cognitive decline in older adults. OBJECTIVE: To investigate the effects of a 1-year progressive, moderate-to-high intensity aerobic exercise intervention on cognitive function, brain volume, and cortical thickness in sedentary but otherwise healthy older adults. METHODS: We randomized 73 older adults to a 1-year aerobic exercise or stretching-and-toning (active control) program. The primary outcome was a cognitive composite score calculated from eight neuropsychological tests encompassing inductive reasoning, long-term and working memory, executive function, and processing speed. Secondary outcomes were brain volume and cortical thickness assessed by MRI, and cardiorespiratory fitness measured by peak oxygen uptake (VO2 ). RESULTS: One-year aerobic exercise increased peak VO2 by ∼10% (p < 0.001) while it did not change with stretching (p = 0.241). Cognitive composite scores increased in both the aerobic and stretching groups (p < 0.001 for time effect), although no group difference was observed. Total brain volume (p < 0.001) and mean cortical thickness (p = 0.001) decreased in both groups over time, while the reduction in hippocampal volume was smaller in the stretching group compared with the aerobic group (p = 0.040 for interaction). Across all participants, improvement in peak VO2 was positively correlated with increases in cognitive composite score (r = 0.282, p = 0.042) and regional cortical thickness at the inferior parietal lobe (p = 0.016). CONCLUSIONS: One-year aerobic exercise and stretching interventions improved cognitive performance but did not prevent age-related brain volume loss in sedentary healthy older adults. Cardiorespiratory fitness gain was positively correlated with cognitive performance and regional cortical thickness.

The effect of vascular health factors on white matter microstructure mediates age-related differences in executive function performance.

Even within healthy aging, vascular risk factors can detrimentally influence cognition, with executive functions (EF) particularly vulnerable. Fronto-parietal white matter (WM) connectivity in part, supports EF and may be particularly sensitive to vascular risk. Here, we utilized structural equation modeling in 184 healthy adults (aged 20-94 years of age) to test the hypotheses that: 1) fronto-parietal WM microstructure mediates age effects on EF; 2) higher blood pressure (BP) and white matter hyperintensity (WMH) burden influences this association. All participants underwent comprehensive cognitive and neuropsychological testing including tests of processing speed, executive function (with a focus on tasks that require switching and inhibition) and completed an MRI scanning session that included FLAIR imaging for semi-automated quantification of white matter hyperintensity burden and diffusion-weighted imaging for tractography. Structural equation models were specified with age (as a continuous variable) and blood pressure predicting within-tract WMH burden and fractional anisotropy predicting executive function and processing speed. Results indicated that fronto-parietal white matter of the genu of the corpus collosum, superior longitudinal fasciculus, and the inferior frontal occipital fasciculus (but not cortico-spinal tract) mediated the association between age and EF. Additionally, increased systolic blood pressure and white matter hyperintensity burden within these white matter tracts contribute to worsening white matter health and are important factors underlying age-brain-behavior associations. These findings suggest that aging brings about increases in both BP and WMH burden, which may be involved in the degradation of white matter connectivity and in turn, negatively impact executive functions as we age.

Functional Connectivity Within and Between n-Back Modulated Regions: An Adult Lifespan Psychophysiological Interaction Investigation.

Introduction: Working memory (WM) and its blood-oxygen-level-dependent-related parametric modulation under load decrease with age. Functional connectivity (FC) generally increases with WM load; however, how aging impacts connectivity and whether this is load-dependent, region-dependent, or associated with cognitive performance is unclear. Methods: This study examines these questions in 170 healthy adults (meanage = 52.99 ± 19.18) who completed functional magnetic resonance imaging scanning during an n-back task (0-, 2-, 3-, and 4-back). The FC was estimated by utilizing a modified generalized psychophysiological interaction approach with seeds from fronto-parietal (FP) and default mode (DM) regions that modulated to n-back difficulty. The FC analyses focused on both connectivity during WM engagement (task vs. control) and connectivity in response to increased WM load (linear slope across conditions). Each analysis utilized within- and between-region FC, predicted by age (linear or quadratic), and its associations with in- and out-of-scanner task performance. Results: Engaging in WM either generally (task vs. control) or as a function of difficulty strengthened integration within- and between-FP and DM regions. Notably, these task-sensitive functional connections were robust to the effects of age. Stronger negative FC between FP and DM regions was also associated with better WM performance in an age-dependent manner, occurring selectively in middle-aged and older adults. Discussion: These results suggest that FC is critical for engaging in cognitively demanding tasks, and its lack of sensitivity to healthy aging may provide a means to maintain cognition across the adult lifespan. Thus, this study highlights the contribution of maintenance in brain function to support working memory processing with aging.

Greater BOLD Variability is Associated With Poorer Cognitive Function in an Adult Lifespan Sample.

Moment-to-moment fluctuations in brain signal assessed by functional magnetic resonance imaging blood oxygenation level dependent (BOLD) variability is increasingly thought to represent important "signal" rather than measurement-related "noise." Efforts to characterize BOLD variability in healthy aging have yielded mixed outcomes, demonstrating both age-related increases and decreases in BOLD variability and both detrimental and beneficial associations. Utilizing BOLD mean-squared-successive-differences (MSSD) during a digit n-back working memory (WM) task in a sample of healthy adults (aged 20-94 years; n = 171), we examined effects of aging on whole-brain 1) BOLD variability during task (mean condition MSSD across 0-2-3-4 back conditions), 2) BOLD variability modulation to incrementally increasing WM difficulty (linear slope from 0-2-3-4 back), and 3) the association of age-related differences in variability with in- and out-of-scanner WM performance. Widespread cortical and subcortical regions evidenced increased mean variability with increasing age, with no regions evidencing age-related decrease in variability. Additionally, posterior cingulate/precuneus exhibited increased variability to WM difficulty. Notably, both age-related increases in BOLD variability were associated with significantly poorer WM performance in all but the oldest adults. These findings lend support to the growing corpus suggesting that brain-signal variability is altered in healthy aging; specifically, in this adult lifespan sample, BOLD-variability increased with age and was detrimental to cognitive performance.

Influence of sample size and analytic approach on stability and interpretation of brain-behavior correlations in task-related fMRI data.

Limited statistical power due to small sample sizes is a problem in fMRI research. Most of the work to date has examined the impact of sample size on task-related activation, with less attention paid to the influence of sample size on brain-behavior correlations, especially in actual experimental fMRI data. We addressed this issue using two large data sets (a working memory task, N = 171, and a relational processing task, N = 865) and both univariate and multivariate approaches to voxel-wise correlations. We created subsamples of different sizes and calculated correlations between task-related activity at each voxel and task performance. Across both data sets the magnitude of the brain-behavior correlations decreased and similarity across spatial maps increased with larger sample sizes. The multivariate technique identified more extensive correlated areas and more similarity across spatial maps, suggesting that a multivariate approach would provide a consistent advantage over univariate approaches in the stability of brain-behavior correlations. In addition, the multivariate analyses showed that a sample size of roughly 80 or more participants would be needed for stable estimates of correlation magnitude in these data sets. Importantly, a number of additional factors would likely influence the choice of sample size for assessing such correlations in any given experiment, including the cognitive task of interest and the amount of data collected per participant. Our results provide novel experimental evidence in two independent data sets that the sample size commonly used in fMRI studies of 20-30 participants is very unlikely to be sufficient for obtaining reproducible brain-behavior correlations, regardless of analytic approach.

Cortical thickness mediates the relationship between DRD2 C957T polymorphism and executive function across the adult lifespan.

Dopamine (DA) signaling is critical for optimal cognitive performance. Aging is accompanied by a change in the strength of this signaling, with a loss of striatal and extrastriatal D2 binding potential. The reduction in dopamine modulation with age negatively influences various aspects of cognition. DRD2 C957T (rs6277) impacts DA D2 receptor density and availability, with C homozygotes linked to lower striatal DA availability and reduced executive functioning (EF), but also high extrastriatal binding potential. Here, we investigated in 176 participants aged 20-94 years whether: (1) DRD2 C carriers differ from T carriers in cortical thickness or subcortical volume in areas of high concentrations of D2 receptors that receive projections from mesocortical or nigrostriatal dopaminergic pathways; (2) whether the DRD2*COMT relationship has any synergistic effects on cortical thickness; (3) whether the effect of DRD2 on brain structure depends upon age; and (4) whether DRD2-related regional thinning affects executive function performance. We show that DRD2 impacts cortical thickness in the superior parietal lobule, precuneus, and anterior cingulate (marginal after FDR correction), while statistically controlling sex, age, and COMT genotype. Specifically, C homozygotes demonstrated thinner cortices than both heterozygotes and/or T homozygotes in an age-invariant manner. Additionally, DRD2 predicted executive function performance via cortical thickness. The results highlight that genetic influences on dopamine availability impact cognitive performance via the contribution of brain structure in cortical regions influenced by DRD2.

Contribution of iron and Aß to age differences in entorhinal and hippocampal subfield volume.

OBJECTIVE: To test the hypothesis that the combination of elevated global ß-AMYLOID (Aß) burden and greater striatal iron content would be associated with smaller entorhinal cortex (ERC) volume, but not hippocampal subfield volumes, we measured volume and iron content using high-resolution MRI and Aß using PET imaging in a cross-sectional sample of 70 cognitively normal older adults. METHODS: Participants were scanned with florbetapir 18F PET to obtain Aß standardized uptake value ratios. Susceptibility-weighted MRI was collected and processed to yield R2* images, and striatal regions of interest (ROIs) were manually placed to obtain a measure of striatal iron burden. Ultra-high resolution T2/PD-weighted MRIs were segmented to measure medial temporal lobe (MTL) volumes. Analyses were conducted using mixed-effects models with MTL ROI as a within-participant factor; age, iron content, and Aß as between-participant factors; and MTL volumes (ERC and 3 hippocampal subfield regions) as the dependent variable. RESULTS: The model indicated a significant 4-way interaction among age, iron, Aß, and MTL region. Post hoc analyses indicated that the 3-way interaction among age, Aß, and iron content was selective to the ERC (ß = -3.34, standard error = 1.33, 95% confidence interval -5.95 to -0.72), whereas a significant negative association between age and ERC volume was present only in individuals with both elevated iron content and Aß. CONCLUSIONS: These findings highlight the importance of studying Aß in the context of other, potentially synergistic age-related brain factors such as iron accumulation and the potential role for iron as an important contributor to the earliest, preclinical stages of pathologic aging.

Beta-amyloid burden predicts poorer mnemonic discrimination in cognitively normal older adults.

One of the earliest indicators of Alzheimer's disease pathology is the presence of beta-amyloid (Αß) protein deposition. Significant amyloid deposition is evident even in older adults who exhibit little or no overt cognitive or memory impairment. Hippocampal-based processes that help distinguish between highly similar memory representations may be the most susceptible to early disease pathology. Amyloid associations with memory have been difficult to establish, possibly because typical memory assessments do not tax hippocampal operations sufficiently. Thus, the present study utilized a spatial mnemonic discrimination task designed to tax hippocampal pattern separation/completion processes in a sample of cognitively normal middle-aged and older adults (53-98 years old) who underwent PET 18F-Florbetapir Αß scanning. The degree of interference between studied and new information varied, allowing for an examination of mnemonic discrimination as a function of mnemonic similarity. Results indicated that greater beta-amyloid burden was associated with poorer discrimination across decreasing levels of interference, suggesting that even subtle elevation of beta-amyloid in cognitively normal adults is associated with impoverished performance on a hippocampally demanding memory task. The present study demonstrates that degree of amyloid burden negatively impacts the ability of aging adults to accurately distinguish old from increasingly distinct new information, providing novel insight into the cognitive expression of beta-amyloid neuropathology.

Frontostriatal white matter connectivity: age differences and associations with cognition and BOLD modulation.

Despite the importance of cortico-striatal circuits to cognition, investigation of age effects on the structural circuitry connecting these regions is limited. The current study examined age effects on frontostriatal white matter connectivity, and identified associations with both executive function performance and dynamic modulation of blood-oxygen-level-dependent (BOLD) activation to task difficulty in a lifespan sample of 169 healthy humans aged 20-94 years. Greater frontostriatal diffusivity was associated with poorer executive function and this negative association strengthened with increasing age. Whole-brain functional magnetic resonance imaging (fMRI) analyses additionally indicated an association between frontostriatal mean diffusivity and BOLD modulation to difficulty selectively in the striatum across 2 independent fMRI tasks. This association was moderated by age, such that younger- and middle-aged individuals showed reduced dynamic range of difficulty modulation as a function of increasing frontostriatal diffusivity. Together these results demonstrate the importance of age-related degradation of frontostriatal circuitry on executive functioning across the lifespan, and highlight the need to capture brain changes occurring in early-to middle-adulthood.

White Matter Microstructure Predicts Focal and Broad Functional Brain Dedifferentiation in Normal Aging.

Ventral visual cortex exhibits highly organized and selective patterns of functional activity associated with visual processing. However, this specialization decreases in normal aging, with functional responses to different visual stimuli becoming more similar with age, a phenomenon termed "dedifferentiation." The current study tested the hypothesis that age-related degradation of the inferior longitudinal fasciculus (ILF), a white matter pathway involved in visual perception, could account for dedifferentiation of both localized and distributed brain activity in ventral visual cortex. Participants included 281 adults, ages 20-89 years, from the Dallas Lifespan Brain Study who underwent diffusion-weighted imaging to measure white matter diffusivity, as well as fMRI to measure functional selectivity to viewing photographs from different categories (e.g., faces, houses). In general, decreased ILF anisotropy significantly predicted both focal and broad functional dedifferentiation. Specifically, there was a localized effect of structure on function, such that decreased anisotropy in a smaller mid-fusiform region of ILF predicted less selective (i.e., more dedifferentiated) response to viewing faces in a proximal face-responsive region of fusiform. On the other hand, the whole ILF predicted less selective response across broader ventral visual cortex for viewing animate (e.g., human faces, animals) versus inanimate (e.g., houses, chairs) images. This structure-function relationship became weaker with age and was no longer significant after the age of 70 years. These findings indicate that decreased white matter anisotropy is associated with maladaptive differences in proximal brain function and is an important variable to consider when interpreting age differences in functional selectivity.

Striatal iron content is linked to reduced fronto-striatal brain function under working memory load.

Non-heme iron accumulation contributes to age-related decline in brain structure and cognition via a cascade of oxidative stress and inflammation, although its effect on brain function is largely unexplored. Thus, we examine the impact of striatal iron on dynamic range of BOLD modulation to working memory load. N â€‹= â€‹166 healthy adults (age 20-94) underwent cognitive testing and an imaging session including n-back (0-, 2-, 3-, and 4-back fMRI), R2*-weighted imaging, and pcASL to measure cerebral blood flow. A statistical model was constructed to predict voxelwise BOLD modulation by age, striatal iron content and an age â€‹× â€‹iron interaction, controlling for cerebral blood flow, sex, and task response time. A significant interaction between age and striatal iron content on BOLD modulation was found selectively in the putamen, caudate, and inferior frontal gyrus. Greater iron was associated with reduced modulation to difficulty, particularly in middle-aged and younger adults with greater iron content. Further, iron-related decreases in modulation were associated with poorer executive function in an age-dependent manner. These results suggest that iron may contribute to differences in functional brain activation prior to older adulthood, highlighting the potential role of iron as an early factor contributing to trajectories of functional brain aging.

Contributions of White Matter Connectivity and BOLD Modulation to Cognitive Aging: A Lifespan Structure-Function Association Study.

The ability to flexibly modulate brain activation to increasing cognitive challenge decreases with aging. This age-related decrease in dynamic range of function of regional gray matter may be, in part, due to age-related degradation of regional white matter tracts. Here, a lifespan sample of 171 healthy adults (aged 20-94) underwent magnetic resonance imaging (MRI) scanning including diffusion-weighted imaging (for tractography) and functional imaging (a digit n-back task). We utilized structural equation modeling to test the hypothesis that age-related decrements in white matter microstructure are associated with altered blood-oxygen-level-dependent (BOLD) modulation, and both in turn, are associated with scanner-task accuracy and executive function performance. Specified structural equation model evidenced good fit, demonstrating that increased age negatively affects n-back task accuracy and executive function performance in part due to both degraded white matter tract microstructure and reduced task-difficulty-related BOLD modulation. We further demonstrated that poorer white matter microstructure integrity was associated with weakened BOLD modulation, particularly in regions showing positive modulation effects, as opposed to negative modulation effects. This structure-function association study provides further evidence that structural connectivity influences functional activation, and the two mechanisms in tandem are predictive of cognitive performance, both during the task, and for cognition measured outside the scanner environment.

Joint contributions of cortical morphometry and white matter microstructure in healthy brain aging: A partial least squares correlation analysis.

Cortical atrophy and degraded axonal health have been shown to coincide during normal aging; however, few studies have examined these measures together. To lend insight into both the regional specificity and the relative timecourse of structural degradation of these tissue compartments across the adult lifespan, we analyzed gray matter (GM) morphometry (cortical thickness, surface area, volume) and estimates of white matter (WM) microstructure (fractional anisotropy, mean diffusivity) using traditional univariate and more robust multivariate techniques to examine age associations in 186 healthy adults aged 20-94 years old. Univariate analysis of each tissue type revealed that negative age associations were largest in frontal GM and WM tissue and weaker in temporal, cingulate, and occipital regions, representative of not only an anterior-to-posterior gradient, but also a medial-to-lateral gradient. Multivariate partial least squares correlation (PLSC) found the greatest covariance between GM and WM was driven by the relationship between WM metrics in the anterior corpus callosum and projections of the genu, anterior cingulum, and fornix; and with GM thickness in parietal and frontal regions. Surface area was far less susceptible to age effects and displayed less covariance with WM metrics, while regional volume covariance patterns largely mirrored those of cortical thickness. Results support a retrogenesis-like model of aging, revealing a coupled relationship between frontal and parietal GM and the underlying WM, which evidence the most protracted development and the most vulnerability during healthy aging.

The role of hippocampal subfield volume and fornix microstructure in episodic memory across the lifespan.

Advancing age is associated with both declines in episodic memory and degradation of medial temporal lobe (MTL) structure. The contribution of MTL to episodic memory is complex and depends upon the interplay among hippocampal subfields and surrounding structures that participate in anatomical connectivity to the cortex through inputs (parahippocampal and entorhinal cortices) and outputs (fornix). However, the differential contributions of MTL system components in mediating age effects on memory remain unclear. In a sample of 177 healthy individuals aged 20-94 we collected high-resolution T1-weighted, ultrahigh-resolution T2/PD, and diffusion tensor imaging (DTI) MRI sequences on a 3T Phillips Achieva scanner. Hippocampal subfield and entorhinal cortex (ERC) volumes were measured from T2/PD scans using a combination of manual tracings and training of a semiautomated pipeline. Parahippocampal gyrus volume was estimated using Freesurfer and DTI scans were used to obtain diffusion metrics from tractography of the fornix. Item and associative episodic memory constructs were formed from multiple tests. Competing structural equation models estimating differential association among these structural variables were specified and tested to investigate whether and how fornix diffusion and volume of parahippocampal gyrus, ERC, and hippocampal subfields mediate age effects on associative and/or item memory. The most parsimonious, best-fitting model included an anatomically based path through the MTL as well as a single hippocampal construct which combined all subfields. Results indicated that fornix microstructure independently mediated the effect of age on associative memory, but not item memory. Additionally, all regions and estimated paths (including fornix) combined to significantly mediate the age-associative memory relationship. These findings suggest that preservation of fornix connectivity and MTL structure with aging is important for maintenance of associative memory performance across the lifespan.

Progress update from the hippocampal subfields group.

INTRODUCTION: Heterogeneity of segmentation protocols for medial temporal lobe regions and hippocampal subfields on in vivo magnetic resonance imaging hinders the ability to integrate findings across studies. We aim to develop a harmonized protocol based on expert consensus and histological evidence. METHODS: Our international working group, funded by the EU Joint Programme-Neurodegenerative Disease Research (JPND), is working toward the production of a reliable, validated, harmonized protocol for segmentation of medial temporal lobe regions. The working group uses a novel postmortem data set and online consensus procedures to ensure validity and facilitate adoption. RESULTS: This progress report describes the initial results and milestones that we have achieved to date, including the development of a draft protocol and results from the initial reliability tests and consensus procedures. DISCUSSION: A harmonized protocol will enable the standardization of segmentation methods across laboratories interested in medial temporal lobe research worldwide.

Frontoparietal cortical thickness mediates the effect of COMT Val158Met polymorphism on age-associated executive function.

Proper dopamine (DA) signaling is likely necessary for maintaining optimal cognitive performance as we age, particularly in prefrontal-parietal networks and in fronto-striatal networks. Thus, reduced DA availability is a salient risk factor for accelerated cognitive aging. A common polymorphism that affects DA D1 receptor dopamine availability, COMT Val158Met (rs4680), influences enzymatic breakdown of DA, with COMT Val carriers having a 3- to 4-fold reduction in synaptic DA compared to COMT Met carriers. Furthermore, dopamine receptors and postsynaptic availability are drastically reduced with aging, as is executive function performance that ostensibly relies on these pathways. Here, we investigated in 176 individuals aged 20-94 years whether: (1) COMT Val carriers differ from their Met counterparts in thickness of regional cortices receiving D1 receptor pathways: prefrontal, parietal, cingulate cortices; (2) this gene-brain association differs across the adult lifespan; and (3) COMT-related regional thinning evidences cognitive consequences. We found that COMT Val carriers evidenced thinner cortex in prefrontal, parietal, and posterior cingulate cortices than COMT Met carriers and this effect was not age-dependent. Further, we demonstrate that thickness of these regions significantly mediates the effect of COMT genotype on an executive function composite measure. These results suggest that poorer executive function performance is due partly to thinner association cortex in dopaminergic-rich regions, and particularly so in individuals who are genetically predisposed to lower postsynaptic dopamine availability, regardless of age.