Multimodal Magnetic Resonance Imaging Assessment of White Matter Aging Trajectories Over the Lifespan of Healthy Individuals

Department of Psychiatry, The David Geffen School of Medicine at UCLA, Los Angeles, California
Biological psychiatry (Impact Factor: 10.26). 09/2012; 72(12). DOI: 10.1016/j.biopsych.2012.07.010
Source: PubMed


Postmortem and volumetric imaging data suggest that brain myelination is a dynamic lifelong process that, in vulnerable late-myelinating regions, peaks in middle age. We examined whether known regional differences in axon size and age at myelination influence the timing and rates of development and degeneration/repair trajectories of white matter (WM) microstructure biomarkers.

Healthy subjects (n = 171) 14-93 years of age were examined with transverse relaxation rate (R(2)) and four diffusion tensor imaging measures (fractional anisotropy [FA] and radial, axial, and mean diffusivity [RD, AxD, MD, respectively]) of frontal lobe, genu, and splenium of the corpus callosum WM (FWM, GWM, and SWM, respectively).

Only R(2) reflected known levels of myelin content with high values in late-myelinating FWM and GWM regions and low ones in early-myelinating SWM. In FWM and GWM, all metrics except FA had significant quadratic components that peaked at different ages (R(2) < RD < MD < AxD), with FWM peaking later than GWM. Factor analysis revealed that, although they defined different factors, R(2) and RD were the metrics most closely associated with each other and differed from AxD, which entered into a third factor.

The R(2) and RD trajectories were most dynamic in late-myelinating regions and reflect age-related differences in myelination, whereas AxD reflects axonal size and extra-axonal space. The FA and MD had limited specificity. The data suggest that the healthy adult brain undergoes continual change driven by development and repair processes devoted to creating and maintaining synchronous function among neural networks on which optimal cognition and behavior depend.

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    • "During adolescence, reduction in CT might be associated with neuronal pruning (Kanai and Rees 2011; Huttenlocher and Dabholkar 1997), which results in more efficient cortical networks (Kharitonova et al. 2013). The frontal lobes are the last region to complete the myelination process; with frontal lobe myelination peaking in the 4th decade of life (Bartzokis et al. 2012). Therefore, thicker cortex in our healthy adult population may confer a functional disadvantage because it reflects either insufficient pruning or myelination. "
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    ABSTRACT: Surface-based cortical thickness (CT) analyses are increasingly being used to investigate variations in brain morphology across the spectrum of brain health, from neurotypical to neuropathological. An outstanding question is whether individual differences in cortical morphology, such as regionally increased or decreased CT, are associated with domain-specific performance deficits in healthy adults. Since CT studies are correlational, they cannot establish causality between brain morphology and cognitive performance. A direct comparison with classic lesion methods is needed to determine whether the regional specificity of CT-cognition correlations is similar to that observed in patients with brain lesions. We address this question by comparing the neuroanatomical overlap of effects when 1) whole brain vertex-wise CT is tested as a correlate of performance variability on a commonly used neuropsychological test of executive function, Trailmaking Test Part B (TMT-B), in healthy adults and 2) voxel-based lesion-symptom mapping (VBLSM) is used to map lesion location to performance decrements on the same task in patients with frontal lobe lesions. We found that reduced performance on the TMT-B was associated with increased CT in bilateral prefrontal regions in healthy adults and that results spatially overlapped in the left dorsomedial prefrontal cortex with findings from the VBLSM analysis in patients with frontal brain lesions. Findings indicate that variations in the structural integrity of the left dorsomedial prefrontal lobe, ranging from individual CT differences in healthy adults to structural lesions in patients with neurological disorders, are associated with poor performance on the TMT-B. These converging results suggest that the left dorsomedial prefrontal region houses a critical region for the complex processing demands of TMT-B, which include visuomotor tracking, sequencing, and cognitive flexibility.
    Brain Imaging and Behavior 09/2015; DOI:10.1007/s11682-015-9455-8 · 4.60 Impact Factor
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    • "Evidence from structural MRI study has shown that the frontal lobe is among the first to become impaired in aging (Raz, 2000). Several DTI studies have also suggested that the anterior WM composed of small, thinly myelinated fibers (Bartzokis et al., 2012; Glasser and Van Essen, 2011) are more susceptible to aging than the posterior WM (e.g., through myelin loss or damage) (Ota et al., 2006; Pfefferbaum et al., 2000; Salat et al., 2005a). Moreover, an anterior-posterior gradient for GM shrinkage and WM degeneration with aging has been consistently reported (Raz et al., 1997; Salat et al., 2005b). "
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    ABSTRACT: Lifespan is a dynamic process with remarkable changes in brain structure and function. Previous neuroimaging studies have indicated age-related microstructural changes in specific white matter tracts during development and aging. However, the age-related alterations in the topological architecture of the white matter structural connectome across the human lifespan remain largely unknown. Here, a cohort of 113 healthy individuals (ages 9-85) with both diffusion and structural MRI acquisitions were examined. For each participant, the high-resolution white matter structural networks were constructed by deterministic fiber tractography among 1024 parcellation units and were quantified with graph theoretical analyses. The global network properties, including network strength, cost, topological efficiency, and robustness, followed an inverted U-shaped trajectory with a peak age around the third decade. The brain areas with the most significantly nonlinear changes were located in the prefrontal and temporal cortices. Different brain regions exhibited heterogeneous trajectories: the posterior cingulate and lateral temporal cortices displayed prolonged maturation/degeneration compared with the prefrontal cortices. Rich-club organization was evident across the lifespan, whereas hub integration decreased linearly with age, especially accompanied by the loss of frontal hubs and their connections. Additionally, age-related changes in structural connections were predominantly located within and between the prefrontal and temporal modules. Finally, based on the graph metrics of structural connectome, accurate predictions of individual age were obtained (r = 0.77). Together, the data indicated a dynamic topological organization of the brain structural connectome across human lifespan, which may provide possible structural substrates underlying functional and cognitive changes with age. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 07/2015; 36(10). DOI:10.1002/hbm.22877 · 5.97 Impact Factor
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    • "Significant associations were preeminent in the right hemisphere , consistent with other studies which found right lateralization of DTI abnormalities in BD (Benedetti et al., 2011b; Caligiuri et al., 2004; Vederine et al., 2011) and with the hypothesis that the right hemisphere may be dominant in mood regulation, as also suggested by a meta-analysis of emotional fMRI study in patients with BD (Houenou et al., 2011). A reduced integrity of myelin sheaths would not necessarily prevent conduction in the involved tracts, but could result in hampering effective functional connectivity by reducing signal speed and thus affecting the capability of neurons in different brain areas to efficiently communicate with each other (Bartzokis et al., 2012; Peters, 2009). Fig. 2. WM tracts where improvement after treatments (delta HDRS scores) inversely correlated with mean (red/yellow) and radial (blue) diffusivity. "
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    ABSTRACT: Changes of white matter (WM) microstructure have been proposed as structural biomarkers of bipolar disorder (BD). The chronotherapeutic combination of repeated total sleep deprivation and morning light therapy (TSD+LT) can acutely reverse depressive symptoms in approximately 60% of patients, and it has been proposed as a model antidepressant treatment to investigate the neurobiological correlates of rapid antidepressant response. We tested if baseline DTI measures can predict response to treatment in 70 in-patients affected by a major depressive episode in the course of BD, treated with chronotherapeutics for one week. We performed whole-brain tract-based spatial statistics with threshold-free cluster enhancement for the DTI measures of WM microstructure integrity: fractional anisotropy, axial, radial, and mean diffusivity. Increased mean and radial water diffusivity correlated with poor antidepressant response to TSD+LT in core WM tracts which are crucial for the functional integrity of the brain, including corpus callosum, corona radiata, cingulum bundle, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, and thalamic radiation. Limitations include issues such as generalizability, possible population stratification, medications and their effects on DTI measures, and no placebo control for chronotherapeutics. We could not consider other factors such as gene-environment interactions. The association of increased radial and mean diffusivity with poor response to chronotherapeutic treatment warrants interest for the study of DTI measures of WM microstructure as markers for treatment response in bipolar depression. Copyright © 2014 Elsevier B.V. All rights reserved.
    Journal of Affective Disorders 11/2014; 174C:233-240. DOI:10.1016/j.jad.2014.11.010 · 3.38 Impact Factor
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