Associations between T1 white matter lesion volume and regional white matter microstructure in aging

White matter lesions, typically manifesting as regions of signal intensity abnormality (WMSA) on MRI, increase in frequency with age. However, the role of this damage in cognitive decline and disease is still not clear, as lesion volume has only loosely been associated with clinical status. Diffusion tensor imaging (DTI) has been used to examine the quantitative microstructural integrity of white matter, and has applications in the examination of subtle changes to tissue that appear visually normal on conventional imaging. The primary goal of this study was to determine whether major macrostructural white matter damage, (total WMSA volume), is associated with microstructural integrity of normal appearing white matter, and if these macrostructural changes fully account for microstructural changes. Imaging was performed in 126 nondemented individuals, ages 43–85 years, with no history of cerebrovascular disease. Controlling for age, greater WMSA volume was associated with decreased fractional anisotropy (FA) in widespread brain regions. Patterns were similar for FA and radial diffusivity but in contrast, WMSA was associated with axial diffusivity in fewer areas. Age was associated with FA in several regions, and many of these effects remained even when controlling for WMSA volume, suggesting the etiology of WMSAs does not fully account for all age‐associated white matter deterioration. These results provide evidence that WMSA volume is associated with the integrity of normal‐appearing white matter. In addition, our results suggest that overt lesions may not account for the association of increasing age with decreased white matter tissue integrity. Hum Brain Mapp 35:1085–1100, 2014. © 2013 Wiley Periodicals, Inc.     

Regional White Matter Signal Abnormalities and Cognitive Correlates Among Geriatric Patients with Treated Cardiovascular Disease

The purpose of this study was to investigate the relations between regional white matter signal abnormalities (WMSA) and cognitive functioning among individuals being treated for cardiovascular risk factors and/or clinical events. Forty-one participants with cardiovascular disease underwent a comprehensive neuropsychological assessment and MRI. Total WMSAs were quantified using a semi-automated thresholding technique. Unique to this study, total WMSA volume was divided into three separate anatomically related regions: WMSA in the periventricular (PERIWMSA) region, WMSA adjacent to subcortical nuclei (SUBWMSA), and WMSA in the deep white matter (DEEPWMSA). A ratio of these measures to total cerebral brain volume was compared to cognitive measures assessing attention, executive functioning, psychomotor speed, immediate and delayed memory, language, and visuospatial functioning. PERIWMSA, SUBWMSA, and total WMSA were significantly associated with performance on measures of attention/processing speed. No other significant relationships between WMSA and cognition were noted. Secondary analyses suggested that PERIWMSA volume was increased in individuals with clinical evidence of atherosclerosis. These results emphasize the utility of studying the associations between regional WMSA and cognitive/functional performance in patients undergoing cardiovascular treatment.     

Sleep duration is associated with white matter microstructure and cognitive performance in healthy adults

Reduced sleep duration and sleep deprivation have been associated with cognitive impairment as well as decreased white matter integrity as reported by experimental studies. However, it is largely unknown whether differences in sleep duration and sleep quality might affect microstructural white matter and cognition. Therefore, the present study aims to examine the cross‐sectional relationship between sleep duration, sleep quality, and cognitive performance in a naturalistic study design, by focusing on the association with white matter integrity in a large sample of healthy, young adults. To address this, 1,065 participants, taken from the publicly available sample of the Human Connectome Project, underwent diffusion tensor imaging. Moreover, broad cognitive performance measures (NIH Cognition Toolbox) and sleep duration and quality (Pittsburgh Sleep Quality Index) were assessed. The results revealed a significant positive association between sleep duration and overall cognitive performance. Shorter sleep duration significantly correlated with fractional anisotropy (FA) reductions in the left superior longitudinal fasciculus (SLF). In turn, FA in this tract was related to measures of cognitive performance and was shown to significantly mediate the association of sleep duration and cognition. For cognition only, associations shift to a negative association of sleep duration and cognition for participants sleeping more than 8 hr a day. Investigations into subjective sleep quality showed no such associations. The present study showed that real‐world differences in sleep duration, but not subjective sleep quality are related to cognitive performance measures and white matter integrity in the SLF in healthy, young adults.     

Premature white matter microstructure in female children with a history of concussion

Childhood concussion may interfere with neurodevelopment and influence cognition. Females are more likely to experience persistent symptoms after concussion, yet the sex-specific impact of concussion on brain microstructure in children is understudied. This study examined white matter and cortical microstructure, based on neurite density (ND) from diffusion-weighted MRI, in 9-to-10-year-old children in the Adolescent Brain Cognitive Development Study with (n = 336) and without (n = 7368) a history of concussion, and its relationship with cognitive performance. Multivariate regression was used to investigate relationships between ND and group, sex, and age in deep and superficial white matter, subcortical structures, and cortex. Partial least square correlation was performed to identify associations between ND and performance on NIH Toolbox tasks in children with concussion. All tissue types demonstrated higher ND with age, reflecting brain maturation. Group comparisons revealed higher ND in deep and superficial white matter in females with concussion. In female but not male children with concussion, there were significant associations between ND and performance on cognitive tests. These results demonstrate a greater long-term impact of childhood concussion on white matter microstructure in females compared to males that is associated with cognitive function. The increase in ND in females may reflect premature white matter maturation.     

Macro- and micro-structural white matter differences correlate with cognitive performance in healthy aging

Studies have shown that white matter (WM) volumetric reductions and overall degradation occur with aging. Nonetheless little is known about the WM alterations that may underlie different cognitive status in older individuals. The main goal of the present work was to identify and characterize possible macro and microstructural WM alterations that could distinguish between older healthy individuals with contrasting cognitive profiles (i.e., “poor” vs “good” cognitive performers). Structural and diffusion magnetic resonance imaging was performed in order to quantify local WM volumes, white matter signal abnormalities (WMSA) volume (a measure of lesion burden) and diffusion tensor imaging scalar maps known to probe WM microstructure. A battery of neurocognitive/psychological tests was administered to assess the cognitive performance. Poor performers showed a higher slope for the positive association between WMSA volume and age compared to good performers. Even when controlling for WMSA volume, poor performers also evidenced lower fractional anisotropy, as well as positive associations with age with higher slopes of regression parameters in radial and axial diffusivity. Altogether results suggest that cognitive performance is related to differences in WM, with poor cognitive performers displaying signs of faster aging in WM.     

Cardiovascular risk factors and small vessel disease of the brain: Blood pressure,white matter lesions,and functional decline in older persons

Several potential vascular risk factors exist for the development and accumulation of subcortical white matter disease in older people. We have reported that in older people followed for up to 4 years white matter hyperintensity (WMH) lesions on magnetic resonance imaging nearly doubled in volume and were associated with alterations in mobility and cognitive function. Herein we review the genetic, metabolic, and vascular risk factors that have been evaluated in association with the development and pathogenesis of WMH in older persons. Our research efforts have focused on systemic hypertension, particularly in the out-of-office setting as 24-hour ambulatory blood pressure (BP) has proven to be a stronger indicator of the progression of WMH in older people and the associated functional decline than doctor’s office BP. Based on relations between 24-hour systolic BP levels, the accrual of WMH, and functional decline, we have designed the INFINITY trial, the first interventional study to use ambulatory BP to guide antihypertensive therapy to address this problem in the geriatric population.     

Apolipoprotein E (APOE) ε4 moderates the relationship between c-reactive protein,cognitive functioning,and white matter integrity

Elevated serum C-reactive protein (CRP) and possessing an APOE ε4 allele are two of the most prominent risk factors for cognitive and neurological dysfunction in older adults, but little is known about the unique or cumulative effects of these risk factors in young-to-middle-aged adults. To further characterize these potential relationships, measures of cognition and microstructural white matter integrity were examined using data from a sample of 329 post-9/11 war veterans that was collected as part of a comprehensive evaluation that included assessment of neuropsychological functioning, MRI scanning, psychiatric diagnoses, health screening, markers of inflammation, and APOE genotypes. Hierarchical linear regression analyses revealed the CRP and APOE ε4 interaction was associated with global cognition (β = -0.633), executive functioning (β = -0.566), and global fractional anisotropy (β = -0.470), such that elevated CRP was associated with worse cognition and white matter integrity in APOE ε4 carriers. Diffusion tensor imaging (DTI) was used to determine if CRP × APOE ε4 presence was associated with regionally specific fractional anisotropy in white matter tracts. Tract-based spatial statistics revealed CRP × APOE ε4 presence was associated with fractional anisotropy in the corpus callosum, right superior longitudinal fasciculus, right posterior corona radiata, as well as the bilateral anterior and superior corona radiatas. This suggests that APOE ε4 carriers may be uniquely vulnerable to the potentially negative impact of elevated systematic inflammation to cognition and microstructural white matter integrity.     

Aging white matter and cognition: Differential effects of regional variations in diffusion properties on memory, executive functions, and speed

Disruption of cerebral white matter has been proposed as an explanation for age-related cognitive declines. However, the role of specific regions in specific cognitive declines remains unclear. We used diffusion tensor imaging to examine the associations between regional microstructural integrity of the white matter and performance on age-sensitive cognitive tasks in a sample of healthy adults (N = 52, age 19-81 years). White matter integrity was assessed by fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in multiple regions of interest (genu and splenium of corpus callosum, internal capsule limbs, prefrontal, temporal, superior/posterior parietal, occipital white matter) and related to processing speed, working memory, inhibition, task switching, and episodic memory. We found that age and regional white matter integrity differentially influenced cognitive performance. Age-related degradation in anterior brain areas was associated with decreased processing speed and poorer working memory, whereas reduced inhibition and greater task switching costs were linked to decline in posterior areas. Poorer episodic memory was associated with age-related differences in central white matter regions. The observed multiple dissociations among specific age-sensitive cognitive skills and their putative neuroanatomical substrates support the view that age-related cognitive declines are unlikely to stem from a single cause.     

Different associations of periventricular and deep white matter lesions with cognition, neuropsychiatric symptoms, and daily activities in dementia

We investigated the associations of periventricular white matter hyperintensities (PWMHs) and deep white matter hyperintensities (DWMHs) with cognition, activities of daily living (ADLs), and neuropsychiatric symptoms in dementia. This was a hospital-based MRI300 study. We recruited patients newly diagnosed with mild-to-moderate dementia caused either by Alzheimer's disease or subcortical ischemic vascular dementia from 13 dementia clinics at university or general hospitals in South Korea. We enrolled 289 patients aged over 50 from August 2007 to March 2008. We compared cognition, ADLs, and neuropsychiatric symptoms among 3 groups according to the severities of PWMHs and DWMHs, respectively, by adjusting for age, vascular risk factors, and level of other WMHs. A higher severity of PWMHs was related to lower cognitive function and severer neuropsychiatric symptoms, whereas basic ADLs were associated with DWMH. Both PWMHs and DWMHs exhibited different associations with cognition, neuropsychiatric symptoms, and daily activities.     

Connections Between Insomnia and Cognitive Aging

Insomnia is a common sleep disorder among older adults,and a risk factor for poor physical and mental health.However,the relationship between insomnia and cognitive health is not well understood.Here,we review observational studies that have investigated whether insomnia is associated with deficits in objective cognitive performance and an increased risk of dementia,magnetic resonance imaging studies that have assessed grey matter volumes and white matter micro structure,and interventional studies that have explored whether the treatment of insomnia can improve cognitive outcomes.There are inconsistent findings regarding impaired performance in objective cognitive tests and reduced grey matter volumes,and limited,emerging,evidence that suggests that insomnia is associated with an increased risk of dementia and reduced white matter integrity.Although the interventional literature is still in its infancy,there is some indication that treatment may have an impact on vigilance.Well-powered studies examining sources of heterogeneity are warranted.     

Interindividual variation in serum cholesterol is associated with regional white matter tissue integrity in older adults

Prior research has demonstrated links among vascular health and the occurrence of stroke, mild cognitive decline, and dementia in older adults. However, little is known about whether normal variation in vascular indicators may be related to changes in neural tissue integrity. Even less is known about how the brain is affected by cholesterol levels in the normal to moderate risk range, leading up to overt disease pathology. This study examined associations between serum lipid levels and DTI indicators of white matter (WM) structural integrity in a sample of 125 generally healthy older adults aged 43–87 years. Whole‐brain voxelwise analysis, controlling for age and gender, revealed low density lipoprotein levels (LDL) as the most robust correlate of regional WM structural integrity of the measured lipids. Higher LDL was associated with decreased WM integrity in right frontal and temporal regions, the superior longitudinal fasciculus and internal/external capsules. Increasing LDL was associated with increased radial and axial diffusivity; however, more widespread statistical effects were found for radial diffusivity. These findings suggest that normal interindividual variation in lipid levels is associated with compromised regional WM integrity, even in individuals below clinical thresholds for hyperlipidemia. Given the prevalence of cholesterol‐associated sequelae in older adults, and mounting evidence suggesting a vascular role in the etiology of dementia, the current data suggest that understanding the relationship between cholesterol and brain tissue microstructure may have important clinical implications for early detection of vascular‐related cognitive disorders and optimal regulation of serum lipids to maintain neural health in older adults. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Aging and Positive Mood: Longitudinal Neurobiological and Cognitive Correlates

ObjectiveDespite the losses commonly associated with aging, older adults seem to possess particularly preserved emotional regulation. To further understand this phenomenon, the authors examined longitudinal trajectories between age, depressive symptoms, brain structure, and cognition.MethodsSeven hundred and sixteen functionally intact older adults (age M = 67.9, 56.8% female), followed longitudinally (visit range: 1–13, M = 2.5), completed cognitive testing and the Geriatric Depression Scale (GDS). A subset (N = 327) underwent 3T brain MRI. Mixed-effects linear regression models were conducted controlling for sex, education, and total intracranial volume.ResultsThere was a significant interaction between age and time on GDS, such that GDS improved with increasing age over time, but attenuated around age 71 (age*time b = 0.10, p <0.001). Fractional anisotropy (FA) and mean diffusivity interacted with age to predict longitudinal changes in GDS (FA: b = -0.02, p = 0.01; MD: b = 0.03, p = 0.007), such that age-related benefits on GDS were attenuated in those with declining FA. Executive function (EF) and processing speed also interacted with age to predict longitudinal changes in GDS (EF: b = -0.04, p = 0.03; speed: b = 0.04, p = 0.04). Again, the positive effect of age on GDS attenuated in those with worsening EF and speed. There were no associations with memory, semantic fluency, or gray matter (p values >0.05).ConclusionEF, processing speed, and white matter integrity moderated the longitudinal relationship between age and mood. Previous studies demonstrate the link between positivity and better cognitive control, leading to improved mood in older adults. Our results are not only consistent, but establish a potential neurobiological correlate. Future research further exploring biological mechanisms driving psychological processes may have important therapeutic implications.     

皮质下缺血性脑血管病白质改变与认知损害初探

目的:对皮质下缺血性脑血管病(SIVD)的临床特征、认知和MRI白质改变进行分析,初步探讨SIVD患者认知损害与MRI白质改变的关系。方法:经过访谈和详细查体,记录患者症状和体征,进行神经心理学评估并行头MRI扫描。依据Erkinjuntti提出MRI诊断标准确定SIVD患者29例。结果:认知正常者、血管性CIND患者和VaD患者的MMSE得分分别为(27.5±1.84)、(23.7±2.06)和(18±1.58)。随着认知功能损害程度的加重,其白质改变的评分增加,具有统计学显著差异。结论:SIVD患者的认知功能损害与其白质改变程度有关。     

Are APOE ? genotype and TOMM40 poly-T repeat length associations with cognitive ageing mediated by brain white matter tract integrity?

Genetic polymorphisms in the APOE ɛ and TOMM40 ‘523'' poly-T repeat gene loci have been associated with significantly increased risk of Alzheimer''s disease. This study investigated the independent effects of these polymorphisms on human cognitive ageing, and the extent to which nominally significant associations with cognitive ageing were mediated by previously reported genetic associations with brain white matter tract integrity in this sample. Most participants in the Lothian Birth Cohort 1936 completed a reasoning-type intelligence test at age 11 years, and detailed cognitive/physical assessments and structural diffusion tensor brain magnetic resonance imaging at a mean age of 72.70 years (s.d.=0.74). Participants were genotyped for APOE ɛ2/ɛ3/ɛ4 status and TOMM40 523 poly-T repeat length. Data were available from 758–814 subjects for cognitive analysis, and 522–543 for mediation analysis with brain imaging data. APOE genotype was significantly associated with performance on several different tests of cognitive ability, including general factors of intelligence, information processing speed and memory (raw P-values all<0.05), independently of childhood IQ and vascular disease history. Formal tests of mediation showed that several significant APOE-cognitive ageing associations—particularly those related to tests of information processing speed—were partially mediated by white matter tract integrity. TOMM40 523 genotype was not associated with cognitive ageing. A range of brain phenotypes are likely to form the anatomical basis for significant associations between APOE genotype and cognitive ageing, including white matter tract microstructural integrity.     

White matter abnormalities are associated with overall cognitive status in blast-related mTBI

Blast-related mild traumatic brain injury (mTBI) is a common injury of the Iraq and Afghanistan Wars. Research has suggested that blast-related mTBI is associated with chronic white matter abnormalities, which in turn are associated with impairment in neurocognitive function. However, findings are inconsistent as to which domains of cognition are affected by TBI-related white matter disruption. Recent evidence that white matter abnormalities associated with blast-related mTBI are spatially variable raises the possibility that the associated cognitive impairment is also heterogeneous. Thus, the goals of this study were to examine (1) whether mTBI-related white matter abnormalities are associated with overall cognitive status and (2) whether white matter abnormalities provide a mechanism by which mTBI influences cognition. Ninety-six Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OEF) veterans were assigned to one of three groups: no-TBI, mTBI without loss of consciousness (LOC) (mTBI-LOC), and mTBI with LOC (mTBI + LOC). Participants were given a battery of neuropsychological tests that were selected for their sensitivity to mTBI. Results showed that number of white matter abnormalities was associated with the odds of having clinically significant cognitive impairment. A mediation analysis revealed that mTBI + LOC was indirectly associated with cognitive impairment through its effect on white matter integrity. These results suggest that cognitive difficulties in blast-related mTBI can be linked to injury-induced neural changes when taking into account the variability of injury as well as the heterogeneity in cognitive deficits across individuals.     

NT-proBNP and changes in cognition and global brain structure: The Rotterdam Study

Objective

To investigate the association between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and changes in cognition and global brain structure.

Methods

In the Rotterdam Study, baseline NT-proBNP was assessed at baseline from 1997 to 2008. Between 1997 and 2016, participants without dementia or stroke at baseline (n = 9566) had repeated cognitive tests (every 3–6 years) for global cognitive function, executive cognitive function, fine manual dexterity, and memory. Magnetic resonance imaging of the brain was performed repeatedly at re-examination visits between 2005 and 2015 for 2607 participants to obtain brain volumes, focal brain lesions, and white matter microstructural integrity as measures of brain structure.

Results

Among 9566 participants (mean age 65.1 ± 9.8 years), 5444 (56.9%) were women, and repeated measures of cognition were performed during a median follow-up time of 5.5 (range 1.1–17.9) years, of whom 2607 participants completed at least one brain imaging scan. Higher levels of NT-proBNP were associated with a faster decline of scores in the global cognitive function (p value = 0.003) and the Word-Fluency test (p value = 0.003) but were not related to a steeper deterioration in brain volumes, global fractional anisotropy, and mean diffusivity, as indicators of white matter microstructural integrity, or focal brain lesions.

Conclusions

Higher baseline NT-proBNP levels were associated with a faster decline in cognition; however, no association with global brain structure was found.     

White matter plasticity and maturation in human cognition

White matter plasticity likely plays a critical role in supporting cognitive development. However, few studies have used the imaging methods specific to white matter tissue structure or experimental designs sensitive to change in white matter necessary to elucidate these relations. Here we briefly review novel imaging approaches that provide more specific information regarding white matter microstructure. Furthermore, we highlight recent studies that provide greater clarity regarding the relations between changes in white matter and cognition maturation in both healthy children and adolescents and those with white matter insult. Finally, we examine the hypothesis that white matter is linked to cognitive function via its impact on neural synchronization. We test this hypothesis in a population of children and adolescents with recurrent demyelinating syndromes. Specifically, we evaluate group differences in white matter microstructure within the optic radiation; and neural phase synchrony in visual cortex during a visual task between 25 patients and 28 typically developing age-matched controls. Children and adolescents with demyelinating syndromes show evidence of myelin and axonal compromise and this compromise predicts reduced phase synchrony during a visual task compared to typically developing controls. We investigate one plausible mechanism at play in this relationship using a computational model of gamma generation in early visual cortical areas. Overall, our findings show a fundamental connection between white matter microstructure and neural synchronization that may be critical for cognitive processing. In the future, longitudinal or interventional studies can build upon our knowledge of these exciting relations between white matter, neural communication, and cognition.     

Improvements in brain and behavior following eradication of hepatitis C

Despite recent advances in treatment, hepatitis C remains a significant public health problem. The hepatitis C virus (HCV) is known to infiltrate the brain, yet findings from studies on associated neurocognitive and neuropathological changes are mixed. Furthermore, it remains unclear if HCV eradication improves HCV-associated neurological compromise. This study examined the longitudinal relationship between neurocognitive and neurophysiologic markers among healthy HCV? controls and HCV+ adults following successful HCV eradication. We hypothesized that neurocognitive outcomes following treatment would be related to both improved cognition and white matter integrity. Participants included 57 HCV+ participants who successfully cleared the virus at the end of treatment (sustained virologic responders [SVRs]) and 22 HCV? controls. Participants underwent neuropsychological testing and, for a nested subset of participants, neuroimaging (diffusion tensor imaging) at baseline and 12 weeks following completion of HCV therapy. Contrary to expectation, group-level longitudinal analyses did not reveal significant improvement in neurocognitive performance in the SVRs compared to the control group. However, a subgroup of SVRs demonstrated a significant improvement in cognition relative to controls, which was related to improved white matter integrity. Indeed, neuroimaging data revealed beneficial effects associated with clearing the virus, particularly in the posterior corona radiata and the superior longitudinal fasciculus. Findings suggest that a subgroup of HCV+ patients experienced improvements in cognitive functioning following eradication of HCV, which appears related to positive changes in white matter integrity. Future research should examine whether any additional improvements in neurocognition and white matter integrity among SVRs occur with longer follow-up periods.     

White matter hyperintensities are significantly associated with cortical atrophy in Alzheimer's disease

BACKGROUND AND OBJECTIVE: Methodological variability in the assessment of white matter hyperintensities (WMH) in dementia may explain inconsistent reports of its prevalence and impact on cognition. We used a method of brain MRI segmentation for quantifying both tissue and WMH volumes in Alzheimer's disease (AD) and examined the association between WMH and structural and cognitive variables. METHODS: A consecutive series of 81 patients meeting NINCDS-ADRDA criteria for probable AD was studied. Nineteen healthy volunteers of comparable age served as the control group. Patients had a complete neurological and neuropsychological evaluation, and a three dimensional MRI was obtained. Images were segmented into grey matter, white matter, and cerebrospinal fluid. WMH were edited on segmented images, and lobar assignments were based on Talairach coordinates. RESULTS: Mild and moderate to severe AD patients had significantly more WMH than controls (p<0.05). WMH preferentially involved the frontal lobes (70%), were inversely correlated with grey matter cortical volume (R(2) = 0.23, p<0.001), and were significantly associated with vascular risk factors and with a worse performance on memory tasks. CONCLUSION: Objective measurements of tissue volumes in AD demonstrated that WMH are significantly related to cortical atrophy and neuropsychological impairment.     

Information processing speed, neural efficiency, and working memory performance in multiple sclerosis: differential relationships with structural magnetic resonance imaging

Multiple sclerosis (MS), a central nervous system (CNS) neurodegenerative disorder, involves lesions of both white and gray matter and reported cognitive impairments that include processing speed (PS), executive function, and working memory (WM). This study closely examined the specifics of these cognitive deficits and their relationship to structural brain damage. A visual n-back task with 3 WM load conditions was used to assess WM performance (task accuracy), PS (reaction time, RT), and a novel measure of processing efficiency (standard deviation of RT, RTSD) in MS patients and controls. These behavioral measures were related to quantitative magnetic resonance imaging (MRI) measures of white and gray matter integrity. Even when MS patients performed as well as controls, as seen for low WM load (0-back), they responded more slowly and were less efficient in their speed of responding. Accuracy findings indicated that the correct match trials were superior to correct nonmatch trials at differentiating MS patients from controls. Further, decreased accuracy during the highest WM load condition was associated with global damage that included both gray and white matter atrophy, while slowed PS and particularly processing inefficiency were associated primarily with white matter atrophy in MS. Importantly, relationships between PS, processing efficiency, performance accuracy, and structural MRI measures were seen only during the highest WM load condition, the condition that required the most executive control. These findings suggest that the MRI/behavioral relationships that were present exclusively during the 2-back condition may reflect connectivity involving frontal cortical systems, the site for executive control.