Microstructural White Matter Properties Mediate the Association between APOE and Perceptual Speed in Very Old Persons without Dementia

Background

Reduced white matter integrity, as indicated by lower fractional anisotropy (FA) and higher mean diffusivity (MD), has been related to poorer perceptual speed (PS) performance. As the ε4 allele has been associated with lower white matter integrity in old age, this represents a potential mechanism through which APOE may affect PS.

Objective

To examine whether the association between APOE and PS is mediated by white matter microstructure in very old persons without dementia.

Method

Participants were selected from the population-based SNAC-K study. After excluding persons with dementia, preclinical dementia, and other neurological disorders, 652 persons (age range 78–90) were included in the study, of which 89 had data on diffusion tensor imaging (DTI). We used structural equation modeling to form seven latent white matter factors (FA and MD) and one latent PS factor. Separate analyses were performed for FA and MD and mediational analyses were carried out for tracts where significant associations were observed to both APOE and PS.

Results

APOE was associated with white matter microstructure in 2 out of 14 tracts; ε4 carriers had significantly lower FA in forceps major and higher MD in the cortico-spinal tract. Allowing the white matter microstructure indicators in these tracts to mediate the association between APOE and PS resulted in a markedly attenuated association between these variables. Bootstrapping statistics in the subsample with DTI data (n = 89) indicated that FA in forceps major significantly mediated the association between APOE and PS (indirect effect: -0.070, 95% bias corrected CIs -0.197 to -0.004).

Conclusion

Lower white matter integrity may represent one of several mechanisms through which APOE affects PS performance in elderly persons free of dementia and preclinical dementia.     

Age-related white matter microstructural differences partly mediate age-related decline in processing speed but not cognition

Aging is associated with declining cognitive performance as well as structural changes in brain gray and white matter (WM). The WM deterioration contributes to a disconnection among distributed brain networks and may thus mediate age-related cognitive decline. The present diffusion tensor imaging (DTI) study investigated age-related differences in WM microstructure and their relation to cognition (episodic memory, visuospatial processing, fluency, and speed) in a large group of healthy subjects (n = 287) covering 6 decades of the human life span. Age related decreases in fractional anisotropy (FA) and increases in mean diffusivity (MD) were observed across the entire WM skeleton as well as in specific WM tracts, supporting the WM degeneration hypothesis. The anterior section of the corpus callosum was more susceptible to aging compared to the posterior section, lending support to the anterior-posterior gradient of WM integrity in the corpus callosum. Finally, and of critical interest, WM integrity differences were found to mediate age-related reductions in processing speed but no significant mediation was found for episodic memory, visuospatial ability, or fluency. These findings suggest that compromised WM integrity is not a major contributing factor to declining cognitive performance in normal aging. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

White Matter Integrity Supports BOLD Signal Variability and Cognitive Performance in the Aging Human Brain

Decline in cognitive performance in old age is linked to both suboptimal neural processing in grey matter (GM) and reduced integrity of white matter (WM), but the whole-brain structure-function-cognition associations remain poorly understood. Here we apply a novel measure of GM processing–moment-to-moment variability in the blood oxygenation level-dependent signal (SD_BOLD)—to study the associations between GM function during resting state, performance on four main cognitive domains (i.e., fluid intelligence, perceptual speed, episodic memory, vocabulary), and WM microstructural integrity in 91 healthy older adults (aged 60-80 years). We modeled the relations between whole-GM SD_BOLD with cognitive performance using multivariate partial least squares analysis. We found that greater SD_BOLD was associated with better fluid abilities and memory. Most of regions showing behaviorally relevant SD_BOLD (e.g., precuneus and insula) were localized to inter- or intra-network “hubs” that connect and integrate segregated functional domains in the brain. Our results suggest that optimal dynamic range of neural processing in hub regions may support cognitive operations that specifically rely on the most flexible neural processing and complex cross-talk between different brain networks. Finally, we demonstrated that older adults with greater WM integrity in all major WM tracts had also greater SD_BOLD and better performance on tests of memory and fluid abilities. We conclude that SD_BOLD is a promising functional neural correlate of individual differences in cognition in healthy older adults and is supported by overall WM integrity.     

Systemic Inflammation in Non-Demented Elderly Human Subjects: Brain Microstructure and Cognition

The purpose of this study was to test the hypothesis that higher levels of systemic inflammation in a community sample of non-demented subjects older than seventy years of age are associated with reduced diffusion anisotropy in brain white matter and lower cognition. Ninety-five older persons without dementia underwent detailed clinical and cognitive evaluation and magnetic resonance imaging, including diffusion tensor imaging. Systemic inflammation was assessed with a composite measure of commonly used circulating inflammatory markers (C-reactive protein and tumor necrosis factor-alpha). Tract-based spatial statistics analyses demonstrated that diffusion anisotropy in the body and isthmus of the corpus callosum was negatively correlated with the composite measure of systemic inflammation, controlling for demographic, clinical and radiologic factors. Visuospatial ability was negatively correlated with systemic inflammation, and diffusion anisotropy in the body and isthmus of the corpus callosum was shown to mediate this association. The findings of the present study suggest that higher levels of systemic inflammation may be associated with lower microstructural integrity in the corpus callosum of non-demented elderly individuals, and this may partially explain the finding of reduced higher-order visual cognition in aging.     

Associations between White Matter Hyperintensities and β Amyloid on Integrity of Projection,Association, and Limbic Fiber Tracts Measured with Diffusion Tensor MRI

The goal of this study was to assess the relationship between Aβ deposition and white matter pathology (i.e., white matter hyperintensities, WMH) on microstructural integrity of the white matter. Fifty-seven participants (mean age: 78±7 years) from an ongoing multi-site research program who spanned the spectrum of normal to mild cognitive impairment (Clinical dementia rating 0–0.5) and low to high risk factors for arteriosclerosis and WMH pathology (defined as WMH volume >0.5% total intracranial volume) were assessed with positron emission tomography (PET) with Pittsburg compound B (PiB) and magnetic resonance and diffusion tensor imaging (DTI). Multivariate analysis of covariance were used to investigate the relationship between Aβ deposition and WMH pathology on fractional anisotropy (FA) from 9 tracts of interest (i.e., corona radiata, internal capsule, cingulum, parahippocampal white matter, corpus callosum, superior longitudinal, superior and inferior front-occipital fasciculi, and fornix). WMH pathology was associated with reduced FA in projection (i.e., internal capsule and corona radiate) and association (i.e., superior longitudinal, superior and inferior fronto-occipital fasciculi) fiber tracts. Aβ deposition (i.e., PiB positivity) was associated with reduced FA in the fornix and splenium of the corpus callosum. There were interactions between PiB and WMH pathology in the internal capsule and parahippocampal white matter, where Aβ deposition reduced FA more among subjects with WMH pathology than those without. However, accounting for apoE ε4 genotype rendered these interactions insignificant. Although this finding suggests that apoE4 may increase amyloid deposition, both in the parenchyma (resulting in PiB positivity) and in blood vessels (resulting in amyloid angiopathy and WMH pathology), and that these two factors together may be associated with compromised white matter microstructural integrity in multiple brain regions, additional studies with a longitudinal design will be necessary to resolve this issue.     

Microstructural abnormalities of uncinate fasciculus as a function of impaired cognition in schizophrenia: A DTI study

Neuropsychological studies have reported that attention, memory, language, motor and emotion processing are impaired in schizophrenia. It is known that schizophrenia involves structural alterations in the white matter of brain that contribute to the pathophysiology of the disorder. Uncinate fasciculus (UNC), a bundle of white matter fibres, plays an important role in the pathology of this disorder and involved in cognitive functions such as memory, language and emotion processing. Therefore, the present study aimed to investigate microstructural changes in UNC fibre in schizophrenia patients relative to controls and its correlation with neuropsychological scores.Diffusion tensor imaging (DTI) and Hindi version of Penn Computerised Neuropsychological Battery test was performed in 14 schizophrenia patients and 14 controls. DTI measures [fractional anisotropy (FA) and mean diffusivity (MD)] from UNC fibre were calculated and a comparison was made between patients and controls. Pearson’s correlation was performed between neuropsychological scores and DTI measures.Schizophrenia patients showed significantly reduced FA values in UNC fibre compared to controls. In schizophrenia patients, a positive correlation of attention, spatial memory, sensorimotor dexterity and emotion with FA was observed. These findings suggest that microstructural changes in UNC fibre may contribute to underlying dysfunction in the cognitive functions associated with schizophrenia.     

Different Patterns of White Matter Degeneration Using Multiple Diffusion Indices and Volumetric Data in Mild Cognitive Impairment and Alzheimer Patients

Alzheimeŕs disease (AD) represents the most prevalent neurodegenerative disorder that causes cognitive decline in old age. In its early stages, AD is associated with microstructural abnormalities in white matter (WM). In the current study, multiple indices of diffusion tensor imaging (DTI) and brain volumetric measurements were employed to comprehensively investigate the landscape of AD pathology. The sample comprised 58 individuals including cognitively normal subjects (controls), amnestic mild cognitive impairment (MCI) and AD patients. Relative to controls, both MCI and AD subjects showed widespread changes of anisotropic fraction (FA) in the corpus callosum, cingulate and uncinate fasciculus. Mean diffusivity and radial changes were also observed in AD patients in comparison with controls. After controlling for the gray matter atrophy the number of regions of significantly lower FA in AD patients relative to controls was decreased; nonetheless, unique areas of microstructural damage remained, e.g., the corpus callosum and uncinate fasciculus. Despite sample size limitations, the current results suggest that a combination of secondary and primary degeneration occurrs in MCI and AD, although the secondary degeneration appears to have a more critical role during the stages of disease involving dementia.     

Obesity is associated with reduced white matter integrity in otherwise healthy adults

Existing work demonstrates that obesity is independently associated with cognitive dysfunction and macrostructural brain changes; however, little is known about the association between obesity and white matter (WM) integrity. We explore this relationship in a large cohort of otherwise healthy subjects. The present study classified 103 adult participants from the Brain Resource International Database between 21 and 86 years of age without history of neurological, medical, or psychiatric illness according to BMI (normal weight, overweight, obese) and subjected them to diffusion tensor imaging (DTI). Resulting fractional anisotropy (FA) indexes for the corpus callosum and fornix were examined in relation to BMI and age in a multiple regression framework. Results indicated that increasing BMI was independently associated with lower FA in the genu, splenium, and fornix, and a BMI × age interaction emerged for FA in the splenium and body of the corpus callosum. When categorized, obese persons demonstrated lower FA than normal and overweight persons for all WM indexes, but no FA differences emerged between overweight and normal persons. Results indicate both a direct association between obesity and reduced WM tract integrity and an interaction between obesity and aging processes on certain WM tracts in otherwise healthy adults. While such findings suggest a possible role for adiposity in WM dysfunction and associated cognitive deficits, prospective studies are needed to clarify the nature of these relationships and elucidate underlying mechanisms.     

Improved sensitivity to cerebral white matter abnormalities in Alzheimer's disease with spherical deconvolution based tractography

Diffusion tensor imaging (DTI) based fiber tractography (FT) is the most popular approach for investigating white matter tracts in vivo, despite its inability to reconstruct fiber pathways in regions with "crossing fibers." Recently, constrained spherical deconvolution (CSD) has been developed to mitigate the adverse effects of "crossing fibers" on DTI based FT. Notwithstanding the methodological benefit, the clinical relevance of CSD based FT for the assessment of white matter abnormalities remains unclear. In this work, we evaluated the applicability of a hybrid framework, in which CSD based FT is combined with conventional DTI metrics to assess white matter abnormalities in 25 patients with early Alzheimer's disease. Both CSD and DTI based FT were used to reconstruct two white matter tracts: one with regions of "crossing fibers," i.e., the superior longitudinal fasciculus (SLF) and one which contains only one fiber orientation, i.e. the midsagittal section of the corpus callosum (CC). The DTI metrics, fractional anisotropy (FA) and mean diffusivity (MD), obtained from these tracts were related to memory function. Our results show that in the tract with "crossing fibers" the relation between FA/MD and memory was stronger with CSD than with DTI based FT. By contrast, in the fiber bundle where one fiber population predominates, the relation between FA/MD and memory was comparable between both tractography methods. Importantly, these associations were most pronounced after adjustment for the planar diffusion coefficient, a measure reflecting the degree of fiber organization complexity. These findings indicate that compared to conventionally applied DTI based FT, CSD based FT combined with DTI metrics can increase the sensitivity to detect functionally significant white matter abnormalities in tracts with complex white matter architecture.     

Interleukin-6, Age,and Corpus Callosum Integrity

The contribution of inflammation to deleterious aging outcomes is increasingly recognized; however, little is known about the complex relationship between interleukin-6 (IL-6) and brain structure, or how this association might change with increasing age. We examined the association between IL-6, white matter integrity, and cognition in 151 community dwelling older adults, and tested whether age moderated these associations. Blood levels of IL-6 and vascular risk (e.g., homocysteine), as well as health history information, were collected. Processing speed assessments were administered to assess cognitive functioning, and we employed tract-based spatial statistics to examine whole brain white matter and regions of interest. Given the association between inflammation, vascular risk, and corpus callosum (CC) integrity, fractional anisotropy (FA) of the genu, body, and splenium represented our primary dependent variables. Whole brain analysis revealed an inverse association between IL-6 and CC fractional anisotropy. Subsequent ROI linear regression and ridge regression analyses indicated that the magnitude of this effect increased with age; thus, older individuals with higher IL-6 levels displayed lower white matter integrity. Finally, higher IL-6 levels were related to worse processing speed; this association was moderated by age, and was not fully accounted for by CC volume. This study highlights that at older ages, the association between higher IL-6 levels and lower white matter integrity is more pronounced; furthermore, it underscores the important, albeit burgeoning role of inflammatory processes in cognitive aging trajectories.     

White Matter Microstructure Alterations: A Study of Alcoholics with and without Post-Traumatic Stress Disorder

Many brain imaging studies have demonstrated reductions in gray and white matter volumes in alcoholism, with fewer investigators using diffusion tensor imaging (DTI) to examine the integrity of white matter pathways. Among various medical conditions, alcoholism and post-traumatic stress disorder (PTSD) are two comorbid diseases that have similar degenerative effects on the white matter integrity. Therefore, understanding and differentiating these effects would be very important in characterizing alcoholism and PTSD. Alcoholics are known to have neurocognitive deficits in decision-making, particularly in decisions related to emotionally-motivated behavior, while individuals with PTSD have deficits in emotional regulation and enhanced fear response. It is widely believed that these types of abnormalities in both alcoholism and PTSD are related to fronto-limbic dysfunction. In addition, previous studies have shown cortico-limbic fiber degradation through fiber tracking in alcoholism. DTI was used to measure white matter fractional anisotropy (FA), which provides information about tissue microstructure, possibly indicating white matter integrity. We quantitatively investigated the microstructure of white matter through whole brain DTI analysis in healthy volunteers (HV) and alcohol dependent subjects without PTSD (ALC) and with PTSD (ALC+PTSD). These data show significant differences in FA between alcoholics and non-alcoholic HVs, with no significant differences in FA between ALC and ALC+PTSD in any white matter structure. We performed a post-hoc region of interest analysis that allowed us to incorporate multiple covariates into the analysis and found similar results. HV had higher FA in several areas implicated in the reward circuit, emotion, and executive functioning, suggesting that there may be microstructural abnormalities in white matter pathways that contribute to neurocognitive and executive functioning deficits observed in alcoholics. Furthermore, our data do not reveal any differences between ALC and ALC+PTSD, suggesting that the effect of alcohol on white matter microstructure may be more significant than any effect caused by PTSD.     

Associations between arterial stiffening and brain structure,perfusion, and cognition in the Whitehall II Imaging Sub-study: A retrospective cohort study

BackgroundAortic stiffness is closely linked with cardiovascular diseases (CVDs), but recent studies suggest that it is also a risk factor for cognitive decline and dementia. However, the brain changes underlying this risk are unclear. We examined whether aortic stiffening during a 4-year follow-up in mid-to-late life was associated with brain structure and cognition in the Whitehall II Imaging Sub-study.Methods and findingsThe Whitehall II Imaging cohort is a randomly selected subset of the ongoing Whitehall II Study, for which participants have received clinical follow-ups for 30 years, across 12 phases. Aortic pulse wave velocity (PWV) was measured in 2007–2009 (Phase 9) and at a 4-year follow-up in 2012–2013 (Phase 11). Between 2012 and 2016 (Imaging Phase), participants received a multimodal 3T brain magnetic resonance imaging (MRI) scan and cognitive tests. Participants were selected if they had no clinical diagnosis of dementia and no gross brain structural abnormalities. Voxel-based analyses were used to assess grey matter (GM) volume, white matter (WM) microstructure (fractional anisotropy (FA) and diffusivity), white matter lesions (WMLs), and cerebral blood flow (CBF). Cognitive outcomes were performance on verbal memory, semantic fluency, working memory, and executive function tests. Of 542 participants, 444 (81.9%) were men. The mean (SD) age was 63.9 (5.2) years at the baseline Phase 9 examination, 68.0 (5.2) at Phase 11, and 69.8 (5.2) at the Imaging Phase. Voxel-based analysis revealed that faster rates of aortic stiffening in mid-to-late life were associated with poor WM microstructure, viz. lower FA, higher mean, and radial diffusivity (RD) in 23.9%, 11.8%, and 22.2% of WM tracts, respectively, including the corpus callosum, corona radiata, superior longitudinal fasciculus, and corticospinal tracts. Similar voxel-wise associations were also observed with follow-up aortic stiffness. Moreover, lower mean global FA was associated with faster rates of aortic stiffening (B = −5.65, 95% CI −9.75, −1.54, Bonferroni-corrected p < 0.0125) and higher follow-up aortic stiffness (B = −1.12, 95% CI −1.95, −0.29, Bonferroni-corrected p < 0.0125). In a subset of 112 participants who received arterial spin labelling scans, faster aortic stiffening was also related to lower cerebral perfusion in 18.4% of GM, with associations surviving Bonferroni corrections in the frontal (B = −10.85, 95% CI −17.91, −3.79, p < 0.0125) and parietal lobes (B = −12.75, 95% CI −21.58, −3.91, p < 0.0125). No associations with GM volume or WMLs were observed. Further, higher baseline aortic stiffness was associated with poor semantic fluency (B = −0.47, 95% CI −0.76 to −0.18, Bonferroni-corrected p < 0.007) and verbal learning outcomes (B = −0.36, 95% CI −0.60 to −0.12, Bonferroni-corrected p < 0.007). As with all observational studies, it was not possible to infer causal associations. The generalisability of the findings may be limited by the gender imbalance, high educational attainment, survival bias, and lack of ethnic and socioeconomic diversity in this cohort.ConclusionsOur findings indicate that faster rates of aortic stiffening in mid-to-late life were associated with poor brain WM microstructural integrity and reduced cerebral perfusion, likely due to increased transmission of pulsatile energy to the delicate cerebral microvasculature. Strategies to prevent arterial stiffening prior to this point may be required to offer cognitive benefit in older age.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03335696","term_id":"NCT03335696"}}NCT03335696

Sana Suri and colleagues investigate differences in brain structure and connectivity associated with aortic stiffening in older adults.     

Alterations in White Matter Microstructure in Neurofibromatosis-1

Neurofibromatosis (NF1) represents the most common single gene cause of learning disabilities. NF1 patients have impairments in frontal lobe based cognitive functions such as attention, working memory, and inhibition. Due to its well–characterized genetic etiology, investigations of NF1 may shed light on neural mechanisms underlying such difficulties in the general population or other patient groups. Prior neuroimaging findings indicate global brain volume increases, consistent with neural over-proliferation. However, little is known about alterations in white matter microstructure in NF1. We performed diffusion tensor imaging (DTI) analyses using tract-based spatial statistics (TBSS) in 14 young adult NF1 patients and 12 healthy controls. We also examined brain volumetric measures in the same subjects. Consistent with prior studies, we found significantly increased overall gray and white matter volume in NF1 patients. Relative to healthy controls, NF1 patients showed widespread reductions in white matter integrity across the entire brain as reflected by decreased fractional anisotropy (FA) and significantly increased absolute diffusion (ADC). When radial and axial diffusion were examined we found pronounced differences in radial diffusion in NF1 patients, indicative of either decreased myelination or increased space between axons. Secondary analyses revealed that FA and radial diffusion effects were of greatest magnitude in the frontal lobe. Such alterations of white matter tracts connecting frontal regions could contribute to the observed cognitive deficits. Furthermore, although the cellular basis of these white matter microstructural alterations remains to be determined, our findings of disproportionately increased radial diffusion against a background of increased white matter volume suggest the novel hypothesis that one potential alteration contributing to increased cortical white matter in NF1 may be looser packing of axons, with or without myelination changes. Further, this indicates that axial and radial diffusivity can uniquely contribute as markers of NF1-associated brain pathology in conjunction with the typically investigated measures.     

Associations between Skeletal Growth in Childhood and Cognitive Function in Mid-Life in a 53-Year Prospective Birth Cohort Study

Background

Several studies have found that shorter stature (height and limb length) in late life is associated with dementia and cognitive impairment. The extent to which childhood environment and early life cognitive function accounts for these associations is not clear.

Methods

We investigated associations of adult trunk height and leg length with cognitive function in middle age, analysing data from the MRC National Survey of Health and Development: a cohort followed from birth to age 53, 1677 of whom had data on all covariates. The four cognitive tests measured verbal ability, word list memory, verbal fluency and speed/concentration. Early life environmental measures included parental education, poverty, parental divorce, physical health, cognitive ability at age 15, own education and own adult social class.

Results

After adjusting for gender, shorter trunk length was associated with lower cognitive function on all four tests and shorter leg length with lower verbal intelligence and word list memory. These associations were only partially attenuated following adjustment for childhood adversity/health but were substantially accounted for by cognitive ability at age 15.

Conclusions

Shorter stature was associated with lower cognitive function at age 53, the majority of this association being accounted for by cognitive function at age 15. Reduced cognitive reserve may well account for later associations between anthropometric measures and dementia.     

Sexual dimorphism in healthy aging and mild cognitive impairment: a DTI study

Previous PET and MRI studies have indicated that the degree to which pathology translates into clinical symptoms is strongly dependent on sex with women more likely to express pathology as a diagnosis of AD, whereas men are more resistant to clinical symptoms in the face of the same degree of pathology. Here we use DTI to investigate the difference between male and female white matter tracts in healthy older participants (24 women, 16 men) and participants with mild cognitive impairment (21 women, 12 men). Differences between control and MCI participants were found in fractional anisotropy (FA), radial diffusion (DR), axial diffusion (DA) and mean diffusion (MD). A significant main effect of sex was also reported for FA, MD and DR indices, with male control and male MCI participants having significantly more microstructural damage than their female counterparts. There was no sex by diagnosis interaction. Male MCIs also had significantly less normalised grey matter (GM) volume than female MCIs. However, in terms of absolute brain volume, male controls had significantly more brain volume than female controls. Normalised GM and WM volumes were found to decrease significantly with age with no age by sex interaction. Overall, these data suggest that the same degree of cognitive impairment is associated with greater structural damage in men compared with women.     

Microstructural White Matter Changes Underlying Cognitive and Behavioural Impairment in ALS – An In Vivo Study Using DTI

Background

A relevant fraction of patients with amyotrophic lateral sclerosis (ALS) exhibit a fronto-temporal pattern of cognitive and behavioural disturbances with pronounced deficits in executive functioning and cognitive control of behaviour. Structural imaging shows a decline in fronto-temporal brain areas, but most brain imaging studies did not evaluate cognitive status. We investigated microstructural white matter changes underlying cognitive impairment using diffusion tensor imaging (DTI) in a large cohort of ALS patients.

Methods

We assessed 72 non-demented ALS patients and 65 matched healthy control subjects using a comprehensive neuropsychological test battery and DTI. We compared DTI measures of fiber tract integrity using tract-based spatial statistics among ALS patients with and without cognitive impairment and healthy controls. Neuropsychological performance and behavioural measures were correlated with DTI measures.

Results

Patients without cognitive impairment demonstrated white matter changes predominantly in motor tracts, including the corticospinal tract and the body of corpus callosum. Those with impairments (ca. 30%) additionally presented significant white matter alterations in extra-motor regions, particularly the frontal lobe. Executive and memory performance and behavioural measures were correlated with fiber tract integrity in large association tracts.

Conclusion

In non-demented cognitively impaired ALS patients, white matter changes measured by DTI are related to disturbances of executive and memory functions, including prefrontal and temporal regions. In a group comparison, DTI is able to observe differences between cognitively unimpaired and impaired ALS patients.     

White Matter Changes of Neurite Density and Fiber Orientation Dispersion during Human Brain Maturation

Diffusion tensor imaging (DTI) studies of human brain development have consistently shown widespread, but nonlinear increases in white matter anisotropy through childhood, adolescence, and into adulthood. However, despite its sensitivity to changes in tissue microstructure, DTI lacks the specificity to disentangle distinct microstructural features of white and gray matter. Neurite orientation dispersion and density imaging (NODDI) is a recently proposed multi-compartment biophysical model of brain microstructure that can estimate non-collinear properties of white matter, such as neurite orientation dispersion index (ODI) and neurite density index (NDI). In this study, we apply NODDI to 66 healthy controls aged 7–63 years to investigate changes of ODI and NDI with brain maturation, with comparison to standard DTI metrics. Using both region-of-interest and voxel-wise analyses, we find that NDI exhibits striking increases over the studied age range following a logarithmic growth pattern, while ODI rises following an exponential growth pattern. This novel finding is consistent with well-established age-related changes of FA over the lifespan that show growth during childhood and adolescence, plateau during early adulthood, and accelerating decay after the fourth decade of life. Our results suggest that the rise of FA during the first two decades of life is dominated by increasing NDI, while the fall in FA after the fourth decade is driven by the exponential rise of ODI that overcomes the slower increases of NDI. Using partial least squares regression, we further demonstrate that NODDI better predicts chronological age than DTI. Finally, we show excellent test—retest reliability of NODDI metrics, with coefficients of variation below 5% in all measured regions of interest. Our results support the conclusion that NODDI reveals biologically specific characteristics of brain development that are more closely linked to the microstructural features of white matter than are the empirical metrics provided by DTI.     

Diffusion Tensor Imaging of the Auditory Neural Pathway for Clinical Outcome of Cochlear Implantation in Pediatric Congenital Sensorineural Hearing Loss Patients

Although conventional structural MRI provides vital information in the evaluation of congenital sensorineural hearing loss (SNHL), it is relatively insensitive to white matter microstructure. Our objective was to evaluate possible changes in microstructure of the auditory pathway in children with congenital sensorineural hearing loss (SNHL), and the possible distinction between good and poor outcome of cochlear implantation (CI) patients by using diffusion tensor imaging (DTI). Twenty-four patients with congenital SNHL and 20 healthy controls underwent conventional MRI and DTI examination using a 1.5T MR scanner. The DTI metrics of fractional anisotropy (FA) and mean diffusivity (MD) of six regions of interest (ROIs) positioned along the auditory pathway—the trapezoid body, superior olivary nucleus, inferior colliculus, medial geniculate body, auditory radiation and white matter of Heschl''s gyrus—was measured in all subjects. Among the 24 patients, 8 patients with a categorie of auditory performance (CAP) score over 6 were classified into the good outcome group, and 16 patients with a CAP score below 6 were classified into the poor outcome group. A significant decrease was observed in FA values while MD values remained unchanged at the six ROIs of SNHL patients compared with healthy controls. Compared to good outcome subjects, poor outcome subjects displayed decreased FA values at all of the ROIs. No changes were observed in MD values. Correlation analyses only revealed strong correlations between FA values and CAP scores, and strong correlations between CAP scores and age at implant were also found. No correlations of FA values with age at implant were observed. Our results show that preoperative DTI can be used to evaluate microstructural alterations in the auditory pathway that are not detectable by conventional MR imaging, and may play an important role in evaluating the outcome of CI. Early cochlear implantation might be more effectively to restore hearing in SNHL patients.     

Microstructural White Matter Changes,Not Hippocampal Atrophy,Detect Early Amnestic Mild Cognitive Impairment

Background

Alzheimer’s disease (AD) is generally considered to be characterized by pathology in gray matter of the brain, but convergent evidence suggests that white matter degradation also plays a vital role in its pathogenesis. The evolution of white matter deterioration and its relationship with gray matter atrophy remains elusive in amnestic mild cognitive impairment (aMCI), a prodromal stage of AD.

Methods

We studied 155 cognitively normal (CN) and 27 ‘late’ aMCI individuals with stable diagnosis over 2 years, and 39 ‘early’ aMCI individuals who had converted from CN to aMCI at 2-year follow up. Diffusion tensor imaging (DTI) tractography was used to reconstruct six white matter tracts three limbic tracts critical for episodic memory function - the fornix, the parahippocampal cingulum, and the uncinate fasciculus; two cortico-cortical association fiber tracts - superior longitudinal fasciculus and inferior longitudinal fasciculus; and one projection fiber tract - corticospinal tract. Microstructural integrity as measured by fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) was assessed for these tracts.

Results

Compared with CN, late aMCI had lower white matter integrity in the fornix, the parahippocampal cingulum, and the uncinate fasciculus, while early aMCI showed white matter damage in the fornix. In addition, fornical measures were correlated with hippocampal atrophy in late aMCI, whereas abnormality of the fornix in early aMCI occurred in the absence of hippocampal atrophy and did not correlate with hippocampal volumes.

Conclusions

Limbic white matter tracts are preferentially affected in the early stages of cognitive dysfunction. Microstructural degradation of the fornix preceding hippocampal atrophy may serve as a novel imaging marker for aMCI at an early stage.     

White matter and cognition in adults who were born preterm

Background and Purpose

Individuals born very preterm (before 33 weeks of gestation, VPT) are at risk of damage to developing white matter, which may affect later cognition and behaviour.

Methods

We used diffusion tensor MRI (DT-MRI) to assess white matter microstructure (fractional anisotropy; FA) in 80 VPT and 41 term-born individuals (mean age 19.1 years, range 17–22, and 18.5 years, range17–22 years, respectively). VPT individuals were part of a 1982–1984 birth cohort which had been followed up since birth; term individuals were recruited by local press advertisement. General intellectual function, executive function and memory were assessed.

Results

The VPT group had reduced FA in four clusters, and increased FA in four clusters relative to the Term group, involving several association tracts of both hemispheres. Clusters of increased FA were associated with more severe neonatal brain injury in the VPT group. Clusters of reduced FA were associated with lower birth weight and perinatal hypoxia, and with reduced adult cognitive performance in the VPT group only.

Conclusions

Alterations of white matter microstructure persist into adulthood in VPT individuals and are associated with cognitive function.