Douglas C. Dean

Investigating white matter development in infancy and early childhood using myelin water faction and relaxation time mapping.

The elaboration of the myelinated white matter is essential for normal neurodevelopment, establishing and mediating rapid communication pathways throughout the brain. These pathways facilitate the synchronized communication required for higher order behavioral and cognitive functioning. Altered neural messaging (or ‘disconnectivity’) arising from abnormal white matter and myelin development may underlie a number of neurodevelopmental psychiatric disorders. Despite the vital role myelin plays, few imaging studies have specifically examined its maturation throughout early infancy and childhood. Thus, direct investigations of the relationship(s) between evolving behavioral and cognitive functions and the myelination of the supporting neural systems have been sparse. Further, without knowledge of the ‘normative’ developmental time-course, identification of early abnormalities associated with developmental disorders remains challenging. In this work, we examined the use of longitudinal (T1) and transverse (T2) relaxation time mapping, and myelin water fraction (MWF) imaging to investigate white matter and myelin development in 153 healthy male and female children, 3 months through 60 months in age. Optimized age-specific acquisition protocols were developed using the DESPOT and mcDESPOT imaging techniques; and mean T1, T2 and MWF trajectories were determined for frontal, temporal, occipital, parietal and cerebellar white matter, and genu, body and splenium of the corpus callosum. MWF results provided a spatio-temporal pattern in-line with prior histological studies of myelination. Comparison of T1, T2 and MWF measurements demonstrates dissimilar sensitivity to tissue changes associated with neurodevelopment, with each providing differential but complementary information.

Brain Differences in Infants at Differential Genetic Risk for Late-Onset Alzheimer Disease: A Cross-sectional Imaging Study

IMPORTANCE Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for the development and evaluation of preventive treatment therapies. OBJECTIVE To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD. DESIGN, SETTING, AND PARTICIPANTS Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status. MAIN OUTCOMES AND MEASURES Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age. RESULTS Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001, uncorrected for multiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions. CONCLUSIONS AND RELEVANCE While our findings should be considered preliminary, this study demonstrates some of the earliest brain changes associated with the genetic predisposition to AD. It raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.

Breastfeeding and early white matter development: A cross-sectional study.

Does breastfeeding alter early brain development? The prevailing consensus from large epidemiological studies posits that early exclusive breastfeeding is associated with improved measures of IQ and cognitive functioning in later childhood and adolescence. Prior morphometric brain imaging studies support these findings, revealing increased white matter and sub-cortical gray matter volume, and parietal lobe cortical thickness, associated with IQ, in adolescents who were breastfed as infants compared to those who were exclusively formula-fed. Yet it remains unknown when these structural differences first manifest and when developmental differences that predict later performance improvements can be detected. In this study, we used quiet magnetic resonance imaging (MRI) scans to compare measures of white matter microstructure (mcDESPOT measures of myelin water fraction) in 133 healthy children from 10 months through 4 years of age, who were either exclusively breastfed a minimum of 3 months; exclusively formula-fed; or received a mixture of breast milk and formula. We also examined the relationship between breastfeeding duration and white matter microstructure. Breastfed children exhibited increased white matter development in later maturing frontal and association brain regions. Positive relationships between white matter microstructure and breastfeeding duration are also exhibited in several brain regions, that are anatomically consistent with observed improvements in cognitive and behavioral performance measures. While the mechanisms underlying these structural differences remains unclear, our findings provide new insight into the earliest developmental advantages associated with breastfeeding, and support the hypothesis that breast milk constituents promote healthy neural growth and white matter development.

Cortical maturation and myelination in healthy toddlers and young children

The maturation of cortical structures, and the establishment of their connectivity, are critical neurodevelopmental processes that support and enable cognitive and behavioral functioning. Measures of cortical development, including thickness, curvature, and gyrification have been extensively studied in older children, adolescents, and adults, revealing regional associations with cognitive performance, and alterations with disease or pathology. In addition to these gross morphometric measures, increased attention has recently focused on quantifying more specific indices of cortical structure, in particular intracortical myelination, and their relationship to cognitive skills, including IQ, executive functioning, and language performance. Here we analyze the progression of cortical myelination across early childhood, from 1 to 6 years of age, in vivo for the first time. Using two quantitative imaging techniques, namely T1 relaxation time and myelin water fraction (MWF) imaging, we characterize myelination throughout the cortex, examine developmental trends, and investigate hemispheric and gender-based differences. We present a pattern of cortical myelination that broadly mirrors established histological timelines, with somatosensory, motor and visual cortices myelinating by 1 year of age; and frontal and temporal cortices exhibiting more protracted myelination. Developmental trajectories, defined by logarithmic functions (increasing for MWF, decreasing for T1), were characterized for each of 68 cortical regions. Comparisons of trajectories between hemispheres and gender revealed no significant differences. Results illustrate the ability to quantitatively map cortical myelination throughout early neurodevelopment, and may provide an important new tool for investigating typical and atypical development.

Modeling healthy male white matter and myelin development: 3 through 60 months of age☆

An emerging hypothesis in developmental and behavioral disorders is that they arise from disorganized brain messaging or reduced connectivity. Given the importance of myelin to efficient brain communication, characterization of myelin development in infancy and childhood may provide salient information related to early connectivity deficits. In this work, we investigate regional and whole brain growth trajectories of the myelin water fraction, a quantitative magnetic resonance imaging measure sensitive and specific to myelin content, in data acquired from 122 healthy male children from 3 to 60 months of age. We examine common growth functions to find the most representative model of myelin maturation and subsequently use the best of these models to develop a continuous population-averaged, four-dimensional model of normative myelination. Through comparisons with an independent sample of 63 male children across the same age span, we show that the developed model is representative of this population. This work contributes to understanding the trajectory of myelination in healthy infants and toddlers, furthering our knowledge of early brain development, and provides a model that may be useful for identifying developmental abnormalities.

White matter development and early cognition in babies and toddlers.

The normal myelination of neuronal axons is essential to neurodevelopment, allowing fast inter‐neuronal communication. The most dynamic period of myelination occurs in the first few years of life, in concert with a dramatic increase in cognitive abilities. How these processes relate, however, is still unclear. Here we aimed to use a data‐driven technique to parcellate developing white matter into regions with consistent white matter growth trajectories and investigate how these regions related to cognitive development. In a large sample of 183 children aged 3 months to 4 years, we calculated whole brain myelin volume fraction (VFM) maps using quantitative multicomponent relaxometry. We used spatial independent component analysis (ICA) to blindly segment these quantitative VFM images into anatomically meaningful parcels with distinct developmental trajectories. We further investigated the relationship of these trajectories with standardized cognitive scores in the same children. The resulting components represented a mix of unilateral and bilateral white matter regions (e.g., cortico‐spinal tract, genu and splenium of the corpus callosum, white matter underlying the inferior frontal gyrus) as well as structured noise (misregistration, image artifact). The trajectories of these regions were associated with individual differences in cognitive abilities. Specifically, components in white matter underlying frontal and temporal cortices showed significant relationships to expressive and receptive language abilities. Many of these relationships had a significant interaction with age, with VFM becoming more strongly associated with language skills with age. These data provide evidence for a changing coupling between developing myelin and cognitive development. Hum Brain Mapp 35:4475–4487, 2014.

Mapping an index of the myelin g-ratio in infants using magnetic resonance imaging

Optimal myelination of neuronal axons is essential for effective brain and cognitive function. The ratio of the axon diameter to the outer fiber diameter, known as the g-ratio, is a reliable measure to assess axonal myelination and is an important index reflecting the efficiency and maximal conduction velocity of white matter pathways. Although advanced neuroimaging techniques including multicomponent relaxometry (MCR) and diffusion tensor imaging afford insight into the microstructural characteristics of brain tissue, by themselves they do not allow direct analysis of the myelin g-ratio. Here, we show that by combining myelin content information (obtained with mcDESPOT MCR) with neurite density information (obtained through NODDI diffusion imaging) an index of the myelin g-ratio may be estimated. Using this framework, we present the first quantitative study of myelin g-ratio index changes across childhood, examining 18 typically developing children 3 months to 7.5 years of age. We report a spatio-temporal pattern of maturation that is consistent with histological and developmental MRI studies, as well as theoretical studies of the myelin g-ratio. This work represents the first ever in vivo visualization of the evolution of white matter g-ratio indices throughout early childhood.

Interactions between white matter asymmetry and language during neurodevelopment.

The human brain is asymmetric in gross structure as well as functional organization. However, the developmental basis and trajectory of this asymmetry is unclear, and its relationship(s) to functional and cognitive development, especially language, remain to be fully elucidated. During infancy and early childhood, in concert with cortical gray matter growth, underlying axonal bundles become progressively myelinated. This myelination is critical for efficient and coherent interneuronal communication and, as revealed in animal studies, the degree of myelination changes in response to environment and neuronal activity. Using a novel quantitative magnetic resonance imaging method to investigate myelin content in vivo in human infants and young children, we investigated gross asymmetry of myelin in a large cohort of 108 typically developing children between 1 and 6 years of age, hypothesizing that asymmetry would predict language abilities in this cohort. While asymmetry of myelin content was evident in multiple cortical and subcortical regions, language ability was predicted only by leftward asymmetry of caudate and frontal cortex myelin content and rightward asymmetry in the extreme capsule. Importantly, the influence of this asymmetry was found to change with age, suggesting an age-specific influence of structure and myelin on language function. The relationship between language ability and asymmetry of myelin stabilized at ∼4 years, indicating anatomical evidence for a critical time during development before which environmental influence on cognition may be greatest.

Association of Amyloid Pathology With Myelin Alteration in Preclinical Alzheimer Disease

Importance The accumulation of aggregated &bgr;-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia. Still, to our knowledge, little is known about AD-related myelin changes, and even when present, they are often regarded as secondary to concomitant arteriosclerosis or related to aging. Objective To assess associations between hallmark AD pathology and novel quantitative neuroimaging markers while being sensitive to white matter myelin content. Design, Setting, and Participants Magnetic resonance imaging was performed at an academic research neuroimaging center on a cohort of 71 cognitively asymptomatic adults enriched for AD risk. Lumbar punctures were performed and assayed for cerebrospinal fluid (CSF) biomarkers of AD pathology, including &bgr;-amyloid 42, total tau protein, phosphorylated tau 181, and soluble amyloid precursor protein. We measured whole-brain longitudinal and transverse relaxation rates as well as the myelin water fraction from each of these individuals. Main Outcomes and Measures Automated brain mapping algorithms and statistical models were used to evaluate the relationships between age, CSF biomarkers of AD pathology, and quantitative magnetic resonance imaging relaxometry measures, including the longitudinal and transverse relaxation rates and the myelin water fraction. Results The mean (SD) age for the 19 male participants and 52 female participants in the study was 61.6 (6.4) years. Widespread age-related changes to myelin were observed across the brain, particularly in late myelinating brain regions such as frontal white matter and the genu of the corpus callosum. Quantitative relaxometry measures were negatively associated with levels of CSF biomarkers across brain white matter and in areas preferentially affected in AD. Furthermore, significant age-by-biomarker interactions were observed between myelin water fraction and phosphorylated tau 181/&bgr;-amyloid 42, suggesting that phosphorylated tau 181/&bgr;-amyloid 42 levels modulate age-related changes in myelin water fraction. Conclusions and Relevance These findings suggest amyloid pathologies significantly influence white matter and that these abnormalities may signify an early feature of the disease process. We expect that clarifying the nature of myelin damage in preclinical AD may be informative on the disease’s course and lead to new markers of efficacy for prevention and treatment trials.

Advances in myelin imaging with potential clinical application to pediatric imaging.

White matter development and myelination are critical processes in neurodevelopment. Myelinated white matter facilitates the rapid and coordinated brain messaging required for higher-order cognitive and behavioral processing. Whereas several neurological disorders such as multiple sclerosis are associated with gross white matter damage and demyelination, other disorders such as epilepsy may involve altered myelination in the efferent or afferent white matter pathways adjoining epileptic foci. Current MRI techniques including T1 weighting, T2 weighting, FLAIR, diffusion tensor imaging, and MR spectroscopy permit visualization of gross white matter abnormalities and evaluation of underlying white matter fiber architecture and integrity, but they provide only qualitative information regarding myelin content. Quantification of these myelin changes could provide new insight into disease severity and prognosis, reveal information regarding spatial location of foci or lesions and the associated affected neural systems, and create a metric to evaluate treatment efficacy. Multicomponent analysis of T1 and T2 relaxation data, or multicomponent relaxometry (MCR), is a quantitative imaging technique that is sensitive and specific to myelin content alteration. In the past, MCR has been associated with lengthy imaging times, but a new, faster MCR technique (mcDESPOT) has made quantitative analysis of myelin content more accessible for clinical research applications. The authors briefly summarize traditional white matter imaging techniques, describe MCR and mcDESPOT, and discuss current and future clinical applications of MCR, with a particular focus on pediatric epilepsy.