Myelination Of Subcortical White Matter Research Articles

Adult age differences in subcortical myelin content are consistent with protracted myelination and unrelated to diffusion tensor imaging indices

Post mortem studies suggest protracted myelination of subcortical white matter into the middle age followed by gradual decline in the late adulthood. To date, however, establishing the proposed inverted-U pattern of age-myelin association proved difficult, as the most common method of investigating white matter, diffusion tensor imaging (DTI), usually reveals only linear associations between DTI indices and age among healthy adults. Here we use a novel method of estimating Myelin Water Fraction (MWF) based on modeling the short spin-spin (T2) relaxation component from multi-echo T2 relaxation imaging data and assess subcortical myelin content within six white matter tracts in a sample of healthy adults (N=61, age 18–84 years). Myelin content evidenced a quadratic relationship with age, in accord with the pattern observed postmortem studies. In contrast, DTI-derived indices that are frequently cited as proxies for myelination, fractional anisotropy (FA) and radial diffusivity (RD), exhibited linear or null relationships with age. Furthermore, the magnitude of age differences in MWF varied across the white matter tracts. Myelin content estimated by MWF was unrelated to FA and correlated with RD only in the splenium. These findings are consistent with the notion that myelination continues throughout the young adulthood into the middle age. The results demonstrate that single-tensor DTI cannot serve as a source of specific proxies for myelination of white matter tracts.

TACE/ADAM17 is essential for oligodendrocyte development and CNS myelination.

Several studies have elucidated the significance of a disintegrin and metalloproteinase proteins (ADAMs) in PNS myelination, but there is no evidence if they also play a role in oligodendrogenesis and CNS myelination. Our study identifies ADAM17, also called tumor necrosis factor-α converting enzyme (TACE), as a novel key modulator of oligodendrocyte (OL) development and CNS myelination. Genetic deletion of TACE in oligodendrocyte progenitor cells (OPs) induces premature cell cycle exit and reduces OL cell survival during postnatal myelination of the subcortical white matter (SCWM). These cellular and molecular changes lead to deficits in SCWM myelination and motor behavior. Mechanistically, TACE regulates oligodendrogenesis by modulating the shedding of EGFR ligands TGFα and HB-EGF and, consequently, EGFR signaling activation in OL lineage cells. Constitutive TACE depletion in OPs in vivo leads to similar alterations in CNS myelination and motor behavior as to what is observed in the EGFR hypofunctional mouse line EgfrWa2. EGFR overexpression in TACE-deficient OPs restores OL survival and development. Our study reveals an essential function of TACE in oligodendrogenesis, and demonstrates how this molecule modulates EGFR signaling activation to regulate postnatal CNS myelination.

Effect of perinatal iron deficiency on myelination and associated behaviors in rat pups

Iron deficiency in early development has been associated with irreversible alterations in brain myelination, but whether these neural changes are mirrored in altered behaviors in rats is not known. The goals were to determine if dietary induced gestational and lactational iron deficiency alters brain myelination and behaviors dependent on that system. Pregnant rats were randomly assigned to control (CN) or iron-deficient (ID) groups by providing iron-sufficient (40 ppm Fe) or iron-deficient (2–6 ppm Fe) diets from gestational day 5 through to weaning of pups. Thereafter, all offspring were fed the iron-sufficient diet. The myelination of subcortical white matter and the fimbria of hippocampus was measured by 2′,3′-cyclic nucleotide 3′-phosphohydrolase (CNPase, marker of oligodendrocyte) density at 25 days of age. Specific behavioral assessments were performed at multiple time points after birth. By contrast, ID rats had significantly lower density of CNPase in the subcortical white matter but the density of CNPase in fimbria of hippocampus was comparable to CN rats. Moreover, ID rats showed significant behavioral impairments in surface righting reflex, negative geotaxis reflex, vibrissae-evoked forelimb placing test and novel object recognition task. In conclusion, perinatal iron deficiency can significantly alter behavioral outcomes which may be due to delayed myelination in specific brain regions.

The neuropathology of phenylketonuria: human and animal studies.

Pathologic changes in the brain of untreated phenylketonuria (PKU) patients occur in structures that develop post-natally, i.e. in myelination of subcortical white matter and spinal cord and in the growth of axons, dendrites and synapses in cerebral cortex. In addition, a small minority of brains show evidence of progressive white matter degeneration (leucodystrophy). The pathologic changes are thought to be due to toxic effects of phenylalanine and/or its metabolites. It is assumed that they can be prevented by dietary therapy during infancy and childhood, but direct confirmation by neuropathologic studies is lacking. The recently discovered genetic mouse mutant Pah(enu2) provides an excellent animal model in which effects of PKU on brain development, including dendritic and synaptic development in cerebral cortex, can be assessed. In human PKU, there needs to be neuropathologic study of the brains from PKU patients, particularly adults, with a history of dietary therapy. Special attention needs to be paid to the study of white matter in such cases, in view of recent reports of white matter lesions on MRI despite dietary treatment. Careful correlation is needed between neuropathology, magnetic resonance imaging white matter changes, dietary history and clinical findings. Finally, neuropathologic investigation is needed to determine whether progressive degeneration of the white matter (leucodystrophy) poses a risk to adults in whom dietary therapy has been discontinued.

Effects of chronic placental insufficiency on brain development in fetal sheep.

Clinical evidence has linked intrauterine compromise such as fetal hypoxemia to poor neurologic outcome in the newborn. In this study we examined the effects of inducing chronic fetal hypoxemia by impairment of placental function on brain development in fetal sheep. Placental insufficiency was induced from 120 to 140 d of gestation (term = 145-148 d) by injection of microspheres into the umbilical circulation in five fetal sheep. Fetal partial pressure of oxygen, PaO2, was reduced from 24.1 +/- 0.5 mm Hg before embolization to 14.8 +/- 0.4 mm Hg after embolization (p < 0.05). In another three fetuses a similar level of hypoxemia (PaO2, 13.8 +/- 0.4 mm Hg) occurred spontaneously. At 140 d of gestation the fetal brains were perfused with fixatives and compared with five control fetuses for the assessment of structural and immunohistochemical alterations. Hypoxemic fetuses demonstrated severe gliosis in the cerebral cortex and reduced myelination of subcortical white matter as visualized by glial fibrillary acidic protein and myelin basic protein staining, respectively (p < 0.05). White matter lesions were observed in two fetuses. The diameter of cerebral capillaries was increased in hypoxemic fetuses (p < 0.05), but there was no change in the number of nitric oxide synthase immunoreactive cells. Growth of neuronal processes was affected in the cerebellum, where there was also a reduction in the number of Purkinje neurons (p < 0.05). These results show that a prolonged period of placental insufficiency, resulting in moderate fetal hypoxemia during the last third of gestation, can affect neurodevelopmental processes that occur late in gestation such as myelination and growth of the cerebellum. This prenatal damage could affect neural connectivity and have functional consequences after birth.