Interaction of iron deficiency anemia and neurofunctions in cognitive development.
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Anemia, Iron-Deficiency↗
Biomedical subjects
M Roncagliolo
Publications and source records attributed to M Roncagliolo.
Dysmyelination, demyelination and reactive astrogliosis in the optic nerve of the taiep rat.
Taiep is an autosomal recessive mutant rat that shows a highly hypomyelinated central nervous system (CNS). Oligodendrocytes accumulate microtubules (MTs) in association with endoplasmic reticulum (ER) membranes forming MT-ER complexes. The microtubular defect in oligodendrocytes, the abnormal formation of CNS myelin and the astrocytic reaction were characterized by immunocytochemical and ultrastructural methods during the first year of life. Optic nerves of both control and taiep rats were processed by the immunoperoxidase method using antibodies against tubulin, myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP). Taiep oligodendrocytes are strongly immunoreactive against tubulin, indicative of a significant accumulation of microtubules. Early differentiated oligodendrocytes observed with electron microscopy show that MT-ER complexes are mainly present in the cell body. This defect increases during the first year of life; oligodendrocytes show large MT-ER complexes projected within oligodendrocyte processes. Using anti-MBP, there was a progressive reduction of immunolabeling in the myelin sheaths as taiep rats grew older. Ultrastructural analysis revealed severely dysmyelinated axons with a frequently collapsed periaxonal collar. However, through age the myelin sheath became gradually infiltrated by MTs, suggesting their contribution to premature loss of myelin in the taiep rat. Axons of one-year-old taiep rats were severely demyelinated. Modifications in astrocytes revealed by the GFAP antibody showed a strong hypertrophy with increased immunostaining in their processes. As demyelination of axons progressed, taiep rats developed a strong astrogliosis. The present findings suggest that in taiep rats the early abnormal myelination of axons affects the adequate maintenance of myelin, leading to a progressive loss of myelin components and severe astrogliosis, features that should be considered in the pathogenesis of dysmyelinating diseases.
Animals↗
Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brainstem responses.
Iron deficiency anemia has long been thought to have effects on the central nervous system (CNS). Finding direct evidence of this in human infants, however, has been challenging. Auditory brainstem responses (ABRs) provide a noninvasive means of examining an aspect of the CNS that is rapidly maturing during the age period when iron deficiency is most common. ABRs represent the progressive activation of the auditory pathway from the acoustic nerve (wave I) to the lateral lemniscus (wave V). The central conduction time (CCT, or wave I-V interpeak latency) is considered an index of CNS development because myelination of nerve fibers and maturation of synaptic relays lead to an exponential reduction in the CCT from birth to 24 mo. In 55 otherwise healthy, 6-mo-old Chilean infants (29 with iron deficiency anemia and 26 nonanemic control infants), the CCT was longer in those who had been anemic at 6 mo, with differences becoming more pronounced at 12- and 18-mo follow-ups despite effective iron therapy. The pattern of results--differences in latencies but not amplitudes, more effects on the late ABR components (waves III and V), and longer CCTs (as an overall measure of nerve conduction velocity)--suggested altered myelination as a promising explanation, consistent with recent laboratory work documenting iron's essential role in myelin formation and maintenance. This study shows that iron deficiency anemia in 6-mo-old infants is associated with adverse effects on at least one aspect of CNS development and suggests the fruitfulness of studying other processes that are rapidly myelinating during the first 2 y of life.
Anemia, Iron-Deficiency↗
Binding of microtubules to transitional elements in oligodendrocytes of the myelin mutant taiep rat.
The presence of microtubules physically bound to smooth endoplasmic reticulum profiles of oligodendrocytes constitutes the most conspicuous feature observed in the myelin mutant taiep rat. The endoplasmic reticulum membranes associated with microtubules were morphologically characterized as transitional elements that constitute the intermediate compartment according to their topographic location close to the cis-Golgi apparatus. The development of this surprising microtubular defect appears to be associated with the early events of myelination. Transitional elements associated with microtubules operate in protein transport from endoplasmic reticulum to cis-Golgi. This microtubular defect could explain the dysmyelination and neurologic alterations observed in taiep rats. Moreover, these findings allow us to propose that there is a blockage of protein traffic at the intermediate compartment of taiep oligodendrocytes, a situation that could explain the hypomyelinated axons observed in this myelin mutant. The binding of microtubules to membranous organelles promotes the stabilization of microtubules, a feature that has important implications regarding its accumulation within the cytoplasm of oligodendrocytes during the temporal evolution of this neurologic disorder. The taiep rat is a myelin mutant with a long survival and could be a useful model for understanding dysmyelinating diseases in which the intracellular transport of myelin components is affected.
Animals↗
Measures of location and dispersion of sleep state distributions within the circular frame of a 12:12 light: dark schedule in the rat.
Distributions within a 12:12 light:dark schedule of wakefulness (W), active sleep (AS), quiet sleep (QS) and of QS rich in delta (QSD) and in spindle (QSS) activities were evaluated for 52 days from 15 rats. Angular statistics were applied for each state by equating their hourly incidence to data distributed around a circle. Measures of location (mean angle, median angle, mode angle, maximum semicircle), dispersion (mean vector, standard deviation, quartile deviation), skewness and kurtosis were computed and their intra- and interindividual variabilities were compared. Mean angles (in hours and after lights-on) averaged 5.5 for QS, 8.6 for AS, 18.4 for W, 1.9 for QSD and 10.6 for QSS. Length of vectors, representing concentration around the mean angle, averaged 0.22 for QS, 0.36 for AS, 0.22 for W, 0.38 for QSD and 0.23 for QSS. Distributions of QS and W were closely related to the light-dark step function. QSD had a leptokurtic distribution, sharply rising at the beginning of the sleep-predominant phase, whereas AS and QSS had smoother distributions reaching maxima in its second half. In rodents as in humans, QSS and AS have opposite distributions to QSD. QSS may contribute to maintain sleep through the resting phase of the light-dark schedule after restorative function associated with delta activity has been fulfilled.
Animals↗
Auditory brainstem responses of children with developmental language disorders.
Brainstem auditory evoked potentials (BAEPs) were recorded from 48 children with language disorders (aged four to nine years old, IQs normal to borderline, normal audiometric thresholds and attending special school) and 20 healthy children (four to eight years old, with normal IQs, audiometry and school-level). The language-disabled group showed significantly lower absolute latency values of the BAEPs than controls. There were no significant differences in the central conduction time of the auditory pathway (I-V interval). Therefore, the only significant difference corresponded to a minor value for the first wave (auditory nerve discharge) of the BAEP. A reduction in the control mechanisms of the sensory inputs at the peripheral level, or a disturbance in the inhibitory mechanisms of cortico-subcortical modulation, might explain these findings.
Aphasia↗
Short-term homeostasis of active sleep and the architecture of sleep in the rat.
1. Sixteen rats were recorded continuously for 3 days using an automated system that detected, quantified, and stored the incidence of cortical delta waves, cortical sigma spindles, hippocampal theta rhythm, and electromyographic activity. A time series then was constructed wherein 15-s epochs were ascribed to one behavioral state: wakefulness (W), quiet sleep (QS), or active sleep (AS, a state also referred to as REM sleep). From those series, AS episodes and non-AS intervals could be determined. Episodes and intervals were defined as lasting at least two epochs and the one-epoch episodes and intervals were incorporated to the ongoing state. 2. Having established the length of each AS episode and non-AS interval, pairings were made, on the one hand between episodes and their preceding intervals, and on the other, between episodes and the intervals that followed. 3. Highly significant correlations were found between the length of AS episodes and the length of the non-AS intervals that followed. Correlations were also significant when calculated separately versus the amount of QS and of W within the following interval. Correlations improved when they were performed against the log of the interval and when only intervals with a predominance of QS were selected. 4. No significant correlation was found between the length of AS episodes and the length of the preceding non-AS intervals, except for a negative one that was present only when the statistical analysis was performed in the unsmoothed array where the one-epoch episodes and intervals were preserved. 5. These results suggest that there is a short-term homeostasis operating within the spontaneous architecture of sleep in rats. This homeostatic mechanism is not manifested by the regulation of the length of AS episodes. Instead, there is a forward regulatory mechanism that, given the duration of an AS episode, permissively controls the interval that the animal may abstain from AS, and hence the timing of the triggering of a new AS episode.
Animals↗
Time course of rat sleep variables assessed by a microcomputer-generated data base.
A microcomputer-based system is described that detects, counts and stores cortical delta and sigma waves, hippocampal theta waves and electromyographic activities in the rat by building matrices with the incidence of those four variables (columns) in 15-second bins (rows). Data tables are submitted to statistical, graphics and spread-sheet software to assess internal organization of sleep episodes and 24-hour distribution of sleep variables. Within sleep episodes, cross-correlograms reveal a delta-sigma-theta sequence, while autocorrelograms quantify clustering and periodicity of variables. Sleep accumulates in the lights-on phase, with high concentration of delta at the beginning of this sleep-predominant phase and of sigma and theta in its second half. These are notable similarities with human sleep architecture. Simple procedures for data reduction into standard behavioral state diagnosis are demonstrated. The low cost of personal computers and data acquisition interfaces facilitates the automation of complex paradigms by ad hoc on-line programs that produce as output a data base that can be processed by standard software, providing a fluid pathway of automated acquisition, analysis and presentation of data.
Animals↗
Progressive deterioration of central components of auditory brainstem responses during postnatal development of the myelin mutant taiep rat.
Auditory brainstem responses (ABRs) were evaluated during the postnatal development (P10-P180) of taiep rats, neurological mutants characterized by early abnormal myelin development and subsequent demyelination of the CNS. The disorder is produced by an autosomal recessive mutation trait that affects the oligodendrocytes but not the Schwann cells. After onset of ABRs (P12-P14), taiep rats and their nonaffected heterozygous littermates that served as controls showed a similar pattern of maturation for wave I. The central waves (In-IV) showed significantly longer latencies in the mutants. By P60-P180, the later waves (III and IV) were frequently difficult to discern. From the onset of ABRs, the interpeak latency I-IV, corresponding to the central conduction time (CCT) of the auditory pathway, showed in taiep rats significantly longer values than controls. After an initial reduction, proportional to that of control rats, the CCT value increased progressively during the second month of the mutants' lives. The electrophysiological results of the present study strongly support the hypothesis that mutation in the taiep rat impairs neuromaturation of the central auditory pathway in the brainstem by affecting the myelination process in the CNS.
Animals↗