Down’s syndrome (DS) is the most common cause of mental retardation in the United States. It occurs with a frequency of one in 700 live births. The disease is caused by the presence of three copies of chromosome 21 as a result of chromosomal mutation (95% nondisjunction, 5% translocation) during cell division, leading to a total of 47 chromosomes instead of the normal number, 46. There are no individuals with the clinical signs of DS who do not have at least partial trisomy of chromosome 21. Conversely, there are no cases of people with trisomy 21 who do not have DS (Patterson, 1987). Patients suffer from a variety of physical and mental problems. Physically, the disease manifests itself in epicanthic folds of the eyes, flattened facial features, unusual palm creases, muscular flaccidity and short stature (Patterson, 1987). Many are born with congenital heart defects and increased risk for cataracts, leukemia and Alzheimer’s disease. In addition to the anatomical abnormalities, DS patients suffer from biochemical imbalances including elevated levels of purines - a condition that can by itself lead to neurological impairment, mental retardation, and immunodeficiencies. The life expectancy for DS patients is approximately 30 years. However, with advancing medical care and therapy more patients are living to the age of 50. All individuals with DS over the age of 35 develop the same kind of abnormal microscopic plaques and neurofibrillary tangles in the brain as people who die from Alzheimer’s disease, the major cause of presenile dementia. Although a vast amount of literature exists on DS, little is known about why the presence of an extra chromosome causes mental retardation. In addition to the small size and irregular dimensions, the structural (i.e. cellular) abnormalities of the DS brain may also help to explain the mental deficiencies suffered. By examining abnormalities in neurons, dendrites, synapses, and neuroglial cells of the CNS much information on the DS brain’s insufficiencies can be elucidated.

The typical, gross morphological characteristics of the DS brain are a round cerebrum, shortened fronto-occipital diameter with steep inclinations of both occipital lobes, small superior temporal gyri perpendicularly oriented, simplicity of convolutions, irregularity of the operculum, and small cerebellum and brain stem. In addition, other anomalies have been described including hydrocephalus, holoprosencephaly, hippocampal hypoplasia, and hypoplasia of the anterior commissure (Becker, 1991). Microscopic examination shows many abnormalities including cortical dysmorphogenesis which includes a decrease of 20 to 50 percent in the number of neurons in the cortical layers, precentral cortex, and the granular cell layers of the temporal, parietal, and occipital lobes.

In order to determine the pattern of cortical development, examination was done on brains of controls and DS fetuses and infants. By 40 weeks gestation, layers of the visual cortex were well defined in the normal infants, whereas cellular distribution was much more diffuse (less differentiated) in DS infants. At four months of age, the same relations were observed where normal neurons were more in number and maturity, whereas DS cell layers were poorly defined (Becker, 1991). This difference undoubtedly alters the spatial configuration among cells thereby affecting their function.

Wisniewski and Bobinski had similar findings in their examination of the hypothalamic nuclei, the arcuate and ventromedial nucleus. In control brains, the arcuate nucleus consisted of isomorphic, densely packed, spindle shaped neurons. Their longitudinal axes were directed toward the infundibulum. In the DS brains, the arcuate nucleus was composed of loosely packed, small, spindle-like neurons. The number of cells per square millimeter was significantly lower in DS than in control brains. Similar findings resulted from study of the ventromedial nucleus. Very evident gliosis was also observed, especially around blood vessels. In comparing the growth of the dendritic tree in normal and DS patients there is a remarkable difference. Through the use of Golgi impregnation, there is strong evidence in DS brains of not only growth cessation, but also dendritic atrophy that is seen in childhood and continues through adulthood. The atrophy is marked by a decrease in dendritic branching, length, and spine frequency (Takashima, 1989). Becker et al . report that the total dendritic length per cell (specifically in the third layer) decreased by almost 50% from the infantile to juvenile DS group, whereas total length increased by 65% in control patients over the same age range. Normally, dendritic expansion occurs continuously, however, this is not seen in DS where atrophy actually begins to occur. Decreased numbers of dendritic spines and abnormalities in the geometry of spines are constant morphological anomalies of neurons in DS children (Ferrer, 1990). This number continues to decline with age. Synaptic ultrastructural abnormalities are clearly evident in DS by using sections stained with both osmium tetroxide and phosphotungstic acid in ethanol. Normally, synaptic density increases with gestation. In DS, a decrease in synaptic density of sensorimotor cortex was observed around 33 weeks gestation. Although cleft size was unchanged, a reduction in both presynaptic and postsynaptic width and length was also observed in the DS brains. These observations suggest an increased inefficiency in synaptic transmission in the DS brain which could contribute to mental retardation. In addition, it has been reported that cholinergic enzyme activity is normal in all brain regions of DS brains, suggesting that DS patients begin life with a normal amount of neurotransmitter level (Kish et al., 1989) which does not account for, or contribute to mental problems.

Astrocytes have a structural function in the CNS and they also contribute to the function of neurons. Their role is to provide a mechanism for exchange of materials between capillaries and neurons, while also providing regulation of extracellular ionic balance. Specifically, the influence of astroglial cells in the pathogenesis of mental retardation is not clear, but logical connections between its components and their function and pathogenesis can be made. The identification and localization of the gene for the beta subunit of the S--100 protein on chromosome 21 has been made. S-100 has been identified as a major component of astrocytes. Although its exact function is not known, S-100 shares sequences and properties with calcium-binding proteins, which suggests a role in calcium signal transduction pathways involved in the regulation of growth and differentiation (Becker et al., 1991). It has been reported that from gestation to middle age, the number of S-100 immunoreactive cells is greatly increased in number in DS temporal lobes, selected areas of the frontal and occipital lobes, hippocampus, and cerebellum. The increase in S-100 positivity shows a probable effect of gene dosage and the disturbance it can cause at a critical stage of brain development and maturation. Postnatal delay in myelin formation is a noted abnormality of Down’s syndrome. This can be attributed to oligodendroglia dysfunction. Delays in myelination have been described in the temporal, frontal and parietal lobes. A nearly 25% myelination delay of tracts was reported, with most occurring in association and intracortical fibers of the fronto-temporal lobe.

Although no specific abnormality of endothelial cells has been identified in Down’s syndrome, vascular alterations have been reported. Minor anomalies such as vascular hypoplasia on the circle of Willis, the frequency of moyamoya disease, and calcification in the parenchymal vessels (small arteries, capillaries) particularly in the basal ganglia, may suggest a changed vasculature perhaps due to the endothelial cells.

Nearly all patients with Down’s syndrome who live beyond the age of 35 develop progressive histopathological lesions of Alzheimer’s disease (De La Monte, 1990). Middle-aged and elderly patients with Down’s syndrome also exhibit the same type of dysfunction’s and cell losses as Alzheimer’s patients in cholinergic, noradrenergic, dopaminergic, and serotonergic systems, as well as a decrease in cerebral blood flow. In both afflictions, an age-related decrease in cognitive function is observed, as well as a correlated increase in the density of neuritic plaques and neurofibrillary tangles of the cerebral cortex. The morphology of these plaques in the hippocampus and the temporal cortex has been examined in DS using immunocytochemical and lectin histochemical methods, as well as silver staining. The earliest changes detectable within these areas in young patients are the appearance of a fine diffuse deposition of amyloid protein and uniform granular accumulation of an oligosaccharide . Following these early signs, more mature DS brains (after the age of 20) exhibit the formation of neurites and the accumulation of neurofibrillary tangles that ultimately lead to cell death (Mann et al., 1989).

The brain of a person with Down’s syndrome develops differently from a normal one. Its size and morphological characteristics, both macro- and microscopic, are undoubtedly altered . Neuronal modifications that result ultimately in improper cortical lamination, reduced dendritic branching and spine formation, and in reduced synaptic efficiency, contribute greatly to the mental retardation observed in Down’s syndrome, as do accompanying abnormalities in astrocytes, oligodendrocytes, and vascularization. Current researchers are attempting to discover the specific correlation between these abnormalities and the presence of a third 21st chromosome. Much work is being done on gene products and their effects on neuroglia. Discoveries in this area may lead to situations that could possibly be corrected by gene therapy in the near future.

BIBLIOGRAPHY:

Allsop, D., Haga, S. I., Haga, C., Ikeda, S. I., Mann, D. M. A., Ishii, T. (1989): Early Senile Plaques in Down’s Syndrome Brains Show a Close Relationship with Cell Bodies of Neurons. Neuropathology and Applied Neurobiology, 15: 531-542.

Becker, L., Mito, T., Takashima, S., Onodera, K. (1991): Growth and Development of the Brain in Down Syndrome. The Morphogenesis of Down Syndrome: 133- 152.

De La Monte, S., Hedley-Whyte, T. (1990): Small Cerebral Hemispheres in Adults with Down’s Syndrome: Contributions of Developmental Arrest and Lesions of Alzheimer’s Disease. Journal of Neuropathology and Experimental Neurology, 49: 509-518.

Ferrer, I., Gullotta, F. (1990): Down’s Syndrome and Alzheimer’s Disease: Dendritic Spine Counts in the Hippocampus. Acta Neuropathol, 79: 680--685.

Mann, D. M. A., Brown, A., Prinja, D., Davies, C. A., Landon, M., Masters, C. L., Beyreuthers, K. (1989): An Analysis of the Morphology of Senile Plaques in Down’s Syndrome Patients of Different Ages Using Immunocytochemical and Lectin Histochemical Techniques. Neuropathology and Applied Neurobiology, 15: 317-329.

Patterson, D. (1987): The Causes of Down Syndrome. Scientific American, 255: 52-60.

Takashima, S., Ieshima, A., Nakamura, H., Becker, L. (1989): Dendrites, Dementia and the Down Syndrome. Brain Development, 11: 131-133.

Wisniewski, K., Bobinski, M. (1991): Hypothalamic Abnormalities in Down Syndrome. The Morphogenesis of Down Syndrome., 153-167.