Cognitive impairment in adults with Down's syndrome: similarities to early cognitive changes in Alzheimer's disease.

Postmortem studies of brains from adults with Down's syndrome (DS) reveal a dramatic age-dependent increase in the incidence of neuropathology associated with Alzheimer's disease (AD). By the age of 40 years, virtually all DS individuals have AD neuropathology. Documentation of cognitive correlates of this phenomenon has been difficult, partly because of the preexisting mental retardation in DS. In the current study, we compared a group of adults with DS, 22 to 51 years old, with a matched control group on various behavioral measures such as savings scores, which are known to be sensitive in detecting early dementia in AD patients. By using the short delayed savings score from the California Verbal Learning Test (a test of verbal memory), a subgroup of DS adults was identified as memory-impaired. This group demonstrated a decline in performance on various other cognitive tests with advancing age, whereas another group identified as having non-memory-impaired DS, and the non-DS controls, showed no evidence of decline with age. These results provide evidence for the presence of early dementia among adults with DS within an age range in which neuropathologic manifestations of AD are predicted to be developing.

Evidence for accelerated skin wrinkling among developmentally delayed individuals with Down's syndrome.

Down's Syndrome (DS) is a genetic disorder involving mental retardation which is reported to be a condition of accelerated aging. However, few studies exist which examine age-dependent changes in DS and these studies fail to include a control group. In the present study a non-invasive, painless, and easily obtainable measure reflecting age-dependent topographical changes of the skin (skin wrinkling) was obtained in 15 DS subjects, 14 developmentally disabled (DD) (mentally retarded) controls (DD controls) and 16 healthy controls of similar ages ranging from 22 to 51 years. The healthy control group failed to show correlations of skin measures with age, as predicted for the age-range of these subjects, based on results of previous studies. However, the DS group showed significant correlations of all skin measures from relatively non-sun-exposed and sun-exposed skin sites, with age. The DD control also showed significant correlations with age of several but not all skin sites and the correlation coefficients tended to be less than that of the DS; at least, when contrasted with the healthy controls the DS showed greater values of several skin measures suggestive of accelerated skin wrinkling. These results provide evidence for accelerated aging of the skin, and possibly greater effects of sun-exposure on skin wrinkling, in DS and possibly (DD) individuals in contrast to healthy individuals without a genetic disorder and without mental retardation.

The role of alterations in free radical metabolism in mediating cognitive impairments in Down's syndrome.

Down's syndrome (DS) is a genetic disorder involving an excess of chromosome 21 (trisomy 21) in approximately 96% of the cases and comprises approximately 15% of the population with mental retardation (Heller, 1969). In addition to the constitutional mental deficiencies associated with the syndrome many DS patients develop dementia associated with Alzheimer's disease (AD) in their later years of life (Thase et al., 1984). The genetic locus for Cu,Zn-superoxide dismutase (SOD1), a key enzyme in free radical metabolism, is located on chromosome 21, and the activity level of this enzyme is elevated by approximately 50% in a variety of cells of DS patients (see Kedziora and Bartosz, 1988; Sinet, 1982). Because alterations in free radical metabolism may be involved in neuronal death and may be associated with a number of pathological manifestations of DS, it is important to understand the role of free radical metabolism in cognitive impairments of DS, the topic discussed in this chapter.

Potentiated 5-hydroxytryptophan induced response suppression in rats following chronic reserpine.

Since reserpine precipitates depression in some hypertensive patients, we tested this drug on our animal model of depression. The present experiment was designed to measure the effects of chronic reserpine treatment on 5-hydroxytryptophan (5-HTP) induced behavioral depression in rats trained on a food reinforcement operant schedule. Based on the Aprison et al. model of depression involving the serotonergic system, we predicted the development of receptor supersensitivity of postsynaptic serotonin (5-HT) receptors due to the decreased release of this neurotransmitter as a consequence of chronic reserpine treatment. Rats were trained on a VI 1 reinforcement schedule and then divided into 3 chronic treatment groups. One received daily injections of a placebo, another 0.025 mg/kg reserpine and the third 0.05 mg/kg reserpine. We found that 5-HTP induced behavioral depression was potentiated in rats chronically treated with reserpine, thus suggesting the development of supersensitive 5-HT receptors. These results support the hypothesis that in some types of human depression a decreased release of 5-HT occurs of sufficient duration to permit the subsequent development of supersensitive 5-HT receptors.

Changes in cytosolic calcium during cholinergic and adrenergic stimulation of the parotid salivary gland.

Ca-selective microelectrodes were used to examine calcium transport during acetylcholine (ACh) and Epinephrine (Ep) stimulation of amylase secretion in the parotid gland. The cytosolic concentration of free ionized Ca2+ ( [Ca]i) determined in unstimulated cells was 0.44 +/- 0.04 microM. By measuring the induced changes in intracellular electrode potentials (ECa, EM) we were able to demonstrate that ACh at 10(-9), 10(-8), 10(-7), 10(-6), and 10(-5) M increased [Ca]i by 0.20 +/- 0.02, 0.61 +/- 0.04, 0.53 +/- 0.02, 0.30 +/- 0.05, and 0.14 +/- 0.03 microM. Similarly, Ep increased [Ca]i by 0.14 +/- 0.01, 0.42 +/- 0.06, 0.31 +/- 0.04, 0.15 +/- 0.03, and 0.05 +/- 0.04, respectively. Removal of extracellular Ca2+ significantly (P less than 0.001) altered the changes in ECa in response to ACh and Ep stimulation, thereby demonstrating that the induced increases in [Ca]i must be due to a transmembrane movement of Ca2+. Enzyme secretion was found to vary with the concentration of the stimulus used. Maximal secretion occurred during stimulation using 10(-7) M and 10(-8) M Ep with a suppression of release at supramaximal concentrations. The dose-response curve for ACh differed in that there were two concentrations of stimulus (2 X 10(-9) and 1 X 10(-6) M ACh) in which the greatest rate of secretion occurred. Concentrations of stimulus which increase [Ca]i between 0.86 +/- 0.06 microM and 0.74 +/- 0.05 appeared to produce optimal amylase secretion, indicating that salivary secretion in the mouse parotid is regulated within a narrow concentration range of cytosolic Ca2+.