Down's syndrome (DS) is the most common genetic cause of mental retardation and probably the earliest identified condition associated with mental retardation (Pulsifer, J Int Neuropsychol Soc 2:159-76 (1996). DS arises from one of three chromosomal abnormalities. Most commonly (95% of cases) DS is the result of trisomy 21, or the presence of an extra chromosome 21 in otherwise diploid cells. Trisomy 21 usually results from nondisjunction of chromosome 21 during meiosis of the gametes, and brings the total number of chromosomes in the adult offspring to 47. DS may also result (in about 2-4% of cases) from translocation events, occurring when a fragment of chromosome 21 becomes attached to another chromosome, most typically chromosome 14. The rarest form of DS(about 1-4% of cases) results from nondisjunction of chromosome 21 during early embryogenesis. Such individuals are mosaic, with both normal and trisomic cells being present.
DS individuals are almost invariably cognitively impaired, with most having an IQ between 40 and 60, although IQ scores within the normal range are possible (Epstein, in Scriver et al. eds., The metabolic basis of inherited diseases, New York: McGraw-Hill (1989)). Generally, significant developmental delays are apparent in DS child in infancy and early childhood (see Pulsifer, supra).
Superimposed on this early cognitive impairment, however, is a more serious deterioration of cognition that begins to appear as individuals with DS age. Adults with DS are at high risk for developing clinical dementia similar to that observed in Alzheimer's disease. Clinical dementia is seen in 25-30% of DS individuals by age 40, and in 75% of DS individuals at age 60 (Lai & Williams, Arch Neuro 46:849-53 (1989); Johanson et al., Dementia 2:159-168 (1991)). Other individuals display marked cognitive deterioration but do not meet the diagnostic criteria for clinical dementia. (Johannsen et al., Dementia 7:221-5 (1996); Burt et al., Am J Ment Retard 103:140-45 (1998)). Reported manifestations of cognitive deterioration in adults with DS include memory loss, anomia, apraxia, and decline in self-help skills (Lott & Lai, Annals Neurology 12:210-215 (1982); Young & Kramer, Mental Retard 29:75-9 (1991); Haxby & Shapiro, in Nadel & Epstein eds., Alzheimer's disease and Down syndrome, New York: Wiley-Liss (1992)). With modern medical treatment, over half of individuals with DS will survive into their fifties, and 13.5% will still be alive at age 68 (Baird & Sadovnick, Hum Genet 82:291-2 (1989)). Accordingly, the problem of cognitive deterioration in adults with DS is severe and growing.
No effective treatment for the cognitive impairment and decline of DS individuals is known. While multiple attempts to treat cognitive deterioration in DS individuals have been reported, none has achieved significant success. Geldmacher et al. (J Geriatr Psychiatry Neurol 10:99-104 (1997)) treated DS adults with selective serotonin-reuptake inhibitors (SSRIs), but reported improvement only of non-cognitive behavioral symptoms. Based on the theory that the cognitive deficits observed in DS may be linked to dysfunction of the cholinergic system, encouraging results in small-scale trials of donepezil (Kishani et al., Lancet 353:1064 (1999)) and nicotine (Seidl et al., Lancet 356:1409-10 (2000)) have been reported. However, randomized clinical trials have yet to validate these studies, and both nicotine and donepezil have drawbacks as therapeutic agents. Piracetam, a drug acting on glutamatergic neurotransmission and reported to enhance cognitive function, has been evaluated in DS children but failed to enhance cognitive function (Lobaugh et al., Arch Pediatr Adolesc Med 155:442-8 (2001)). Thus, there is a need for an effective therapy to prevent, inhibit, or reverse the cognitive deterioration seen in DS adults.
Cortisol, a glucocorticoid hormone which is secreted in response to ACTH (corticotropin), shows circadian rhythm variation, and further, is an important element in responsiveness to many physical and psychological stresses. It has been proposed that, with age, the cortisol regulatory system becomes hyperactivated in some individuals, resulting in hypercortisolemia. It has additionally been postulated that high levels of cortisol are neurotoxic, particularly in the hippocampus, a brain structure that is thought to be central to the processing and temporary storage of complex information and memory (see, e.g., Sapolsky et al., Ann. NY Acad. Sci. 746:294-304, 1994; Silva, Annu. Rev. Genet. 31:527-546, 1997; de Leon et al., J. Clin. Endocrinol & Metab. 82:3251, 1997; Maeda et al., supra).
Studies of human subjects who have received treatment with exogenous glucocorticoids at therapeutic levels have suggested that glucocorticoids may play a role in short-term, reversible memory impairment. (see, e.g., Wolkowitz et al., Am J. Psychiatry 147:1297-1303, 1990; Keenan et al., Neurology 47:1396-1402, 1996; Newcomer et al., Arch Gen. Psychiatry 56:527-533, 1999). Furthermore, it has been suggested that basal levels of cortisol that are chronically at the high end of the normal range, i.e., levels that correspond to peak circadian values or approximate those levels seen during stress, contribute to the impaired cognitive performance and loss of hippocampal-mediated memory function observed in aging (see, e.g., Lupien et al., J. Neurosci. 14:2893-2903, 1994; Lupien et al., Nat. Neurosci 1:69-73, 1998).
Basal cortisol levels are similar in DS and non-DS individuals (Murdoch et al., J Ment Defic Res 23:157-62 (1979); Ramunni et al., J Endocrinol Invest 22S10:5708 (1999)). Impaired activity of the HPA axis in response to ACTH has been reported in DS individuals (Murdoch et al., supra) but the significance of this finding is unknown. Hence, there has been no evidence prior to this invention that a glucocorticoid receptor antagonist can be an effective agent to prevent or reverse cognitive deterioration in adults with DS, especially in patients having cortisol levels that fall within a normal range. Many of the actions of cortisol are mediated by binding to the type I (mineralocorticoid) receptor, which is preferentially occupied, relative to the type II (glucocorticoid) receptor, at physiological cortisol levels. As cortisol levels increase, more glucocorticoid receptors are occupied and activated. Because cortisol plays an essential role in metabolism, inhibition of all cortisol-mediated activities, however, would be fatal. Therefore, antagonists that specifically prevent type II glucocorticoid receptor functions, but do not antagonize type I mineralocorticoid receptor functions are of particular use in this invention. RU486 and similar antagonists are examples of this category of receptor antagonists.
The present inventors have determined that glucocorticoid receptor antagonists such as RU486 are effective agents for preventing or reversing cognitive deterioration in DS adults with normal, increased, or decreased cortisol levels. The present invention therefore fulfills the need for an effective preventive measure for cognitive deterioration in DS patients by providing methods of administering glucocorticoid receptor antagonists to improve cognitive function in DS patients.
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