Mark H. Fleisher, MD
Down Syndrome (DS) is one of the most common genetic disorders and is associated with both mental retardation and early onset dementia. These facts have made it a focus of interest for researchers and clinicians interested in developmental disabilities and neurodegenerative disorders. For many years no significant treatment options have been available for the dementia associated with DS or for Senile Dementia of the Alzheimer Type (SDAT), which are remarkably similar disorders from the standpoint of cytopathological changes in the human brain. More recent developments have created a greater understanding of the development and onset of these disorders as well as in treatment options that are available. Current therapeutic interventions exist that have the potential to stabilize or improve the clinical status and quality of life of persons with DS and the associated early onset dementia.
Down Syndrome is one of the most common genetic disorders documented at birth, and therefore makes a significant contribution to the total number of persons with mental retardation. Estimates suggest that the frequency of trisomy 21 in the United States is approximately 1 in 650 to 1,000 live births. An important risk factor for trisomy 21 is maternal age, as the frequency of trisomic births increases as maternal age increases. For a 30-year-old mother the risk of having a child with DS is about 0.1%, but by age 40 the chances increase dramatically to about 0.9%.
Approximately 95% of trisomic 21 individuals have three copies of chromosome 21, and in about 5% of these individuals one copy has been translocated to the acrocentric area of another chromosome, which is typically number 14 or number 21. Experts feel that in less than 4% of the free trisomic individuals there is mosaicism for both a trisomic and a normal cell line.
DS is associated with a very high rate of dementia that most commonly affects individuals in their fifth decade and beyond. There are few if any, significant differences in cytopathology between Senile Dementia of the Alzheimer Type (SDAT) and the dementia associated with DS. Phenotypically, reports show that the dementia associated with DS is identical to that of SDAT, at least to the extent that there has been no separate diagnostic classification within the DSMIV system for the Alzheimer-like dementia associated with DS. It should be noted that the underlying mental retardation of DS creates a more complex clinical presentation that suggests more diversity in symptomatology than with SDAT. Despite the similarities that exist in cognitive impairment, there are significant differences between SDAT and the dementia complex associated with DS. In order to appreciate some of these differences it may be useful to compare patients with SDAT and persons with DS with or without symptoms of dementia.
Persons with DS develop the neuropathologic hallmarks of Alzheimer disease (AD) at a much earlier age than individuals with AD without trisomy 21. Characteristic senile plaques and neurofibrillary tangles are present in the brain of virtually all individuals with DS over 40 years of age. Whether or not the triplication of the amyloid precursor protein (APP) gene is the direct or sole cause of this phenomenon is unknown, although there are indications that this may be the case.
Several chromosomes have been implicated in familial and non-familial early-onset AD and these do not involve trisomy 21. None of these forms of early onset AD are as common as that seen in DS. Several researchers have noted that the relative protective benefit or risks associated with the APOE2 and APOE4 alleles in dementia of DS are similar to that for SDAT (Tyrrell et al., 1998).
As a group, individuals with DS and dementia are younger and tend to be in better general health than individuals in their seventh, eighth, or ninth decades of life. These latter individuals, having lived decades longer, are thus exposed to increased risks for infectious diseases, traumatic events and other health complications associated with the aging process. Important age related risk factors for cognitive decline would include hypertension and vascular diseases. While abnormal amyloid protein may be found from a very early age in persons with DS, the presence of neurofibrillary tangles is more closely related in time to the onset of dementia symptoms. A prodromal stage of several years that typically lacks the cardinal symptoms of AD may further distinguish the two disorders.
Multiple factors may be present that increase or decrease the risks for progression of the AD irrespective of the etiology. Seemingly, despite the early presence of histological findings of AD in DS, other elements are present that either modulate the course beneficially or portend a worsening course at an earlier age. Other factors that may play a role in disease progression require further study. Suggestions have been made for more than ten years that anti-inflammatory agents may influence neuronal degeneration, but only recently has the potential scope and impact of the human brains inflammatory responses been clinically demonstrated in HIV related dementia and researched in SDAT.
Other factors that may have a role in these processes include a partial beneficial effect of estrogen for persons with SDAT and a possible protective role for anti-oxidants or free radical scavengers in SDAT. These are areas of far too little knowledge with regard to SDAT, and almost nothing has been elucidated for DS and the associated dementia. Despite these immense research gaps in clinical and basic science areas, a continuing strong belief exists that, at least at an immediate neuronal-cognitive processing level, a relative cholinergic deficit exists. On the basis of this supposition, primary clinical interventions are based on cholinergic therapy via cholinesterase inhibition. Secondary direct therapeutic interventions may be important features of a therapeutic regimen in treating persons with DS and AD, just as they are for SDAT.
One of our most significant observations is that individuals with DS and AD may have a more robust response to cholinergic intervention than do persons who suffer from SDAT and are treated with the same single agent. This appears to be the case based on our clinical experience with donepezil.
In 1997 donepezil, a reversible cholinesterase inhibitor was introduced to the healthcare market in the United States for the treatment of mild to moderate SDAT. Its primary effect is to inhibit the enzyme acetylcholinesterase, thereby making acetylcholine more readily available as a neurotransmitter to do the work of memory. In several clinical trials, donepezil had been studied in hundreds of subjects with SDAT, where it has been shown to be effective for some patients in improving cognitive deficits. This preparation is considered a palliative treatment that may temporarily halt further cognitive decline.
As of this writing there have been only two published reports of a clinical trial using a cholinesterase inhibitor in persons with DS and AD (Kishnani et al., 1999; Hemingway-Eltomey & Lerner, 1999). In the first, more significant of the two reports, investigators conducted an open label trial of donepezil. In this study two subjects met the DSM-IV criteria of dementia and two subjects were diagnosed as possibly having dementia. This study confirmed the possible beneficial effects of cholinergic therapy. Additionally, the report showed no clinically significant medical problems that would be unique to persons with DS. One important conclusion was that the authors felt that their results strongly argued for wider clinical trials of cholinergic therapy for this condition in persons with DS.
In our neurodevelopmental psychiatry clinic, we began using donepezil as innovative therapy in February of 1997 for persons with DS and mild to moderate dementia. Currently, (March, 2000) the first two people with DS and dementia who were started on donepezil continue to function at a significantly higher level than before treatment. This sustained improvement in cognitive deficits for more than three years is much greater than that reported for geriatric patients with SDAT. We continue to use donepezil as our first line intervention for this condition.
No therapeutic intervention has been scientifically established to be safe, tolerable and effective specifically for AD in persons with DS. Only three cholinesterase inhibitors are currently approved in the U.S. for AD, donepezil, rivastigmine and tacrine. Many other agents are being studied for the treatment of SDAT, and one of these, galantamine, will probably soon be approved by the U.S. Food and Drug Administration.
Theoretical treatment options currently applied by some geriatric psychiatrists for the treatment of AD include free radical scavengers or anti-oxidants such as Vitamin E, estrogen not indicated as hormone replacement therapy, and anti-inflammatory medications. None are curative, and even palliative results for second line options are merely speculative at this point. The safest and easiest to administer is Vitamin E. Many unanswered questions exist regarding the use of estrogen for relatively young persons for whom the risk of exposure may be measured in years. Current nonsteroidal anti-inflammatory agents (NSAIDs) such as ibuprofen may pose a significant risk for gastro-intestinal (GI) disorders in persons with limited self-reporting skills. The recent introduction of the NSAID medications that selectively inhibit cyclooxygenase-2 (COX), sparing COX-1, such as rofecoxib and celecoxib, are reported to be statistically safer with regard to GI disorders. Their possible beneficial role in central nervous system inflammatory processes is unknown. Another potent anti-inflammatory agent with a possibly beneficial profile is thalidomide. Clinical trials are currently underway studying this highly regulated investigational drug for SDAT.
Clearly many significant unanswered questions remain to be answered in our understanding of the pathogenesis of neurodegenerative disorders, particularly in regard to the dementia associated with DS and SDAT. No curative interventions exist at this time for these disorders, but there are reasonably safe and effective therapeutic options that may stabilize or improve the state of these dementing disorders. Currently, cholinergic medications offer the best chance to improve the quality of life for persons with DS. The potential remains for new cholinergic modalities to be even more effective than current options. Recent advances in our understanding of the role of inflammatory cellular processes within the central nervous system have a significant potential to further improve the currently available treatment options.
Hemingway-Eltomey, J. M., & Lerner, A. J., 1999. Adverse effects of donepezil in treating Alzheimers disease associated with Downs syndrome [letter]. American Journal of Psychiatry, 156, 1470.
Kishnani, P. S., Sullivan, J. A., Walter, B. K., Spiridigliozzi, G. A., Doraiswamy, P. M., & Krishnan, K. R. (1999). Cholinergic therapy for Downs syndrome.
Lancet, 353, 1064-1065.
Tyrrell, J., Cosgrave, M., Hawi, Z., McPherson, J., OBrien, C., McCalvert,J., McLaughlin, M., Lawlor, B., & Gill, M. (1998). A protective effect of apolipoprotein E e2 allele on dementia in Downs syndrome. Biological Psychiatry, 43, 397-400.
For further information, please contact:
Mark H. Fleisher, M.D.
Associated Professor of Psychiatry
Director, Neurodevelopmental Psychiatry Clinic
985578 Nebraska Medical Center
Omaha, NE, 68198-5578