News & Views Archives

Issue No. 3, Spring 2005

Many parents have contacted us for information on a range of topics from the use of vitamin supplements to the development of Alzheimer’s disease. These are just the kind of requests we need, because it shows us what your real concerns are. We will try to address these topics in the News & Views section of our website. The topic for our current issue was inspired by a phone call from a mother who inquired about the drug donepezil and its application in people with Down syndrome. We hope that you will find this review informative.

For those of you living in the Bay Area, you may find Via Rehabilitation Services a great resource. Among many services, Via operates a camp and recreation facility for children and adults (ages 5 and older) with physical and developmental disabilities called camp Costanoan. Ten one week camp sessions are offered during the summer, and respite weekends run from October to May. Of particular interest may be the one-week session (July 24 - 29) designed specifically for individuals with Down syndrome aged 8-20 years. This session will focus on physical activity and sport skill development. For more information, please call Camp and Recreation Director Rick Frazier at (408) 243-7861.

In the spotlight

The Use of Donepezil in Down Syndrome
By Sietske Heyn, Ph.D.

Before going into details about donepezil in Down syndrome, it will be useful to describe what we have learned so far from its use in Alzheimer’s disease (AD). AD is a neurodegenerative disorder characterized by a gradual and relentless progression of cognitive, functional and behavioral deficits (McKhann et al., 1984). The exact cause and development of AD is not known. However, in the early phases of the disease, one can already find a cholinergic deficit in the brain (Davies & Maloney, 1976; Bowen et al., 1976). The cholinergic system consists of a network of cells, mainly located in the cortex and hippocampus. These cells communicate primarily through the neurotransmitter acetylcholine (ACh) and play a major role in higher cognitive functions such as learning, memory and attention.

According to the cholinergic hypothesis (for review see Francis et al., 1999; Bartus, 2000), the symptoms of AD are directly related to the degeneration of cholinergic neurons. How does such a deficit lead to cognitive impairments in AD? ACh is a neurotransmitter released from synapses in the cholinergic system that enhances normal neurotransmission (See left panel in Figure 2). This enhancement is a necessary part of learning, memory and attention. When levels of ACh decrease, as is the case in AD, cognitive abilities decline, because communication between synapses is compromised.

Figure 2. 1) Normal neurotransmission: ACh (blue dots) is released from the presynaptic nerve terminal (cell1), diffuses through the synaptic cleft and binds to receptors on the postsynaptic terminal (cell2). 2a) After synaptic transmission, ACh is removed from the synaptic cleft via degradation by AChE. 2b) AChE inhibitors suppress AChE, thereby prolonging the time that ACh is available for binding to receptors on the postsynaptic terminal.

The cholinergic hypothesis led to the idea that perhaps one could ameliorate the cholinergic deficit by increasing the amount of available ACh. Normally, once ACh has conveyed its message, an enzyme called acetylcholinesterase (AChE) breaks ACh down into its constituents so that it can be recycled and reused (See Figure 2a). Reagents were sought that would prevent cholinesterase from cleaning up ACh, thereby prolonging its availability for communication between cells (See Figure 2b).

To date, four so called cholinesterase inhibitors have been approved for clinical use in AD (For a review see Ibach and Haen, 2004 and Francis et al., 1999). The first of these was tacrine (Cognex), followed by donepezil (Aricept), rivastigmine (Exelon) and galantamine (Reminyl). Today, tacrine has fallen out of favor due to liver toxicity. The other three agents are widely used in the AD population. All inhibitors appear to have a modest effect in improving symptoms of AD by slowing down the speed by which the disease develops. However, not all people benefit from taking cholinesterase inhibitors. Generally, these drugs appear to be well tolerated, with minimal side effects (Francis et al., 1999).

Figure 3. Example of a synapse. Electron micograph of excitatory spiny synapses (s) formed on the dendrites of a rodent hippocampal pyramidal cell. The presynaptic bouton contains many small synaptic vesicles filled with neurotransmitters. Neurotransmitters are released at the synaptic junction (darkly stained areas) by the fusion of these vesicles with the plasma membrane. The neurotransmitter then binds to receptors on the postsynaptic terminals formed on these spines.

What does all of the above have to do with Down syndrome? Unfortunately, most people with Down syndrome develop neuropathology consistent with AD when they get older (For a review see Oliver and Holland, 1986). How many individuals with Down syndrome actually develop signs of dementia due to this pathology is still not clear (Zigman et al., 1996). Since AD and Down syndrome share cholinergic dysfunction of the brain, and cholinesterase inhibitors may have some benefits for people with AD, it is not unreasonable to assume that people with Down syndrome may benefit from these drugs as well. In contrast to the general AD population (Ibach and Haen, 2004), there have only been a handful of studies so far examining the effect of cholinesterase inhibitors in Down syndrome (For a review see Prasher, 2004). With the exception of one very recent report on rivastigmine (Prasher et al., 2005), all these studies have focused on donepezil.

The first such studies discussed mostly the safety and tolerability of the drug in older individuals (Age range 22-65 years). In general, donepezil appears to be well tolerated in people with Down syndrome (Kishnani et al., 1999; Kishnani et al., 2001; Lott et al., 2002; Heller et al., 2003; Heller et al., 2004; Kondoh et al., 2005; Prasher et al. 2002). Most of the adverse events were mild, transient and dose-related. However, several groups reported that some individuals had to discontinue therapy, due to intolerable adverse effects such as agitation, aggressions, urinary incontinence, forgetfulness, abdominal pain, vomiting and diarrhea (Hemingway-Eltomey and Lerner, 1999; Cipriani et al., 2002; Prasher et al., 2002). In some studies, individuals tolerated donepezil at 3 mg (Kondoh et al., 2005) or 5 mg, but could not tolerate 10 mg (Prasher et al., 2002), which is the maximum dose prescribed for people with AD without Down syndrome. Several researchers have suggested that since people with Down syndrome appear to be more sensitive to this treatment, keeping people on 5 mg for a longer period of time (6 weeks instead of one week) before increasing the dose to 10 mg may prevent the occurrence of some more severe side effects (Kishnani et al., 2001; Kondoh et al., 2005). Interestingly, many of the side effects were also noted in the placebo group, albeit at a lower frequency (Prasher et al., 2002).

Most studies report that there is a therapeutic effect of donepezil in some individuals with Down syndrome and AD (Kondoh et al., 2005, Prasher et al., 2002; Kishnani et al., 1999; Prasher et al., 2003; Lott et al., 2002; Heller et al., 2003; Heller et al., 2004). Positive effects include a reduction in the deterioration of cognitive functioning, neuropsychiatric symptoms and in adaptive skills (For a review see Prasher, 2004). However, not all individuals respond to donepezil. In one study (Pasher et al., 2002) for example, about 50% of individuals showed some cognitive improvement while taking donepezil. In the same study, 31% of individuals who were taking a placebo also improved. In another study (Kishnani et al., 1999) three out of four individuals showed some sign of cognitive improvement.

Recently, a few researchers have started testing donepezil in younger individuals with Down syndrome (Heller et al., 2003; Heller et al., 2004), with the idea that perhaps donepezil may increase cognition, language competence and general quality of life in people with Down syndrome who are not yet showing signs of mental decline. In one 24-week open-label clinical trial (Heller et al., 2003), 6 individuals with Down syndrome aged 20 to 41 years were recruited to study the effect on certain language domains. An overall improvement in expressive language was observed. The researchers point out that there appears to be a correlation between IQ and improvement in language performance: the individuals with higher IQ at the outset of the study tended to benefit most from treatment. The researchers also point out that it is problematic to find appropriate language assessment tests for this population: the language tests for 5 to 6 year olds lack the content relevant to adults with DS.

Another 22-week pilot clinical trial (Heller et al., 2004) assessed the effect of donepezil on language in 7 children (aged 8 to13 years). Donepezil was dosed at 2.5 mg for 8 weeks and then increased to 5 mg for the remaining 8 weeks. No child experienced serious adverse side effects or withdrew from the study. Improvements were found in expressive and receptive language performance, with largest improvements in word and sentence structure subtests.

Currently, a randomized, doubled-blind, placebo-controlled trial is underway to study cognition and function in young adults (18- 35 years old) with Down syndrome (Selzter et al., 2004). 123 individuals were assigned to either donepezil or placebo. So far no serious adverse effects have been reported. Various cognitive assessments were taken before the study began, at 6 weeks and at 12 weeks. Results of the study have yet to be published. Dr. Barbara Sommer at Stanford University was part of the team involved in assessing some of the participating individuals. According to Dr. Sommer, donepezil - even in doses up to 10 mg - was safe in these young adults. The data is still being analyzed for publication. While larger studies will be necessary before making definitive comments on donepezil’s routine use in Down syndrome, this first placebo controlled study does point to positive trends in intellectual function, particularly in the older men (over 24) in this preliminary trial.

What can be concluded from the studies on donepezil in Down syndrome?

In interpreting therapeutic outcome of donepezil, one needs to consider that most of the studies in people with Down syndrome to date are pilot studies. Due to the small number of subjects in each trial or case study, none of them have enough statistical power to draw strong conclusions. In addition, each study is using different assessment parameters to evaluate the therapeutic effect of donepezil. Therefore, one cannot compare the potential cognitive or quality of life improvements between studies.

Despite somewhat differing experiences in various research groups, the overall conclusion from the limited number of studies is that donepezil may be beneficial in the treatment of AD in Down syndrome, as well as improve language skills and quality of life in younger adults without symptoms of dementia. Almost every published study to date suggests that larger trials are necessary to further assess the potential benefits of donepezil in individuals with Down syndrome.

A final word of caution: While donepezil and other cholinesterase inhibitors may improve cognition in some individuals with Down syndrome for a period of time, it is important to keep in mind that they will not halt the progress of the underlying disorder.


References

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