Individuals with trisomy 21, or Down syndrome (DS), develop a clinical syndrome of dementia that has the same clinical and neuropathologic characteristics of AD as described in individuals without DS. The only difference is the early age of onset of AD in individuals with DS. These patients present with clinical symptoms in their late 40s or early 50s.
Pathophysiology: The reason AD is more frequent in individuals with DS is not known. All recognized mutations and some risk factors (age, head trauma) for AD are associated with increased production of amyloid beta. Amyloid beta-42, a neurotoxic fragment of the amyloid precursor protein (APP), is released when APP is catabolized. This accumulation results in selective and progressive loss of neurons due to poorly understood mechanisms. The hippocampus, amygdala, and mesotemporal regions are affected most frequently, followed by other neocortical areas.
Cells that produce neurotransmitters in the nucleus basalis of Meynert (acetylcholine), locus ceruleus (epinephrine), and midbrain raphe nuclei (serotonin) also are affected. This is consistent with the clinical presentation. This process involves a certain degree of asymmetry, which explains the protean clinical characteristics. Individuals with greater frontal and temporal lobe damage may experience increased agitation and psychiatric disorders. Individuals with greater damage in the left hemisphere may experience language disturbances. Neuronal death is followed by disease of related neurons, probably due to lack of neurotrophic factors. A certain degree of neuronal plasticity provides a limited balance, keeping the individual functioning at a normal level for a period of time, although the disease process is active.
A complementary hypothesis suggests that different thresholds exist for the presentation of clinical symptoms, depending on the cognitive reserve of the individual. Greater brain weight, larger number of neurons, and higher educational level may increase cognitive reserve.
ased on these 2 interrelated hypotheses, DS individuals develop symptoms earlier in life because of their increased production of amyloid beta-42 and their smaller cognitive reserve.
Frequency:
- In the US: Several studies document that most if not all individuals with DS develop AD. This is unrelated to the degree of mental retardation; AD is not more prominent in individuals with mental retardation from other causes. Due to better clinical management, most persons with DS now reach the age of 40 years. Thus, the frequency of AD is likely to increase.
he percentage of people with DS and AD varies in some of the epidemiologic studies presented. A review of these studies showed that 10-25% of patients had AD when aged 40-49 years, 20-50% had AD when aged 50-59 years, and 60-75% had AD when older than 60 years.
- Internationally: No particular geographic distribution exists. A similar clinical picture has been described in other countries.
Mortality/Morbidity: The disease is responsible for the sharp decline in survival in DS patients older than 45 years.
Race: No documentation exists that race influences prevalence.
Sex: Few studies have evaluated the influence of sex, and some of the results are contradictory. For example, sex was not associated with earlier onset in some studies, while other studies found that women were at increased risk of earlier onset than men. Some earlier conclusions are presented below.
- Women with DS who are aged 40-65 years are at a higher risk for AD than men with DS who are of comparable age.
- Women with DS and menopause at age 46 years or younger had earlier onset and increased risk of AD than those with menopause after age 46 years.
Age:
- Age and the presence of trisomy 21 are the most important factors in disease development.
- The neuropathologic findings related to AD have been described in all DS individuals older than 35 years.
- Early clinical signs and symptoms are observed at the end of the fifth decade to the beginning of the sixth decade of life. Mean age at the time of clinical diagnosis is 51 ± 6 years.
Medical Care: The following medications have been used or found to be useful in AD. Only one (donepezil) was evaluated in individuals with DS.
- Cholinesterase inhibitors - Tacrine, donepezil, rivastigmine, galantamine.
- Antioxidants - Alpha-tocopherol (vitamin E) and selegiline
- Estrogen replacement therapy
- NSAIDs and COX-2 inhibitors
- N-methyl-D-aspartate antagonists (NMDA)
Surgical Care:
- Some patients may require placement of a feeding tube.
- Some patients may need a tracheostomy.
Consultations:
- Consult a neurologist and/or gerontologist for diagnosis, advice, and follow-up care.
- Consult rehabilitation specialists.
- In advanced stages, consult an ethics specialist regarding decisions for resuscitation and/or hospice care.
Diet:
- No particular diet is required. As the disease progresses, dysphagia may become a prominent feature and changes in food texture usually are recommended. A dietitian's help may be needed at this stage.
- n advanced stages, limited intake may be associated with severe weight loss. At this point, consider a feeding tube.
Medication
The following medications have been recommended or used in individuals with AD. The cholinesterase inhibitor donepezil is the only drug investigated in individuals with DS. A few studies in persons with DS and AD have reported that donepezil slowed down the progression of the disorder and/or improved the condition somewhat. Some studies reported adverse effects, such as urinary incontinence; however, other studies found tolerance to be very good.
Drug Category: Cholinesterase inhibitors -- The nucleus basalis of Meynert degenerates in AD, leading to a deficiency in CAT that results in deficient production of ACh in the cerebral cortex. This cholinergic deficiency is associated with behavioral changes, mainly memory dysfunction, observed in AD. Inhibitors of AChE, the enzyme that metabolizes ACh, may improve symptoms of AD. These drugs do not have clinically significant drug-drug interactions. These drugs can exacerbate stomach ulcers, asthma, and cardiac arrhythmias.
Drug Name | Tacrine (Cognex) -- Indicated in early stages of dementia; centrally acting, reversible cholinesterase inhibitor that slows degradation of ACh produced by remaining cholinergic neurons; these effects in turn increase ACh concentrations in cerebral cortex. Use is very limited because of adverse effects. |
---|---|
Adult Dose | 10 mg PO qid; increase by 40 mg/d with adjustments q6wk; not to exceed 160 mg/d |
Pediatric Dose | Disease state not seen in children |
Contraindications | Documented hypersensitivity; history of jaundice (>3 mg/dL bilirubin) associated with tacrine |
Interactions | Inhibits hepatic microsomal enzyme CYP450 and potentiates theophylline and cimetidine effects; increases toxicity of cholinesterase inhibitors, succinylcholine, or cholinergic agonists; antagonized by cigarette smoke; concomitant administration of NSAIDs may cause GI bleeding |
Pregnancy | C - Safety for use during pregnancy has not been established. |
Precautions | Caution in bladder outlet obstruction, sick sinus syndrome, cardiovascular disease, peptic ulcer, and asthma; increased serum transaminases may occur |
Drug Name | Donepezil (Aricept) -- Noncompetitively inhibits centrally active AChE, which in turn may increase concentrations of ACh available for synaptic transmission in CNS; indicated in mild forms of AD. The only drug with clinical trials in persons with DS. |
---|---|
Adult Dose | Initially 5 mg/d PO hs; may increase up to 10 mg qhs after 4-6 wk |
Pediatric Dose | Disease state not seen in children |
Contraindications | Documented hypersensitivity |
Interactions | Agents that affect CYP450, CYP2D6, and CYP3A4 enzymes may affect rate of elimination; antagonizes anticholinergic medications; effects of succinylcholine, cholinesterase inhibitors, or cholinergic agonists are increased when administered concurrently; monitor for GI bleeding when using concomitantly with NSAIDs |
Pregnancy | C - Safety for use during pregnancy has not been established. |
Precautions | Caution in sick sinus syndrome, other supraventricular cardiac conduction disorders, or asthma |
Drug Name | Rivastigmine (Exelon) -- Indicated in mild-to-moderate dementia. Competitive and reversible inhibitor of acetylcholinesterase. While mechanism of action unknown, may reversibly inhibit cholinesterase, which may in turn increase concentrations of ACh available for synaptic transmission in CNS and enhance cholinergic function. Effect may lessen as disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that acetylcholinesterase inhibitors alter the course of underlying dementia. |
---|---|
Adult Dose | Initially 1.5 mg bid; if tolerated, increase by 1.5 mg bid q2wk; usual range, 6-12 mg; not to exceed 12 mg/d; take with meals |
Pediatric Dose | Disease state not seen in children |
Contraindications | Documented hypersensitivity |
Interactions | May reduce effects of anticholinergics; increases effects of cholinergic agonists and neuromuscular blockers; risk of bradycardia increases when administered concurrently with beta-blockers without ISA, calcium channel blockers diltiazem or verapamil, or digoxin |
Pregnancy | B - Usually safe but benefits must outweigh the risks. |
Precautions | May cause significant nausea, vomiting, anorexia, and weight loss (occurs frequently during titration phase, and in women); if significant adverse effects occur, patient should discontinue treatment for several doses, then restart at same or next lower dose; if treatment stopped for several days, initiate treatment at lowest daily dose; caution in history of peptic ulcer disease, concurrent NSAID use, sick sinus syndrome, urinary obstruction, pulmonary conditions such as COPD or asthma, and bradycardia or supraventricular conduction conditions |
Drug Name | Galantamine (Reminyl) -- Indicated in AD. Recent studies showed some benefits in vascular dementia and vascular dementia combined with AD. |
---|---|
Adult Dose | Initially, 4 mg bid for 1 mo; if well tolerated, increase by 4 mg bid qmo; not to exceed 12 mg bid; take with meals |
Pediatric Dose | Disease state not seen in children |
Contraindications | Documented hypersensitivity; severe renal dysfunction (ie, <10> |
Interactions | Coadministration with other cholinesterase inhibitors (eg, succinylcholine) may increase toxicity; CYP450-2D6 or -3A4 inhibitors (eg, cimetidine, ketoconazole, ritonavir, paroxetine, erythromycin) may decrease elimination and increase serum levels |
Pregnancy | B - Usually safe but benefits must outweigh the risks. |
Precautions | Decrease dose in moderate renal insufficiency or moderate-to-severe hepatic impairment; caution in asthma; may cause bradycardia or AV block; syncope may occur with doses >24 mg/d; cholinergic adverse effects are dose related |
Drug Name | Selegiline (Eldepryl) -- An irreversible MAOI that has been used experimentally in treating AD; acts as a "suicide" substrate for the enzyme where MAO converts it to an active moiety that combines irreversibly with active site or enzyme's essential FAD cofactor; blocks breakdown of dopamine; in parkinsonism, extends duration of action from each dose of L-dopa; often allows for L-dopa dose reduction; because of greater affinity for type B than for type A active sites, can serve as a selective inhibitor of MAO type B at recommended dose; however, at doses >10 mg/d, significant MAO-A inhibition may occur; no evidence that additional benefit is obtained from doses >10 mg/d. A large double-blind placebo-control study failed to showed any benefit in slowing the progression of the disease. No studies in DS have been reported. |
---|---|
Adult Dose | Initially 5 mg PO qd, increased gradually up to 10 mg/d |
Pediatric Dose | Disease state not seen in children |
Contraindications | Concomitant use of opioids (eg, meperidine); concurrent administration of SSRIs; antidepressants can probably be used, although concerns exist regarding rare interactions |
Interactions | At least 3-5 wk should lapse between discontinuation of fluoxetine and initiation of MAOIs to prevent fatal interactions that have been reported with MAO type A inhibitors; in general, avoid administering MAOIs concomitantly with opioids; severe agitation, hallucinations, and death have occurred with concomitant administration with meperidine |
Pregnancy | C - Safety for use during pregnancy has not been established. |
Precautions | Adverse effects include nausea, dizziness, and syncope |
Drug Name | Alpha-tocopherol (vitamin E, Vita-Plus E, E-Complex-600) -- Protects polyunsaturated fatty acids in cell membranes from attack by free radicals. No studies published using vitamin E in DS. One study involving persons with DS is in progress. A double-blind, placebo-controlled trial with 2000 IU of vitamin E suggested that vitamin E delayed admission to nursing home, functional decline, and death but did not affect cognitive decline in persons with moderate-to-severe AD. Vitamin E 2000 IU/d is considered standard therapy for persons with AD; however, a government panel recommended a lower dose of no more than 1000 IU because of the possibility of coagulation disorders. |
---|---|
Adult Dose | 2000 IU PO qd has been used in the treatment of AD (daily requirement is 10-30 mg/d) |
Pediatric Dose | Disease state not seen in children |
Contraindications | Documented hypersensitivity |
Interactions | Increases effect of PO anticoagulants; mineral oil decreases absorption when used concomitantly; delays absorption of iron |
Pregnancy | A - Safe in pregnancy |
Precautions | May induce vitamin K deficiency; large doses have been associated with necrotizing enterocolitis |
Drug Name | Memantine (Namenda, Axura) -- Indicated for moderate-to-severe Alzheimer disease. NNMDA antagonist. NMDA receptor stimulation in the CNS by glutamate (an excitatory amino acid) is hypothesized to contribute to Alzheimer symptoms. |
---|---|
Adult Dose | 5 mg PO qd initially; gradually titrate to a 20-mg/d target dose using following dosage regimen (allow >1 wk between each dosage increase): 5 mg PO bid; then, 5 mg PO every am and 10 mg PO every pm; then, 10 mg PO bid |
Pediatric Dose | Disease state not seen in children |
Contraindications | Documented hypersensitivity |
Interactions | Coadministration with drugs causing alkaline urine (eg, sodium bicarbonate, carbonic anhydrase inhibitors) may decrease clearance by 80%; thus, accumulation and toxicity may occur; coadministration with other NMDA antagonists (eg, amantadine, ketamine, dextromethorphan) may increase toxicity risk; concurrent use with other drugs renally eliminated via tubular secretion (eg, hydrochlorothiazide, triamterene, cimetidine, ranitidine, quinidine, nicotine) may alter plasma levels of either drug |
Pregnancy | B - Usually safe but benefits must outweigh the risks. |
Precautions | Common adverse effects include dizziness (7%), headache (6%), and constipation (5%); predominantly excreted renally; no data support use in severe renal impairment |