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Figure 1. Major Areas of the Brain Figure 2. Brain Changes in Preclinical Alzheimer’s
Disease
Corpus Callosum Cerebral Cortex
Cerebral
Cortex
Thalamus
Hypothalamus
Cerebellum
Hippocampus
Brain Stem
Hippocampus Entorhinal
Cortex
Side view of the brain Reprinted with permission from Alzheimer’s Disease Education and Referral
Center Web site. Available at: http://www.alzheimers.org/unraveling/04.htm.
Accessed June 17, 2005.1
Copyright ©2002, Christy Krames.
Dementia patients also appear to have reduced num- nases COX-1 and COX-2, in the AD brain.28 It is inter-
bers of glutamate reuptake sites or abnormal expres- esting to note that the inflammation in AD is chronic
sion of a glutamate transporter, which may be linked and localized to discrete areas of the brain, as are the
to NFT formation.22,23 other types of cellular damage with AD.29
Donepezil Mild to moderate 5 mg or 10 mg; treatment with a 10-mg dose Nausea, diarrhea, insomnia, vomiting, muscle
should not be considered until patients have been cramps, fatigue, and anorexia
on a daily dose of 5 mg for 4 to 6 weeks to avoid
adverse events
Rivastigmine Mild to moderate 3–6 mg twice daily; starting dose: 1.5 mg twice daily; Nausea, vomiting, loss of appetite, dyspepsia,
increase to 3 mg twice daily after 2 weeks; other asthenia, and weight loss
dose increases should be separated by at least 2 weeks
Galantamine Mild to moderate 8–12 mg twice daily, preferably with morning and Nausea and vomiting
evening meals; 24 mg/d may provide additional
benefit for some patients, but it is associated with
more adverse events; starting dose: 4 mg twice daily;
increase to initial maintenance dose after at least 4 weeks
Memantine Moderate to severe Target dose: 20 mg/day; starting dose: 5 mg/day; Confusion, dizziness, headache, and constipation
titration: increase in 5-mg increments to 10 mg/d (5 mg
twice daily), 15 mg/d (5 mg and 10 mg as separate
doses), 20 mg/d (10 mg twice daily); minimum
recommended interval between dose increases is
1 week; can be taken with or without food
*Tacrine continues to remain on the market, but it is rarely used because of its potential hepatotoxicity and other adverse events.
†Based on clinical studies.
AD = Alzheimer’s disease.
Data from Donepezil US prescribing information38; Galantamine US prescribing information39; Memantine US prescribing information40; Rivastigmine US prescribing information.41
months. Current studies of AD drugs are focusing on sus 0.82 ± 0.71 (rivastigmine) and -8.0 (historical place-
longer follow-up, other AD-related indications (eg, bo) versus -3.8 (rivastigmine).52,53 In the 2-year study, cog-
mild cognitive impairment [MCI] and more severe nitive decline slowed by 35% in those patients receiving
stages of AD), nursing home placement, vascular risk rivastigmine compared to a historical placebo group.54
factors, and the pathophysiology of AD. Improvement with rivastigmine was also observed in a
subgroup of moderately severe patients.55 The long-term
Long-term follow-up efficacy of galantamine was shown in 3 studies. In an
There has been 1 long-term study of donepezil that 18.5-month study, patients taking galantamine enjoyed
extended to 4.9 years, an extension of an original 14- sustained cognitive benefits during the entire study dura-
week study.42 The results showed evidence of clinical tion.56 In two 3-year studies, galantamine was associated
benefit (ie, maintenance of baseline scores for cogni- with a roughly 50% slower cognitive decline compared to
tion measures) during the first 6 to 9 months of open- predicted rates of decline in a clinically similar historical
label treatment, with gradual cognitive decline after 9 control sample of patients with AD.57,58
months. The treatment group was compared to histor-
ical controls, which was a serious methodological Disease severity
problem for this study. The rate of cognitive decline Donepezil has shown significant benefit on mea-
throughout the nearly 5-year study was slower for sures of cognition compared to placebo in patients
those patients receiving donepezil than the estimates with “early stage” (mild) AD.59 An important observa-
for patients who had not been treated.51 The benefits tion in this study population is that the placebo group
with rivastigmine have been shown in studies of 1- and showed virtually no signs of cognitive decline (as mea-
2-years’ duration. In the 1-year studies, differences in sured by the Mini-Mental State Examination
cognitive decline as measured by the AD assessment [MMSE]) during the study period, whereas in studies
scale-cognitive subscale were -4.45 ± 0.8 (placebo) ver- of patients with mild to moderate AD, patients receiv-
ing placebo showed cognitive decline in MMSE scores donepezil tended to stabilize over time, rather than to
during the study.59 Therefore, the extent of observed improve over baseline, “suggesting that clinicians
donepezil benefit may depend on the level of AD should aim for stability rather than actual improve-
severity. At the other end of the severity spectrum, ment in ADLs.”64 This is an important message to con-
donepezil was compared to placebo in patients with vey to patients and their caregivers as AD progresses
moderate to severe AD and showed significant benefit and they consider treatment with a cholinesterase
in cognition measures at all time points during the 6- inhibitor. Another study showed not only slower
month study.60 decline in ADLs and IADLs with donepezil treatment
Two studies have analyzed the effect of rivastigmine but also less decline in the components required for
based on disease severity, but from a different approach. completing each ADL (initiation, planning and orga-
In a 1-year study, patients were classified as slowly pro- nization, and effective performance).65 Caregiver bur-
gressive or rapidly progressive, based on the magnitude den was also measured as time required with the
of response seen in the first 6 months of the study. The patient for ADLs/IADLs and stress levels. Caregivers
final results showed notable and significant differences in reported spending a mean of 52.4 fewer minutes/day
response to rivastigmine between these 2 groups of on ADLs and 17.2 fewer minutes/day on IADLs with
patients, with patients who were rapidly progressive donepezil-treated patients. Almost all components of
obtaining greater benefit from rivastigmine treatment.61 the caregiver stress scale favored donepezil. The
In a 12-month study of patients with mild AD or MCI, authors also noted the importance of stabilizing cogni-
cognitive function was slightly improved or maintained tive function because the placebo group did not show
in the patients with mild AD and unchanged or slightly a floor effect (ie, patients never reached a point at
worsened in the patients with MCI (both groups receiv- which further decline was not measurable).65
ing rivastigmine); cognitive function was markedly wors- Rivastigmine has beneficial effects on ADLs, as
ened in untreated patients with AD.62 shown in a retrospective analysis of 3 studies.66 Also,
ADL impairment differed across the stages of AD.
Functional measures Table 2 lists the ADLs with a significant change from
Researchers are now turning to more “clinically rel- baseline based on 3 levels of severity.66
evant” outcomes, such as functional decline (ie, ability A secondary analysis of a 5-month study showed that
to perform activities of daily living [ADLs] or instru- galantamine treatment resulted in little or no decline
mental ADLs [IADLs]), nursing home placement, and from baseline in ADL measures compared to significant
effect on caregiver burden. ADLs focus on basic func- decline in the placebo group.48,67 Galantamine treatment
tioning, such as toileting, feeding, dressing, bathing, resulted in maintenance or improvement in ADL and
walking, and grooming. IADLs are more complex IADL measures, with significant improvement over
activities, which most adults of normal mental capaci- placebo in 3 of 6 basic ADLs (toileting, bathing, and
ty can perform, such as operating household appli- grooming) and 6 of 17 IADLs (conversation, managing
ances, paying bills and managing money, shopping, personal belongings, current events, writing, hobbies,
preparing meals, and participation in hobbies. The and operating household appliances).67 ADL stabiliza-
effect on ADLs is important for several reasons. ADLs tion was seen throughout the range of AD severity, but
instill and maintain a sense of independence and self- the greatest differences were observed in those patients
efficiency, which is critical for patients’ and caregivers’ with severe disease.67
quality of life. In AD, loss of ADLs is enduring and is Regarding caregiver time, galantamine also has
a significant predictor of institutionalization.63 notable effects. Pooled data from two 6-month studies
Therefore, preservation of ADLs is a critical outcome show that caregivers reported spending a mean of 32
with important and permanent ramifications. fewer minutes per day with galantamine-treated
A 1-year study of donepezil versus placebo suggest- patients than with placebo-treated patients, a savings
ed that donepezil use may have effects on delaying loss of approximately 3.5 hours per week. In patients with
of ADLs. Patients taking donepezil were 31% less like- moderate AD, the benefits were even greater—a mean
ly to experience functional decline (ie, losing the abil- daily time savings of 53 minutes or more than 6 hours
ity to perform an ADL or IADL) than those taking per week. Similarly, galantamine-treated patients could
placebo.64 The authors noted that patients on spend 27 more minutes per day unsupervised and, in the
moderate AD group, the benefit was extended to spend- Jakimovich, in which donepezil was administered to a
ing 68 more minutes per day unsupervised.68 patient with severe AD, behavioral problems, and sev-
The profound consequences of maintaining ADLs eral comorbidities following admission to a long-term
is illustrated in a case study from Tariot and care facility.69 The positive effects of donepezil treat-
Table 2. ADLs Affected Based on Degree of AD Severity with Rivastigmine or Placebo Treatment
This table shows the ADLs as listed in the PDS that were significantly changed from baseline during the study in the observed cases dataset. AD severity was measured
by the GDS and divided into 3 groups. As the GDS score increases, the severity of AD increases.
*Indicates P <.05 for rivastigmine versus placebo in the intent-to-treat dataset.
AD = Alzheimer’s disease; ADL = activity of daily living; GDS = Global Deterioration Scale; PDS = Progressive Deterioration Scale.
Reprinted with permission from Potkin et al. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:713-720.66
ment included engagement in meaningful conversa- behavior. If no change is observed, a different drug in
tions about family events and current events seen on this class can be tried.
television, although he was amnesic for details; coher-
ent periods of (factually correct) reminiscence on his Head-to-head comparisons
life; and improved ability to perform ADLs, including Direct comparisons of cholinesterase inhibitors are
independent toileting, reduced belligerent and sexual- rare in the published literature. A comparison of galan-
ly inappropriate behavior, discontinuation of haloperi- tamine to donepezil revealed no significant differences
dol, ability to travel to a family event, and restoration between the 2 treatment groups at study end (52
of walking ability; none of which were possible when weeks) in measures of ADLs and neuropsychiatric
he was admitted to the nursing facility.69 symptoms.72 However, cognition measures showed a
greater benefit with galantamine treatment, maintain-
Nursing home placement ing baseline levels with galantamine but worsening
Nursing home placement is another important mile- with donepezil.72
stone in AD progression. The desire and decision to
place patients with AD in full-time nursing care varies Cholinesterase inhibitors and anticholinergic drugs
with each patient (based on severity of disease and neu- Anticholinergic drugs are part of many therapeutic
ropsychiatric symptoms) and the caregiver’s circum- drug classes and are commonly prescribed. They are
stances, including financial resources and caregiver notorious for producing undesirable cognitive effects,
ability. In general, families probably prefer to keep the to which patients with AD are especially sensitive.
patient at home as long as possible. Conversely, some Their concurrent use is likely to negate any of the cog-
caregivers would prefer to place a patient under full- nitive benefit with cholinesterase inhibition. A cross-
time professional care, but cannot afford to do so. If the sectional study of Iowa Medicaid beneficiaries aged 50
patient is a widow/er and the adult children live far years and older indicated that a surprising 35.4% of
away, the preference may be for earlier placement these patients received concurrent anticholinergic
because geographic constraints prohibit at-home care. agents with cholinesterase inhibitors. Roughly 33% of
Studies of cholinesterase inhibitors’ effect on nursing patients received an anticholinergic agent within 90
home placement have yielded mixed results, possibly days (before or after) of starting the cholinesterase
because of these varying influential factors. inhibitor.73 Nurses should evaluate their patients’ drug
One study of donepezil versus placebo estimated profiles at each visit, especially when a cholinesterase
(conservatively) that proper use of donepezil over 9 to inhibitor is prescribed, to avoid this unfortunate situ-
12 months (ie, therapeutic doses and high compliance ation. Negating the effects of cholinesterase inhibitors
rates) resulted in a delay of nursing home placement of incurs significant burden and cost to the patient and
21.4 months for a first-time dementia-related place- the healthcare industry.
ment and 17.5 months for permanent placement.70
The authors note that “doctors and caregivers need to NMDA ANTAGONISTS
be educated that, in the same way as the actual bene- Memantine is the only NMDA antagonist
fits of treating hypertension or hyperlipidemia are seen approved for the treatment of AD. Its efficacy was
only after years of treatment, treatment of AD with demonstrated in 2 randomized, double-blind, place-
donepezil needs to be maintained to see important bo-controlled studies in the United States.74,75 In addi-
long-term benefits.”70 A study in the United Kingdom tion to those studies, memantine was compared to
of donepezil showed no difference in institutionaliza- placebo in patients already receiving stable doses of
tion after 3 years of follow-up, but the decision to donepezil and showed an added benefit when coad-
place patients in nursing homes or even to treat with a ministered with this cholinesterase inhibitor, with
cholinesterase inhibitor was based on different factors regard to measures of cognition, ADLs, global out-
from those in the US healthcare system.71 In clinical come, and behavior.75 An oral solution of memantine
practice, a typical drug trial for a cholinesterase was recently approved by the FDA, which offers an
inhibitor would be approximately 4 months (for titra- alternative that may make administration easier for
tion up to the therapeutic and best-tolerated dose) to patients who have trouble swallowing tablets or prefer
see some stabilization in memory, function, and/or taking medication in liquid form.
some recent case-control studies suggest decreased risk of the meantime, we have 4 drugs with proven efficacy,
AD with statins, but this is not fully supported by albeit modest, in at least some patients with AD.
prospective studies.86-88 Statins may offer a neuroprotec- Although some may argue, based on clinical studies,
tive or anti-inflammatory effect, rather than prevent that the effect of cholinesterase inhibitors or meman-
accumulation of β-amyloid plaques.85 tine is minimal, in reality any preservation of function
There are limited clinical studies of statins for AD. and delay of nursing home placement in an individual
Atorvastatin showed some clinical benefit in cognition patient has important and permanent consequences.
after 1 year of treatment (compared to placebo), but The primary care nurse, in identifying and managing
the difference was not statistically significant.89 It a patient with AD, needs to understand each of the
should be noted that this was a pilot study; the final following aspects of AD treatment: the expected out-
participant numbers at 12 months were low (n = 46).89 comes with these drugs and their impact on the
Another study of simvastatin (6 months) showed sig- patient and caregiver, the importance of reiterating
nificant reductions in cerebrospinal fluid levels of these expectations to the patient and caregiver, the
some but not all AD-related proteins (eg, tau, phos- common concurrent prescribing of cholinesterase
phorylated tau, β amyloid, and other proteins) and inhibitors with anticholinergic drugs in older adults,
slight improvement in cognition.90 Clearly, more stud- the use of newer agents as possible preventive treat-
ies are needed, but thus far data do not support a role ments for AD, and any updates in recommended treat-
for statins in the treatment of AD. ment strategies from leading medical organizations.
Because of the profound and sometimes rapid loss of
THERAPEUTIC CHOICES memory and function with AD, the importance of try-
The American Psychiatric Association and the ing at least 1 of these treatments in a patient with AD
American Academy of Neurology (AAN) have published cannot be overstated.
consensus guidelines on the treatment of patients with
dementia.91-93 The American Geriatrics Society has
endorsed the AAN guidelines, and guidelines for family
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