Professional Documents
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or prevailing theories. Early therapeutic agents receiv- of older ones (physostigmine, tacrine,
ing approval included psychostimulants, ergoloids, galantamine, and metrifonate), the main
ta E,
da AS
vasodilators, and various drug cocktails. For example, problem confronting researchers was how
the ergot-alkaloid co-dergocrine mesylate (Hydergine) to best test their efficacy and safety in
ica MB
2
Table 1. Characteristics of clinical trials of AChE inhibitors and considerations when interpreting results.
Patient selection
Diagnosis ‘Probable AD’ DAT (DSM-IV criteria) or both, Criteria differ with respect to
(McKhann criteria) or sometimes no specific criteria impairment of social function
Concomitant medical Some stable medical Medical conditions and medications Highly variable criterion among AD
conditions conditions allowed allowed if not expected to interfere trials
with AD or assessment
Concomitant psychiatric No significant behavioral Occasionally, behavioral conditions Great degree of flexibility on the
conditions symptoms such as delusions, allowed if they do not interfere with part of the protocols and
agitations, or significant cognitive assessment investigators
depression
Age None Broad age ranges allowed. Mean age in AD are approximately
Minimums vary from 40–60; 70–72 years. May affect
maximum 80–90 years performance and illness course
Dementia severity 10–26 MMSE as high as 27 or as low May use broader ranges to better
on the MMSE as eight; occasional very narrow reflect actual AD populations.
ranges, e.g. 17–22, etc. Sometimes use more restrictive
ranges to ensure more mildly
impaired or more ‘testable’
patients
Trial designs
Parallel group Sometimes there is an open or Crossover designs difficult to
randomized withdrawal phase understand because of carry-over
and disease progression effects.
Main comparison is drug group
versus placebo group. Open
phase is not controlled and must
not be over interpreted
Duration of trial 24–26 weeks 12–52 weeks Longer trials more likely to be
clinically relevant because allow
time for the placebo group to
worsen. Twelve-week trials used
as pivotal with both tacrine and
donepezil; 26 weeks used as
pivotal for rivastigmine
Intervention groups Two treatments and one One treatment and one placebo; Multiple groups allow assessment
placebo group; some fixed dosages of a dose-response relationship;
ability to adjust dosage two groups may allow investigators
to know treatment assignment;
fixed doses often lead to
underdosing and/or higher rates
of side effects
Sample size 500–600 200–800 Varies depending on number of
(approximately) treatment groups, sites, intent.
Larger sample more likely to show
statistical significance
Outcomes
Cognitive Alzheimer’s Disease Total ADAS; other ADAS-Cog has become
Assessment Scale- neuropsychological subscales standard. When interpreting
Cognitive subscale or batteries; the SKT differences both the changes
from baseline and the difference
between drugs and placebo
group should be inspected
Clinical global Interview-based With or without informant interview Experienced clinician may
Impression of Change CIBIC, CIBIC+, ADCS-CGIC, assess meaningful clinical change
NYU-CIBIC+ on a 7-point scale
ADL Progressive Deterioration Other ADL scales such as the ADL scales vary in their metric
Scale ADCS-ADL, IDDD, DADS quantities and sensitivity to change
Extension phase Open treatment Open withdrawal
3
Continued on page 4
1. Purpose and overall quality of the trial to be absolute improvement over baseline in the treat-
Early clinical trials are often of small size, shorter ment group in order to show statistical significance as
duration, and use highly selected patients and limited the placebo group does not decline over this period of
dosages. Their purpose is to assess for evidence of time. However, 6-month trials can take advantage of
efficacy and safety to proceed to more definitive trials. the expected decline in the placebo group, and hence
They are often published after the drug is licensed, to the treatment effect is a combination of improvement
add further evidence to the pivotal trial results. Phase with medication and deterioration with placebo.
III trials are definitive efficacy studies used for licens-
ing approval and are usually performed over a period 4. Outcomes
of 3 or 6 months (see below). Outcomes measured using both the ADAS-Cog and a
CGIC should show statistically significant improve-
2. Patient selection ments for registration purposes in the USA. In addi-
Typically, the criteria listed in Table 2 are used for tion, statistically significant ADL or behavioral benefits
patient inclusion and exclusion in pivotal phase III on validated scales are required by European and
trials of new therapeutic agents for AD. Clinicians Canadian authorities. After the assessment of efficacy,
reviewing such criteria should be aware that they do safety considerations become important.
not always yield a representative group of AD
patients, typical of the population as a whole [13]. For 5. Statistics and reporting
example, ‘real world’ AD patients often present with When looking at the statistics and reporting of clinical
co-morbid medical conditions requiring polyphar- trials a number of questions should be asked:
macy, suffer behavioral problems such as delusions,
agitation or aggression, or are too cognitively Was the assignment of patients to treatment random-
impaired to participate in phase II or III trials. ized throughout the trial and the period being
Therefore the critical issue is the extent to which reported?
results of trials containing highly selected groups of In AD trials, randomization is nearly always performed
patients can be generalized to the population seen by at least initially, and thus allows for a valid contempor-
physicians in the community. In a recent study we aneous comparison. However, there is sometimes a
found that less than 10% of AD out-patients enrolled pre-randomization selection phase. In addition, the
in several California AD diagnostic clinics would have end of the trial often includes a non-randomized
fulfilled criteria to enter the typical phase III AD clinical follow-up period. Results from the latter should be
trials [13]. interpreted cautiously since patients who continue in
the follow-up phase may represent a population who
3. Trial designs do better on medication or have slower rates of
Pivotal studies of AD therapies should conform to a decline than the initial patient population.
placebo-controlled, parallel-group design of at least
6 months duration. Although some of the pivotal trials Were all the patients who entered the trial accounted
used to evaluate tacrine and donepezil were of and attributed for in the conclusions?
12 weeks’ duration, these are now considered to be In some studies, only patients who complete the trial
too short. This is because in 3-month trials there has are included in the statistical analysis. This could result
in an assessment which is biased.
However, it should be noted that in
Table 2. Typical standard inclusion and exclusion criteria for conventional AD studies. addition to adverse events and
perceived lack of efficacy, patients
Inclusion criteria*
often drop out of studies because of
● Presence of probable AD (NINCDS-ADRDA criteria) [6]
study design issues such as an unreal-
● MMSE score between 10–26 [3]
istic dosage regimen or assessment
● Modified ischemic score <5 [14]
demands.
● CT or MRI scan consistent with AD and showing no evidence of focal lesions
● Good physical health (confirmed by medical history, physical examination,
Were the treatment groups similar at
neurological examination, ECG and laboratory tests) other than dementia
the beginning of the trial?
● Normal blood pressure
Randomization can sometimes fail,
● Minimum educational level to complete the tests
resulting in differences between drug
● Outpatient status
and placebo groups in characteristics
● Presence of a responsible caregiver
such as age or test performance.
Exclusion criteria Unfortunately the use of statistics to
● History of psychiatric or neurological conditions ‘correct’ for such differences can alter
● Concurrent physical illness the effect size or p value of the study.
● Abnormal laboratory findings This failure is sometimes seen in
*Will vary from trial to trial smaller studies. For example, in the
vitamin E/selegiline study reported by
4
Sano, et al., corrections for variations in cognitive
function between the treatment groups at baseline Table 3. A checklist for evaluating published articles.
resulted in significantly different reported outcomes
● Who were the subjects? How were they selected?
[10].
● What was the intervention? Was it randomized?
● Was the study of long enough duration to accomplish
What were the actual results? its intended purpose?
Often results of studies are reported as ‘p values’ with ● Were patients, health workers and study personnel
authors emphasizing very low values for example ‘blind’ to treatment?
‘p=0.00001.’ It should be remembered that results ● How was treatment tolerated? What proportion finished
are more than a p value, that p values can be manipu- the study?
lated by changing the statistical model transforming ● Were patients analyzed in the groups to which they
were randomized?
data, and changing the sample size and do not reflect
● Did the analysis compare patients in the treatment
magnitude of effect. Results of studies should be group(s) with those in the placebo group?
examined with respect to the actual estimates of the ● Were all clinically important outcomes considered?
effect sizes. ● Did the author report the magnitudes of therapeutic
effects? Were side effects fully reported?
How large was the treatment effect? ● Were the results of the study valid?
Effect sizes help a clinician to judge how ‘large’ a thera- ● Will the results help me in caring for my patients?
peutic effect is. One way to look at size of effect is to ● Can the results be applied to my patients?
estimate the difference in response rates (or event rates) ● Are the likely treatment benefits worth the potential
harm costs?
between drug and placebo. For example, one study
might report that 80% of patients responded to med-
ication and that 60% responded to placebo. Another
might report that 40% responded to drug and 20% to
placebo. These two studies have approximately similar Conclusions
magnitudes of effect in that approximately 20 more On the basis of the above discussion, a checklist can be
patients out of 100 treated are benefiting from drug proposed to evaluate reports of AD trials (Table 3).
therapy in either study. However, the first study appears
superficially to have a larger effect size because of The process of asking and answering these questions
the 80% ‘response rate’ to drug. High placebo could help clinicians to better interpret the reported
response rates are often ignored – pharmaceutical results of clinical trials, and better assess whether or not
marketers understand this point, and clinicians should the results apply to their patients.
also.
5
Continued on page 8
Assessing and monitoring
ADL in clinical practice
an interview with Dr Douglas Galasko
Dr Galasko is currently Assistant Professor of Neurosciences at the University of California, San
Diego. His main interests are the diagnosis, clinical assessment and treatment of Alzheimer’s disease
(AD). He has recently collaborated with a group of dementia specialists to develop a detailed
inventory for measuring activities of daily living (ADL) in AD through the AD Co-operative Study.
Assessments of functional ability are becoming an would be appropriate for use in AD. However it should
essential part of the diagnostic process of dementia be noted that an ADL battery designed specifically for
and in the evaluation of response to treatment inter- AD would be likely to contain a better pool of infor-
vention with therapeutic agents. Traditionally, treat- mation, and I would recommend the use of such scales
ment for AD had been targeted at cognitive function. when assessing and monitoring instrumental ADL.
However, prospective data from studies with
cholinesterase inhibitors (tacrine and, more recently, What ADL-specific scales have been used in clinical
rivastigmine) have shown a direct benefit of drug trials examining pharmacotherapy? Can the results
treatment on ADL. Alzheimer Insights recently spoke to be translated into everyday clinical practice?
Dr Galasko about new developments in the assess- At present there is a lack of consensus on which
ment and monitoring of ADL in clinical practice. instruments should be used to assess ADL. This has
resulted in a variety of scales being employed in clini-
Can you comment briefly on the sequential loss of cal trials. The majority of the instruments are caregiver
ADL seen over the clinical course of AD? questionnaires from which ADL scores are derived.
Functional loss in AD follows a fairly predictable Examples include the Progressive Deterioration Scale
course with impairments often divided into two (PDS) [1], the Physical Self-Maintenance Scale (PSMS)
groups – instrumental and basic ADL. Instrumental [2], and the Interview for Deterioration in Daily Living
ADL, which comprise complex activities, tend to be Activities in Dementia (IDDD) scale [3]. Results from
impaired early in the course of the disease. Examples studies with certain cholinesterase inhibitors have
include managing finances, shopping and carrying out shown that in patients who receive treatment, ADL
hobbies and pastimes. Later in the course of the dis- performance stabilizes and in some cases slightly
ease, basic ADL become impaired. These are more fun- improves, while the placebo group shows decline.
damental over-learned tasks required for self-care such Although these scales used in clinical trials are
as dressing, washing, eating, and toileting. not ideal for clinical practice, the principle of track-
ing change in a key group of ADL over time is
Are there any functional losses, which may alert the useful. In addition, the concept that treatment of
physician to the presence of mild cognitive symptomatic AD cases with certain cholinesterase
impairment? inhibitors may lead to ADL maintenance, may be use-
Mild cognitive impairment is a strong predictor of AD ful for clinical practice.
and may be the earliest recognizable stage. The
degree of functional impairment at this stage may be Can features of specific scales be developed for use
minimal. Key items the physician should focus on as simple and quick standardized tools for use in
would include driving ability, performance in work, clinical practice?
ability to balance a checkbook or manage finances The first step in developing a tool in this way would
and difficulties in remembering appointments. be to identify which items within the scales are the
most sensitive to tracking change. This could be done
Is it important for the physician to use ADL scales by statistical techniques or by cross-comparisons of a
designed specifically for AD patients, or can number of studies. The wordings and rating methods
clinicians use scales developed for geriatric used in clinical trial scales are usually not ideal or con-
patients or for medical patients in general? sistent for translation into a day-to-day user-friendly
Regardless of why the scale was developed, provided scale. One way to overcome this problem would be to
it can be shown to track progression and measure sub-divide activities in terms of assistance needed by
functional impairment in a group of AD patients, it the patient.
6
In your opinion, which instrument is preferable – Assessment Questionnaire [6] are suitable for use in
one which uses direct observation of the patients or clinical practice. A number of instruments are currently
one which uses questionnaires aimed at caregivers? under development as a result of their use in clinical
Each of these methods has advantages and draw- trials. For example, the IDDD has been modified in
backs. Direct observation simulates the performance order to promote its more widespread use, and other
of a select group of ADL items, such as using a tele- more detailed batteries are being refined and shortened.
phone or making change in an office setting. This
allows direct observation of the patient’s performance, What would be the criteria for an ideal ‘GP friendly’
which can be scored. However, this approach is often ADL tool to assess the effects of pharmacotherapy
time consuming and samples a relatively small set of for AD patients in the clinic?
ADL. In addition, a patient’s performance in an office The ideal battery should be relatively brief, compre-
may be different to that at home. For these reasons I hensive, and designed so that it can be completed by
would recommend clinicians to use caregiver ques- the informant in the waiting room or by specialist
tionnaires. They are generally more comprehensive nursing staff if physician time is scarce. It should also
and capture patients’ actual behavior over a longer be sensitive enough to capture the patients’ current
interval of time. However, the wording of question- ability as well as monitoring change over time. Finally
naires needs to be crafted carefully in order to accu- it should contain a mixture of instrumental and basic
rately record information. activities. At present none of the available scales meet
these criteria. However, combining one of the basic
What are the most important basic criteria to ADL scales with a modified instrumental scale would
consider when choosing a functional assessment satisfy most of the requirements I have discussed.
scale?
Firstly, I would target the scale to the population of Will ADL assessment and monitoring become
patients – for example patients may be community- common clinical practice in the future?
based or institutionalized. Similarly in a clinical study, At present, the monitoring and assessing of ADL in
the level of cognitive function and the goals and dura- clinical practice is still in its infancy. Indeed, issues
tion of the study should be considered. The scale should regarding the role of GPs in monitoring cognitive
include activities that cover an appropriate range of change are only now permeating into the general prac-
functioning. If a wide spectrum of patients are to be tice environment. However, I believe that recent studies
assessed the scale should be broad and comprehensive. on AD do suggest a value of using some type of struc-
If a group of institutionalized patients are being moni- tured ADL scale to obtain reliable and predictable
tored the scale could be more selective. Other issues I information to supplement cognitive monitoring.
would consider include the ease of use of the scale, the
reliability of the information collected, whether the ADL
scores correlate with other measures such as cognition,
and the ability of the scale to measure change over a
. . . recent studies on AD do suggest a
period of time. In terms of the scale’s ability to measure value of using some type of structured
specific functional difficulties, I would suggest that the ADL scale to obtain reliable and
most important issue would be the ability of the scale
to provide an index of the patient’s overall level of func-
predictable information . . .
tional ability and degree of independence.
References
1. DeJong R, et al. Measurement of quality-of-life changes
. . . the Blessed Dementia Scale, the in patients with Alzheimer’s disease. Clin Ther 1989; 11:
545–554.
Lawton-Brody Instrument and the
2. Lawton MP, Brody E. Assessment of older people: self-
Functional Assessment Questionnaire maintaining and instrumental activities of daily living.
are suitable for use in clinical practice. Gerontologist 1969; 179–186.
3. Teunisse S, et al. Assessing the severity of dementia:
patient and caregiver. Arch Neurol 1991; 48: 274–277.
4. Katz S, et al. The index of ADL: a standardized measure
Are any standardized ADL tools available to of biological and psychosocial function. J Am Med Assoc
assess/monitor ADL in clinical practice? 1963; 185: 914–919.
Several instruments have been developed to measure 5. Blessed G, et al. The association between quantitative
basic ADL, all of which are similar in content. Two measures of dementia and of senile change in the cere-
examples include the Katz ADL scale [4] and the bral grey matter of elderly subjects. Br J Psychiatry
Physical Self-Maintenance Scale [2]. Currently few 1968; 114: 797–811.
instruments exist to measure instrumental ADL. Of 6. Pfeffer RI, et al. Measurement of Functional Activities in
those available, the Blessed Dementia Scale [5], the older adults in the community. J Gerontol 1982;
Lawton-Brody Instrument [2] and the Functional 37: 323–329.
7
Continued from page 5
8. Rosen WG, et al. A new rating scale for the Alzheimer’s of the literature. Aust NZ J Psychiatry 1986; 20(2):
disease. Am J Psychiatry 1984; 141: 1356–1364. 237–240.
9. Schneider LS, et al. Validity and reliability of the 12. Qizilbash N, et al. Cholinesterase inhibition for
Alzheimer’s Disease Cooperative Study-Clinical Global Alzheimer disease: a meta-analysis of the tacrine trials.
Impression of Change. The Alzheimer’s Disease Dementia Trialists’ Collaboration. J Am Med Assoc
Cooperative Study. Alzheimer Dis Assoc Disord 1997; 1998; 280(20): 1777–1782.
11(Suppl 2): S22–S32. 13. Schneider LS, et al. Eligibility of Alzheimer’s disease
10. Sano M, et al. A controlled trial of selegiline, α-toco- clinical patients for clinical trials. J Am Geriatr Soc
pherol or both as treatment for Alzheimer’s disease. 1997; 45(8): 923–928.
N Engl J Med 1997; 336: 1216–1222. 14. Rosen WG, et al. Pathological verification of ischemic
11. Jorm AF. Effects of cholinergic enhancement therapies on score in differentiation of dementias. Ann Neurol 1980;
memory function in Alzheimer’s disease: a meta-analysis 7(5): 486–487.1984; 34: 939–944.
8
Alzheimer images
How do acetylcholinesterase inhibitors interact with the enzyme in the brain? Molecular models of
acetylcholine, rivastigmine, tacrine and donepezil
The X-ray structure of acetylcholinesterase (AChE) iso- donepezil and AChE as well as interactions of both
lated from Torpedo californica was solved by the aromatic rings of donepezil with aromatic amino acids
group of Sussman, et al. at the Weizmann Institute in of the AChE are predicted (Figure 4) [5]. The com-
1991 [1]. Because of the very fast reaction of ACh pound hinders the interaction of ACh in the active
with AChE, the natural neurotransmitter could not be center and inhibits reversibly its breakdown.
co-crystallized with the protein. Therefore the
Weizmann group simulated the docking situation of References
ACh with AChE (Figure 1). On the basis of these data 1. Sussman JL, et al. Atomic structure of acetyl-
deposited in the Brookhaven Protein Data Bank (entry cholinesterase from Torpedo californica: a prototypic
1ACE), we built a molecular model of the adduct of acetylcholine-binding protein. Science 1991; 253:
872–879.
rivastigmine to the X-ray structure of AChE, to under-
stand its mode of inhibition in more detail (Figure 2) [2]. 2. Enz A, Floersheim P. Cholinesterase inhibitors: an
overview of their mechanisms of action. In: Becker R,
The final state of this simulation leads to a geometry
Giacobini E, editors. Alzheimer’s Disease: From
of low energy in which the non-covalent interaction
Molecular Biology to Therapy. Boston: Birkhäuser, 1996;
between rivastigmine and the residues in the active 212–215.
center were retained. The figure shows one possible
3. Harel M, et al. Quaternary ligand binding to aromatic
mode by which rivastigmine fits into the active site of residues in the active-site gorge of acetylcholinesterase.
AChE, fulfilling chemical and structural requirements Proc Nat Acad Sci 1993; 90: 9031–9035.
for stereoselective active-site-directed inhibition. The 4. Pang Y-P, Kozikowski AP. Prediction of the binding of
experimental structure of the AChE/tacrine complex E2020 in acetylcholinesterase by docking studies with
show a strong interaction of the aromatic moieties the SYSDOC program. In: Sanz F, et al., editors. QSAR
bound solely to the hydrophobic sites (Figure 3) [3]. and Molecular Modeling: Concepts Computational Tools
and Biological Applications. Prous Science Publishers,
In a similar way we modeled the binding of donepezil 1995; 562–566.
to AChE. The geometry of the final model with the low- 5. Enz A, Floersheim P, unpublished.
est energy resembled closely the geometry reported by
Pang and Kozikowski [4]. Polar interactions between Images supplied by Dr Albert Enz, Novartis Pharma AG, Basel, Switzerland
Figure 1. Acetylcholine (Model: Sussman, et al. [1]). Figure 2. Rivastigmine (Model: Enz and Floersheim [2]).
Figure 3. Tacrine (Model: Harel, et al. [3]). Figure 4. Donepezil (Model: Enz and Floersheim [5]).
9
Clinical interpretation and
application of genetic tests in
Alzheimer’s disease
Professor G. Wilcock, Frenchay Hospital, University of Bristol, Bristol, UK
Gordon Wilcock is Chair in Care of the Elderly at the University of Bristol, UK. His current interests
include the selection, development and evaluation and new therapeutic approaches to AD and
research into the relevance of genetic factors to disease expression and the response to therapy.
Understanding the genetics of Alzheimer’s disease (APO) E-ε4 allele. Associations between many other
(AD) has become both complex and controversial, genes and sporadic AD have been reported. Some
since many of the more recent findings are not consis- involve polymorphisms, i.e. naturally occurring varia-
tently confirmed. This can make it difficult for those tions in gene structure, rather than mutations. One of
without an in-depth understanding of current genetic these is butyryl cholinesterase, an enzyme involved in
techniques to appreciate the relevance and implica- the breakdown of acetylcholine, an important neuro-
tions of such results to daily clinical practice. transmitter that is reduced in the AD brain. For many
others a clear association seems less obvious, e.g.
We have come a long way since John Hardy’s group polymorphisms in the genes for angiotensin convert-
first reported a mutation in a sub-group of families ing enzyme, α1 antichymotrypsin and bleomycin
with early-onset autosomal dominant AD linked to hydrolase – although reasonable hypothetical associa-
chromosome 21 [1]. This defect in the amyloid precur- tions exist for each case.
sor protein (APP) gene, together with others in the
same gene, and also mutations on chromosomes 1 Recently, a new mutation has been described involving
and 14, are now known to account for some 30% to a gene on chromosome 12 [2] – a common variant of
40% of early-onset familial AD (FAD) (Figure 1). the gene for a protein called α2 macroglobulin. It is
However, a large number of genetic risk factors prob- found in about 20% of the general population, and
ably exist and contribute to the development of AD the authors report that it confers a similar degree of
in most non-familial cases. risk for AD to that associated with APOE-ε4. However,
this finding has not been confirmed by all
investigators.
N N
1 2 3 4 5 6 7 1 2 3 4 5 6 7
C C
These genetic findings are extremely
Presenilin 2 Presenilin 1
important to our understanding of the
chromosome 1 chromosome 14 pathology of AD, and the development of
treatment, but we may fairly ask what is
their current relevance to the clinician in
general practice?
beta/A4
APO-E APP 751
LRP LRP
lipid
The mutations in the APP gene on chromo-
OUT IN
10
practice at present. Although some could emerge as statements have been issued. In general, it is agreed
important factors in the development or rate of pro- that:
gression of AD, this is not yet sufficiently well estab- ● APOE genotyping is not recommended as a means
lished for any of them to be relevant for screening or of predicting future risk of AD in individuals who
testing programs. are symptom-free
● APOE genotyping may be a useful adjunct to diag-
Apolipoprotein E nosis in a symptomatic person, but it should not
The gene for APOE exists in three allelic variations, ε2, be used as the sole diagnostic test
ε3 and ε4. One of these, APOE-ε4, is indisputably ● It is essential to remember that disclosure of geno-
linked to late-onset AD, and there have been debates type has implications in respect of access to coun-
as to whether it could help predict the risk of develop- selling and support, and practical issues such as
ing the disease, or be of diagnostic utility. This insurability and employability of the individuals
association was first reported in 1993 [3] and has concerned.
since been confirmed in many studies. However, it has
become clear that possession of the ε4 allele is neither Therefore, it is debatable whether at present, routine
necessary nor sufficient to cause the disease. Hence, it APOE genotyping is appropriate for diagnosis,
must be considered a risk factor, that may well interact although it remains an extremely important area for
with other genetic or environmental factors before the research.
disease develops. APOE-ε4 could interact with some
In conclusion, genetic testing is clearly of value in
of the other associated genetic factors mentioned
appropriate contexts in relation to early-onset FAD,
above, or with environmental factors such as toxins or
and extremely important in these and all other cases
viruses, and a link with a herpes simplex virus (HSV-1)
for research purposes. However, genetic testing
has been suggested [4]. However, further investigation
requires further refinement before it can be applied to
of these potential interacting factors is required.
routine clinical practice.
In brief
Cognitive deficits predate symptoms in familial scores on tests of verbal memory and performance IQ
Alzheimer’s disease by several years 1–5 years before becoming symptomatic compared
with subjects who remained well (p=0.003 and p=0.03,
Measurable cognitive decline is present 2–3 years respectively). The Mini-Mental State Examination
before symptoms appear, and 4–5 years before indi- (MMSE) was found to be insensitive to change at this
viduals fulfill the criteria for probable Alzheimer’s dis- early stage. Similarly, visual inspection of early MRI
ease (AD) according to a recent investigation by Fox, scans was found not to predict dementia. However,
et al. reported in Brain [1]. The prospective study, the authors argued that measurable neuropsychologi-
performed over a 6-year period in asymptomatic indi- cal deficits must reflect neuronal dysfunction or death,
viduals at risk of familial AD, showed that 10 subjects which may be detectable with improved imaging tech-
who went on to develop AD had significantly reduced niques or biochemical markers. Which combination of
11
Continued on page 12
tests is of greatest diagnostic use in an individual case Modest delays in Alzheimer’s disease onset
remains to be determined – although the inclusion of are of significant benefit
verbal memory function tests may be of benefit. In
conclusion, detection of early changes in cognitive Modest delays in disease onset can have a significant
function may pave the way for therapeutic intervention impact in terms of reducing the growing burdens and
at a stage when most cognitive function is still preserved. costs associated with Alzheimer’s disease (AD),
according to a report in the American Journal of
Rivastigmine for Alzheimer’s disease: a review Public Health [3]. The study aimed to project the
of three studies future prevalence and incidence of AD in the US and
quantify the potential impact of disease-delaying
In a supplement to the International Journal of interventions using a model which used age-specific
Geriatric Psychopharmacology focusing on improved incidence rates. The authors estimated the number of
treatment options in Alzheimer’s disease (AD), Americans with AD in 1997 at 2.32 million (range
Schneider, et al. [2] review the pooled results of three 1.09–4.58 million) and predicted that the number
phase III trials in the international clinical program for was likely to increase four-fold over the next 50 years.
rivastigmine (Exelon®). The authors note that riva- They noted that therapeutic intervention could delay
stigmine, a ‘pseudo-irreversible’, sub-type selective the onset of AD by approximately 5 years and reduce
inhibitor of acetylcholinesterase, has been investigated the expected prevalence by 1.15 million after
in the largest clinical trial program conducted to date 10 years (2007) and 4.04 million after 50 years
for an antidementia medication – the three trials (2047). Of note, a modest 6-month delay, achiev-
reviewed here included 2,126 patients with mild-to- able with some of the currently available therapies,
moderately severe probable AD. Patients were rep- could result in nearly 100,000 and 380,000 fewer
resentative of those typically encountered in routine persons afflicted with AD than projected after 10
clinical practice and were treated for 26 weeks with a and 50 years, respectively. Brookmeyer, et al. cal-
flexible dose range of rivastigmine (6–12 mg/day or culate that this may correspond to an annual saving
1–4 mg/day), a fixed-dose regimen, or placebo. In all of US $4.7 billion at 10 years after the initiation of
three trials, rivastigmine-treated patients showed sig- the intervention – and nearly US $18 billion annually
nificant benefit on measures of cognition (Alzheimer’s after 50 years.
Disease Assessment Scale – cognitive subscale) and
the clinician’s assessment of change (Clinician
Interview-Based Impression of Change incorporating References
1. Fox NC, et al. Presymptomatic cognitive deficits in indi-
caregiver information). In the two pivotal trials viduals at risk of familial Alzheimer’s disease: a longitudi-
patients also showed significant improvement in activ- nal prospective study. Brain 1998; 121: 1631–1639.
ities of daily living (e.g. performing chores, dressing
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The opinions expressed in this publication are those of the authors and are not to be construed as the opinions or
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