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ISSN 1360–8495 February 1999

Alzheimer Insi hts


A N I N T E R N A T I O N A L E D U C A T I O N A L N E W S L E T T E R
SCIENTIFIC EDITOR
Ezio Giacobini MD PhD, Geneva
EXECUTIVE EDITOR Volume 5, No. 1
Sara Caldwell BSc, Macclesfield
INSIDE
SENIOR EDITOR
Stephen Jones BSc, Macclesfield Assessing and monitoring ADL in clinical
EDITORIAL ASSISTANT
practice 6
Rachelle Comish, Macclesfield Alzheimer images 9
EDITORIAL BOARD
Lon S Schneider MD, Los Angeles Clinical interpretation and application of
Bengt Winblad MD PhD, Stockholm genetic tests in Alzheimer’s disease 10
Jacques Touchon MD, Montpellier
In brief 11
Lutz Frölich MD, Frankfurt

Interpreting and applying


clinical trial results in
Alzheimer’s disease
Professor Lon Schneider, University of Southern California (USC) School of
Medicine, USA
Lon Schneider is Professor of Psychiatry, Neurology and Gerontology at the USC. He is also a
member of the Board of Directors of the American Association for Geriatric Psychiatry and
participated on the American Psychiatric Association Committee for Practice Guidelines in
Alzheimer’s and Other Dementias.
The last decade has seen two major events in the clin- outcome measures, made interpretation of results from
ical pharmacology of Alzheimer’s disease (AD). The such trials difficult, even though many reported signif-
first, well documented in the scientific literature, has icant findings. Questions raised included:
been the advent of acetylcholinesterase (AChE)
inhibitors as a treatment for the cognitive signs and ● Who were the patients being treated?
symptoms of AD. The second, which has received less ● How were they selected?
attention, has been the standardization of clinical trial
● What outcomes were measured?
designs for antidementia drugs. These two ‘revolu-
tions’ are closely related. ● What was the duration of the response?
● Were the outcomes clinically relevant?
Historical considerations
Prior to the 1980s, treatments for dementia received With the development of new AChE inhibitors (such
approval based upon clinical experience, empiricism, as rivastigmine and donepezil), and the renaissance
se e
ba th

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

was approved by the US Food and Drugs clinical trials.


ed E

Administration (FDA) for the treatment of ‘senile men-


M in

tal decline’ [1]. Such diagnostic vagueness coupled


ta ed

with the lack of pathological models and inappropriate Continued on page 2


rp ex
ce d
Ex w in
No
Regulatory and methodological concerns impression of change rating such as one of several
The increase in the number of potential treatments for clinical global impressions of change (CGIC) scales [9]
AD led to regulatory bodies paying greater attention has become the measure of clinical meaningfulness.
to methodological aspects of clinical trials. After con-
sultation with experts in the field of AD and drug One of the major limitations to the FDA de facto stan-
development, the US FDA proposed a draft set dards is that improvements in functional activities or
of guidelines for the development of AD drug behavior are not recognized therapeutic goals.
treatments [2]. In brief, guidelines required that trials However, behavioral symptoms are present in most
use double-blind, placebo-controlled, parallel-group patients with dementia and improved functional status
designs; patients meet accepted diagnostic criteria for may have a major impact on prolonging the indepen-
primary dementia, and finally that improvement on an dence of the patient [10]. Such limitations have to
accepted cognitive instrument should be judged to be some degree been addressed by the Canadian Health
clinically meaningful. Authority and the European Medical Evaluation
Authority (EMEA) by requiring that new antidementia
The requirement that a drug show clinically meaningful drugs show effects on ADL or behavior in addition to
effects was proposed to address concerns that small cognitive benefits. Such measures have been used in
but measurable drug-related memory improvement more recent pivotal trials for AChE inhibitors e.g. the
may be observed on psychometric scales. For US regu- benefits of rivastigmine on ADL have been evaluated
latory purposes, behavioral or functional changes (e.g. prospectively using the domain-specific Progressive
performance of activities of daily living [ADL]) and Deterioration Scale (PDS).
brief cognitive screening measures, such as the Mini-
Mental State Examination (MMSE) [3] were of sec- Experimental study designs
ondary importance, even though observed behavioral The majority of early clinical trials examining the effi-
changes could be considered to be as clinically mean- cacy of antidementia agents were non-standardized.
ingful as changes in cognition. Differences among trials included patient numbers,
dose of medication, duration of therapy, outcomes
In 1993, the AChE inhibitor tacrine was approved in investigated, statistical analysis employed, and use of
the US on the basis of results from two ‘adequate and either parallel-group or crossover designs. These ele-
well controlled studies’ of 12 and 30 weeks duration, ments are critical to the interpretation of clinical
which fulfilled the FDA’s draft criteria. Subsequently, in results, as they determine the apparent magnitude and
late 1996, donepezil was approved on the basis of statistical significance of reported response rates.
similar criteria, this time using a 12- and 24-week
trial. For example, the various study designs and outcome
measures employed in clinical trials with the AChE
Diagnosis inhibitor physostigmine resulted in difficulties in inter-
The advent and acceptance of research-based diag- preting the drug’s effects. The majority of studies
nostic criteria for AD [4–6] together with an improved included small sample sizes, used crossover designs
understanding of the underlying pathology of the dis- and a variety of cognitive and behavioral batteries.
ease (in part involving cholinergic neurodegeneration), This led to the unsatisfactory use of a meta-analysis
provided the initial framework for the design of new to evaluate the agent’s overall effect [11]. Similar
strategies and clinical trials. Such diagnostic criteria problems were observed in the clinical development
were reliable and valid in terms of reproducibility, and of tacrine. Although the agent was approved by the
correlated with the neuropathology of AD and the FDA based on one 30-week and one 12-week clinical
clinical progression of the disease [7]. trial, the variety of different trial designs and out-
comes used by various investigators hampered clinical
Choice of outcomes assessment of the drug effects which varied greatly
Previous studies with nootropics and ergoloid deriva- from trial to trial. Such issues with tacrine have
tives measured a variety of behavioral symptoms and been discussed recently in a publication by Qizilbash,
various aspects of cognition. Unfortunately, such et al. [12].
measures were made using clinician-administered
scales which combined ratings of individual functions Interpreting results
into one total score. In addition the scales did not Following the approval of tacrine, the designs of clini-
utilize psychometric assessments or principles. cal trials examining new therapeutic agents for AD
have become standardized. Important, albeit subtle,
In antidementia drug trials, the Alzheimer’s Disease variations amongst trials have led to differences in
Assessment Scale – cognitive subscale (ADAS-Cog) [8] reported results, however (Table 1).
has become the standard cognitive/neuropsychological
change measure. The reason for this may simply be a Consideration of the overall trial is an important first
matter of precedence – this was the scale used in the step in interpreting results. This can be done using a
tacrine trials. In addition, a clinician’s interview-based series of stages which are listed on pages 4 and 5.

2
Table 1. Characteristics of clinical trials of AChE inhibitors and considerations when interpreting results.

Criterion Typical ‘standard’ Variations Comment

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

Statistics Often the most confusing

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.

A related way of understanding an ‘effect size’ when a References


researcher reports the proportion of patients improved 1. Schneider LS, Olin JT. Overview of clinical trials of
is knowing the ‘number to treat’ i.e., the number of hydergine in dementia. Arch Neurol 1994; 51(8):
patients needed to be treated for one patient to benefit 787–798.
(or to prevent one bad outcome). In mathematical terms 2. Leber P. Guidelines for the clinical evaluation of anti-
it is the inverse of the ‘response difference’ between the dementia drugs, 1st draft. Rockville, MD: US Food and
drug and placebo response rate. For example, in each Drug Administration, 1990.
of the examples above, five patients need to be treated 3. Folstein MF, et al. ‘Mini-mental state’. A practical
(1/(0.80–0.60 and 1/(0.40–0.20), respectively) in order method of grading the cognitive state of patients for the
for one to benefit. clinician. J Psychiatr Res 1975; 12: 189–198.
4. American Psychiatric Association. Diagnostic and statist-
How precise was the estimate of the treatment effect? ical manual of mental disorders, 3rd edition, revised.
In some cases, when the mean difference between drug Washington DC: American Psychiatric Association,
1987.
and placebo is large there can still be a high degree of
variability in response among patients. This is indicated 5. American Psychiatric Association. Diagnostic and statist-
ical manual of mental disorders, 4th edition, revised.
by the presence of a wide standard deviation or a broad
Washington DC: American Psychiatric Association,
confidence interval around the mean difference in the 1994.
outcome measure (the 95% confidence interval indi-
6. McKhann G, et al. Clinical diagnosis of Alzheimer’s dis-
cates the range within which the ‘true’ value is likely to ease: report of the NINCDS-ADRDA work group under
lie with 95% certainty). Broader confidence intervals the auspices of the Department of Health and Human
indicate greater probabilities of random errors in the Services task force on Alzheimer’s disease. Neurology
outcomes. The heterogeneity of AD, sample selection, 1984; 34: 939–944.
and imperfect outcome procedures or instruments can 7. Mirra SS. The CERAD neuropathology protocol and con-
all contribute to this uncertainty. The mean difference sensus recommendations for the postmortem diagnosis
in scores needs to be examined in the context of the of Alzheimer’s disease: a commentary. Neurobiol Aging
variability. 1997; 18(4 Suppl): S91–S94.

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.

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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.

1999 meetings calendar


14–17 March 12th Annual Meeting of the American Association for Geriatric Psychiatry,
New Orleans, Louisiana, USA
11–14 April International Congress on Clinical Pharmacy, Orlando, Florida, USA
17–24 April 51st Meeting of the American Academy of Neurology, Toronto, Ontario, Canada
12–16 May 54th Annual Convention of the Society of Biological Psychiatry, Washington,
DC, USA
15–20 May 152nd Annual Meeting of the American Psychiatric Association, Washington,
DC, USA
20–23 May 56th Annual Meeting of the American Geriatrics Society, Philadelphia,
Pennsylvania, USA
1–4 June 39th Annual Meeting of the New Clinical Drug Evaluation Unit (NCDEU),
Boca Raton, Florida, USA
5–9 June 9th Meeting of the European Neurological Society (ENS), Milan, Italy
30 June –2 July 9th Alzheimer Europe Meeting and Alzheimer’s Disease Society 20th
Anniversary Conference – ‘A Meeting of Minds: Care and Science in Dementia’,
London, UK
7–11 July 4th European Congress of Gerontology, Berlin, Germany
11–16 July 5th World Congress of Neuroscience, Jerusalem, Israel
6–11 August 11th World Congress of Psychiatry, Hamburg, Germany
15–21 August 9th Congress of the International Psychogeriatric Association, Vancouver,
British Columbia, Canada
7–11 September 4th Congress of the European Federation of Neurological Societies (EFNS),
Lisbon, Portugal
21–25 September 12th Congress of the European College of Neuropsychopharmacology (ECNP),
Lisbon, Portugal
3–6 October First International Congress on Vascular Dementia, Geneva, Switzerland

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

some 21, and the mutations on chromo-


APOE-e 4
APP somes 1 and 14, are sufficiently well
chromosome 19 chromosome 21 established to be used as the basis for
genetic screening in suspected cases of
early onset FAD. This is important to some
Figure 1. Genetic factors. members of affected families, and is helpful
when there is appropriate access to genetic
counselling and support. However, the muta-
Genes which do not cause early-onset FAD are prob- tions occur so infrequently that, at a clinical level, they
ably best considered as risk factors which do not are only relevant to members of the families involved.
inevitably lead to the disease, but which may increase
the likelihood of its development, or affect the age at Presently, with the exception of APOE polymorphisms,
which symptoms first appear. The most well estab- I would suggest that other putative genetic risk factor
lished of these ‘risk factor genes’ is the apolipoprotein genes are only of theoretical interest in routine clinical

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.

More recently, a study of just under 5,000 elderly indi- References


viduals, including nearly 700 aged 85 and over [5] 1. Goate A, et al. Segregation or a missense mutation in
suggested that the APOE genotype predicts not the amyloid precursor protein gene with familial
whether an individual will develop AD, but rather at Alzheimer’s disease. Nature 1991; 349: 704–706.
what age those individuals who are predisposed to 2. Blacker D, et al. Alpha-2 macroglobulin is genetically
develop it will show the onset of symptoms. associated with Alzheimer disease. Nature Gen 1998;
19: 357–360.
Although the APOE-ε4 allele is clearly of clinical rele- 3. Strittmatter WJ, et al. Apolipoprotein E: high avidity
binding to β-amyloid and increased frequency of type 4
vance – as it is present in, at most, 60–75% of all AD
allele in late-onset familial Alzheimer disease. Proc Natl
patients – it does not form a good basis for the
Acad Sci 1993; 90: 1977–1981.
screening of asymptomatic individuals. Therefore, is it
4. Itzhaki RF, et al. Herpes simplex virus type 1 in brain
helpful in improving our diagnostic accuracy? A recent
and risk for Alzheimer’s disease. Lancet 1997; 349:
study [6] concluded that APOE genotyping alone does 241–244.
not allow sufficient sensitivity or specificity to be used
5. Meyer MR, et al. APOE genotype predicts when – not
as a diagnostic test. However, when used with clinical whether – one is predisposed to develop Alzheimer
criteria, it improves the specificity of the diagnosis. disease. Nature Gen 1998; 19: 321–322.
6. Mayeux R, et al. Utility of the Apolipoprotein E genotype
A number of groups have considered the utility in the diagnosis of Alzheimer’s disease. N Engl
of APOE genotyping in AD, and several consensus J Med 1998; 338: 8, 506–511.

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
2. Schneider LS, et al. Systematic review of the efficacy
and eating properly – measured prospectively by the of rivastigmine for patients with Alzheimer’s disease.
domain-specific Progressive Deterioration Scale) likely Int J Geriatric Psychopharmacol 1998; 1(Suppl 1):
reducing some burden of care for the caregiver. S26–S34.
Schneider, et al. also noted that results from a pooled 3. Brookmeyer R, et al. Projections of Alzheimer’s disease in
analysis of the studies confirmed the efficacy of the United States and the public health impact of delay-
rivastigmine in the treatment of both the cognitive and ing disease onset. Am J Public Health 1998; 88(9):
functional deficits of mild-to-moderately severe AD. 1337–1342.

Alzheimer Insights is an educational newsletter specially devoted to clinical or biomedical matters. The publishers reserve
copyright and renewal on all published materials, and such material may not be reproduced in any form without the written
permission of Gardiner-Caldwell Communications Ltd.

The opinions expressed in this publication are those of the authors and are not to be construed as the opinions or
recommendations of Novartis Pharma AG. Consult full prescribing information on any drugs or devices discussed.

Alzheimer Insights is published by Gardiner-Caldwell Communications Ltd, with the support of an educational grant from
Novartis Pharma AG, Basel, Switzerland.

Please direct all correspondence to:


The Editor, Alzheimer Insights
Gardiner-Caldwell Communications Ltd, Victoria Mill
Windmill Street, Macclesfield, Cheshire SK11 7HQ, UK Novartis Pharma AG
© 1999 Gardiner-Caldwell Communications Limited CH-4002 Basel, Switzerland

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