|
||||||||||||||||
|
||||||||||||||||
|
||||||||||||||||
|
| ||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 1
Alzheimer’s Diagnostic Guideline Validation:
Exploration of Next Steps:
Workshop Summary
INTRODUCTION
At the request of the Alzheimer’s Association, the Institute of Medicine
(IOM) Forum on Neuroscience and Nervous System Disorders planned
and hosted a 2-hour public workshop at the 2011 Alzheimer’s Associa-
tion International Conference (AAIC).1 Held in Paris, France, on July 18,
2011, the session brought together key stakeholders to discuss next steps
in the validation of the new diagnostic guidelines for Alzheimer’s disease
(AD), specifically, the revised guidelines recently proposed in papers by the
International Working Group for New Research Criteria for the Diagnosis
of Alzheimer’s Disease, and three working groups under the auspices of the
National Institute on Aging (NIA) and the Alzheimer’s Association.
Gabrielle Silver, global strategic marketing leader for neurology at GE
Healthcare and co-chair of the session, charged invited panelists and session
participants to consider
• the similarities and differences between the two proposed diagnos-
tic guidelines; and
• the lessons learned from the validation of biomarkers for cardio-
vascular disease that may be relevant to AD, including strategies
1 The role of the ad hoc planning committee of the IOM Forum on Neuroscience and Ner-
vous System Disorders was limited to developing this session for the AAIC 2011 meeting. This
summary has been prepared by the rapporteurs as a factual overview of the presentations at
the session. Statements, recommendations, and opinions expressed are those of individual pre-
senters and participants, and are not necessarily endorsed or verified by the IOM or the Forum.
1
OCR for page 2
2 ALZHEIMER’S DIAGNOSTIC GUIDELINE VALIDATION
used in the adoption of the new technology, incorporation of bio-
marker testing in clinical practice, and impact of targeting a sur-
rogate marker of disease incidence; and
• the studies needed (types, design, execution) for validation and
standardization of biomarkers for diagnosing pre-dementia and
predicting progression to the dementia phase of AD.
This report is limited to a review of workshop speaker presentations
and commentary by panelists and participants and is not intended to be a
thorough review of all published literature.
BACKGROUND
Currently, the most widely used AD diagnostic guidelines are those
proposed in 1984 by the National Institute of Neurological and Com-
municative Disorders and Stroke (NINCDS, now the National Institute of
Neurological Disorders and Stroke [NINDS]) and the Alzheimer’s Disease
and Related Disorders Association (ADRDA, now the Alzheimer’s Associa-
tion). William Thies, chief medical and scientific officer for the Alzheimer’s
Association and co-chair of the session, noted that in 1984, there was a
sense that AD was a binary condition. However, scientific advances over
the past decade now indicate that AD is a continuous, progressive cognitive
disease, most likely beginning asymptomatically many years before demen-
tia is apparent. This presents challenges when trying to study the patient
population including characterizing patients as normal, at risk, prodromal,
or having clinical dementia.
In 2007, the International Working Group for New Research Criteria
for the Diagnosis of Alzheimer’s Disease proposed revisions to the long-
standing NINCDS-ADRDA guidelines, followed by nomenclature clarifica-
tions in 2010 (Dubois et al., 2007, 2010). Phillip Scheltens, director of the
Alzheimer Center at the VU University Medical Center, The Netherlands,
and a senior author of the 2007 and 2010 International Working Group
publications, said that one goal of the group was to update the guidelines
to encompass earlier stages of AD, or prodomal AD.
With similar intent, in 2010, three working groups convened by the
NIA and Alzheimer’s Association issued revised guidelines for the diag-
nosis of AD in a set of four publications (Albert et al., 2011; Jack et al.,
2011; McKhann et al., 2011; Sperling et al., 2011). Each of these efforts,
the International Working Group and the NIA-AA efforts, included inter-
national participants and individuals who took part in both efforts. The
NIA-AA guidelines are split into three sets of diagnostic criteria: the first
OCR for page 3
3
WORKSHOP SUMMARY
Normal
Prodromal/
Cognitive Function
MCI due to AD
Prevention Clinical
of Onset
Dementia
Slow
Progression
Treat
Symptoms and
Slow Decline
Disease Progression
FIGURE 1 Therapeutic implications of Alzheimer’s disease course.
SOURCE: Thies presentation at the AAIC session.
defining preclinical stages of AD, the second focused on diagnosis of mild
cognitive impairment (MCI) due to AD,1
Figure and the third, which is most simi-
lar to the original NINCDS-ADRDA criteria, on the diagnosis of dementia
due to AD.
Publication of the International Working Group and NIA-AA guide-
lines, Thies said, reflects a consensus in the field that new guidelines are
needed, incorporating the spectrum of cognitive function associated with
AD pathophysiological processes (normal, mild impairment, and dementia).
Most significantly, both the International Working Group and NIA-AA
guidelines present a framework for the incorporation of biomarkers in the
diagnosis of AD; however, many researchers feel that more work is needed
to determine the validity of these guidelines and their potential utility in
both the research and clinical setting.
Thies noted that there are therapeutic implications of validated predic-
tive and diagnostic biomarkers of AD, including the potential ability to not
only treat symptoms and slow cognitive decline of patients with clinical
dementia, but also to slow disease progression of those in the prodromal
stage, and even perhaps to prevent disease onset in the normal population
(Figure 1).
OCR for page 4
4 ALZHEIMER’S DIAGNOSTIC GUIDELINE VALIDATION
COMPARING THE GUIDELINES
Scheltens provided a brief comparison of the International Working
Group and NIA-AA guidelines on the basis of terminology, cognitive guide-
lines, biomarker guidelines, and potential implementation challenges.
Although there are minor differences in terminology between the two
guidelines, the main difference is that for the symptomatic predementia
stage, the NIA-AA retained the term “MCI due to AD,” while the Inter-
national Working Group chose the term “prodromal AD” to refer to this
stage.
Regarding the cognitive guidelines, the International Working Group
chose memory impairment as the starting point. The NIA-AA criteria took
a more liberal standpoint, Scheltens said, in that they kept the term mild
cognitive impairment, and also included dementia.
The biomarker guidelines differ more significantly. The International
Working Group considered cerebrospinal fluid (CSF) amyloid b (Ab) or
tau protein biomarkers, structural magnetic resonance imaging (sMRI),
and positron emission tomography (PET) all as suitable evidence of brain
amyloid or neuronal injury, without any hierarchy (Dubois et al., 2007). In
contrast, the NIA-AA guidelines make a distinct separation between neuro-
nal injury markers (e.g., CSF tau, hippocampal injury, and MRI evidence
of neurodegeneration) and brain amyloid markers (e.g., PET and CSF Ab).
The NIA-AA guidelines use the two sets of markers together to define cer-
tainty of the diagnosis as high (both markers positive), intermediate (one
marker positive and the other absent), low (both markers negative), or
uninformative (one marker positive and the other negative).
The strength of the International Working Group criteria, Scheltens
said, is that it is disease-driven, focusing on the disease in the brain. A
limitation is the lack of a specific hierarchy of biomarkers, which was not
possible given the knowledge at the time, Scheltens noted. Also, the new
term “prodromal AD” led to some confusion, which is why the lexicon
paper was subsequently published (Dubois et al., 2010).
The strengths of the NIA-AA guidelines included retention of the MCI
definition, taking into account the additional evidence on the use of bio-
markers available at the time (targeting the two stages, amyloid deposition
and neuronal injury), and recognition of the hierarchy of the biomarkers.
A limitation, Scheltens said, is the publication of three sets of guidelines to
address, in effect, the same issues.
Challenges to Implementation of the Revised AD Diagnostic Criteria
One issue not yet resolved, Scheltens said, is how to deal with conflict-
ing biomarker results (e.g., low Ab with normal tau, elevated phospho-tau
OCR for page 5
5
WORKSHOP SUMMARY
with a normal Ab, or normal PET scan and abnormal Ab). Standardization
and validation of each of the marker methodologies is also needed, espe-
cially as the focus moves from diagnostic to prognostic (i.e., assessing the
biomarker profile of preclinical patients to predict progression to dementia).
While the guidelines were developed specifically for research use (i.e.
identification of patients with AD, or those with the potential to progress to
AD, for enrollment in clinical trials), Scheltens noted that these guidelines
will inevitably be used in clinical practice. Advancing the diagnosis of AD
raises a variety of questions. For example, how will biomarkers be incor-
porated into clinical practice? Are there ethical issues? For example, will
patients labeled as having the potential for AD be treated earlier? What is
the practical impact of asymptomatic patients being labeled as having AD
based on a biomarker (e.g., driving, insurance)? In addition, implementa-
tion of the guidelines requires that Alzheimer’s centers may have to develop
a higher level of sophistication with regard to technologies (e.g., PET scan-
ners) and methodology (e.g. biomarker testing), as well as staff understand-
ing and expertise. There may be costs associated with the acquisition and
use of these platforms and the education of staff.
Overall, Scheltens commented, the field is moving in a direction of
diagnosing AD before the onset of dementia. The advent of clinical bio-
markers to the field will enable opportunities for earlier definitive diagnosis
and intervention. Current recommendations for revisions to AD diagnostic
guidelines call for biomarkers as evidence of AD, but there is still work to
be done (e.g., hierarchy, standards, validation, normal values) and issues to
be addressed (e.g., ethics, practicality).
VALIDATING THE NEW DIAGNSOTIC GUIDELINES:
LESSONS LEARNED FROM
CARDIOVASCULAR DISEASE AND CHOLESTEROL
Over the years, better prevention and earlier diagnosis and treatment
of cardiovascular disease has been made possible, in part, by testing for
markers of risk such as increased serum cholesterol. Robert Mahley, senior
investigator at the J. David Gladstone Institutes of Cardiovascular Disease
and Neurological Disease and professor of pathology and medicine and at
the University of California, San Francisco, described some of the lessons
learned from studies of cardiovascular disease, cholesterol, and treatment
approaches that could help inform strategy development for the validation
and use of biomarkers in the diagnosis of AD.
OCR for page 6
6 ALZHEIMER’S DIAGNOSTIC GUIDELINE VALIDATION
Coronary Heart Disease
Coronary heart disease (CHD) deaths have decreased significantly in
the United States over the past several decades; over the 20-year period
from 1980 to 2000, the CHD death rate per 100,000 individuals was re-
duced by nearly half (Ford et al., 2007). Mahley attributed this reduction
to two major causes: advances in evidence-based medical therapies (e.g.,
better initial treatment, more effective revascularization techniques such
as angioplasty and bypass surgery, and secondary prevention following a
myocardial infarction), and change in risk factors associated with heart
disease (e.g., reduction in total plasma cholesterol levels, better control of
blood pressure, decreased smoking, and an increased understanding of the
importance of exercise).
Despite the overall reduction in cardiac-related deaths, heart disease
remains the number one cause of death in the United States, and in almost
all other industrialized countries of the world, accounting for more than 30
percent of deaths. It is estimated that in 2011 there will be 785,000 new
myocardial infarctions (MIs) in the United States and 470,000 recurrent
MIs (Roger et al., 2011).
Success Factors in Reducing Cardiac Deaths
Mahley offered three key factors contributing to the downward trend
in cardiac deaths.
Strong basic science foundation. There is a large body of knowl-
•
edge on cholesterol including origin, control of synthesis, transport
via lipoproteins, importance of apolipoproteins, metabolic func-
tion, arterial wall accumulation, effect of diet, effect of genetic
mutations, and development of relevant animal models.
Successful drug trial reporting reductions in cardiovascular events.
•
Results reported in 1984 from the Coronary Primary Prevention
Trial showed a 1 to 2 percent reduction in CHD for every 1 percent
reduction in low-density lipoprotein (LDL) cholesterol, and that
greater adherence to the drug therapy regimen resulted in greater
reduction.
Strong expert consensus. An NIH consensus conference, held in
•
1984 and reported in 1985, issued conclusions based on a strong
scientific foundation and the results of the Coronary Primary Pre-
vention Trial. The experts’ primary conclusion was that cholesterol
is a causative factor in CHD, and that levels must be reduced (Con-
sensus Conference, 1985).
OCR for page 7
7
WORKSHOP SUMMARY
Lipid Research Coronary Primary Prevention Trial
The Lipid Research Clinics Coronary Primary Prevention Trial
(LRC-CPPT) was the first trial to demonstrate that lowering cholesterol
prevents MIs (Lipid Research Clinics Program, 1984a,b). The randomized,
double-blind study, which began in the 1970s, enrolled 3,800 men with no
history of heart disease, but with very high cholesterol levels, in excess of
260 mg/dl. Participants received cholestyramine, a bile acid sequestrant,
and were followed for 7 years.
The overall results indicated that total cholesterol and LDL were de-
creased by 13 percent and 20 percent, respectively, and there was a 19 per-
cent decrease in cardiac events (definite CHD; non-fatal MI). Participants
who adhered to the protocol fully, taking all doses of cholestyramine, had
larger reductions in cholesterol (35 percent decrease) and cardiac events
(49 percent decrease).
NIH Consensus Conference
The subsequent 1984 NIH Consensus Conference launched the Na-
tional Cholesterol Education Program to educate both physicians and the
public about heart disease and cholesterol. Around the time of the confer-
ence, Mahley said, total serum cholesterol of greater than 260 mg/dl was
considered too high. By 1995, it was thought that cholesterol in excess of
220 mg/dl was probably too high. More recently, levels in excess of 200
mg/dl are considered too high.
A survey in 1986 showed that only 34 percent of physicians actually
considered LDL cholesterol as important in heart disease. In 1995, 75
percent of physicians surveyed accepted the importance of cholesterol in
CHD (Cleeman and Lenfant, 1998). Mahley noted that the general public
came to recognize the importance of cholesterol in heart disease through
NIH publications and through popular magazines such as Woman’s Day.
The NIH Consensus Conference also helped to establish Adult Treat-
ment Panels (ATP) that meet periodically to establish treatment guidelines.
Each successive panel report has issued a lower target LDL level, such that
levels of less than 100 mg/dl are now considered to be most protective.
The Lipid Hypothesis and Drug Development
Despite the clinical evidence, the “lipid hypothesis” of CHD was some-
what controversial, and Mahley said that the national media coverage of
whether the role of cholesterol was fact or fiction resulted in much unwar-
ranted confusion (Steinberg, 2006).
The lipid hypothesis proposed that hypercholesterolemia, or high LDL,
OCR for page 8
8 ALZHEIMER’S DIAGNOSTIC GUIDELINE VALIDATION
was a causative factor but not the only causative factor, of heart disease.
Additional factors include other dyslipidemias; high blood pressure; meta-
bolic syndrome, diabetes, and insulin resistance; obesity; smoking; lack
of exercise; and a pro-coagulant state involved in thrombosis. The lipid
hypothesis also proposed that correction of LDL cholesterol would reduce
progression of CHD. Dietary studies and clinical trials were conducted,
and statins, HMG CoA reductase inhibitors, ultimately became the gold
standard to test the hypothesis. Based on the combined results of clinical
trials of various statins, it is now generally accepted that there is a 20 per-
cent reduction in major vascular events for every 40 mg/dl LDL cholesterol
lowered.
There are now data demonstrating pleiotropic effects that may have
both direct and indirect impacts on CHD risk. Statins have been shown to
also directly affect inflammation, endothelial cell function, plaque stability,
and thrombosis; changes in these have been shown to indirectly decrease
CHD (Robinson, 2008). Lowering cholesterol with statins is a major mech-
anism responsible for the decrease in coronary heart disease which has lead
to statins becoming the “standard of care.” Statins are now used in higher
doses, with wider age groups, and in low-risk patients. This widespread use
and acceptance of the value of statins may have the unintended effect of
decreasing research into new mechanisms of action for lowering cholesterol
and therefore the development of new treatments. This may be of particular
concern in light of the growing number of statin-intolerant patients.
Mahley described the Framingham Heart Study, which assessed lifetime
risk for CHD associated with multiple risk factors. For example, an indi-
vidual with an optimal risk burden at age 50 (normal blood pressure, low
total cholesterol, absence of diabetes, nonsmoker) would be anticipated to
have a 5 to 8 percent risk of CHD-related events over the rest of their life-
span. However, having any two or more risk factors at age 50 increases the
predicted risk to 50 to 70 percent. Those with an optimal risk profile have
a mean life expectancy of at least 10 years longer than those with a risk
burden. Together these studies confirm that atherosclerosis and CHD are
complex, involving multiple risk factors and multiple pathways to disease,
and thus require multiple therapeutic approaches.
Reasons for Partial Success
In clinical trials statins reduced cardiovascular events relative to pla-
cebo by 25-35 percent, but this means that drug therapy did not prevent
two-thirds to three-fourths of CHD events (Kastelein, 2005). Mahley sug-
gests several reasons for this partial success.
OCR for page 9
9
WORKSHOP SUMMARY
Too Late
A major issue facing the cardiovascular field is “how early is early?”
When should cardiac assessment and intervention begin? Atherosclerosis
begins in childhood or young adulthood, but the practice is to wait until
there are signs of CHD to treat. This, Mahley said, is too late. In studies of
Korean War casualties (average age 22 years), 33 percent had fatty streaks
in their coronary arteries, which in some cases is a precursor of atheroscle-
rosis (Enos et al., 1953). In another study, healthy organ donors in their
20s showed that 37 percent had raised lesions in their coronary arteries,
another indication of early atherosclerosis (Tuzcu et al., 2001). Of individu-
als who survive the first 2 days following an MI and receive the best current
standard of care, 20 to 30 percent will die from CHD within 1 year and 40
to 50 percent of individuals will die will die within 5 years after the first MI.
Mahley noted that a clinical trial to prove that early treatment could
reduce CHD will probably never be done; the event rate in young men and
women is too low, and such a primary prevention study would likely re-
quire hundreds of thousands of subjects, and 20 or more years of follow-up.
Too Short
Most clinical trials are about 5 years long, but cholesterol and other
risk factors can be lifelong problems. Thus, the typical study period is
too short to be fully informative. There is now evidence that lifelong low
cholesterol confers protection. The liver protein, proprotein convertase
subtilisin/kexin type 9 (PCSK9), functions as a regulator of LDL receptors
on the cell surface. In a small portion of the population, less than 2 percent,
there is a loss-of-function mutation that causes low LDL from birth. Levels
of LDL in these individuals ranges from 70 to 110 mg/dl, 15 to 28 percent
lower than that seen in the general population. These individuals have a 47
to 88 percent reduction in CHD risk (Cohen et al., 2006).
Based on 5-year clinical trials, a 28 percent reduction in cholesterol
would result in a 25 to 35 percent drop in CHD. How does this short study
translate to the lifelong impact of reduced LDL? Maximal time is needed
to achieve a maximal effect.
Too Little
Perhaps the current recommendations for target cholesterol levels are
not aggressive enough to protect the majority of individuals, Mahley said.
An LDL of 100 to 130 mg/dl may still be too high. Optimal LDL levels
are less than 100 mg/dl, and Mahley opined, perhaps closer to 70 mg/dl.
Humans tend to have LDL levels of 140 to 150 mg/dl, where lower species
OCR for page 10
10 ALZHEIMER’S DIAGNOSTIC GUIDELINE VALIDATION
(e.g., mouse, rat, hamster, rabbit, monkey) have LDL cholesterol levels of
20 to 50 mg/dl. Perhaps optimal levels for humans are similar to levels seen
in animals.
Too Narrow
Finally, the approach to reducing CHD may be too narrow. As CHD
is a complex disease with multiple mechanisms, LDL cholesterol-lowering
drugs (i.e., statins) alone may not be enough. High-risk patients may benefit
from combination therapy such as aspirin, beta-blockers, and cholesterol
lowering drugs (“ABC therapy”). There are also other dyslipidemias, such
as low high-density-lipoprotein (HDL) cholesterol or high triglycerides,
that warrant intervention. Metabolic syndrome is a management challenge
for providers, involving the control of obesity, insulin resistance, coagula-
tion disorders, high triglycerides, and low HDL cholesterol. Hypertension,
Mahley said, is one of the best examples of a multi-factorial disease requir-
ing multiple drugs for treatment. In addressing CHD, lifestyle modification
is also important (e.g., smoking cessation, increased exercise, improved
diet) (Libby et al., 2011).
Lessons for AD Research
Mahley suggested that the barriers to progress for reducing CHD offer
lessons for AD research. The same questions will need to be answered for
AD.
Too late: When should treatment be started? Both CHD and AD are
typically late-onset diseases. Although CHD begins in young adulthood, the
average age of the first MI is 65 to 70 years. Clinical symptoms of AD are
most commonly diagnosed after the age of 65, however there are predictive
signs that could be detected earlier. For example, studies suggest that those
who carry the apolipoprotein variant gene, ApoE4, are at higher risk for
AD and begin cognitive decline earlier than those with the wildtype ApoE3
gene (Caselli et al., 2009).
Too short: How long should patients be followed in AD clinical trials?
As Mahley noted earlier, clinical trials of CHD interventions typically run
for 5 years, and require several thousand patients for adequate statistical
power, and are likely too short to really see an effect. For AD, he said, there
is not yet enough clinical data to be able to predict how many patients are
needed and how long the studies must continue, to observe the effects of
an intervention.
Too little: How low (or high) should target values for key AD biomark-
ers be set? For CHD, no lower detrimental level for cholesterol has yet been
OCR for page 11
11
WORKSHOP SUMMARY
established and perhaps “the lower the better.” Ultimately, cells can make
what they need. In AD, however, the function of Ab is not fully understood.
What should the target level of Ab be for amyloid reduction clinical trials?
Some studies suggest that high levels of Ab impair long-term potentiation
(LTP) and memory (Cleary et al., 2005; Lambert et al., 1998), and other
studies show that low Ab levels impair LTP, synaptic plasticity, and memory
(Puzzo et al., 2011; Weyer et al., 2011).
Too narrow: What are the causative factors of AD? What are the treat-
ment targets? There is strong genetic data supporting the role of the amy-
loid pathway in AD, however, clinical trials seeking to change the course
of the disease with amyloid-targeting drugs have been inconclusive. Tau
protein is part of the AD pathogenesis, and studies have shown that reduc-
tion of tau is beneficial in amyloid animal models. Inflammation may play
a direct role in the central nervous system pathology in AD, and microglial
activation and cytokine generation may also be therapeutic targets. Finally,
ApoE4 is a major risk factor for AD (a major gene and causative factor);
65 to 80 percent of patients with AD have at least one copy of the ApoE4
allele (Mahley et al., 2006).
In summary, Mahley said, AD, like CHD, is a complex disease requir-
ing multiple therapeutic approaches. A strong basic science foundation and
integration of data from multiple types of studies is essential to understand
the potentially multiple causes, interacting pathways, and risk factors.
MOVING FORWARD:
VALIDATION OF THE NEW DIAGNOSTIC GUIDELINES
Following the presentations, Mahley was joined for a panel discussion
by David Brooks, professor at Imperial College and medical advisor to GE
Healthcare; Charles DeCarli, director of the Alzheimer’s Disease Center
at the University of California, Davis; and Monique Breteler, professor at
the German Center for Neurodegenerative Diseases (DZNE), Germany.
Panelists discussed the role of the new guidelines in both clinical trials
and in practice, and the importance of standardization as the first step to
validation.
Standardization
The focus of AD research has long been diagnosis and treatment, but
the availability of biomarkers is moving research into the presymptomatic,
preclinical phases. It was clear throughout the discussion that a key chal-
lenge to validation and implementation of the new guidelines is the lack
of standardization of biomarker tests. Approaches to measuring Ab, for
example, are not standardized and different groups use different cutoff
OCR for page 12
12 ALZHEIMER’S DIAGNOSTIC GUIDELINE VALIDATION
points and ranges. It was also noted that there are not yet validated neuro-
psychological measures sensitive enough to detect cognitive effects of drugs
in asymptomatic patients.
The first step, Brooks said, to developing biomarkers that are cheaper
to standardize is to better define what should be measured. Is it beta-amy-
loids? If so, in what form? Soluble Ab in spinal fluid? What do the results
mean? Should inflammatory markers that are elevated in MCI and AD be
measured? Proteomic profiles? The more that can be understood about the
disease, the easier it will be to develop and test for a “fingerprint” of AD,
to assess risk and identify those who would benefit from early treatment.
Mahley noted that the cardiovascular field spent a lot of time early on
standardizing methodology. From a sampling standpoint, serum choles-
terol may be easier to monitor than Ab in cerebral spinal fluid, but at the
time, cholesterol was not easy to measure. Lipid clinics around the country
worked with the Centers for Disease Control and Prevention (CDC) to set
up and be qualified as standard reference laboratories, allowing for com-
parison of results from across the U.S. He suggested that standardization
of Ab methodology should be first on the list of tasks.
A participant pointed out that in the Framingham Heart Study, the cho-
lesterol data was being collected before it was known that cholesterol was
important for heart disease. Some participants commented that in moving
forward with AD clinical trials and longitudinal, population-based studies
it will be important to collect as much data as possible on a broad group
of potential markers. The addition of standardized methods during these
studies to assess and quantify patient quality of life and cognitive abilities
would be valuable.
A participant drew attention to the differences in terminology between
the International Working Group and the NIA-AA terminology and sug-
gested that standardization of terminology is also needed. It was noted that
MCI is an early feature of many diseases, and the use of the term MCI is not
going to disappear because one of the guidelines now uses prodromal AD.
It is important to make clear that one is discussing MCI that has evidence
of AD pathology.
Validation
If the ultimate goal is to produce affordable, effective, and safe ways of
screening elderly patients for abnormal pathology to facilitate early treat-
ment, Brooks said, then biomarker tests must be validated in controlled
clinical trials.
However, because the new guidelines also apply to individuals in the
prodromal stages of AD when symptoms are not apparent, there is a
need to conduct population-level studies of “normal” individuals as well.
OCR for page 13
13
WORKSHOP SUMMARY
DeCarli added that, for various reasons, the healthy control population in a
clinical trial is not reliably representative of the broader general population,
as has been observed on some of the Alzheimer’s Disease Neuroimaging
Initiative (ADNI) clinical trials.
A participant noted that in CHD, the endpoints (MI or death) are
clear-cut and easily counted. In AD, the progression from MCI to severe
cognitive impairment is a slope, and cognitive decline also occurs in indi-
viduals who do not have AD. What endpoints will be used to validate the
surrogate markers of AD? Research in this area, including careful measures
of trajectories of cognitive decline, could be valuable.
It was also noted that conversion to dementia is the major outcome in
MCI clinical trials. The precision of that diagnosis, and the differentiation
of MCI from dementia, is absolutely fundamental. Currently, the diagnosis
hinges entirely on the judgment of the skilled clinician. The draft DSM-V
criteria and the NIA-AA guidelines focus on independence of function.
One can have mild functional impairment with mild MCI. Dementia is the
point when one loses independence in those functions. However, whether
a patient remains independent in function is highly dependent on the level
of support they have. There is a need for a clear consensus on what this
functional impairment has to look like before it constitutes a diagnosis of
dementia. Breteler said that rather than defining an absolute cutoff, it may
be more important to agree on what rate of decline, or increased rate of
decline, constitutes the progression to dementia. While participants and
speakers frequently noted that cognition is a continuum, some felt that
a binary outcome may still be needed to operationalize change. DeCarli
pointed out that there have been more than five clinical trials looking at the
conversion of MCI to dementia using adjudication committees to reliably
establish the diagnosis. Many suggested, however, that as the guidelines
move into clinical practice, the definitions and endpoints will have to be
crisper, and that clarity will only come from successful clinical trials.
The New Guidelines in Clinical Research and in Practice
The new guidelines will facilitate measurement of some of the early
biomarkers of AD in people who are cognitively normal, DeCarli said.
Measuring biomarkers of amyloid pathology in people who are otherwise
asymptomatic could help expand the understanding of the role and mecha-
nisms of amyloid abnormalities in the brain. It may also help determine
at what point in the process, and how aggressively, to attempt to alter
amyloid deposition in the brain to have a meaningful effect on disease and
clinical profile. Implementing new diagnostic criteria in clinical trials will
also provide data that can help in establishing the risk of AD for people
who are asymptomatic.
OCR for page 14
14 ALZHEIMER’S DIAGNOSTIC GUIDELINE VALIDATION
Breteler suggested that biomarker data can be used to define more
homogeneous groups within the very heterogeneous population of AD
patients. This could help facilitate more specific, targeted clinical trials and
help to identify effects in specific subgroups.
Another benefit of having validated biomarkers of prodromal AD will
be the ability to conduct epidemiological studies of Alzheimer’s disease ver-
sus Alzheimer’s dementia. Breteler noted that measurement of cholesterol
has been very successfully used in studies because it is a relatively inexpen-
sive test requiring only a blood sample. To better understand prodromal
AD in the population at large and develop preventive interventions, Breteler
suggested that there is a need for easier, cheaper, standardized, more acces-
sible biomarker tests for the early stages of AD.
A participant from industry discussed the development and recruitment
of the first prodromal AD clinical trial based on the International Working
Group guidelines, and the specific challenges of operationalizing the guide-
lines. He opined that even with the methodology standardization issues,
there is still overwhelming evidence that Alzheimer’s pathology reflected
through CSF biomarkers predicts progression to Alzheimer’s dementia. His
view is that these studies can be done now, and will improve incrementally
as better, standardized assays are available. The available assays for these
biomarkers can be carefully used, in parallel to the other mechanisms, to
identify those at risk and enrich the study population of a trial.
Although the new guidelines geared toward defining preclinical AD
are clearly defined as being for research purposes only, some participants
acknowledged that there will be great interest in applying these guidelines
in the clinic as well. Specifically, biomarkers may be a useful diagnostic tool
when incorporated into the examination by skilled physicians. Individuals
in their 50s and 60s are eager to know their risk, often because a parent or
grandparent has AD.
Overall, the panel agreed that the new guidelines are not an end point,
and it will be important to continue to incorporate new insights and chal-
lenge the existing thinking. Moving forward, revisiting the guidelines on a
regular basis as new data becomes available will be important, as well as
maintaining a multidisciplinary global dialogue.
