Guidelines Bring Needed Change, Though Not Enough for Some
( 2 Articles Available, 0 Articles Pending )
U.S. guidelines for assessing Alzheimer's disease (AD) neuropathology are getting a much-needed facelift. The existing ones, in place since 1997, had fallen out of step with the current understanding of AD as a disease with a long preclinical stage. The new ones, developed by a committee set up by the National Institute on Aging (NIA) and the Alzheimer's Association (AA), recommend a full evaluation of the neuropathologic changes in the brains of deceased patients regardless of whether or not they had clinical symptoms of dementia. This means someone who died cognitively intact can afterwards be found to have had Alzheimer's pathology.
The new guidelines are viewed as a welcome change in the community, although they stirred up quite a bit of discussion, particularly about the technical aspects of how to measure brain lesions. This two-part series summarizes what's new and what was debated at this year's Alzheimer's Association International Conference in Paris, where a draft document of the guidelines was first presented. Read also a comment from 25 researchers of the BrainNet Europe Consortium calling for harmonization between U.S. and European approaches.
New Neuropathologic Guidelines for AD Almost Ready for Primetime
New U.S. guidelines for the neuropathologic assessment of Alzheimer’s disease (AD) and related conditions are getting close to being finalized. A committee set up by the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) drafted recommendations that no longer require a prior diagnosis of dementia for a postmortem assessment of AD. This would bring neuropathology in line with the diagnostic guidelines for AD published in April of this year (see ARF related news story and ARF Webinar). “The clinical guidelines now say that you can make a diagnosis of Alzheimer’s before the dementia stage, but the neuropathological criteria said that you had to have a diagnosis of dementia to make an assessment. So we were just tripping over words,” said Thomas Montine at the University of Washington in Seattle, who co-chaired the NIA-AA committee together with Bradley Hyman of Massachusetts General Hospital in Boston. “The new guidelines we are proposing recognize the reality that the disease process starts before dementia. They also acknowledge that there are other disease processes that commonly co-occur with Alzheimer’s,” Montine said.
The neuropathologic guidelines will be subject to approval at a meeting of the Alzheimer’s Disease Research Centers (ADRCs) to be held 23-24 September 2011 in San Diego, California. They will consist of a revised version of a draft document discussed at the Alzheimer's Association International Conference (AAIC) held this past July in Paris, France, where the issue was first presented and the AD community was invited to comment. The public comment period closed on 1 September 2011. Following the upcoming presentation at the ADRC meeting, the guidelines may be further revised and then submitted for publication, according to Creighton (Tony) Phelps, director of the ADRC program at the NIA. “We want to make sure that there are no lingering doubts, and achieve consensus,” he said. “We want to hear any criticism now rather than after the guidelines are published.” So far, they received 47 written comments on their draft document. “The feedback has been mostly positive, but we had some substantive criticisms that we took to heart and revised the document accordingly,” said Montine. In addition, leading neuropathologists of the BrainNet Europe (BNE) consortium last week considered the NIA-AA draft guidelines. Although BNE did not provide feedback to the NIA-AA committee during the open comment period, they now share their joint perspective, as well as their experience over the past years with assessing how to achieve agreement among neuropathologists at different sites (see BNE comment below). The NIA-AA committee, which comprises 15 members—14 based in the U.S. and one in France—started its deliberations in the fall of 2010.
Disentangling Clinical Diagnosis and Pathology
The biggest change with the new guidelines—the separation of the disease’s clinical and pathological aspects—is by all accounts being viewed as a welcome revision by AD researchers and clinicians. The earlier neuropathological criteria published in 1997, referred to as the NIA-Reagan criteria, required a history of dementia for the neuropathologic examination to occur. Those results were then used to determine whether the person’s dementia was due to AD or some other cause. The new guidelines enable the pathologist to describe all the changes in the deceased person’s brain according to a set of specified measurements, regardless of whether the person had cognitive symptoms. This approach is new to the AD field, but many other conditions already uphold this same distinction between pathology and disease. For example, many men have age-related prostate alterations, but only a small percentage will develop symptomatic prostate cancer. In essence, a common disease process causes detectable lesions in more people than those who have clinical symptoms at the time of death.
The new neuropathologic guidelines base the assessment of AD-related changes on measurements of amyloid-β (Aβ) load, the number and types of amyloid plaques, and the number of neurofibrillary tangles and their locations. “We have given a lot of attention to pathology,” said Montine. “The new guidelines are more prescriptive in what to measure than the earlier ones. We describe what to evaluate in much more detail.” The procedures were based on a literature review and the analysis of the National Alzheimer's Coordinating Center (NACC) database, a large compilation of clinical and pathological assessment data taken of each patient who comes into the memory clinics of the ADRCs across the country (see ARF interview with Bud Kukull, head of the NACC). The new guidelines also provide criteria for the assessment of other conditions that can give rise to dementia in the elderly, such as dementia with Lewy bodies (DLB, aka LBD), frontotemporal lobe dementia, vascular dementia, and dementia related to Parkinson’s disease (aka PDD).
The NIA-AA guidelines recommend that genetic risk markers and biomarkers be used in research settings to complement the neuropathologic data for the postmortem evaluation of AD. Recently, biomarker studies have taken to comparing the diagnostic value of the biomarker at hand to that of the clinical diagnosis and the postmortem pathologic assessment. This research has, in some cases, begun to question the decades-old status of postmortem neuropathology as the bona fide diagnostic gold standard for AD. But for now, the pathological assessment remains the gold standard with the new NIA-AA guidelines. “In the future it may very well be that biomarkers will be used as surrogates for neuropathologic changes, but we are not there yet,” said Phelps.
Learn Your ABCs
The 1997 guidelines relied on two sets of criteria for measuring amyloid plaques and tangles. The first set, established by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), consists of a semi-quantitative assessment of neocortical neuritic plaques, a class of amyloid plaques made up primarily of Aβ deposits surrounded by dystrophic neurites (Mirra et al., 1991). The second set of criteria rely on a staging system for neurofibrillary tangles developed by Heiko and Eva Braak, which describes six stages of AD neuropathology based on where the neurofibrillary changes occur in the brain (Braak and Braak, 1991; see also online Seminar by Braak). The combined CERAD and Braak scores provide a measure for the likelihood that a patient’s dementia was due to AD. For example, that likelihood would be “high” if the CERAD score was “frequent” and Braak stage V, but it would be “low” with a CERAD “infrequent” score and Braak stage I or II.
At the 2011 AAIC presentation, Hyman explained that the committee applied the 1997 criteria to the NACC database and found that the criteria worked well in predicting the cognitive status of people at either end of the spectrum. In other words, people whose brains were full of pathology usually had a dementia diagnosis and those with no pathology tended to be relatively cognitively normal. People whose brains had intermediate pathology according to the 1997 criteria had a 50-50 chance of having dementia. But the problem was that there were few people with substantial pathologic change and no prior diagnosis of dementia, whereas there were some people with little neuropathologic change and dementia. The 1997 criteria could not capture these cases, which are dubbed to be "off-the-diagonal."
The new guidelines address this limitation. The proposed recommendations would measure three characteristics through what is referred to as an ABC protocol:
A is for Aβ deposits, as measured according to the phases of deposition published by the German pathologist Dietmar Thal and colleagues (Thal et al., 2002).
B is for the Braak and Braak neurofibrillary tangles staining protocol.
C is for the CERAD scoring system.
Putting together the three scores gives a probability that the observed neuropathologic changes are related to AD. So, for example, a patient who has neocortical and hippocampal Aβ deposits (score A2), Braak stage I or II (score B1) and a CERAD score "sparse" (score C1) has a low level of AD-related neuropathology. Someone with neocortical, hippocampal, and neostriatal Aβ (score A3), Braak stage III or IV (score B2) and a CERAD score of "frequent" (score C3) would have an intermediate level of AD-related pathology.
The guidelines stipulate which brain regions to examine and what to look for. They suggest techniques for detecting pathology (i.e., staining with a stain coupled to antibodies against Aβ or tau versus a non-specific stain such as thioflavin S or silver), but they do not go as far as prescribing any particular method. “We did not feel there was a consensus on the best methodology to use,” said Montine.
That contrasts with the experience of the BrainNet Europe Consortium, according to Irina Alafuzoff at Uppsala University in Sweden. “Silver staining gives poor results. If different labs use it, they will get very different measurements. It has so many pitfalls that we decided we should not use it within BrainNet,” she said. “Counting lesions also gives very different results [from lab to lab].” Several studies conducted in the last four years (Alafuzoff et al., 2008; Alafuzoff et al., 2008; Alafuzoff et al., 2009; Alafuzoff et al., 2009) have shown that by using immunohistochemistry for Aβ and tau to measure amyloid and NFT load, the consortium members could achieve 80 percent agreement in their pathological assessments of autopsy samples from the same brain. BrainNet Europe neuropathologists are now preparing to publish their own recommendations based on these findings. However, Alafuzoff is concerned that “the U.S. and Europe will now be following different guidelines and it will be difficult to compare results.”
Montine pointed out that, unlike BrainNet, which is a research consortium, the NIA-AA guidelines are meant to assist both neuropathologists working in a clinical setting and those working in research settings. He acknowledged that having consistent methods is important in a research setting when you need to stringently compare results, but it is less critical when using the assessment to make a clinical diagnosis. It would be difficult for many clinics to conduct studies using more expensive antibody-based stains. “We wanted to be both scientifically rigorous but practically useful to people,” he said.
This issue is but one of many aspects of the guidelines that were openly debated at the 2011 AICC conference. Part 2 of this series summarizes highlights of that discussion.—Laura Bonetta.
This is Part 1 of a two-part series. See also Part 2.
Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak H, Bugiani O, Del-Tredici K, Ferrer I, Gelpi E, Giaccone G, Graeber MB, Ince P, Kamphorst W, King A, Korkolopoulou P, Kovács GG, Larionov S, Meyronet D, Monoranu C, Parchi P, Patsouris E, Roggendorf W, Seilhean D, Tagliavini F, Stadelmann C, Streichenberger N, Thal DR, Wharton SB, Kretzschmar H.
Staging of neurofibrillary pathology in Alzheimer's disease: a study of the BrainNet Europe Consortium.
Brain Pathol. 2008 Oct;18(4):484-96.
PubMed.
Alafuzoff I, Thal DR, Arzberger T, Bogdanovic N, Al-Sarraj S, Bodi I, Boluda S, Bugiani O, Duyckaerts C, Gelpi E, Gentleman S, Giaccone G, Graeber M, Hortobagyi T, Höftberger R, Ince P, Ironside JW, Kavantzas N, King A, Korkolopoulou P, Kovács GG, Meyronet D, Monoranu C, Nilsson T, Parchi P, Patsouris E, Pikkarainen M, Revesz T, Rozemuller A, Seilhean D, Schulz-Schaeffer W, Streichenberger N, Wharton SB, Kretzschmar H.
Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium.
Acta Neuropathol. 2009 Mar;117(3):309-20.
PubMed.
Alafuzoff I, Ince PG, Arzberger T, Al-Sarraj S, Bell J, Bodi I, Bogdanovic N, Bugiani O, Ferrer I, Gelpi E, Gentleman S, Giaccone G, Ironside JW, Kavantzas N, King A, Korkolopoulou P, Kovács GG, Meyronet D, Monoranu C, Parchi P, Parkkinen L, Patsouris E, Roggendorf W, Rozemuller A, Stadelmann-Nessler C, Streichenberger N, Thal DR, Kretzschmar H.
Staging/typing of Lewy body related alpha-synuclein pathology: a study of the BrainNet Europe Consortium.
Acta Neuropathol. 2009 Jun;117(6):635-52.
PubMed.
Draft Guidelines Spark Discussion, Highlight Unknowns in Field
A committee convened by the National Institute on Aging (NIA) and Alzheimer’s Association (AA) has revised the postmortem assessment of Alzheimer’s disease neuropathology. In essence, postmortem brains will receive a composite "ABC" score of A) measurements of amyloid-β (Aβ) deposits determined by Thal et al., 2002; B) the locations of neurofibrillary tangles according to Braak and Braak, 1991; and C) the number and types of neuritic plaques according to scoring established by the Consortium to Establish a Registry for AD (CERAD). The biggest change from the current NIH-Reagan guidelines is that the neuropathological assessment of AD will no longer require a prior diagnosis of dementia (see Part 1).
Last July’s Alzheimer's Association International Conference (AAIC) in Paris, France, featured a special session dedicated to the topic, in which committee members introduced the new guidelines and then conducted a question-and-answer period with the audience. Questions were answered by Thomas Montine of the University of Washington, Seattle, and Bradley Hyman of the Massachusetts General Hospital, Boston, who co-chaired the committee. The summary of this discussion, below reflects some of the unanswered questions in the AD field. Since then, the committee has fielded comments from the research community and will present an updated draft for approval at a meeting of the Alzheimer’s Disease Research Centers on 23-24 September 2011 in San Diego, California. If all goes according to plan, the new guidelines will be published in early 2012. (Note that questions and answers below were edited for clarity; in some cases similar responses were combined.)
Is the Diagnosis of AD Based on Pathological or Clinical Criteria?
Some AD researchers believe that the neuropathologist should make the diagnosis of AD, whereby “one plaque, one tangle” is sufficient for such a conclusion. Others, however, think that the neuropathologist can only make the conclusion of AD-related changes, and the actual diagnosis is based on clinical findings. The second position prevailed in the draft document presented by the NIA-AA committee.
Montine: What do we do with someone who has high levels of plaques and tangles but was cognitively intact at death? The majority opinion was that the surest ground is to report our observations, the neuropathologic changes that we see, independent of clinical standing. If we were to adopt this approach, the clearest way to answer this question is to say we observe neuropathologic changes of AD.
Hyman: I agree. We try to disambiguate the term AD, which historically connotes both a neuropathologic and a clinical entity. The science has changed to the point where we now think of AD as a long disease process with a long preclinical stage that has the neuropathologic characteristics of AD but no overt symptoms. We can draw an analogy with atherosclerosis and angina; you see the former, but the patient does not yet have the latter. Asking the neuropathologist to determine what a person’s MMSE [Mini-Mental State Exam] score would have been is like asking a pathologist who sees atherosclerosis under the microscope if that patient had heart pain walking up the steps. There are certainly individuals in whom there is a clinicopathologic disconnect; we have to understand that in terms of the spectrum of disease rather than be confused by the nomenclature.
Does CERAD Scoring Need to Go Into the Neuropathologic Assessment of AD?
The two defining characteristics of AD are presence of amyloid deposits and of neurofibrillary tangles. One view in the field is that measuring those two parameters is sufficient to characterize AD-related pathology without any need for the CERAD score, which is a semi-quantitative measure of neuritic plaques. The NIA-AA committee recommended using CERAD as part of the neuropathologic examination.
Hyman: This was a matter of a good deal of discussion. We agreed that we do not know exactly how much each individual criterion contributes to the assessment of AD-related pathology. We all felt that molecular-defined lesions, the Aβ, and tau deposits are well established. But we do not yet understand as well the alterations that occur around plaques and which lesions damage the brain most. So we are still uncertain which of these lesions are most informative with regard to neural dysfunction; we decided to record them all until research has sorted that out.
Montine: The idea of having both the Thal phases and CERAD came from our realizing that we knew less than we thought we knew. The first measure is topographically based and the second is density-based. Humility dictated that we include both until we understand their significance to brain function better.
Why Not Specify Techniques for Detecting Plaques and Tangles?
The draft document recommended certain techniques for detecting AD-associated pathology, but the committee decided to leave it up to neuropathologists to choose their method. Several members of the audience thought that more guidance was needed, charging that “liberalism” might lead to inconsistencies. It may also lead to differences in the protocols used in the U.S. compared to Europe and Japan. In Europe, for example, BrainNet has spent several years comparing different methods. Their findings suggest that immunohistochemistry yields the most consistent results among labs.
Montine: In the report, we recommend a preferred stain for each of the elements in the ABC score. There were strongly held opinions on what is the optimal method. The danger is each has its own nuances and collects slightly different data. We are not agnostic on this point. We do recommend certain stains over others, but we stop short of saying everyone must do it this way. We do prefer certain sets of stains, and they are largely antibody-based.
Our panel had robust discussions on whether to recommend particular reagents, particular antibodies. We know research questions would benefit from that. But it would not help all audiences. Researchers will find those antibodies on their own. It is not really the role of a national committee like ours to proscribe particular reagents. We welcome comments from researchers in Europe and Japan.
What Are the Implications for the NACC and Other Databases?
Audience members suggested that the committee should recommend a system, either National Alzheimer’s Coordinating Center (NACC) or Alzheimer’s Disease Cooperative Study (ADCS), where neuropathological and clinical data are collected in a database. Ideally, that would be a database other international groups could contribute to.
Montine: We plan to immediately work with Budd Kukull [at the University of Washington, Seattle], who runs the NACC to revise its database to reflect these changes in neuropathologic guidelines. That will happen once the new criteria are finalized. We will likely proscribe methods that researchers at all Alzheimer’s Disease Research Centers would use.
Nigel Cairns (Washington University in St. Louis, Missouri, and a member of the NIA-AA committee): I am the neuropathology coordinator for the Alzheimer’s Disease Neuroimaging Initiative (ADNI). I also do neuropath for the Dominantly Inherited Alzheimer Network (DIAN). For each of these large projects, we are using standard neuropathologic protocols, standard stains, which are not mandated by these new guidelines. The data from different sites are then submitted to a central database.
Montine: Is that assessment compatible or incompatible with these new criteria?
Cairns: It is entirely compatible. We are using three sets of criteria: we do Khachaturian (Khachaturian, 1985), CERAD, and the NIH-Reagan guidelines.
What to Make of Tangles in Braak Stages I to IV When There Is No Amyloid?
Montine: We do not know exactly what these cases represent. They may represent AD in evolution. But pathologists should be warned that if they see tangle-only, they should evaluate other tauopathies before settling on AD. We say it is not AD.
Hyman: After a lot of discussion, the committee’s consensus was that it’s best to be humble and go with describing what we see and not overreaching on conclusions.
What Is the Recommendation for Other Characteristics of AD?
Other features of AD pathology include synapse loss, neuron loss, atrophy, gliosis, and other neuronal lesions like TDP-43 immunoreactive inclusions, granulovacuolar degeneration, and Hirano bodies, as well as congophilic amyloid angiopathy.
Montine: The report is at 28 pages and going…. TDP-43 and white matter are in there. In our discussions about this, we discovered that we each held strong views on what these other characteristics mean and how to evaluate them, but there are almost no head-to-head comparisons.
Is the Morphology of Plaques Important?
There is a lot of history, literature, and debate about the relative meaning of diffuse, dense, compacted, neuritic, cotton-wool, and other shapes of plaques to disease mechanism.
Hyman: It is safe to say that the issue of morphology had plenty of airtime in the committee’s discussions. We did not find consensus on what the different morphologies mean for neural or cognitive function. There are many opinions. We hit barriers there. We could not even reach a consensus on what to call many types of plaques. The committee’s view is that this should be excluded from the guidelines.—Gabrielle Strobel.
This concludes a two-part series. See also Part 1.
Comments
No Available Comments
Make a Comment
To make a comment you must login or register.