This is Part 1 of a two-part series. See also Part 2.
21 September 2011. 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.
- Draft Guidelines Spark Discussion, Highlight Unknowns in Field
- Revised Diagnostic Criteria for Alzheimer’s Are Published
- Tom Fagan Interviews Bud Kukull
- Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991 Apr;41(4):479-86. PubMed.
- Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59. PubMed.
- Thal DR, Rüb U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002 Jun 25;58(12):1791-800. PubMed.
- 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.
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- 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.