Susan Jeffrey

September 01, 2011

September 1, 2011 — Community feedback closes today for those intending to weigh in on proposed guidelines from the National Institute on Aging and the Alzheimer's Association (NIA-AA) for the neuropathologic assessment of Alzheimer's disease (AD).

The proposed NIA-AA guidelines were discussed during a dedicated session in July at the Alzheimer's Association International Conference (AAIC) 2011, and the draft document since has been posted to the association's Web site, where the scientific community and the public were invited to respond until September 1.

The document is the fourth such guideline proposed recently by the NIA/AA: 3 diagnostic guidelines outlining clinical criteria for the diagnosis of dementia resulting from AD, mild cognitive impairment resulting from AD, and a new preclinical stage of AD were published in April this year. Draft documents of those guidelines were first presented for comment from the community at last year's AAIC meeting, which was then called the International Conference on Alzheimer's Disease.

Dr. Creighton H. Phelps

Creighton H. Phelps, PhD, director of the Alzheimer's Disease Centers Program in the Division of Neuroscience at the NIA, said he anticipates that the most controversial changes being proposed relate to a firmer division between the clinical aspects of the disease and the underlying neuropathology.

"Classically, it's all been one big pool, [AD], whether you're talking about clinically or pathology, but they may not be coherent," Dr. Phelps told Medscape Medical News. "We know that people die with these Alzheimer's changes in the brain, and they are entirely normal — had no dementia, had no [mild cognitive impairment] — but the pathologists were looking and saying, because you have plaques and tangles, they had to be demented, and they weren't. You can't diagnose dementia from a slide."

The current criteria, the NIA/Reagan Institute of the Alzheimer Association Consensus Recommendations for the Postmortem Diagnosis of Alzheimer's Disease, were published in 1997 and are referred to in this new document as the "1997 Criteria."

The 1997 Criteria required a history of dementia, and the neuropathologic examination was meant to help determine whether AD was the underlying cause of the patient's dementia, the authors point out. However, the clinical picture of dementia has become more complex, with the inclusion now of milder symptoms and the recent recognition of a preclinical phase of the disease.

You can't diagnose dementia from a slide.

"There is consensus to disentangle the clinicopathologic term 'Alzheimer disease' from AD neuropathologic change," the document notes. "The former refers to clinical signs and symptoms of cognitive and behavioral changes that are typical for patients who have substantial AD neuropathologic change and is the focus of recent NIA-AA sponsored consensus reports on 3 defined stages in a clinical continuum that include preclinical, mild cognitive impairment, and dementia. The latter refers to the presence and extent of neuropathologic changes of AD observed at autopsy regardless of the clinical setting."

Dementia can also arise from other conditions, including Lewy Body dementia, frontotemporal lobe dementia, vascular dementia, or dementia related to Parkinson's disease, Dr. Phelps noted.

"Indeed, pathologic findings for all potentially contributing diseases need to be recorded and then integrated with clinical findings in the neuropathology report for each person," the authors suggest.

ABC Score

Charles Duyckaerts, MD, PhD, head of neuropathology at Groupe Hospitalier Pitié-Salpêtrière and the Centre de Recherche Institut du Cerveau et de la Moelle, in Paris, France, was also a coauthor of the proposed neuropathologic criteria. He supports this "disentangling" of symptoms and pathology.

Dr. Charles Duyckaerts

"I think that separating the clinical data and the pathological data is absolutely necessary; otherwise you are influenced by the clinician and don't take into account what was called the 'off-diagonal' cases," or those with many lesions but few symptoms, or few lesions and many symptoms, he told Medscape Medical News. "If you don't separate the clinical data and the pathology, you tend to forget those cases, and they are there."

Now the perspective has changed, he said. "The neuropathologist is supposed to describe the changes and to evaluate their severity, and that's all. Then the clinician is supposed to evaluate the clinical status of the patient, and by bringing these 2 pieces of information together, you finally make the diagnosis which is clinical-pathological."

The main issues, then, were to give guidance on how to evaluate the severity of the lesions in a given patient, and how to convey the number of lesions quantitatively, he noted.

In the new document, the committee recommends an "ABC" staging protocol for the neuropathologic changes of AD, based on 3 morphologic characteristics of the disease: A is for amyloid, B is for Braak neurofibrillary tangle staging protocol, and C is for the Consortium to Establish a Registry for AD (CERAD) neuritic plaque scoring system.

"Putting together [the] ABC scores, you end up with a given probability that the changes you are examining are related to [AD], clinical or preclinical," Dr. Duyckaerts said.

However, there was some debate about the relative utility of the "C" part of the criteria, he added. "The pathology is really covered by the amyloid pathology and the tau pathology, and why is it necessary to add this CERAD plaque score?" he speculates. "I personally think sooner or later the score will be an 'AB' score, and the 'C' will drop."

The draft document suggests that because the relative independent value of these 3 parameters is not currently known, in the future those data should be collected, and their relative value evaluated.

Another area of some discussion was about which staining techniques should be used, "because obviously you see what you stain," he said wryly. Some participants endorsed use of both specific methods, such as immunohistochemistry with antibodies, as well as nonspecific stains, such as thioflavin S, used by many American pathologists.

Obviously, you see what you stain.

"It was decided to be liberal and to accept also those types of staining," Dr. Duyckaerts noted. However, "there were some remarks from the scientists, who were saying that we should perhaps have been more restrictive in our choice, to limit the staining techniques to immunohistochemistry with tau and amyloid-β, but that's the way it was. Personally, I would have preferred to use only immunohistochemistry, because I think with immunohistochemistry you know exactly what you are staining," he added. "With other stains you don't."

The draft document notes the discussion around this point, which the authors say "highlights the need for more data." Issues to be addressed when comparing different strategies to assess lesion burden, they write, "include brain lesions investigated, volume of tissue examined, differing sensitivity and specificity among tests, standardization across laboratories and groups of neuropathologists, and ultimately, correlation with function."

Gold Standard

Finally, the document endorses the use of genetic risk and biomarkers, including chemical and neuroimaging markers, in research settings to complement the neuropathologic data for the postmortem diagnosis of AD.

Dr. Phelps added that such biomarkers are not yet part of the pathological diagnosis, but efforts now are being made to develop biomarkers in living patients on a parallel track with the pathology.

"Someday, biomarkers are probably going to replace pathology," he said. "Once they're validated, which means that we know they're tracking with the disease, and that they're standardized, then we may not need the pathology.

"Pathology has been the 'gold standard,' and what we're saying now it's probably not going to be the gold standard," he concluded.

Feedback on the new document has been fairly minimal so far, according to a spokesperson for the AA.

Dr. Phelps said he doesn't expect quite as much feedback and controversy with this document as they had with the 3 documents that were published earlier this year on the clinical phases of disease. Those documents, once published, were substantially altered from those first unveiled at the International Conference on Alzheimer's Disease meeting in 2010, particularly on the topic of use of biomarkers in diagnosis of AD, largely based on community feedback.

"I think this one is a bit more solid; I don't anticipate quite as many changes," Dr. Phelps said. "What we're hearing in the feedback even in this meeting was that people weren't contesting our basic premise," he said in an interview during the AAIC meeting in July.

After comments are considered, they hope to have the final draft by October, he added, "and hopefully published by January."

"Guidelines for the Neuropathologic Assessment of Alzheimer's Disease: Proposed Recommendations from the National Institute on Aging and the Alzheimer's Association Workgroup."

Alzheimer's Association International Conference (AAIC) 2011: Plenary Session. Presented July 17, 2011.

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