Final Guideline on Neuropathologic Assessment of AD

Megan Brooks

January 26, 2012

January 26, 2012 — A panel from the United States and Europe charged with updating the 1997 consensus guidelines for the neuropathologic assessment of Alzheimer's disease (AD) has concluded its work.

The revised guidelines from the National Institute on Aging and the Alzheimer's Association (NIA-AA) for the neuropathologic assessment of AD are published in the January issue of Alzheimer's & Dementia.

"The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation," the report reads.

No Major Changes

As previously reported by Medscape Medical News, 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 was posted on the association's Web site, on which the scientific community and public were invited to respond until September 1, 2011.

Dr. Thomas Montine

"We got a fair amount of feedback" on the draft guidelines, panel member Thomas J. Montine, MD, PhD, Alvord Professor and Interim Chair, Department of Pathology, University of Washington, Seattle, noted in an interview with Medscape Medical News. Yet in the end, there were few changes from the draft to the final guidelines. "We just tidied up some very minor details," Dr. Montine said.

The revised NIA-AA guidelines replace the NIA/Ronald and Nancy Reagan Institute of the Alzheimer Association Consensus Recommendations for the Postmortem Diagnosis of Alzheimer's Disease, published in 1997 and referred to 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. 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.

3 Major Points

The revised guidelines have 3 major points, Dr. Montine said. "The first is that it's no longer necessary that someone carry a clinical diagnosis of dementia in order to make a pathological diagnosis of [AD]. We have separated those 2 entities because we now understand that there is a preclinical stage of the disease. That's the major philosophical point," Dr. Montine said.

"The second point is more on the technical side," he said. The guidelines recommend the "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 neuritic plaque scoring system.

For all cases, regardless of clinical history, the guidelines state that reporting should follow the format of these examples: "Alzheimer Disease Neuropathologic Changes: A1, B0, C0" or "Alzheimer Disease Neuropathologic Changes: A3, B3, C3." The ABC score is then transformed into 1 of 4 levels of AD neuropathologic change: not, low, intermediate, or high.

"It is important to recognize," the document states, "that pathologic evaluation can be applied to specimens from surgery as well as autopsy; however, regional evaluation will be limited in biopsy specimens."

The third point deals with comorbidity. Although AD is the most common cause of dementia and can exist in a "pure" form, it commonly coexists with pathologic changes of other diseases that can also contribute to cognitive impairment, the document notes. The most common comorbidities are Lewy body disease, vascular brain injury, and hippocampal sclerosis, as well as other neuropathologic changes such as argyrophilic grain disease and TDP-43 inclusions.

The revised guidelines, Dr. Montine said, "are much more explicit in the evaluation of these comorbidities." It is "critical to document the type and extent of comorbidity in brains of individuals with AD neuropathologic change," the guidelines state. They include minimum recommended brain regions to be sampled and evaluated, as well as preferred methods of analysis.

The guidelines also state that genetic risk and biomarkers, including chemical and neuroimaging markers, be used in research settings to complement the neuropathologic data for the postmortem diagnosis of AD. They emphasize that no single finding or combination of findings from these modalities currently is known to better define the disease state than neuropathologic examination.

"We recognize that this is a rapidly advancing field of investigation and that in the future some combination of genetic testing and biomarkers may be useful as a surrogate for neuropathologic changes or functional decline," the guidelines read.

In September, at AAIC 2011, Creighton H. Phelps, PhD, director of the Alzheimer's Disease Centers Program in the Division of Neuroscience at the National Institute on Aging, told Medscape Medical News, "Someday, biomarkers are probably going to replace pathology. 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."

Areas for Further Research

As part of the guidelines, the committee highlights several key areas for further research. One issue is the relative value of evaluating both amyloid plaque (the A in the ABC score) and neuritic plaque score (the B in the ABC score) in the assessment of neuropathologic change.

This was a "major point of discussion" among committee members, the committee members say. Because the independent value of these 2 parameters is currently not known, the committee suggests collecting data on both and evaluating their independent value in future studies.

Another "major issue going forward" is standardization, Dr. Montine said. "We need to make [a] stronger effort to standardize across centers so when we try to do large multicenter or multinational imaging, genomic, or biomarker studies, the different pathology groups can each speak the same language," he explained.

"Right now, we're not doing things exactly the same way, so the next technical hurdle, at least within the Alzheimer's center network, is to get ourselves organized so we have common protocols. We've already started that, and I think we'll have that done within the year," he predicted.

Alzheimers Dement. 2012;8:1-13. Abstract

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