Are New Diagnostic Guidelines for Alzheimer's, MCI Valid?

Deborah Brauser

August 02, 2012

August 2, 2012 (Vancouver, British Columbia) — The validity of diagnostic guidelines for Alzheimer's disease (AD) has been a topic of debate since the guidelines were published by the National Institute on Aging and the Alzheimer's Association in April 2011.

However, investigators presenting 2 abstracts here at the Alzheimer's Association International Conference (AAIC) 2012 found that splitting the disease's progression into 3 phases (preclinical AD, mild cognitive impairment [MCI], and AD dementia) "works quite well."

The researchers applied the new diagnostic criteria for MCI to more than 150 elderly individuals from the Mayo Clinic Study of Aging (MCSA) and found that 67% of the participants had amyloid deposition, neurodegeneration, or both.

"As such, about two thirds of the participants were thought to be highly likely to develop dementia due to Alzheimer's," said principal investigator Ronald Petersen, PhD, MD, director of the Mayo Clinic AD Research Center in Rochester, Minnesota, in a release.

"Interestingly, a significant number...had no evidence of any biomarker positivity, and another group had evidence of brain cell loss but no amyloid. The latter group likely represents non-Alzheimer's causes of MCI, such as vascular disease," added Dr. Petersen.

The second study evaluated almost 450 MCSA participants considered "cognitively normal." It showed that those who were considered to be in any of 3 preclinical AD stages were significantly more likely to develop cognitive impairment than those who had negative biomarkers.

In other words, the new preclinical AD guidelines "identify a group of cognitively normal persons who are at risk for cognitive decline," said lead investigator David Knopman, MD, also from the Mayo Clinic.

"Before the proposal of these new diagnostic guidelines, there was no single, generally accepted way to identify the disease in its earliest phases. As these 2 new reports show, we are making good progress in that direction," said William Thies, PhD, chief medical and scientific officer of the Alzheimer's Association, in a release.

MCI Certainty

The MCSA includes individuals between the ages of 70 and 89 years who live in Minnesota. For the first study, investigators evaluated 156 of the participants who had been previously diagnosed with MCI.

The new diagnostic criteria for MCI outline 3 levels of certainty based on the availability of imaging biomarkers — uninformative, intermediate, and highest.

Amyloid deposition was evaluated using Pittsburgh compound B (PiB) positron emission tomography (PET). Neurodegeneration was assessed by hippocampal volume — using magnetic resonance imaging (MRI) — and by 18-fluorodeoxyglucose PET.

Results showed that 16% of the patients did not have any imaging biomarkers for MCI (considered to be "uninformative"), 12% had amyloid deposition alone (considered to indicate "intermediate certainty"), and 55% had evidence of both amyloid deposition and neurodegeneration (considered to indicate "highest certainty").

In addition, the presence of the apolipoprotein (APOE) E4 gene mutation was highly correlated with the presence of amyloid deposition.

Still, "the utility of these biomarkers for predicting AD will be determined by the clinical outcome of these subjects," write the researchers.

"Exciting New Window"

In the second study, 443 MCSA participants considered cognitively normal also underwent MRI, PiB, and 18-fluorodeoxyglucose PET.

"The newly developed criteria for preclinical AD are based on the presence of abnormal B-amyloid biomarkers," explain the investigators.

Stage 1 of the preclinical AD pathway is the abnormal amyloid levels alone; stage 2 consists of the abnormal levels plus evidence of brain neurodegeneration; and stage 3 consists of both biomarkers plus "subtle cognitive changes."

Results showed that of all participants, 43% did not have abnormal images, 31% were considered to be in the phase 1, 2, or 3 preclinical AD pathway, 23% were considered to have a suspected non-Alzheimer pathophysiology/non-amyloid pathway (sNAP), and 3% were not classified.

Those who were between phases 1 and 3 were at a significantly higher risk of progressing to cognitive impairment than were those who did not have abnormal imaging biomarkers (P < .001).

In addition, the participants who were found to be in preclinical AD phase 2 or 3 were significantly more likely to progress to cognitive impairment than were those who were in the sNAP group (P = .04).

No significant differences were found between the sNAP and negative biomarkers groups.

"Abnormal B-amyloid imaging with neurodegeneration carried a higher risk than neurodegeneration alone, [and] proxies for cerebrovascular disease were not disproportionately increased in the sNAP group," write the investigators.

"The use of these advanced imaging tools...offers us an exciting new window to identify the markers that may eventually lead to dementia," added Dr. Knopman.

Dementia Prevention?

Dr. Thies told Medscape Medical News that last year's diagnostic guidelines were based on "the opinions of lots of experts" and were meant to include not only Alzheimer's dementia ("a category very familiar to us") but also a group with measurable cognitive difficulties and a group with no cognitive problems but with some biomarker evidence of Alzheimer's type pathology.

"Those criteria, as they were created, were based on an overview of all the literature we had. Then, it was important to validate them and see that they work — that you can actually divide up people into the 3 categories and do it consistently," said Dr. Thies.

"So we're happy to see data coming out that validates the criteria. It builds confidence in their use."

He noted that presymptomatic/preclinical AD and MCI due to AD are primarily research areas right now.

"But one of the reasons that we are investigating those as much as we are is that we see the possibilities of actually treating Alzheimer's pathology long before people become demented — possibly 15 to 20 years before — and in so doing, actually prevent dementia from occurring," said Dr. Thies.

"That's a really attractive picture," he concluded.

Both studies were funded by the National Institute on Aging, Robert H. and Clarice Smith, and the Abigail Van Buren Alzheimer's Disease Research Program. The study authors and Dr. Thies have disclosed no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2012. Abstract 01-10-01 presented July 15, 2012. Abstract 04-04-04 presented July 18, 2012.

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