New Criteria May Aid Earlier, More Accurate Diagnosis of aMCI

Damian McNamara

October 10, 2019

Taking a patient's sex into account may facilitate earlier diagnosis of amnestic mild cognitive impairment (aMCI) in women by adjusting for the so-called life-long "female advantage" in verbal memory performance, which can mask early signs of dementia, new research suggests.

Investigators at the University of California San Diego School of Medicine found "the application of sex-specific cut scores for defining verbal memory improves diagnostic accuracy in both sexes and may result in earlier detection of memory impairment in women and avoid false diagnoses in men."

Using the new criteria researchers found that approximately 10% of female patients who were previously deemed "cognitively normal" actually had a diagnosis of aMCI.

Conversely, when the new criteria were applied to men, approximately 10% previously diagnosed with aMCI were actually cognitively normal.

"These results suggest that typical, non–sex-specific aMCI diagnostic criteria lead to a 20% diagnostic error rate in opposite directions across sexes," note the researchers, led by Erin E. Sundermann, PhD.

In contrast, the results further suggest, "that the application of sex-specific cut scores for defining verbal memory impairment improves diagnostic accuracy in both sexes and may result in earlier detection of memory impairment in women and avoid false diagnoses in men."

"The take-home message is that because women do better on verbal memory tests over their lifetime compared to men, it's possible this may actually serve as a disadvantage in terms of not getting diagnosed with aMCI in early disease stages," Sundermann told Medscape Medical News.

"And it's important to diagnosis this early because the interventions and treatments we currently have are likely more effective in the early stages," she said.

The study was published online October 9 in Neurology.

No Sex-Specific Adjustment

Despite the fact that the "female advantage" is well-documented, normative data for verbal memory tests do not adjust for sex, the investigators note.

Although the verbal memory advantage among women is not novel, "it's never been looked at in the context of diagnosing aMCI and Alzheimer's disease, and how that advantage might impact diagnostic accuracy for those diseases," Sundermann said.

To address this gap in the literature, investigators calculated sex-specific and typical norms/cut scores for impairment on the Rey Auditory Verbal Learning Test (RAVLT) in the Mayo Clinic Study of Aging.

Norms/cut scores were applied to 453 women and 532 men with a mean age of 73 years and a mean education level of 16 years from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Investigators compared 631 individuals with normal cognition and 354 diagnosed with aMCI using conventional, non–sex-specific Jak/Bondi diagnostic criteria.

Results revealed that women outperformed men on the RAVLT, with a mean score of 42.3 (standard deviation [SD], 11.5) vs 35.6 (SD, 11.1), respectively.

Women also scored higher than men on the RAVLT Delayed Recall test, with a mean score of 6.2 (SD, 4.5) vs 4.5 (SD, 3.9). These differences were statistically significant (P < .001).

The rate of aMCI diagnosis was also significantly higher in men when using the traditional criteria cutoff scores (P < .001). "However, this sex difference was eliminated when sex-specific cut scores were used," the researchers note (P = .62).

Imaging Markers

Researchers also evaluated markers associated with risk for development of Alzheimer disease, including cortical amyloid deposition and hippocampal volume. 

Findings for both imaging markers "supported that [some of the] women that we previously called normal actually do have aMCI. It was also the same for the men," Sundermann said.  

Using the new sex-specific criteria, some men that would have been diagnosed with aMCI "had brain changes that looked more like a normal profile," she added. Apolipoprotein E allele status also supported these findings.

"We found the rates of this allele were much higher in the false-negative women — those that would be erroneously labeled as normal using traditional criteria — compared to true positives or those who had aMCI according to both diagnostic criteria," Sundermann said.

The findings, she added, need to be replicated. "This was an initial test of this, and ideally we would want to replicate this in other cohorts to make sure it holds."

Going forward, investigators want to explore the mechanism behind the greater ability of women to compensate for brain changes associated with early Alzheimer's disease risk.

"We're looking at brain metabolism — a measure of brain efficiency — to see if women have greater brain efficiency that allows them to compensate for pathology," Sundermann said.

Important Lesson

Commenting on the findings for Medscape Medical News, Thomas R. Vidic, MD, a fellow of the American Academy of Neurology and practicing general neurologist at the Elkhart Clinic, Indiana, described the study as "a great example that we need to study individual patient populations and not just generalize. We have reached out to nonhomogenous groups by sex, race, or age, but then we usually bundle the data together."

"This example shows how analyzing subsets of data may allow us to be more accurate," Vidic added. "This may be difficult in rare conditions, but with diseases such as Alzheimer's, we may be able to be more accurate at an earlier stage."

Sundermann and Vidic have reported no relevant financial relationships. The study was supported by grants from the National Institutes of Health (NIH). The ADNI database is supported by grants from the NIH and US Department of Defense.

Neurology. Published online October 9, 2019. Abstract

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