Fornix Changes May Be First Clue to Cognitive Decline

Pauline Anderson

September 11, 2013

Previous research has concentrated on changes to the hippocampus as a predictor of conversion from normal cognition to cognitive impairment, but emerging data suggest that properties of the fornix region of the brain might be better at predicting cognitive decline among healthy elderly people.

A new study, published online September 9 in JAMA Neurology, links fornix body volume and axial diffusivity to cognitive changes, raising the possibility that deterioration in this region of the brain is the first biological sign of cognitive decline.

"When we're looking at very early signals, it seems that we can pick up changes in white matter, ie the fornix, earlier than we can pick up changes in the hippocampus, and that those could be used as predictors of changes for anything in the gray matter ie the hippocampus," said lead author Evan Fletcher, PhD, project scientist, Imaging of Dementia and Aging Laboratory, Department of Neurology, University of California, Davis.

These fornix changes could eventually be used as biomarkers to determine which cognitively normal patients might be headed for cognitive impairment. "In clinical practice, this might be used to get an early snapshot of what might be occurring down the road," said Dr. Fletcher.

Target fornix volumes might even be developed as ballpark safety areas for cognitive health, similar to target cholesterol levels that, if achieved, can help guard against heart disease.

Fornix Volume Changes

The fornix consists of axons emerging from the cornu ammonis 1 and subfields of the hippocampus. The hippocampus-fornix circuitry is essential to episodic memory consolidation.

Dr. Evan Fletcher

The current study included 102 cognitively normal participants with an average age of 73 years, recruited into the Longitudinal Cohort of the Alzheimer Disease Center of the University of California, Davis. Each participant received multidisciplinary clinical evaluations at baseline and annual follow-up examinations. Evaluations included a detailed medical history and physical and neurologic examinations. Diagnosis of cognitive syndromes — mild cognitive impairment (MCI) and Alzheimer's disease (AD) — were made according to standardized criteria.

Each participant underwent structural T1-weighted MRI to identify and measure volumes in white matter tissue and gray matter tissue. Researchers compared measures of fornix morphometry and microstructural integrity with measures of hippocampus subfield morphometry as predictors of conversion from normal cognition to MCI.

Of the 102 cognitively normal participants, 20 converted to MCI (18 participants) or AD (2 participants). The average time to conversion was 3 years. The "converters" were followed up for an average of 4.4 years. The 82 nonconverters were followed up for an average of 3.8 years.

The study found that fornix body white volume was independently associated with risk for conversion (mean hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.24 - 0.89; P = .02).

The researchers can only speculate as to what's causing changes in fornix volume. For now, there are 2 possible hypotheses, said Dr. Fletcher. One is that it's related to loss of neuron cell bodies in the hippocampus (the fornix is composed of axons primarily coming out of the hippocampus), which leads to axon deterioration, said Dr. Fletcher. Another possibility is that the volume changes are related to elevated levels of β-amyloid protein, which are known to be injurious to neurons and may also be injurious to the myelin coating of axons, he said.

During the study, participants also underwent diffusion-tensor imaging sequences. The analysis found that fornix axial diffusivity was associated with risk for conversion (mean HR, 1.25; 95% CI, 1.02 - 1.46; P = .005).

Diffusivity is a measure of how strongly water molecules diffuse in a particular direction. The theory is that when axons and myelin coatings are intact, water diffusion will occur in a strongly directional fashion, along fiber bundles that are represented by those axons, explained Dr. Fletcher. If the myelin sheathing is degenerated, there will be sideways leakage (radial diffusivity), and if axons are deteriorated, there will be increased free flow within that myelin tube (axial diffusivity).

"That's what we found; we found increased axial diffusivity, indicating that in fact what probably has happened is that the axons had somewhat deteriorated and then the brain's clean-up system had removed these protein fragments and allowed greater water flow in the direction of the fornix itself, suggesting the axon structure had been lost," said Dr. Fletcher.

Greater age was also associated with increased risk for conversion to cognitive impairment (P < .001).

However, hippocampus volume was not significant as a predictor of decline, although it was significantly associated with fornix volume and diffusivity (P = .004).

Until recently, many scientists were convinced that gray matter losses are the primary signals of AD, but it seems, at least from this research, that white matter changes are just as important, if not more so. "What we're saying is that we can see the changes in the white matter — in the fornix in particular — at an earlier stage and more dramatically than we can see changes in the hippocampus," said Dr. Fletcher.

Vascular Risk Scores

Interestingly, vascular risk scores and brain white matter hyperintensity burden were not significantly associated with fornix measures, reducing the prospect that cerebrovascular disease burden is a significant driver for fornix degeneration. Even when the researchers looked at a particular type of white matter hyperintensity that is related to a specific vascular disease, they found "that had absolutely no bearing on whether or not a person who was initially cognitively normal converted to MCI over time; that didn't enter into it at all," said Dr. Fletcher.

Fornix changes could eventually be used to identify patients at high risk for cognitive decline. Dr. Fletcher used the analogy of high cholesterol being a marker for increased risk for atherosclerosis or heart disease, with target levels of cholesterol now being used to reduce risk.

"Maybe one could do the same kind of thing for the fornix," said Dr. Fletcher. "If you get a good MRI of a person's fornix and evaluate fornix volume and possibly the myelination of the microstructural integrity, and if you could see that it is in a certain low range, that would be a signal of increased risk for later cognitive impairment. The problem is, you can't really say what that range is right now."

What also remains unknown is how to maintain fornix volume, aside from the general recommendations to eat well and exercise regularly.

The study couldn't determine the difference in fornix volume changes between participants who developed MCI and those who got dementia because only 2 developed the latter, said Dr. Fletcher. "We simply made a distinction between those who stayed normal over time and those that eventually were diagnosed as converting from normal to cognitive impairment."

The new paper adds important new information to the hunt for a better understanding of the sequence of events that leads from normal cognition to dementia. "I think our study offers a little piece of that puzzle," said Dr. Fletcher.

But he and his research team want to learn more about what fornix volume loss actually means. "We want to understand more of the dynamics of what's going on," he said. "The white matter tracts, and particularly the fornix, are showing losses early on, but we want to find out what's causing that loss because ultimately, if we know what's causing it, then we could know how to intervene and maybe ameliorate that."

Right Questions

Reached for comment on the study, Adam Brickman, PhD, assistant professor, neuropsychology, Columbia University, College of Physicians and Surgeons, New York, New York, said the researchers "asked the right type of questions. For example, can we pinpoint or localize anatomical changes that occur in the aging brain that might be harbingers of future cognitive decline."

Dr. Brickman added that the researchers "did a nice job" of demonstrating that a particular white matter fiber tract is relevant to people who are perhaps on a downward trajectory.

He also thought the researchers were right to focus on hippocampal subfields. "We typically lump all these structures together as a single unit, and it's nice that they really are starting to think about the subfields, which are really molecularly distinct and potentially play very different roles in cognitive functioning in general," he told Medscape Medical News.

However, it wasn't clear to Dr. Brickman whether the study looked at the entorhinal cortex, which is part of the larger hippocampal formation not usually included in the hippocampal proper.

"Certainly there is a lot of work to suggest that the very, very earliest changes in Alzheimer's disease occur in the entorhinal cortex, which feeds directly into the hippocampus," said Dr. Brickman. "They [the authors] were sort of looking at the hippocampal outputs; I would have loved for them to have looked at hippocampal inputs."

The authors have disclosed no relevant financial relationships.

JAMA Neurol. Published online September 9, 2013. Abstract

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