13 September 2013. Shrinkage of a bundle of white matter fibers that carry signals from the hippocampus could warn of impending cognitive decline in normal elderly, according to research published in the September 9 JAMA Neurology. Based on longitudinal magnetic resonance imaging (MRI) data, scientists at the University of California, Davis, report that degeneration in the fornix, the primary output projection of the hippocampus, predicted who would become cognitively impaired better than did the established marker of neurodegeneration in Alzheimer’s disease—hippocampal atrophy itself. Consistent with other recent imaging studies, the new findings support a “paradigm shift in which white matter structures are seen to play a critical role in early cognitive decline, perhaps more so than gray matter,” claimed UC Davis’ Evan Fletcher, who led the study with senior author Charles DeCarli. While the data suggests that fornix imaging could prove a valuable early diagnostic, developing it for clinical use would require much additional work to simplify data collection and interpretation.
Disintegration of the fornix can be seen on diffusion MRI scans that pick up subtle white matter changes. In prior work, this measure predicted conversion from MCI to AD (see Lee et al., 2012; Mielke et al., 2012; ARF related news story). Other studies found that loss of the myelin sheath around white matter axons in the fornix correlated with cognitive decline not only in MCI patients but also in healthy elderly and asymptomatic carriers of presenilin 1 mutations, suggesting that the fornix frays early in the disease process (Oishi et al., 2011; Ringman et al., 2007).
In the present study, Fletcher and colleagues took a closer look at fornix variables in a cognitively normal cohort. They measured size and structural integrity of this small brain region, as well as hippocampal volume, in 102 healthy people of average age was 73 years who underwent diffusivity and structural MRI scans at baseline and four years later. Hippocampal volume correlated with two fornix measures—white matter volume and axial diffusivity (a measure of axonal integrity). This was expected given the shared circuitry of these brain structures. The surprise came when the scientists assessed how well each brain measure predicted conversion to MCI or AD. The fornix variables foretold cognitive decline whereas hippocampal volume did not. “The fornix changes show up earlier and appear to be a better biomarker,” Fletcher said.
The findings fit with recent papers reporting that fornix white matter damage, but not hippocampal atrophy, predicted conversion from normal cognition to amnestic MCI (Zhuang et al., 2013; Zhuang et al., 2012). These studies only looked at diffusivity, whereas the present analysis also includes volume. The structure MRI used to size up the fornix MRI achieves twice the resolution of diffusivity images and may provide more robust measurements of small structures such as the fornix, Fletcher noted.
Some scientists find the results compelling. The data “show the promise of fornix variables as predictors of cognitive decline, and could help recruit individuals at risk of MCI for clinical trials,” suggested Michelle Mielke of the Mayo Clinic, Rochester, Minnesota (see full comment below). However, there are several methods to quantify volume and diffusivity of the fornix. "A consistent methodology would need to be established,” Mielke wrote in an email to Alzforum.
Claudia Metzler-Baddeley of Cardiff University in the U.K. said she would have liked to see imaging of other brain regions, to show that the white matter changes were specific for the fornix. Another limitation was the small number of people who developed MCI or AD—only 20 of the 102 participants became cognitively impaired during the study’s ~4-year timeframe and only two of those were diagnosed with AD.
Perminder Sachdev of the University of New South Wales, Australia, pointed out that diffusivity images “require a lot of sophisticated processing that is not readily available for clinical purposes.” Predicting future cognitive decline in normal seniors will likely require a variety of markers, including white matter and gray matter structures as well as functional information, Sachdev noted (see full comment below).
Meanwhile, clinical trials are marching ahead on the idea that the fornix is more surgically accessible for implanting electrodes than the hippocampus. Some researchers believe that deep brain stimulation (DBS) to improve communication between these brain areas could help people with AD. Recruitment is underway for a multi-center 12-month Phase 2 AD trial of fornix DBS, said Constantine Lyketsos, a principal investigator at the study’s Johns Hopkins Bayview site in Maryland.—Esther Landhuis
Fletcher E, Raman M, Huebner P, Liu A, Mungas D, Carmichael O, DeCarli C. Loss of Fornix White Matter Volume as a Predictor of Cognitive Impairment in Cognitively Normal Elderly Individuals. JAM Neurol. 9 Sep 2013. Abstract.