Fornix First—Atrophy Foreshadows Decline in Normal Aging?

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 multicenter 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

Comments

  1. This is not the first longitudinal study to examine the fornix as a predictor of MCI in cognitively normal elderly. Zhuang and colleagues also reported that cognitively normal individuals who developed amnestic MCI had lower fornix fractional anisotropy (FA) compared to those that did not develop amnestic MCI (Zhuang et al., 2012). Further, Ringman et al. showed that FA was decreased in the columns of the fornix of presymptomatic PS1 mutation carriers compared to non-carriers, suggesting the fornix may be affected early in the disease process (Ringman et al., 2007). However, this is the first study to systematically compare fornix body volume and measures of white matter integrity (including FA and diffusivity) with hippocampal atrophy as a predictor of MCI. The present study shows the promise of fornix variables as predictors of cognitive decline, and could help identify individuals at risk of MCI for clinical trials. However, as there are currently several methods to quantify fornix volume, FA, and diffusivity, a consistent methodology would first need to be established – particularly one that could easily be used in the clinic setting. Future research should also examine the relationship and timing of longitudinal changes in hippocampal volume and changes in the fornix volume and white matter integrity as this may provide important in vivo clues regarding the neuroanatomical progression of AD.

    References:

    Zhuang L, Sachdev PS, Trollor JN, Kochan NA, Reppermund S, Brodaty H, Wen W. Microstructural white matter changes in cognitively normal individuals at risk of amnestic MCI. Neurology. 2012 Aug 21;79(8):748-54. PubMed.

    Ringman JM, O'Neill J, Geschwind D, Medina L, Apostolova LG, Rodriguez Y, Schaffer B, Varpetian A, Tseng B, Ortiz F, Fitten J, Cummings JL, Bartzokis G. Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer's disease mutations. Brain. 2007 Jul;130(Pt 7):1767-76. PubMed.

    View all comments by Michelle Mielke

  2. This is a competent paper that addresses a topical issue. The study is well-conducted and comes from a group known for their rigorous neuroimaging studies of ageing and dementia. There are however some limitations.

    There has been a spate of papers addressing this topic in recent years. Two recent papers are worthy of specific mention. One was published by our group earlier this year and concluded that “Limbic white matter tracts are preferentially affected in the early stages of cognitive dysfunction. Microstructural degradation of the fornix preceding hippocampal atrophy may serve as a novel imaging marker for aMCI at an early stage,” (see Zhuang et al., 2013 and Douaud et al., 2013). The authors’ work supports earlier reports that abnormality of the fornix is an early feature, possibly predating hippocampal volume loss (Zhuang et al., 2012). Our study showed that white matter integrity in the precuneus, parahippocampal cingulum, and parahippocampal gyrus white matter was also compromised in normal people who went on to develop MCI later. We also recently (Sachdev et al, Current Opinion in Psychiatry) argued for AD “as a disease of the white matter, referring to a neglected area in this field (Sachdev et al., 2013). The fornix as an early abnormality has previously been commented on by others (Mielke et al., 2012; Oishi and colleagues referred to the “Fornix sign” in a similar context ((Oishi et al., 2011).

    One of the limitations of such work is that Diffusion Tensor Imaging analysis requires sophisticated processing that is not readily available for clinical purposes. Further work is therefore needed to make this user-friendly before one can consider clinical studies to test its predictive value. Moreover, it is unlikely that one marker will be robust enough, and one would most likely need to combine a variety of markers to predict future cognitive decline and AD. This would include both white matter and grey matter structures, and structural and functional information.

    References:

    Zhuang L, Sachdev PS, Trollor JN, Reppermund S, Kochan NA, Brodaty H, Wen W. Microstructural white matter changes, not hippocampal atrophy, detect early amnestic mild cognitive impairment. PLoS One. 2013;8(3):e58887. PubMed.

    Douaud G, Menke RA, Gass A, Monsch AU, Rao A, Whitcher B, Zamboni G, Matthews PM, Sollberger M, Smith S. Brain microstructure reveals early abnormalities more than two years prior to clinical progression from mild cognitive impairment to Alzheimer's disease. J Neurosci. 2013 Jan 30;33(5):2147-55. PubMed.

    Zhuang L, Sachdev PS, Trollor JN, Kochan NA, Reppermund S, Brodaty H, Wen W. Microstructural white matter changes in cognitively normal individuals at risk of amnestic MCI. Neurology. 2012 Aug 21;79(8):748-54. PubMed.

    Sachdev PS, Zhuang L, Braidy N, Wen W. Is Alzheimer's a disease of the white matter?. Curr Opin Psychiatry. 2013 May;26(3):244-51. PubMed.

    Mielke MM, Okonkwo OC, Oishi K, Mori S, Tighe S, Miller MI, Ceritoglu C, Brown T, Albert M, Lyketsos CG. Fornix integrity and hippocampal volume predict memory decline and progression to Alzheimer's disease. Alzheimers Dement. 2012 Mar;8(2):105-13. PubMed.

    Oishi K, Mielke MM, Albert M, Lyketsos CG, Mori S. The Fornix Sign: A Potential Sign for Alzheimer's Disease Based on Diffusion Tensor Imaging. J Neuroimaging. 2011 Aug 17; PubMed.

    View all comments by Perminder Sachdev

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References

News Citations

  1. Who Will Progress to AD? Brain Microstructure Offers Clues

Paper Citations

  1. Lee DY, Fletcher E, Carmichael OT, Singh B, Mungas D, Reed B, Martinez O, Buonocore MH, Persianinova M, Decarli C. Sub-Regional Hippocampal Injury is Associated with Fornix Degeneration in Alzheimer's Disease. Front Aging Neurosci. 2012;4:1. PubMed.
  2. Mielke MM, Okonkwo OC, Oishi K, Mori S, Tighe S, Miller MI, Ceritoglu C, Brown T, Albert M, Lyketsos CG. Fornix integrity and hippocampal volume predict memory decline and progression to Alzheimer's disease. Alzheimers Dement. 2012 Mar;8(2):105-13. PubMed.
  3. Oishi K, Mielke MM, Albert M, Lyketsos CG, Mori S. The Fornix Sign: A Potential Sign for Alzheimer's Disease Based on Diffusion Tensor Imaging. J Neuroimaging. 2011 Aug 17; PubMed.
  4. Ringman JM, O'Neill J, Geschwind D, Medina L, Apostolova LG, Rodriguez Y, Schaffer B, Varpetian A, Tseng B, Ortiz F, Fitten J, Cummings JL, Bartzokis G. Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer's disease mutations. Brain. 2007 Jul;130(Pt 7):1767-76. PubMed.
  5. Zhuang L, Sachdev PS, Trollor JN, Reppermund S, Kochan NA, Brodaty H, Wen W. Microstructural white matter changes, not hippocampal atrophy, detect early amnestic mild cognitive impairment. PLoS One. 2013;8(3):e58887. PubMed.
  6. Zhuang L, Sachdev PS, Trollor JN, Kochan NA, Reppermund S, Brodaty H, Wen W. Microstructural white matter changes in cognitively normal individuals at risk of amnestic MCI. Neurology. 2012 Aug 21;79(8):748-54. PubMed.

External Citations

  1. Phase 2 AD trial

Further Reading

Papers

  1. Lee DY, Fletcher E, Carmichael OT, Singh B, Mungas D, Reed B, Martinez O, Buonocore MH, Persianinova M, Decarli C. Sub-Regional Hippocampal Injury is Associated with Fornix Degeneration in Alzheimer's Disease. Front Aging Neurosci. 2012;4:1. PubMed.
  2. Zhuang L, Sachdev PS, Trollor JN, Reppermund S, Kochan NA, Brodaty H, Wen W. Microstructural white matter changes, not hippocampal atrophy, detect early amnestic mild cognitive impairment. PLoS One. 2013;8(3):e58887. PubMed.
  3. Zhuang L, Sachdev PS, Trollor JN, Kochan NA, Reppermund S, Brodaty H, Wen W. Microstructural white matter changes in cognitively normal individuals at risk of amnestic MCI. Neurology. 2012 Aug 21;79(8):748-54. PubMed.
  4. Sachdev PS, Zhuang L, Braidy N, Wen W. Is Alzheimer's a disease of the white matter?. Curr Opin Psychiatry. 2013 May;26(3):244-51. PubMed.
  5. Mielke MM, Okonkwo OC, Oishi K, Mori S, Tighe S, Miller MI, Ceritoglu C, Brown T, Albert M, Lyketsos CG. Fornix integrity and hippocampal volume predict memory decline and progression to Alzheimer's disease. Alzheimers Dement. 2012 Mar;8(2):105-13. PubMed.
  6. Oishi K, Mielke MM, Albert M, Lyketsos CG, Mori S. The Fornix Sign: A Potential Sign for Alzheimer's Disease Based on Diffusion Tensor Imaging. J Neuroimaging. 2011 Aug 17; PubMed.

Primary Papers

  1. 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. JAMA Neurol. 2013 Nov 1;70(11):1389-95. PubMed.

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