. 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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  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.


    . Microstructural white matter changes in cognitively normal individuals at risk of amnestic MCI. Neurology. 2012 Aug 21;79(8):748-54. PubMed.

    . Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer's disease mutations. Brain. 2007 Jul;130(Pt 7):1767-76. PubMed.

  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.


    . Microstructural white matter changes, not hippocampal atrophy, detect early amnestic mild cognitive impairment. PLoS One. 2013;8(3):e58887. PubMed.

    . 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.

    . Microstructural white matter changes in cognitively normal individuals at risk of amnestic MCI. Neurology. 2012 Aug 21;79(8):748-54. PubMed.

    . Is Alzheimer's a disease of the white matter?. Curr Opin Psychiatry. 2013 May;26(3):244-51. PubMed.

    . Fornix integrity and hippocampal volume predict memory decline and progression to Alzheimer's disease. Alzheimers Dement. 2012 Mar;8(2):105-13. PubMed.

    . The Fornix Sign: A Potential Sign for Alzheimer's Disease Based on Diffusion Tensor Imaging. J Neuroimaging. 2011 Aug 17; PubMed.

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