Diffusion indices on magnetic resonance imaging and neuropsychological performance in amnestic mild cognitive impairment

Background

Magnetic resonance diffusion tensor imaging (DTI) shows promise in the early detection of microstructural pathophysiological changes in the brain.

Objectives

To measure microstructural differences in the brains of participants with amnestic mild cognitive impairment (MCI) compared with an age‐matched control group using an optimised DTI technique with fully automated image analysis tools and to investigate the correlation between diffusivity measurements and neuropsychological performance scores across groups.

Methods

34 participants (17 participants with MCI, 17 healthy elderly adults) underwent magnetic resonance imaging (MRI)‐based DTI. To control for the effects of anatomical variation, diffusion images of all participants were registered to standard anatomical space. Significant statistical differences in diffusivity measurements between the two groups were determined on a pixel‐by‐pixel basis using gaussian random field theory.

Results

Significantly raised mean diffusivity measurements (p<0.001) were observed in the left and right entorhinal cortices (BA28), posterior occipital–parietal cortex (BA18 and BA19), right parietal supramarginal gyrus (BA40) and right frontal precentral gyri (BA4 and BA6) in participants with MCI. With respect to fractional anisotropy, participants with MCI had significantly reduced measurements (p<0.001) in the limbic parahippocampal subgyral white matter, right thalamus and left posterior cingulate. Pearson''s correlation coefficients calculated across all participants showed significant correlations between neuropsychological assessment scores and regional measurements of mean diffusivity and fractional anisotropy.

Conclusions

DTI‐based diffusivity measures may offer a sensitive method of detecting subtle microstructural brain changes associated with preclinical Alzheimer''s disease.Substantial effort is currently being focused towards improving the diagnosis of early Alzheimer''s disease. The term mild cognitive impairment (MCI) is often used to describe the transitional stage between normal ageing and dementia. Owing to the heterogeneity of MCI, not all participants with MCI will have predementia Alzheimer''s disease.¹ Peterson et al² suggested the criteria for a subtype of MCI, so‐called amnestic MCI, which is presumed to present a typical prodrome of dementia in Alzheimer''s disease. People with amnestic MCI have a 10–15% annual conversion rate to Alzheimer''s disease compared with 1–2% in the normal elderly population.² Neuroimaging studies conducted on participants with MCI using magnetic resonance imaging (MRI) morphological analysis have consistently reported atrophic changes primarily in the medial temporal lobe and, to a lesser extent, in the thalamus and cingulate gyrus.^3,4,5 Furthermore, the degree of atrophy in temporal lobe structures correlates with performance on memory tasks³ and with density of neurofibrillar tangles at autopsy.⁶ These findings support the concept that MRI‐based neuroimaging studies together with neuropsychological assessment may enable identification of participants with MCI which may progress to Alzheimer''s disease, and evaluation of the efficacy of novel treatments.Recent studies using diffusion tensor magnetic resonance imaging (DTI) have shown microstructural changes in the hippocampus of participants with MCI that may not be apparent using standard anatomical imaging.^7,8,9 DTI measures the random motion of bulk water in cerebral tissue. When the random motion of water is restricted preferentially in one direction when compared with the orthogonal planes, such as occurs in white matter, diffusion is referred to as anisotropic; in contradistinction, bulk water motion in the cerebrospinal fluid is equal in all directions and is thus referred to as isotropic. Fractional anisotropy, a quantitative measurement of the degree of anisotropy, can be used to probe the integrity of white matter fibre tracts.¹⁰ The mean diffusivity is a quantitative measurement of the bulk mean motion of water considered in all directions and is used to interrogate pathological changes in cerebral tissue, such as ischaemia in patients with stroke.¹⁰ DTI studies in patients with MCI have shown raised mean diffusivity in the hippocampus and other temporal lobe regions, using manually traced regions of interest (ROI).^7,8,9 Although the precise neural correlates of altered mean diffusivity measurements are uncertain, increased mean diffusivity most likely results from loss of neurones, axons and dendrites, resulting in an increase in extracellular space and raised water diffusivity in these regions.⁷ It is unknown whether such microstructural changes, detectable by DTI, are due to amyloid or neurofibrillar tangle formation or some other neuropathological process in Alzheimer''s disease. However, the finding of a negative correlation between hippocampal diffusivity and volume in people with MCI indicates that both measurements are sensitive to early Alzheimer''s disease neuropathology.⁷ Using manually defined ROI analyses, a recent study has identified marked changes in volume, mean diffusivity and fractional anisotropy indices in the hippocampus in participants with MCI compared with age‐matched controls.⁹ Specifically, compared with volume measurements, raised left hippocampal mean diffusivity was found to be a strong independent predictor of poor verbal memory performance in both controls and participants with MCI.In this study, we investigated whether mean diffusivity and fractional anisotropy measurements differed between participants with MCI and age‐matched controls, using an optimised DTI protocol¹¹ and a fully automated voxel‐by‐voxel method of data analysis. This approach assesses the entire brain, rather than just one structure, and circumvents any operator‐introduced errors in the manual selection of ROI for analysis. In addition, we investigated the relationship between measurements of water diffusivity and performance on memory and other cognitive tasks across participants.