Abstract
The study of multiple indices of diffusion, including axial (DA), radial (DR) and mean diffusion (MD), as well as fractional anisotropy (FA), enables WM damage in Alzheimer's disease (AD) to be assessed in detail. Here, tract-based spatial statistics (TBSS) were performed on scans of 40 healthy elders, 19 non-amnestic MCI (MCIna) subjects, 14 amnestic MCI (MCIa) subjects and 9 AD patients. Significantly higher DA was found in MCIna subjects compared to healthy elders in the right posterior cingulum/precuneus. Significantly higher DA was also found in MCIa subjects compared to healthy elders in the left prefrontal cortex, particularly in the forceps minor and uncinate fasciculus. In the MCIa versus MCIna comparison, significantly higher DA was found in large areas of the left prefrontal cortex. For AD patients, the overlap of FA and DR changes and the overlap of FA and MD changes were seen in temporal, parietal and frontal lobes, as well as the corpus callosum and fornix. Analysis of differences between the AD versus MCIna, and AD versus MCIa contrasts, highlighted regions that are increasingly compromised in more severe disease stages. Microstructural damage independent of gross tissue loss was widespread in later disease stages. Our findings suggest a scheme where WM damage begins in the core memory network of the temporal lobe, cingulum and prefrontal regions, and spreads beyond these regions in later stages. DA and MD indices were most sensitive at detecting early changes in MCIa.
Highlights
Alzheimer’s disease (AD) is thought to begin with biochemical and structural changes at the synaptic level which impinge on cognitive function and lead to neuronal death and the degeneration of white matter (WM) tracts [1]
Detection of diffusional changes in mild cognitive impairment (MCI) Small areas of significantly higher fractional anisotropy (FA) were found in MCIna relative to control in the midbody of the corpus callosum (Figure 1)
Our findings indicate that early neurodegenerative changes occurring in MCIna and MCIa can be detected with multiple indices of diffusion
Summary
Alzheimer’s disease (AD) is thought to begin with biochemical and structural changes at the synaptic level which impinge on cognitive function and lead to neuronal death and the degeneration of white matter (WM) tracts [1]. A significant proportion of those with MCI may represent a prodromal state of AD, with an estimated 10–15% of MCI subjects progressing to dementia every year [2] Within this framework, an ability to accurately classify MCI subjects into those with and without underlying AD pathology is vital as diseasemodifying compounds which target amyloid beta (Ab) accumulation may only work in the earliest preclinical stages of AD [3]. There is evidence for direct WM damage occurring as a result of oligodendrocyte death and reactive gliosis [9] Another concept of AD pathology is the retrogenesis theory which posits that WM degeneration follows a pattern that is the reverse of myelogenesis with late-myelinating pathways being first affected by AD, and early-myelinating pathways affected later in the disease [10]
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