Research Article: Sensitivity of restriction spectrum imaging to memory and neuropathology in Alzheimer’s disease

Date Published: August 2, 2017

Publisher: BioMed Central

Author(s): Emilie T. Reas, Donald J. Hagler, Nathan S. White, Joshua M. Kuperman, Hauke Bartsch, Karalani Cross, Richard Q. Loi, Akshara R. Balachandra, M. J. Meloy, Christina E. Wierenga, Douglas Galasko, James B. Brewer, Anders M. Dale, Linda K. McEvoy.


Diffusion imaging has demonstrated sensitivity to structural brain changes in Alzheimer’s disease (AD). However, there remains a need for a more complete characterization of microstructural alterations occurring at the earliest disease stages, and how these changes relate to underlying neuropathology. This study evaluated the sensitivity of restriction spectrum imaging (RSI), an advanced diffusion magnetic resonance imaging (MRI) technique, to microstructural brain changes in mild cognitive impairment (MCI) and AD.

MRI and neuropsychological test data were acquired from 31 healthy controls, 12 individuals with MCI, and 13 individuals with mild AD, aged 63–93 years. Cerebrospinal fluid amyloid-β levels were measured in a subset (n = 38) of participants. RSI measures of neurite density (ND) and isotropic free water (IF) were computed in fiber tracts and in hippocampal and entorhinal cortex gray matter, respectively. Analyses evaluated whether these measures predicted memory performance, correlated with amyloid-β levels, and distinguished impaired individuals from controls. For comparison, analyses were repeated with standard diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA) and mean diffusivity.

Both RSI and DTI measures correlated with episodic memory and disease severity. RSI, but not DTI, measures correlated with amyloid-β42 levels. ND and FA in the arcuate fasciculus and entorhinal cortex IF most strongly predicted recall performance. RSI measures of arcuate fasciculus ND and entorhinal cortex IF best discriminated memory impaired participants from healthy participants.

RSI is highly sensitive to microstructural changes in the early stages of AD, and is associated with biochemical markers of AD pathology. Reduced ND in cortical association fibers and increased medial temporal lobe free-water diffusion predicted episodic memory, distinguished cognitively impaired from healthy individuals, and correlated with amyloid-β. Although further research is needed to assess the sensitivity of RSI to preclinical AD and disease progression, these results suggest that RSI may be a promising tool to better understand neuroanatomical changes in AD and their association with neuropathology.

The online version of this article (doi:10.1186/s13195-017-0281-7) contains supplementary material, which is available to authorized users.

Partial Text

By the time of symptom onset in Alzheimer’s disease (AD), characteristic neuroanatomical changes have already begun to manifest. Although cognitive impairments are just emerging, cortical atrophy and white matter degeneration are detectable using magnetic resonance imaging (MRI) [1]. By the time these structural changes appear, the underlying neuropathology may render interventions to halt disease progression ineffective. Development of noninvasive tools to assess neural microstructure is critical to better characterize the earliest neurodegenerative events in AD, which in turn may permit the timely detection of incipient cognitive impairment and more effective intervention.

This study evaluated RSI metrics for sensitivity to disease status and cognitive deficits in MCI and AD. RSI-based measures of gray and white matter microstructure correlated with disease severity, functional ability, memory, and Aβ load.

This study identified novel diffusion imaging markers of microstructural changes in brain gray and white matter in MCI and AD. Reduced neurite density in multiple white matter tracts and increased medial temporal lobe free water diffusion strongly associated with memory deficits, disease status, and pathophysiology. These findings suggest that RSI is highly sensitive to microstructural changes in the early stages of neurodegenerative memory disease, supporting its potential utility as an early biomarker of preclinical neuropathological events.




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