Memory-related white matter tract integrity in amyotrophic lateral sclerosis: an advanced neuroimaging and neuropsychological study

We aimed to investigate structural changes in vivo in memory-related white matter tracts (i.e., perforant pathway zone [PPZ]; uncinate fasciculus [UF]; fornix) using diffusion tensor tractography and evaluate possible associations with memory performance in nondemented patients with amyotrophic lateral sclerosis (ALS). Forty-two ALS patients and 25 healthy controls (HCs) underwent a 30-directional diffusion-weighted imaging on a 3T MR scanner, followed by tractography of PPZ, UF, and fornix and analysis of fractional anisotropy (FA), axial diffusivity and radial diffusivity (Dr). Patients were administered neuropsychological measures of verbal (list learning via Rey Auditory Verbal Learning Test [RAVLT] and prose memory via Babcock Story Recall Test) and nonverbal (Rey's Complex Figure Test) episodic memory. After correcting for multiple comparisons, ALS patients showed increased Dr in the left PPZ compared to HC. We then fitted a multivariate general linear model within ALS patients with neuropsychological measures as dependent variables and age, age2, gender, verbal IQ, and diffusion tensor tractography metrics with at least medium effect size differences between ALS and HC as independent variables. We found that (1) left PPZ FA, gender, and verbal IQ contributed to RAVLT-Total Learning; (2) left PPZ FA, left UF Dr, and gender contributed to RAVLT-Immediate Recall; and (3) left PPZ FA and left UF axial diffusivity contributed to Babcock Story Recall Test-Immediate and Delayed Recall. Advanced neuroimaging techniques verified in this study previously reported neuropathological findings regarding PPZ degeneration in ALS. We also detected a unique contribution of microstructural changes in hippocampal and frontotemporal white matter tracts on patients' memory profile.