Ex vivo T2 relaxation: associations with age-related neuropathology and cognition

Abstract

The transverse relaxation time constant, T(2), is sensitive to brain tissue's free water content and the presence of paramagnetic materials such as iron. In this study, ex vivo magnetic resonance imaging was used to investigate alterations in T(2) related to Alzheimer's disease (AD) pathology and other types of neuropathology common in old age, as well as the relationship between T(2) alterations and cognition. Cerebral hemispheres were obtained from 371 deceased older adults. Using fast spin-echo imaging with multiple echo times, T(2) maps were produced and warped to a study-specific template. Hemispheres underwent neuropathologic examination for identification of AD pathology and other common age-related neuropathologies. Voxelwise linear regression was carried out to detect regions of pathology-related T(2) alterations and, in separate analyses, regions in which T(2) alterations were linked to antemortem cognitive performance. AD pathology was associated with T(2) prolongation in white matter of all lobes and T(2) shortening in the basal ganglia and insula. Gross infarcts were associated with T(2) prolongation in white matter of all lobes, and in the thalamus and basal ganglia. Hippocampal sclerosis was associated with T(2) prolongation in the hippocampus and white matter of the temporal lobe. After controlling for neuropathology, T(2) prolongation in the frontal lobe white matter was associated with lower performance in the episodic, semantic, and working memory domains. In addition, voxelwise analysis of in vivo and ex vivo T(2) values indicated a positive relationship between the two, though further investigation is necessary to accurately translate findings of the present study to the in vivo case.

Keywords: Cognition; Gross infarct; Hippocampal sclerosis; MRI; Neuroimaging; Voxelwise.

Figure 1

Slices from a typical masked proton density-weighted image volume (TE = 13 ms), a T₂-weighted image volume (TE = 52 ms), and estimated T₂ map from an individual postmortem cerebral hemisphere, shown in the same orientation and resolution as the natively acquired sagittal slices.

Figure 2

(A) Sagittal, (B) axial, and (C) coronal views showing regions of significant T₂ prolongation (orange) and T₂ shortening (blue) associated with a high summary score of AD pathology, according to a combined linear regression analysis that simultaneously considered AD pathology, acute and chronic gross infarcts, and hippocampal sclerosis (and covariates). The grayscale underlay is the study-specific template (proton density-weighted). Alphanumeric labels are those cluster identifiers introduced in Table 3.

Figure 3

(A) Sagittal, (B) axial, and (C) coronal views showing regions of significant T₂ prolongation and T₂ shortening associated with the number of chronic gross infarcts per cerebral hemisphere, according to a combined linear regression analysis that simultaneously considered AD pathology, acute and chronic gross infarcts, and hippocampal sclerosis (and covariates). The grayscale underlay is the study-specific template (proton density-weighted). Alphanumeric labels are those cluster identifiers introduced in Table 3.

Figure 4

(A) Sagittal, (B) axial, and (C) coronal views showing regions of significant T₂ prolongation and T₂ shortening associated with the number of acute gross infarcts per cerebral hemisphere, according to a combined linear regression analysis that simultaneously considered AD pathology, acute and chronic gross infarcts, and hippocampal sclerosis (and covariates). The grayscale underlay is the study-specific template (proton density-weighted). Alphanumeric labels are those cluster identifiers introduced in Table 3.

Figure 5

(A) Sagittal, (B) axial, and (C) coronal views region of significant T₂ prolongation associated with hippocampal sclerosis, according to a combined linear regression analysis that simultaneously considered AD pathology, acute and chronic gross infarcts, and hippocampal sclerosis (and covariates). The grayscale underlay is the study-specific template (proton density-weighted). Alphanumeric labels are those cluster identifiers introduced in Table 3.

Figure 6

Sagittal views of the regions in which episodic memory (EP), semantic memory (SE), and working memory (WO) deficits were significantly associated with T₂ prolongation, according to linear regression models that also considered neuropathology measures and demographic covariates. Colors indicate the amount of additional variance in working memory explained by T₂, beyond that accounted for by neuropathology and demographics. The grayscale underlay is the study-specific template (proton density-weighted).

Figure 7

Ex vivo T₂ values versus in vivo T₂ values for corresponding voxels within seven regions of interest located in white matter and subcortical gray matter (one color per region). The mean ex vivo T₂ value for a given voxel was calculated across 28 ex vivo hemispheres registered to a template. The mean in vivo T₂ value for each voxel was calculated across 28 in vivo hemispheres registered to the same template. Slopes for all regression lines were significantly positive (R² values displayed, p < 10⁻¹⁵ for all).