Antemortem volume loss mirrors TDP-43 staging in older adults with non-frontotemporal lobar degeneration

Abstract

Over the past decade, the transactive response DNA-binding protein of 43 kDa (TDP-43) has been recognized as a major protein in normal and pathological ageing, increasing the risk of cognitive impairment and dementia. In conditions distinct from the frontotemporal lobar degenerations, TDP-43 appears to progress in a stereotypical pattern. In the present study, we aimed at providing a better understanding of the effects of TDP-43 and other age-related neuropathologies on cross-sectional grey matter volume in a cohort of non-FTLD subjects. We included 407 individuals with an antemortem MRI and post-mortem brain tissue from the Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic Alzheimer's Disease Patient Registry, or the Mayo Clinic Study of Aging. All individuals were assigned pathological stages for TDP-43, tau, amyloid-β, Lewy bodies, argyrophilic grain disease and vascular pathologies. Robust regressions were performed in regions of interest and voxel-wise to explore the relationships between TDP-43 stages and grey matter volume while controlling for other pathologies. Grey matter volumes adjusted for pathological and demographic variables were also computed for each TDP-43-positive case to further characterize the sequential involvement of brain structures associated with TDP-43, irrespective of the TDP-43 staging scheme. Robust regressions showed that the extent of TDP-43 pathology was associated with the extent of grey matter atrophy. Specifically, we found that the volume in medial temporal regions (i.e. amygdala, entorhinal cortex, hippocampus) decreased progressively with advancing TDP-43 stages. Importantly, these effects were of similar magnitude to those related to tau stages. Additional analyses using adjusted grey matter volume demonstrated a sequential pattern of volume loss associated with TDP-43, starting within the medial temporal lobe, followed by early involvement of the temporal pole, and eventually encompassing additional temporal and frontal regions. Altogether, this study demonstrates the major and independent contribution of TDP-43 pathology on neurodegeneration and provides further insight into the regional distribution of TDP-43 in non-FTLD subjects. Along with previous studies, these findings emphasized the importance of targeting TDP-43 in future clinical trials to prevent its detrimental effect on grey matter volume and, eventually, cognition.

Keywords: TDP-43; neuropathology; radiological-pathological study; tau; β-amyloid.

Figure 1

Results of robust regressions showing the effect of TDP-43 stages on grey matter volume. Values represent the percentage of volume change, with 95% confidence intervals, associated with TDP-43 stages compared to the TDP-43-negative group. Colours indicate results that survived Bonferroni correction for multiple comparisons (orange, α = 0.05, P < 0.004, 14 models considered) or an uncorrected threshold of P < 0.05 (blue). Columns indicate the pathological staging, and rows show the brain regions (i.e. dependent variables) ordered according to their progressive involvement with TDP-43 pathology.

Figure 2

Results of voxel-wise robust regressions showing the effect of TDP-43 stages on grey matter volume. Values represent the percentage of volume change associated with TDP-43 stages compared to the TDP-43-negative group. Coronal slices show both P < 0.001 FDR-corrected (yellow) and P < 0.001 uncorrected (red) results (k > 500 mm³). Results are presented in neurological convention. L = left; R = right.

Figure 3

Effect of W-score threshold on the percentage of TDP-43-positive cases showing more grey matter atrophy than TDP-43-negative cases. W-scores were computed using the TDP-43-negative cases (n = 252) as the reference group, and represent grey matter volume adjusted for Braak stage, Lewy body stage, diffuse and neuritic amyloid-β plaques, argyrophilic grain disease, vascular pathology, and covariates. Colours were used for the regions showing most frequently grey matter atrophy in the TDP-43-positive versus TDP-43-negative cases. Brain regions on the right are ordered by the area under the curve.

Figure 4

Pairwise conditional probability matrix showing the probability of grey matter volume loss in each brain region compared to other brain regions in TDP-43-positive cases. Reading the plot from left to right, the conditional probability estimates (%) show the estimated probability that the region on the left shows grey matter volume loss before the region on the right. Reading from top to bottom, the entries show the estimated probability that the region below shows grey matter volume loss before the region above. Dots indicate results that were statistically significant at the P < 0.01 level (black) and that survived Bonferroni correction for multiple comparisons (red, α = 0.05, P < 0.00006, 903 models considered). P-values were assessed using exact McNemar’s test, and a region was considered having grey matter volume loss when W-score < –1.65 (i.e. volume below the 95th percentiles of the TDP-43-negative group after accounting for pathological scores and covariates).

Figure 5

Frequency map of grey matter atrophy in TDP-43-positive cases compared to TDP-43-negative cases. Values represent the percentage of TDP-43-positive cases having significantly more atrophy than the TDP-43-negative group (W-score < –1.65) accounting for Braak stage, Lewy body stage, diffuse and neuritic amyloid-β plaques, argyrophilic grain disease, vascular pathology, age at MRI, time MRI to death, sex, total intracranial volume, and MRI magnetic field. Results are presented in neurological convention. L = left; R = right.