Introduction

Limbic-predominant age-related transactive response DNA binding protein 43 (TDP-43) encephalopathy neuropathological change (LATE-NC) is common in older adults and is associated with neurodegeneration, cognitive impairment and dementia¹. Structural MRI studies of LATE-NC conducted so far have mostly focused on specific gray matter regions^1–5. Deformation-based morphometry (DBM) is an image analysis technique that describes localized structural abnormalities at the voxel level from the non-linear deformation fields that align MRI scans to a common anatomical template⁶. In this work, we investigated the voxel-wise association of LATE-NC with brain morphometric anomalies by combining DBM on ex-vivo MRI with detailed neuropathology data in a large number of community-based older adults that came to autopsy (N=897). Furthermore, we investigated morphometric differences across LATE-NC stages and identified the earliest stage of the pathology exhibiting significant morphometric anomalies.

Methods

Participants, MRI, neuropathology
Cerebral hemispheres were acquired from 897 deceased older adults participating in four epidemiological cohort studies of aging: Rush Memory and Aging Project, Religious Orders Study⁷, Minority Aging Research Study, and Rush Alzheimer’s Disease Center African American Clinical Core⁸. Hemispheres were imaged ex-vivo on 3T clinical MRI scanners within approximately 1-month postmortem while immersed in 4% formaldehyde solution, using a 2D spin-echo sequence (Fig.1) with multiple echo times ranging from 10–50ms and 0.6×0.6×1.5mm³ voxel size (Fig.2A). The images from the first echo were non-linearly registered to an ex-vivo brain hemisphere template using ANTs⁹ (Fig.1). The logarithm of the Jacobian determinant (LogJ) of the deformation fields was calculated in each voxel, and the resulting LogJ maps were smoothed by a 4mm FWHM Gaussian filter⁶. Following ex-vivo MRI, hemispheres underwent detailed neuropathologic examination by a board-certified neuropathologist (Fig.2B).

Statistical analyses
Voxel-wise linear regression was used to test the association between deformations shown in the LogJ maps and LATE-NC stages, controlling for other age-related neuropathologies (Alzheimer’s disease, Lewy bodies, arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts), demographics (age at death, sex, education), postmortem intervals, and scanners. Statistical tests were performed using FSL’s PALM tool with 10,000 permutations and threshold-free cluster enhancement¹⁰. To identify the earliest LATE-NC stage exhibiting morphometric abnormalities, LogJ values were compared between LATE-NC stages 1–5 and stage 0, using voxel-wise linear regression and controlling for the same variables as described above. Statistical significance was set at p<0.05 after family-wise error rate (FWER) adjustment to correct for multiple comparisons.

Results

Voxel-wise linear regression revealed an independent association of LATE-NC with significantly lower volume in both gray and white matter regions within the temporal and frontal lobes and basal ganglia (p<0.05) (Fig.3). Significantly lower volume was observed in amygdala, hippocampus, entorhinal, parahippocampal, temporal pole, inferior temporal, middle temporal, fusiform, medial orbitofrontal, lateral orbitofrontal, insula, accumbens, and putamen cortices (Fig.3). Groupwise comparison of LogJ values revealed significant morphometric anomalies in LATE-NC stages 1–5 compared to stage 0 (p<0.05) (Fig.4). The spatial pattern included small temporal lobe areas in stages 1–2, more temporal lobe tissue as well as basal ganglia tissue in stage 3, and finally also included frontal lobe areas in stages 4–5 (Fig.4).

Discussion

The present study investigated the voxel-wise association of LATE-NC with brain morphometric anomalies by combining DBM on ex-vivo MRI with detailed neuropathology data in a large number of community-based older adults. Our results revealed an independent association of LATE-NC with lower tissue volume in a spatial pattern that is consistent with the known distribution of LATE-NC^1,11–13. A comparison across stages revealed significant lower tissue volume as early as LATE-NC stage 1, suggesting that MRI is sensitive to the early stages of the disease.

Conclusion

The present study in autopsied brains from a large number of community-based older adults showed an independent association of LATE-NC with lower volume in gray and white matter areas of the temporal and frontal lobes and basal ganglia. This pattern is consistent with the known distribution of LATE-NC in the brain and may potentially be used in combination with other imaging and clinical information towards the development of a marker of this devastating neuropathology. Finally, morphometric anomalies were detected as early as LATE-NC stage 1, suggesting that MRI is sensitive to the early stages of the disease.

References

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