Brainstem pathology in amyotrophic lateral sclerosis and primary lateral sclerosis: A longitudinal neuroimaging study

Abstract

Background: Brainstem pathology is a hallmark feature of ALS, yet most imaging studies focus on cortical grey matter alterations and internal capsule white matter pathology. Brainstem imaging in ALS provides a unique opportunity to appraise descending motor tract degeneration and bulbar lower motor neuron involvement.

Methods: A prospective longitudinal imaging study has been undertaken with 100 patients with ALS, 33 patients with PLS, 30 patients with FTD and 100 healthy controls. Volumetric, vertex and morphometric analyses were conducted correcting for demographic factors to characterise disease-specific patterns of brainstem pathology. Using a Bayesian segmentation algorithm, the brainstem was segmented into the medulla, pons and mesencephalon to measure regional volume reductions, shape analyses were performed to ascertain the atrophy profile of each study group and region-of-interest morphometry was used to evaluate focal density alterations.

Results: ALS and PLS patients exhibit considerable brainstem atrophy compared to both disease- and healthy controls. Volume reductions in ALS and PLS are dominated by medulla oblongata pathology, but pontine atrophy can also be detected. In ALS, vertex analyses confirm the flattening of the medullary pyramids bilaterally in comparison to healthy controls and widespread pontine shape deformations in contrast to PLS. The ALS cohort exhibit bilateral density reductions in the mesencephalic crura in contrast to healthy controls, central pontine atrophy compared to disease controls, peri-aqueduct mesencephalic and posterior pontine changes in comparison to PLS patients. CONCLUS: ions: Computational brainstem imaging captures the degeneration of both white and grey matter components in ALS. Our longitudinal data indicate progressive brainstem atrophy over time, underlining the biomarker potential of quantitative brainstem measures in ALS. At a time when a multitude of clinical trials are underway worldwide, there is an unprecedented need for accurate biomarkers to monitor disease progression and detect response to therapy. Brainstem imaging is a promising addition to candidate biomarkers of ALS and PLS.

Keywords: Amyotrophic lateral sclerosis; Brainstem; Longitudinal study; Medulla; Mesencephalon; Motor neuron disease; Neuroimaging; Pons; Primary lateral sclerosis.

Fig. 1

The volumetric profile of the brainstem in ALS, PLS, disease and healthy controls. Corners: Estimate marginal means of the medulla, pons, midbrain are plotted for each study group adjusted for age, gender, education and total intracranial volumes. Centre: Percentage volumetric change is plotted with reference to healthy controls. ALS_T1: ALS patients first time point, ALS_T2: ALS patients second time point, FTD: patients with frontotemporal dementia, HC: healthy controls, PLS: patients with primary lateral sclerosis.

Fig. 2

Anatomical patterns of brainstem pathology based on vertex analyses correcting for age, gender, education and total intracranial volumes. Shape deformation in ALS are shown compared to healthy controls (A), disease controls (B) and PLS patients (C). 3D brainstem mesh is presented in blue (A), green (B) and pink (C). Patterns of atrophy is illustrated in orange with respect to healthy controls (A), in red with reference to disease controls (B) and blue in comparison to PLS patients (C). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Morphometric changes in the brainstem A, Morphometric brainstem alterations in ALS patients compared to healthy controls at p < .05 TFCE FWE corrected for age, gender, education and TIV. B, Morphometric brainstem alterations in ALS patients compared to disease controls (FTD) at p < .05 TFCE FWE corrected for age, gender, education and TIV. C, Morphometric brainstem alterations in ALS patients compared to PLS patients at p < .05 TFCE FWE corrected for age, gender, education and TIV. Statistical maps are presented in MNI space, MNI coordinates are provided under each view, and the brainstem mask is presented as a white underlay. Radiological convention is used; Lt – Left, Rt – Right.