Structural and functional brain connectome in motor neuron diseases: A multicenter MRI study

Abstract

Objective: To investigate structural and functional neural organization in amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), and progressive muscular atrophy (PMA).

Methods: A total of 173 patients with sporadic ALS, 38 patients with PLS, 28 patients with PMA, and 79 healthy controls were recruited from 3 Italian centers. Participants underwent clinical, neuropsychological, and brain MRI evaluations. Using graph analysis and connectomics, global and lobar topologic network properties and regional structural and functional brain connectivity were assessed. The association between structural and functional network organization and clinical and cognitive data was investigated.

Results: Compared with healthy controls, patients with ALS and patients with PLS showed altered structural global network properties, as well as local topologic alterations and decreased structural connectivity in sensorimotor, basal ganglia, frontal, and parietal areas. Patients with PMA showed preserved global structure. Patient groups did not show significant alterations of functional network topologic properties relative to controls. Increased local functional connectivity was observed in patients with ALS in the precentral, middle, and superior frontal areas, and in patients with PLS in the sensorimotor, basal ganglia, and temporal networks. In patients with ALS and patients with PLS, structural connectivity alterations correlated with motor impairment, whereas functional connectivity disruption was closely related to executive dysfunction and behavioral disturbances.

Conclusions: This multicenter study showed widespread motor and extramotor network degeneration in ALS and PLS, suggesting that graph analysis and connectomics might represent a powerful approach to detect upper motor neuron degeneration, extramotor brain changes, and network reorganization associated with the disease. Network-based advanced MRI provides an objective in vivo assessment of motor neuron diseases, delivering potential prognostic markers.

Figure 1. MRI processing pipeline

(Ia) Gray matter was parcellated in 220 similarly sized brain regions, which included cerebral cortex and basal ganglia but excluded the cerebellum. (Ib) Diagram reports diffusion tensor MRI and resting-state fMRI preprocessing steps and construction of brain structural and functional connectomes. Structural and functional matrices were the input for 3 distinctive analyses: (II) global and lobar graph analysis, (III) connectivity analysis, and (IV) correlation analysis. AAL = automated anatomical labeling; FA = fractional anisotropy.

Figure 2. Summary of altered structural and functional metrics in the different motor neuron disease variants

Three shades of green are used to define the severity of damage in terms of percentage of altered metrics (global and lobar analyses) and percentage of altered connections between 2 lobes (connectivity analysis). The 3 shades of green depict the following ranks: 1%–25% (light green), 26%–50% (medium green), and 51%–75% (dark green). White background represents the absence of alterations. ALS = amyotrophic lateral sclerosis; BG = basal ganglia; FA = fractional anisotropy; FI = fronto-insular; O = occipital; P = parietal; PLS = primary lateral sclerosis; S = sensorimotor; T = temporal.

Figure 3. Graph analysis properties of brain lobar networks in patients with amyotrophic lateral sclerosis (ALS), patients with primary lateral sclerosis (PLS), and patients with progressive muscular atrophy (PMA) and healthy controls (HC)

Boxplot of structural nodal strength, path length, local efficiency, and clustering coefficient of each brain lobe are shown for patient groups and matched HC. The red horizontal line in each box plot represents the median, the 2 lines just above and below the median represent the 25th and 75th percentiles, whiskers represent the minimum and maximum values, and all the dots outside the confidence interval are considered as outliers. *p < 0.05. All the comparisons were adjusted for age, sex, and MRI scanner. ALS = amyotrophic lateral sclerosis; PLS = primary lateral sclerosis; PMA = progressive muscular atrophy.

Figure 4. Subnetworks showing altered structural and functional connectivity in patients with amyotrophic lateral sclerosis (ALS), patients with primary lateral sclerosis (PLS), and patients with progressive muscular atrophy (PMA) relative to healthy controls (HC) and between patient groups

Altered structural (A) and functional (B) connections are represented in magenta and orange, respectively. All the comparisons were adjusted for age, sex, and MRI scanner. Six shades of blue were used to define the belonging of each node to different lobes starting with light blue (frontal lobe) to dark blue (posterior lobe, i.e., occipital). A = anterior; FA = fractional anisotropy; P = posterior.

Figure 5. Subnetworks showing overlapping affected connections

Overlapping affected connections in ALS and patients with PLS in structural and functional MRI (A) and overlapping structural and functional affected connections within the two groups (B) are represented in red. Six shades of blue were used to define the belonging of each node to different lobes starting with light blue (frontal lobe) to dark blue (posterior lobe, i.(E), occipital). A = anterior; ALS = amyotrophic lateral sclerosis; FA = fractional anisotropy; L = left; P = posterior; PLS = primary lateral sclerosis; R = right.

Figure 6. Characterization of the relationship between structural and functional MRI metrics and clinical/cognitive data in patients with amyotrophic lateral sclerosis (ALS) and patients with primary lateral sclerosis (PLS)

Each row shows structural and functional brain proprieties (see table e-7, data available from Dryad, https://doi.org/10.5061/dryad.v15dv41t3, for details on brain parcellation) and each column clinical and cognitive scores in ALS (A) and PLS (B). Color scale represents Pearson correlation coefficient. Red square alone or with a hash indicates statistical significance, respectively, at a threshold of p < 0.05 and p < 0.001. Δdp = Disease progression rate; ALSFRS-r = Amyotrophic Lateral Sclerosis Functional Rating Scale–revised; BG = basal ganglia; CST = card sorting test; FA = fractional anisotropy; FBI = frontal behavioral inventory; FRONT-INS = frontoinsular; Inf = inferior; Mid = middle; MMSE = Mini-Mental State Examination; MRC = Medical Research Council; p = part; PAR = parietal; SENSMOT = sensorimotor; SF = semantic fluency; Sup = superior; Supp = supplementary; UMN = upper motor neuron.