Motor cortical patterns of upper motor neuron pathology in amyotrophic lateral sclerosis: A 3 T MRI study with iron-sensitive sequences

Donatelli, Graziella; Costagli, Mauro; Cecchi, Paolo; Migaleddu, Gianmichele; Bianchi, Francesca; Frumento, Paolo; Siciliano, Gabriele; Cosottini, Mirco

doi:10.1016/j.nicl.2022.103138

Cited by 8 publications

(11 citation statements)

References 63 publications

(118 reference statements)

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“…This suggests that iron accumulation in L6 may provide an earlier marker of pathology than the degeneration of L5(b) 5 . Our data also show that iron accumulates most strongly in the first-affected cortical field, as expected [17][18][19] , and that this is specific to L6. However, in our data, the degree of iron accumulation (% of pQSM pathology) does not predict whether or not a given cortical field is behaviourally affected.…”

Section: Discussionsupporting

confidence: 85%

“…These maps reveal that demyelination is minimal compared to iron and calcium accumulation. As expected 17–19 , iron accumulation is higher in the first-affected cortical field compared to the other fields (excluding the contralateral field given evidence of highly symmetric pQSM increases 19 ; see filled red arrows in Fig.3 ). This effect is specific to L6 (first-affected: M = 8.95, SD = 7.94, others: M = 2.49, SD = 1.68; t (6)= 2.81, p = .013, d = .95, 95% CI [−.04 2.22]), while there are no significant differences in L5b (first-affected: M = 6.66, SD = 8.19, others: M = 2.78, SD = 2.60; t (6)= 1.82, p = .056, d = .54, 95% CI [−.27 1.50]), L5a (first-affected: M = 4.66, SD = 3.56, others: M = 3.54, SD = 2.45; t (6)= 1.50, p = .089, d = .31, 95% CI [−.25 .95]) or Ls (first-affected: M = 3.11, SD = 2.44, others: M = 3.02, SD = 1.94; t (6)= .17, p = .436, d = .03, 95% CI [−.57 .65]).…”

Section: Resultssupporting

confidence: 68%

“…These maps reveal that demyelination is minimal compared to iron and calcium accumulation. As expected [17][18][19] , iron accumulation is higher in the first-affected cortical field compared to the other fields (excluding the contralateral field given evidence of highly symmetric pQSM increases 19 ; see filled red arrows in Fig. 3).…”

Section: Iron Accumulates In First-affected Cortical Fieldsupporting

confidence: 69%

“…Previous MRI studies have shown iron accumulation in M1 of ALS-patients [12][13][14] , which has been approximately localised to deep M1, where it reflects neuroinflammation and microglia activation 6,15 , in addition to UMN impairment 16 . Moreover, iron accumulation strongly affects the topographic area corresponding to the symptom onset site (i.e., first-affected) [17][18][19] . We previously showed that the topographic areas of M1 are microstructurally-distinct in healthy adults and can therefore be referred to as cortical fields 10 , emphasising the need for precise localisation.…”

Section: Introductionmentioning

confidence: 99%

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Multimodal layer modelling revealsin-vivopathology in ALS

Northall

Doehler

Weber

et al. 2023

Preprint

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Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterised by the loss of motor control. Current understanding of ALS pathology is largely based on the post-mortem investigation of advanced disease. A precise in-vivo description of the microstructural changes that characterize early disease stages, and their subsequent development, is therefore lacking. Recent advances in ultra-high field (7T) MRI modelling allow us to investigate microcircuits, such as cortical layers, in-vivo. These automated methods reveal microarchitectural changes in the sub-millimeter range. To apply these methods of in-vivo histology to living ALS-patients, we used sub-millimeter qT1 and QSM data with functional localizers of cortical fields. We precisely characterized the in-vivo pathology in the primary motor cortex (M1) in 12 ALS-patients, in reference to 12 age-, gender-, education- and handedness-matched controls. Longitudinal sampling was performed for a subset of patients. We calculated multimodal pathology maps separately for the superficial layers (layers 2-3), layer 5a, layer 5b and layer 6 of M1 to identify hotspots of demyelination, iron and calcium accumulation in M1, both in behaviorally affected and non-affected cortical fields. Multimodal in-vivo pathology maps reveal critical insights into ALS disease mechanisms. We show that despite layer-specific substance accumulation, the principal layer architecture of M1 is preserved in early disease stages. We identify multiple, small hotspots of pathology within, but also beyond, the first-affected cortical field. In addition, we localize iron accumulation to layer 6, and calcium accumulation to the superficial layer and layer 5a. Longitudinal data show that hotspots of non-topographic calcium accumulation tend to precede demyelination at later time points, where the middle-superficial layers are most affected. These microstructural changes were in accordance with the loss of motor control, as assessed using quantitative behavioral markers of motor function. We show that layer-specific markers of in-vivo pathology can be identified in ALS-patients with a single 7T-MRI measurement after first diagnosis, and that such data provide critical insights into the individual disease state. Our data highlight the non-topographic architecture of ALS disease spread, and the role of calcium rather than iron accumulation in predicting future demyelination. We also highlight a potentially important role of low-myelin borders, that are known to connect to multiple areas within the M1 architecture, in disease spread. Our findings highlight the importance of in-vivo histology for the diagnosis and prognosis of neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 85%

Section: Resultssupporting

confidence: 68%

Section: Iron Accumulates In First-affected Cortical Fieldsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

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Multimodal layer modelling revealsin-vivopathology in ALS

Northall

Doehler

Weber

et al. 2023

Preprint

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“…The prior for the effect of geodesic distance on qT1 was set to normal (mean = 0 for all layers, same standard deviations as reported for the intercepts). QSM and aQSM priors were also informed by previous studies (Acosta-Cabronera et al 2018, Donatelli et al 2022). Signed QSM (QSM) values were allowed to vary between -0.125 and 0.125, aQSM values were allowed to vary between 0 and 0.125.…”

Section: Methodsmentioning

confidence: 99%

The 3D Structural Architecture of the Human Hand Area is Non-Topographic

Doehler

Northall

Liu

et al. 2022

Preprint

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The functional topography of the human primary somatosensory cortex (S1) hand area is a widely studied model system to understand sensory organization and plasticity. It is so far unclear whether or not the underlying 3D structural architecture also shows a topographic organization. We used 7T MRI data to quantify layer-specific myelin, iron and mineralization in relation to population receptive field maps of individual finger representations. This 3D description allowed us to identify a characteristic profile of layer-specific myelin and iron deposition in the S1 hand area, but revealed an absence of structural differences between individual finger representations, and an absence of low-myelin borders between individual fingers. Both, however, were detected between the hand and the face areas. Using markers of responsivity, precision and sensorimotor integration, we additionally phenotyped these microstructural features with respect to their relation to BOLD signal change and behavior. We conclude that the 3D structural architecture of the human hand area is non-topographic, other than in some monkey species, which suggests a high degree of flexibility for functional finger organization and plasticity in humans.

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Motor band sign is specific for amyotrophic lateral sclerosis and corresponds to motor symptoms

Zejlon,

Sennfält,

Finnsson

et al. 2024

Ann Clin Transl Neurol

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ObjectiveMagnetic resonance imaging can detect neurodegenerative iron accumulation in the motor cortex, called the motor band sign. This study aims to evaluate its sensitivity/specificity and correlations to symptomatology, biomarkers, and clinical outcome in amyotrophic lateral sclerosis.MethodsThis prospective study consecutively enrolled 114 persons with amyotrophic lateral sclerosis and 79 mimics referred to Karolinska University Hospital, and also 31 healthy controls. All underwent 3‐Tesla brain susceptibility‐weighted imaging. Three raters independently assessed motor cortex susceptibility with total and regional motor band scores. Survival was evaluated at a median of 34.2 months after the imaging.ResultsThe motor band sign identified amyotrophic lateral sclerosis with a sensitivity of 59.6% and a specificity of 91.1% versus mimics and 96.8% versus controls. Higher motor band scores were more common with genetic risk factors (p = 0.032), especially with C9orf72 mutation, and were associated with higher neurofilament light levels (std. β 0.22, p = 0.019). Regional scores correlated strongly with focal symptoms (medial region vs. gross motor dysfunction, std. β −0.64, p = 0.001; intermediate region vs. fine motor dysfunction, std. β −0.51, p = 0.031; lateral region vs. bulbar symptoms std. β −0.71, p < 0.001). There were no associations with cognition, progression rate, or survival.InterpretationIn a real‐life clinical setting, the motor band sign has high specificity but relatively low sensitivity for identifying amyotrophic lateral sclerosis. Associations with genetic risk factors, neurofilament levels and somatotopic correspondence to focal motor weakness suggest that the motor band sign could be a suitable biomarker for diagnostics and clinical trials in amyotrophic lateral sclerosis.

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Motor cortical patterns of upper motor neuron pathology in amyotrophic lateral sclerosis: A 3 T MRI study with iron-sensitive sequences

Cited by 8 publications

References 63 publications

Multimodal layer modelling revealsin-vivopathology in ALS

Multimodal layer modelling revealsin-vivopathology in ALS

The 3D Structural Architecture of the Human Hand Area is Non-Topographic

Motor band sign is specific for amyotrophic lateral sclerosis and corresponds to motor symptoms

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