Layer-specific vulnerability is a mechanism of topographic map aging

Northall, Alicia; Doehler, Juliane; Weber, Miriam; Vielhaber, Stefan; Schreiber, Stefanie; Kuehn, Esther

doi:10.1016/j.neurobiolaging.2023.04.002

Cited by 10 publications

(53 citation statements)

References 59 publications

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“…We also acquired a whole-brain, 1.5 mm isotropic resolution functional image (81 slices, repetition time = 2000 ms, echo time = 25 ms, field-of-view read = 212 mm, GRAPPA 2, interleaved acquisition) using an EPI gradient-echo BOLD sequence. The functional imaging involved a blocked-design paradigm with 12-second periods of body part movements (left/right foot, left/right hand, tongue) alternated with 15-seconds of rest (as described previously 10 ). Before scanning, participants were trained in the movements and patients with difficulty were encouraged to conduct a reduced amount of movement precisely.…”

Section: Methodsmentioning

confidence: 99%

“…We then performed a vertex-wise linear regression analysis to predict qT1 values from mean curvature for each cortical layer in M1, on a subject specific basis, according to an existing approach 43 . The raw residuals of the regression models are referred to as ‘decurved’ qT1, following our previously published approach 10 . We then applied a data-driven approach to identify cortical layers in M1 from group-averaged decurved qT1 profiles separately for patients and controls 9–10 (see Fig.1B for details, see Supplementary Fig.1 for right hemisphere).…”

Section: Methodsmentioning

confidence: 99%

“…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. Moreover, we showed that the lower-limb (LL), upper-limb (UL) and face (F) fields show distinct levels of age-related iron accumulation 10 , highlighting the importance of using age-matched controls. In addition to iron, calcium is also dysregulated in ALS, where increased calcium is associated with glutamate excitotoxicity and motor neuron death in animal models 20–21 .…”

Section: Introductionmentioning

confidence: 99%

“…The present study aimed to provide a systematic description of in-vivo pathology in ALS-patients. We used topographic layer imaging 24 to characterise pathology with respect to both cortical layers and fields 10 . Sub-millimeter qT1 and QSM data, along with functional localisers, were collected from 12 ALS-patients and 12 age-, gender-, education- and handedness-matched controls.…”

Section: Introductionmentioning

confidence: 99%

“…We used increased positive QSM (pQSM) values as a marker of iron 6,15 , increased qT1 values as a marker of (de)myelination 27 , and decreased (more negative) negative QSM (nQSM) as a marker of calcium 28 . We extracted microstructural profiles from each cortical layer (superficial, layer 5a, layer 5b, layer 6) according to a previously published approach 9–10 , and calculated multimodal in-vivo pathology maps. We then tested whether (i) the mean cortical thickness is decreased and/or the layer architecture of M1 is degenerated in patients compared to controls, (ii) iron accumulation is layer-specific in ALS, (iii) the accumulation of iron and calcium is topographic ( i.e., largely restricted to the first-affected cortical field) or atopographic ( i.e., not restricted to the first-affected cortical field), (iv) iron and/or calcium accumulation hotspots precede demyelination, (v) the low-myelin borders remain intact or disrupt over disease progression and show specifically high or specifically low substance accumulation and (vi) a very-slow progressing patient shows a distinct pathology profile compared to other patients.…”

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: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multimodal layer modelling revealsin-vivopathology in ALS

Northall

Doehler

Weber

et al. 2023

Preprint

Self Cite

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Multimodal layer modelling reveals in vivo pathology in amyotrophic lateral sclerosis

Northall,

Doehler,

Weber

et al. 2023

Brain

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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 post-mortem investigations at advanced disease stages. A systematic in-vivo description of the microstructural changes that characterise early-stage ALS, and their subsequent development, is so far lacking. Recent advances in ultra-high field (7 T) MRI data modelling allow us to investigate cortical layers in-vivo. Given the layer-specific and topographic signature of pathology in ALS, we combined submillimeter structural 7T-MRI data (qT1, QSM), functional localisers of body parts (upper limb, lower limb, face) and automated layer modelling to systematically describe pathology in the primary motor cortex (M1), in 12 living ALS-patients with reference to 12 age-, gender-, handedness- and education-matched controls. Longitudinal sampling was performed for a subset of patients. We calculated multimodal pathology maps for each layer (superficial layer, layer 5a, layer 5b, layer 6) of M1 to identify hotspots of demyelination, iron and calcium accumulation in different cortical fields. We show preserved mean cortical thickness and layer architectures of M1, despite significantly increased iron in layer 6 and significantly increased calcium in layer 5a and superficial layer, in patients compared to controls. The behaviorally first-affected cortical field shows significantly increased iron in L6 compared to other fields, while calcium accumulation is atopographic and significantly increased in the low-myelin borders between cortical fields compared to the fields themselves. A subset of patients with longitudinal data shows that the low-myelin borders are particularly disrupted, and that calcium hotspots but to a lesser extent iron hotspots precede demyelination. Finally, we highlight that a very-slow progressing patient (P4) shows a distinct pathology profile compared to the other patients. Our data shows 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. Importantly, the distinct pathology profile of a very-slow progressing patient (P4) highlights a distinction between disease duration and pathology progression. Our findings demonstrate the importance of in-vivo histology for the diagnosis and prognosis of neurodegenerative diseases such as ALS.

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The ageing central nervous system in multiple sclerosis: the imaging perspective

Filippi,

Preziosa,

Barkhof

et al. 2024

Brain

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The interaction between ageing and multiple sclerosis is complex and carries significant implications for patient care. Managing multiple sclerosis effectively requires an understanding of how ageing and multiple sclerosis impact brain structure and function. Ageing inherently induces brain changes, including reduced plasticity, diminished grey matter volume, and ischaemic lesion accumulation. When combined with multiple sclerosis pathology, these age-related alterations may worsen clinical disability. Ageing may also influence the response of multiple sclerosis patients to therapies and/or their side-effects, highlighting the importance of adjusted treatment considerations. Magnetic resonance MRI is highly sensitive to age- and multiple sclerosis-related processes. Accordingly, MRI can provide insights into the relationship between ageing and multiple sclerosis, enabling a better understanding of their pathophysiological interplay and informing treatment selection. This review summarizes current knowledge on the immuno-pathological and MRI aspects of ageing in the central nervous system in the context of multiple sclerosis. Starting from immunosenescence, ageing-related pathological mechanisms, and specific features like enlarged Virchow-Robin spaces, this review then explores clinical aspects, including late-onset multiple sclerosis, the influence of age on diagnostic criteria, and comorbidity effects on imaging features. The role of MRI in understanding neurodegeneration, iron dynamics, and myelin changes influenced by ageing and how MRI can contribute to defining treatment effects in ageing multiple sclerosis patients, are also discussed.

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Layer-specific vulnerability is a mechanism of topographic map aging

Cited by 10 publications

References 59 publications

Multimodal layer modelling revealsin-vivopathology in ALS

Multimodal layer modelling revealsin-vivopathology in ALS

Multimodal layer modelling reveals in vivo pathology in amyotrophic lateral sclerosis

The ageing central nervous system in multiple sclerosis: the imaging perspective

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