White matter damage and degeneration in traumatic brain injury

10.1016/j.tins.2024.07.003

<논문요약>

White Matter Injury as a Key Determinant in Long-term TBI Effects

TBI as an Ongoing Condition

• TBI is now viewed as a complex ongoing condition

• Can become a chronic burden over time

• Disrupts neural circuits across brain regions

Impact on White Matter Tracts

• All forms of TBI can damage neurons and axons in white matter tracts

• Single moderate to severe TBI can lead to persistent axon injury

• Repeated head injuries can exhibit chronic phase degeneration of white matter

Functional Consequences

• Slows and desynchronizes information processing

• Impairs cognitive functions, particularly processing speed

• Strong relationship with impaired daily life function

Axonal Injury as Central to White Matter Damage in TBI

Characteristics of Axonal Injury

• Hallmark pathology of TBI

• Most damage due to secondary injury processes

• Dispersed pattern of individual damaged axons among intact axons

Animal Models of Axonal Injury

• Closed head impact produces dispersed axonal injury

• Direct cortical impact results in cortical damage and axon degeneration

• Fluid percussion model causes neuronal atrophy and diffuse axon degeneration

Progression of Axonal Injury to White Matter Tract Degeneration

Neuroimaging in TBI

• CT for acute phase visualization

• MRI for increased sensitivity and additional modalities

• DTI for detecting microstructural changes in white matter tracts

Diffusion Tensor Imaging (DTI)

• Sensitive to microstructure of aligned myelinated axons

• Fractional anisotropy (FA) as a measure of axon damage

• Limitations in specificity and confounding factors

Advanced Neuroimaging Techniques

• Diffusion tractography for evaluating white matter tract continuity

• Functional MRI for assessing functional connectivity

• T1/T2-weighted ratio for measuring myelination

Post-traumatic Neurodegeneration

• MRI studies characterize brain atrophy in chronic phase TBI

• Distinct pattern of degeneration in central white matter tracts

• Increased risk of cerebral atrophy in older TBI patients

TBI Impairment of Axonal Transport and Cytoskeleton

Disruption of Axonal Transport

• TBI forces sever microtubule bundles

• Impairs transport of vesicles and organelles

• Causes accumulation and swelling at damage sites

Molecular Pathways of Axon Degeneration

• NMNAT2/SARM1 pathway in axon survival and degeneration

• Studies using Sarm1 gene deletion show reduced axon degeneration

• Potential for neuroprotective modulation of SARM1 pathway

Cytoskeleton Collapse and Protein Degradation

• Condensed axoplasm due to cytoskeleton collapse

• Neurofilament degradation as a biomarker

• Tau phosphorylation and aggregation in TBI and CTE

TBI Disruption of Axon-Myelin Interactions

Demyelination and Its Effects

• Loss of myelin sheaths around intact axons

• Disrupts fast, high-fidelity signal transmission

• Impairs metabolic support from oligodendrocytes

Remyelination and Myelin Plasticity

• Spontaneous remyelination possible after demyelination

• Activity-regulated myelin remodeling in adult CNS

• Formation of myelin outfoldings in TBI

Node of Ranvier Disruption

• Critical for electrical signal conduction

• Abnormal structure and molecular domains in TBI

• Potential therapeutic target for axon function recovery

Dynamic Cellular Responses in White Matter Injury Progression

Glial Cell Responses

• Microglia and astrocyte activation

• Early reparative roles and potential chronic inflammation

• Interactions with oligodendrocytes and axons

Cellular Stress Responses

• Activation of stress signaling pathways (e.g., ISR, UPR)

• Chronic activation contributing to white matter degeneration

• Potential therapeutic targets for reducing injury and cognitive deficits

Molecular Profiling and Transcriptomics

• Characterization of cell-type and state-specific gene expression

• Single-cell RNA sequencing and spatial transcriptomics

• Insights into cellular responses and potential therapeutic targets

Aging and White Matter Vulnerability in TBI

Increased Risk and Complications

• Higher risk of TBI, particularly from falls

• Complications due to cognitive decline and comorbidities

• TBI as a risk factor for neurodegenerative diseases

Accelerated Brain Aging

• Increased brain atrophy in first years after TBI

• Progression of atrophy with advancing age

• Interaction with cerebrovascular pathology and tau accumulation

Age-related Changes in White Matter Processes

• Disruption of NAD+ bioenergetics in axons

• Altered cellular responses to damage and stress

• Reduced remyelination capacity in older animals

Conclusion and Future Perspectives

• Importance of accurate mapping of white matter damage and degeneration

• Need for better interpretation of neuroimaging findings

• Potential for therapeutic interventions targeting early reparative cellular responses

• Ongoing research to understand pathophysiology and identify targets of intervention

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Abstract

Traumatic brain injury (TBI) is a complex condition that can resolve over time but all too often leads to persistent symptoms, and the risk of poor patient outcomes increases with aging. TBI damages neurons and long axons within white matter tracts that are critical for communication between brain regions; this causes slowed information processing and neuronal circuit dysfunction. This review focuses on white matter injury after TBI and the multifactorial processes that underlie white matter damage, potential for recovery, and progression of degeneration. A multiscale perspective across clinical and preclinical advances is presented to encourage interdisciplinary insights from whole-brain neuroimaging of white matter tracts down to cellular and molecular responses of axons, myelin, and glial cells within white matter tissue.