Skin Changes May Help Diagnose ALS Earlier

Exploring the Skin–Brain Connection in ALS

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to the death of motor neurons in the brain and spinal cord. This neuronal loss results in severe muscle weakness and eventual paralysis. The disease typically advances quickly, and most patients succumb to respiratory failure within three to five years of onset.

There are two forms of ALS: sporadic (sALS), which accounts for about 90% of cases, and familial (fALS), which represents the remaining 10%. Despite ongoing research, ALS remains difficult to diagnose in its early stages. Clinical evaluations and electromyography are currently the primary tools for diagnosis, but they often lead to delays of up to 16 months. Blood markers lack specificity, cerebrospinal fluid sampling carries risks, and neuroimaging is not always conclusive.

This diagnostic delay limits the effectiveness of available treatments such as riluzole, AMX0035, and tofersen, which may slow disease progression but do not halt it. Therefore, the need for early, accurate, and non-invasive biomarkers is urgent.

Interestingly, researchers are now turning to the skin—a tissue that shares a common embryonic origin with the nervous system—as a potential source of diagnostic clues.

Why Skin? Shared Origins with the Nervous System

The skin and the central nervous system (CNS) both develop from the neuroectoderm during embryogenesis. This shared origin suggests that molecular and cellular processes in the skin could mirror changes in the nervous system. For example, keratinocytes in the skin express NMDA receptors involved in memory and learning, and they also participate in immune regulation through the hypothalamic-pituitary-adrenal axis.

This close relationship between the skin and the nervous system is already being studied in other neurodegenerative diseases. For instance, deposits of alpha-synuclein in the skin have been used to detect Parkinson’s disease before neurological symptoms emerge.

Could similar skin changes be used to diagnose ALS earlier?

Structural Changes in ALS Skin

The study reviewed a range of skin abnormalities in ALS patients, starting with its structure. In ALS-affected skin, researchers found:

• Reduced and disorganized collagen bundles

• Deposition of amorphous material in the dermis

• Fragmentation and separation of collagen fibers

• Thickened blood vessel walls

These features make the skin feel soft and leathery and are sometimes associated with a “delayed return phenomenon” when pressed. Even in presymptomatic patients with genetic mutations linked to ALS (e.g., C9orf72), tissue-engineered skin models showed early signs of abnormalities like epidermal undifferentiation and collagen disorganization.

Nerve Fiber Loss and Autonomic Dysfunction

Beyond structure, ALS skin shows reduced nerve fiber density. This reflects a broader pattern of sensory and autonomic nervous system involvement in ALS.

Patients often experience:

• Impaired sweating due to reduced sweat gland nerve fiber density

• Changes in thermal sensation

• Decreased pilomotor nerve fiber density with structural nerve damage

These changes were linked to symptoms such as numbness and pain, and they correlated with validated clinical scores like the Small Fiber Neuropathy Symptom Inventory Questionnaire.

Blood Vessel Changes and Angiogenin Reduction

Skin biopsies have revealed thickened walls in the small dermal blood vessels of ALS patients. Electron microscopy detected “onion-skin” formations and duplications of the basement membrane. A protein called angiogenin (ANG), which supports blood vessel growth, was found at reduced levels in ALS skin, particularly in the nuclei of epidermal cells. This reduction could impair vascular health in the skin and possibly reflect broader systemic changes.

ALS-Related Protein Aggregation in Skin Cells

One of the study’s most striking findings was the abnormal aggregation of ALS-associated proteins in skin tissues and fibroblasts. These proteins included:

• SOD1: Aggregated in fibroblasts from patients with known SOD1 mutations.

• TDP-43: Elevated in skin tissue and fibroblasts, especially in patients with upper limb onset.

• FUS: Mislocalized and prone to aggregation under stress, particularly in mutation carriers.

• VCP, UBQLN2, VAPB, and PGRN: All linked to protein degradation systems and found to form aggregates or show altered expression in ALS skin.

These changes suggest that protein misfolding and impaired protein clearance occur not just in neurons but also in peripheral tissues like the skin.

Mitochondrial Dysfunction in ALS Skin

Mitochondria in skin cells of ALS patients also show signs of damage:

• Reduced size and disrupted shape

• Loss of outer membrane integrity and internal structures

• Decreased ATP production

• Increased oxidative stress

However, results varied across studies, possibly due to differences in patient samples and disease stages.

Inflammatory Responses in Skin

ALS has long been associated with inflammation in the brain and spinal cord. Similar patterns are now being observed in the skin. Specifically:

• Reduced regulatory T lymphocytes (Tregs)

• Increased expression of inflammatory cytokines like IL-6 and TNF-α

• Weakened response to skin antigen tests

These findings reinforce the role of immune dysregulation in ALS and suggest that skin inflammation might serve as a peripheral indicator of disease progression.

Additional Molecular Changes

Several other proteins and molecules were found to be altered in ALS skin:

• Increased: MMP-9, IGF-I, VEGF, HGF, cystatin C, laminin 1, and hyaluronic acid

• Decreased: Galectin-1, which affects fibroblast activity and axonal health

MMP-9 in particular may link skin pathology to spinal cord degeneration, making it a promising candidate for further study.

The Path Ahead: Skin as a Diagnostic Window

The study concludes that skin could serve as a practical and minimally invasive medium to detect ALS-related changes early. “Tests assessing skin autonomic and sensory nerve function, skin biopsies analyzing structural changes, MMP-9 expression, and immune biomarkers such as tuberculin reactivity could serve as non-invasive tools for ALS detection and monitoring its progression,” the authors noted.

While the current data are promising, larger-scale studies are needed to validate these biomarkers across diverse ALS populations.

Funding and Disclosure

This research was supported by the National Natural Science Foundation of China and other regional funding bodies. The authors declared no conflicts of interest.

If you’re a researcher in neurodegeneration or biomarker development, these findings offer a compelling reason to further investigate the skin as a source of early diagnostic information in ALS. As research advances, skin-based diagnostics may one day become part of routine clinical practice for ALS monitoring and intervention.