EC Neurology

Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disorder marked by the selective loss of upper and lower motor neurons. Despite decades of research, conventional treatments remain limited to symptom management and modest extensions of survival, with no therapies capable of altering the disease's fundamental trajectory. Recent advances in molecular neurobiology have highlighted the critical role of chronic neuroinflammation, oxidative stress, mitochondrial failure, and neuroendocrine disruption as central, interlinked drivers of ALS pathogenesis. These discoveries demand a paradigm shift toward a system-based, personalized therapeutic model.

This paper introduces a comprehensive clinical strategy developed by Millennium Health Centers, built around a 28-point biomarker panel designed to detect subtle imbalances across inflammatory, oxidative, hormonal, and metabolic domains. By leveraging this diagnostic insight, the Millennium Protocol guides the application of precision nutraceuticals to downregulate pro-inflammatory cytokines and reactive oxygen species, alongside bioidentical hormone replenishment to restore neurosteroid balance and hypothalamic-pituitary axis integrity. Together, these interventions aim to reestablish systemic and neuronal homeostasis, mitigate ongoing neurodegeneration, and meaningfully enhance function and quality of life for individuals affected by ALS. This integrative approach represents a promising frontier in ALS care and warrants broader investigation through observational and interventional trials.

Keywords: Neuroinflammation; Peroxynitrite; Pregnenolone; DHEA; IGF-1

1. Saresella M., et al. “Innate immune system dysregulation in ALS: a role for microglia and inflammation”. Frontiers in Immunology 7 (2016): 594.
2. McCauley ME and Baloh RH. “Inflammation in ALS/FTD pathogenesis”. Acta Neuropathologica 5 (2019): 715-730.
3. Correia AS., et al. “Increased microglial activation and pro-inflammatory cytokine release in ALS patients”. Neurobiology of Aging 3 (2015): 1083-1090.
4. Thonhoff JR., et al. “Neuroinflammatory mechanisms in ALS pathogenesis”. Current Opinion in Neurology 5 (2018): 635-639.
5. Moreno-García L., et al. “Inflammation as a driver of ALS progression: therapeutic opportunities”. Cells12 (2020): 2633.
6. Henkel JS., et al. “Regulation of inflammation in ALS: mechanisms and therapeutic opportunities”. Journal of Neuroinflammation (2009).
7. Zhao W., et al. “Neuroinflammation induced by activated microglia and astrocytes is associated with disease progression in ALS”. Neurobiology of Disease (2010).
8. Gordon ML. “The neuroinflammatory path to neuropsychiatric illness”. ResearchGate (2023).
9. Turner MR., et al. “Systemic inflammation and complement activation in ALS”. Neurology (2004).
10. Gurney ME., et al. “Pathogenic mechanisms in ALS: neuroinflammation and excitotoxicity”. Trends in Neurosciences (1996).
11. Dongqing Gu., et al. “Trauma and amyotrophic lateral sclerosis: a systematic review and meta-analysis”. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration3-4 (2021): 170-185.
12. Liu, Y., et al. “Traumatic brain injury and risk of amyotrophic lateral sclerosis: A meta-analysis”. Neuroepidemiology1 (2023): 23-32.
13. Turner MR., et al. “Head and other physical trauma requiring hospitalization is associated with increased risk of ALS”. Journal of Neurology, Neurosurgery and Psychiatry8 (2016): 851-852.
14. Peters TL., et al. “Occupation and amyotrophic lateral sclerosis: A population-based case-control study”. Journal of Occupational and Environmental Medicine9 (2017): 867-873.
15. Chen H., et al. “Head injury and amyotrophic lateral sclerosis”. American Journal of Epidemiology7 (2007): 810-816.
16. Gallo V., et al. “Smoking and risk for amyotrophic lateral sclerosis: Analysis of the EPIC cohort”. Annals of Neurology4 (2009): 378-385.
17. Papeix C., et al. “Environmental risk factors for ALS: A review of epidemiologic studies”. Revue Neurologique10 (2020): 688-698.
18. Peters TL., et al. “Trauma and other environmental risk factors for ALS: A review of the evidence”. NeuroToxicology 69 (2018): 278-294.
19. McKee A., et al. “The spectrum of disease in chronic traumatic encephalopathy”. Brain 1 (2016): 22-48.
20. Gonzalez P., et al. “Neurosteroids in neurodegenerative diseases: implications for hormone therapy in ALS”. Journal of Neuroendocrinology2 (2019): e12680.
21. Choi CJ., et al. “Low testosterone and cognitive decline in ALS: neuroendocrine implications”. Hormones and Behavior 122 (2020): 104743.
22. Pera MC., et al. “Role of the GH/IGF-1 axis in ALS: new insights and clinical data”. Journal of Clinical Medicine 5 (2021): 945.
23. Zhang R., et al. “IGF-1 treatment reduces motor neuron death and disease severity in a mouse model of ALS”. Nature Medicine (2000).
24. Hu J., et al. “Hypothalamic-pituitary-adrenal axis dysregulation in ALS: a central contributor to neurodegeneration”. Neurobiology of Disease 179 (2023): 106004.
25. Jacobs E. “Thyroid function and amyotrophic lateral sclerosis: a mendelian randomization study” (2025).
26. Gordon ML. “Clinical application of the 28-point biomarker panel”. Millennium Health Centers (2024).
27. Gordon ML. “Understanding the 28-point biomarker panel, the handbook”. Millennium Health Centers, pending release (2025).
28. Rinaldi C., et al. “Sex steroids and neuroprotection in ALS: beyond testosterone”. Endocrinology 9 (2022): bqac104.
29. Moianu A., et al. “Exploring the role of metabolic hormones in amyotrophic lateral sclerosis”. International Journal of Molecular Sciences10 (2024): 5059.
30. Murugan S., et al. “The neurosteroid pregnenolone promotes degradation of key proteins in the innate immune signaling to suppress inflammation”. Journal of Biological Chemistry12 (2019): 4596-4607.
31. Wang JM., et al. “Regeneration in a degenerating brain: potential of allopregnanolone as a neuroregenerative agent”. Current Alzheimer Research5 (2007): 510-517.
32. Quinn TA., et al. “Dehydroepiandrosterone (DHEA) and DHEA Sulfate: Roles in Brain Function and Disease”. Sex Hormones in Neurodegenerative Processes and Diseases (2018).
33. Militello A., et al. “The serum level of free testosterone is reduced in amyotrophic lateral sclerosis”. Journal of the Neurological Sciences1 (2002): 67-70.
34. Mooradian AD and Haas MJ. “Role of thyroid hormone in neurodegenerative disorders of older people”. Cells 2 (2025): 140.
35. Morselli LL., et al. “Growth hormone secretion is impaired in amyotrophic lateral sclerosis”. Clinical Endocrinology3 (2006): 385-388.
36. Freire de Carvalho J., et al. “Quality of life and muscle strength improvement in an amyotrophic lateral sclerosis patient after nutraceuticals”. Vestnik of Saint Petersburg University. Medicine3 (2020): 221-227.
37. Goncharova PS., et al. “Nutrient effects on motor neurons and the risk of amyotrophic lateral sclerosis”. Nutrients11 (2021): 3804.
38. Calabrese V., et al. “Nutraceutical strategies to target neuroinflammation and oxidative stress in ALS”. CNS and Neurological Disorders - Drug Targets 3 (2020): 165-177.
39. Machado LS., et al. “Omega-3 fatty acids as modulators of neuroinflammation in ALS: clinical and preclinical insights”. CNS Drugs10 (2018): 905-917.
40. Es-sai B., et al. “Gamma-tocopherol: a comprehensive review of its”. Molecules3 (2025): 653.
41. Ulatowski L., et al. “The tocopherol transfer protein mediates vitamin E trafficking between cerebellar astrocytes and neurons”. Journal of Biological Chemistry3 (2022): 101712.
42. Cores Á., et al. “Quinones as neuroprotective agents”. Antioxidants7 (2023): 1464.
43. Bilsland LG., et al. “Increasing mitochondrial biogenesis protects against oxidative stress and neurodegeneration in ALS”. Neuron (2008).
44. Manfredi G and Kawamata H. “Mitochondrial dysfunction and oxidative stress in ALS”. Archives of Biochemistry and Biophysics 591 (2016): 19-26.
45. Chen Y., et al. “Oxidative stress in ALS: mechanisms and therapeutic perspectives”. Free Radical Biology and Medicine 146 (2020): 144-158.
46. Rizzo G., et al. “Mitochondrial dynamics in ALS: a therapeutic target?” Frontiers in Aging Neuroscience 10 (2018): 15.
47. Johri A. “Disrupted mitochondrial metabolism and neurodegeneration in ALS”. Journal of Neurochemistry 6 (2019): 744-762.
48. Zhao Z., et al. “Targeting mitochondrial ROS in ALS therapy: progress and promise”. Redox Biology 50 (2022): 102256.
49. Rayner MLD., et al. “The combination of neurotropic B vitamins (B1, B6, and B12) is superior to individual B vitamins in promoting neurite growth in vitro”. In Vitro Cellular and Developmental Biology - Animal3 (2025): 264-267.
50. Novak V., et al. “Therapeutic potential of polyphenols in amyotrophic lateral sclerosis and frontotemporal dementia”. Antioxidants8 (2021): 1328.
51. Maier A., et al. “ALSFRS-R-SE: an adapted, annotated, and self-explanatory version of the revised amyotrophic lateral sclerosis functional rating scale”. Neurological Research and Practice1 (2022): 60.