5 Pillars of Neurodegeneration
Centered on Pathophysiological Dysfunction
Dysregulation of the brainβs biomechanical system is a complex, multifactorial pathogenesis. Homeostatic modification and optimization necessitates an integrative therapeutic paradigm. Effective interventions require coordinated modulation across molecular, cellular, and musculoskeletal (MSK) levels.
This framework identifies five core, interconnected pathophysiological pillars through which homeostatic dysfunction contributes to neurodegenerative pathogenesis. It integrates anatomical, mechanical, vascular, immune, and metabolic consequences.
Clinical Relevance
The 5 Pillar framework is a mechanistic model for:
- Understanding idiopathic or atypical neurodegeneration with brainstem features
- Evaluating chronic subclinical musculoskeletal dysfunction in early-stage neurodegeneration
- Informing therapeutic strategies targeting alignment, drainage, and inflammation
The Framework
1. Glymphatic & Detoxification Failure
Diagnostics and therapeutics framework for glymphatic flow, CSF dynamics, sleep-linked clearance, and detoxification support.
Details
1. Glymphatic & Detoxification Failure
Diagnostics and therapeutics framework for glymphatic flow, CSF dynamics, sleep-linked clearance, and detoxification support.
- Diagnostics
- Upright / seated fMRI with CSF flow β (Jonathan Verderame et al., 2025) (Fumio Suzuki et al., 2008) (Giulia Michelini et al.,) (John W. Gilbert et al.,)
- Digital motion xray β (Xiaoli Si et al., 2022)
- (CBCT) (3D) Upright Cone Beam Computed Tomography (3D) β π (Hauser et al.,)
- Phase-contrast MRI (CSF pulsatility) β π‘ (B Battal et al., 2011) (Edward D. Boyd et al., 2024) (Adam M. Wright et al., 2024)
- Sleep study (slow-wave sleep β glymphatic clearance) β π’ (Xie et al., 2013)
- AQP4Evaluation of AQP-4 antibody assays β π (Patrick J. Waters et al., 2014)
- Plasma biomarkers (GFAP, NfL) β π‘ (X Huang Β· 2025)
- Therapeutics
- NAC nasal spray β (Kurano et. al., 2022)
- Niacin β (Sorrentino et al., 2009) (Giri et al., 2019)
- CBT-I / circadian entrainment β π’ (Trauer et al., 2015)
- Lateral sleep / head positioning β π‘ (Lee et al., 2015)
- Effects of exercise on sleep in NDD β π’ (Adeel A. Memon et al., 2020)
- Photobiomodulation (near-infrared) β π (Ayodeji Abijo)
- Non-invasive vagal nerve stimulation β π‘ (Alexandra Evancho et al., 2024)
- Manual lymphatic / craniosacral β π΅ (Yijia Feng., et al 2025)
- Nasal breathing / COβ tolerance β π (Jose M. Moris, et al., 2023)
- Breath work β (Lagana et al., 2022) (Vakhtin et al., 2025) (Lim et. al., 2025)
2. Neurovascular Dysfunction (NVU, BBB, Glycocalyx)
Diagnostics and therapeutics framework for perfusion, vascular integrity, and inflammatory endothelial burden.
Details
2. Neurovascular Dysfunction (NVU, BBB, Glycocalyx)
Diagnostics and therapeutics framework for perfusion, vascular integrity, and inflammatory endothelial burden.
- Diagnostics
- ASL MRI perfusion β π’ (Kevin Lee, et al., 2024)
- Carotid duplex ultrasound β π’ (Hye-Yeon Choi, 2021)
- Transcranial Doppler β π’ (Marc Ribo, MD, PhD 2024)
- OCT-A retinal microvasculature β π‘ (O'Bryhim et al., 2018)
- Glycocalyx (GlycoCheck) β π (Nieuwdorp et al., 2008)
- hs-CRP, IL-6, TNF-Ξ± β π’ (Osman Shabir et al., 2018)
- Therapeutics
- Exercise for endothelial repair β π’ (Tao et al., 2023)
- Nitric oxide supplementation β π‘ (Lundberg et al., 2008) (LourenΓ§o et al., 2021) (Tripodi et al., 2025)
- GLP-1 receptor agonists β π‘ (Gejl et al., 2016)
- Omega-3s / polyphenols β π’ (Yurko-Mauro et al., 2010)
- BP variability optimization β π’ (Rothwell et al., 2010)
- Vasodilating medications β π (Webb et al., 2019)
3. Brainstem & Neuromechanical Dysfunction
Diagnostics and therapeutics framework for craniocervical biomechanics, autonomic regulation, and neuromotor restoration.
Details
3. Brainstem & Neuromechanical Dysfunction
Diagnostics and therapeutics framework for craniocervical biomechanics, autonomic regulation, and neuromotor restoration.
- Diagnostics
- Upright MRI (flexion/extension) β π‘ (Jonathan Verderameet al., 2025)
- Craniocervical instability imaging β π (Marco Muccio et al., 2021)
- Autonomic testing (HRV, tilt) β π’ (Jacquie R Baker et al., 2024)
- Therapeutics
- Precision upper cervical correction β π (Bakris et al., 2007)
- Neuromuscular re-education β π‘ (Jose A Santiago et al., 2023)
- Postural & respiratory retraining β π‘ (Courtney, 2009)
- Vagal tone restoration β π‘ (Bretherton et al., 2019)
4. Neuroinflammation & Immune Dysfunction
Diagnostics and therapeutics framework for cytokine burden, viral immune triggers, and immune-modulating adjuncts.
Details
4. Neuroinflammation & Immune Dysfunction
Diagnostics and therapeutics framework for cytokine burden, viral immune triggers, and immune-modulating adjuncts.
- Diagnostics
- Cytokine profiling β π‘ (Heneka et al., 2015)
- Viral reactivation (EBV, HHV-6) β π‘ (Flamand et al., 1993) (Almulla et al., 2025)
- Autoimmune encephalitis panels β π’ (Graus et al., 2016)
- CSF oligoclonal bands β π’ (Dobson et al., 2013)
- Therapeutics
- Low-dose naltrexone β π‘ (Younger et al., 2014)
- Microglial calming (PEA, curcumin) β π‘ (Skaper et al., 2014) (Ludwig MD et al., 2017) (Skaper et al.,)
- Gutβimmune axis repair β π‘ (Cryan et al., 2019) (Kanmani Suganya et al,.)
- Stress / HPA-axis regulation β π’ (McEwen, 2017)
- High ventilation breathwork β π (Jinho Jhang et al.,) (Amy Amla Kartar et al.,)
- Thymosin alpha-1 β π (Ge Wang et al., 2017)
- Thymosin beta 4 frag 17-23 β π (Peng-Ming Zeng et al., 2025)
- BPC 157 β π (JakΕ‘a VukojeviΔ et al., 2021)
- KPV β π (Benjamin A. Benita et al., 2024)
- SS31 β π (Marcus J Calkins et al 2012)
5. Bioenergetic & Metabolic Collapse
Diagnostics and therapeutics framework for metabolic resilience, mitochondrial performance, and targeted bioenergetic recovery.
Details
5. Bioenergetic & Metabolic Collapse
Diagnostics and therapeutics framework for metabolic resilience, mitochondrial performance, and targeted bioenergetic recovery.
- Diagnostics
- Plasma metabolomics β π (Trushina et al., 2013)
- Lactate / pyruvate ratios β π‘ (Kurihara et al., 2021)
- Insulin resistance markers β π’ (Arnold et al., 2018)
- Therapeutics
- NADβΊ precursors β π (Martens et al., 2018)
- NRCl β π΅ (Jessie Hawkins et al., 2024)
- CoQ10 / ALCAR β π‘ (M. Flint Beal, 2002)
- Ketogenic metabolic therapy β π‘ (Tadeu P D Oliveira et al) (Matthew C L Phillips et al.,)
- Exercise β mitochondrial biogenesis β π’ (Steiner et al., 2011)
- NRF2 activation β π (Cuadrado et al., 2019)
- Photobiomodulation β π (Hamblin, 2017)
- Urolitin A β π‘ (Yujun Hou et al., 2024)
Legend
- π’ Strong = multiple human studies / meta-analyses / guideline-supported
- π‘ Moderate = human trials or strong observational + mechanistic support
- π Emerging = early human data or strong animal/mechanistic evidence
- π΅ Experimental = limited pilot or case-series data