I recently had a Parkinson’s patient—the first—who deteriorated significantly despite neuromodulation. During a re-evaluation, I diagnosed him with PSP—due to the vertical gaze palsy. Here is my research on this dreadful disease, which I actually classify as bulbar amyotrophic lateral sclerosis.
Progressive Supranuclear Palsy (PSP) Research
1 Epidemiology, Patients, Causes
Progressive supranuclear palsy (PSP) is a rare neurodegenerative tauopathy affecting older adults, with a mean age at onset around 63-65 years. It is more common in men than women, with incidence rates consistently higher in males across age groups Golbe et al 1994, J Neural Transm Suppl Bower et al 1997, Neurology.
Prevalence estimates range from 1 to 18 per 100,000, with pooled meta-analysis suggesting around 7 per 100,000 Lyons et al 2023, J Neurol.
Incidence rates vary from 0.16 to 2.6 per 100,000 person-years, increasing with age and showing a trend of rising over time in some studies Stang et al 2020, J Parkinsons Dis Takigawa et al 2016, Brain Behav.
PSP is predominantly sporadic, but multifactorial etiology involves genetic susceptibility (e.g., MAPT gene variants) interacting with environmental factors like oxidative stress, neurotoxins, and potential inflammation triggers.
No definitive environmental causes are established, but studies suggest oxidative damage and mitochondrial dysfunction contribute Vanacore et al 2001, Neurol Sci Barer et al 2022, Brain Sci.
Patients are typically elderly with progressive parkinsonism, postural instability, and cognitive decline, often misdiagnosed initially as Parkinson’s disease.
2 Brain Areas and Networks Affected
PSP primarily starts in subcortical regions, including the brainstem (e.g., midbrain), basal ganglia, and deep nuclei like the substantia nigra and subthalamic nucleus.
Atrophy begins with pronounced volume loss in these areas bilaterally Palleis et al 2025, Mov Disord Gardner et al 2013, Ann Neurol.
It extends to frontal and parietal cortical regions, with tau pathology propagating from epicenters in subcortical and frontal lobes to interconnected areas, following a network-like pattern potentially via trans-neuronal tau spread Wang et al 2022, J Clin Invest.
Affected networks include frontal-subcortical circuits, cortico-brainstem interactions, and intrinsic connectivity networks like the default mode and motor networks, showing hypoconnectivity and functional reorganization.
Microglial activation correlates with pathology in these regions Garcia-Cordero et al 2024, Ann Neurol.
If the disease spreads from nerve to nerve, then it’s a PRION disease!!! Just like ALS, the nerves also infect themselves through misfolded SOD.
3 Typical Early Symptoms
Early symptoms of PSP often involve mobility issues, with gait instability and falls being the most common initial presentation in about 69% of cases.
Backward falls occur early, often within the first year.
Visual disturbances like vertical supranuclear gaze palsy (especially downward), diplopia (61%), photophobia (43%), and eyelid apraxia (43%) are frequent.
Speech and swallowing problems emerge soon after, within 1-2 years.
Cognitive and behavioral changes, including apathy and frontal dysfunction, may appear early but are less dominant initially Nath et al 2003, Neurology Kanazawa et al 2013, Parkinsonism Relat Disord Armstrong et al 2011, Clin Exp Optom.
Prediagnostic non-motor symptoms can include mood changes, dizziness, and sleep disturbances Santacruz et al 1998, Neurology.
4 Genetic Causes
PSP is mostly sporadic, but genetic factors play a role. The MAPT gene (encoding tau protein) is the strongest risk locus, with common variants like the H1 haplotype increasing susceptibility in sporadic cases, and rare mutations causing familial PSP (15 known mutations, earlier onset). LRRK2 mutations are a rare monogenic cause, overlapping with Parkinson’s disease. Other genes like DCTN1 may mimic PSP phenotypes. GWAS identify loci implicating pathways in tau splicing, mitochondrial function, and inflammation. Familial clusters suggest recessive inheritance or linkage disequilibrium with tau Rojo et al 1999, Brain Im et al 2015, J Mov Disord Müller et al 2025, Acta Neuropathol Wen et al 2021, J Parkinsons Dis. Environmental interactions with these genetics likely trigger disease.
5 Biochemical Causes, Pathways, and Potential Off-Label/Repurposed Interventions
Biochemical causes center on tauopathy, with hyperphosphorylation and aggregation of tau protein as hallmarks. Pathways include:
- Tau hyperphosphorylation: Triggered by kinases (e.g., GSK-3β, CDK5) activated by oxidative stress or mitochondrial dysfunction, leading to tau detachment from microtubules.
- Microtubule instability: Detached tau impairs axonal transport, shifting toward 4-repeat isoforms in PSP.
- Tau aggregation: Hyperphosphorylated tau forms insoluble aggregates (neurofibrillary tangles), activating unfolded protein response (UPR) via PERK pathway.
- UPR activation and ER stress: Leads to caspase-3 activation and apoptosis, exacerbating neuronal loss.
- Mitochondrial dysfunction: Upstream, with energy failure promoting tau aggregation; involves impaired complex I, oxidative damage.
- Neuroinflammation: Microglial activation and cytokine release (e.g., IL-1β, TNFα) amplify tau pathology.
For interventions (focusing on repurposed drugs, supplements with evidence)
- Tau phosphorylation/aggregation: Lithium (repurposed from bipolar) inhibits GSK-3β, reducing phosphorylation; limited trials in tauopathies. Methylene blue (antimalarial repurposed) may dissolve aggregates.
- UPR/ER stress: Trazodone (antidepressant repurposed) modulates UPR; suggested for tauopathies but no PSP-specific trials. PERK inhibitors experimental.
- I have great results seen with Trazodone in early Alzheimer!
- Mitochondrial: CoQ10 (supplement) targets energy failure, positive in phase II for PSP. Carnitine supplementation improved tremors/fatigue in a malnourished PSP case. Thiamine (vitamin B1) reversed symptoms in a PSP case with deficiency.
- Apoptosis: Caspase inhibitors experimental, no repurposed yet.
Off-label drugs like levodopa show poor response; antidepressants (e.g., SSRIs) for behavioral symptoms. Evidence levels low (case reports, small trials).
I did 2023 an intensiv Research about cause and options for Parkinson which explains very detailled the causal chain of AGGRAGATION –> UPR –> APOPTOSIS and what to do. Important to know – especially: Spermidine and Trazodone
6 Cytokines, Inflammation, and Countermeasures
Cytokines are involved in PSP, with elevated IL-1β in substantia nigra and correlations between IL-1β, TNFα, IL-6, TGFβ, and microglial activation in affected regions Fernández-Botrán et al 2011, Parkinsonism Relat Disord.
This suggests neuroinflammation drives progression.
Anti-inflammatory drugs like ibuprofen reduce PSP risk in epidemiological studies. Cytokine inhibitors (e.g., anti-TNF antibodies like infliximab, off-label) or general anti-inflammatories may slow progression; no PSP trials yet.
Supplements like omega-3 (anti-inflammatory) lack direct evidence.
Fecal microbiota transplant improved symptoms in a trial, possibly via gut-brain inflammation modulation.
7 Infections from Teeth, Gum, Sinuses
No PubMed evidence links dental infections, gum disease, cavitations, or sinus infections to PSP causation or progression. Searches yielded no results.
8 Heavy Metals or Aluminum
No PubMed studies associate heavy metals or aluminum with PSP etiology or risk. Searches returned no relevant findings.
9 EMF, Earth Radiation, Energetic Fields
Limited evidence: One case report showed transcranial AC pulsed weak electromagnetic fields (PEMF) at picotesla flux density reduced freezing (50%) and falling (80-90%) in a PSP patient, improving parkinsonian symptoms over 6 months. No data on earth radiation or other fields. Frequency therapy lacks PSP-specific evidence.
10 Other Evidence-Based Therapies
Supplements: Carnitine and thiamine (as above). PEMF (as above) shows promise in case. No controlled trials for frequency therapy.
Integrative approaches emphasize mitochondrial support (CoQ10, B-vitamins, alpha-lipoic acid) based on dysfunction evidence.
References
- Armstrong et al 2011 Clin Exp Optom
- Barer et al 2022 Brain Sci
- Bower et al 1997 Neurology
- Driver-Dunckley et al 2023 J Neuropathol Exp Neurol
- Fernández-Botrán et al 2011 Parkinsonism Relat Disord
- Garcia-Cordero et al 2024 Ann Neurol
- Gardner et al 2013 Ann Neurol
- Golbe et al 1988 Neurology
- Golbe et al 1994 J Neural Transm Suppl
- Im et al 2015 J Mov Disord
- Kanazawa et al 2013 Parkinsonism Relat Disord
- Lyons et al 2023 J Neurol
- Müller et al 2025 Acta Neuropathol
- Nath et al 2000 Parkinsonism Relat Disord
- Nath et al 2003 Neurology
- Palleis et al 2025 Mov Disord
- Rojo et al 1999 Brain
- Santacruz et al 1998 Neurology
- Schrag et al 1999 Lancet
- Stang et al 2020 J Parkinsons Dis
- Swallow et al 2022 Neuroepidemiology
- Takigawa et al 2016 Brain Behav
- Vanacore et al 2001 Neurol Sci
- Viscidi et al 2021 Front Neurol
- Wang et al 2022 J Clin Invest
- Wen et al 2021 J Parkinsons Dis
Picture (c) Grok 4.0
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