PD-001 · Parkinson's: α-Synuclein / Lewy Body Engine · VIZASL

PHASES

BIOMARKERS

EEG

NPs

Braak PD Staging PROVEN

Stage 1–2 · Gut + Brainstem (pre-motor)

α-Syn first in enteric nervous system + dorsal vagal nucleus. Olfactory bulb. No motor symptoms. Gut-first hypothesis — ascends retrogradely via vagus nerve.

Braak et al. 2003 Neurobiol Aging · SORRY: gut-first not universal — brain-first subtype documented.

Stage 3–4 · Substantia Nigra (motor onset)

DA neurons of SNc degenerate. Dopamine 80% depleted before cardinal motor symptoms appear. Lewy bodies in SNc and locus coeruleus.

Spillantini et al. 1997 Nature (α-syn in Lewy bodies) · 80% threshold: Fearnley & Lees 1991

Stage 5–6 · Cortical Spread

Neocortical Lewy bodies. Cognitive decline (PDD). Autonomic dysfunction. REM sleep behavior disorder as prodromal marker.

Postuma et al. 2019 Lancet Neurol (RBD as PD prodrome)

PINK1/Parkin Mitophagy

Dysfunctional mitochondria not cleared → oxidative stress → α-syn misfolding. PINK1 phosphorylates Parkin on damaged mitochondria → ubiquitination → mitophagy. Proven in familial PD. SORRY: role in sporadic PD (90% of cases) is OPEN.

Kitada et al. 1998 Nature (Parkin) · Valente et al. 2004 Science (PINK1)

Symptomatic — Proven

Levodopa (L-DOPA) PROVEN

Gold standard since 1967. With carbidopa (peripheral DDC inhibitor). Wearing-off and dyskinesia develop over 5–10yr of use.

Cotzias et al. 1967 NEJM

DBS — Deep Brain Stimulation PROVEN

STN or GPi stimulation (130–185Hz). Disrupts pathological β bursts. Reduces tremor, rigidity, dyskinesia. NOT disease-modifying.

Lang & Lozano 1998 NEJM · Deuschl et al. 2006 NEJM (RCT)

NO DISEASE-MODIFYING THERAPY (2026) BIG SORRY

No drug slows neurodegeneration in PD. CoQ10, creatine, riluzole, minocycline — all failed rigorous trials. Every apparent signal evaporated under scrutiny.

SORRY: Central failure of PD research. No approved DMT 2026.

Prasinezumab (anti-α-syn) Phase 3

Anti-aggregated α-syn mAb. Phase 2 subgroup signal in fast-progressors. Phase 3 ongoing. Primary endpoint missed in full Phase 2 cohort.

Pagano et al. 2021 Nat Med

Biomarkers

α-syn RT-QuIC PROVEN	Seed amplification in CSF/skin. Sensitivity 90%+. Game-changer for ante-mortem PD diagnosis. Shahnawaz et al. 2020 Lancet Neurol
DAT-SPECT PROVEN	DaTscan — FDA cleared. Reduced DA transporter uptake = nigrostriatal loss. Gold standard functional imaging.
Plasma NfL STRONG	Elevated, correlates with progression rate. Non-specific — not diagnostic alone.
GBA genotyping	~10% of PD. Faster progression, higher dementia risk. Target for GBA-directed trials. Sidransky 2009 NEJM
Skin biopsy α-syn EMERGING	Phospho-α-syn in dermal nerves. ~75–80% sensitivity. SORRY: not standardized across labs.

Neurophysiology in PD

β-excess 13–30Hz PROVEN	Pathological β synchronisation in STN + M1. Correlates with tremor/akinesia. DBS disrupts β bursts — this IS the mechanism. Kühn et al. 2006 Brain
β burst duration	Long β bursts = symptom severity. Short bursts = normal. Duration not mean power is the pathological signal. Tinkhauser et al. 2017 Brain
θ in STN (4–8Hz)	θ oscillations specifically during tremor episodes. Distinct from β. Correlates with tremor amplitude. Zaidel et al. 2009
γ-loss (>60Hz)	HFOs reduced in motor cortex. Correlates with DA depletion. Restored by L-DOPA. Brücke et al. 2012

Thinkbeat Bridge

β-excess = OSCILLATING → progressive DA loss → SLOW_MONOTONE motor output → full akinesia = CHAOTIC (no movement signal). DBS at 130–185Hz is a frequency injection above the β band — it overrides the pathological synchrony. The treatment IS a δ-control mechanism.

Novel Patterns (8)

PROVENNP-PD-001 · α-Syn fibrils are STRAIGHT not helical (unlike tau PHF) — structurally distinct prion-like seeding · Spillantini 1997 Nature

PROVENNP-PD-002 · Braak gut-first staging: ENS → brainstem → SNc → cortex · bottom-up ascending pathology (opposite of AD) · Braak 2003 Neurobiol Aging

PROVENNP-PD-003 · 80% DA depletion before motor symptoms — enormous pre-clinical window · no validated blood biomarker for population screening

PROVENNP-PD-004 · DBS mechanism: disrupts pathological β bursts (13–30Hz) in STN-M1 loop · burst duration not mean power is the pathological signal

PROVENNP-PD-005 · GBA = most common genetic PD risk (~10%) · lysosomal dysfunction → α-syn clearance failure · Sidransky 2009 NEJM

OPENNP-PD-006 · PINK1/Parkin mitophagy proven in familial PD — role in sporadic PD (90%) OPEN

PROVENNP-PD-007 · α-syn RT-QuIC seed amplification: 90%+ sensitivity · democratises ante-mortem PD diagnosis · Shahnawaz 2020 Lancet Neurol

SORRYNP-PD-008 · No DMT exists (2026) · every neuroprotective trial has failed · defining open problem of PD research

Open Sorries (6)

SORRY-1: No DMT — no drug slows neurodegeneration. Every trial has failed.
SORRY-2: Gut-first not universal — brain-first PD subtype exists with unknown prevalence.
SORRY-3: PINK1/Parkin in sporadic PD — pathway proven in familial; role in 90% of cases is OPEN.
SORRY-4: MAO-B inhibitor neuroprotection vs symptomatic masking — DATATOP debate unresolved.
SORRY-5: DBS exact mechanism (inhibition/activation/desynchronisation) still debated.
SORRY-6: Pre-clinical timing — 80% depletion window may be 5 or 20 years; no individual predictor.