Vendors prospective tail, Braak Staging table (1-6 / HindBrain → Neocortex), Dx prodromal narrative, Zheng 2019 arrival-time chart, Masuda-Suzukake α-syn fibrils diagram, Takeda Braak / Propagation slides

-the highest number they can afford at this stage per donor (definitely > 2 million cells per donor)

Braak Staging

	prodromal			Early clinical	Late clinical
	1	2	3 (threshold between preSx & Sx)	4	5	6
Braak	HindBrain
Braak's 처음 제안 (?)	Dorsal motor X nucleus (he lowest part of the brainstem;)	Gain setting neuclei	SN, LC, Amygldala	temporal limbic cortex (transentorhinal region), Mesocortex, thalamus	Neocortex higher order association,	Neocortex (primary & secondary)
Braak 2005 (Braak, 2006 #1323)	medulla oblongata/pontine tegmentum and anterior olfactory structures		SN and other forebrain	and other nuclei of the basal mid- and ebrain	neocortex
DA	?	?	↓
Sx	olfactory	REM sleep 이상, ↓ cognition (?)	Tremor		Gait, Postural instability especially in younger people, especially prior to the development of bilateral symptoms (Up to 40% of people diagnosed with PD may experience falls and 10% may have falls weekly, the number of falls being related to the severity of PD
		autonomic	Bradykinesia: Rigidity		↓ cognition Anterior cingulate cortex (는 mesocortex 인데도 stage 5라네 (Braak 2005))	dementia
DAT	Normal (Oertel, 2017 #1324)		normal

Dx 전 5-7년긴 prodromal phase 임 (2017 Darweesh)

In 2015, the Movement Disorders Society published research criteria for the diagnosis of prodromal Parkinson’s disease (Berg et al., 2015). Subsequent efforts to retrospectively apply these criteria in elderly populations have shown that they are capable of identifying individuals who go on to develop disease (Mahlknecht et al., 2016). Enriching these cohorts using additional risk factors known to be associated with synopathies is likely to further facilitate the identification of high-risk individuals. Several studies such as the Parkinson’s Associated Risk Study (PARS), the Tu¨bingen Evaluation of Risk Factors for Early Detection of Neurodegeneration (TREND) study, and PREDICT-PD are now exploring this possibility.

(Zheng, 2019 #1646) Regional arrival time of misfolded α-syn:

SN is epicenter as used here is similar to “best propagator” [10] and identifies the region most likely to trigger an outbreak rather than the first affected site. Our model is consistent with the substantia nigra acting as a propagator of disease from brainstem to supratentorial areas [19]. We suggest that this may result from its high concentrations of α-syn and widespread connections.

{Masuda-Suzukake, 2013 #1777} suppl fig8. mouse aSyn PFF Model, (GP는 SN에서는 one synapse away가 아니네?)

Abnormal α-syn fibrils (intracerebral injection to SN)

• Substantia nigra (+/+/+)
  • Superior colliculus (-/+/++)
  • Amygdala, central nucleus (++/+++/+++)
    • Insular cortex (+/+/+)
    • Stria terminalis (-/++/+++)
    • Hypothalamus (+/+/++)
    • Septal nucleus (-/+/+)
  • Striatum (+/+/+)
    • Globus pallidus (-/+/+)
    • Thalamus (+/+/++)
      • Cingulate cortex (-/+/+)
  • Entorhinal cortex (+/++/++)
    • Dentate gyrus (+/++/+++)
      • Hippocampal CA1,3 (+/+/++)
        • Fimbria (-/+/+++)
          • Fornix (-/+/++)

Braak Staging of Parkinson’s Disease (Takeda slide)

The ascending pathological process within the PD brain

Brain-stage labels (bottom-to-top in brain illustration):

• Stage 1
• Stage 2
• Stage 3
• Stage 4
• Stages 5+6

Bar legend (left-to-right):

• Dorsal motor X nucleus
• Gain setting nuclei
• Substantia nigra, amygdala
• Mesocortex, thalamus
• Neocortex higher order association
• Neocortex (primary & secondary)

X-axis: 1 / 2 / 3 / 4 / 5 / 6 (Braak stage), Time (years) →

• The widely-used scheme proposed by Braak and colleagues categorises PD into discrete six neuropathological stages. All of the affected neurons eventually develop Lewy pathology
• The first two stages involve early α-synuclein deposition associated with the appearance of non-motor symptoms, such as olfactory (smell) and autonomic (vital) dysfunction. As the disease progresses, other aspects of brain function may become impaired, causing sleep dysregulation and/or depression in some individuals
• Stages 3 and 4 mark the transition from prodromal stage to clinically overt PD, as the disease spreads from the brainstem up into the midbrain and forebrain. The classic symptoms of PD — bradykinesia, tremor, and muscular rigidity — start to appear as the substantia nigra loses its capacity to produce dopamine, and intrinsic compensatory mechanisms are overwhelmed. Diagnosis typically occurs around this point
• Stage 5 is characterised by poor balance and an increased susceptibility to falls, as well as the onset of cognitive impairment. By Stage 6, the patient is likely to be significantly physically disabled and cognitive decline may well have progressed to PD dementia
• The Braak staging scheme is a useful concept to distinguish between the different phases of PD. However, in reality, patients vary considerably in the extent to which they conform to this model. There exists a wide variety of different disease processes, each of which manifests with the clinical and physiological features of PD

Reference: Lundbeck Institute Campus - Parkinson’s disease (neurobiology and aetiology)

Takeda Pharmaceuticals International — Confidential, for internal use; Proprietary business information — 14

Propagation of α-synuclein Pathology: Human (PD) (Takeda slide)

Braak Stage (PD) — visible region labels in the brain illustration:

• Stage 6 — Neocortex
• Stage 5 — Mesocortex, allocortex
• Stage 4 — Basal mid- and forebrain, hypothalamus, thalamus

Propagation of Protein Aggregates: Human (AD, PD) (Takeda slide)

Propagation of Aβ, tau, and α-synuclein inclusions in human brain.

	Aβ	Tau	α-synuclein
top row	Phase 1	Stages I-II	Stages 1-2
middle row	Phases 2/3	Stages III-IV	Stages 3-4
bottom row	Phases 4/5	Stages V-VI	Stages 5-6

Uncertain Spans

location	transcription	uncertainty
Propagation Aggregates table	Phase 1 / Stages I-II / Stages 1-2 etc.	row labels are inferred from visible stage tokens next to each brain image; full image-row alignment cannot be confirmed because the images are partially clipped at the bottom edge and continue in 20240722_182725.