Patient Selection, nGD biomarker grid, Models / Omics, BMx Milestones, Patient recruitment, GBA vs UPDRS vs MOCA

Patient Selection

patient group	rationale	exclude / note
PD + GBA (Heteroz)	PD patients bearing GBA1 mutation, tend to have earlier onset, [10].
	↓ ↓ GBA expression & activity (greater reduction than in sporadic PD only)
Sporadic PD	being a carrier for a pathological mutation in GBA1 is one of the strongest genetic risk factors for PD	"Scan Without Evidence of Dopaminergic Deficit" (SWEDD), SWEDD subjects were unlikely to progress in motor disability
	sporadic PD patients have low levels of GCase in the brain and cerebrospinal fluid [11-13].
	↓ GBA expression & activity
	reduction of DAT expression levels by SPECT neuroimaging of subjects with early motor deficits (2018 EMA)
GD	Non-neuronopathic (type 1) and Neuronopathic (type 2/3) GD
PDD	PD patients bearing GBA1 mutation, tend to have earlier onset, a greater prevalence of cognitive decline as well as more severe cognitive impairment compared to those without the mutation [10].
High-risk population	e.g., individuals with inherited PD or recognized prodromal symptoms such as REM Sleep Behavior Disorder, hyposmia, or novel measures of increased risk

nGD biomarker / study-design grid

	PS	PK	TE / Target occupancy	TF (Target Function)	Pathway Modulation	Disease Modifying	Physiologic response	Pathophysiologic process	Clinical endpoint
Genotype/pheotype				GBA in blood (Alcalay 2015)
Clinical
nGD
Allometric scaling
Nonclinical
In vitro

Model

• cell-based systems
  • iPS
    • well-characterized, replication sets of iPS cell lines from sporadic, dominant, and recessive PD cases
    • iPS-derived neurons or glia
• In vivo
  • that can be detected and modulated in vivo with therapeutic approaches
    • e.g. enzyme activity in accessible peripheral compartments or CNS

Omics / Imaging / Neurophysiologic / CSF proteomics

Omics	develop PD signatures by collecting high-dimensional molecular data (e.g., whole genome sequencing, transcriptomics, epigenomics, metabolomics, proteomics, iPS cell phenotypic data), a
imaging	diffusion tensor imaging (DTI) or connectivity maps generated using MRI or blood-oxygen-level dependent (BOLD) MRI
neurophysiologic	diffusion tensor imaging (DTI) or connectivity maps generated using MRI or blood-oxygen-level dependent (BOLD) MRI
CSF proteomics	CSF proteomics approaches in conjunction with labeling of the proteins via deuterated water ingestion
(right side)	Axonal transport

Questions

• Interaction
• Prodromal?
• Segmentation?
• TE: PET?

Resources / BMx Milestones

resource	note
https://scienceofparkinsons.com/2019/11/25/gcase/	So good, plain english

BMx Milestones: BPS - BMx Platform Start, BFA - BMx Feasibility Assessment, BTV - BMx Technical Validation, BCS - BMx Candidate Selected

Patient recruitment feasibility

210204 Jaya) GBA studies that may be sources of subjects:

Christine Klein’s study now includes 3000 GBA carriers. She is building a registry and these patients can be contacted for clinical trials via the study sites or the study. She was able to identify a few centers with GBA patients, and these centers could be a resource. To contact these patients, we would need to reach out to the sites, perhaps going through Christine as lead PI. https://www.michaeljfox.org/grant/global-database-people-inherited-parkinsons-disease

Fox insight study has been offering genetic testing through 23andMe. At least 5000 people have genotyped. Data is located in Fox Den. ICF permits recontact through the study itself, but sponsors cannot reach out to these subjects. However, they do send a newsletter to the MJFF community and they can mention clinical trials in this newsletter (most of their Fox insight study subjects were found through the MJFF community).

ceri’s feedback version)

Liaison early with patient advocacy groups and genotyping studies that have identified large numbers of GBA carriers.

The projected sample sizes may be attainable given Takeda’s strong collaborations with the MJFF and PD Foundations.

Already genotyped

The MJFF-funded study on inherited PD (principal investigator: Christine Klein MD) has identified >3000 GBA carriers who can be contacted for clinical trial participation, while the PPMI sub-study on GBA1 has identified ~200 GBA carriers. In addition, the PD GENEration study (Parkinson’s Foundation) is genotyping approximately 15,000 individuals with PD and can contact patients.

Screening

Assuming that 5% of the 930,000 PD patients in the US are heterozygous for GBA1, there is a potential population of around 46,000 GBA1 positive PD patients worldwide. While most of these patients have not been genotyped and identified, routine genotyping of PD patients in clinical practice is anticipated to become increasingly common over the next several years (reference: discussion with Tanya Simuni MD).

GBA vs UPDRS vs MOCA

	GBA geneotype vs UPDRS	GBA activity vs UPDRS	GBA geneotype vs GBA activity	GBA genotype vs Cognition	GBA activity vs Cognition
longitudinal	(Maple-Grødem, 2021 #2654) fig2., fig3 (sample size) 20240416 (Maple-Grødem, 2021 #2654) js calculation UPDRS III progression: 'difference between GBA-PD vs non-GBA-PD in progression rate' : ~29% (js calcu) GBA carriers showed faster annual increase in UPDRS scores measuring ADL (1.5 point per year, 95% confidence interval [CI] 1.1-2.0) and motor symptoms (2.2 points per year, 95% CI 1.3-3.1) compared to noncarriers (ADL, 1.0 point per year, 95% CI 0.9-1.1, p = 0.003; motor, 1.3 point per year, 95% CI 1.1-1.6, p = 0.007)	?????? Hamid to model? Note) longitudinal GBA activity change in iPD: (Alcalay, 2020 #2656) fig2&3 (suppl 엑셀의 raw data 일일이 보면 우측 Huh 2020 자료처럼 GBA-PD에선 longi decrease있는지 확인가능하겠네.	(Huh 2020') fig 3	(Ren, 2023 #2657) fig2	(Oftedal, 2023 #2655) fig 2
	(Ren, 2023 #2657) fig1, Supplementary Figure 2 ((Sphagetti plot), (from fig1) 'difference between GBA-PD vs non-GBA-PD in progression rate': ~38% (js calcu)
	2021 Avenali phd dissertation FIG3	(Alcalay, 2020 #2656) fig4	(Alcalay, 2020 #2656) fig1	2021 Avenali phd dissertation FIG3
	(Omer, 2022 #2659, Biogen) UPDRS 가 MOCA 가)	(Alcalay, 2020 #2656) fig?	Huh 2020'	(Omer, 2022 #2659, Biogen) Cf) UPDRS 와 MOCA 가 GBA-PD vs ipd 간 =	(Omer, 2022 #2659) Biogen CF) UPDRS 가 MOCA 가 GBA-PD vs ipd 간 =
			genotype		Activity
		(Huh 2020') fig 2,			Activity-DBS

Clinical dev Scenarios

• GBA w MCI/Dementia: MOCA slope
• GBA w/o Dementia: development of dementia (proportion, or Survival Analysis for the Time to Develop Dementia)

Task: 5/11 proportion of PD-MCI and PDD in GBA-PD!

Task: 찾자! proportion of PD-MCI and PDD in GBA-PD!

Uncertain Spans

location	transcription	uncertainty
BMx milestones	leading icon before BPS	the line begins with a small symbol that is preserved as decoration only.
GBA vs UPDRS / longitudinal cell	?????? Hamid to model?	reads as written; the row of question marks is preserved verbatim as a placeholder.
Bottom continuation	genotype / Activity / Activity-DBS row labels	the bottom rows are partly clipped at the photo edge and continue in 20240722_182320.