(Pieperhoff, 2022 #2051) early PD 37명, HC 27명, longitudinal MRI	the later MRI sessions. This may also explain why atrophy did not impinge on frontal areas in this sample. It is expected that more broadly distributed progression in later stages of the disease will eventually lead to cognitive deficits. JS: 아래 종합하면 UPDRS 의 dynamic change 가 MRI volume change 보다 10배 더 sensitive 하네! [baseline에서] Group difference: SN에서(마저) 겨우 2.98 or 3.32% 차이, 이외 sensory, motor and orbitofrontal cortices, areas in the frontal operculum, inferior frontal sulcus, hippocampus and entorhinal cortex, 에서 차이나니 FDR에서 다 not signifincnat UPDRS-III at baseline had negative associations mainly with regions in the left inferior parietal, occipital and inferior frontal cortex, and it [longitudinal analysis] UPDRS III: 약 ↑10%/y, 이에 반해... Volume change diff.: Difference between groups (percent/year) (이게 즉 control-corrected annual atrophy rate이겠네): whole brain volume 의 경우처럼 PD -0.33%/year (PD), HC: -0.14%/year 로서 PD가 약 2배 빨리 ATRphy 하기는 하나, BG포함 모든 Region에서 기본적으로 PD에서 Longi atrophy rate 가 너무 작네 (모두 <1%/year) (ventricle 확장이 겨우 >1%).. GM: significantly accelerated volume decreases in PD patients in the occipital & temporal lobes, the inferior parietal lobule, in the insula, putamen and NBM. WM: 심지어 WM was less affected than GM (이러니 NFL 이 별로 안 나오나보다) Worse clinical scores (MMSE, PDQ-39, UPDRS-III) were in particular associated with volume decreases of cortical areas, amygdala and basal forebrain nuclei, but not of BG. The observed longitudinal patterns of accelerated volume decrease in PD patients largely coincide with the pattern of α-syn pathology in PD stages as proposed by Braak and colleagues. UPDRS III was longitudinally associated with regions in the medial temporal lobe, cerebellum and thalamus
VTA	Lesser than SNc
((McGregor and Nelson 2019, PMID)2nd	brainstem nuclei, including autonomic areas like DMN of the vagus, motor nuclei such as the pedunculopontine nucleus, and neuromodulatory nuclei like LC and raphe
Limbic ((McGregor and Nelson 2019, PMID)2nd
cortex	Human, MRI: A very little Gray matter atrophy even at advanced stages (Agosta et al. 2013, PMID), (the only region showing additional atrophy in moderate vs. mild PD cases was the thalamus.) Braak theory : stage 5,6 a seminal study using cortical thickness measurements in PD patients showed thinning of the inferior parietal, frontal, occipital, and temporal cortices compared with healthy controls at a corrected significant level [Pereira et al., in press].
White matter	(Agosta et al. 2013, PMID) Damage, DTI, HUMAN Patient microstructural WM changes that were widespread and involved the brainstem, cerebellum, thalamocortical pathways, olfactory tracts, as well as the interhemispheric, limbic, and the majority of corticocortical association tracts DTI: reduced fractional anisotropy (FA) in the posterior SN in PD [106], and changes in FA in the nigrostriatal tract appear to correlate with clinical severity [107]. Furthermore, reduced nigral FA correlates with increased free water in PD, and, when assessed using a bitensor model, increases with disease progression [108].

(Bernheimer, 1973 #1749)

Postmortem, 39 PD cases, no normal control, Disease duration 9.3 SD 0.9

Neurogenomics Partnership

Genome Canada

https://www.genomecanada.ca/en/programs/large-scale-science/past-competitions/strategic-initiatives/international-consortium

[Takeda] this year is pilot phase with the focus of PD/RBD. Daria in TBOS is leading this consortium, focuses include PD/RBD patients WGS, clinical phenotyping including imaging and wearable device data, and microglia phenotyping. Yuya is leading the microglia phenotyping part, where LRRK2 patient-derived PBMC, PBMC-derived directly converted microglia, and iPSC microglia will be profiled and compared each other. → Slide '20200924 LRRK2 microglia v2.pptx' Sample: (20200916, SZ: PI에 물어보겠다, 아마 CSF는 못 한다고 prodromal 위주라고)

Open MTA (2018~), PBMC Sujihata san's group

[NeuroGenomics Partnership (NGP)]

Neuro Genomics Partnership 2020-2021

Structure: 5 Modules over 5 years

Takeda involvement: Module 1, 2, 3: Y1-Y5 $6MLN

Year 1 – focus on RBD and prodromal PD: Total Y1: $1.66M. Go/No-Go after Y1

— Takeda — Goals

• To find out which genetic signatures cause rapid phenoconversion from RBD → PD
• To find out ePOC readouts
• Pt selection (?, how)

Module	1	2	3	4	5
Title	Genome sequencing	Deep phenotyping	iPSC functional Genomics	Target-enabling tools and screens	Personalized clinical trials
IT / DATA INFRASTRUCTURE / AI / INTEGRATION
Module deliverables	16,000 patients sequenced Sample collection WGS / Exome plus Bio-informatics	6,000 patients deeply phenotyped Clinical data Neuropsychology Wearables MRI / MEG DaTscan (for TAK-341)	500 patient iPSC lines made iPSC lines, 2D cultures, organoids Develop cell-based assays	20 screens 10 probes 100 antibodies Assays from M3 to screen in GWAS and patient lines Chemical probes Antibodies	Five phase 1 trials Two phase 2 trials (Year 4 onwards) Data from M1-4 for stratified clinical trials National rare diseases clinical trials network
Direct costs (USD)	$12.5M	$17.2M	$20.3M	$12.8M	$7.2M
Takeda Y1 budget	$0.92M	$0.54M	$0.2M
Deliverables Y1	700 RBD pts	60 RBD and 60 controls 60 PD pts in-kind from QPN	LRRK2 microglia (+isogenics) from iPSC and PBMCs

Direct costs total: $70M. Total Y1: $1.66M.

Year	Module		theme	means	Deliverables
1	1	Genome sequencing	Conversion RBD → PD	Genetics	WGS of 700 RBD patients (out of 16,000 planned for 5Y)
	2	Deep phenotyping	Conversion RBD → PD	Patient phenotype	Deep phenotyping: Clinical data, Neuropsychology, Wearables, MRI / MEG, DaTscan (for TAK-341) for 60 RBD and controls + 60 PD pts in-kind from QPN (out of 6,000 planned for 5Y)
	3	iPSC functional genomics	LRRK2 - microglia	LRRK2 PD microglia-like cells	transcriptome data, phenotype using of iPS-microglia and PBMC-microglias, : iPSC functional genomics: LRRK2 microglia (+isogenics) from iPSC and PBMCs, 3 mutant / 3 controls, establishment of protocol (out of 500 iPSCs planned for 5Y)
	4	Target-enabling tools and screens			20 screens 10 probes 100 antibodies Assays from M3 to screen in GWAS and patient lines Chemical probes Antibodies
	5	Personalized clinical trials			Five p1 trials, Two p2 trials (Year 4 onwards) Data from M1-4 for stratified clinical trials National rare diseases clinical trials network

Meeting 20220727 @Clotilde Degroot, Ms.:

	Recruited	Screen failed	Withdraw or dropped out	ok	Blood*
PD	24	2	1	21	19
RBD	34	0	2	32	32**
CTRL	13	0	1	12	4

**RBD: 15 have samples at the MNI and the rest is at Sacré-Cœur (Ron Postuma’s site). They should also have a second sample at 12 months recruitment.

	NGP	C-BIG (w TDC)
	MNI, McGill University	Outside of NGP (?)
	C-BIG (has the Tissue and Data committee)	Sacré-Coeur
		TDC (?), NGP will probably need additional time to give you access to samples at Sacré-Coeur.

Currently only 3 longi plasma samples from PD, 1 HC

Future: 60 longi plasma samples from PD in 12 m, and same number from HC (under NGP)

MDS-UPDRS worsening 부터 확인필요치 않나?

we have longitudinal MDS-UPDRS for 15 of them.

• CSF: - 13 samples from a single PD patient.
• • 300 CSF samples from 14 different “control” patients as “normal pressure hydrocephalus”.

Before submitting a proposal for access to C-BIG material and/or data to the Tissue and Data Committee (TDC), the applicant must obtain approval for the research study by a duly constituted Research Ethics Board (REB) from the institution from which the project originates.

Clinical Biospecimen Imaging and Genetic Repository (C-BIG)

Application form 작성시 아래 활용하자: 8. DATA PROTECTION. Recipient acknowledges the importance of data privacy of individuals to whom accessed data and samples may relate and commits to comply with all applicable federal, provincial and local laws and regulations relating to data protection and the privacy of subject health information, not to attempt to identify subjects, and not to combine accessed or derived data with other sources of data that would lead to the identification of any individual

[Reporting] It is the view of the MNI that this goal is achieved if research results remain publicly accessible without any restrictions…5.3 Recipient will provide Provider with a written report on the progress of the Research Project described in in Schedule “A” within thirty days of the end of each

Anniversary year of this Agreement; → They mentionned that they have always found a compromise with all groups for the type and timing of some return of the possible results.

Niemann-Pick disease (partially visible at bottom edge)

	Type A	Type B	Type C
Cause	caused by mutations in the …		two genotypes related to (Loss of function) mutations in the NPC1 gene (95%) (NPD-C1: chromosome 18q11-q12, MIM 257220) or to …

Uncertain Spans

location	transcription	uncertainty
Pieperhoff longitudinal-analysis bullet	BG포함 모든 Region에서 기본적으로 PD에서 Longi atrophy rate 가 너무 작네	The Korean clause ends with 너무 작네 per source visual; OCR variants suggested 너무 직네/너무 적네.
cortex row prose	[Pereira et al., in press]	Citation ends with in press; the closing bracket is truncated at the right edge of the cell but the period after press is legible.
Niemann-Pick Type A/B causes	caused by mutations in the …	Status-bar capture only shows the first part of the cause sentence; the gene name and remaining clause are below the visible area.
Niemann-Pick MIM token	MIM 257220	The MIM number reads as 257220 from the partially visible cell; the closing parenthesis is truncated.