Disease area biomarker table tail (CSF p65-Ub / Functional mito CSF BM / imaging / α-syn / Lysosome rows), Omics resources (Silberring 2010 #1148), DJ-1 (Park7) block, DLB vs PDD vs MSA comparison table opener (Prevalence / Incidence / Onset / Life expectancy / Dementia / RBD / Visual hallucination / Parkinsonism / Autonomic Sx / Four core indicative diagnostic biomarkers / Supportive / Clinical Dx / DATscan / Mokette / Nocker reference table)
Disease area TM strategy (continued)
(Tail rows of the prior page’s Project relevance / Candidate BM table)
| Pathway | Project relevance | Candidate BM | BM discovery (identification) | Assay development |
|---|---|---|---|---|
| CSF p65-Ub (mitophagy marker) | Identified in Parkin-PD patients (brain CSF Plan) Validation in Parkin-PD patients CSF (now contacting NCNP) | assay development started (BFA by FY21 Q1) | ||
| Functional mitochondrial CSF BM | Some molecular markers (membrane potential, ATP) change in Parkin-PD patients (fibroblast). Plan: - Will discuss with Prof Yamane (Niigata univ collaboration) - Validate in Parkin-PD patient brain (Niigata univ collaboration) - Validate in Parkin-PD patient CSF (MJFF univ collaboration) | To be developed Fill will start in 2021 May | ||
| Functional mitochondrial imaging | Brain imaging tools (eg NAD+, 31P MRS) are available but not tested in PD. Plan | Already established | ||
| α-syn | SNCA ASO SNCA HDO GBA activator, GBA GT NLRP3i | p-aSyn (CSF) | Identified in iPD patients (brain and CSF) | BFV achieved (FY20 Q3) |
| Oligomeric aSyn (CSF) | Identified in iPD patients (brain and CSF) | RT-Quic PS started (seeding-based assay) Non seeding-based assay to be proposed (Waseda univ collaboration) | ||
| aSyn PET α-Syn Retina Cortical α-MRI | Identified in iPD patients (brain) GBA-LBD patients show greater cortical LBs and α-MRI signal accelerated cognitive dysfunction. Plan: - A natural history study may define a-MRI for cortical thinning | Animal model needs to be developed | ||
| Lysosome | GBA activator GBA GT | Lysosomal autophagy markers and general lysosomal markers | - Will discuss with Prof Yamane for a natural history study by Dec 2020. - Several markers identified in GBA-PD patients brain plan: - Validation in GBA-PD patients CSF from NCNP in 2021 - Assessment in GBA animal model (ARNJ) | Cathepsin activity assay started (BFA by FY21 Q3) May add other lysosomal assay depending on animal model findings. |
Omics
- At least cell model required
- Resource: (Silberring, 2010 #1148) Good!
DJ-1 (Park7)
- Location: cytoplasm, mitochondrial matrix, and intermembrane space.
- DJ-1 is a mitochondrial protein involved in the protection against oxidative stress (Xiong et al. 2009; Do-1 also promotes ubiquitination and the degradation of Parkin substrates via interaction with Parkin and PINK1 (Xiong et al. 2009; Repaso-Aguilar et al. 2015); Do-1 mutations result in increased oxidative stress and impaired mitochondrial dynamics and function (Manabeni Kim et al. 2004; Repaso et al. 2007).
- Function:
- KO → No abnormalities
- (KD) results in dopamine-knockdown reduces dopamine-Parkinsonism that develops in the mid-twenties, resembling Parkin- and PINK1-linked forms.
DLB vs PDD vs MSA
| DLB | PDD | MSA | |
|---|---|---|---|
| Prevalence | 0.4% of people over 65 (PD 1%사용 ?) (양성장 1018), (Chia, 2013 #1284) 1.4 million cases in US States, 301,000 (95% CI 275,000 - 328,000), (Marras et al. 2018; Aarsland and Kurtz, 2018) | PMDD: 80% after 20y in PD 30% in PD (Marras et al. 2018; Aarsland and Kurtz, 2018) | (Meissner, 2020 #1907) MSA prevalence: rare disease, with 4 per 100,000. (Marras et al. 2018; 동시 1차 한 가 1차 병이 발다.) OS: in the United States, a rare disease is defined as a condition that affects fewer than 200,000 people in the US. |
| Incidence | 2018; Aarsland and Kurtz, 2018) | ||
| Prodromal | RBD, 1,000 people develop each year | ||
| Onset | 74y8 | 0, 9; SDF1? | (Wenning, 2013 #1077) 56.2 y (std 8.4) The age at presenting suggesting latencies to H&Y IV and V of 9 (MSA) and 14 years (PD), respectively. |
| D-FF | cognitive symptom 가 motor symptom 가 발현 | 1 motor 가 cognitive symptom | Rapid, survival from onset 9.8 y (Wenning 2013); 6-10y; MSA-P group requires a wheelchair within 5 y of onset of motor symptoms, whereas wheelchair-dependency occurs on average after 6.7 years from disease-onset |
| Life expectancy | survival from onset: 5.5 - 7.7 y, survival from diagnosis between 1.9 and 6.3 years | Sudden death: infection akinetic-rigid syndrome (i.e. slowness of initiation of movement resembling PD) | |
| Dementia | three most common cognitive symptoms in DLB are impairments of attention (Aarsland MacDonnard 2008, Bradshaw, and visuospatial functions; (in red episodic memory) DLB have a slighter decline of decline than PDD (271 versus 1.8 MMSE points/year) (Aarsland et al, 2017) | ||
| RBD | in 80% of DLB | Less common than in DLB | CbI ataxia (Poor coordination/unsteady walking, double vision) pill-rolling rest tremor is uncommon [45] and, in contrast to PD, postural instability emerges early |
| Parkinsonism | in 85% of DLB | ||
| Visual hallucination | in 80% of DLB | Less common than in DLB | pattern of widespread, severe and rapidly progressive generalized autonomic failure with adrenergic dysfunction clearly points towards a diagnosis of MSA [54] MSA patients showing intact or mildly impaired olfaction with |
| Autonomic Sx | < 10% of cause of | ||
| Four core indicative diagnostic biomarkers (Mokketh, 2005 #2729 / Emre, 2007 #2730) | fluctuating cognition, visual hallucinations, RBD and Parkinsonism | PD and MSA-Parc frequently indistinguishable in the early disease stages | |
|
MSA-P: predominantly parkinsonian features. The putamen is hypotensive on T2-weighted MRI and may show an increased nominal hyposignal of the putamen (so-called T2 thinning). MSA-C: predominantly cerebellar ataxia. (size of the cerebellum and brainstem) may be abnormally low; in some cases, where T2 reflects atrophy of the pontocerebellar fibers that manifest in T2 signal intensity in its atrophic zone. | |||
| Supportive |
[DAT in the BG on PET or SPECT imaging 123iodine-metaiodobenzylguanidine (123MIBG) shown on myocardial scintigraphy loss of atonia during REM sleep evidenced on polysomnography From PET, SPECT, CT or MRI brain imaging studies, or EEG monitoring [13]; lack of damage to medial temporal lobe, reduced | ||
| Clinical Dx | Probable DLB | occipital activity prominent slow-wave activity dementia and at least two core features are present, or one core feature with at least one indicative biomarker is present | |
| Possible DLB | dementia and only one core feature are present, or no core features are present, but at least one indicative biomarker is present | ||
| Site Dx | PD | DLB is diagnosed when cognitive symptoms begin before or at the same time as parkinsonism. PDD would be the diagnosis when PD is well established before the dementia occurs; that is, the onset of dementia is more than a year after the onset of parkinsonism symptoms[1] | |
| Autopsy | generally non-responsive to dopamine medications (Nocker, 2012 #1075) 8 MSA-P patients (age 60, disease duration 2.4 y, UPDRS-III 40), 11 sPD Brainstem / Striatum Cross 1.5y0 / Cross sectional / 1.3y0 I, than sPD No further (1) / sectional / 17.50% (1) I, than sPD No further (1) / 35% (1) From above Nocker 2012 Table 1. Calculated samples sizes for the number of patients needed in each group for a therapeutic trial to detect the effect of a putative neuroprotective drug therapy resulting in a reduction in volume... | ||
| DATscan | From Nocker 2012 20 33 50 | ||
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| DLB Prevalence cell | (양성장 1018) | reads as written (likely OCR garble of 양성장 Korean / English mix); preserved verbatim. |