biomarkers
| What biomarkers may be most sensitive to disease progression? | What might be good biomarkers for mitochondrial function in PD? | Stratification by GBA activity, mutation, lysosomal pannel |
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Skin Biopsy
- b- Upper arm punch skin biopsy
- i) (Auburger et al. 2012, PMID) Skin fibroblasts can be easily isolated from 2 mm punch skin biopsies, a procedure, which does not need stitches and
- ii) (Antony et al. 2020, PMID) After local anaesthesia
- iii) it should be performed by a dermatologist and is not a routine measure in the management of PD patients, thus requiring written consent and ethics commission approval
- iv) (Au - Burbulla and Au - Krüger 2012, PMID) : video protocol https://www.jove.com/video/4228/the-use-primary-human-fibroblasts-for-monitoring-mitochondrial
- Detailed Protocol : NINDS ICF form, S4 protocol
Sleep / Outcome measures
| Epworth sleepiness scale |
ESS is a self-administered questionnaire with 8 questions. Respondents are asked to rate, on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in eight different activities. The ESS score (the sum of 8 item scores, 0-3) can range from 0 to 24. The higher the ESS score, the higher that person's average sleep propensity in daily life (ASP), or their 'daytime sleepiness'. The questionnaire takes no more than 2 or 3 minutes to answer. 0-5 Lower Normal Daytime Sleepiness 6-10 Higher Normal Daytime Sleepiness 11-12 Mild Excessive Daytime Sleepiness (10점 초과자가 concern) 13-15 Moderate Excessive Daytime Sleepiness 16-24 Severe Excessive Daytime Sleepiness |
Prevalence
좌측에서 ESS 보면 baseline: 16%,
Species difference
| Kung 2005 |
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STMN2
| Clustering | DEG | Response to Perturbation | |||
|---|---|---|---|---|---|
| In vitro | (Fernandes, 2020 #1296) iPSC-derived (js: not sure if this fro PD patients, probably not) human dopamine neurons, differences in gene expression profiles between these closely related populations of neurons th | DAn1 | In DAn1 neurons, top DEGs included genes associated with dopamine neuronal lineage(LMO3, POU2F2, NR4A2, LMX1A, DDC, and DRD2) and genes associated with PD (MAPT, SNCA, UCHL1, and ATP13A2) addition, we found upregulation of BDNF and genes involved with cytoskeleton dynamics and neuron projection,including members of the stathmin family (STMN2, STMN1, andSTMN4) and tubulin genes (e.g., TUBB2A, TUBB2B | synaptic signaling and vesicle trafficking (Figures 2A, 2C, and 2D) | |
| DAn2 | DAn2 neurons presented with upregulation of genes associated with oxidative phosphorylation (e.g.,MT-CO1,MT-ND3,COX17) exocytosis, apoptosis, response to OS (e.g., CST3, PON2, SEPP1) and ER stress | synaptic signaling, neuron projection, cell death regulation,and cholesterol biosynthesis, with SNCA and MAPT being amongthe top downregulated genes (as opposed to DAn1 neurons) | |||
| Additionally, I found an interesting paper describing STMN2 reduction in Parkinson's disease. Based on transcriptome network analysis of gene expression signature from substantia nigra of PD brain, STMN2 was identified as a key network driver for neuron-specific synaptic signaling gene module most associated with PD. They also commented that STMN2 is reduced in PD patients. With your iPS-neurons showing STMN2 reduction, is it worth to think about creating iPS-DA neurons with STMN2 phenotypes? We can discuss further with Maiko and Kamiguchi-san... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868244/ | |||||
Speech
| PD prototype | Finally, speech difficulties occur in up to 90% of patients with PD over the course of the disease and significantly affect their social interactions and quality of life. Speech impairment in PD is likely the result of the combined effect of impaired motor control and cognitive deficits. Analysis of speech in patients with PD provides data that are complementary to measures of walking and other complex motor tasks. Furthermore, speech data can be collected both passively and actively in the clinic and at home with very little patient burden; as such it is an attractive measurement modality to assess disease progression. Based on the results of the ongoing TAK-071-2002 study, the usability and acceptability of in-clinic and at-home speech assessments will be ascertained for the PD patients. Additionally, exploratory analysis of the speech data will indicate if there are speech biomarkers that are sensitive to change from baseline in disease progression and can be measured with a digital device. If successful, this measurement modality could be deployed in future clinical trials for PD to measure additional PD biomarkers. |
Stratification
- Carling 2020
| in skin fibroblasts of 100 sPD patients and 50 age-matched controls | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Mito-sPD | Lyso-sPD | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Definition | The five sPD patients with the most marked reduction in ATP levels -12/100 sPD patients had ATP levels reduced by >2SD -4/100 sPD patients having ATP levels >3SD lower than the control mean | the five patients with the most marked increase in the number of lysosomes lysosome counts >3SD greater than the control mean (5/100) cf) 15/100 sPD patients had a lysosome count >2SD greater average | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DEGs from RNA-Seq | 84 genes were differentially expressed (vs age-mated controls) | 342 genes were differentially expressed (vs age-mated controls) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| cxxxiii) 의 complete list가 Supplmentary table 3, or 4에 있다는데 그런 file 찾을 수 없네. cxxxiv) There was no overlap in differentially expressed genes (DEG) between the two subgroups* | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| VarElect results |
Table 4 Top 10 results for unadjusted mitochondrial-dysfunctional DEGs from VarElect. Investigation of DEGs using online tool VarElect with the terms "Mitochondria" and "Parkinson's Disease" in mito-sPD compared to controls indicates a number of genes score highly for association with these terms, including well-established PD genes. Gene symbol represents official HGNC symbol. Matched Phenotypes indicates the terms inputted into VarElect which have been associated with each gene. Results are ranked by VarElect score.
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Table 1 Top 10 results for lysosomal-dysfunctional DEGs from VarElect. Investigation of DEGs using online tool VarElect with the terms "Lysosome" and "Parkinson's Disease" indicates a number of genes score highly for association with these terms. Gene symbol represents official HGNC symbol. Matched Phenotypes indicates the terms inputted into VarElect which have been associated with each gene. Results are ranked by the VarElect score.
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Uncertain Spans
- STMN2 / In vitro 셀의 자필성 메모 “(js: not sure if this fro PD patients, probably not)” — typo
fro는 원문 그대로 보존. - Stratification 표 cxxxiii) 줄의 “Supplmentary”는 사진에서도 그렇게 적혀 있어 typo 가능성이 있으나 원문 그대로 옮김.