| (Shen, 2020 #1800) | α-syn PFF based mouse model | we injected preformed α-syn fibrils into the sublaterodorsal tegmental nucleus and performed regular polysomnographic recordings and parkinsonian behavioural and histopathological studies in these mice. As a result, we recapitulated RBD-like behaviours in the mice and further showed that the α-synopathy and neuron degeneration identified within the sublaterodorsal tegmental nucleus acted as the neuropathological substrates. |
GBA → RBD
- Penetrance (GBA → RBD)
- No report?
- Odds Ratio (GBA in RBD)
- (Gan-Or et al. 2015, PMID 26401515) idiopathic RBD patients (n = 265) and our in-house controls (n = 189). (OR) of 2.63 (95% CI 1.30–5.29, P = 0.0052) for all variants, and OR of 3.46 (95% CI 1.40–8.56, P = 0.0045) for the pathogenic variants. We further compared the frequency of GBA mutations in the RBD cohort to a pooled population from all studies that performed full sequencing of the GBA gene in European controls (Table S1). In this pooled control group, 40/2240 (1.8%) individuals were carriers of GBA mutations, resulting in an OR of 6.24 (95% CI 3.76–10.35, P < 0.0001).
- 20210830 Gan-Or: With RBD, 10-12% of population have GBA mutations
- 10.2% of European RBD patients had a known pathogenic GBA mutation, corresponding to an OR=6.2. When the PD risk variants p.E326K and T369M are included, the proportion of GBA pathogenic variants in RBD rises to 14% [3].
- among patients with idiopathic RBDs there is an increased frequency of GBA mutations (2.6–11.6% of RBD patients vs. 0.4–1.8% of the controls) [65,91,93].
- the odds ratio (OR) for RBD was 6.24 (95% CI 3.76–10.35, P < 0.0001) [65].
- Subjects with homozygous GBA mutations, thus affected with GD, and heterozygous carriers with no PD, presented significant worsening of rapid eye movement sleep behavior disorder scores over a period of time of two years compared with non-carrier subjects [92].
- The presence of GBA mutations does not seem to increase the risk among RBD patients of phenoconverting into PD [93]
- GBA may play a role in the development of RBDs, but not necessarily in determining more severe phenotypes.
- Penetrance
GBA → RBD → PD
- RBD seems to be more frequent in PD patients with GBA mutations compared with patients without this mutation (OR 3.13) [48,65,67,76].
- RBDs are also more frequent in PD patients with concomitant GD than in heterozygous carriers [48].
RBD → PD
- (Schenck et al. 2013, PMID 23347909) Up to 81% of the patients initially diagnosed with idiopathic RBD eventually developed neurodegenerative diseases in long-term follow-up studies. (majority is α-synopathy)
- RBD has been reported to be present in 15-72% of PD patients and is associated with poor parkinsonian symptoms, higher daily levodopa dosage, poor autonomic symptoms and cognitive impairment in PD patients. 2,9-13
RBD in PD
Initial (?) Braak staging
PSYCHIATRIC OUTCOMES IN PD
| Variable | PD Subjects | |||||
|---|---|---|---|---|---|---|
| Baseline (N = 423) | Year 1 (N = 395) | Year 2 (N = 378) | Year 3 (N = 366) | Year 4 (N = 346) | Year 5 (N = 316) | |
| GDS-15 | ||||||
| N | 423 | 395 | 377 | 366 | 343 | 314 |
| <5 | 364 (86.1%) | 330 (83.5%) | 310 (82.2%) | 304 (83.1%) | 283 (82.5%) | 251 (79.9%) |
| 5 or above | 59 (13.9%) | 65 (16.5%) | 67 (17.8%) | 62 (16.9%) | 60 (17.5%) | 63 (20.1%) |
| STAI State | ||||||
| N | 422 | 395 | 378 | 364 | 343 | 313 |
| <40 | 318 (75.4%) | 305 (77.2%) | 295 (78.0%) | 292 (80.2%) | 276 (80.5%) | 246 (78.6%) |
| 40 or above | 104 (24.6%) | 90 (22.8%) | 83 (22.0%) | 72 (19.8%) | 67 (19.5%) | 67 (21.4%) |
| MDS-UPDRS Part I Psychosis | ||||||
| N | 423 | 395 | 378 | 366 | 343 | 316 |
| 0 | 410 (96.9%) | 376 (95.2%) | 350 (92.6%) | 327 (89.3%) | 300 (87.5%) | 276 (87.3%) |
| 1 or above | 13 (3.1%) | 19 (4.8%) | 28 (7.4%) | 39 (10.7%) | 43 (12.5%) | 40 (12.7%) |
| MDS-UPDRS Part I Apathy | ||||||
| N | 423 | 395 | 378 | 366 | 343 | 316 |
| 0-1 | 412 (97.4%) | 366 (92.7%) | 343 (90.7%) | 338 (92.3%) | 309 (90.1%) | 278 (88.0%) |
| 2 or above | 11 (2.6%) | 29 (7.3%) | 35 (9.3%) | 28 (7.7%) | 34 (9.9%) | 38 (12.0%) |
| MDS-UPDRS Part I Fatigue | ||||||
| N | 422 | 395 | 378 | 366 | 345 | 316 |
| 0-1 | 375 (88.9%) | 329 (83.3%) | 301 (79.6%) | 293 (80.1%) | 262 (75.9%) | 216 (68.4%) |
| 2 or above | 47 (11.1%) | 66 (16.7%) | 77 (20.4%) | 73 (19.9%) | 83 (24.1%) | 100 (31.6%) |
| MDS-UPDRS Part I Insomnia | ||||||
| N | 422 | 395 | 378 | 366 | 345 | 316 |
| 0-1 | 323 (76.5%) | 272 (68.9%) | 253 (66.9%) | 236 (64.5%) | 198 (57.4%) | 175 (55.4%) |
| 2 or above | 99 (23.5%) | 123 (31.1%) | 125 (33.1%) | 130 (35.5%) | 147 (42.6%) | 141 (44.6%) |
| Epworth Sleepiness Scale | ||||||
| N | 423 | 395 | 377 | 364 | 343 | 313 |
| <10 | 357 (84.4%) | 329 (83.3%) | 292 (77.5%) | 264 (72.5%) | 246 (71.7%) | 216 (69.0%) |
| 10 or above | 66 (15.6%) | 66 (16.7%) | 85 (22.5%) | 100 (27.5%) | 97 (28.3%) | 97 (31.0%) |
| RBDSQ | ||||||
| N | 420 | 393 | 378 | 365 | 342 | 312 |
| <6 | 311 (74.0%) | 288 (73.3%) | 253 (66.9%) | 239 (65.5%) | 216 (63.2%) | 193 (61.9%) |
| 6 or above | 109 (26.0%) | 105 (26.7%) | 125 (33.1%) | 126 (34.5%) | 126 (36.8%) | 119 (38.1%) |
| QUIP | ||||||
| N | 422 | 395 | 378 | 366 | 343 | 313 |
| No disorders | 335 (79.4%) | 341 (86.3%) | 301 (79.6%) | 280 (76.5%) | 251 (73.2%) | 228 (72.8%) |
| Any 1 or more disorders* | 87 (20.6%) | 54 (13.7%) | 77 (20.4%) | 86 (23.5%) | 92 (26.8%) | 85 (27.2%) |
| (Hu, 2015 #1794) | Patients with PRBD have higher frequency of rigidity-bradykinesia type of PD, PRBD group has longer disease duration, more advanced disease stage, severer motor symptoms, higher incidence of rigidity-bradykinesia type of PD and more non-motor symptoms. |
RBD → Dementia
- 20210830 Gan-Or: Those with RBD develop dementia as well as PD very quickly. If you look at them 5 years into their neurodegenerative disease, they quickly develop both dementia/MCI and Parkinson’s. Some happen to develop the motor symptoms first, or the cognitive symptoms first, but they pretty quickly have both motor and cognitive symptoms
RBD → MSA
20210830 Gan-Or: 5% convert from RBD to MSA
RBD → PDD/DLB
20210830 Gan-Or: 50% convert from RBD to PDD/DLB
Unmet Needs across Parkinson’s Patient Populations
| Increasing Neuronal Degeneration → | ||||
|---|---|---|---|---|
| At Risk | Prodromal | Early / Mild | Intermediate / Moderate | Advanced / Severe |
Disease Modification (green tile, spans Prodromal → Advanced/Severe)
| ||||
Treatment of Non-Motor Symptoms (Psychosis, Dementia) (pink tile, spans Intermediate/Moderate → Advanced/Severe)
| ||||
Treatment of Motor Response Complications: PD-LID* and Wearing OFF** (grey tile, spans Intermediate/Moderate → Advanced/Severe)
| ||||
Legend: Motor & Non-Motor Function · Non-Motor Function · Motor Function · Complications
Increasing Therapeutic Importance ↑
Note: * LID = Levodopa Induced Dyskinesia. ** Wearing OFF = shortened time of periods of benefit between levodopa doses. † Current SOC for PD-LID is amantadine, which causes hallucinations.
22 — Takeda Pharmaceuticals International — Confidential, for internal use. Proprietary business information
GBA pathway in RBD
| brain | CSF | SERUM | |
|---|---|---|---|
| Huebecker et al. 2019, PMID 30703585 |
Uncertain Spans
- “(Shen, 2020 #1800)” — top row’s reference cell; the year/citation key is partially clipped above the visible top of the page; transcribed from the OCR evidence as “(Shen, 2020 #1800)“.
- RBDSQ “<6” Year 2 row — value “253 (66.9%)” sits one row above its label cell in the source layout due to the row-strip break; transcribed against the row label as the source intends.
- GBA pathway “brain” / “CSF” / “SERUM” columns — body of the table is empty in the visible portion (figure panels occupy the cells); the cells are left blank and the figure is preserved as evidence rather than embedded.
- “Increasing Therapeutic Importance” — the slide’s vertical-axis arrow label is visible on the left edge of the slide image; transcribed verbatim from the source.