purpose for measuring gait variability in PD patients in a clinical trial and will also demonstrate the sensitivity to change of gait variability as digital biomarker. Based on the results of this study, this digital gait assessment tool could be successfully deployed in future clinical trials for PD. It would be beneficial to directly measure Falls in PD patients, as this would be a more accurate assessment than a surrogate measure like in-clinic gait variability. There are exploratory digital tools that can accurately measure falls in healthy volunteers, but it remains to be seen if these digital tools can accurately assess falls in PD patients. In the ongoing TAK071-2002 study, the patients are wearing a wearable pendant sensor for the entire duration of the study that generates 2 digital endpoints; in-home activity (number of steps taken, assessed every 15 minutes) and number of falls. Based on the results of this study, this wearable pendant sensor for measuring falls directly will be validated against the gold standard for fall reporting (daily fall diaries) in PD patients. Additionally, the usability and acceptability of the wearable pendant sensor will also be assessed in the context of use (at-home measurement) for the clinical population (PD patients at risk of falls). If successful, this digital device could be deployed in future clinical trials for PD to directly quantify number of falls as an outcome measure.
Prevalence of PD
- N. Maserejian, L. Vinikoor-Imler, A. Dilley. Estimation of the 2020 Global Population of Parkinson’s Disease (PD) [abstract]. Mov Disord. 2020; 35 (suppl 1).
https://www.mdsabstracts.org/abstract/estimation-of-the-2020-global-population-of-parkinsons-disease-pd/. Accessed May 4, 2023.
- Globally, an estimated 9.4M (95% CI) (7.7M, 11.2M) live with PD in 2020. Country-specific numbers include: US 930K (794K, 1.1M); Japan 344K (278K, 425K); Germany 266K (209K, 318K); France 157K(127K, 192K); Italy 149K(125K, 181K); UK 142K (117K, 174K); Spain 120K (97K, 150K). [Image 1]
- The prevalence of PD is between 0.1% and 0.3% in the general population
- between 1% and 2% in persons 65 years of age or older (Toda and Harada, 2010).
- Approximately 85% of the general PD population is H&Y 1-3, according to this reference (GBD 2016 Parkinson’s Disease Collaborators. Global, regional, and national burden of Parkinson’s disease, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2018; published online Oct 1. http://dx.doi.org/10.1016/S1474-4422(18)30295-3. )
Prodromal PD
Prodromal PD studies
| (HPRO-PD) | A large longitudinal investigation | |
| PARS |
Definition of Prodromal PD
PPMI
[Siderowf 2023’] Prodromal participants included individuals without a diagnosis of Parkinson’s disease, but who had prodromal features associated with risk of Parkinson’s disease, including RBD (confirmed by polysomnogram) or otherwise unexplained severe hyposmia (defined as at or less than the 15th percentile using the University of Pennsylvania Smell Identification Test [UPSIT; Sensonics, Philadelphia, PA, USA]) in olfactory perform ance based on internal population norms
P2P
Resource; Clinical Study Protocol Phase II-III.pdf 에 있는 inclusion criteria:
- Prodromal aSN as defined by presence of any of the following: a. Idiopathic RBD (probable or definite) as per established diagnostic criteria b. Hyposmia defined as <15% for age and sex c. Other prodromal features that qualify for enrollment in PPMI prodromal cohort.
- Presence of DAT deficit at baseline as defined by lowest putamen SBR<65 percentile for age and sex
MDS research criteria for prodromal PD
(the probability that any individual has prodromal PD) is: clinical PD conversion을 계산하는 거 아니네.
- Updated in 2019 (Heinzel, 2019 #1489)
TABLE 1. LRs of risk and prodromal markers
| LR+ | LR- | ||
|---|---|---|---|
| Risk markers | Male sex | 1.2 (male) | 0.8 (female) |
| Regular pesticide exposure | 1.5 | NA | |
| Occupational solvent exposure | 1.5 | NA | |
| Nonuse of caffeine | 1.35 | 0.88 | |
| Nonsmoking | |||
| Current smoker | NA | 0.51 | |
| Never smoker | 1.2 | NA | |
| Former smoker | NA | 0.91 | |
| First-degree relative with PD | 2.5 | NA | |
| or | |||
| Known gene mutation (with intermediate-strength penetrance) | LR+ dependent on age-related penetrance, see Table 2 | NA | |
| or | |||
| Polygenic risk score (PRS) | 1.57 (highest quartile of PRS scores) | 0.45 (lowest quartile) | |
| SN hyperechogenicity | 3.4 | 0.38 | |
| Diabetes mellitus (type II) | 1.5 | 0.97 | |
| Physical inactivity | 1.3 | 0.91 | |
| Low plasma urate levels | 1.8 (in men) | 0.88 (in men) | |
| Prodromal markers | PSG-proven RBD | 130 | 0.65 |
| Possible RBD (questionnaire) | 2.8 | 0.89 | |
| Dopaminergic PET/SPECT clearly abnormal (eg, <65% normal, 2 SDs below mean) | 43.3 | 0.66 | |
| Subthreshold parkinsonism (UPDRS-III >3 excluding action tremor or MDS-UPDRS-III >6 excluding postural and action tremor) | 9.6 | 0.55 | |
| or | |||
| Abnormal quantitative motor testing | 3.5 | 0.60 | |
| Olfactory loss | 6.4 | 0.40 | |
| Constipation | 2.5 | 0.82 | |
| Excessive daytime somnolence | 2.7 | 0.86 | |
| Orthostatic hypotension (OH) – neurogenic OH | 18.5 | 0.80 | |
| Symptomatic OH | 3.2 | ||
| Erectile dysfunction | 3.4 (in men) | 0.87 (in men) | |
| Urinary dysfunction | 2.0 | 0.90 | |
| Depression (± anxiety) | 1.6 | 0.88 | |
| Global cognitive deficit | 1.8 | 0.88 | |
NA, not applicable.
TABLE 2. Age-related penetrance of intermediate-strength genetic mutations
| Age groups (years) | PD risk at different ages | ||||
|---|---|---|---|---|---|
| Noncarriers | GBA mutation carriers6 (eg. N370S, L444P) | GBA: LR+ | LRRK2 mutation carriers7 (p.G2019S) | LRRK2: LR+ | |
| 50–54 | 0.4% | 8% | 20.0 | ~1% | 2.5 |
| 55–59 | 0.75% | 11% | 14.7 | 3% | 4.0 |
| 60–64 | 1.25% | 14% | 11.2 | 7% | 5.6 |
| 65–69 | 2.0% | 18% | 9.0 | 15% | 7.5 |
| 70–74 | 2.5% | 21% | 8.4 | 29% | 11.6 |
| 75–79 | 3.5% | 25% | 7.1 | 32% | 9.1 |
| 80+ | 4% | 30% | 7.5 | 42% | 10.5 |
On-line calculator
Validation
- The criteria have been validated in the general population and in cohorts at risk for PD such as RBD [26,27,28,29,30,31].
By (Postuma, 2017 #1098).
Dx criteria 가 따로 있는 게 아니라 element가 있고 (RB, DATscan, Subthreshold motor Sx, hyposmia, hypotension), 이것들을 계산해서 probable prodromal PD 라고 진단하는 거구나.
Calculation of the probability of prodromal PD
Assumptions:
- probable prodromal PD would be defined as an 80% likelihood of neurodegenerative Lewy body disease being present
- average prodromal PD duration is 10 years
- research purpose only
[limitation]
- It is uncertain that markers are truly ind- ependent.
- Eg 1) constipation, REM SBD and hyposmia are common when considered individually, as expected, their co-occurrence was found to be rare in individuals without PD. It is indeed difficult to think of a highly prevalent underlying pathology other than prodromal PD Eg 2) combination of hyposmia and DAT deficit was highly predictive of conversion to PD within 4 years of clinical follow-up. (Jennings, 2017 #1180)
위 표에서 Baseline (prior) probability를 establish.
Table 3 Likelihood Ratio Thresholds for Diagnosis of Prodromal PD
| Age | Prior Probability (%) | LR for Probable Prodromal PD |
|---|---|---|
| 50–54 | 0.4 | 1000 |
| 55–59 | 0.75 | 515 |
| 60–64 | 1.25 | 300 |
| 65–69 | 2.0 | 180 |
| 70–74 | 2.5 | 155 |
| 75–79 | 3.5 | 110 |
| >80 | 4.0 | 95 |
아래 표에서 LR (Likelihood ratio)를 계산
Table 2 Prodromal Markers of PD
| LR + | LR − | |
|---|---|---|
| Risk markers | ||
| Male sex | 1.2 (male) | 0.8 (female) |
| Regular pesticide exposure | 1.5 | n/a |
| Occupational solvent exposure | 1.5 | n/a |
| Nonuse of caffeine | 1.35 | 0.88 |
| Former smoker | n/a | 0.8 |
| Sibling had PD with age onset <50 | 7.5 | n/a |
| Any other first degree relative with PD | 2.5 | n/a |
| Known gene mutation | Berg et al. (2015) | n/a |
예 (worked example)
A 58-year-old man is being evaluated for possible prodromal PD. He reports no occupational pesticide exposure, does not drink coffee, and was a former smoker. He has idiopathic RBD, olfactory loss, constipation, preserved erectile function, no depression or anxiety, and no daytime somnolence. Quantitative motor testing was in the borderline/low-normal range (there was no expert examination available), so results were uncertain
Prior probability (age 58): 0.75%
total LR ¼ 1.2 (male) _ 1.0 (pesticide) _ 1.35 (coffee) _ 0.8 (former smoker) _ 130 (RBD) _ 4.0 (olfaction) _ 2.2 (constipation) _ 0.90 (normal erection) _ 0.85 (no depression or anxiety) _ 0.88 (no somnolence) _ 1.0 (borderline motor testing result omitted) = 998.
Uncertain Spans
- “[Image 1]” — the Maserejian 2020 prevalence bullet ends with the literal token “[Image” cut off at the line break in the source; transcribed as “[Image 1]” (the trailing “1]” is the next-line continuation as printed).
- “Possible RBD (questionnaire)” LR+ — column position on this row shows “2.8” but the visible row strip places the 2.8 just below the questionnaire row in the source crop; transcribed as printed.
- “total LR ¼ 1.2 (male)” — the source uses the unicode glyph “¼” where ”=” is expected (typographic artifact of the original PDF rendering); transcribed as printed.
- “Subthreshold parkinsonism” LR+ row — the LR+ value 9.6 sits one row above its label cell in the source layout due to multi-line wrapping; transcribed against the row label as the source intends.