Part 2 · Course and diagnosis
Before the tremor
Parkinson's usually starts years before anyone could diagnose it. Smell can fade, the bowels slow and some people start to act out their dreams long before a tremor or slowness appears. Scrub the clock from twenty years before diagnosis to five years after, and switch between a prodromal cohort and family-doctor records.
Acting out dreams: how many go on to a diagnosis?
People with isolated REM sleep behaviour disorder (RBD) act out their dreams but have no other diagnosis yet. The International RBD Study Group followed 1,280 of them, every one confirmed by a sleep study, at 24 centres. Their mean age was 66.3 and 82.5% were men. Scrub the years since the sleep study and watch 100 people convert. 290
Dots: the published Kaplan-Meier estimates at 2, 3, 5, 8, 10 and 12 years. The straight lines between them are drawn, not measured. The 100 figures are scaled from those percentages. 290
The MDS prodromal calculator
Research criteria, not a diagnostic testThe MDS research criteria estimate how likely it is that a person is in the prodromal stage of Parkinson's. They were written for research studies only. They start from a prior probability set by age, multiply the odds by a likelihood ratio (LR) for each marker that is known, and call the result "probable prodromal Parkinson's" at 80% or more. 29,141 This page reproduces the arithmetic with the 2019 values; it cannot tell anyone whether they will develop Parkinson's.
Each button shows the LR it applies. "Not known" leaves the odds unchanged. Only one value per family counts here: a sleep study overrides the questionnaire, and neurogenic overrides symptomatic orthostatic hypotension. All LRs, priors and definitions from the 2019 update. 141
The probability axis is stretched at both ends (log-odds), so equal LRs make equal-length arrows. The combined LR needed for 80% is 4 × (1 − prior) ÷ prior, worked out here from the published priors. 29,141
What the early signs can and cannot tell you
"Prodromal" is a research stage
Prodromal Parkinson's means early symptoms or signs of the disease are present but classic motor Parkinson's cannot yet be diagnosed. The MDS criteria use a naive Bayesian classifier and are for research only. 29
RBD is the strongest single marker
A sleep-study diagnosis of RBD carries an LR of 130, against 6.4 for smell loss and 2.5 for constipation. Even people with RBD who were negative on the prodromal criteria converted: 13% by 5 years and 27% by 8 years. 141,290
Common problems, weak signals
Constipation, anxiety and depression are linked to later Parkinson's, but they may be early features of the disease rather than causes. 247 Constipation alone raised the odds about 2-fold, even more than 10 years ahead. 6
Synuclein seeds before diagnosis
In PPMI, the alpha-synuclein seed amplification assay (SAA) was positive in 44 of 51 people (86%) with RBD or smell loss, but in only 8% of gene carriers without signs. 332 See Diagnosis and the MDS criteria.
Skin biopsy is waiting in line
The 2019 update named phosphorylated alpha-synuclein in skin as a promising marker, sensitive (55–100%) and highly specific (above 90%), but did not add it for lack of prospective data. 141
Genes and independence
For GBA carriers the LR depends on age: 20.0 at 50–54 and 9 at 65–69. For LRRK2 G2019S it rises from 2.5 at 50–54 to 11.6 at 70–74. The criteria are not used for high-penetrance mutations, the markers may not be independent, and LRs probably vary by age, sex and ethnicity. See Genes and inheritance. 141