How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder

One of the major challenges in Parkinson's Disease research is in developing neuroprotective treatments - treatments actually prevent the death of dopaminergic neurons, rather than just temporarily topping up dopamine levels.

Developing such neuroprotective treatments is made difficult because, at the time of diagnosis, up to half of the dopaminergic neurons in the substantia nigra may have already died (Fearnley and Lees, 1991; Stoessl, 2007). In order to rescue this population of neurons, it will be crucial to be able to intervene as early as possible. This means diagnosis of PD must occur earlier too. See this post for more information on the imporance of predicting PD.

Thankfully, several risk factors for PD, such as REM-sleep Behaviour Disorder and subtle motor signs may provide early clues as to who will develop PD and may enable us to diagnose the disease early.

A recent study by Postuma et al. used patients with REM-sleep behaviour disorder (RBD) and therefore a high chance of developing PD to test for subtle motor symptoms in the years preceeding diagnosis with PD (Postuma et al., 2012). This has helped confirm the existence of a 'prodromal' phase of PD, prior to full onset of the disease, where subtle motor symptoms exist. The authors showed that these subtle motor symptoms may enable us to predict PD in patients who have not yet fully developed the disease.

What is REM-sleep Behaviour Disorder?

Normally while asleep our bodies are paralysed to prevent us acting out our dreams. In people with RBD, this paralysis does not occur and dreams are acted out during sleep. These dreams may be violent and quite distressing and can result in injury either to the patient or their bed partner.

RBD is a significant risk factor for PD. Over half of patients with RBD go on to develop PD (although this may take up to 13 years), compared with less than 1% of the normal population (Schenk et al., 1996, Iranzo et al., 2006; Postuma et al., 2009)

What the authors did in this study

78 patients with RBD and 156 age-matched controls were signed-up to have an appointment with a neurologist every year for 5 years. At this appointment, the neurologist would perform a few simple tests of motor function, take a UPDRS* score and decide whether the patient could be diagnosed with PD or not (based on currently used criteria set out by the UK Brain Bank).

The authors used this information to answer 4 key questions:

1. When does motor Parkinsonism start?
2. Which features start first?
3. Which measures are most sensitive and specific in predicting PD?
4. Are the prodromes for PD and dementia with Lewy Bodies different?

 What the authors found

• When does motor Parkinsonism start? - The authors found that patients who went on to develop PD showed worsening scores in the motor tests, starting around 3-4 years before diagnosis. For instance in the alternate-tap test the patients who went on to develop PD had a lower taps per minute than those who did not develop PD, even 4-5 years before diagnosis.

Patients who developed PD showed declining alternate-tap test scores from 5 years before diagnosis with PD. The dotted line shows test scores of healthy controls which remained constant at around 190 taps/min. From Postuma et al., 2012.

• Which features start first? - The authors calculated that bradykinesia (slowness of movement) started first, followed by rigidity and gait abnormalities. Evidence of tremor only showed up 1.3 years before diagnosis. Voice and facial features also appeared earlier than gait and limb features.

• Which measures are most sensitive and specific in predicting PD? - 3 years prior to diagnosis, one of the motor tests (the alternate tap test) had 80% sensitivity and 75% specificity. A modified version of the UPDRS score (with tremor removed because this was the least helpful feature for early diagnosis) had a predicted sensitivity of 94% and specificity of 97% 2 years prior to diagnosis.

• Are the prodromes for PD and dementia with Lewy Bodies different? - Patients with RBD are also at risk of developing dementia with Lewy bodies (DLB), which is a form of dementia sharing characteristics with both Alzheimer's and Parkinson's disease. The data suggested that DLB may have a prodromal period which is almost twice as long as the prodromal period for PD (implying that the underlying neurodegenerative process in DLB is slower than that in PD).

Discussion

The advantages of a 'prospective' study design: A major strength of this study is that the authors started the motor tests and UPDRS scoring on participants prior to their developing PD. Previous studies have relied on measuring the rate of progresssion of symptoms in patients who have already developed PD and then back-extrapolating to determine when these these patients would have first deviated from baseline.

Why choose patients with RBD? The incidence of PD in the general population is quite low, so thousands of healthy individuals would have to be followed up in order to catch a few people who eventually develop PD. This group's innovative solution was to use patients with RBD to 'enrich' their cohort with people much more likely to develop PD. However, it is possible that these patients with RBD who develop PD represent a subtype of PD patients with slightly different features to 'typical' PD patients. Therefore, there is a need to confirm these results with similar studies in healthy cohorts (just as the PREDICT-PD project is doing).

Sample size: Additionally, because some participants dropped out and others developed diseases other than PD, the total number of patients with PD included in the analysis ended up quite small (only 20). This limited the strength of the analyses the authors were able to perform. However, the study is still ongoing and as the participants are followed-up, more will develop PD, allowing stronger conclusions to be made about the nature and duration of the prodromal period.

How does this fit in with what we already know about the prodromal phase of PD? Importantly, these findings fit with data from imaging studies and the back extrapolation of motor progression in established disease, both of which point towards the existence of a prodromal period of 4-5 years duration (Moeller and Eidelberg, 1997; Fearnley and Lees, 1991).

Overall, this study confirms the existence of a prodromal phase of PD, provides information on the nature and duration of this prodrome and suggests that simple motor tests could be used to help diagnose Parkinson's disease early.

Jargon buster:
UPDRS score: The Unified Parkinson's Disease Rating Scale is a score taken by a clinician, to assess the severity of a patients symptoms. It consists of several sections each of which consists of lots of questions, with the aim of making assessment more objective.

References:

Fearnley, J., & Lees, A. (1991). Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain, 2283-301.

Iranzo, A., Molinuevo, J., Santamaria, J., Serradell, M., Marti, M., & Valldeoriola, F. (2006). Rapid-eeye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurology, 572-7.

Moeller, J., & Eidelberg, D. (1997). Divergent expression of regional metabolic topographies in Parkinson's disease and normal ageing. Brain, 2197-206.

Postuma, R., Gagnon, J., Vendette, M., Fantini, M., Massicotte-Marquez, J., & Montplaisir, J. (2009). Quantifying the risk of neurodegenerative disease in indiopathic REM sleep behaviour disorder. Neurology, 1296-300.

Postuma, R., Lang, A., Gagnon, J., Pelletier, A., & Montplaisir, J. (2012). How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder. Brain.

Schneck, C., Bundlie, S., & Mahowald, M. (1996). Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosied with idiopathic rapid eye movement sleep behaviourdisorder. Neurology, 388-93.

Soessl, A. (2007). Positron emission tomography in premotor Parkinson's disease. Parkinsonism Relat Disord, S421-4.