Do thinking problems develop before Parkinson's?

Many of the blog posts from the PREDICT team have highlighted the fact that Parkinson's affects many more aspects of life than just movement. Whilst the core features are still thought of as slowing down, becoming stiff and developing tremor, problems such as constipation, sleep difficulties and thinking and memory problems are all commonly seen. 

The thinking problems may even be present before diagnosis - testing for specific difficulties could be helpful in the efforts to pick up people at the earliest stages. This research paper used data from a large international study of healthy people who we know are at risk of Parkinson's including people with a sleep disorder strongly related to Parkinson's, people with smell loss and people with genetic mutations associated with Parkinson's.

They found that people with the sleep disorder performed worse on tests of attention and visual function than all the other groups. The groups with smell loss and genetic mutations performed at a similar level across tests and were comparable to people who had already developed Parkinson's. Unfortunately there was no comparison to people without these risk factors, so we can't make any conclusions about whether these groups perform worse than the general population.

I think this finding points to the fact that, just as Parkinson's disease is different in every individual, the route into the disease is also likely to be different. It is also helpful in pointing us towards the specific tests which may be useful in the earliest stages - we have included short tests of attention and memory in the new online PREDICT-PD study www.predictpd.com and I will be very interested to see how our findings compare to these results.

-anna

https://www.ncbi.nlm.nih.gov/pubmed/30125297 

Cognition among individuals along a spectrum of increased risk for Parkinson's disease.

Chahine LM, Urbe L, Caspell-Garcia C, Aarsland D, Alcalay R, Barone P, Burn D, Espay AJ, Hamilton JL, Hawkins KA, Lasch S, Leverenz JB, Litvan I, Richard I, Siderowf A, Coffey CS, Simuni T, Weintraub D; Parkinson’s Progression Markers Initiative. 

Several characteristics associated with increased risk for Parkinson's disease (PD) have been identified, including specific genotypes and various non-motor symptoms. Characterizing non-motor features, such as cognitive abilities, among individuals considered at-risk for PD is essential to improving prediction of future neurodegeneration. METHODS: Participants belonging to the following cohorts of the Parkinson Progression Markers Initiative (PPMI) study were included: de novo PD with dopamine transporter binding deficit (n = 423), idiopathic REM sleep behavior disorder (RBD, n = 39), hyposmia (n = 26) and non-PD mutation carrier (NMC; Leucine-rich repeat kinase 2 (LRRK2) G2019S (n = 88) and glucocerebrosidase (GBA) gene (n = 38) mutations)). Inclusion criteria enriched the RBD and hyposmia cohorts, but not the NMC cohort, with individuals with dopamine transporter binding deficit. Baseline neuropsychological performance was compared, and analyses were adjusted for age, sex, education, and depression. RESULTS: The RBD cohort performed significantly worse than the hyposmia and NMC cohorts on Symbol Digit Modality Test (mean (SD) 32.4 (9.16) vs. 41.8 (9.98), p = 0.002 and vs. 45.2 (10.9), p<0.001) and Judgment of Line Orientation (11.3 (2.36) vs.12.9 (1.87), p = 0.004 and vs. 12.9 (1.87), p<0.001). The RBD cohort also performed worse than the hyposmia cohort on the Montreal Cognitive Assessment (25.5 (4.13) vs. 27.3 (1.71), p = 0.02). Hyposmics did not differ from PD or NMC cohorts on any cognitive test score. CONCLUSION: Among individuals across a spectrum of risk for PD, cognitive function is worse among those with the characteristic most strongly associated with future risk of PD or dementia with Lewy bodies, namely RBD.

Non-motor features of PD... new report from the HPFS

Here we see evidence to support the fact that it you have a combination of smell loss, probable REM sleep behaviour disorder and constipation, you are more likely to have Parkinson's... this is not surprising because we have seen this in lots of other studies but it is nice to see it all brought together in one study.

The comments are as follows... odds ratios (ORs) in this context are a little bit meaningless. How does one interpret an odds ratio of 160, let alone an OR of 1323 other than to say it looks like a lot?? By comparison, if you look at ORs between an established risk factor (such as smoking) and disease outcome (such as lung cancer), the ORs are between 20-40. It is not a criticism of the approach; in PREDICT-PD we too have traditionally modelled ORs. However, we rank an individual's OR against the ORs of everyone else in the cohort, meaning that, whilst not their literal risk, it is correct in relation to all other participants in the cohort.   

The combination of the three factors has a positive predictive value of 35% - meaning that if you have all three together there is a 35% chance of you having a diagnosis of PD. Long story short... these three non-motor features, in combination, still look like some of the most useful for recognising PD... either in those that have a diagnosis or who are in the prodromal phase...

- Alastair Noyce

https://jnnp.bmj.com/content/early/2018/08/03/jnnp-2018-318275.long

The relationship between thermoregulation and REM Sleep Behaviour Disorder in parkinson's Disease

A new study by Zhong and colleagues has found that in patients with PD, sleep problems (specifically RBD) appear to be related to problems in regulating body temperature at night. This gives rise to two interesting questions:

• Could the dysfunction in both the 'sleep' and 'thermoregulatory' systems share a common pathology?

• Could core body temperature profiling help in predicting PD?

What is RBD?
REM-sleep behavior disorder (RBD) is a disorder in which patients act out their dreams during the night. It is associated with PD – patients with RBD have an increased risk of developing PD and patients with PD have an increased risk of going on to develop RBD.

What did the authors do?
This was a case-control study comparing 12 patients with PD (cases) with 11 healthy, age-matched 'controls'. The authors measured core body temperautre over a 24-hour period, rest-activity patterns over the day and night (using actigraphy) and sleep patterns (using polyosmnography).

What the study found We know that body temperature fluctuates over a 24 hour period and should normally be cooler at night and warmer during the day (see fig. 1)

 

Fig 1. Schematic diagram showing a typical nocturnal core-body temperature profile (Zhong et al, 2013)

The authors found that patients with PD showed less of a nocturnal drop in body temperature than age-matched controls. They also found that the 'mesor' core body temperature (the average point around which temperature fluctuates) was lower in the patients with PD.

Among the patients with PD, those with self-reported RBD (higher RBDSQ scores) showed even less of a nocturnal drop in core body temperature (CBT amplitude) See fig 2.

Fig 2. A strong negative correlation was found between the nocturnal drop in core body temperature (CBT amplitude) and self-reported symptoms of RBD (RBDSQ) (Zhong et al, 2013)

Reduced noctunral CBT amplitude was also correlated with a lower fraction of time spent in REM sleep and an increase in sleep onset latency (the amount of time taken to fall asleep after going to bed), which are known to be important aspects of the sleep dysfunction suffered by some patients with PD

Could the dysfunction in both the 'sleep' and 'thermoregulatory' systems share a common pathology?

Lewy body pathology is known to affect key regions in the brainstem (pons and medulla) involved in thermoregulation, circadian rhythms and sleep. See fig 3.

Fig 3. Simplified schematic diagram highlighting the neural circuitry of the circadian-homeostatic-ultradian system and the functional neuroanatomical overlap with the thermoregulatory system.

 Possible links between thermoregulatory system dysfunction and sleep dysfunciton include:

• The Ascending Arousal System (AAS) - the AAS is known to be disrupted in PD and has an improtant role in the initation and maintenace of sleep as well as projections to the ultradian system and the medullary autonomic centers (meaning it may influence both sleep architecture and thermoregulation
• The medullary autonomic region, which plays a role in thermoregulation and is a key link between the SCN, the brain's master pacemaker, and the pineal gland, which secretes melatonin (a key hormone involved in both sleep and circadian rhythms)

It is therefore likely that some sort of common pathology results in the disruption of systems controlling both sleep and thermoregulation, however, it is impossible to conclude this for certain from this data alone.

Could core body temperature profiling help in predicting PD?

This reduced nocturnal drop in body temperature has previously been reported for patients with PD (Pierangeli et al, 2001; Suzuki et al, 2007). If these changes in body temperature regulation begin during the prodromal phase of the dsiease, it may be possible to use body temperature profiling to rpedict the development of PD.

However, in this study, the differnce in nocturnal amplitude between patients with PD and controls only just reached statistical significance (p=0.04) and the size of the effect was not that large either. Therefore, even if prodromal PD patients do have slightly abnormal body temperature profiles, core body temperature is unlikely to deliver much predictive power (at least, not on its own).

Additionally, this study suffers from the limitation of very small sample sizes (only 12 patients and 11 controls). Therefore, the effects observed may be due to chance alone and there may have been additional interesting associations (such as earlier sleep onset among patients with PD) that this study was simply not powered to detect.

Nonetheless, this is a very interesting study which provides new insights into body temperature regulation and sleep disorders in PD.

Jargon-buster:
Ultradian rhythms: Ultradian rhythms are bodily rhythms with a period shorter than 24 hours, including the cycling between REM and NRM stages of sleep (compare with circadian rhythms which occur over a 24 hour period).
Actigraphy: a method of measuring rest-activity patterns throughout the day, usually with a motion-detesting wrist watch.
Polysomnography: the measurement of lots of different physiological variables (heart rate, breathing rate, movement, EEG) to determine sleep patterns
RBDSQ: The RBD Screening Questionaire - a questionaire which has been designed to help diagnose RBD

References:

Pierangeli G, Provini F, Maltoni P, Barletta G, Contin M, Lugaresi E, Montagna P, Cortelli P (2001) Nocturnal body core temperature falls in Parkinson's disease but not in Multiple-System Atrophy. Mov Disord 16: 226-232

Suzuki K, Miyamoto T, Miyamoto M, Kaji Y, Takekawa H, Hirata K (2007) Circadian variation of core body temperature in Parkinson disease patients with depression: a potential biological marker for depression in Parkinson disease. Neuropsychobiology 56: 172-179

George Zhong,, Samuel Bolitho,, Ronald Grunstein,, Sharon Linda Naismith,, & Simon John Geoffrey Lewis (2013). The Relationship between Thermoregulation and REM Sleep Behaviour Disorder in Parkinson’s Disease PLOS ONE DOI: 10.1371/journal.pone.0072661

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.