The cost-effectiveness of deep brain stimulation in combination with best medical therapy, versus best medical therapy alone, in advanced Parkinson's disease

J Neurol. 2013 Oct 25. [Epub ahead of print]

Eggington S, Valldeoriola F, Chaudhuri KR, Ashkan K, Annoni E, Deuschl G.

Source

Medtronic International Trading Sàrl, Route du Molliau 31, 1131, Tolochenaz, Switzerland, simon.eggington@medtronic.com.

Abstract

Parkinson's disease (PD) is a complex progressive movement disorder leading to motor and non-motor symptoms that become increasingly debilitating as the disease advances, considerably reducing quality of life. Advanced treatment options include deep brain stimulation (DBS). While clinical effectiveness of DBS has been demonstrated in a number of randomised controlled trials (RCT), evidence on cost-effectiveness is limited. The cost-effectiveness of DBS combined with BMT, versus BMT alone, was evaluated from a UK payer perspective. Individual patient-level data on the effect of DBS on PD symptom progression from a large 6-month RCT were used to develop a Markov model representing clinical progression and capture treatment effect and costs. A 5-year time horizon was used, and an incremental cost-effectiveness ratio (ICER) was calculated in terms of cost per quality-adjusted life-years (QALY) and uncertainty assessed in deterministic sensitivity analyses. Total discounted costs in the DBS and BMT groups over 5 years were £68,970 and £48,243, respectively, with QALYs of 2.21 and 1.21, giving an incremental cost-effectiveness ratio of £20,678 per QALY gained. Utility weights in each health state and costs of on-going medication appear to be the key drivers of uncertainty in the model. The results suggest that DBS is a cost-effective intervention in patients with advanced PD who are eligible for surgery, providing good value for money to health care payers.

What are people with Parkinson's disease really impaired on when it comes to making decisions? A meta-analysis of the evidence.

Neurosci Biobehav Rev. 2013 Oct 21. pii: S0149-7634(13)00229-7. doi: 10.1016/j.neubiorev.2013.10.005. [Epub ahead of print]

Ryterska A, Jahanshahi M, Osman M.

Source

Biological and Experimental Psychology, School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London, E1 4NS, UK.

Abstract

Parkinson's disease (PD) is associated with motor and cognitive impairment caused by dopamine dysregulation in the basal ganglia. Amongst a host of cognitive deficits, evidence suggests that decision-making is impaired in patients with PD, but the exact scope of this impairment is still unclear. The aim of this review was to establish which experimental manipulations commonly associated with studies involving decision-making tasks were most likely to generate impairments in performance in PD patients. This allowed us to address the question of the exact scope of the decision-making deficits in PD and to hypothesize about the role of the basal ganglia in decision-making processes. We conducted a meta-analysis of available literature, which revealed that the two key predictors of impairment in PD were the feedback structure of the decision-making task and the medication status of patients while performing the tasks. Rather than a global impairment in decision-making ability, these findings suggest that deficiencies in choice-behavior in patients with PD stems from dysfunctions at the outcome evaluation stage of the decision-making process.

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

Delayed gastric emptying in Parkinson's disease

- In the future exploration of the gut may yield a biomarker that can be used for early detection of Parkinson's  and as part of a strategy for neuroprotection. Nonetheless, a deeper understanding about gut function in those with established disease is vitally important and will hopefully lead to improvements for current patients.

Mov Disord. 2013 Oct 21. doi: 10.1002/mds.25708. [Epub ahead of print]

Marrinan S, Emmanuel AV, Burn DJ.

Source

Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.

Abstract

Gastrointestinal symptoms are evident in all stages of Parkinson's disease (PD). Most of the gastrointestinal abnormalities associated with PD are attributable to impaired motility. At the level of the stomach, this results in delayed gastric emptying. The etiology of delayed gastric emptying in PD is probably multifactorial but is at least partly related to Lewy pathology in the enteric nervous system and discrete brainstem nuclei. Delayed gastric emptying occurs in both early and advanced PD but is underdetected in routine clinical practice. Recognition of delayed gastric emptying is important because it can cause an array of upper gastrointestinal symptoms, but additionally it has important implications for the absorption and action of levodopa. Delayed gastric emptying contributes significantly to response fluctuations seen in people on long-term l-dopa therapy. Neurohormonal aspects of the brain-gut axis are pertinent to discussions regarding the pathophysiology of delayed gastric emptying in PD and are also hypothesized to contribute to the pathogenesis of PD itself. Ghrelin is a gastric-derived hormone with potential as a therapeutic agent for delayed gastric emptying and also as a novel neuroprotective agent in PD. Recent findings relating to ghrelin in the context of PD and gastric emptying are considered. This article highlights the pathological abnormalities that may account for delayed gastric emptying in PD. It also considers the wider relevance of abnormal gastric pathology to our current understanding of the etiology of PD.

Parkinson's Disease and Cancer: A Register-based Family Study

Am J Epidemiol. 2013 Oct 18. [Epub ahead of print]

Wirdefeldt K, Weibull CE, Chen H, Kamel F, Lundholm C, Fang F, Ye W.

Abstract

We wanted to compare cancer incidence rates between Parkinson's disease (PD) patients and persons without PD, as well as between siblings of these groups. We conducted a family-based matched cohort study based on nationwide Swedish health registries and the Swedish Multi-Generation Register. We assessed risk of incident cancer in PD patients (n = 11,786) during 1964-2009 versus a matched cohort of PD-free individuals (n = 58,930) and in siblings of PD patients (n = 16,841) versus siblings of PD-free individuals (n = 84,205). Hazard ratios with 95% confidence intervals were estimated using Cox proportional hazards regression. Cancer occurrence was slightly higher in PD patients than in PD-free individuals (hazard ratio (HR) = 1.05, 95% confidence interval (CI): 1.00, 1.10), largely because of cancers arising within 1 year before or after the index date for PD, but risk of smoking-related cancers was lower (HR = 0.87, 95% CI: 0.79, 0.96). PD patients had a higher risk of melanoma both up to 1 year before the PD index date (HR = 1.53, 95% CI: 1.23, 1.91) and from 1 year after the index date onward (HR = 1.46, 95% CI: 1.01, 2.10). In the sibling comparison, cancer occurrence was largely similar. These results indicate that melanoma risk is higher among PD patients and that mechanisms other than familial ones explain the association.

Head injuries and Parkinson's disease in a case-control study

- Further evidence that head trauma increases risk of neurodegenerative disease

Occup Environ Med. 2013 Sep 18. doi: 10.1136/oemed-2013-101444. [Epub ahead of print]

Harris MA, Shen H, Marion SA, Tsui JK, Teschke K.

Source

School of Occupational and Public Health, Ryerson University, , Toronto, Ontario, Canada.

Abstract

BACKGROUND:

Head injury is a hypothesised risk factor for Parkinson's disease, but there is a knowledge gap concerning the potential effect of injury circumstances (eg, work-related injuries) on risk. The objective of this study is to address this gap while addressing issues of recall bias and potential for reverse causation by prediagnosis symptoms.

METHODS:

We conducted a population based case-control study of Parkinson's disease in British Columbia, Canada (403 cases, 405 controls). Interviews queried injury history; whether injuries occurred at work, in a motor vehicle accident or during sports. Participants were also asked to report their suspicions about the causes of Parkinson's disease to provide an indicator of potential recall bias. Associations were estimated with logistic regression, adjusted for age, sex and smoking history.

RESULTS:

Associations were strongest for injuries involving concussion (OR: 2.08, 95% CI 1.30 to 3.33) and unconsciousness (OR: 2.64, 95% CI 1.39 to 5.03). Effects remained for injuries that occurred long before diagnosis and after adjustment for suspicion of head injury as a cause of Parkinson's disease. Injuries that occurred at work were consistently associated with stronger ORs, although small numbers meant that estimates were not statistically significant.

CONCLUSIONS:

This study adds to the body of literature suggesting a link between head injury and Parkinson's disease and indicates further scrutiny of workplace incurred head injuries is warranted.

Cognitive deficits in mild Parkinson's disease are associated with distinct areas of grey matter atrophy

J Neurol Neurosurg Psychiatry. 2013 Oct 16. doi: 10.1136/jnnp-2013-305805. [Epub ahead of print]

Mak E, Zhou J, Tan LC, Au WL, Sitoh YY, Kandiah N.

Source

Department of Neurology, National Neuroscience Institute, Singapore.

Abstract

BACKGROUND AND OBJECTIVES:

The neuroanatomical substrates underlying cognitive impairment in Parkinson's disease (PD) remain poorly understood. To address this gap, we compared the grey matter atrophy patterns in PD patients with mild cognitive impairment (PD-MCI) with PD patients having no cognitive impairment (PD-NCI), and examined relationships between atrophic regions and cognitive performance in specific domains.

METHODS:

90 non-demented PD patients (64.95±7.54 years, Hoehn and Yahr=1.88±0.39) were classified using formal diagnostic criteria as PD-MCI (n=23) or PD-NCI (n=67). Grey matter volume differences were examined using voxel-based morphometry on structural MRI, and multivariate linear regressions were employed to assess the relationships between cognitive performance in specific domains and atrophic regions.

RESULTS:

Patients with PD-MCI had lower global cognition scores compared with PD-NCI (Mini Mental State Examination: 26.9 vs28.4, p=0.011; Montreal Cognitive Assessment: 24.5 vs 27.0, p<0.001). The PD-MCI group demonstrated significantly poorer performance on executive function, attention, memory and language abilities. Patients with PD-MCI had reductions in grey matter volumes in the left insular, left superior frontal and left middle temporal areas compared to PD-NCI. Multiple regressions controlling for age, education and cardiovascular risk factors revealed significant positive correlations between left insular atrophy and executive-attention dysfunction.

CONCLUSIONS:

Domain specific cognitive impairment in mild PD is associated with distinct areas of grey matter atrophy. These regions of atrophy are demonstrable early in the disease course and may serve as a biomarker for dementia in PD.

Subtle gait changes in patients with REM sleep behavior disorder

Mov Disord. 2013 Oct 15. doi: 10.1002/mds.25653. [Epub ahead of print]

McDade EM, Boot BP, Christianson TJ, Pankratz VS, Boeve BF, Ferman TJ, Bieniek K, Hollman JH, Roberts RO, Mielke MM, Knopman DS, Petersen RC.

Source

Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

Abstract

Many people with rapid eye movement (REM) sleep behavior disorder (RBD) have an underlying synucleinopathy, the most common of which is Lewy body disease. Identifying additional abnormal clinical features may help in identifying those at greater risk of evolving to a more severe syndrome. Because gait disorders are common in the synucleinopathies, early abnormalities in gait in those with RBD could help in identifying those at increased risk of developing overt parkinsonism and/or cognitive impairment. We identified 42 probable RBD subjects and 492 controls using the Mayo Sleep Questionnaire and assessed gait velocity, cadence, and stride dynamics with an automated gait analysis system. Cases and controls were similar in age (79.9 ± 4.7 and 80.1 ± 4.7, P = 0.74), Unified Parkinson's Disease Rating Scale Part III (UPDRS) score (3.3 ± 5.5 and 1.9 ± 4.1, P = 0.21) and Mini-Mental State Examination scores (27.2 ± 1.9 and 27.7 ± 1.6, P = 0.10). A diagnosis of probable RBD was associated with decreased velocity (-7.9 cm/s; 95% confidence interval [CI], -13.8 to -2.0; P < 0.01), cadence (-4.4 steps/min; 95% CI, -7.6 to -1.3; P < 0.01), significantly increased double limb support variability (30%; 95% CI, 6-60; P = 0.01), and greater stride time variability (29%; 95% CI, 2-63; P = 0.03) and swing time variability (46%; 95% CI, 15-84; P < 0.01). Probable RBD is associated with subtle gait changes prior to overt clinical parkinsonism. Diagnosis of probable RBD supplemented by gait analysis may help as a screening tool for disorders of α-synuclein.

"Smart glasses" to be developed to improve gait of Parkinson's patients

Researchers at the University of Twente in The Netherlands have begun developing a new app for intelligent glasses, such as Google Glass, which may soon make it possible to improve the gait of patients suffering from Parkinson's disease and to decrease their risk of falling.

The gait of Parkinson's patients is often disturbed: sometimes this presents as a shuffling movement witht he patient taking small steps, or it may result in the patient constantly looking for additional support. Gait disturbance also increases the chance of a fall, despite the progresses made in medications. 

Researchers have established that the gait of patients improves when they regulatly see or hear a pattern. Examples might include stripes on the floor or the regular ticking of a metronome.

Researchers at the University of Twente are now looking at the possibility of using intelligent glasses, such as Google Glass, that are just coming on to the consumer market, to provide patients with regular visual or audible patterns which would help improve gait. These patterns may take the form of moving or flashing stripes or shapes which the patient sees through the glasses, or music with varying tempos. The latest intelligent glasses already have inbuilt cameras and accelrometers. By using these, it will be possible to determine which approach works best for each individual patient.

"This is an innovative and relatively simple adaptation of a piece of technology already under development, which has the potential to greatly benefit the lives of patients. However, this use of intelligent glasses is still in the early stages of development and will require proper testing to prove that it is able to improve the gait of patients with PD." - Joseph Masters

View the full press release here.

The Mild Cognitive Impairment Stage of Dementia With Lewy Bodies and Parkinson Disease: A Comparison of Cognitive Profiles

Alzheimer Dis Assoc Disord. 2013 Oct 11. [Epub ahead of print]

Yoon JH, Lee JE, Yong SW, Moon SY, Lee PH.

Source

*Department of Neurology, Ajou University School of Medicine, Suwon †Department of Neurology ‡Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.

Abstract

BACKGROUND::

Recent studies have demonstrated that structural and pathologic changes are more severe in patients with dementia with Lewy bodies (DLB) than in those with Parkinson disease with dementia (PDD). We investigated neuropsychological characteristics of patients with mild cognitive impairment (MCI) stage of DLB (DLB-MCI) and PD (PD-MCI) based on the hypothesis that the pathologic differences between DLB and PDD can influence cognitive profiles in the MCI stage of these diseases.

METHODS::

Baseline demographic characteristics and neuropsychological data obtained from patients with DLB-MCI (n=20) and PD-MCI (n=46) were compared.

RESULTS::

The patients with DLB-MCI showed poorer cognitive performance in the Stroop, Go-No-Go, and semantic fluency tests compared with those with PD-MCI. In addition, patients with DLB-MCI had lower scores on visual and verbal memory performance and in the visuospatial domain compared with PD-MCI patients.

CONCLUSIONS::

Our results demonstrate that patients with DLB-MCI have more severe cognitive impairment in frontal executive, memory, and visuospatial functions than those with PD-MCI. These data suggest that differences in pathologic substrates between PDD and DLB may begin in the MCI stage of the 2 diseases and may lead to differences in cognitive profiles.

NEWSFLASH! An oral compound that MAY have the potential to prevent neurodegeneration.

Moreno JA, Halliday M, Mooloy C, et al. Oral Treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice.Sci. Transl. Med. 5, 206ra138 (2013)
http://stm.sciencemag.org/content/5/206/206ra138

It will have been hard to avoid news of this study - the popular press as well as the neuroscience world has been swept up in the exciting possible implications of the article by Julie Moreno et al.  We at PREDICT-PD are also cautiously optimistic about the results they report and the potential for developing a treatment to prevent the neurodegeneration seen in Parkinson's Disease as well as other diseases such as Alzheimer's. But we are still a long way from any disease modifying treatment, and it's worth having a closer look at the study to pick apart what they've really demonstrated.

What did they do?

The authors used an oral treatment in a mouse model of prion disease*.  Whilst prion diseases have some similarity to Parkinson's Disease in that they both involve misfolded versions of normal proteins (the prion protein in prion disease and alpha synuclein in PD), they are certainly not the same.  Whilst both cause neurodegeneration, prion diseases usually progress far more quickly, suggesting that the mechanisms causing cell death in these conditions may be quite different.  The hallmark of prion diseases is their ability to be transmitted between organisms, with the protein itself being the infective agent and causing abnormal folding in other proteins. Some researchers have suggested that Parkinson's disease may share similar features (Olanow and Brundin, 2013), but this is still a controversial view.  In any case, we should be very careful before extrapolating these results from prion disease to PD or other common neurodegenerative diseases.

What did they test? 

The compound, which has the catchy name "GSK2606414", is an inhibitor of PERK (protein kinase RNA–like endoplasmic reticulum kinase).  To understand what PERK does, and why inhibiting it might prevent neurodegeneration, a bit of biology:

Bip = binding immunoglobulin, eIF2 = eukaryotic initiation factor 2

When brain cells notice that proteins are not folding correctly, they respond by activating the above pathway and reducing the amount of protein produced (presumably a protective mechanism). However, if protein translation is reduced by too much, neurons may be unable to synthesise the important proteins they need for their funciton and survival. The authors of this paper had previously shown that this is what goes wrong in prion disease and that blocking this pathway could be protective (Moreno et al, 2012).

Interestingly, increased levels of both PERK and eIF2 have also been found in the brains of patients with Parkinson's (Hoozemans et al, 2007), implicating pathological activation of this pathway as an aspect of the neurodegenerative process, so it certainly seems to be a rational drug target in PD too.

What was the compound shown to do?

Importantly, the authors first showed that the compound penetrates the blood brain barrier, so would be available to work where it is needed.

The drug reduced the signs of prion disease in the mice and resulted in behavioural improvements. The mice treated with GSK2606414 showed less hindlimb paralysis (an important sign of prion disease) and better mobility than those who did not receive the treatment. Although dementia and memory loss are difficult to assess in mice, the authors demonstrated that the treated mice performed better in a simple memory test and that they burrowed more than the untreated animals (mice with neurodegenerative diseases have been shown to burrow less).

When rodents are left with a tube full of food pellets (as shown above), it is their natural tendency to burrow into the food. The pellets displaced from the tube after 2 hours are weighed and recorded. Mice with neurodegenerative diseases are known to burrow less, but the mice given the treatment burrowed as normal.

Not only did the drug result in behavioural improvements but it was also truly neuroprotective: it halted the death of neurons across the brain. Finally, analysis of samples of the mice brains revealed that the drug was acting via the molecular pathways expected of it; the drug inhibited PERK activation and restored the translation of important proteins, exactly as it was designed to.

So what's not to like?

As previously mentioned, the compound was tested in a mouse model of prion disease, which, despite its similarities with PD, is not the same disease. In addition, the mice suffered from side effects (specifically, weight loss and hyperglycemia*) likely due to effects of the drug outside the brain. Development of the compound to reduce side effects, perhaps by targetting neurons more specifically, would would be necessary before it moves into human trials.

Even if this treatment does prove to be effective in animal models of Alzheimer’s or Parkinson’s disease, there is no guarantee it will work in humans. Countless drug trials for these diseases have failed over the last ten years, even after encouraging results in animal trials, so there is reason to remain cautious. If the drug proves to be safe in humans, there will be important questions to be answered about when it is given - presumably treatment would need to start early in the disease process to prevent neurodegeneration before it becomes disabling.  As we've previously discussed, in PD a significant amount of neurodegeneration occurs before the diagnosis is made, suggesting that even at diagnosis may be too late.

Nonetheless, this is the first time an oral treatment has been shown to completely stop neurodegeneration in its tracks and it represents an important step forward in the search for a definitive treatment for both Parkinson's disease and Alzheimer's disease.

- Anna and Joe

Jargon buster:
Prion diseases are a group of rare progressive neurodegenerative disorders caused by abnormal, misfolded proteins called prions. They are transmissable (can be spread from person to person), but most cases are sporadic.
Translation is the stage of protein production in which single amino acids are put together to form a polypeptide (protein).
Hyperglycaemia: high blood sugar levels (which is what occurs in diabetes).
____
Hoozemans JJ, van Haastert Es, Nijholt DA, et al. Activation of the unfolded protein response in Parkinson's disease. Biochem. Biophys. Res. Commun. 354, 707-711 (2007)

Olanow CW, Brundin P. Parkinson's disease and alpha synuclein: is Parkinson's disease a prion-like disorder? Mov. Disord. 28(1), 31-40 (2013)

Moreno JA, Radford H, Peretti D, Steinert JR, Verity, N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori C, Barrett A, Tsaytler P, Bertolotti A, Willis AE, Bushell M, Malluci GR, Sustained translational repression by eIF2a-P mediates prion neurodegeneration. Nature 485, 507-511 (2012)

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.

Prevalence and features of peripheral neuropathy in Parkinson's disease patients under different therapeutic regimens

Parkinsonism Relat Disord. 2013 Sep 25. pii: S1353-8020(13)00337-4. doi: 10.1016/j.parkreldis.2013.09.007. [Epub ahead of print]

Mancini F, Comi C, Oggioni GD, Pacchetti C, Calandrella D, Coletti Moja M, Riboldazzi G, Tunesi S, Dal Fante M, Manfredi L, Lacerenza M, Cantello R, Antonini A.

Source

Parkinson's Disease and Movement Disorders Centre, Neurology Unit, San Pio X Clinic, Fondazione Opera San Camillo, Milan, Italy.

Abstract

BACKGROUND:

Recent reports suggest increased frequency of peripheral neuropathy (PN) in Parkinson's disease (PD) patients on levodopa compared with age-matched controls particularly during continuous levodopa delivery by intestinal infusion (CLDII). The aim of this study is to compare frequency, clinical features, and outcome of PN in PD patients undergoing different therapeutic regimens.

METHODS:

Three groups of consecutive PD patients, 50 on intestinal levodopa (CLDII), 50 on oral levodopa (O-LD) and 50 on other dopaminergic treatment (ODT), were enrolled in this study to assess frequency of PN using clinical and neurophysiological parameters. A biochemical study of all PN patients was performed.

RESULTS:

Frequency of PN of no evident cause was 28% in CLDII, 20% in O-LD, and 6% in ODT patients. Clinically, 71% of CLDII patients and all O-LD and ODT PN patients displayed a subacute sensory PN. In contrast, 29% of CLDII patients presented acute motor PN. Levodopa daily dose, vitamin B12 (VB12) and homocysteine (hcy) levels differed significantly in patients with PN compared to patients without PN.

CONCLUSIONS:

Our findings support the relationship between levodopa and PN and confirm that an imbalance in VB12/hcy may be a key pathogenic factor. We suggest two different, possibly overlapping mechanisms of PN in patients on CDLII: axonal degeneration due to vitamin deficiency and inflammatory damage. Whether inflammatory damage is triggered by vitamin deficiency and/or by modifications in the intestinal micro-environment should be further explored. Proper vitamin supplementation may prevent peripheral damage in most cases.

Comparative Efficacy and Acceptability of Antidepressants in Parkinson's Disease: A Network Meta-Analysis

Interesting finding overall. Clinical experience tends to favour SSRI's and SNRI's in PD, not only in terms of efficacy but also side effect profile.

- Alastair Noyce

PLoS One. 2013 Oct 2;8(10):e76651.

Liu J, Dong J, Wang L, Su Y, Yan P, Sun S.

Source

Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Abstract

BACKGROUND:

Depression is a common non-motor symptom in patients with Parkinson's disease (PD). There are many kinds of antidepressants being used, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and Dopamine agonists which are suggested as alternative antidepressants for the treatment of depression in PD. Which one should we choose first? Literatures have shown inconsistent results.

METHODS:

We conducted a network meta-analysis of randomized controlled trials to compare the efficacy and acceptability of therapeutic methods for the treatment of depression in Parkinson's disease.

RESULTS:

We used the odds ratios (OR) as effect size firstly and the results indicated no statistical significance between each compared intervention. Then we used the logarithm of the individual odds ratios as effect size. With efficacy of TCAs as the standard of comparison, the degree of incoherence (a measure of how closely the entire network fits together) was small (ω =  4.824827e-05). The logor were: SSRIs -0.69 (95% CI -1.28- -0.10); Pramipexole -0.73 (-1.71- -0.26); Pergolide -1.97 (-3.67- 0.27); SNRIs -0.86 (-1.86- 0.15); Placebo -1.24 (-1.99- -0.50). With Placebo as the standard of comparison, the logor were: TCAs 1.24 (0.50- 1.99); SSRIs 0.55 (-0.03- 1.13); Pramipexole 0.51 (-0.12- 1.15); Pergolide -0.73 (-2.25- 0.80); SNRIs 0.38 (-0.42- 1.19); TCAs, pramipexole, pergolide and SNRIs showed better profile of acceptability, leading to significant fewer discontinuations than that of SSRIs.

CONCLUSIONS:

There is insufficient evidence to support antidepressant efficacy for SSRIs, pramipexole, pergolide and SNRIs. TCAs might be the best choice when starting antidepressant treatment in patients of Parkinson's disease because it has the most favorable balance between benefits and acceptability, followed by pramipexole and SNRIs, SSRIs might be the last choice.

Why we need to be able to PREDICT PD

A very simple overview of PD pathology:

Parkinson’s disease is a complex disorder, but one of the most important aspects of the pathology is the death of neurons in a region of the brain called the substantia nigra. These neurons project to the striatum, where they release a chemical called dopamine. In PD, the death of these neurons leads to reduced levels of dopamine in the striatum, which in turn results in symptoms such as slowness in movement and rigidity.

Parkinson's Disease involves death of dopamine releasing neurons which project from the substantia nigra to the caudate nucleus and putamen (collectively called the striatum)

The need for new ‘neuroprotective’ treatments

Current treatments for PD (such as levodopa) revolve around restoring striatal dopamine to normal levels. However, these drugs may cause intolerable side-effects and their effectiveness declines over time. Furthermore, these ‘dopaminergic’ therapies cannot help with symptoms which are not caused by deficits in dopamine.

The real problem is that all our current treatments are symptomatic – they address only the shortfall in dopamine levels, rather than actually providing neuroprotection (i.e. halting or reversing the process of cell death which occurs).

Why have neuroproective treatments been so hard to develop?

One of the most important reasons that neuroprotective treatments have been so hard to develop is that 70-80% of striatal dopamine is already lost by the time diagnosis is made (Fearnley & Lees, 1991; Stoessl, 2007).

 

Loss of dopaminergic (DA) neurones in the substantia nigra occurs perhaps 5-6 years before the onset of PD (solid line). If we can predict PD early, perhaps we can slow this cell loss and delay the onset of symptoms (dashed line).

This means that once we have identified patients with PD the damage has already been done and it would be too late for neuroprotective treatments to prevent the development of parkinsonian symptoms (Streffer et al, 2012).

Why are projects such as PREDICT-PD so important?

Projects like PREDICT-PD are important because being able to identify people likely to go on to develop PD will allow trials of neuroprotective therapies to be started earlier in the disease process (Postuma et al, 2010; Postuma & Montplaisir, 2009; Streffer et al, 2012). These neuroprotective treatments would then stand a much better chance of preventing or slowing the onset of PD.

How might we be able to predict PD?

Fortunately, there may be some clues as to an individual’s risk of PD which emerge before the onset of sympotms. PD is believed to have a ‘prodromal’ phase where non-motor symptoms (such as smell loss and depression) or even very subtle motor symptoms may emerge, before the full onset of the disease (Hawkes, 2008; Postuma et al, 2012a). These prodromal symptoms include:

• Non-motor symptoms 
• Loss of smell (Shah et al., 2009)
• Depression (Reijnders et al, 2008)
• 'Autonomic' nervous system dysfunction
• Constipation (Abott et al, 2001; Savica et al, 2009)
• Variability in heart rate and other cardiac autonomic abnormalities (Palma et al, 2013)
• Sleep problems (Boeve, 2013; Videnovic & Golombek, 2013)
• Cognitive impairment (Aarsland et al, 2010; Williams-Gray et al 2013)
• Problems with vision (Postuma et al, 2012a)
•  Subtle motor symptoms - slowed movment, tremor etc. (Postuma et al 2012b)

There are also environmental and genetic risk factors for PD – such as exposure to pesiticides (which increases risk of PD) smoking or coffee drinking (which decrease risk of PD), family history of PD (genetic risk factors) or previous head injury (Noyce et al, 2012). 

Combining information on risk of PD across all these different areas may allow the disease to be accurately predicted and for disease-modifying treatments to be started much earlier in the disease course, where they are more likely to provide beneficial effects.

For more information on how the PREDICT-PD project is going about achieving this, click here.

Jargon buster:

Substantia nigra: a region of the midbrain containing neurons which project to the striatum, where they release dopamine

Striatum: a region of the brain involved in control of movement (including starting and stoping movements) in addition to other functions

Dopamine: a neurotramsitter (a signalling chemical used by neurons to communicate with one another) whose levels are reduced in PD

Prodrome: an early symptom or group of symptoms which may indicate the start of a disease before the classically defined onset of that disease e.g. a rash which may occur before the onset of an infectious disease or the loss of smell which may occur prior to developing PD

Autonomic nervouss ystem: the division of the nervous system which controls bodily functions such as heart rate, breathing rate, digestion, urination and sexual functions.

References:

Aarsland D, Bronnick K, Williams-Gray C, Weintraub D, Marder K, Kulisevsky J, Burn D, Barone P, Pagonabarraga J, Allcock L, Santangelo G, Foltynie T, Janvin C, Larsen JP, Barker RA, Emre M (2010) Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis. Neurology 75: 1062-1069

Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, Grandinetti A, Blanchette PL, Popper JS, Ross GW (2001) Frequency of bowel movements and the future risk of Parkinson's disease. Neurology 57: 456-462

Boeve BF (2013) Idiopathic REM sleep behaviour disorder in the development of Parkinson's disease. Lancet Neurol 12: 469-482

Fearnley JM, Lees AJ (1991) Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 114 ( Pt 5): 2283-2301

Hawkes CH (2008) The prodromal phase of sporadic Parkinson's disease: does it exist and if so how long is it? Mov Disord 23: 1799-1807

Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Giovannoni G, Lees AJ, Schrag A (2012) Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann Neurol 72: 893-901

Palma JA, Carmona-Abellan MM, Barriobero N, Trevino-Peinado C et al. (2013) Is cardiac function impaired in premotor Parkinson's disease? a retrospective cohort study. Mov Disord 28: 591-596

Postuma RB, Aarsland D, Barone P, Burn DJ, Hawkes CH, Oertel W, Ziemssen T (2012a) Identifying prodromal Parkinson's disease: pre-motor disorders in Parkinson's disease. Mov Disord 27: 617-626

Postuma RB, Gagnon JF, Montplaisir J (2010) Clinical prediction of Parkinson's disease: planning for the age of neuroprotection. J Neurol Neurosurg Psychiatry 81: 1008-1013

Postuma RB, Lang AE, Gagnon JF, Pelletier A, Montplaisir JY (2012b) How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder. Brain 135: 1860-1870

Postuma RB, Montplaisir J (2009) Predicting Parkinson's disease - why, when, and how? Parkinsonism Relat Disord 15 Suppl 3: S105-109

Reijnders JS, Ehrt U, Weber WE, Aarsland D, Leentjens AF (2008) A systematic review of prevalence studies of depression in Parkinson's disease. Mov Disord 23: 183-189; quiz 313

Savica R, Carlin JM, Grossardt BR, Bower JH, Ahlskog JE, Maraganore DM, Bharucha AE, Rocca WA (2009) Medical records documentation of constipation preceding Parkinson disease: A case-control study. Neurology 73: 1752-1758

Shah M, Deeb J, Fernando M, Noyce A, Visentin E, Findley LJ, Hawkes CH (2009) Abnormality of taste and smell in Parkinson's disease. Parkinsonism Relat Disord 15: 232-237

Stoessl AJ (2007) Positron emission tomography in premotor Parkinson's disease. Parkinsonism Relat Disord 13 Suppl 3: S421-424

Streffer JR, Grachev ID, Fitzer-Attas C, Gomez-Mancilla B, Boroojerdi B, Bronzova J, Ostrowitzki S, Victor SJ, Fontoura P, Alexander R (2012) Prerequisites to launch neuroprotective trials in Parkinson's disease: an industry perspective. Mov Disord 27: 651-655

Videnovic A, Golombek D (2013) Circadian and sleep disorders in Parkinson's disease. Exp Neurol 243: 45-56

Williams-Gray CH, Mason SL, Evans JR, Foltynie T, Brayne C, Robbins TW, Barker RA (2013) The CamPaIGN study of Parkinson's disease: 10-year outlook in an incident population-based cohort. J Neurol Neurosurg Psychiatry