PLAIN ENGLISH: Does removal of the appendix impact the risk of Parkinson's Disease?

Multiple large news organisations yesterday were reporting the results of a study showing that people who have had appendectomies (surgical removal of the appendix) have a lower chance of developing Parkinson's disease. Its a neat paper which links large amounts of data from medical databases and histology results (looking at tissue under the microscope) on a much smaller number of patients.

First they looked at the Swedish National Patient Registry, a database of 1,698,000 people followed up for 52 years, and identified anyone who had a history of an appendectomy (551,647 people). They then matched these patients to two 'control' patients who had not had appendectomies but were similar in age, sex and geographical to the original patients. They interestingly found that the chance of having Parkinson's disease was 19.3% lower in the participants with appendectomies than the 'control' participants who had not had appendectomies. They also found that the participants who had appendectomies and developed Parkinson's on average developed Parkinson's 1.6 years later than the Parkinson's patients who still had their appendix. Interestingly this effect was not observed in participants who had known genetic mutations causing their Parkinson's suggesting that if the appendix has any effect on the development of Parkinson's it is only in patients whose Parkinson's has an 'environmental' trigger or cause.

This part of the study was not novel or new and previous similar studies have been done and found no association between appendectomy and PD. In a Canadian study they actually found a higher rate of PD in patients who had appendectomies in the past 5 years. So despite the results of this study being very interesting they are not backed up by previous studies.

The novel part of this study is the histological analysis where the researchers analysed the 48 peoples appendixes under the microscope. These participants did not have PD. The appendixes were analysed under the microscope for clumps of protein which have stuck together that we call 'aggregates of α-syneuclein'. These are the key feature of PD that can be found in PD patients brains at autopsy. In other words the misfolded protein that causes PD when it is seen in the brain can be seen in young, healthy peoples appendix. These misfolded proteins were detected in both young and old people.

There are some problems with this study; first is that in large databases it is very difficult to know the accuracy of the Parkinson's diagnosis and previous studies investigating the reliability of this found only a 70.8% chance that it is reliable. They also only examined the appendix under the microscope and did not check any other tissues to compare.

This study does provide some food for thought; at the end of the paper the authors hypothesise that the appendix is the source of the misfolded protein that then spreads through the gut and up the vagus nerve to the brain thereby causing Parkinson's disease. This gut to brain model of the development of Parkinson's disease is often discussed and is a popular research topic at the moment. However the results of this study should still be taken with a pinch of salt because there are a number of large scale similar studies that precede this study that do not come to the same conclusion, that doesn't stop it being interesting though!

Heads Up: Head injuries and Parkinson's

There has been a lot of publicity over the last year about the links between neurodegenerative disease and multiple mild head injuries incurred in many common sports including football and rugby, for example Alan Shearer's BBC documentary on the links between dementia and football.  Chronic traumatic encephalopathy (CTE) is a term that has been coined to describe patients who develop behavioural, mood, cognitive and motor disturbances after prolonged exposure to mild head injuries and show abnormal protein folding in the brain.


Alan Shearer, footballer (from the BBC documentary Alan Shearer: Dementia, Football and Me) https://www.bbc.co.uk/programmes/b09g0gzk)

This disease process bears similarities to Parkinson's Disease in that normal proteins become misfolded and then aggregate into abnormal deposits which is then associated with brain cell death. We have also known for a long time that previous history of head injuries and concussion increases your risk of Parkinson's. The study below, of almost 700 individuals including a significant number of athletes who had died and agreed to have an autopsy looks in more detail at the links between these conditions.

Overall, they found that people who had repeated head injury during life were much more likely to have the abnormal protein found in Parkinson's, alpha-synuclein, as well as the tau protein, which has been described in CTE. More exposure to head injury - for example greater than 8 years of playing contact sport increased the likelihood of Parkinson's-type pathology. They go on to look at the relationships between the different forms of protein and show that the distribution of the Parkinson's protein alpha-synculein is similar whether or not there was evidence of CTE and likely accounts for the movement problems seen in CTE.

Descriptions of protein-related brain diseases are ever expanding and I believe will guide us in  understanding the causes of Parkinson's and how the disease progresses. By studying the processes by which mild head injury leads to protein misfolding and how the different proteins interact we are gaining new mechanistic insights which we hope will lead to promising new treatments. From a prevention point of view, the neurological dangers of repetitive mild head injury are increasingly clear - while the authors here showed that playing more than 8 years of competitive sport was significantly associated with more pathology, we still need more data before we can develop clear recommendations for both our patients and the wider public. 

-Anna 

https://academic.oup.com/jnen/advance-article/doi/10.1093/jnen/nly065/5059623

Lewy Body Pathology and Chronic Traumatic Encephalopathy Associated With Contact Sports.

Adams JW, Alvarez VE, Mez J, Huber BR, Tripodis Y, Xia W, Meng G, Kubilus CA, Cormier K, Kiernan PT, Daneshvar DH, Chua AS, Svirsky S, Nicks R, Abdolmohammadi B, Evers L, Solomon TM, Cherry JD, Aytan N, Mahar I, Devine S, Auerbach S, Alosco ML, Nowinski CJ, Kowall NW, Goldstein LE, Dwyer B, Katz DI, Cantu RC, Stern RA, Au R, McKee AC, Stein TD

Traumatic brain injury has been associated with increased risk of Parkinson disease and parkinsonism, and parkinsonism and Lewy body disease (LBD) can occur with chronic traumatic encephalopathy (CTE). To test whether contact sports and CTE are associated with LBD, we compared deceased contact sports athletes (n = 269) to cohorts from the community (n = 164) and the Boston University Alzheimer disease(AD) Center (n = 261). Participants with CTE and LBD were more likely to have β-amyloid deposition, dementia, and parkinsonism than CTE alone (p < 0.05). Traditional and hierarchical clustering showed a similar pattern of LBD distribution in CTE compared to LBD alone that was most frequently neocortical, limbic, or brainstem. In the community-based cohort, years of contact sports play were associated with neocortical LBD (OR = 1.30 per year, p = 0.012), and in a pooled analysis a threshold of >8 years of play best predicted neocortical LBD (ROC analysis, OR = 6.24, 95% CI = 1.5-25, p = 0.011), adjusting for age, sex, and APOE ɛ4 allele status. Clinically, dementia was significantly associated with neocortical LBD, CTE stage, and AD; parkinsonism was associated with LBD pathology but not CTE stage. Contact sports participation may increase risk of developing neocortical LBD, and increased LBD frequency may partially explain extrapyramidal motor symptoms sometimes observed in CTE.

Changing Tack

In a very wide ranging and well written review, two leaders of the Parkinson’s field lay down set the terms of engagement and (to mix my combative metaphors), lay down the gauntlet in the quest to find disease modifying treatments.

After defining three kinds of ‘disease modification’ (neuroprotection: preventing the progression of PD; neurorescue: repairing damaged brain cells; neurorestoration: replacing what has been lost), they provide a brief but comprehensive overview of why every attempt so far has failed, from both a mechanistic perspective as well as a methodological perspective.

The key messages to take from this article are thus:

1.     We really need to stop thinking of Parkinson’s as a single condition. As well as many different ways that people experience their Parkinson’s (the different phenotypes), there are also many different molecular and cellular processes. Each person will likely have a different milieu of process that results in their particular phenotype.

2.     Once we can do this, we can start approaching disease modification in a more personalised way. This means recruiting the people with the right kind of Parkinson’s, at the right time, to the right study. We need to become much more sophisticated in the way we study new treatments, probably recruiting very specific groups of participants, for example people with particular genetic changes related to their Parkinson’s, and testing cocktails of treatments, rather than our current blunderbuss approach.

3.     Given that Parkinson’s is a complex, and slowly progressive condition, we must have better progression markers on which to design our studies.

This is going to require a lot of work, with the Parkinson’s population, scientists, clinicians, and industry. In order to get the highly effective treatments that our oncologists have avaiable to them, we need to change the terms of warfare.

What can we all do in the mean time? Pay attention to these three battles. Not necessarily throw the baby out with the bathwater if a particular study doesn’t prove miraculous (which it almost certainly won’t). And if you have Parkinson’s: exercise more!

At PREDICT-PD towers, we strongly believe that identifying the disease earlier, in the prodromal phase, will bring us closer to many of these objectives. Earlier disease is more likely to be simpler disease; it may be possible to identify early phenotypes that map onto particular pathological pathways; we have an opportunity to identify biomarkers that predict the development of established Parkinson’s, thus giving an ideal method of proving efficacy of new treatments.

RNR

Disease modification in Parkinson's Disease: Current approaches, challenges, and future considerations.

Anthony E Lang and Alberto J Espay.

Mov Disord, 2018 vol. 386 p. 896.

http://doi.wiley.com/10.1002/mds.27360

The greatest unmet therapeutic need in Parkinson's disease is the development of treatment that slows the relentless progression of the neurodegenerative process. The concept of "disease modification" encompasses intervention types ranging from those designed to slow the underlying degeneration to treatments directed at regenerating or replacing lost neurons. To date all attempts to develop effective disease-modifying therapy have failed. Many reasons have been proposed for these failures including our rudimentary understanding of disease pathogenesis and the assumption that each targeted mechanisms of disease apply to most patients with the same clinical diagnosis. Here we review all aspects of this broad field including general concepts and past challenges followed by a discussion of treatment approaches under the following 4 categories: (1) α-synuclein, (2) pathogenic mechanisms distinct from α-synuclein (most also potentially triggered by α-synuclein toxicity), (3) non-SNCA genetic subtypes of "PD," and (4) possible disease-modifying interventions not directly influencing the underlying PD pathobiology. We emphasize treatments that are currently under active clinical development and highlight a wide range of important outstanding questions and concerns that will need to be considered to advance the field of disease modification in PD. Critically, it is unknown whether the dysfunctional molecular pathways/organelles amenable to modification occur in a sequential fashion across most clinically affected individuals or manifest differentially in independent molecular subtypes of PD. It is possible that there is no "order of disruption" applicable to most patients but, rather, "type of disruption" applicable to subtypes dependent on unknown factors, including genetic variability and other causes for heterogeneity in PD. Knowing when (early vs late), which (eg, synaptic transmission, endosomal sorting and maturation, lysosomal degradation, mitochondrial biogenesis), and in whom (PD subtype) specific disrupted cell pathways are truly pathogenic versus compensatory or even protective, will be important in considering the use of single or combined ("cocktails") putative disease-modifying therapies to selectively target these processes. Beyond the current phase 2 or 3 studies underway evaluating treatments directed at oxidative stress (inosine), cytosolic Ca2+ (isradipine), iron (deferiprone), and extracellular α-synuclein (passive immunization), and upcoming trials of interventions affecting c-Abl, glucagon-like peptide-1, and glucocerebrosidase, it might be argued that further trials in populations not enriched for the targeted pathogenic process are doomed to repeat the failures of the past. © 2018 International Parkinson and Movement Disorder Society.

Do subjects with minimal motor features have prodromal PD?

This is a study of potentially vital importance to our understand of the prodrome(s) of PD. Here the authors show that people with mild parkinsonian signs (subtle bradykinesia, tremor, rigidity, gait disturbance) have Parkinson's disease pathology at post-mortem. The authors observed no PD pathology in participants without mild parkinsonian signs, moderate PD pathology in those with mild parkinsonian signs and frank PD pathology in those with a clinical diagnosis of PD. Some caution should be exercised that the group with mild parkinsonian signs was significantly older than the other two groups, but the pattern of pathology was not typically age-related.

Their observation add further weight the notion that there is a significant motor aspect to the phase of PD before diagnosis, as suggested by our group and others... (the citations in this paper relating to the previous literature on prodromal motor symptoms are a little light if you ask me ! 😀)... 

However this new study could turn out to be a landmark one. I (and some others) have long been asserting that the term 'premotor' may not be an appropriate one. Unless we have laid eyes on people with idiopathic anosmia, RBD or other non-motor prodromal features, then we can't be sure that there are no motor signs. The really important thing to work on now is characterising what specifically starts to change in terms of motor function in those that will eventually go on to get a diagnosis of PD? This is a major focus of the PREDICT-PD study over the next 3 years... and we are exploring this in a variety of ways...

Ann Neurol. 2018 Feb 8. doi: 10.1002/ana.25179. [Epub ahead of print]
Chu Y, Buchman AS, Olanow CW, Kordower JH.

http://onlinelibrary.wiley.com/doi/10.1002/ana.25179/full

BACKGROUND: Understanding the pathological changes underlying mild motor features of the eldery and defining a patient population with prodromal Parkinson's disease (PD) are of great clinical importance. It remains unclear, however, how to accurately and specifically diagnose prodromal PD. We examined whether older adults with minimal parkinsonian motor features have nigrostriatal degeneration and α-synuclein pathology consistent with prodromal PD.

METHODS: Brain sections were obtained from older adults with a clinical diagnosis of PD (N=21) and without a clinical diagnosis of PD (N=27) who underwent motor examination proximate to death. Cases without PD were further dichotomized into no motor deficit (n=9) or minimal motor features (n-18) groups using a modified Unified Parkinson's Disease Rating Scale. We performed quantitative unbiased stereological analyses of dopaminergic neurons/terminals and α-synuclein accumulation in the nigrostriatal system.

RESULTS: In all subjects with minimal motor features, there were significant reductions in dopaminergic neurons and terminals in the substantia nigra and putamen that was intermediate between subjects with no motor deficit and PD. Phosphorylated α-synuclein inclusions were observed in the substantia nigra that were of similar density to what was seen in PD. Furthermore, there was greater Lewy neuritic pathology in the putamen relative to PD patients. Lastly, neurons with α-synuclein inclusions displayed reductions in tyrosine hydroxylase expression that was comparable in subjects with both minimal motor features and PD.

INTERPRETATION: Minimal motor features in older adults may represent prodromal PD and identify at risk individuals for testing putative neuroprotective interventions that could slow or prevent PD progression.

This article is protected by copyright. All rights reserved. © 2018 American Neurological Association.

On Thinking and Feeling

Sarah Getz and Bonnie Levin have published a broad and wideranging review of cognitive and neuropsychiatric symptoms in early PD.

The bottom line of this article underscores the tennet that PD is not just a movement disorder!

Although a noticeable proportion of people with PD may develop dementia, a significant body of work has shown that even at the earliest stages (including the prodromal or pre-motor stages), there are detectable memory deficits. One particular aspect of difficulty is in ‘executive function’ – the thinking process that allows for planning, initiating and concentrating on a task as well as ‘thinking outside the box’. I think this has interesting significance when considering the daily function of people with Parkinson’s, such as driving (see an earlier blog post from the PREDICT-PD blog).

Depression, fatigue and apathy are all very common symptoms that have a major impact on the quality of life of people with PD, not to mention their family and caregivers. Fatigue has been reported to occur in up to 2 in every 3 people with PD and has been described as the most debilitating symptom. Apathy is a real danger – muscles, be they physical, cognitive or emotional, need use. Apathy robs the person of the drive to exercise those muscles and thereby jeopardises their future ability to move, think and feel as they once did. It goes hand in hand with depression and also with increasing disability do to PD.

As we learn more about these less visible aspects of PD, we now need to search for ways to treat them. This is particularly important as the bedrock of PD treatment may make some aspects of thinking and feeling worse.

RNR

 https://doi.org/10.1093/arclin/acx091

Cognitive and Neuropsychiatric Features of Early Parkinson's Disease.

Getz SJ, Levin B.

Arch Clin Neuropsychol. 2017 Nov 1;32(7):769–85. 

The clinical definition of Parkinson's disease (PD) is based on cardinal motor features including bradykinesia as well as an additional symptom of tremor, postural instability, or rigidity. Evidence from neuropathological, imaging, and clinical research suggests a premotor, early phase of PD pathology. Further understanding of the earliest biomarkers of PD is crucial for the development of neuroprotective, disease modifying, cognitive, and psychiatric interventions. Recent research has explored early non-motor markers of PD pathology. This issue is especially timely as the International Parkinson and Movement Disorder Society has recently provided a research definition for prodromal PD which includes combinations of prodromal markers and risk factors aimed at identifying target populations for disease-prevention trials. In this review of early PD, we will outline early non-motor symptoms, early cognitive and neuropsychiatric features, neuropsychological assessment strategies, emerging evidence for early biomarkers, and treatment recommendations.

What's in a name? Parkinson's Disease (Lewy bodies subtype) vs Lewy Body Dementia

This is a timely paper given ongoing questions about nomenclature in Parkinsons. Previously, people who developed dementia and then problems with movement were classified as having dementia with lewy bodies, whereas those who developed dementia after their initial movement problems were given a diagnosis of Parkinson's Disease dementia. For those who develop both problems around the same time, the diagnostic label can feel quite arbitrary. The MDS guidelines in 2015 challenged this paradigm by allowing for a diagnosis of Parkinson's disease in the context of dementia - suggesting the term PD (dementia with Lewy bodies subtype). 

But more recently the DLB consortium brought out specific guidelines for diagnosis of DLB - suggesting we still use this diagnostic term where dementia occurs before or concurrently with parkinsonism. They do acknowledge that "in practice the term that is most appropriate to the clinical situation should be used and generic terms such as lewy body disease may be helpful". 

Classifying both diseases along the same continuum is largely in keeping with their underlying pathophysiology. Both are characterised by lewy body inclusions of alpha-synuclein protein in the brain - and are likely to be different outward manifestations of the same underlying process. A further line of evidence for this is that rapid eye movement sleep behaviour disorder, which confers increased risk of both diseases, is also now recognised to be characterised by lewy body pathology. 

In this paper in JNNP, authors from Bologna aimed to look at the validity of guidelines for diagnosis of DLB, performing a systematic review and meta-analysis of papers in which the authors had corroborated the clinical diagnosis with pathological assessment of brain tissue. They included studies with over 1500 patients and looked at diagnostic criteria over time, finding overall that with revised criteria over time, the sensitivity (likelihood of correct diagnosis) increased but specificity (likelihood of not having the disease after being given the diagnosis) declined. We seem to be picking up more of the people who truly have the disease but also diagnosing more people with the disease who don't have it. 

Part of the problem is overlap of clinical symptoms - some patients with Alzheimer's disease present similarly to those with dementia with lewy bodies. But the study also underlines the issues with our classification, some of those 'misdiagnosed' had Parkinson's Disease. If we start to consider both as part of a spectrum of lewy body diseases Parkinson's wouldn't be a misdiagnosis - which challenges both our conceptions of disease (clinical vs pathological entity) and diagnosis. What do you think?

-Anna

Accuracy of clinical diagnosis of dementia with Lewy bodies: a systematic review and meta-analysis

Giovanni Rizzo, Simona Arcuti, Massimiliano Copetti, Maria Alessandria, Rodolfo Savica, Andrea Fontana, Rocco Liguori, Giancarlo Logroscino

Background 

The diagnosis of dementia with Lewy bodies (DLB) is based on diagnostic clinical criteria, which were updated over the years.

Objective 

To evaluate, through a systematic review, accuracy of the diagnostic criteria, testing a possible improvement over time.

Methods 

We searched on MEDLINE and SCOPUS databases for studies reporting diagnostic parameters regarding the clinical diagnosis of DLB until October 2016. We performed meta-analysis, using a Bayesian approach, on those using pathological examination as gold standard, subclassified based on the different diagnostic criteria used.

Results 

We selected 22 studies on 1585 patients. Pooled sensitivity, specificity and accuracy were 60.2%, 93.8%, 79.7%, respectively, for criteria antecedents to McKeith 1996. For McKeith 1996-possible, pooled sensitivity, specificity and accuracy were 65.6%, 80.6%, 77.9% in early stages and 72.3%, 64.3%, 66% in late stages, respectively. For McKeith 1996-probable, pooled sensitivity, specificity and accuracy were 19.4%, 95.1%, 77.7% in early stages and 48.6%, 88%, 79.2% in late stages, respectively. McKeith criteria 2005 were evaluated only in late stages: pooled sensitivity, specificity and accuracy were 91.3%, 66.7% and 81.6%, respectively, for possible diagnosis (only one study) and 88.3%, 80.8%, 90.7% for probable diagnosis, decreasing to 85.6%, 77.1% and 81.7% if only considering clinical settings focused on dementia diagnosis and care.

Conclusions and relevance 

Diagnostic criteria have become more sensitive and less specific over time, without substantial change in the accuracy. Based on current data, about 20% of DLB diagnosis are incorrect. Future studies are needed to evaluate if the recently released revised consensus criteria will improve the diagnostic accuracy of DLB.

http://dx.doi.org/10.1136/jnnp-2017-316844