Parkinsonism type 1 through infinity

# # # # Many researchers argue that there is no such thing as “Parkinson’s” (a singular disease that has a specific causal event and similar outcome). They also suggest that holding on to this idea is hurting our ability to develop better therapies to treat the condition. In today’s post, we will explore this idea further and look at a recent review article addressing it. # # # #

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Source: Azquotes

Nosology is the branch of medical science that deals with the classification of diseases.

The goal of nosology is to have “a description whose primary purpose is enabling a diagnostic label to be put on the situation” (Source).

Note here the use of the word ‘situation‘, instead of ‘disease‘ in the sentence above. Much of what doctors and clinicians face in medicine are not specific diseases. Rather, they are situations (or conditions) that need to be treated.

Think of stroke. It “is a medical condition in which poor blood flow to the brain causes cell death” (Source). Certain diseases (for example, diabetes or heart disease) may result in an individual having a stroke, but the stroke itself is typically a very individual condition/situation. And this is what clinicians attempt to treat.

We often think of diseases as being defined by a specific cause. Like the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection that leads to COVID-19. But even here the situation that doctors face can vary widely – some infected people die, while others are completely asymptomatic carriers of the virus.

Where are you going with this? You don’t think Parkinson’s is a ‘disease’?

I don’t like to give opinions here. Rather, I dodge questions like that by offering the thoughts of other (more intelligent) individuals.

But it does make one wonder if “considering Parkinson’s as a single entity potentially impairs our understanding of the causative molecular mechanisms, approaches for patient stratification, identification of biomarkers, and the development of therapeutic approaches to Parkinson’s” (Source).

And this line of thinking is not new.

Back in 2008, the late renowned movement disorder specialist Prof Bill Weiner published this review:

Title: There is no Parkinson disease.
Author: Weiner WJ.
Journal: Arch Neurol. 2008 Jun;65(6):705-8.
PMID: 18541790               (This report is OPEN ACCESS if you would like to read it)

In this review, Prof Weiner started by suggesting to the reader that the “definition of Parkinson disease has always been confusing, and I hope to convince the reader that there is no single Parkinson disease and that there never has been“.

Prof Bill Weiner. Source: Tribpub

He began by stating that “neurologists agree that parkinsonism is a syndrome in which resting tremor, bradykinesia, cogwheel rigidity, and impaired postural reflexes are the predominant signs“. And this leads to the question: “How did this syndrome come to be called Parkinson disease?” And he then dives deep into the history of this thing we know as Parkinson’s.

Beginning well before James Parkinson, Prof Weiner highlights many comments over the ages from various sources, including the pathologist Joseph Greenfield who in 1955 wrote: “[James] Parkinson clearly accepted paralysis agitans as a disease, and this conception was accepted by Gowers and most other writers during the 19th Century. However, during more recent years, many have considered the symptoms of tremor and rigidity as a syndrome which may be caused by various lesions”.

And this historical section finished with a quote from Prof Stanley Fahn (for those unfamiliar with the fraternity of neurology, there are very few higher on the ladder than Stan. His legacy is legend and his career fascinating – among other things, he was Muhammad Ali’s neurologist).

Prof Stanley Fahn. Source: Roar

In 1989, Prof Fahn wrote “Parkinson’s disease, although of unknown etiology today, undoubtedly will be subdivided in the future into different varieties and etiologies”.

Next Prof Weiner looked at the pathology of this thing that we call “Parkinson’s”, He begins Tretiakoff’s 1919 thesis which reported that all of the nine postmortem cases with “Parkinson’s disease” exhibited loss of dopamine neurons in the substantia nigra region of the midbrain.

The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinsonian brain (right). Source:Memorangapp

But Prof Weiner makes a point that only 6 of those 9 cases Tretiakoff looked at presented Lewy bodies – the pathological hallmark of “Parkinson’s” (Click here for a previous SoPD post on Tretiakoff & Lewy bodies).

And since that first report “there have been many autopsy series of Parkinson disease in which Lewy bodies have not been 100% present” (Click here and here to read some examples). In fact, there have also been reports of seemingly normal individuals who have alpha synuclein deposits. In one study of 744 deceased individuals without Parkinson’s, the researchers assessed dopamine neuronal loss and the presence of Lewy bodies, and they found that approximately a third of the cases had evidence of dopamine cell loss and about 17% of the cases presented Lewy bodies (Click here to read that report). Other studies have reported similar results (Click here to read an example).

Given the irregularities of alpha synuclein-based pathology, Prof Weiner worried that there would be “an inherent bias if you define Parkinson disease as only those cases with Lewy bodies in the substantia nigra; then, of course, you can achieve 100% diagnostic accuracy of your definition”.

Next Prof Weiner turned his attention to what he thought will be the “final straw that will break the nosologic back of Parkinson disease“: the accumulating genetic evidence of different subtypes. At the time of his writing the piece, only 5 genetic risk variants had been discovered. And since then another ~90 regions of DNA have been associated with an increased risk of Parkinson’s (Click here to read a previous SoPD post on this topic). But many of these genetic variations are very rare (even within the PD community) and collectively they only account for about 25% of cases. So I’m not sure that genetics has provided Prof Weiner with a means of stratifying Parkinson’s.

Prof Weiner admits to “having no desire to “defrock” James Parkinson and a fondness for eponyms“, but he suggested that (back in 2008) we should start to use the term “Parkinson diseases“. Or perhaps with the discovery of more genetic subtypes, the label of “Parkinsonism type 1 through infinity” (with infinity leaving open the number of potential subtypes).

The academic arguments about labels of diseases/situations/sydromes/whatever might bore the lay person to tears, but nosology is important.

Why?

Well, it brings us back to the “considering Parkinson’s as a single entity” quote near the top of this post. And in the second half of his write up, Prof Weiner asked “Is it possible that recent neuroprotective trials for Parkinson disease have failed because numerous subtypes of Parkinson disease are lumped together?” Are we really targeting the right disease with the right drug if there are lots of different types of Parkinson’s all recruited into the same clinical trials? Could a drug that might work for one subtype of Parkinson’s be considered “a failure” because it has been tested on anyone with “Parkinson’s”. It is a very fair point as we move towards what the research community call an age of precision medicine.

In concluding this paper, Prof Weiner lays down the gauntlet and declares that “there is no single Parkinson disease” and proposes that we “simply diagnose parkinsonism by the number, as we do spinocerebellar degenerations“.

Interesting. What does the research community think of this idea?

There have certainly been proponents of this line of thinking. But to date, the shift has struggled from the lack of truly defined subtypes. And this has left the field somewhat in limbo – agreeing that we are not dealing with a singular disease, but unable to define the alternative groupings.

Most simply refer to “Parkinson’s” in the singular for simplicity sake.

Recently some New Zealand researchers (Go kiwis!) have taken on the topic in an interesting new perspective article. Prof Justin O’Sullivan and colleagues propose that “diagnosis should shift away from the clinical definitions, towards biologically defined diseases that collectively form PD, to enable informative patient stratification“.

Prof O’Sullivan, Dr Farrow & Prof Cooper. Source: Auckland

Here is their perspective piece:

Title: Redefining the hypotheses driving Parkinson’s diseases research.
Authors: Farrow SL, Cooper AA, O’Sullivan JM.
Journal: NPJ Parkinsons Dis. 2022 Apr 19;8(1):45.
PMID: 35440633                (This report is OPEN ACCESS if you would like to read it)

In their review, Prof O’Sullivan and colleagues begin by pointing out that “the failure of nineteen Phase 3 intervention trials targeting modification of disease progression illustrates a limitation”  of looking at Parkinson’s as a single disease. They then highlight the utility of the genetic analyses, like genome-wide association studies (GWAS), that have allowed us to identify many genetic variations that are associated not only with risk of developing Parkinson’s, but also genetic mutations associated with different rates of symptom progression.

But, they note that “the conglomeration of data across multiple different Parkinson diseases dilutes the frequency of specific disease-associated variants and thus reduces the ability to identify those variants that contribute to the trajectory of each individual disease”.

To address this situation, they propose to view “Parkinson’s” as “a group of diseases with different but overlapping aetiologies” (causes). And they use a conceptual model “where each disease within PD is represented by a mountain within a range of mountain“.

Source: PMC

They suggest that “an individual’s genetic risk is represented by the position in the valley (i.e., basecamp) where the individual starts climbing—this position naturally limits the mountain(s) that can be ascended and the route(s) that can be taken” . The peaks of the mountain represent various types of Parkinson’s, and there are different pathways to those peaks. And the number of peaks is currently unknown.

Environmental factors at basecamp also influence the course of an individual’s trajectory. They interact with the individual’s genetic situation, altering details like age of onset (of climbing the mountain) or whether an individual even starts to develop Parkinson’s. And there are a wide range of potential environmental factors – from stress and sleep to diet and the microbiome of the gut, from exercise and pollutants to inflammation and viral infections. All sorts of things could be influencing the initial start to the climb up the mountain range.

In addition, “there are commonalities across individual diseases that contribute to PD” (and as such these are shared across the different mountains within the mountain range). And the researchers suggest that “treating these commonalities would provide treatment for a larger group of patients”, but they suggest that for disease modification a more sub-type disease specific treatment is required.

And how do they propose to approach the search for these sub-types?

They propose that it is genetic characteristics “that initially “set the stage” and determine which basecamp and mountain an individual will start ascending in their journey towards Parkinson’s”, and that these genetic features may vary across different tissues in the body of any individual.

This results in the “need to look beyond the tissue- and cell-types that are traditionally associated with PD pathology to gain a greater understanding of the mechanisms through which genetic risk may be manifested”. In other words, by just focusing on the brain we are not going to get very far.

Thus, they propose to combination of various analytical approaches (genetic, metabolomic, lipodomic, etc) to better characterise the subtypes, and they provide a deep discussion of how these difference methods could be applied.

There is also a call for consideration of “n-of-1” approaches in Parkinson’s research. We have previously discussed the concept of an individualised focus on the SoPD (Click here to read an example of this), and in this report the researchers suggest that this is essential “to identify the combinations and relative contributions of the genetic, pathological and environmental factors in each unique circumstance” that drive the development of the condition.

Importantly, the researchers propose that diagnosis of “Parkinson’s” ideally should shift away from the classical clinical definitions that neurologists have used up to this point, and more towards biologically defined disease criteria that can collectively identify certain subtypes. Such an approach would hopefully enable more informative patient stratification, and this may greatly aid the development of novel therapeutics for treating the various forms of “Parkinson’s”.

So what does it all mean?

I want you to think of a “Pine tree”.

The Pine tree that you are envisaging (I am assuming: a tall evergreen woody trees that bear seed cones with bundles of needles) belongs to a family in the genus Pinus of the larger family Pinaceae.

Interesting fact: The pinus family includes more than 120 different species worldwide:

Source: PMC

Thus, when one neurologist in the UK imagines what a pine tree looks like, there will probably be tiny, subtle differences to what a neurologist in China might be thinking of.

I hope that one day soon we will have the means to be able to subtype the condition that we currently know as “Parkinson’s” into more informative groupings (the same way we do with “pine trees”), and this will allow for the targeting of more mechanistically precise treatments. And eventually, perhaps even a more individualistic method of treatment will become available and we will be focusing on treating each individual case.

But importantly, for future generations the tools that we would use in this stratification of the “Parkinson’s” subtypes will be employed at earlier stages in the development of the conditions, allow for earlier intervention and the eventual eradication of the conditions that currently plague 10 million-plus individuals across the globe..

 

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The banner for today’s post was sourced from BBC