Last year – two years after actor Robin Williams died – his wife Susan Schneider Williams wrote an essay entitled The terrorist inside my husband’s head, published in the journal Neurology.
It is a heartfelt/heartbreaking insight into the actor’s final years. It also highlights the plight of many who are diagnosed with Parkinson’s disease, but experience an array of additional symptoms that leave them feeling that something else is actually wrong.
Today’s post is all about Dementia with Lewy bodies (or DLB). In particular, we will review the latest refinements and recommendations of the Dementia with Lewy Bodies Consortium, regarding the clinical and pathologic diagnosis of DLB.
Robin Williams. Source: Quotesgram
On the 28th May of 2014, the actor Robin Williams was diagnosed with Parkinson’s disease.
At the time, he had a slight tremor in his left hand, a slow shuffling gait and mask-like face – some of the classical features of Parkinson’s disease.
According to his wife, the diagnosis gave the symptoms Robin had been experiencing a name. And this brought her a sense of relief and comfort. Now they could do something about the problem. Better to know what you are dealing with rather than be left unsure and asking questions.
But Mr Williams sensed that something else was wrong, and he was left unsure and asking questions. While filming the movie Night at the Museum 3, Williams experienced panic attacks and regularly forgot his lines. He kept asking the doctors “Do I have Alzheimer’s? Dementia? Am I schizophrenic?”
Williams took his own life on the 11th August 2014, and the world mourned the tragic loss of a uniquely talented performer.
When the autopsy report came back from the coroner, however, it indicated that the actor had been misdiagnosed.
He didn’t have Parkinson’s disease.
What he actually had was Dementia with Lewy bodies (or DLB).
What is Dementia with Lewy bodies?
In Silicon valley (California), everyone is always looking for the “next killer app” – the piece of software (or application) that is going to change the world. The revolutionary next step that will solve all of our problems.
The title of today’s post is a play on the words ‘killer app’, but the ‘app’ part doesn’t refer to the word application. Rather it relates to the Alzheimer’s disease-related protein Amyloid Precursor Protein (or APP). Recently new research has been published suggesting that APP is interacting with a Parkinson’s disease-related protein called Leucine-rich repeat kinase 2 (or LRRK2).
The outcome of that interaction can have negative consequences though.
In today’s post we will discuss what is known about both proteins, what the new research suggests and what it could mean for Parkinson’s disease.
Seattle. Source: Thousandwonders
In the mid 1980’s James Leverenz and Mark Sumi of the University of Washington School of Medicine (Seattle) made a curious observation.
After noting the high number of people with Alzheimer’s disease that often displayed some of the clinical features of Parkinson’s disease, they decided to examined the postmortem brains of 40 people who had passed away with pathologically confirmed Alzheimer’s disease – that is, an analysis of their brains confirmed that they had Alzheimer’s.
What the two researchers found shocked them:
Title: Parkinson’s disease in patients with Alzheimer’s disease.
Authors: Leverenz J, Sumi SM.
Journal: Arch Neurol. 1986 Jul;43(7):662-4.
Of the 40 Alzheimer’s disease brains that they looked at nearly half of them (18 cases) had either dopamine cell loss or Lewy bodies – the characteristic features of Parkinsonian brain – in a region called the substantia nigra (where the dopamine neurons are located). They next went back and reviewed the clinical records of these cases and found that rigidity, with or without tremor, had been reported in 13 of those patients. According to their analysis 11 of those patients had the pathologic changes that warranted a diagnosis of Parkinson’s disease.
And the most surprising aspect of this research report: Almost all of the follow up studies, conducted by independent investigators found exactly the same thing!
It is now generally agreed by neuropathologists (the folks who analyse sections of brain for a living) that 20% to 50% of cases of Alzheimer’s disease have the characteristic round, cellular inclusions that we call Lewy bodies which are typically associated with Parkinson disease. In fact, in one analysis of 145 Alzheimer’s brains, 88 (that is 60%!) had chemically verified Lewy bodies (Click here to read more about that study).
A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia
Oh, and if you are wondering whether this is just a one way street, the answer is “No sir, this phenomenon works both ways”: the features of the Alzheimer’s brain (such as the clustering of a protein called beta-amyloid) are also found in many cases of pathologically confirmed Parkinson’s disease (Click here and here to read more about this).
So what are you saying? Alzheimer’s and Parkinson’s disease are the same thing???
Please excuse our use of UK slang in the title of this post, but a group of Australian researchers have recently discovered something really interesting about Parkinson’s disease.
And being a patriotic kiwi, it takes something REALLY interesting for me to even acknowledge that other South Pacific nation. This new finding, however, could be big.
In today’s post, we will review new research dealing with a protein called SOD1, and discuss what it could mean for the Parkinson’s community.
The number of dark pigmented dopamine cells in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source: Adaptd from Memorangapp
Every Parkinson’s-associated website and every Parkinson’s disease researchers will tell you exactly the same thing when describing the two cardinal features in the brain of a person who died with Parkinson’s disease:
- The loss of certain types of cells (such as the dopamine producing cells of the substantia nigra region of the brain – see the image above)
- The clustering (or aggregation) of a protein called Alpha synuclein in tightly packed, circular deposits, called Lewy bodies (see image below).
A Lewy body inside a cell. Source: Adapted from Neuropathology-web
The clustered alpha synuclein protein, however, is not limited to just the Lewy bodies. In the affected areas of the brain, aggregated alpha synuclein can be seen in the branches of cells – see the image below where alpha synuclein has been stained brown on a section of brain from a person with Parkinson’s disease.
Examples of Lewy neurites (indicated by arrows). Source: Wikimedia
Now, one of the problems with our understanding of Parkinson’s disease is disparity between the widespread presence of clustered alpha synuclein and very selective pattern of cell loss. Alpha synuclein aggregation can be seen distributed widely around the affected areas of the brain, but the cell loss will be limited to specific populations of cells.
If the disease is killing a particular population of cells, why is alpha synuclein clustering so wide spread?
So why is there a difference?
We don’t know.
It could be that the cells that die have a lower threshold for alpha synuclein toxicity (we discussed this is a previous post – click here?).
But this question regarding the difference between these two features has left many researchers wondering if there may be some other protein or agent that is actually killing off the cells and then disappearing quickly, leaving poor old alpha synuclein looking rather guilty.
Poor little Mr “A Synuclein” got the blame, but his older brother actually did it! Source: Youtube
And this is a very serious discussion point.
This year of 2017 represents the 200th anniversary of James Parkinson’s first description of Parkinson’s disease, but it also represents the 20th anniversary since the association between alpha synuclein and PD was first established. We have produced almost 7,000 research reports on the topic of alpha synuclein and PD during that time, and we currently have ongoing clinical trials targetting alpha synuclein.
But what if our basic premise – that alpha synuclein is the bad guy – is actually wrong?
Is there any evidence to suggest this?
We are just speculating here, but yes there is.
For example, in a study of 904 brains, alpha synuclein deposits were observed in 11.3% of the brains (or 106 cases), but of those cases only 32 had been diagnosed with a neurodegenerative disorder (Click here to read more on this). The remaining 74 cases had demonstrated none of the clinical features of Parkinson’s disease.
So what else could be causing the cell death?
Well, this week some scientists from sunny Sydney (Australia) reported a protein that could fit the bill.
Sydney. Source: Vagabond
The interesting part of their finding is that the protein is also associated with another neurodegenerative condition: Amyotrophic lateral sclerosis.
Remind me again, what is Amyotrophic lateral sclerosis?
Parkinson’s disease and Amyotrophic lateral sclerosis (ALS) are the second and third most common adult-onset neurodegenerative conditions (respectively) after Alzheimer’s disease. We recently discussed ALS in a previous post (Click here to read that post).
ALS, also known as Lou Gehrig’s disease and motor neuron disease, is a neurodegenerative condition in which the neurons that control voluntary muscle movement die. The condition affects 2 people in every 100,000 each year, and those individuals have an average survival time of two to four years.
You may have heard of ALS due to it’s association with the internet ‘Ice bucket challenge‘ craze that went viral in 2014-15.
The Ice bucket challenge. Source: Forbes
What is the protein associated with ALS?
In 1993, scientists discovered that mutations in the gene called SOD1 were associated with familial forms of ALS (Click here to read more about this). We now know that mutations in the SOD1 gene are associated with around 20% of familial cases of ALS and 5% of sporadic ALS.
The SOD1 gene produces an enzyme called Cu-Zn superoxide dismutase.
This enzyme is a very powerful antioxidant that protects the body from damage caused by toxic free radical generated in the mitochondria.
SOD1 protein structure. Source: Wikipedia
One important note here regarding ALS: the genetic mutations in the SOD1 gene do not cause ALS by affecting SOD1’s antioxidant properties (Click here to read more about this). Rather, researchers believe that the cell death seen in SOD1-associated forms of ALS is the consequences of some kind of toxic effect caused by the mutant protein.
So what did the Aussie researchers find about SOD1 in Parkinson’s disease?
This week, the Aussie researchers published this research report:
Title: Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated withneuronal loss in Parkinson’s disease brain.
Authors: Trist BG, Davies KM, Cottam V, Genoud S, Ortega R, Roudeau S, Carmona A, De Silva K, Wasinger V, Lewis SJG, Sachdev P, Smith B, Troakes C, Vance C, Shaw C, Al-Sarraj S, Ball HJ, Halliday GM, Hare DJ, Double KL.
Journal: Acta Neuropathol. 2017 May 19. doi: 10.1007/s00401-017-1726-6.
Given that oxidative stress is a major feature of Parkinson’s disease, the Aussie researchers wanted to investigate the role of the anti-oxidant enzyme, SOD1 in this condition. And what they found surprised them.
Heck, it surprised us!
Two areas affected by Parkinson’s disease – the substantia nigra (where the dopamine neurons reside; SNc in the image below) and the locus coeruleus (an area in the brain stem that is involved with physiological responses to stress; LC in the image below) – exhibited little or no SOD1 protein in the control brains.
But in the Parkinsonian brains, there was a great deal of SOD1 protein (see image below).
SO1 staining in PD brain and Control brains. Source: Springer
In the image above, you can see yellowish-brown stained patches in both the PD and control images. This a chemical called neuromelanin and it can be used to identify the dopamine-producing cells in the SNc and LC. The grey staining in the PD images (top) are cells that contain SOD1. Note the lack of SOD1 (grey staining) in the control images (bottom).
Approximately 90% of Lewy bodies in the Parkinson’s affected brains contained SOD1 protein. The investigators did report that the levels of SOD1 protein varied between Lewy bodies. But the clustered (or ‘aggregated’) SOD1 protein was not just present with alpha synuclein, often it was found by itself in the degenerating regions.
The researchers occasional saw SOD1 aggregation in regions of age-matched control brains, and they concluded that a very low level of SOD1 must be inherent to the normal ageing process.
But the density of SOD1 clustering was (on average) 8x higher in the SNc and 4x higher in the LC in the Parkinsonian brain compared to age-matched controls. In addition, the SOD1 clustering was significantly greater in these regions than all of the non-degenerating regions of the same Parkinson’s disease brains.
The investigators concluded that these data suggest an association between SOD1 aggregation and neuronal loss in Parkinson’s disease. Importantly, the presence of SOD1 aggregations “closely reflected the regional pattern of neuronal loss”.
They also demonstrated that the SOD1 protein in the Parkinsonian brain was not folded correctly, a similar characteristic to alpha synuclein. A protein must fold properly to be able to do it’s assigned jobs. By not folding into the correct configuration, the SOD1 protein could not do it’s various functions – and the investigators observed a 66% reduction in SOD1 specific activity in the SNc of the Parkinson’s disease brains.
Interestingly, when the researchers looked at the SNc and LC of brains from people with ALS, they identified SOD1 aggregates matching the SOD1 clusters they had seen in these regions of the Parkinson’s disease brain.
Is this the first time SOD1 has been associated with Parkinson’s disease?
No, but it is the first major analysis of postmortem Parkinsonian brains. SOD1 protein in Lewy bodies has been reported before:
Title: Cu/Zn superoxide dismutase-like immunoreactivity is present in Lewy bodies from Parkinson disease: a light and electron microscopic immunocytochemical study
Authors: Nishiyama K, Murayama S, Shimizu J, Ohya Y, Kwak S, Asayama K, Kanazawa I.
Journal: Acta Neuropathol. 1995;89(6):471-4.
The investigators behind this study reported SOD1 protein was present in Lewy bodies, in the substantia nigra and locus coeruleus of brains from five people with Parkinson’s disease. Interestingly, they showed that SOD1 is present in the periphery of the Lewy body, similar to alpha synuclein. Both of these protein are present on the outside of the Lewy body, as opposed to another Parkinson’s associated protein, Ubiquitin, which is mainly present in the centre (or the core) of Lewy bodies (see image below).
A more recent study also demonstrated SOD1 protein in the Parkinsonian brain, including direct interaction between SOD1 and alpha synuclein:
Title: α-synuclein interacts with SOD1 and promotes its oligomerization
Authors: Helferich AM, Ruf WP, Grozdanov V, Freischmidt A, Feiler MS, Zondler L, Ludolph AC, McLean PJ, Weishaupt JH, Danzer KM.
Journal: Mol Neurodegener. 2015 Dec 8;10:66.
PMID: 26643113 (This article is OPEN ACCESS if you would like to read it)
These researchers found that alpha synuclein and SOD1 interact directly, and they noted that Parkinson’s disease related mutations in alpha synuclein (A30P, A53T) and ALS associated mutation in SOD1 (G85R, G93A) modify the binding of the two proteins to each other. They also reported that alpha synuclein accelerates SOD1 aggregation in cell culture. This same group of researchers published another research report last year in which they noted that aggregated alpha synuclein increases SOD1 clustering in a mouse model of ALS (Click here for more on this).
Are there any genetic mutations in the SOD1 gene that are associated with Parkinson’s disease?
Two studies have addressed this question:
Title: Sequence of the superoxide dismutase 1 (SOD 1) gene in familial Parkinson’s disease.
Authors: Bandmann O, Davis MB, Marsden CD, Harding AE.
Journal: J Neurol Neurosurg Psychiatry. 1995 Jul;59(1):90-1.
PMID: 7608718 (This article is OPEN ACCESS if you would like to read it)
And then in 2001, a second analysis:
Title: Genetic polymorphisms of superoxide dismutase in Parkinson’s disease.
Authors: Farin FM, Hitosis Y, Hallagan SE, Kushleika J, Woods JS, Janssen PS, Smith-Weller T, Franklin GM, Swanson PD, Checkoway H.
Journal: Mov Disord. 2001 Jul;16(4):705-7.
Both studies found no genetic variations in the SOD1 gene that were more frequent in the Parkinson’s affected community than the general population. So, no, there are no SOD1 genetic mutations that are associated with Parkinson’s disease.
Are there any treatments targeting SOD1 that could be tested in Parkinson’s disease?
Great question. Yes there are. And they have already been tested in models of PD:
Title: The hypoxia imaging agent CuII(atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson’s disease.
Authors: Hung LW, Villemagne VL, Cheng L, Sherratt NA, Ayton S, White AR, Crouch PJ, Lim S, Leong SL, Wilkins S, George J, Roberts BR, Pham CL, Liu X, Chiu FC, Shackleford DM, Powell AK, Masters CL, Bush AI, O’Keefe G, Culvenor JG, Cappai R, Cherny RA, Donnelly PS, Hill AF, Finkelstein DI, Barnham KJ.
Title: J Exp Med. 2012 Apr 9;209(4):837-54.
PMID: 22473957 (This article is OPEN ACCESS if you would like to read it)
CuII(atsm) is a drug that is currently under clinical investigation as a brain imaging agent for detecting hypoxia (damage caused by lack of oxygen – Click here to read more about this).
The researchers conducting this study, however, were interested in this compound for other reasons: CuII(atsm) is also a highly effective scavenger of a chemical called ONOO, which can be very toxic. CuII(atsm) not only inhibits this toxicity, but it also blocks the clustering of alpha synuclein. And given that CuII(atsm) is capable of crossing the blood–brain barrier, these investigators wanted to assess the drug for its ability to rescue model of Parkinson’s disease.
And guess what? It did!
And not just in one model of Parkinson’s disease, but FOUR!
The investigators even waited three days after giving the neurotoxins to the mice before giving the CuII(atsm) drug, and it still demonstrated neuroprotection. It also improved the behavioural features of these models of Parkinson’s disease.
Is CuII(atsm) being tested for anything else in Clinical trials?
Yes, there is a clinical trial ongoing for ALS in Australia.
The Phase I study, being run by Collaborative Medicinal Development Pty Limited, is a dose escalating study of Cu(II)ATSM to determine if this drug is safe for use in ALS (Click here for more on this study).
Cu(II)ATSM is an orally administered drug that inhibits the activity of misfolded SOD1 protein. It has been shown to paradoxically increase mutant SOD1 protein in a mouse model of ALS, but it also provides neuroprotection and improves the outcome for these mice (Click here to read more on this).
If this trial is successful, it would be interesting to test this drug on a cohort of people with Parkinson’s disease. Determining which subgroup of the Parkinson’s affected community would most benefit from this treatment is still to be determined. There is some evidence published last year that suggests people with genetic mutations in the Parkinson’s associated gene PARK2 could benefit from the approach (Click here to read more on this). More research, however, is needed in this area.
So what does it all mean?
Right, so summing up, a group of Australian researchers have reported that the ALS associated protein SOD1 is closely associated with the cell death that we observe in the brains of people with Parkinson’s disease.
They suggest that this could highlight a common mechanisms of toxic SOD1 aggregation in both Parkinson’s disease and ALS. Individuals within the Parkinson’s affected community do not appear to have any genetic mutations in the SOD1 gene, which makes this finding is very interesting.
What remains to be determined is whether SOD1 aggregation is a “primary pathological event”, or if it is secondary to some other disease causing agent. We are also waiting to see if a clinical trial targeting SOD1 in ALS is successful. If it is, there may be good reasons for targeting SOD1 as a novel treatment for Parkinson’s disease.
The banner for today’s post was sourced from Pinterest
Last week a new piece of Parkinson’s disease research has been widely discussed in the media.
It involves Hepatitis – the viral version of it at least.
In today’s post we will review the research and discuss what it may mean for Parkinson’s disease.
A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia
A definitive diagnosis of Parkinson’s disease can only be made at the postmortem stage with an examination of the brain. Until that moment, all cases of Parkinson’s disease are ‘suspected’.
Critical to that postmortem diagnosis is the presence of circular shaped, dense clusters of proteins, called Lewy bodies (see the image above for a good example).
What causes Lewy bodies? We don’t know, but many people have theories.
This is Friedrich Heinrich Lewy (1885-1950).
Friedrich Lewy. Source: Lewy Body Society
As you can probably guess, Friedrich was the first to discover the ‘Lewy body’. His finding came by examining the brains of 85 people who died with Parkinson’s disease between 1908 – 1923.
In 1931, Friedrich Lewy read a paper at the International Congress of Neurology in Bern. During that talk he noted the similarities between the circular inclusions (called ‘negri bodies’) in the brains of people who suffered from rabies and his own Lewy bodies (observed in Parkinson’s disease).
A Negri body in a cell affected by rabies (arrow). Source: Nethealthbook
Given the similarities, Lewy proposed a viral cause for Parkinson’s disease.
Now, the idea that Parkinson’s disease could have a viral component has existed for a long time – even before Lewy made his conclusion. As we have previous mentioned, theories of viral causes for Parkinson’s have been circulating ever since the 1918 flu pandemic (Click here to read our post on this topic).
An example of post-encephalitic Parkinsonism. Source: Baillement
About the same time as the influenza virus was causing havoc around the world, another condition began to appear called ‘encephalitis lethargica‘ (also known as post-encephalitic Parkinsonism). This disease left many of the victims in a statue-like condition, both motionless and speechless – similar to Parkinson’s disease. Initially, it was assumed that the influenza virus was the causal factor, but more recent research has left us not so sure anymore.
Since then there, however, has been additional bits of evidence suggesting a viral role in Parkinson’s disease. Such as this report:
Title: Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration.
Author: Jang H, Boltz D, Sturm-Ramirez K, Shepherd KR, Jiao Y, Webster R, Smeyne RJ.
Journal: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14063-8.
The researchers in this study found that when they injected the highly infectious H5N1 influenza virus into mice, the virus progressed from the periphery (outside the brain) into the brain itself, where it induced Parkinson’s disease-like symptoms. The virus also caused a significant increase in the accumulation of the Parkinson’s associated protein Alpha Synuclein. Importantly, they witnessed the loss of dopamine neurons in the midbrain of the mice 60 days after resolution of the infection – that cell loss resembling what is observed in the brains of people with Parkinson’s disease.
The Parkinson’s associated protein alpha synuclein has also recently demonstrated anti-viral properties:
Title: Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain.
Authors: Beatman EL, Massey A, Shives KD, Burrack KS, Chamanian M, Morrison TE, Beckham JD.
Journal: J Virol. 2015 Dec 30;90(6):2767-82. doi: 10.1128/JVI.02949-15.
PMID: 26719256 (This article is OPEN ACCESS if you would like to read it)
David Beckham (not the football player) and his research colleagues introduced West nile virus to brain cells grown in cell culture and they observed an increase in alpha synuclein production. They also found that the brains of people with West nile infections had increased levels of alpha synuclein.
The researchers then injected West Nile virus into both normal mice and genetically engineered mice (which produced no alpha synuclein) and they found that the genetically engineered mice which produced no alpha synuclein died quicker than the normal mice. They reported that there was an almost 10x increase in viral production in the genetically engineered mice. This suggested to them that alpha synuclein may be playing a role in protecting cells from viral infections.
Interesting, but what about this new data involving Hepatitis?
Yes, indeed. Let’s move on.
Wait a minute, what is Hepatitis exactly?
The name Hepatitis comes from the Greek: Hepat – liver; and itis – inflammation, burning sensation. Thus – as the label suggests – Hepatitis is inflammation of liver tissue.
Hepatitis and the liver. Source: HealthandLovepage
It can be caused by infectious agents (such as viruses, bacteria, and parasites), metabolic changes (induced by drugs and alcohol), or autoimmune/genetic causes (involving a genetic predisposition).
The most common cause of hepatitis is viral.
There are five main types of viral hepatitis (labelled A, B, C, D, and E). Hepatitis A and E are mainly spread by contaminated food and water. Both hepatitis B and hepatitis C are commonly spread through infected blood (though Hepatitis B is mainly sexually transmitted). Curiously, Hepatitis D can only infect people already infected with hepatitis B.
Hepatitis A, B, and D are preventable via the use of immunisation. A vaccine for hepatitis E has been developed and is licensed in China, but is not yet available elsewhere
Hepatitis C, however, is different.
There is currently no vaccine for it, mainly because the virus is highly variable between strains and the virus mutates very quickly, making an effective vaccine a difficult task. A number of vaccines under development (Click here for more on this).
What is known about Hepatitis C and the brain?
Quite a bit.
Similar to HIV (which we discussed in a previous post), the hepatitis C virus (HCV) enters the brain via infected blood-derived macrophage cells. In the brain, it is hosted by microglial cells, which results in altered functioning of those microglial cells. This causes problems for neuronal cells – including dopamine neurons. For example, people infected with HCV have reduced dopamine transmission, based on brain imaging studies (Click here and here for more on this result).
Have there been connections between hepatitis C virus and Parkinson’s disease before?
Title: Hepatitis C virus infection: a risk factor for Parkinson’s disease.
Authors: Wu WY, Kang KH, Chen SL, Chiu SY, Yen AM, Fann JC, Su CW, Liu HC, Lee CZ, Fu WM, Chen HH, Liou HH.
Journal: J Viral Hepat. 2015 Oct;22(10):784-91.
The researchers in this study used data collected from a community-based screening program in north Taiwan which involved 62,276 people. The World Health Organisation (WHO) estimates that the prevalence of hepatitis C viral infection worldwide is approximately 2.2–3%, representing 130–170 million people. Taiwan is a high risk area for hepatitis, with antibodies for hepatitis viruses in Taiwan present in 4.4% in the general population (Source).
The researchers found that the significant association between hepatitis C viral infections and Parkinson’s disease – that is to say, a previous infection of hepatitis C increased the risk of developing Parkinson’s disease (by 40%). The researchers then looked at what the hepatitis C and B viral infections do to dopamine neurons growing in cell culture. They found that hepatitis C virus induced 60% dopaminergic cell death, while hepatitis B had no effect.
This study was followed up a few months later, by a second study suggesting an association between Hepatitis C virus and Parkinson’s disease:
Title: Hepatitis C virus infection as a risk factor for Parkinson disease: A nationwide cohort study.
Authors: Tsai HH, Liou HH, Muo CH, Lee CZ, Yen RF, Kao CH.
Journal: Neurology. 2016 Mar 1;86(9):840-6.
The researchers in this study wanted to investigate whether hepatitis C could be a risk factor for Parkinson’s disease. They did this by analyzing data from 2000-2010 drawn again from the Taiwan National Health Insurance Research Database.
The database included 49,967 people with either hepatitis B, hepatitis C or both, in addition to 199,868 people without hepatitis. During the 12 year period, 270 participants who had a history of hepatitis developed Parkinson’s disease (120 still had hepatitis C). This compared with 1,060 participants who were free of hepatitis, but went on to develop Parkinson’s disease.
When the researchers controlled for potentially confounding factors (such as age, sex, etc), the researchers found participants with hepatitis C had a 30% greater risk of developing Parkinson’s disease than the controls.
So if this has been demonstrated, why is this new study last week so important?
The answer is very simple: This study is not based on statistics from Taiwan – this new study has found the same result from a new population.
Title: Viral hepatitis and Parkinson disease: A national record-linkage study.
Authors: Pakpoor J, Noyce A, Goldacre R, Selkihova M, Mullin S, Schrag A, Lees A, Goldacre M.
Journal: Neurology. 2017 Mar 29. [Epub ahead of print]
These researchers used the English National Hospital Episode Statistics database and linked it to mortality data collected from 1999 till 2011. They too have found a strong association between hepatitis C and Parkinson’s disease (standardized rate ratio 1.51, 95% CI 1.18–1.9).
Curiously (and different from the previous studies), the researchers in this study also found a strong association for hepatitis B and Parkinson’s disease (standardized rate ratio 1.76, 95% CI 1.28–2.37). And these associations appear to be specific to Hepatitis B and C, as the investigators did not find any association between autoimmune hepatitis, chronic hepatitis, or HIV.
One important caveat with this new study, however, is that the authors could not
control for lifestyle factors (such as smoking or alcohol consumption). In addition, their system of linking medical records may underestimate the numbers of patients with
Parkinson’s disease as it would not take into account people with Parkinson’s disease who do not seek medical advice or those who are misdiagnosed (given a wrong diagnosis – it does happen!).
Regardless of these cautionary notes, the results still add to the accumulating evidence of an association between the virus that causes Hepatitis and the neurodegenerative condition of Parkinson’s disease.
But what about those people with Parkinson’s disease who have never had Hepatitis?
Yeah, this is a good question.
But there is a rather uncomfortable answer to it.
Here’s the rub: “Approximately 70%–80% of people with acute Hepatitis C do not have any symptoms” (Source: Centre for Disease Control). That is to say, the majority of people infected with the Hepatitis C virus will not be aware that they are infected. Some of those people who are infected may think that they have a case of the flu (HCV symptoms include fever, fatigue, loss of appetite,…), while others will simply not display any symptoms at all.
So many people with Parkinson’s disease may have had HCV, but never been aware of it.
And this is the really difficult part of researching the causal elements of Parkinson’s disease.
The responsible agent may actually leave little or no sign that they were ever present. For a long time, people have suggested that Parkinson’s disease is caused by a thief in the night – some agent that comes in, causes a problem and disappears without detection.
Perhaps Hepatitis is that thief.
But hang on a second, 60–70% of HCV infected people will go on to develop chronic liver disease (Source). Do people with Parkinson’s disease have liver issue?
Umm, well actually, in some cases: yes.
There have been studies of liver function in Parkinson’s disease where abnormalities have been found (Click here for more on this). And dopamine cell dysfunction has been seen in people with cirrhosis issues (Click here for more on this). In fact, the prevalence of Parkinsonism in people with cirrhosis has been estimated to be as high as 20% (and Click here for more on that).
So what are we saying? Hepatitis causes Parkinson’s disease???
No, we are not saying that.
Proving causality is the hardest task in science.
In addition, there have been a few studies in the past that have looked at viral infections as the cause of Parkinson’s disease that found strong associations with other viruses. For example this study:
Title: Infections as a risk factor for Parkinson’s disease: a case-control study.
Authors: Vlajinac H, Dzoljic E, Maksimovic J, Marinkovic J, Sipetic S, Kostic V.
Journal: Int J Neurosci. 2013 May;123(5):329-32.
In this study, the researchers found that Parkinson’s Disease was also significantly associated to mumps, scarlet fever, influenza, and whooping cough as well as herpes simplex 1 infections. They found no association between Parkinson’s disease and Tuberculosis, measles or chickenpox though.
This result raises the tantalizing possibility that other viruses may also be involved with the onset of Parkinson’s disease (it should be added though that this study was based on only 110 people with Parkinson’s (compared with 220 controls) in one particular geographical location (Belgrade, Serbia)).
So different viruses may cause Parkinson’s disease?
We are not saying that either, but we would like to see more research on this topic.
And the situation may actually be more complicated than we think.
Recently, it has been reported that previous infection with flaviviruses (such as dengue) actually enhances the effect of Zika virus infect (Click here to read more on this). That is to say, a prior infection by one particular virus may exacerbate the infection of another virus. It could be that a previous infection by one virus increases that chance that a later infection by another virus – a particular combination of viral infections – may result in Parkinsonian symptoms (we are simply speculating here).
Add to this complicated situation, the sheer number of unknown viruses. It is estimated that there are a minimum of 320,000 mammalian viruses still awaiting discovery (Click here for the source of this statistic), thus it is possible that additional unknown viruses may be involved with disease initiation for conditions like Parkinson’s disease.
A gang of unknown thieves in the night perhaps?
So what does it all mean?
Summing up: last week a new study was published that supported previous results that Hepatitis C viral infections could increase the risk of developing Parkinson’s disease. The results are important because they replicate previous findings from a different population of people.
The findings do not immediately mean that people with Hepatitis C are going to develop Parkinson’s disease, but it does suggest that they may be more vulnerable. The findings also suggest that more research is needed on the role of viral/infectious agents in the development of Parkinson’s disease.
We would certainly like to see more research in this area.
The banner for today’s post was sourced from Youtube