‘Parkinsonisms’ refer to a group of neurological conditions that cause movement features similar to those observed in Parkinson’s disease. They include multiple system atrophy (MSA) and Progressive supranuclear palsy (PSP) and idiopathic Parkinson’s.
Newly published research now shines a light on a possible mechanism for differentiating between multiple system atrophy and idiopathic Parkinson’s.
In today’s post we will look at what multiple system atrophy is, review the new research report, and discuss what these results could mean for the Parkinson’s community.
Brain immaging of multiple system atrophy–related spatial covariance pattern (MSARP) and Parkinson disease–related spatial covariance pattern (PDRP). Source: Neurology
For a long time I have been looking to write a piece of Multiple system atrophy.
I have been contacted by several readers asking for more information about it, and the only thing really delaying me – other than the tsunami of Parkinson’s related research that I am currently trying to write posts for – was the lack of a really interesting piece of research to base the post around.
Guess what came into my inbox yesterday:
Title: Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication.
Authors: Woerman AL, Kazmi SA, Patel S, Aoyagi A, Oehler A, Widjaja K, Mordes DA, Olson SH, Prusiner SB.
Journal: Proc Natl Acad Sci U S A. 2017 Dec 26. pii: 201719369.
This is a really interesting piece of research, that continues a line of other really interesting research.
And if it is independently replicated and verified, it will have massive implications for the Parkinson’s community, particularly those affected by Multiple System Atrophy.
But before we deal with that, let’s start with the obvious question:
What is Multiple System Atrophy?
Some people say that the eyes are the gateway to the soul.
Maybe. I don’t know. Poetic stuff though.
Research published recently, however, suggests that the eyes may also provide a useful aid in the diagnosis of Parkinson’s disease. In today’s post we will review what results have been published and try to understand what they mean for our understanding of this condition.
A schematic of the human eyeball. Source: NIDDK image library
The fact that you can see and read this page is a miraculous thing.
Amazing not just because light is entering your eye, being focused on a particular point in the back of the eyeball and then being turned into a signal that is transmitted to your brain for further analysis, but also because of all the other activities involved with sight. The muscle movements, for example, which are required for turning the eyeball the small fractions necessary for reading this sentence from left to right.
And then there is also the blood supply, keeping the whole system working. This feature is of particular interest to today’s post, as research published last week suggests that there are differences in the blood flow of the eyeball between people with and without Parkinson’s disease.
The anatomy of an eyeball
The human eyeball is – on the macro level – a fairly simple structure.
You have the Iris, which regulates the amount of light entering the eye. At the centre of the iris, you have a central opening called the pupil, which can dilate and constrict as required. Covering these is the cornea, a transparent circular skin. These structures all sit over the lens which helps to refract incoming light and focus it onto the retina. And the retina, of course, is the light sensitive layer that lines the interior of the eye – allowing us to see.
The anatomy of the eye. Source: GemClinic
Within the retina are specialised cells of two sorts:
- Rod cells (about 125 million of them per eye) which are necessary for seeing in dim light.
- Cone cells (6-7 million of these) which can be further divided into three types, each sensitive to different primary colours – red, green or blue.
These specialised ‘photoreceptive’ cells send signals down through the layers of the retina to what are called retinal ganglion cells which are the key conduits in the sending of information to the brain.
All of these cells require a constant blood supply, from arteries and veins spreading across the retina, and this a key part of our discussion today (see below).
So what have eyeballs got to do with Parkinson’s disease?
Good question. People with Parkinson’s disease often complain of from visual issues, such as reduced visual acuity, low contrast sensitivity and disturbed colour vision.
And there has been some research into the eyes with regards to Parkinson’s disease. A few weeks ago, this particular study was published:
Title: The retina as an early biomarker of neurodegeneration in a rotenone-induced model of Parkinson’s disease: evidence for a neuroprotective effect of rosiglitazone in the eye and brain.
Authors: Normando EM, Davis BM, De Groef L, Nizari S, Turner LA, Ravindran N, Pahlitzsch M, Brenton J, Malaguarnera G, Guo L, Somavarapu S, Cordeiro MF.
Journal: Acta Neuropathol Commun. 2016 Aug 18;4(1):86. doi: 10.1186/s40478-016-0346-z.
PMID: 27535749 (This article is OPEN ACCESS if you would like to read it)
The researchers in this study used a rodent model of Parkinson’s disease (rotenone-induced). In this model, the animals started losing dopamine cell loss in the brain at 60 days after the model of Parkinson’s disease was chemically induced.
The scientists examined the eyes of the rats at 10, 20, 40 and 60 days of the study. At the 20 day time point, the researchers began to see increased retinal ganglion cell death and swelling of the retinal layers in the eyes. These changes were obviously occurring well before the cell loss is observed in the brain, which leads the authors to ask whether the eyes could potentially used as an early indicator of Parkinson’s disease.
Of particular interest in this study was the use of Rosiglitazone to protect the retinal cells (AND the dopamine neurons in this rodent model of Parkinson’s disease). Rosiglitazone is an anti-diabetic drug. It works as an insulin sensitizer, by binding to fat cells and making them more responsive to insulin (we have previously discussed the curious relationship between Parkinson’s disease and diabetes (click here for more on this), and this result reinforces that connection). The scientists found that giving the drug once every 3 days had very beneficial effects of the survival of the retinal cells. They also observed significant neuroprotection after delaying the treatment for 10 days and then just giving one round of treatment, suggesting that a lot of the drug is not required for positive results.
EDITORIAL NOTE HERE: Before readers start to get any crazy ideas about sourcing and self medicating with Rosiglitazone, it is important to note that there are serious side effects associated with this class of drug. It has been associated with heart disease and stroke (click here to read more), and it should only be taken by people with diabetes and under the strict supervision of a qualified physician. It it mentioned here purely for educational purposes.
So obviously what is required is an examination of the eyes of people with Parkinson’s disease
Yep. And conveniently, in the same week as the previous study came out, this second study was also published:
Title: Evaluation of Retinal Vessel Morphology in Patients with Parkinson’s Disease Using Optical Coherence Tomography.
Authors: Kromer R, Buhmann C, Hidding U, Keserü M, Keserü D, Hassenstein A, Stemplewitz B.
Journal: PLoS One. 2016 Aug 15;11(8):e0161136.
PMID: 27525728 (This article is OPEN ACCESS if you would like to read it)
The researchers examined 49 people with Parkinson’s disease and 49 age- and sex-matched healthy controls. Blood vessels within the retina were identified and then divided into arteries and veins, based on their shape (using computer software). The results of the study indicate significant differences in the morphology of retinal veins in people with Parkinson’s disease when compared to controls.
Interestingly, the retinal effect was more significant on the side of the body firstly affected by Parkinson’s disease (a very common feature of Parkinson’s is that initially the condition will affect one side of the body more than the other).
What does it all mean?
For generations, we have focused on the clinical motor features of Parkinson’s disease (slowness, rigidity, and a resting tremor) when trying to determine if someone has the condition. Now we are learning that there may be other parts of the body that we should be investigating, which could not only provide us with novel diagnostic tools for earlier detection of the disease, but those areas may also provide us with new insights into disease onset and spread as well.
I may be getting a bit ahead of myself here but the possibilities are exciting and we’ll keep you abreast of these new findings as they come to us.
The banner for today’s post was sourced from the Photoforum.
Diagnosing Parkinson’s disease is actually hard work, and mistakes can be made (click here for more on this). A new criteria has been proposed by a group of experts. In today’s post we will have a look at what is included (and excluded) from this new criteria for Parkinson’s disease.
Brain imaging of a normal brain (left) and two Parkinsonian brains. Source: the Lancet
In the United Kingdom, the most commonly used criteria for Parkinson’s disease is the UK Brain bank criteria. It is a three step criteria that clinicians can use in their assessments of individuals suspected of having Parkinson’s disease.
The UK Brain bank criteria. Source: Scielo
In the USA, many physicians use the United Parkinson’s Disease Rating Scale (UPDRS) for diagnosing Parkinson’s disease. UPDRS is a rating scale of Parkinson’s features. There is also a growing trend towards the use of a brain imaging technique called a DAT-Scan, which is an FDA-approved approach for differentiating Parkinson’s disease from essential tremor (but it cannot distinguish between PD and parkinsonian subtypes).
DAT-Scan. Source: GEHealthcare
Ok, so why do we need a new criteria from Parkinson’s disease?
There have been major advances made since Dr James Parkinson first described Parkinson’s disease in 1817 (200 year anniversary coming up!!!). All that progress is changing in the way we look at the condition, for example only in the last two decades has our understanding of the genetics underlying Parkinson’s really started to blossom.
Scientific advances have also complicated our view of Parkinson’s disease. To date, a definitive diagnosis of Parkinson’s disease can only be made at the postmortem stage, with an analysis of the brain itself. That examination involves looking for clusters of proteins in the brain, called Lewy bodies. Recently, however, it has been observed that many people with Parkinson’s disease that have a mutation in the Lrrk2 gene do not have Lewy bodies. Why this is? We do not know. It is one of many complicating factors in the diagnosis of Parkinson’s disease.
Given this state of affairs, it was decided that an updated definition/criteria for Parkinson’s disease was required.
Who decides what is Parkinson’s disease?
In 2014, the International Parkinson and Movement Disorder Society (MDS) organised a task force with the goal of providing an updated definition/criteria for Parkinson’s disease.
That group of experts held two ‘brainstorming’ teleconferences and then a physical meeting that all attended. From those meetings a first draft document was produced. Over the next 6 months a revision process was undertaken. The final version of the new criteria was ratified in San Diego (California) in June 2015.
What is the new criteria?
If you would like to read the new criteria in full – you can find it by clicking here.
Below we present a layman summary of the criteria. Central to the new criteria is firstly establishing that an individual has Parkinsonism, and then determining if Parkinson’s disease is the cause of that Parkinsonism.
Now that sounds a bit weird, but it does make sense. Here is how it works: Parkinsonism embodies a set of conditions that are characterized by tremor, bradykinesia, rigidity, and postural instability. Parkinson’s disease is the most common type of parkinsonism. Another form of Parkinsonism is vascular parkinsonism, in which blood vessel issues cause the tremor, bradykinesia, and rigidity features. Approximately 7% of people who are diagnosed with parkinsonism have developed their features after using (or treatment with) particular medications (such as neuroleptic antipsychotics). Thus, it is important to determine that a person’s parkinsonism is caused by Parkinson’s disease itself.
How do you establish Parkinsonism?
Ever since Dr James Parkinson’s first description of Parkinson’s disease, the clinical criteria for the parkinsonism have centred around the motor features. The new criteria continues this tradition, defining of Parkinsonism being based on the three cardinal motor features. These are:
Bradykinesia, which is defined as slowness of movement AND decrement in amplitude or speed as movements are continued (eg. progressive hesitations/halts). Bradykinesia can be evaluated by using finger tapping, hand movements, pronation-supination movements (for example, twisting the forearm so that the palm is facing up and then down), toe tapping, and foot tapping.
Pronation-supination movements. Source: YogiDoc
Importantly: Although bradykinesia can also occur in the voice, the face, and axial or gait domains, limb bradykinesia must be documented to establish a diagnosis of Parkinsonism.
Rigidity – Rigidity is determined on the “slow passive movement of major joints with the patient in a relaxed position and the examiner manipulating the limbs and neck.”
Rigidity deals with resistance and is referred to as ‘Lead-pipe rigidity’. This occurs when an increase in muscle tone causes a sustained resistance to passive movement (without fluctuations) through an entire range of motion.
Cogwheel rigidity is a combination of lead-pipe rigidity and tremor, presenting as a jerky resistance to passive movement – caused by muscles tensing and relaxing. Cogwheel rigidity is often present in Parkinson’s disease, but without lead-pipe rigidity Cogwheeling does not fulfill minimum requirements for rigidity.
Resting Tremor – this involves the shaking of 4 to 6-Hz in a fully resting limb. Importantly, for diagnosis of Parkinson’s disease, the tremor must be suppressed during movement initiation. The assessment of resting tremor can be made during the entire period of examination. And although postural instability is a feature of Parkinson’s disease, alone it does not qualify for a diagnosis of the condition.
Once it has been determined that the person has parkinsonism, the examiner will then determine whether the patient meets criteria for Parkinson’s disease as the cause of this parkinsonism. This determination is based on three requirements:
- Absence of absolute exclusion criteria
- At least two supportive criteria
- No red flags
1. Absolute Exclusion Criteria
The exclusion criteria is a list of clinical aspects that indicate alternative possible causes of Parkinsonism. The presence of any of the following features will result in Parkinson’s disease being ruled out as the cause of the Parkinsonism:
– Indications of cerebellar abnormalities, such as cerebellar gait, limb ataxia, or cerebellar oculomotor abnormalities.
– Downward vertical supranuclear gaze palsy (difficulty looking down), or selective slowing of downward vertical eye movements
– Diagnosis of probable behavioral variant frontotemporal dementia (BvFTD) or primary progressive aphasia (a rare neurological syndrome in which language capabilities become slowly and progressively impaired, while other mental functions remain preserved)
– The Parkinsonian motor features restricted to only the lower limbs for more than 3 years
– Treatment with any dopamine receptor blockers or dopamine-depleting agents in doses and a time-course consistent with drug-induced parkinsonism
– The absence of any observable response to a high-dose of levodopa
– Unequivocal cortical sensory loss (eg., graphesthesia or the ability to recognize writing on the skin purely by the sensation of touch), clear limb ideomotor apraxia, or progressive aphasia
– Normal functional neuroimaging of the presynaptic dopaminergic system (this could be the DATScan mentioned above)
– Documentation of an alternative condition known to produce parkinsonism and plausibly connected to the patient’s symptoms
2. Supportive Criteria
The Supportive criteria is a list of clinical findings that support the indication that the Parkinsonism is caused by Parkinson’s disease. These include:
- An obvious beneficial response (return to normal or near-normal level of functioning) in response to dopaminergic therapy (L-dopa treatment)
- The presence of levodopa-induced dyskinesias
- Resting tremor of a limb, documented on clinical examination
- Positive results from at least one ancillary diagnostic test. Currently available tests that meet this criterion include:
- Olfactory loss (adjusted for age and sex)
- Metaiodobenzylguanidine scintigraphy (say that three times really fast!)
3. Red Flags
Red flags are indications of an alternative explanation for the Parkinsonism. While the presence of red flags can be counterbalanced by supportive criteria items, if there are more than two red flags, clinically probable PD cannot be diagnosed. The red fags include:
- Rapid progression of gait impairment requiring regular use of wheelchair within 5 years of onset of features
- A complete absence of progression of motor symptoms or signs over 5 or more years unless stability is related to treatment
- Early bulbar dysfunction, defined as one of severe dysphonia, dysarthria (speech unintelligible most of the time), or severe dysphagia (requiring soft food, NG tube, or gastrostomy feeding) within the first 5 years of disease.
- Inspiratory respiratory dysfunction defined as either diurnal or nocturnal inspiratory stridor or frequent inspiratory sighs
- Severe autonomic failure in the first 5 y of disease. This can include Orthostatic hypotension or severe urinary incontinence or urinary retention in the first 5 years of disease.
- Recurrent (>1/y) falls because of impaired balance within 3 years of onset.
- The presence of disproportionate anterocollis (dystonic in nature) or contractures of hand or feet within the first 10 years.
- Absence of any of the common nonmotor features of disease despite 5 years disease duration. These include sleep dysfunction, constipation, daytime urinary urgency, Hyposmia, Psychiatric dysfunction (depression, anxiety, or hallucinations)
- Otherwise unexplained pyramidal tract signs, defined as pyramidal weakness or clear pathologic hyperreflexia (excluding mild reflex asymmetry in the more affected limb, and isolated extensor plantar response).
- Bilateral symmetric parkinsonism throughout the disease course. The patient or caregiver reports bilateral symptom onset with no side predominance, and no side predominance is observed on objective examination.
This new criteria for Parkinson’s disease will now be through a period of clinical evaluation and may be adjusted based on that assessment process.
It is interesting to see the condition becoming more defined and specified.
The banner for today’s post was sourced from Help to buy SES
This is Dr Henri Huchard (1844-1910; a French neurologist and cardiologist):
In 1875, he described the case was of a child who, at just 3 years of age, presented with all the clinical features of Parkinson’s disease. Since that report, there have been many studies detailing the condition that has come to be known as ‘juvenile Parkinsonism‘. Currently the youngest person diagnosed with Parkinson’s disease is a young lady from Oklahoma. She was diagnosed at 10-years of age, but had shown symptoms since the age of 2.
We are going to explore juvenile Parkinson’s disease in future post, but today’s post will review some new research that looks at the differences in Parkinson’s disease features of people diagnosed at different ages.
For most members of the general public, Parkinson’s disease is considered a condition of the elderly. And this is a fair line of thinking given what they probably observe out there in the big wide world.
A few years ago though, Parkinson’s UK commissioned and published a report of the statistics/demographics of Parkinson’s disease in the UK (Click here for a copy of that report). In that report, they present this table:
It illustrates the estimated number of people in each age bracket that have Parkinson’s disease. As you can see, the bulk of the people affected are over the age of 60. But this does not mean that Parkinson’s disease is simply a condition of the aged. It is believed that worldwide at least 5% of diagnoses are to people below the age of 50 – this is considered early onset Parkinson’s disease.
There are many people – actor Michael J Fox among them – who have been diagnosed below the age of 40.
Actor Michael J Fox was diagnosed with Parkinson’s disease at age 30.
Source: MJFox foundation
Given this wide spectrum of age of onset, it is curious that more research has not been conducted comparing the differences in features of the condition between the different age groups. This situation, however was remedied recently:
Title: Age at onset and Parkinson disease phenotype.
Authors: Pagano G, Ferrara N, Brooks DJ, Pavese N.
Journal: Neurology. 2016 Feb 10.
The investigators in this study took 422 people who had recently been diagnosed with Parkinson’s disease (none of them were on any anti-Parkinson’s medication, eg. L-dopa). The subjects were divided into 4 groups according to their age at diagnosis:
- younger than 50 years (58 subjects)
- 50-59 years (117 subjects)
- 60-69 years (168 subjects)
- older than 70 years (79 subjects)
The researchers then investigated differences in:
- side of onset (left or right; dominant or non-dominant side of the body)
- type of symptoms (rigidity or tremor, etc)
- localization of symptoms occurrence (eg. arms, legs, etc)
- severity of motor features (rigidity, tremor,…)
- severity of nonmotor features (memory, attention,…)
- severity nigrostriatal function (brain imaging of the dopamine system)
- CSF biomarkers (Chemicals in the cerebrospinal fluid which surrounds the brain)
Curiously in all of the four groups, a quarter of the people had a family history of Parkinson’s disease. Familial history could suggest a genetic connection, and the genetic aspect of Parkinson’s disease has generally been associated with the early onset group. But this does not appear to be the case in this study – there was no bias towards the younger onset group.
Asymmetry of motor features onset (eg. tremor, etc) was apparent in 97.8% of the total population, with 55% of those subjects having symptoms on their dominant side. It is interesting to note here, however, that the young onset group were the only group in which the non-dominant side was more affected than the dominant. Similarly, almost all of the symmetrical onset individuals (exhibiting no asymmetry in their motor features) were in the oldest group.
In all four groups, the arm was the more likely site of motor features (this was the case in approx. 85% in all groups). When considering other sites of onset, the head was more frequent in the older groups than the younger group, while the leg was more common in the younger group than the older group.
The older the age at onset the more severe the motor (eg. resting tremor, and postural instability scores) and nonmotor features (including autonomic, olfactory, and cognitive functions). This was accompanied by a greater dopaminergic dysfunction on the brain scan, and a reduction of alpha synuclein floating around in the cerebrospinal fluid.
Rigidity was more common in the young-onset group.
There were no differences between the groups in terms of issues associated with activities of daily living, measures of depression and anxiety, impulsive control, or sleep problems.
What does it all mean?
Why these difference exist and what they might tell us about the condition is yet to be determined. The results are interesting when one considers that the subjects had similar disease duration (they had all just been diagnosed; within 6 months of diagnosis). This suggests that the observed differences may be specific to the different age groups. A direct contribution of the aging process, however, has to be considered when assessing the older group.
This kind of analysis is necessary as it is the only way small details about the disease can be determined. We thought this was an interesting study
An inconvenient truth:
The diagnosis of Parkinson’s disease can only be definitively achieved at the postmortem stage.
There is currently no diagnostic test for this task and we are reliant on the training and skills of the neurologists making the diagnosis. Brain imaging techniques (such as DAT-scans) are great, but they can only aid physicians in their final decision.
And those decisions are not always right.
In 1992, a study looking at the brains of 100 subjects who had died with Parkinson’s disease, found that 24% of the cases did not fulfill the pathological requirements for the diagnosis of Parkinson’s disease. That study was:
Title: Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases.
Authors: Hughes AJ, Daniel SE, Kilford L, Lees AJ.
Journal: Journal of Neurol Neurosurg Psychiatry. 1992 Mar;55(3):181-4.
Unfortunately, despite years of research, it would appear that there is still a large degree of error in the clinical diagnosis of Parkinson’s disease. A study published in 2014 in the journal Neurology that suggested that there is currently a 15% rate of misdiagnosis. That study was:
Title: Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study.
Authors: Adler CH, Beach TG, Hentz JG, Shill HA, Caviness JN, Driver-Dunckley E, Sabbagh MN, Sue LI, Jacobson SA, Belden CM, Dugger BN.
Journal: Neurology. 2014 Jul 29;83(5):406-12.
It has to be said that clinicians face a very difficult task in diagnosing Parkinson’s disease. The variety of features (symptoms) that patients present with in the clinic, and the lack of diagnostic tools, leave neurologists making a judgement based largely on clinical observations.
But this degree of error ultimately has a huge impact on clinical studies and trials: if 10-20% of the participants are not Parkinsonian, are we really going to observe an accurate result?
Better diagnostic tests/tools are critically required.
Title: Potential utility of autoantibodies as blood-based biomarkers for early detection and diagnosis of Parkinson’s disease.
Authors: DeMarshall CA, Han M, Nagele EP, Sarkar A, Acharya NK, Godsey G, Goldwaser EL, Kosciuk M, Thayasivam U, Belinka B, Nagele RG; Parkinson’s Study Group Investigators.
Journal: Immunol Letters, 168(1), 80-8.
PMID: 26386375 (this article is OPEN access if you would like to read it)
The researchers took 398 subjects, including 103 early-stage Parkinson’s disease subjects and they collected blood samples from them. They then screened the blood for 9,486 different autoantibodies that could be useful as biomarkers for Parkinson’s disease.
Antibodies are produced by our immune system to determine what is ‘self’ and not ‘self’. They are the foundation of our defenses against the big, bad germ/bacteria world. Autoantibodies are antibodies produced by our immune system that are directed against our own tissues. They target ‘self’.
And yeah, that is bad. Autoantibodies are associated with autoimmune diseases such as Lupus.
We are not sure why we produce autoantibodies. The causes of their production vary greatly and are not well understood. In Parkinson’s disease, however, autoantibodies may be produced as a result of the cell death in the brain. Some of the debris resulting from the dying cells will make its way into the bloodstream, to be removed from the body. Whilst in the blood, some of that debris could trigger the immune system, thus resulting in the production of autoantibodies.
De Marshall et al (the researchers who conducted this study) were hoping to take advantage of this autoantibody production and use them as biomarkers to not only differentiate between people with and without Parkinson’s disease, but also to differentiate between different stages of Parkinson’s disease (see the figure below).
Attempting to differentiate between different stages of Parkinson’s disease. Source: Immuno Letters
The researchers found that using the top 50 autoantibodies that they associated with Parkinson’s disease, they could successfully differentiate between people with and without Parkinson’s disease with 90% prediction accuracy in a blind analysis (they actually found that just the top 4 autoantibodies were enough).
Interestingly, the researchers then compared the early Parkinson’s group with a mild-moderate Parkinson’s group and they found that they could differentiate between the two groups with an overall accuracy of 97.5%!
These are very exciting results and we will be following this work with interest – not only from the standpoint of biomarkers, but also the role of autoantibodies in Parkinson’s disease.