Following on nicely from our last post, we are delighted to publicise our latest peer-reviewed publication.
This will come out in a special edition of the European Journal of Neuroscience, dedicated to the memory of Tom Isaacs. Tom was the founder and leader of the Cure Parkinson's Trust - a truly dynamic leader and a real disruptive presence (in all the right ways) within Parkinson's research. We are honoured to have our names and our ideas as testimonial to him in this way.
It is clear that Parkinson's is more of an umbrella condition than one single entity. For instance, some people have significant tremor, while others have none. Some progress very slowly, and a decade from diagnosis have barely any more symptoms - others progress more quickly. For many Parkinson's affects mainly movement while others have many non-motor symptoms. It is likely (although not yet proven) that these different subtypes of Parkinson's have a different underlying process causing them.
It therefore stands to reason that the earliest phases are also different. In our article we lay out the evidence that Parkinson's that comes from people with a particular kind of sleep disorder (REM sleep behavioural disorder), smell loss, and genetic forms do all look different. The evidence is not bomb-proof, but in Predict-PD we will be able to shed light on both the sleep disorder, smell loss and try and pick apart differences in the general population.
To see the article, please see the journal website. Please also remember to talk to friends and family to read more about the study and sign up themselves: www.predictpd.com
RNR
Sunday 18 November 2018
Friday 16 November 2018
Do thinking problems develop before Parkinson's?
Many of the blog posts from the PREDICT team have highlighted the fact that Parkinson's affects many more aspects of life than just movement. Whilst the core features are still thought of as slowing down, becoming stiff and developing tremor, problems such as constipation, sleep difficulties and thinking and memory problems are all commonly seen.
The thinking problems may even be present before diagnosis - testing for specific difficulties could be helpful in the efforts to pick up people at the earliest stages. This research paper used data from a large international study of healthy people who we know are at risk of Parkinson's including people with a sleep disorder strongly related to Parkinson's, people with smell loss and people with genetic mutations associated with Parkinson's.
They found that people with the sleep disorder performed worse on tests of attention and visual function than all the other groups. The groups with smell loss and genetic mutations performed at a similar level across tests and were comparable to people who had already developed Parkinson's. Unfortunately there was no comparison to people without these risk factors, so we can't make any conclusions about whether these groups perform worse than the general population.
I think this finding points to the fact that, just as Parkinson's disease is different in every individual, the route into the disease is also likely to be different. It is also helpful in pointing us towards the specific tests which may be useful in the earliest stages - we have included short tests of attention and memory in the new online PREDICT-PD study www.predictpd.com and I will be very interested to see how our findings compare to these results.
-anna
https://www.ncbi.nlm.nih.gov/pubmed/30125297
The thinking problems may even be present before diagnosis - testing for specific difficulties could be helpful in the efforts to pick up people at the earliest stages. This research paper used data from a large international study of healthy people who we know are at risk of Parkinson's including people with a sleep disorder strongly related to Parkinson's, people with smell loss and people with genetic mutations associated with Parkinson's.
They found that people with the sleep disorder performed worse on tests of attention and visual function than all the other groups. The groups with smell loss and genetic mutations performed at a similar level across tests and were comparable to people who had already developed Parkinson's. Unfortunately there was no comparison to people without these risk factors, so we can't make any conclusions about whether these groups perform worse than the general population.
I think this finding points to the fact that, just as Parkinson's disease is different in every individual, the route into the disease is also likely to be different. It is also helpful in pointing us towards the specific tests which may be useful in the earliest stages - we have included short tests of attention and memory in the new online PREDICT-PD study www.predictpd.com and I will be very interested to see how our findings compare to these results.
-anna
https://www.ncbi.nlm.nih.gov/pubmed/30125297
Cognition among individuals along a spectrum of increased risk for Parkinson's
disease.
Chahine LM, Urbe L, Caspell-Garcia C, Aarsland D, Alcalay R,
Barone P, Burn D, Espay AJ, Hamilton JL, Hawkins KA, Lasch S,
Leverenz JB, Litvan I, Richard I, Siderowf A, Coffey CS,
Simuni T, Weintraub D; Parkinson’s Progression Markers Initiative.
Several characteristics associated with increased risk for
Parkinson's disease (PD) have been identified, including specific genotypes and
various non-motor symptoms. Characterizing non-motor features, such as cognitive
abilities, among individuals considered at-risk for PD is essential to improving
prediction of future neurodegeneration.
METHODS: Participants belonging to the following cohorts of the Parkinson
Progression Markers Initiative (PPMI) study were included: de novo PD with
dopamine transporter binding deficit (n = 423), idiopathic REM sleep behavior
disorder (RBD, n = 39), hyposmia (n = 26) and non-PD mutation carrier (NMC;
Leucine-rich repeat kinase 2 (LRRK2) G2019S (n = 88) and glucocerebrosidase (GBA)
gene (n = 38) mutations)). Inclusion criteria enriched the RBD and hyposmia
cohorts, but not the NMC cohort, with individuals with dopamine transporter
binding deficit. Baseline neuropsychological performance was compared, and
analyses were adjusted for age, sex, education, and depression.
RESULTS: The RBD cohort performed significantly worse than the hyposmia and NMC
cohorts on Symbol Digit Modality Test (mean (SD) 32.4 (9.16) vs. 41.8 (9.98), p =
0.002 and vs. 45.2 (10.9), p<0.001) and Judgment of Line Orientation (11.3 (2.36)
vs.12.9 (1.87), p = 0.004 and vs. 12.9 (1.87), p<0.001). The RBD cohort also
performed worse than the hyposmia cohort on the Montreal Cognitive Assessment
(25.5 (4.13) vs. 27.3 (1.71), p = 0.02). Hyposmics did not differ from PD or NMC
cohorts on any cognitive test score.
CONCLUSION: Among individuals across a spectrum of risk for PD, cognitive
function is worse among those with the characteristic most strongly associated
with future risk of PD or dementia with Lewy bodies, namely RBD.
Wednesday 14 November 2018
Magnetic resonance T1w/T2w ratio: A parsimonious marker for Parkinson's disease
I love it when something simple yet really effective...
We are in an era when imaging and laboratory investigations are ever more complex and expensive, and here we have a wonderful study showing that a very simple, cheap and easily-obtained ratio from an MRI scan can be used to accurately diagnose Parkinson's. Importantly the researchers were not satisfied with showing this once and went on to demonstrate similarly impressive results in a separate patient and control group.
Now it is important for other researchers to replicate these findings and to work how far back they go... could it be used to detect people in the pre-symptomatic/pre-diagnostic phase??
Du G, Lewis MM, Sica C, Kong L, Huang X
Ann Neurol 2018 Nov 8
Objective
Newer MRI techniques have shown promise in capturing early Parkinson's disease (PD)‐related changes in the substantia nigra pars compacta (SNc), the key pathological loci. Their translational value, however, is hindered by technical complexity and inconsistent results.
Methods
A novel yet simple MRI contrast, the T1w/T2w ratio, was used to study 76 PD patients and 70 controls. The T1w/T2w ratio maps were analyzed using both voxel‐based and region‐of‐interest approaches in normalized space. The sensitivity and specificity of the SN T1w/T2w ratio in discriminating between PD and controls also were assessed. In addition, its diagnostic performance was tested in a subgroup of PD patients with disease duration ≤2 years (PDE). A second independent cohort of 73 PD and 49 controls was used for validation.
Results
Compared to controls, PD patients showed a higher T1w/T2w ratio in both the right (cluster size=164 mm3, p<0.0001) and left (cluster size=213 mm3, p<0.0001) midbrain that was located ventrolateral to the red nucleus and corresponded to the SNc. The region‐of‐interest approach confirmed the group difference in the SNc T1w/T2w ratio between PD and controls (p<0.0001). The SNc T1w/T2w ratio had high sensitivity (0.908) and specificity (0.80) to separate PD and controls (AUC=0.926), even for PDE patients (AUC=0.901, sensitivity=0.857, specificity=0.857). These results were validated in the second cohort.
Interpretation
The T1w/T2w ratio can detect PD‐related changes in the SN and may be used as a novel, parsimonious in vivo biomarker for the disease, particularly early stage patients, with high translational value for clinical practice and research.
Friday 9 November 2018
Why does Parkinson's cause constipation?
When people think of Parkinson's disease they often think of tremors however often people who actually have Parkinson's are more concerned by the symptoms that are not to do with movement and tremors (non-motor symptoms). The commonest of these symptoms are constipation, tiredness, difficulty sleeping, anxiety and needing to pass urine multiple times at night. These symptoms are not always as immediately obvious to people without Parkinson's but they can be extremely troubling. In this blog I want to talk a bit more about constipation and why people with Parkinson's get constipation.
Constipation is when it is more difficult to go for a poo or when the amount of time between opening your bowels increases. Usually your poo will become a lot harder when this happens and sometimes can result in a bloated feeling and pain in your tummy. So the question is how does Parkinson's, a brain disease, affect your bowels in this way?
The answer lies in looking at the large intestine. This is a large pipe near the end of the path from your mouth to your bum (the GI tract). By the time your dinner reaches the large colon it has mainly been digested and had all of the useful vitamins, protein and carbohydrates removed from it. This means that when your dinner reaches the large colon it is made up of waste products (poo) and lots of water; in fact it is so watery at this point that it is completely liquid. The role of the large colon is to turn this liquid into a solid poo and to get the water out of it so that you can stay hydrated. So what changes in Parkinson's disease?
In Parkinson's disease if you measure the amount of time it takes a piece of food to move from the beginning of the large intestine to exiting out of your bum it would take double the amount of time that it would take a healthy person. In other words: poo moves through the large intestine at half the speed if you have Parkinson's. Because the large intestine is so good at draining water from your poo, the poo becomes much drier and harder as the large intestine has double the amount of time to remove as much water as possible. This explains why people with Parkinson's have drier harder poos and subsequently have more constipation.
The large intestine pushes food along it by tensing the muscles around it in a rhythmic way that propels the poo downstream. Like the rest of the body, in Parkinson's, these movements become much slower. The reason for this is not as clear but is probably due to the layer of nerve cells around the gut wall called the enteric nervous system. Studies where they have looked at samples of the gut wall have found build ups of Lewy Bodies (the characteristic thing found in the brain in Parkinson's) also in the gut wall. It is possible that this build up is what also causes the slowness in the gut.
It is important to remember that there are many other things that cause constipation other than Parkinson's. There are many medications that can be tried to help improve constipation but some of the simple things that can help are increasing the amount of water you drink or increasing the amount of fibre that you eat, but discuss with your doctor if this is a problem for you.
Constipation is when it is more difficult to go for a poo or when the amount of time between opening your bowels increases. Usually your poo will become a lot harder when this happens and sometimes can result in a bloated feeling and pain in your tummy. So the question is how does Parkinson's, a brain disease, affect your bowels in this way?
The answer lies in looking at the large intestine. This is a large pipe near the end of the path from your mouth to your bum (the GI tract). By the time your dinner reaches the large colon it has mainly been digested and had all of the useful vitamins, protein and carbohydrates removed from it. This means that when your dinner reaches the large colon it is made up of waste products (poo) and lots of water; in fact it is so watery at this point that it is completely liquid. The role of the large colon is to turn this liquid into a solid poo and to get the water out of it so that you can stay hydrated. So what changes in Parkinson's disease?
In Parkinson's disease if you measure the amount of time it takes a piece of food to move from the beginning of the large intestine to exiting out of your bum it would take double the amount of time that it would take a healthy person. In other words: poo moves through the large intestine at half the speed if you have Parkinson's. Because the large intestine is so good at draining water from your poo, the poo becomes much drier and harder as the large intestine has double the amount of time to remove as much water as possible. This explains why people with Parkinson's have drier harder poos and subsequently have more constipation.
The large intestine pushes food along it by tensing the muscles around it in a rhythmic way that propels the poo downstream. Like the rest of the body, in Parkinson's, these movements become much slower. The reason for this is not as clear but is probably due to the layer of nerve cells around the gut wall called the enteric nervous system. Studies where they have looked at samples of the gut wall have found build ups of Lewy Bodies (the characteristic thing found in the brain in Parkinson's) also in the gut wall. It is possible that this build up is what also causes the slowness in the gut.
It is important to remember that there are many other things that cause constipation other than Parkinson's. There are many medications that can be tried to help improve constipation but some of the simple things that can help are increasing the amount of water you drink or increasing the amount of fibre that you eat, but discuss with your doctor if this is a problem for you.
Curr
Treat Options Neurol. 2018 Oct 25;20(12):54. doi:
10.1007/s11940-018-0539-9.
Gastrointestinal
Dysfunction in Parkinson's Disease.
Pfeiffer
RF
Author information
Abstract
PURPOSE OF REVIEW:
During the past
25 years, there has been an explosion of information regarding the
occurrence of gastrointestinal dysfunction in Parkinson's disease. In
this review, the clinical features of gastrointestinal dysfunction in Parkinson's disease will
be described and information regarding the potential role of the enteric
nervous system and the gut microbiome in the genesis of Parkinson's disease will
be addressed.
RECENT FINDINGS:
Recognition is
growing regarding the role that gastroparesis and small intestinal dysfunction
may play in Parkinson's disease, especially with regard to erratic
responses to anti-Parkinson medication. The presence of enteric nervous
system involvement in Parkinson's disease is now well
established, but whether the enteric nervous system is the starting point
for Parkinson's disease pathology remains a source of debate.
The potential role of the gut microbiome also is beginning to emerge.
Gastrointestinal dysfunction is a prominent nonmotor feature of Parkinson's disease and
dysfunction can be found along the entire length of the gastrointestinal tract.
The enteric nervous system is clearly involved in Parkinson's disease.
Whether it is the initial source of pathology is still a source of controversy.
There also is growing recognition of the role that the gut microbiome may play
in Parkinson's disease, but much more research is needed to fully
assess this aspect of the disorder.
Thursday 1 November 2018
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!
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!
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