Statins are famous, and their fame lies in their ability to bust cholesterol, the villain in many medical disorders such as heart attack (myocardial infarction) and stroke. Some may add that statins are infamous, and this is partly because of their side effects such as muscle pain. Love them or hate them, we can’t get away from statins…even as the debate rages about their benefits and downsides.
It is not surprising therefore that the statin debate will filter into neurology. The sticking point here however has nothing to do with cholesterol busting, but all to do with whether statins increase or reduce the risk of developing Parkinson’s disease (PD). Strange as it may seem, statins and PD have a long history. And a positive one generally, I hasten to add. There is a large body of evidence to suggest a protective effect of statins on PD as reflected in the following studies:
The authors of this paper set out to investigate ‘the controversy surrounding the role of statins in Parkinson’s disease’. In this retrospective analysis of over 2,000 people with PD, and a similar number of control subjects, theauthors found that statins significantly increased the risk of developing PD. This is clearly a conclusion looking for a fight!
I must admit I was totally unaware there was any controversy about statins and PD. I was therefore curious to find out what studies are out there fuelling it. Which other trials have bucked the trend and reported an increased risk of PD from statins? And where best to find the answers but in PubMed, the repository of all human knowledge! And I found that there were only a few studies that did not report a protective effect of statins on PD, and these studies concluded, quite reasonably, that they found no relationship between PD and statins. Here are a few of the studies:
These papers reporting the absence of evidence seem happy to engage in an amicable debate to resolve the question.
One study however stood out like a sore thumb because it positively reported a negative effect of statins on PD (try and work that out!). This 2015 study, also published in Movement Disorders, is titled Statins,plasmacholesterol, and risk of Parkinson’s disease: a prospective study. The paper concludes that “statin use may be associated with a higher PD risk, whereas higher total cholesterol may be associated with lower risk“. Not only are the authors arguing that statins are bad for PD, they are also suggesting that cholesterol is good! This is a paper that was itching for fisticuffs.
What is a jobbing neurologist to do? What are the millions of people on statins to do? Whilst awaiting further studies, I will say stay put. Go with the bulk of the evidence! And keep track of TheSimvastatin Trial, funded by TheCure Parkinson’s Trust. This trial is looking at the benefit of statins in slowing down PD. And surely, very soon, the science will lead to a resolution of the argument-all you need to do is keep track of everything PD in Neurochecklists.
Restless legs syndrome (RLS) does what it says on the can. Victims need to only sit or lie down for a few seconds before creepy-crawly sensations literally drive them up the wall. The discomfort is as insatiable as the urge to move is uncontrollable. It is, literally again, a nightmare; a frantic evening quickly followed by a frenetic night.
Neurologists rarely struggle to make the diagnosis of RLS. And with the efforts of support groups such as the RLS foundation, patients are now well-informed about the diagnosis. To the chagrin of the neurologists, patients often come with a list of medications they have tried, and failed.
The list of RLS risk factors is quite long. Some of these are modifiable, and the ‘must-exclude’ condition here, iron deficiency, requires checking the level of ferritin in blood. Other modifiable risk factors are quite diverse such as obesity, migraine, and even, surprisingly, myasthenia gravis (MG). Most RLS risk factors, such as peripheral neuropathy and Parkinson’s disease (PD), are unfortunately irreversible; in these cases some form of treatment is required.
Parkinson’s disease (PD) is probably the most iconic neurological disorder. It has diverse manifestations, typical of many neurological diseases. PD is a result of brain dopamine deficiency, and its clinical picture is dominated by motor symptoms- tremor, rigidity and bradykinesia (slowing of movements). It however also manifests with a variety of non-motor symptomswhich rival the motor symptoms in their impact. PD is responsive to treatment with several oral medications such as levodopa, infusions such as apomorphine, and interventions such as deep brain stimulation (DBS).
Regardless of the intervention used, PD is a neurodegenerative disorder that grinds, slowly and steadily, along a chronic progressive course. This often manifests with disabling features such as freezing, hallucinations, and dyskinesias (drug-induced writhing movements). These symptoms creep or barge in unannounced, challenging the wits of the neurologist, and pushing the resolve of patients and their families to the limit. What hope does research offer to smooth the journey for people with PD? Here are my top 7.
1. Increasing evidence for the benefit of exercise
Dyskinesias are abnormal, fidgety movements that develop as side effects of the drugs used to treat PD. Most people with dyskinesias are not overly concerned about the movements because the alternative, disabling freezing and immobility, is worse. Dyskinesias are however energy-sapping, and are distressing for family members. Amantadine is one drug neurologists add-on to improve dyskinesias, but many people do not tolerate or benefit from this. The suggestion that lithium may help dyskinesias is therefore welcome news. The report comes from a study in mice reported in the journal Brain Research titled The combination of lithium and l-Dopa/Carbidopa reduces MPTP-induced abnormal involuntary movements (AIMs). A long way to go yet, but hope.
What a great thing, the blood-brain barrier, protecting the brain from all the bugs and toxins running amok in the bloodstream. This iron-clad fence unfortunately also effectively keeps out, or limits the entrance of, many beneficial drugs which need to get to the brain to act. As with all borders however, there are always people ready to break through, without leaving any tracks behind. And the people in this case are neurosurgeons who have successfully bypassed the blood brain barrier, and safely ‘transported’ PD drugs in to the brain. They did this by removing a portion of the blood brain barrier of mice, and replaced it with a piece of the tissue which lines the inside of the nose, a procedure called nasal mucosal grafting. They then delivered glial derived neurotrophic factor (GDNF), a protein that treats PD in mice, across the graft. The neurosurgeons explained all this in their paper titled Heterotopic mucosal grafting enables the delivery of therapeutic neuropeptides across the blood brain barrier. You may however prefer the simpler version from the Boston Business Journal (can you believe it!) titled A new way to treat Parkinson’s disease may be through your nose.It will however take time before human trials of nasal mucosal grafting…this is science after all, not science fiction!
6. Fetal stem cell transplantation
It doesn’t seem too long ago when all ethical hell broke loose because some scientists were transplanting fetal tissue into human brains. I thought the clamour had put this procedure into the locker, never to be resurrected. Apparently not; fetalstem cell transplantation (SCT) is back, reminiscent of Arnold Schwarzenegger in the Terminator films. Learn more of this comeback in this piece from New Scientist titled Fetal cells injected into a man’s brain to cure his Parkinson’s. The work is from Roger Barker‘s team at the University of Cambridge, and they are planning a big study into this named TRANSNEURO. Watch this space
7. Pluripotent stem cell transplantation
The future of stem cell transplantation probably lies with pluripotent, rather than fetal cells. The idea is to induce skin cells, called fibroblasts, to transform into dopamine-producing cells. Fibroblasts can do this because they are pluripotent cells; that is they are capable of becoming whatever type of cells you want, so long as you know the magic words. In this case, the words are likely to be the transcription factors Mash1, Nurr1 and Lmx1a. Beats ‘open sesame‘, and surely less controversial than fetal cells. Researchers are taking this procedure very seriously indeed, setting out ground rules in articles such as Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. This was publishedin the journal Nature, but you may prefer the easier read in New Scientist titled Brain cells made from skin could treat Parkinson’s. But don’t get too excited…pluripotent stem cell transplantation is barely at the starting line yet.
There is so much more going on in the field of Parkinson’s disease to cover in one blog post. I will review neuroprotection in Parkinson’s disease in a coming post. In the meantime, here are links to 12 interesting articles and reviews on the future of PD:
Neurology is a broad specialty covering a staggering variety of diseases. Some neurological disorders are vanishingly rare, but many are household names, or at least vaguely familiar to most people. These are the diseases which define neurology. Here, in alphabetical order, is my list of the top 60 iconic neurological diseases, with links to previous blog posts where available.
The Neurology Lounge has a way to go to address all these diseases, but they are all fully covered in neurochecklists. In a future post, I will look at the rare end of the neurological spectrum and list the 75 strangest and most exotic neurological disorders.
Multiple system atrophy (MSA) is a mimic of Parkinson’s disease (PD). Neurologists suspect MSA in people with apparent PD who, in addition, have other defining features. In many people with MSA their prominent symptoms are cerebellar dysfunction (MSA-C), and these have unsteadiness and incoordination of movements. In other people with MSA the predominant symptoms are of Parkinsonism, and this type is called MSA-P.
Making a diagnosis of MSA is gratifying, but treating it is frustrating. Only about a third of people with MSA respond to the standard PD medication, Levodopa. Furthermore, MSA confers a shortened life expectancy. It is therefore important that neurologists resolve the mystery of MSA, and they are indeed hacking away at its cutting-edge.
The general assumption is that MSA is acquired rather than inherited. This assumption did not dissuade neurologists from looking for MSA genetic risk factors, and their quest has led to the discovery of a candidate MSA gene. This is called coenzyme Q2 4-hydroxybenzoate polyprenyltransferase, or simply the COQ2 gene. This gene was first touted in a 2013 paper in the New England Journal of Medicine titled Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy. Using whole genome sequencing, the authors identified COQ2 gene mutations in both sporadic and familial cases of MSA. Another paper in Neurology in 2016, titled New susceptible variant of COQ2 gene in Japanese patients with sporadic multiple system atrophy, reported that the COQ2 gene mutation is more likely in MSA-C than in other types of MSA.
When neurologists are considering the diagnosis of MSA, they come up against many disorders jostling to confuse them. There are of course PD and related conditions such as progressive supranuclear palsy (PSP). There is also the endless list of conditions which cause either cerebellar or autonomic dysfunction. The neurologist is usually cautious to exclude these known differential diagnoses of MSA. But what happens when they come across a mimic that isn’t in the textbooks? Such is the situation with this case report published in Movement Disorders of Concomitant Facioscapulohumeral Muscular Dystrophy and Parkinsonism Mimicking Multiple System Atrophy.
This case defies the law of parsimony, Occam’s razor. To paraphrase, this law states that a single diagnosis is the most likely cause for a patient’s clinical features. Clearly in some cases such as this, the neurologist must disregard William of Occam,and make multiple diagnoses.
Neurologists often request some tests to confirm their suspicion of MSA. The usual investigation is the painless but claustrophobic magnetic resonance imaging (MRI). In MSA, this shows shrinking or atrophy of the cerebellum. It may alsoshow the hot cross bun sign, a characteristic pattern of shrinking of the chunky middle section of the brainstem, the pons.
Some neurologists are not satisfied with this culinary sign and have explored other radiological indicators of MSA. They studied an MRI technique called diffusion tensor imaging tractography (DTI tractography) and reported their findings in the Journal of Neurology. Their paper titled Characteristic diffusion tensor tractography in multiple system atrophy reports that DTI tractography appears to distinguish MSA-C from other causes of cerebellar dysfunction.
Biomarkers again, so soon after my previous blog post, What is the state of parkinson’s disease biomarkers. The whole idea behind biomarkers is their potential to make for an easier and earlier diagnosis. They are all the rage in neurodegenerative diseases, and MSA can’t be an exception. The first potential MSA biomarker is α-synuclein, the abnormal protein that is found in the brains of people with PD, MSA and Lewy body disease (LBD), the so-called synucleopathies. Researchers have now discovered that α-synuclein also resides in the skin. They carried out skin biopsies in people with PD and MSA and found skin deposits of α-synuclein in both. Writing in the journal Movement Disorders, they showed that in PD, the deposits were mainly in autonomic nerve fibers, whilst in MSA they were in the larger somatic nerves. Time to brush up those skin biopsy skills!
The second potential biomarker is optical coherence tomography (OCT). This is reported in Movement Disorders in a paper titled Progressive retinal structure abnormalities in multiple system atrophy. The authors used OCT to measure the thickness of the retina of the eye. They demonstrated that the retina is thin in both PD and MSA, but the thinning advances more rapidly in MSA than in PD. If confirmed, this would be a handy, and painless, biomarker.
The objective of all research is to arrive at effective treatments. There is unfortunately no bright treatment looming in the MSA horizon because the research so far have produced disappointing results. Such failures include Rifampicin, Fluoxetine and Lithium. There is however no scarcity of potential therapeutic candidates. The most exciting is a vaccine against MSA. For this and other research efforts read this excellent review in Advances in Clinical Neurology and Rehabilitation (ACNR) titled Updates on potential therapeutic targets in MSA.
Neurologists are always cautious when making a diagnosis of Parkinson’s disease (PD). This shouldn’t be the case because PD is not difficult to recognise-at least not most of the time. For one, PD has classical clinical signs- the trio of resting tremor, slow movements (bradykinesia), and stiffness (rigidity). For another, it is asymmetrical, starting and remaining worse on one side of the body.
All these features are however vague in the early stages of PD. To make matters worse, there are many other diseases that mimic PD. These include multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Lewy body disease (LBD), corticobasal degeneration (CBD), and even SWEDDS (if it exists at all!). And always lurking in the shadows, waiting to catch the neurologist out, are dystonic tremor and essential tremor.
These PD mimics challenge and intrigue neurologists in equal measure. They contribute to the delayed and missed diagnosis of PD in 20% of cases. Are there shortcuts out there to improve our diagnostic accuracy? A simple test perhaps? Maybe some biomarker? Here are 6 budding contestants.
1. Dopamine transporter (DAT) scans
DAT scans are now in general, even if not universal, use. They help to distinguish PD from conditions such as essential tremor or drug-induced Parkinsonism. DAT scans are however expensive, and they do not distinguish PD from many of its other mimics such as MSA, PSP, (you know the roll call). There are indications that DAT scans may be normal in cases of PD. We therefore clearly need better, cheaper (and newer!) PD biomarkers than DAT scans.
2. Cerebrospinal fluid (CSF) biomarkers
Perhaps the answer is in a spinal tap or lumbar puncture (LP). A lumbar puncture is a simple but dreaded test. It is however useful for giving us access to the cerebrospinal fluid (CSF) that bathes the brain and spinal cord. Analysis of the CSF often gives the game away in many neurological disorders. It is not surprising therefore that researchers looked at a panel of nine CSF biomarkersthat may identify PD. The paper, published in the JNNP, suggests that there may be biomarker roles for neurofilament light chain (NFL), soluble amyloid precursor protein (sAPP), and α-synuclein (of course). CSF α-synuclein is the focus of another paper in BioMedCentral whichreports that one form, oligomeric α-synuclein, is theone to watch out for.
Another set of CSF biomarkers is related to blood vessel formation (angiogenesis). I came across this in a paper in Neurology titled Increased CSF biomarkers of angiogenesis in Parkinson disease. The authors are referring to vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2. Others are placental growth factor (PlGF), angiopoietin 2 (Ang2), and interleukin-8. Enough to keep researchers busy for a while.
3. Peripheral blood biomarkers
Even the most compliant patient would prefer to have a blood test rather than a spinal tap. Thankfully there are some blood-based biomarkers in the offing. One set are called α-synuclein blood transcripts (SNCA transcripts). The authors of an article published in the journal Brain report that SNCA transcripts are consistently reduced in the blood of people with early PD. The accompanying editorial however cautions on the utility of these SNCA transcripts because low levels are also seen in some people who do not have PD. The true value of SNCA transcripts may lie in their ability to predict cognitive decline, but how many people really want to know that?
Other potential blood based biomarkers mentioned are uric acid and epidermal growth factor (EGF).
4. Retinal optical coherence tomography (OCT)
Even better than blood and spinal fluid biomarkers would be something totally painless. And to the rescue comes retinal optical coherence tomography (OCT). OCT uses light waves to take pictures of the retina. This allows measurement of the size of different parts of the retina; the area of interest in PD is called the foveal pit. A paper in Movement Disorders reports that OCT is a sensitive marker of PD. The authors show that the foveal pit in PD has a unique form; it is shallow in the superior-inferior and the nasal-temporal slopes. Perhaps neurologists will soon be running to ophthalmologists, cap-in-hand, to save their blushes.
5. Salivary gland α-synuclein
Back to painful biomarkers I’m afraid, all in aid of clinching an early diagnosis you must understand. This time it’s salivary gland biopsy. Some eager researchers took biopsy samples of the submandibular salivary glands of people with early PD. They then looked for, and found, α-synuclein in about 75% of them. Their paper is published in Movement Disorders titled Peripheral Synucleinopathy in Early Parkinson’s Disease: Submandibular Gland Needle Biopsy Findings. Unfortunately 20% of control subjects without PD also had α-synuclein in their salivary glands. Could these people have pre-manifest PD? We must await larger and longer studies before we start needling away at the salivary glands of the worried-well.
Neurologists do not break into a sweat when they make the diagnosis of essential tremor (ET). Theoretically, at least, they shouldn’t. Essential tremor presents with an obvious shaking of the hands when performing tasks; this is unlike the tremor of Parkinson’s disease which is typically at rest. Neurologists also have handy evidence-based treatment guidelines which recommend medications such as Propranolol and Primidone.
Essential tremor is however anything but straightforward. Tremor is a feature of many other medical and neurological diseases. Neurologists also know that essential tremor may mimic Parkinson’s disease and dystonic tremor. To muddy the waters further, essential tremor also has non-motor symptoms such as cognitivedifficulties. And to add to the frustration, the touted evidence-based treatments, when tolerated, rarely work well enough. These twists and turns that accompany essential tremor are the reasons a review article in Practical Neurology labelled it ‘deceptively simple‘. This deception extends to the core puzzle in essential tremor-what causes it? Here are two tantalising suggestions which attempt to answer this question.
Is essential tremor a neurodegenerative disease?
Neurodegeneration is the usual suspect when neurologists are looking for ‘a cause’. With essential tremor the focus has been on the cerebellum, the part of the brain that co-ordinates movements. This is logical because tremor is a classical symptom of diseases of the cerebellum. This link, circumstantial as it is, has led researchers to interrogate the cerebellum in essential tremor. In doing this they also wondered if the problem is neurodegenerative. The logic behind this line of thinking is explained in a paper published in JAMA Neurology in 2009 titled, Essential tremors: a family of neurodegenerative disorders?
Pursuing this lead, some researchers have tried to hone down on which of the different types of cerebellar cells is involved in essential tremor. Writing in the journal Movement Disorders, the authors are convinced that the seat of neurodegeneration in essential tremor is the Purkinje cell. Purkinje cells are unique cerebellar cells which are vulnerable to all sorts of insults. The researchers in this case demonstrated significantly fewer Purkinje cells in the brains of people with essential tremor than in control subjects without the disease. And they attributed this pathology to neurodegeneration (what else?). The answer to a long-standing riddle, or a hasty conclusion?
Is essential tremor a channelopathy?
Neurologists have known for a long time that essential tremor has a strong genetic element. The diagnosis always feels more certain when there is another family member with tremor. The exact nature of this genetic link is however uncertain. Into this void comes a research paper suggesting that people with essential tremor may have abnormal cellular channels. Channels are proteins in the cell wall that let electrolytes like sodium and potassium in and out, and channelopathies are diseases that affect these channels. The authors of this paper studied a large essential tremor family who also suffer with epilepsy, a typical channel disorder. And the genetic tests they carried out revealed an abnormality in the SCN4A sodium channel. Correlation or causation? The mystery only deepens, I think.
As researchers dig deeper, they will have to decide if it’s neurodegeneration or channelopathy. Or perhaps both. This may then open the doors to better treatments for the disease, confining Propranolol and Primidone to the history books.