The last time I wrote about Parkinson’s I had not yet become Doc Gumshoe. It was quite a few years ago, and I was working on a continuing medical education project in support of donepezil (Aricept, from Eisai/Pfizer). Aricept, as you may know, is one of a very few drugs approved for the treatment of Alzheimer’s. My particular CME project had nothing to do with Alzheimer’s, but focused on the mechanism of action of donepezil/Aricept, and how it could be effective in minimizing certain of the effects of Parkinson’s. And it was that mechanism that took me into the thicket of Parkinson’s. We will make our way into that thicket later on.
One particular little patch of that thicket is why there are two terms attached to Parkinson’s. Parkinson’s Disease is one term, and Parkinsonism is the other. Why are there two terms? Do they basically mean the same thing? If not, how are they different?
Here’s what my Harrison’s Principles of Internal Medicine, usually my Bible, has to say on the subject:
“Parkinsonism is a syndrome consisting of a variable combination of tremor, rigidity, bradykinesia, and a characteristic of gait and posture. Parkinson’s disease is a chronic progressive disorder in which idiopathic Parkinsonism occurs without evidence of more widespread neurologic involvement.”
That would imply that in Parkinsonism, in contrast with Parkinson’s disease, there is evidence of a more widespread neurologic involvement. But how is that idiopathic Parkinsonism?
The American Parkinson’s Disease Association, in their website, just says:
“ ‘Parkinsonism’ means ‘looks like Parkinson’s disease.’ To neurologists this means that the person has a somewhat flexed posture, moves slowly, is stiff and usually walks slowly, with small steps and reduced or no arm swing.”
They go on to note that persons with Parkinsonism respond less well to levodopa, a drug that is frequently used not only to treat Parkinson’s Disease, but to confirm the diagnosis – that is, if the patient responds to levodopa, it’s likely to be Parkinson’s Disease, and if not, then not Parkinson’s Disease.
Another distinction is that if a person with the characteristic movement disorder also experiences dementia, then that person is considered to have Parkinson’s disease and not just Parkinsonism.
Unless there’s a need to distinguish one from the other, I will stay with a more general term: “Parkinson’s.”
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What are the symptoms of Parkinson’s?
Let’s start with the obvious symptoms. These are mostly related to movement; sometimes your muscles are doing things without your telling them to, or else failing to do the things you ask them to do. You find that your hands tremble even when you’re trying to keep them steady. Your thumb and forefinger rub together, as though you are rolling little pills. You may also find that when you try to move your arms or legs, you have to exert yourself to overcome a sense of rigidity. And sometimes when you move your limbs, instead of a smooth movement, you find that you are moving in little rachety bursts, with stops in between, almost as though your muscles were controlled by an escapement mechanism, like the second hand of an old wind-up clock. Those types of rigidity are known as “lead-pipe rigidity” and “cog-wheel rigidity.”
Persons with Parkinson’s are most commonly affected by bradykinesia, meaning slowness of movement. Instead of walking with normal steps and a normally erect posture, swinging their arms in contrary motion with their feet, they take small steps and walk with a hunched-over posture. Sometimes it looks as though they are running, although with tiny steps. This is called “festination.” My guess is that comes from the Latin phrase, festina lente, which means “make haste slowly.” However, they may also be subject to sudden stops in their motion, as though their feet had gotten stuck to the floor.
Another common feature of Parkinson’s is muddled rotational behavior – for example, if turning from the stove to the kitchen sink requires a quarter turn to the right, people with Parkinson’s are apt to do a three-quarter turn to the left. Similarly, Parkinsonians standing and having a conversation may appear to be doing a little dance with the person they are conversing with.
As the disease progresses, Parkinson’s tends to bring on postural instability and an impaired sense of balance. This leads to frequent falls and, in consequence, more broken bones and reduced mobility.
Parkinsonism also affects speech, facial expression, and manual dexterity. Persons with advanced Parkinson’s tend to speak indistinctly in a monotone and lack facial expression. And their handwriting tends to get smaller and more cramped as the disease progresses.
Why does this happen?
The precise cause of Parkinson’s is not known, but the question of what’s going on in the brain to bring about the symptoms has at least been answered at the most general level. When we want to do something – walk, tie our shoelaces, pick up a coffee mug – the instructions go from the motor cortex through a number of brain segments and are sent to the other parts of the body via the corticospinal tracts. These are sometimes referred to as the pyramidal tracts because of their pyramid-like structure in the medulla oblongata.
Parkinson’s is sometimes called an extrapyramidal disorder, because those instructions to the muscles do not come in the normal way through the corticospinal tracts. There is a loss of dopaminergic projection from the substantia nigra, a part of the brain central to motor control. And also, there is a loss of dopamine receptor stimulation and an increase in dopamine receptor inhibition. Inhibition of the thalamus is abnormally increased, and movements initiated by the cerebral cortex are not facilitated.
(I acknowledge that the explanation above is far from crystal clear. Perhaps it is enough to say that the transmission of instructions in the brains of people with Parkinson’s is thoroughly messed up.)
One of the mechanisms that bring about the symptoms of Parkinson’s is the loss of neurons in the midbrain. These neurons normally provide dopamine input to a part of the brain that is critical in movement control. Loss of these neurons and depletion of dopamine are related to a diminishing of the function of the motor cortex. By the end of their lives, persons with Parkinson’s experience cell death in up to 70% of the dopamine-releasing neurons. Some others neurotransmitters are similarly depleted, including norepinephrine, which can contribute not only to the movement disorders, but also to depression, which is another frequent Parkinson’s symptom.
So, although the root cause of Parkinson’s remains unknown, dopamine depletion is a feature that clinicians can readily address, and treatment with levodopa (about which a great deal more later) has become the standard.
Another characteristic of Parkinson’s is the presence of granules known as Lewy bodies in various parts of the brain. This is especially associated with dementia, which we’ll discuss later.
Possible causes of Parkinson’s
Here’s an exceedingly rare instance of when smoking may actually be good for you. Smokers evidently have a reduced lifetime risk of developing Parkinson’s. Why this should be is unclear. To a lesser degree, a lifetime of indulging in caffeinated drinks apparently is also linked with a reduced risk of Parkinson’s. Note that the risk reductions from smoking and coffee-drinking are not sufficient for clinicians to tell their patients to go ahead and get a cup of coffee and a cigarette. But increased exposure to pesticides is linked with an increased risk of developing Parkinson’s. A history of head injury has also been associated with Parkinson’s.
Parkinson’s is quite strongly associated with genetic factors. About 15% of persons with Parkinson’s have a first-degree relative who has the disease, and perhaps 10% of Parkinsonians have some form of the disease that is due to mutation in one of several specific genes. Having any one of these possible mutations, of which at least 17 have been identified, increases the risk of developing Parkinson’s. Mutations in one particular gene, labeled GBA1, increase the likelihood of Parkinson’s by a factor of 20 or 30. In the population at large, about 1% have a GBA1 mutation, but in persons with Parkinson’s, about 5% have that mutation.
As noted earlier, brain cell death is an underlying characteristic of Parkinson’s, and an immediate cause of the symptoms. A likely mechanism consists of an accumulation of a protein called alpha-synuclein bound to ubiquitin in the brain cells, forming insoluble proteins termed Lewy bodies. As Lewy bodies accumulate in sections of the brain, symptoms of Parkinson’s gradually appear. The earliest symptoms may be non-motor symptoms. For example, if the Lewy bodies appear in the olfactory bulb, the individual may experience a loss of the sense of smell. If they appear in other parts of the brain – the medulla oblongata, or the pontine tegmentum – the individual may lose some automatic functions, like blinking, or the ability to fall asleep.
Lewy bodies are especially common in the cortical areas of persons with dementia, including dementia with Parkinson’s and some other forms of dementia. The neurofibrillary tangles and amyloid plaques that are commonly seen in persons with Alzheimer’s disease are not generally present in individuals with Parkinson’s. It is not impossible, however, for certain individuals to be affected by both conditions.
Thus, Parkinson’s appears to perpetrate its harms through two distinct mechanisms. First, the death of brain cells that support the distribution of dopamine, and thus, the critical lack of dopamine in the brain, has a direct causative effect on the Parkinson’s related movement disorders. Also, the proliferation of Lewy bodies leads to increasing dementia as Parkinson’s progresses. The specific mechanisms through which Lewy bodies cause dementia are not fully understood; it may be as simple a matter as interruption of communication between neurons. Or it may be something more complex.
Diagnosis of Parkinson’s
Even though the site of Parkinson’s pathology is the brain, brain imaging has mixed results in the diagnosis of Parkinson’s. Computed tomography (CT) scans of Parkinson’s patients usually appear normal. Magnetic resonance imaging (MRI) has the capacity to distinguish patterns in the brain that are characteristic of Parkinson’s. CT and MRI may be used to rule out other diseases, such as encephalitis and transient ischemic events, that can be secondary causes of some Parkinson’s symptoms.
The key pathological mechanism of Parkinson’s, at least with regard to motor disorders, is a marked decline in dopamine transport in the basal ganglia. This can be accurately observed and measured with positron emission tomography (PET) scans and single-photon emission computerized tomography (SPECT) scans. A specific diagnostic test for Parkinson’s was approved by the FDA in 2011. In this test, and injection of Ioflupane I 123 (also known as phenyltropane) is followed by a SPECT scan. This test, the DaTScan, is FDA approved specifically as a means of distinguishing Parkinson’s from essential tremor, a disorder not linked with dopamine deficiency. The specific target of the test is the dopamine transport mechanism. This test does not distinguish Parkinson ’s disease from Parkinsonism. However, in cases where a potentially risky procedure is being contemplated, such as deep brain stimulation surgery (of which more later) it can be important to distinguish between Parkinson’s and essential tremor. It needs to be pointed out that DaTScans need to be performed by highly experienced clinicians, because interpretation of the results is entirely by eye. There are no hard numbers on which to base the diagnosis.
Because deficiency in dopamine transport is an essential feature of Parkinson’s, a frequent diagnostic procedure is directed specifically at that mechanism. Administering levodopa to individuals with Parkinson’s-like symptoms and checking for improvement in these symptoms helps to confirm the Parkinson’s diagnosis. Significant improvement in motor symptoms after dosing with levodopa suggests that the individual in question is affected by Parkinson’s disease, and not the less precise Parkinsonism diagnosis, since response to levodopa is one of the distinctions between those two terms.
Dementia related to Parkinson’s disease
Having Parkinson’s disease increases a person’s chances of becoming demented by two to six times over the population at large. Nearly 80% of people with Parkinson’s have some dementia, with the ensuing consequences to the quality of life of patient and caregivers.
Dementia associated with Parkinson’s disease leads to executive dysfunction, which includes difficulties with a great many essential daily life activities including planning, abstract thinking, rule acquisition, inhibition of inappropriate actions, working memory, and attention. Behavior is also affected, including impulse control disorders, which can lead to pathological gambling, compulsive sexual behavior, binge eating, reckless generosity, and compulsive shopping.
Persons with Parkinson’s disease may also experience mood alterations, such as depression, apathy, and anxiety. About a third of Parkinson’s disease patients may have generalized anxiety disorders including social phobia, panic disorders, and obsessive-compulsive disorders. At some point, nearly half of individuals with Parkinson’s disease experience hallucinations or delusions. In some patients, this may progress to paranoid ideation.
Parkinson’s dementia is considerably different than, for example, Alzheimer’s dementia, which is primarily limited to memory. Parkinson’s disease dementia can overlap with deficits in a number of other functions, such as sleep disorders and disturbances in the autonomic nervous system, which can cause episodes of dangerously low blood pressure, urinary incontinence, constipation, an impaired sense of smell, disturbed vision, pain, tingling, and numbness.
Any and all of the symptoms of Parkinson’s dementia can emerge years before the full emergence and diagnosis of the disease.
Parkinson’s Treatment Options
The first words in many discussions of this topic are often “There is no cure for Parkinson’s” or some variation of that. That sounds like the tolling of the funeral bell. However, the progression of Parkinson’s is slow. The age at which a person is likely to begin experiencing the symptoms of Parkinson’s is about 60 years, and sometimes later. And many people live for 20 years or longer with Parkinson’s.
The objectives of the treatment options for Parkinson’s are the slowing and, to whatever extent is possible, controlling the symptoms of Parkinson’s – both the motor symptoms and those relating to dementia. Because dopamine depletion is the immediate cause of the Parkinson’s-related movement disorders, drugs that in some way address the dopamine deficit are the basis for treatment.
The immediate obstacle facing clinicians in overcoming the dopamine deficit is that dopamine itself does not cross the blood-brain barrier; thus, it cannot be given directly to patients. However, levodopa, which is a precursor of dopamine, does to some extent (5% to 10%) pass through the blood-brain barrier and enters the brain where it is converted to dopamine. The action of levodopa, at least for a time, diminishes the motor symptoms of Parkinson’s.
Levodopa is always given with another agent, a dopa decarboxylase inhibitor, and sometimes also with a catechol-o-methyl transferase (COMT) inhibitor. These agents are used to extend the effectiveness of levodopa, which on its own tends to taper off quickly.
Sometimes the initiation of levodopa treatment is deferred so as to postpone the inevitable onset of levodopa’s side effects. Alternative agents are monoamine oxydase inhibitors and dopamine agonists. Clinicians are warned that the initiation of levodopa therapy should not be postponed for too long, as the motor symptoms of Parkinson’s increase in the patient and the patient’s quality of life is adversely affected.
The adverse effects produced by levodopa are a direct consequence of the percentage of the drug that does not pass the blood-brain barrier. That portion of the drug travels to other parts of the body, where it causes a wide variety of side effects, including hallucinations, excessive fatigue, nausea and vomiting, fast or irregular heart-beat, dizziness when changing from a sitting to a standing position, high blood pressure, convulsions, fever, and involuntary movements.
Long-term users of levodopa may experience fluctuations in its effectiveness. A person with Parkinson’s can cycle through phases with good response to the drug and reduced symptoms – the so-called “on” state – and also through phases with poor response to the drug and worse symptoms – the “off” state. Long-term levodopa users may also develop involuntary movements called dyskinesias. However, withdrawing levodopa treatment during the “off” state or in response to dyskinesias is in itself risky, since it may trigger other dangerous side effects.
Levodopa is a naturally-occurring amino-acid isomer; dopamine was synthesized from this isomer in the early 20th century, and in the years prior to World War II an enzyme was discovered in kidney tissue that converted levodopa to dopamine. Despite its shortcomings, levodopa has been the most commonly used treatment for Parkinson’s for about 50 years.
A number of dopamine agonists are used to defer the initiation of levodopa treatment. Among these are bromocriptine, pergolide, pramiprexole, ropinirole, pribedil, cabergoline, apomorphine, and lisuride. These agents are not as effective as levodopa itself in managing Parkinson’s motor symptoms, but in the initial stages of Parkinson’s, they may be preferable to levodopa itself, with all its attendant adverse effects.
The dopamine agonists themselves are not without adverse effects. These include drowsiness, hallucinations, insomnia, and constipation. In some cases, dopamine agonists have been associated with impulse control disorders, which may include a range of compulsive activities such as shopping, eating, gambling, and sex.
Another class of drugs used to postpone the initiation of levodopa therapy are the monoamine oxidase B (MAO-B) inhibitors. Monoamine oxidase B is an enzyme that breaks down dopamine, serotonin, and other neurotransmitters, so inhibiting that enzyme favors the action of those neurotransmitters. However, these agents produce more adverse effects and are generally less effective than levodopa in controlling the motor symptoms of Parkinson’s. MAO inhibitors were among the earliest drugs used to treat depression.
Treatment for Parkinson’s-related dementia
Dementia is a common feature of Parkinson’s, especially in older patients with Parkinson’s disease of long standing. The prevalence of dementia in Parkinson’s is about six times higher than in the general population, and depending on the definition of dementia and study design, this prevalence ranges as high as 93% in patients with Parkinson’s. Overall, the prevalence of dementia in Parkinson’s is about 40%. There is a degree of uncertainty regarding the diagnoses of Parkinson’s-related dementia versus dementia with Lewy bodies; some authorities prefer the latter diagnosis if the onset of dementia occurs within 12 months of the onset of Parkinson’s symptoms.
A characteristic of Parkinson’s dementia is a deficit in cholinergic activity in the brain. Acetylcholine, a vital neurotransmitter, is essential to the functioning of both the central nervous system and the peripheral nervous system. Cholinergic projections from the basal forebrain to the cerebral cortex and the hippocampus are central to cognitive functioning in those areas. In the peripheral nervous system, acetylcholine activates muscles and is a major neurotransmitter in the autonomic nervous system. In other words, acetylcholine is vital to cognition and also to the normal functioning of such essential nervous system functions as breathing and heart-beat.
An enzyme, acetyl cholinesterase, converts acetylcholine into its inactive metabolites. This is essential for proper muscle function. But disruption of the supply of acetylcholine to the neocortex impairs learning of simple tasks and the acquisition of factual information, while disruption to the hippocampus and adjacent cortical areas in the brain produces a reaction similar to amnesia. Thus, excessive activity of that enzyme may lead to cognitive defects related to dementia.
That relationship has led investigators to evaluate the possible effectiveness of inhibiting cholinesterase as a means of mitigating dementia. A cholinesterase inhibitor, rivastigmine, (Exelon, from Novartis) was compared with placebo in a 2010 study enrolling 541 patients. (Maidment I, Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004747.) Rivastigmine produced statistically significant and clinically meaningful improvements in cognitive function in treated patients, while about 10% of patients receiving placebo experienced meaningful worsening of cognition. However, tolerability was a significant issue. A higher proportion of patients treated with rivastigmine dropped out of the study due to adverse effects, including nausea, tremor, and vomiting. At the same time, significantly fewer patients receiving rivastigmine died during the study than subjects receiving placebo.
Another cholinesterase inhibitor, donepezil (Aricept, from Eisai/Pfizer), which I mentioned in the opening paragraph of this piece, is effective in preventing cognitive decline in patients with Parkinson’s. A paper in 2002 (D. Aarsland, J Neurol Neurosurg Psychiatry. 2002 Jun;72(6):708-12.) demonstrated clearly that treatment with donepezil resulted in significantly improved scores on a widely used assessment tool, the mini mental state examination (MMSE). At the conclusion of the study, 42% of subjects treated with donepezil had improved MMSE scores, versus 17% of subjects in the placebo group. Improvements in MMSE scores are considered highly meaningful in patients with Parkinson’s, since in such patients the norm tends to be steady decline in cognitive abilities.
A more recent study confirmed that donepezil definitely slowed cognitive decline in Parkinson’s patients. Despite that benefit, donepezil had no effect with regard to prevention or delay of the onset of psychosis in these patients. (Sawada H., J Neurol Neurosurg Psychiatry. 2018 Dec;89(12):1332-13400). In the study population, about 40% of subjects with non-demented Parkinson’s had visual and auditory hallucinations and delusions. Psychosis, according to the principal author, can be triggered by a number of conditions such as inflammation, and also by several medications including dopamine agonists, anticholinergic drugs, or amantadine (Symmetrel). Amantadine has been used as an antiviral and is sometimes used as treatment for the early stages of Parkinson’s. It has also been used to minimize the involuntary movement disorders that sometimes emerge with levodopa use.
Amantadine addresses the n-methyl-d-aspartate (NMDA) receptor. Another drug also addressing that receptor is memantine (Namenda, Forest Laboratories; many generics available). Memantine is also one of the drugs FDA-approved for treating Alzheimer’s. It has demonstrated modest effectiveness in addressing some of the Parkinson’s dementia symptoms, and may be useful in persons not able to tolerate cholinesterase inhibitors.
Surgery as treatment for Parkinson’s
Surgery was formerly a fairly standard form of treatment for Parkinson’s. The procedure involved placing an electrode into the specific areas of the brain that control the motor impulses affected by Parkinson’s. The electrode, termed a neurostimulator, sends electrical impulses to parts of the brain such as the thalamus, the globus pallidus, or the subthalamic nucleus. Deep brain stimulation by this means can provide some respite from the motor fluctuations and tremors that many individuals affected by Parkinson’s experience.
Deep brain stimulation has not been so commonly employed since levodopa became the standard for treating Parkinson’s-related motor disorders, based on better outcomes. However, in individuals with motor fluctuations or tremors inadequately controlled by medication, deep brain stimulation continues to be an option. Deep brain stimulation is to be avoided in persons with neuropsychiatric issues.
Where do we come out?
The unfortunate answer is, no closer to a genuine cure than where we were at the beginning of this piece. The strategy with Parkinson’s seems to be to try to manage the symptoms as they emerge – don’t bring out the heavy artillery at the start of the battle. Physical therapy is strongly recommended for persons with Parkinson’s, both to maintain mobility, flexibility, and strength, but also to improve overall quality of life. Effective physical therapy can go a long way to countering Parkinson’s-related movement disorders.
Other therapies include deep diaphragmatic breathing exercises which can improve chest wall motility and vital capacity. And treatment for speech disorders stemming from Parkinson’s has been shown to be highly effective.
What all these therapeutic options are trying to accomplish is to delay, to the greatest degree possible, the progression of Parkinson’s. And judging by the many individuals who have been engaged in a struggle with Parkinson’s that continues, sometimes for decades, this rear-guard action can be successful. No, it does not culminate in a declaration of victory over Parkinson’s, but the preservation of a degree of quality of life is a reasonable goal.
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As you see, Doc Gumshoe has avoided any mention of the coronavirus pandemic, even though it has intruded in nearly every waking (and many sleeping!) moments. Our small town has 58 confirmed cases and there have been four fatalities. About one third of the cases and three of the fatalities took place in a senior citizens’ residential facility. The town is mostly shut down. We mostly have enough food on hand, as well as plenty of wine and a lot of books. We hope that all the denizens of Gumshoe world are in good health and good spirits. I will look for something a bit more cheerful and optimistic for my next missive. Best to all, and thanks for the comments. Michael Jorrin (aka Doc Gumshoe)
[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) who writes for us about topics in health and medicine a couple times a month. He does not generally cover investment topics, but has agreed to our trading rules.]