Parkinsons

Symptoms and MSA

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9/6/24

A list of Issues

What’s the value of making a list of the symptoms that I’ve been experiencing after a year and a half of suffering  from Parkinson’s? For one thing, Parkinson’s is a disease with a host of issues that varies from one individual to another. A comparison of my problems with someone else’s may be valuable in distinguishing Parkinson’s symptoms from some other difficulties. A more pressing reason in my case, has to do with another disease that I may be afflicted with: multiple system atrophy (MSA).

MSA is a disease whose manifestations are very similar to Parkinson’s. In fact, it is extremely difficult to distinguish between the two disorders. One distinctive feature is that MSA doesn’t usually respond to carbidopa/levodopa therapy and that’s what seems to be happening in my case. And that’s why I’ve become interested in it.

So what is MSA and how does it differ from Parkinson’s? Like Parkinson’s, MSA is a neurological alpha-synucleinopathy (alpha-synuclein clumps are often observed in brain tissue) in which one’s brain cells die over time. Even for experts, it’s difficult to distinguish between the two diseases. It’s a less common disease characterized by faster progression. And, like Parkinson’s, there’s no cure. However, MSA affects autonomic functions much more than Parkinson’s. The result is that swallowing becomes more difficult. Blood pressure is less well controlled (standing up suddenly can result in a rapid drop in blood pressure), and urinary and bowel dysfunctions are more often observed.

If I had a choice between the two diseases, I would choose Parkinson’s over MSA. Rapidity of progression and reduced time to death are important factors. But I have no choice. Regardless of the disorder that I’m afflicted with, below I list the symptoms that I’m currently experiencing:

  • Weakness on my left side.
  • “Pisa syndrome” – body leans to the right when seated or standing.
  • Difficulty changing position in bed.
  • Drooling.
  • Accumulation of mucus in my throat when lying on my back.
  • Lack of dexterity when using my left hand – difficulty with typing and with buttons.
  • Slowness of movement. Short steps.
  • Inability to swim using the crawl.
  • Frequent loss of balance.
  • Constipation.
  • Lack of energy, lethargy, fogginess.
  • Tremors.
  • Worst of all, my golf game has gone to pot.

On the positive side, as I can tell I have no cognitive issues and my ability to smell seems normal. According to my neurologist, these symptoms don’t allow for a definitive diagnosis of MSA, but they don’t rule it out. The only way to be sure is to do a brain section upon autopsy. I probably will not be interested in learning the results when that happens.

In time, the likelihood is that some or all of these issues will get worse. I’m not looking forward to it.

Ropinirole -2

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8/27/24
My Progress

I finished applying the rotigotine patch a few days ago. I had worked up to 8 mg per day. It didn’t help. If anything, it seemed to make matters worse. I cut back to 4 mg and then stopped. Given these negative results, I had to decide what to do next. My neurologist recommended that I try going back to ropinirole. Perhaps, she suggested, I hadn’t given it enough time or reached a sufficient dose. So I started taking that medicine on August 21st. I’m currently up to 1 mg three times a day. I hope to increase to 3 mg three times a day in two weeks. However, again, to date I‘ve see no improvement.In fact, things seem to be much worse. I’m not sure what the next step should be.

In the next section, I’ll discuss, as promised, a technique for directly operating on brain tissue in an effort to alleviate some of the symptoms of Parkinson’s. Focused ultrasound is one of two such procedures. The other is deep brain stimulation (DBS). (I’ve taken some of this discussion from https://www.michaeljfox.org/news/focused-ultrasound)


Focused Ultrasound

Focused ultrasound and DBS are both surgical procedures that aim to ease Parkinson’s movement symptoms. They’re options for people who have tremors or slow movement that isn’t responding to medication.


Focused ultrasound and DBS work in the same general brain areas but in different ways. With focused ultrasound (FUS), doctors use ultrasound beams to destroy brain cells that cause movement problems. (It’s a bit like using a magnifying glass to focus sunlight rays on a leaf to burn a tiny hole.) The neurologists performing the procedure use MRI imaging to guide the ultrasound beams to tiny areas. Doctors target different brain cells to treat different symptoms.


DBS uses a more subtle approach. DBS delivers electrical pulses to similar regions to interrupt abnormal signaling. In DBS surgery, doctors insert thin wires into the brain and a battery below the collarbone.


The two procedures offer different advantages and disadvantages. Focused ultrasound is irreversible, while DBS may be reversed by removing the system or turning it off. Focused ultrasound is non-invasive — there are no incisions and there is no hardware placed in the body. Focused ultrasound is a one-time procedure that does not require adjustment. DBS needs regular programming to find the right electrical stimulation settings to maximize benefit and limit side effects.


During the focused ultrasound procedure, a patient is awake. No general anesthesia, surgical incisions or implanted hardware is involved. Doctors use MRI brain scans to direct ultrasound beams to the targeted brain location. (For tremor, it’s the thalamus and for other Parkinson’s motor symptoms, it’s the globus pallidus interna.) The photo below shows what the procedure looks like.


Focused ultrasound typically decreases symptoms immediately. It does not require adjustment, programming or additional procedures. But it is irreversible and permanent. Possible side effects may include headache, numbness and tingling, and imbalance or gait issues.


In 2018, the FDA approved focused ultrasound for Parkinson’s tremor. In 2021, the government expanded FDA approval to include other Parkinson’s symptoms, such as stiffness or bradykinesia (slow movement), as well as dyskinesia (uncontrolled, involuntary movement). 


Currently, focused ultrasound is approved for treatment on only one side of the brain, meaning it can only alleviate symptoms on one side of the body. But ongoing research is evaluating the possible benefits and safety of both-sided focused ultrasound in different brain targets.


I have an appointment with my neurologist in a couple of weeks. I aim to ask her about the possibility of using this technique to help my condition.

Ropinirole

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8/7/24
Ropinirole/Selegiline

For those of you who’ve been following my blog, you know that I’ve been trying Neupro, (rotigotine), delivered via a transdermal patch, for the last couple of weeks. It’s a little early to say, but as far as I can tell, there has been no significant improvement in my bradykinesia (slow movement) – 0r for that matter, any other negative symptoms associated with Parkinson’s. I haven’t yet got to the highest dose – that will happen next week– but if the lack of progress continues, the next step as recommended by my neurologist,will be to slowly go off of the patch and transition to ropinirole, another dopamine agonist.


Ropinirole is taken by mouth, 1 mg three times a day for the first week increasing to 3 mg three times a day by week three. I am not holding out much hope. Ropinirole is an agonist and so far my success rate with that class of medication has been poor.

Anticipating a lack of progress with ropinirole, I’ve started looking into alternative therapies. These fall into three categories:

First, other drugs that work by different mechanisms than than the agonists I’ve mentioned above. Selegiline, for example, inhibits a specific enzyme that breaks down dopamine in the brain, thus increasing its concentration. Rasagiline is a related drug that acts in a similar manner.

A second potential strategy dispenses with medication and instead requires direct manipulation of parts of the brain. For example, deep brain stimulation, a process requiring implanting an electrode in the part of the brain that controls movement, is a procedure that has been widely used in cases where other approaches have failed. The electrode is controlled by a pacemaker-like device, or neurostimulator, that is implanted under the skin in the upper chest. I’ll discuss this and another procedure, called focused ultrasound, in a forthcoming blog.

A third possible treatment is experimental and not yet available to the general public: the transplanting of dopamine-producing stem cells into the brain. These are intended to make up for the loss of neurons caused by Parkinson’s disease. They offer the possibility of a cure, unlike the other remedies listed above that only address of the symptoms of the disease. I’ll leave the discussion of stem cell treatments for another day.

Selegiline

As you know, dopamine is synthesized from L-DOPA. In turn, dopamine acts either as a neurotransmitter or a neuromodulator in the brain. Lack of dopamine, of course, is responsible for the symptoms of Parkinson’s disease. Too much dopamine can also be a problem.To prevent the accumulation of an excessive of dopamine, dopamine is broken down into inactive metabolites by a set of several enzymes acting in sequence beginning with the enzyme monoamine oxidase. In the end, the main end-product of these steps is homovanillic acid, which has no known biological activity and is eliminated in the urine.

Selegiline is a small molecule that binds to monoamine oxidase and prevents it from carrying out its function. The result is an increase in the amount of dopamine in the brain. What are the advantages and disadvantages of taking this drug? (From https://davisphinneyfoundation.org/selegiline-for-parkinsons-symptom-management/)

Advantages
1. It may show fewer side effects than dopamine agonists 
2. It may help curb, depression, or anxiety

MAO inhibitors have a long history of use as a treatment for depression, and there is some evidence that–even at doses approved for use in Parkinson’s–selegiline may still affect depression.
3. It may help with gate dysfunction 
4. May decrease daytime sleepiness
5. It is possible that the medication may have a neuroprotective effect, although that has not been shown definitively 

Disadvantages
1. In clinical trials for selegiline, the most common side effects included nausea, lightheadedness, and abdominal pain.
2. Selegiline is broken down into amphetamine and desmethylselegiline, two substances that can cause adverse events including headache, insomnia, and irritability.

My intention is to speak with my neurologist and discuss whether taking selegiline is something to be considered, especially in view of the fact that the medications I’ve been taking have been ineffective. I have an appointment with her in a few weeks.

G Protein Coupled Receptor

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7/28/24

In my last post, I wrote a little about receptors. In this one, I’ll elaborate on that discussion.

Dopamine is, among other things, a neurotransmitter and a neuromodulator. What’s the difference? Neurotransmitters allow communication between individual neurons. They are released by one neuron and travel to another across what is called a synapse, where they produce a response. Neuromodulators, on the other hand, influence many neurons at once. However, both functions require the binding of dopamine to its receptor. How does this work?

I’ve drawn a picture to illustrate the process. The figure on the right shows a simplified cartoon of a dopamine receptor. It’s the blue spring-like structure. It’s called a G protein-coupled receptor (GPCR) because it interacts with another protein, called G, located in the interior of the cell. Notice that the receptor twists snake-like around both sides of the cell membrane, with one end situated in the interior of the cell and the other in the exterior. It is in the part of the protein outside the cell where dopamine binds (agonists, which have a similar shape to dopamine, can also bind there). When it does so, it results in a change in conformation of the protein at its other end—in the interior. This change in conformation allows signals outside the cell to communicate with the contents within.

The next figure illustrates that the right-hand portion of the receptor has changed its shape due to the binding of dopamine at the other end of the molecule. This interior end interacts with the G protein, a protein consisting of three subunits: alpha, beta, and gamma. The alpha subunit has a substance called GDP (guanosine diphosphate, for those who want to know) bound to it. GDP is a small molecule with two phosphates at its end. When the receptor engages the G protein, the GDP is replaced with GTP, an energetic molecule with three phosphates bound. What happens next is shown in the next figure.

The G protein breaks apart, releasing the alpha subunit. It now interacts with components in the interior of the cell. One such component is an enzyme called adenyl cyclase. This enzyme becomes active and begins synthesizing cyclic AMP, an important molecule that interacts with a whole series of other molecules, influencing a variety of physiological processes. This, of course, is a simplification—not the whole story by a lot. For example, there are five different dopamine receptors—D1 through D5, all of which do different things. The process itself is also more complicated than I’ve shown. You can get a more detailed picture by going to the Wikipedia entry under G protein-coupled receptors.

 
 

Neupro

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7/19/24 – Rotigotine

A few words about my new therapy, a transdermal patch marketed under the name Neupro.

Nepro is designed to deliver a dopamine agonist, rotigotine, through the skin. The keyword here is “agonist”, what does it mean, and how is this particular agonist meant to relieve Parkinson symptoms?

Addressing the first question first, an agonist is a small molecule that impersonates the action of another substance that has a physiological function. In this case, the small molecule being imitated is dopamine, a neurotransmitter that is deficient in Parkinson’s patients. Recall, the gold standard in Parkinson treatment is to relieve this lack of dopamine with carbidopa/levodopa. The levodopa in this combination is converted into dopamine when it gets transported across the blood brain barrier and into the brain. Once it reaches its destination, the newly formed dopamine substitutes for the missing dopamine lacking in Parkinson’s patients.

Dopamine has many functions, but all of them rely on its binding to a receptor. This is getting complicated. What’s a receptor?

Many receptors sit on the surface of cells and communicate signals to the interior. Receptors are proteins that bind small molecules like hormones and neurotransmitters. There are thousands of different receptors throughout our bodies and each one specifically binds a particular small molecule. Each receptor has a site on its surface with a three dimensional shape that is complementary to the small molecule being bound. The small molecule falls into this site and causes the receptor protein to change the shape. In turn this change of shape is communicated to the interior of the cell, causing some actions occur.

There are several dopamine receptors and the complementary dopamine-binding sites that these receptors share also respond to an agonist like rotigotine, thereby eliciting the same response. Thus rotigotine produces the same effect as dopamine. Then why use it instead of dopamine?

I posed this question to Perplexity, my favorite AI assistant. Here are several reasons it came up with:

Better absorption and delivery: Rotigotine is administered through a transdermal patch, which allows for steady delivery of the medication over 24 hours. This provides more consistent blood levels compared to oral medications or direct dopamine administration.

Blood-brain barrier penetration: Unlike dopamine, rotigotine can cross the blood-brain barrier, allowing it to directly act on dopamine receptors in the brain.

Longer half-life: Rotigotine has a longer duration of action compared to dopamine, which is rapidly metabolized in the body.

Convenience: The transdermal patch formulation of rotigotine offers a once-daily application, which can improve medication adherence for patients.

Bypassing gastrointestinal issues: The transdermal delivery system avoids potential absorption issues related to gastrointestinal problems, which can be common in Parkinson’s disease patients.

I’ve been on the patch for only three days. I’ll let you know how it goes in the future.

Back from Harper’s Ferry

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7/16/2024

Gail and I just returned from a trip to Harpers Ferry and Shepherdstown, West Virginia. Shepherdstown, one of the oldest towns in the state, has retained much of its nineteenth-century heritage. With a population of less than 2,000 souls, it attracts visitors from all over the Mid-Atlantic region. Gail and I flew there to meet with four of our oldest friends and, with them, to attend the Contemporary American Theater Festival. We saw two plays. The last was a one-man show held in the historic Shepherdstown Opera House. Built in 1910, the venue was never an opera house at all. Instead, it offered a mix of entertainment, primarily silent moving picture shows and vaudeville performances. These continued for several years, establishing the theater as a cultural hub in the town. The theater was renovated recently. It is a small space, but it was a perfect fit for the one-man show, “The Happiest Man on Earth,” that we saw. The play, about one man’s experience in the Holocaust, is very powerful and wonderfully acted.

With regard to Parkinson’s, this past week saw a rapid acceleration in the severity of the disorder. I am walking slower, speaking softer, drooling more often, having more difficulty rising from a chair, and am more tired. I’ve tried increasing the dose of ropinirole and going off of it for a day. Neither strategy seemed to help. My neurologist has suggested Neupro, a patch that delivers medicine transdermally, bypassing the intestines. Whether this works or not will be determined in the next few weeks. I started on the medicine today.

Spreadsheet

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7/8/24

My Recent Absence: A Brief Explanation

It’s been a while since my last post. Here’s a brief list of reasons for my absence:

1. Deteriorating Touch Typing: My left hand has little control over key presses, often holding down keys inappropriately or not pressing hard enough for the computer to respond. I’ve resorted to ‘hunt and peck’ typing with my right hand, making writing a chore. Please excuse any typos.

2. Lack of Positive News: My Parkinson’s has progressed much faster than anticipated, resulting in a loss of energy. I’m doing less overall, including writing.

3. Website Maintenance Challenges: Maintaining a website can be burdensome. I greatly admire those who post regularly, even if it’s just once a month.

I can’t promise the situation will improve, but I wanted to provide an update on my condition.

Tracking My Symptoms

Frank C. Church, PhD, hosts an excellent website (Journey with Parkinson’s) that deals with the disorder. Among many valuable suggestions, he recommends that sufferers keep an ongoing record of their symptoms. I’ve expanded on this idea:

– I’ve created a spreadsheet listing my symptoms.
– Each symptom is assigned a value from 0 (no problem) to 5 (pretty awful).
– I update it approximately every week.
– I sum all the values and graph the results to track progression over time.

This method has been helpful in monitoring my condition and providing data for discussions with my healthcare providers. Here’s a snapshot of the latest update.

The symptoms listed in blue at the left are the ones that are supposed to respond to carbidopa/levodopa. However, for what ever reason – as is evident from the spreadsheet – I’m seeing no improvement in these, or any other symptoms. That’s unusual, but not unprecedented. My neurologist recommended that I try a dopamine agonist- ropinirole – and I’ve been on that for a month. But it too seems to have no effect.

One neurologist that I talked to suggested that sometimes these drugs don’t get from the gut into the blood stream. There is a medication – a patch – that might solve that problem, if indeed that’s why the drugs aren’t working, I’m going to try it and will post the results.

What I’m taking

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8/29/23

When i was diagnosed with PK, I looked around for supplements that might be helpful in slowing the disease. These are the ones that I’m currently taking.

(Be aware, these are my choices. My disease may be different than that of others. Certainly, my physiology, metabolism, and biochemistry will be different. Therefore these supplements are not intended as suggestions for anyone else but me. In other words, I’m not offering medical advice. I’m not a physician and am therefore not competent to do so).

  1. Carbidopa/Levodopa 25/100. This is not a supplement. It was prescribed by my physician. It is the recommended drug to treat Parkinson’s symptoms. I take it three times a day. It seems to have lessened the tremors.
  2. Vitamin B-12 – 2500 mcg. My general practitioner told me to take this vitamin because my blood tests showed that I was low in it. i take it once a day.
  3. Taurine – 500 mg. Taurine is a sulfur-containing amino acid that is abundant in the brain, bile, and many tissues. It’s not found in proteins and its structure is different than the familiar amino acids. Humans synthesize taurine (so it’s not a vitamin) and it is found in meats but not in vegetables. Several small studies have suggested that it its concentration diminishes with age and that it’s reduced in people with Parkinson’s. It may be that taking a supplement may be helpful in slowing the disease but the evidence isn’t overwhelming. I take one tablet per day.
  4.  Hydroxy-methyl-butyrate – 1 gram. Several articles have indicated that this ketone body may have some ameliorating effect on Parkinson’s, but I’m taking it because there’s some evidence that it helps prevent muscle loss in aging individuals.
  5. Vitamin D – 2500 UI. Like B12, I’m taking this vitamin because my blood test indicate that I’m deficient.

In addition to these supplements, I’m consuming a small container of Activa yogurt every morning. There’s some indication that the gut biome has an effect on Parkison’s, so I’m hopefully changing its composition with this probiotic.

 

 

Symptoms and Therapy

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8/28/23

A few Parkinson’s sites have suggested that sufferers keep a diary of symptoms. I’m much too undisciplined to do that on a regular basis. But here’s one entry.

So far, the disease has been more a nuisance than a disability. The major problem that I’m having with it is that my typing has gone to pot. While I don’t actually feel my hands shaking, when I’m over the keyboard I often hit the wrong key and the same key repeatedly. It takes me twice as long to type something as it had when I was younger. BTW, this isn’t a recent phenomenon. I first noticed this behavior two years ago. It caused me to purchase another keyboard (it didn’t help).

Another symptom I’ve noticed is that for the first time in my life I’ve been getting headaches. Not really severe ones. More like my head is swelling. This feeling is often accompanied by a feeling of light-headness, kind of like when I’ve had a bit too much too drink.

My sense of balance is a little off, but not too much. And I’ve experienced REM sleep disorder, another common symptom of Parkinson’s. It hasn’t happened often. On three occasions, I’ve acted out dreams when I’ve been sleeping, much to the consternation of my wife.

Of course, I’m walking slower, slouching a bit, and I’ve noticed a little difficulty in speaking sometimes. Mucus accumulates in my throat when I’m lying on my back.

Thankfully, I’ve not lost my sense of smell or had difficulty sleeping. My urologist told me that Parkinson’s people often have an increased urgency to urinate, but that hasn’t happened to me either. And finally, it hasn’t hurt my golf game, although my swing has slowed down a bit. And the constipation that I’ve been experiencing for the last few months, is getting better.

I guess my biggest issue is what the future will hold. How fast will the disease progress? What will the next symptom be? What kind of long term plans should I make?

Next time, I’ll talk about the medications I’ve added to the standard carbidopa/levodopa therapy that the doctor prescribed.

New Thoughts

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7/14/2023

One of the benefits of being a Professor Emeritus is that the job comes, at least at Rutgers, with free access to the scientific literature. The title ‘Emeritus’ seems august but the fact is that if offers few perks. For example, I don’t get paid, and the University doesn’t provide an office (although, since I’m in Texas, an office wouldn’t be of much use anyway). But I often need to read scientific articles. And without university affiliation, they’re expensive, often costing more than $50 per article. The journals allow you to look at an abstract of an article that you might be interested in, but don’t allow access to the full text. Often that means that the contents aren’t really pertinent to the subject that I’m investigating, resulting in a waste of  my money.

All is is preface to the fact that I’ve been looking for a good scientific review article on Parkinson’s. Many of the ones that I’ve examined are directed at non-scientists who have the disease. I’ve saught to find one that is more technical. For that I’ve turned to Google Scholar and used it to search through scientific and medical journals. In this post, I’ll go over some insights that I’ve gleaned from an article that I’ve located in the journal Lancet, a prestigious British publication.

The article is by Bastiaan R. Bloem, Michael S Okun, and Christine Klein and is in Lancet 397: 2284–303 (2021). I’ll try to summarize some of its more salient points, some that haven’t been emphasized in the popular literature.

The first point the authors make is that the prevalence of Parkinson’s disease is increasing. They state that “Parkinson’s disease might even be the fastest growing neurological condition worldwide.” Part of reason for this increase is that people are living longer, and Parkinson’s is a disease of the elderly. In addition, the medical community is more aware of the disease’s symptoms and diagnosis is more accurate. But even after taking age and diagnostic accuracy into account, the incidence of Parkinson’s seems to rising more than other neurological diseases. Why? No one knows.

A second point that I haven’t seen emphasized has to do with the variation in the  disease. “Various observations suggest that Parkinson’s disease might not exist as a single entity.” Moreover, “,,, every person has their own unique Parkinson’s disease. …, an extreme notion would be to say that there are over 6 million different variations of Parkinson’s disease in the world.” The authors point out that this variation has important implications, including the need for personalized care and individualized treatments.

Then there’s the question of diagnosis. “Up to 20% of people with Parkinson’s disease do not have a tremor; however, bradykinesia [slow movement] is always present.” I didn’t know that.The article emphasizes that diagnostic errors are common. “In clinical trials of early-stage Parkinson’s disease, up to 15% of people with the disease are diagnosed incorrectly.”

I had never heard the word ‘prodromal’. It’s a medical term for symptoms that occur before the onset of the clinical phase of disease. With regard to Parkinson’s, constipation is a common prodromal symptom. The symptom most predictive of Parkinson’s, the authors conclude, is REM-based sleep disorder. According to the Mayo Clinic’s website,  “Rapid eye movement (REM) sleep behavior disorder is a sleep disorder in which you physically act out vivid, often unpleasant dreams with vocal sounds and sudden, often violent arm and leg movements during REM sleep — sometimes called dream-enacting behavior.” I’ve had two of these episodes, both occurring before I was diagnosed with Parkinson’s.

The article also addresses therapy. Their analysis of the literature indicates that there is wide variation in reaction to levodopa therapy among people with Parkinson’s. Some people become resistant to the treatment. One possible explanation is that intestinal bacteria may harbor DOPA decarboxylase enzymes, converting DOPA into dopamine before it reaches the brain. For those people, an alternative route of administration of the drug might be helpful. For example,CVT–301, a self- administered levodopa oral inhalation powder, has been shown to improve symptoms in a clinical study.

My interest was centered on the final issue that the article addressed: slowing down progression of the disease through drug intervention.  They mention several drugs that have been repurposed, that is, agents directed at other diseases but under investigation for  Parkinson’s therapy. The cough suppressant, ambroxol, for example is being tested in clinical trials. I found an article on the drug terazosin, used to treat benign prostate hypertrophy, that may have some modest effect on Parkinson’s. I’ve begun using the drug myself.

Here is the article’s conclusion:

Parkinson’s disease has been recognized for over 200 years. Together, the various forms of Parkinson’s disease create fast-growing health-care issues with enormous global impact. Fortunately, Parkinson’s disease is treatable, particularly when the interventions are delivered with a personalised approach, and by well trained experts.

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