The earliest symptoms of Parkinson’s

Problems with sleep and anxiety may be some of the earliest symptoms of Parkinson’s. But how are changes in the brain causing them?

We know that there are many areas of the brain that are affected in Parkinson’s. While there is ongoing debate about where Parkinson’s starts and how it spreads, we are starting to learn about how changes in parts of the brain explain some of Parkinson’s earliest symptoms, such as changes in sleep, smell, mood and constipation.

So what do we know about these symptoms and what’s causing them?

1. A sleep problem that could predict Parkinson’s

Many people with Parkinson’s experience sleep and night-time problems. While they can be experienced at any stage of the condition, they are often seen in the early stages and may be present years to decades before diagnosis.

Now, evidence is mounting that one particular sleep problem may be one of the earliest symptoms of the condition. Dr Michele Hu, who is leading the groundbreaking Discovery study at Oxford University, explains:

“In the very earliest stages of Parkinson’s, some people develop a condition called rapid eye movement (REM) sleep behaviour disorder, which causes them to act out their dreams, often shouting out, or thrashing around in their sleep. We are studying people with and without this sleep disorder to understand how Parkinson’s develops.”

Some research suggests more than 80 percent of people with REM sleep disorder later developed a neurodegenerative condition such as Parkinson’s, multiple system atrophy or dementia with Lewy bodies (although more recent studies have found this risk of Parkinson’s to be considerably lower). So learning more about this symptom could help us to predict Parkinson’s or diagnose it earlier. However, the presence of this disorder alone is not sufficient to predict a future diagnosis, and not everyone will experience sleep problems before a Parkinson’s diagnosis.

While more research is still needed on the risk of Parkinson’s in those with REM sleep behaviour disorder, researchers agree that changes in the brain that cause the disorder may be one of the earliest changes in Parkinson’s.

Why does Parkinson’s cause sleep problems?

It is likely that areas of the brain associated with sleep problems in Parkinson’s include a part of the brainstem known as the locus coeruleus, as well as the hypothalamus.

The locus coeruleus is an interesting area of the brainstem. Despite its small size, it has a powerful effect on the brain as it produces the hormone and neurotransmitter, noradrenaline, that is responsible for our fight or flight response.

While problems in this area of the brain are more commonly linked to changes in stress and anxiety, researchers are starting to find other ways that changes in this area of the brain may be linked to other symptoms in Parkinson’s including dementia and sleep. Indeed, there is an ongoing phase 2 study, being conducted by Jazz Pharmaceuticals, investigating if a dopamine and noradrenaline reuptake inhibitor, JZP-110, can reduce daytime sleepiness. And also interest in the possibility that drugs targeting noradrenaline signalling may be able to delay the onset of cognitive decline.

2. Can you smell this?

Another early symptom in Parkinson’s linked to the presence of alpha-synuclein bundles involves changes in our ability to smell. Research suggests around 75% of people with Parkinson’s have a poorer sense of smell compared to other people of the same age. And, compared to those with the best smelling ability, one study found that men who had the worse sense of smell were 5 times more likely to develop Parkinson’s at a later date.

This symptom has led researchers to investigate the potential of ‘scratch and sniff’ tests as a way to improve diagnosis by helping to separate Parkinson’s from other similar conditions. And may also allow researchers to identify people in the earliest stages of Parkinson’s years before diagnosis.

Why does Parkinson’s cause changes in smell?

Researchers believe changes in the olfactory system, and in particular an area known as the anterior olfactory nucleus, is probably the cause.

In Braak’s theory, changes here are believed to precede those in the substantia nigra.

You can read more about how Parkinson’s may spread through the brain in our previous blog post ‘What brain areas are affected in Parkinson’s?’

3. Can Parkinson’s put you in a bad mood?

Areas of the brain that are affected in Parkinson’s are also linked to changes in mood and mental health. Research suggests that both depression and anxiety are linked to Parkinson’s and, as such, may have use as a predictive factor.

For many these symptoms can have a greater impact on quality of life than symptoms such as tremor or stiffness. This is probably why stress and anxiety was voted as the second top priority area for research to improve everyday life, and as a result we have a number of ongoing research projects that aim to tackle this symptom and develop solutions.

You can read more about one of these projects in our previous ‘Anxiety and Parkinson’s: ask the expert’ blog post.

Why does Parkinson’s affect people’s mood?

There are a couple of brain areas that are likely involved — the locus coeruleus and raphe nuclei.

The locus coeruleus is believed to play a role in how we respond to stress, and changes in this brain region in Parkinson’s have been linked to the development or worsening of anxiety. These effects are likely due to changes in noradrenaline signalling. While, with a role in the regulation of serotonin signalling (a.k.a the happy hormone), changes in the raphe nuclei have been linked to depression. Indeed, types of antidepressants known as SSRIs (selective serotonin re-uptake inhibitors), are believed to act here.

Interestingly, while SSRIs are the most widely prescribed type of antidepressants in Parkinson’s, another type of medication called tricyclic antidepressants are being investigated for their potential neuroprotective capabilities in Parkinson’s. Research is ongoing in this area.

4. A problem with the bowels

Many people with Parkinson’s notice changes in their digestion — for example, digestive and bowel problems. And we also know that people who experience constipation are at an increased risk of Parkinson’s, and that symptoms of constipation may pre-date other Parkinson’s symptoms by over a decade.

Why does Parkinson’s cause changes in digestion and the gut?

Changes in the gut, which are associated with Parkinson’s could be to blame for this symptom. Indeed, over the last decade, researchers have become interested in the tiny micro-organisms that live in the gut and how Parkinson’s may influence them.

You can read more about bacteria in the gut in our blog post ‘A gut feeling about Parkinson’s’.

However, areas of the lower brainstem are also linked to this symptom.

Our digestion, along with other bodily functions we don’t have to think about, such our breathing and heartbeat, are controlled by the part of the nervous system known as the autonomic nervous system. We know that an area of the brain called the dorsal motor nucleus of the vagus helps to control the autonomic nervous system, and regulates the interaction between the gut and the brain. And when Parkinson’s spreads to this area of the brain it could to alter the signals being sent by the autonomic nervous system and change digestion.

The effect Parkinson’s has on the autonomic signalling is also believed to be responsible for other symptoms. Many of our autonomic functions may be affected, causing symptoms related to blood pressure, sweating and the need to urinate, and this has been reported to affect daily life of over 50% of those with Parkinson’s.

Research into early symptoms

So why are researchers interested in early symptoms of Parkinson’s? One reason relates to the fact that there is currently no definitive diagnostic tool for Parkinson’s. If a test that can detect the earliest stages of the condition were discovered, it would improve diagnosis. But detecting early symptoms could do much more.

Identifying the changes that happen in the earliest stages of the condition could help us predict Parkinson’s. And many scientists believe that prediction is the key to new and better treatments that slow progression.

You can read more about how prediction is key to unlocking treatments that stop Parkinson’s in this blog post.

Understanding how Parkinson’s is affecting all these other areas of the brain is also essential for developing better treatments that tackle all the symptoms of the condition. And it would help explain why people with Parkinson’s differ so much, knowledge that has the potential to transform treatment.