Early signs of Parkinson’s disease

Learn how to spot early warning signs of Parkinson’s disease

What are the typical first symptoms of Parkinson’s disease (PD)? This seems like a straightforward question, but it is not simple to answer. Today we will explain the early symptoms of PD and how our understanding of those symptoms is informing how PD is diagnosed, and potentially how it will one day be treated.

Non-Motor Symptoms Typically Show First

Parkinson’s symptoms can broadly be divided into two categories – motor and non-motor.  Motor symptoms are ones that affect movements and include rest tremor, stiffness, slowness, difficulty with balance, shuffling gait, expressionless face, and others. Non-motor symptoms are ones that do not affect movement and include mood disorders, cognitive disorders, sleep disorders, blood pressure variability, constipation, urinary frequency, pain syndromes, and others.

It turns out that non-motor symptoms often precede motor symptoms, sometimes by decades! Typically, there are certain non-motor symptoms that are the most likely to appear early. These include:

1. Depression
2. Constipation
3. Loss of smell
4. Sleep disorders – specifically rapid eye movement behavior sleep disorder (RBD), a condition in which individuals talk or move during sleep, essentially acting out their dreams.

Once motor symptoms develop, it is incredibly common for people with PD to look back and be able to identify one or more of these non-motor symptoms that was present first.

Why do non-motor symptoms develop earlier?

One theory is that Lewy bodies (clumps of the abnormally accumulated protein, alpha-synuclein, found within nerve cells of PD patients’ brains) develop in the lowest parts of the brainstem first, causing specific non-motor symptoms that are controlled by the lower brain stem including constipation, sleep disorders, and depression. Over time, the Lewy bodies migrate up the brainstem until they reach the midbrain, where they cause the motor symptoms of rest tremor, slowness, and stiffness. This theory explains why particular non-motor symptoms are often the first to appear in PD.

“Pre-motor” Parkinson’s as an early stage of the disease

Because non-motor symptoms are an early part of PD referred to as “pre-motor” PD or “prodromal PD”, the research community is rethinking the definition of PD. Currently PD is defined clinically, by detecting motor symptoms such as slowness, stiffness, and tremor during a clinical exam.

Researchers are instead working to develop a biological definition of PD based on testing for biomarkers – laboratory or imaging tests that show an abnormality in the disease state. Changing from a clinical diagnosis to a biomarker-based diagnosis would expand the definition of disease to include people who have positive biomarkers, but only have non-motor symptoms, or no symptoms at all.

New breakthroughs for biomarkers for early detection of Parkinson’s

Until recently, there were no biomarkers available to detect PD, hence the reliance on the clinical exam. However, there are now biomarkers that demonstrate the presence of disease and these include:

1. Alpha-synuclein pathology in cerebral spinal fluid: Abnormal accumulation of alpha-synuclein protein in the brain is a hallmark of Parkinson’s disease. An assay called seed amplification assay (SAA)  was developed which detects alpha-synuclein aggregates (or clusters) in the cerebral spinal fluid (CSF). This test is marketed under the name SAAmplify-aSyn by Amprion.
2. Phosphorylated alpha-synuclein: Research has demonstrated that phosphorylation, or the attachment of a phosphate group, onto the alpha-synuclein molecule can result in a particularly harmful form of alpha-synuclein. Phosphorylated alpha-synuclein can be found in nerves all over the body of a person with PD, including in nerve fibers of the skin. These nerves can be accessed for study in a lab via a skin biopsy. A commercially available skin biopsy, known as Syn-One is from CND Life Sciences.
3. DaTscan:A DaTscan, or dopamine transporter scan, is a method of imaging the dopamine system in the brain. In this test, a radioactive tracer, Ioflupane, also known as DaTscan, is injected into the blood, where it circulates around the body and makes its way into the brain. It attaches itself to the dopamine transporter, a molecule found on dopamine neurons. Several hours after the tracer has been injected, special imaging equipment scans the head to detect the presence of DaTscan. People with PD will typically have a smaller signal in a part of the brain called the striatum, where the ends of the dopamine neurons are meant to be.

Two proposed biological definitions of Parkinson’s

1. Neuronal synuclein disease (NSD): Here, researchers define a new pathologic condition, which includes conditions in which both abnormally aggregated alpha-synuclein (detected with an abnormal SAA) and dopaminergic neuron dysfunction/degeneration (detected by an abnormal DaTscan) are present.
2. SynNeurGe: This definition combines pathological alpha-synuclein in tissues such as skin or CSF, evidence of underlying neurodegeneration defined by neuroimaging (DaTscan), and genetic changes that increase the risk of PD.

What do I do if I have early non-motor symptoms of Parkinson’s?

You or someone you know may be concerned that you exhibit the classic early non-motor symptoms of Parkinson’s disease including loss of smell or REM behavioral disorder (RBD), and that you may be at risk for PD. If this is the case and you want to look into it further, your next step should be to make a non-urgent appointment with a neurologist, who will conduct a neurological exam, the results of which may be normal or may show subtle motor symptoms consistent with PD.

What if I’m worried I have Parkinson’s but not any early non-motor symptoms?

If there are no motor symptoms present, the question of next steps is more complicated. Despite significant advances in the field of biomarkers for PD, it is not currently standard clinical practice to perform a biomarker test on people with only non-motor symptoms of PD to determine whether or not they have abnormal alpha-synuclein or a dopamine deficiency.

Some argue that because there is unfortunately no neuroprotective drug that has been proven to delay or prevent the progression of symptoms of PD, the medical community should not advocate screening for PD in the same way that it advocates for cancer screenings, for example. When we have a neuroprotective medication or technology for PD, then screenings for PD will become essential.

Others argue that the decision of whether or not to pursue biomarker testing should be made by the person with symptoms, following a discussion with their physician and in fact a potential neuroprotective treatment is available, and that is exercise. It is therefore prudent for a person who is experiencing only the non-motor symptoms of PD – whether they’ve been tested or not – to start or increase their level of exercise. For information on exercise and wellness for people with PD, take a look at our free Be Active & Beyond booklet.

Studies of patients with only non-motor symptoms

In recent years, there has been a shift to studying the population of people with non-motor symptoms only to better understand what happens to them over time.

One major study that is gathering information on people without a PD diagnosis but who have smell loss and/or RBD (as well as people with PD and normal controls) is the Parkinson’s Progression Markers Initiative. This study gathers information over time to further understand the development and evolution of characteristics in people with prodromal symptoms as well as people with PD. It is a great resource for researchers who can use the information collected to study various research questions. For example, the reliability of the SAAmplify-aSyn biomarker test was tested using PPMI data. 

In addition, the research world is considering the planning of a clinical trial focused on preventing PD in the people who only have non-motor symptoms such as REM behavior sleep disorder. A series of conferences which APDA has helped to sponsor have been held to discuss the following issues to help prepare for such a clinical trial:

• Who? Which population of people should be considered for such a trial? (Two potential groups are people with RBD and people with a genetic mutation that increases their risk of PD)
• What? What medication should be tried and for how long?
• How? How should the medication be assessed? Which outcome measures should be considered?

A similar initiative is being developed by NAPS (North American Prodromal Synucleinopathy) Consortium, a group of nine medical centers located across North America who are enrolling people with RBD in a registry. Clinical information is collected on the participants and they undergo neurologic testing. Blood samples are taken from participants as well. The goal is to have a well-characterized group of people with RBD ready to participate in a clinical trial for a neuroprotective medication when such a trial opens for enrollment.

The first motor symptoms of Parkinson’s disease

When people ask “what are the early signs and symptoms of PD?” the answer they are typically expecting is one that involves motor symptoms. Early motor symptoms of PD (which usually, but not always, start after the appearance of at least one non-motor symptom) can be a subtle rest tremor of one of the arms or hands (sometimes of just one finger).

Tremor, an early motor symptom

A rest tremor is one that occurs when the limb is completely at rest. If the tremor occurs when the limb is suspended against gravity or actively moving, this may still be a sign of PD but may also be a sign of essential tremor.

Stiffness and freezing, other early motor symptoms

The initial motor symptom of PD may be a sense of stiffness in one limb, sometimes interpreted as an orthopedic problem (e.g. frozen shoulder). This sense of stiffness may be noted when a person is trying to get on his/her coat, for example. A person may also experience a sense of slowness of one hand or a subtle decrease in dexterity of one hand. For example, it may be hard to manipulate a credit card out of a wallet or perform a fast, repetitive motor task such as whisking an egg. A person may notice that one arm does not swing when he/she walks or that one arm is noticeably less active than the other when performing tasks. Another motor sign may be a stoop with walking or a slowing down of walking. A family member may notice that the person blinks infrequently or has less expression in his/her face and voice.

These motor symptoms may be very subtle. Bottom line – if you are concerned that you may have an early motor or non-motor symptom of Parkinson’s disease, make an appointment with a neurologist for a neurologic exam to discuss your concerns.

Tips and takeaways

• The first symptom of PD often does not involve a problem with movements.
• However, many of the non-motor symptoms associated with PD are quite common in the general population, so don’t panic. These symptoms are often only noted as consistent with PD once the motor symptoms emerge.
• Motor symptoms that tend to occur first are subtle rest tremors, changes in facial expression, slowing down of walking and decreased arm swing on one side with walking.
• If you are concerned about any motor or non-motor symptoms, make an appointment with a neurologist. It is very helpful if you can make note of how often the symptoms affect you so you can give the doctor the most information possible.
• Exercise may be neuroprotective and may alter the progression of PD, so get moving! (with your doctor’s approval, of course). Get a free copy of APDA’s Be Active and Beyond booklet and check out the virtual exercise classes available.