In October, the Parkinson Association of Northern California (PANC) hosted a session on the prodrome of Parkinson’s disease (PD). A “prodrome” is when we can see some symptoms of early Parkinson’s disease (PD) but not enough to warrant a diagnosis. Another term for prodrome is “preclinical.”  The session focused on the prodromal stage’s symptoms and genes that may predict a future PD diagnosis. The speaker was movement disorder specialist Dr. Kathleen Poston, with Stanford.  The session was part of the PANC’s 2021 Annual Education Conference.  

According to Dr. Poston, PD is diagnosed when a person has bradykinesia (slow movement) and either muscle rigidity or resting tremors. Non-motor features are a major component of prodromal disease, and may be present decades before the diagnosis. These include constipation, REM sleep behavior disorder (RBD), anxiety, and loss of smell. 

Pathological studies (like the Braak staging model) had set PD to be a dopaminergic disease, but it is actually a multisystem neurodegeneration that starts before dopamine neurons are impacted. 

Dr. Poston noted that it is difficult to study people before they are diagnosed with PD, so the most common way is to study a large population and follow up with people who exhibit the symptoms that may make them at risk of PD, such as loss of smell and sleep disorders.  Additionally, through genetic testing, those who have a strong family history of PD or known genetic risk factors (such as the LRRK2 and GBA gene) may be at a greater risk of developing PD. Those with certain genes but not diagnosed with PD may still have gait issues, olfactory loss, and RBD. 

Currently, researchers do not know how to predict who will develop PD, or when they will develop PD.  However, Dr. Poston says that through research it may soon be possible to identify prodromal symptoms.  Identifying prodromal symptoms can lead to a neuroprotective therapy that could eventually prevent symptoms from progressing to a PD diagnosis. 

For a recording of this session, please see this Parkinson Association of Northern California’s YouTube webpage here.

See my notes below of the October 23rd session. 

Regards, 

– Joëlle Kuehn

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 “The Prodrome of Parkinson’s Disease”- Session Notes

Speaker:  Kathleen Poston, MD, MS, chief, movement disorder center, Stanford University Medical Center

Session Host:  Parkinson Association of Northern California

Session Date:  October 23, 2021

Summary by:  Joëlle Kuehn, Stanford Parkinson’s Community Outreach

PD is diagnosed when:

A person is found on exam to have bradykinesia (slow, low amplitude movement) plus either:

• Muscle rigidity (increased muscle tone to passive movement)
• Resting tremor (primarily in the resting position)

By 2010 we knew:

• PD is gradual-onset with a definable prodromal window
• Non-motor features are a major component of prodromal disease
• Pathological studies (like the Braak staging model) had set PD to be a dopaminergic disease, but it is actually a multisystem neurodegeneration that starts before dopamine neurons are impacted

Non-motor symptoms in PD:

• Not all happen to all patients
• Can precede diagnosis or happen in early stages of diagnosis:
  • REM sleep behavior disorder and insomnia:  One of most specific to PD
  • Depression / anxiety
  • Loss of smell:  One of most specific to PD
  • Constipation
  • Orthostatic hypotension
  • Sexual problems
  • Urinary dysfunction
  • Mild cognitive impairment
• Later in disease:
  • Dementia and psychosis
  • Severe orthostatic hypotension or autonomic dysregulation
  • Urinary incontinence
  • Severe dysphagia and choking

How has prodromal PD been studied?

• Hard to study people before they are diagnosed
• Most generalizable way to document prodromal markers is to use population-based studies
• PD has a 2% lifetime prevalence.  It’s difficult to directly examine large populations of prodromal PD 
• Before 2009, the only studies were in smaller family or high-risk cohorts or large epidemiological studies designed for other purposes or adapted mid-stream to assess PD
  • Example – Honolulu Asia Aging study:
    • Took large numbers of individuals in Hawaii and followed them every year with motor testing, cognitive testing, 
    • Initially focused on cardiac risk factors but studied a lot of brain aspects as well
    • Continued to follow people until they passed away, at which the individuals donated their brain to research
    • Could then see which of those people progressed in PD
    • It was a difficult and decades long study, and was not efficient
• Three groups of patients that have been studied: 
  • Older adults with olfactory (smell) loss
  • Older adults with isolated REM sleep behavior disorder (iRBD)
  • Older adults with a strong family history or known genetic risk factors for PD

Parkinson At-Risk Syndrome (PARS) study: 

• Older adults with olfactory loss
• Baseline:  scratch-and-sniff smell tests that look for smell loss in older adults
• Sent out thousands of tests
• Anyone who had lower than what was expected for age on the scratch-and-sniff test were invited to come in and get a brain scan done to see if they had evidence of risk for PD
• Of those that came in, a few people showed a dopamine deficiency through a dopamine scan (DaT Scan) and were diagnosed with PD.  Note: scans are not necessary to diagnose PD!
• Four years later, looking at those diagnosed with PD, they noticed many had sleep problems
• Showed sleep disorders as a prodrome 

Rapid eye movement (REM) sleep behavior disorder (RBD):

• Characterized by dream enactment behaviors that occur during the phase of sleep called REM sleep
• Typically during REM sleep a person’s body is without muscle tone (atonia), meaning they can’t move
• In RBD, people are without atonia during the REM phase of sleep, and therefore have the muscle ability to move while they are dreaming
• A lot of times, this is caused by medications for obstructive sleep apnea  
• Most patients with the isolated form (not caused by medication, sleep apnea, etc.) of RBD (iRBD) are eventually diagnosed with a clinical form of alpha-synucleinopathy, such as PD, dementia with Lewy bodies (DLB), or multiple system atrophy (MSA)  
• Overlapping/similar symptoms in people with RBD who progress to synucleinopathy (they have MSA, DLB, PD)       
• Two published studies in people with five years of follow up documenting iRBD (isolated REM sleep behavior disorder) found there was a 38-45% conversion rate to PD over the 5 years
• Follow up demonstrated that over 80% had prodromal neurodegeneration
• In some cases, symptoms of iRBD were documented more than 25 years before onset 

There are also common genes that can increase risk of PD:

• If you have the genes, you are at greater risk of PD
• Most genes are extremely rare (only one family has them), but two are considered common.  Common genes:
  • LRRK2 mutation:  Non-manifesting carriers (have genes but don’t have PD) had subtle gait abnormalities on quantitative step testing, particularly with dual task conditions, as well as decreased arm swing and increased intra-individual walking variability
  • GBA mutation:  Non-manifesting carriers (have genes but don’t have PD) of GBA mutations were found to have iRBD, autonomic dysfunction, olfactory loss, constipation, and mild cognitive impairment
• Note: Having the genes doesn’t mean they get PD

We do not know how to predict who will develop PD, or when they will develop PD. 

PPMI – studying prodromal PD:

• Multi-center, multi-continent, deep phenotyping study sponsored by the Michael J. Fox Foundation (MJFF)
• PD cohort:  423 newly diagnosed, drug naive (no drug treatments yet) and 196 older adults 
• Prodromal cohort:
  • Olfactory dysfunction or iRBD, with and without DAT scan showing abnormality
  • Genetic cohort:  LRRK2 and GBA mutation carriers, but without a PD diagnosis
• They were followed annually with motor, cognitive, imaging, and plasma/CSF biomarkers  

 Practical uses for identifying prodromal PD?

• Prodromal PD is not benign:  Already having symptoms
• At PD diagnosis, many patients already have symptoms for several years:  Anxiety, apathy, autonomic dysfunction, motor deficits 
• Practical use, and why it is researched, is to improve population health
• The discovery of any neuroprotective therapy would instantly change the diagnosis of prodromal PD from being a research/academic issue to a clinical need