Jun 27, 2022
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Parkinson’s disease (PD) – a progressive nervous system disorder that affects movement and whose symptoms begin gradually – is incurable, but the earlier it is diagnosed, the more the symptoms can be delayed and slowed. 

PD is the second most common neurodegenerative disease in the world. Tremors, stiffness, the slowing of movement (bradykinesia) and slurred speech are common symptoms. One’s steps may become shorter when walking. It may be difficult to get out of a chair. Patients may drag their feet as they try to walk. Muscle stiffness and pain may occur in any part of the body. One’s posture may become stooped or one may have balance problems; a decreased ability to perform unconscious movements, including blinking, smiling or swinging the arms; one may speak softly, quickly, slur or hesitate before talking. 

At a more advanced stage, Parkinson’s patients may difficulties with swallowing, chewing and eating; sleep and bladder problems

Bladder problems. Parkinson’s disease may cause bladder problems and difficulty falling or staying asleep. 

But in the early stages, it’s hard to identify the problem.  Neurologists still lack a validated lab-based methodology or biomarker, for diagnosing it definitively.  Instead, they have to rely mostly on a clinical diagnosis based on the appearance of specific motor symptoms that indicate a patient is suffering from the disease. 

The loss of dopamine cells in the brain is what gives rise to the motor symptoms. Unfortunately, by the time the disease is diagnosed, too many dopamine cells have been lost, limiting the prospects for normal functioning. Available treatments such as medications target the symptoms of PD but cannot reverse the progression of the disease. 

Now, however, researchers at the Hebrew University of Jerusalem (HUJI) have discovered a chain of cellular and physiological events that have the potential to provide help in diagnosing the disease years earlier.   

Prof. Joshua Goldberg of the department of medical neurobiology headed a team that included Prof. Jochen Roeper of Goethe University in Frankfurt, Germany. They published their findings in the journal Science Advances under the title “α-Synuclein–induced Kv4 channelopathy in mouse vagal motoneurons drives nonmotor Parkinsonian symptoms.” 

The scientists suggested that one possible key for diagnosing Parkinson’s disease earlier is to better understand the physiological process underlying constipation, which is a common – while not usually discussed – non-motor symptom of PD. In fact, constipation can appear up to two decades before PD diagnosis. 

The way to this latest discovery goes all the way back to 1912 when Dr. Friedrich Lewy first published the existence of a buildup of tiny deposits of protein waste within brain cells called Lewy bodies.  Two decades ago, researchers elaborated on this finding and described how these Lewy bodies spread throughout the brain of PD patients.  But while this finding was viewed as a potentially groundbreaking, the Lewy bodies remain clinically inaccessible preventing the ability to determine whether a person has them, even though they may be lurking in the brain for many years before diagnosis. 

So the HUJI-led team focused on trying to link the Lewy body buildup with specific known non-motor symptoms of Parkinson’s.  These included anxiety, sleep disorder, loss of the sense of smell and especially constipation. They thought that the Lewy bodies were building up in specific areas of the brain and killing the brain cells that control the healthy functioning of relevant parts of the body. 

One of the first locations where Lewy bodies are found in the brain is an area that affects movement in the gastrointestinal system, thus providing a potential explanation for constipation in Parkinson’s patients. The problem with this proposition is that Lewy bodies do not necessarily kill brain cells and may instead represent the cells’ coping mechanism. Goldberg’s team looked for a mechanistic explanation tying Lewy bodies to constipation that does not depend on them killing brain cells.

 They over-expressed a specific protein named alpha-synuclein that was already known to aggregate as the main constituent of Lewy bodies in mouse brain cells that control gastrointestinal motility.  The result was that the over-expression of the protein caused these brain cells to shrink and their electrical activity to slow down, directly affecting the physiological properties that led to the constipation.  It is thus likely that this is the process that also occurs in humans in the early stages of PD.

“As far as we know, this is the first time that anyone has described a causal chain of events connecting between how alpha-synuclein protein impacts brain cells and the early symptoms that we have long known predate this disease,” Goldberg declared. 

On a diagnostic level, he said, this finding may help physicians detect the disease earlier in the future. “Consider a 55-to-60-year-old patient suffering from constipation. We may someday design a test based on the neural changes we discovered to determine whether there is a neural factor at play which could hint to Parkinson’s.”  

While he admits that this is still hypothetical, “one day in the future, we are confident that we will be able to identify a variety of biomarkers – including physiological ones like the one we propose that will allow us to definitively diagnose the disease far earlier than we are currently able.”

 The potential behind such an early diagnosis is enormous because at present there are no therapies capable of stopping the progression of the disease.  The hope is that with early intervention certain therapies that are unsuccessful at a later stage may actually be able to halt the progression of Parkinson’s disease.