Limits. Can we treat Parkinson´s even before the first symptoms appear?

Parkinson’s Disease is a complex neurological disorder commonly described by its dominant motor issues like tremors and stiffness, accounting for the characteristic Parkinsonian look.

But the truth is that Parkinson’s encompasses a much broader range of symptoms. Sleep disorders and gastrointestinal problems show us that Parkinson’s involves brain areas beyond traditional motor regions. Neurobehavioral changes like depression and anxiety are early-stage non-motor symptoms, while in advanced stages disturbed executive and intellectual functions.

Emerging research suggests that Parkinson’s extend even beyond the brain, affecting nerves throughout the body. For example, recent genetic studies found mutations that impair not only central nervous function but also peripheral processes.

When compromised nerves become sufficiently dysfunctional, a functional threshold in the nervous system is breached, and the classic motor symptoms appear, and the person is diagnosed. The first symptoms appear when dopamine-producing neurons are depleted beyond a critical threshold, often after long periods where the system has been able to compensate.

Age
Critical to understanding both the threshold for when the symptoms "breach" and the progressive nature of disease symptoms is the profound age dependency.

Age dependency is observed across all major neurodegenerative disorders. These observations underscore the conclusion that a series of complex interactions must occur over time, leading to functional deficits later in life.

The neuron's vulnerability is influenced by genetic, metabolic, connectivity, or environmental factors. In Parkinson´s, it seems to be a combination of all these factors that gradually - with advancing age - compromises the nerve cells toward their threshold.

The different thresholds in Parkinson´s
In conditions like Parkinson's disease, this concept of thresholds is essential to understanding why symptoms can appear early in simpler systems but later in more complex ones. 

The brain cells thresholds represent critical points in brain function where compensatory systems fail and symptoms become noticeable both for the patient and the world around the patient.

In Parkinson’s and other neurological disorders, brain networks can undergo considerable deterioration before reaching a tipping point. This resilience is largely due to complex compensatory strategies where undamaged areas of interconnected neural networks and chemical processes in the brain adapt by redistributing activity. The more complex, the better the possibility to compensate.

In other words, the threshold is higher in complex systems that are highly functionally integrated than in more linear autonomic and peripheral systems, which depend on automatic reflexive arcs.

Certain brain regions, especially those linked to movement and cognition, maintain function until around 70% of synaptic connections (synapses being the communication point between neuron) are lost, while simpler autonomic functions, like those controlling heart rate or digestion, are predicted to occur at ranges of 25 % of dysfunctional synapses or less.

These mechanisms underscore why symptoms often appear at different times and in various forms across all patients, depending on which brain systems are affected and the extent to which that part of the system can adapt.

Compensatory mechanisms for motor symptoms
In the early stages of Parkinson`s, brain circuits can change how neurons fire, allowing them to maintain equilibrium despite abnormal rhythms and disrupted signaling. For instance, in Parkinson's disease, the brain cells' dopamine transmission is altered in the early stages to stabilize motor functions.

Dopamine is a molecule used as a messenger between brain cells in parts of our motor system in the brain. In parkinsons, dopamine-producing brain cells are gradually lost, and the brain cells compensate by reducing dopamine reuptake.

Re-uptake is a normal mechanism where the brain "recycles" molecules to save energy. After dopamine is released to send a message about some movement, the brain cells take it back in to keep the right balance. By reducing re-uptake, the availability of dopamine in deficient areas outside the cell is increased - and the system continues to work as normal for a while.

These adaptive responses are central to the brain’s resilience, especially through adjustments within local networks that temporarily compensate for loss.

The brain also recruits alternative pathways to support failing primary circuits. As neurons in the key motor pathways degenerate, adjacent areas like the pre-supplementary motor cortex take on motor control, while regions like the cerebellum (that coordinate movement) work harder during tasks.

However, compensatory capacity is finite. Over time, the extensive structural and connectivity changes in Parkinson's reach a limit beyond where re-uoptake and re-organising cannot compensate enough, functions cannot be maintained, and symptoms become inevitable.

Can Parkinson's be prevented or postponed?
When understanding Parkinson´s through the concept of different functional thresholds in different areas of the brain, it becomes evident that treatments focused solely on a single molecular target may be insufficient.

Instead, focusing on comprehensive, early interventions across interconnected systems may better prevent functional decline. By identifying early biomarkers for the disease, in the blood, cerebrospinal fluid, or peripheral tissues - presymptomatic intervention, could shift focus from simply addressing symptoms to enhancing neuron health before critical thresholds are crossed.

Targeting functional thresholds through interventions like deep brain stimulation or cell replacement therapies shows promise, as these approaches aim to restore network functionality.

By reinforcing adaptability within affected systems, treatments can potentially sustain brain health for extended periods.

About the scientific paper:

First author: Luc Jordi, USA
Published: Progress in Neurobiology, November 2024
Link to paper: https://www.sciencedirect.com/science/article/pii/S0301008224001096?via%3Dihub