Parkinson’s disease (PD) is characterized by slowness of movement and tremors, which often appear asymmetrically in patients. The new PD model described in this review article published in the Parkinson’s Disease Journal may explain these confusing asymmetric motor symptoms and other known variations such as varying degrees of constipation and sleep disturbances.

PD is a heterogeneous disorder. Symptoms and the rate at which symptoms progress vary greatly from patient to patient. In three quarters of patients, motor symptoms initially appear on one side of the body. Some patients develop constipation, loss of smell, trouble sleeping, and other symptoms years before diagnosis, but others do not. Although it is possible to define several subtypes of PD characterized by similar constellations of symptoms, the underlying causes of these differences are poorly understood. It is believed that neuron-to-neuron aggregation and propagation of alpha-synuclein protein is involved.

The origin and connectome model of alpha-synuclein (SOC) presented by Per Borghammer, MD, PhD, DMSc, Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark, proposes a unifying model, which may explain much of this variation between patients. The SOC model is fundamentally based on two ideas: the location or origin of the first aggregates of alpha-synuclein, and the importance played by the neural connectome in the transmission of alpha-synuclein pathology to other parts of the system. nervous.

This model was developed by integrating already available evidence from clinical and imaging studies of patients, animal models of PD, and post-mortem findings in brain tissue from patients with PD. This unifying model seems able to explain why PD is often an asymmetric disease in the first place, but also why some patients have more asymmetry than others and others no asymmetry at all. It also explains why certain subtypes of PD seem to exist, including why constipation and sleep disturbances only appear before diagnosis in some patients.

Imaging studies of live patients with PD and studies of biopsies and intestinal and brain tissue from biobanks clearly suggest that patients with PD have different patterns of neuronal damage. In some patients the brain is damaged before the peripheral nervous system, and in others the reverse pattern is observed. This new model, which is an extended version of the body-first versus brain-first hypothesis that we described in this journal in 2019, offers a simple explanation of motor asymmetry, while simultaneously offering explanations. for several other unexplained PD phenomena. “

Dr Per Borghammer, MD, PhD, DMSc, Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark

The model postulates that the first instance of pathological alpha-synuclein usually begins in one location and then spreads from that original site using authorized neural connections. The site of origin can be in the enteric nervous system of the gut, leading to a first body PD subtype. This type is characterized by early symptoms originating from the intestine and other peripheral organs as well as symptoms of sleep originating from the lower parts of the brainstem.

In contrast, the first alpha-synuclein pathology can also start inside the brain, leading to a brain-first subtype. “These patients will often develop motor symptoms quite quickly, whereas the symptoms of sleep and autonomic symptoms do not develop until later,” noted Dr Borghammer. “In the later stages of the disease, the two types of patients will have a similar burden of motor and non-motor symptoms, but at the beginning they are very different.”

The second component of the SOC model concerns how neurons are connected to each other, known as neural connectivity. A cerebral hemisphere primarily communicates with itself with only 1% of neural connections crossing the midline to the other hemisphere. Therefore, if the first occurrence of pathological alpha-synuclein occurs in one place in the brain, it will by definition occur in the left or right hemisphere. Subsequent spread of the pathology will therefore occur primarily through “same side” connections, including with dopamine cells on the same side of the brain. This leads to asymmetric damage to dopaminergic neurons causing asymmetric motor symptoms in patients.

“In short, we believe that motor asymmetry in PD needs to be understood in a brain first vs body first context. In brain-first PD, the initial pathology begins in one hemisphere and initially damages that hemisphere via the same lateral connections, leading to marked asymmetry, ”noted Dr. Borghammer. “Over time, the other hemisphere is also involved, as evidenced by the increasingly symmetrical motor symptoms in the patient.”

Dr Borghammer explained that the model also predicts that all-body PD patients will be different and generally have more symmetrical motor symptoms. This is because the pathology spreads from the gut to the brain in a more symmetrical fashion due to overlapping left / right connections in the peripheral nervous system. This then leads to a “wave” of pathology that spreads inside the brain, which is more symmetrical than that seen in brain-first patients. They therefore exhibit dopamine loss and more symmetrical motor symptoms, and this is exactly what clinical and imaging studies report. The model also predicts that at diagnosis, body-first patients already have a larger and more symmetrical load of alpha-synuclein pathology, which in turn promotes faster disease progression and accelerated cognitive decline. .

“It is known that patients with body-first type PD are at increased risk of developing dementia. According to the SOC model, this increased risk stems from the fact that at the time of a diagnosis of PD, the alpha-synuclein pathology is more widespread, more symmetrical and shows a greater involvement of certain brainstem neurons, themselves involved. in cognitive decline and dementia, ”added Dr. Borghammer.

Asked about the future prospects of the SOC model, Dr Borghammer replied that it will now be tested in future studies. “A good scientific model must be testable and falsifiable, and the current model meets these requirements. The scientific community must now investigate whether the SOC model has more explanatory power than previous models of PD pathogenesis. not a complete description of what is wrong with PD and needs to be further refined, ”he concluded.

PD is a slowly progressive disorder that affects movement, muscle control, and balance and is characterized by a wide range of motor and non-motor symptoms. It is the second most common age-related neurodegenerative disorder, affecting around 3% of the population by age 65 and up to 5% of people over 85.

Source:

Journal reference:

Borghammer, P., (2021) The α-synuclein origin and connectome model (SOC model) of Parkinson’s disease: explanation of motor asymmetry, non-motor phenotypes and cognitive decline. Journal of Parkinson’s Disease. doi.org/10.3233/JPD-202481.



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