Mountain range model for heterogeneity within Parkinson’s disease

Movement disorders

By Mardi Chapman

26 Apr 2022

It’s time to break down the entity of Parkinson’s disease (PD) into its many diseases with different clinical presentations, patterns of progression, genetics and aetiologies, experts say.

According to a Perspectives article published in npj Parkinson’s Disease, the focus on the common pathological end-point of Lewy bodies and the loss of dopaminergic neurons led to the development of effective symptomatic therapies such as levodopa.

“However, the failure of nineteen phase 3 intervention trials targeting modification of disease progression illustrates a limitation of this focus,” the article said.

Its Australian and New Zealand authors, including Associate Professor Antony Cooper from the Garvan Institute’s Parkinson’s Disease and Neurodegeneration Lab, presented their PD Mountain Range model.

It features multiple starting points based on age, environment, comorbidities, sex and genetics and multiple routes influenced by intrinsic factors such as gut microbiome and extrinsic factors such as diet and exercise.

“These routes are not independent, merging and diverging, meaning it is likely that individuals can switch between the routes dependent on their particular combination of intrinsic and extrinsic factors.”

They said the application of genome-wide association studies (GWAS) to the study of PD enables identification of the genetic basis of risk that exists long before the disease initiates.

“However, the genetic variants that have been associated with PD by GWAS (e.g. 90 genetic loci) only explain between 16-36% of the heritability of PD.”

“Advances within the fields of single-cell transcriptomics and bulk-cell analyses will provide additional insights that begin to untangle the relative contributions of genetics and the environment to PD risk manifestation.”

They said disease biomarkers for the different diseases that collectively form PD are urgently needed.

“The need to define individual diseases as opposed to merging them into a single entity is in line with the prediction made by Espay and Lang that smaller, smarter clinical trials are needed to move away from this ‘homogeneous’ clinical Parkinson’s phenotype.”

The authors predicted technological advances in the lab and in wearable devices, together with a network medicine approach used in other complex conditions such as cardiovascular disease and cancer will help move the field forward towards novel targets and new therapies.

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