Advances in Parkinson’s disease research: one step closer to identify subjects in the prodromal stage, predicting conversion and potential for disease-modifying therapy

Identification of people with prodromal PD enables early intervention to slow or alter its progression

The incidence of Parkinson’s disease (PD) is increasing. The reasons are unknown. Identifying people with prodromal PD to enable early intervention to slow or alter its progression and disease-modifying therapies are therefore receiving increasing attention. Recent advances in these fields were presented to a large symposium audience at AAT-ADPD.

Pesticides, pollutants in the air, water and soil, brain surgery and head trauma, and infections are among the suspected causes for an increase in the incidence of PD in Western Europe and the United States, said Walter Rocca, Professor of Health Sciences Research, Mayo Clinic, Rochester, USA. But no-one is sure of the reasons. It is also possible that the causes – which could be individual, societal or environmental – differ between men and women, or people with different forms of PD.

The incidence of neurodegenerative diseases is increasing

Kenneth Marek, president and senior scientist at the Institute for Neurodegenerative Disorders Institute for Neurodegenerative Disorders, Neurology, New Haven, USA highlighted the heterogeneous nature of PD and that there are probably many different aetiologies.

In all cases, the underlying neurodegeneration begins many years before the cardinal motor and nonmotor signs and symptoms arise, said Dr Marek, and intervening therapeutically in this prodromal phase might slow down or halt progression to clinical PD.

Identifying people with prodromal PD

Biomarkers used to identify potential prodromal PD patients include genetic mutations, REM sleep behaviour disorder, olfactory dysfunction (hyposmia), autonomic dysfunction such as constipation, and tissue synuclein, explained Dr Marek. But there is a need for a screening procedure that can be applied to a large population.

Loss of smell is a common first symptom in people with PD, so a smell identification test, the UPSIT (University of Pennsylvania Smell Identification Test) has been evaluated by Dr Marek and his collaborators as a preliminary screening tool for large-scale use in their Parkinson Associated Risk Study (PARS). The UPSIT together with a questionnaire was sent to study participants by mail so the test could be completed at home.

Therapeutic intervention in prodromal PD might slow or halt progression to clinical PD

All participants who were identified as hyposmic by the UPSIT and who agreed to further investigation were invited for dopamine transporter (DAT) imaging. Their DAT status at baseline was then defined as:

  • DAT deficit — ≤65% or less of age-expected lowest putamen specific binding ratio (SBR)
  • DAT in an indeterminate range— greater than 65 to 80% of age-expected lowest putamen SBR
  • No DAT deficit — greater than 80% age-expected lowest putamen SBR

Two-thirds of the 21 study participants, who had both hyposmia and a DAT deficit, developed PD within 4 years of the baseline.1

Dr Marek concluded that the combination of hyposmia and a DAT deficit is highly predictive of conversion to PD within 4 years.

It therefore appears that testing for hyposmia using the UPSIT followed by DAT imaging is a screening test for prodromal PD that could be applied to a large population.

Disease-modifying therapy: targeting alpha-synuclein through the glucocerebrosidase 1 (GBA1) pathway

 An important risk factor for the development of PD is a mutation of the GBA1 gene, said Anthony Schapira, Professor of Neurological Science, UCL Institute of Neurology, London.

It is estimated that 5–10% of PD patients have a GBA1 mutation, but not all carriers develop PD; 30% of carriers will develop the disease by 80 years of age.2

The exact mechanism by which GBA1 mutations increase risk of PD is still unknown. However bidirectional reciprocal relationship has been demonstrated between GBA1 enzyme activity (GCase) and levels of alpha-synuclein, explained Professor Schapira. Alpha-synuclein is the main constituent of Lewy bodies, which are the characteristic intraneuronal protein inclusions in PD; and it is a major therapeutic target.

GCase is translated in the Endoplasmic Reticulum (ER) and then transported to the lysosome via the Golgi. Lysosomal dysfunction is thought to have a central role in PD pathogenesis through degradation and/or clearance of alpha-synuclein.

One potential way to increase GCase and therefore decrease alpha-synuclein levels is to use a chaperone that targets the mutant protein in the ER and transfers it via the Golgi to the lysosome, where it dissociates restoring GCase activity.3

Increasing GCase decreases alpha-synuclein levels

Professor Schapira and his colleagues carried out a proof of principle study to confirm the safety of a chaperone in 10 GBA1-positive and 10 GBA1-negative PD patients. The primary endpoint was to prove the safety of the chaperone and to demonstrate it crossed the blood-brain barrier.

The study showed that the chaperone was tolerated and there seemed to be no major safety issues. Its concentration in the cerebrospinal fluid was approximately 10% of that in blood, and it engaged with its target in a significant concentration, at least in the periphery.

References
  1. Jennings D, Siderowf A, Stern M, Seibyl J, Eberly S, Oakes D, Marek K; PARS Investigators. Conversion to Parkinson disease in the PARS hyposmic and dopamine transporter-deficit prodromal cohort. JAMA Neurol. 2017;74:933-40.
  2. Migdalska‐Richards A, Schapira AHV. The relationship between glucocerebrosidase mutations and Parkinson disease. J Neurochem. 2016;139(Suppl 1):77-90.
  3. Gegg ME, Schapira AHV. The role of glucocerebrosidase in Parkinson disease pathogenesis. FEBS J. 2018 Jan 31.
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