Clinical trials and Biomarkers in Parkinsonism

Clinical Trials

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Its clinical manifestation and diagnosis is based on bradykinesia in combination with rigidity and/or resting tremor. PD patients also suffer from non-motor symptoms including depression, loss of smell, sleep disorders, anxiety and cognitive impartment. The neuropathological diagnosis is based on loss of dopaminergic neurons in the substantia nigra pars compacta  and the presence of abnormal α-synuclein-enriched inclusions called Lewy bodies. Unfortunately, currently available therapies only alleviate symptoms, by enhancing dopamine neurotransmission, without modifying disease progression. 

We have developed an excellent reputation and platform for conducting clinical trials. The major motivation for the clinical research is therefore to identify therapies that slow down  PD. The fact that we follow GBA-PD patients enabled us to be part of the Venglustat/MOVES-PD study. In this precision medicine study, a synthesis inhibitor of the substrate for GCase, glycosylceramide, was tested in GBA-PD patients. We were leading a first-in-human trial with intraputamenal delivery of CDNF in PD. CDNF is safe in advanced PD and we observe an improvement in some patients.

We were leading for phase IIA study in which we found that a myeloperoxidase inhibitor, AZD3241, reduces microglia activity, measured by 11CPBR28-PET in PD (Jucaite et al., 2015) and MSA. Given the role of inflammation and lipids in PD, we now conduct a safety and proof-of-concept study with Montelukast. In a nationwide population‐based case‐control epidemiological study, we found a significantly decreased incidence of PD among individuals with a recorded intake of a DPP‐4 inhibitor or a GLP‐1R agonist (Svenningsson et al., 2016). We have obtained GLP-1R agonist Exenatide  and placebo and started to perform an academic double-blind, placebo-controlled experimental medicine trial in early PD patients. In addition of being engaged in clinical trials to find disease modifying therapies against PD, we have recently led for a phase II study with IRL752 for the treatment of dementia in PD (Svenningsson et al 2020, Mov Dis) and a phase Ib study with IRL790 against L-Dopa-induced dyskinesias in PD (Svenningsson et al 2018 NPJ). Together with Neurolixis and with support from Parkinson UK and MJFF, we will conduct a study with NLX-112 against L-Dopa-induced dyskinesias in PD.  

Cerebrospinal fluid biomarkers for Parkinson’s Disease and Atypical Parkinsonian Syndromes  

Biomarker analyses of Cerebrospinal fluid (CSF) is used for the diagnosis of Alzheimer’s disease and is the preferred biosample to address diagnostic and prognostic information related to neurodegenerative disorders. PD shares symptomatology with several other rare neurodegenerative disorders collectively named atypical parkinsonism syndromes (APS). APS include corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), vascular parkinsonism and dementia with Lewy bodies (DLB). The diagnostic challenges caused by the overlapping clinical features of PD and APS are reflected in the low diagnostic accuracy. The accurate discrimination between APS and PD is critical for patients as the disease progression, and subsequent functional decline, is often more rapid in APS.  

In our studies, we use targeted or unbiased large-scale proteomic and metabolomic approaches to screen for novel promising markers for PD and related disorders. We try to identify specific biomarkers for each of disorders and targets that can differentiate, with good specificity, between PD and APS, a common challenge in clinical diagnosis.  Most of these studies are conducted using CSF samples from the Biopark cohort, a longitudinal PD cohort with about 600 well characterised patients managed by Prof Svenningsson.

Researchers: Wojciech Paslawski, Ellen Hertz, Yachao He, Per Svenningsson

Selected publications: 

Ecto-GPR37: a potential biomarker for Parkinson’s disease. Morató X, Garcia-Esparcia P, Argerich J, Llorens F, Zerr I, Paslawski W, Borràs E, Sabidó E, Petäjä-Repo UE, Fernández-Dueñas V, Ferrer I, Svenningsson P, Ciruela F. Transl Neurodegener. 2021 Feb 26;10(1):8. doi: 10.1186/s40035-021-00232-7.

Cerebrospinal Fluid Proteins Altered in Corticobasal Degeneration. Paslawski W, Bergström S, Zhang X, Remnestål J, He Y, Boxer A, Månberg A, Nilsson P, Svenningsson P. Movement Disorders. 2021 Mar 4. doi: 10.1002/mds.28543.

Cerebrospinal Fluid Levels of Kininogen-1 Indicate Early Cognitive Impairment in Parkinson’s Disease. Markaki I, Bergström S, Tsitsi P, Remnestål J, Månberg A, Hertz E, Paslawski W, Sorjonen K, Uhlén M, Mangone G, Carvalho S, Rascol O, Meissner WG, Magnin E, Wüllner U, Corvol JC, Nilsson P, Svenningsson P. Movement Disorders. 2020 Nov;35(11):2101-2106. doi: 10.1002/mds.28192.

α-synuclein−lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson’s disease patients. Paslawski, W. et al. Proceedings of the National Academy of Sciences 116, 15226-15235, doi:10.1073/pnas.1821409116 (2019). 

24S-Hydroxycholesterol Correlates With Tau and Is Increased in Cerebrospinal Fluid in Parkinson’s Disease and Corticobasal Syndrome. Björkhem, I., Patra, K., Boxer, A. L. & Svenningsson, P. Frontiers in neurology 9, 756, doi:10.3389/fneur.2018.00756 (2018). 

Blood Biomarkers in Parkinson’s Disease

Plasma has in recent years regained recognition as a promising biosample for biomarkers, particularly for neurodegenerative diseases.

Studies using modern highly sensitive methods have been able to detect many of the CSF biomarkers in plasma, and even given rise to novel candidate markers. The clinical convenience of drawing blood compared to performing spinal taps, in combination with many neurodegenerative diseases such as PD displaying peripheral pathology, makes plasma a potentially superior medium for biomarkers.

We are attempting to find similar reliable plasma biomarkers for Parkinson’s disease (PD) using several approaches:

  • Shotgun proteomics, such as untargeted mass spectrometry, to discover novel biomarkers for PD and different PD complications.
  • Targeted disease biomarkers, related to PD pathophysiology using immunoassays, quantifying immunological and neurodegenerative markers.
  • Targeted validations of candidate biomarkers, from discovery, proteomic or CSF studies.
  • Early prognostic biomarker to predict disease phenotype (such as cognitive decline), using longitudinal clinical data.

The plasma samples from the BioPark cohort are mainly analysed at the Svenningsson lab at King’s College London.

Researchers: Shervin Khousousi, Per Svenningsson

Selected publications: 

Plasma IL-6 and IL-17A Correlate with Severity of Motor and Non-Motor Symptoms in Parkinson’s Disease. H. F. Green, S. Khosousi, P. Svenningsson, J Parkinson’s Disease. 9, 705–709 (2019)

Immunological phenotype of cells derived from PD patients  

There is growing evidence that both innate and adaptive immune systems are involved in the onset and in the progression of PD.  We have a large collection of PBMC samples in the BioPark cohort to perform immunological studies in PD. To address these questions, we use state-of-the-art flow cytometry (FACS), biochemistry and imaging techniques. We hope that this study in immune-related PD progression may result in establishing novel therapy protocols.  

In addition, we’re also interested in biomarkers and bio-predictors for PD. This led us to investigate specific actin-binding proteins that are part of signaling pathways affected by PD in immune cells. These findings together with other prospective biomarkers in plasma/serum may contribute to advances in diagnostics of PD.   

Researchers: Dejan Mamula, Per Svenningsson

Selected publications: 

Alterations of p11 in brain tissue and peripheral blood leukocytes in Parkinson’s disease. Green, H., Zhang, X., Tiklova, K., Volakakis, N., Brodin, L., Berg, L., Greengard, P., Perlmann, T., Svenningsson, P., 2017.  Proc. Natl. Acad. Sci. U. S. A. https://doi.org/10.1073/pnas.1621218114