The role of glycemic control in Parkinson’s disease

The role of glycemic control in Parkinson’s disease 

The interplay between glycemic control and Parkinson’s Disease (PD) has long been recognized but not fully understood. The term “brain insulin resistance” has been suggested to describe decreased sensitivity of CNS pathways to insulin, followed by disturbances in synaptic, metabolic and immune response functions (Hoyer 1998). Strategies to normalize insulin sensitivity in neurons have thus been in the spotlight of clinical trials aiming to establish whether they may provide neuroprotective actions.  

Aims  

a. to identify and validate biofluid and digital biomarkers of glucometabolic derangement in PD cohorts. 

b. to investigate the effect of glucometabolic derangement on PD-associated motor and cognitive symptom progression. 

c. to investigate the efficacy of antidiabetic drugs in PD. 

d. to evaluate the role of 18F-fluorodeoxyglucose (FDG)-PET spatial covariance patterns in the identification of disease- and treatment-specific biomarkers in PD. 

Hypothesis 

We hypothesize that disturbance in glucose homeostasis is present in a portion of patients with neurodegenerative diseases, including PD, and may contribute to the definition of subgroups that may benefit by therapies that regulate insulin sensitivity and glucose control. 

We aim to test this hypothesis by investigating digital, biochemical and imaging markers of eating behavior and glucose metabolism in the periphery and the brain, in PD patients. Furthermore, we aim to study the efficacy of anti-diabetic agents against disease progression, in PD, and the correlation between treatment-effect and glucose control.  

Methods 

  1. A large observational, prospective cohort of >400 PD patients is established since 2011. Patients are evaluated annually, and clinical, biochemical, imaging and digital biomarkers of disease and symptom progression are collected. 
  1. Multi-center cohort of 450 well-described PD patients and healthy controls (www.aetionomy.eu). 
  1. A randomized-controlled trial that aims to investigate the efficacy of the GLP-1 RA Exenatide in early PD is ongoing at the Center for Neurology, Academic Specialist Center (NCT04305002). Multimodal biomarkers based on FDG-PET, plasma and cerebrospinal fluid samples, wearable accelerometer, clinical scales of motor symptoms, cognition, psychiatric symptoms and sleep disturbances, are collected in order to enable a more holistic approach to the disease evaluation. 

Researchers: Ioanna Markaki, Panagiota Tsitsi, Evita Papathoma, Theodora Ntetsika, Per Svenningsson

Selected publications: 

Euglycemia indicates favorable motor outcome in Parkinson’s disease. Markaki I, Ntetsika T, Sorjonen K, Svenningsson P. Movement Disorders. 2021 (In Press) DOI: 10.1002/mds.28545. 

Novel targeted therapies in Parkinson’s Disease. Ntetsika T, Papathoma E, Markaki I. Molecular Medicine. 2021 (In Press). doi: 10.1186/s10020-021-00279-2.

Fixation duration and pupil size as diagnostic tools in Parkinson’s Disease. Tsitsi P,  Nilsson Benfatto M,  Öqvist Seimyr G,  Larsson O,  Svenningsson P,  Markaki I.  Journal of Parkinson’s Disease. 2021 (In Press). DOI: 10.3233/JPD-202427

Cerebrospinal Fluid Levels of Kininogen-1 Indicate Early Cognitive Impairment in Parkinson’s Disease. Markaki I,  Bergstrom S,  Tsitsi P,  Remnestal J,  Manberg A,  Hertz E,  Paslawski W,  Sorjonen K,  Uhlen M,  Mangone G,  Carvalho S,  Rascol O,  Meissner WG,  Magnin E,  Wullner U,  Corvol JC,  Nilsson P,  Svenningsson P. Movement Disorders. 2020. 35;11 2101-2106. DOI: 10.1002/mds.28192

Repurposing GLP1 agonists for neurodegenerative diseases. Markaki I,  Winther K,  Catrina SB,  Svenningsson P. International review of neurobiology 2020 155; 91-112. DOI: 10.1016/bs.irn.2020.02.007 

Decreased Cerebrospinal Fluid Aβ42 in Patients with Idiopathic Parkinson’s Disease and White Matter Lesions. Markaki I,  Klironomos S,  Svenningsson P. Journal of Parkinson’s disease 2019 9;2 361-367. DOI: 10.3233/JPD-181486