Andreas Dammann Andersen

Cerebrospinal fluid biomarkers for Parkinson's disease - a systematic review.

Diagnosis of Parkinsons disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow early and more precise diagnosis and monitoring of dopamine replacement strategies and disease modifying treatments. Developments in analytical chemistry allow the detection of large numbers of molecules in plasma or cerebrospinal fluid, associated with the pathophysiology or pathogenesis of PD. This systematic review includes cerebrospinal fluid biomarker studies focusing on different disease pathways: oxidative stress, neuroinflammation, lysosomal dysfunction and proteins involved in PD and other neurodegenerative disorders, focusing on four clinical domains: their ability to (1) distinguish PD from healthy subjects and other neurodegenerative disorders as well as their relation to (2) disease duration after initial diagnosis, (3) severity of disease (motor symptoms) and (4) cognitive dysfunction. Oligomeric alpha‐synuclein might be helpful in the separation of PD from controls. Through metabolomics, changes in purine and tryptophan metabolism have been discovered in patients with PD. Neurofilament light chain (NfL) has a significant role in distinguishing PD from other neurodegenerative diseases. Several oxidative stress markers are related to disease severity, with the antioxidant urate also having a prognostic value in terms of disease severity. Increased levels of amyloid and tau‐proteins correlate with cognitive decline and may have prognostic value for cognitive deficits in PD. In the future, larger longitudinal studies, corroborating previous research on viable biomarker candidates or using metabolomics identifying a vast amount of potential biomarkers, could be a good approach.

Changes in kynurenine pathway metabolism in Parkinson patients with L-DOPA-induced dyskinesia

L‐3,4‐Dihydroxyphenylalanine (L‐DOPA) is the most effective drug in the symptomatic treatment of Parkinsons disease, but chronic use is associated with L‐DOPA‐induced dyskinesia in more than half the patients after 10 years of treatment. L‐DOPA treatment may affect tryptophan metabolism via the kynurenine pathway. Altered levels of kynurenine metabolites can affect glutamatergic transmission and may play a role in the development of L‐DOPA‐induced dyskinesia. In this study, we assessed kynurenine metabolites in plasma and cerebrospinal fluid of Parkinsons disease patients and controls. Parkinson patients (n = 26) were clinically assessed for severity of motor symptoms (UPDRS) and L‐DOPA‐induced dyskinesia (UDysRS). Plasma and cerebrospinal fluid samples were collected after overnight fasting and 1–2 h after intake of L‐DOPA or other anti‐Parkinson medication. Metabolites were analyzed in plasma and cerebrospinal fluid of controls (n = 14), Parkinson patients receiving no L‐DOPA (n = 8), patients treated with L‐DOPA without dyskinesia (n = 8), and patients with L‐DOPA‐induced dyskinesia (n = 10) using liquid chromatography‐mass spectrometry. We observed approximately fourfold increase in the 3‐hydroxykynurenine/kynurenic acid ratio in plasma of Parkinsons patients with L‐DOPA‐induced dyskinesia. Anthranilic acid levels were decreased in plasma and cerebrospinal fluid of this patient group. 5‐Hydroxytryptophan levels were twofold increased in all L‐DOPA‐treated Parkinsons patients. We conclude that a higher 3‐hydroxykynurenine/kynurenic acid ratio in plasma may serve as a biomarker for L‐DOPA‐induced dyskinesia. Longitudinal studies including larger patients cohorts are needed to verify whether the changes observed here may serve as a prognostic marker for L‐DOPA‐induced dyskinesia.

Cerebrospinal fluid levels of catecholamines and its metabolites in Parkinson's disease: Effect of L‐DOPA treatment and changes in levodopa‐induced dyskinesia

Levodopa (l‐DOPA, l‐3,4‐dihydroxyphenylalanine) is the most effective drug in the symptomatic treatment of Parkinsons disease (PD), but chronic use initiates a maladaptive process leading to l‐DOPA‐induced dyskinesia (LID). Risk factors for early onset LID include younger age, more severe disease at baseline and higher daily l‐DOPA dose, but biomarkers to predict the risk of motor complications are not yet available. Here, we investigated whether CSF levels of catecholamines and its metabolites are altered in PD patients with LID [PD‐LID, n = 8)] as compared to non‐dyskinetic PD patients receiving l‐DOPA (PD‐L, n = 6), or not receiving l‐DOPA (PD‐N, n = 7) as well as non‐PD controls (n = 16). PD patients were clinically assessed using the Unified Parkinsons Disease Rating Scale and Unified Dyskinesia Rating Scale and CSF was collected after overnight fasting and 1–2 h after oral intake of l‐DOPA or other anti‐Parkinson medication. CSF catecholamines and its metabolites were analyzed by HPLC with electrochemical detection. We observed (i) decreased levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid in PD patients not receiving l‐DOPA (ii) higher dopamine (DA) levels in PD‐LID as compared to controls (iii) higher DA/l‐DOPA and lower DOPAC/DA ratios in PD‐LID as compared to PD‐L and (iv) an age‐dependent increase of DA and decrease of DOPAC/DA ratio in controls. These results suggest increased DA release from non‐DA cells and deficient DA re‐uptake in PD‐LID. Monitoring DA and DOPAC in CSF of l‐DOPA‐treated PD patients may help identify patients at risk of developing LID.