Baseline predictors for progression 4 years after Parkinson's disease diagnosis in the De Novo Parkinson Cohort (DeNoPa)

Mollenhauer, Brit; Zimmermann, Johannes; Sixel‐Döring, Friederike; Focke, Niels K.; Wicke, Tamara; Ebentheuer, Jens; Schaumburg, Martina; Lang, Elisabeth; Friede, Tim; Trenkwalder, Claudia

doi:10.1002/mds.27492

Cited by 143 publications

(149 citation statements)

References 55 publications

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“…The reasons for this positive association of serum NfL and age is explained by structural alterations of the axons with ageing, including vascular disease, metabolic changes, and inflammation. All of these have also been shown to play a role in PD progression 22 , which may also influence the NfL levels in blood.…”

Section: Discussionmentioning

confidence: 99%

Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson’s Disease Progression

Mollenhauer

Dakna

Liu

et al. 2019

Preprint

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Background: Alterations in neurofilament light chain (NfL), reflecting axonal damage, have been proposed as a biomarker for neurological disorders including Parkinson's disease (PD). Methods:We measured NfL concentrations by immunoassay in (1) a set of longitudinal CSF samples from 82 PD, 14 other neurodegenerative disorders (OND), and 53 healthy controls (HC);(2) A cross-sectional cohort with paired CSF and serum samples from subjects with 151 PD, 344 OND, and 20 HC, and (3a) a large longitudinal validation cohort with serum samples from 375 PD, 178 HC, and 57 prodromal Lewy Body disorder with hyposmia or isolated REM sleep behaviour disorder (iRBD), (3b) 216 symptomatic and 298 asymptomatic LRRK2, GBA, and SNCA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI). Mean differences in serum NfL levels between diagnostic groups, and correlation with motor signs, cognitive measures and dopamine transporter imaging, were assessed. Linear mixed effects models were used to assess longitudinal changes in log10 (NfL) in relation to demographic, clinical, and imaging variables. Findings:In the longitudinal cohort (1) NfL in CSF increased over time and was significantly positively correlated with MDS-UPDRS III motor and total scores in the PD group (p=0·0231 and 0·0081). In the cross-sectional cohort (2) the paired CSF and serum NfL samples were highly correlated (Spearman's rank ߩ ො ൌ 0 7 3 ; p<10^-6). In the large validation cohort (3a) mean baseline serum NfL was higher in PD (13 ±7·2pg/ml), hyposmics (15±15·1pg/ml), and iRBD (17±8pg/ml) compared with HC (12±6·7pg/ml) but was highest in the seven OND cases (18±7pg/ml). In the genetic cohort (3b), serum NfL levels were lower in asymptomatic than in symptomatic mutation carriers. There was a significant (age-adjusted) longitudinal increase in serum NfL in PD compared with HC. Serum NfL values were significantly positively associated with longitudinal MDS-UPDRS motor and total scores, as well as age. Interpretation: We identified NfL as the first blood-based PD progression biomarker. NfL levels in serum samples are increased in PD compared to HC, increase significantly over time in PD, and correlate with a clinical measure of disease severity. Although the specificity of NfL in PD is low and additional, more specific biomarkers are needed, serum NfL is the first blood-based biomarker candidate that could support disease stratification (PD vs. OND), track clinical progression, and might be used to assess responsiveness to neuroprotective treatments. M o l l e n h a u e r 5Neurofilaments are highly phosphorylated neuronal cytoskeleton components composed of three subunits of differing molecular weight maintaining neuronal structure and determining axonal calibre. The 68 kDa neurofilament light chain (NfL) is essential for the assembly of the complex as it forms its backbone and is released into extracellular fluids in response to axonal damage. 6,7 Several studies have shown elevated levels of NfL in the CSF of patients suffering from neurodegenerativ...

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Section: Discussionmentioning

confidence: 99%

Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson’s Disease Progression

Mollenhauer

Dakna

Liu

et al. 2019

Preprint

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“…This combination of characteristics may be a factor in the susceptibility of the substantia nigra pars compacta dopamine neurons in patients with poor regulation of glucose metabolism. Consistent with this situation is the observation that in early‐stage PD patients in the De Novo Parkinson Cohort, disease progression was faster in the participants who had CV disease risk factors, unregulated blood glucose, high uric acid levels, and inflammation …”

Section: Contributions From the Basic Sciencesmentioning

confidence: 99%

“…Consistent with this situation is the observation that in early-stage PD patients in the De Novo Parkinson Cohort, disease progression was faster in the participants who had CV disease risk factors, unregulated blood glucose, high uric acid levels, and inflammation. 74 Changes in lipid metabolism also play a role in both CV disease and PD. Oxidized LDLs are a major contributor to atherosclerotic plaque formation.…”

Section: Glucose Lipid and Cholesterol Metabolismmentioning

confidence: 99%

Understanding the Links Between Cardiovascular Disease and Parkinson's Disease

et al. 2019

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Studies investigating the associations between genetic or environmental factors and Parkinson's disease (PD) have uncovered a number of factors shared with cardiovascular disease, either as risk factors or manifestations of cardiovascular disease itself. Older age, male sex, and possibly type 2 diabetes are examples. On the other hand, coffee consumption and physical activity are each associated with a lower risk of both PD and cardiovascular disease. This observation raises questions about the underlying pathophysiological links between cardiovascular disease and PD. There is evidence for common mechanisms in the areas of glucose metabolism, cellular stress, lipid metabolism, and inflammation. On the other hand, smoking and total/low‐density lipoprotein cholesterol appear to have opposite associations with cardiovascular disease and PD. Thus, it is uncertain whether the treatment of cardiovascular risk factors will impact on the onset or progression of PD. The available data suggest that a nuanced approach is necessary to manage risk factors such as cholesterol levels once the associations are better understood. Ultimately, the choice of therapy may be tailored to a patient's comorbidity profile. This review presents the epidemiological evidence for both concordant and discordant associations between cardiovascular disease and PD, discusses the cellular and metabolic processes that may underlie these links, and explores the implications this has for patient care and future research. © 2019 International Parkinson and Movement Disorder Society

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“…Additionally, higher cholesterol may be associated with a lower risk of incident PD. These findings are counterintuitive within the context of cardiovascular health and risk factors, and tend to conflict with our current understanding of the role these play in the development of neurodegenerative diseases, including PD and AD, as well as our understanding of their role in disease progression …”

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confidence: 99%

“…These findings are counterintuitive within the context of cardiovascular health and risk factors, and tend to conflict with our current understanding of the role these play in the development of neurodegenerative diseases, including PD and AD, as well as our understanding of their role in disease progression. 11 Epidemiological studies are fraught with difficulties and the potential for methodological confounders and biases. Data ascertainment is typically dependent on insurance databases which are reliant on accurate clinical diagnosis and declaration, which in practice may be an under-or over-representation.…”

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confidence: 99%