The identification of disease-modifying therapies is the Holy Grail of PD research, but to date no drug has been approved as such a therapy.1
There are numerous disease-modifying therapies currently in the pipeline attempting to modify the underlying pathomechanisms. In recent years, the results of molecular genetics and biomarker research have raised hopes of earlier diagnosis and new neuroprotective therapeutic approaches. 2
With disease-modifying treatment strategies on the horizon, the use of biomarkers for identifying and stratifying individual patients in the earliest stages of Parkinson's disease (PD) is key for ideal treatment at or even before symptom onset. 3
These biomarkers will also serve to monitor treatment success in clinical trials. Promising examples of blood biomarkers in PD, such as alpha-synuclein species and neurofilament light chain, are under investigation. 2
/// What is NFL?
In one study to determine whether neurofilament light chain protein in CSF (cNfL), a sensitive biomarker of neuroaxonal damage, reflects disease severity or can predict survival in PWP (PD). 4
Higher cNfL in the early phase of PD was associated with greater severity of all cardinal motor symptoms except tremor and with shorter survival and impaired olfaction. cNfL concentrations above the median conferred an overall 5.8 times increased hazard of death during follow-up period. After adjustment for age and sex, higher cNfL correlated with striatal dopamine transporter uptake deficits and lower fractional anisotropy in diffusion tensor imaging of several axonal tracts.
cNfL shows usefulness as a biomarker of disease severity and to predict survival in PD. The present results indicate that the cNfL concentration reflects the intensity of the neurodegenerative process, which could be important in future clinical trials.
Neurofilament light chain is a marker of axonal degeneration. Its measurement from peripheral blood was recently made possible by new technology. 5
Serum neurofilament light chain (sNfL) is a biomarker of neuronal damage that is used to monitor disease activity, response to treatment and to prognosticate disease course in people with neurodegenerative disease.6
Elevated blood neurofilament light chain (NfL), which indicates the loss of neuronal integrity, is emerging as a diagnostic and outcome-predicting biomarker for neurological diseases. 7
Blood levels of neurofilament light chain (NfL) provide an easily accessible fluid biomarker that might allow capturing of the conversion from prodromal to manifest PD. 3
Conversely, significant downregulation of blood NfL levels were positively correlated with a reduced probability of having a PD diagnosis. 7
///Potential use for NFL
This study assessed longitudinal serum NfL levels in subjects converting from prodromal to manifest sporadic PD (converters), comparing at-risk subjects with matched controls over time. 3
While NfL levels were normal at the prodromal stage, subjects converting to the manifest motor stage showed a significant intra-individual acceleration of the age-dependent increase of NfL levels. 3
The temporal dynamics of intraindividual NfL blood levels might mark the conversion to clinically manifest PD, providing a potential stratification biomarker for individual disease onset and set the stage for novel precision medicine approaches to the treatment of PD. 3
Likewise, plasma EV NfL in patients with PD correlated with the severity of akinetic rigidity. PD patients with optimal EV NfL (lowest quartile) had 6.66 point lower Unified Parkinson's Disease Rating Scale-III score after adjustment for age, sex, and disease duration. 8
This suggests a possible correlation between plasma EV NfL with the severity of motor symptoms within PD patients, especially with akinetic rigidity type. 8
This study sought to determine whether plasma neurofilament light chain (NfL) concentration reflects and corelates with imaging brain white matter integrity changes seen in patients with early Parkinson's disease (PD). 5
137 early PD patients and 51 healthy controls were included. Plasma NfL levels were measured. 3T MRI including diffusion tensor imaging was acquired for analysis of association between NfL and both fractional anisotropy (FA) and mean diffusivity (MD) in white matter tracts and subcortical nuclei. 5
A pattern of brain microstructural changes consistent with neurodegeneration was associated with increased plasma NfL in most of the frontal lobe and right internal capsule, with decreased FA and increased MD. 5
The same clusters were also associated with poorer global cognition. A significant cluster in the left putamen was associated with increased NfL, with a significantly greater effect in PD than controls. 5
Thus plasma NfL may be associated with brain microstructure, as measured using diffusion tensor imaging, in patients with early PD. Higher plasma NfL was associated with a frontal pattern of neurodegeneration that also correlates with cognitive performance. This may support a future role for plasma NfL as an accessible biomarker for neurodegeneration and cognitive dysfunction in PD. 5
The positive, negative, and overall percentages of agreement between the clinical diagnosis and plasma total α-synuclein diagnosis was determined. The results demonstrate the usefulness of the plasma total α-synuclein concentration to discriminate PD patients from NCs and reveal the elevation of the plasma NfL level in PD patients. 9
Serum NfL concentrations were associated with Hoehn & Yahr stages. During follow-up, baseline NfL levels were associated with time to cognitive decline 10
Serum NfL was associated with NT-proBNP linking neuronal and cardiac damage in advanced PD patients. 10
In advanced PD patients, serum NfL concentrations are associated with motor function, cognitive decline and subclinical cardiac damage. 10
///Non-motor PD+
To delineate the impact of non-motor markers (REM sleep behavior disorder (RBD), orthostatic hypotension (OH), cardiac sympathetic denervation, hyposmia) on neuronal injury in early-stage Parkinson's disease (PD), we measured the plasma NFL levels of PD patients and evaluated its relationship with these signs. 11
OH was assessed using a tilt-table test. Other clinical parameters such as RBD, Unified Parkinson's Disease Rating Scale, Smell Identification Test (CCSIT), white matter hyperintensity (WMH), cardiac MIBG and striatal dopamine transporter (DAT) uptake were assessed.
Plasma NFL levels were measured during a 2 year follow-up period. 70 patients remained PD, 5 patients converted to Parkinson-plus or Atypical Parkinsonian syndrome (P + converter) and 2 were lost to follow-up. 11
In this study, NFL level did not differ between PD and control groups, but PD patients with Orthostatic Hypotension had higher levels compared with those without OH. The P + converter group had the highest plasma NFL level. 11
In a multiple regression analysis, OH, age, and disease duration independently correlated with plasma NFL level. This finding adds biomarker-based evidence for poor clinical outcomes associated with OH in patients with PD. 11
Serum neurofilament light chain (NfL) levels are associated with disease severity in early Parkinson's disease (PD). We assessed the association of serum NfL with motor and cognitive function and decline in advanced PD patients. 10
Serum samples were collected from patients with clear signs of parkinsonism, but with uncertain diagnosis at the inclusion. Clinical diagnoses of Parkinson disease (PD) and atypical parkinsonism disorders (APDs , Parkinson’s Plus) were established after 3 years of follow-up and updated again after a maximum of 12 years in cases where longer follow-up data were available. 12
Serum NFL was quantified in patients with PD and APD/P Plus, multiple system atrophy, progressive supranuclear palsy and 53 non-neurologic controls. 12
Serum NFL levels were elevated and differentiated the APD group from PD and control patients with accuracy levels up to 91% (sensitivity = 86% and specificity = 85%). 12
Serum NFL strongly correlated with CSF NFL levels in all groups and with age in PD and controls. 12
In this study, the probability of having APD was 76% (positive predictive value) and of having PD 92% (negative predictive value). 12
The authors conclude that serum NFL levels are markedly elevated in APD compared to PD and discriminate APDs from PD with high accuracy. Serum NFL may be a useful clinical biomarker to identify APD, even at stages when clinical symptoms are not yet conclusive. 12
///Cognition
Our results associating plasma NfL levels with cognitive dysfunction in PD are consistent with previous studies carried out in several countries/district, based on our meta-analysis. 13
Cognitive dysfunction is a disabling complication in Parkinson's disease (PD). Accuracy of diagnosis of mild cognitive impairment in PD (PD-MCI)
Plasma NfL levels objectively differentiates PD-MCI from PD-NC patients and may serve as a plasma biomarker for predicting progression to dementia in PD. Plasma levels of p-tau181 does not seem to help in differentiating PD-MCI or to predict future cognitive deterioration.14
However, the relationship between plasma NFL and cognitive decline in dementia due to Parkinson's disease (PD) remains to be elucidated. Plasma NFL was significantly higher in the PDD group, compared with the PDND group. High plasma NFL correlated with poor cognition in AD and PD, but not with motor symptoms in PD. Plasma NFL may represent a biomarker of cognitive decline in AD and PD, with more specificity for AD. 15
Plasma and CSF NfL levels correlated substantially; NfL was highest in neurocognitive disorders. PD participants with high plasma NfL were more likely to develop incident cognitive impairment. Plasma NfL is a useful prognostic biomarker for PD, predicting clinical conversion to mild cognitive impairment or dementia. 16
Plasma neurofilament light chain (NfL) is a marker of neuronal damage in different neurological disorders and might predict disease progression in dementia with Lewy bodies (DLB). The study enrolled 45 controls and 44 DLB patients (including 17 prodromal cases) At baseline, plasma NfL levels were higher in both probable DLB and prodromal cases compared to controls. Plasma NfL emerged as the best predictor of cognitive decline compared to age, sex, and baseline severity variables. The study supports the role of plasma NfL as a useful prognostic biomarker from the early stages of DLB. 17
Serum NfL levels were significantly increased in the PD group and were also related to worse cognitive performance and a cortical macro and microstructural compromise. These associations were observed both cross-sectionally and longitudinally within a one-year follow-up period. Topographically, NfL levels reflected posterior-cortical deterioration rather than frontal damage. Importantly, NfL levels were not associated with striatal SPECT-DAT uptake or β-amyloid burden. Our results show that serum NfL levels reflect cortical neurodegeneration from the very early stages of PD. Moreover, its brain structural correlates and its lack of relationship with dopaminergic depletion or amyloidosis suggests that NfL could track the underlying pathological process leading to PD dementia. 18
///Conclusions
Neurofilament light chain in serum samples is increased in Parkinson's disease patients versus healthy controls, increases over time and with age, and correlates with clinical measures of Parkinson's disease severity. Although the specificity of neurofilament light chain for Parkinson's disease is low, it is the first blood-based biomarker candidate that could support disease stratification of Parkinson's disease versus other cognate/neurodegenerative disorders, track clinical progression, and possibly assess responsiveness to neuroprotective treatments. 19
….references
1. Giuliano, C., Cerri, S., Cesaroni, V. & Blandini, F. Relevance of Biochemical Deep Phenotyping for a Personalised Approach to Parkinson’s Disease. Neuroscience 511, 100–109 (2023).
2. Tönges, L., Kwon, E. H. & Klebe, S. Monogenetic Forms of Parkinson’s Disease - Bridging the Gap Between Genetics and Biomarkers. Front. Aging Neurosci. 14, 822949 (2022).
3. Wilke, C. et al. Intraindividual Neurofilament Dynamics in Serum Mark the Conversion to Sporadic Parkinson’s Disease. Mov. Disord. Off. J. Mov. Disord. Soc. 35, 1233–1238 (2020).
4. Bäckström, D. et al. NfL as a biomarker for neurodegeneration and survival in Parkinson disease. Neurology 95, e827–e838 (2020).
5. Welton, T. et al. Plasma Neurofilament Light Concentration Is Associated with Diffusion-Tensor MRI-Based Measures of Neurodegeneration in Early Parkinson’s Disease. J. Park. Dis. 12, 2135–2146 (2022).
6. Benkert, P. et al. Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. Lancet Neurol. 21, 246–257 (2022).
7. Chen, J.-H., Chan, L., Chung, C.-C., Bamodu, O. A. & Hong, C.-T. Blood Neurofilament Light Chain in Parkinson’s Disease: Comparability between Parkinson’s Progression Markers Initiative (PPMI) and Asian Cohorts. J. Clin. Med. 10, 5085 (2021).
8. Chung, C.-C., Chan, L., Chen, J.-H., Bamodu, O. A. & Hong, C.-T. Neurofilament light chain level in plasma extracellular vesicles and Parkinson’s disease. Ther. Adv. Neurol. Disord. 13, 1756286420975917 (2020).
9. Lin, W.-C., Lu, C.-H., Chiu, P.-Y. & Yang, S.-Y. Plasma Total α-Synuclein and Neurofilament Light Chain: Clinical Validation for Discriminating Parkinson’s Disease from Normal Control. Dement. Geriatr. Cogn. Disord. 49, 401–409 (2020).
10. Niemann, L. et al. Serum neurofilament is associated with motor function, cognitive decline and subclinical cardiac damage in advanced Parkinson’s disease (MARK-PD). Parkinsonism Relat. Disord. 90, 44–48 (2021).
11. Park, D. G., Kim, J. W., An, Y.-S., Chang, J. & Yoon, J. H. Plasma neurofilament light chain level and orthostatic hypotension in early Parkinson’s disease. J. Neural Transm. Vienna Austria 1996 128, 1853–1861 (2021).
12. Marques, T. M. et al. Serum NFL discriminates Parkinson disease from atypical parkinsonisms. Neurology 92, e1479–e1486 (2019).
13. Zhu, Y. et al. Association between plasma neurofilament light chain levels and cognitive function in patients with Parkinson’s disease. J. Neuroimmunol. 358, 577662 (2021).
14. Pagonabarraga, J. et al. Dissociable contribution of plasma NfL and p-tau181 to cognitive impairment in Parkinson’s disease. Parkinsonism Relat. Disord. 105, 132–138 (2022).
15. Lin, Y.-S., Lee, W.-J., Wang, S.-J. & Fuh, J.-L. Levels of plasma neurofilament light chain and cognitive function in patients with Alzheimer or Parkinson disease. Sci. Rep. 8, 17368 (2018).
16. Aamodt, W. W. et al. Neurofilament Light Chain as a Biomarker for Cognitive Decline in Parkinson Disease. Mov. Disord. Off. J. Mov. Disord. Soc. 36, 2945–2950 (2021).
17. Pilotto, A. et al. Plasma Neurofilament Light Chain Predicts Cognitive Progression in Prodromal and Clinical Dementia with Lewy Bodies. J. Alzheimers Dis. JAD 82, 913–919 (2021).
18. Sampedro, F. et al. Serum neurofilament light chain levels reflect cortical neurodegeneration in de novo Parkinson’s disease. Parkinsonism Relat. Disord. 74, 43–49 (2020).
19. Mollenhauer, B. et al. Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson’s Disease Progression. Mov. Disord. Off. J. Mov. Disord. Soc. 35, 1999–2008 (2020).
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