<scp>CSF NFL</scp> in a Longitudinally Assessed <scp>PD</scp> Cohort: Age Effects and Cognitive Trajectories

Lerche, Stefanie; Wurster, Isabel; Röben, Benjamin; Zimmermann, Milan; Machetanz, Gerrit; Wiethoff, Sarah; Dehnert, Monique; Rietschel, Lea; Riebenbauer, Benjamin; Deuschle, Christian; Stransky, Elke; Lieplt-Scarfone, Inga; Gasser, Thomas; Brockmann, Kathrin

doi:10.1002/mds.28056

Cited by 41 publications

(42 citation statements)

References 15 publications

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“…In the MSA cohort, pNfL levels slightly positively correlated with the presence of orthostatic hypotension, whereas no significant associations were found in the PSP/CBS and DLB groups. Thus, our results confirm that both cNfL and pNfL concentrations might represent markers of disease severity in PD/PDD, reflecting the intensity of the neurodegenerative process, which could be of importance in future clinical trials 18 – 21 . The lack of a significant association between NfL values and motor impairment in the MSA and PSP/CBS groups likely depends on the more severe and rapidly progressing neurodegeneration seen in these diseases compared to that in PD 22 .…”

Section: Discussionsupporting

confidence: 79%

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Neurofilament light chain and α-synuclein RT-QuIC as differential diagnostic biomarkers in parkinsonisms and related syndromes

Quadalti

Calandra‐Buonaura

Baiardi

et al. 2021

npj Parkinsons Dis.

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Neurofilament light chain (NfL) and α-synuclein oligomeric seeds (α-syn-s) are promising biomarkers for patients with parkinsonism. We assessed their performance in discriminating Parkinson disease (PD) from atypical parkinsonisms (APDs) and evaluated the association between NfL levels and clinical measures of disease severity. We measured NfL in cerebrospinal fluid (CSF) and/or plasma by immunoassays and α-syn-s in CSF by real-time quaking-induced conversion (RT-QuIC) in patients with PD (n = 153), multiple system atrophy (MSA) (n = 80), progressive supranuclear palsy/cortico-basal syndrome (PSP/CBS) (n = 58), dementia with Lewy bodies (n = 64), isolated REM-sleep behaviour disorder (n = 19), and isolated autonomic failure (n = 30). Measures of disease severity included disease duration, UPDRS-III score, Hoehn and Yahr stage, orthostatic hypotension, MMSE score, and CSF amyloid-beta profile. Both CSF NfL (cNfL) and plasma NfL (pNfL) levels were markedly elevated in APDs, and allowed differentiation with PD (vs. APDs, cNfL AUC 0.96; pNfL AUC 0.95; vs. MSA cNfL AUC 0.99; pNfL AUC 0.97; vs. PSP/CBS cNfL AUC 0.94; pNfL AUC 0.94). RT-QuIC detected α-syn-s in 91.4% of PD, but only 2.5% of APDs (all MSA). In PD/PDD, motor scales significantly correlated with cNfL levels. Although pNfL and both cNfL and α-syn-s accurately distinguished PD from APDs, the combined assessment of CSF markers provided a higher diagnostic value (PD vs. APDs AUC 0.97; vs. MSA AUC 0.97; vs. PSP/CBS AUC 0.99) than RT-QuIC alone (p = 0.047 vs. APDs; p = 0.002 vs MSA; p = 0.007 vs PSP/CBS), or cNfL alone (p = 0.011 vs. APDs; p = 0.751 vs MSA; p = 0.0001 vs. PSP/CBS). The results support the use of these assays in specialised clinics.

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Section: Discussionsupporting

confidence: 79%

“…Spearman’s correlation (rho), univariate and multivariate linear regression models adjusted for age were used to evaluate the association of clinical variables with pNfL and cNFL values, stratified for the diagnostic groups. The results are presented as Beta coefficients (β) and 95% CI 21 .…”

Section: Methodsmentioning

confidence: 99%

Neurofilament light chain and α-synuclein RT-QuIC as differential diagnostic biomarkers in parkinsonisms and related syndromes

Quadalti

Calandra‐Buonaura

Baiardi

et al. 2021

npj Parkinsons Dis.

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“…Certain questions remain regarding the adoption of NfL as a biomarker of diagnosis in PD [ 27 ], such as: what is the probable explanation for documented elevated CSF NfL value only in patients with PD spanning more than 2 years? [ 28 ]. Furthermore, another study found that the temporal dynamics of serum NfL levels in individuals were associated with the conversion from prodromal to PD, suggesting that NfL may not be an early, PD-specific diagnostic biomarker [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Blood Neurofilament Light Chain in Parkinson’s Disease: Comparability between Parkinson’s Progression Markers Initiative (PPMI) and Asian Cohorts

Chen

Chan

Chung

et al. 2021

JCM

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Elevated blood neurofilament light chain (NfL), which indicates the loss of neuronal integrity, is increasingly implicated as a diagnostic and outcome-predicting biomarker for neurological diseases. However, its diagnostic implication for Parkinson’s disease (PD) remains unclear, with conflicting data reported by several studies. This may result from the demographic heterogeneity of the studied cohorts. The present study investigated the comparability of blood NfL between a domestic, single-centered PD cohort from Shuang Ho Hospital (SHH) in Taiwan, with the large international, multi-center cohort, Parkinson’s Progression Markers Initiative (PPMI). In the SHH PD cohort, with 61 people with PD (PwP) and 25 healthy non-PD controls, plasma NfL unexpectedly was significantly higher in the control group than PwP (14.42 ± 13.84 vs. 9.39 ± 6.91 pg/mL, p = 0.05). Interestingly, subgroup analysis revealed a non-significant difference of plasma NfL levels in male PwP compared with controls (8.58 ± 6.21 vs. 7.25 ± 4.43 pg/mL, p =0.575), whereas NfL levels were significantly lower in the female PwP group than in their healthy control peers (10.29 ± 7.62 vs. 17.79 ± 15.52 pg/mL, p = 0.033). Comparative analysis of the SHH and PPMI cohorts revealed a comparable gender-stratified distribution of blood NfL based on approximate theoretical quantiles. After adjusting for age and gender, no apparent difference in NfL value distribution was observed between the SHH and PPMI cohorts’ control or PD groups. Significant downregulation of blood NfL levels were positively correlated with a reduced probability of having a PD diagnosis in both cohorts. These results demonstrated that the adjustment for demographic background enhances comparability between cohorts, and may be required to eliminate covariate/confounder-associated conflict in blood NfL results between different PD studies. This experience may be beneficial to other researchers around the world who are saddled with limited study participants, especially as data from small cohort sizes are often at greater risk of being skewed by specific variables.

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“…Genetic screening for mutations in GBA, LRRK2, parkin , PINK1 and DJ1 was done as previously described [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson’s disease and dementia with Lewy bodies

Brockmann

Quadalti

Lerche

et al. 2021

acta neuropathol commun

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The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. Misfolded alpha-synuclein (α-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded α-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in GBA, parkin, PINK1, DJ1, and LRRK2. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to α-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC α-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive α-Syn seeding in 93% of patients carrying severe GBA mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe GBA mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with GBA mutations showed positive α-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between α-Syn seeding activity and reduced CSF levels of proteins linked to α-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF.These findings highlight the value of α-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting α-Syn.

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CSF NFL in a Longitudinally Assessed PD Cohort: Age Effects and Cognitive Trajectories

Cited by 41 publications

References 15 publications

Neurofilament light chain and α-synuclein RT-QuIC as differential diagnostic biomarkers in parkinsonisms and related syndromes

Neurofilament light chain and α-synuclein RT-QuIC as differential diagnostic biomarkers in parkinsonisms and related syndromes

Blood Neurofilament Light Chain in Parkinson’s Disease: Comparability between Parkinson’s Progression Markers Initiative (PPMI) and Asian Cohorts

Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson’s disease and dementia with Lewy bodies

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