Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression

Zetterberg, Henrik; Skillbäck, Tobias; Mattsson, Niklas; Trojanowski, John Q.; Portelius, Erik; Shaw, Leslie M.; Weiner, Michael W.; Blennow, Kaj

doi:10.1001/jamaneurol.2015.3037

Cited by 413 publications

(439 citation statements)

References 31 publications

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“…Using a subset of cases for which NfL measurements were available (FTLD = 92, CON = 28), we observed that the FTLD vs. CON model (AUC:0.94; P < 0.0001) performed similar to NfL alone (AUC:0.94 P < 0.0001, Fig. S3), a non‐disease specific marker that optimally discriminate FTLD cases from controls 27, 32, 33, 34…”

Section: Resultsmentioning

confidence: 92%

“…In a subset of cases, we observed that the FTLD vs. CON model achieved similar performance to that observed for NfL alone. However, CSF NfL is a nonspecific disease biomarker that is upregulated in other disorders such as AD 27, 32, 34. Importantly, recent studies showed that the ratio between NfL and the soluble β fragment of amyloid precursor protein (sAPP β )53 or the combination of TDP43 with p/tTau ratio54 could optimally discriminate FTLD patients from CON in a large cohort, promising data that need to be replicated in independent cohorts.…”

Section: Discussionmentioning

confidence: 99%

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Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Campo

Galimberti

Elias

et al. 2018

Ann Clin Transl Neurol

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ObjectiveFrontotemporal lobar degeneration (FTLD) is the second most prevalent dementia in young patients and is characterized by the presence of two main protein aggregates in the brain, tau (FTLD‐Tau) or TDP43 (FTLD‐TDP), which likely require distinct pharmacological therapy. However, specific diagnosis of FTLD and its subtypes remains challenging due to largely overlapping clinical phenotypes. Here, we aimed to assess the clinical performance of novel cerebrospinal fluid (CSF) biomarkers for discrimination of FTLD and its pathological subtypes.Methods YKL40, FABP4, MFG‐E8, and the activities of catalase and specific lysosomal enzymes were analyzed in patients with FTLD‐TDP (n = 30), FTLD‐Tau (n = 20), AD (n = 30), DLB (n = 29), and nondemented controls (n = 29) obtained from two different centers. Models were validated in an independent CSF cohort (n = 188).Results YKL40 and catalase activity were increased in FTLD‐TDP cases compared to controls. YKL40 levels were also higher in FTLD‐TDP compared to FTLD‐Tau. We identified biomarker models able to discriminate FTLD from nondemented controls (MFG‐E8, tTau, and Aβ 42; 78% sensitivity and 83% specificity) and non‐FTLD dementia (YKL40, pTau, p/tTau ratio, and age; 90% sensitivity, 78% specificity), which were validated in an independent cohort. In addition, we identified a biomarker model differentiating FTLD‐TDP from FTLD‐Tau (YKL40, MFGE‐8, βHexA together with βHexA/tHex and p/tTau ratios and age) with 80% sensitivity and 82% specificity.InterpretationThis study identifies CSF protein signatures distinguishing FTLD and the two main pathological subtypes with optimal accuracy (specificity/sensitivity > 80%). Validation of these models may allow appropriate selection of cases for clinical trials targeting the accumulation of Tau or TDP43, thereby increasing their efficiency and facilitating the development of successful therapies.

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Section: Resultsmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Campo

Galimberti

Elias

et al. 2018

Ann Clin Transl Neurol

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“…This protein is detectable in the cerebrospinal fluid (CSF) of presymptomatic and symptomatic C9orf72 expansion carriers,10, 11, 14 and poly(GP) levels in CSF from (G 4 C 2 ) 66 ‐expressing mice correlate with ASO‐induced decreases in G 4 C 2 RNA expression, RNA foci burden, and DPR protein levels within their brain 11. In addition, neurofilament light chain (NfL) is a potential marker of disease severity and progression for ALS, FTD, as well as other neurodegenerative diseases, including Alzheimer's disease 15, 16, 17. This marker for axonal injury is also increased in symptomatic but not presymptomatic C9orf72 expansion carriers, and correlates with prognosis and disease severity in genetic FTD 18, 19…”

Section: Introductionmentioning

confidence: 99%

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Meeter

Gendron

Sias

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72‐associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume.MethodsWe measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel‐wise analyses.ResultsPoly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.InterpretationThis study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72‐associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

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“…9 ). Correlation of CSF NFL with accelerated cognitive decline, changes in white matter and increased brain atrophy is found in patients with mild cognitive impairment 12 . Recently, elevated NFL levels were also described in the serum/plasma of AD patients [13][14][15] .…”

Section: Introductionmentioning

confidence: 97%

Neurofilaments and tau proteins in cerebrospinal fluid and serum in dementias and neuroinflammation

Fialová¹,

Bartoš²,

Švarcová³

2017

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Aims. The aim of this study was to evaluate the diagnostic potential of cerebrospinal fluid (CSF) and serum levels of neurocytoskeletal proteins and their ratios for the diagnosis of dementias and to assess the differences in neurocytoskeletal proteins between neurodegeneration and neuroinflammation. Methods. CSF and serum levels of neurofilament light subunits (NFL) and neurofilament heavy subunits (NFH) as well as CSF levels of total tau (t-tau) and phosphorylated tau (p-tau) proteins were determined using ELISA in 20 Alzheimer's disease patients (AD group), 13 patients with other dementias (OD group), 17 patients with inflammatory aseptic neuro-infections (IP), and 20 aged-matched cognitively normal elderly persons (NC group). Results. The ratio CSF p-tau/t-tau was significantly higher in the NC group than that in the AD or OD groups (P<0.0005 for each group). The CSF NFH/p-tau and CSF NFL/p-tau ratios were significantly lower in AD patients than OD patients (P≤0.003). Serum and CSF NFL and CSF NFH levels were significantly higher in OD patients than AD patients (P≤0.03).The lowest values of the CSF NFL/NFH ratio were found in the IP group and they significantly differed from those in normal controls (P<0.0001) and any dementia group (IP vs. AD P<0.0001; IP vs. OD P=0.03). Conclusion. CSF tau proteins and their index differentiated between AD or OD patients and cognitively normal subjects, while CSF levels of neurofilaments expressed as their index seem to contribute to the discrimination between patients with neuroinflammation and normal controls or AD patients.

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Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression

Cited by 413 publications

References 31 publications

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Neurofilaments and tau proteins in cerebrospinal fluid and serum in dementias and neuroinflammation

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