Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice

Wilke, Carlo; Haas, Eva; Reetz, Kathrin; Faber, Jennifer; García-Moreno, Héctor; Santana, Magda M.; Warrenburg, Bart P. van de; Hengel, Holger; Lima, Manuela; Filla, Alessandro; Dürr, Alexandra; Melegh, Béla; Masciullo, Marcella; Infante, Jon; Giunti, Paola; Neumann, Manuela; Vries, Jeroen J de; Almeida, Luís Pereira de; Rakowicz, Maria; Jacobi, Heike; Schüle, Rebecca; Kaeser, Stephan A.; Kuhle, Jens; Klockgether, Thomas; Schöls, Lüdger; Barro, Christian; Hübener‐Schmid, Jeannette; Synofzik, Matthis; Deuschle, Christian; Stransky, Elke; Brockmann, Kathrin; Schulz, Jörg B.; Balikó, László; Gaalen, Judith van; Raposo, Mafalda; Jeromin, Andreas

doi:10.15252/emmm.201911803

Cited by 86 publications

(180 citation statements)

References 48 publications

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“…The higher rate of age‐related annual cNfL increase in controls compared to HSP patients may further indicate a declining number of upper motor neuron axons in HSP cases as the source of cNfL as the disease progresses. Similar temporal dynamics of sNfL have recently been described in Spinocerebellar ataxia type 3 (SCA3) 20 and Friedreich’s ataxia, 21 representing two other slowly progressive neurodegenerative disorders. The temporal dynamics of NfL over the disease course, here deduced from cohort‐based analyses, will have to be confirmed in serial measurements of NfL in HSP patients.…”

Section: Discussionsupporting

confidence: 70%

Neurofilament light chain is a cerebrospinal fluid biomarker in hereditary spastic paraplegia

Keßler

Serna-Higuita

Rattay

et al. 2021

Ann Clin Transl Neurol

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Objective Despite the need for diagnostics and research, data on fluid biomarkers in hereditary spastic paraplegia (HSP) are scarce. We, therefore, explore Neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) of patients with hereditary spastic paraplegia and provide information on the influence of demographic factors. Methods The study recruited 59 HSP cases (33 genetically confirmed) and 59 controls matched in age and sex. Neurofilament light chain levels were assessed by enzyme‐linked immunosorbent assay. The statistical analysis included the effects of age, sex, and genetic status (confirmed vs. not confirmed). Results Levels of CSF NfL were significantly increased in patients with hereditary spastic paraplegia compared to controls (median 741 pg/mL vs. 387 pg/mL, p < 0.001). Age (1.4% annual increase) and male sex (81% increase) impacted CSF NfL levels in patients. The age‐dependent increase of CSF NfL levels was steeper in controls (2.6% annual increase). Thus, the CSF NfL ratio of patients and matched controls—expressing patients’ fold increases in CSF NfL—declined considerably with age. Interpretation CSF NfL is a reliable cross‐sectional biomarker in hereditary spastic paraplegia. Sex is a relevant factor to consider, as male patients have remarkably higher CSF NfL levels. While levels also increase with age, the gap between patients and controls is narrowing in older subjects. This indicates distinct temporal dynamics of CSF NfL in patients with hereditary spastic paraplegia, with a rise around phenotypic conversion and comparatively static levels afterward.

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Section: Discussionsupporting

confidence: 70%

Neurofilament light chain is a cerebrospinal fluid biomarker in hereditary spastic paraplegia

Keßler

Serna-Higuita

Rattay

et al. 2021

Ann Clin Transl Neurol

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“…Therefore, it is crucial that newly established biomarkers are disease specific and that there is a correlation between surrogate and clinical endpoints [16]. As for many other neurodegenerative diseases, neurofilament light chain (NfL) is shown to be increased in preataxic mutation carriers already 7.5 years before disease onset also in SCA3 even correlating with disease severity [17][18][19]. However, NfL only reflects general axonal damage which captures disease progression and disease severity and, therefore, acts as a progression and severity biomarker.…”

Section: Introductionmentioning

confidence: 99%

PolyQ-expanded ataxin-3 protein levels in peripheral blood mononuclear cells correlate with clinical parameters in SCA3: a pilot study

et al. 2020

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In view of upcoming clinical trials, quantitative molecular markers accessible in peripheral blood are of critical importance as prognostic or pharmacodynamic markers in genetic neurodegenerative diseases such as Spinocerebellar Ataxia Type 3 (SCA3), in particular for signaling target engagement. In this pilot study, we focused on the quantification of ataxin-3, the protein altered in SCA3, in human peripheral blood mononuclear cells (PBMCs) acquired from preataxic and ataxic SCA3 mutation carriers as well as healthy controls, as a molecular marker directly related to SCA3 pathophysiology. We established two different highly sensitive TR-FRET-based immunoassays to measure the protein levels of either total full-length, non-expanded and expanded, ataxin-3 or specifically polyQ-expanded ataxin-3. In PBMCs, a clear discrimination between SCA3 mutation carrier and controls were seen measuring polyQ-expanded ataxin-3 protein level. Additionally, polyQ-expanded ataxin-3 protein levels correlated with disease progression and clinical severity as assessed by the Scale for the Assessment and Rating of Ataxia. Total full-length ataxin-3 protein levels were directly influenced by the expression levels of the polyQ-expanded ataxin-3 protein, but were not correlated with clinical parameters. Assessment of ataxin-3 levels in fibroblasts or induced pluripotent stem cells allowed to distinguish mutation carriers from controls, thus providing proof-of-principle validation of our PBMC findings across cell lines. Total full-length or polyQ-expanded ataxin-3 protein was not detectable by TR-FRET assays in other biofluids like plasma or cerebrospinal fluid, indicating the need for ultra-sensitive assays for these biofluids. Standardization studies revealed that tube systems, blood sampling, and PBMC preparation may influence ataxin-3 protein levels indicating a high demand for standardized protocols in biomarker studies. In conclusion, the polyQ-expanded ataxin-3 protein is a promising candidate as a molecular target engagement marker in SCA3 in future clinical trials, determinable even in—easily accessible—peripheral blood biomaterials. These results, however, require validation in a larger cohort and further standardization of modifying conditions.

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“…To account for possible variation of study variables with age, a z score for each preataxic subject in relation to the predicted value by regression with age in controls was calculated, as previously reported. 20 The threshold for statistical significance was P < 0.05 after adjustment, and the analyses were performed using PASW Statistics version 18.0 (SPSS Inc. Released, 2009) and R version 4.0.0 (R Core Team, 2020).…”

Section: Analysesmentioning

confidence: 99%

“…The narrowness of the remaining range for pre‐ataxic subjects (from 0 to 2.5 points) explains why SARA did not detect progression in the preclinical period 9 . A few other instruments applied in preclinical individuals raised insufficient data 9,12‐20 …”

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confidence: 99%

Pre‐ataxic Changes of Clinical Scales and Eye Movement in Machado–Joseph Disease: BIGPRO Study

et al. 2021

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Background The pathological burden of spinocerebellar ataxia type 3, also known as Machado–Joseph disease (SCA3/MJD), accumulates before the beginning of symptoms. Our study aims at validating biomarkers for disease progression since pre‐ataxic periods. We report on baseline findings of clinical scales and oculomotor neurophysiology. Methods Ataxic (Scale for the Assessment and Rating of Ataxia > 2.5) and at 50% risk subjects were included. The latter were subdivided into noncarriers, pre‐ataxic carriers near (PAN), or pre‐ataxic carriers far from (PAFF) ataxia onset (AO), with 4 years from the predicted age at onset being the cutoff. The subjects were assessed by Neurological Examination Score for Spinocerebellar Ataxia (NESSCA), International Cooperative Ataxia Rating Scale (ICARS), Inventory of Non‐Ataxic Signs (INAScount), Composite Cerebellar Functions Score and SCA Functional Index, and video‐oculography, including the regression slope of vestibulo‐ocular reflex gain (VORr), main sequence of volitional and reflexive vertical saccades, slow‐phase velocity of central and gaze‐evoked (SPV‐GE) nystagmus, and vertical pursuit gain. Correction for multiple comparisons was performed; the threshold for statistical significance was P < 0.05. Results A total of 35 ataxic, 14 PAN, 24 PAFF, and 22 noncarriers were included. All variables showed significant differences between groups and correlated to time to onset or time after onset, among all 73 SCA3/MJD carriers; none significantly changed with age in controls. NESSCA, ICARS, INAScount, VORr, main sequence of volitional saccades, and SPV‐GE not only distinguished PAN from controls but also correlated with time left to AO. Conclusions Clinical scales and video‐oculography variables were already altered in pre‐ataxic SCA3/MJD carriers and worsened with time. NESSCA, ICARS, INAScount, VORr, main sequence of vertical volitional saccades, and SPV‐GE are good candidates to measure preclinical changes in SCA3/MJD. © 2021 International Parkinson and Movement Disorder Society

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Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice

Cited by 86 publications

References 48 publications

Neurofilament light chain is a cerebrospinal fluid biomarker in hereditary spastic paraplegia

Neurofilament light chain is a cerebrospinal fluid biomarker in hereditary spastic paraplegia

PolyQ-expanded ataxin-3 protein levels in peripheral blood mononuclear cells correlate with clinical parameters in SCA3: a pilot study

Pre‐ataxic Changes of Clinical Scales and Eye Movement in Machado–Joseph Disease: BIGPRO Study

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