Evolution of Clinical Outcome Measures and Biomarkers in Sporadic Adult‐Onset Degenerative Ataxia

Oender, Demet; Faber, Jennifer; Wilke, Carlo; Schaprian, Tamara; Lakghomi, Asadeh; Mengel, David; Schöls, Ludger; Traschütz, Andreas; Fleszar, Zofia; Dufke, Claudia; Vielhaber, Stefan; Machts, Judith; Giordano, Ilaria; Grobe‐Einsler, Marcus; Klopstock, Thomas; Stendel, Claudia; Boesch, Sylvia; Nachbauer, Wolfgang; Timmann-Braun, Dagmar; Thieme, Andreas; Kamm, Christoph; Dudešek, Aleš; Tallaksen, Chantal; Wedding, Iselin Marie; Filla, Alessandro; Schmid, Matthias; Synofzik, Matthis; Klockgether, Thomas

doi:10.1002/mds.29324

Cited by 10 publications

(9 citation statements)

References 53 publications

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“…Plasma Neuro lament Light Chain (NfL) SIMOA assay Plasma NfL concentrations were determined in duplicates, as previously described 114 , using the SIMOA NF-light Advantage kit on a Quanterix HD1 analyzer (Quanterix, Billerica, MA) by a blinded experimenter according to the manufacturer's instructions. Comparisons of marker levels were performed using Kruskal-Wallis tests followed by Dunn's correction for multiple comparisons due to non-Gaussian distributions.…”

Section: R Tau Immunoassaymentioning

confidence: 99%

Plasma extracellular vesicle Tau isoform ratios and TDP-43 inform about molecular pathology in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Chatterjee,

Özdemir,

Fritz

et al. 2023

Preprint

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Low-invasive biomarkers are urgently needed for the detection of molecular pathology in Frontotemporal Dementia (FTD), FTD spectrum disorders and Amyotrophic Lateral Sclerosis (ALS). This is particularly true in behavior variant FTD (bvFTD), in which premortem biomarkers are missing to distinguish underlying Tau from TAR DNA binding protein (TDP-43) pathology. This lack of biomarkers prevents the stratification of patients for intervention trials and constitutes a major obstacle for the development of disease-modifying therapies. Extracellular vesicles (EVs) have been implicated in neurodegenerative disease pathology, contributing to the release and potentially to intercellular transmission of pathologically aggregated proteins. Here, we show that plasma EVs contain quantifiable amounts of TDP-43 and full-length Tau, which allows the quantification of 3 repeat (3R) and 4 repeat (4R) Tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R Tau ratios were determined in a pilot and validation study of 704 patients, including 37 genetic and 31 neuropathologically proven cases. Diagnostic groups comprised patients with the TDP-43 proteinopathy ALS, the 4R tauopathy Progressive Supranuclear Palsy (PSP), bvFTD as a group with either Tau or TDP-43 pathology, and healthy controls (HC). Compared to HC, plasma EV 3R/4R Tau ratios were decreased in PSP, unchanged in ALS, and increased in a subset of bvFTD patients, consistent with Tau pathology in approximately 40% of cases with bvFTD. EV Tau ratio discriminated between PSP and bvFTD, ALS and healthy controls (AUC 0.96-0.99), and between bvFTD and ALS (AUC 0.90) as well as HC (AUC 0.91). Plasma EV TDP-43 levels were increased in ALS and in those bvFTD patients who did not display high EV Tau ratios. Plasma EV TDP-43 discriminated patients with ALS from HC (AUC 0.99), bvFTD (AUC 0.91) and PSP (AUC 0.99). The combination of EV Tau ratio and EV TDP-43 was reliably able to discriminate between TDP-43 and Tau pathology in bvFTD. This blood-based classification was confirmed in genetic and autopsy proven cases. Both markers strongly correlated with the neurodegeneration marker neurofilament light chain (NfL) as well as with clinical and neuropsychological markers of disease severity in ALS (TDP-43 with ECAS, ALS-FRS-R), bvFTD (TDP-43 and Tau ratio with CDR-SB, CDR plus NACC FTLD) and PSP (Tau ratio with PSP-RS). Taken together, the combination of both markers may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, the stratification of patients for therapeutic trials and bears the potential of a biomarker to monitor disease progression and target engagement.

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Section: R Tau Immunoassaymentioning

confidence: 99%

Plasma extracellular vesicle Tau isoform ratios and TDP-43 inform about molecular pathology in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Chatterjee,

Özdemir,

Fritz

et al. 2023

Preprint

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“…1)? Patient‐reported outcomes intuitively are most meaningful but do not necessarily reflect ataxia severity and generally show a slower progression, with the notable exception of ADL in FRDA and MSA‐C 6,27,28 . Furthermore, PROM‐Ataxia has recently been validated, but long‐term follow‐up data are lacking as of yet 29 .…”

Section: Implications and Challenges For Clinical Trial Designmentioning

confidence: 99%

“…Oender and colleagues report the results of a prospective multicenter registry study including 404 patients with sporadic adult-onset ataxia without a known genetic or acquired cause. 6 They examined the evolution of various clinician-reported outcomes, patientreported outcomes, MRI parameters, and plasma neurofilament light chain (NfL) levels in individuals with SAOA and MSA-C, as well as the accuracy of these biomarkers to distinguish between both patient groups and their predictive potential to identify subjects who may convert to MSA-C. In addition to pons volume, the authors separately evaluated the presence and severity of T2 hyperintensities in the pons and middle cerebellar peduncles (MCPs) in a semi-quantitative manner and summarized these, along with MCP diameter, in a newly established six-point Pons and MCP Abnormality Score (PMAS).…”

Section: Clinical Measures and Multimodal Biomarkers In Msa-c And Saoamentioning

confidence: 99%

“…1)? Patient-reported outcomes intuitively are most meaningful but do not necessarily reflect ataxia severity and generally show a slower progression, with the notable exception of ADL in FRDA and MSA-C. 6,27,28 Furthermore, PROM-Ataxia has recently been validated, but longterm follow-up data are lacking as of yet. 29 Regarding clinician-reported outcomes, in particular SARA, considerable day-to-day fluctuations have been reported, questioning the value of a single assessment before and after any intervention.…”

Section: Implications and Challenges For Clinical Trial Designmentioning

confidence: 99%

“…This issue of Movement Disorders features a series of articles on dominantly inherited SCAs, MSA-C, SAOA, and Friedreich ataxia (FRDA) that share this important outcome theme. [5][6][7][8]…”

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confidence: 99%

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Preparing for Disease‐Modification Trials in Degenerative Cerebellar Ataxias: Which Endpoints to Choose?

Maas

2023

Movement Disorders

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Building on decades of observational and preclinical studies, the field of degenerative ataxias is currently preparing or-in the case of multiple system atrophy of cerebellar type (MSA-C) and, very recently, spinocerebellar ataxia type 3 (SCA3)-already actively conducting trials with possible disease-modifying therapies. [1][2][3] Despite potentially exciting developments, a number of fundamental questions need to be answered in the upcoming years. These not only involve practical matters, such as identifying the optimal dose and administration schedule in phase I studies, but also importantly relate to the selection of clinically meaningful and responsive outcome measures and stratification of patients. Additional key issues for MSA-C will be to accurately diagnose and include patients at the earliest disease stages and distinguish them with reasonable certainty from other disorders, in particular immunemediated ataxias, hereditary ataxias, and sporadic adult-onset ataxia with unknown etiology (SAOA). 4 Delineating and predicting natural disease evolution with clinical rating scales, patient-reported outcomes, observerindependent metrics, (infratentorial) MRI measures, and biofluid markers constitutes an essential prerequisite for conducting meaningful disease-modification trials. This issue of Movement Disorders features a series of articles on dominantly inherited SCAs, MSA-C, SAOA, and Friedreich ataxia (FRDA) that share this important outcome theme. [5][6][7][8]

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MRI‐ARSACS: An Imaging Index for Autosomal Recessive Spastic Ataxia of Charlevoix‐Saguenay (ARSACS) Identification Based on the Multicenter PROSPAX Study

Scaravilli,

Negroni,

Senatore

et al. 2024

Movement Disorders

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BackgroundAutosomal recessive spastic ataxia of Charlevoix‐Saguenay (ARSACS) and hereditary spastic paraplegia type 7 (SPG7) represent the most common genotypes of spastic ataxia (SPAX). To date, their magnetic resonance imaging (MRI) features have only been described qualitatively, and a pure neuroradiological differential diagnosis between these two conditions is difficult to achieve.ObjectivesTo test the performance of MRI measures to discriminate between ARSACS and SPG7 (as an index of common SPAX disease).MethodsIn this prospective multicenter study, 3D‐T1‐weighted images of 59 ARSACS (35.4 ± 10.3 years, M/F = 33/26) and 78 SPG7 (54.8 ± 10.3 years, M/F = 51/27) patients of the PROSPAX Consortium were analyzed, together with 30 controls (45.9 ± 16.9 years, M/F = 15/15). Different linear and surface measures were evaluated. A receiver operating characteristic analysis was performed, calculating area under the curve (AUC) and corresponding diagnostic accuracy parameters.ResultsThe pons area proved to be the only metric increased exclusively in ARSACS patients (P = 0.02). Other different measures were reduced in ARSACS and SPG7 compared with controls (all with P ≤ 0.005). A cut‐off value equal to 1.67 of the pons‐to‐superior vermis area ratio proved to have the highest AUC (0.98, diagnostic accuracy 93%, sensitivity 97%) in discriminating between ARSACS and SPG7.ConclusionsEvaluation of the pons‐to‐superior vermis area ratio can discriminate ARSACS from other SPAX patients, as exemplified here by SPG7. Hence, we hereby propose this ratio as the Magnetic Resonance Index for the Assessment and Recognition of patients harboring SACS mutations (MRI‐ARSACS), a novel diagnostic tool able to identify ARSACS patients and useful for discriminating ARSACS from other SPAX patients undergoing MRI. © 2024 International Parkinson and Movement Disorder Society.

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Evolution of Clinical Outcome Measures and Biomarkers in Sporadic Adult‐Onset Degenerative Ataxia

Cited by 10 publications

References 53 publications

Plasma extracellular vesicle Tau isoform ratios and TDP-43 inform about molecular pathology in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Plasma extracellular vesicle Tau isoform ratios and TDP-43 inform about molecular pathology in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Preparing for Disease‐Modification Trials in Degenerative Cerebellar Ataxias: Which Endpoints to Choose?

MRI‐ARSACS: An Imaging Index for Autosomal Recessive Spastic Ataxia of Charlevoix‐Saguenay (ARSACS) Identification Based on the Multicenter PROSPAX Study

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