Baseline Clinical and Blood Biomarkers in Patients With Preataxic and Early-Stage Disease Spinocerebellar Ataxia 1 and 3

READISCA Consortium Collaborators

doi:10.1212/WNL.0000000000207088

Baseline Clinical and Blood Biomarkers in Patients With Preataxic and Early-Stage Disease Spinocerebellar Ataxia 1 and 3

READISCA Consortium Collaborators

Center for Magnetic Resonance Research

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

Background and Objectives In spinocerebellar ataxia, ataxia onset can be preceded by mild clinical manifestation, cerebellar and/or brainstem alterations, or biomarker modifications. READISCA is a prospective, longitudinal observational study of patients with spinocerebellar ataxia type 1 (SCA1) and 3 (SCA3) to provide essential markers for therapeutic interventions. We looked for clinical, imaging, or biological markers that are present at an early stage of the disease. Methods We enrolled carriers of a pathologic ATXN1 or ATXN3 expansion and controls from 18 US and 2 European ataxia referral centers. Clinical, cognitive, quantitative motor, neuropsychological measures and plasma neurofilament light chain (NfL) measurements were compared between expansion carriers with and without ataxia and controls. Results We enrolled 200 participants: 45 carriers of a pathologic ATXN1 expansion (31 patients with ataxia [median Scale for the Assessment and Rating of Ataxia: 9; 7-10] and 14 expansion carriers without ataxia [1; 0-2]) and 116 carriers of a pathologic ATXN3 expansion (80 patients with ataxia [7; 6-9] and 36 expansion carriers without ataxia [1; 0-2]). In addition, we enrolled 39 controls who did not carry a pathologic expansion in ATXN1 or ATXN3. Plasma NfL levels were significantly higher in expansion carriers without ataxia than controls, despite similar mean age (controls: 5.7 pg/mL, SCA1: 18.0 pg/mL [p < 0.0001], SCA3: 19.8 pg/mL [p < 0.0001]). Expansion carriers without ataxia differed from controls by significantly more upper motor signs (SCA1 p = 0.0003, SCA3 p = 0.003) and by the presence of sensor impairment and diplopia in SCA3 (p = 0.0448 and 0.0445, respectively). Functional scales, fatigue and depression scores, swallowing difficulties, and cognitive impairment were worse in expansion carriers with ataxia than those without ataxia. Ataxic SCA3 participants showed extrapyramidal signs, urinary dysfunction, and lower motor neuron signs significantly more often than expansion carriers without ataxia. Discussion READISCA showed the feasibility of harmonized data acquisition in a multinational network. NfL alterations, early sensory ataxia, and corticospinal signs were quantifiable between preataxic participants and controls. Patients with ataxia differed in many parameters from controls and expansion carriers without ataxia, with a graded increase of abnormal measures from control to preataxic to ataxic cohorts.

Original language	English (US)
Pages (from-to)	E1836-E1848
Journal	Neurology
Volume	100
Issue number	17
DOIs	https://doi.org/10.1212/WNL.0000000000207088
State	Published - Apr 25 2023

Bibliographical note

Funding Information:
S. Tezenas du Montcel receives research support from Biogen. S.H. Subramony receives research support from National Ataxia Foundation, Biohaven, NIH, FDA, MDA, Wyck Foundation, FARA, Reata, PTC therapeutics, Retrotope, Avidity Biosciences, Fulcrum therapeutics, Reneo Pharma, and AAVANTIBio and serves on the Scientific Advisory Board for Reata, Avidity, and Dyne therapeutics. G. Öz consults for IXICO Technologies Limited and uniQure biopharma B.V., serves on the Scientific Advisory Board of BrainSpec Inc., and receives research support from Biogen. T. Ashizawa received grants from NAF and Biogen and participates in Biohaven clinical trials NCT03952806 and NCT03701399. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

Funding Information:
The READISCA investigators thank all participants for their enduring willingness and interest in this research. We extend gratitude to all study coordinators at READISCA sites (readisca.org/readisca-team/#Coordinators) and Chantel Potvin for outstanding project management. We further thank the National Ataxia Foundation for assistance with traveling logistics of participants. This work was supported by the National Institute of Neurological Disorders and Stroke grant U01 NS104326 to T.A., H.L.P., G.O., A.D., and T.K. D. Morgan received a Michigan ADRC grant (P30 AG072931).

Funding Information:
This work was supported by the National Institute of Neurological Disorders and Stroke grant U01 NS104326 to T.A., H.L.P., G.O., A.D., and T.K. D. Morgan received a Michigan ADRC grant (P30 AG072931).

Publisher Copyright:
© 2023 Lippincott Williams and Wilkins. All rights reserved.

Keywords

Humans
Prospective Studies
Spinocerebellar Ataxias
Cerebellar Ataxia
Cerebellum
Biomarkers
Machado-Joseph Disease/diagnosis

PubMed: MeSH publication types

Observational Study
Journal Article
Research Support, N.I.H., Extramural

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10.1212/WNL.0000000000207088

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@article{1aff3e6c83494196abff5a56e1013aa1,

title = "Baseline Clinical and Blood Biomarkers in Patients With Preataxic and Early-Stage Disease Spinocerebellar Ataxia 1 and 3",

abstract = "Background and Objectives In spinocerebellar ataxia, ataxia onset can be preceded by mild clinical manifestation, cerebellar and/or brainstem alterations, or biomarker modifications. READISCA is a prospective, longitudinal observational study of patients with spinocerebellar ataxia type 1 (SCA1) and 3 (SCA3) to provide essential markers for therapeutic interventions. We looked for clinical, imaging, or biological markers that are present at an early stage of the disease. Methods We enrolled carriers of a pathologic ATXN1 or ATXN3 expansion and controls from 18 US and 2 European ataxia referral centers. Clinical, cognitive, quantitative motor, neuropsychological measures and plasma neurofilament light chain (NfL) measurements were compared between expansion carriers with and without ataxia and controls. Results We enrolled 200 participants: 45 carriers of a pathologic ATXN1 expansion (31 patients with ataxia [median Scale for the Assessment and Rating of Ataxia: 9; 7-10] and 14 expansion carriers without ataxia [1; 0-2]) and 116 carriers of a pathologic ATXN3 expansion (80 patients with ataxia [7; 6-9] and 36 expansion carriers without ataxia [1; 0-2]). In addition, we enrolled 39 controls who did not carry a pathologic expansion in ATXN1 or ATXN3. Plasma NfL levels were significantly higher in expansion carriers without ataxia than controls, despite similar mean age (controls: 5.7 pg/mL, SCA1: 18.0 pg/mL [p < 0.0001], SCA3: 19.8 pg/mL [p < 0.0001]). Expansion carriers without ataxia differed from controls by significantly more upper motor signs (SCA1 p = 0.0003, SCA3 p = 0.003) and by the presence of sensor impairment and diplopia in SCA3 (p = 0.0448 and 0.0445, respectively). Functional scales, fatigue and depression scores, swallowing difficulties, and cognitive impairment were worse in expansion carriers with ataxia than those without ataxia. Ataxic SCA3 participants showed extrapyramidal signs, urinary dysfunction, and lower motor neuron signs significantly more often than expansion carriers without ataxia. Discussion READISCA showed the feasibility of harmonized data acquisition in a multinational network. NfL alterations, early sensory ataxia, and corticospinal signs were quantifiable between preataxic participants and controls. Patients with ataxia differed in many parameters from controls and expansion carriers without ataxia, with a graded increase of abnormal measures from control to preataxic to ataxic cohorts.",

keywords = "Humans, Prospective Studies, Spinocerebellar Ataxias, Cerebellar Ataxia, Cerebellum, Biomarkers, Machado-Joseph Disease/diagnosis",

author = "{READISCA Consortium Collaborators} and {du Montcel}, {Sophie Tezenas} and Emilien Petit and Titilayo Olubajo and Jennifer Faber and Pauline Lallemant-Dudek and Khalaf Bushara and Susan Perlman and Subramony, {Sub H.} and David Morgan and Brianna Jackman and Paulson, {Henry Lauris} and G{\"u}lin {\"O}z and Thomas Klockgether and Alexandra Durr and Tetsuo Ashizawa",

note = "Funding Information: S. Tezenas du Montcel receives research support from Biogen. S.H. Subramony receives research support from National Ataxia Foundation, Biohaven, NIH, FDA, MDA, Wyck Foundation, FARA, Reata, PTC therapeutics, Retrotope, Avidity Biosciences, Fulcrum therapeutics, Reneo Pharma, and AAVANTIBio and serves on the Scientific Advisory Board for Reata, Avidity, and Dyne therapeutics. G. {\"O}z consults for IXICO Technologies Limited and uniQure biopharma B.V., serves on the Scientific Advisory Board of BrainSpec Inc., and receives research support from Biogen. T. Ashizawa received grants from NAF and Biogen and participates in Biohaven clinical trials NCT03952806 and NCT03701399. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures. Funding Information: The READISCA investigators thank all participants for their enduring willingness and interest in this research. We extend gratitude to all study coordinators at READISCA sites (readisca.org/readisca-team/#Coordinators) and Chantel Potvin for outstanding project management. We further thank the National Ataxia Foundation for assistance with traveling logistics of participants. This work was supported by the National Institute of Neurological Disorders and Stroke grant U01 NS104326 to T.A., H.L.P., G.O., A.D., and T.K. D. Morgan received a Michigan ADRC grant (P30 AG072931). Funding Information: This work was supported by the National Institute of Neurological Disorders and Stroke grant U01 NS104326 to T.A., H.L.P., G.O., A.D., and T.K. D. Morgan received a Michigan ADRC grant (P30 AG072931). Publisher Copyright: {\textcopyright} 2023 Lippincott Williams and Wilkins. All rights reserved.",

year = "2023",

month = apr,

day = "25",

doi = "10.1212/WNL.0000000000207088",

language = "English (US)",

volume = "100",

pages = "E1836--E1848",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams and Wilkins",

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TY - JOUR

T1 - Baseline Clinical and Blood Biomarkers in Patients With Preataxic and Early-Stage Disease Spinocerebellar Ataxia 1 and 3

AU - READISCA Consortium Collaborators

AU - du Montcel, Sophie Tezenas

AU - Petit, Emilien

AU - Olubajo, Titilayo

AU - Faber, Jennifer

AU - Lallemant-Dudek, Pauline

AU - Bushara, Khalaf

AU - Perlman, Susan

AU - Subramony, Sub H.

AU - Morgan, David

AU - Jackman, Brianna

AU - Paulson, Henry Lauris

AU - Öz, Gülin

AU - Klockgether, Thomas

AU - Durr, Alexandra

AU - Ashizawa, Tetsuo

N1 - Funding Information: S. Tezenas du Montcel receives research support from Biogen. S.H. Subramony receives research support from National Ataxia Foundation, Biohaven, NIH, FDA, MDA, Wyck Foundation, FARA, Reata, PTC therapeutics, Retrotope, Avidity Biosciences, Fulcrum therapeutics, Reneo Pharma, and AAVANTIBio and serves on the Scientific Advisory Board for Reata, Avidity, and Dyne therapeutics. G. Öz consults for IXICO Technologies Limited and uniQure biopharma B.V., serves on the Scientific Advisory Board of BrainSpec Inc., and receives research support from Biogen. T. Ashizawa received grants from NAF and Biogen and participates in Biohaven clinical trials NCT03952806 and NCT03701399. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures. Funding Information: The READISCA investigators thank all participants for their enduring willingness and interest in this research. We extend gratitude to all study coordinators at READISCA sites (readisca.org/readisca-team/#Coordinators) and Chantel Potvin for outstanding project management. We further thank the National Ataxia Foundation for assistance with traveling logistics of participants. This work was supported by the National Institute of Neurological Disorders and Stroke grant U01 NS104326 to T.A., H.L.P., G.O., A.D., and T.K. D. Morgan received a Michigan ADRC grant (P30 AG072931). Funding Information: This work was supported by the National Institute of Neurological Disorders and Stroke grant U01 NS104326 to T.A., H.L.P., G.O., A.D., and T.K. D. Morgan received a Michigan ADRC grant (P30 AG072931). Publisher Copyright: © 2023 Lippincott Williams and Wilkins. All rights reserved.

PY - 2023/4/25

Y1 - 2023/4/25

N2 - Background and Objectives In spinocerebellar ataxia, ataxia onset can be preceded by mild clinical manifestation, cerebellar and/or brainstem alterations, or biomarker modifications. READISCA is a prospective, longitudinal observational study of patients with spinocerebellar ataxia type 1 (SCA1) and 3 (SCA3) to provide essential markers for therapeutic interventions. We looked for clinical, imaging, or biological markers that are present at an early stage of the disease. Methods We enrolled carriers of a pathologic ATXN1 or ATXN3 expansion and controls from 18 US and 2 European ataxia referral centers. Clinical, cognitive, quantitative motor, neuropsychological measures and plasma neurofilament light chain (NfL) measurements were compared between expansion carriers with and without ataxia and controls. Results We enrolled 200 participants: 45 carriers of a pathologic ATXN1 expansion (31 patients with ataxia [median Scale for the Assessment and Rating of Ataxia: 9; 7-10] and 14 expansion carriers without ataxia [1; 0-2]) and 116 carriers of a pathologic ATXN3 expansion (80 patients with ataxia [7; 6-9] and 36 expansion carriers without ataxia [1; 0-2]). In addition, we enrolled 39 controls who did not carry a pathologic expansion in ATXN1 or ATXN3. Plasma NfL levels were significantly higher in expansion carriers without ataxia than controls, despite similar mean age (controls: 5.7 pg/mL, SCA1: 18.0 pg/mL [p < 0.0001], SCA3: 19.8 pg/mL [p < 0.0001]). Expansion carriers without ataxia differed from controls by significantly more upper motor signs (SCA1 p = 0.0003, SCA3 p = 0.003) and by the presence of sensor impairment and diplopia in SCA3 (p = 0.0448 and 0.0445, respectively). Functional scales, fatigue and depression scores, swallowing difficulties, and cognitive impairment were worse in expansion carriers with ataxia than those without ataxia. Ataxic SCA3 participants showed extrapyramidal signs, urinary dysfunction, and lower motor neuron signs significantly more often than expansion carriers without ataxia. Discussion READISCA showed the feasibility of harmonized data acquisition in a multinational network. NfL alterations, early sensory ataxia, and corticospinal signs were quantifiable between preataxic participants and controls. Patients with ataxia differed in many parameters from controls and expansion carriers without ataxia, with a graded increase of abnormal measures from control to preataxic to ataxic cohorts.

AB - Background and Objectives In spinocerebellar ataxia, ataxia onset can be preceded by mild clinical manifestation, cerebellar and/or brainstem alterations, or biomarker modifications. READISCA is a prospective, longitudinal observational study of patients with spinocerebellar ataxia type 1 (SCA1) and 3 (SCA3) to provide essential markers for therapeutic interventions. We looked for clinical, imaging, or biological markers that are present at an early stage of the disease. Methods We enrolled carriers of a pathologic ATXN1 or ATXN3 expansion and controls from 18 US and 2 European ataxia referral centers. Clinical, cognitive, quantitative motor, neuropsychological measures and plasma neurofilament light chain (NfL) measurements were compared between expansion carriers with and without ataxia and controls. Results We enrolled 200 participants: 45 carriers of a pathologic ATXN1 expansion (31 patients with ataxia [median Scale for the Assessment and Rating of Ataxia: 9; 7-10] and 14 expansion carriers without ataxia [1; 0-2]) and 116 carriers of a pathologic ATXN3 expansion (80 patients with ataxia [7; 6-9] and 36 expansion carriers without ataxia [1; 0-2]). In addition, we enrolled 39 controls who did not carry a pathologic expansion in ATXN1 or ATXN3. Plasma NfL levels were significantly higher in expansion carriers without ataxia than controls, despite similar mean age (controls: 5.7 pg/mL, SCA1: 18.0 pg/mL [p < 0.0001], SCA3: 19.8 pg/mL [p < 0.0001]). Expansion carriers without ataxia differed from controls by significantly more upper motor signs (SCA1 p = 0.0003, SCA3 p = 0.003) and by the presence of sensor impairment and diplopia in SCA3 (p = 0.0448 and 0.0445, respectively). Functional scales, fatigue and depression scores, swallowing difficulties, and cognitive impairment were worse in expansion carriers with ataxia than those without ataxia. Ataxic SCA3 participants showed extrapyramidal signs, urinary dysfunction, and lower motor neuron signs significantly more often than expansion carriers without ataxia. Discussion READISCA showed the feasibility of harmonized data acquisition in a multinational network. NfL alterations, early sensory ataxia, and corticospinal signs were quantifiable between preataxic participants and controls. Patients with ataxia differed in many parameters from controls and expansion carriers without ataxia, with a graded increase of abnormal measures from control to preataxic to ataxic cohorts.

KW - Humans

KW - Prospective Studies

KW - Spinocerebellar Ataxias

KW - Cerebellar Ataxia

KW - Cerebellum

KW - Biomarkers

KW - Machado-Joseph Disease/diagnosis

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UR - http://www.scopus.com/inward/citedby.url?scp=85153802704&partnerID=8YFLogxK

U2 - 10.1212/WNL.0000000000207088

DO - 10.1212/WNL.0000000000207088

M3 - Article

C2 - 36797067

AN - SCOPUS:85153802704

SN - 0028-3878

VL - 100

SP - E1836-E1848

JO - Neurology

JF - Neurology

IS - 17

ER -

Baseline Clinical and Blood Biomarkers in Patients With Preataxic and Early-Stage Disease Spinocerebellar Ataxia 1 and 3

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PubMed: MeSH publication types

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