Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice
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ABSTRACT:
SUBMITTER: Carlo Wilke
PROVIDER: S-SCDT-EMM-2019-11803 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross-species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock-in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross-sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 knock-in mice, here also starting already at the presymptomatic stage, closely following ataxin-3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross-species validated biomarkers in both ataxic and preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity-to-onset and, potentially, treatment-response markers in both human and preclinical SCA3 trials.
| S-EPMC7338806 | biostudies-literature
Project description:We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1(Delta18/Delta18)), encoding inositol 1,4,5-triphosphate receptor 1. A previously reported spontaneous Itpr1 mutation in mice causes a phenotype identical to that observed here. In both models in-frame deletion within Itpr1 leads to a decrease in the normally high level of Itpr1 expression in cerebellar Purkinje cells. Spinocerebellar ataxia 15 (SCA15), a human autosomal dominant disorder, maps to the genomic region containing ITPR1; however, to date no causal mutations had been identified. Because ataxia is a prominent feature in Itpr1 mutant mice, we performed a series of experiments to test the hypothesis that mutation at ITPR1 may be the cause of SCA15. We show here that heterozygous deletion of the 5' part of the ITPR1 gene, encompassing exons 1-10, 1-40, and 1-44 in three studied families, underlies SCA15 in humans.
| S-EPMC1892049 | biostudies-literature
Project description:Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3) is the most common autosomal dominant ataxia. In view of the development of targeted therapies for SCA3, precise knowledge of stage-dependent fluid and MRI biomarker changes is needed. We analyzed cross-sectional data of 292 SCA3 mutation carriers including 57 pre-ataxic individuals, and 108 healthy controls from the European Spinocerebellar ataxia type 3/Machado-Joseph Disease Initiative (ESMI) cohort. Blood concentrations of mutant ATXN3 and neurofilament light (NfL) were determined, and volumes of pons, cerebellar white matter (CWM) and cerebellar grey matter (CGM) were measured on MRI. Mutant ATXN3 concentrations were high before and after ataxia onset, while NfL continuously increased and deviated from normal 11.9 years before onset. Pons and CWM volumes decreased, but the deviation from normal was only 2.0 years (pons) and 0.3 years (CWM) before ataxia onset. We propose a staging model of SCA3 that includes an initial asymptomatic carrier stage followed by the biomarker stage defined by absence of ataxia, but a significant rise of NfL. The biomarker stage leads into the ataxia stage, defined by manifest ataxia. The present analysis provides a robust framework for further studies aiming at elaboration and differentiation of the staging model of SCA3.
| S-EPMC10168503 | biostudies-literature
Project description:Background and objectivesIn 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.MethodsWe 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.ResultsWe 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.DiscussionREADISCA 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.Trial registration informationClinicalTrials.gov NCT03487367.
| S-EPMC10136009 | biostudies-literature
Project description: Not available
| S-EPMC10083001 | biostudies-literature
Project description:BackgroundIn polyglutamine (polyQ) diseases, the identification of modifiers and the construction of prediction model for progression facilitate genetic counseling, clinical management and therapeutic interventions.MethodsData were derived from the longest longitudinal study, with 642 examinations by International Cooperative Ataxia Rating Scale (ICARS) from 82 SCA3 participants. Using different time scales of disease duration, we performed multiple different linear, quadratic and piece-wise linear growth models to fit the relationship between ICARS scores and duration. Models comparison was employed to determine the best-fitting model according to goodness-of-fit tests, and the analysis of variance among nested models.ResultsAn acceleration was detected after 13 years of duration: ICARS scores progressed 2.445 (SE: 0.185) points/year before and 3.547 (SE: 0.312) points/year after this deadline. Piece-wise growth model fitted better to studied data than other two types of models. The length of expanded CAG repeat (CAGexp) in ATXN3 gene significantly influenced progression. Age at onset of gait ataxia (AOga), a proxy for aging process, was not an independent modifier but affected the correlation between CAGexp and progression. Additionally, gender had no significant effect on progression rate of ICARS. The piece-wise growth models were determined as the predictive models, and ICARS predictions from related models were available.ConclusionsWe first confirmed that ICARS progressed as a nonlinear pattern and varied according to different stages in SCA3. In addition to ATXN3 CAGexp, AOga or aging process regulated the progression by interacting with CAGexp.
| S-EPMC9107762 | biostudies-literature
Project description:ObjectivesSpinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a polyglutamine disorder with no current disease-modifying treatment. Conformational changes in mutant ataxin-3 trigger different pathogenic cascades, including reactive oxygen species (ROS) generation; however, the clinical relevance of oxidative stress elements as peripheral biomarkers of SCA3/MJD remains unknown. We aimed to evaluate ROS production and antioxidant defense capacity in symptomatic and presymptomatic SCA3/MJD individuals and correlate these markers with clinical and molecular data with the goal of assessing their properties as disease biomarkers.MethodsMolecularly confirmed SCA3/MJD carriers and controls were included in an exploratory case-control study. Serum ROS, measured by 2',7'-dichlorofluorescein diacetate (DCFH-DA) as well as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) antioxidant enzyme activities, levels were assessed.ResultsFifty-eight early/moderate stage symptomatic SCA3/MJD, 12 presymptomatic SCA3/MJD, and 47 control individuals were assessed. The DCFH-DA levels in the symptomatic group were 152.82?nmol/mg of protein [95% confidence interval (CI), 82.57-223.08, p?<?0.001] higher than in the control and 243.80?nmol/mg of protein (95% CI, 130.64-356.96, p?<?0.001) higher than in the presymptomatic group. The SOD activity in the symptomatic group was 3?U/mg of protein (95% CI, 0.015-6.00, p?=?0.048) lower than in the presymptomatic group. The GSH-Px activity in the symptomatic group was 13.96?U/mg of protein (95% CI, 5.90-22.03, p?<?0.001) lower than in the control group and 20.52?U/mg of protein (95% CI, 6.79-34.24, p?<?0.001) lower than in the presymptomatic group and was inversely correlated with the neurological examination score for spinocerebellar ataxias (R?=?-0.309, p?=?0.049).ConclusionEarly/moderate stage SCA3/MJD patients presented a decreased antioxidant capacity and increased ROS generation. GSH-Px activity was the most promising oxidative stress disease biomarker in SCA3/MJD. Further longitudinal studies are necessary to identify both the roles of redox parameters in SCA3/MJD pathophysiology and as surrogate outcomes for clinical trials.
| S-EPMC5611390 | biostudies-literature
Project description:A 58-year-old man consulted our hospital due to a 2-year history of dysarthria and a 1-month history of blepharospasm. In addition to the ataxic dysarthria and blepharospasm, a neurological examination demonstrated slight ataxia of the trunk and lower limbs. Brain MRI demonstrated atrophy of the upper portion of the cerebellar vermis. Gene analysis established a diagnosis of spinocerebellar ataxia type 31 (SCA31). Single photon emission computed tomography (SPECT) with the three-dimensional stereotaxic ROI template (3DSRT) software program demonstrated hyperperfusion in the lenticular nucleus and thalamus. Although the association between SCA31 and blepharospasm in our patient remains unclear, we considered that this combination might be more than coincidental.
| S-EPMC6028682 | biostudies-other
Project description:PurposeTo analyze the relation between ophthalmologic and motor changes in spinocerebellar ataxia type 7 (SCA7).Patients and methodsThis was a case series study. Sixteen SCA7 patients underwent a comprehensive ophthalmic examination, including ocular extrinsic motility testing, color vision test, and optical coherence tomography of the optic nerve and macula. Changes in the corneal endothelium, electroretinographic patterns, and a complete neurologic evaluation using the Scale for the Assessment and Rating of Ataxia (SARA) were evaluated. Correlations of endothelial cell density (ECD) with number of CAG repetitions and the SARA scores were estimated.ResultsAll patients showed various degrees of visual impairment mainly due to macular deterioration. Notably, they also presented decreased ECD. Pairwise correlations of ECD with number of CAG repeats and severity of motor symptoms quantified with the SARA scores were inverse (r=-0.46, P=0.083 and r=-0.64, P=0.009, respectively). Further analyses indicated an average ECD decrease of 48 cells/mm2 (P=0.006) per unit of change on the number of CAG repeats, and of 75 cells/mm2 (P=0.001) per unit of change on the SARA scores.ConclusionsThe results agree with previous ophthalmological findings regarding the widespread effect of SCA7 mutation on the patient's visual system. However, the results also show a significant negative correlation of decreased ECD with both CAG repetitions and SARA scores. This suggests that motor systems could degenerate in parallel with visual systems, although more research is needed to determine whether the degeneration is caused by the same mechanisms.
| S-EPMC5770701 | biostudies-other
Project description:Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), may be the most common dominantly inherited ataxia in the world. Here I will review historical, clinical, neuropathological, genetic, and pathogenic features of MJD, and finish with a brief discussion of present, and possible future, treatment for this currently incurable disorder. Like many other dominantly inherited ataxias, MJD/SCA3 shows remarkable clinical heterogeneity, reflecting the underlying genetic defect: an unstable CAG trinucleotide repeat that varies in size among affected persons. This pathogenic repeat in MJD/SCA3 encodes an expanded tract of the amino acid glutamine in the disease protein, which is known as ataxin-3. MJD/SCA3 is one of nine identified polyglutamine neurodegenerative diseases which share features of pathogenesis centered on protein misfolding and accumulation. The specific properties of MJD/SCA3 and its disease protein are discussed in light of what is known about the entire class of polyglutamine diseases.
| S-EPMC3568768 | biostudies-literature