Anna Castaldo

Progression characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study

BACKGROUND The European Friedreichs Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreichs ataxia. We used data from EFACTS to assess disease progression and the predictive value of disease-related factors on progression, and estimated sample sizes for interventional randomised clinical trials. METHODS We enrolled patients with genetically confirmed Friedreichs ataxia from 11 European study sites in Austria, Belgium, France, Germany, Italy, Spain, and the UK. Patients were seen at three visits-baseline, 1 year, and 2 years. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF), and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. We estimated the yearly progression for each outcome with linear mixed-effect modelling. This study is registered with ClinicalTrials.gov, number NCT02069509, and follow-up assessments and recruitment of new patients are ongoing. FINDINGS Between Sept 15, 2010, and Nov 21, 2013, we enrolled 605 patients with Friedreichs ataxia. 546 patients (90%) contributed data with at least one follow-up visit. The progression rate on SARA was 0·77 points per year (SE 0·06) in the overall cohort. Deterioration in SARA was associated with younger age of onset (-0·02 points per year [0·01] per year of age) and lower SARA baseline scores (-0·07 points per year [0·01] per baseline point). Patients with more than 353 GAA repeats on the shorter allele of the FXN locus had a higher SARA progression rate (0·09 points per year [0·02] per additional 100 repeats) than did patients with fewer than 353 repeats. Annual worsening was 0·10 points per year (0·03) for INAS, -0·04 points per year (0·01) for SCAFI, 0·93 points per year (0·06) for ADL, and -0·02 points per year (0·004) for EQ-5D-3L. PVF performance improved by 0·99 words per year (0·14). To detect a 50% reduction in SARA progression at 80% power, 548 patients would be needed in a 1 year clinical trial and 184 would be needed for a 2 year trial. INTERPRETATION Our results show that SARA is a suitable clinical rating scale to detect deterioration of ataxia symptoms over time; ADL is an appropriate measure to monitor changes in daily self-care activities; and younger age at disease onset is a major predictor for faster disease progression. The results of the EFACTS longitudinal analysis provide suitable outcome measures and sample size calculations for the design of upcoming clinical trials of Friedreichs ataxia. FUNDING European Commission.

Stance instability in preclinical SCA1 mutation carriers: A 4-year prospective posturography study

OBJECTIVE We aimed to study postural balance in preclinical Spinocerebellar ataxia type 1 (SCA1) mutation carriers to identify and observe specific motor functional deficit before evident clinical manifestation. METHODS Participants were 9 asymptomatic SCA1 mutation carriers (6M/3F), aged 31.8±7years (range 22-44), and 17 age-matched non-carrier controls (5M/12F) (age 18-42). Subjects underwent postural tests on a force platform (Tetrax®-IBS, Sunlight Medical Ltd.) with and without visual feedback. Amount of body sway was represented by stability index (ST). Tests were repeated after 2- and 4-years. Estimated years to onset were calculated. RESULTS In controls, ST was unchanged from baseline to 4-year evaluations in all standing conditions. SCA1 mutation carriers performed similarly to controls in the postural tasks with open eyes, whereas in conditions without visual feedback SCA1 carriers had significantly higher ST than controls at all longitudinal evaluations. Close-to-disease onset carriers (≤7years) showed more prominent time-dependent stance abnormalities (p<0.0001 for all comparisons). CONCLUSIONS Traceable and progressive postural abnormalities can be observed in preclinical close-to-onset SCA1 carriers. Quantitative analysis of stance could represent a promising outcome measure in clinical trials including preclinical subjects.

Monitoring disease progression in spinocerebellar ataxias: implications for treatment and clinical research

ABSTRACT Introduction: Spinocerebellar ataxias (SCAs) are autosomal dominant diseases characterized by progressive gait and limb incoordination, disequilibrium, dysarthria, and eye movement disturbances. Approximately 40 genetic subtypes of SCAs are known and classified according to the causative disease gene/locus. With the possibility of the specific genetic diagnosis in patients and at-risk family members, several clinical scales and functional tests have been validated and used in ataxic patients with the purposes of measuring the entity of disease progression in natural history studies and the possible slowing of neurological impairment in therapeutic trials. Areas covered: This paper reviews the most widely used clinical scales and quantitative tests that contributed in monitoring disease progression of the most common forms of SCAs. Expert commentary: The currently available and validated clinical scales and quantitative performance scores are adequate to measure disease severity, but may require a considerable number of subjects and a long period of treatment to allow the recognition of beneficial effect of interventional therapies. Advanced MRI techniques are a consistent biomarker and maybe useful to track disease progression from the preclinical to the manifest ataxic phase in association with appropriate clinical or paraclinical investigations.

F6 Does premanifest HD perform worse in arithmetic? Symbol digit and calculation tests confirm early cognitive impairment in preHD and correlate with brain MRI abnormalities

Objectives We aimed to identify markers of cognitive and structural brain abnormalities in premanifest Huntington’s disease subjects (preHD). Participants and methods We enrolled 29 preHD (13F/16 M, age 36.5 years, CAG range 37–48; UHDRS-TMS <5) and 25 sex-age matched controls (14F/11 M, age 35.7 years). Subjects underwent 3 Tvolumetric brain MRI (Philips Achieva). Anatomical data were segmented with FreeSurfer. The cognitive battery included: MMSE, Calculation test, Stroop, Verbal fluency, Symbol Digit Modalities Test (SDMT), Trail Making Test, Attentive Matrices test, Digit Span forward and reversal. Estimated years-to-onset were obtained using Langbehn’s method. Results PreHD and controls did not differ in total intracranial volume, caudate volumes, and cortical thickness, and presented scores within normal range in all cognitive tests. However, preHD scored significantly worse than controls in SDMT (p = 0.048), in MMSE (p = 0.0013) and in Calculation test (p = 0.014). Analyses of sub-item of the Calculation test showed that preHD, and in particular the group of close-to-onset preHD (−16 years), made specifically more mistakes than controls in the subtraction task (p = 0.0089), while preHD and controls did not differ in multiplications. The SDMT score correlated with left occipital cortical thickness (p = 0.0029) and Calculation test total score with caudate nucleus volumes (p = 0.032). Conclusions We confirm that SDMT can identify very early abnormalities in preHD and the scores directly correlate with occipital cortical thickness. The results of the Calculation test suggest that preHD have selective executive deficits in calculation, as demonstrated in the subtraction process, while in the multiplication task, implying mainly memory retrieval, no differences were found.

E7 Posturography and mri study in premanifest huntington’s disease subjects to investigate stance abnormalities and early markers of neurodegeneration

Objectives Premanifest Huntington’s disease mutation carriers (preHD) are known to present functional and neuroradiological abnormalities before the motor onset. This study evaluated brain morphometry and posture in preHD. Participants and methods 29 preHD (13F/16 M, mean age 36.5 years, CAG range 37–48) and 25 sex-age matched controls were enrolled (14F/11 M, mean age 35.7 years). Inclusion criteria were: CAG expansion > 36; UHDRS-TMS <5. Subjects underwent 3 T brain MRI (Philips Achieva) for morphometry (T2-weighted images in axial/coronal planes and T1-weighted 3 D Turbo Field Echo sequence). Anatomical data were segmented with FreeSurfer. Postural sway was assessed with a force platform testing the stance in wide/narrow base with open/closed eyes (Kistler, CH). Estimated years to onset was calculated using Langbehn model. Results PreHD and controls did not differ in total intracranial volume, caudate volumes, and cortical thickness. Only in close-to-onset preHD caudate volumes and occipital cortical thickness were reduced in comparison with controls (p = 0.002; p = 0.0098) and far-from-onset preHD (p = 0.002; p = 0.007). Caudate volumes and occipital cortical thickness directly correlated with years to onset (ρ = 0.58, 0.74; p = 0.003, p < 0.0001 respectively). Posturography parameters were similar in pre-HD and controls for all conditions, except for wide-base-closed-eyes test, in which preHD presented a greater number of sway peaks (p = 0.006). In close-to-onset preHD the number of sway peaks was greater than controls (p = 0.001) and far-from-onset preHD (p = 0.016). Conclusions Our study confirms that caudate volumes and occipital cortical thickness are the earliest markers of brain degeneration in the preHD. Posturography may represent a simple and rapid test to investigate early stance abnormalities.

I16 Very slow disease progression in two hd patients carrying 40 and 45 cag repeats: a 10-year follow-up observational report

Objective To describe atypical longitudinal disease progression in Huntington’s disease (HD). Subjects and methods We selected two HD subjects from a cohort of 104 Italian patients participating in the REGISTRY-Enroll-HD study. Patient 1 is a 66 year-old man presenting depressive symptoms at age 46. First motor symptoms, noticed at age 51 (9 year later than expected from his CAG length), were mild eye movement defects and difficulties in tongue protrusion. He had very few choreic movements. Genetic test showed 20/45 CAG repeats. At age 56 UHDRS-TMS was 15 and TFC 11. In this subject both motor and cognitive impairment progressed very slowly during follow-up. After 10-year UHDRS-TMS was 28 and TFC 5. The change per year in the cognitive tests were: Symbol-Digit-Modalities-Test 0/y (baseline = 20); Verbal Fluency −0.3/year; Color-Naming −3.6/year; Word-Reading +0.7/year; and Stroop-Interferences −0.6/year. Patient 2 is a 59 year-old man, who presented motor symptoms at age 49 (11 years earlier than expected). At baseline TFC was 13 and UHDRS-TMS was 9. Genetic test showed 19/40 CAG repeats. After 10 years UHDRS-TMS was 18 and TFC 10. Cognitive tests are available only for the last 6 years of follow-up. The changes per year were: Symbol-Digit-Modalities-Test −2.3/year (baseline = 26); Verbal Fluency −1/year; Color-Naming −14.3/year; Word-Reading −2.8/year, and Stroop-Interferences −4.2/year. For both patients volumetric brain MRI and multi-tissue DNA analyses are performed. Conclusion The identification of HD individuals with atypically mild motor and/or cognitive progression may allow the study of possible genetic/epigenetic modifying factor/s significantly slowing the clinical disease progression.

MRI evidence of cerebellar and extraocular muscle atrophy differently contributing to eye movement abnormalities in SCA2 and SCA28 diseases

PURPOSE Spinocerebellar ataxias type 2 and 28 (SCA2, SCA28) are autosomal dominant disorders characterized by progressive cerebellar and oculomotor abnormalities. We aimed to investigate cerebellar, brainstem, and extraocular muscle involvement in the mitochondrial SCA28 disease compared with SCA2. METHODS We obtained orbital and brain 1.5 T-magnetic resonance images (MRI) in eight SCA28 subjects, nine SCA2, and nine age-matched healthy subjects. Automated segmentation of cerebellum and frontal lobe was performed using Freesurfer software. Manual segmentations for midbrain, pons, and extraocular muscles were performed using OsiriX. RESULTS Eye movement abnormalities in SCA2 subjects were characterized by slow horizontal saccades. Subjects with SCA28 variably presented hypometric saccades, saccadic horizontal pursuit, impaired horizontal gaze holding, and superior eyelid ptosis. Quantitative brain MRI demonstrated that cerebellar and pons volumes were significantly reduced in both SCA2 and SCA28 subjects compared with controls (P < 0.03), and in SCA2 subjects compared with SCA28 (P < 0.01). Midbrain and frontal lobe volumes were also significantly reduced in SCA2 compared to controls (P < 0.03), whereas these volumes did not differ between SCA2 and SCA28 and between SCA28 and control subjects. The extraocular muscle areas were 37% to 48% smaller in SCA28 subjects compared with controls (P < 0.002), and 14% to 36% smaller compared with SCA2 subjects (P < 0.03). Extraocular muscle areas did not differ between SCA2 and controls. CONCLUSIONS Our MRI findings support the hypothesis of different cerebellar and extraocular myopathic contributions in the eye movement abnormalities in SCA2 and SCA28 diseases. In SCA28, a myopathic defect selectively involving the extraocular muscles supports a specific impairment of mitochondrial energy metabolism.

N01 A 6-years experience of genetic counselling in Huntington disease (2006–2011): constant socio-demographic profile of at-risk individuals requesting genetic predictive test

Objective To report a 6-year experience of a programme for predictive test (PT) in Huntington disease (HD). Participants and Methods At-risk individuals for HD, aged >18 years, performed three consecutive visits, and an optional follow-up visit at 4–6 months. Symptom Check List 90 Revised (SCL90 R), and Beck Depression Inventory (BDI) tests were administered. The psychiatrist/psychologist did not meet the at-risk subjects during the PT, but cooperated with the multidisciplinary team integrating psychological support at the disclosure of genetic results. Results From 2006 and 2011, 159 individuals (78M/81F) at-risk for HD underwent the programme for PT. The mean age was 37.4±11.6 years (range 16–77) Married subjects were 51.3%. Positive symptoms at the SCL90R test were 26.0± 17.6 (range 1–78). Age, sex, marital status and results at psychological tests were similar in each year of the study. Only years of education were significantly lower for the subjects asking for PT in 2011 (10 years) in comparison with the subjects performing PT in 2006 (13.3) (p=0.0065). None of the subjects had clinically relevant depressive symptoms (BDI scores <19). Thirty-four subjects (21.3%) did not complete the programme. Seventy-three per cent of cases presented only mild psychological distress not requiring psychological support; while in 27% of cases psychological support was recommended (86% were mutation carriers) (p=0.0001). No suicidal attempts, self-harming or psychotic episodes were associated with the disclosure of unfavourable genetic results. Conclusions During the 6 years of the programme we did not observe significant adverse events. Socio-demographic characteristics of the at-risk HD population undergoing PT remained similar from 2006 to 2011, except for education.