Department of Medical Genetics, University of Campinas (UNICAMP), Campinas, Brazil

3. Department of Medical Genetics, University of Campinas (UNICAMP), Campinas, Brazil

Correspondence to: Marcondes C. França Júnior,

Department of Neurology,

University of Campinas;

R. Tessália Vieira de Camargo, 126, 13083-887,

Campinas, Brazil.

E-mail: mcfrancajr@uol.com.br

Word Count: Body (3447 words); Abstract (233 words)

References: 50

Table Count: 02

Picture Count: 04

Running Title: SCA1 Structural Damage.

Keywords: SCA1, Spinocerebellar ataxia type 1; FreeSurfer; Atlas-based analysis; CERES.

Disclosures:

-Casseb reports grants from FAPESP

-Rezende reports grants from FAPESP;

-Dr Faber reports grants from CNPq (Brazilian National Council for Scientific and - Technological Development) during the conduct of the study;

-Dr Martinez reports grants from FAPESP during the conduct of this study;

-Dr Lopes-Cendes reports grants from FAPESP and CNPq, during the conduct of the study.

-Dr França Jr reports grants from FAPESP and CNPq.

-Dr Barsottini reports grants from FAPESP and CNPq, during the conduct of the study. -Dr Pedroso reports grants from FAPESP and CNPq, during the conduct of the study.

-Dr. Martins Jr. reports grants from FAPESP during the conduct of this study.

Funding: This work was supported by the São Paulo Research Foundation (FAPESP).

Contribution of the authors:

1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript: A. Writing of the first draft, B. Review and Critique;

Carlos Roberto Martins Jr: 1A,1B, 1C, 2A, 2B, 2C, 3A

Alberto Rolim Muro Martinez: 1B, 2A, 2B, 3B

Ingrid Faber Vasconcelos: 1A, 2C, 3B

Thiago Junqueira de Rezende: 1A, 2C, 3B

Rafael Casseb: 1A, 2C, 3B

Jose Luiz Pedroso: 1A, 2C, 3B

Orlando Graziani Povoas Barsottini: 1B, 2C, 3B

Íscia Lopes-Cendes: 1B, 2C, 3B

Marcondes C França Jr: 1A, 1B, 1C, 2A, 2B, 2C, 3B

Full Financial Disclosures of all Authors for the Past Year:

Carlos Roberto Martins Jr: none

Alberto Rolim Muro Martinez: none

Ingrid Faber Vasconcelos: none

Thiago Junqueira de Rezende: none

Rafael Casseb: none

Jose Luiz Pedroso: none

Orlando Graziani Povoas Barsottini: none

Íscia Lopes-Cendes: none

Marcondes C França Jr: received research support from PTC therapeutics, Cristália and Pfizer; took part in advisory boards for Genzyme, Pfizer, Baxter and CSL- Behring; Received travel Grant from Pfizer, Baxter and PTC therapeutics; gave lectures as a speaker for Pfizer, PTC therapeutics, CSL-Behring and Baxter.

Abbreviations:

ACE-R = Addenbrooke’s cognitive examination revised; AD = axial diffusivity; BDI = Beck Depression Inventory; CNS = central nervous system; CST = corticospinal tract; DTI = diffusion tensor imaging; eTIV = estimated total intracranial volume; FA = fractional anisotropy; GM = gray matter; LH = left hemisphere; MD = mean diffusivity; RD = radial diffusivity; RH = right hemisphere; Roi = region of interest ; SC = spinal cord; SARA = scale for the assessment and rating of ataxia; VBM = Voxel-based morphometry; WM = white matter.

Abstract

Spinocerebellar ataxia type 1 is an autosomal dominant disorder caused by a CAG repeat expansion in ATXN1, characterized by progressive cerebellar and extracerebellar symptoms. MRI-based studies in SCA1 focused in the cerebellum and connections, but there are few data about supratentorial/spinal damage and its clinical relevance. We have thus designed this multimodal MRI study to uncover the structural signature of SCA1. To accomplish that, a group of 33 patients and 33 age- and gender-matched healthy controls underwent MRI on a 3T scanner. All patients underwent a comprehensive neurological and neuropsychological evaluation. We correlated the structural findings with the clinical features of the disease. In addition, we evaluated the disease progression looking at differences in SCA1 subgroups defined by disease duration. Ataxia and pyramidal signs were the main symptoms. Neuropsychological evaluation disclosed cognitive impairment in 53% with predominant frontotemporal dysfunction. Gray matter analysis unfolded cortical thinning of primary and associative motor areas with more restricted impairment of deep structures. Deep gray matter atrophy was associated with motor handicap and poor cognition skills. White matter integrity loss was diffuse in the brainstem, but restricted in supratentorial structures. Cerebellar cortical thinning was found in multiple areas and correlated not only with motor disability, but also with verbal fluency. Spinal cord atrophy correlated with motor handicap. Comparison of MRI findings in disease duration-defined subgroups identified a peculiar pattern of progressive degeneration and suggested a possible associated neurodevelopmental problem.

Introduction

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disorder, characterized by progressive cerebellar ataxia, pyramidal signs, extracerebellar features and non-motor symptoms, as well as mild cognitive decline (Bürk et al., 1996; Bürk et al., 2003). Onset of SCA1 is usually in the fourth decade of life and affected families show anticipation (Banfi et al., 1994; Chong et al., 1995). SCA1 is caused by a CAG expansion within the coding region of ATXN1. The CAG repeat region is localized in exon 8 and translated into a polyglutamine tract in the amino terminal half of the protein (Banfi et al., 1994; Tong et al., 2001; Orr et al., 1993). Healthy individuals have a CAG-repeat number of 39 or less, affected patients have more than 44 repeats and intermediate alleles (39-44) result in reduced penetrance. Abnormal ataxin-1 aggregates into small intranuclear inclusions and interferes with the normal function of the protein leading to neuronal toxicity (Duyckearts et al., 1999; Scho¨ls et al., 2004)

Like other neurodegenerative disorders, cognitive impairment, usually mild, is observed in 20–30% of the cases (Scho¨ls et al., 1997; Filla et al., 2000). Several studies disclose impaired executive function, attention, visuo-spatial perception, verbal fluency, immediate and delayed memory (Bürk et al., 2003; Klinke et al., 2010; Bürk et al., 2007). In some patients, restlessness and emotional lability, without full blown dementia, characterize the mental status (Kameya et al., 1995). Significant mental retardation, however, has been reported only in individuals with very large CAG expansions and onset before 15 years of age (Scho¨ls et al., 2004; Schmitz- Hu¨bsch et al., 2008).

Neuroimaging techniques are powerful tools in the assessment of many closely related neurodegenerative disorders (Hanganu et al., 2014; Min et al., 2014; França et al., 2009; Lopes et al., 2013). Such tools demonstrate in vivo structural abnormalities and provide a better understanding of the disease mechanisms and progression. Notwithstanding, no large studies have been conducted to investigate the extent of neurodegeneration and how it affects sequentially certain neuronal populations in SCA1. In particular, little is known about the extent of cortical and

subcortical damage in the disease, and how such damage correlates with the clinical phenotype.

Based on this, our aim is to provide clinical characterization concerning motor and cognitive features of the disease, correlating these findings with anatomical aspects. Moreover, we aim to delineate how the disease course influences the structural damage, giving insights into the natural history of the disease. To accomplish that, we employed multimodal MRI, looking at the brain and spinal cord in a large cohort of patients with SCA1 at different stages of the disease.

Materials and Methods