Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine

Spinal and encephalic structural damage in spinocerebellar ataxia type 1 : characterization and clinical correlates

Orientador: Marcondes Cavalcante França JuniorTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: A ataxia espinocerebelar do tipo 1 (SCA1) é uma doença neurodegenerativa cuja expressão clínica predominante é a ataxia cerebelar progressiva associada à hiperreflexia profunda e às alterações sacádicas. Causada por expansão instável de uma sequência CAG no gene ATXN1 no cromossomo 6, foi a primeira ataxia espinocerebelar que teve seu substrato genético elucidado. Apesar disso, existem poucos estudos acerca de seus aspectos clínicos e morfológicos, principalmente no que diz respeito às manifestações não motoras e suas correlações estruturais. Desta forma, o objetivo deste trabalho é caracterizar, clínica e morfologicamente, os pacientes com SCA1, utilizando escalas clínicas bem estabelecidas e técnicas multimodais de ressonância magnética. Para tanto, foram recrutados 33 pacientes adultos com teste molecular positivo para SCA1 acompanhados nos serviços de neurologia da UNICAMP e UNIFESP. Os pacientes foram submetidos a exame neurológico pormenorizado, enfatizando aspectos motores e não-motores. Para a graduação da ataxia utilizou-se a Scale for the Assessment and Rating of Ataxia (SARA). Para avaliação de sintomas não-motores utilizou-se a Modified Fatigue Impact Scale (MFIS) para fadiga, Epworth Sleepiness Scale (ESS) para sonolência excessiva diurna, Beck Depression Inventory (BDI) para depressão e Addenbrooke¿s Cognitive Examination ¿ Revised (ACE-R) para cognição. O dano estrutural encefálico e medular foi avaliado por imagens de ressonância magnética ponderadas em T1 e DTI. Para análise, foram utilizadas as ferramentas FreeSurfer, T1 MultiAtlas, DTI MultiAtlas, CERES e SpineSeg. Com o objetivo de avaliar evolutivamente a SCA1, os pacientes foram divididos em três grupos de acordo com o tempo de doença. Variáveis clínicas e imaginológicas foram comparadas nesses grupos a fim de determinar, temporalmente, o padrão evolutivo das alterações no SNC. Os sintomas motores correlacionaram-se diretamente com o dano dos núcleos rubros, medular e cerebelar. Os níveis de fadiga foram significativamente maiores nos pacientes comparado aos controles e apresentaram relação direta com depressão e duração da doença. A depressão foi mais frequente nos pacientes e correlacionou-se com aspectos motores, entretanto, não houve correlação com áreas encefálicas. As alterações cognitivas foram importantes, principalmente nos domínios de memória e fluência, os quais correlacionaram-se diretamente com atrofia na amígdala e lóbulo VIII cerebelar, respectivamente. Evidenciou-se redução da área e aumento da excentricidade significativos na medula cervical dos pacientes quando comparados aos controles. A redução da área medular correlacionou-se diretamente com aspectos motores, apresentando duração e CAGn como possíveis determinantes. Avaliações transversais do encéfalo revelaram danos significativos em áreas primárias e associativas em córtex cerebral, substância cinzenta profunda, córtex cerebelar e subtância branca encefálica, principalmente em regiões infratentoriais. Do ponto de vista evolutivo, verificou-se padrão lesional em sentido caudo-cranial. Por fim, fomos capazes de caracterizar fenoticamente a SCA1 e correlacionar seus aspectos clínicos e estruturaisAbstract: Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease expressed clinically by progressive cerebellar ataxia associated with deep hyperreflexia and saccadic alterations. Caused by unstable expansions of a CAG sequence in the ATXN1 gene on chromosome 6, it was the first spinocerebellar ataxia that had its genetic substrate elucidated. Despite this, there are few studies about its clinical and morphological aspects, mainly regarding non-motor manifestations and their structural correlations. In this way, the objective of this study is to characterize, clinically and morphologically, patients with SCA1, using well-established clinical scales and multimodal magnetic resonance techniques. We have thus evaluated 33 consecutive adult patients regularly followed at UNICAMP and UNIFESP and 33 healthy age-and-sex matched controls. All patients had molecular confirmation of SCA1. The patients underwent detailed neurological examination, emphasizing motor and non-motor aspects. For ataxia quantification, the Scale for the Assessment and Rating of Ataxia (SARA) was used. For the evaluation of non-motor symptoms, we used the Modified Fatigue Impact Scale (MFIS) for fatigue, Epworth Sleepiness Scale (ESS) for excessive daytime sleepiness, Beck Depression Inventory (BDI) for depression and Addenbrooke's Cognitive Examination ¿ Revised (ACE-R) for cognition aspects. The encephalic and spinal structural damage were evaluated by DTI and T1-weighted magnetic resonance imaging. For MRI analyses, the tools FreeSurfer, T1 MultiAtlas, DTI MultiAtlas, CERES and SpineSeg were used. Attempting to analyse the evolution pattern, the patients were divided into three groups according to the disease duration. Clinical and imaging variables were compared in these groups to determine the evolutionary pattern of CNS changes. Motor symptoms correlated to damage of red nuclei, spinal cord and cerebellar cortex. Fatigue levels were significantly higher in patients compared to controls and were directly related to depression and disease duration. Depression was more frequent in patients and correlated to motor aspects, however, there was no association with brain areas. Cognitive alterations were important, especially in memory and fluency domains, which correlated directly to atrophy in the amygdala and cerebellar lobe VIII, respectively. Significant area reduction and eccentricity increase were observed in patients' cervical spinal cord when compared to controls. The reduction of the cord area correlated directly to motor aspects; and duration and CAGn were possible determinants. Cross-sectional brain evaluations revealed significant damage in primary and associative areas in cerebral cortex, deep gray matter, cerebellar cortex and encephalic white matter, especially in infratentorial regions. Analysis of disease course disclosed a caudal-cranial pattern of damage in the CNS. Finally, we were able to phenotypically characterize SCA1 and to correlate its clinical and structural aspectsDoutoradoFisiopatologia MédicaDoutor em Ciência

Neuroradiological Findings in the Spinocerebellar Ataxias

Background: The spinocerebellar ataxias (SCAs) are a group of autosomal dominant degenerative diseases characterized by cerebellar ataxia. Classified according to gene discovery, specific features of the SCAs – clinical, laboratorial, and neuroradiological (NR) – can facilitate establishing the diagnosis. The purpose of this study was to review the particular NR abnormalities in the main SCAs. Methods: We conducted a literature search on this topic. Results: The main NR characteristics of brain imaging (magnetic resonance imaging or computerized tomography) in SCAs were: (1) pure cerebellar atrophy; (2) cerebellar atrophy with other findings (e.g., pontine, olivopontocerebellar, spinal, cortical, or subcortical atrophy; “hot cross bun sign”, and demyelinating lesions); (3) selective cerebellar atrophy; (4) no cerebellar atrophy. Discussion: The main NR abnormalities in the commonest SCAs, are not pathognomonic of any specific genotype, but can be helpful in limiting the diagnostic options. We are progressing to a better understanding of the SCAs, not only genetically, but also pathologically; NR is helpful in the challenge of diagnosing the specific genotype of SCA

Microstructural MRI basis of the cognitive functions in patients with Spinocerebellar ataxia type 2

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum. The particular atrophy pattern results in some typical clinical features mainly including motor deficits. In addition, the presence of cognitive impairments, involving language, visuospatial and executive functions, has been also shown in SCA2 patients and it is now widely accepted as a feature of the disease. The aim of the study is to investigate the microstructural patterns and the anatomo-functional substrate that could account for the cognitive symptomatology observed in SCA2 patients. In the present study, diffusion tensor imaging (DTI) based-tractography was performed to map the main cerebellar white matter (WM) bundles, such as Middle and Superior Cerebellar Peduncles, connecting cerebellum with higher order cerebral regions. Damage-related diffusivity measures were used to determine the pattern of pathological changes of cerebellar WM microstructure in patients affected by SCA2 and correlated with the patients' cognitive scores. Our results provide the first evidence that WM diffusivity is altered in the presence of the cerebellar cortical degeneration associated with SCA2 thus resulting in a cerebello-cerebral dysregulation that may account for the specificity of cognitive symptomatology observed in patients

Structural and connectivity parameters reveal spared connectivity in young patients with non-progressive compared to slow-progressive cerebellar ataxia

INTRODUCTION: Within Pediatric Cerebellar Ataxias (PCAs), patients with non-progressive ataxia (NonP) surprisingly show postural motor behavior comparable to that of healthy controls, differently to slow-progressive ataxia patients (SlowP). This difference may depend on the building of compensatory strategies of the intact areas in NonP brain network. METHODS: Eleven PCAs patients were recruited: five with NonP and six with SlowP. We assessed volumetric and axonal bundles alterations with a multimodal approach to investigate whether eventual spared connectivity between basal ganglia and cerebellum explains the different postural motor behavior of NonP and SlowP patients. RESULTS: Cerebellar lobules were smaller in SlowP patients. NonP patients showed a lower number of streamlines in the cerebello-thalamo-cortical tracts but a generalized higher integrity of white matter tracts connecting the cortex and the basal ganglia with the cerebellum. DISCUSSION: This work reveals that the axonal bundles connecting the cerebellum with basal ganglia and cortex demonstrate a higher integrity in NonP patients. This evidence highlights the importance of the cerebellum-basal ganglia connectivity to explain the different postural motor behavior of NonP and SlowP patients and support the possible compensatory role of basal ganglia in patients with stable cerebellar malformation

Diffusion Magnetic Resonance Imaging Microstructural Abnormalities in Multiple System Atrophy: A Comprehensive Review

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by autonomic failure, ataxia, and/or parkinsonism. Its prominent pathological alterations can be investigated using diffusion magnetic resonance imaging (dMRI), a technique that exploits the characteristics of water random motion inside brain tissue. The aim of this report was to review currently available literature on the application of dMRI in MSA and to describe microstructural abnormalities, diagnostic applications, and pathophysiological correlates. Sixty-four published studies involving microstructural investigation using dMRI in MSA were included. Widespread microstructural abnormalities of white matter were described, especially in the middle cerebellar peduncle, corticospinal tract, and hemispheric fibers. Gray matter degeneration was identified as well, with diffuse involvement of subcortical structures, especially in the putamina. Diagnostic applications of dMRI were mostly explored for the differential diagnosis between MSA parkinsonism and Parkinson's disease. Recently, machine learning algorithms for image processing and disease classification have demonstrated high diagnostic accuracy, showing potential for translation into clinical practice. To a lesser extent, clinical correlates of microstructural abnormalities have also been investigated, and abnormalities related to motor, ocular, and cognitive impairments were described. dMRI in MSA has contributed to in vivo identification of known pathological abnormalities. Translation into clinical practice of the latest advancements for the differential diagnosis between MSA and other forms of parkinsonism seems feasible. Current limitations involve the possibility of correctly diagnosing MSA in the very early stages, when the clinical diagnosis is most uncertain. Furthermore, pathophysiological correlates of microstructural abnormalities remain understudied. (c) 2022 International Parkinson and Movement Disorder Society

Cerebellum and neurodegenerative diseases: Beyond conventional magnetic resonance imaging

The cerebellum plays a key role in movement control and in cognition and cerebellar involvement is described in several neurodegenerative diseases. While conventional magnetic resonance imaging (MRI) is widely used for brain and cerebellar morphologic evaluation, advanced MRI techniques allow the investigation of cerebellar microstructural and functional characteristics. Volumetry, voxel-based morphometry, diffusion MRI based fiber tractography, resting state and task related functional MRI, perfusion, and proton MR spectroscopy are among the most common techniques applied to the study of cerebellum. In the present review, after providing a brief description of each technique's advantages and limitations, we focus on their application to the study of cerebellar injury in major neurodegenerative diseases, such as multiple sclerosis, Parkinson's and Alzheimer's disease and hereditary ataxia. A brief introduction to the pathological substrate of cerebellar involvement is provided for each disease, followed by the review of MRI studies exploring structural and functional cerebellar abnormalities and by a discussion of the clinical relevance of MRI measures of cerebellar damage in terms of both clinical status and cognitive performance

Cerebellum and neurodegenerative diseases: Beyond conventional magnetic resonance imaging

The cerebellum plays a key role in movement control and in cognition and cerebellar involvement is described in several neurodegenerative diseases. While conventional magnetic resonance imaging (MRI) is widely used for brain and cerebellar morphologic evaluation, advanced MRI techniques allow the investigation of cerebellar microstructural and functional characteristics. Volumetry, voxel-based morphometry, diffusion MRI based fiber tractography, resting state and task related functional MRI, perfusion, and proton MR spectroscopy are among the most common techniques applied to the study of cerebellum. In the present review, after providing a brief description of each technique's advantages and limitations, we focus on their application to the study of cerebellar injury in major neurodegenerative diseases, such as multiple sclerosis, Parkinson's and Alzheimer's disease and hereditary ataxia. A brief introduction to the pathological substrate of cerebellar involvement is provided for each disease, followed by the review of MRI studies exploring structural and functional cerebellar abnormalities and by a discussion of the clinical relevance of MRI measures of cerebellar damage in terms of both clinical status and cognitive performance

Developmental hypomyelination in Wolfram syndrome: New insights from neuroimaging and gene expression analyses

Wolfram syndrome is a rare multisystem disorder caused by mutations in WFS1 or CISD2 genes leading to brain structural abnormalities and neurological symptoms. These abnormalities appear in early stages of the disease. The pathogenesis of Wolfram syndrome involves abnormalities in the endoplasmic reticulum (ER) and mitochondrial dynamics, which are common features in several other neurodegenerative disorders. Mutations in WFS1 are responsible for the majority of Wolfram syndrome cases. WFS1 encodes for an endoplasmic reticulum (ER) protein, wolframin. It is proposed that wolframin deficiency triggers the unfolded protein response (UPR) pathway resulting in an increased ER stress-mediated neuronal loss. Recent neuroimaging studies showed marked alteration in early brain development, primarily characterized by abnormal white matter myelination. Interestingly, ER stress and the UPR pathway are implicated in the pathogenesis of some inherited myelin disorders like Pelizaeus-Merzbacher disease, and Vanishing White Matter disease. In addition, exploratory gene-expression network-based analyses suggest that WFS1 expression occurs preferentially in oligodendrocytes during early brain development. Therefore, we propose that Wolfram syndrome could belong to a category of neurodevelopmental disorders characterized by ER stress-mediated myelination impairment. Further studies of myelination and oligodendrocyte function in Wolfram syndrome could provide new insights into the underlying mechanisms of the Wolfram syndrome-associated brain changes and identify potential connections between neurodevelopmental disorders and neurodegeneration