Longitudinal imaging highlights preferential basal ganglia circuit atrophy in Huntington's disease

Huntington's disease is caused by a CAG repeat expansion in the Huntingtin gene (HTT), coding for polyglutamine in the Huntingtin protein, with longer CAG repeats causing earlier age of onset. The variable 'Age' × ('CAG'-L), where 'Age' is the current age of the individual, 'CAG' is the repeat length and L is a constant (reflecting an approximation of the threshold), termed the 'CAG Age Product' (CAP) enables the consideration of many individuals with different CAG repeat expansions at the same time for analysis of any variable and graphing using the CAG Age Product score as the X axis. Structural MRI studies have showed that progressive striatal atrophy begins many years prior to the onset of diagnosable motor Huntington's disease, confirmed by longitudinal multicentre studies on three continents, including PREDICT-HD, TRACK-HD and IMAGE-HD. However, previous studies have not clarified the relationship between striatal atrophy, atrophy of other basal ganglia structures, and atrophy of other brain regions. The present study has analysed all three longitudinal datasets together using a single image segmentation algorithm and combining data from a large number of subjects across a range of CAG Age Product score. In addition, we have used a strategy of normalizing regional atrophy to atrophy of the whole brain, in order to determine which regions may undergo preferential degeneration. This made possible the detailed characterization of regional brain atrophy in relation to CAG Age Product score. There is dramatic selective atrophy of regions involved in the basal ganglia circuit-caudate, putamen, nucleus accumbens, globus pallidus and substantia nigra. Most other regions of the brain appear to have slower but steady degeneration. These results support (but certainly do not prove) the hypothesis of circuit-based spread of pathology in Huntington's disease, possibly due to spread of mutant Htt protein, though other connection-based mechanisms are possible. Therapeutic targets related to prion-like spread of pathology or other mechanisms may be suggested. In addition, they have implications for current neurosurgical therapeutic approaches, since delivery of therapeutic agents solely to the caudate and putamen may miss other structures affected early, such as nucleus accumbens and output nuclei of the striatum, the substantia nigra and the globus pallidus

Multi-Vendor and Multisite Evaluation of Cerebrovascular Reactivity Mapping Using Hypercapnia Challenge

Cerebrovascular reactivity (CVR), which measures the ability of cerebral blood vessels to dilate or constrict in response to vasoactive stimuli such as CO2 inhalation, is an important index of the brain\u27s vascular health. Quantification of CVR using BOLD MRI with hypercapnia challenge has shown great promises in research and clinical studies. However, in order for it to be used as a potential imaging biomarker in large-scale and multi-site studies, the reliability of CO2-CVR quantification across different MRI acquisition platforms and researchers/raters must be examined. The goal of this report from the MarkVCID small vessel disease biomarkers consortium is to evaluate the reliability of CO2-CVR quantification in three studies. First, the inter-rater reliability of CO2-CVR data processing was evaluated by having raters from 5 MarkVCID sites process the same 30 CVR datasets using a cloud-based CVR data processing pipeline. Second, the inter-scanner reproducibility of CO2-CVR quantification was assessed in 10 young subjects across two scanners of different vendors. Third, test-retest repeatability was evaluated in 20 elderly subjects from 4 sites with a scan interval of less than 2 weeks. In all studies, the CO2 CVR measurements were performed using the fixed inspiration method, where the subjects wore a nose clip and a mouthpiece and breathed room air and 5% CO2 air contained in a Douglas bag alternatively through their mouth. The results showed that the inter-rater CoV of CVR processing was 0.08 ± 0.08% for whole-brain CVR values and ranged from 0.16% to 0.88% in major brain regions, with ICC of absolute agreement above 0.9959 for all brain regions. Inter-scanner CoV was found to be 6.90 ± 5.08% for whole-brain CVR values, and ranged from 4.69% to 12.71% in major brain regions, which are comparable to intra-session CoVs obtained from the same scanners on the same day. ICC of consistency between the two scanners was 0.8498 for whole-brain CVR and ranged from 0.8052 to 0.9185 across major brain regions. In the test-retest evaluation, test-retest CoV across different days was found to be 18.29 ± 17.12% for whole-brain CVR values, and ranged from 16.58% to 19.52% in major brain regions, with ICC of absolute agreement ranged from 0.6480 to 0.7785. These results demonstrated good inter-rater, inter-scanner, and test-retest reliability in healthy volunteers, and suggested that CO2-CVR has suitable instrumental properties for use as an imaging biomarker of cerebrovascular function in multi-site and longitudinal observational studies and clinical trials

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

Regional cerebral blood perfusion changes in chronic stroke survivors as potential brain correlates of the functional outcome following gamiied home-based rehabilitation (IntelliRehab)—a pilot study

Background: Hospital-based stroke rehabilitation for stroke survivors in developing countries may be limited by staffing ratios and length of stay that could hamper recovery potential. Thus, a home-based, gamified rehabilitation system (i.e., IntelliRehab) was tested for its ability to increase cerebral blood flow (CBF), and the secondary impact of changes on the upper limb motor function and functional outcomes. Objective: To explore the effect of IntelliRehab on CBF in chronic stroke patients and its correlation with the upper limb motor function. Methods: Two-dimensional pulsed Arterial Spin Labelling (2D-pASL) was used to obtain CBF images of stable, chronic stroke subjects (n = 8) over 3-months intervention period. CBF alterations were mapped, and the detected differences were marked as regions of interest. Motor functions represented by Fugl-Meyer Upper Extremity Assessment (FMA) and Stroke Impact Scale (SIS) were used to assess the primary and secondary outcomes, respectively. Results: Regional CBF were significantly increased in right inferior temporal gyrus and left superior temporal white matter after 1-month (p = 0.044) and 3-months (p = 0.01) of rehabilitation, respectively. However, regional CBF in left middle fronto-orbital gyrus significantly declined after 1-month of rehabilitation (p = 0.012). Moreover, SIS-Q7 and FMA scores significantly increased after 1-month and 3-months of rehabilitation. There were no significant correlations, however, between CBF changes and upper limb motor function. Conclusions: Participants demonstrated improved motor functions, supporting the benefit of using IntelliRehab as a tool for home-based rehabilitation. However, within-participant improvements may have limited potential that suggests the need for a timely administration of IntelliRehab to get the maximum capacity of improvement

Multi-Granularity Whole-Brain Segmentation Based Functional Network Analysis Using Resting-State fMRI

In this work, we systematically analyzed the effects of various nodal definitions, as determined by a multi-granularity whole-brain segmentation scheme, upon the topological architecture of the human brain functional network using the resting-state functional magnetic resonance imaging data of 19 healthy, young subjects. A number of functional networks were created with their nodes defined according to two types of anatomical definitions (Type I and Type II) each of which consists of five granularity levels of whole brain segmentations with each level linked through ontology-based, hierarchical, structural relationships. Topological properties were computed for each network and then compared across levels within the same segmentation type as well as between Type I and Type II. Certain network architecture patterns were observed in our study: (1) As the granularity changes, the absolute values of each node's nodal degree and nodal betweenness change accordingly but the relative values within a single network do not change considerably; (2) The average nodal degree is generally affected by the sparsity level of the network whereas the other topological properties are more specifically affected by the nodal definitions; (3) Within the same ontology relationship type, as the granularity decreases, the network becomes more efficient at information propagation; (4) The small-worldness that we observe is an intrinsic property of the brain's resting-state functional network, independent of the ontology type and the granularity level. Furthermore, we validated the aforementioned conclusions and measured the reproducibility of this multi-granularity network analysis pipeline using another dataset of 49 healthy young subjects that had been scanned twice

Neuroimaging in Friedreich's ataxia : new approaches and clinical aplication

Orientadores: Marcondes Cavalcante França Junior, Andreia Vasconcellos FariaTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: A ataxia de Friedreich (FRDA) é a ataxia autossômica recessiva mais comum no mundo. Clinicamente, é caracterizada por início precoce, alterações sensoriais e ataxia de lenta progressão. Os estudos de imagem têm focado somente em estruturas infratentoriais, desconsiderando o envolvimento de estruturas supratentoriais, diferenças fenotípicas e duração da doença, bem como a evolução do dano neurológico. Portanto, o objetivo deste trabalho é avaliar, por meio de imagens de ressonância magnética multimodal, pacientes com ataxia de Friedreich a fim de compreender a evolução do dano encefálico, identificar o padrão de dano encefálico entre os fenótipos da doença, os sítios de depósitos de ferro extra-cerebelares e as primeiras estruturas acometidas na doença. A fim de atingir todos os objetivos, foram recrutados 25 pacientes adultos com a forma clássica da doença, 13 pacientes com início tardio e 12 pacientes pediátricos. Para quantificar a gravidade da doença foi utilizada a escala FARS. O dano estrutural de substância cinza e branca foi avaliado via imagens de ressonância magnética ponderadas em T1, T2 e DTI. Para análise de tais imagens foram utilizadas as ferramentas FreeSurfer, T1 MultiAtlas, DTI Multiatlas, SPM, SpineSeg e TBSS. As comparações de grupos revelaram comprometimento microestrutural multifocal na substância branca encefálica na FRDA, com dano extenso nos pedúnculos cerebelares, corpo caloso e tratos piramidais. Encontramos também alterações na substância cinzenta no núcleo denteado do cerebelo, tronco e córtex motor. Nós não identificamos mudanças volumétricas longitudinais, porém análises prospectivas da substância branca identificaram anormalidades microestruturais progressivas no corpo caloso, tratos piramidais e pedúnculos cerebelares superiores após um ano de seguimento. A respeito do estudo comparando o tipo clássico e o tipo tardio (cFRDA vs. LOFA), nós mostramos que ambos os fenótipos possuem um padrão de anormalidades similares, mas não idênticas. Embora sutis, as diferenças estruturais encontradas ajudam a explicar a variabilidade fenotípica entre estas duas apresentações da doença. Por exemplo, o maior dano microestrutural no trato córtico-espinhal no grupo LOFA ajuda a explicar os sinais piramidais mais exuberantes neste grupo. Não fomos capazes de identificar depósitos de ferro cerebrais nos pacientes com FRDA. Neste sentido, tais depósitos ficariam restritos somente ao núcleo denteado do cerebelo. Por fim, fomos capazes de observar que a manifestação inicial da doença, vista em pacientes pediátricos, se concentra na medula espinhal e no pedúnculo cerebelar inferiorAbstract: Friedreich¿s ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide; it is characterized by early onset, sensory abnormalities and slowly progressive ataxia. Besides that, most of neuroimaging studies have been focused only in infratentorial structures of adult patients. Furthermore, studies comparing different phenotypes of disease does not exist. Therefore, the objective of this study is to assess, using multimodal magnetic (MRI) resonance imaging, patients with Friedreich ataxia to better comprehend the progression of brain damage, to identify the pattern of damage across disease phenotypes, to identify areas with abnormal iron deposits in the brain and to characterize the structures initially damaged in early disease stages. To accomplish that, we enrolled 25 adult patients with classical FRDA, 13 patients with late-onset FRDA and 12 pediatric patients. The FARS scale was employed to quantify the disease severity. To assess the structural damage in gray and white matter, we acquired T1-weighted, T2-weighted and DTI images of the brain. To evaluate these images, we used the following tools: FreeSurfer, T1 MultiAtlas, SPM, DTI MultiAtlas, SpineSeg and TBSS. After group comparisons, there was widespread microstructural damage in the cerebral white matter, including cerebellar peduncles, corpus callosum and pyramidal tracts of patients with FRDA. We also found gray matter volumetric reduction in the dentate nuclei of the cerebellum, brainstem and motor cortex. We did not find volumetric reduction over time, but there was progressive white matter microstructural damage in the corpus callosum, pyramidal tracts and superior cerebellar peduncles after 1 year of follow-up. Regarding the disease phenotypes, we found that both classical FRDA and LOFA have similar, but not identical neuroimaging signatures. Although subtle, the structural differences might help to explain the phenotypic differences seen in both conditions. The corticospinal tracts are damaged in both conditions, but more severely in the late-onset FRDA group, which may explain why pyramidal signs are more evident in the latter subgroup. We failed to identify iron deposits in brain regions other than the dentate nuclei of patients with FRDA. Finally, we found that the spinal cord and inferior cerebellar peduncles are the structures compromised in pediatric patients with FRDADoutoradoFisiopatologia MédicaDoutor em Ciências2014/19786-7, 2015/09793-9FAPES

Test-retest reproducibility of a multi-atlas automated segmentation tool on multimodality brain MRI

The increasing use of large sample sizes for population and personalized medicine requires high-throughput tools for imaging processing that can handle large amounts of data with diverse image modalities, perform a biologically meaningful information reduction, and result in comprehensive quantification. Exploring the reproducibility of these tools reveals the specific strengths and weaknesses that heavily influence the interpretation of results, contributing to transparence in science. We tested-retested the reproducibility of MRICloud, a free automated method for whole-brain, multimodal MRI segmentation and quantification, on two public, independent datasets of healthy adults. Results The reproducibility was extremely high for T1-volumetric analysis, high for diffusion tensor images (DTI) (however, regionally variable), and low for resting-state fMRI. Conclusion In general, the reproducibility of the different modalities was slightly superior to that of widely used software. This analysis serves as a normative reference for planning samples and for the interpretation of structure-based MRI studies.910FAPESP – Fundação de Amparo à Pesquisa Do Estado De São Paulo2107/13102-7; 2013/07559-

Automated Generation of Radiologic Descriptions on Brain Volume Changes From T1-Weighted MR Images: Initial Assessment of Feasibility

Purpose: To examine the feasibility and potential difficulties of automatically generating radiologic reports (RRs) to articulate the clinically important features of brain magnetic resonance (MR) images.Materials and Methods: We focused on examining brain atrophy by using magnetization-prepared rapid gradient-echo (MPRAGE) images. The technology was based on multi-atlas whole-brain segmentation that identified 283 structures, from which larger superstructures were created to represent the anatomic units most frequently used in RRs. Through two layers of data-reduction filters, based on anatomic and clinical knowledge, raw images (~10 MB) were converted to a few kilobytes of human-readable sentences. The tool was applied to images from 92 patients with memory problems, and the results were compared to RRs independently produced by three experienced radiologists. The mechanisms of disagreement were investigated to understand where machine–human interface succeeded or failed.Results: The automatically generated sentences had low sensitivity (mean: 24.5%) and precision (mean: 24.9%) values; these were significantly lower than the inter-rater sensitivity (mean: 32.7%) and precision (mean: 32.2%) of the radiologists. The causes of disagreement were divided into six error categories: mismatch of anatomic definitions (7.2 ± 9.3%), data-reduction errors (11.4 ± 3.9%), translator errors (3.1 ± 3.1%), difference in the spatial extent of used anatomic terms (8.3 ± 6.7%), segmentation quality (9.8 ± 2.0%), and threshold for sentence-triggering (60.2 ± 16.3%).Conclusion: These error mechanisms raise interesting questions about the potential of automated report generation and the quality of image reading by humans. The most significant discrepancy between the human and automatically generated RRs was caused by the sentence-triggering threshold (the degree of abnormality), which was fixed to z-score >2.0 for the automated generation, while the thresholds by radiologists varied among different anatomical structures