Ventricular volume expansion in presymptomatic genetic frontotemporal dementia

Objective: To characterize the time course of ventricular volume expansion in genetic frontotemporal dementia (FTD) and identify the onset time and rates of ventricular expansion in presymptomatic FTD mutation carriers. Methods: Participants included patients with a mutation in MAPT, PGRN, or C9orf72, or first-degree relatives of mutation carriers from the GENFI study with MRI scans at study baseline and at 1 year follow-up. Ventricular volumes were obtained from MRI scans using FreeSurfer, with manual editing of segmentation and comparison to fully automated segmentation to establish reliability. Linear mixed models were used to identify differences in ventricular volume and in expansion rates as a function of time to expected disease onset between presymptomatic carriers and noncarriers. Results: A total of 123 participants met the inclusion criteria and were included in the analysis (18 symptomatic carriers, 46 presymptomatic mutation carriers, and 56 noncarriers). Ventricular volume differences were observed 4 years prior to symptom disease onset for presymptomatic carriers compared to noncarriers. Annualized rates of ventricular volume expansion were greater in presymptomatic carriers relative to noncarriers. Importantly, time-intensive manually edited and fully automated ventricular volume resulted in similar findings. Conclusions: Ventricular volume differences are detectable in presymptomatic genetic FTD. Concordance of results from time-intensive manual editing and fully automatic segmentation approaches support its value as a measure of disease onset and progression in future studies in both presymptomatic and symptomatic genetic FTD

Advances in neuroimaging in frontotemporal dementia

Frontotemporal dementia (FTD) is a clinically and neuroanatomically heterogeneous neurodegenerative disorder with multiple underlying genetic and pathological causes. Whilst initial neuroimaging studies highlighted the presence of frontal and temporal lobe atrophy or hypometabolism as the unifying feature in patients with FTD, more detailed studies have revealed diverse patterns across individuals, with variable frontal or temporal predominance, differing degrees of asymmetry, and the involvement of other cortical areas including the insula and cingulate, as well as subcortical structures such as the basal ganglia and thalamus. Recent advances in novel imaging modalities including diffusion tensor imaging, resting-state functional magnetic resonance imaging and molecular positron emission tomography imaging allow the possibility of investigating alterations in structural and functional connectivity and the visualisation of pathological protein deposition. This review will cover the major imaging modalities currently used in research and clinical practice, focusing on the key insights they have provided into FTD, including the onset and evolution of pathological changes and also importantly their utility as biomarkers for disease detection and staging, differential diagnosis and measurement of disease progression. Validating neuroimaging biomarkers that are able to accomplish these tasks will be crucial for the ultimate goal of powering upcoming clinical trials by correctly stratifying patient enrolment and providing sensitive markers for evaluating the effects and efficacy of disease-modifying therapies

Medição manual da volumetria do hipocampo utilizando o visualizador Osirix®

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Ciências da Saúde, 2013.Introdução: As técnicas usadas para medição volumétrica em uso com execução mais simples ou complexa incluem métodos manuais, semiautomáticos e automáticos com diferentes programas e protocolos. Apesar do avanço tecnológico nesta área, o traçado manual continua sendo o método mais eficaz e de menor custo, entretanto, é o que mais consome tempo, limitando sua aplicação clínica. O programa Osirix é um visualizador DICOM (Comunicação de Imagens Digitais em Medicina), baseado em plataforma Apple, distribuído em várias versões, incluindo uma de 32bits que é gratuita. É uma aplicação com bom desempenho e amplamente difundida entre os radiologistas e demais especialistas que utilizam imagens na sua prática diária. Objetivo: Desenvolver uma técnica de medição volumétrica manual do hipocampo utilizando o visualizador Osirix, versão 5,6 e realizar a comparação interobservador da medição do hipocampo com a mesma técnica. Materiais e Métodos: Foi utilizado o visualizador Osirix gratuito, com imagens de sequência volumétrica SPGR ponderadas em T1, com cortes de 1mm de espessura; intervalo de 0,1mm, obtidas em aparelho de ressonância magnética (RM) GE de 1,5T, com bobina de 8 canais. Foi usada uma delimitação visual específica do hipocampo. No mínimo dez cortes foram escolhidos para o traçado manual das regiões de interesse (ROI), preferencialmente quando houvesse uma mudança na sua conformação visual. Em seguida, selecionou-se na barra de ferramentas o comando ROI, opção ROI volume (volume da área de interesse) e generate missing ROI (gerar áreas de interesse), para gerar as áreas subsequentes automaticamente podendo ser corrigidas manualmente em caso de erros do programa. Finalmente, repetiu-se a sequência ROI e ROI volume, mas dessa vez com o comando compute volume (computar volume) para calcular o volume total de todas as áreas de interesse e gerar uma imagem correspondente em três dimensões (3D). Os coeficientes de correlação intraclasse foram calculados, com um intervalo de 95% de confiança, como uma medida de confiabilidade relativa entre as volumetrias dos leitores. Estes coeficientes foram calculados para uma análise de variância (ANOVA) a dois fatores baseado em concordância absoluta. A técnica foi aplicada em 12 pacientes com idade média de 75 anos, sexo feminino, cognitivamente normal e que realizaram RM devido a outras queixas, como cefaleia, e não apresentavam anormalidades estruturais. As medidas foram realizadas por dois médicos residentes do terceiro ano (R3) de radiologia e uma geriatra, esta sem experiência prévia em manipular imagens de RM. Resultados: Após a análise estatística, verificou-se que todos os coeficientes de correlação intraclasse apresentaram valores abaixo de 0,40 que indica uma baixa concordância entre os avaliadores. Conclusão: A medição volumétrica do hipocampo utilizando o visualizador Osirix tem a vantagem de ser acessível e ter um custo baixo comparado com as técnicas automáticas. Contudo, o procedimento é trabalhoso, demanda tempo e não houve uma correção para a atrofia relacionada ao envelhecimento e a variabilidade individual. A análise estatística evidenciou uma baixa concordância entre os avaliadores o que reforça a necessidade de maior treinamento na delimitação do hipocampo relatado na literatura. _______________________________________________________________________________________ ABSTRACTIntroduction: The techniques used for volume measurement from simple to more complex methods include manual, semiautomatic and automatic measurements with a variety of programs and protocols. Despite technological advances, manual tracing remains the most effective and least costly, however it’s more time-consuming and this limits its clinical use. Osirix™ is a DICOM™ (Digital Imaging and Communications in Medicine), viewer, based on an Apple™ platform, available in several versions, including a 32 bits that is free of charge. It performs well and is widespread among radiologists and other specialists who use images in their daily practice. Objective: To develop a technique for hippocampal manual volumetric measurement using the DICOM viewer Osirix™ version 5.6 and compare the interater measurement of the hippocampus with the same technique. Materials and Methods: We used the free viewer Osirix™, with images obtained by T1-weighted gradient echo SPGR volumetric sequence, 1mm thick slices with 0.1mm interval on a 1.5 T MRI (magnetic resonance imaging) GE with an 8 channel head coil. A specific delineation of the hippocampus was used. At least ten slices were chosen to manually trace the region of interest (ROI), preferably where there were changes in its visual conformation. Next, in the toolbar, we selected the following sequence of commands: “ROI”, “ROI volume” and “generate missing ROI” and the software generated automatically the missing ROI that was corrected manually in case of errors. Finally, the sequence was repeated, “ROI”, “ROI volume”, but this time with the final command being “compute volume” to calculate the total volume of all the areas of interest and generate a corresponding three dimensional (3D) image. The Intraclass Correlation Coefficient (ICC) was calculated with 95% confidence interval, 10 as a measure of the reliability between volumetric ratings. These coefficients were calculated on a two-way ANOVA model based on absolute agreement. This technique was applied in 12 patients with mean age of 75, female, cognitively normal and who had MRI performed due to other complaints, such as headache, that showed no structural abnormalities. Two third year radiology residents and 1 geriatrician with limited MRI experience performed the measurements. Results: The statistical analysis found that all ICC had values below 0.40, indicating a weak correlation among raters. Conclusion: The manual volumetric hippocampus measurement with Osirix™ has the advantage of being accessible and of low cost compared to automatic techniques. This technique is time consuming and there was no correction for aging atrophy or individual variability. Statistical analysis demonstrated a weak correlation among raters which confirms the importance of training the researchers on the delineation of the hippocampus

Cognitive Profiles and Atrophy Ratings on MRI in Senior Patients With Mild Cognitive Impairment

In this cross-sectional study, we sought to describe cognitive and neuroimaging profiles of Memory clinic patients with Mild Cognitive Impairment (MCI). 51 MCI patients and 51 controls, matched on age, sex, and socio-economic status (SES), were assessed with an extensive neuropsychological test battery that included a measure of intelligence (General Ability Index, “GAI,” from WAIS-IV), and structural magnetic resonance imaging (MRI). MCI subtypes were determined after inclusion, and z-scores normalized to our control group were generated for each cognitive domain in each MCI participant. MR-images were scored by visual rating scales. MCI patients performed significantly worse than controls on 23 of 31 cognitive measures (Bonferroni corrected p = 0.001), and on 8 of 31 measures after covarying for intelligence (GAI). Compared to nonamnestic MCI patients, amnestic MCI patients had lower test results in 13 of 31 measures, and 5 of 31 measures after co-varying for GAI. Compared to controls, the MCI patients had greater atrophy on Schelten's Medial temporal lobe atrophy score (MTA), especially in those with amnestic MCI. The only structure-function correlation that remained significant after correction for multiple comparisons was the MTA—long delay recall domain. Intelligence operationalized as GAI appears to be an important moderator of the neuropsychological outcomes. Atrophy of the medial temporal lobe, based on MTA scores, may be a sensitive biomarker for the functional episodic memory deficits associated with MCI

Early Markers of Dysfunction in Frontotemporal Dementia

Frontotemporal Dementia (FTD) is a neurodegenerative disorder that results in atrophy within the frontal and/or temporal lobes. Clinically, patients with FTD present with progressive deterioration in behaviour and/or language abilities. FTD has a strong genetic component with approximately 40% of patients reporting a family history. Specifically, mutations in microtubule-associated protein tau (MAPT), progranulin (GRN) and expanded repeats in the chromosome 9 open reading frame 72 (C9orf72) are the main genetic causes of FTD. Currently, no disease-modifying treatments exist, and off-label medications have been used for symptomatic management of behaviours. Substantial progress has been made to understand the underlying pathology of the disease and clinical trials targeting FTD are in progress. As clinical trials begin, the identification of disease markers will be critical to measure treatment effects, indicate when treatments should be initiated and serve as potential targets for treatments. Therefore, there is a critical need to identify disease markers in FTD. The present work aimed to elucidate behavioural, structural, and functional changes in FTD from the preclinical to the symptomatic disease stage. Study I delineated the initial symptoms in patients with genetic FTD and in at-risk gene mutation carriers (preclinical mutation carriers and non-mutation carriers). This study revealed gene-specific patterns of initial symptoms during the preclinical and symptomatic disease period. Study II examined the brain’s ventricular volumes in genetically at-risk mutation carriers. Preclinical mutation carriers exhibited larger ventricular volume (i.e. greater neuronal atrophy), relative to biologically related mutation non-carriers. Study III delineated the functional neural correlates underlying disinhibition and behavioural flexibility in patients with FTD. Relative to healthy controls, patents with FTD exhibited decreased activity within the ventral and dorsal lateral regions of the prefrontal cortex. This study reveals that patients with FTD exhibit aberrant neural functioning relative to healthy controls in a task indexing behavioural flexibility. Overall, this work suggests that behavioural and neuroanatomical disease-alteration occur during the preclinical disease stage and functional neural deficits underlying behavioural difficulties can be detected in symptomatic patients. These results may be applied to future clinical trial designs to assess the efficacy of treatments and determine potential treatment targets

The Cognitive and Neural Basis for Apathy in Frontotemporal Degeneration

The syndrome of apathy, defined as a reduction in goal-directed behavior (GDB), has profound consequences for morbidity and mortality in the patient and for family-caregiver burden. Apathy is one of the primary neuropsychiatric syndromes associated with the disruption of the frontal-striatal system, but the behavioral and biological mechanisms underlying apathy are not well understood. Apathy is especially prevalent in behavioral variant frontotemporal degeneration (bvFTD). In a sample of 20 apathetic adults with bvFTD and 17 normal controls (NC), impairments in three components of GDB--initiation, planning and motivation--were examined using a novel computerized reaction time test. Employing structural neuroimaging techniques, I then examined the neural basis of GDB in these apathetic bvFTD participants. I found evidence that apathy is associated with an impairment in any of the three GDB components. Initiation, planning, and motivation each map onto three distinct brain regions in the frontal lobe that work together in a large-scale neural network. Furthermore, I was able to identify participants with specific subtypes of apathy, depending on the impaired GDB mechanism. I developed and submitted a proposal for continued study of the phenomenon; the proposal was awarded. The long-term potential impact of this beginning program of research is profound for patients with neurodegenerative disease, their caregivers, and families. Current treatment of apathy has been hindered due to poor understanding of the mechanisms underlying this condition. This work will lead to a better understanding of these mechanisms and structures fundamental to the behavior, and, with this knowledge, tailored interventions can be designed and implemented by professional and lay caregivers. Thus, a more precise characterization of apathy will allow providers to implement the most appropriate therapy for a given patient

MRI Measures of Neurodegeneration as Biomarkers of Alzheimer's Disease

Indiana University-Purdue University Indianapolis (IUPUI)Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease. Many researchers believe that an effective AD treatment will prevent the development of disease rather than treat the disease after a diagnosis. Therefore, the development of tools to detect AD-related pathology in early stages is an important goal. In this report, MRI-based markers of neurodegeneration are explored as biomarkers of AD. In the first chapter, the sensitivity of cross-sectional MRI biomarkers to neurodegenerative changes is evaluated in AD patients and in patients with a diagnosis of mild cognitive impairment (MCI), a prodromal stage of AD. The results in Chapter 1 suggest that cross-sectional MRI biomarkers effectively measure neurodegeneration in AD and MCI patients and are sensitive to atrophic changes in patients who convert from MCI to AD up to 1 year before clinical conversion. Chapter 2 investigates longitudinal MRI-based measures of neurodegeneration as biomarkers of AD. In Chapter 2a, measures of brain atrophy rate in a cohort of AD and MCI patients are evaluated; whereas in Chapter 2b, these measures are assessed in a pre-MCI stage, namely older adults with cognitive complaints (CC) but no significant deficits. The results from Chapter 2 suggest that dynamic MRI-based measures of neurodegeneration are sensitive biomarkers for measuring progressive atrophy associated with the development of AD. In the final chapter, a novel biomarker for AD, visual contrast sensitivity, was evaluated. The results demonstrated contrast sensitivity impairments in AD and MCI patients, as well as slightly in CC participants. Impaired contrast sensitivity was also shown to be significantly associated with known markers of AD, including cognitive impairments and temporal lobe atrophy on MRI-based measures. The results of Chapter 3 support contrast sensitivity as a potential novel biomarker for AD and suggest that future studies are warranted. Overall, the results of this report support MRI-based measures of neurodegeneration as effective biomarkers for AD, even in early clinical and preclinical disease stages. Future therapeutic trials may consider utilizing these measures to evaluate potential treatment efficacy and mechanism of action, as well as for sample enrichment with patients most likely to rapidly progress towards AD

Longitudinal neuroimaging measures of volumetric change across the frontotemporal dementia spectrum

Frontotemporal dementia (FTD) is a common cause of young onset dementia, encompassing several clinical, genetic and pathological subgroups. Currently there are no treatments, but there are promising candidates in development. However, proven biomarkers of disease progression in FTD are lacking and urgently needed to facilitate these trials. Investigating large sporadic and genetic FTD cohorts, this thesis provides a comprehensive comparison of longitudinal neuroimaging measures of structural change within the clinical, genetic and pathological FTD subgroups. Effect size and sample size estimates are computed to explore the feasibility of these brain measures as surrogate markers of disease progression in order to detect disease-modifying treatment effects. The first project compares 17 automated techniques for extracting whole-brain atrophy measures. Many of the techniques showed great promise, producing sample sizes of substantially less than 100 patients required to detect a disease-modifying effect. Significant differences in performance were found between both techniques and patient subgroups, highlighting the importance of informed biomarker choice in matching the optimal marker to the patient group to be enrolled in a trial. In the following chapters, I explored lobar and subcortical change across the disease spectrum. The different patient subgroups presented with unique profiles of change but, interestingly, automated measures of temporal lobe, caudate and thalamic atrophy proved to be particularly sensitive markers of change, producing low sample size estimates across the FTD subgroups. Importantly, I found significantly increased rates of amygdala, hippocampus, caudate and thalamic atrophy in differing patterns across presymptomatic mutation carriers, providing the first comprehensive assessment of the utility of such markers for early therapeutic intervention at this ideal stage before symptoms develop. In summary, this work expands current knowledge and builds on the limited longitudinal investigations currently available in FTD, as well as providing valuable information about the potential of non-invasive biomarkers for sporadic and genetic FTD trials