25 research outputs found

    Reliability of brain atrophy measurements in multiple sclerosis using MRI: an assessment of six freely available software packages for cross-sectional analyses

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    PURPOSE: Volume measurement using MRI is important to assess brain atrophy in multiple sclerosis (MS). However, differences between scanners, acquisition protocols, and analysis software introduce unwanted variability of volumes. To quantify theses effects, we compared within-scanner repeatability and between-scanner reproducibility of three different MR scanners for six brain segmentation methods. METHODS: Twenty-one people with MS underwent scanning and rescanning on three 3 T MR scanners (GE MR750, Philips Ingenuity, Toshiba Vantage Titan) to obtain 3D T1-weighted images. FreeSurfer, FSL, SAMSEG, FastSurfer, CAT-12, and SynthSeg were used to quantify brain, white matter and (deep) gray matter volumes both from lesion-filled and non-lesion-filled 3D T1-weighted images. We used intra-class correlation coefficient (ICC) to quantify agreement; repeated-measures ANOVA to analyze systematic differences; and variance component analysis to quantify the standard error of measurement (SEM) and smallest detectable change (SDC). RESULTS: For all six software, both between-scanner agreement (ICCs ranging 0.4–1) and within-scanner agreement (ICC range: 0.6–1) were typically good, and good to excellent (ICC > 0.7) for large structures. No clear differences were found between filled and non-filled images. However, gray and white matter volumes did differ systematically between scanners for all software (p < 0.05). Variance component analysis yielded within-scanner SDC ranging from 1.02% (SAMSEG, whole-brain) to 14.55% (FreeSurfer, CSF); and between-scanner SDC ranging from 4.83% (SynthSeg, thalamus) to 29.25% (CAT12, thalamus). CONCLUSION: Volume measurements of brain, GM and WM showed high repeatability, and high reproducibility despite substantial differences between scanners. Smallest detectable change was high, especially between different scanners, which hampers the clinical implementation of atrophy measurements

    A Longitudinal Method for Simultaneous Whole-Brain and Lesion Segmentation in Multiple Sclerosis

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    In this paper we propose a novel method for the segmentation of longitudinal brain MRI scans of patients suffering from Multiple Sclerosis. The method builds upon an existing cross-sectional method for simultaneous whole-brain and lesion segmentation, introducing subject-specific latent variables to encourage temporal consistency between longitudinal scans. It is very generally applicable, as it does not make any prior assumptions on the scanner, the MRI protocol, or the number and timing of longitudinal follow-up scans. Preliminary experiments on three longitudinal datasets indicate that the proposed method produces more reliable segmentations and detects disease effects better than the cross-sectional method it is based upon

    Neurofilament as a blood marker for diagnosis and monitoring of primary progressive aphasias

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    Objective: To assess the utility of serum neurofilament for diagnosis and monitoring of primary progressive aphasia (PPA) variants. Methods: We investigated neurofilament light chain (NF-L) levels in blood of 99 patients with PPA (40 with nonfluent variant PPA [nfvPPA], 38 with semantic variant PPA [svPPA], 21 with logopenic variant PPA [lvPPA]) and compared diagnostic performance with that reached by CSF NF-L, phosphorylated neurofilament heavy chain (pNF-H), b-amyloid (Ab(1)-42), tau, and phosphorylated tau. The longitudinal change of blood NF-L levels was measured and analyzed for correlation with functional decline and brain atrophy. Results: Serum NF-L is increased in PPA compared to controls and discriminates between nfvPPA/svPPA and lvPPA with 81% sensitivity and 67% specificity (cutoff 31 pg/mL). CSF NF-L, pNF-H, tau, phosphorylated tau, and Ab1-42 achieved similar performance, and pNF-H was the only marker for discrimination of nfvPPA from svPPA/lvPPA. In most patients with nfvPPA and svPPA, but not lvPPA, serum NF-L increased within follow-up. The increase correlated with functional decline and progression of atrophy of the left frontal lobe of all patients with PPAs and the right middle frontal gyrus of patients with nfvPPA and svPPA. Conclusions: Blood level of NF-L can aid the differential diagnosis of PPA variants, especially in combination with CSF pNF-H. Because serum NF-L correlates with functional decline and atrophy in the disease course, it qualifies as an objective disease status marker. Extended follow-up studies with cases of known neuropathology are imperative

    Atrophy in the Thalamus But Not Cerebellum Is Specific for C9orf72 FTD and ALS Patients - An Atlas-Based Volumetric MRI Study

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    Background: The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a C9orf72 mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to C9orf72 mutation carriers. Objective: This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls. Methods: Atlas-based volumetry was performed in 13 affected C9orf72 FTD, ALS and FTD/ALS patients, 45 sporadic FTD and FTD/ALS patients and 19 healthy controls. Volumes and laterality indices showing significant differences between mutation carriers and sporadic patients were subjected to binary logistic regression to determine the best predictor of mutation carrier status. Results: Compared to sporadic patients, mutation carriers showed a significant volume reduction of the thalamus, which was most striking in the occipital, temporal and prefrontal subregion of the thalamus. Disease severity measured by mini mental status examination (MMSE) and FTD modified Clinical Dementia Rating Scale Sum of Boxes (FTD-CDR-SOB) significantly correlated with volume reduction in the aforementioned thalamic subregions. No significant atrophy of cerebellar regions could be detected. A logistic regression model using the volume of the prefrontal and the laterality index of the occipital subregion of the thalamus as predictor variables resulted in an area under the curve (AUC) of 0.88 while a model using overall thalamic volume still resulted in an AUC of 0.82. Conclusion: Our data show that thalamic atrophy in C9orf72 mutation carriers goes beyond the expected atrophy in the prefrontal and temporal subregion and is in good agreement with the cortical atrophy pattern described in C9orf72 mutation carriers, indicating a retrograde degeneration of functionally connected regions. Clinical relevance of the detected thalamic atrophy is illustrated by a correlation with disease severity. Furthermore, the findings suggest MRI volumetry of the thalamus to be of high predictive value in differentiating C9orf72 mutation carriers from patients with sporadic FTD

    Serum neurofilament light chain in behavioral variant frontotemporal dementia

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    Objective To determine the association of serum neurofilament light chain (NfL) with functional deterioration and brain atrophy during follow-up of patients with behavioral variant frontotemporal dementia (bvFTD). Methods Blood NfL levels from 74 patients with bvFTD, 26 with Alzheimer disease (AD), 17 with mild cognitive impairment (MCI), and 15 healthy controls (Con) at baseline and follow-up were determined and analyzed for the diagnostic potential in relation to functional assessment (Clinical Dementia Rating Scale Sum of Boxes [CDR-SOB], frontotemporal lobar degeneration-related CDR-SOB, Mini-Mental State Examination [MMSE]) and brain volumetry. Results At baseline, serum NfL level correlated with CSFNfL (bvFTD r = 0.706, p < 0.0001;AD/MCI r = 0.666, p = 0.0003). Highest serum levels were observed in bvFTD (p < 0 0.0001 vs Con and MCI, p = 0.0078 vs AD, respectively). Discrimination of bvFTD from Con/MCI/AD was possible with 91%/74%/74% sensitivity and 79%/74%/58% specificity. At follow-up, serum NfL increased in bvFTD and AD (p = 0.0039 and p = 0.0006, respectively). At baseline and follow-up, NfL correlated with functional scores of patients with bvFTD (e.g., CDR-SOB [baseline] r = 0.4157, p = 0.0006;[follow-up] r = 0.5629, p < 0.0001) and with atrophy in the gray and white matter of many brain regions including frontal and subcortical areas (e.g., frontal lobe: r = -0.5857, p < 0.0001;95% confidence interval -0.7415 to -0.3701). For patients with AD/MCI, NfL correlated with the functional performance as well (e.g., CDR-SOB [baseline] r = 0.6624, p < 0.0001;[follow-up] r = 0.5659, p = 0.0003) but not with regional brain volumes. Conclusions As serum NfL correlates with functional impairment and brain atrophy in bvFTD at different disease stages, we propose it as marker of disease severity, paving the way for its future use as outcome measure for clinical trials. Classification of evidence This study provides Class III evidence that for patients with cognitive problems, serum NfL concentration discriminates bvFTD from other forms of dementia

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

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    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

    Translation of quantitative MRI analysis tools for clinical neuroradiology application

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    Quantification of imaging features can assist radiologists by reducing subjectivity, aiding detection of subtle pathology, and increasing reporting consistency. Translation of quantitative image analysis techniques to clinical use is currently uncommon and challenging. This thesis explores translation of quantitative imaging support tools for clinical neuroradiology use. I have proposed a translational framework for development of quantitative imaging tools, using dementia as an exemplar application. This framework emphasises the importance of clinical validation, which is not currently prioritised. Aspects of the framework were then applied to four disease areas: hippocampal sclerosis (HS) as a cause of epilepsy; dementia; multiple sclerosis (MS) and gliomas. A clinical validation study for an HS quantitative report showed that when image interpreters used the report, they were more accurate and confident in their assessments, particularly for challenging bilateral cases. A similar clinical validation study for a dementia reporting tool found improved sensitivity for all image interpreters and increased assessment accuracy for consultant radiologists. These studies indicated benefits from quantitative reports that contextualise a patient’s results with appropriate normative reference data. For MS, I addressed a technical translational challenge by applying lesion and brain quantification tools to standard clinical image acquisitions which do not include a conventional T1-weighted sequence. Results were consistent with those from conventional sequence inputs and therefore I pursued this concept to establish a clinically applicable normative reference dataset for development of a quantitative reporting tool for clinical use. I focused on current radiology reporting of gliomas to establish which features are commonly missed and may be important for clinical management decisions. This informs both the potential utility of a quantitative report for gliomas and its design and content. I have identified numerous translational challenges for quantitative reporting and explored aspects of how to address these for several applications across clinical neuroradiology

    BONE LOSS IN RELATION TO HYPOTHALAMIC ATROPHY IN ALZHEIMER'S DISEASE

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    Epidemiologic projections indicate that the incidence of Alzheimer's disease (AD) will increase dramatically in the coming decades due largely to the demographics of the disease and our aging population. Associated cognitive and physical decline greatly contributes to disability in older adults and places considerable burden on the health system, patients, and caregivers. Bone loss and increased risk of fractures are associated with AD, however little is known about mechanisms of this association. The body of presented work extends the literature on a relationship between bone loss and AD. Overall, the presented work provides initial evidence that accelerated bone loss observed in individuals in the early stages of AD may be partially due to distortion of central regulatory mechanisms by neurodegeneration. This is the first work to demonstrate that hypothalamic atrophy is related to bone loss and this relationship may be mediated by leptin-dependent mechanisms in humans in the early stages of AD. The work in Chapter 2 assessed bone health in the earliest clinical stages of AD in comparison to non-demented aging and examined the relationship of bone mineral density (BMD) with cognitive performance and brain atrophy, both of which are used as surrogate markers of neurodegeneration. We tested the hypothesis that bone density would be lower in early AD and associated with brain atrophy and cognitive decline. The results of this cross-sectional study supported our hypothesis and found that BMD is reduced in men and women in the earliest clinical stages of AD and associated with brain atrophy and memory decline, suggesting that central mechanisms may contribute to bone loss in early Alzheimer's disease. AD is associated with pathological changes in the hypothalamus, a key regulatory structure of bone remodeling. The aim of Chapter 3 was to extend previous findings of the association between BMD and neuroimaging markers of neurodegeneration by looking at global and regional, hypothalamus specifically, measures of brain volume in early AD and non-demented aging. The results demonstrated that in early AD, low BMD was associated with low volume of gray matter in brain structures predominantly affected by AD early in the disease, including the hypothalamus, cingulate, and parahippocampal gyri and in the left superior temporal gyrus and left inferior parietal cortex. No relationship between BMD and regional gray matter volume was found in non-demented controls. These results suggest that central mechanisms of bone remodeling may be disrupted by neurodegeneration. There is very limited guidance in the literature regarding useful and reliable techniques for studying hypothalamic anatomy using neuroimaging. In Chapter 4, we compared an automated neuroimaging technique - voxel-based morphometry (VBM) - to a "gold standard" manual method assessing volumetry of the hypothalamus. The atlas-based VBM volumetry showed promise as a useful tool for regional volumetry of the hypothalamus and has advantages over manual tracing as it is currently used. The results of this study provided guidance for method selection in future work. In Chapter 5, we further examined the hypothesis that AD may influence bone density in cortical skeletal sites directly through atrophy of the hypothalamus, the major central regulatory structure of bone remodeling. We previously reported in cross-section that BMD was lower in those with early AD and suggested that brain atrophy, specifically of the hypothalamus, was associated with lower BMD in AD. We now examined if similar results were apparent in a two year longitudinal study to extend our previous finding of an association between hypothalamic atrophy and bone density. We also explore predictors of bone loss in AD and healthy aging. Our results demonstrate that bone loss may be accelerated in AD compared with non-demented controls. For AD participants, bone loss was associated with hypothalamic atrophy over two years. Additionally, bone loss was associated with baseline levels of the vitamin D. For non-demented participants, bone loss was associated with age, female gender and decline in physical activity. Different predictors of bone loss may suggest that mechanisms of bone loss may differ in aging and AD and that neurodegeneration may contribute to bone loss in early AD. These results extend and strengthen the cross-sectional observations in Chapters 2&3. The purpose of the work presented in Chapter 6 was to further extend previous observations by assessing the roles of leptin, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) , two important regulators of hypothalamic control of bone remodeling, in mediating relationship between hypothalamic structural changes and bone loss in AD. We used a hypothetical model with statistical structural equation or path modeling to examine if leptin, GH, and IGF-I may mediate the relationship between hypothalamic structural changes. The model demonstrated that hypothalamic atrophy had a direct relationship with bone loss. There was no apparent association between baseline IGF-1 and leptin with bone loss but we observed changes in both leptin and IGF-1 over two years that were associated with hypothalamic atrophy. Leptin increased over two years in AD and increase in leptin was associated with hypothalamic atrophy. On the other hand, IGF-1 declined over two year and this decrease was associated with increase in leptin. These results suggest that it is conceivable that central regulatory mechanisms of bone mass may be disturbed by neurodegeneration leading to bone loss in participants in the early stages of AD. In summary, this body of work demonstrates that bone density is reduced in women and men with early stages of AD and continues to decline over time, exceeding bone loss in non-demented older adults. While the causes of bone loss in AD remain unclear, the observed association of hypothalamic atrophy with bone loss suggests neurodegeneration may play a role in bone loss observed in AD and highlights a need for further studies. This work also corroborates other studies on the importance of vitamin D and physical activity for bone health. The findings of this body of work are important because evidence that bone loss in AD is associated with the atrophy in regions involved in the central regulation of bone mass may be relevant to therapeutic strategies to prevent or treat bone loss in AD and neurodegenerative diseases

    Image acquisition and quality assurance in the Boston Adolescent Neuroimaging of Depression and Anxiety study

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    The Connectomes Related to Human Diseases (CRHD) initiative was developed with the Human Connectome Project (HCP) to provide high-resolution, open-access, multi-modal MRI data to better understand the neural correlates of human disease. Here, we present an introduction to a CRHD project, the Boston Adolescent Neuroimaging of Depression and Anxiety (BANDA) study, which is collecting multimodal neuroimaging, clinical, and neuropsychological data from 225 adolescents (ages 14–17), 150 of whom are expected to have a diagnosis of depression and/or anxiety. Our transdiagnostic recruitment approach samples the full spectrum of depressed/anxious symptoms and their comorbidity, consistent with NIMH Research Domain Criteria (RDoC). We focused on an age range that is critical for brain development and for the onset of mental illness. This project sought to harmonize imaging sequences, hardware, and functional tasks with other HCP studies, although some changes were made to canonical HCP methods to accommodate our study population and questions. We present a thorough overview of our imaging sequences, hardware, and scanning protocol. We detail similarities and dif-ferences between this study and other HCP studies. We evaluate structural-, diffusion-, and functional-image-quality measures that may be influenced by clinical factors (e.g., disorder, symptomatology). Signal-to-noise and motion estimates from the first 140 adolescents suggest minimal influence of clinical factors on image quality. We anticipate enrollment of an additional 85 participants, most of whom are expected to have a diagnosis of anxiety and/or depression. Clinical and neuropsychological data from the first 140 participants are currently freely available through the National Institute of Mental Health Data Archive (NDA)
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