Study protocol: Insight 46 - a neuroscience sub-study of the MRC National Survey of Health and Development.

BACKGROUND: Increasing age is the biggest risk factor for dementia, of which Alzheimer's disease is the commonest cause. The pathological changes underpinning Alzheimer's disease are thought to develop at least a decade prior to the onset of symptoms. Molecular positron emission tomography and multi-modal magnetic resonance imaging allow key pathological processes underpinning cognitive impairment - including ß-amyloid depostion, vascular disease, network breakdown and atrophy - to be assessed repeatedly and non-invasively. This enables potential determinants of dementia to be delineated earlier, and therefore opens a pre-symptomatic window where intervention may prevent the onset of cognitive symptoms. METHODS/DESIGN: This paper outlines the clinical, cognitive and imaging protocol of "Insight 46", a neuroscience sub-study of the MRC National Survey of Health and Development. This is one of the oldest British birth cohort studies and has followed 5362 individuals since their birth in England, Scotland and Wales during one week in March 1946. These individuals have been tracked in 24 waves of data collection incorporating a wide range of health and functional measures, including repeat measures of cognitive function. Now aged 71 years, a small fraction have overt dementia, but estimates suggest that ~1/3 of individuals in this age group may be in the preclinical stages of Alzheimer's disease. Insight 46 is recruiting 500 study members selected at random from those who attended a clinical visit at 60-64 years and on whom relevant lifecourse data are available. We describe the sub-study design and protocol which involves a prospective two time-point (0, 24 month) data collection covering clinical, neuropsychological, ß-amyloid positron emission tomography and magnetic resonance imaging, biomarker and genetic information. Data collection started in 2015 (age 69) and aims to be completed in 2019 (age 73). DISCUSSION: Through the integration of data on the socioeconomic environment and on physical, psychological and cognitive function from 0 to 69 years, coupled with genetics, structural and molecular imaging, and intensive cognitive and neurological phenotyping, Insight 46 aims to identify lifetime factors which influence brain health and cognitive ageing, with particular focus on Alzheimer's disease and cerebrovascular disease. This will provide an evidence base for the rational design of disease-modifying trials.

Detailed volumetric analysis of the hypothalamus in behavioral variant frontotemporal dementia.

Abnormal eating behaviors are frequently reported in behavioral variant frontotemporal dementia (bvFTD). The hypothalamus is the regulatory center for feeding and satiety but its involvement in bvFTD has not been fully clarified, partly due to its difficult identification on MR images. We measured hypothalamic volume in 18 patients with bvFTD (including 9 MAPT and 6 C9orf72 mutation carriers) and 18 cognitively normal controls using a novel optimized multimodal segmentation protocol, combining 3D T1 and T2-weighted 3T MRIs (intrarater intraclass correlation coefficients ≥0.93). The whole hypothalamus was subsequently segmented into five subunits: the anterior (superior and inferior), tuberal (superior and inferior), and posterior regions. The presence of abnormal eating behavior was assessed with the revised version of the Cambridge Behavioural Inventory (CBI-R). The bvFTD group showed a 17% lower hypothalamic volume compared with controls (p < 0.001): mean 783 (standard deviation 113) versus 944 (73) mm(3) (corrected for total intracranial volume). In the hypothalamic subunit analysis, the superior parts of the anterior and tuberal regions and the posterior region were significantly smaller in the bvFTD group compared with controls. There was a trend for a smaller hypothalamic volume, particularly in the superior tuberal region, in those with severe eating disturbance scores on the CBI-R. Differences were seen between the two genetic subgroups with significantly smaller volumes in the MAPT but not the C9orf72 group compared with controls. In summary, bvFTD patients had lower hypothalamic volumes compared with controls. Different genetic mutations may have a differential impact on the hypothalamus.

Cluster analysis of quantitative parametric maps from DCE-MRI: application in evaluating heterogeneity of tumor response to antiangiogenic treatment.

PURPOSE: The objective of this study was to compare a clustering approach to conventional analysis methods for assessing changes in pharmacokinetic parameters obtained from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) during antiangiogenic treatment in a breast cancer model. MATERIALS AND METHODS: BALB/c mice bearing established transplantable her2+ tumors were treated with a DNA-based antiangiogenic vaccine or with an empty plasmid (untreated group). DCE-MRI was carried out by administering a dose of 0.05 mmol/kg of Gadocoletic acid trisodium salt, a Gd-based blood pool contrast agent (CA) at 1T. Changes in pharmacokinetic estimates (K(trans) and vp) in a nine-day interval were compared between treated and untreated groups on a voxel-by-voxel analysis. The tumor response to therapy was assessed by a clustering approach and compared with conventional summary statistics, with sub-regions analysis and with histogram analysis. RESULTS: Both the K(trans) and vp estimates, following blood-pool CA injection, showed marked and spatial heterogeneous changes with antiangiogenic treatment. Averaged values for the whole tumor region, as well as from the rim/core sub-regions analysis were unable to assess the antiangiogenic response. Histogram analysis resulted in significant changes only in the vp estimates (p<0.05). The proposed clustering approach depicted marked changes in both the K(trans) and vp estimates, with significant spatial heterogeneity in vp maps in response to treatment (p<0.05), provided that DCE-MRI data are properly clustered in three or four sub-regions. CONCLUSIONS: This study demonstrated the value of cluster analysis applied to pharmacokinetic DCE-MRI parametric maps for assessing tumor response to antiangiogenic therapy.

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis.

BACKGROUND: Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. METHODS: We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. FINDINGS: Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1). INTERPRETATION: Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. FUNDING: Centres of Excellence in Neurodegeneration.

The NifTK software platform for image-guided interventions: platform overview and NiftyLink messaging.

PURPOSE: To perform research in image-guided interventions, researchers need a wide variety of software components, and assembling these components into a flexible and reliable system can be a challenging task. In this paper, the NifTK software platform is presented. A key focus has been high-performance streaming of stereo laparoscopic video data, ultrasound data and tracking data simultaneously. METHODS: A new messaging library called NiftyLink is introduced that uses the OpenIGTLink protocol and provides the user with easy-to-use asynchronous two-way messaging, high reliability and comprehensive error reporting. A small suite of applications called NiftyGuide has been developed, containing lightweight applications for grabbing data, currently from position trackers and ultrasound scanners. These applications use NiftyLink to stream data into NiftyIGI, which is a workstation-based application, built on top of MITK, for visualisation and user interaction. Design decisions, performance characteristics and initial applications are described in detail. NiftyLink was tested for latency when transmitting images, tracking data, and interleaved imaging and tracking data. RESULTS: NiftyLink can transmit tracking data at 1,024 frames per second (fps) with latency of 0.31 milliseconds, and 512 KB images with latency of 6.06 milliseconds at 32 fps. NiftyIGI was tested, receiving stereo high-definition laparoscopic video at 30 fps, tracking data from 4 rigid bodies at 20-30 fps and ultrasound data at 20 fps with rendering refresh rates between 2 and 20 Hz with no loss of user interaction. CONCLUSION: These packages form part of the NifTK platform and have proven to be successful in a variety of image-guided surgery projects. Code and documentation for the NifTK platform are available from http://www.niftk.org . NiftyLink is provided open-source under a BSD license and available from http://github.com/NifTK/NiftyLink . The code for this paper is tagged IJCARS-2014.

Automated hippocampal segmentation in patients with epilepsy: available free online.

PURPOSE: Hippocampal sclerosis, a common cause of refractory focal epilepsy, requires hippocampal volumetry for accurate diagnosis and surgical planning. Manual segmentation is time-consuming and subject to interrater/intrarater variability. Automated algorithms perform poorly in patients with temporal lobe epilepsy. We validate and make freely available online a novel automated method. METHODS: Manual hippocampal segmentation was performed on 876, 3T MRI scans and 202, 1.5T scans. A template database of 400 high-quality manual segmentations was used to perform automated segmentation of all scans with a multi-atlas-based segmentation propagation method adapted to perform label fusion based on local similarity to ensure accurate segmentation regardless of pathology. Agreement between manual and automated segmentations was assessed by degree of overlap (Dice coefficient) and comparison of hippocampal volumes. KEY FINDINGS: The automated segmentation algorithm provided robust delineation of the hippocampi on 3T scans with no more variability than that seen between different human raters (Dice coefficients: interrater 0.832, manual vs. automated 0.847). In addition, the algorithm provided excellent results with the 1.5T scans (Dice coefficient 0.827), and automated segmentation remained accurate even in small sclerotic hippocampi. There was a strong correlation between manual and automated hippocampal volumes (Pearson correlation coefficient 0.929 on the left and 0.941 on the right in 3T scans). SIGNIFICANCE: We demonstrate reliable identification of hippocampal atrophy in patients with hippocampal sclerosis, which is crucial for clinical management of epilepsy, particularly if surgical treatment is being contemplated. We provide a free online Web-based service to enable hippocampal volumetry to be available globally, with consequent greatly improved evaluation of those with epilepsy.