Multi-class glioma segmentation on real-world data with missing MRI sequences: comparison of three deep learning algorithms.

This study tests the generalisability of three Brain Tumor Segmentation (BraTS) challenge models using a multi-center dataset of varying image quality and incomplete MRI datasets. In this retrospective study, DeepMedic, no-new-Unet (nn-Unet), and NVIDIA-net (nv-Net) were trained and tested using manual segmentations from preoperative MRI of glioblastoma (GBM) and low-grade gliomas (LGG) from the BraTS 2021 dataset (1251 in total), in addition to 275 GBM and 205 LGG acquired clinically across 12 hospitals worldwide. Data was split into 80% training, 5% validation, and 15% internal test data. An additional external test-set of 158 GBM and 69 LGG was used to assess generalisability to other hospitals' data. All models' median Dice similarity coefficient (DSC) for both test sets were within, or higher than, previously reported human inter-rater agreement (range of 0.74-0.85). For both test sets, nn-Unet achieved the highest DSC (internal = 0.86, external = 0.93) and the lowest Hausdorff distances (10.07, 13.87 mm, respectively) for all tumor classes (p < 0.001). By applying Sparsified training, missing MRI sequences did not statistically affect the performance. nn-Unet achieves accurate segmentations in clinical settings even in the presence of incomplete MRI datasets. This facilitates future clinical adoption of automated glioma segmentation, which could help inform treatment planning and glioma monitoring.

Evaluation of novel data-driven metrics of amyloid ß deposition for longitudinal PET studies.

PURPOSE: Positron emission tomography (PET) provides in vivo quantification of amyloid-ß (Aß) pathology. Established methods for assessing Aß burden can be affected by physiological and technical factors. Novel, data-driven metrics have been developed to account for these sources of variability. We aimed to evaluate the performance of four of these amyloid PET metrics against conventional techniques, using a common set of criteria. METHODS: Three cohorts were used for evaluation: Insight 46 (N=464, [18F]florbetapir), AIBL (N=277, [18F]flutemetamol), and an independent test-retest data (N=10, [18F]flutemetamol). Established metrics of amyloid tracer uptake included the Centiloid (CL) and where dynamic data was available, the non-displaceable binding potential (BPND). The four data-driven metrics computed were the amyloid load (Aß load), the Aß-PET pathology accumulation index (Aß index), the Centiloid derived from non-negative matrix factorisation (CLNMF), and the amyloid pattern similarity score (AMPSS). These metrics were evaluated using reliability and repeatability in test-retest data, associations with BPND and CL, variability of the rate of change and sample size estimates to detect a 25% slowing in Aß accumulation. RESULTS: All metrics showed good reliability. Aß load, Aß index and CLNMF were strong associated with the BPND. The associations with CL suggest that cross-sectional measures of CLNMF, Aß index and Aß load are robust across studies. Sample size estimates for secondary prevention trial scenarios were the lowest for CLNMF and Aß load compared to the CL. CONCLUSION: Among the novel data-driven metrics evaluated, the Aß load, the Aß index and the CLNMF can provide comparable performance to more established quantification methods of Aß PET tracer uptake. The CLNMF and Aß load could offer a more precise alternative to CL, although further studies in larger cohorts should be conducted.

Longitudinal amyloid and tau PET imaging in Alzheimer's disease: A systematic review of methodologies and factors affecting quantification.

Deposition of amyloid and tau pathology can be quantified in vivo using positron emission tomography (PET). Accurate longitudinal measurements of accumulation from these images are critical for characterizing the start and spread of the disease. However, these measurements are challenging; precision and accuracy can be affected substantially by various sources of errors and variability. This review, supported by a systematic search of the literature, summarizes the current design and methodologies of longitudinal PET studies. Intrinsic, biological causes of variability of the Alzheimer's disease (AD) protein load over time are then detailed. Technical factors contributing to longitudinal PET measurement uncertainty are highlighted, followed by suggestions for mitigating these factors, including possible techniques that leverage shared information between serial scans. Controlling for intrinsic variability and reducing measurement uncertainty in longitudinal PET pipelines will provide more accurate and precise markers of disease evolution, improve clinical trial design, and aid therapy response monitoring.

Software compatibility analysis for quantitative measures of [18F]flutemetamol amyloid PET burden in mild cognitive impairment.

RATIONALE: Amyloid-ß (Aß) pathology is one of the earliest detectable brain changes in Alzheimer's disease pathogenesis. In clinical practice, trained readers will visually categorise positron emission tomography (PET) scans as either Aß positive or negative. However, adjunct quantitative analysis is becoming more widely available, where regulatory approved software can currently generate metrics such as standardised uptake value ratios (SUVr) and individual Z-scores. Therefore, it is of direct value to the imaging community to assess the compatibility of commercially available software packages. In this collaborative project, the compatibility of amyloid PET quantification was investigated across four regulatory approved software packages. In doing so, the intention is to increase visibility and understanding of clinically relevant quantitative methods. METHODS: Composite SUVr using the pons as the reference region was generated from [18F]flutemetamol (GE Healthcare) PET in a retrospective cohort of 80 amnestic mild cognitive impairment (aMCI) patients (40 each male/female; mean age = 73 years, SD = 8.52). Based on previous autopsy validation work, an Aß positivity threshold of ≥ 0.6 SUVrpons was applied. Quantitative results from MIM Software's MIMneuro, Syntermed's NeuroQ, Hermes Medical Solutions' BRASS and GE Healthcare's CortexID were analysed using intraclass correlation coefficient (ICC), percentage agreement around the Aß positivity threshold and kappa scores. RESULTS: Using an Aß positivity threshold of ≥ 0.6 SUVrpons, 95% agreement was achieved across the four software packages. Two patients were narrowly classed as Aß negative by one software package but positive by the others, and two patients vice versa. All kappa scores around the same Aß positivity threshold, both combined (Fleiss') and individual software pairings (Cohen's), were ≥ 0.9 signifying "almost perfect" inter-rater reliability. Excellent reliability was found between composite SUVr measurements for all four software packages, with an average measure ICC of 0.97 and 95% confidence interval of 0.957-0.979. Correlation coefficient analysis between the two software packages reporting composite z-scores was strong (r2 = 0.98). CONCLUSION: Using an optimised cortical mask, regulatory approved software packages provided highly correlated and reliable quantification of [18F]flutemetamol amyloid PET with a ≥ 0.6 SUVrpons positivity threshold. In particular, this work could be of interest to physicians performing routine clinical imaging rather than researchers performing more bespoke image analysis. Similar analysis is encouraged using other reference regions as well as the Centiloid scale, when it has been implemented by more software packages.

Commercial volumetric MRI reporting tools in multiple sclerosis: a systematic review of the evidence.

PURPOSE: MRI is integral to the diagnosis of multiple sclerosis (MS) and is important for clinical prognostication. Quantitative volumetric reporting tools (QReports) can improve the accuracy and objectivity of MRI-based assessments. Several QReports are commercially available; however, validation can be difficult to establish and does not currently follow a common pathway. To aid evidence-based clinical decision-making, we performed a systematic review of commercial QReports for use in MS including technical details and published reports of validation and in-use evaluation. METHODS: We categorized studies into three types of testing: technical validation, for example, comparison to manual segmentation, clinical validation by clinicians or interpretation of results alongside clinician-rated variables, and in-use evaluation, such as health economic assessment. RESULTS: We identified 10 companies, which provide MS lesion and brain segmentation and volume quantification, and 38 relevant publications. Tools received regulatory approval between 2006 and 2020, contextualize results to normative reference populations, ranging from 620 to 8000 subjects, and require T1- and T2-FLAIR-weighted input sequences for longitudinal assessment of whole-brain volume and lesions. In MS, six QReports provided evidence of technical validation, four companies have conducted clinical validation by correlating results with clinical variables, only one has tested their QReport by clinician end-users, and one has performed a simulated in-use socioeconomic evaluation. CONCLUSION: We conclude that there is limited evidence in the literature regarding clinical validation and in-use evaluation of commercial MS QReports with a particular lack of clinician end-user testing. Our systematic review provides clinicians and institutions with the available evidence when considering adopting a quantitative reporting tool for MS.

Quantification of amyloid PET for future clinical use: a state-of-the-art review.

Amyloid-ß (Aß) pathology is one of the earliest detectable brain changes in Alzheimer's disease (AD) pathogenesis. The overall load and spatial distribution of brain Aß can be determined in vivo using positron emission tomography (PET), for which three fluorine-18 labelled radiotracers have been approved for clinical use. In clinical practice, trained readers will categorise scans as either Aß positive or negative, based on visual inspection. Diagnostic decisions are often based on these reads and patient selection for clinical trials is increasingly guided by amyloid status. However, tracer deposition in the grey matter as a function of amyloid load is an inherently continuous process, which is not sufficiently appreciated through binary cut-offs alone. State-of-the-art methods for amyloid PET quantification can generate tracer-independent measures of Aß burden. Recent research has shown the ability of these quantitative measures to highlight pathological changes at the earliest stages of the AD continuum and generate more sensitive thresholds, as well as improving diagnostic confidence around established binary cut-offs. With the recent FDA approval of aducanumab and more candidate drugs on the horizon, early identification of amyloid burden using quantitative measures is critical for enrolling appropriate subjects to help establish the optimal window for therapeutic intervention and secondary prevention. In addition, quantitative amyloid measurements are used for treatment response monitoring in clinical trials. In clinical settings, large multi-centre studies have shown that amyloid PET results change both diagnosis and patient management and that quantification can accurately predict rates of cognitive decline. Whether these changes in management reflect an improvement in clinical outcomes is yet to be determined and further validation work is required to establish the utility of quantification for supporting treatment endpoint decisions. In this state-of-the-art review, several tools and measures available for amyloid PET quantification are summarised and discussed. Use of these methods is growing both clinically and in the research domain. Concurrently, there is a duty of care to the wider dementia community to increase visibility and understanding of these methods.

Presumed small vessel disease, imaging and cognition markers in the Alzheimer's Disease Neuroimaging Initiative.

MRI-derived features of presumed cerebral small vessel disease are frequently found in Alzheimer's disease. Influences of such markers on disease-progression measures are poorly understood. We measured markers of presumed small vessel disease (white matter hyperintensity volumes; cerebral microbleeds) on baseline images of newly enrolled individuals in the Alzheimer's Disease Neuroimaging Initiative cohort (GO and 2) and used linear mixed models to relate these to subsequent atrophy and neuropsychological score change. We also assessed heterogeneity in white matter hyperintensity positioning within biomarker abnormality sequences, driven by the data, using the Subtype and Stage Inference algorithm. This study recruited both sexes and included: controls: [n = 159, mean(SD) age = 74(6) years]; early and late mild cognitive impairment [ns = 265 and 139, respectively, mean(SD) ages =71(7) and 72(8) years, respectively]; Alzheimer's disease [n = 103, mean(SD) age = 75(8)] and significant memory concern [n = 72, mean(SD) age = 72(6) years]. Baseline demographic and vascular risk-factor data, and longitudinal cognitive scores (Mini-Mental State Examination; logical memory; and Trails A and B) were collected. Whole-brain and hippocampal volume change metrics were calculated. White matter hyperintensity volumes were associated with greater whole-brain and hippocampal volume changes independently of cerebral microbleeds (a doubling of baseline white matter hyperintensity was associated with an increase in atrophy rate of 0.3 ml/year for brain and 0.013 ml/year for hippocampus). Cerebral microbleeds were found in 15% of individuals and the presence of a microbleed, as opposed to none, was associated with increases in atrophy rate of 1.4 ml/year for whole brain and 0.021 ml/year for hippocampus. White matter hyperintensities were predictive of greater decline in all neuropsychological scores, while cerebral microbleeds were predictive of decline in logical memory (immediate recall) and Mini-Mental State Examination scores. We identified distinct groups with specific sequences of biomarker abnormality using continuous baseline measures and brain volume change. Four clusters were found; Group 1 showed early Alzheimer's pathology; Group 2 showed early neurodegeneration; Group 3 had early mixed Alzheimer's and cerebrovascular pathology; Group 4 had early neuropsychological score abnormalities. White matter hyperintensity volumes becoming abnormal was a late event for Groups 1 and 4 and an early event for 2 and 3. In summary, white matter hyperintensities and microbleeds were independently associated with progressive neurodegeneration (brain atrophy rates) and cognitive decline (change in neuropsychological scores). Mechanisms involving white matter hyperintensities and progression and microbleeds and progression may be partially separate. Distinct sequences of biomarker progression were found. White matter hyperintensity development was an early event in two sequences.

Technical and clinical validation of commercial automated volumetric MRI tools for dementia diagnosis-a systematic review.

Developments in neuroradiological MRI analysis offer promise in enhancing objectivity and consistency in dementia diagnosis through the use of quantitative volumetric reporting tools (QReports). Translation into clinical settings should follow a structured framework of development, including technical and clinical validation steps. However, published technical and clinical validation of the available commercial/proprietary tools is not always easy to find and pathways for successful integration into the clinical workflow are varied. The quantitative neuroradiology initiative (QNI) framework highlights six necessary steps for the development, validation and integration of quantitative tools in the clinic. In this paper, we reviewed the published evidence regarding regulatory-approved QReports for use in the memory clinic and to what extent this evidence fulfils the steps of the QNI framework. We summarize unbiased technical details of available products in order to increase the transparency of evidence and present the range of reporting tools on the market. Our intention is to assist neuroradiologists in making informed decisions regarding the adoption of these methods in the clinic. For the 17 products identified, 11 companies have published some form of technical validation on their methods, but only 4 have published clinical validation of their QReports in a dementia population. Upon systematically reviewing the published evidence for regulatory-approved QReports in dementia, we concluded that there is a significant evidence gap in the literature regarding clinical validation, workflow integration and in-use evaluation of these tools in dementia MRI diagnosis.

Automated quantitative MRI volumetry reports support diagnostic interpretation in dementia: a multi-rater, clinical accuracy study.

OBJECTIVES: We examined whether providing a quantitative report (QReport) of regional brain volumes improves radiologists' accuracy and confidence in detecting volume loss, and in differentiating Alzheimer's disease (AD) and frontotemporal dementia (FTD), compared with visual assessment alone. METHODS: Our forced-choice multi-rater clinical accuracy study used MRI from 16 AD patients, 14 FTD patients, and 15 healthy controls; age range 52-81. Our QReport was presented to raters with regional grey matter volumes plotted as percentiles against data from a normative population (n = 461). Nine raters with varying radiological experience (3 each: consultants, registrars, 'non-clinical image analysts') assessed each case twice (with and without the QReport). Raters were blinded to clinical and demographic information; they classified scans as 'normal' or 'abnormal' and if 'abnormal' as 'AD' or 'FTD'. RESULTS: The QReport improved sensitivity for detecting volume loss and AD across all raters combined (p = 0.015* and p = 0.002*, respectively). Only the consultant group's accuracy increased significantly when using the QReport (p = 0.02*). Overall, raters' agreement (Cohen's κ) with the 'gold standard' was not significantly affected by the QReport; only the consultant group improved significantly (κs 0.41➔0.55, p = 0.04*). Cronbach's alpha for interrater agreement improved from 0.886 to 0.925, corresponding to an improvement from 'good' to 'excellent'. CONCLUSION: Our QReport referencing single-subject results to normative data alongside visual assessment improved sensitivity, accuracy, and interrater agreement for detecting volume loss. The QReport was most effective in the consultants, suggesting that experience is needed to fully benefit from the additional information provided by quantitative analyses. KEY POINTS: • The use of quantitative report alongside routine visual MRI assessment improves sensitivity and accuracy for detecting volume loss and AD vs visual assessment alone. • Consultant neuroradiologists' assessment accuracy and agreement (kappa scores) significantly improved with the use of quantitative atrophy reports. • First multi-rater radiological clinical evaluation of visual quantitative MRI atrophy report for use as a diagnostic aid in dementia.

Clinical evaluation of automated quantitative MRI reports for assessment of hippocampal sclerosis.

OBJECTIVES: Hippocampal sclerosis (HS) is a common cause of temporal lobe epilepsy. Neuroradiological practice relies on visual assessment, but quantification of HS imaging biomarkers-hippocampal volume loss and T2 elevation-could improve detection. We tested whether quantitative measures, contextualised with normative data, improve rater accuracy and confidence. METHODS: Quantitative reports (QReports) were generated for 43 individuals with epilepsy (mean age ± SD 40.0 ± 14.8 years, 22 men; 15 histologically unilateral HS; 5 bilateral; 23 MR-negative). Normative data was generated from 111 healthy individuals (age 40.0 ± 12.8 years, 52 men). Nine raters with different experience (neuroradiologists, trainees, and image analysts) assessed subjects' imaging with and without QReports. Raters assigned imaging normal, right, left, or bilateral HS. Confidence was rated on a 5-point scale. RESULTS: Correct designation (normal/abnormal) was high and showed further trend-level improvement with QReports, from 87.5 to 92.5% (p = 0.07, effect size d = 0.69). Largest magnitude improvement (84.5 to 93.8%) was for image analysts (d = 0.87). For bilateral HS, QReports significantly improved overall accuracy, from 74.4 to 91.1% (p = 0.042, d = 0.7). Agreement with the correct diagnosis (kappa) tended to increase from 0.74 ('fair') to 0.86 ('excellent') with the report (p = 0.06, d = 0.81). Confidence increased when correctly assessing scans with the QReport (p < 0.001, η2p = 0.945). CONCLUSIONS: QReports of HS imaging biomarkers can improve rater accuracy and confidence, particularly in challenging bilateral cases. Improvements were seen across all raters, with large effect sizes, greatest for image analysts. These findings may have positive implications for clinical radiology services and justify further validation in larger groups. KEY POINTS: • Quantification of imaging biomarkers for hippocampal sclerosis-volume loss and raised T2 signal-could improve clinical radiological detection in challenging cases. • Quantitative reports for individual patients, contextualised with normative reference data, improved diagnostic accuracy and confidence in a group of nine raters, in particular for bilateral HS cases. • We present a pre-use clinical validation of an automated imaging assessment tool to assist clinical radiology reporting of hippocampal sclerosis, which improves detection accuracy.

Implementation of clinical tractography for pre-surgical planning of space occupying lesions: An investigation of common acquisition and post-processing methods compared to dissection studies.

BACKGROUND AND PURPOSE: There is limited standardization of acquisition and processing methods in diffusion tractography for pre-surgical planning, leading to a range of approaches. In this study, a number of representative acquisition variants and post processing methods are considered, to assess their importance when implementing a clinical tractography program. METHODS: Diffusion MRI was undertaken in ten healthy volunteers, using protocols typical of clinical and research scanning: a 32-direction diffusion acquisition with and without peripheral gating, and a non-gated 64 diffusion direction acquisition. All datasets were post-processed using diffusion tensor reconstruction with streamline tractography, and with constrained spherical deconvolution (CSD) with both streamline and probabilistic tractography, to delineate the cortico-spinal tract (CST) and optic radiation (OR). The accuracy of tractography results was assessed against a histological atlas using a novel probabilistic Dice overlap technique, together with direct comparison to tract volumes and distance of Meyer's loop to temporal pole (ML-TP) from dissections studies. Three clinical case studies of patients with space occupying lesions were also investigated. RESULTS: Tracts produced by CSD with probabilistic tractography provided the greatest overlap with the histological atlas (overlap scores of 44% and 52% for the CST and OR, respectively) and best matched tract volume and ML-TP distance from dissection studies. The acquisition protocols investigated had limited impact on the accuracy of the tractography. In all patients, the CSD based probabilistic tractography created tracts with greatest anatomical plausibility, although in one case anatomically plausible pathways could not be reconstructed without reducing the probabilistic threshold, leading to an increase in false positive tracts. CONCLUSIONS: Advanced post processing techniques such as CSD with probabilistic tractography are vital for pre-surgical planning. However, overall accuracy relative to dissection studies remains limited.

Hippocampal profiling: Localized magnetic resonance imaging volumetry and T2 relaxometry for hippocampal sclerosis.

OBJECTIVE: Hippocampal sclerosis (HS) is the most common cause of drug-resistant temporal lobe epilepsy, and its accurate detection is important to guide epilepsy surgery. Radiological features of HS include hippocampal volume loss and increased T2 signal, which can both be quantified to help improve detection. In this work, we extend these quantitative methods to generate cross-sectional area and T2 profiles along the hippocampal long axis to improve the localization of hippocampal abnormalities. METHODS: T1-weighted and T2 relaxometry data from 69 HS patients (32 left, 32 right, 5 bilateral) and 111 healthy controls were acquired on a 3-T magnetic resonance imaging (MRI) scanner. Automated hippocampal segmentation and T2 relaxometry were performed and used to calculate whole-hippocampal volumes and to estimate quantitative T2 (qT2) values. By generating a group template from the controls, and aligning this so that the hippocampal long axes were along the anterior-posterior axis, we were able to calculate hippocampal cross-sectional area and qT2 by a slicewise method to localize any volume loss or T2 hyperintensity. Individual patient profiles were compared with normative data generated from the healthy controls. RESULTS: Profiling of hippocampal volumetric and qT2 data could be performed automatically and reproducibly. HS patients commonly showed widespread decreases in volume and increases in T2 along the length of the affected hippocampus, and focal changes may also be identified. Patterns of atrophy and T2 increase in the left hippocampus were similar between left, right, and bilateral HS. These profiles have potential to distinguish between sclerosis affecting volume and qT2 in the whole or parts of the hippocampus, and may aid the radiological diagnosis in uncertain cases or cases with subtle or focal abnormalities where standard whole-hippocampal measurements yield normal values. SIGNIFICANCE: Hippocampal profiling of volumetry and qT2 values can help spatially localize hippocampal MRI abnormalities and work toward improved sensitivity of subtle focal lesions.