A systematic review of (semi-)automatic quality control of T1-weighted MRI scans.

PURPOSE: Artifacts in magnetic resonance imaging (MRI) scans degrade image quality and thus negatively affect the outcome measures of clinical and research scanning. Considering the time-consuming and subjective nature of visual quality control (QC), multiple (semi-)automatic QC algorithms have been developed. This systematic review presents an overview of the available (semi-)automatic QC algorithms and software packages designed for raw, structural T1-weighted (T1w) MRI datasets. The objective of this review was to identify the differences among these algorithms in terms of their features of interest, performance, and benchmarks. METHODS: We queried PubMed, EMBASE (Ovid), and Web of Science databases on the fifth of January 2023, and cross-checked reference lists of retrieved papers. Bias assessment was performed using PROBAST (Prediction model Risk Of Bias ASsessment Tool). RESULTS: A total of 18 distinct algorithms were identified, demonstrating significant variations in methods, features, datasets, and benchmarks. The algorithms were categorized into rule-based, classical machine learning-based, and deep learning-based approaches. Numerous unique features were defined, which can be roughly divided into features capturing entropy, contrast, and normative measures. CONCLUSION: Due to dataset-specific optimization, it is challenging to draw broad conclusions about comparative performance. Additionally, large variations exist in the used datasets and benchmarks, further hindering direct algorithm comparison. The findings emphasize the need for standardization and comparative studies for advancing QC in MR imaging. Efforts should focus on identifying a dataset-independent measure as well as algorithm-independent methods for assessing the relative performance of different approaches.

Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study.

INTRODUCTION: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid-ß (Aß) accumulation based on Centiloids (CL) in pre-dementia populations. METHODS: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease-Prognostic and Natural History Study (AMYPAD-PNHS) and Insight46 who underwent [18F]flutemetamol, [18F]florbetaben or [18F]florbetapir amyloid-PET were included. A normative strategy was used to define reliable accumulation by estimating the 95th percentile of longitudinal measurements in sub-populations (NPNHS = 101/750, NInsight46 = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision-recall analyses. Accumulation rates were examined using linear mixed-effect models. RESULTS: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aß-accumulators. Rates of amyloid accumulation were tracer-independent, lower for APOE ε4 non-carriers, and for subjects with higher levels of education. DISCUSSION: Our results support a 12-20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations.

Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals.

INTRODUCTION: Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. METHODS: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. RESULTS: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. DISCUSSION: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. HIGHLIGHTS: Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.

Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3.

BACKGROUND: Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease-related alterations, in particular, in the preataxic stage, in which clinical scales are lacking sensitivity. OBJECTIVE: The objective of this study was to quantify regional brain volumes and upper cervical spinal cord areas in spinocerebellar ataxia type 3 in vivo across the entire time course of the disease. METHODS: We applied a brain segmentation approach that included a lobular subsegmentation of the cerebellum to magnetic resonance images of 210 ataxic and 48 preataxic spinocerebellar ataxia type 3 mutation carriers and 63 healthy controls. In addition, cervical cord cross-sectional areas were determined at 2 levels. RESULTS: The metrics of cervical spinal cord segments C3 and C2, medulla oblongata, pons, and pallidum, and the cerebellar anterior lobe were reduced in preataxic mutation carriers compared with controls. Those of cervical spinal cord segments C2 and C3, medulla oblongata, pons, midbrain, cerebellar lobules crus II and X, cerebellar white matter, and pallidum were reduced in ataxic compared with nonataxic carriers. Of all metrics studied, pontine volume showed the steepest decline across the disease course. It covaried with ataxia severity, CAG repeat length, and age. The multivariate model derived from this analysis explained 46.33% of the variance of pontine volume. CONCLUSION: Regional brain and spinal cord tissue loss in spinocerebellar ataxia type 3 starts before ataxia onset. Pontine volume appears to be the most promising imaging biomarker candidate for interventional trials that aim at slowing the progression of spinocerebellar ataxia type 3. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

An Automatic Gait Analysis Pipeline for Wearable Sensors: A Pilot Study in Parkinson's Disease.

The use of wearable sensors allows continuous recordings of physical activity from participants in free-living or at-home clinical studies. The large amount of data collected demands automatic analysis pipelines to extract gait parameters that can be used as clinical endpoints. We introduce a deep learning-based automatic pipeline for wearables that processes tri-axial accelerometry data and extracts gait events-bout segmentation, initial contact (IC), and final contact (FC)-from a single sensor located at either the lower back (near L5), shin or wrist. The gait events detected are posteriorly used for gait parameter estimation, such as step time, length, and symmetry. We report results from a leave-one-subject-out (LOSO) validation on a pilot study dataset of five participants clinically diagnosed with Parkinson's disease (PD) and six healthy controls (HC). Participants wore sensors at three body locations and walked on a pressure-sensing walkway to obtain reference gait data. Mean absolute errors (MAE) for the IC events ranged from 22.82 to 33.09 milliseconds (msecs) for the lower back sensor while for the shin and wrist sensors, MAE ranges were 28.56-64.66 and 40.19-72.50 msecs, respectively. For the FC-event detection, MAE ranges were 29.06-48.42, 40.19-72.70 and 36.06-60.18 msecs for the lumbar, wrist and shin sensors, respectively. Intraclass correlation coefficients, ICC(2,k), between the estimated parameters and the reference data resulted in good-to-excellent agreement (ICC ≥ 0.84) for the lumbar and shin sensors, excluding the double support time (ICC = 0.37 lumbar and 0.38 shin) and swing time (ICC = 0.55 lumbar and 0.59 shin). The wrist sensor also showed good agreements, but the ICCs were lower overall than for the other two sensors. Our proposed analysis pipeline has the potential to extract up to 100 gait-related parameters, and we expect our contribution will further support developments in the fields of wearable sensors, digital health, and remote monitoring in clinical trials.

Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort.

BACKGROUND: We classified non-demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles. MATERIALS AND METHODS: From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut-offs of 1000 pg/mL for amyloid beta (Aß)1-42 and 27 pg/mL for p-tau181 were validated using Gaussian mixture models. Given strong correlation of p-tau and t-tau (R2  = 0.98, P < 0.001), neurodegeneration was defined by age-adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages. RESULTS: Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A-T-N-, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non-Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P < 0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T-N- compared to A-T-N- (P < 0.001). DISCUSSION: In non-demented individuals along the AD continuum, p-tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.

Quantitative amyloid PET in Alzheimer's disease: the AMYPAD prognostic and natural history study.

INTRODUCTION: The Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) Prognostic and Natural History Study (PNHS) aims at understanding the role of amyloid imaging in the earliest stages of Alzheimer's disease (AD). AMYPAD PNHS adds (semi-)quantitative amyloid PET imaging to several European parent cohorts (PCs) to predict AD-related progression as well as address methodological challenges in amyloid PET. METHODS: AMYPAD PNHS is an open-label, prospective, multi-center, cohort study recruiting from multiple PCs. Around 2000 participants will undergo baseline amyloid positron emission tomography (PET), half of whom will be invited for a follow-up PET 12 at least 12 months later. RESULTS: Primary include several amyloid PET measurements (Centiloid, SUVr, BPND , R1 ), and secondary are their changes from baseline, relationship to other amyloid markers (cerebrospinal fluid and visual assessment), and predictive value of AD-related decline. EXPECTED IMPACT: Determining the role of amyloid PET for the understanding of this complex disease and potentially improving secondary prevention trials.

The impact of automated hippocampal volumetry on diagnostic confidence in patients with suspected Alzheimer's disease: A European Alzheimer's Disease Consortium study.

INTRODUCTION: Hippocampal volume is a core biomarker of Alzheimer's disease (AD). However, its contribution over the standard diagnostic workup is unclear. METHODS: Three hundred fifty-six patients, under clinical evaluation for cognitive impairment, with suspected AD and Mini-Mental State Examination ≥20, were recruited across 17 European memory clinics. After the traditional diagnostic workup, diagnostic confidence of AD pathology (DCAD) was estimated by the physicians in charge. The latter were provided with the results of automated hippocampal volumetry in standardized format and DCAD was reassessed. RESULTS: An increment of one interquartile range in hippocampal volume was associated with a mean change of DCAD of -8.0% (95% credible interval: [-11.5, -5.0]). Automated hippocampal volumetry showed a statistically significant impact on DCAD beyond the contributions of neuropsychology, 18F-fluorodeoxyglucose positron emission tomography/single-photon emission computed tomography, and cerebrospinal fluid markers (-8.5, CrI: [-11.5, -5.6]; -14.1, CrI: [-19.3, -8.8]; -10.6, CrI: [-14.6, -6.1], respectively). DISCUSSION: There is a measurable effect of hippocampal volume on DCAD even when used on top of the traditional diagnostic workup.

Robustness of automated hippocampal volumetry across magnetic resonance field strengths and repeat images.

BACKGROUND: Low HCV has recently been qualified by the European Medicines Agency as a biomarker for enrichment of clinical trials in predementia stages of Alzheimer's disease. For automated methods to meet the necessary regulatory requirements, it is essential they be standardized and their performance be well characterized. METHODS: The within-image and between-field strength reproducibility of automated hippocampal volumetry using the Learning Embeddings for Atlas Propagation (or LEAP) algorithm was assessed on 153 Alzheimer's Disease Neuroimaging Initiative subjects. RESULTS: Tests/retests at 1.5 T and 3 T, and a comparison between 1.5 T and 3 T, yielded average unsigned variabilities in HCVs of 1.51%, 1.52%, and 2.68%. A small bias between field strengths (mean signed difference, 1.17%; standard deviation, 3.07%) was observed. CONCLUSIONS: The measured reproducibility characteristics confirm the suitability of using automated magnetic resonance imaging analyses to assess HCVs quantitatively and to represent a fundamental characterization that is critical to meet the regulatory requirements for using hippocampal volumetry in clinical trials and health care.

Coalition Against Major Diseases/European Medicines Agency biomarker qualification of hippocampal volume for enrichment of clinical trials in predementia stages of Alzheimer's disease.

BACKGROUND: Regulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development. METHODS: The Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data. RESULTS: The literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011. CONCLUSIONS: We summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.

Alzheimer's Disease and Small Vessel Disease Differentially Affect White Matter Microstructure.

OBJECTIVE: Alzheimer's disease (AD) and cerebral small vessel disease (cSVD), the two most common causes of dementia, are characterized by white matter (WM) alterations diverging from the physiological changes occurring in healthy aging. Diffusion tensor imaging (DTI) is a valuable tool to quantify WM integrity non-invasively and identify the determinants of such alterations. Here, we investigated main effects and interactions of AD pathology, APOE-ε4, cSVD, and cardiovascular risk on spatial patterns of WM alterations in non-demented older adults. METHODS: Within the prospective European Prevention of Alzheimer's Dementia study, we selected 606 participants (64.9 ± 7.2 years, 376 females) with baseline cerebrospinal fluid samples of amyloid ß1-42 and p-Tau181 and MRI scans, including DTI scans. Longitudinal scans (mean follow-up time = 1.3 ± 0.5 years) were obtained in a subset (n = 223). WM integrity was assessed by extracting fractional anisotropy and mean diffusivity in relevant tracts. To identify the determinants of WM disruption, we performed a multimodel inference to identify the best linear mixed-effects model for each tract. RESULTS: AD pathology, APOE-ε4, cSVD burden, and cardiovascular risk were all associated with WM integrity within several tracts. While limbic tracts were mainly impacted by AD pathology and APOE-ε4, commissural, associative, and projection tract integrity was more related to cSVD burden and cardiovascular risk. AD pathology and cSVD did not show any significant interaction effect. INTERPRETATION: Our results suggest that AD pathology and cSVD exert independent and spatially different effects on WM microstructure, supporting the role of DTI in disease monitoring and suggesting independent targets for preventive medicine approaches.

Continuous ß-Amyloid CSF/PET Imbalance Model to Capture Alzheimer Disease Heterogeneity.

BACKGROUND AND OBJECTIVES: Discordance between CSF and PET biomarkers of ß-amyloid (Aß) might reflect an imbalance between soluble and aggregated species, possibly reflecting disease heterogeneity. Previous studies generally used binary cutoffs to assess discrepancies in CSF/PET biomarkers, resulting in a loss of information on the extent of discordance. In this study, we (1) jointly modeled Aß-CSF/PET data to derive a continuous measure of the imbalance between soluble and fibrillar pools of Aß, (2) investigated factors contributing to this imbalance, and (3) examined associations with cognitive trajectories. METHODS: Across 822 cognitively unimpaired (n = 261) and cognitively impaired (n = 561) Alzheimer's Disease Neuroimaging Initiative individuals (384 [46.7%] females, mean age 73.0 ± 7.4 years), we fitted baseline CSF-Aß42 and global Aß-PET to a hyperbolic regression model, deriving a participant-specific Aß-aggregation score (standardized residuals); negative values represent more soluble relative to aggregated Aß and positive values more aggregated relative to soluble Aß. Using linear models, we investigated whether methodological factors, demographics, CSF biomarkers, and vascular burden contributed to Aß-aggregation scores. With linear mixed models, we assessed whether Aß-aggregation scores were predictive of cognitive functioning. Analyses were repeated in an early independent validation cohort of 383 Amyloid Imaging to Prevent Alzheimer's Disease Prognostic and Natural History Study individuals (224 [58.5%] females, mean age 65.2 ± 6.9 years). RESULTS: The imbalance model could be fit (pseudo-R2 = 0.94) in both cohorts, across CSF kits and PET tracers. Although no associations were observed with the main methodological factors, lower Aß-aggregation scores were associated with larger ventricular volume (ß = 0.13, p < 0.001), male sex (ß = -0.18, p = 0.019), and homozygous APOE-ε4 carriership (ß = -0.56, p < 0.001), whereas higher scores were associated with increased uncorrected CSF p-tau (ß = 0.17, p < 0.001) and t-tau (ß = 0.16, p < 0.001), better baseline executive functioning (ß = 0.12, p < 0.001), and slower global cognitive decline (ß = 0.14, p = 0.006). In the validation cohort, we replicated the associations with APOE-ε4, CSF t-tau, and, although modestly, with cognition. DISCUSSION: We propose a novel continuous model of Aß CSF/PET biomarker imbalance, accurately describing heterogeneity in soluble vs aggregated Aß pools in 2 independent cohorts across the full Aß continuum. Aß-aggregation scores were consistently associated with genetic and AD-associated CSF biomarkers, possibly reflecting disease heterogeneity beyond methodological influences.

Association of Vascular Risk Factors and Cerebrovascular Pathology With Alzheimer Disease Pathologic Changes in Individuals Without Dementia.

BACKGROUND AND OBJECTIVES: Vascular risk factors (VRFs) and cerebral small vessel disease (cSVD) are common in patients with Alzheimer disease (AD). It remains unclear whether this coexistence reflects shared risk factors or a mechanistic relationship and whether vascular and amyloid pathologies have independent or synergistic influence on subsequent AD pathophysiology in preclinical stages. We investigated links between VRFs, cSVD, and amyloid levels (Aß1-42) and their combined effect on downstream AD biomarkers, that is, CSF hyperphosphorylated tau (P-tau181), atrophy, and cognition. METHODS: This retrospective study included nondemented participants (Clinical Dementia Rating < 1) from the European Prevention of Alzheimer's Dementia (EPAD) cohort and assessed VRFs with the Framingham risk score (FRS) and cSVD features on MRI using visual scales and white matter hyperintensity volumes. After preliminary linear analysis, we used structural equation modeling (SEM) to create a "cSVD severity" latent variable and assess the direct and indirect effects of FRS and cSVD severity on Aß1-42, P-tau181, gray matter volume (baseline and longitudinal), and cognitive performance (baseline and longitudinal). RESULTS: A total cohort of 1,592 participants were evaluated (mean age = 65.5 ± 7.4 years; 56.16% F). We observed positive associations between FRS and all cSVD features (all p < 0.05) and a negative association between FRS and Aß1-42 (ß = -0.04 ± 0.01). All cSVD features were negatively associated with CSF Aß1-42 (all p < 0.05). Using SEM, the cSVD severity fully mediated the association between FRS and CSF Aß1-42 (indirect effect: ß = -0.03 ± 0.01), also when omitting vascular amyloid-related markers. We observed a significant indirect effect of cSVD severity on P-tau181 (indirect effect: ß = 0.12 ± 0.03), baseline and longitudinal gray matter volume (indirect effect: ß = -0.10 ± 0.03; ß = -0.12 ± 0.05), and baseline cognitive performance (indirect effect: ß = -0.16 ± 0.03) through CSF Aß1-42. DISCUSSION: In a large nondemented population, our findings suggest that cSVD is a mediator of the relationship between VRFs and CSF Aß1-42 and affects downstream neurodegeneration and cognitive impairment. We provide evidence of VRFs indirectly affecting the pathogenesis of AD, highlighting the importance of considering cSVD burden in memory clinics for AD risk evaluation and as an early window for intervention. These results stress the role of VRFs and cerebrovascular pathology as key biomarkers for accurate design of anti-amyloid clinical trials and offer new perspectives for patient stratification.

Amyloid-PET imaging predicts functional decline in clinically normal individuals.

BACKGROUND: There is good evidence that elevated amyloid-ß (Aß) positron emission tomography (PET) signal is associated with cognitive decline in clinically normal (CN) individuals. However, it is less well established whether there is an association between the Aß burden and decline in daily living activities in this population. Moreover, Aß-PET Centiloids (CL) thresholds that can optimally predict functional decline have not yet been established. METHODS: Cross-sectional and longitudinal analyses over a mean three-year timeframe were performed on the European amyloid-PET imaging AMYPAD-PNHS dataset that phenotypes 1260 individuals, including 1032 CN individuals and 228 participants with questionable functional impairment. Amyloid-PET was assessed continuously on the Centiloid (CL) scale and using Aß groups (CL < 12 = Aß-, 12 ≤ CL ≤ 50 = Aß-intermediate/Aß± , CL > 50 = Aß+). Functional abilities were longitudinally assessed using the Clinical Dementia Rating (Global-CDR, CDR-SOB) and the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q). The Global-CDR was available for the 1260 participants at baseline, while baseline CDR-SOB and A-IADL-Q scores and longitudinal functional data were available for different subsamples that had similar characteristics to those of the entire sample. RESULTS: Participants included 765 Aß- (61%, Mdnage = 66.0, IQRage = 61.0-71.0; 59% women), 301 Aß± (24%; Mdnage = 69.0, IQRage = 64.0-75.0; 53% women) and 194 Aß+ individuals (15%, Mdnage = 73.0, IQRage = 68.0-78.0; 53% women). Cross-sectionally, CL values were associated with CDR outcomes. Longitudinally, baseline CL values predicted prospective changes in the CDR-SOB (bCL*Time = 0.001/CL/year, 95% CI [0.0005,0.0024], p = .003) and A-IADL-Q (bCL*Time = -0.010/CL/year, 95% CI [-0.016,-0.004], p = .002) scores in initially CN participants. Increased clinical progression (Global-CDR > 0) was mainly observed in Aß+ CN individuals (HRAß+ vs Aß- = 2.55, 95% CI [1.16,5.60], p = .020). Optimal thresholds for predicting decline were found at 41 CL using the CDR-SOB (bAß+ vs Aß- = 0.137/year, 95% CI [0.069,0.206], p < .001) and 28 CL using the A-IADL-Q (bAß+ vs Aß- = -0.693/year, 95% CI [-1.179,-0.208], p = .005). CONCLUSIONS: Amyloid-PET quantification supports the identification of CN individuals at risk of functional decline. TRIAL REGISTRATION: The AMYPAD PNHS is registered at www.clinicaltrialsregister.eu with the EudraCT Number: 2018-002277-22.

Segmentation of MR images via discriminative dictionary learning and sparse coding: application to hippocampus labeling.

We propose a novel method for the automatic segmentation of brain MRI images by using discriminative dictionary learning and sparse coding techniques. In the proposed method, dictionaries and classifiers are learned simultaneously from a set of brain atlases, which can then be used for the reconstruction and segmentation of an unseen target image. The proposed segmentation strategy is based on image reconstruction, which is in contrast to most existing atlas-based labeling approaches that rely on comparing image similarities between atlases and target images. In addition, we propose a Fixed Discriminative Dictionary Learning for Segmentation (F-DDLS) strategy, which can learn dictionaries offline and perform segmentations online, enabling a significant speed-up in the segmentation stage. The proposed method has been evaluated for the hippocampus segmentation of 80 healthy ICBM subjects and 202 ADNI images. The robustness of the proposed method, especially of our F-DDLS strategy, was validated by training and testing on different subject groups in the ADNI database. The influence of different parameters was studied and the performance of the proposed method was also compared with that of the nonlocal patch-based approach. The proposed method achieved a median Dice coefficient of 0.879 on 202 ADNI images and 0.890 on 80 ICBM subjects, which is competitive compared with state-of-the-art methods.

Sparse reduced-rank regression detects genetic associations with voxel-wise longitudinal phenotypes in Alzheimer's disease.

Scanning the entire genome in search of variants related to imaging phenotypes holds great promise in elucidating the genetic etiology of neurodegenerative disorders. Here we discuss the application of a penalized multivariate model, sparse reduced-rank regression (sRRR), for the genome-wide detection of markers associated with voxel-wise longitudinal changes in the brain caused by Alzheimer's disease (AD). Using a sample from the Alzheimer's Disease Neuroimaging Initiative database, we performed three separate studies that each compared two groups of individuals to identify genes associated with disease development and progression. For each comparison we took a two-step approach: initially, using penalized linear discriminant analysis, we identified voxels that provide an imaging signature of the disease with high classification accuracy; then we used this multivariate biomarker as a phenotype in a genome-wide association study, carried out using sRRR. The genetic markers were ranked in order of importance of association to the phenotypes using a data re-sampling approach. Our findings confirmed the key role of the APOE and TOMM40 genes but also highlighted some novel potential associations with AD.

Multi-region analysis of longitudinal FDG-PET for the classification of Alzheimer's disease.

Imaging biomarkers for Alzheimer's disease are desirable for improved diagnosis and monitoring, as well as drug discovery. Automated image-based classification of individual patients could provide valuable diagnostic support for clinicians, when considered alongside cognitive assessment scores. We investigate the value of combining cross-sectional and longitudinal multi-region FDG-PET information for classification, using clinical and imaging data from the Alzheimer's Disease Neuroimaging Initiative. Whole-brain segmentations into 83 anatomically defined regions were automatically generated for baseline and 12-month FDG-PET images. Regional signal intensities were extracted at each timepoint, as well as changes in signal intensity over the follow-up period. Features were provided to a support vector machine classifier. By combining 12-month signal intensities and changes over 12 months, we achieve significantly increased classification performance compared with using any of the three feature sets independently. Based on this combined feature set, we report classification accuracies of 88% between patients with Alzheimer's disease and elderly healthy controls, and 65% between patients with stable mild cognitive impairment and those who subsequently progressed to Alzheimer's disease. We demonstrate that information extracted from serial FDG-PET through regional analysis can be used to achieve state-of-the-art classification of diagnostic groups in a realistic multi-centre setting. This finding may be usefully applied in the diagnosis of Alzheimer's disease, predicting disease course in individuals with mild cognitive impairment, and in the selection of participants for clinical trials.

Impact of cerebral blood flow and amyloid load on SUVR bias.

BACKGROUND: Despite its widespread use, the semi-quantitative standardized uptake value ratio (SUVR) may be biased compared with the distribution volume ratio (DVR). This bias may be partially explained by changes in cerebral blood flow (CBF) and is likely to be also dependent on the extent of the underlying amyloid-ß (Aß) burden. This study aimed to compare SUVR with DVR and to evaluate the effects of underlying Aß burden and CBF on bias in SUVR in mainly cognitively unimpaired participants. Participants were scanned according to a dual-time window protocol, with either [18F]flutemetamol (N = 90) or [18F]florbetaben (N = 31). The validated basisfunction-based implementation of the two-step simplified reference tissue model was used to derive DVR and R1 parametric images, and SUVR was calculated from 90 to 110 min post-injection, all with the cerebellar grey matter as reference tissue. First, linear regression and Bland-Altman analyses were used to compare (regional) SUVR with DVR. Then, generalized linear models were applied to evaluate whether (bias in) SUVR relative to DVR could be explained by R1 for the global cortical average (GCA), precuneus, posterior cingulate, and orbitofrontal region. RESULTS: Despite high correlations (GCA: R2 ≥ 0.85), large overestimation and proportional bias of SUVR relative to DVR was observed. Negative associations were observed between both SUVR or SUVRbias and R1, albeit non-significant. CONCLUSION: The present findings demonstrate that bias in SUVR relative to DVR is strongly related to underlying Aß burden. Furthermore, in a cohort consisting mainly of cognitively unimpaired individuals, the effect of relative CBF on bias in SUVR appears limited. EudraCT Number: 2018-002277-22, registered on: 25-06-2018.

The Open-Access European Prevention of Alzheimer's Dementia (EPAD) MRI dataset and processing workflow.

The European Prevention of Alzheimer Dementia (EPAD) is a multi-center study that aims to characterize the preclinical and prodromal stages of Alzheimer's Disease. The EPAD imaging dataset includes core (3D T1w, 3D FLAIR) and advanced (ASL, diffusion MRI, and resting-state fMRI) MRI sequences. Here, we give an overview of the semi-automatic multimodal and multisite pipeline that we developed to curate, preprocess, quality control (QC), and compute image-derived phenotypes (IDPs) from the EPAD MRI dataset. This pipeline harmonizes DICOM data structure across sites and performs standardized MRI preprocessing steps. A semi-automated MRI QC procedure was implemented to visualize and flag MRI images next to site-specific distributions of QC features - i.e. metrics that represent image quality. The value of each of these QC features was evaluated through comparison with visual assessment and step-wise parameter selection based on logistic regression. IDPs were computed from 5 different MRI modalities and their sanity and potential clinical relevance were ascertained by assessing their relationship with biological markers of aging and dementia. The EPAD v1500.0 data release encompassed core structural scans from 1356 participants 842 fMRI, 831 dMRI, and 858 ASL scans. From 1356 3D T1w images, we identified 17 images with poor quality and 61 with moderate quality. Five QC features - Signal to Noise Ratio (SNR), Contrast to Noise Ratio (CNR), Coefficient of Joint Variation (CJV), Foreground-Background energy Ratio (FBER), and Image Quality Rate (IQR) - were selected as the most informative on image quality by comparison with visual assessment. The multimodal IDPs showed greater impairment in associations with age and dementia biomarkers, demonstrating the potential of the dataset for future clinical analyses.

Fast and robust extraction of hippocampus from MR images for diagnostics of Alzheimer's disease.

Assessment of temporal lobe atrophy from magnetic resonance images is a part of clinical guidelines for the diagnosis of prodromal Alzheimer's disease. As hippocampus is known to be among the first areas affected by the disease, fast and robust definition of hippocampus volume would be of great importance in the clinical decision making. We propose a method for computing automatically the volume of hippocampus using a modified multi-atlas segmentation framework, including an improved initialization of the framework and the correction of partial volume effect. The method produced a high similarity index, 0.87, and correlation coefficient, 0.94, with semi-automatically generated segmentations. When comparing hippocampus volumes extracted from 1.5T and 3T images, the absolute value of the difference was low: 3.2% of the volume. The correct classification rate for Alzheimer's disease and cognitively normal cases was about 80% while the accuracy 65% was obtained for classifying stable and progressive mild cognitive impairment cases. The method was evaluated in three cohorts consisting altogether about 1000 cases, the main emphasis being in the analysis of the ADNI cohort. The computation time of the method is about 2 minutes on a standard laptop computer. The results show a clear potential for applying the method in clinical practice.