Usefulness of Tc-99m Sestamibi studies for monitoring response to therapy in patients with high grade gliomas: a preliminary study

Congrès sous l’égide de la Société Française de Génie Biologique et Médical (SFGBM).National audienceEarly and late Sestamibi studies were acquired in addition to conventional MRI protocol in 14 patients with high-grade gliomas to monitor an antiangiogenic treatment. Global and local indices were deduced from these SPECT studies and were compared with progression free survival (PFS) and overall survival (OS). Variations of intensity in late studies were not correlated with PFS, but were related to OS. This suggests the possible role of Sestamibi for monitoring response to treatment

Predicting progression to Alzheimer’s disease from clinical and imaging data: a reproducible study

International audienceVarious machine learning approaches have been developed for predicting progression to Alzheimer’s disease (AD) in patients with mild cognitive impairment (MCI) from MRI and PET data. Objective comparison of these approaches is nearly impossible because of differences at all steps, from data management to image processing and evaluation procedures. Moreover, with a few exceptions, these papers rarely compare their results to that obtained with clinical/cognitive data only, a critical point to demonstrate the practical utility of neuroimaging in this context. We previously proposed a framework for the reproducible evaluation of ML algorithms for AD classification. This framework was applied to AD classification using unimodal neuroimaging data (T1 MRI and FDG PET). Here, we extend our previous work to the combination of multimodal clinical and neuroimaging data for predicting progression to AD among MCI patients. All the code is publicly available at: https://github.com/aramis-lab/AD-ML

Three simple ideas for predicting progression to Alzheimer's disease

International audienceIn spite of the amount of research done in the prediction of the progression of mild cognitive impaired (MCI) subjects to Alzheimer's disease (AD), there is still room for further improvement. Sophisticated methods have been proposed, some reaching classification accuracies of up to 85%. In the present paper, we propose a combination of simple ideas to determine if they allow to obtain similar accuracies when predicting MCI to AD conversion. We present three approaches making use of ADNI database. We set a performance baseline using only demographic and clinical data (gender, education level, APOE4, MMSE, CDR sum of boxes, ADASCog) that provides a balanced accuracy of 76% (AUC of 0.84). When using imaging data, an important finding is that when an SVM is trained for discriminating between cognitive normal (CN) subjects and AD patients, and the resulting classifier is applied to MCI subjects to predict conversion, performance using FDG PET data improves to 76% of balanced accuracy and an AUC of 0.82. The third approach, consisting of multimodal data, namely the combination of the scores obtained from SVM for T1w and FDG PET data, and the demographic and clinical data, provided the best prediction results (80% balanced accuracy, AUC of 0.88). These prediction accuracies, resulting from the combination simple ideas, are in line with state-of-the-art results, and provide a new baseline to compare more sophisticated methods against. All the code of the framework and the experiments will be publicly available at https://gitlab.icm-institute.org/aramislab/AD-ML

Applicability of in vivo staging of regional amyloid burden in a cognitively normal cohort with subjective memory complaints: the INSIGHT-preAD study.

BACKGROUND:Current methods of amyloid PET interpretation based on the binary classification of global amyloid signal fail to identify early phases of amyloid deposition. A recent analysis of 18F-florbetapir PET data from the Alzheimer's disease Neuroimaging Initiative cohort suggested a hierarchical four-stage model of regional amyloid deposition that resembles neuropathologic estimates and can be used to stage an individual's amyloid burden in vivo. Here, we evaluated the validity of this in vivo amyloid staging model in an independent cohort of older people with subjective memory complaints (SMC). We further examined its potential association with subtle cognitive impairments in this population at elevated risk for Alzheimer's disease (AD). METHODS:The monocentric INSIGHT-preAD cohort includes 318 cognitively intact older individuals with SMC. All individuals underwent 18F-florbetapir PET scanning and extensive neuropsychological testing. We projected the regional amyloid uptake signal into the previously proposed hierarchical staging model of in vivo amyloid progression. We determined the adherence to this model across all cases and tested the association between increasing in vivo amyloid stage and cognitive performance using ANCOVA models. RESULTS:In total, 156 participants (49%) showed evidence of regional amyloid deposition, and all but 2 of these (99%) adhered to the hierarchical regional pattern implied by the in vivo amyloid progression model. According to a conventional binary classification based on global signal (SUVRCereb = 1.10), individuals in stages III and IV were classified as amyloid-positive (except one in stage III), but 99% of individuals in stage I and even 28% of individuals in stage II were classified as amyloid-negative. Neither in vivo amyloid stage nor conventional binary amyloid status was significantly associated with cognitive performance in this preclinical cohort. CONCLUSIONS:The proposed hierarchical staging scheme of PET-evidenced amyloid deposition generalizes well to data from an independent cohort of older people at elevated risk for AD. Future studies will determine the prognostic value of the staging approach for predicting longitudinal cognitive decline in older individuals at increased risk for AD

Age and sex impact plasma NFL and t-Tau trajectories in individuals with subjective memory complaints : a 3-year follow-up study

Background Plasma neurofilament light (NFL) and total Tau (t-Tau) proteins are candidate biomarkers for early stages of Alzheimer's disease (AD). The impact of biological factors on their plasma concentrations in individuals with subjective memory complaints (SMC) has been poorly explored. We longitudinally investigate the effect of sex, age, APOE epsilon 4 allele, comorbidities, brain amyloid-beta (A beta) burden, and cognitive scores on plasma NFL and t-Tau concentrations in cognitively healthy individuals with SMC, a condition associated with AD development. Methods Three hundred sixteen and 79 individuals, respectively, have baseline and three-time point assessments (at baseline, 1-year, and 3-year follow-up) of the two biomarkers. Plasma biomarkers were measured with an ultrasensitive assay in a mono-center cohort (INSIGHT-preAD study). Results We show an effect of age on plasma NFL, with women having a higher increase of plasma t-Tau concentrations compared to men, over time. The APOE epsilon 4 allele does not affect the biomarker concentrations while plasma vitamin B12 deficiency is associated with higher plasma t-Tau concentrations. Both biomarkers are correlated and increase over time. Baseline NFL is related to the rate of A beta deposition at 2-year follow-up in the left-posterior cingulate and the inferior parietal gyri. Baseline plasma NFL and the rate of change of plasma t-Tau are inversely associated with cognitive score. Conclusion We find that plasma NFL and t-Tau longitudinal trajectories are affected by age and female sex, respectively, in SMC individuals. Exploring the influence of biological variables on AD biomarkers is crucial for their clinical validation in blood

Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies

Ataxia with ocular motor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia (ARCA) associated with oculomotor apraxia, hypoalbuminaemia and hypercholesterolaemia. The gene APTX, which encodes aprataxin, has been identified recently. We studied a large series of 158 families with non‐Friedreich progressive ARCA. We identified 14 patients (nine families) with five different missense or truncating mutations in the aprataxin gene (W279X, A198V, D267G, W279R, IVS5+1), four of which were new. We determined the relative frequency of AOA1 which is 5%. Mutation carriers underwent detailed neurological, neuropsychological, electrophysiological, oculographic and biological examinations, as well as brain imaging. The mean age at onset was 6.8± 4.8 years (range 2-18 years). Cerebellar ataxia with cerebellar atrophy on MRI and severe axonal sensorimotor neuropathy were present in all patients. In contrast, oculomotor apraxia (86%), hypoalbuminaemia (83%) and hypercholesterolaemia (75%) were variable. Choreic movements were frequent at onset (79%), but disappeared in the course of the disease in most cases. However, a remarkably severe and persistent choreic phenotype was associated with one of the mutations (A198V). Cognitive impairment was always present. Ocular saccade initiation was normal, but their duration was increased by the succession of multiple hypometric saccades that could clinically be confused with ‘slow saccades'. We emphasize the phenotypic variability over the course of the disease. Cerebellar ataxia and/or chorea predominate at onset, but later on they are often partially masked by severe neuropathy, which is the most typical symptom in young adults. The presence of chorea, sensorimotor neuropathy, oculomotor anomalies, biological abnormalities, cerebellar atrophy on MRI and absence of the Babinski sign can help to distinguish AOA1 from Friedreich's ataxia on a clinical basis. The frequency of chorea at onset suggests that this diagnosis should also be considered in children with chorea who do not carry the IT15 mutation responsible for Huntington's diseas

Brain A beta load association and sexual dimorphism of plasma BACE1 concentrations in cognitively normal individuals at risk for AD

Introduction: Successful development of effective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted therapies for early stages of Alzheimer's disease requires biomarker-guided intervention strategies. Methods: We investigated whether key biological factors such as sex, apolipoprotein E (APOE epsilon 4) allele, and age affect longitudinal plasma BACE1 concentrations in a large monocenter cohort of individuals at risk for Alzheimer's disease. We explored the relationship between plasma BACE1 concentrations and levels of brain amyloid-beta (A beta) deposition, using positron emission tomography global standard uptake value ratios. Results: Baseline and longitudinal mean concentrations of plasma BACE1 were significantly higher in women than men. We also found a positive significant impact of plasma BACE1 on baseline A beta-positron emission tomography global standard uptake value ratios. Discussion: Our results suggest a sexual dimorphism in BACE1-related upstream mechanisms of brain A beta production and deposition. We argue that plasma BACE1 should be considered in further biomarker validation and qualification studies as well as in BACE1 clinical trials. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association

Individual Analysis of Molecular Brain Imaging Data Through Automatic Identification of Abnormality Patterns

International audienceWe introduce a pipeline for the individual analysis of positron emission tomography (PET) data on large cohorts of patients. This pipeline consists for each individual of generating a subject-specific model of healthy PET appearance and comparing the individual's PET image to the model via a novel regularised Z-score. The resulting voxel-wise Z-score map can be interpreted as a subject-specific abnormality map that summarises the pathology's topographical distribution in the brain. We then propose a strategy to validate the abnormality maps on several PET tracers and automatically detect the underlying pathology by using the abnormality maps as features to feed a linear support vector machine (SVM)-based classifier. We applied the pipeline to a large dataset comprising 298 subjects selected from the ADNI2 database (103 cognitively normal, 105 late MCI and 90 Alzheimer's disease subjects). The high classification accuracy obtained when using the abnormality maps as features demonstrates that the proposed pipeline is able to extract for each individual the signal characteristic of dementia from both FDG and Florbetapir PET data

A pipeline for the analysis of 18F-FDG PET data on the cortical surface and its evaluation on ADNI

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MiRNA-15b and miRNA-125b are associated with regional Aβ-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints.

There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer's disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of brain-enriched miRNAs in a monocentric cohort of cognitively normal individuals with subjective memory complaints, a condition associated with increased risk of AD. Second, we investigated the impact of age, sex, and the Apolipoprotein E ε4 (APOE ε4) allele, on the identified miRNA plasma concentrations. In addition, we explored the cross-sectional and longitudinal association of the miRNAs plasma concentrations with regional brain metabolic uptake using amyloid-β (Aβ)-positron emission tomography (Aβ-PET) and 18F-fluorodeoxyglucose-PET (18F-FDG-PET). We identified a set of six brain-enriched miRNAs-miRNA-125b, miRNA-146a, miRNA-15b, miRNA-148a, miRNA-26b, and miRNA-100. Age, sex, and APOE ε4 allele were not associated with individual miRNA abundance. MiRNA-15b concentrations were significantly lower in the Aβ-PET-positive compared to Aβ-PET-negative individuals. Furthermore, we found a positive effect of the miRNA-15b*time interaction on regional metabolic 18F-FDG-PET uptake in the left hippocampus. Plasma miRNA-125b concentrations, as well as the miRNA-125b*time interaction (over a 2-year follow-up), were negatively associated with regional Aβ-PET standard uptake value ratio in the right anterior cingulate cortex. At baseline, we found a significantly negative association between plasma miRNA-125b concentrations and 18F-FDG-PET uptake in specific brain regions. In an asymptomatic at-risk population for AD, we show significant associations between plasma concentrations of miRNA-125b and miRNA-15b with core neuroimaging biomarkers of AD pathophysiology. Our results, coupled with existing experimental evidence, suggest a potential protective anti-Aβ effect of miRNA-15b and a biological link between miRNA-125b and Aβ-independent neurotoxic pathways