Ludovic Fillon

Contrast-Based Fully Automatic Segmentation of White Matter Hyperintensities: Method and Validation

White matter hyperintensities (WMH) on T2 or FLAIR sequences have been commonly observed on MR images of elderly people. They have been associated with various disorders and have been shown to be a strong risk factor for stroke and dementia. WMH studies usually required visual evaluation of WMH load or time-consuming manual delineation. This paper introduced WHASA (White matter Hyperintensities Automated Segmentation Algorithm), a new method for automatically segmenting WMH from FLAIR and T1 images in multicentre studies. Contrary to previous approaches that were based on intensities, this method relied on contrast: non linear diffusion filtering alternated with watershed segmentation to obtain piecewise constant images with increased contrast between WMH and surroundings tissues. WMH were then selected based on subject dependant automatically computed threshold and anatomical information. WHASA was evaluated on 67 patients from two studies, acquired on six different MRI scanners and displaying a wide range of lesion load. Accuracy of the segmentation was assessed through volume and spatial agreement measures with respect to manual segmentation; an intraclass correlation coefficient (ICC) of 0.96 and a mean similarity index (SI) of 0.72 were obtained. WHASA was compared to four other approaches: Freesurfer and a thresholding approach as unsupervised methods; k-nearest neighbours (kNN) and support vector machines (SVM) as supervised ones. For these latter, influence of the training set was also investigated. WHASA clearly outperformed both unsupervised methods, while performing at least as good as supervised approaches (ICC range: 0.87–0.91 for kNN; 0.89–0.94 for SVM. Mean SI: 0.63–0.71 for kNN, 0.67–0.72 for SVM), and did not need any training set.

Prospective associations between white matter hyperintensities and lower extremity function

Objective To evaluate the relationship of white matter hyperintensities (WMH) with decline in lower extremity function (LEF) over approximately 3 years in dementia-free older adults with memory complaints. Methods We obtained brain MRI data from 458 community-dwelling adults, aged 70 years or over, at baseline, and from 358 adults over an average follow-up of 963 days. We evaluated LEF using the Short Physical Performance Battery (SPPB). We related baseline WMH volumes and progression to SPPB scores over time, using mixed-effect linear regressions. For the secondary analyses, we categorized baseline WMH volume into quartiles, and dichotomized the WMH progression to compare fast and slow progression. Results Baseline WMH volume (β = −0.017, 95% confidence interval [CI] −0.025 to −0.009), as well as WMH progression (β = −0.002, 95% CI −0.003 to −0.001), significantly associated with a decline in SPPB performance in adjusted analyses. Compared with the lowest quartile of baseline WMH volume, the highest quartile associated with a decline in SPPB performance (β = −0.301, 95% CI −0.558 to −0.044). Fast progression also associated with a decline in SPPB performance. We found clinically meaningful differences in the SPPB, with higher scores in participants with slow progression of WMH, at both 24 and 36 months. Conclusions Baseline level and WMH progression associated with longitudinal decline in SPPB performance among older adults. We detected clinically meaningful differences in SPPB performance on comparing fast with slow progression of WMH, suggesting that speed of WMH progression is an important determinant of LEF during aging.

Association Between Red Blood Cells Omega-3 Polyunsaturated Fatty Acids and White Matter Hyperintensities: The MAPT Study

ObjectivesThe association between circulating biomarkers of red blood cells (RBC) omega-3 polyunsaturated fatty acids (PUFAs) and cerebral white matter hyperintensities (WMH) on the brain MRI remains yet unclear. We investigated the cross-sectional and prospective associations of RBC omega-3 PUFAs with WMH in dementia-free older adults with subjective memory complaints.DesignParticipants were 234 older adults with assessments for both PUFA and MRI near to baseline; among them, 79 also had an MRI assessment at 3-year follow-up. The measurement of WMH volume was obtained by an automated segmentation algorithm. We related individual or combinational baseline RBC omega-3 PUFAs levels with baseline WMH volumes and WMH evolution over 3 years. We carried out multiple (cross-sectional) and mixed-effect (prospective analysis, with random effects at participant’s level) linear regressions with adjustment for age, sex, time interval between date of blood draw for measurement of fatty acids and date of brain MRI, the status of APOE e4 carrier, body mass index, and vascular risk factors. Associations were considered significant at p ≤ 0.006 to take into account multiplicity (8 comparisons).ResultsNone of the eight RBC omega-3 PUFAs tested was significantly associated with WMH at both cross-sectional and prospective analyses.ConclusionsWe did not find any association between omega-3 PUFAs and WMH in non-demented older adults with memory complaints. A longer longitudinal study with data on omega-3 PUFAs and WMH would contribute important information to this field.

Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer's disease

Although brain neuroinflammation may play an instrumental role in the pathophysiology of Alzheimers disease, its actual impact on disease progression remains controversial, being reported as either detrimental or protective. This work aimed at investigating the temporal relationship between microglial activation and clinical progression of Alzheimers disease. First, in a large cohort of patients with Alzheimers disease we analysed the predictive value of microglial activation assessed by 18F-DPA-714 PET imaging on functional, cognitive and MRI biomarkers outcomes after a 2-year follow-up. Second, we analysed the longitudinal progression of 18F-DPA-714 binding in patients with Alzheimers disease by comparison with controls, and assessed its influence on clinical progression. At baseline, all participants underwent a clinical assessment, brain MRI, 11C-PiB, 18F-DPA-714 PET imaging and TSPO genotyping. Participants were followed-up annually for 2 years. At the end of the study, subjects were asked to repeat a second 18F-DPA-714-PET imaging. Initial 18F-DPA-714 binding was higher in prodromal (n = 33) and in demented patients with Alzheimers disease (n = 19) compared to controls (n = 17). After classifying patients into slow and fast decliners according to functional (Clinical Dementia Rating change) or cognitive (Mini-Mental State Examination score decline) outcomes, we found a higher initial 18F-DPA-714 binding in slow than fast decliners. Negative correlations were observed between initial 18F-DPA-714 binding and the Clinical Dementia Rating Sum of Boxes score increase, the MMSE score loss and the progression of hippocampal atrophy. This suggests that higher initial 18F-DPA-714 binding is associated with better clinical prognosis. Twenty-four patients with Alzheimers disease and 15 control subjects performed a second DPA-PET. We observed an increase of 18F-DPA-714 in patients with Alzheimers disease as compared with controls (mean 13.2% per year versus 4.2%) both at the prodromal (15.8%) and at the demented stages (8.3%). The positive correlations between change in 18F-DPA-714 binding over time and the three clinical outcome measures (Clinical Dementia Rating, Mini-Mental State Examination, hippocampal atrophy) suggested a detrimental effect on clinical Alzheimers disease progression of increased neuroinflammation after the initial PET examination, without correlation with PiB-PET uptake at baseline. High initial 18F-DPA-714 binding was correlated with a low subsequent increase of microglial activation and favourable clinical evolution, whereas the opposite profile was observed when initial 18F-DPA-714 binding was low, independently of disease severity at baseline. Taken together, our results support a pathophysiological model involving two distinct profiles of microglial activation signatures with different dynamics, which differentially impact on disease progression and may vary depending on patients rather than disease stages.

Cerebral microbleeds and CSF Alzheimer biomarkers in primary progressive aphasias

Objective To reveal the prevalence and localization of cerebral microbleeds (CMBs) in the 3 main variants of primary progressive aphasia (PPA) (logopenic, semantic, and nonfluent/agrammatic), to identify the relationship with underlying Alzheimer pathology, and to explore whether CMBs contribute to language breakdown. Methods We used a cross-sectional design in a multicenter cohort of 82 patients with PPA and 19 similarly aged healthy controls. MRI allowed for rating CMBs (2-dimensional gradient recalled echo T2*, susceptibility weighted imaging sequences) and white matter hyperintensities. CSF Alzheimer disease biomarker analyses available in 63 of the 82 patients provided the stratification of PPA into subgroups with patients who had or did not have probable underlying Alzheimer pathology. Results The prevalence of CMBs was higher in patients with PPA (28%) than in controls (16%). They were more prevalent in logopenic PPA (50%) than in semantic PPA (18%) and nonfluent/agrammatic PPA (17%). The localization of CMBs was mainly lobar (81%) with no difference between the PPA variants. CMBs were more frequent in PPA patients with positive than with negative CSF Alzheimer disease biomarkers (67% vs 20%). Patients with and without lobar CMBs had similar volumes of white matter hyperintensities. Language and general cognitive impairment in PPA was unrelated to CMB rates. Conclusions CMB prevalence in PPA is higher than in healthy controls. CMBs were most prevalent in the logopenic variant, were related to underlying Alzheimer pathology, and did not affect the language/cognitive impairment. Our findings also suggest that CMB detection with MRI contributes to PPA variant diagnosis, especially of logopenic PPA, and provides an estimator of the underlying neuropathology.

Neural correlates of episodic memory in the Memento cohort

The free and cued selective reminding test is used to identify memory deficits in mild cognitive impairment and demented patients. It allows assessing three processes: encoding, storage, and recollection of verbal episodic memory.

Associations between white matter hyperintensities and cognitive decline over three years in non-dementia older adults with memory complaints

We investigated whether the baseline level and overtime changes of white matter hyperintensities (WMH) would be associated with cognitive decline over three years in non-demented older adults with memory complaints. 109 participants with baseline magnetic resonance imaging (MRI) and follow-up cognitive assessments up to 3-year were included; among them, 82 also had a follow-up MRI assessment over three years. WMH volume was obtained by an automated segmentation algorithm. Baseline WMH volumes and change between baseline and follow-up WMH were related to cognitive scores over time using mixed-effect linear regressions. Secondary stratified analyses according to Clinical Dementia Rating (CDR) status, APOE4 status, and presence of amyloid in the brain were conducted using similar regression models. Change in WMH volume overtime was associated with declines in COWAT (β=-0.239; 95% CI=-0.381, -0.096, p=0.001). Baseline WMH was not associated to any of the cognitive tests. Secondary analysis found that baseline WMH was associated to declines in TMT-A in APOE4 non-carriers (β=0.343; 95% CI=0.121, 0.564, p=0.003) and CDR 0 groups (β=0.307; 95% CI=0.095, 0.519, p=0.005); in CDR 0 group, overtime changes in WMH was associated to declines on both TMT-A (β=0.698; 95% CI=0.270, 1.126, p=0.002) and TMT-B (β=2.573; 95% CI=1.200, 3.947, p<0.001). Changes in WMH volume are associated with declines in information processing speed and executive function in non-demented older adults with memory complaints. Overtime changes in WMH volume is probably a better determinant of cognitive function in the elderly than baseline WMH volume.

PROGRESSION OF CORTICAL MICROGLIAL ACTIVATION IN ALZHEIMER’S DISEASE: A TWO-YEAR LONGITUDINAL PET STUDY USING [ 18 F]DPA-714

Lorraine Hamelin, Julien Lagarde, Guillaume Doroth ee, MarieClaude Potier, H el ene Corne, Ludovic Fillon, Fabien Caill e, Philippe Gervais, Michel Bottlaender, Marie Sarazin, Neurology of Memory and Language, Universit e Paris Descartes, Sorbonne Paris Cit e, INSERM UMR S894, Centre Hospitalier Sainte Anne, Paris, France; INSERM-UPMC UMRS 938, Centre de Recherche Saint-Antoine, Paris, France; Brain and Spine Institute (ICM), UPMC/Inserm UMR-S 975, CNRS UMR 7225, Paris, France; Sorbonne Universit es, Universit e Pierre et Marie Curie (UPMC), Paris, France; CATI Project, Paris, France; CEA, Orsay, France; NeuroSpin, Institut d’Imagerie Biom edicale, Direction des Sciences du Vivant, Commissariat a l’Energie Atomique, Gif sur Yvette, France; Neurologie de la M emoire et du Langage, Universit e Paris Descartes, Sorbonne Paris Cit e, INSERM UMR S894, Centre Hospitalier Sainte Anne, Paris, France. Contact e-mail: J.LAGARDE@ ch-sainte-anne.fr

THE INSIGHT COHORT: BASELINE ANALYSIS OF STRUCTURAL MR IMAGING IN ASYMPTOMATIC SUBJECTS AT RISK FOR ALZHEIMER'S DISEASE

cal Alzheimer’s disease Cognitive Composite (PACC). The PACC is comprised of the Logical Memory delayed recall, Free and Cued Selective Reminding Test (FCSRT) total cued recall score, the MMSE total score, and the Digit Symbol total score. Age, sex, and education were covaried. Results: In the full sample, Ab+ CNs showed significantly more decline in PACC compared to AbCNs (beta1⁄4-0.08, p-value1⁄40.03), and this difference was significant when examining individual components of the PACC separately (p-values<0.04). When both Ab status and inferior temporal Tau were modeled as simultaneous predictors in the subset of 130 CN, Ab status was not significant (beta1⁄4-0.006, p1⁄40.82) whereas higher Tau was associated with decline (beta1⁄40.47, p1⁄40.0007). Inclusion of an interaction term between Ab and inferior temporal Tau revealed a significant effect (p1⁄40.02), such that the association between inferior temporal Tau and decline in PACC was only present among Ab+ CN. Among Ab+ CN, inferior temporal Tau was significantly associated with decline in individual PACC components (p-values<0.05) with the exception of the FCSRT (p1⁄40.12). Inferior temporal Tau was not associated with decline in any individual test among AbCN (p-values>0.63).Conclusions:Greater risk of short-term decline in Ab+ CN that also have elevated Tau is consistent with the current conceptualization of preclinical AD. These high risk individuals may be ideal candidates for prevention trials using cognitive endpoints. However, whether efficacy of anti-amyloid treatment will be optimal in Ab+ CN with either elevated or low Tau is unknown.

Age differences in the association of white matter lesions with the occurrence of dementia: The memento cohort

Background:Florbetapir PET imaging has been validated in autopsy studies as reflecting the presence and quantity of amyloid pathology. This imaging has promise as a potential biomarker for AD and may allow the identification of individuals in the preclinical stages of the illness. If a sensitive screen for amyloid status could be developed this could enrich the enrollment of clinical trials for AD, thus reducing cost and participant burden. Our aim for the current study was to use item analysis of a broad cognitive battery to identify a set of items that would maximally predict cerebral amyloid pathology. Methods:The KU Self-Regulation and Cognitive Control Questionnaire (SRCCQ) is a 20-Item self-report questionnaire that measures changes in a participants’ metamemory for self-regulatory behaviors. Participants were asked to rate each item on the basis of change in current functional ability compared to five years ago and severity of current problems. We developed the SRCCQ to select items that produce good sensitivity to amyloid pathology. Sixty participants completed a lengthy self-report measure during their initial visit at the at the University of Kansas Alzheimer’s Disease Center. All participants also underwent PET imaging to evaluate amyloid pathology. Discriminant item analysis was conducted to examine sensitivity of the SRCCQ in detecting amyloid pathology. Results: SRCCQ measure showed 83% sensitivity to amyloid status and 67% overall accuracy detection. Item analysis revealed that highly predictive items on the SRCCQ were conceptually interrelated; most sampled similar facets of self-regulatory behaviors. Notably subjective memory complaints did not discriminatewell in this sample of participants. Conclusions:There is limited progress in the area of early detection screening tools for AD. Strong screening measures that come in the form of questionnaires and self-reports would greatly benefit busy primary care settings where time and resources are limited. Developing a simple screening tool that identifies participants with elevated cerebral amyloid bridges the gap between effective screening tolls and busy primary care settings. Items on the SRCCQ focused on self-regulatory behaviors which demonstrated good sensitivity to amyloid status. Measuring self-regulation and metamemory will be important for developing screening tools used in secondary prevention initiatives.