Anne Sophie Salabert

Florbetapir imaging in cerebral amyloid angiopathy-related hemorrhages

Objective: To assess whether 18F-florbetapir, a PET amyloid tracer, could bind vascular amyloid in cerebral amyloid angiopathy (CAA) by comparing cortical florbetapir retention during the acute phase between patients with CAA-related lobar intracerebral hemorrhage (ICH) and patients with hypertension-related deep ICH. Methods: Patients with acute CAA-related lobar ICH were prospectively enrolled and compared with patients with deep ICH. 18F-florbetapir PET, brain MRI, and APOE genotype were obtained for all participants. Cortical florbetapir standard uptake value ratio (SUVr) was calculated with the whole cerebellum used as a reference. Patients with CAA and those with deep ICH were compared for mean cortical florbetapir SUVr values. Results: Fifteen patients with acute lobar ICH fulfilling the modified Boston criteria for probable CAA (mean age = 67 ± 12 years) and 18 patients with acute deep ICH (mean age = 63 ± 11 years) were enrolled. Mean global cortical florbetapir SUVr was significantly higher among patients with CAA-related ICH than among patients with deep ICH (1.27 ± 0.12 vs 1.12 ± 0.12, p = 0.001). Cortical florbetapir SUVr differentiated patients with CAA-ICH from those with deep ICH (area under the curve = 0.811; 95% confidence interval [CI] 0.642–0.980) with a sensitivity of 0.733 (95% CI 0.475–0.893) and a specificity of 0.833 (95% CI 0.598–0.948). Conclusions: Cortical florbetapir uptake is increased in patients with CAA-related ICH relative to those with deep ICH. Although 18F-florbetapir PET can label vascular β-amyloid and might serve as an outcome marker in future clinical trials, its diagnostic value in acute CAA-related ICH seems limited in clinical practice.

Cross-Sectional and Prospective Associations Between β-Amyloid in the Brain and Chair Rise Performance in Nondementia Older Adults With Spontaneous Memory Complaints

Background: The objectives of this study were to examine the cross-sectional and prospective associations of muscle functional performance as assessed by a chair rise test and brain amyloid load among nondemented older adults with spontaneous memory complaints. Methods: This is a secondary analysis, with an observational design, using data from the MAPT randomized controlled trial. Individuals assessed for brain amyloid load (florbetapir F18 positron emission tomography) and without clinical dementia (N = 269 aged 75.2±4.2 years; 60.2% women) participated in the study. Cortical and regional standard uptake value ratios (SUVRs) were obtained. The main outcome measure was the 5-repetition chair rise performance (maximum speed—higher is better), which was assessed at baseline and at 6, 12, 24, and 36 months. Adjusted multiple linear (cross-sectional) and mixed-effect (overtime) regressions were performed. Results: Any of mean cortical (regions of interest) and each regional SUVRs (anterior cingulate, anterior putamen, caudate, hippocampus, medial orbitofrontal cortex, occipital cortex, parietal cortex, pons, posterior cingulate, posterior putamen, precuneus, semioval center, and temporal cortex) were not associated to chair rise after adjustment for multiplicity. These findings were obtained for both cross-sectional and prospective associations. Conclusions: Brain amyloid was not found to be associated to chair rise performance in nondemented older adults with memory complaints. Potential mechanisms on the links, if any, of amyloid load with physical performance are probably not dependent on muscle function.

Cross-sectional associations of total plasma homocysteine with cortical β-amyloid independently and as a function of omega 3 polyunsaturated fatty acid status in older adults at risk of dementia

ObjectivesElevated total plasma homocysteine is a risk factor for Alzheimer’s disease (AD) and there is some evidence that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can modulate the effects of homocysteine-lowering B vitamins on AD related pathologies. Hence we investigated the relationship between total plasma homocysteine and cortical β-amyloid (Aβ) in older adults at risk of dementia. The role of erythrocyte membrane n-3 PUFAs (omega 3 index) on this relationship was also explored.DesignThis is a cross-sectional study using data from the Multidomain Alzheimer Preventive Trial (MAPT); a randomised controlled trial.SettingFrench community dwellers aged 70 or over reporting subjective memory complaints, but free from a diagnosis of clinical dementia.ParticipantsIndividuals were from the MAPT trial (n = 177) with data on total plasma homocysteine at baseline and cortical Aβ load.MeasurementsCortical-to-cerebellar standard uptake value ratios were assessed using [18F] florbetapir positron emission tomography (PET). Total baseline plasma homocysteine was measured using an enzymatic cycling assay. Baseline omega 3 index was measured using gas chromatography. Cross-sectional associations were explored using adjusted multiple linear regression models.ResultsWe found that total baseline plasma homocysteine was not significantly associated with cortical Aβ as demonstrated using multiple linear regression models adjusted for age, sex, education, cognitive status, time interval between baseline and PET-scan, omega-3 index, MAPT group allocation and Apolipoprotein E ε4 status (B-coefficient -0.001, 95 % CI: -0.008,0.006, p = 0.838). Exploratory analysis showed that homocysteine was however significantly associated with cortical Aβ in subjects with low baseline omega-3 index (< 4.72 %) after adjustment for Apolipoprotein E ε4 status (B-coefficient 0.041, 95 % CI: 0.017,0.066, p = 0.005, n = 10), but not in subjects with a high baseline omega-3 index (B-coefficient -0.010, 95 % CI: -0.023,0.003, p = 0.132, n = 66).ConclusionsThe role of n-3 PUFAs on the relationship between homocysteine and cerebral Aβ warrants further investigation.

Cross-sectional associations of cortical β-amyloid with erythrocyte membrane long-chain polyunsaturated fatty acids in older adults with subjective memory complaints

Omega‐3 (n‐3) and 6 (n‐6) polyunsaturated fatty acids (PUFAs) have been associated with reduced cognitive decline in observational studies. Hence, we examined the cross‐sectional associations between cortical β‐amyloid (Aβ) and erythrocyte membrane PUFAs in 61 non‐demented elderly individuals reporting subjective memory complaints from the Multidomain Alzheimer Preventive Trial placebo arm. Cortical‐to‐cerebellar standard uptake value ratios were obtained using [18F] florbetapir positron emission tomography. Fatty acids were measured in erythrocyte membranes by gas chromatography. Associations were explored using adjusted multiple linear regression models and were considered significant at p ≤ 0.005 after correction for multiple testing (10 comparisons). We found no significant associations between cortical Aβ and erythrocyte membrane PUFAs. The associations closest to significance after adjustment were those between Aβ and erythrocyte membrane arachidonic acid (without apolipoprotein E status adjustment: B‐coefficient, 0.03; CI, 0.01, 0.05; p = 0.02. Including Apolipoprotein E adjustment: B‐coefficient, 0.03; CI, 0.00, 0.06; p = 0.04) and Aβ and erythrocyte membrane linoleic acid (without apolipoprotein E status adjustment: B‐coefficient, −0.02; CI, −0.04, 0.00; p = 0.02. Including Apolipoprotein E adjustment: B‐coefficient, −0.02; CI, −0.04, 0.00; p = 0.09). Furthermore, the association between Aβ and erythrocyte membrane arachidonic acid seemed to be specific to Apolipoprotein E ε4 non‐carriers (B‐coefficient 0.03, CI: 0.00, 0.06, p = 0.03, n = 36). In contrast, no association was found between Aβ and erythrocyte membrane linoleic acid in Apolipoprotein E ε4 stratified analysis. Investigating the relationships between Aβ and PUFAs longitudinally would provide further evidence as to whether fatty acids, particularly arachidonic acid and linoleic acid, might modulate cognition through Aβ‐dependent mechanisms.

Cross-sectional Associations of Fatigue with Cerebral β-Amyloid in Older Adults at Risk of Dementia

Fatigue is a common symptom in the elderly and has also been associated with impaired cognition in older adults. Hence, we sought to explore the cross-sectional relationship between fatigue and cerebral β-amyloid (Aβ) in 269 elderly individuals reporting subjective memory complaints from the Multidomain Alzheimer Preventive Trial. Standard uptake value ratios (SUVRs) were generated by [18F] florbetapir positron emission tomography (PET) using the cerebellum as a reference. Cortical-to-cerebellar SUVRs (cortical-SUVRs) were obtained using the mean signal from the frontal cortex, temporal cortex, parietal cortex, precuneus, anterior cingulate, and posterior cingulate. Other brain regions independently assessed were the anterior cingulate, anterior putamen, caudate, hippocampus, medial orbitofrontal cortex, occipital cortex, parietal cortex, pons, posterior cingulate, posterior putamen, precuneus, semioval center, and temporal cortex. Fatigue was defined according to two questions retrieved from the Center for Epidemiological Studies-Depression scale. Chronic fatigue was defined as meeting fatigue criteria at two consecutive clinical visits 6 months apart between study baseline and 1 year (visits were performed at baseline, 6 months and 1 year then annually). Cross-sectional associations between fatigue variables and cerebral Aβ were explored using fully adjusted multiple linear regression models. We found no statistically significant cross-sectional associations between fatigue assessed at the clinical visit closest to PET and Aβ in any brain region. Similarly, chronic fatigue was not significantly associated with Aβ load. Sensitivity analysis in subjects with a Clinical Dementia Rating of 0.5 showed that fatigue reported at the clinical visit closest to PET was, however, weakly associated with increased Aβ in the hippocampus (B-coefficient: 0.07, 95% CI: 0.01, 0.12, p = 0.016). These preliminary results suggest that fatigue might be associated with Aβ in brain regions associated with Alzheimer’s disease in subjects in the early stages of disease.

Assessment of Translocator Protein Density, as Marker of Neuroinflammation, in Major Depressive Disorder: A Pilot, Multicenter, Comparative, Controlled, Brain PET Study (INFLADEP Study)

Background: Major depressive disorder (MDD) is a serious public health problem with high lifetime prevalence (4.4–20%) in the general population. The monoamine hypothesis is the most widespread etiological theory of MDD. Also, recent scientific data has emphasized the importance of immuno-inflammatory pathways in the pathophysiology of MDD. The lack of data on the magnitude of brain neuroinflammation in MDD is the main limitation of this inflammatory hypothesis. Our team has previously demonstrated the relevance of [18F] DPA-714 as a neuroinflammation biomarker in humans. We formulated the following hypotheses for the current study: (i) Neuroinflammation in MDD can be measured by [18F] DPA-714; (ii) its levels are associated with clinical severity; (iii) it is accompanied by anatomical and functional alterations within the frontal-subcortical circuits; (iv) it is a marker of treatment resistance. Methods: Depressed patients will be recruited throughout 4 centers (Bordeaux, Montpellier, Tours, and Toulouse) of the French network from 13 expert centers for resistant depression. The patient population will be divided into 3 groups: (i) experimental group—patients with current MDD (n = 20), (ii) remitted depressed group—patients in remission but still being treated (n = 20); and, (iii) control group without any history of MDD (n = 20). The primary objective will be to compare PET data (i.e., distribution pattern of neuroinflammation) between the currently depressed group and the control group. Secondary objectives will be to: (i) compare neuroinflammation across groups (currently depressed group vs. remitted depressed group vs. control group); (ii) correlate neuroinflammation with clinical severity across groups; (iii) correlate neuroinflammation with MRI parameters for structural and functional integrity across groups; (iv) correlate neuroinflammation and peripheral markers of inflammation across groups. Discussion: This study will assess the effects of antidepressants on neuroinflammation as well as its role in the treatment response. It will contribute to clarify the putative relationships between neuroinflammation quantified by brain neuroimaging techniques and peripheral markers of inflammation. Lastly, it is expected to open innovative and promising therapeutic perspectives based on anti-inflammatory strategies for the management of treatment-resistant forms of MDD commonly seen in clinical practice. Clinical trial registration (reference: NCT03314155): https://www.clinicaltrials.gov/ct2/show/NCT03314155?term=neuroinflammation&cond=depression&cntry=FR&rank=1

Chronically raised C-reactive protein is inversely associated with cortical β-amyloid in older adults with subjective memory complaints

Background: Inflammation promotes amyloidogenesis in animals and markers of inflammation are associated with &bgr;‐amyloid (A&bgr;) in humans. Hence, we sought to examine the cross‐sectional associations between chronically elevated plasma C reactive protein (CRP) and cortical A&bgr; in 259 non‐demented elderly individuals reporting subjective memory complaints from the Multidomain Alzheimer Preventive Trial (MAPT). Methods: Cortical‐to‐cerebellar standard uptake value ratios were obtained using [18F] florbetapir positron emission tomography (PET). CRP was measured in plasma using immunoturbidity. Chronically raised CRP was defined as having 2 consecutively high CRP readings (>3mg/l≤10mg/l) between study baseline and the 1year visit (visits were performed at baseline, 6months, 1year and then annually). Associations were explored using adjusted multiple linear regression. Results: Chronically raised CRP was found to be inversely associated with cortical A&bgr; (B‐coefficient: −0.054, SE: 0.026, p=0.040) and this association seemed to be specific to apolipoprotein E (Apo E) &egr;4 carriers (B‐coefficient: −0.130, SE: 0.058, p=0.027). CRP as an isolated reading measured closest to PET scan was also inversely associated with cortical A&bgr; when CRP was treated as a dichotomized variable (high CRP>3mg/l≤10mg/l, B‐coefficient: −0.048, SE: 0.023, p=0.043). Conclusions: Our preliminary findings suggest that inflammation might be beneficial in the early stages of Alzheimers disease as the immune systems attempts to combat A&bgr; pathology particularly in ApoE &egr;4 carriers. Investigating the temporal relationships between cerebral A&bgr; and a panel of inflammatory markers would provide further evidence as to whether chronic inflammation might modulate amyloidogenesis in vivo. HIGHLIGHTSChronically raised C‐ reactive protein was inversely associated with cortical &bgr;‐amyloid.This association seemed to be specific to apolipoprotein E &egr;4 carriers.Inflammation might be beneficial in the early stages of Alzheimers disease as the immune systems attempts to combat &bgr;‐amyloid pathology.

Association of cortical β-amyloid with erythrocyte membrane monounsaturated and saturated fatty acids in older adults at risk of dementia

ObjectivesWe examined the relationships between erythrocyte membrane monounsaturated fatty acids (MUFAs) and saturated fatty acids (SFAs) and cortical β-amyloid (Aβ) load in older adults reporting subjective memory complaints.DesignThis is a cross-sectional study using data from the Multidomain Alzheimer Preventive Trial (MAPT); a randomised controlled trial.SettingFrench community dwellers aged 70 or over reporting subjective memory complaints, but free from a diagnosis of clinical dementia.ParticipantsParticipants of this study were 61 individuals from the placebo arm of the MAPT trial with data on erythrocyte membrane fatty acid levels and cortical Aβ load.MeasurementsCortical-to-cerebellar standard uptake value ratios were assessed using [18F] florbetapir positron emission tomography (PET). Fatty acids were measured in erythrocyte cell membranes using gas chromatography. Associations between erythrocyte membrane MUFAs and SFAs and cortical Aβ load were explored using adjusted multiple linear regression models and were considered significant at p ≤ 0.005 (10 comparisons) after correction for multiple testing.ResultsWe found no significant associations between fatty acids and cortical Aβ load using multiple linear regression adjusted for age, sex, education, cognition, PET-scan to clinical assessment interval, PET-scan to blood collection interval and apolipoprotein E (ApoE) status. The association closest to significance was that between erythrocyte membrane stearic acid and Aβ (B-coefficient 0.03, 95 % CI: 0.00,0.05, p = 0.05). This association, although statistically non-significant, appeared to be stronger amongst ApoE ε4 carriers (B-coefficient 0.04, 95 % CI: -0.01,0.09, p = 0.08) compared to ApoE ε4 non-carriers (B-coefficient 0.02, 95 % CI: -0.01,0.05, p = 0.18) in age and sex stratified analysis.ConclusionFuture research in the form of large longitudinal observational study is needed to validate our findings, particularly regarding the potential association of stearic acid with cortical Aβ.