Djilali Adel

AV45 is an 18F-labeled amyloid-tracer that has been introduced for Alzheimer Disease (AD) diagnosis. AV45-PET in elderly subjects has not been documented yet. This work aimed to evaluate patterns of ß-amyloid deposits in elderly volunteers who don't meet the criteria of AD or dementia using principal component analysis (PCA). Methods: AV-45 ancillary study is based on the Multidomain Alzheimer Preventive Trial (MAPT) survey including 271 subjects. MAPT Study is a 3-years, randomized trial enrolling elderly volunteers (>70years), on the basis of at least one of this criteria: subjective memory complaint spontaneously expressed (with a MMSE>24), limitation in one in instrumental activity of daily living , and slow walking-speed (speed ≤ 0.8 m/s). PET-scans were spatially normalized with AV-45 template provided by Avid-Radiopharmaceutical using SPM8. A semi-automated quantitative analysis was applied, and the cortical-to-cerebellar signal ratio was compute in 80 VOIs (Brodman...

Multidomain intervention (physical and cognitive training, nutritional advices), is supposed to reduce the risk of cognitive decline in prefrail older people. FDG-PET and MRI have been proposed as biomarkers of neurodegeneration. The Aim of this study is to assess the effect of Multidomain Alzheimer preventive program on brain metabolism and gray matter change after one year practice. Methods: All subjects were enrolled in MAPT neuroimaging study, an ancillary study of MAPT (3-year, randomized controlled trial), who don't meet the criteria of dementia or AD, on the basis of at least one of following criteria: subjective memory complaints spontaneously expressed, limitation in one instrumental activity of daily living, and slow walking speed (speed≤0.8m/s). We enrolled 68 subjects (77±4 yo) in Toulouse University Hospital. They were randomized in two groups, the active multidomain group and the control group. Among them 15 controls and 15 multidomain intervention underwent a FDG-...

Objectives: The purpose of this study is to evaluate the prevalence of ß-amyloid burden in elderly people who don’t meet criteria of dementia or Alzheimer disease, as assessed by AV45-PET scans, and the concordance between visual assessment and SUVr quantification. Methods: A multicenter study from the Multidomain Alzheimer Preventive Trial (MAPT), acquisitions of 15 min, and 50 min after a bolus injection of AV-45 was performed. The study enrolling elderly volunteers aged of 70years and over with an MMSE>24. The images were visually assessed by three trained observers on a binary scale (+ / -) blinded of clinical data. Then a semi-automatic quantification was performed on six cortical regions (Clark et.al.) to obtain SUVr taking the cerebellum as reference region. The SUVr is the cortical average over six regions (temporal, parietal, frontal, precuneus, anterior-cingulate and posterior-cingulate). Results: 271 subjects (162F, 109M) aged of 76.6 ± 4.6 years were included. 33.2% o...

The N-methyl-d-aspartate receptor (NMDAr) is an ionotropic receptor that mediates excitatory transmission. NMDAr overexcitation is thought to be involved in neurological and neuropsychiatric disorders such as Alzheimer disease and schizophrenia. We synthesized [(18)F]-fluoroethylnormemantine ([(18)F]-FNM), a memantine derivative that binds to phencyclidine (PCP) sites within the NMDA channel pore. These sites are primarily accessible when the channel is in the active and open state. Radiosynthesis was carried out using the Raytest® SynChrom R&D fluorination module. Affinity of this new compound was determined by competition assay. We ran a kinetic study in rats and computed a time-activity curve based on a volume-of-interest analysis, using CARIMAS® software. We performed an ex vivo autoradiography, exposing frozen rat brain sections to a phosphorscreen. Adjacent sections were used to detect NMDAr by immunohistochemistry with an anti-NR1 antibody. As a control of the specificity of our compound for NMDAr, we used a rat anesthetized with ketamine. Correlation analysis was performed with ImageJ software between signal of autoradiography and immunostaining. Fluorination yield was 10.5% (end of synthesis), with a mean activity of 3145MBq and a specific activity above 355GBq/μmol. Affinity assessment allowed us to determine [(19)F]-FNM IC50 at 6.1 10(-6)M. [(18)F]-FMN concentration gradually increased in the brain, stabilizing at 40minutes post injection. The brain-to-blood ratio was 6, and 0.4% of the injected dose was found in the brain. Combined ex vivo autoradiography and immunohistochemical staining demonstrated colocalization of NMDAr and [(18)F]-FNM (r=0.622, p<0.0001). The highest intensity was found in the cortex and cerebellum, and the lowest in white matter. A low and homogeneous signal corresponding to unspecific binding was observed when PCP sites were blocked with ketamine. [(18)F]-FNM appears to be a promising tracer for imaging NMDAr activity for undertaking preclinical studies in perspective of clinical detection of neurological or neuropsychological disorders.

OBJECTIVE: The Multidomain Alzheimer Preventive Trial
(MAPT study) was designed to assess the efficacy of isolated
supplementation with omega-3 fatty acid, an isolated
multidomain intervention (consisting of nutritional counseling,
physical exercise, cognitive stimulation) or a combination of the
two interventions on the change of cognitive functions in frail
subjects aged 70 years and older for a period of 3 years.
Ancillary neuroimaging studies were additionally implemented
to evaluate the impact of interventions on cerebral metabolism
(FDG PET scans) and atrophy rate (MRIs), as well as brain
amyloïd deposit (AV45 PET scans).
DESIGN, PATIENTS: 1680 subjects (mean age: 75.3 years;
female: 64.8 %), enrolled by 13 memory clinics, were
randomized into one of the following four groups: omega-3
supplementation alone, multidomain intervention alone,
omega-3 plus multidomain intervention, or placebo.
Participants underwent cognitive, functional and biological
assessments at M6, M12, M24 and M36 visits. The primary
endpoint is a change of memory function at 3 years, as assessed
by the Free and Cued Selective Reminding test. All participants
will be followed for 2 additional years after the 3-years
intervention (MAPT PLUS extension study).
INTERVENTIONS: 1/ Omega-3 supplementation: two soft
capsules daily as a single dose, containing a total of 400 mg
docosahexaenoic acid (DHA), i.e., 800 mg docosahexaenoic acid
per day, for 3 years. 2/ Multidomain intervention: collective
training sessions conducted in small groups (6–8 participants)
in twelve 120-minute sessions over the first 2 months (two
sessions a week for the first month, and one session a week the
second month) then a 60-minute session per month in the
following three areas: nutrition, physical activity, and cognition
until the end of the 3 years. In addition to the collective
sessions, individualized preventive outpatient visits exploring
possible risk factors for cognitive decline are performed at
baseline, M12 and M24.
BASELINE POPULATION: For cognition, the mean MMSE at
baseline was 28.1 (± 1.6). About 58% and 42% of participants
had a CDR score equal to 0 and 0.5, respectively. Regarding
mobility status, 200 (11.9%) had a 4-m gait speed lower or equal
to 0.8 m/s. According to the Fried criteria, 673 (42.1%)
participants were considered pre frail, and 51 (3.2%) frail. The
red blood cell DHA content was 26.1 ± 8.1 μg/g. Five hundred
and three participants underwent baseline MRI. AV45 PET
scans were performed in 271 individuals and preliminary
results showed that 38.0% had a cortical SUVR > 1.17, which
gave an indication of significant brain amyloïd deposit.
DISCUSSION: The MAPT trial is presently the first largest and
longest multidomain preventive trial relevant to cognitive
decline in older adults with subjective memory complaints. The
multidomain intervention designed for the MAPT trial is likely
to be easily implemented within the general population.

AV-45 amyloid biomarker is known to show uptake in white matter in patients with Alzheimer's disease (AD), but also in the healthy population. This binding, thought to be of a non-specific lipophilic nature, has not yet been investigated. The aim of this study was to determine the differential pattern of AV-45 binding in white matter in healthy and pathological populations. We recruited 24 patients presenting with AD at an early stage and 17 matched, healthy subjects. We used an optimized positron emission tomography-magnetic resonance imaging (PET-MRI) registration method and an approach based on an intensity histogram using several indices. We compared the results of the intensity histogram analyses with a more canonical approach based on target-to-cerebellum Standard Uptake Value (SUVr) in white and grey matter using MANOVA and discriminant analyses. A cluster analysis on white and grey matter histograms was also performed. White matter histogram analysis revealed significant differences between AD and healthy subjects, which were not revealed by SUVr analysis. However, white matter histograms were not decisive to discriminate groups, and indices based on grey matter only showed better discriminative power than SUVr. The cluster analysis divided our sample into two clusters, showing different uptakes in grey, but also in white matter. These results demonstrate that AV-45 binding in white matter conveys subtle information not detectable using the SUVr approach. Although it is not more efficient than standard SUVr in discriminating AD patients from healthy subjects, this information could reveal white matter modifications.