Evaluation of amyloid status in a cohort of elderly individuals with memory complaints: validation of the method of quantification and determination of positivity thresholds.

OBJECTIVE: Our aim is to validate the process steps implemented by the French CATI platform to assess amyloid status, obtained from 18F-Florbetapir PET scans, in a cohort of 318 cognitively normal subjects participating in the INSIGHT-preAD study. Our objective was to develop a method with partial volume effect correction (PVEC) on untransformed PET images, using an automated pipeline ("RACHEL") adapted to large series of patients and including quality checks of results. METHODS: We compared RACHEL using different options (with and without PVEC, different sets of regions of interest), to two other methods validated in the literature, referred as the "AVID" and "CAEN" methods. A standard uptake value ratio (SUVR) was obtained with the different methods for participants to another French study, IMAP, including 26 normal elderly controls (NEC), 11 patients with mild cognitive impairment (MCI) and 16 patients with Alzheimer's disease (AD). We determined two cutoffs for RACHEL method by linear correlation with the other methods and applied them to the INSIGHT-preAD subjects. RESULTS: RACHEL including PVEC and a combination of the whole cerebellum and the pons as a reference region allowed the best discrimination between NEC and AD participants. A strong linear correlation was found between RACHEL and the other two methods and yielded the two cutoffs of 0.79 and 0.88. According to the more conservative threshold, 19.8% of the INSIGHT-preAD subjects would be considered amyloid positive, and 27.7% according to the more liberal threshold. CONCLUSIONS: With our method, we clearly discriminated between NEC with negative amyloid status and patients with clinical AD. Using a linear correlation with other validated cutoffs, we could infer our own positivity thresholds and apply them to an independent population. This method might be useful to the community, especially when the optimal cutoff could not be obtained from a population of healthy young adults or from correlation with post-mortem results.

Optimization of brain PET imaging for a multicentre trial: the French CATI experience.

BACKGROUND: CATI is a French initiative launched in 2010 to handle the neuroimaging of a large cohort of subjects recruited for an Alzheimer's research program called MEMENTO. This paper presents our test protocol and results obtained for the 22 PET centres (overall 13 different scanners) involved in the MEMENTO cohort. We determined acquisition parameters using phantom experiments prior to patient studies, with the aim of optimizing PET quantitative values to the highest possible per site, while reducing, if possible, variability across centres. METHODS: Jaszczak's and 3D-Hoffman's phantom measurements were used to assess image spatial resolution (ISR), recovery coefficients (RC) in hot and cold spheres, and signal-to-noise ratio (SNR). For each centre, the optimal reconstruction parameters were chosen as those maximizing ISR and RC without a noticeable decrease in SNR. Point-spread-function (PSF) modelling reconstructions were discarded. The three figures of merit extracted from the images reconstructed with optimized parameters and routine schemes were compared, as were volumes of interest ratios extracted from Hoffman acquisitions. The net effect of the 3D-OSEM reconstruction parameter optimization was investigated on a subset of 18 scanners without PSF modelling reconstruction. RESULTS: Compared to the routine parameters of the 22 PET centres, average RC in the two smallest hot and cold spheres and average ISR remained stable or were improved with the optimized reconstruction, at the expense of slight SNR degradation, while the dispersion of values was reduced. For the subset of scanners without PSF modelling, the mean RC of the smallest hot sphere obtained with the optimized reconstruction was significantly higher than with routine reconstruction. The putamen and caudate-to-white matter ratios measured on 3D-Hoffman acquisitions of all centres were also significantly improved by the optimization, while the variance was reduced. CONCLUSIONS: This study provides guidelines for optimizing quantitative results for multicentric PET neuroimaging trials.

CATI: A Large Distributed Infrastructure for the Neuroimaging of Cohorts.

This paper provides an overview of CATI, a platform dedicated to multicenter neuroimaging. Initiated by the French Alzheimer's plan (2008-2012), CATI is a research project called on to provide service to other projects like an industrial partner. Its core mission is to support the neuroimaging of large populations, providing concrete solutions to the increasing complexity involved in such projects by bringing together a service infrastructure, the know-how of its expert academic teams and a large-scale, harmonized network of imaging facilities. CATI aims to make data sharing across studies easier and promotes sharing as much as possible. In the last 4 years, CATI has assisted the clinical community by taking charge of 35 projects so far and has emerged as a recognized actor at the national and international levels.

Impaired driving performance associated with effect of time duration in patients with primary insomnia.

STUDY OBJECTIVES: To evaluate driving performance and psychomotor vigilance in patients with primary insomnia. DESIGN: After 1 night of polysomnography, participants performed a 1-h simulated monotonous driving task and a psychomotor vigilance task (PVT). Self-ratings of sleepiness, mood, and driving performance were completed. SETTING: This study was conducted at the CHU of Caen Sleep Unit and the University of Caen. PARTICIPANTS: Twenty-one primary insomnia patients and 16 good sleepers. INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS: Results revealed a larger standard deviation of lateral position (P = 0.023) and more lane crossings (P = 0.03) in insomnia patients than in good sleepers. Analyses of effect of time on task performance showed that the impairment in patients occurred after 20 min of driving, which was not the case for good sleepers. No difference between groups was found for the PVT, neither for the mean reaction time (RT) (P = 0.43) nor the number of lapses (P = 0.21) and the mean slowest 10% 1/RT (P = 0.81). Patients rated their sleepiness level higher (P = 0.06) and their alertness level lower (P = 0.007) than did good sleepers (P = 0.007). The self-evaluation of the driving performance was not different between groups (P = 0.15). CONCLUSIONS: These findings revealed that primary insomnia is associated with a performance decrement during a simulated monotonous driving task. We also showed that patients are able to drive safely only for a short time. It appears advisable for clinicians to warn patients about their impaired driving performance that could lead to an increased risk of driving accidents.

Effects of three therapeutic doses of codeine/paracetamol on driving performance, a psychomotor vigilance test, and subjective feelings.

RATIONALE: Some recent pharmacoepidemiological studies revealed an elevated risk of driving accidents after opioid analgesics uses. Among analgesics, codeine is often associated with paracetamol in numerous pharmaceutical specialties. OBJECTIVES: The objective of this study was to evaluate the dose-effect relationship of three usual therapeutic doses of codeine/paracetamol on driving ability, psychomotor performance, subjective alertness, in link with blood concentrations in healthy young volunteers. METHODS: Driving performance, responses to psychomotor vigilance tests, and scales reflecting alertness were evaluated during the morning after drug intake in a double-blind, randomized, placebo-controlled study. Sixteen healthy volunteers (23.4 ± 2.7 years old, 8 men and 8 women) participated in this balanced, cross-over study. Three doses of codeine/paracetamol (20/400, 40/800, 60/1200 mg) were evaluated against placebo. Two blood samples were collected, 1 and 4 h after drug intake. In serum, codeine and morphine concentrations were determined in serum using high-performance liquid chromatography electrospray ionization-tandem mass spectrometry, and paracetamol concentrations using fluorescence polarization immunoassay. RESULTS: Driving and psychomotor performance were not affected by any of the three codeine/paracetamol doses. However, significant, though modest, correlations were observed between the driving parameters and both morphine and codeine blood concentrations. CONCLUSIONS: This study did not reveal any significant impairment in performance due to the three therapeutic doses used in healthy young volunteers. However, the relationships between drug blood concentration and behavioral measures suggest that an inter-subject variability in blood concentration may influence the power of the observed drug effect.

Zolpidem and zopiclone impair similarly monotonous driving performance after a single nighttime intake in aged subjects.

RATIONALE: Although hypnotics are primarily used by older people, the residual effects the morning after a single nighttime intake of the two most commonly prescribed hypnotics, zolpidem (Zp) and zopiclone (Zc), on older middle-aged drivers have not been evaluated and compared. METHODS: Sixteen healthy subjects, 55 to 65 years of age, participated in this double-blind, balanced, cross-over study. Zc (7.5 mg), Zp (10 mg) and flunitrazepam (Fln) (1 mg) or a placebo was administered at each subject's home at 11.00 pm. The next morning, at 9.00 am, the subjects had to drive in a simulated monotonous driving environment for 1 h. During each morning session, two blood samples were collected, and subjective feelings of alertness were completed three times. RESULTS: In comparison to placebo, Zp and Zc equivalently and significantly impaired the standard deviation of lateral position, the standard deviation of speed and the number of road exits. Detectable blood concentrations were found with Zp in 11 subjects at 8.30 am and at 1.30 pm. The subjective alertness factor was significantly impaired with Zp. CONCLUSIONS: This is the first study revealing residual effects of Zp on driving performance in ageing drivers which are similar to that of Zc. Studying the effects of medication in different age ranges appears useful to complete the studies on behavioural-pharmacological effects of medication. To reduce the incidence of driving accidents due to prescription drugs, patients should be warned at the time of treatment initiation that they should avoid driving.

Residual effects of hypnotic drugs in aging drivers submitted to simulated accident scenarios: an exploratory study.

RATIONALE: The effects of hypnotic drugs on driving performance are most often evaluated on young healthy subjects by using a monotonous motorway driving test. The effects of drugs in urban driving situations have not yet been evaluated in any age group. Our objectives were to assess residual effects of the most prescribed hypnotics, zolpidem and zopiclone, on older middle-age drivers' capacities in an urban situation. MATERIALS AND METHODS: Sixteen healthy subjects aged 55 to 65 years underwent this double-blind, balanced, cross-over study. Zopiclone (7.5 mg), zolpidem (10 mg), and flunitrazepam (1 mg; used as positive control) or a placebo were administered at each subject's home at 11:00 PM: under the supervision of an investigator. The next morning, the subjects had to drive in a simulated urban environment where accident scenarios were introduced. Accident scenarios were implemented using data from real accident cases. RESULTS: Hypnotics did not significantly increase the number of collisions. However, significantly higher speeds were found with zopiclone and flunitrazepam; moreover, zolpidem and zopiclone induced modifications of the lateral position of the car on the road. CONCLUSIONS: This study did not reveal any major residual effects of the hypnotics studied on driving performance in aging drivers. However, the urban driving situations used here for the first time in the evaluation of drugs revealed some modifications in driving habits which could lead to risky behavior. It thus appears that urban driving simulations are useful for gaining knowledge about the effects of drugs on driving behavior.