In vivo imaging of synaptic loss in Alzheimer's disease with [18F]UCB-H positron emission tomography.

PURPOSE: Loss of brain synapses is an early pathological feature of Alzheimer's disease. The current study assessed synaptic loss in vivo with positron emission tomography and an 18F-labelled radiotracer of the synaptic vesicle protein 2A, [18F]UCB-H. METHODS: Twenty-four patients with mild cognitive impairment or Alzheimer's disease and positive [18F]Flutemetamol amyloid-PET were compared to 19 healthy controls. [18F]UCB-H brain uptake was quantified with Logan graphical analysis using an image-derived blood input function. SPM12 and regions-of-interest (ROI) analyses were used for group comparisons of regional brain distribution volumes and for correlation with cognitive measures. RESULTS: A significant decrease of [18F]UCB-H uptake was observed in several cortical areas (11 to 18% difference) and in the thalamus (16% difference), with the largest effect size in the hippocampus (31% difference). Reduced hippocampal uptake was related to patients' cognitive decline (ROI analysis) and unawareness of memory problems (SPM and ROI analyses). CONCLUSIONS: The findings thus highlight predominant synaptic loss in the hippocampus, confirming previous autopsy-based studies and a recent PET study with an 11C-labelled SV2A radiotracer. [18F]UCB-H PET allows to image in vivo synaptic changes in Alzheimer's disease and to relate them to patients' cognitive impairment.

Influence of COMT Genotype on Antero-posterior Cortical Functional Connectivity Underlying Interference Resolution.

Genetic variability related to the catechol-O-methyltransferase (COMT) gene (Val(158)Met) has received increasing attention as a possible modulator of executive functioning and its neural correlates. However, this attention has generally centered on the prefrontal cortices because of the well-known direct impact of COMT enzyme on these cerebral regions. In this study, we were interested in the modulating effect of COMT genotype on anterior and posterior brain areas underlying interference resolution during a Stroop task. More specifically, we were interested in the functional connectivity between the right inferior frontal operculum (IFop), an area frequently associated with inhibitory efficiency, and posterior brain regions involved in reading/naming processes (the 2 main non-executive determinants of the Stroop effect). The Stroop task was administered during functional magnetic resonance imaging scanning to 3 groups of 15 young adults divided according to their COMT Val(158)Met genotype [Val/Val (VV), Val/Met (VM), and Met/Met (MM)]. Results indicate greater activity in the right IFop and the left middle temporal gyrus in homozygous VV individuals than in Met allele carriers. In addition, the VV group exhibited stronger positive functional connectivity between these 2 brain regions and stronger negative connectivity between the right IFop and left lingual gyrus. These results confirm the impact of COMT genotype on frontal functions. They also strongly suggest that differences in frontal activity influence posterior brain regions related to a non-executive component of the task. Particularly, changes in functional connectivity between anterior and posterior brain areas might correspond to compensatory processes for performing the task efficiently when the available dopamine level is low.

Age-related decline in cognitive control: the role of fluid intelligence and processing speed.

BACKGROUND: Research on cognitive control suggests an age-related decline in proactive control abilities whereas reactive control seems to remain intact. However, the reason of the differential age effect on cognitive control efficiency is still unclear. This study investigated the potential influence of fluid intelligence and processing speed on the selective age-related decline in proactive control. Eighty young and 80 healthy older adults were included in this study. The participants were submitted to a working memory recognition paradigm, assessing proactive and reactive cognitive control by manipulating the interference level across items. RESULTS: Repeated measures ANOVAs and hierarchical linear regressions indicated that the ability to appropriately use cognitive control processes during aging seems to be at least partially affected by the amount of available cognitive resources (assessed by fluid intelligence and processing speed abilities). CONCLUSIONS: This study highlights the potential role of cognitive resources on the selective age-related decline in proactive control, suggesting the importance of a more exhaustive approach considering the confounding variables during cognitive control assessment.

The neural bases of proactive and reactive control processes in normal aging.

INTRODUCTION: Research on cognitive control suggests an age-related decline in proactive control abilities (anticipatory control), whereas reactive control (following conflict detection) seems to remain intact. As proactive and reactive control abilities are associated with specific brain networks, this study investigated age-related effects on the neural substrates associated with each kind of control. METHODS: In an event-related fMRI study, a modified version of the Stroop task was administered to groups of 20 young and 20 older healthy adults. Based on the theory of dual mechanisms of control, the Stroop task has been built to induce proactive or reactive control depending on task context. RESULTS: Behavioral results (p<0.05) indicated faster processing of interfering items in the mostly incongruent (MI) than the mostly congruent (MC) context in both young and older participants. fMRI results showed that reactive control is associated with increased activity in left frontal areas for older participants. For proactive control, decreased activity in the bilateral anterior cingulate cortex was associated with more activity in the right middle frontal gyrus in the older than the younger group. CONCLUSION: These observations support the hypothesis that aging affects the neural networks associated with reactive and proactive cognitive control differentially. These age-related changes are very similar to those observed in young adults with low dopamine availability, suggesting that a general mechanism (prefrontal dopamine availability) may modulate brain networks associated with various kinds of cognitive control.

Relationship between grey matter integrity and executive abilities in aging.

This cross-sectional study was designed to investigate grey matter changes that occur in healthy aging and the relationship between grey matter characteristics and executive functioning. Thirty-six young adults (18-30 years old) and 43 seniors (60-75 years old) were included. A general executive score was derived from a large battery of neuropsychological tests assessing three major aspects of executive functioning (inhibition, updating and shifting). Age-related grey matter changes were investigated by comparing young and older adults using voxel-based morphometry and voxel-based cortical thickness methods. A widespread difference in grey matter volume was found across many brain regions, whereas cortical thinning was mainly restricted to central areas. Multivariate analyses showed age-related changes in relatively similar brain regions to the respective univariate analyses but appeared more limited. Finally, in the older adult sample, a significant relationship between global executive performance and decreased grey matter volume in anterior (i.e. frontal, insular and cingulate cortex) but also some posterior brain areas (i.e. temporal and parietal cortices) as well as subcortical structures was observed. Results of this study highlight the distribution of age-related effects on grey matter volume and show that cortical atrophy does not appear primarily in "frontal" brain regions. From a cognitive viewpoint, age-related executive functioning seems to be related to grey matter volume but not to cortical thickness. Therefore, our results also highlight the influence of methodological aspects (from preprocessing to statistical analysis) on the pattern of results, which could explain the lack of consensus in literature.

Modulating effect of COMT genotype on the brain regions underlying proactive control process during inhibition.

INTRODUCTION: Genetic variability related to the catechol-O-methyltransferase (COMT) gene (Val(158)Met polymorphism) has received increasing attention as a possible modulator of cognitive control functions. METHODS: In an event-related functional magnetic resonance imaging (fMRI) study, a modified version of the Stroop task was administered to three groups of 15 young adults according to their COMT Val(158)Met genotype [Val/Val (VV), Val/Met (VM) and Met/Met (MM)]. Based on the theory of dual mechanisms of control (Braver et al., 2007), the Stroop task has been built to induce proactive or reactive control processes according to the task context. RESULTS: Behavioral results did not show any significant group differences for reaction times but Val allele carriers individuals are less accurate in the processing of incongruent items. fMRI results revealed that proactive control is specifically associated with increased activity in the anterior cingulate cortex (ACC) in carriers of the Met allele, while increased activity is observed in the middle frontal gyrus (MFG) in carriers of the Val allele. CONCLUSION: These observations, in keeping with a higher cortical dopamine level in MM individuals, support the hypothesis of a COMT Val(158)Met genotype modulation of the brain regions underlying proactive control, especially in frontal areas as suggested by Braver et al.