Malo Gaubert

Cognitive and Brain Profiles Associated with Current Neuroimaging Biomarkers of Preclinical Alzheimer's Disease

Neuroimaging biomarkers, namely hippocampal volume loss, temporoparietal hypometabolism, and neocortical β-amyloid (Aβ) deposition, are included in the recent research criteria for preclinical Alzheimers disease (AD). However, how to use these biomarkers is still being debated, especially regarding their sequence. Our aim was to characterize the cognitive and brain profiles of elders classified as positive or negative for each biomarker to further our understanding of their use in the preclinical diagnosis of AD. Fifty-four cognitively normal individuals (age = 65.8 ± 8.3 years) underwent neuropsychological tests (structural MRI, FDG-PET, and Florbetapir-PET) and were dichotomized into positive or negative independently for each neuroimaging biomarker. Demographic, neuropsychological, and neuroimaging data were compared between positive and negative subgroups. The MRI-positive subgroup had lower executive performances and mixed patterns of lower volume and metabolism in AD-characteristic regions and in the prefrontal cortex. The FDG-positive subgroup showed only hypometabolism, predominantly in AD-sensitive areas extending to the whole neocortex, compared with the FDG-negative subgroup. The amyloid-positive subgroup was older and included more APOE ε4 carriers compared with the amyloid-negative subgroup. When considering MRI and/or FDG biomarkers together (i.e., the neurodegeneration-positive), there was a trend for an inverse relationship with Aβ deposition such that those with neurodegeneration tended to show less Aβ deposition and the reverse was true as well. Our findings suggest that: (1) MRI and FDG biomarkers provide complementary rather than redundant information and (2) relatively young cognitively normal elders tend to have either neurodegeneration or Aβ deposition, but not both, suggesting additive rather than sequential/causative links between AD neuroimaging biomarkers at this age. SIGNIFICANCE STATEMENT Neuroimaging biomarkers are included in the recent research criteria for preclinical Alzheimers disease (AD). However, how to use these biomarkers is still being debated, especially regarding their sequence. Our findings suggest that MRI and FDG-PET biomarkers should be used in combination, offering an additive contribution instead of reflecting the same process of neurodegeneration. Moreover, the present study also challenges the hierarchical use of the neuroimaging biomarkers in preclinical AD because it suggests that the neurodegeneration observed in this population is not due to β-amyloid deposition. Rather, our results suggest that β-amyloid- and tau-related pathological processes may interact but not necessarily appear in a systematic sequence.

Brain activity and functional coupling changes associated with self-reference effect during both encoding and retrieval.

Information that is processed with reference to oneself, i.e. Self-Referential Processing (SRP), is generally associated with better remembering compared to information processed in a condition not related to oneself. This positive effect of the self on subsequent memory performance is called as Self-Reference Effect (SRE). The neural basis of SRE is still poorly understood. The main goal of the present work was thus to highlight brain changes associated with SRE in terms of activity and functional coupling and during both encoding and retrieval so as to assess the relative contribution of both processes to SRE. For this purpose, we used an fMRI event-related self-referential paradigm in 30 healthy young subjects and measured brain activity during both encoding and retrieval of self-relevant information compared to a semantic control condition. We found that SRE was associated with brain changes during the encoding phase only, including both greater activity in the medial prefrontal cortex and hippocampus, and greater functional coupling between these brain regions and the posterior cingulate cortex. These findings highlight the contribution of brain regions involved in both SRP and episodic memory and the relevance of the communication between these regions during the encoding process as the neural substrates of SRE. This is consistent with the idea that SRE reflects a positive effect of the reactivation of self-related memories on the encoding of new information in episodic memory.

Association between educational attainment and amyloid deposition across the spectrum from normal cognition to dementia: neuroimaging evidence for protection and compensation

The brain mechanisms underlying the effect of intellectual enrichment may evolve along the normal aging Alzheimers disease (AD) cognitive spectrum and may include both protective and compensatory mechanisms. We assessed the association between early intellectual enrichment (education, years) and average cortical florbetapir standardized uptake value ratio as well as performed voxel-wise analyses in a total of 140 participants, including cognitively normal older adults, mild cognitive impairment (MCI), and AD patients. Higher education was associated with lower cortical florbetapir positron emission tomography (florbetapir-PET) uptake, notably in the frontal lobe in normal older adults, but with higher uptake in frontal, temporal, and parietal regions in MCI after controlling for global cognitive status. No association was found in AD. In MCI, we observed an increased fluorodeoxyglucose positron emission tomography (FDG-PET) uptake with education within the regions of higher florbetapir-PET uptake, suggesting a compensatory increase. Early intellectual enrichment may be associated with protection and compensation for amyloid beta (Aβ) deposition later in life, before the onset of dementia. Previous investigations have been controversial as regard to the effects of intellectual enrichment variables on Aβ deposition; the present findings call for approaches aiming to evaluate mechanisms of resilience across disease stages.

Neural Correlates of Self and Its Interaction With Memory in Healthy Adolescents.

Adolescence is marked by the development of personal identity and is associated with structural and functional changes in brain regions associated with Self processing. Yet, little is known about the neural correlates of self-reference processing and self-reference effect in adolescents. This functional magnetic resonance imaging study consists of a self-reference paradigm followed by a recognition test proposed to 30 healthy adolescents aged 13-18 years old. Results showed that the rostral anterior cingulate cortex is specifically involved in self-reference processing and that this specialization develops gradually from 13 to 18 years old. The self-reference effect is associated with increased brain activation changes during encoding, suggesting that the beneficial effect of Self on memory may occur at encoding of self-referential information, rather than at retrieval.

Distinct influence of specific versus global connectivity on the different Alzheimer’s disease biomarkers

See Franzmeier and Dyrba (doi:10.1093/brain/awx304) for a scientific commentary on this article. nnnRecent findings suggest that the topography and propagation of lesions in Alzheimer’s disease are related to functional connectivity, either showing that regions of high global connectivity are more vulnerable or that lesions propagate neuron-to-neuron from a starting area called the epicentre, thus involving specific connectivity. However, the relative influence of specific and global connectivity and their differential impact on the three main neuroimaging biomarkers of the disease (atrophy, hypometabolism and amyloid-β deposition) have never been investigated to date. Forty-two healthy elderly subjects and 35 amyloid-β positive amnestic mild cognitive impairment and Alzheimer’s disease patients underwent resting-state functional MRI, anatomical T1-weighted MRI, 18F-fluorodeoxyglucose-PET and florbetapir-PET scans. All patients also underwent follow-up T1-weighted MRI, 18F-fluorodeoxyglucose-PET and florbetapir-PET scans 18 months later to assess the lesion propagation. The epicentre was defined per modality as the most altered region at baseline in patients compared to controls. Maps of global and specific functional connectivity were computed from the resting-state functional MRI data of the healthy elderly subjects. Global connectivity corresponds to the connectivity strength of each grey matter area with the rest of the brain (i.e. all other grey matter areas) while specific connectivity refers to the connectivity of a single specific brain region (the epicentre) with the rest of the brain (i.e. all other brain regions). Maps of baseline alterations and propagation were computed for grey matter atrophy, hypometabolism and amyloid-β deposition in patients. Regression analyses were performed across the 239 brain regions to assess the links between global or specific functional connectivity in healthy elderly subjects and Alzheimer’s disease-related baseline disruptions or alteration propagation. Atrophy at baseline was predicted by specific connectivity and inversely correlated with global connectivity, while hypometabolism and amyloid-β deposition were positively influenced by both global and specific connectivity. Regarding longitudinal changes, atrophy spread in regions with high specific connectivity while hypometabolism propagated in areas showing high global connectivity. This is the first study to show that global connectivity has an opposite relationship with atrophy versus hypometabolism and amyloid-β deposition, suggesting that the high level of functional connectivity found in hubs exerts a differential influence on these Alzheimer’s disease lesions. These results sustain the hypotheses of higher vulnerability of hubs to hypometabolism and amyloid-β deposition versus transneuronal propagation of atrophy from the epicentre to connected regions, in Alzheimer’s disease. Global and specific connectivity exert a differential influence on, and provide complementary information to predict, the topography of Alzheimer’s disease lesions and their propagation.

Cortical and subcortical gray matter bases of cognitive deficits in REM sleep behavior disorder

Objective To investigate cortical and subcortical gray matter abnormalities underlying cognitive impairment in patients with REM sleep behavior disorder (RBD) with or without mild cognitive impairment (MCI). Methods Fifty-two patients with RBD, including 17 patients with MCI, were recruited and compared to 41 controls. All participants underwent extensive clinical assessments, neuropsychological examination, and 3-tesla MRI acquisition of T1 anatomical images. Vertex-based cortical analyses of volume, thickness, and surface area were performed to investigate cortical abnormalities between groups, whereas vertex-based shape analysis was performed to investigate subcortical structure surfaces. Correlations were performed to investigate associations between cortical and subcortical metrics, cognitive domains, and other markers of neurodegeneration (color discrimination, olfaction, and autonomic measures). Results Patients with MCI had cortical thinning in the frontal, cingulate, temporal, and occipital cortices, and abnormal surface contraction in the lenticular nucleus and thalamus. Patients without MCI had cortical thinning restricted to the frontal cortex. Lower patient performance in cognitive domains was associated with cortical and subcortical abnormalities. Moreover, impaired performance on olfaction, color discrimination, and autonomic measures was associated with thinning in the occipital lobe. Conclusions Cortical and subcortical gray matter abnormalities are associated with cognitive status in patients with RBD, with more extensive patterns in patients with MCI. Our results highlight the importance of distinguishing between subgroups of patients with RBD according to cognitive status in order to better understand the neurodegenerative process in this population.

Increased florbetapir binding in the temporal neocortex from age 20 to 60 years

Objective: To improve our understanding of early β-amyloid (Aβ) accumulation processes using florbetapir-PET scan in 20- to 60-year-old individuals. Methods: Seventy-six cognitively normal individuals aged 20 to 60 years, 57 cognitively normal older individuals (61–84 years old), and 70 patients with mild cognitive impairment or probable Alzheimer disease (AD) underwent a florbetapir-PET scan. Images were spatially normalized and scaled using the whole cerebellum. The relationship with age was assessed on the mean neocortical standardized uptake value ratio (SUVR) and voxelwise in the younger group to assess early Aβ accumulation processes. To compare the topography of early-age-related vs AD-related changes, Aβ increase in patients vs cognitively normal older adults was also assessed. Results: A linear increase of Aβ deposition from 20 to 60 years old was found on the mean neocortical SUVR, and more specifically on the temporal neocortex. By contrast, increase in patients predominated in frontal and medial parietal areas. The temporal increase in healthy participants was still significant when including only the 20- to 50-year-old individuals and controlling for several possible methodologic confounds. Conclusions: Florbetapir binding increases linearly from 20 to 60 years old in the temporal lobe. Pending replication, including with other PET tracers, this study suggests that the well-described medial frontal and parietal accumulation in late adulthood and AD might superimpose to a physiologic accumulation of Aβ, starting from young adulthood, in temporal lobes.

Functional brain alterations during self-reference processing in adolescents with sexual abuse-related post-traumatic stress disorder: A preliminary report

ABSTRACT We proposed to explore the functional brain changes during a self-reference processing (SRP) task in adolescents with sexual abuse-related post-traumatic stress disorder (N = 10), compared with healthy adolescents (N = 10). While patients showed no behavioral disturbances in (SRP), they exhibited changes in activity and connectivity in regions involved in emotional regulation (amygdala and dorsal prefrontal cortex) and semantic memory (temporal and ventrolateral prefrontal regions). These preliminary results suggest that these alterations may have an effect on self-esteem which may contribute to a possible retention and impairment of symptoms in adulthood.

Neural Correlates of Self-Reference Effect in Early Alzheimer’s Disease

Information that is processed with reference to the self (i.e., self-referential processing, SRP) is generally associated with better remembering than information processed in a semantic condition. This benefit of self on memory performance is called self-reference effect (SRE). In the present study, we assessed changes in the SRE and SRP-related brain activity in patients diagnosed with mild cognitive impairment or early Alzheimers disease (MCI/AD). Fifteen patients with confirmed amyloid-β deposits (positive florbetapir-PET scan) and 28 healthy controls (negative florbetapir-PET scan) were included. Participants either had to judge personality trait adjectives with reference to themselves (self condition) or to a celebrity (other condition), or determine whether these adjectives were positive or not (semantic condition). These adjectives were then presented with distractors in a surprise recognition task. Functional MRI data were acquired during both the judgment and recognition tasks. The SRE was observed in controls, but reduced in patients. Both controls and patients activated cortical midline structures when judging items with reference to themselves, but patients exhibited reduced activity in the angular gyrus. In patients, activity at encoding in the angular gyrus positively correlated with subsequent recognition accuracy in the self condition (self accuracy). This region also exhibited significant hypometabolism and Aβ burden, both related to self accuracy. By contrast, there were no differences in brain activity during recognition, either between the self and semantic conditions, or between groups. These results highlight SRE impairment in patients with MCI/AD, despite intact activity in cortical midline structures, and suggest that dysfunction of the angular gyrus is related to this impairment.

Musical Expertise Increases Top–Down Modulation Over Hippocampal Activation during Familiarity Decisions

The hippocampus has classically been associated with episodic memory, but is sometimes also recruited during semantic memory tasks, especially for the skilled exploration of familiar information. Cognitive control mechanisms guiding semantic memory search may benefit from the set of cognitive processes at stake during musical training. Here, we examined using functional magnetic resonance imaging, whether musical expertise would promote the top–down control of the left inferior frontal gyrus (LIFG) over the generation of hippocampally based goal-directed thoughts mediating the familiarity judgment of proverbs and musical items. Analyses of behavioral data confirmed that musical experts more efficiently access familiar melodies than non-musicians although such increased ability did not transfer to verbal semantic memory. At the brain level, musical expertise specifically enhanced the recruitment of the hippocampus during semantic access to melodies, but not proverbs. Additionally, hippocampal activation contributed to speed of access to familiar melodies, but only in musicians. Critically, causal modeling of neural dynamics between LIFG and the hippocampus further showed that top–down excitatory regulation over the hippocampus during familiarity decision specifically increases with musical expertise – an effect that generalized across melodies and proverbs. At the local level, our data show that musical expertise modulates the online recruitment of hippocampal response to serve semantic memory retrieval of familiar melodies. The reconfiguration of memory network dynamics following musical training could constitute a promising framework to understand its ability to preserve brain functions.