Thomas Beaudry

Neural signature of reconsolidation impairments by propranolol in humans.

BACKGROUND The retrieval of consolidated memories may result in their destabilization, requiring a restabilization process called reconsolidation. During reconsolidation, memories become sensitive to psychological and pharmacological modifications again, thus providing an opportunity to alter unwanted memories. Although such reconsolidation manipulations might open the door to novel treatment approaches for psychiatric disorders such as posttraumatic stress disorder, the brain mechanisms underlying reconsolidation processes in humans are completely unknown. Here, we asked whether a β-adrenergic receptor antagonist might interfere with the reconsolidation of emotional episodic memories and what brain mechanisms are involved in these effects. METHODS Healthy participants were administered the β-adrenergic receptor antagonist propranolol or a placebo before they reactivated previously learned neutral and emotional material. Recognition memory was tested 24 hours later. Functional magnetic resonance images were collected during reactivation and recognition testing. RESULTS Propranolol during reactivation specifically reduced the subsequent memory for emotional pictures; memory for neutral pictures remained unaffected. This emotional memory impairment was associated with significantly increased activity in the amygdala and the hippocampus for correctly recognized pictures at test. Most interestingly, the same structures were active (but not modulated by propranolol) during memory reactivation. Memory reactivation alone or propranolol without reactivation had no effect on subsequent memory. CONCLUSIONS Our results demonstrate how the consequences of memory reconsolidation processes are represented in the human brain, suggesting that the brain areas that are recruited during reactivation undergo changes in activity that are associated with subsequent memory recall.

VoxelStats: A MATLAB Package for Multi-Modal Voxel-Wise Brain Image Analysis

In healthy individuals, behavioral outcomes are highly associated with the variability on brain regional structure or neurochemical phenotypes. Similarly, in the context of neurodegenerative conditions, neuroimaging reveals that cognitive decline is linked to the magnitude of atrophy, neurochemical declines, or concentrations of abnormal protein aggregates across brain regions. However, modeling the effects of multiple regional abnormalities as determinants of cognitive decline at the voxel level remains largely unexplored by multimodal imaging research, given the high computational cost of estimating regression models for every single voxel from various imaging modalities. VoxelStats is a voxel-wise computational framework to overcome these computational limitations and to perform statistical operations on multiple scalar variables and imaging modalities at the voxel level. VoxelStats package has been developed in Matlab® and supports imaging formats such as Nifti-1, ANALYZE, and MINC v2. Prebuilt functions in VoxelStats enable the user to perform voxel-wise general and generalized linear models and mixed effect models with multiple volumetric covariates. Importantly, VoxelStats can recognize scalar values or image volumes as response variables and can accommodate volumetric statistical covariates as well as their interaction effects with other variables. Furthermore, this package includes built-in functionality to perform voxel-wise receiver operating characteristic analysis and paired and unpaired group contrast analysis. Validation of VoxelStats was conducted by comparing the linear regression functionality with existing toolboxes such as glim_image and RMINC. The validation results were identical to existing methods and the additional functionality was demonstrated by generating feature case assessments (t-statistics, odds ratio, and true positive rate maps). In summary, VoxelStats expands the current methods for multimodal imaging analysis by allowing the estimation of advanced regional association metrics at the voxel level.

Psychological, endocrine, and neural correlates of attentional bias in subclinical depression

ABSTRACT Background: Our knowledge with respect to psychological, endocrine, and neural correlates of attentional bias in individuals with high vulnerability to developing depression – the subclinically depressed, still remains limited. Design: The study used a 2 × 2 mixed design. Methods: Attentional bias toward happy and sad faces in healthy (N = 26) and subclinically depressed individuals (N = 22) was assessed via a neuroimaging dot-probe attention task. Participants also completed trait and state psychological measures and provided saliva samples for cortisol analysis. Results: The subclinical group showed attentional bias toward happy faces; past use of problem-focused coping strategies when dealing with a personally relevant stressor as well as state levels of anxiety, together, contributed to this bias. In the control group, the happy attentional bias was positively correlated with activity in the right caudate. In the subclinical group, the bias was negatively associated with the left fusiform gyrus and positively with the left inferior parietal lobule and bilateral putamen. We observed group differences in association between cortisol levels during the task and neural activity during happy attentional bias processing within the key regions involved in attention. Conclusions: The attentional bias toward happy faces may reflect an active coping attempt by the subclinical participants.

Epistasis analysis links immune cascades and cerebral amyloidosis.

BackgroundSeveral lines of evidence suggest the involvement of neuroinflammatory changes in Alzheimer’s disease (AD) pathophysiology such as amyloidosis and neurodegeneration. In fact, genome-wide association studies (GWAS) have shown a link between genes involved in neuroinflammation and AD. In order to further investigate whether interactions between candidate genetic variances coding for neuroinflammatory molecules are associated with brain amyloid β (Aβ) fibrillary accumulation, we conducted an epistasis analysis on a pool of genes associated with molecular mediators of inflammation.Methods[18F]Florbetapir positron emission tomography (PET) imaging was employed to assess brain Aβ levels in 417 participants from ADNI-GO/2 and posteriorly 174 from ADNI-1. IL-1β, IL4, IL6, IL6r, IL10, IL12, IL18, C5, and C9 genes were chosen based on previous studies conducted in AD patients. Using the [18F]florbetapir standardized uptake value ratio (SUVR) as a quantitative measure of fibrillary Aβ, epistasis analyses were performed between two sets of markers of immune-related genes using gender, diagnosis, and apolipoprotein E (APOE) as covariates. Voxel-based analyses were also conducted. The results were corrected for multiple comparison tests. Cerebrospinal fluid (CSF) Aβ1-42/phosphorylated tau (p-tau) ratio concentrations were used to confirm such associations.ResultsEpistasis analysis unveiled two significant single nucleotide polymorphism (SNP)-SNP interactions (false discovery rate (FDR) threshold 0.1), both interactions between C9 gene (rs261752) and IL6r gene (rs4240872, rs7514452). In a combined sample, the interactions were confirmed (p ≤ 10–5) and associated with amyloid accumulation within cognitively normal and AD spectrum groups. Voxel-based analysis corroborated initial findings. CSF biomarker (Aβ1-42/p-tau) confirmed the genetic interaction. Additionally, rs4240872 and rs7514452 SNPs were shown to be associated with CSF and plasma concentrations of IL6r protein.ConclusionsCertain allele combinations involving IL6r and C9 genes are associated with Aβ burden in the brain. Hypothesis-driven search for epistasis is a valuable strategy for investigating imaging endophenotypes in complex neurodegenerative diseases.

Intraoperative Maintenance of Normoglycemia with Insulin and Glucose Preserves Verbal Learning after Cardiac Surgery

Objective The hyperglycemic response to surgery may be a risk factor for cognitive dysfunction. We hypothesize that strict maintenance of normoglycemia during cardiac surgery preserves postoperative cognitive function. Methods As part of a larger randomized, single-blind, interventional efficacy study on the effects of hyperinsulinemic glucose control in cardiac surgery (NCT00524472), consenting patients were randomly assigned to receive combined administration of insulin and glucose, titrated to preserve normoglycemia (3.5–6.1 mmol L−1; experimental group), or standard metabolic care (blood glucose 3.5–10 mmol L−1; control group), during open heart surgery. The patients’ cognitive function was assessed during three home visits, approximately two weeks before the operation, and two months and seven months after surgery. The following tests were performed: Rey Auditory Verbal Learning Task (RAVLT for verbal learning and memory), Digit Span Task (working memory), Trail Making A & B (visuomotor tracking and attention), and the Word Pair Task (implicit memory). Questionnaires measuring specific traits known to affect cognitive performance, such as self-esteem, depression, chronic stress and social support, were also administered. The primary outcome was to assess the effect of hyperinsulinemic-normoglycemic clamp therapy versus standard therapy on specific cognitive parameters in patients receiving normoglycemic clamp, or standard metabolic care. Results Twenty-six patients completed the study with 14 patients in the normoglycemia and 12 patients in the control group. Multiple analysis of covariance (MANCOVA) for the RAVLT showed a significant effect for the interaction of group by visit (F = 4.07, p = 0.035), and group by visit by recall (F = 2.21, p = 0.04). The differences occurred at the second and third visit. MANCOVA for the digit span task, trail making and word pair association test showed no significant effect. Conclusions Preserving intraoperative normoglycemia by intravenous insulin and glucose may prevent the impairment of memory function, both short and long-term, after cardiac surgery.

P.o.n.d.e.r.: A cognitive training and prevention program — design, methodology, and first results

important given the trend toward earlier and more accurate diagnosis of dementia and the emphasis on providing person-centered care. SHARE’s approach involves discussions led by a SHARE counselor with both “SHARE partners”. This approach has shown great promise in previous trials for improving a variety of outcomes for both individuals. Moreover, SHARE has been found to be feasible and acceptable to early-stage families: persons who have early-stage dementia are often fully aware of the meaning of their diagnosis and able to communicate care choices and preferences. This presentation will describe the SHARE Program and report on the results of its randomized controlled trial with 130 care dyads (e.g., improved carer symptoms of depression, lessened relationship strain, and increased service use). Discussion will focus on the utility of a dyadic approach, future directions for the SHARE program, and the implications for enhancing the shortand longterm well-being of both care partners.

How to follow up and cluster subjects by longitudinal changes of fibrillary amyloid imaging and CSF biomarkers? a 24-month follow up

Figure 1. Vertex-based multivariate linear regression model showing the effect of amyloid load on the rate of hypo-metabolism in each disease stage, corrected for baseline glucose metabolism, age, gender and apoe genotype. Only LMCI and AD stages show positive effect from amyloid load on hypometabolism in temporo-parietal and precuneus regions. Sulantha S. Mathotaarachchi, Sara Mohades, Monica Shin, Thomas Beaudry, Andrea Lessa Benedet, Tharick Ali Pascoal, Seqian Wang, Sarinporn Manitsirikul, Maxime J. Parent, Min Su Kang, Vladimir Fonov, Chang Oh Chung, Sr., Serge Gauthier, Pedro RosaNeto, McGill University, Montreal, QC, Canada; McGill Centre for Studies in Aging, Montreal, QC, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, QC, Canada; McGill Centre for Studies in Aging, Verdun, QC, Canada; McGill University Centre for Studies in Aging, Verdun, QC, Canada; Image Processing Laboratory, Montreal Neurological Institute, McGill University, Montreal, QC, Canada; Centre for Studies on Prevention of Alzheimer’s Disease (StoP-AD Centre), Douglas Mental Health Institute, Montreal, QC, Canada; Douglas Hospital Research Centre, Montreal, QC, Canada; Translational Imaging Laboratory, Montreal, QC, Canada. Contact e-mail: sulantha.s@gmail.com

Should a global or a regional measure of amyloidosis be used in a longitudinal study

Figure 1. Vertex-based multivariate linear regression model showing the effect of amyloid load on the rate of hypo-metabolism in each disease stage, corrected for baseline glucose metabolism, age, gender and apoe genotype. Only LMCI and AD stages show positive effect from amyloid load on hypometabolism in temporo-parietal and precuneus regions. Sulantha S. Mathotaarachchi, Sara Mohades, Monica Shin, Thomas Beaudry, Andrea Lessa Benedet, Tharick Ali Pascoal, Seqian Wang, Sarinporn Manitsirikul, Maxime J. Parent, Min Su Kang, Vladimir Fonov, Chang Oh Chung, Sr., Serge Gauthier, Pedro RosaNeto, McGill University, Montreal, QC, Canada; McGill Centre for Studies in Aging, Montreal, QC, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, QC, Canada; McGill Centre for Studies in Aging, Verdun, QC, Canada; McGill University Centre for Studies in Aging, Verdun, QC, Canada; Image Processing Laboratory, Montreal Neurological Institute, McGill University, Montreal, QC, Canada; Centre for Studies on Prevention of Alzheimer’s Disease (StoP-AD Centre), Douglas Mental Health Institute, Montreal, QC, Canada; Douglas Hospital Research Centre, Montreal, QC, Canada; Translational Imaging Laboratory, Montreal, QC, Canada. Contact e-mail: sulantha.s@gmail.com

NEURODEGENERATION AND CORTICAL ATROPHY IN [18F]FLORBETAPIR ACCUMULATORS AND NON-ACCUMULATORS

BBSI n 18 22 26 23 49 104 LS Mean (SE) 13.17 (2.06) 13.46 (1.91) 15.72 (1.80) 16.03 (1.89) 15.77 (1.25) 14.5 (8.5) VBSI n 20 22 29 24 53 104 LS Mean (SE) 4.46 (0.59) 4.25 (0.57) 5.31 (0.54) 4.36 (0.55) 4.85 (0.35) 4.43 (3.17) LHBSI n 21 22 29 24 53 104 LS Mean (SE) 0.136 (0.020) 0.119 (0.020) 0.186 (0.018) 0.191 (0.019) 0.188 (0.013) 0.340 (0.190) RHBSI n 21 22 29 24 53 LS Mean (SE) 0.135 (0.020) 0.110 (0.020) 0.176 (0.018) 0.171 (0.019) 0.173 (0.013)

Regional distribution of fibrillar amyloid deposition in the brain as a function of CSF beta-amyloid 1-42 and biomarkers of neurodegeneration

polygenetic profilewas predictive of age of AD diagnosis, AD vs control, and MCI conversion to AD over a three-year period. It was alsoweakly correlated to cognitive performance as measured by the modified ADAS-Cog and MMSE scores. As previously shown, imaging data is highly predictive of AD vs control and MCI conversion; we also show that it is correlated to age of AD diagnosis and cognitive performance. When imaging and genetic information is combined, all predictivemeasures improve (Tables 3& 4). Predictions using a polygenetic profile suggest that most of the MCI subjects are AD-like, whichmay indicate increased risk or environmental effects that have delayed the onset ofAD (Figure 1).Conclusions:Wedemonstrate that a polygenetic profile is predictive of AD, both in terms of AD vs control and in the approximate age of AD diagnosis. When combined with imaging data, the polygenetic profile improves prediction accuracy.