Jared Rowley

In vivo and in vitro validation of reference tissue models for the mGluR5 ligand [11C]ABP688

The primary objective of this study was to verify the suitability of reference tissue-based quantification methods of the metabotropic glutamate receptor type 5 (mGluR5) with [11C]ABP688. This study presents in vivo (Positron Emission Tomography (PET)) and in vitro (autoradiography) measurements of mGluR5 densities in the same rats and evaluates both noninvasive and blood-dependent pharmacokinetic models for the quantification of [11C]ABP688 binding. Eleven rats underwent [11C]ABP688 PET scans. In five animals, baseline scans were compared with blockade experiments with the antagonist 1,2-methyl-6-(phenylethynyl)-pyridine (MPEP), and arterial blood samples were drawn and corrected for metabolites. Afterward, saturation-binding autoradiography was performed. Blocking with MPEP resulted in an average decrease of the total distribution volume (VT) between 43% and 58% (thalamus and caudate-putamen, respectively) but had no significant effect on cerebellar VT (mean reduction: −0.01%). Comparing binding potential (BPND) based on the VT with noninvasively determined BPND revealed an average negative bias of 0.7% in the caudate-putamen and an average positive bias of 3.1% in the low-binding regions. Scan duration of 50 minutes is required. The cerebellum is a suitable reference region for the quantification of mGluR5 availability as measured with [11C]ABP688 PET in rats. Blood-based and reference region-based PET quantification shows a significant linear relationship to autoradiographic determinations.

Dissociation between Brain Amyloid Deposition and Metabolism in Early Mild Cognitive Impairment

Background The hypothetical model of dynamic biomarkers for Alzheimer’s disease (AD) describes high amyloid deposition and hypometabolism at the mild cognitive impairment (MCI) stage. However, it remains unknown whether brain amyloidosis and hypometabolism follow the same trajectories in MCI individuals. We used the concept of early MCI (EMCI) and late MCI (LMCI) as defined by the Alzheimer’s disease Neuroimaging Initiative (ADNI)-Go in order to compare the biomarker profile between EMCI and LMCI. Objectives To examine the global and voxel-based neocortical amyloid burden and metabolism among individuals who are cognitively normal (CN), as well as those with EMCI, LMCI and mild AD. Methods In the present study, 354 participants, including CN (n = 109), EMCI (n = 157), LMCI (n = 39) and AD (n = 49), were enrolled between September 2009 and November 2011 through ADNI-GO and ADNI-2. Brain amyloid load and metabolism were estimated using [18F]AV45 and [18F]fluorodeoxyglucose ([18F]FDG) PET, respectively. Uptake ratio images of [18F]AV45 and [18F]FDG were calculated by dividing the summed PET image by the median counts of the grey matter of the cerebellum and pons, respectively. Group differences of global [18F]AV45 and [18F]FDG were analyzed using ANOVA, while the voxel-based group differences were estimated using statistic parametric mapping (SPM). Results EMCI patients showed higher global [18F]AV45 retention compared to CN and lower uptake compared to LMCI. SPM detected higher [18F]AV45 uptake in EMCI compared to CN in the precuneus, posterior cingulate, medial and dorsal lateral prefrontal cortices, bilaterally. EMCI showed lower [18F]AV45 retention than LMCI in the superior temporal, inferior parietal, as well as dorsal lateral prefrontal cortices, bilaterally. Regarding to the global [18F]FDG, EMCI patients showed no significant difference from CN and a higher uptake ratio compared to LMCI. At the voxel level, EMCI showed higher metabolism in precuneus, hippocampus, entorhinal and inferior parietal cortices, as compared to LMCI. Conclusions The present results indicate that brain metabolism remains normal despite the presence of significant amyloid accumulation in EMCI. These results suggest a role for anti-amyloid interventions in EMCI aiming to delay or halt the deposition of amyloid and related metabolism impairment.

White Matter Abnormalities and Structural Hippocampal Disconnections in Amnestic Mild Cognitive Impairment and Alzheimer’s Disease

The purpose of this project was to evaluate white matter degeneration and its impact on hippocampal structural connectivity in patients with amnestic mild cognitive impairment, non-amnestic mild cognitive impairment and Alzheimer’s disease. We estimated white matter fractional anisotropy, mean diffusivity and hippocampal structural connectivity in two independent cohorts. The ADNI cohort included 108 subjects [25 cognitively normal, 21 amnestic mild cognitive impairment, 47 non-amnestic mild cognitive impairment and 15 Alzheimer’s disease]. A second cohort included 34 subjects [15 cognitively normal and 19 amnestic mild cognitive impairment] recruited in Montreal. All subjects underwent clinical and neuropsychological assessment in addition to diffusion and T1 MRI. Individual fractional anisotropy and mean diffusivity maps were generated using FSL-DTIfit. In addition, hippocampal structural connectivity maps expressing the probability of connectivity between the hippocampus and cortex were generated using a pipeline based on FSL-probtrackX. Voxel-based group comparison statistics of fractional anisotropy, mean diffusivity and hippocampal structural connectivity were estimated using Tract-Based Spatial Statistics. The proportion of abnormal to total white matter volume was estimated using the total volume of the white matter skeleton. We found that in both cohorts, amnestic mild cognitive impairment patients had 27-29% white matter volume showing higher mean diffusivity but no significant fractional anisotropy abnormalities. No fractional anisotropy or mean diffusivity differences were observed between non-amnestic mild cognitive impairment patients and cognitively normal subjects. Alzheimer’s disease patients had 66.3% of normalized white matter volume with increased mean diffusivity and 54.3% of the white matter had reduced fractional anisotropy. Reduced structural connectivity was found in the hippocampal connections to temporal, inferior parietal, posterior cingulate and frontal regions only in the Alzheimer’s group. The severity of white matter degeneration appears to be higher in advanced clinical stages, supporting the construct that these abnormalities are part of the pathophysiological processes of Alzheimer’s disease.

Characterization of age/sex and the regional distribution of mGluR5 availability in the healthy human brain measured by high-resolution [ 11 C]ABP688 PET

PurposeMetabotropic glutamate receptor type 5 (mGluR5) is a G protein-coupled receptor that has been implicated in several psychiatric and neurological diseases. The radiopharmaceutical [11C]ABP688 allows for in vivo quantification of mGluR5 availability using positron emission tomography (PET). In this study, we aimed to detail the regional distribution of [11C]ABP688 binding potential (BPND) and the existence of age/sex effects in healthy individuals.MethodsThirty-one healthy individuals aged 20 to 77 years (men, n = 18, 45.3 ± 18.2 years; females, n = 13, 41.5 ± 19.6 years) underwent imaging with [11C]ABP688 using the high-resolution research tomograph (HRRT). We developed an advanced partial volume correction (PVC) method using surface-based analysis in order to accurately estimate the regional variation of radioactivity. BPND was calculated using the simplified reference tissue model, with the cerebellum as the reference region. Surface-based and volume-based analyses were performed for 39 cortical and subcortical regions of interest per hemisphere.ResultsWe found the highest [11C]ABP688 BPND in the lateral prefrontal and anterior cingulate cortices. The lowest [11C]ABP688 BPND was observed in the pre- and post-central gyri as well as the occipital lobes and the thalami. No sex effect was observed. Associations between age and [11C]ABP688 BPND without PVC were observed in the right amygdala and left putamen, but were not significant after multiple comparisons correction.ConclusionsThe present results highlight complexities underlying brain adaptations during the aging process, and support the notion that certain aspects of neurotransmission remain stable during the adult life span.

Resting state executive control network adaptations in amnestic mild cognitive impairment.

Executive dysfunction is frequently associated with episodic memory decline in amnestic mild cognitive impairment (aMCI) patients. Resting state executive control network (RS-ECN) represents a novel approach to interrogate the integrity of brain areas underlying executive dysfunction. The present study aims to investigate RS-ECN in aMCI and examine a possible link between changes in brain functional connectivity and declines in executive function. aMCI individuals (n = 13) and healthy subjects (n = 16) underwent cognitive assessment including executive function and high field functional magnetic resonance imaging. Individual RS-ECN maps were estimated using a seed-based cross-correlation method. Between groups RS-ECN functional connectivity comparison was assessed using voxel-wise statistic parametric mapping. aMCI individuals had reduced RS-ECN connectivity in the anterior cingulate cortex (ACC) and dorsal lateral prefrontal cortex (DLPFC), bilaterally. In contrast, aMCI showed increased connectivity in ventral lateral and anterior prefrontal cortex, bilaterally. Connectivity strength was associated with executive function in the ACC (r = 0.6213, p = 0.023) and right DLPFC (r = 0.6454, p = 0.017). Coexistence between connectivity declines and recruitment of brain regions outside the RS-ECN as reported here fits a brain reserve conceptual framework in which brain networks undergo remodeling in aMCI individuals.

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.

Differential impact of amyloidosis and tau pathology on brain metabolism

a small cluster in the frontal area. In contrast, CSF t-tau or p-tau showed correlation with [18F]florbetapir in frontal, temporal and parietal brain regions. No correlation was shown between global [18F]FDGSUVR and the binding of amyloid imaging agents (Figure1). Conclusions: The pattern of regional deposition of fibrillary amyloid in the brain is non-linearly associated with CSF Ab1-42 concentrations. However the link between p-tau, t-tau and fibrillary amyloid deposition seems to be dependent on the amyloid-imaging agent. While imaging and CSF measures of amyloid pathology are equivalent, [18F]FDG uptake seems to provide independent information from regional deposition of fibrillary amyloid.

WHITE MATTER ABNORMALITIES AND STRUCTURAL PARIETAL DISCONNECTIONS IN ALZHEIMER'S DISEASE

Lucas Porcello Schilling, Eduardo Rigon Zimmer, Antoine Leuzy, Andrea Lessa Benedet, Tharick Pascoal, Sara Mohades, Sulantha Mathotaarachch, Laksanun Cheewakriengkrai, Monica Shin, Maxime Parent, Min Su Kang, Sarinporn Manitsirikul, Daliah Farajat, Seqian Wang, Jessica Di Ciero, Thomas Beaudry, Simon Eskildsen, Jared Rowley, Felix Carbonell, Vladmir Fonov, Serge Gauthier, Pedro Rosa-Neto, McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; PUCRS, Porto Alegre, Quebec, Brazil; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; Aarhus University, Aarhus, Denmark. Canada; Biospective Inc., Montreal, Quebec, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada. Contact e-mail: lucaspschilling@gmail.com

Posterior cingulate network adaptation in Alzheimer's disease

onto the baseline image and a level set algorithm was applied to refine the shape and smooth the boundary. The MTL of the baseline image was then mapped onto the subject’s follow-up image to measure volume change. Algorithm Validation: Baseline and 24 month follow-up 1.5 Tesla 3D T 1 -weighted anatomical images from theA lzheimer disease neuroimaging initiative (ADNI) were randomly selected for 50 normal subjects, 50 people with mild cognitive impairment (MCI) and 50 people with AD. Change in MTL volume was compared to change in hippocampal volume measured by Freesurfer. Results: The average (mm 3) DMTL (6SEM) was 68.1(635.1) in normal, 187.1(637.7) in MCI, and 300.3(633.8) in AD groups. There was a significant difference between all groups (one way ANOVA, p<0.0001). A repeatedmeasures t -test showed that therewas a significant different betweenNEC/MCI (p<0.05),NEC/AD(p<0.0001) andMCI/ AD (p<0.05). Results for Freesurfer were similar but did not detect significant differences between the MCI and AD groups. Conclusions: A significant difference in MTL atrophy was detected with the new segmentation approach between normal elderly, people with MCI and people with AD. This fully automated segmentation algorithmmay increase themeasurement accuracy associated with structural change and can be extended to measure any brain region.

Association between cortical thickness and CSF biomarkers in mild cognitive impairment and Alzheimer’s disease

Sara Mohades, Jonathan Dubois, Maxime Parent, Laksanun Cheewakriengkrai, Jared Rowley, Monica Shin, Thomas Beaudry, Simon Eskildsen, Antoine Leuzy, Marina Tedeschi Dauar, Vladimir Fonov, Serge Gauthier, Pedro RosaNeto, McGill Center-McGill Centre for Studies in Aging, Montreal, Quebec, Canada; McGill Universtiy, Montreal, Quebec, Canada; McGill University, Verdun, Quebec, Canada; McGill Centre for Studies in Aging, Montreal, Quebec, Canada; Aarhus University, Aarhus, Denmark; Montreal Neurological Institute, Montreal, Quebec, Canada; Alzheimer’s Disease Research Unit, McGill Center for Studies in Aging, Montreal, Quebec, Canada; McGill Universtiy-McGill Center for Studies in Aging, Montreal, Quebec, Canada. Contact e-mail: sara.mohades@gmail.com