Joseph Therriault

Anosognosia predicts default mode network hypometabolism and clinical progression to dementia

Objective To identify the pathophysiologic mechanisms and clinical significance of anosognosia for cognitive decline in mild cognitive impairment. Methods We stratified 468 patients with amnestic mild cognitive impairment into intact and impaired awareness groups, determined by the discrepancy between the patient and the informant score on the Everyday Cognition questionnaire. Voxel-based linear regression models evaluated the associations between self-awareness status and baseline β-amyloid load, measured by [18F]florbetapir, and the relationships between awareness status and regional brain glucose metabolism measured by [18F]fluorodeoxyglucose at baseline and at 24-month follow-up. Multivariate logistic regression tested the association of awareness status with conversion from amnestic mild cognitive impairment to dementia. Results We found that participants with impaired awareness had lower [18F]fluorodeoxyglucose uptake and increased [18F]florbetapir uptake in the posterior cingulate cortex at baseline. In addition, impaired awareness in mild cognitive impairment predicted [18F]fluorodeoxyglucose hypometabolism in the posterior cingulate cortex, left basal forebrain, bilateral medial temporal lobes, and right lateral temporal lobe over 24 months. Furthermore, participants with impaired awareness had a nearly 3-fold increase in likelihood of conversion to dementia within a 2-year time frame. Conclusions Our results suggest that anosognosia is linked to Alzheimer disease pathophysiology in vulnerable structures, and predicts subsequent hypometabolism in the default mode network, accompanied by an increased risk of progression to dementia. This highlights the importance of assessing awareness of cognitive decline in the clinical evaluation and management of individuals with amnestic mild cognitive impairment.

Cerebrospinal fluid phosphorylated tau, visinin-like protein-1, and chitinase-3-like protein 1 in mild cognitive impairment and Alzheimer’s disease

BackgroundVisinin-like protein-1 (VILIP-1) and chitinase-3-like protein 1 (CHI3L1 or YKL-40) in cerebrospinal fluid (CSF) are newly discovered markers indicating neuronal damage and microglial activation, respectively. Phosphorylated tau (p-tau) reflects the neuropathology of Alzheimer’s disease (AD) and is useful as diagnostic markers for AD. However, it is unknown whether these biomarkers have similar or complementary information in AD.MethodsWe stratified 121 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database into cognitively normal (CN), stable mild cognitive impairment (sMCI), progressive MCI (pMCI), and dementia due to AD. Analysis of covariance (ANOVA) and chi-square analyses, Spearman correlation, and logistic regression models were performed to test the demographic, associations between biomarkers, and diagnostic accuracies, respectively. Linear mixed-effects models were used to evaluate the effects of CSF amyloid-β (Aβ) on above biomarkers within diagnostic groups, the combination of diagnostic group and Aβ status as predictor, and CSF biomarkers as predictors of AD features, including cognition measured by Mini–Mental State Examination (MMSE) and brain structure and white matter hyperintensity (WMH) measured by magnetic resonance imaging (MRI).ResultsP-tau, VILIP-1, and YKL-40 were all predictors of AD diagnosis, but combinations of biomarkers did not improve the diagnostic accuracy (AUC 0.924 for p-tau, VILIP-1, and YKL-40) compared to p-tau (AUC 0.922). P-tau and VILIP-1 were highly correlated (r = 0.639, p < 0.001) and strongly associated with Aβ pathology across clinical stages of AD, while YKL-40 was correlated with Aβ pathology in CN and AD groups. VILIP-1 was associated with acceleration of cognitive decline, hippocampal atrophy, and expansion of ventricles in longitudinal analyses. YKL-40 was associated with hippocampal atrophy at baseline and follow-up, while p-tau was only associated with worsening WMH at baseline.ConclusionsCSF levels of p-tau, VILIP-1, and YKL-40 may have utility for discriminating between cognitively normal subjects and patients with AD. Increased levels of both VILIP-1 and YKL-40 may be associated with disease degeneration. These CSF biomarkers should be considered for future assessment in the characterization of the natural history of AD.

UNBIASED ASSESSMENT OF GLOBAL AMYLOID LOAD AS DETERMINED BY VOXEL-WISE RECEIVER OPERATING CHARACTERISTIC ANALYSIS

the uncinate fasciculus in preclinical autosomal dominant Alzheimer’s disease Note: the interaction group by EC tau pathology on tract diffusivity is plotted and statistical significance for the interaction is provided in the panels (corrected for age, robust regressions). Note the limited range in tau pathology in the noncarriers. Abbreviations: FA 1⁄4 Fractional Anisotropy, MD 1⁄4 Mean Diffusivity, AxD 1⁄4 Axial Diffusivity, RD 1⁄4 Radial Diffusivity, EC 1⁄4 Entorhinal cortex, UF 1⁄4 uncinate fasciculus Poster Presentations: Monday, July 23, 2018 P898

CORRELATION BETWEEN CSF T-TAU AND P-TAU WITH [18F]MK6240 IN THE DIAGNOSIS OF ALZHEIMER’S DISEASE

between stages of AD progression when examined independently. The significance of TI and TSS in combined models dropped substantially, indicating that information used by these metrics is largely redundant (Table 2, Figures 1&3). However, TI remained statistically significant in combined models, suggesting that unique information above TSS information is conveyed with this approach (Table 2). Conclusions:Both TI and TSS can monitor progression of tau pathology in AD individuals. However, TSS could hold advantages in clinical trial settings and atypical dementia identification by retaining much of the information while shifting analytic emphasis to peripheral areas with relatively low binding affinity. Further investigation of TSS with a larger sample sizes is needed.

REGIONAL PATTERNS OF TAU DEPOSITION DRIVEN BY LOCAL AMYLOID ACCUMULATION RECAPITULATE BRAAK STAGES IN AD

QC, Canada; Translational Neuroimaging Laboratory, McGill University, Verdun, QC, Canada; Cerebral Imaging Centre, Douglas Research Centre, Verdun, QC, Canada; Douglas Hospital Research Centre, Verdun, QC, Canada; McGill Centre for Studies in Aging, Verdun, QC, Canada; Douglas Hospital Research Centre, Montreal, QC, Canada; McConnell Brain Imaging Centre, McGill University, Montr eal, QC, Canada; McGill University Research Centre for Studies in Aging, Canada, Verdun, QC, Canada. Contact e-mail: peter.ms.kang@gmail.com

THE SYNERGISTIC INTERACTION BETWEEN AMYLOID AND TAU DISRUPTS LOCAL AND GLOBAL RESTING STATE FMRI CONNECTIVITY

P3-096 THE SYNERGISTIC INTERACTION BETWEEN AMYLOID AND TAU DISRUPTS LOCAL AND GLOBAL RESTING STATE FMRI CONNECTIVITY Melissa Savard, Sulantha Mathotaarachchi, Min Su Kang, Tharick A. Pascoal, Joseph Therriault, Andrea Lessa Benedet, Mira Chamoun, Emilie M. Thomas, Serge Gauthier, Pedro RosaNeto, McGill University Research Centre for Studies in Aging, Verdun, QC, Canada; Translational Neuroimaging Laboratory-McGill University, Verdun, QC, Canada; Douglas Hospital Research Centre, Verdun, QC, Canada. Contact e-mail: melissa_savard2@hotmail.com

THE EFFECT OF PROTON PUMP INHIBITORS AND CYP2C19 ON AMYLOID PATHOLOGY

IC-P-063 THE EFFECT OF PROTON PUMP INHIBITORS AND CYP2C19 ON AMYLOID PATHOLOGY Andrea Lessa Benedet, Sulantha Mathotaarachchi, Tharick A. Pascoal, Yasser Iturria Medina, Melissa Savard, Joseph Therriault, Min-Su Kang, Mira Chamoun, Serge Gauthier, Alan C. Evans, Aurelie Labbe, Pedro RosaNeto, Coordenaç~ao de Aperfeiçoamento de Pessoal de N ıvel Superior Foundation, Brasilia, Brazil; Translational Neuroimaging Laboratory, McGill University, Verdun, QC, Canada; Douglas Hospital Research Centre, Verdun, QC, Canada; McGill Centre for Integrative Neuroscience, McGill University, Montreal, QC, Canada; Douglas Hospital Research Centre, Montreal, QC, Canada; Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada; McGill University Research Centre for Studies in Aging, Verdun, QC, Canada; HEC Montr eal, Montreal, QC, Canada; McGill University Research Centre for Studies in Aging, Canada, Verdun, QC, Canada. Contact e-mail: andrea.benedet@mail.mcgill.ca

LATERAL TEMPORAL AMYLOID LOAD PREDICTS THE PROGRESSION TO ALZHEIMER’S DEMENTIA

Fig. 4. Each row of the matrix corresponds to a study participant and each column to one of the 6 identified components of coordinated Ab deposition. Absence or presence of amyloid is denoted by gray and red, respectively. Amyloid deposition in the 6 components shows a consistent hierarchical nesting across participants. Few participants show distribution profiles that do not conform to the hierarchical nesting.

Cerebrospinal fluid synaptosomal-associated protein 25 is a key player in synaptic degeneration in mild cognitive impairment and Alzheimer’s disease

BackgroundThere is accumulating evidence that synaptic loss precedes neuronal loss and correlates best with impaired memory formation in Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) is a newly discovered marker indicating synaptic damage. We here test CSF SNAP-25 and SNAP-25/amyloid-β42 (Aβ42) ratio as a diagnostic marker for predicting cognitive decline and brain structural change in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.MethodsWe stratified 139 participants from the ADNI database into cognitively normal (CN; n = 52), stable mild cognitive impairment (sMCI; n = 22), progressive MCI (pMCI; n = 47), and dementia due to AD (n = 18). Spearman correlation was performed to test the relationships between biomarkers. Overall diagnostic accuracy (area under the curve (AUC)) was obtained from receiver operating curve (ROC) analyses. Cox proportional hazard models tested the effect of CSF SNAP-25 and SNAP-25/Aβ42 measures on the conversion from MCI to AD. Relationships between the CSF SNAP-25 levels, SNAP-25/Aβ42 ratio, and diagnostic groups were tested with linear regressions. Linear mixed-effects models and linear regression models were used to evaluate CSF SNAP-25 and SNAP-25/Aβ42 as predictors of AD features, including cognition measured by the Mini-Mental State Examination (MMSE) and brain structure and white matter hyperintensity (WMH) measured by magnetic resonance imaging (MRI).ResultsCSF SNAP-25 and SNAP-25/Aβ42 were increased in patients with pMCI and AD compared with CN, and in pMCI and AD compared with sMCI. Cognitively normal subjects who progressed to MCI or AD during follow-up had increased SNAP-25/Aβ42 ratio compared with nonprogressors. CSF SNAP-25, especially SNAP-25/Aβ42, offers diagnostic utility for pMCI and AD. CSF SNAP-25 and SNAP-25/Aβ42 significantly predicted conversion from MCI to AD. In addition, elevated SNAP-25/Aβ42 ratio was associated with the rate of hippocampal atrophy in pMCI and the rate of change of cognitive impairment in CN over the follow-up period.ConclusionsThese data suggest that both CSF SNAP-25 and SNAP-25/Aβ42 ratio are already increased at the early clinical stage of AD, and indicate the promise of CSF SNAP-25 and SNAP-25/Aβ42 ratio as diagnostic and prognostic biomarkers for the earliest symptomatic stage of AD.

FDG-PET POWER TO PREDICT MEMORY DECLINE IN ALZHEIMER’S DISEASE DEPENDS ON DISEASE PHASE AND AMYLOID AND TAU STATUS

temporal progression of disease is unclear. We used a novel MRI phasing algorithm, based on pathological staging studies, to test the hypothesis that non-amnestic AD has disease originating and spreading in neocortex.Methods:We inferred the anatomical origin and progression of disease in each AD variant based on the frequency of regional atrophy patterns in cross-sectional MRI from 131 patients with AD, confirmed through autopsy or CSF results. Disease progression models were computed separately for typical amnestic AD (aAD, 38 scans), logopenic variant primary progressive aphasia (lvPPA, 97 scans), posterior cortical atrophy (PCA, 54 scans), corticobasal syndrome (CBS, 31 scans), and behavioural/ dysexecutive-variant AD (bvAD, 39 scans). For each AD variant, 4 phases of atrophy were defined in 120 anatomical regions-of-interest (ROIs) using a grey matter volume threshold of Z< -1.0 relative to elderly controls. The origin of disease (Phase 1) was inferred from the most frequently atrophied 10% of ROIs; similarly, Phases 2, 3, and 4 comprised ROIs in the 2nd, 3rd, and 4th deciles of atrophy frequency. Results:We observed a unique distribution of atrophy for each phenotype. Phase 1 ROIs in our model represent the anatomical origin of disease, including: MTL for the aAD group (relatively spared in other phenotypes), left lateral temporal lobe for lvPPA, occipito-parietal cortex for PCA, temporo-parietal cortex for CBS, and fronto-temporal cortex for bvAD. Disease phase was significantly correlated with MMSE score and disease duration, independently of age. Conclusions: Our neuroimaging data showed unique maps of progressive atrophy for each AD variant. The classification of patients into phases was validated by correlations with disease duration and neuropsychological performance. We propose these results represent maps of distinct anatomic progression, with non-amnestic phenotypes showing neocortical origin and spread of disease.