Melissa Savard

Brain properties predict proximity to symptom onset in sporadic Alzheimer’s disease

Estimated years to symptom onset (EYO) is a measurement developed to track disease progression in patients with genetic Alzheimer’s disease. Vogel et al. apply this concept to individuals with a parental history of sporadic Alzheimer’s disease. A neuroimaging-based model successfully predicts EYO and years to clinical conversion in unseen data. See Tijms and Visser (doi:10.1093/brain/awy113) for a scientific commentary on this article.

Subtypes of functional brain connectivity as early markers of neurodegeneration in Alzheimer's disease

Highlights Reliable functional brain network subtypes accompany cognitive impairment in AD Symptom-related subtypes exist in the default-mode, limbic and salience networks A limbic subtype is associated with a familial risk of AD in healthy older adults Limbic subtypes also associate with beta amyloid deposition and ApoE4 In Brief We found reliable subtypes of functional brain connectivity networks in older adults, associated with AD-related clinical symptoms in patients as well as several AD risk factors/biomarkers in asymptomatic individuals. Summary The heterogeneity of brain degeneration has not been investigated yet for functional brain network connectivity, a promising biomarker of Alzheimer’s disease. We coupled cluster analysis with resting-state functional magnetic resonance imaging to discover connectivity subtypes in healthy older adults and patients with cognitive disorders related to Alzheimer’s disease, noting associations between subtypes and cognitive symptoms in the default-mode, limbic and salience networks. In an independent asymptomatic cohort with a family history of Alzheimer’s dementia, the connectivity subtypes had good test-retest reliability across all tested networks. We found that a limbic subtype was overrepresented in these individuals, which was previously associated with symptoms. Other limbic subtypes showed associations with cerebrospinal fluid Aβ1-42 levels and ApoE4 genotype. Our results demonstrate the existence of reliable subtypes of functional brain networks in older adults and support future investigations in limbic connectivity subtypes as early biomarkers of Alzheimer’s degeneration.

Deficit in Central Auditory Processing as a Biomarker of Pre-Clinical Alzheimer's Disease

Prevention of dementia due to Alzheimer’s disease (d/AD) requires interventions that slow the disease process prior to symptom onset. To develop such interventions, one needs metrics that assess pre-symptomatic disease progression. Familiar measures of progression include cerebrospinal fluid (CSF) biochemical and imaging analyses, as well as cognitive testing. Changes in the latter can sometimes be difficult to distinguish from effects of “normal” aging. A different approach involves testing of “central auditory processing” (CAP), which enables comprehension of auditory stimuli amidst a distracting background (e.g., conversation in a noisy bar or restaurant). Such comprehension is often impaired in d/AD. Similarly, effortful or diminished auditory comprehension is sometimes reported by cognitively healthy elders, raising the possibility that CAP deficit may be a marker of pre-symptomatic AD. In 187 cognitively and physically healthy members of the aging, AD family history-positive PREVENT-AD cohort, we therefore evaluated whether CAP deficits were associated with known markers of AD neurodegeneration. Such markers included CSF tau concentrations and magnetic resonance imaging volumetric and cortical thickness measures in key AD-related regions. Adjusting for age, sex, education, pure-tone hearing, and APOE ɛ4 status, we observed a persistent relationship between CAP scores and CSF tau levels, entorhinal and hippocampal cortex volumes, cortical thickness, and deficits in cognition (Repeatable Battery for Assessment of Neuropsychological Status total score, and several of its index scales). These cross-sectional observations suggest that CAP may serve as a novel metric for pre-symptomatic AD pathogenesis. They are therefore being followed up longitudinally with larger samples.

Bi-directional Association of Cerebrospinal Fluid Immune Markers with Stage of Alzheimer’s Disease Pathogenesis

Immune mechanisms may be important in the pathogenesis of Alzheimer’s disease (AD). Yet, studies comparing cerebrospinal fluid (CSF) and plasma immune marker levels of healthy and demented individuals have yielded conflicting results. We analyzed CSF from 101 members of the parental history-positive PREVENT-AD cohort of healthy aging adults, and 237 participants without dementia from the initial cohort of the Alzheimer’s Disease Neuroimaging Initiative (ADNI-1). Following recent practice, we used the biomarkers total-tau and amyloid-β1-42 to allocate participants from each study into four stages of AD pathogenesis: Stage 0 (no abnormality), Stage 1 (reduced amyloid-β1-42), Stage 2 (reduced amyloid-β1-42 and increased total-tau), or “Suspected Non-Alzheimer Pathology” (elevated total-tau only). Investigating the PREVENT-AD participants’ CSF assay results for 19 immune/inflammatory markers, we found six that showed a distinct bi-directional relationship with pathogenetic stage. Relative to Stage 0, these were diminished at Stage 1 but strongly increased at Stage 2. Among the ADNI participants (90 healthy controls and 147 with mild cognitive impairment), we found that 23 of 83 available CSF markers also showed this distinct pattern. These results support recent observations that immune activation may become apparent only after the onset of both amyloid and tau pathologies. Unexpectedly, they also suggest that immune marker activity may diminish along with earliest appearance of amyloid-β plaque pathology. These findings may explain discordant results from past studies, and suggest the importance of characterizing the extent of AD pathology when comparing clinical groups.

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

CSF IMMUNE MARKERS PREDICT DECREASED AD SYMPTOM SEVERITY AND PROGRESSION

University Medical Center, Amsterdam, Netherlands; Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, Netherlands; VU University Medical Center, Alzheimer Center, Amsterdam Neuroscience, Amsterdam, Netherlands; Clinical Memory Research Unit, Lund University, Malm€o, Sweden; Department of Neurology, Sk ane University Hospital, Lund, Sweden; Clinical Memory Research Unit, Lund University, Lund, Sweden; Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden; Alzheimer Center Limburg, Maastricht University, Maastricht, Netherlands; Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, Netherlands. Contact e-mail: i.vanmaurik@vumc.nl

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.