Anne Labonté

Association between apolipoprotein a-i levels and white matter hyperintensities depends on CSF tau levels in a high-risk cohort of aging cognitively normal persons: The prevent-alzheimer's disease study

Values Nelly Joseph-Mathurin, Yi Su, Andrei Vlassenko, Lars Couture, Tyler Blazey, Karl A. Friedrichsen, Christopher J. Owen, Russ C. Hornbeck, Lisa Cash, Trish A. Stevenson, Beau Ances, Chengjie Xiong, Virginia Buckles, Krista L. Moulder, John C. Morris, Randall Bateman, Marcus E. Raichle, Tammie L. S. Benzinger,Washington University School ofMedicine, St Louis, MO, USA. Contact e-mail: mathurinn@npg.wustl.edu

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.

EARLY INCREASE IN TAU-PET SIGNAL IS ASSOCIATED WITH Aβ BURDEN, CSF P-TAU LEVELS AND COGNITION IN COGNITIVELY NORMAL LATE-MIDDLE-AGED ADULTS

9 individuals AD (N1⁄45; MMSE1⁄417.267), MCI (N1⁄41;MMSE1⁄426), FTD (N1⁄42; MMSE1⁄429.561), CN (N1⁄41, MMSE1⁄429); aged 56 to 70 yo. All participants had complete cognitive assessments. We observed that CSF T-tau and P-tau were highly correlated with [F]MK6240 uptake. The regions with the highest correlation were the entorhinal cortex (t-tau: R1⁄4 0.85, p 1⁄4 0.003; p-tau: R1⁄4 0.89, p 1⁄4 0.001), the temporal lobe (t-tau: R1⁄4 0.69, p1⁄4 0.03; p-tau: R1⁄4 0.81, p1⁄4 0.008), and the anterior cingulate (t-tau: R1⁄4 0.95, p < 0.001; p-tau: R1⁄4 0.89, p 1⁄4 0.001). Additionally, as expected, CSF Ab and [F]NAV4669 uptake were reversely correlated. Conclusions: The associations between CSF T-tau or P-tau with [18F]MK6240 support the concept that pair helical filament availability and monomeric forms of CSF p-tau and t-tau similarly reflects the tau pathology in vivo.

INCREASED PRO-INFLAMMATORY SIGNALING AND EVIDENCE OF ALZHEIMER’S DISEASE PATHOLOGY IN HEALTHY OLDER ADULTS AT RISK FOR AD

and anti-asthmatic drug Montelukast elevated hippocampal neurogenesis, reduced neuroinflammation, and improved learning and memory.Methods:AsMontelukast is known to have a low bioavailability, we were now aiming to optimize the pharmacology of Montelukast by improving its formulation.Results:In a Phase I study, we demonstrated that an oral film formulation of Montelukast (Montelukast VersaFilm) is safe and tolerable in healthy subjects, reduces the first-pass-effect and has a 52% higher bioavailability compared to the regular Montelukast tablet. Of importance for any CNSactive drugs, we detected Montelukast in the cerebrospinal fluid of the Montelukast VersaFilm treated healthy volunteers clearly indicating blood brain barrier penetrance. Of note, Montelukast, in contrast to many other CNS penetrating drugs, has an excellent safety and tolerability profile.We are at this stage preparing a Phase II trial to demonstrate efficacy of the Montelukast VersaFilm to improve cognitive function in AD. Conclusions:Montelukast VersaFilm might be a novel effective therapeutic entering the field of Alzheimer’s Disease to improve cognitive function.

CSF INFLAMMATORY AND LIPID TRANSPORTER PROTEINS PREDICT GREY MATTER DENSITY LONGITUDINAL CHANGES

AUC 0.91 (0.808-1.000) (Figure1). The a priori liberal threshold had identical sensitivity and specificity as the ROC-derived threshold. These thresholds also distinguished between Thal phases 0-2 and 3-5 (Figure2). The a prioriconservative threshold had sensitivity of 0.68 (0.48-0.83) and specificity of 1.00 (0.861.0). Conclusions:The a priori liberal threshold (7.47 Centiloids) and the ROC-derived threshold (9.50 Centiloids) showed excellent sensitivity/specificity, and could be considered for detection of early amyloid signal. By the time of AAIC we anticipate processing at least 100 additional cases currently being provided by multiple sites in order to validate these preliminary results.

Mapping the progression of CSF and imaging biomarkers in “at-risk” healthy subjects: The prevent-ad program

to assess effects of naproxen on the trajectory of such changes. Both BIOCARD and PREVENT-AD are evaluating analytic methods that can interpret multiple biomarker results as indicators of disease progress toward subsequent symptom onset. Conclusions:The talks that follow will describe the two studies’ progress in pre-symptomatic biomarker research toward improving the selection of participants and promising interventions for prevention trials.

Olfactory identification is associated with CSF tau/abeta42 ratios in cognitively normal adults at high risk of Alzheimer's disease

neurophysiological events associated with declarative memory consolidation, like slow oscillatory activity and so-called spindles, are often altered in older healthy adults, particularly in Alzheimer’s disease and its precursor mild cognitive impairment (MCI). A possibility to enhance endogenous slow wave activity and thereby improve declarative memory consolidation is provided by transcranial slow oscillating stimulation (tSOS) during sleep, as was previously shown in young subjects (Marshall et al. 2006, Nature). Here we assessed whether tSOS applied during an afternoon nap enhances slow oscillations and the consolidation of declarative memories in healthy older adults. Methods: Using a within subject design, 18 subjects aged 58-77 years were assessed for visualspatial (remembering pictures and their location on a screen) and verbal (word-pair associative learning) memory before and after a 90-minute nap either comprising weak tSOS at 0.75 Hz or sham (no) stimulation. Throughout the naps electroencephalographic (EEG) activity was recorded and fast Fourier transform was applied to compute the spectral power within three frequency bands of interest in 1 minute stimulation-free intervals immediately following 5 stimulation blocks: slow wave activity (<1Hz), slow spindle (812Hz) and fast spindle activity (12-15Hz). A mixed model analysis was used to evaluate the impact of tSOS on log transformed slow oscillations and spindle activity. Repeated measures ANOVA were conducted to access the stimulation effect on memory consolidation. Results: Inducing tSOS during a daytime nap significantly improved memory retention performance in the picture recognition task (F1⁄44.73, p1⁄4.04) but not retention performance in the wordpair tasks (p>1). The EEG power analysis revealed that tSOS significantly enhances slow oscillatory activity (b1⁄4-.17, SE1⁄4.08, p1⁄4.03) but not slow spindle (b1⁄4-.08, SE1⁄4.04, p1⁄4.09) and fast spindle activity (p>1). Conclusions:We demonstrate that tSOS applied during a brief period of daytime sleep improves the consolidation of visual memories, emphasizing its potential to counteract cognitive decline in older adults. Mechanisms may include its impact on slow oscillatory activity, indicated by parallel increase in slow oscillatory activity. Assessment of MCI patients is ongoing and will be additionally shown and discussed.