Two-Year Prognostic Utility of Plasma p217+tau across the Alzheimer's Continuum.

BACKGROUND: Plasma p217+tau has shown high concordance with cerebrospinal fluid (CSF) and positron emission tomography (PET) measures of amyloid-ß (Aß) and tau in Alzheimer's Disease (AD). However, its association with longitudinal cognition and comparative performance to PET Aß and tau in predicting cognitive decline are unknown. OBJECTIVES: To evaluate whether p217+tau can predict the rate of cognitive decline observed over two-year average follow-up and compare this to prediction based on Aß (18F-NAV4694) and tau (18F-MK6240) PET. We also explored the sample size required to detect a 30% slowing in cognitive decline in a 2-year trial and selection test cost using p217+tau (pT+) as compared to PET Aß (A+) and tau (T+) with and without p217+tau pre-screening. DESIGN: A prospective observational cohort study. SETTING: Participants of the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and Australian Dementia Network (ADNeT). PARTICIPANTS: 153 cognitively unimpaired (CU) and 50 cognitively impaired (CI) individuals. MEASUREMENTS: Baseline p217+tau Simoa® assay, 18F-MK6240 tau-PET and 18F-NAV4694 Aß-PET with neuropsychological follow-up (MMSE, CDR-SB, AIBL-PACC) over 2.4 ± 0.8 years. RESULTS: In CI, p217+tau was a significant predictor of change in MMSE (ß = -0.55, p < 0.001) and CDR-SB (ß =0.61, p < 0.001) with an effect size similar to Aß Centiloid (MMSE ß = -0.48, p = 0.002; CDR-SB ß = 0.43, p = 0.004) and meta-temporal (MetaT) tau SUVR (MMSE: ß = -0.62, p < 0.001; CDR-SB: ß = 0.65, p < 0.001). In CU, only MetaT tau SUVR was significantly associated with change in AIBL-PACC (ß = -0.22, p = 0.008). Screening pT+ CI participants into a trial could lead to 24% reduction in sample size compared to screening with PET for A+ and 6-13% compared to screening with PET for T+ (different regions). This would translate to an 81-83% biomarker test cost-saving assuming the p217+tau test cost one-fifth of a PET scan. In a trial requiring PET A+ or T+, p217+tau pre-screening followed by PET in those who were pT+ would cost more in the CI group, compared to 26-38% biomarker test cost-saving in the CU. CONCLUSIONS: Substantial cost reduction can be achieved using p217+tau alone to select participants with MCI or mild dementia for a clinical trial designed to slow cognitive decline over two years, compared to participant selection by PET. In pre-clinical AD trials, p217+tau provides significant cost-saving if used as a pre-screening measure for PET A+ or T+ but in MCI/mild dementia trials this may add to cost both in testing and in the increased number of participants needed for testing.

Surface-based mixed effects multilevel analysis of grouped human electrocorticography.

Electrocorticography (ECoG) in humans yields data with unmatched spatio-temporal resolution that provides novel insights into cognitive operations. However, the broader application of ECoG has been confounded by difficulties in accurately depicting individual data and performing statistically valid population-level analyses. To overcome these limitations, we developed methods for accurately registering ECoG data to individual cortical topology. We integrated this technique with surface-based co-registration and a mixed-effects multilevel analysis (MEMA) to control for variable cortical surface anatomy and sparse coverage across patients, as well as intra- and inter-subject variability. We applied this surface-based MEMA (SB-MEMA) technique to a face-recognition task dataset (n=22). Compared against existing techniques, SB-MEMA yielded results much more consistent with individual data and with meta-analyses of face-specific activation studies. We anticipate that SB-MEMA will greatly expand the role of ECoG in studies of human cognition, and will enable the generation of population-level brain activity maps and accurate multimodal comparisons.

The role of the amygdala and rostral anterior cingulate in encoding expected outcomes during learning.

Successful passive avoidance learning is thought to require the use of learned stimulus-reinforcement associations to guide decision making [Baxter, M.G., Murray, E.A., 2002. The amygdala and reward. Nature Reviews. Neuroscience 3, 563-573]. The current experiment investigated the neural correlates of successful passive avoidance learning in 19 healthy adults. Behaviorally, subjects showed a distinct pattern of performance: early indiscriminate responding to stimuli (pre-criterion performance), followed by relatively rapid learning before a plateau of successful performance (post-criterion performance). Neural responses to post-criterion correct responses were compared with neural responses to both incorrect responses and pre-criterion correct responses. Post-criterion correct responding was associated with increased activation in regions including rostral anterior cingulate, insula, caudate, hippocampal regions, and the amygdala.

Understanding neural system dynamics through task modulation and measurement of functional MRI amplitude, latency, and width.

Estimates of hemodynamic amplitude, delay, and width were combined to investigate system dynamics involved in lexical decision making. Subjects performed a lexical decision task using word and nonword stimuli rotated 0 degrees, 60 degrees, or 120 degrees. Averaged hemodynamic responses to repeated stimulation were fit to a Gamma-variate function convolved with a heavyside function of varying onset and duration to estimate each voxel's activation delay and width. Consistent with prolonged reaction times for the rotated stimuli and nonwords, the motor cortex showed delayed hemodynamic onset for both conditions. Language areas such as the lingual gyrus, middle temporal gyrus, fusiform gyrus, and precuneus all showed delayed hemodynamic onsets to rotated stimuli but not to nonword stimuli. The inferior frontal gyrus showed both increased onset latency for rotated stimuli and a wider hemodynamic response to nonwords, consistent with prolonged processing in this area during the lexical decision task. Phonological processing areas such as superior temporal and angular gyrus showed no delay or width difference for rotated stimuli. These results suggest that phonological routes but not semantic routes to the lexicon can proceed regardless of stimulus orientation. This study demonstrates the utility of estimating hemodynamic delay and width in addition to amplitude allowing for more quantitative measures of brain function such as mental chronometry.

Spatial heterogeneity of the nonlinear dynamics in the FMRI BOLD response.

Recent studies of blood oxygenation level dependent (BOLD) signal responses averaged over a region of interest have demonstrated that the response is nonlinear with respect to stimulus duration. Specifically, shorter duration stimuli produce signal changes larger than expected from a linear system. The focus of this study is to characterize the spatial heterogeneity of this nonlinear effect. A series of MR images of the visual and motor cortexes were acquired during visual stimulation and finger tapping, respectively, at five different stimulus durations (SD). The nonlinearity was assessed by fitting ideal linear responses to the responses at each SD. This amplitude, which is constant for different SD in a linear system, was normalized by the amplitude of the response to a blocked design, thus describing the amount by which the stimulus is larger than predicted from a linear extrapolation of the response to the long duration stimulus. The amplitude of the BOLD response showed a nonlinear behavior that varied considerably and consistently over space, ranging from almost linear to 10 times larger than a linear prediction at short SD. In the motor cortex different nonlinear behavior was found in the primary and supplementary motor cortexes.

Analysis and use of FMRI response delays.

In this study, we implemented a new method for measuring the temporal delay of functional magnetic resonance imaging (fMRI) responses and then estimated the statistical distribution of response delays evoked by visual stimuli (checkered annuli) within and across voxels in human visual cortex. We assessed delay variability among different cortical sites and between parenchyma and blood vessels. Overall, 81% of all responsive voxels showed activation in phase with the stimulus while the remaining voxels showed antiphase, suppressive responses. Mean delays for activated and suppressed voxels were not significantly different (P < 0.001). Cortical flat maps showed that the pattern of activated and suppressed voxels was dynamically induced and depended on stimulus size. Mean delays for blood vessels were 0.7-2.4 sec longer than for parenchyma (P < 0.01). However, both parenchyma and blood vessels produced responses with long delays. We developed a model to identify and quantify different components contributing to variability in the empirical delay measurements. Within-voxel changes in delay over time were fully accounted for by the effects of empirically measured fMRI noise with virtually no measurable variability associated with the stimulus-induced response itself. Across voxels, as much as 47% of the delay variance was also the result of fMRI noise, with the remaining variance reflecting fixed differences in response delay among brain sites. In all cases, the contribution of fMRI noise to the delay variance depended on the noise power at the stimulus frequency. White noise models significantly underestimated the fMRI noise effects.