how they are used in the general population, factors that predict use, and their effectiveness is unknown. Objective(s): To describe the use of these medications in a population-based longitudinal study, characteristics of individuals that use these drugs, and to preliminary assess their impact on mortality. Methods: 302 individuals with incident AD, identified in a population-based sample of elderly persons in Cache County, Utah, were followed longitudinally with in-home visits for a mean of 2.8 years (range: 0.1-9.8) after diagnosis. T-tests and Fischer's exact tests were used to determine baseline differences in demographic, health, and functional characteristics between those who had ever regularly used a dementia medication over the follow-up compared to those who did not. Regular use was defined as taking the medication Ͼ4 times per week. Cox proportional hazards regressions were used to assess the association between use of these medications and mortality. Covariates included baseline age, GMHR, MMSE, and dementia duration, education and presence of an APOE E4 allele. Results: 54 participants (18.2%) regularly used cholinesterase inhibitors or memantine at any point over the follow-up. Regular users were significantly younger (80.9 vs. 86.6, pϽ0.001), more likely to have an APOE E4 allele (57.4% vs. 39.5%, pϽ0.01), and less likely to die over the follow-up (36.8% vs. 69.4%, pϽ0.001). Notably, there were no differences in self-reported health characteristics between the two groups at the time of diagnosis. Preliminary assessments with Cox proportional hazards suggest a reduced risk of mortality with use of a dementia medication. There was a dose response effect such that individuals taking a medication over 2 or more visits were less likely to die compared to those taking a medication at 1 visit or not at all. Conclusions: Less than 20% of participants in this population-based study regularly took cholinesterase inhibitors or memantine. Baseline health characteristics did not explain use. Preliminary results suggest that use of these medications may be associated with reduced mortality. Additional analyses with time-dependent analyses and more cases are needed to confirm these findings.

microglia activation are incompletely understood. Src tyrosine kinase is important in the regulation of a variety of cellular functions, including inflammation. We previously found that overexpressing the M-CSF receptor (M-CSFR; encoded by c-fms) on microglia leads to rescue of neurons from NMDA-induced excitotoxicity. Objectives: We sought to determine if Src signaling mediates M-CSFR-induced neuroprotection. Methods: We examined the effects of M-CSFR overexpression on Src kinase levels and activity. We also tested whether LPS, a potent inflammatory stimulus, activated Src. To determine the specificity of M-CSFR activation of Src, we quantified the activity of the Src-family kinase Lyn. A mutagenesis approach was used to block M-CSFR-induced Src activation, and the effects on microglial neuroprotection were examined. We also tested whether a Src dominant negative (DN) construct would block M-CSFRinduced neuroprotection. Results: Western analysis showed that microglial M-CSFR activation resulted in a greater than 2 fold increase in Src expression, whereas an enzymatic assay showed a greater than 3.5 fold increase in Src kinase activity. Microglia treatment with LPS did affect Src activity. M-CSFR activation had no effect on Lyn activity. In the M-CSFR, tyrosine position c-fms Y559 binds Src and induces activation by phosphorylation. Position c-fms Y807 , the global c-fms activation site, indirectly affects Src activation. Using co-cultures consisting of microglia overexpressing the M-CSFR and rat organotypic hippocampal cultures subjected to NMDA-induced excitotoxicity, overexpression of the Y559F or Y807F c-fms mutant constructs in microglia resulted in a loss of neurprotection. Similarly, microglial expression of a Src DN form resulted in loss of M-CSFR-induced neuroprotection, and also inhibited microglial proliferation. Increasing the number of microglia expressing the Src DN form in co-culture only partially restored neuroprotection. Adding exogenous M-CSF also partially restored neuroprotection by Src DN-treated microglia in co-cultures. Conclusions: Our results show that the Src signal transduction pathway is important in microglial neuroprotection. Identification of downstream Src kinase targets in microglia could lead to new pharmacological treatments for AD (Funding: Alzheimer's Association and NIH MH57833).

Cognitively intact elderly research volunteers at the University of Kentucky have been recruited, followed longitudinally, and autopsied with extensive neuropathological evaluations since 1989. To date, the cohort has recruited 1,030 individuals with 552 participants being actively followed, 363 deceased, and 273 autopsied. An extensive database has been constructed with continuous updates that include textured clinical, neuropsychological, neuroimaging, and pathological information. The history, demographics, clinical observations, and pathological features of this research cohort are described. We also explain some of the evolving methodologies and the academic contributions that have been made due to this motivated group of older Kentuckians.

Background: Practice effects are a known threat to reliability and validity in clinical trials. Few studies have investigated the potential influence of practice on repeated screening measures in longitudinal clinical trials with a focus on dementia prevention. The current study investigates whether practice effects exist on a screening measure commonly used in aging research, the Memory Impairment Screen (MIS). Methods: The PREADViSE trial is a clinical intervention study evaluating the efficacy of vitamin E and selenium for Alzheimer's disease prevention. Participants are screened annually for incident dementia with the MIS. Participants with baseline and three consecutive follow-ups who made less than a perfect score at one or more assessments were included in the current analyses (N=1,803). An additional subset of participants with four consecutive assessments but who received the same version of the MIS at baseline and first follow-up (N=301) was also assessed to determine the effects of alternate forms on mitigating practice. We hypothesized that despite efforts to mitigate practice effects with alternate versions, MIS scores would improve with repeated screening. Linear mixed models were used to estimate mean MIS scores over time.

of the ten patients we also recorded the electroencephalogram (EEG). EEG were recorded at T0 and at T1 for 5 five minutes through 21 electrodes following the 10-20 0 International System with a sampling frequency of 1024 Hz, a bandpass of 0,5-500 Hz, and a sensibility of 7 uV/mm. EEG were analyzed in the frequency domain (power spectrum and coherence). Results: AtDCS improved the accuracy of the word recognition task (p¼0.0068), CtDCS significantly worsened it (p¼0.011), and StDCS left it unchanged. tDCS left the visual attention RTs unchanged. AtDCS and CtDCS produced specific, differential, and significant effects over the mean power spectral density, the inter-and intra-hemispheric coherence in all the electrodes (p<0.0001). In particular, whereas AtDCS increased the occipital intra-hemispheric coherence in the gamma band (p¼0,047), CtDCS increased it in the d band (p¼0,021). Conclusions: tDCS delivered over the T-P cortex modulated cortical electrophysiological activity and improved a recognition memory task in patients with probable AD.

This e-book sets forth the notion that the emerging fi eld of geomedicine will produce a new type of medical intelligence that will leverage national spatial data infrastructures to benefi t personal human health. Linking one’s own personal health status to specifi c geographic factors can provide another set of powerful information tools that medical professionals can use to improve the quality of the care they deliver. Geomedicine, in the future, will mean that we will experience an increase in the number of patients who benefi t from a more precise clinical understanding of the links between their health and where they live, work, and play. At the present time, very little of health-relevant geographic information is available to a clinician at the time of a medical diagnostic encounter, and it is certainly not a typical part of a comprehensive medical record. Leveraged by a geographic information system (GIS), information on a patient&apos;s potential environmental exposures can...

Multi-echo fMRI, particularly the multi-echo independent component analysis (ME-ICA) algorithm, has previously proven useful for increasing the sensitivity and reducing false positives for functional MRI (fMRI) based resting state connectivity studies. Less is known about its efficacy for task-based fMRI, especially at the single subject level. This work, which focuses exclusively on individual subject results, compares ME-ICA to single-echo fMRI and a voxel-wise T2 * weighted combination of multi-echo data for task-based fMRI under the following scenarios: cardiac-gated block designs, constant repetition time (TR) block designs, and constant TR rapid event-related designs. Performance is evaluated primarily in terms of sensitivity (i.e., activation extent, activation magnitude, percent detected trials and effect size estimates) using five different tasks expected to evoke neuronal activity in a distributed set of regions. The ME-ICA algorithm significantly outperformed all other evaluated processing alternatives in all scenarios. Largest improvements were observed for the cardiac-gated dataset, where ME-ICA was able to reliably detect and remove non-neural T1 signal fluctuations caused by non-constant repetition times. Although ME-ICA also outperformed the other options in terms of percent detection of individual trials for rapid event-related experiments, only 46% of all events were detected after ME-ICA; suggesting additional improvements in sensitivity are required to reliably detect individual short event occurrences. We conclude the manuscript with a detailed evaluation of ME-ICA outcomes and a discussion of how the ME-ICA algorithm could be further improved. Overall, our results suggest that ME-ICA constitutes a versatile, powerful approach for advanced denoising of task-based fMRI, not just resting-state data.

Human face recognition is often attributed to configural processing; namely, processing the spatial relationships among the features of a face. If configural processing depends on fine-grained spatial information, do visuospatial mechanisms within the dorsal visual pathway contribute to this process? We explored this question in human adults using functional magnetic resonance imaging and transcranial magnetic stimulation (TMS) in a same-different face detection task. Within localized, spatial-processing regions of the posterior parietal cortex, configural face differences led to significantly stronger activation compared to featural face differences, and the magnitude of this activation correlated with behavioral performance. In addition, detection of configural relative to featural face differences led to significantly stronger functional connectivity between the right FFA and the spatial processing regions of the dorsal stream, whereas detection of featural relative to configural face differences led to stronger functional connectivity between the right FFA and left FFA. Critically, TMS centered on these parietal regions impaired performance on configural but not featural face difference detections. We conclude that spatial mechanisms within the dorsal visual pathway contribute to the configural processing of facial features and, more broadly, that the dorsal stream may contribute to the veridical perception of faces.

Animate and inanimate objects differ in their intermediate visual features. For instance, animate objects tend to be more curvilinear compared to inanimate objects (e.g., Levin, Takarae, Miner, & Keil, 2001). Recently, it has been demonstrated that these differences in the intermediate visual features of animate and inanimate objects are sufficient for categorization: Human participants viewing synthesized images of animate and inanimate objects that differ largely in the amount of these visual features classify objects as animate/inanimate significantly above chance (Long, Stormer, & Alvarez, 2017). A remaining question, however, is whether the observed categorization is a consequence of top-down cognitive strategies (e.g., rectangular shapes are less likely to be animals) or a consequence of bottom-up processing of their intermediate visual features, per se, in the absence of top-down cognitive strategies. To address this issue, we repeated the classification experiment of Long et al. (2017) but, unlike Long et al. (2017), matched the synthesized images, on average, in the amount of imagebased and perceived curvilinear and rectilinear information. Additionally, in our synthesized images, global shape information was not preserved, and the images appeared as texture patterns. These changes prevented participants from using top-down cognitive strategies to perform the task. During the experiment, participants were presented with these synthesized, texture-like animate and inanimate images and, on each trial, were required to classify them as either animate or inanimate with no feedback given. Participants were told that these synthesized images depicted abstract art patterns. We found that participants still classified the synthesized stimuli significantly above chance even though they were unaware of their classification performance. For both object categories, participants depended more on the curvilinear and less on the rectilinear, image-based information present in the stimuli for classification. Surprisingly, the stimuli most consistently classified as animate were the most dangerous animals in our sample of images. We conclude that bottom-up processing of intermediate features present in the visual input is sufficient for animate/ inanimate object categorization and that these features may convey information associated with the affective content of the visual stimuli.

Configural face processing is considered to be vital for face perception. If configural face processing requires an evaluation of spatial information, might this process involve interactions between ventral stream face-processing regions and dorsal stream visuospatial-processing regions? We explored this possibility using thetaburst stimulation (TBS) with fMRI in humans. Participants were shown two faces that differed in either the shape (featural differences) or the spatial configuration (configural differences) of their features. TBS applied on dorsal location-processing regions: 1) reduced fMRI activity within ventral stream face-processing regions during configural but not featural face processing; and 2) reduced functional connectivity between these face regions significantly more for configural than featural face processing. No changes occurred when TBS was delivered on the vertex control site for either face task. We conclude that ventral stream face-processing regions receiv...

Human face recognition is often attributed to configural processing; namely, processing the spatial relationships among the features of a face. If configural processing depends on fine-grained spatial information, do visuospatial mechanisms within the dorsal visual pathway contribute to this process? We explored this question in human adults using functional magnetic resonance imaging and transcranial magnetic stimulation (TMS) in a same-different face detection task. Within localized, spatial-processing regions of the posterior parietal cortex, configural face differences led to significantly stronger activation compared to featural face differences, and the magnitude of this activation correlated with behavioral performance. In addition, detection of configural relative to featural face differences led to significantly stronger functional connectivity between the right FFA and the spatial processing regions of the dorsal stream, whereas detection of featural relative to configural face differences led to stronger functional connectivity between the right FFA and left FFA. Critically, TMS centered on these parietal regions impaired performance on configural but not featural face difference detections. We conclude that spatial mechanisms within the dorsal visual pathway contribute to the configural processing of facial features and, more broadly, that the dorsal stream may contribute to the veridical perception of faces.

Configural face processing is considered to be vital for face perception. If configural face processing requires an evaluation of spatial information, might this process involve interactions between ventral stream face-processing regions and dorsal stream visuospatial-processing regions? We explored this possibility using thetaburst stimulation (TBS) with fMRI in humans. Participants were shown two faces that differed in either the shape (featural differences) or the spatial configuration (configural differences) of their features. TBS applied on dorsal locationprocessing regions: 1) reduced fMRI activity within ventral stream face-processing regions during configural but not featural face processing; and 2) reduced functional connectivity between these face regions significantly more for configural than featural face processing. No changes occurred when TBS was delivered on the vertex control site for either face task. We conclude that ventral stream face-processing regions receive visuospatial information from dorsal stream location-processing regions during configural face processing.

Multi-echo fMRI, particularly the multi-echo independent component analysis (ME-ICA) algorithm, has previously proven useful for increasing the sensitivity and reducing false positives for functional MRI (fMRI) based resting state connectivity studies. Less is known about its efficacy for task-based fMRI, especially at the single subject level. This work, which focuses exclusively on individual subject results, compares ME-ICA to single-echo fMRI and a voxel-wise T2 * weighted combination of multi-echo data for task-based fMRI under the following scenarios: cardiac-gated block designs, constant repetition time (TR) block designs, and constant TR rapid event-related designs. Performance is evaluated primarily in terms of sensitivity (i.e., activation extent, activation magnitude, percent detected trials and effect size estimates) using five different tasks expected to evoke neuronal activity in a distributed set of regions. The ME-ICA algorithm significantly outperformed all other evaluated processing alternatives in all scenarios. Largest improvements were observed for the cardiac-gated dataset, where ME-ICA was able to reliably detect and remove non-neural T1 signal fluctuations caused by non-constant repetition times. Although ME-ICA also outperformed the other options in terms of percent detection of individual trials for rapid event-related experiments, only 46% of all events were detected after ME-ICA; suggesting additional improvements in sensitivity are required to reliably detect individual short event occurrences. We conclude the manuscript with a detailed evaluation of ME-ICA outcomes and a discussion of how the ME-ICA algorithm could be further improved. Overall, our results suggest that ME-ICA constitutes a versatile, powerful approach for advanced denoising of task-based fMRI, not just resting-state data.

Growing evidence suggests that the functional specialization of the two cortical visual pathways may not be as distinct as originally proposed. Here, we explore possible contributions of the dorsal “where/how” visual stream to shape perception and, conversely, contributions of the ventral “what” visual stream to location perception in human adults. Participants performed a shape detection task and a location detection task while undergoing fMRI. For shape detection, comparable BOLD activation in the ventral and dorsal visual streams was observed, and the magnitude of this activation was correlated with behavioral performance. For location detection, cortical activation was significantly stronger in the dorsal than ventral visual pathway and did not correlate with the behavioral outcome. This asymmetry in cortical profile across tasks is particularly noteworthy given that the visual input was identical and that the tasks were matched for difficulty in performance. We confirmed the as...

Although object perception involves encoding a wide variety of object properties (e.g., size, color, viewpoint), some properties are irrelevant for identifying the object. The key to successful object recognition is having an internal representation of the object identity that is insensitive to these properties while accurately representing important diagnostic features. Behavioral evidence indicates that the formation of these kinds of invariant object representations takes many years to develop. However, little research has investigated the developmental emergence of invariant object representations in the ventral visual processing stream, particularly in the lateral occipital complex (LOC) that is implicated in object processing in adults. Here, we used an fMR adaptation paradigm to evaluate age-related changes in the neural representation of objects within LOC across variations in size and viewpoint from childhood through early adulthood. We found a dissociation between the neur...