Shaney Flores

Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study

Background Models of Alzheimer disease propose a sequence of amyloid-β (Aβ) accumulation, hypometabolism, and structural declines that precede the onset of clinical dementia. These pathological features evolve both temporally and spatially in the brain. This study aimed to characterize where in the brain and when in the course of the disease neuroimaging biomarkers become abnormal. Methods We analyzed data from mutation non-carriers, asymptomatic carriers, and symptomatic carriers collected between January 1st 2009 and December 31st 2015 from families carrying PSEN1, PSEN2, or APP mutations enrolled in the Dominantly Inherited Alzheimer’s Network. We analyzed [11C]Pittsburgh Compound B positron emission tomography (PiB PET), [18F]Fluorodeoxyglucose (FDG PET), and structural magnetic resonance imaging (MRI) data using regions of interest to assess change throughout the brain. We estimated rates of biomarker change as a function of estimated years from symptom onset at baseline using linear mixed-effects models and determined the earliest point at which biomarker trajectories differed between mutation carriers and non-carriers. Findings PiB PET was available for 346 individuals, with 162 having longitudinal imaging; FDG PET was available for 352 (175 longitudinal); and MRI data was available for 377 (201 longitudinal). We found a sequence to pathological changes, with rates of Aβ deposition in mutation carriers being significantly different from non-carriers first (on average across regions that showed a significant difference at −18·9 (sd 3·3) years before expected onset), followed by hypometabolism (−14·1 years, sd 5·1) and lastly structural declines (−4·7 years, sd 4·2). This biomarker ordering was preserved in most, but not all, regions. The temporal emergence within a biomarker varied across the brain, with the precuneus being the first cortical region in each modality to show divergence between groups (−22·2 years before expected onset for Aβ accumulation, −18·8 years for hypometabolism, and −13·0 years for cortical thinning). Interpretation Mutation carriers had elevations in Aβ deposition, reduced glucose metabolism, and cortical thinning which preceded the expected onset of dementia. Accrual of these pathologies varied throughout the brain, suggesting differential regional and temporal vulnerabilities to Aβ, metabolic decline, and structural atrophy, which should be taken into account when using biomarkers in a clinical setting as well as designing and evaluating clinical trials.

Event segmentation improves event memory up to one month later.

When people observe everyday activity, they spontaneously parse it into discrete meaningful events. Individuals who segment activity in a more normative fashion show better subsequent memory for the events. If segmenting events effectively leads to better memory, does asking people to attend to segmentation improve subsequent memory? To answer this question, participants viewed movies of naturalistic activity with instructions to remember the activity for a later test, and in some conditions additionally pressed a button to segment the movies into meaningful events or performed a control condition that required button-pressing but not attending to segmentation. In 5 experiments, memory for the movies was assessed at intervals ranging from immediately following viewing to 1 month later. Performing the event segmentation task led to superior memory at delays ranging from 10 min to 1 month. Further, individual differences in segmentation ability predicted individual differences in memory performance for up to a month following encoding. This study provides the first evidence that manipulating event segmentation affects memory over long delays and that individual differences in event segmentation are related to differences in memory over long delays. These effects suggest that attending to how an activity breaks down into meaningful events contributes to memory formation. Instructing people to more effectively segment events may serve as a potential intervention to alleviate everyday memory complaints in aging and clinical populations.

How are false memories distinguishable from true memories in the Deese–Roediger–McDermott paradigm? A review of the findings

This article reviewed the literature comparing true and false memories. Although false memory experience is typically characterized as compellingly similar to true memory experience, research also indicates many distinctions between these two types of memory. The primary focus of this article was on comparing these two types of memory in the Deese–Roediger–McDermott paradigm on a number of independent and dependent measures. Studies that compared true and false memories in recall and recognition rates over retention intervals, as a function of list word presentation duration, list presentation repetition, in recall and recognition latencies, output serial position, phenomenological experiences (conscious and unconscious discrimination between these two types of memories), and neurophysiological processes were reviewed. The conclusion is that the degree to which false memory is experienced and observed as similar to or the same as true memory is a function of a number of variables in the process of acquiring and measuring the memory.

Distraction shrinks space

Research investigating how people remember the distance of paths they walk has shown two apparently conflicting effects of experience during encoding on subsequent distance judgments. By the feature accumulation effect, discrete path features such as turns, houses, or other landmarks cause an increase in remembered distance. By the distractor effect, performance of a concurrent task during path encoding causes a decrease in remembered distance. In this study, we ask the following: What are the conditions that determine whether the feature accumulation or the distractor effect dominates distortions of space? In two experiments, blindfolded participants were guided along two legs of a right triangle while reciting nonsense syllables. On some trials, one of the two legs contained features: horizontally mounted car antennas (gates) that bent out of the way as participants walked past. At the end of the second leg, participants either indicated the remembered path leg lengths using their hands in a ratio estimation task or attempted to walk, unguided, straight back to the beginning. In addition to response mode, visual access to the paths and time between encoding and response were manipulated to determine whether these factors would affect feature accumulation or distractor effects. Path legs with added features were remembered as shorter than those without, but this result was significant only in the haptic response mode data. This finding suggests that when people form spatial memory representations with the intention of navigating in room-scale spaces, interfering with information accumulation substantially distorts spatial memory.

Effects of cues to event segmentation on subsequent memory

To remember everyday activity it is important to encode it effectively, and one important component of everyday activity is that it consists of events. People who segment activity into events more adaptively have better subsequent memory for that activity, and event boundaries are remembered better than event middles. The current study asked whether intervening to improve segmentation by cuing effective event boundaries would enhance subsequent memory for events. We selected a set of movies that had previously been segmented by a large sample of observers and edited them to provide visual and auditory cues to encourage segmentation. For each movie, cues were placed either at event boundaries or event middles, or the movie was left unedited. To further support the encoding of our everyday event movies, we also included post-viewing summaries of the movies. We hypothesized that cuing at event boundaries would improve memory, and that this might reduce age differences in memory. For both younger and older adults, we found that cuing event boundaries improved memory—particularly for the boundaries that were cued. Cuing event middles also improved memory, though to a lesser degree; this suggests that imposing a segmental structure on activity may facilitate memory encoding, even when segmentation is not optimal. These results provide evidence that structural cuing can improve memory for everyday events in younger and older adults.

The effects of weak versus strong relational judgments on response bias in Two-Alternative-Forced-Choice recognition: Is the test criterion-free?

It is widely believed that a Two-Alternative-Forced-Choice (2AFC) in an old/new recognition memory test is made by comparing the two items and choosing the item with the higher strength. For this reason, it is considered to be criterion-free by some researchers. We found evidence that subjects probabilistically compromised the comparison by choosing the left item when they recognized it as old. Using both normal test pairs (comprised of one new and one old item) and two types of null pairs (comprised of both-new or both-old items), we found that a left-biased choice was coupled with higher hit and false alarm rates and a shorter left than right-choice RT for the normal pairs, consistent with the hypothesis of a bias for making a choice on the basis of a left individual-item recognition. For the null pairs, RT was much longer for the both-new than for the both-old pairs, providing additional evidence for basing decision on an individual-items absolute, rather than a relative, familiarity. Additionally, subjects gave higher confidence ratings to choices for the both-old than the normal and both-new pairs, again suggesting that their decision was based on absolute familiarity of the items. The results were found to be not due to a fast-response instruction. A comparative judgment experiment in which subjects chose the item higher or lower in an attribute magnitude did not show the response side bias and RT asymmetry. The presence of bias in the former, and the absence of it in the latter can be explained by a weak versus strong relational judgment in the former and the latter type of 2AFC, respectively. We discuss the implications these findings have for the use of the 2AFC as a method for testing recognition memory.

APOE ε4 genotype predicts memory for everyday activities

The apolipoprotein E (ApOE) ε4 allele is associated with neuropathological buildup of amyloid in the brain, and with lower performance on some laboratory measures of memory in some populations. In two studies, we tested whether ApOE genotype affects memory for everyday activities. In Study 1, participants aged 20–79 years old (n = 188) watched movies of actors engaged in daily activities and completed memory tests for the activities in the movies. In Study 2, cognitively healthy and demented older adults (n = 97) watched and remembered similar movies, and also underwent structural MRI scanning. All participants provided saliva samples for genetic analysis. In both samples we found that, in older adults, ApOE ε4 carriers demonstrated worse everyday memory performance than did ε4 noncarriers. In Study 2, ApOE ε4 carriers had smaller medial temporal lobes (MTL) volumes, and MTL volume mediated the relationship between ApOE genotype and everyday memory performance. These everyday memory tasks measure genetically determined cognitive decline that can occur prior to a clinical diagnosis of dementia. Further, these tasks are easily administered and may be a useful clinical tool in identifying ε4 carriers who may be at risk for MTL atrophy and further cognitive decline that is a common characteristic of the earliest stages of Alzheimer’s disease.

Age differences in spatial memory for mediated environments.

Compared with younger adults, older adults have more difficulty with navigation and spatial memory in both familiar and unfamiliar domains. However, the cognitive mechanisms underlying these effects have been little explored. We examined three potential factors: (a) use of and coordination across spatial reference frames, (b) nonspatial cognitive abilities, and (c) the ability to segment a route into effective chunks. In two experiments, healthy young and older adults watched videos of navigation in a novel environment and had to remember the placement of landmarks along the route. Participants completed three spatial memory tasks—a virtual pointing task, a distance estimation task, and sketch map drawing—for each route. The pointing task depends on updating and accessing the updated egocentric reference frame relative to other frames. Map drawing may rely more on environment-centered processing. The distance estimation task could be solved using either frame of reference. Last, participants segmented each route. In a separate session, working memory, processing speed, and verbal memory were assessed. Older adults performed less well on all spatial tasks compared with younger adults; aging had a stronger negative effect on pointing performance. This may point to impairments in older adults’ ability to update and coordinate information across reference frames. Performance on all spatial tasks was predicted by nonspatial task performance. Segmentation did not predict spatial memory. These results underline the importance of situating age differences in navigation in the context of basic transformations of spatial reference frames, and also in the context of nonspatial cognitive abilities.

Dynamic Prediction During Perception of Everyday Events

The ability to predict what is going to happen in the near future is integral for daily functioning. Previous research suggests that predictability varies over time, with increases in prediction error at those moments that people perceive as boundaries between meaningful events. These moments also tend to be points of rapid change in the environment. Eye tracking provides a method for continuous measurement of prediction as participants watch a movie of an actor performing a series of actions. In two studies, we used eye tracking to study the time course of prediction around event boundaries. In both studies, viewers looked at objects that were about to be touched by the actor shortly before the objects were contacted, demonstrating predictive looking. However, this behavior was modulated by event boundaries: looks to to-be-contacted objects near event boundaries were less likely to be early and more likely to be late, compared to looks to objects contacted within events. This result is consistent with theories proposing that event segmentation results from transient increases in prediction error. Significance Statement The ability to predict what will happen in the near future is integral for adaptive functioning, and although there has been extensive research on predictive processing, the dynamics of prediction at the second by second level during the perception of naturalistic activity has never been explored. The current studies therefore describe results from a novel task, the Predictive Looking at Action Task (PLAT) that can be used to investigate the dynamics of predictive processing. Demonstrating the utility of this task to investigate predictive processing, this task was applied to study the predictions made by Event Segmentation Theory, which suggests that people experience event boundaries at times of change and unpredictability in the environment. The results of these studies are of interest to communities investigating the dynamic comprehension and segmentation of naturalistic events and to communities studying visual perception of naturalistic activity.

Utilizing the Centiloid scale in cross-sectional and longitudinal PiB PET studies

Amyloid imaging is a valuable tool for research and diagnosis in dementing disorders. Successful use of this tool is limited by the lack of a common standard in the quantification of amyloid imaging data. The Centiloid approach was recently proposed to address this problem and in this work, we report our implementation of this approach and evaluate the impact of differences in underlying image analysis methodologies using both cross-sectional and longitudinal datasets. The Centiloid approach successfully converts quantitative amyloid burden measurements into a common Centiloid scale (CL) and comparable dynamic range. As expected, the Centiloid values derived from different analytical approaches inherit some of the inherent benefits and drawbacks of the underlying approaches, and these differences result in statistically significant (p < 0.05) differences in the variability and group mean values. Because of these differences, even after expression in CL, the 95% specificity amyloid positivity thresholds derived from different analytic approaches varied from 5.7 CL to 11.9 CL, and the reliable worsening threshold varied from −2.0 CL to 11.0 CL. Although this difference is in part due to the dependency of the threshold determination methodology on the statistical characteristics of the measurements. When amyloid measurements obtained from different centers are combined for analysis, one should not expect Centiloid conversion to eliminate all the differences in amyloid burden measurements due to variabilities in underlying acquisition protocols and analysis techniques.