The Effect of Shape Familiarity on Object-Based Attention

Thesis advisor: Sean MacEvoyHumans can pay attention both to particular locations in space (“space-based attention”) and to specific objects (“object-based attention”). The goal of this study was to understand the role of object familiarity and complexity in the control of object-based attention. We used a well-known manifestation of object-based attention known as same-object advantage (SOA) to test this. In SOA, participants are faster at detecting a target event that takes place in a cued object than one that takes place in an uncued object, even when the distance between cue and target is kept fixed. To control shape familiarity, objects in the current study were randomly-generated irregular polygons known as Attneave shapes. Experiment 1 showed that SOA exists for these irregular shapes, even when participants are unfamiliar with them. In Experiment 2, participants first underwent training designed to familiarize them with a subset of the Attneave shapes used in Experiment 1. Again there was a significant SOA. If object-based attention is dependent upon object familiarity, we hypothesized that SOA, measured in terms of reaction time, should be greater in Experiment 2 than Experiment 1. Although there was a numerical increase in the reaction time signature of SOA in Experiment 2, this effect was not significant. While this does not strictly support our hypothesis, several aspects of this study suggest that object familiarity does play some role in mediating object-based attention.Thesis (BS) — Boston College, 2013.Submitted to: Boston College. College of Arts and Sciences.Discipline: Psychology Honors Program.Discipline: Psychology

Investigating regional amyloid accumulation and cerebral blood flow reductions in aging and Alzheimer's disease

Alzheimer’s disease (AD) is a form of dementia characterized by a long preclinical phase during which amyloid (Aβ) and tau proteins aggregate into plaques and tangles, respectively. The prevailing hypothesis holds that Aβ aggregation sets off a series of events, including tau aggregation and neurodegeneration, which ultimately leads to cognitive decline. Study of Aβ and tau aggregation has been facilitated in recent years by advances in positron emission tomography (PET), which allow serial imaging to understand what early factors affect clinical outcomes and progression to AD. Through this work, we know that older adults with high Aβ have greater levels of neurodegeneration and are at higher risk for developing AD. However, Aβ may be at its most toxic before it aggregates into insoluble plaques. This may mean that by the time global thresholds for Aβ positivity are reached, soluble forms of Aβ may have already begun the AD pathological cascade. As such, it is important to identify early levels of abnormal Aβ before cognitive decline and, to the extent that it is possible, before Aβ pathology is high everywhere. The first project focuses on identifying early regions of Aβ deposition in cognitively normal older adults through PET imaging and creating a time course of regional Aβ burden. We found that parietal and frontal regions exhibited slightly earlier Aβ pathology than other studied regions, but that they all reached their peak accumulation rates within an eight-year span. Aβ accumulation in all brain regions studied was also similarly associated with apolipoprotein ε4 allele, a genetic risk factor for sporadic AD, and tau pathology. These results indicate that spread from one region to another is unlikely. Neurodegeneration is widely thought to occur later in AD than Aβ and tau aggregation and can be studied with both PET and MRI measures. These measures do not always concur, so it can be useful to have both measures available. However, the main PET measure of neurodegeneration, [18F] Fluorodeoxyglucose (FDG), which measures glucose metabolism, has been discontinued in many research studies because it adds an additional scan and radiation exposure. Thus, the second project investigates the use of relative delivery (R1), a proxy of cerebral blood flow derived from dynamic PET scans (which are often collected in research protocols), as an alternative measure to FDG. We found that R1 and FDG were highly correlated with one another and with MRI-based neurodegeneration measures. They were also similarly associated with cognition in AD patients. This confirms that R1 can be used instead of FDG in situations where the latter is unavailable and may be particularly useful when dynamic PET scans are already being acquired. Although cerebral blood flow is a proxy for neurodegeneration, it also reflects vascular function. A major question is whether vascular dysfunction leads to Aβ and tau accumulation, or whether changes in cerebral blood flow simply reflect neurodegeneration. Longitudinal investigations of Aβ, tau, and cerebral blood flow can help answer this question. The third project investigates change in R1 related to baseline Aβ/tau, and vice versa. We found that baseline Aβ predicted change in R1, but the opposite was not true, indicating that Aβ accumulation is upstream of cerebral blood flow and therefore it is less likely that blood flow changes drive amyloid deposition. Tau and R1 were correlated cross-sectionally and showed weak bidirectional longitudinal relationships that will require further study to untangle. Taken together, these results further our understanding of the temporal dynamics of AD pathology and lend support to the Aβ cascade hypothesis. Our results indicate that the identification of a stable “early Aβ” region across studies with Aβ-PET is unlikely, and that cerebral blood flow measured with R1 is a proxy for neurodegeneration rather than reflecting early vascular pathology that incites AD

Poorer aging trajectories are associated with elevated serotonin synthesis capacity.

The dorsal raphe nucleus (DRN) is one of the earliest targets of Alzheimers disease-related tau pathology and is a major source of brain serotonin. We used [18F]Fluoro-m-tyrosine ([18F]FMT) PET imaging to measure serotonin synthesis capacity in the DRN in 111 healthy adults (18-85 years-old). Similar to reports in catecholamine systems, we found elevated serotonin synthesis capacity in older adults relative to young. To establish the structural and functional context within which serotonin synthesis capacity is elevated in aging, we examined relationships among DRN [18F]FMT net tracer influx (Ki) and longitudinal changes in cortical thickness using magnetic resonance imaging, longitudinal changes in self-reported depression symptoms, and AD-related tau and β-amyloid (Aβ) pathology using cross-sectional [18F]Flortaucipir and [11C]Pittsburgh compound-B PET respectively. Together, our findings point to elevated DRN [18F]FMT Ki as a marker of poorer aging trajectories. Older adults with highest serotonin synthesis capacity showed greatest temporal lobe cortical atrophy. Cortical atrophy was associated with increasing depression symptoms over time, and these effects appeared to be strongest in individuals with highest serotonin synthesis capacity. We did not find direct relationships between serotonin synthesis capacity and AD-related pathology. Exploratory analyses revealed nuanced effects of sex within the older adult group. Older adult females showed the highest DRN synthesis capacity and exhibited the strongest relationships between entorhinal cortex tau pathology and increasing depression symptoms. Together these findings reveal PET measurement of the serotonin system to be a promising marker of aging trajectories relevant to both AD and affective changes in older age

Rates of β-amyloid deposition indicate widespread simultaneous accumulation throughout the brain

Amyloid plaque aggregation is a pathologic hallmark of Alzheimer's disease (AD) that occurs early in the disease. However, little is known about its progression throughout the brain. Using Pittsburgh Compound B (PIB)-PET imaging, we investigated the progression of regional amyloid accumulation in cognitively normal older adults. We found that all examined regions reached their peak accumulation rates 24-28 years after an estimated initiation corresponding to the mean baseline PIB-PET signal in amyloid-negative older adults. We also investigated the effect of increased genetic risk conferred by the apolipoprotein-E ɛ4 allele on rates of amyloid accumulation, as well as the relationship between regional amyloid accumulation and regional tau pathology, another hallmark of AD, measured with Flortaucipir-PET. Carriers of the ɛ4 allele had faster amyloid accumulation in all brain regions. Furthermore, in all regions excluding the temporal lobe, faster amyloid accumulation was associated with greater tau burden. These results indicate that amyloid accumulates near-simultaneously throughout the brain and is associated with higher AD pathology, and that genetic risk of AD is associated with faster amyloid accumulation

Age-Related Increases in Tip-of-the-tongue are Distinct from Decreases in Remembering Names: A Functional MRI Study

Tip-of-the-tongue (TOT) experiences increase with age and frequently heighten concerns about memory decline. We studied 73 clinically normal older adults participating in the Harvard Aging Brain Study. They completed a functional magnetic resonance imaging (fMRI) task that required remembering names associated with pictures of famous faces. Older age was associated with more self-reported TOT experiences and a decrease in the percentage of remembered names. However, the percentage of TOT experiences and the percentage of remembered names were not directly correlated. We mapped fMRI activity for recollection of famous names and TOT and examined activity in the hippocampal formation, retrosplenial cortex, and lateral prefrontal cortex. The hippocampal formation was similarly activated in recollection and TOT experiences. In contrast, the retrosplenial cortex was most active for recollection and lateral prefrontal cortex was most active for TOT experiences. Together, the results confirm that age-related increases in TOT experiences are not only solely the consequence of age-related decline in recollection, but also likely reflect functional alterations in the brain networks that support retrieval monitoring and cognitive control. These findings provide behavioral and neuroimaging evidence that age-related TOT experiences and memory failure are partially independent processes

Tau accumulation in clinically normal older adults is associated with hippocampal hyperactivity.

Animal studies demonstrate that hyperactive neurons facilitate early accumulation and spread of tau and amyloid-β proteins in the pathological cascade of Alzheimer's disease (AD). Human neuroimaging studies have linked hippocampal hyperactivity to amyloid-β accumulation, apolipoprotein ε4 (APOE4) and clinical progression from prodromal AD to clinical dementia. The relationship between hippocampal hyperactivity and early AD molecular pathology (amyloid-β and tau accumulation) prior to clinical symptoms remains to be elucidated. Here, we studied 120 clinically normal older humans (80 females/40 males) enrolled in the Harvard Aging Brain Study. We measured functional magnetic resonance imaging (fMRI) activity during successful memory encoding and amyloid-β accumulation with PiB-PET imaging. Additionally, we measured tau accumulation using AV1451 PET imaging in a subset of 87 participants. In this subset, we found that inferior temporal tau accumulation was associated with increased fMRI activity in the hippocampus, but showed no clear association with amyloid. Together, the findings support a hypothetical model of the evolution of preclinical AD that place hippocampal hyperactivity concurrent with spread of tau pathology to neocortical regions prior to clinical impairment.The circumstances under which the hippocampus becomes hyperactive in preclinical stages of Alzheimer's disease (AD) have thus far remained elusive. Recent advances in positron emission tomography (PET) tracers now enable in-vivo characterization of amyloid-β and tau accumulation. Here, we combine amyloid and tau PET with functional magnetic resonance imaging (fMRI) to examine the association between Alzheimer's disease pathology and memory-related brain activity in clinically normal older adults. We found an association between increased hippocampal activity and tau accumulation in the inferior temporal cortex. These data suggest that the pathogenesis of hippocampal hyperactivity occurs concurrent with the spread of tau pathology from the entorhinal cortex to the neocortex, prior to the clinical manifestations of Alzheimer's disease

Interactive versus additive relationships between regional cortical thinning and amyloid burden in predicting clinical decline in mild AD and MCI individuals

The biological mechanisms that link Beta-amyloid (Aβ) plaque deposition, neurodegeneration, and clinical decline in Alzheimer's disease (AD) dementia, have not been completely elucidated. Here we studied whether amyloid accumulation and neurodegeneration, independently or interactively, predict clinical decline over time in a group of memory impaired older individuals [diagnosed with either amnestic mild cognitive impairment (MCI), or mild AD dementia]. We found that baseline Aβ-associated cortical thinning across clusters encompassing lateral and medial temporal and parietal cortices was related to higher baseline Clinical Dementia Rating Sum-of-Boxes (CDR-SB). Baseline Aβ-associated cortical thinning also predicted CDR-SB over time. Notably, the association between CDR-SB change and cortical thickness values from the right lateral temporo-parietal cortex and right precuneus was driven by individuals with high Aβ burden. In contrast, the association between cortical thickness in the medial temporal lobe (MTL) and clinical decline was similar for individuals with high or low Aβ burden. Furthermore, amyloid pathology was a stronger predictor for clinical decline than MTL thickness. While this study validates previous findings relating AD biomarkers of neurodegeneration to clinical impairment, here we show that regions outside the MTL may be more vulnerable and specific to AD dementia. Additionally, excluding mild AD individuals revealed that these relationships remained, suggesting that lower cortical thickness values in specific regions, vulnerable to amyloid pathology, predict clinical decline already at the prodromal stage

Phases of Hyperconnectivity and Hypoconnectivity in the Default Mode and Salience Networks Track with Amyloid and Tau in Clinically Normal Individuals

Alzheimer's disease (AD) is characterized by two hallmark molecular pathologies: amyloid aβ1-42 and Tau neurofibrillary tangles. To date, studies of functional connectivity MRI (fcMRI) in individuals with preclinical AD have relied on associations with in vivo measures of amyloid pathology. With the recent advent of in vivo Tau-PET tracers it is now possible to extend investigations on fcMRI in a sample of cognitively normal elderly humans to regional measures of Tau. We modeled fcMRI measures across four major cortical association networks [default-mode network (DMN), salience network (SAL), dorsal attention network, and frontoparietal control network] as a function of global cortical amyloid [Pittsburgh Compound B (PiB)-PET] and regional Tau (AV1451-PET) in entorhinal, inferior temporal (IT), and inferior parietal cortex. Results showed that the interaction term between PiB and IT AV1451 was significantly associated with connectivity in the DMN and salience. The interaction revealed that amyloid-positive (aβ+) individuals show increased connectivity in the DMN and salience when neocortical Tau levels are low, whereas aβ+ individuals demonstrate decreased connectivity in these networks as a function of elevated Tau-PET signal. This pattern suggests a hyperconnectivity phase followed by a hypoconnectivity phase in the course of preclinical AD.SIGNIFICANCE STATEMENT This article offers a first look at the relationship between Tau-PET imaging with F18-AV1451 and functional connectivity MRI (fcMRI) in the context of amyloid-PET imaging. The results suggest a nonlinear relationship between fcMRI and both Tau-PET and amyloid-PET imaging. The pattern supports recent conjecture that the AD fcMRI trajectory is characterized by periods of both hyperconnectivity and hypoconnectivity. Furthermore, this nonlinear pattern can account for the sometimes conflicting reports of associations between amyloid and fcMRI in individuals with preclinical Alzheimer's disease

Heterogeneity in Suspected Non-Alzheimer Disease Pathophysiology Among Clinically Normal Older Individuals.

A substantial proportion of clinically normal (CN) older individuals are classified as having suspected non-Alzheimer disease pathophysiology (SNAP), defined as biomarker negative for β-amyloid (Aβ-) but positive for neurodegeneration (ND+). The etiology of SNAP in this population remains unclear. To determine whether CN individuals with SNAP show evidence of early Alzheimer disease (AD) processes (ie, elevated tau levels and/or increased risk for cognitive decline). This longitudinal observational study performed in an academic medical center included 247 CN participants from the Harvard Aging Brain Study. Participants were classified into preclinical AD stages using measures of Aβ (Pittsburgh Compound B [PIB]-labeled positron emission tomography) and ND (hippocampal volume or cortical glucose metabolism from AD-vulnerable regions). Classifications included stages 0 (Aβ-/ND-), 1 (Aβ+/ND-), and 2 (Aβ+/ND+) and SNAP (Aβ-/ND+). Continuous levels of PiB and ND, tau levels in the medial and inferior temporal lobes, and longitudinal cognition were examined. Data collection began in 2010 and is ongoing. Data were analyzed from 2015 to 2016. Evidence of amyloid-independent tau deposition and/or cognitive decline. Of the 247 participants (142 women [57.5%]; 105 men [42.5%]; mean age, 74 [range, 63-90] years), 64 (25.9%) were classified as having SNAP. Compared with the stage 0 group, the SNAP group was not more likely to have subthreshold PiB values (higher values within the Aβ- range), suggesting that misclassification due to the PiB cutoff was not a prominent contributor to this group (mean [SD] distribution volume ratio, 1.08 [0.05] for the SNAP group; 1.09 [0.05] for the stage 1 group). Tau levels in the medial and inferior temporal lobes were indistinguishable between the SNAP and stage 0 groups (entorhinal cortex, β = -0.005 [SE, 0.036]; parahippocampal gyrus, β = -0.001 [SE, 0.027]; and inferior temporal lobe, β = -0.004 [SE, 0.027]; P ≥ .88) and were lower in the SNAP group compared with the stage 2 group (entorhinal cortex, β = -0.125 [SE, 0.041]; parahippocampal gyrus, β = -0.074 [SE, 0.030]; and inferior temporal lobe, β = -0.083 [SE, 0.031]; P ≤ .02). The stage 2 group demonstrated greater cognitive decline compared with all other groups (stage 0, β = -0.239 [SE, 0.042]; stage 1, β = -0.242 [SE, 0.051]; and SNAP, β = -0.157 [SE, 0.044]; P ≤ .001), whereas the SNAP group showed a diminished practice effect over time compared with the stage 0 group (β = -0.082 [SE, 0.037]; P = .03). In this study, clinically normal adults with SNAP did not exhibit evidence of elevated tau levels, which suggests that this biomarker construct does not represent amyloid-independent tauopathy. At the group level, individuals with SNAP did not show cognitive decline but did show a diminished practice effect. SNAP is likely heterogeneous, with a subset of this group at elevated risk for short-term decline. Future refinement of biomarkers will be necessary to subclassify this group and determine the biological correlates of ND markers among Aβ- CN individuals