Kelly O'Keefe

Amyloid deposition is associated with impaired default network function in older persons without dementia

Alzheimers disease (AD) has been associated with functional alterations in a distributed network of brain regions linked to memory function, with a recent focus on the cortical regions collectively known as the default network. Posterior components of the default network, including the precuneus and posterior cingulate, are particularly vulnerable to early deposition of amyloid beta-protein, one of the hallmark pathologies of AD. In this study, we use in vivo amyloid imaging to demonstrate that high levels of amyloid deposition are associated with aberrant default network functional magnetic resonance imaging (fMRI) activity in asymptomatic and minimally impaired older individuals, similar to the pattern of dysfunction reported in AD patients. These findings suggest that amyloid pathology is linked to neural dysfunction in brain regions supporting memory function and provide support for the hypothesis that cognitively intact older individuals with evidence of amyloid pathology may be in early stages of AD.

Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline

Background: Previous cross-sectional fMRI studies in subjects with prodromal Alzheimer disease (AD) have reported variable results, ranging from hypoactivation, similar to patients with AD, to paradoxically increased activation or hyperactivation compared to cognitively normal older individuals. We have hypothesized that subjects in early phases of prodromal AD may experience a period of hippocampal hyperactivation, followed by loss of hippocampal activation as the disease progresses. Methods: We studied 51 older individuals without dementia (Clinical Dementia Rating [CDR] at baseline of 0, n = 21, and 0.5, n = 30) with longitudinal clinical and neuropsychological assessments, as well as fMRI during a face-name associative memory paradigm. Whole brain and region-of-interest analyses were applied to the longitudinal fMRI data. Results: Subjects classified as CDR 0 at baseline showed no difference in fMRI activity over 2 years, whereas those who were CDR 0.5 at baseline demonstrated a decrease in fMRI activity in the right hippocampus (p < 0.001). Dividing the subjects on the basis of their clinical and neuropsychological change over the 2 years, we found that subjects with more rapid decline demonstrated both the highest hippocampal activation at baseline, and the greatest loss of hippocampal activation. These findings remained significant after accounting for age, hippocampal volume, and APOE ε4 carrier status. Conclusions: Clinical decline is associated with loss of hippocampal activation in older subjects. Longitudinal fMRI provides a reliable indicator of brain activation over time, and may prove useful in identifying functional brain changes associated with cognitive decline on the trajectory toward clinical Alzheimer disease.

Intrinsic connectivity between the hippocampus and posteromedial cortex predicts memory performance in cognitively intact older individuals.

Coherent fluctuations of spontaneous brain activity are present in distinct functional-anatomic brain systems during undirected wakefulness. However, the behavioral significance of this spontaneous activity has only begun to be investigated. Our previous studies have demonstrated that successful memory formation requires coordinated neural activity in a distributed memory network including the hippocampus and posteromedial cortices, specifically the precuneus and posterior cingulate (PPC), thought to be integral nodes of the default network. In this study, we examined whether intrinsic connectivity during the resting state between the hippocampus and PPC can predict individual differences in the performance of an associative memory task among cognitively intact older individuals. The intrinsic connectivity, between regions within the hippocampus and PPC that were maximally engaged during a subsequent memory fMRI task, was measured during a period of rest prior to the performance of the memory paradigm. Stronger connectivity between the hippocampal and posteromedial regions during rest predicted better performance on the memory task. Furthermore, hippocampal-PPC intrinsic connectivity was also significantly correlated with episodic memory measures on neuropsychological tests, but not with performance in non-memory domains. Whole-brain exploratory analyses further confirmed the spatial specificity of the relationship between hippocampal-default network posteromedial cortical connectivity and memory performance in older subjects. Our findings provide support for the hypothesis that one of the functions of this large-scale brain network is to subserve episodic memory processes. Research is ongoing to determine if impaired connectivity between these regions may serve as a predictor of memory decline related to early Alzheimers disease.

Hippocampal Hyperactivation Associated with Cortical Thinning in Alzheimer's Disease Signature Regions in Non-Demented Elderly Adults

Alzheimers disease (AD) is associated with functional and structural alterations in a distributed network of brain regions supporting memory and other cognitive domains. Functional abnormalities are present in mild cognitive impairment (MCI) with evidence of early hyperactivity in medial temporal lobe regions, followed by failure of hippocampal activation as dementia develops. Atrophy in a consistent set of cortical regions, the “cortical signature of AD,” has been reported at the stage of dementia, MCI, and even in clinically normal (CN) older individuals predicted to develop AD. Despite multiple lines of evidence for each of these findings, the relationship between this structural marker of AD-related neurodegeneration and this functional marker of the integrity of the episodic memory system has not yet been elucidated. We investigated this relationship in 34 nondemented older humans (CN, N = 18; MCI, N = 16). Consistent with previous studies, we found evidence of hippocampal hyperactivation in MCI compared with CN. Additionally, within this MCI group, increased hippocampal activation correlated with cortical thinning in AD-signature regions. Even within the CN group, increased hippocampal activity was negatively correlated with cortical thinning in a subset of regions, including the superior parietal lobule (r = −0.66; p < 0.01). These findings, across a continuum of nondemented and mildly impaired older adults, support the hypothesis that paradoxically increased hippocampal activity may be an early indicator of AD-related neurodegeneration in a distributed network.

What Goes Down Must Come Up: Role of the Posteromedial Cortices in Encoding and Retrieval

The hypothesis that the neural network supporting successful episodic memory retrieval overlaps with the regions involved in episodic encoding has garnered much interest; however, the role of the posteromedial regions remains to be fully elucidated. Functional magnetic resonance imaging (fMRI) studies during successful encoding typically demonstrate deactivation of posteromedial cortices, whereas successful retrieval of previously encoded information has been associated with activation of these regions. Here, we performed an event-related fMRI experiment during an associative face-name encoding and retrieval task to investigate the topography and functional relationship of the brain regions involved in successful memory processes. A conjunction analysis of novel encoding and subsequent successful retrieval of names revealed an anatomical overlap in bilateral posteromedial cortices. In this region, a significant negative correlation was found: Greater deactivation during encoding was related to greater activation during successful retrieval. In contrast, the hippocampus and prefrontal cortex demonstrated positive activation during both encoding and retrieval. Our results provide further evidence that posteromedial regions constitute critical nodes in the large-scale cortical network subserving episodic memory. These results are discussed in relation to the default mode hypothesis, the involvement of posteromedial cortices in successful memory formation and retention, as well as potential implications for aging and neurodegenerative disease.

Evidence of Altered Posteromedial Cortical fmri Activity in Subjects at Risk for Alzheimer Disease

The posteromedial cortices and other regions of the “default network” are particularly vulnerable to the pathology of Alzheimer disease (AD). In this study, we performed functional magnetic resonance imaging (fMRI) to investigate whether the presence of apolipoprotein E (APOE) ϵ4 allele and degree of memory impairment were associated with the dysfunction of these brain regions. Seventy-five elderly subjects ranging from cognitively normal to mild AD, divided into ϵ4 carriers and noncarriers, underwent fMRI during a memory-encoding task. Across all subjects, posteromedial and ventral anterior cingulate cortices (key components of the default network) as well as right middle and inferior prefrontal regions demonstrated reduced task-induced deactivation in the ϵ4 carriers relative to noncarriers. Even among cognitively normal subjects, ϵ4 carriers demonstrated reduced posteromedial deactivation compared with the noncarriers in the same regions which demonstrated failure of deactivation in AD patients. Greater failure of posteromedial deactivation was related to worse memory performance (delayed recall) across all subjects and within the range of cognitively normal subjects. In summary, the posteromedial cortical fMRI response pattern is modulated both by the presence of APOE ϵ4 and episodic memory capability. Altered fMRI activity of the posteromedial areas of the brain default network may be an early indicator of risk for AD.

Reliability of functional magnetic resonance imaging associative encoding memory paradigms in non-demented elderly adults.

Functional magnetic resonance imaging (fMRI) holds significant potential to aid in the development of early interventions to improve memory function, and to assess longitudinal change in memory systems in aging and early Alzheimers disease (AD). However, the test–retest reliability of hippocampal activation and of “beneficial” deactivation in the precuneus has yet to be fully established during memory encoding tasks in older subjects. Using a mixed block and event‐related face‐name associative encoding paradigm, we assessed the reliability of hippocampal activation and default network deactivation over a 4‐ to 6‐week interscan interval in 27 older individuals who were cognitively normal [Clinical Dementia Rating (CDR) Scale = 0; n = 18] or mildly impaired (CDR = 0.5; n = 9). Reliability was assessed in whole brain maps and regions of interest using both a full‐task paradigm of six functional runs as well as an abbreviated paradigm of the first two functional runs, which would be advantageous for use in clinical trials. We found reliable hippocampal signal response across both block‐ and event‐related designs in the right hippocampus. Comparable reliability in hippocampal activation was found in the full and the abbreviated paradigm. Similar reliability in hippocampal activation was observed across both CDR groups overall, but the CDR 0.5 group was more variable in left hippocampal activity. Task‐related deactivation in the precuneus demonstrated much greater variability than hippocampal activation in all analyses. Overall, these results are encouraging for the utility of fMRI in “Proof of Concept” clinical trials investigating the efficacy of potentially therapeutic agents for treatment of age‐related memory changes, cognitive impairment, and early AD. Hum Brain Mapp, 2011.

P1-295: Longitudinal functional MRI demonstrates loss of hippocampal activation associated with clinical decline in nondemented older subjects

with a focus on the dorsolateral prefrontal cortex (DLPFC) as a region of interest because of its role in executive functions and working memory, and because of its frequent involvement in fMRI studies of cognitive tasks. Methods: Four patients with mild AD and eight healthy older adults were scanned on a 4-Tesla Varian-Oxford human imaging system. The subjects were instructed to remain relaxed while focusing their eyes on a central fixation for over 60 seconds. Functional images were acquired using two-shot spiral readout; 22 axial slices of 5.5 0.5mm. Data were processed using independent component analysis and artifacts attributed to physical and physiological sources were filtered. The time course of the representative resting state components (ICs) that were common across AD and healthy subjects were identified and analyzed applying GLM (p 0.001, uncorrected, extent 6). Signal changes, measured as the percentage difference between the highest and lowest of three consecutive fMRI data points during a scan were calculated. Results: The fMRI signals filtered for known imaging signal to noise ratio and physiological variations fluctuated during the resting phase. Three ICs were identified across subjects with each being characterized as a low frequency response ( 0.08Hz). Within the DFPLC, both the mean percentage change of the signal and the statistics in the contrast maps (i.e., for an IC) were greater in AD patients than in cognitively healthy older subjects. Conclusions: Regular patterns of fluctuations in fMRI indices of neural activity exist during rest and patients with mild AD demonstrated increased resting-state DLPFC activity. These resting state differences may reflect an early neurocompensatory response to AD.

P1-221: Amyloid deposition related to cortical thinning

three or more times with a follow-up of at least one year were selected resulting in 120 subjects with two scans and a clinical/pathological diagnosis (Table 1). Subjects’ scans were reviewed as a single first scan (method 1), the two unregistered presented side-by-side (method 2), and the registered pair (method 3). Separate assessments were made by a neuro-radiologist and a clinician. For each method each reviewer had to make both a main and a specific (subtype) diagnosis.

IC-P2-077: Amyloid deposition related to cortical thinning

blind to group status. Scans were then segmented into separate tissue classes using an adaptive fuzzy C-means algorithm. Volumes of gray matter and white matter tissue as well as total brain volume were calculated. Results: At both Time 1 and Time 2, the high-risk sample showed significantly smaller white matter volumes (Time 1 p 0.05, Time 2 p 0.04). Change across the time points, however, did not significantly differ between groups (control -50ccm, high-risk -53.28ccm). Conclusions: While the similar rate of white matter loss across groups may reflect aging, this would not provide an explanation for the initial significantly smaller white matter volume seen in the high-risk group. Further study will be needed to more fully understand the significance of reduced white matter volume as it relates to AD.