Caroline Sullivan

Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden

Disruption of functional connectivity between brain regions may represent an early functional consequence of β-amyloid pathology prior to clinical Alzheimers disease. We aimed to investigate if non-demented older individuals with increased amyloid burden demonstrate disruptions of functional whole-brain connectivity in cortical hubs (brain regions typically highly connected to multiple other brain areas) and if these disruptions are associated with neuronal dysfunction as measured with fluorodeoxyglucose-positron emission tomography. In healthy subjects without cognitive symptoms and patients with mild cognitive impairment, we used positron emission tomography to assess amyloid burden and cerebral glucose metabolism, structural magnetic resonance imaging to quantify atrophy and novel resting state functional magnetic resonance imaging processing methods to calculate whole-brain connectivity. Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism. Subtle connectivity disruptions and hypometabolism were already present in amyloid-positive asymptomatic subjects. Voxel-based morphometry measures indicate that these findings were not solely a consequence of regional atrophy. Whole-brain connectivity values and metabolism showed a positive correlation with each other and a negative correlation with amyloid burden. These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimers disease pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimers-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.

Subjective cognitive complaints and amyloid burden in cognitively normal older individuals.

Accumulating evidence suggests that subjective cognitive complaints (SCC) may indicate subtle cognitive decline characteristic of individuals with preclinical Alzheimers disease (AD). In this study, we sought to build upon previous studies by associating SCC and amyloid-β deposition using positron emission tomography with Pittsburgh Compound B (PiB-PET) in cognitively normal older individuals. One-hundred thirty one subjects (mean age 73.5±6) were administered three subjective cognitive questionnaires and a brief neuropsychological battery. A relationship between a subjective memory complaints composite score and cortical PiB binding was found to be significant, even after controlling for depressive symptoms. By contrast, there were no significant relationships between objective cognitive measures of memory and executive functions and cortical PiB binding. Our study suggests that SCC may be an early indicator of AD pathology detectable prior to significant objective impairment.

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.

Impaired default network functional connectivity in autosomal dominant Alzheimer disease

Objective: To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network. Methods: Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participants estimated years from expected symptom onset (eYO). Results: We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO. Conclusion: Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.

Age and amyloid-related alterations in default network habituation to stimulus repetition.

The neural networks supporting encoding of new information are thought to decline with age, although mnemonic techniques such as repetition may enhance performance in older individuals. Accumulation of amyloid-β, one hallmark pathology of Alzheimers disease (AD), may contribute to functional alterations in memory networks measured with functional magnetic resonance imaging (fMRI) prior to onset of cognitive impairment. We investigated the effects of age and amyloid burden on fMRI activity in the default network and hippocampus during repetitive encoding. Older individuals, particularly those with high amyloid burden, demonstrated decreased task-induced deactivation in the posteromedial cortices during initial stimulus presentation and failed to modulate fMRI activity in response to repeated trials, whereas young subjects demonstrated a stepwise decrease in deactivation with repetition. The hippocampus demonstrated similar patterns across the groups, showing task-induced activity that decreased in response to repetition. These findings demonstrate that age and amyloid have dissociable functional effects on specific nodes within a distributed memory network, and suggest that functional brain changes may begin far in advance of symptomatic Alzheimers disease.

Differential Functional Response in the Posteromedial Cortices and Hippocampus to Stimulus Repetition During Successful Memory Encoding

The reduction of neural activity in response to repeated stimuli, repetition suppression, is one of the most robust experience‐related cortical dynamics known to cognitive neuroscience. Functional magnetic resonance imaging (fMRI) studies during episodic memory encoding have demonstrated repetition suppression in the hippocampus and this reduction has been linked to successful memory formation. An emerging body of functional imaging evidence suggests that the posteromedial cortex, in addition to the medial temporal lobes, may have a pivotal role in successful episodic memory. This area typically deactivates during initial memory encoding, but its functional changes in response to repetitive encoding remain poorly specified. Here, we investigate the repetition‐related changes in the posteromedial cortex as well as the hippocampus while the participants underwent an fMRI experiment involving repetitive encoding of face–name pairs. During the first encoding trial of face–name pairs, significant activation in the hippocampus was observed. The second and third encoding trials demonstrated a repetition suppression effect in the hippocampus, indicated by a stepwise decrease of activation. In contrast, the posteromedial cortex demonstrated significant deactivation during the initial encoding trial of face–name pairs. The second and third encoding trials demonstrated a stepwise decrease of deactivation, repetition enhancement, with activity at or above baseline levels in the final encoding trial. These findings demonstrate that hippocampus repetition suppression as well as posteromedial repetition enhancement is related to successful encoding processes and are discussed in relation to the default mode hypothesis as well as potential implications for understanding late‐life amnestic disorders. Hum Brain Mapp, 2013.

Increased amyloid deposition and parental history of Alzheimer's disease is related to altered default network activity during successful encoding in cognitively normal older adults

and late life (age 68) (aSES) in a healthy sample without dementia. We hypothesize that cSES will influence late life brain volume. Specifically, we hypothesize that cSES will influence the size of regional brain structures, including the hippocampus.Methods:We followed up volunteers born in 1936 who had participated in the Scottish Mental Survey of 1947, when they sat the Moray House Test (MHT), a test of mental ability. In a follow-up study, a subgroup (N 1⁄4 320) was invited to undergo MRI examination; 250/320 (77%) agreed to MRI and 248 satisfactory image datasets were obtained. Exploratory structural equation modelling was performed. The model is summarized in Figure 1. Briefly, cSES has a direct effect on education (EDU), aSES and brain volume (hippocampal or total brain volume). The model also has indirect effects EDU and aSES. The model also adjusts for the influence of childhood intelligence (MHT) and sex. We examined two models; Model A exploring the predictors of hippocampal volume and Model B exploring the predictors of whole brain volume. Results:Table 1 shows the regression weights for models A and B. Model A shows a significant association between the cSES and hippocampal volume after adjusting for MHT, OCC, SEX and EDU. Model B shows that none of the hypothesized causal variables have a significant influence on total brain volume. In both cases, the model provided an excellent fit to the data. Conclusions: We have shown a significant association between cSES and hippocampal volumes in late life. This result is consistent with the proposal that early life conditions have a profound effect on brain structural and function. Here, we find evidence that these effects persist for more than 50 years. Table 1 The regression weights for each causal affect in the model. FO – Father occupation, PR – Number of public rooms in the childhood home, SAN – Sanitation in the family home, MHT – Moray House Test score, cSES – Childhood socioeconomic status, SEX – gender, EDUeducation (in years), aSES –Adult socioeconomic status, DI –Deprivation index, OCC–Occupation classification, HIP – latent hippocampal volume, LHV – Left Hippocampal volume, RHV Right hippocampal volume, BV – Brain volume *p<.05

Amyloid Burden in Late MCI Subjects Related to Failure of Hippocampal Activation

IC-P-130 AMYLOID BURDEN IN LATE MCI SUBJECTS RELATED TO FAILURE OF HIPPOCAMPAL ACTIVATION Caroline Sullivan, Deepti Putcha, Aaron Schultz, Dorene Rentz, Meghan Frey, Lauren Olson, Katherine Frishe, Gad Marshall, John A. Becker, Keith A. Johnson, Reisa A. Sperling, Brigham and Women’s Hospital, Boston, MA, USA; Massachusetts General Hospital, Boston, MA, USA. Contact e-mail: csullivan21@partners.org