Patrizia Vannini

Functional Alterations in Memory Networks in Early Alzheimer’s Disease

The hallmark clinical symptom of early Alzheimer’s disease (AD) is episodic memory impairment. Recent functional imaging studies suggest that memory function is subserved by a set of distributed networks, which include both the medial temporal lobe (MTL) system and the set of cortical regions collectively referred to as the default network. Specific regions of the default network, in particular, the posteromedial cortices, including the precuneus and posterior cingulate, are selectively vulnerable to early amyloid deposition in AD. These regions are also thought to play a key role in both memory encoding and retrieval, and are strongly functionally connected to the MTL. Multiple functional magnetic resonance imaging (fMRI) studies during memory tasks have revealed alterations in these networks in patients with clinical AD. Similar functional abnormalities have been detected in subjects at-risk for AD, including those with genetic risk and older individuals with mild cognitive impairment. Recently, we and other groups have found evidence of functional alterations in these memory networks even among cognitively intact older individuals with occult amyloid pathology, detected by PET amyloid imaging. Taken together, these findings suggest that the pathophysiological process of AD exerts specific deleterious effects on these distributed memory circuits, even prior to clinical manifestations of significant memory impairment. Interestingly, some of the functional alterations seen in prodromal AD subjects have taken the form of increases in activity relative to baseline, rather than a loss of activity. It remains unclear whether these increases in fMRI activity may be compensatory to maintain memory performance in the setting of early AD pathology or instead, represent evidence of excitotoxicity and impending neuronal failure. Recent studies have also revealed disruption of the intrinsic connectivity of these networks observable even during the resting state in early AD and asymptomatic individuals with high amyloid burden. Research is ongoing to determine if these early network alterations will serve as sensitive predictors of clinical decline, and eventually, as markers of pharmacological response to potential disease-modifying treatments for AD.

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.

Explaining the encoding/retrieval flip: memory-related deactivations and activations in the posteromedial cortex

The posteromedial cortex (PMC) is strongly linked to episodic memory and age-related memory deficits. The PMC shows deactivations during a variety of demanding cognitive tasks as compared to passive baseline conditions and has been associated with the default-mode of the brain. Interestingly, the PMC exhibits opposite levels of functional MRI activity during encoding (learning) and retrieval (remembering), a pattern dubbed the encoding/retrieval flip (E/R-flip). Yet, the exact role of the PMC in memory function has remained unclear. This review discusses the possible neurofunctional and clinical significance of the E/R-flip pattern. Regarding neurofunctional relevance, we will review four hypotheses on PMC function: (1) the internal orienting account, (2) the self-referential processing account, (3) the reallocation account, and (4) the bottom-up attention account. None of these accounts seem to provide a complete explanation for the E/R-flip pattern in PMC. Regarding clinical relevance, we review work on aging and Alzheimers disease, indicating that amyloid deposits within PMC, years before clinical memory deficits become apparent. High amyloid burden within PMC is associated with detrimental influences on memory encoding, in particular, the attenuation of beneficial PMC deactivations. Finally, we discuss functional subdivisions within PMC that help to provide a more precise picture of the variety of signals observed within PMC. Collective data from anatomical, task-related fMRI and resting-state studies all indicate that the PMC is composed of three main regions, the precuneus, retrosplenial, and posterior cingulate cortex, each with a distinct function. We will conclude with a summary of the findings and provide directions for future research.

Reduced neuronal efficacy in progressive mild cognitive impairment : A prospective fMRI study on visuospatial processing

Mild cognitive impairment (MCI) often refers to the preclinical stage of dementia, where the majority develop Alzheimers disease (AD). Given that neurodegenerative burden and compensatory mechanisms might exist before accepted clinical symptoms of AD are noticeable, the current prospective study aimed to investigate the functioning of brain regions in the visuospatial networks responsible for preclinical symptoms in AD using event-related functional magnetic resonance imaging (fMRI). Eighteen MCI patients were evaluated and clinically followed for approximately 3 years. Five progressed to AD (PMCI) and eight remained stable (SMCI). Thirteen age-, gender- and education-matched controls also participated. An angle discrimination task with varying task demands was used. Brain activation patterns as well as task demand-dependent and -independent signal changes between the groups were investigated by using an extended general linear model including individual performance (reaction time [RT]) of each single trial. Similar behavioral (RT and accuracy) responses were observed between MCI patients and controls. A network of bilateral activations, e.g. dorsal pathway, which increased linearly with increasing task demand, was engaged in all subjects. Compared with SMCI patients and controls, PMCI patients showed a stronger relation between task demand and brain activity in left superior parietal lobules (SPL) as well as a general task demand-independent increased activation in left precuneus. Altered brain function can be detected at a group level in individuals that progress to AD before changes occur at the behavioral level. Increased parietal activation in PMCI could reflect a reduced neuronal efficacy due to accumulating AD pathology and might predict future clinical decline in patients with MCI.

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.

Amyloid Deposition Is Linked to Aberrant Entorhinal Activity among Cognitively Normal Older Adults

Normal aging is often difficult to distinguish from the earliest stages of Alzheimers disease. Years before clinical memory deficits manifest, amyloid-β deposits in the cortex in many older individuals. Neuroimaging studies indicate that a set of densely connected neocortical regions, referred to as the default network, is especially vulnerable to amyloid-β deposition. Yet, the impact of amyloid-β on age-related changes within the medial temporal lobe (MTL) memory system is less clear. Here we demonstrate that cognitively normal older humans, compared with young adults, show reduced ability to modulate hippocampal activations and entorhinal deactivations during an episodic memory task. Among older adults, amyloid-β deposition was associated with failure to modulate activity in entorhinal cortex, but not hippocampus. Furthermore, we show that entorhinal regions demonstrating amyloid-β-related dysfunction are directly connected to the neocortical regions of the default network. Together these findings link neocortical amyloid-β deposition to neuronal dysfunction specifically in entorhinal cortex, while aging is associated with more widespread functional changes across the MTL.

Task demand modulations of visuospatial processing measured with functional magnetic resonance imaging

Brain imaging based on functional magnetic resonance imaging (fMRI) provides a useful tool to examine neural networks and cerebral structures subserving visuospatial function. It allows not only the qualitative determination of which areas are active during task processing, but also estimates the quantitative contribution of involved brain regions to different aspects of spatial processing. In this study, we investigated in 10 healthy subjects how the amount of task (computational) demand in an angle discrimination task was related to neural activity as measured with event-related fMRI. Task demand, indicated by behavioral performance, was modulated by presenting clocks with different angular disparity and length of hands. Significant activations were found in the cortical network subserving the visual and visuospatial processing, including the right and left superior parietal lobules (SPL), striate visual areas, and sensorimotor areas. Both blood oxygenation level-dependent (BOLD) signal strength and spatial extent of activation in right as well as left SPL increased with task demand. By contrast, no significant correlation or a very weak correlation was found between the task demand and the BOLD signal as well as between task demand and spatial extent of activations in the striate visual areas and in the sensorimotor areas. These results support the hypothesis that increased computational demand requires more brain resources. The brain regions that are most specialized for the execution of the visuospatial task can be assessed by relating the imposed task demand to the functional activation measured.

Subjective cognitive concerns, amyloid-β, and neurodegeneration in clinically normal elderly

Objective: To determine whether neuroimaging biomarkers of amyloid-β (Aβ) and neurodegeneration (ND) are associated with greater self-reported subjective cognitive concerns (SCC) in clinically normal older individuals. Methods: A total of 257 participants underwent Pittsburgh compound B PET, PET with fluorodeoxyglucose 18F, and structural MRI, as well as a battery of neuropsychological measures including several questionnaires regarding SCC. Individuals were classified into 4 biomarker groups: biomarker negative (Aβ−/ND−), amyloidosis alone (Aβ+/ND−), amyloidosis plus ND (Aβ+/ND+), and ND alone (Aβ−/ND+). Results: Both Aβ and ND were independently associated with greater SCC controlling for objective memory performance. By contrast, neither Aβ nor ND was associated with objective memory performance controlling for SCC. Further examination revealed greater SCC in individuals with Aβ or ND positivity compared to biomarker-negative individuals. In addition, greater SCC predicted Aβ positivity when controlling for ND status. Conclusions: When individuals were grouped by biomarker status, those who were positive on Aβ or ND had the highest report of SCC compared to biomarker-negative individuals. Findings were consistent when SCC was used to predict Aβ positivity. Taken together, results suggest that both Aβ and ND are associated with SCC, independent of objective memory performance. Enrichment of individuals with SCC may increase likelihood of Aβ and ND markers in potential participants for secondary prevention trials.

The encoding/retrieval flip: Interactions between memory performance and memory stage and relationship to intrinsic cortical networks

fMRI studies have linked the posteromedial cortex to episodic learning (encoding) and remembering (retrieval) processes. The posteromedial cortex is considered part of the default network and tends to deactivate during encoding but activate during retrieval, a pattern known as the encoding/retrieval flip. Yet, the exact relationship between the neural correlates of memory performance (hit/miss) and memory stage (encoding/retrieval) and the extent of overlap with intrinsic cortical networks remains to be elucidated. Using task-based fMRI, we isolated the pattern of activity associated with memory performance, memory stage, and the interaction between both. Using resting-state fMRI, we identified which intrinsic large-scale functional networks overlapped with regions showing task-induced effects. Our results demonstrated an effect of successful memory performance in regions associated with the control network and an effect of unsuccessful memory performance in the ventral attention network. We found an effect of memory retrieval in brain regions that span the default and control networks. Finally, we found an interaction between memory performance and memory stage in brain regions associated with the default network, including the posteromedial cortex, posterior parietal cortex, and parahippocampal cortex. We discuss these findings in relation to the encoding/retrieval flip. In general, the findings demonstrate that task-induced effects cut across intrinsic cortical networks. Furthermore, regions within the default network display functional dissociations, and this may have implications for the neural underpinnings of age-related memory disorders.

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.