Functional magnetic resonance imaging of semantic memory as a presymptomatic biomarker of Alzheimer's disease risk

Extensive research efforts have been directed toward strategies for predicting risk of developing Alzheimer's disease (AD) prior to the appearance of observable symptoms. Existing approaches for early detection of AD vary in terms of their efficacy, invasiveness, and ease of implementation. Several non-invasive magnetic resonance imaging strategies have been developed for predicting decline in cognitively healthy older adults. This review will survey a number of studies, beginning with the development of a famous name discrimination task used to identify neural regions that participate in semantic memory retrieval and to test predictions of several key theories of the role of the hippocampus in memory. This task has revealed medial temporal and neocortical contributions to recent and remote memory retrieval, and it has been used to demonstrate compensatory neural recruitment in older adults, apolipoprotein E ε4 carriers, and amnestic mild cognitive impairment patients. Recently, we have also found that the famous name discrimination task provides predictive value for forecasting episodic memory decline among asymptomatic older adults. Other studies investigating the predictive value of semantic memory tasks will also be presented. We suggest several advantages associated with the use of semantic processing tasks, particularly those based on person identification, in comparison to episodic memory tasks to study AD risk. Future directions for research and potential clinical uses of semantic memory paradigms are also discussed. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Age-Related Changes in the Functional Network Underlying Specific and General Autobiographical Memory Retrieval: A Pivotal Role for the Anterior Cingulate Cortex

Age-related changes in autobiographical memory (AM) recall are characterized by a decline in episodic details, while semantic aspects are spared. This deleterious effect is supposed to be mediated by an inefficient recruitment of executive processes during AM retrieval. To date, contrasting evidence has been reported on the neural underpinning of this decline, and none of the previous studies has directly compared the episodic and semantic aspects of AM in elderly. We asked 20 young and 17 older participants to recall specific and general autobiographical events (i.e., episodic and semantic AM) elicited by personalized cues while recording their brain activity by means of fMRI. At the behavioral level, we confirmed that the richness of episodic AM retrieval is specifically impoverished in aging and that this decline is related to the reduction of executive functions. At the neural level, in both age groups, we showed the recruitment of a large network during episodic AM retrieval encompassing prefrontal, cortical midline and posterior regions, and medial temporal structures, including the hippocampus. This network was very similar, but less extended, during semantic AM retrieval. Nevertheless, a greater activity was evidenced in the dorsal anterior cingulate cortex (dACC) during episodic, compared to semantic AM retrieval in young participants, and a reversed pattern in the elderly. Moreover, activity in dACC during episodic AM retrieval was correlated with inhibition and richness of memories in both groups. Our findings shed light on the direct link between episodic AM retrieval, executive control, and their decline in aging, proposing a possible neuronal signature. They also suggest that increased activity in dACC during semantic AM retrieval in the elderly could be seen as a compensatory mechanism underpinning successful AM performance observed in aging. These results are discussed in the framework of recently proposed models of neural reorganization in aging.     

Gender-Specific Differences in the Relationship between Autobiographical Memory and Intertemporal Choice in Older Adults

As the population of older adults grows, their economic choices will have increasing impact on society. Research on the effects of aging on intertemporal decisions shows inconsistent, often opposing results, indicating that yet unexplored factors might play an essential role in guiding one''s choices. Recent studies suggest that episodic future thinking, which is based on the same neural network involved in episodic memory functions, leads to reductions in discounting of future rewards. As episodic memory functioning declines with normal aging, but to greatly variable degrees, individual differences in delay discounting might be due to individual differences in the vitality of this memory system in older adults. We investigated this hypothesis, using a sample of healthy older adults who completed an intertemporal choice task as well as two episodic memory tasks. We found no clear evidence for a relationship between episodic memory performance and delay discounting in older adults. However, when additionally considering gender differences, we found an interaction effect of gender and autobiographical memory on delay discounting: while men with higher memory scores showed less delay discounting, women with higher memory scores tended to discount the future more. We speculate that this gender effect might stem from the gender-specific use of different modal representation formats (i.e. temporal or visual) during assessment of intertemporal choice options.     

PRKCA Polymorphism Changes the Neural Basis of Episodic Remembering in Healthy Individuals

Everyday functioning relies on episodic memory, the conscious retrieval of past experiences, but this crucial cognitive ability declines severely with aging and disease. Vulnerability to memory decline varies across individuals however, producing differences in the time course and severity of memory problems that complicate attempts at diagnosis and treatment. Here we identify a key source of variability, by examining gene dependent changes in the neural basis of episodic remembering in healthy adults, targeting seven polymorphisms previously linked to memory. Scalp recorded Event-Related Potentials (ERPs) were measured while participants remembered words, using an item recognition task that requires discrimination between studied and unstudied stimuli. Significant differences were found as a consequence of a Single Nucleotide Polymorphism (SNP) in just one of the tested genes, PRKCA (rs8074995). Participants with the common G/G variant exhibited left parietal old/new effects, which are typically seen in word recognition studies, reflecting recollection-based remembering. During the same stage of memory retrieval participants carrying a rarer A variant exhibited an atypical pattern of brain activity, a topographically dissociable frontally-distributed old/new effect, even though behavioural performance did not differ between groups. Results replicated in a second independent sample of participants. These findings demonstrate that the PRKCA genotype is important in determining how episodic memories are retrieved, opening a new route towards understanding individual differences in memory.     

Memory for events and their spatial context: models and experiments

The computational role of the hippocampus in memory has been characterized as: (i) an index to disparate neocortical storage sites; (ii) a time-limited store supporting neocortical long-term memory; and (iii) a content-addressable associative memory. These ideas are reviewed and related to several general aspects of episodic memory, including the differences between episodic, recognition and semantic memory, and whether hippocampal lesions differentially affect recent or remote memories. Some outstanding questions remain, such as: what characterizes episodic retrieval as opposed to other forms of read-out from memory; what triggers the storage of an event memory; and what are the neural mechanisms involved? To address these questions a neural-level model of the medial temporal and parietal roles in retrieval of the spatial context of an event is presented. This model combines the idea that retrieval of the rich context of real-life events is a central characteristic of episodic memory, and the idea that medial temporal allocentric representations are used in long-term storage while parietal egocentric representations are used to imagine, manipulate and re-experience the products of retrieval. The model is consistent with the known neural representation of spatial information in the brain, and provides an explanation for the involvement of Papez''s circuit in both the representation of heading direction and in the recollection of episodic information. Two experiments relating to the model are briefly described. A functional neuroimaging study of memory for the spatial context of life-like events in virtual reality provides support for the model''s functional localization. A neuropsychological experiment suggests that the hippocampus does store an allocentric representation of spatial locations.     

Dissociating episodic from semantic access mode by mutual information measures: evidence from aging and Alzheimer's disease.

Re-thinking the semantic vs. episodic distinction with new experimental paradigms, we have designed a simple classification task to assess episodic and semantic access modes to memory for famous faces. The task requires to post 54 cards into nine mail boxes arranged in a 3x3 (nationality by field of activity) array, allowing for a quantitative analysis of the distribution of their responses, in particular of their classification errors. By using an information theoretical approach, we have developed an index of the concentration of errors, i.e. the metric content index. High levels of metric content indicate strong dependence of the classification performance on perceived relations among the set of stimuli, and therefore a preferred semantic access mode. We have found (1) a significant effect of age on the metric content, indicative of a shift from episodic to semantic access in older subjects (Experiment 1); (2) a significant correlation between the metric content and relevant measures assessing episodic and semantic retrieval mode in the Remember (R)/Know (K) paradigm introduced by Tulving [Tulving, E. 1985. Memory and consciousness. Can. Psychol. 26, 1-12] (Experiment 2); (3) a significant increase in metric content in early Alzheimer's disease patients compared to normal controls, consistent with their specific impairment in episodic access (Experiment 3).     

The Hippocampus Remains Activated over the Long Term for the Retrieval of Truly Episodic Memories

The role of the hippocampus in declarative memory consolidation is a matter of intense debate. We investigated the neural substrates of memory retrieval for recent and remote information using functional magnetic resonance imaging (fMRI). 18 young, healthy participants learned a series of pictures. Then, during two fMRI recognition sessions, 3 days and 3 months later, they had to determine whether they recognized or not each picture using the "Remember/Know" procedure. Presentation of the same learned images at both delays allowed us to track the evolution of memories and distinguish consistently episodic memories from those that were initially episodic and then became familiar or semantic over time and were retrieved without any contextual detail. Hippocampal activation decreased over time for initially episodic, later semantic memories, but remained stable for consistently episodic ones, at least in its posterior part. For both types of memories, neocortical activations were observed at both delays, notably in the ventromedial prefrontal and anterior cingulate cortices. These activations may reflect a gradual reorganization of memory traces within neural networks. Our data indicate maintenance and strengthening of hippocampal and cortico-cortical connections in the consolidation and retrieval of episodic memories over time, in line with the Multiple Trace theory (Nadel and Moscovitch, 1997). At variance, memories becoming semantic over time consolidate through strengthening of cortico-cortical connections and progressive disengagement of the hippocampus.     

Priming picture naming with a semantic task: an fMRI investigation

Prior semantic processing can enhance subsequent picture naming performance, yet the neurocognitive mechanisms underlying this effect and its longevity are unknown. This functional magnetic resonance imaging study examined whether different neurological mechanisms underlie short-term (within minutes) and long-term (within days) facilitation effects from a semantic task in healthy older adults. Both short- and long-term facilitated items were named significantly faster than unfacilitated items, with short-term items significantly faster than long-term items. Region of interest results identified decreased activity for long-term facilitated items compared to unfacilitated and short-term facilitated items in the mid-portion of the middle temporal gyrus, indicating lexical-semantic priming. Additionally, in the whole brain results, increased activity for short-term facilitated items was identified in regions previously linked to episodic memory and object recognition, including the right lingual gyrus (extending to the precuneus region) and the left inferior occipital gyrus (extending to the left fusiform region). These findings suggest that distinct neurocognitive mechanisms underlie short- and long-term facilitation of picture naming by a semantic task, with long-term effects driven by lexical-semantic priming and short-term effects by episodic memory and visual object recognition mechanisms.     

How Are ‘Barack Obama’ and ‘President Elect’ Differentially Stored in the Brain? An ERP Investigation on the Processing of Proper and Common Noun Pairs

Background

One of the most debated issues in the cognitive neuroscience of language is whether distinct semantic domains are differentially represented in the brain. Clinical studies described several anomic dissociations with no clear neuroanatomical correlate. Neuroimaging studies have shown that memory retrieval is more demanding for proper than common nouns in that the former are purely arbitrary referential expressions. In this study a semantic relatedness paradigm was devised to investigate neural processing of proper and common nouns.

Methodology/Principal Findings

780 words (arranged in pairs of Italian nouns/adjectives and the first/last names of well known persons) were presented. Half pairs were semantically related (“Woody Allen” or “social security”), while the others were not (“Sigmund Parodi” or “judicial cream”). All items were balanced for length, frequency, familiarity and semantic relatedness. Participants were to decide about the semantic relatedness of the two items in a pair. RTs and N400 data suggest that the task was more demanding for common nouns. The LORETA neural generators for the related-unrelated contrast (for proper names) included the left fusiform gyrus, right medial temporal gyrus, limbic and parahippocampal regions, inferior parietal and inferior frontal areas, which are thought to be involved in the conjoined processing a familiar face with the relevant episodic information. Person name was more emotional and sensory vivid than common noun semantic access.

Conclusions/Significance

When memory retrieval is not required, proper name access (conspecifics knowledge) is not more demanding. The neural generators of N400 to unrelated items (unknown persons and things) did not differ as a function of lexical class, thus suggesting that proper and common nouns are not treated differently as belonging to different grammatical classes.     

Deterioration in Motor Function Over Time in Older Adults With Type 2 Diabetes is Associated with Accelerated Cognitive Decline

Objective: Type 2 diabetes (T2D) is associated with motor impairments and a higher dementia risk. The relationships of motor decline with cognitive decline in T2D older adults has rarely been studied. Using data from the Israel Diabetes and Cognitive Decline study (N = 892), we examined associations of decline in motor function with cognitive decline over a 54-month period.Methods: Motor function measures were strength (handgrip) and gait speed (time to walk 3 m). Participants completed a neuropsychologic battery of 13 tests transformed into z-scores, summarized into 4 cognitive domains: episodic memory, attention/working memory, executive functions, and language/semantic categorization. The average of the 4 domains’ z-scores defined global cognition. Motor and cognitive functions were assessed in 18-months intervals. A random coefficients model delineated longitudinal relationships of cognitive decline with baseline and change from baseline in motor function, adjusting for sociodemographic, cardiovascular, and T2D-related covariates.Results: Slower baseline gait speed levels were significantly associated with more rapid decline in global cognition (P = .004), language/semantic categorization (P = .006) and episodic memory (P = .029). Greater decline over time in gait speed was associated with an accelerated rate of decline in global cognition (P = .050), attention/working memory (P = .047) and language/semantic categorization (P<.001). Baseline strength levels were not associated with cognitive decline but the rate of declining strength was associated with an accelerated decline in executive functions (P = .025) and language/semantic categorization (P = .006).Conclusion: In T2D older adults, the rate of decline in motor function, beyond baseline levels, was associated with accelerated cognitive decline, suggesting that cognitive and motor decline share common neuropathologic mechanisms in T2D.     

Functional neuroanatomy of the autobiographical memory

Autobiographical memory refers to events and information about personal life and the self. Within autobiographical memory, many authors make a difference between episodic and semantic components. Study of retrograde amnesia gives information about memory consolidation. According to the "standard model" of consolidation, the medial temporal lobe plays a time-limited role in retrieval memory. Functional neuroanatomy studies of autobiographical memory are very few and many are recent. These studies concern which brain regions are involved in the autobiographical retrieval, episodic or semantic autobiographical memory and consolidation process. Results show that autobiographical retrieval depends on specific brain regions like frontal cortex. Concerning memory consolidation, findings are most consistent with the idea that hippocampal complex is involved in both recent and remote memories.     

The neural basis of episodic memory: evidence from functional neuroimaging

We review some of our recent research using functional neuroimaging to investigate neural activity supporting the encoding and retrieval of episodic memories, that is, memories for unique events. Findings from studies of encoding indicate that, at the cortical level, the regions responsible for the effective encoding of a stimulus event as an episodic memory include some of the regions that are also engaged to process the event 'online'. Thus, it appears that there is no single cortical site or circuit responsible for episodic encoding. The results of retrieval studies indicate that successful recollection of episodic information is associated with activation of lateral parietal cortex, along with more variable patterns of activity in dorsolateral and anterior prefrontal cortex. Whereas parietal regions may play a part in the representation of retrieved information, prefrontal areas appear to support processes that act on the products of retrieval to align behaviour with the demands of the retrieval task.     

The Influence of Perceptual Training on Working Memory in Older Adults

Normal aging is associated with a degradation of perceptual abilities and a decline in higher-level cognitive functions, notably working memory. To remediate age-related deficits, cognitive training programs are increasingly being developed. However, it is not yet definitively established if, and by what mechanisms, training ameliorates effects of cognitive aging. Furthermore, a major factor impeding the success of training programs is a frequent failure of training to transfer benefits to untrained abilities. Here, we offer the first evidence of direct transfer-of-benefits from perceptual discrimination training to working memory performance in older adults. Moreover, using electroencephalography to evaluate participants before and after training, we reveal neural evidence of functional plasticity in older adult brains, such that training-induced modifications in early visual processing during stimulus encoding predict working memory accuracy improvements. These findings demonstrate the strength of the perceptual discrimination training approach by offering clear psychophysical evidence of transfer-of-benefit and a neural mechanism underlying cognitive improvement.     

Dissociating memory retrieval processes using fMRI: evidence that priming does not support recognition memory

We employed event-related fMRI to constrain cognitive accounts of memory retrieval. Studies of explicit retrieval reveal that lateral and medial parietal, dorsal middle frontal gyrus, and anterior prefrontal cortex respond more for studied than new words, reflecting a correlate of "retrieval success." Studies of implicit memory suggest left temporal cortex, ventral and dorsal inferior frontal gyrus respond less for studied than new words, reflecting a correlate of "conceptual priming." In the present study, responses for old and new items were compared during performance on explicit recognition (old/new judgement) and semantic (abstract/concrete judgement) tasks. Regions associated with priming were only modulated during the semantic task, whereas regions associated with retrieval success were modulated during both tasks. These findings constrain functional-anatomic accounts of the networks, suggesting that processes associated with priming do not support explicit recognition judgments.     

A Potential Spatial Working Memory Training Task to Improve Both Episodic Memory and Fluid Intelligence

One current challenge in cognitive training is to create a training regime that benefits multiple cognitive domains, including episodic memory, without relying on a large battery of tasks, which can be time-consuming and difficult to learn. By giving careful consideration to the neural correlates underlying episodic and working memory, we devised a computerized working memory training task in which neurologically healthy participants were required to monitor and detect repetitions in two streams of spatial information (spatial location and scene identity) presented simultaneously (i.e. a dual n-back paradigm). Participants’ episodic memory abilities were assessed before and after training using two object and scene recognition memory tasks incorporating memory confidence judgments. Furthermore, to determine the generalizability of the effects of training, we also assessed fluid intelligence using a matrix reasoning task. By examining the difference between pre- and post-training performance (i.e. gain scores), we found that the trainers, compared to non-trainers, exhibited a significant improvement in fluid intelligence after 20 days. Interestingly, pre-training fluid intelligence performance, but not training task improvement, was a significant predictor of post-training fluid intelligence improvement, with lower pre-training fluid intelligence associated with greater post-training gain. Crucially, trainers who improved the most on the training task also showed an improvement in recognition memory as captured by d-prime scores and estimates of recollection and familiarity memory. Training task improvement was a significant predictor of gains in recognition and familiarity memory performance, with greater training improvement leading to more marked gains. In contrast, lower pre-training recollection memory scores, and not training task improvement, led to greater recollection memory performance after training. Our findings demonstrate that practice on a single working memory task can potentially improve aspects of both episodic memory and fluid intelligence, and that an extensive training regime with multiple tasks may not be necessary.     

Prenatal administration of arginine vasopressin impairs memory retrieval in adult rats

Eight pregnant female rats were chronically treated via an osmotic pump with arginine vasopressin or placebo during days 13 to 19 gestation. All offspring were tested as adults in either a discrimination task or a 25 day retention of a passive avoidance response. The results revealed that rats whose mother had been treated with vasopressin did not differ from controls on the acquisition or reversal of a brightness discrimination; however, they did require more trials to reach criterion during the ten day memory test of discrimination reversal. Further, treatment resulted in impaired memory retrieval in male rats on the 25 day memory test, while female rats were not affected. Treatment did not influence body weight. The results indicated that vasopressin administered during the prenatal period of development may have had a teratogenic effect on memory retrieval.     

Theories of episodic memory

Theories of episodic memory need to specify the encoding (representing), storage, and retrieval processes that underlie this form of memory and indicate the brain regions that mediate these processes and how they do so. Representation and re-representation (retrieval) of the spatiotemporally linked series of scenes, which constitute an episode, are probably mediated primarily by those parts of the posterior neocortex that process perceptual and semantic information. However, some role of the frontal neocortex and medial temporal lobes in representing aspects of context and high-level visual object information at encoding and retrieval cannot currently be excluded. Nevertheless, it is widely believed that the frontal neocortex is mainly involved in coordinating episodic encoding and retrieval and that the medial temporal lobes store aspects of episodic information. Establishing where storage is located is very difficult and disagreement remains about the role of the posterior neocortex in episodic memory storage. One view is that this region stores all aspects of episodic memory ab initio for as long as memory lasts. This is compatible with evidence that the amygdala, basal forebrain, and midbrain modulate neocortical storage. Another view is that the posterior neocortex only gradually develops the ability to store some aspects of episodic information as a function of rehearsal over time and that this information is initially stored by the medial temporal lobes. A third view is that the posterior neocortex never stores these aspects of episodic information because the medial temporal lobes store them for as long as memory lasts in an increasingly redundant fashion. The last two views both postulate that the medial temporal lobes initially store contextual markers that serve to cohere featural information stored in the neocortex. Lesion and functional neuroimaging evidence still does not clearly distinguish between these views. Whether the feeling that an episodic memory is familiar depends on retrieving an association between a retrieved episode and this feeling, or by an attribution triggered by a priming process, is unclear. Evidence about whether the hippocampus and medial temporal lobe cortices play different roles in episodic memory is conflicting. Identifying similarities and differences between episodic memory and both semantic memory and priming will require careful componential analysis of episodic memory.     

When Music and Long-Term Memory Interact: Effects of Musical Expertise on Functional and Structural Plasticity in the Hippocampus

The development of musical skills by musicians results in specific structural and functional modifications in the brain. Surprisingly, no functional magnetic resonance imaging (fMRI) study has investigated the impact of musical training on brain function during long-term memory retrieval, a faculty particularly important in music. Thus, using fMRI, we examined for the first time this process during a musical familiarity task (i.e., semantic memory for music). Musical expertise induced supplementary activations in the hippocampus, medial frontal gyrus, and superior temporal areas on both sides, suggesting a constant interaction between episodic and semantic memory during this task in musicians. In addition, a voxel-based morphometry (VBM) investigation was performed within these areas and revealed that gray matter density of the hippocampus was higher in musicians than in nonmusicians. Our data indicate that musical expertise critically modifies long-term memory processes and induces structural and functional plasticity in the hippocampus.     

BDNF VAL66MET polymorphism and memory decline across the spectrum of Alzheimer's disease

The brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism has been shown to moderate the extent to which memory decline manifests in preclinical Alzheimer's disease (AD). To date, no study has examined the relationship between BDNF and memory in individuals across biologically confirmed AD clinical stages (i.e., Aβ+). We aimed to understand the effect of BDNF on episodic memory decline and clinical disease progression over 126 months in individuals with preclinical, prodromal and clinical AD. Participants enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study who were Aβ + (according to positron emission tomography), and cognitively normal (CN; n = 238), classified as having mild cognitive impairment (MCI; n = 80), or AD (n = 66) were included in this study. Cognition was evaluated at 18 month intervals using an established episodic memory composite score over 126 months. We observed that in Aβ + CNs, Met66 was associated with greater memory decline with increasing age and were 1.5 times more likely to progress to MCI/AD over 126 months. In Aβ + MCIs, there was no effect of Met66 on memory decline or on disease progression to AD over 126 months. In Aβ + AD, Val66 homozygotes showed greater memory decline, while Met66 carriers performed at a constant and very impaired level. Our current results illustrate the importance of time and disease severity to clinicopathological models of the role of BDNF Val66Met in memory decline and AD clinical progression. Specifically, the effect of BDNF on memory decline is greatest in preclinical AD and reduces as AD clinical disease severity increases.