Muireann Irish

Considering the role of semantic memory in episodic future thinking: evidence from semantic dementia

Semantic dementia is a progressive neurodegenerative condition characterized by the profound and amodal loss of semantic memory in the context of relatively preserved episodic memory. In contrast, patients with Alzheimers disease typically display impairments in episodic memory, but with semantic deficits of a much lesser magnitude than in semantic dementia. Our understanding of episodic memory retrieval in these cohorts has greatly increased over the last decade, however, we know relatively little regarding the ability of these patients to imagine and describe possible future events, and whether episodic future thinking is mediated by divergent neural substrates contingent on dementia subtype. Here, we explored episodic future thinking in patients with semantic dementia (n=11) and Alzheimers disease (n=11), in comparison with healthy control participants (n=10). Participants completed a battery of tests designed to probe episodic and semantic thinking across past and future conditions, as well as standardized tests of episodic and semantic memory. Further, all participants underwent magnetic resonance imaging. Despite their relatively intact episodic retrieval for recent past events, the semantic dementia cohort showed significant impairments for episodic future thinking. In contrast, the group with Alzheimers disease showed parallel deficits across past and future episodic conditions. Voxel-based morphometry analyses confirmed that atrophy in the left inferior temporal gyrus and bilateral temporal poles, regions strongly implicated in semantic memory, correlated significantly with deficits in episodic future thinking in semantic dementia. Conversely, episodic future thinking performance in Alzheimers disease correlated with atrophy in regions associated with episodic memory, namely the posterior cingulate, parahippocampal gyrus and frontal pole. These distinct neuroanatomical substrates contingent on dementia group were further qualified by correlational analyses that confirmed the relation between semantic memory deficits and episodic future thinking in semantic dementia, in contrast with the role of episodic memory deficits and episodic future thinking in Alzheimers disease. Our findings demonstrate that semantic knowledge is critical for the construction of novel future events, providing the necessary scaffolding into which episodic details can be integrated. Further research is necessary to elucidate the precise contribution of semantic memory to future thinking, and to explore how deficits in self-projection manifest on behavioural and social levels in different dementia subtypes.

Investigating the enhancing effect of music on autobiographical memory in mild Alzheimer's disease.

The enhancing effect of music on autobiographical memory recall in mild Alzheimer’s disease individuals (n = 10; Mini-Mental State Examination score >17/30) and healthy elderly matched individuals (n = 10; Mini-Mental State Examination score 25–30) was investigated. Using a repeated-measures design, each participant was seen on two occasions: once in music condition (Vivaldi’s ‘Spring’ movement from ‘The Four Seasons’) and once in silence condition, with order counterbalanced. Considerable improvement was found for Alzheimer individuals’ recall on the Autobiographical Memory Interview in the music condition, with an interaction for condition by group (p < 0.005). There were no differences in terms of overall arousal using galvanic skin response recordings or attentional errors during the Sustained Attention to Response Task. A significant reduction in state anxiety was found on the State Trait Anxiety Inventory in the music condition (p < 0.001), suggesting anxiety reduction as a potential mechanism underlying the enhancing effect of music on autobiographical memory recall.

The Pivotal Role of Semantic Memory in Remembering the Past and Imagining the Future

Episodic memory refers to a complex and multifaceted process which enables the retrieval of richly detailed evocative memories from the past. In contrast, semantic memory is conceptualized as the retrieval of general conceptual knowledge divested of a specific spatiotemporal context. The neural substrates of the episodic and semantic memory systems have been dissociated in healthy individuals during functional imaging studies, and in clinical cohorts, leading to the prevailing view that episodic and semantic memory represent functionally distinct systems subtended by discrete neurobiological substrates. Importantly, however, converging evidence focusing on widespread neural networks now points to significant overlap between those regions essential for retrieval of autobiographical memories, episodic learning, and semantic processing. Here we review recent advances in episodic memory research focusing on neurodegenerative populations which has proved revelatory for our understanding of the complex interplay between episodic and semantic memory. Whereas episodic memory research has traditionally focused on retrieval of autobiographical events from the past, we also include evidence from the recent paradigm shift in which episodic memory is viewed as an adaptive and constructive process which facilitates the imagining of possible events in the future. We examine the available evidence which converges to highlight the pivotal role of semantic memory in providing schemas and meaning whether one is engaged in autobiographical retrieval for the past, or indeed, is endeavoring to construct a plausible scenario of an event in the future. It therefore seems plausible to contend that semantic processing may underlie most, if not all, forms of episodic memory, irrespective of temporal condition.

In vivo and post-mortem memory circuit integrity in frontotemporal dementia and Alzheimer’s disease

Behavioural variant frontotemporal dementia can present with episodic memory deficits as severe as those in Alzheimers disease. Little is known of the integrity of grey matter areas and white matter tracts of the Papez memory circuit in these diseases. The integrity of the Papez circuit (hippocampus, fornix, mammillary bodies, anterior thalamus, cingulate cortex) was investigated in vivo and at post-mortem in behavioural variant frontotemporal dementia and Alzheimers disease cohorts using voxel-based morphometry, diffusion tensor imaging and manual volumetric tracing. Our findings indicate that behavioural variant frontotemporal dementia and Alzheimers disease show similar degrees of hippocampal atrophy in vivo, but patients with behavioural variant frontotemporal dementia show greater hippocampal atrophy at post-mortem, with the frontotemporal lobar degeneration with TDP-43 inclusions subtype being particularly affected. Cingulate cortex findings show an expected atrophy pattern with behavioural variant frontotemporal dementia being affected more anteriorly and Alzheimers disease showing more posterior atrophy. More importantly, subcortical Papez circuit regions (fornix and anterior thalamus) were affected in behavioural variant frontotemporal dementia only, with atrophy in these regions determining the degree of amnesia in behavioural variant frontotemporal dementia. Hippocampal atrophy does not appear to be an efficient diagnostic marker for underlying behavioural variant frontotemporal dementia or Alzheimers disease pathology, although for behavioural variant frontotemporal dementia, episodic memory deficits in conjunction with marked hippocampal atrophy emerge as potential biomarkers for frontotemporal lobar degeneration with TDP-43 inclusions pathology. Sub-regions of the Papez circuit were differentially affected in behavioural variant frontotemporal dementia and Alzheimers disease with subcortical regions determining the degree of episodic memory deficits in behavioural variant frontotemporal dementia. Subcortical atrophy should be taken into account when establishing whether the severe amnesia observed in a patient is likely to be due to behavioural variant frontotemporal dementia or Alzheimers disease pathology.

Common and unique gray matter correlates of episodic memory dysfunction in frontotemporal dementia and Alzheimer's disease.

Conflicting evidence exists regarding the integrity of episodic memory in the behavioral variant of frontotemporal dementia (bvFTD). Recent converging evidence suggests that episodic memory in progressive cases of bvFTD is compromised to the same extent as in Alzheimers disease (AD). The underlying neural substrates of these episodic memory deficits, however, likely differ contingent on dementia type. In this study we sought to elucidate the neural substrates of episodic memory performance, across recall and recognition tasks, in both patient groups using voxel‐based morphometry (VBM) analyses. We predicted that episodic memory dysfunction would be apparent in both patient groups but would relate to divergent patterns of neural atrophy specific to each dementia type. We assessed episodic memory, across verbal and visual domains, in 19 bvFTD, 18 AD patients, and 19 age‐ and education‐matched controls. Behaviorally, patient groups were indistinguishable for immediate and delayed recall, across verbal and visual domains. Whole‐brain VBM analyses revealed regions commonly implicated in episodic retrieval across groups, namely the right temporal pole, right frontal lobe, left paracingulate gyrus, and right anterior hippocampus. Divergent neural networks specific to each group were also identified. Whereas a widespread network including posterior regions such as the posterior cingulate cortex, parietal and occipital cortices was exclusively implicated in AD, the frontal and anterior temporal lobes underpinned the episodic memory deficits in bvFTD. Our results point to distinct neural changes underlying episodic memory decline specific to each dementia syndrome. Hum Brain Mapp 35:1422–1435, 2014.

Impaired capacity for autonoetic reliving during autobiographical event recall in mild Alzheimer's disease

The capacity to mentally travel back in time and relive past events via autonoetic consciousness has been shown to be compromised even in the early stages of Alzheimers disease (AD). To further understand the unravelling of the recollective experience in pathological ageing, we investigated autobiographical memory (ABM) using the Episodic Autobiographical Memory Interview (EAMI) in thirty middle-aged and thirty healthy elderly controls, and twenty patients with mild AD. Of key interest was the recall of contextual details and the behavioural markers predictive of autonoetic reliving. AD patients exhibited significant difficulties in recalling contextual details across all life epochs on the EAMI manifesting in a negative temporal gradient from the Early Adulthood epoch onwards. Overall there was a low incidence of autonoetic consciousness during ABM recall across all participant groups and life epochs when compared with previous studies. AD patients showed a compromised capacity to mentally relive past memories (AD<healthy elderly<middle-aged controls), across all life epochs on the EAMI. AD patients tended to recall past events as semanticised accounts divested of rich sensory-perceptual imagery. The impoverished capacity to generate egocentric or self-referential imagery resulted in the production of fragmented and depersonalised accounts of formerly evocative events and likely stems from medial temporal and frontal pathology exhibited from early stages of the disease.

Right anterior temporal lobe dysfunction underlies theory of mind impairments in semantic dementia.

Semantic dementia is a progressive neurodegenerative disorder characterized by the amodal and profound loss of semantic knowledge attributable to the degeneration of the left anterior temporal lobe. Although traditionally conceptualized as a language disorder, patients with semantic dementia display significant alterations in behaviour and socioemotional functioning. Recent evidence points to an impaired capacity for theory of mind in predominantly left-lateralized cases of semantic dementia; however, it remains unclear to what extent semantic impairments contribute to these deficits. Further the neuroanatomical signature of such disturbance remains unknown. Here, we sought to determine the neural correlates of theory of mind performance in patients with left predominant semantic dementia (n=11), in contrast with disease-matched cases with behavioural-variant frontotemporal dementia (n=10) and Alzheimers disease (n=10), and healthy older individuals (n=14) as control participants. Participants completed a simple cartoons task, in which they were required to describe physical and theory of mind scenarios. Irrespective of subscale, patients with semantic dementia exhibited marked impairments relative to control subjects; however, only theory of mind deficits persisted when we covaried for semantic comprehension. Voxel-based morphometry analyses revealed that atrophy in right anterior temporal lobe structures, including the right temporal fusiform cortex, right inferior temporal gyrus, bilateral temporal poles and amygdalae, correlated significantly with theory of mind impairments in the semantic dementia group. Our results point to the marked disruption of cognitive functions beyond the language domain in semantic dementia, not exclusively attributable to semantic processing impairments. The significant involvement of right anterior temporal structures suggests that with disease evolution, the encroachment of pathology into the contralateral hemisphere heralds the onset of social cognitive deficits in this syndrome.

Discrete Neural Correlates for the Recognition of Negative Emotions: Insights from Frontotemporal Dementia

Patients with frontotemporal dementia have pervasive changes in emotion recognition and social cognition, yet the neural changes underlying these emotion processing deficits remain unclear. The multimodal system model of emotion proposes that basic emotions are dependent on distinct brain regions, which undergo significant pathological changes in frontotemporal dementia. As such, this syndrome may provide important insight into the impact of neural network degeneration upon the innate ability to recognise emotions. This study used voxel-based morphometry to identify discrete neural correlates involved in the recognition of basic emotions (anger, disgust, fear, sadness, surprise and happiness) in frontotemporal dementia. Forty frontotemporal dementia patients (18 behavioural-variant, 11 semantic dementia, 11 progressive nonfluent aphasia) and 27 healthy controls were tested on two facial emotion recognition tasks: The Ekman 60 and Ekman Caricatures. Although each frontotemporal dementia group showed impaired recognition of negative emotions, distinct associations between emotion-specific task performance and changes in grey matter intensity emerged. Fear recognition was associated with the right amygdala; disgust recognition with the left insula; anger recognition with the left middle and superior temporal gyrus; and sadness recognition with the left subcallosal cingulate, indicating that discrete neural substrates are necessary for emotion recognition in frontotemporal dementia. The erosion of emotion-specific neural networks in neurodegenerative disorders may produce distinct profiles of performance that are relevant to understanding the neurobiological basis of emotion processing.

Frontotemporal Dementia Associated With the C9ORF72 Mutation: A Unique Clinical Profile

IMPORTANCE While advances have been made in characterizing the C9ORF72 clinical phenotype, the hallmark features that discriminate between carriers and noncarriers remain unclear. OBJECTIVES To determine the frequency of the C9ORF72 mutation in a frontotemporal dementia (FTD) cohort and to define the clinical, neuropsychological, behavioral, and imaging features of C9ORF72 mutation carriers in comparison with noncarriers in a well-defined behavioral-variant (bv)-FTD cohort. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study of patients assessed during a 5-year period from January 1, 2008, to December 31, 2012, at an FTD specialist referral center (FRONTIER). A total of 114 consecutive patients with FTD, FTD-amyotrophic lateral sclerosis (ALS), and corticobasal syndrome were assessed at FRONTIER. Patients with bvFTD who carried the C9ORF72 mutation (n = 10) were compared with noncarriers (n = 19) and a healthy control group (n = 35). These were matched for age, sex, and education history. Blood sampling for gene analysis was performed after informed consent was obtained. MAIN OUTCOMES AND MEASURES Clinical, behavioral, cognitive, and neuropsychological deficits, cortical atrophy on a magnetic resonance imaging visual rating scale, and family history as quantified by the Goldman Scale. RESULTS In a cohort of 114 FTD cases, 14 patients expressed the C9ORF72 mutation, representing a frequency rate of 34% in bvFTD and 17% in FTD-ALS. Family histories of ALS (P = .001) and psychiatric disorders (P = .02) were significantly more common in mutation carriers. The C9ORF72 carriers were also more likely to experience psychotic symptoms (P = .03). The degree of brain atrophy was significantly less in the C9ORF72 cohort, and in many the progression was slow. Presenting features of C9ORF72 carriers were compared against International Consensus Diagnostic Criteria for bvFTD, and most cases failed to satisfy criteria for probable bvFTD. CONCLUSIONS AND RELEVANCE The C9ORF72 mutation appears to be a common cause of bvFTD. Many of the C9ORF72 carriers have a family history of ALS or psychiatric illness. Psychotic features emerged as the most discriminating clinical feature between mutation carriers and noncarriers. Progression is often slow and brain atrophy is less pronounced than in nonmutation cases of bvFTD. These findings have clinical relevance for both diagnosis and selection of patients for genetic testing.

Self-projection and the default network in frontotemporal dementia

Converging evidence suggests that when individuals are left to think to themselves, a so-called default network of the brain is engaged, allowing the individual to daydream, reflect on their past, imagine possible future scenarios, and consider the viewpoints of others. These flexible self-relevant mental explorations enable the anticipation and evaluation of events before they occur, and are essential for successful social interactions. Such self-projective efforts are particularly vulnerable to disruption in frontotemporal dementia (FTD), a neurodegenerative disorder involving damage to the frontal and temporal lobes of the brain. In this Review, we explore how the progressive degeneration of the neural networks in two subtypes of FTD—the behavioral variant and semantic dementia—affects key structures of the default network and putative self-projective functions. We examine the available evidence from studies of autobiographical memory, episodic future thinking, theory of mind, moral reasoning, and economic decision-making in these neurodegenerative diseases. Finally, we propose that the mapping of default-network functions onto discrete subsystems of the default network may need revision in light of neuropsychological and clinical evidence from studies in patients with FTD.