The underlying mechanisms of verbal fluency deficit in frontotemporal dementia and semantic dementia

Verbal fluency tasks are commonly used to explore semantic memory and executive functions. The aim of this study was to gain a better understanding of the cognitive and neural mechanisms underlying verbal fluency impairment in the frontal variant of frontotemporal dementia (fv-FTD) and in semantic dementia (SD). Semantic and phonemic fluency tasks were performed by 36 fv-FTD and SD patients and 18 elderly controls. We also carried out a neuropsychological investigation of semantic memory, working memory and shifting and updating processes. We performed correlative and regression analyses of fluency scores and neuropsychological data. In addition, patients underwent a resting positron emission tomography examination, and statistical parametric mapping was used to establish correlations between resting-state FDG uptake in the whole brain and fluency scores for each patient group. Both patient groups displayed impaired performances on both fluency tasks compared with controls, but with different patterns. While fv-FTD patients scored higher than SD patients on semantic fluency, their performances on the phonemic task did not differ. Correlation and regression analyses clearly demonstrated that the fv-FTD patients’ performances on both fluency tasks depended on their executive abilities, while those of the SD patients were hampered by the impairment of their semantic memory store. Correlations with resting FDG uptake were consistent with the results of the cognitive study. In fv-FTD, both fluency performances were related to the metabolism of the frontal lobes, while we observed significant correlations between performances on both fluency tasks and the left temporal lobe metabolism in SD.     

Semantic dementia: Aspects of the early diagnosis

Semantic dementia is a lobar atrophy syndrome, related to a degeneration of anterior temporal regions, and characterized by a very predominant impairment of semantic memory. Whereas the diagnosis is relatively easy to establish in the typical form and if the patient is seen early, the emergence of possible additional cognitive or psycho-behavioural disorders can lead to a misdiagnosis in favour of a frontotemporal dementia syndrome or even probable Alzheimer's disease.     

Patterns of autobiographical memory impairment according to disease severity in semantic dementia

Studies of autobiographical memory in semantic dementia (SD) have yielded either a reversed temporal gradient or spared performances across the entire lifetime. This discrepancy might be owing to the fact that these studies did not take into account disease severity. Our aim was to study patterns of autobiographical memory impairment according to disease severity and to unravel their mechanisms in 14 SD patients, using an autobiographical memory task assessing overall and strictly episodic memories across the entire lifetime. We divided our patients in 2 subgroups of 7 patients each, one mild and one moderate according to their level of disease severity. The results indicated for the mild subgroup selective preserved performances for the most recent time period (last 12 months period) for both autobiographical memory scores. In the moderate subgroup, performances were impaired for both scores whatever the time period. Within-group comparisons across time periods showed a recency effect and a reminiscence bump in the mild subgroup and only a less important recency effect in the moderate subgroup, suggesting that with disease severity, old memories (reminiscence bump) tend to vanish and even recent memories are less well retrieved. A correlation analysis was carried out on the entire group, between the overall autobiographical memory score and performances provided by a general cognitive evaluation (semantic memory, executive functions, working and episodic memory). The results of this analysis reflect that mechanisms of disruption of autobiographical memory in SD predominantly involve a deficit of storage of semantic information in addition to faulty executive retrieval strategies. Finally, our result and those of the literature suggest the existence of 3 distinct autobiographical memory impairment patterns in SD according to disease severity: firstly preserved performances whatever the time period, secondly a reversed temporal gradient with a reminiscence bump and thirdly the appearance of a “step-function”.     

语义性痴呆患者语义记忆障碍特征研究

目的探讨语义性痴呆(SD)患者语义记忆障碍的特点,揭示语义记忆的神经解剖机制。方法对9例早期SD患者(病程≤3年)进行详细的神经系统查体、影像学检查和语义记忆评估。语义记忆评估选用常见的动物(生命类)和日常用具(非生命类),统计每一例SD患者对物体名称和功能记忆的正确比例,比较患者对生命类和非生命类物体记忆之间的差异。结果临床上早期SD患者出现广泛的语义记忆损害,所有患者均无感觉或运动方面的症状及体征,颅脑磁共振检查发现所有患者均以左侧颞叶前部萎缩为主,初级感觉皮层和运动皮层正常。所有患者对生命类和非生命类物体的名称及功能均有遗忘,对名称的遗忘更严重。2例患者对生命类物体名称和功能的遗忘较非生命类物体严重,另2例对非生命类物体名称和功能的遗忘重于生命类。结论颞极是语义记忆储存的主要部位,此部位损害后,各种语义记忆普遍受损。语义复合体(名称、知觉和功能)中物体的功能较词语表征更加核心和牢固。部分SD患者存在"语义范畴特异性损害",而且模式并不固定。     

Differing neuropsychological and neuroanatomical correlates of abnormal reading in early-stage semantic dementia and dementia of the Alzheimer type

Individuals with semantic dementia (SD) were differentiated neuropsychologically from individuals with dementia of the Alzheimer type (DAT) at very mild-to-mild stages (clinical dementia rating 0.5 or 1). A picture naming and recognition memory experiment provided a particularly useful probe for early identification, with SD individuals showing preserved picture recognition memory and impaired naming, and DAT individuals tending to show the reverse dissociation. The identification of an early SD group provided the opportunity to inform models of reading by exploring the influence of isolated lexical semantic impairment on reading regular words. Results demonstrated prolonged latency in both SD and DAT group reading compared to a control group but exaggerated influence of frequency and length only for the SD group. The SD reading pattern was associated with focal atrophy of the left temporal pole. These cognitive-neuroanatomical findings suggest a role for the left temporal pole in lexical/semantic components of reading and demonstrate that cortical thickness differences in the left temporal pole correlate with prolonged latency associated with increased reliance on sublexical components of reading.     

Profiles of recent autobiographical memory retrieval in semantic dementia, behavioural-variant frontotemporal dementia, and Alzheimer's disease

Episodic autobiographical memory (ABM) comprises recollection for events that are grounded within a specific spatiotemporal context, and usually accompanied by perceptual and emotional information. The neural substrates mediating ABM retrieval are those harbouring significant pathology in semantic dementia (SD) and behavioural-variant frontotemporal dementia (bvFTD), the most common subtypes of FTD. Relatively little is known, however, regarding the differential patterns of contextual details during episodic ABM retrieval across these dementia syndromes. This study investigated episodic ABM retrieval under free and probed recall conditions from 4 time periods with the aim to identify disease-specific profiles of episodic ABM contextual details. Episodic ABM was measured in 25 SD and 15 bvFTD patients and their performance contrasted to that of 17 Alzheimer's disease (AD) patients and 19 age-matched controls. Critically, SD patients showed relatively preserved recent ABM in comparison with remote epochs. In contrast, bvFTD and AD patients showed a reduced capacity to recall specific and contextually rich ABMs across all life epochs, in both free and probed recall conditions. Analyses of the recent period (last 12 months) provided evidence for different profiles of contextual episodic details recalled in dementia syndromes. Following probing, SD patients’ recall deficits emanated exclusively from compromised Emotion/Thoughts and Spatiotemporal details. In contrast, bvFTD patients were significantly impaired across all categories of contextual details whereas AD patients showed deficits for Event and Emotion/Thoughts details only. As the largest study of ABM in FTD to date, these findings emphasise the differential impairment of recent ABM contextual details contingent on the underlying disease pathology. In addition, these results point towards the importance of investigating the constituent elements of emotion processing and strategic retrieval processes as potential variables mediating recent episodic ABM retrieval.     

Repeat and Point: differentiating semantic dementia from progressive non-fluent aphasia

To determine whether a new, simple, quick measure, the Repeat and Point test, reliably differentiates between semantic dementia (SD) and progressive non-fluent aphasia (PNFA). Fifteen patients with SD, six patients with PNFA and 18 healthy controls were administered the Repeat and Point test. Participants were required to repeat 10 multi-syllabic concrete nouns and, following each repetition, to point to the word's pictorial referent amongst an array of six semantically and perceptually similar foils. Patients with SD were consistently impaired relative to PNFA patients and controls on the comprehension (pointing) component of the task, whereas patients with PNFA showed no significant deficit on pointing but were impaired at the production (repeating) component. Discriminant function analysis confirmed perfect classification of the individual patients into their respective groups: criteria involving a ratio of the two scores are provided. The Repeat and Point test is particularly appropriate for routine use in a clinical context: it is quick and easy to administer and score; it reliably discriminated between the two patient groups, SD and PNFA; and it offers a simple rule of thumb, i.e., the Repeat-to-Point ratio, to aid in the diagnosis of these two language variants of frontotemporal dementia (FTD).     

Colour knowledge in semantic dementia: it is not all black and white

In three experiments we assessed the colour knowledge of patients with semantic dementia, a neuro-degenerative condition that gradually erodes conceptual knowledge. In Experiment 1, the patients’ colour naming performance correlated strongly with their object naming for frequency-matched items, with no patient showing better-than-expected naming of colours relative to objects. In Experiment 2, where patients were asked to colour black-and-white line drawings of common objects, all patients were impaired relative to controls, and performance correlated strongly with degree of semantic deficit. The fact that patients often erroneously selected green for fruits or vegetables, and brown for animals, suggests some preservation of general knowledge about the colours that typify a given domain. In Experiment 3, patients were given pairs of identical line drawings of familiar animals, fruits and vegetables—one of each pair coloured correctly, and one incorrectly—and were asked to choose the correct one. When the target's colour was characteristic of the domain, patients scored well; but when the distractor had a typical hue and the target's colour was unusual (e.g. a green versus an orange carrot), performance was far poorer. The results are discussed with reference to alternative theories about the neural basis of conceptual knowledge.     

Retrieval mechanisms for autobiographical memories: insights from the frontal variant of frontotemporal dementia

Very few studies have investigated autobiographical memory in the frontal variant of frontotemporal dementia (fv-FTD). The aim of this study was therefore to unravel the mechanisms of autobiographical memory disruption in general and in the anterograde and retrograde components of amnesia in particular, in patients suffering from fv-FTD. An autobiographical memory task assessing overall (AM) and strictly episodic memories (EM) from five lifetime periods covering the entire lifespan revealed the absence of a temporal gradient for both scores, suggesting the existence of a retrieval deficit. An analysis of the correlation between these two scores and a general cognitive assessment of executive function, working, episodic (i.e. new learning ability) and semantic memory, and behavioural changes highlighted the considerable involvement of executive function, semantic memory and, to a lesser degree, episodic memory and behavioural changes. Moreover, step-wise regression analyses performed on the EM score revealed that the executive function was a better predictor of the retrograde component than of the anterograde component, which was linked principally to new episodic learning ability. All these results confirm the impact of executive dysfunction on autobiographical deficits in fv-FTD, and suggest that the mechanisms at the root of autobiographical memory disruption may also involve difficulties in new episodic learning and semantic storage, though this may be due to the fact that we studied an advanced form of fv-FTD.     

Quantifier processing can be dissociated from numerical processing: Evidence from semantic dementia patients

Quantifiers such as frequency adverbs (e.g., “always”, “never”) and quantity pronouns (e.g., “many”, “none”) convey quantity information. Whether quantifiers are processed as numbers or as general semantics has been a matter of much debate. Some neuropsychological and fMRI studies have found that the processing of quantifiers depends on the numerical magnitude comprehension system, but others have found that quantifier processing is associated with semantic representation. The selective impairment of language in semantic dementia patients provides a way to examine the above controversy. We administered a series of neuropsychological tests (i.e., language processing, numerical processing and semantic distance judgment) to two patients with different levels of severity in semantic dementia (mild vs. severe). The results showed that the two patients had intact numerical knowledge, but impairments in semantic processing. Moreover, the patient with severe/late semantic dementia showed more impairment in quantifier and semantic processing than the patient with mild/early semantic dementia. We concluded that quantifier processing is associated with general semantic processing, not with numerical processing.     

Autobiographical memory in semantic dementia: New insights from two patients using fMRI

Episodic autobiographical memory (EAM) consists of personal events embedded within a specific spatiotemporal context. Patients with semantic dementia (SD) generally show preserved recent EAMs, but a controversy remains concerning their ability to retrieve remote ones. Only one fMRI study examined remote autobiographical memory in SD through a longitudinal case study (Maguire, Kumaran, Hassabis, & Kopelman, 2010). Here, we propose a cross-sectional study to test the hippocampo-neocortical up-regulation hypothesis, through a multimodal approach (gray matter volume, activation, connectivity analyses), directly comparing recent and remote autobiographical memory retrieval and collecting data to asses phenomelogical re-experiencing. EAM retrieval recruits a distributed network of brain regions, notably the hippocampus which is shown to be atrophied in SD, although some studies report no hippocampal atrophy in SD. Using fMRI, we examined recent and remote EAM retrieval in two SD patients with different profiles of hippocampal atrophy, compared to 12 healthy elders (HE). JPL presented severe bilateral hippocampal atrophy, while EP showed sparing of both hippocampi. Behaviourally, JPL was impaired at retrieving EAMs from both life periods and showed poorer use of visual mental imagery than HE, while EP retrieved memories which were as episodic as those of HE for both periods and relied on greater use of visual mental imagery than HE. Neuroimaging results showed that, for JPL, hyperactivations of the residual hippocampal tissue and of frontal, lateral temporal, occipital and parietal cortices did not efficiently compensate his autobiographical memory deficit. EP however presented hyperactivations in similar neocortical regions which appeared to be more efficient in compensating for atrophy elsewhere, since EP's EAM retrieval was preserved. Functional connectivity analyses focusing on the hippocampus showed how the residual hippocampal activity was connected to other brain areas. For JPL, recent autobiographical retrieval was associated with connectivity between the posterior hippocampus and middle occipital gyrus, while for EP, connectivity was detected between the anterior hippocampus and numerous regions (medial temporal, occipital, temporal, frontal, parietal) for both recent and remote periods. These findings suggest that intensification of hippocampal atrophy in SD strongly affects both recent and remote autobiographical recollection. Up-regulation of neocortical regions and functional hippocampal–neocortical connectivity within the autobiographical network may be insufficient to compensate the lifelong episodic memory deficit for patients with extensive hippocampal atrophy.     

Memory consolidation and the hippocampus: further evidence from studies of autobiographical memory in semantic dementia and frontal variant frontotemporal dementia.

Studies of autobiographical memory in semantic dementia have found relative preservation of memories for recent rather than remote events. As semantic dementia is associated with progressive atrophy to temporal neocortex, with early asymmetric sparing of the hippocampus, this neuropsychological pattern suggests that the hippocampal complex plays a role in the acquisition and retrieval of recent memories, but is not necessary for the recall of older episodic events. In an alternative view of memory consolidation, however, the hippocampus plays a role in the retrieval of all autobiographical memories, regardless of the age of the memory [Curr. Opin. Neurobiol. 7(1997)217]. This 'multiple trace theory' predicts that patients with semantic dementia should show no effects of time in their autobiographical recall. In this article, we ask whether it is possible to reconcile the data from semantic dementia with the multiple trace theory by investigating whether the time-dependent pattern of autobiographical retrieval seen in the disease is due to (i) patients showing this effect being exceptional in their presentation; and/or (ii) patients with semantic dementia exhibiting impaired strategic retrieval from concomitant frontal damage. A series of experiments in patients with semantic dementia, the frontal variant of frontotemporal dementia and Alzheimer's disease clearly demonstrates that neither of these two factors can explain the documented effect of time seen in semantic dementia. Nonetheless, we discuss how damage to semantic knowledge could result in an autobiographical memory deficit and suggest that data from semantic dementia may be consistent with both views of hippocampal involvement in long-term memory.     

Phonological learning in semantic dementia

Patients with semantic dementia (SD) have anterior temporal lobe (ATL) atrophy that gives rise to a highly selective deterioration of semantic knowledge. Despite pronounced anomia and poor comprehension of words and pictures, SD patients have well-formed, fluent speech and normal digit span. Given the intimate connection between phonological STM and word learning revealed by both neuropsychological and developmental studies, SD patients might be expected to show good acquisition of new phonological forms, even though their ability to map these onto meanings is impaired. In contradiction of these predictions, a limited amount of previous research has found poor learning of new phonological forms in SD. In a series of experiments, we examined whether SD patient, GE, could learn novel phonological sequences and, if so, under which circumstances. GE showed normal benefits of phonological knowledge in STM (i.e., normal phonotactic frequency and phonological similarity effects) but reduced support from semantic memory (i.e., poor immediate serial recall for semantically degraded words, characterised by frequent item errors). Next, we demonstrated normal learning of serial order information for repeated lists of single-digit number words using the Hebb paradigm: these items were well-understood allowing them to be repeated without frequent item errors. In contrast, patient GE showed little learning of nonsense syllable sequences using the same Hebb paradigm. Detailed analysis revealed that both GE and the controls showed a tendency to learn their own errors as opposed to the target items. Finally, we showed normal learning of phonological sequences for GE when he was prevented from repeating his errors. These findings confirm that the ATL atrophy in SD disrupts phonological processing for semantically degraded words but leaves the phonological architecture intact. Consequently, when item errors are minimised, phonological STM can support the acquisition of new phoneme sequences in patients with SD.     

Autobiographical memory in semantic dementia: A longitudinal fMRI study

Whilst patients with semantic dementia (SD) are known to suffer from semantic memory and language impairments, there is less agreement about whether memory for personal everyday experiences, autobiographical memory, is compromised. In healthy individuals, functional MRI (fMRI) has helped to delineate a consistent and distributed brain network associated with autobiographical recollection. Here we examined how the progression of SD affected the brain's autobiographical memory network over time. We did this by testing autobiographical memory recall in a SD patient, AM, with fMRI on three occasions, each one year apart, during the course of his disease. At the outset, his autobiographical memory was intact. This was followed by a gradual loss in recollective quality that collapsed only late in the course of the disease. There was no evidence of a temporal gradient. Initially, AM's recollection was supported by the classic autobiographical memory network, including atrophied tissue in hippocampus and temporal neocortex. This was subsequently augmented by up-regulation of other parts of the memory system, namely ventromedial and ventrolateral prefrontal cortex, right lateral temporal cortex, and precuneus. A final step-change in the areas engaged and the quality of recollection then preceded the collapse of autobiographical memory. Our findings inform theoretical debates about the role of the hippocampus and neocortical areas in supporting remote autobiographical memories. Furthermore, our results suggest it may be possible to define specific stages in SD-related memory decline, and that fMRI could complement MRI and neuropsychological measures in providing more precise prognostic and rehabilitative information for clinicians and carers.     

Personal experience and arithmetic meaning in semantic dementia

Arithmetic skills are generally claimed to be preserved in semantic dementia (SD), suggesting functional independence of arithmetic knowledge from other aspects of semantic memory. However, in a recent case series analysis we showed that arithmetic performance in SD is not entirely normal. The finding of a direct association between severity of patients’ semantic disorder and arithmetic impairment pointed to a closer relationship between semantic memory and arithmetic knowledge than previously acknowledged. The present study aimed to determine whether arithmetic performance in SD is subject to the same influences as has been found in other semantic domains, namely an autobiographical effect. SD patients were assessed on their ability to perform arithmetic in personally relevant compared to non-personal contexts. Patients who were regular, current followers of the television game show Countdown performed better on a simplified version of the show's number game compared to a conventional written calculation task, whereas patients with no experience of Countdown demonstrated the opposite pattern. SD patients showed better knowledge of multiplication table ‘facts’ when these were embedded in a situation relevant to their daily lives compared to a non-personal arithmetic task. They also performed better on a written calculation task when problems were presented as a monetary transaction compared to a standard arithmetic problem. A reference group of patients with Alzheimer's disease (AD) showed the reverse pattern. The findings provide convincing evidence that autobiographical relevance influences SD patients’ arithmetic performance. Moreover, they challenge current views on conceptual number knowledge as a unitary, abstract competence.     

“Pre-semantic” cognition revisited: Critical differences between semantic aphasia and semantic dementia

Patients with semantic dementia show a specific pattern of impairment on both verbal and non-verbal “pre-semantic” tasks, e.g., reading aloud, past tense generation, spelling to dictation, lexical decision, object decision, colour decision and delayed picture copying. All seven tasks are characterised by poorer performance for items that are atypical of the domain and “regularisation errors” (irregular/atypical items are produced as if they were domain-typical). The emergence of this pattern across diverse tasks in the same patients indicates that semantic memory plays a key role in all of these types of “pre-semantic” processing. However, this claim remains controversial because semantically impaired patients sometimes fail to show an influence of regularity. This study demonstrates that (a) the location of brain damage and (b) the underlying nature of the semantic deficit affect the likelihood of observing the expected relationship between poor comprehension and regularity effects. We compared the effect of multimodal semantic impairment in the context of semantic dementia and stroke aphasia on the seven “pre-semantic” tasks listed above. In all of these tasks, the semantic aphasia patients were less sensitive to typicality than the semantic dementia patients, even though the two groups obtained comparable scores on semantic tests. The semantic aphasia group also made fewer regularisation errors and many more unrelated and perseverative responses. We propose that these group differences reflect the different locus for the semantic impairment in the two conditions: patients with semantic dementia have degraded semantic representations, whereas semantic aphasia patients show deregulated semantic cognition with concomitant executive deficits. These findings suggest a reinterpretation of single-case studies of comprehension-impaired aphasic patients who fail to show the expected effect of regularity on “pre-semantic” tasks. Consequently, such cases do not demonstrate the independence of these tasks from semantic memory.     

A combined neuropsychological and neuroimaging study of topographical and non-verbal memory in semantic dementia

A combined neuropsychological and neuroimaging investigation was carried out on a patient (O.I.) with semantic dementia who had asymmetrical temporal lobe atrophy, greater on the left. His performance on tests of verbal memory was gravely impaired. Similarly, his visual memory as indexed by recognition of unfamiliar faces was impaired. By contrast, his recognition memory for topographical memoranda (e.g. buildings, landscapes) and ability to find his way around was preserved. In order to identify the neural substrates supporting the preserved recognition of static topographical memoranda, O.I. was scanned using positron emission tomography (PET) during the encoding and recognition of building and landscape stimuli. In common with control subjects, during encoding O.I. activated parahippocampal cortex bilaterally, along with bilateral temporo-parietal, retrosplenial and left frontal cortices. During recognition, both patient and controls activated right parahippocampal, right superior parietal and right frontal cortices. Notably, control subjects, but not O.I., also activated at encoding the precuneus and at recognition the retrosplenial cortex. This allows the conclusion that these two areas while involved may not be necessary for topographical memory. Interestingly, the patient also activated regions that were not evident in control subjects both during encoding and recognition. These additional areas of activation may be necessary in a compensatory role. Overall, these data represent the first reported assessment of the functional integrity of degenerating brain tissue and its contribution to preserved topographical memory. The combination of the neuropsychological and neuroimaging approaches may provide insights into the functional-anatomy of memory while having clinical utility for the assessment of residual brain tissue.     

Autobiographical memory in semantic dementia: implication for theories of limbic-neocortical interaction in remote memory

We examined autobiographical memory performance in two patients with semantic dementia using a novel measure, the Autobiographical Interview [Levine, Svoboda, Hay, Winocur, & Moscovitch (2002). Aging and autobiographical memory: Dissociating episodic from semantic retrieval. Psychology and Aging, 17, 677-689], that is capable of dissociating episodic and personal semantic recall under varying levels of retrieval support. Earlier reports indicated that patients with semantic dementia demonstrate autobiographical episodic memory loss following a "reverse gradient" by which recent memories are preserved relative to remote memories. We found limited evidence for this pattern at conditions of low retrieval support. When structured probing was provided, patients' autobiographical memory performance was similar to that of controls. Retesting of one patient after 1 year indicated that retrieval support was insufficient to bolster performance following progressive prefrontal volume loss, as documented with quantified structural neuroimaging. These findings are discussed in relation to theories of limbic-neocortical interaction in autobiographical memory.