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Semantic Dementia (SD) is a neurodegenerative disease characterised by progressive deterioration of semantic knowledge, resulting in diminished understanding of concepts, whether encountered in verbal or non-verbal form. Over the past three decades, a number of studies employing a range of treatment techniques and learning methods have examined whether patients with SD can relearn previously known concepts or learn and retain new information. In this article, we review this research, addressing two main questions: a) Can aspects of semantic knowledge that are 'lost' due to degeneration be re-acquired? b) How much do other memory systems (working and episodic memory) interact with and depend on semantic memory? Several studies demonstrate successful relearning of previously known words and concepts in SD, particularly after regular, prolonged practice; but this success tends to diminish once practice ceases, and furthermore often fails to generalise to other instances of the same object/concept. This pattern suggests that, with impaired semantic knowledge, learning relies to an abnormal extent on perceptual factors, making it difficult to abstract away from the specific visual or other perceptual format in which a given concept has been trained. Furthermore, the impact of semantic 'status' of a word or object on both working and episodic memory indicates pervasive interaction of these other memory systems with conceptual knowledge., Competing Interests: Declaration of competing interest The authors of this work declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Although behavioral variant frontotemporal dementia (bvFTD) is classically defined by behavioral and socio-emotional changes, impairments often extend to other cognitive functions. These include early speech and language deficits related to the disease's core neural disruptions. Yet, their scope and clinical relevance remains poorly understood. This systematic review characterizes such disturbances in bvFTD, considering clinically, neuroanatomically, genetically, and neuropathologically defined subgroups. We included 181 experimental studies, with at least 5 bvFTD patients diagnosed using accepted criteria, comparing speech and language outcomes between bvFTD patients and healthy controls or between bvFTD subgroups. Results reveal extensive and heterogeneous deficits across cohorts, with (a) consistent lexico-semantic, reading & writing, and prosodic impairments; (b) inconsistent deficits in motor speech and grammar; and (c) relative preservation of phonological skills. Also, preliminary findings suggest that the severity of speech and language deficits might be associated with global cognitive impairment, predominantly temporal or fronto-temporal atrophy and MAPT mutations (vs C9orf72). Although under-recognized, these impairments contribute to patient characterization and phenotyping, while potentially informing diagnosis and management., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Frontotemporal dementia (FTD) is a progressive neurodegenerative disease. Diagnosis of FTD, especially the behavioural variant, is challenging because of symptomatic overlap with psychiatric disorders (depression, schizophrenia, bipolar disorder). Olfactory dysfunction is common in both FTD and psychiatric disorders, and often appears years before symptom onset. This systematic review analysed 74 studies on olfactory function in FTD, depression, schizophrenia and bipolar disorder to identify differences in olfactory dysfunction profiles, focusing on the most common smell measures: odour identification and discrimination. Results revealed that FTD patients were severely impaired in odour identification but not discrimination; in contrast, patients diagnosed with schizophrenia showed impairments in both measures, while those diagnosed with depression showed no olfactory impairments. Findings in bipolar disorder were mixed. Therefore, testing odour identification and discrimination differentiates FTD from depression and schizophrenia, but not from bipolar disorder. Given the high prevalence of odour identification impairments in FTD, and that smell dysfunction predicts neurodegeneration in other diseases, olfactory testing seems a promising avenue towards improving diagnosis between FTD and psychiatric disorders., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Although tool use disorders are frequent in neurodegenerative diseases, the question of which cognitive mechanisms are at stake is still under debate. Memory-based hypotheses (i.e., the semantic knowledge hypothesis and the manipulation knowledge hypothesis) posit that tool use relies solely on stored information about either tools or gestures whereas a reasoning-based hypothesis (i.e., the technical-semantic hypothesis) suggests that loss of semantic knowledge can be partially compensated by technical reasoning about the physical properties of tools and objects., Method: These three hypotheses were tested by comparing performance of 30 healthy controls, 30 patients with Alzheimer's disease and 13 patients with semantic dementia in gesture production tasks (i.e., pantomime of tool use, single tool use, real tool use) and tool or gesture recognition tasks (i.e., functional and contextual matching, recognition of tool manipulation). Individual, item-based patterns of performance were analyzed to answer the following question: Could participants demonstrate the use of tools about which they had lost knowledge? With this aim in mind, "validation" and "rebuttal" frequencies were calculated based on each prediction., Results: Predictions from the technical-semantic hypothesis were more frequently observed than memory-based predictions. A number of patients were able to use and demonstrate the use of tools for which they had lost either semantic or manipulation knowledge (or both)., Conclusions: These data lead to question the role of different types of memory in tool use. The hypothesis of stored, tool-specific knowledge does not predict accurately clinical performances at the individual level. This may lead to explore the influence of either additional memory systems (e.g., personal/impersonal memory) or other modes of reasoning (e.g., theory of mind) on tool use skills., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Behavioural variant frontotemporal dementia (bvFTD) is characterized by behavioural and social cognitive disturbances, while various psychiatric and neurodegenerative disorders may have similar clinical symptoms. Since neurodegenerative disorders are eventually progressive, whereas primary psychiatric disorders are not, this study aimed to investigate whether the change in clinical symptoms over time differed between groups and which biomarkers predicted rate of decline. Disease trajectories (median follow-up = 3 years) of frontal and stereotyped behaviour, general and frontal cognitive functioning, and social cognition were examined in bvFTD (n = 34), other neurodegenerative (n = 28) and primary psychiatric disorders (n = 43), all presenting with late-onset frontal lobe syndrome (45-75 years), using linear mixed models. To gain more insight in underlying pathological processes driving disease progression, we studied the association of baseline cerebrospinal fluid (CSF) (neurofilament light (NfL) and YKL-40 levels, phosphotau 181 to total tau ratio) and neuroimaging markers with disease trajectories. Frontal behavioural symptoms (e.g., disinhibition, apathy) worsened over time in bvFTD, whereas they improved in psychiatric disorders and remained stable in other neurodegenerative disorders. General and frontal cognitive decline was observed in bvFTD and other neurodegenerative disorders, but not in psychiatric disorders. None of the groups showed change in stereotypy and social cognition. For all diagnostic groups, higher CSF NfL levels were associated with faster frontal cognitive decline. A modest association was observed between caudate volume and stereotyped behaviour. Tracking frontal behavioural symptoms and cognition has potential to distinguish bvFTD from other disorders. CSF NfL levels seem to be associated with decline in frontal cognitive functioning., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Although commonly interpreted as a marker of episodic memory during neuropsychological exams, relatively little is known regarding the neurobehavior of "total learning" immediate recall scores. Medial temporal lobes are clearly associated with delayed recall performances, yet immediate recall may necessitate networks beyond traditional episodic memory. We aimed to operationalize cognitive and neuroanatomic correlates of total immediate recall in several aging syndromes. Demographically-matched neurologically normal adults (n=91), individuals with Alzheimer's disease (n=566), logopenic variant primary progressive aphasia (PPA) (n=34), behavioral variant frontotemporal dementia (n=97), semantic variant PPA (n=71), or nonfluent/agrammatic variant PPA (n=39) completed a neurocognitive battery, including the CVLT-Short Form trials 1-4 Total Immediate Recall; a majority subset also completed a brain MRI. Regressions covaried for age and sex, and MMSE in cognitive and total intracranial volume in neuroanatomic models. Neurologically normal adults demonstrated a heterogeneous pattern of cognitive associations with total immediate recall (executive, speed, delayed recall), such that no singular cognitive or neuroanatomic correlate uniquely predicted performance. Within the clinical cohorts, there were syndrome-specific cognitive and neural associations with total immediate recall; e.g., semantic processing was the strongest cognitive correlate in svPPA (partial r=0.41), while frontal volumes was the only meaningful neural correlate in bvFTD (partial r=0.20). Medial temporal lobes were not independently associated with total immediate recall in any group (ps>0.05). Multiple neurobehavioral systems are associated with "total learning" immediate recall scores that importantly differ across distinct clinical syndromes. Conventional memory networks may not be sufficient or even importantly contribute to total immediate recall in many syndromes. Interpreting learning scores as equivalent to episodic memory may be erroneous., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A middle-aged Japanese man presented with slowly progressive asymmetric weakness of legs and arm but had neither ptosis nor dysphagia. He had a family history of similar condition suggestive of autosomal dominant inheritance. A muscle biopsy showed mixture of neurogenic atrophy and myopathy with rimmed vacuoles. Furthermore we found intranuclear inclusions that had a fine structure mimicking that of inclusions reported in oculopharyngeal muscular dystrophy (OPMD). Immunohistochemical staining for polyadenylate-binding nuclear protein 1, which is identified within the nuclear inclusions of OPMD, demonstrated nuclear positivity in this case. However, OPMD was thought unlikely based on the clinical features and results of genetic analyses. Instead, a novel mutation in valosin-containing protein, c.376A>T (p.Ile126Phe), was revealed. A diagnosis of inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia was made. This is the first report of polyadenylate-binding nuclear protein 1-positive nuclear inclusions in the muscle of this condition., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Episodic memory impairment represents one of the hallmark clinical features of patients with Alzheimer's disease (AD) attributable to the degeneration of medial temporal and parietal regions of the brain. In contrast, a somewhat paradoxical profile of relatively intact episodic memory, particularly for non-verbal material, is observed in semantic dementia (SD), despite marked atrophy of the hippocampus. This retrospective study investigated the neural substrates of episodic memory retrieval in 20 patients with a diagnosis of SD and 21 disease-matched cases of AD and compared their performance to that of 35 age- and education-matched healthy older Controls. Participants completed the Rey Complex Figure and the memory subscale of the Addenbrooke's Cognitive Examination-Revised as indices of visual and verbal episodic recall, respectively. Relative to Controls, AD patients showed compromised memory performance on both visual and verbal memory tasks. In contrast, memory deficits in SD were modality-specific occurring exclusively on the verbal task. Controlling for semantic processing ameliorated these deficits in SD, while memory impairments persisted in AD. Voxel-based morphometry analyses revealed significant overlap in the neural correlates of verbal episodic memory in AD and SD with predominantly anteromedial regions, including the bilateral hippocampus, strongly implicated. Controlling for semantic processing negated this effect in SD, however, a distributed network of frontal, medial temporal, and parietal regions was implicated in AD. Our study corroborates the view that episodic memory deficits in SD arise very largely as a consequence of the conceptual loading of traditional tasks. We propose that the functional integrity of frontal and parietal regions enables new learning to occur in SD in the face of significant hippocampal and anteromedial temporal lobe pathology, underscoring the inherent complexity of the episodic memory circuitry., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Anomia therapy typically aims to improve patients' communication ability through targeted practice in naming a set of particular items. For such interventions to be of maximum benefit, the use of trained (or relearned) vocabulary must generalise from the therapy setting into novel situations. We investigated relearning in three patients with semantic dementia, a condition that has been associated with poor generalisation of relearned vocabulary. We tested two manipulations designed to improve generalisation of relearned words by introducing greater variation into the learning experience. In the first study, we found that trained items were retained more successfully when they were presented in a variety of different sequences during learning. In the second study, we found that training items using a range of different pictured exemplars improved the patients' ability to generalise words to novel instances of the same object. However, in one patient this came at the cost of inappropriate over-generalisations, in which trained words were incorrectly used to name semantically or visually similar objects. We propose that more variable learning experiences benefit patients because they shift responsibility for learning away from the inflexible hippocampal learning system and towards the semantic system. The success of this approach therefore depends critically on the integrity of the semantic representations of the items being trained. Patients with naming impairments in the context of relatively mild comprehension deficits are most likely to benefit from this approach, while avoiding the negative consequences of over-generalisation., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We present two patients in whom the combination of lesion site and cognitive performance was uniquely informative about the organisation and functional anatomy of semantic memory. One had had a single lobar stroke with an unusual distribution, largely destroying the whole of the left temporal lobe ventral to the superior temporal sulcus. The other patient had had herpes simplex encephalitis with destruction that was confined to the left cerebral hemisphere. The lesion again mainly encompassed the left temporal lobe, but also extended to the left inferior frontal gyrus. Cognitive outcomes in the two patients were compared with each other and with published results from patients with semantic dementia. This is because, whereas the majority of semantic dementia patients present with more prominent atrophy of the left rostroventral temporal lobe, they invariably have a degree of atrophy in the mirror region on the right that progresses. Semantic dementia therefore provides no clear evidence about the specific role of the left rostroventral temporal lobe. The two patients showed a highly consistent cognitive profile. Their deficits were also similar in many respects to that observed in patients with mild-moderate semantic dementia, including severe anomia that was not resolved by phonological cues and impairment on non-verbal as well as verbal semantic tasks. Certain key features of the semantic dementia profile, however-including sensitivity to the familiarity and typicality of the stimulus materials-appeared only in tasks requiring verbal output in these two patients with unilateral left temporal lesions. Results in these cases provide some of the first definitive evidence regarding the specific functions of the left anterior temporal lobe., (Copyright © 2014. Published by Elsevier Ltd.)

The ability to perceive, learn and recognise faces is a complex ability, which is key to successful social interactions. This ability is proposed to be coordinated by neural regions in the occipital and temporal lobes, specialised for face perception and memory. While previous studies have suggested that memory for faces is compromised in some dementia syndromes, it remains unclear whether this simply reflects more generalised memory deficits. Here, we examined basic face perception (Identity-Matching), face recognition (Cambridge Face Memory Task) and object recognition (Cambridge Car Memory Task) in 11 semantic dementia (SD) patients (8 left-lateralised, 3 right-lateralised) and 13 behavioural-variant frontotemporal dementia (bvFTD) patients, compared with 11 controls. On the Identity-Matching task, bvFTD were impaired compared to controls, with a similar trend observed in the SD group. Importantly, both bvFTD and SD also demonstrated impaired face recognition. In contrast, only bvFTD showed impaired object recognition, with SD performing within normal limits on this task. Voxel-based morphometry analyses revealed that Identity-Matching and face recognition were associated with partly dissociable regions including the fusiform cortex and anterior temporal lobe. Object-memory was associated with thalamic integrity in the bvFTD group only. These results reveal that face perception and face memory deficits are common in bvFTD and SD, and have been previously underestimated. These deficits are due to neurodegeneration of key regions within the 'core' and 'extended' face processing system, providing convergent evidence of the neural regions supporting face perception. From a clinical perspective, impaired ability to recognise faces is common in bvFTD and SD and therefore strategies to improve face perception and memory may be beneficial for these patients., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

To investigate how basic aspects of perception are shaped by acquired knowledge about the world, we assessed colour perception and cognition in patients with semantic dementia (SD), a disorder that progressively erodes conceptual knowledge. We observed a previously undocumented pattern of impairment to colour perception and cognition characterized by: (i) a normal ability to discriminate between only subtly different colours but an impaired ability to group different colours into categories, (ii) normal perception and memory for the colours red, green, and blue but impaired perception and memory for colours lying between these regions of a fully-saturated and luminant spectrum, and (iii) normal naming of polar colours in the opponent-process colour system (red, green, blue, yellow, white, and black) but impaired naming of other basic colours (brown, gray, pink, and orange). The results suggest that fundamental aspects of perception can be shaped by acquired knowledge about the world, but only within limits., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2013 Published by Elsevier Ltd.)

Semantic dementia (SD) is associated with a progressive, relatively selective, degeneration of semantic memory (both verbal and nonverbal facts and knowledge). Episodic memory, however, is thought to be relatively preserved. This study aimed to further assess the nonverbal, incidental, episodic memory profile associated with SD using deferred imitation, which measures recall by the nonverbal imitation of novel action sequences after a 24-h delay. The performance of six individuals with SD was compared to that of 10 healthy age- and education-matched controls. After a baseline phase, where sets of objects were presented for manipulation to measure the spontaneous production of relevant action sequences, participants were shown eight novel three-step action sequences with the sets of objects. The component actions of the sequences were causally related in four of the eight series and arbitrarily related in the remaining four, to investigate the influence of sequence structure on memory performance. All participants produced more target actions and pairs in the arbitrary sequences 24-h after demonstration compared to baseline, indicating memory for the sequences, but only the control group showed significant memory for the order of the causal sequences (pairs). Furthermore, and perhaps more strikingly, only the control participants showed a recall advantage for the causal relative to the arbitrary sequences, indicating that they, but not the patients, could take advantage of the semantic nature of these sequences. Together these findings suggest that individuals with SD show some nonverbal episodic memory, even after a 24-h delay, and that new anterograde memory can to some extent be established without significant support from semantic memory., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Polysomnograhic (PSG) studies in Alzheimer's disease (AD) show REM sleep abnormalities, which may be indicative for the deterioration of cholinergic pathways and probably closely linked to declarative memory impairment. To clarify the specificity of the association between sleep and cognitive impairment in dementia, we compared AD patients with patients suffering from frontotemporal dementia (FTD) with regard to PSG and neuropsychological variables. 15 AD and 6 FTD patients underwent polysomonography and a neuropsychological battery (CERAD-NB). Group differences (age: AD > FTD; education level: AD < FTD) were considered as covariates. Polysomnography revealed a trend towards increased REM latency and reduced REM sleep in AD, as well as a decrease of stage 2 sleep, however, at least partly due to effects of age. Declarative memory was more impaired in AD than in FTD, but this difference disappeared when adjusted for covariates. While no relationship was found between REM sleep and CERAD-NB parameters, strong positive correlations between stage 2 sleep and declarative memory measures were observed, which were also detectable when analyzing both groups separately. Based on these results we conclude that REM sleep alterations may be specific for AD, distinguishable from other dementia diagnoses, whereas NonREM stage 2 sleep may be related to declarative memory formation in dementia independent of subtype., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Occupation has been associated with cognitive reserve in healthy aging and Alzheimer's disease. Here we assess the relationship between cerebral metabolic deficits in behavioral variant frontotemporal dementia (bvFTD) and occupation characteristics. Using factor analysis, we derived verbal, physical and visuospatial occupation scores from the US Department of Labor, Occupational Information Network and related these scores to regional cerebral metabolic rate of glucose utilization in 31 patients diagnosed with behavioral variant bvFTD, controlling for cognitive status (CERAD neuropsychological assessment battery), gender and education. Regression analyses showed a marked inverse association between glucose metabolism and (a) verbal occupation scores in left prefrontal cortex and, (b) physical occupation characteristics in right supplementary motor area. We concluded that, consistent with the cognitive reserve hypothesis, lifelong occupation characteristics are related to focal cerebral metabolic deficits in bvFTD. Specific occupation demands spanning decades may strengthen cognitive resistance to pathology., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Figure copy is the most common method of visual spatial assessment in dementia evaluations, but performance on this test may be multifactorial. We examined the neuroanatomical substrates of figure copy performance in 46 patients with Alzheimer's disease (AD) and 48 patients with the behavioral variant of Frontotemporal dementia (bvFTD). A group of 94 neurologically healthy controls were studied for comparison. In AD, poor figure copy correlated significantly with right parietal cortex volumes but not with right dorsolateral prefrontal cortex volumes, whereas in bvFTD, figure copy performance correlated significantly with right dorsolateral prefrontal cortex volumes and there was only a trend with right parietal cortex volumes. The cognitive processes associated with figure copy performance also differed by diagnostic group such that figure copy was associated with spatial perception and attention in AD and with spatial planning and working memory in bvFTD. Spatial planning accounted for unique variance in the figure copy performance of bvFTD even after accounting for spatial perception, attention, and working memory. These results suggest that figure copy performance in AD and bvFTD is not anatomically specific and is differentially impacted by bottom-up and top-down aspects of visual spatial processing. Alternative methods of visual spatial assessment for dementia evaluations are proposed., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

We report the first Australian families with inclusion-body myopathy, Paget's disease of the bone and frontotemporal dementia (IBMPFD). The clinical characteristics of the two pedigrees are described including a previously undescribed phenotypic feature of pyramidal tract dysfunction in one family member. A novel mutation in the valosin-containing protein (VCP) gene (p.Arg155Leu) was found in one family while the other family had a previously reported mutation (p.Leu198Trp). Our findings broaden the phenotypic spectrum of IBMPFD and further emphasise the resemblance to amyotrophic lateral sclerosis in some cases., (2010 Elsevier B.V. All rights reserved.)

The paper reviews convergent evidence on the ability to attribute mental states to one's self and to others (i.e., theory of mind, ToM) in patients affected by the behavioural variant of frontotemporal dementia (bv-FTD). This disease represents a particular challenge for researchers and clinicians, due to its insidious onset and ambiguous clinical features, which frequently render difficult a precise and timely diagnosis. The paper proposes a way to shed new light on the hypothesis that the neuropsychiatric profile of individuals with bv-FTD can be at least partially explained by a deficit in ToM ability. We examined both neuroimaging data on the neural correlates of ToM ability in healthy participants and studies investigating the progressive cerebral atrophy in patients with bv-FTD. Our findings suggest a link between the progressive degeneration of the anterior regions of medial frontal structures characterising the early stages of the bv-FTD and the ToM deficit these patients show. They also suggest the importance of using ToM tests during the diagnostic process of bv-FTD.

Inclusion body myopathy associated with Paget's disease and frontotemporal dementia (IBMPFD) is caused by mutations in the valosin containing protein (VCP) gene. The disease is associated with progressive proximal muscle weakness, inclusions and vacuoles in muscle fibers, malfunction in the bone remodeling process resulting in Paget's disease, and premature frontotemporal dementia. VCP is involved in several cellular processes related to the endoplasmic reticulum associated degradation of proteins. To understand the pathological mechanisms underlying the myopathy in IBMPFD, we have studied the cellular consequences of VCP mutations in human primary myoblasts. Our results revealed that patients' myoblasts accumulate large vacuoles. Lysosomal membrane proteins Lamp1 and Lamp2 show increased molecular weights in patients' myoblasts due to differential N-glycosylation. Additionally, mutant myoblasts show increased autophagy when cultured in the absence of nutrients, as well as defective cell fusion and increased apoptosis. Our results elucidate that VCP mutations result in disturbances in several cellular processes, which will help us in the understanding of the pathological mechanisms resulting in muscle weakness and other features of VCP associated disease.