Progression of behavioural disturbances in frontotemporal dementia: a longitudinal observational study.

BACKGROUND AND PURPOSE: Behavioural disturbances are the core features of frontotemporal dementia (FTD); however, symptom progression is still not well characterized during the entire course of the disease. The aim of the present study was to investigate behavioural symptoms at baseline and during the disease course in a large cohort of patients with behavioural variant FTD (bvFTD), non-fluent/agrammatic variant primary progressive aphasia (nfvPPA) and semantic variant primary progressive aphasia (PPA). METHODS: We evaluated 403 patients with FTD, 167 of whom had at least 1-year follow-up evaluation (for a total of 764 assessments). Behavioural symptoms were assessed and rated through the Neuropsychiatric Inventory (NPI) and Frontal Behavioural Inventory (FBI). Disease severity was evaluated through the Frontotemporal Lobar Degeneration -Clinical Dementia Rating scale (FTLD-CDR). Linear mixed models were used to model behavioural measures (NPI, FBI and the five FBI-behavioural core criteria scores) as a function of disease severity (FTLD-CDR score) and clinical phenotype. RESULTS: At baseline, patients with bvFTD showed more behavioural disturbances compared with those with nfvPPA (P = 0.004). Negative symptoms (apathy and loss of empathy) showed a trend to an increase throughout the course of the disease in both bvFTD and PPA (P < 0.001 until intermediate stages). Positive symptoms (disinhibition, perseverations and hyperorality) increased until intermediate phases (P < 0.001) followed by a progressive reduction in later phases, whereas they were less common in nfvPPA throughout the disease course. CONCLUSION: We demonstrated that behavioural disturbances differed in FTD and with disease severity. Positive symptoms appeared to improve in the advanced stages, highlighting the importance of taking into account the disease severity as outcome measure in clinical trials.

Neural correlates of altered insight in frontotemporal dementia: a systematic review.

Altered insight into disease or specific symptoms is a prominent clinical feature of frontotemporal dementia (FTD). Understanding the neural bases of insight is crucial to help improve FTD diagnosis, classification and management. A systematic review to explore the neural correlates of altered insight in FTD and associated syndromes was conducted. Insight was fractionated to examine whether altered insight into different neuropsychological/behavioural objects is underpinned by different or compatible neural correlates. 6 databases (Medline, Embase, PsycINFO, Web of Science, BIOSIS and ProQuest Dissertations & Theses Global) were interrogated between 1980 and August 2019. 15 relevant papers were found out of 660 titles screened. The studies included suggest that different objects of altered insight are associated with distinctive brain areas in FTD. For example, disease unawareness appears to predominantly correlate with right frontal involvement. In contrast, altered insight into social cognition potentially involves, in addition to frontal areas, the temporal gyrus, insula, parahippocampus and amygdala. Impaired insight into memory problems appears to be related to the frontal lobes, postcentral gyrus, parietal cortex and posterior cingulate. These results reflect to a certain extent those observed in other neurodegenerative conditions like Alzheimer's disease (AD) and also other brain disorders. Nevertheless, they should be cautiously interpreted due to variability in the methodological aspects used to reach those conclusions. Future work should triangulate different insight assessment approaches and brain imaging techniques to increase the understanding of this highly relevant clinical phenomenon in dementia.

The use of spelling for variant classification in primary progressive aphasia: Theoretical and practical implications.

Currently, variant subtyping in primary progressive aphasia (PPA) requires an expert neurologist and extensive language and cognitive testing. Spelling impairments appear early in the development of the disorder, and the three PPA variants (non-fluent - nfvPPA; semantic - svPPA; logopenic - lvPPA) reportedly show fairly distinct spelling profiles. Given the theoretical and empirical evidence indicating that spelling may serve as a proxy for spoken language, the current study aimed to determine whether spelling performance alone, when evaluated with advanced statistical analyses, allows for accurate PPA variant classification. A spelling to dictation task (with real words and pseudowords) was administered to 33 PPA individuals: 17 lvPPA, 10 nfvPPA, 6 svPPA. Using machine learning classification algorithms, we obtained pairwise variant classification accuracies that ranged between 67 and 100%. In additional analyses that assumed no prior knowledge of each case's variant, classification accuracies ranged between 59 and 70%. To our knowledge, this is the first time that all the PPA variants, including the most challenging logopenic variant, have been classified with such high accuracy when using information from a single language task. These results underscore the rich structure of the spelling process and support the use of a spelling task in PPA variant classification.

Relationship Turmoil and Emotional Empathy in Frontotemporal Dementia.

BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is characterized by marked deficits in empathy and social behavior; however, the effect of these symptoms on partner relationships has not been quantitatively measured. OBJECTIVE: We aimed to determine the effect of empathy loss and behavioral symptoms on partner and familial relationship status in bvFTD. We ascertained whether patients were currently in marriage/partner relationships or were separated/divorced, the timing and duration of these relationships, and whether the patients had relationship infidelity. We investigated the relationship status of 483 patients (156 with bvFTD, 38 with nonfluent variant primary progressive aphasia, 72 with semantic variant primary progressive aphasia, 49 with corticobasal syndrome, 45 with progressive supranuclear palsy syndrome, and 123 with Alzheimer disease) over the course of follow-up, and correlated relationship status with patients' first visit Interpersonal Reactivity Index and Neuropsychiatric Inventory. RESULTS: Relationship dissolution and infidelity were significantly more frequent among patients with bvFTD than in the other groups. Across all patients, empathy loss was associated with relationship dissolution. In the bvFTD group, patients who experienced relationship dissolution or infidelity had significantly lower empathy than those who did not. CONCLUSIONS: Changes in relationship status differed across dementia groups and were associated with empathy decline.

Emergence of artistic talent in progressive nonfluent aphasia: a case report.

Some patients with frontotemporal lobar degeneration have developed artistic skills after the onset mainly in painting and music. Most of these cases have semantic dementia (SD), one of the frontotemporal lobar degeneration subtypes. In previously reported cases, the paintings made by patients with SD were usually hyper realistic, without a significant symbolic or abstract component. Here, we report on a patient with progressive nonfluent aphasia (PNFA), another frontotemporal lobar degeneration subtype, who started making creative bamboo crafts after PNFA onset. His techniques were completely his original; he devised the shapes of the crafts and made them without samples. His work did not become an obsessive preoccupation. The artistic style expressed by patients with PNFA differs from that expressed by patients with SD. Therefore, the underlying mechanisms for the emergence of artistic talent might differ between SD and PNFA.

Aphasia in Progressive Supranuclear Palsy: As Severe as Progressive Non-Fluent Aphasia.

BACKGROUND: Adynamic speech is characteristic of progressive supranuclear palsy (PSP), but higher language deficits have been reported inconsistently, in the context of clinical and pathological overlaps with progressive non-fluent aphasia (PNFA). OBJECTIVE: The present study tested two hypotheses: 1) PSP and PNFA display impaired single word repetition, object naming, semantic knowledge, and syntactic comprehension; and 2) PSP have reduced speed on timed cognitive tasks. METHODS: Structured clinical and neuropsychological assessments of language were performed on patients with clinically defined PSP and PNFA. Language was tested using the Sydney Language Battery (SYDBAT) and the Test of Reception of Grammar (TROG). RESULTS: In total, 144 participants were studied (PSP 22, PNFA 29, and Control 93). PSP patients had prominent eye movement abnormalities, parkinsonism, and falls. All 4 PSP patients who underwent postmortem examination had 4-Repeat tauopathy, with PSP pathology in 3. The frequency and severity of impairment on the SYDBAT (naming, word comprehension, semantic association), and TROG (syntactic comprehension) did not differ between PSP and PNFA, but PSP were significantly slower on timed non-language cognitive tests. CONCLUSION: Tested formally, aphasia may be seen in PSP, with a severity similar to that seen in PNFA.

Behavioural and neuropsychiatric disturbance in three clinical subtypes of frontotemporal dementia: A Clinical Research Center for Dementia of South Korea-FTD Study.

OBJECTIVES: To characterise the behavioural and neuropsychiatric disturbances of patients with three clinical subtypes of frontotemporal dementia (FTD): behavioural variant FTD (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA). METHODS: Consecutive series of 66 patients with bvFTD, 58 patients with SD and 21 patients with PNFA were compared using the Frontal Behavioural Inventory (FBI) and the Neuropsychiatric Inventory (NPI). RESULTS: Patients with bvFTD had more behavioural and neuropsychiatric disturbances than patients with PNFA based on the total scores of FBI and NPI. When comparing subtotal and item scores of FBI and NPI, there were some significant differences among three clinical subtypes of FTD. CONCLUSION: There are some distinct patterns of behavioural and neuropsychiatric disturbance among three clinical subtypes of FTD.

Altered sense of humor in dementia.

Sense of humor is potentially relevant to social functioning in dementias, but has been little studied in these diseases. We designed a semi-structured informant questionnaire to assess humor behavior and preferences in patients with behavioral variant frontotemporal dementia (bvFTD; n = 15), semantic dementia (SD; n = 7), progressive nonfluent aphasia (PNFA; n = 10), and Alzheimer's disease (AD; n = 16) versus healthy age-matched individuals (n = 21). Altered (including frankly inappropriate) humor responses were significantly more frequent in bvFTD and SD (all patients) than PNFA or AD (around 40% of patients). All patient groups liked satirical and absurdist comedy significantly less than did healthy controls. This pattern was reported premorbidly for satirical comedy in bvFTD, PNFA, and AD. Liking for slapstick comedy did not differ between groups. Altered sense of humor is particularly salient in bvFTD and SD, but also frequent in AD and PNFA. Humor may be a sensitive probe of social cognitive impairment in dementia, with diagnostic, biomarker and social implications.

Behavioral Evolution of Progressive Semantic Aphasia in Comparison with Nonfluent Aphasia.

BACKGROUND: Patients with primary progressive aphasia (PPA) usually develop significant behavioral disturbances with progression of the disease. We tested our clinical observation that development of disruptive agitation is more likely in semantic than in nonfluent PPA and examined which clinical variables could be associated with this behavior. METHODS: We retrospectively analyzed neuropsychiatric scores and the need for behavioral treatments in semantic PPA (n = 41) and nonfluent PPA (n = 39) cases and compared first (1-3 years since the onset of symptoms) and last (5-13 years since the onset) evaluations. Clinical variables and laterality of temporal atrophy were associated with symptoms in semantic PPA cases. RESULTS: The semantic PPA group developed more frequent (p = 0.03) and intense agitation (p = 0.0008) and had a greater need for antipsychotic drugs (p = 0.001) than the nonfluent PPA group. Presence of agitation was clearly associated with psychotic symptoms (delusions/hallucinations) but was not associated with gender, age at onset, duration of the disease, or laterality of temporal atrophy. In contrast, nonfluent PPA cases were more frequently depressed and treated with antidepressants (p = 0.0007). There were no differences in anxiety, irritability, apathy, perseverations, hyperorality, or abnormal motor behavior. CONCLUSIONS: Semantic PPA in advanced disease is frequently associated with agitation and psychotic symptoms with fewer mood symptoms, while nonfluent PPA maintains a high prevalence of depression. This implies different treatment and care and support needs for each group.

The Language Profile of Behavioral Variant Frontotemporal Dementia.

BACKGROUND: The language profile of behavioral variant frontotemporal dementia (bvFTD) remains to be fully defined. OBJECTIVE: We aimed to quantify the extent of language deficits in this patient group. METHODS: We assessed a cohort of patients with bvFTD (n = 24) in relation to patients with semantic variant primary progressive aphasia (svPPA; n = 14), nonfluent variant primary progressive aphasia (nfvPPA; n = 18), and healthy age-matched individuals (n = 24) cross-sectionally and longitudinally using a comprehensive battery of language and general neuropsychological tests. Neuroanatomical associations of language performance were assessed using voxel-based morphometry of patients' brain magnetic resonance images. RESULTS: Relative to healthy controls, and after accounting for nonverbal executive performance, patients with bvFTD showed deficits of noun and verb naming and single word comprehension, diminished spontaneous propositional speech, and deterioration in naming performance over time. Within the bvFTD group, patients with MAPT mutations had more severe impairments of noun naming and single word comprehension than patients with C9orf72 mutations. Overall the bvFTD group had less severe language deficits than patients with PPA, but showed a language profile that was qualitatively similar to svPPA. Neuroanatomical correlates of naming and word comprehension performance in bvFTD were identified predominantly in inferior frontal and antero-inferior temporal cortices within the dominant hemispheric language network. CONCLUSIONS: bvFTD is associated with a language profile including verbal semantic impairment that warrants further evaluation as a novel biomarker.

Auditory hedonic phenotypes in dementia: A behavioural and neuroanatomical analysis.

Patients with dementia may exhibit abnormally altered liking for environmental sounds and music but such altered auditory hedonic responses have not been studied systematically. Here we addressed this issue in a cohort of 73 patients representing major canonical dementia syndromes (behavioural variant frontotemporal dementia (bvFTD), semantic dementia (SD), progressive nonfluent aphasia (PNFA) amnestic Alzheimer's disease (AD)) using a semi-structured caregiver behavioural questionnaire and voxel-based morphometry (VBM) of patients' brain MR images. Behavioural responses signalling abnormal aversion to environmental sounds, aversion to music or heightened pleasure in music ('musicophilia') occurred in around half of the cohort but showed clear syndromic and genetic segregation, occurring in most patients with bvFTD but infrequently in PNFA and more commonly in association with MAPT than C9orf72 mutations. Aversion to sounds was the exclusive auditory phenotype in AD whereas more complex phenotypes including musicophilia were common in bvFTD and SD. Auditory hedonic alterations correlated with grey matter loss in a common, distributed, right-lateralised network including antero-mesial temporal lobe, insula, anterior cingulate and nucleus accumbens. Our findings suggest that abnormalities of auditory hedonic processing are a significant issue in common dementias. Sounds may constitute a novel probe of brain mechanisms for emotional salience coding that are targeted by neurodegenerative disease.

The prevalence of depressive symptoms in frontotemporal dementia: a meta-analysis.

BACKGROUND: Depression is common in Alzheimer's and vascular dementia and is associated with poorer outcomes; however, less is known about the impact of depression on frontotemporal dementia (FTD). Here, we conducted a meta-analysis of diagnostic methods and the prevalence of depressive symptoms in FTD. METHODS: PubMed, EMBASE and PsychINFO were queried for 'depression' and/or 'depressive mood' in behavioral- and language-variant FTD. The prevalence and diagnosis of depressive symptoms were extracted from relevant studies and the results pooled using a random-effects model. RESULTS: We included 29 studies in this meta-analysis, with sample sizes ranging from 3 to 73 (n = 870). The omnibus estimated event rate of depressed mood was 0.334 (33%; 95% CI: 0.268-0.407). Symptoms were most commonly assessed via standardized neuropsychiatric rating scales, with other methods including subjective caregiver reports and chart reviews. The study results were heterogeneous due to the variability in diagnostic methods. CONCLUSIONS: Depressive symptoms similar to those in other dementias are commonly detected in FTD. However, the diagnostic methods are heterogeneous, and symptoms of depression often overlap with manifestations of FTD. Having a standardized diagnostic approach to depression in FTD will greatly facilitate future research in this area.

Ecological assessment of emotional enhancement of memory in progressive nonfluent aphasia and Alzheimer's disease.

BACKGROUND: Events which are imbued with emotion are typically remembered vividly and with more confidence than similar non-emotional events. The extent that emotional enhancement of memory is compromised in neurodegenerative disorders is unclear, despite differential effects of dementia on emotion processing ability. OBJECTIVE: To examine emotional enhancement of memory using an ecologically valid task in progressive nonfluent aphasia (PNFA), an expressive language subtype of frontotemporal dementia, in comparison to Alzheimer's disease (AD) and matched-controls. METHODS: Twenty-five dementia patients (13 PNFA, 12 AD) and 10 controls viewed either an emotionally arousing or a closely matched non-emotional story. Multiple-choice recognition memory was tested after a 1-hour delay. The alternate story was presented two weeks later. RESULTS: PNFA showed a similar level of memory for the emotional and neutral story, whereas both controls and AD remembered significantly more details from the emotional than the neutral story. Correlation analyses indicated that in PNFA, emotional story memory correlated with reduced emotion recognition, whereas in AD, neutral story memory correlated with visual recall memory performance only. Furthermore, in PNFA, reduced emotional memory enhancement was associated with increased carer stress and depression. CONCLUSION: Emotional memory enhancement is absent in PNFA, whereas emotion facilitates memory for real-life events in AD. Disrupted emotional memory enhancement in PNFA is associated with reduced emotion recognition ability, suggesting that widespread emotion processing dysfunction is present in this disease. Crucially, loss of emotional enhancement influences carer wellbeing, which represents an important avenue for future studies to examine.

Grammatical comprehension deficits in non-fluent/agrammatic primary progressive aphasia.

IMPORTANCE: Grammatical comprehension difficulty is an essential supporting feature of the non-fluent/agrammatic variant of primary progressive aphasia (naPPA), but well-controlled clinical measures of grammatical comprehension are unavailable. OBJECTIVE: To develop a measure of grammatical comprehension and examine this comparatively in PPA variants and behavioural-variant frontotemporal degeneration (bvFTD) and to assess the neuroanatomic basis for these deficits with volumetric grey matter atrophy and whole-brain fractional anisotropy (FA) in white matter tracts. DESIGN: Case-control study. SETTING: Academic medical centre. PARTICIPANTS: 39 patients with variants of PPA (naPPA=12, lvPPA=15 and svPPA=12), 27 bvFTD patients without aphasia and 12 healthy controls. MAIN OUTCOME MEASURE: Grammatical comprehension accuracy. RESULTS: Patients with naPPA had selective difficulty understanding cleft sentence structures, while all PPA variants and patients with bvFTD were impaired with sentences containing a centre-embedded subordinate clause. Patients with bvFTD were also impaired understanding sentences involving short-term memory. Linear regressions related grammatical comprehension difficulty in naPPA to left anterior-superior temporal atrophy and reduced FA in corpus callosum and inferior frontal-occipital fasciculus. Difficulty with centre-embedded sentences in other PPA variants was related to other brain regions. CONCLUSIONS AND RELEVANCE: These findings emphasise a distinct grammatical comprehension deficit in naPPA and associate this with interruption of a frontal-temporal neural network.

Sporadic Creutzfeldt-Jakob disease presenting as progressive nonfluent aphasia with speech apraxia.

Progressive non-fluent aphasia (PNFA) is typically associated with pathological changes consistent with frontotemporal lobar degeneration. A 65-year-old male presented with effortful speech, markedly impaired naming and features of speech apraxia, consistent with PNFA. Perceptuospatial function, calculation and executive function were intact. Brain SPECT showed left perisylvian hypoperfusion. He deteriorated profoundly over the subsequent eight months, with appearances on diffusion-weighted magnetic resonance imaging typical of sporadic Creutzfeldt-Jakob disease, which was confirmed pathologically at postmortem examination. While the presence of PNFA with speech apraxia is thought to predict underlying tauopathy, sporadic Creutzfeldt-Jakob disease may mimic this presentation and present in a highly circumscribed form not previously described.

Flavour identification in frontotemporal lobar degeneration.

BACKGROUND: Deficits of flavour processing may be clinically important in frontotemporal lobar degeneration (FTLD). OBJECTIVE: To examine flavour processing in FTLD. METHODS: We studied flavour identification prospectively in 25 patients with FTLD (12 with behavioural variant frontotemporal dementia (bvFTD), eight with semantic variant primary progressive aphasia (svPPA), five with non-fluent variant primary progressive aphasia (nfvPPA)) and 17 healthy control subjects, using a new test based on cross-modal matching of flavours to words and pictures. All subjects completed a general neuropsychological assessment, and odour identification was also assessed using a modified University of Pennsylvania Smell Identification Test. Brain MRI volumes from the patient cohort were analysed using voxel-based morphometry to identify regional grey matter associations of flavour identification. RESULTS: Relative to the healthy control group, the bvFTD and svPPA subgroups showed significant (p<0.05) deficits of flavour identification and all three FTLD subgroups showed deficits of odour identification. Flavour identification performance did not differ significantly between the FTLD syndromic subgroups. Flavour identification performance in the combined FTLD cohort was significantly (p<0.05 after multiple comparisons correction) associated with grey matter volume in the left entorhinal cortex, hippocampus, parahippocampal gyrus and temporal pole. CONCLUSIONS: Certain FTLD syndromes are associated with impaired flavour identification and this is underpinned by grey matter atrophy in an anteromedial temporal lobe network. These findings may have implications for our understanding of abnormal eating behaviour in these diseases.

Logopenic aphasia in Alzheimer's disease: clinical variant or clinical feature?

BACKGROUND: Primary progressive aphasia (PPA) is a clinical syndrome characterised by progressive decline in components of the language system. Recent evidence suggests that the logopenic/phonological (LPA) variant is a reliable in vivo marker of Alzheimer related pathology. The aim of this study was to determine if patients with clinically typical early stage Alzheimer's disease (AD) display a characteristic language disorder that resembles LPA, or if LPA is a clinical manifestation of an atypical form of AD. METHODS: Spoken language samples were obtained using the Cookie Theft picture description task from 18 post mortem confirmed cases of AD, where speech samples were taken at the first point of clinical diagnosis, and 18 post mortem confirmed healthy controls. Spoken samples were transcribed from tape recordings and analysed using the scoring system described by Wilson et al. RESULTS: Group comparisons between normal controls and AD patients showed no significant overall differences. Individual review of the linguistic variables compared with the PPA variants showed that a third of patients had normal language (n=6). The remainder showed varied patterns of linguistic impairment. In the majority of the affected group, the most salient feature was a reduction in one or more measures of syntactic complexity. One patient's deficit was comparable to that found in LPA. CONCLUSIONS: The impairment found in clinically typical early stage AD did not correspond consistently to the linguistic profiles described in any of the sub-syndromes of PPA. The only reliably distinguishing feature was a reduction across a range of syntactic complexity measures. The findings suggest that LPA represents an atypical clinical presentation of AD rather than a common clinical feature of typical AD.

Accent processing in dementia.

Accented speech conveys important nonverbal information about the speaker as well as presenting the brain with the problem of decoding a non-canonical auditory signal. The processing of non-native accents has seldom been studied in neurodegenerative disease and its brain basis remains poorly understood. Here we investigated the processing of non-native international and regional accents of English in cohorts of patients with Alzheimer's disease (AD; n=20) and progressive nonfluent aphasia (PNFA; n=6) in relation to healthy older control subjects (n=35). A novel battery was designed to assess accent comprehension and recognition and all subjects had a general neuropsychological assessment. Neuroanatomical associations of accent processing performance were assessed using voxel-based morphometry on MR brain images within the larger AD group. Compared with healthy controls, both the AD and PNFA groups showed deficits of non-native accent recognition and the PNFA group showed reduced comprehension of words spoken in international accents compared with a Southern English accent. At individual subject level deficits were observed more consistently in the PNFA group, and the disease groups showed different patterns of accent comprehension impairment (generally more marked for sentences in AD and for single words in PNFA). Within the AD group, grey matter associations of accent comprehension and recognition were identified in the anterior superior temporal lobe. The findings suggest that accent processing deficits may constitute signatures of neurodegenerative disease with potentially broader implications for understanding how these diseases affect vocal communication under challenging listening conditions.

Episodic memory in frontotemporal dementia: a critical review.

This review offers a critical appraisal of the literature on episodic memory performance in frontotemporal dementia. Historically, description of patients diagnosed with what was then known as Pick's disease included the presence of memory deficits and an underlying amnestic syndrome was noted in some of these patients. Over the last 20 years, however, the clinical view has been that episodic memory processing is relatively intact in the frontotemporal dementia syndrome. In particular, patients with the subtypes of behavioural variant frontotemporal dementia and progressive non-fluent aphasia are reported to perform within normal limits on standard memory tests. In the third clinical presentation of frontotemporal dementia, semantic dementia, relatively intact episodic memory against a significantly impaired semantic memory was regarded as the hallmark. This position was instrumental in the development of clinical diagnostic criteria for frontotemporal dementia in which amnesia was explicitly listed as an exclusion criterion for the disease. The relative intactness of episodic memory, therefore, appeared to be a useful diagnostic marker to distinguish early frontotemporal dementia from Alzheimer's disease, in which early episodic memory disturbance remains the most common clinical feature. We argue that recent evidence questions the validity of preserved episodic memory in frontotemporal dementia, particularly in behavioural variant frontotemporal dementia. In semantic dementia, a complex picture emerges with preservation of some components of episodic memory, notably recognition-based visual memory and recall of recent autobiographical events. We propose a critical synthesis of recent neuropsychological evidence on retrograde and anterograde memory in light of neuroimaging and neuropathological findings, demonstrating involvement of medial temporal structures in frontotemporal dementia, structures known to be critical for episodic memory processing. We further argue that the multifactorial nature of most memory tests commonly used clinically fail to capture the memory deficits in frontotemporal dementia and that sensitive assessment tools of memory are needed. Together, recent clinical and experimental findings and the historical evidence represent a strong case for a re-evaluation of the importance of memory disturbance in the clinical diagnosis of frontotemporal dementia.