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Objective Apathy is the most prevalent and disabling non-cognitive symptom of dementia and affects 90% of patients across the disease course. Despite its pervasiveness, how apathy manifests across dementia syndromes and the neurobiological mechanisms driving these symptoms are poorly understood. Here, we applied the multidimensional ABC model of apathy, which recognizes Affective, Behavioural and Cognitive apathy, in Alzheimer's disease (AD) and behavioural-variant frontotemporal dementia (bvFTD). Methods One hundred and twenty-two patients (53 AD; 69 bvFTD) were included. Informants completed the Neuropsychiatric Inventory (NPI), Cambridge Behavioral Inventory and Disability and Dementia scale to quantify Affective, Behavioural and Cognitive apathy. All patients underwent structural magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) was employed to identify brain regions correlated with increased Affective, Behavioural and Cognitive apathy. Results On the NPI, 60% of AD and 84% of bvFTD patients had some degree of apathy, but bvFTD had more severe and more frequent symptoms than AD. Importantly, bvFTD patients had higher affective and cognitive apathy whereas AD had higher cognitive apathy only. Neuroimaging analyses revealed that affective apathy was associated with the ventral prefrontal cortex; behavioural apathy with the basal ganglia; and cognitive apathy with the dorsomedial prefrontal cortex. Finally, affective and behavioural apathy significantly predicted carer burden. Conclusions Our results support the notion that apathy is multidimensional and manifests differently across dementia syndromes. Thus, novel interventions which target these divergent mechanisms will be necessary to improve motivation and goal-directed behaviour in people with dementia.

The aim of this study was to determine in a systematic manner if theA validated semistructured family history interview was conducted in a large cohort of patients with FTD and ALS (n = 89), with and without theA significant HR of 4.9 (95% confidence interval [CI]: 1.9-13.9,Overall, the results from this study suggest that a psychiatric phenotype exists within

Face processing plays a central role in human communication, with the eye region a particularly important cue for discriminating emotions. Indeed, reduced attention to the eyes has been argued to underlie social deficits in a number of clinical populations. Despite well-established impairments in facial affect recognition in behavioural-variant frontotemporal dementia, whether these patients also have perturbed facial scanning is yet to be investigated. The current study employed eye tracking to record visual scanning of faces in 20 behavioural-variant frontotemporal dementia patients and 21 controls. Remarkably, behavioural-variant frontotemporal dementia patients displayed more fixations to the eyes of emotional faces, compared to controls. Neural regions associated with fixations to the eyes included the left inferior frontal gyrus, right cerebellum and middle temporal gyrus. Our study is the first to show such compensatory functions in behavioural-variant frontotemporal dementia and suggest a feedback-style network, including anterior and posterior brain regions, is involved in early face processing.

This chapter discusses the use of the third version of the Addenbrooke’s Cognitive Examination, ACE-III, which has evolved from the early ACE via the ACE-R. The major difference between the ACE-III and earlier versions is the removal of the MMSE which was previously incorporated within the longer test. The chapter describes the ACE-III in full together with scoring criteria and normative data. The ACE-III is freely available and can be downloaded from http://www.ftdrg.org. It has been translated into over 20 languages and is in widespread use in cognitive clinics around the world. The section on the ACE-III is followed by suggestions for ‘add-on’ bedside tasks that test areas not well covered by the ACE-III, such as tests for remote memory, frontal executive function, language, calculation, praxis, neglect phenomena, and complex visuoperceptual abilities and prosopagnosia.

This chapter discusses cognitive functions with a largely distributed neural basis within the framework of contemporary cognitive neuroscience. The following are described: arousal/attention, memory (short-term, or working memory; episodic memory; semantic memory; and implicit memory), and higher-order cognitive function such as planning, problem-solving and set-shifting, motivation, inhibitory control, social cognition, and emotion processing. Each function in placed in the context of its neural basis, with a brief description of the disorders that may affect these cognitive abilities. Methods of assessment at the bedside and by using neuropsychological tasks are also outlined.

This chapter discusses standardized mental test schedules. Many brief standardized assessment tools have been advocated over the past two or three decades but many have largely fallen into disuse. This chapter focuses, therefore, on two of the most commonly used brief assessment schedules: the Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment (MoCA) with an analysis of their strengths, weaknesses, and applications. The MoCA is freely available and a link to the website is included. They are contrasted with the ACE-III which is described in Chapter 7. The chapter also describes two longer tests which are widely used in dementia research: the Mattis Dementia Rating Scale (DRS) and the Cambridge Cognitive Examination–Revised (CAMCOG-R). Finally, it includes a description of the Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-Cog), which is used widely in drug evaluation studies.

Background:Primary progressive aphasia (PPA) affects a range of language and cognitive domains that impact on conversation. Little is known about conversation breakdown in the semantic variant of PPA (svPPA, also known as semantic dementia). This study investigates conversation of people with svPPA.Methods:Dyadic conversations about everyday activities between seven individuals with svPPA and their partners, and seven control pairs were video recorded and transcribed. Number of words, turns, and length of turns were measured. Trouble-indicating behaviors (TIBs) and repair behaviors were categorized and identified as successful or not for each participant in each dyad.Results:In general, individuals with svPPA were active participants in conversation, taking an equal proportion of turns, but indicating a great deal of more trouble in conversation, shown by the significantly higher number of TIBs than evidenced by partners or control participants. TIBs were interactive (asking for confirmation with a shorter repetition of the original utterance or a repetition which included a request for specific information) and non-interactive (such as failing to take up or continue the topic or a minimal response) and unlike those previously reported for people with other PPA variants and dementia of the Alzheimer type. Communication behaviors of the partner were critical to conversational success.Conclusions:Examination of trouble and repair in 10-min conversations of individuals with svPPA and their important communication partners has potential to inform speech pathology interventions to enhance successful conversation, in svPPA and should be an integral part of the comprehensive care plan.

Autobiographical memory is typically held to comprise episodic and semantic elements, with the vast majority of studies to date focusing on profiles of episodic details in health and disease. In this context, ‘non-episodic’ elements are often considered to reflect semantic processing, or are discounted from analyses entirely. Mounting evidence suggests that rather than reflecting one unitary entity, semantic autobiographical information may contain discrete subcomponents, which vary in their relative degree of semantic or episodic content. The current study aimed to (i) review the existing literature to formally characterise the variability in analysis of ‘non-episodic’ content (i.e., external details) on the Autobiographical Interview and (ii) use these findings to create a theoretically-grounded framework for coding external details. Our review exposed discrepancies in the reporting and interpretation of external details across studies, reinforcing the need for a new, consistent approach. We validated our new external details scoring protocol (the ‘NExt’ taxonomy) in patients with Alzheimer’s disease (n = 18) and semantic dementia (n = 13), and 20 healthy older Control participants, and compared profiles of the NExt subcategories across groups and time periods. Our results revealed increased sensitivity of the NExt taxonomy in discriminating between autobiographical memory profiles of patient groups, when compared to traditionally used internal and external detail metrics. Further, remote and recent autobiographical memories displayed distinct compositions of the NExt detail types. This study is the first to provide a fine-grained and comprehensive taxonomy to parse external details into intuitive subcategories, and to validate this protocol in neurodegenerative disorders.

Social relevance has an enhancing effect on learning and subsequent memory retrieval. The ability to learn from and remember social interactions may impact on susceptibility to financial exploitation, which is elevated in individuals with dementia. The current study aimed to investigate learning and memory of social interactions, the relationship between performance and financial vulnerability and the neural substrates underpinning performance in 14 Alzheimer's disease (AD) and 20 behavioural-variant frontotemporal dementia (bvFTD) patients and 20 age-matched healthy controls. On a “trust game” task, participants invested virtual money with counterparts who acted either in a trustworthy or untrustworthy manner over repeated interactions. A non-social “lottery” condition was also included. Participants’ learning of trust/distrust responses and subsequent memory for the counterparts and nature of the interactions was assessed. Carer-rated profiles of financial vulnerability were also collected. Relative to controls, both patient groups showed attenuated learning of trust/distrust responses, and lower overall memory for social interactions. Despite poor learning performance, both AD and bvFTD patients showed better memory of social compared to non-social interactions. Importantly, better memory for social interactions was associated with lower financial vulnerability in AD, but not bvFTD. Learning and memory of social interactions was associated with medial temporal and temporoparietal atrophy in AD, whereas a wider network of frontostriatal, insular, fusiform and medial temporal regions was implicated in bvFTD. Our findings suggest that although social relevance influences memory to an extent in both AD and bvFTD, this is associated with vulnerability to financial exploitation in AD only, and is underpinned by changes to different neural substrates. Theoretically, these findings provide novel insights into potential mechanisms that give rise to vulnerability in people with dementia, and open avenues for possible interventions.

Introduction The diagnostic utility of in vivo amyloid β (Aβ) imaging to aid in the clinical distinction between frontotemporal dementia (FTD) and Alzheimer's disease remains unclear without data on the prevalence and severity of Aβ in pathologically confirmed FTD syndromes. Methods Aβ was assessed in 98 autopsy-confirmed FTD and 36 control cases, and the pathological accuracy of 11 C-Pittsburgh compound B (PiB)–positron emission tomography imaging was assessed in a subset of FTD cases ( n = 15). Results Aβ was identified in a similar proportion of FTD syndromes and age-matched controls and increases with age. Alzheimer's disease pathology was identified in all cases with high PiB retention and in one case with low PiB retention. We further demonstrate a strong regional correlation between volume fraction of histological Aβ with PiB standard uptake value ratio scaled to the white matter. Discussion The present study provides a pathologic reference to assist in the interpretation of in vivo assessments in FTD syndromes.

Background/Aims: Although some patients with primary progressive aphasia (PPA) exhibit novel or improved skills after the onset of dementia, these changes have yet to be quantified. Therefore, this study systematically explored and identified the emergence of positive behaviours after dementia onset. Methods: This study included 48 carers of patients with PPA: 12 nonfluent/agrammatic PPA (nfvPPA), 22 semantic variant PPA (svPPA), and 14 logopenic variant PPA (lvPPA). The presence and frequency of positive behaviour changes after dementia onset were established using the Hypersensory and Social/Emotional Scale (HSS). Results: Scores on Sensitivity to Details, Visuospatial Activities, and Music Activities differed significantly among the groups. More specifically, svPPA was associated with increased visuospatial activity, but only in the mild stage of the disease; nfvPPA was associated with increased visuospatial activity and decreased music activity, while lvPPA exhibited the reverse profile. Conclusions: The results demonstrate that subsets of PPA patients show novel or increased positive behaviours following dementia onset, and differences among subtypes may be helpful for improving diagnostic accuracy. Additionally, harnessing these skills may improve the quality of life of both patients and carers.

BACKGROUND The early and selective loss of von Economo neurons in the anterior cingulate cortex has been linked to behavioral deficits in frontotemporal dementia (FTD). Importantly, whether these neurons are also targeted in patients with the C9ORF72 repeat expansion has yet to be established. This is of particular interest given the recent evidence highlighting the thalamus rather than anterior cingulate cortex as a region of significant degeneration in patients with the C9ORF72 repeat expansion. OBJECTIVE To assess the von Economo neuron density and thalamus volumes in behavioral variant FTD (bvFTD) cases with the C9ORF72 repeat expansion, sporadic bvFTD, sporadic ALS, and controls. METHODS Volumetric and quantitative cell counting methods were employed to assess the von Economo neuron density and thalamus volumes in 37 pathologically-confirmed cases comprised of patients with bvFTD (n = 13) cases with the C9ORF72 repeat expansion (62% with psychosis), sporadic bvFTD (n = 8), sporadic amyotrophic lateral sclerosis (n = 7) and controls (n = 9). RESULTS von Economo neuron density was significantly reduced in sporadic bvFTD cases only. Thalamus degeneration was identified only in bvFTD cases with the C9ORF72 repeat expansion, and to a similar extent in cases with and without psychosis. No significant difference in von Economo neuron density or thalamus degeneration was seen between bvFTD cases with or without the C9ORF72 repeat expansion. CONCLUSION The present histological findings converge with neuroimaging results to corroborate the anterior cingulate cortex as a core region involved in sporadic bvFTD, and the thalamus as a major region targeted in patients with the C9ORF72 expansion.

The importance of assessing social cognition to characterize dementia syndromes is increasingly recognized, with lower social cognition capacity associated with reduced functional independence and greater carer burden. Emotion recognition is impaired in both behavioural-variant frontotemporal dementia and semantic dementia, yet the social and behavioural changes observed in these syndromes in everyday situations varies. To date, most studies have investigated isolated, context-free stimuli indexing recognition of facial emotions only. Here, we aimed to investigate how contextual information (i.e. emotional body language) influences emotion recognition, within the framework of the Social Context Network Model. Thirty-one patients with frontotemporal dementia (19 behavioural-variant frontotemporal dementia; 12 semantic dementia) and 20 healthy age- and education-matched controls were assessed on three tasks which varied contextual cues: (i) face alone; (ii) context alone; and (iii) face embedded in context. Voxel-based morphometry was used to identify neural correlates of task performance. Our results demonstrated that both behavioural-variant frontotemporal dementia and semantic dementia patients performed worse than controls in recognizing emotions from face alone and context alone. Importantly, performance differed when faces were presented in context. While both behavioural-variant frontotemporal dementia and semantic dementia patients performed similarly to controls on congruent items (i.e. face emotion and body emotion are the same) (P-values 4 0.05), patients with behavioural-variant frontotemporal dementia performed worse than both controls (P 5 0.001) and patients with semantic dementia (P = 0.044) for incongruent items (i.e. face emotion and body emotion are different). Neuroimaging analyses revealed that abnormal contextual influence was associated with lower integrity of the right parahippocampal gyrus/amygdala and left precentral gyrus. Together, these results indicate that patients with behavioural-variant frontotemporal dementia are over-reliant on external contextual information. Conversely, in semantic dementia and controls, contextual influence varies, with the degree of contextual influence appearing to be mediated, at least in part, by the facial expression depicted. The profile in behavioural-variant frontotemporal dementia is reminiscent of the ‘environmental dependency syndrome’ described in frontal lesion patients. It also converges with recent evidence of abnormal face perception in this group. From a theoretical perspective, our findings demonstrate that the capacity to incorporate contextual body language is dependent on the integrity of both contextual association brain regions (i.e. parahippocampal gyrus), as well as regions necessary for processing dynamic body movements. Clinically, these results open new avenues for rehabilitation of social impairments in dementia. Fil: Kumfor, Fiona. Arc Centre of Excellence in Cognition and its Disorders; Australia. University of Sydney; Australia Fil: Ibáñez Barassi, Agustín Mariano. Universidad Autónoma del Caribe; Colombia. Arc Centre of Excellence in Cognition and its Disorders; Australia. Universidad Adolfo Ibañez; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina Fil: Hutchings, Rosalind. University of Sydney; Australia. Arc Centre of Excellence in Cognition and its Disorders; Australia Fil: Hazelton, Jessica L.. University of Sydney; Australia Fil: Hodges, John R.. University of Sydney; Australia Fil: Piguet, Olivier. Arc Centre of Excellence in Cognition and its Disorders; Australia. University of Sydney; Australia

Age is a critical factor in the prevalence of tauopathies, including Alzheimer's disease. To observe how an aging phenotype interacts with and affects the pathological intracellular accumulation of hyperphosphorylated tau, the tauopathy mouse model pR5 (expressing P301L mutant human tau) was back-crossed more than ten times onto a senescence-accelerated SAMP8 background to establish the new strain, SApT. Unlike SAMP8 mice, pR5 mice are characterized by a robust tau pathology particularly in the amygdala and hippocampus. Analysis of age-matched SApT mice revealed that pathological tau phosphorylation was increased in these brain regions compared to those in the parental pR5 strain. Moreover, as revealed by immunohistochemistry, phosphorylation of critical tau phospho-epitopes (P-Ser202/P-Ser205 and P-Ser235) was significantly increased in the amygdala of SApT mice in an age-dependent manner, suggesting an age-associated effect of tau phosphorylation. Anxiety tests revealed that the older cohort of SApT mice (10 months vs. 8 months) exhibited a behavioural pattern similar to that observed for age-matched tau transgenic pR5 mice and not the SAMP8 parental mice. Learning and memory, however, appeared to be governed by the accelerated aging background of the SAMP8 strain, as at both ages investigated, SAMP8 and SApT mice showed a decreased learning capacity compared to pR5 mice. We therefore conclude that accelerated aging exacerbates pathological tau phosphorylation, leading to changes in normal behaviour. These findings further suggest that SApT mice may be a useful novel model in which to study the role of a complex geriatric phenotype in tauopathy. ispartof: Aging Cell vol:16 issue:2 pages:377-386 ispartof: location:England status: published

The objectives of this observational study were to (1) compare spousal and child caregiver burden; (2) compare co-resident and live-out child caregiver burden; and (3) investigate factors influencing spousal and child caregiver burden. Data was collected from 90 caregivers of people with frontotemporal degeneration (FTD) recruited from the Frontotemporal Dementia Research Group (Frontier) at Neuroscience Research, Australia. Of this caregiver group, 43 were spousal caregivers and 47 were child caregivers. Caregiver burden and emotional state were evaluated using the short Zarit Burden Interview and the short version of the Depression, Anxiety and Stress Scale-21. The Social Network Index was applied to ascertain the social network of the caregiver, while the Intimate Bond Measure was used to evaluate the current quality of the relationship between the caregiver and the person with dementia. The Frontotemporal Dementia Rating Scale was used to assess severity of dementia. Spousal and child caregivers experienced similar levels of burden, depression, anxiety, and stress, regardless of disease severity. Co-resident child caregivers had smaller social networks and greater burden than live-out caregivers. Dementia severity was key in spousal caregiver burden, whereas caregiver depression was most important in child caregiver burden. Child and spousal caregivers of individuals with FTD share similar levels of burden, influenced by different factors. Future interventions need to account for these differences.

Biomarkers represent a critical research area in neurodegeneration disease as they can contribute to studying potential disease‐modifying agents, fostering timely therapeutic interventions, and alleviating associated financial costs. Functional connectivity (FC) analysis represents a promising approach to identify early biomarkers in specific diseases. Yet, virtually no study has tested whether potential FC biomarkers prove to be reliable and reproducible across different centers. As such, their implementation remains uncertain due to multiple sources of variability across studies: the numerous international centers capable conducting FC research vary in their scanning equipment and their samples’ socio‐cultural background, and, more troublingly still, no gold‐standard method exists to analyze FC. In this unprecedented study, we aim to address both issues by performing the first multicenter FC research in the behavioral‐variant frontotemporal dementia (bvFTD), and by assessing multiple FC approaches to propose a gold‐standard method for analysis. We enrolled 52 bvFTD patients and 60 controls from three international clinics (with different fMRI recording parameters), and three additional neurological patient groups. To evaluate FC, we focused on seed analysis, inter‐regional connectivity, and several graph‐theory approaches. Only graph‐theory analysis, based on weighted‐matrices, yielded consistent differences between bvFTD and controls across centers. Also, graph metrics robustly discriminated bvFTD from the other neurological conditions. The consistency of our findings across heterogeneous contexts highlights graph‐theory as a potential gold‐standard approach for brain network analysis in bvFTD. Hum Brain Mapp 38:3804–3822, 2017. © 2017 Wiley Periodicals, Inc.

Objectives:With comparable baseline performance on executive functions (EF) and memory between Alzheimer’s disease (AD) and behavioral-variant frontotemporal dementia (bvFTD), it is currently unclear if both diseases can be distinguished longitudinally on these measures reliably.Methods:A total of 111 participants (33 AD, 31 bvFTD, and 47 controls) were followed-up annually over a 4-year period and tested on measures of EF, memory, and orientation. Linear mixed-effect models were constructed using disease severity as a nuisance variable to examine profiles of neuropsychological performance decline.Results:At baseline, overlap in terms of cognitive impairment between bvFTD and AD on multiple EF, memory, and orientation measures was present. Longitudinally, only disinhibition (Hayling total errors) appeared sensitive to discriminating AD from bvFTD; however, only after the first annual follow-up. Subgroup analyses on smaller samples revealed comparable profiles on EF tasks at baseline and over time between bvFTD and AD who presented with impaired EF at presentation, and on memory and orientation tasks between AD and bvFTD who presented with severe amnesia.Conclusions:Our results replicate previous findings showing only moderate discriminability between AD and bvFTD at clinical presentation on EF and memory measures. More importantly, we also show that longitudinal trajectories strongly overlap for both dementias on these measures. Disinhibition emerged as the sole measure that in the long run was significantly more impaired in bvFTD. Future studies should use tests designed to target cortical regions that are specifically impaired in bvFTD, such as the ventromedial prefrontal cortex, to improve the accurate discrimination of these diseases. (JINS, 2017,23, 34–43)

Background: Aproportion of patients with frontotemporal dementia (FTD) also develop amyotrophic lateral sclerosis (ALS). Objective: We aimed to establish the risk of developing ALS in patients presenting with FTD and to identify the relevant clinical variables associated with progression from FTD to FTD-ALS. Methods: Of 218 consecutive patients with FTD, 10.1% had a dual FTD-ALS diagnosis at presentation. The remaining 152 FTD patients with follow-up of at least 12 months were included in the present study. We calculated the rate of progression to FTD-ALS and compared the baseline characteristics of FTD patients who developed ALS to those who did not develop ALS. Results: Five percent of FTD patients developed ALS. The incidence rate of ALS was 6.7/100 patient-years in patients with FTD symptoms since 1 year, which declined with duration of FTD symptoms. No FTD patients developed ALS after 5 years. Five out of 8 FTD patients who developed ALS had presented with a mixed behavioral variant FTD and progressive non-fluent aphasia (bvFTD+PNFA) phenotype, 2 with bvFTD, and 1 with PNFA. Progression to FTD-ALS was significantly more frequent in patients with bvFTD+ PNFA compared to those without this phenotype (p < 0.0001, OR 38.3, 95% CI: 7.3 to 199.2), and in FTD patients who carried the C9orf72 repeat expansion compared to those without the repeat expansion (p = 0.02, OR 8.0, 95% CI: 1.7 to 38.6). Conclusions: FTD patients with a mixed bvFTD+PNFA phenotype and with a C9orf72 repeat expansion should be closely monitored for the possible development of ALS. The risk of developing ALS in FTD appears to decline with the duration of FTD symptoms.

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive visual dysfunction and parietal, occipital, and occipitotemporal atrophy. The aim of this study was to compare the impact of PCA and typical Alzheimer's disease (tAD) on everyday functional abilities and neuropsychiatric status. The Cambridge Behavioural Inventory-Revised was given to carers of 32 PCA and 71 tAD patients. PCA patients showed significantly greater impairment in everyday skills and self-care while the tAD group showed greater impairment in aspects of memory and orientation, and motivation. We suggest that PCA poses specific challenges for those caring for people affected by the condition.

Background: Primary progressive aphasia (PPA) affects a range of language domains that impact on communication. Little is known about the nature of conversation breakdown in PPA. The identification of trouble in conversation, its repair and the success of repairs has been used effectively to examine conversation breakdown in neurogenic language disorders such as dementia of the Alzheimer type (DAT) and acute onset aphasia. This study investigated trouble and repair in the conversations of people with PPA.Aims: The first aim of this study is to describe the contributions of individuals with PPA and their conversation partner to conversation. The second aim is to describe the trouble that occurs in dyadic conversations between three individuals with PPA and their communication partner. The third aim is to describe the repair behaviours used by the individuals with PPA and their communication partners.Methods & Procedures: Dyadic conversations about everyday activities between three individuals with PPA and ...

We aimed to explore the nature of verbal repetition deficits and infer the cognitive systems involved in primary progressive aphasia (PPA) and Alzheimer's disease (AD). A total of 63 patients (13 semantic variant (sv-PPA), 17 nonflu- ent/agrammatic variant (nfv-PPA), 10 logopenic variant (lv-PPA), 23 AD) and 13 matched healthy controls completed a battery of tests that included naming, word comprehension, digit span, repetition of multisyllabic single words, monosyllabic word span presented under similar and dissimilar phonological conditions, and sentence repetition. All patient groups displayed some level of impairment, however, specific patterns emerged in each variant. Participants with sv-PPA were the least impaired, showing marginal difficulties exclusively for sentence repetition, whereas those with lv-PPA had the worst overall performance. Cases with nfv-PPA showed compromised repetition of multisyllabic and phonologically similar words. The deficit in cases with AD was confined to span tasks. These distinctive patterns of language impairments can assist in the differential diagnosis of PPA variants and point toward the vulnerability of specific cognitive systems in each syndrome. 10 11 12 13 14 15 16 17 18 19

There is need for a valid, sensitive and short instrument capable of detecting and quantifying behavioural changes in ALS, which can be utilized in clinical and research settings. This study aimed to 1) develop and validate such an instrument; 2) verify the most common behavioural symptoms; and 3) investigate longitudinal changes over a six-month period. Two hundred and nineteen patients were included. The development sample (n = 140) was used to determine the most appropriate items to include in the new tool, the Motor Neuron Disease Behavioural Instrument (MiND-B) * , via a data-driven approach. An independent sample (n = 79) validated the tool. A more comprehensive sample (n = 50, sub-classified into ALS and ALS plus) was utilized to verify if the MiND-B could detect ALS plus patients. Finally, 20 ALS patients completed the MiND-B after a six-month period. Apathy, disinhibition and stereotypical behaviour were all found to be very common symptoms in ALS occurring in 75%, 66% and 58%, respectively, of cases. Notably, the MiND-B could identify ALS plus patients without standard cognitive assessments. In conclusion, the MiND-B tool can detect patients with ALS plus reliably, by means of questions to the informant. This test could enable ALS centres to evaluate non-motor symptoms and adapt management and decision-making approaches as necessary. *only available in the online version of the journal. Please find this material with the following direct link to the article: http://www.informahealthcare.com/(DOI: 10.3109/21678421.2014.896927).

Despite accruing evidence for relative preservation of episodic memory in the semantic variant of primary progressive aphasia (previously semantic dementia), the neural basis for this remains unclear, particularly in light of their well-established hippocampal involvement. We recently investigated the Papez network of memory structures across pathological subtypes of behavioural variant frontotemporal dementia and demonstrated severe degeneration of all relay nodes, with the anterior thalamus in particular emerging as crucial for intact episodic memory. The present study investigated the status of key components of Papez circuit (hippocampus, mammillary bodies, anterior thalamus, cingulate cortex) and anterior temporal cortex using volumetric and quantitative cell counting methods in pathologically-confirmed cases with semantic variant of primary progressive aphasia (n = 8; 61-83 years; three males), behavioural variant frontotemporal dementia with TDP pathology (n = 9; 53-82 years; six males) and healthy controls (n = 8, 50-86 years; four males). Behavioural variant frontotemporal dementia cases with TDP pathology were selected because of the association between the semantic variant of primary progressive aphasia and TDP pathology. Our findings revealed that the semantic variant of primary progressive aphasia and behavioural variant frontotemporal dementia show similar degrees of anterior thalamic atrophy. The mammillary bodies and hippocampal body and tail were preserved in the semantic variant of primary progressive aphasia but were significantly atrophic in behavioural variant frontotemporal dementia. Importantly, atrophy in the anterior thalamus and mild progressive atrophy in the body of the hippocampus emerged as the main memory circuit regions correlated with increasing dementia severity in the semantic variant of primary progressive aphasia. Quantitation of neuronal populations in the cingulate cortices confirmed the selective loss of anterior cingulate von Economo neurons in behavioural variant frontotemporal dementia. We also show that by end-stage these neurons selectively degenerate in the semantic variant of primary progressive aphasia with preservation of neurons in the posterior cingulate cortex. Overall, our findings demonstrate for the first time, severe atrophy, although not necessarily neuronal loss, across all relay nodes of Papez circuit with the exception of the mammillary bodies and hippocampal body and tail in the semantic variant of primary progressive aphasia. Despite the longer disease course in the semantic variant of primary progressive aphasia compared with behavioural variant frontotemporal dementia, we suggest here that the neural preservation of crucial memory relays (hippocampal→mammillary bodies and posterior cingulate→hippocampus) likely reflects the conservation of specific episodic memory components observed in most patients with semantic variant of primary progressive aphasia.

Corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) represent challenging neurodegenerative disorders for clinicians and nonclinical scientists alike. Although initially lumped together as "Parkinson's-Plus" syndromes, CBS and PSP are clinically and pathologically distinct from Parkinson's disease. It is now clear that behavioral and cognitive changes are common in both syndromes and affect impact quality of life and carer burden considerably. We briefly review the clinical, pathological, and neuroradiological features of each syndrome, followed by more detailed descriptions of the behavioral and cognitive deficits encountered in CBS and PSP. Clinically and pathologically heterogeneous, CBS is characterized by a wide range of cognitive and behavioral disturbances. impairments in executive function and memory are common, but nonspecific. In contrast, deficits in language and visuospatial abilities appear to be more distinctive features of CBS; the relevance of specific patterns of impairment to the underlying histopathology, or prognosis, remains to be fully elucidated. As in CBS, behavioral and cognitive changes are almost universal in PSP, with a wide range of reported deficits. Apathy is very common, often paradoxically accompanied by impulsivity. Executive dysfunction is prominent, but memory and visuospatial deficits also occur. An emerging field is the study of social cognition, which appears impaired in both syndromes. As therapeutic strategies for neurodegenerative pathologies emerge, more specific diagnostic tools in CBS and PSP will be required. Careful clinicopathological correlation, and the development of biomarkers for specific histopathologies, will be important milestones on the road to effective treatments.

Background: Anomia is a common and debilitating symptom for many dementia sufferers, but is particularly marked in patients with the semantic variant of primary progressive aphasia, semantic dementia (SD). Recent studies have demonstrated that through cognitive training these patients can re-learn the names of objects, but it remains unclear whether this translates to improved use of these relearned words in contexts other than picture naming. Methods: Five SD patients completed a 2-month, online word training program and were assessed pre- and post-intervention on picture naming and spoken word-picture-matching plus two novel ecological tasks: video description and responses to verbal requests. Results: All participants showed clear gains in naming the trained pictures (p < 0.001). Importantly, improvements were also observed for four out of the five patients on the video description task. Milder patients also demonstrated improved comprehension of verbal instructions. Severe SD patients showed improvements on matching trained words to pictures. As expected, improvements were not found for untrained items. Conclusion: There was clear evidence of generalization especially in patients with milder semantic impairments. Future studies should investigate the utility of this training in other forms of dementia.

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

Diagnosis of tauopathies such as Alzheimer's disease (AD) still relies on post-mortem examination of the human brain. A non-invasive method of determining brain tau burden in vivo would allow a better understanding of the pathophysiology of tauopathies. The purpose of the study was to evaluate (18)F-THK523 as a potential tau imaging tracer.Ten healthy elderly controls, three semantic dementia (SD) and ten AD patients underwent neuropsychological examination, MRI as well as (18)F-THK523 and (11)C-Pittsburgh compound B (PIB) positron emission tomography (PET) scans. Composite memory and non-memory scores, global and hippocampal brain volume, and partial volume-corrected tissue ratios for (18)F-THK523 and (11)C-PIB were estimated for all participants. Correlational analyses were performed between global and regional (18)F-THK523, (11)C-PIB, cognition and brain volumetrics.(18)F-THK523 presented with fast reversible kinetics. Significantly higher (18)F-THK523 retention was observed in the temporal, parietal, orbitofrontal and hippocampi of AD patients when compared to healthy controls and SD patients. White matter retention was significantly higher than grey matter retention in all participants. The pattern of cortical (18)F-THK523 retention did not correlate with Aβ distribution as assessed by (11)C-PIB and followed the known distribution of tau in the AD brain, being higher in temporal and parietal areas than in the frontal region. Unlike (11)C-PIB, hippocampal (18)F-THK523 retention was correlated with several cognitive parameters and with hippocampal atrophy.(18)F-THK523 does not bind to Aβ in vivo, while following the known distribution of paired helical filaments (PHF)-tau in the brain. Significantly higher cortical (18)F-THK523 retention in AD patients as well as the association of hippocampal (18)F-THK523 retention with cognitive parameters and hippocampal volume suggests (18)F-THK523 selectively binds to tau in AD patients. Unfortunately, the very high (18)F-THK523 retention in white matter precludes simple visual inspection of the images, preventing its use in research or clinical settings.

Objective To assess the impact of new clinical diagnostic criteria for frontotemporal dementia (FTD) syndromes, including primary progressive aphasias (PPA), on prior clinical diagnosis and to explore clinicopathological correlations. Methods 178 consecutive neuropathologically ascertained cases initially diagnosed with a FTD syndrome were collected through specialist programmes: the Cambridge Brain Bank, UK, and Sydney Brain Bank, Australia. 135 cases were reclassified using the revised diagnostic criteria into behavioural variant (bvFTD), semantic variant PPA (sv-PPA), non-fluent/agrammatic variant PPA (nfv-PPA) and logopenic variant PPA (lv-PPA). Pathological diagnoses included FTLD-tau, FTLD-TDP, FTLD-FUS, FTLD-UPS, FLTD-ni and Alzheimer9s disease (AD). Statistical analyses included χ 2 tests, analyses of variance and discriminant statistics. Results Comparison of the original and revised diagnosis revealed no change in 90% of bvFTD and sv-PPA cases. By contrast, 51% of nfv-PPA cases were reclassified as lv-PPA, with apraxia of speech and sentence repetition assisting in differentiation. Previous patterns of pathology were confirmed, although more AD cases occurred in FTD syndromes (10% bvFTD, ∼15% sv-PPA and ∼30% nfv-PPA) than expected. AD was the dominant pathology (77%) of lv-PPA. Discriminant analyses revealed that object agnosia, phonological errors and neuropsychiatric features differentiated AD from FTLD. Conclusions This study provides pathological validation that the new criteria assist with separating PPA cases with AD pathology into the new lv-PPA syndrome and found that a number of diagnostic clinical features (disinhibition, food preferences and naming) did not assist in discriminating the different FTD syndromes.

Background: Based upon the profile linguistic and speech deficits, the current International Criteria for diagnosis and classification of primary progressive aphasia (PPA) suggest the distinction of semantic, nonfluent/agrammatic and logopenic variants, each of which is commonly associated with specific pathology and distribution of brain atrophy. Although the vast majority of cases fit in this tripartite schema, some cases remain unclassifiable because of the presence of overlapping deficits, or conversely, because of the presence of isolated deficits.Aims: In this review, we describe relevant clinical features that characterise each variant and discuss emerging issues derived from the application of the International Criteria.Main Contribution: Based on a hierarchical approach that comprises the evaluation of single-word comprehension, motor speech disorder, agrammatism and sentence repetition, we propose a heuristic solution aimed to reduce the number of cases with ambiguous identification and thereby ...

Progressive and relatively circumscribed loss of semantic knowledge, referred to as semantic dementia (SD) which falls under the broader umbrella of frontotemporal dementia, was officially identified as a clinical syndrome less than 50 years ago. Here, we review recent neuroimaging, pathological, and genetic research in SD. From a neuroimaging perspective, SD is characterised by hallmark asymmetrical atrophy of the anterior temporal pole and anterior fusiform gyrus, which is usually left lateralised. Functional magnetic resonance imaging (fMRI) studies have revealed widespread changes in connectivity, implicating the anterior temporal regions in semantic deficits in SD. Task-related fMRI have also demonstrated the relative preservation of frontal and parietal regions alongside preserved memory performance. In addition, recent longitudinal studies have demonstrated that, with disease progression, atrophy encroaches into the contralateral temporal pole and medial prefrontal cortices, which reflects emerging changes in behaviour and social cognition. Notably, unlike other frontotemporal dementia subtypes, recent research has demonstrated strong clinicopathological concordance in SD, with TDP43 type C as the most common pathological subtype. Moreover, an underlying genetic cause appears to be relatively rare in SD, with the majority of cases having a sporadic form of the disease. The relatively clear diagnosis, clinical course, and pathological homogeneity of SD make this syndrome a promising target for novel disease-modifying interventions. The development of neuroimaging markers of disease progression at the individual level is an important area of research for future studies to address, in order to assist with this endeavour.

IntroductionAccurate prediction of the underlying neuropathology in behavioural variant frontotemporal dementia (bvFTD) is essential for future targeted therapy trials and prognostication. Alzheimer’s disease (AD) pathology has been reported in a significant proportion of patients with clinical bvFTD. We sought to determine whether detailed clinical and neuroradiological assessment was sufficient to distinguish bvFTD with AD pathology from bvFTD with frontotemporal lobar degeneration (FTLD).MethodsTwo patients with clinically diagnosed probable bvFTD but AD pathology at autopsy, were identified. The clinical, neuropsychological and imaging features of these patients were compared with those of ten patients with clinically probable bvFTD and proven FTLD pathology (tau, TDP-43, FUS).ResultsBoth patients with AD pathology presented with behavioural symptoms typical of bvFTD as well as memory impairment. Executive function, memory and visuospatial skills were impaired in both pathologic groups. Language skills were relatively spared in those with AD pathology. Neuropsychiatric symptoms were frequent in both groups but significant depression and anxiety were seen only in those with FTLD pathology. Dementia severity and caregiver burden were similar. The degree or topographical distribution of atrophy on MRI did not differ.ConclusionsAlzheimer’s pathology may cause bvFTD symptoms which are otherwise indistinguishable to those caused by FTLD pathology. While there may be subtle differences in patterns of cognitive deficits, standard neuropsychological testing is insufficient to discern the underlying pathology. Similarly, structural imaging cannot be used to reliably identify AD pathology. Better access to amyloid biomarkers may be needed to more accurately define bvFTD caused by AD pathology.

IntroductionPsychotic symptoms are now recognised to occur in patients with MND, often in association with FTD, and particularly in C9orf72 expansion carriers. As yet the impact of these symptoms on the clinical disease state is unknown and the relationship between severity and nature of these symptoms is not well understood. This study aimed to comprehensively explore the relationship between psychotic symptoms, clinical features, cognitive status and survival.MethodsIn total 148 participants; MND (n=100) and MND-FTD (n=48), were enrolled in the study. A detailed clinical interview in addition to a neurological, neuropsychological and behavioural assessment, genetic testing and brain MRI was undertaken in each participantResultsPsychotic symptoms were present in 25% of the cohort. The majority of participants in the psychosis cohort were male (83%) and were negative for the C9orf72 expansion (70%). Psychotic symptoms in younger patients were more likely to be florid, require medication and delay diagnosis. Within the MND subgroup, patients with psychotic symptoms were more impaired in the cognitive subdomains of attention, memory and executive functioning and exhibited more disinhibition, apathy and stereotypy, than patients without psychotic symptoms (all pp>0.2). Symptoms of depression were more common in those without psychotic symptoms (p>0.1). Survival was prolonged for patients with psychotic symptoms (HR=4.7, 95% CI: 2.1–10, pConclusionMND with psychosis represents a distinct clinical, cognitive and behavioural phenotype that has a positive impact on survival and may represent an overlap with psychiatric disorders.

Objectives: To investigate patient susceptibility to neuropsychiatric symptoms in the context of progression of more classic motor symptoms in amyotrophic lateral sclerosis (ALS) and to examine the impact of neuropsychiatric symptoms on survival. Methods: The study cohort consisted of 219 patients with ALS (limb onset = 159; bulbar onset = 60), with neuropsychiatric symptoms measured using the Motor Neuron Disease Behavioural Scale and more classic ALS symptoms assessed by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised. For detection of symptom susceptibility (neuropsychiatric vs classic motor), a Rasch analysis was applied (n = 219). Cox proportional hazard regression models were used for the survival analysis (n = 115 patients), which incorporated neuropsychiatric and classic motor symptoms. Results: Rasch analysis demonstrated that neuropsychiatric symptoms appeared earlier than classic motor features of ALS. However, differences in neuropsychiatric scores did not affect survival: patients with abnormalities in neuropsychiatric domains did not exhibit a different rate of survival than those without (χ 2 , 3.447, p = 0.328, −2 log-likelihood 377.341). Conclusions: Neuropsychiatric symptoms appear before classic motor features in ALS, which corroborates the notion that ALS and frontotemporal dementia lie on a disease continuum. The early detection of neuropsychiatric symptoms will be critical to inform clinical decisions and alleviate carer burden. Importantly, subtle neuropsychiatric symptoms alone do not affect survival in ALS, which in turn confirms their pervasive nature in ALS.

This is the type of book that seems unimaginable to contemplate writing these days: a comprehensive monograph covering all aspects of a complex disorder. It is the work of a master researcher at the peak of his career and reflects 25 years of dedication to understanding frontotemporal dementia (FTD). Over the past 15 years, the group of outstanding researchers led by Bruce Miller at UCSF has contributed more to our understanding of this disorder than any other group in the world. The book is a fitting summary of these contributions but gives appropriate acknowledgement to the others around the world who have also contributed to the field. It is certainly timely, given the discovery in 2011 of the C9orf72 gene expansion which accounts for a sizeable proportion of familial FTD and motor neuron disease. The discovery links, at a genetic level, the growing overlap between these two apparently disparate disorders. After an excellent historical introduction, the book is divided into chapters dealing with each of the main clinical presentations of FTD, followed by overviews of the related disorders, namely FTD with amyotrophic lateral sclerosis (motor neuron disease, MND), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). There follows a primer on FTD pathology and a section on genetics. One of the most interesting chapters deals with reflections on psychology and philosophy, and finally there is an overview of management and treatment options. It is beautifully illustrated and written with the type of clarity and integration that can only come from a single author book. Bruce’s ability to synthesize genetics, cell biology, neuropathology, neuroimaging and psychology is inspiring. I can think of no better place to start for someone embarking on a research career in FTD or indeed clinicians encountering these patients who want …

Frontotemporal dementia is a degenerative brain condition characterized by focal atrophy affecting the frontal and temporal lobes predominantly. Changes in white matter with disease progression and their relationship to grey matter atrophy remain unknown in FTD. This study aimed to establish longitudinal white matter changes and compare these changes to regional grey matter atrophy in the main FTD subtypes. Diffu- sion and T1-weighted images were collected from behavioral-variant FTD (bvFTD: 12), progressive non-fluent aphasia (PNFA: 10), semantic dementia (SD: 11), and 15 controls at baseline and 12 months apart. Changes in white matter integrity were established by fractional anisotropy, mean, axial and radial diffusivity measure- ments using tract-based spatial statistics. Patterns of cortical grey matter atrophy were measured using voxel- based morphometry. At baseline, bvFTD showed severe cross-sectional changes in orbitofrontal and anterior temporal tracts, which progressed to involve posterior temporal and occipital white matter over the 12- month. In PNFA, cross-sectional changes occurred bilaterally in frontotemporal white matter (left > right), with longitudinal changes more prominent on the right. Initial white matter changes in SD were circum- scribed to the left temporal lobe, with longitudinal changes extending to bilateral frontotemporal tracts. In contrast, progression of grey matter change over time was less pronounced in all FTD subtypes. Mean diffu- sivity was most sensitive in detecting baseline changes while fractional anisotropy and radial diffusivity revealed greatest changes over time, possibly reflecting different underlying pathological processes with dis- ease progression. Our results indicate that investigations of white matter changes reveal important differences across FTD syndromes with disease progression. Hum Brain Mapp 00:000-000, 2013. V C 2013 Wiley Periodicals, Inc.

Amyotrophic lateral sclerosis (ALS) is a multisystem disease that overlaps with frontotemporal dementia (FTD). Although FTD patients exhibit prominent deficits in emotion perception and social cognition, these domains have received relatively little attention in ALS. Moreover, direct comparisons between ALS and FTD on emotion processing tasks remain lacking. Twenty-nine patients with ALS (16 with coexisting FTD (FTD-ALS) and 13 without dementia), 25 behavioural variant FTD patients and 30 healthy controls completed neuropsychological and emotion tasks (Ekman Caricatures and the TASIT). Both ALS and FTD patient groups showed significant deficits on the emotion tasks compared to controls. After dividing ALS patients into those with and without FTD, only the patients with coexisting FTD (FTD-ALS) were impaired. FTD-ALS and FTD patient groups displayed similar levels of impairment, even after controlling for measures of general cognition, and demonstrated similar profiles across different types of emotions. We conclude that patients with FTD-ALS and FTD show similar, significant impairments in emotional processing. By contrast, ALS patients without dementia exhibit preserved emotion processing. Performance on emotion processing tasks may provide a useful clinical tool in identifying those with early FTD-ALS.

The enhancing effect of emotion on subsequent memory retrieval is well established. Patients with frontotemporal dementia show profound emotion processing difficulties, yet the extent to which such deficits attenuate emotional enhancement of memory remains unknown. Here, we studied the intersection between emotion and memory using a visual forced-choice recognition test for negative and neutral stimuli in 34 patients with frontotemporal dementia compared with 10 patients with Alzheimer's disease and 15 control subjects. Control subjects and patients with Alzheimer's disease recognized more emotional than neutral items, as demonstrated by a significant interaction between emotion and memory for true recognition. This emotional enhancement effect was notably absent in the frontotemporal dementia cohort, with comparable recognition performance regardless of emotional content. Voxel-based morphometry analyses revealed distinct neural substrates for overall memory versus emotional memory performance. Overall memory performance correlated with the hippocampus, precuneus and posterior cingulate, regions crucial for successful episodic memory performance. Emotional enhancement of memory, by contrast, was associated exclusively with the integrity of the right orbitofrontal and subcallosal cortex. Our findings demonstrate differential disruption of emotional enhancement of memory in neurodegenerative disorders, and point toward the potentially pivotal role of the orbitofrontal cortex in supporting the successful retrieval of emotionally charged negative stimuli.

Introduction Impulsive behaviours commonly manifest in treated Parkinson's disease (PD) patients, and, are typically viewed as sequelae of dopaminergic therapy. However, recent evidence shows that impulsivity in those patients may not only depend on medication status. Instead, there is the suggestion that dopaminergic therapy interacts with existing neuroanatomical and/or neurochemical abnormalities, to produce impulsive behaviour in certain vulnerable patients. Methods In this study, we investigated whether grey matter atrophy in fronto-striatal brain regions contributes to inhibitory dysfunction – a key feature of impulsive behaviour – in PD. Importantly, we contrasted 25 PD patients with 11 behavioural variant frontotemporal dementia (bvFTD) patients, who have well-established inhibitory dysfunction and related grey matter atrophy. We employed a questionnaire to assess impulsive behaviours (Barrett Impulsiveness Scale), and measures of verbal inhibitory function (Hayling Test) and response inhibitory function (a go/no-go task). Behavioural analyses were conducted to examine performance in the PD and bvFTD patients and in 15 healthy controls. Scores on the verbal and response inhibition tasks were also entered as covariates in a region of interest voxel-based morphometry analysis, to determine the grey matter correlates. Results PD patients showed impairments in inhibitory function, though to a milder degree than bvFTD patients. In the Parkinson's sample, frontal atrophy (namely, orbitofrontal and right inferior frontal cortex) was shown to correlate with verbal disinhibition, and striatal atrophy (right nucleus accumbens) was associated with response disinhibition, whereas a more distributed pattern of fronto-striatal atrophy was associated with the bvFTD patients' performance on inhibitory measures. Conclusions These results provide the first evidence that disinhibition in PD is related to fronto-striatal grey matter atrophy. Our study adds support to the hypothesis that impulsivity in PD is not solely mediated by dopaminergic medication effects, but that fronto-striatal structural abnormalities contribute to impulsive behaviours in these patients.

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

Background There is a gap in the systematic description and investigation of functional disability in corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). Additionally, the relations between disability, apraxia, cognitive and behavioural changes are not well understood in atypical parkinsonian syndromes. Methods Fifty patients were included in this study (CBS = 18; PSP = 11), including a subgroup of primary progressive aphasia-nonfluent variant (PPA-nfv = 21) who were used as a control group given the clinic-pathological overlap. Functional disability (basic and instrumental activities of daily living), general cognition and behavioural changes were evaluated at baseline, with a subgroup of patients being reassessed after 16 months. Results The corticobasal syndrome group had the most marked disability in basic activities in comparison to progressive supranuclear palsy and primary progressive aphasia-nonfluent variant. Longitudinal decline was marked for all three groups. In a linear regression examining factors behind functional disability in CBS and PSP, memory dysfunction emerged as the main factor (48.5%), followed by apraxia (14.9%) and atypical parkinsonian symptoms (9.6%). Conclusions Memory dysfunction is the most important factor in functional disability in CBS and PSP, which has to be taken into consideration in disease management, prognosis and planning of services to fully address patients' and families' needs.

There is great need to understand variables behind carer burden, especially in FTD. Carer burden is a complex construct, and its factors are likely to vary depending on the type of dementia, carer characteristics and cultural background. Objective: The present study aimed to compare profiles and severity of carer burden, depression, anxiety and stress in carers of FTD patients in India in comparison to Australia; to investigate which carer variables are associated with carer burden in each country. Methods: Data of 138 participants (69 dyads of carers-patients) from India and Australia (India, n=31; Australia, n=38). Carer burden was assessed with the short Zarit Burden Inventory; carer depression, anxiety and stress were measured with the Depression, Anxiety and Stress-21. Dementia severity was determined with the Frontotemporal Dementia Rating Scale (FTD-FRS), and a range of demographic variables regarding the carer and patient were also obtained. Results: Overall, levels of carer burden were not significantly different across India and Australia, despite more hours delivering care and higher dementia severity in India. Variables associated with burden, however, differed between countries, with carer depression, anxiety and stress strongly associated with burden in India. By contrast, depression, stress, and dementia severity were associated with burden in Australia. Conclusion: This study demonstrated that variables associated with carer burden in FTD differ between cultures. Consequently, cultural considerations should be taken into account when planning for interventions to reduce burden. This study suggests that addressing carers' skills and coping mechanisms are likely to result in more efficacious outcomes than targeting patient symptoms alone. RESUMO Há uma grande necessidade de se entender as variáveis por trás da sobrecarga do cuidador, especialmente em DFT. A sobrecarga é um construto complexo e os fatores provavelmente estão ligados ao tipo de demência, características do cuidador e origens culturais. Objetivo: O presente estudo objetivou comparar perfis e gravidade da sobrecarga, depressão, ansiedade e estresse nos cuidadores dos pacientes com DFT da Índia em comparação aos da Austrália; investigar que variáveis do cuidador estão associadas à sobrecarga em cada país. Métodos: Dados de 138 participantes (69 pares cuidadores-pacientes) da Índia e Austrália (Índia, n=31) e Austrália (n=38). A sobrecarga do cuidador foi avaliada através da versão curta do Inventário de Sobrecarga de Zarit; depressão, ansiedade e estresse do cuidador através com o Depression, Anxiety and Stress-21. A gravidade da demência foi determinada com a Frontotemporal Dementia Rating Scale (FTD-FRS), e uma gama de variáveis demográficas do cuidador e do paciente foram também obtidas. Resultados: De modo geral os níveis de sobrecarga do cuidador não foram significativamente diferentes entre Índia e Austrália, apesar do maior tempo despendido no cuidado e gravidade da demência na Índia. As variáveis associadas à sobrecarga, todavia, diferiram entre os países, com depressão do cuidador, ansiedade e estresse fortemente associados com sobrecarga na Índia. Em contraste, depressão, estresse e gravidade da demência foram associados à sobrecarga na Austrália. Conclusão: Este estudo demonstrou que variáveis associadas à sobrecarga do cuidador na DFT difere entre culturas. Consequentemente, aspectos culturais devem ser levados em consideração quando se planeja intervenções para redução da sobrecarga. Este estudo sugere que programas direcionados às habilidades e meios de se lidar com a situação dos cuidadores são provavelmente mais eficazes do que aqueles só aos sintomas do paciente.

Objective: To characterize the patterns of brain atrophy in patients with amyotrophic lateral sclerosis (ALS) with and without cognitive and neuropsychiatric symptoms, in comparison to controls and patients with ALS–frontotemporal dementia (FTD). Methods: A total of 57 participants (ALS = 22; ALS-FTD = 17; controls = 18) were included, following current ALS and FTD criteria. Patients with ALS were further subclassified into ALS with cognitive and behavioral symptoms (ALS-plus; n = 8) and those without (ALS; n = 14). By definition, ALS-plus did not reach the diagnostic threshold for ALS-FTD. All patients underwent neuropsychological and neuropsychiatric assessments, and underwent a brain MRI. Voxel-based morphometry analysis was conducted to establish patterns of brain atrophy. Results: Cortical atrophy in ALS was linked to neuropsychiatric and cognitive changes (ALS-plus vs ALS). Patients with ALS-plus had significant atrophy across motor and somatosensory as well as adjacent frontal and parietal areas, even after strict multiple comparison correction. By contrast, patients with ALS showed no significant cortical atrophy, and only brainstem atrophy. Importantly, atrophy in ALS-plus was not as widespread as in ALS-FTD, with ALS-plus atrophy mostly confined to motor and somatosensory areas, while atrophy in ALS-FTD also included substantial frontal and temporal atrophy. Conclusions: The present findings establish that cortical atrophy in ALS is highly dependent upon neuropsychiatric and cognitive changes. Previous inconsistent findings of cortical atrophy in ALS likely relate to the inclusion of cognitively affected patients and patients with pure motor ALS.