An attentional and working memory theory of hallucination vulnerability in frontotemporal dementia.

The rate and prevalence of hallucinations in behavioural variant frontotemporal dementia is well established. The mechanisms for underlying vulnerability however are the least well described in FTD compared with other neuropsychiatric conditions, despite the presence of these features significantly complicating the diagnostic process. As such, this present study aimed to provide a detailed characterization of the neural, cognitive and behavioural profile associated with a predisposition to hallucinatory experiences in behavioural variant frontotemporal dementia. In total, 153 patients with behavioural variant frontotemporal dementia were recruited sequentially for this study. A group of patients with well characterized hallucinations and good-quality volumetric MRI scans (n = 23) were genetically and demographically matched to a group without hallucinations (n = 23) and a healthy control cohort (n = 23). All patients were assessed at their initial visit by means of a detailed clinical interview, a comprehensive battery of neuropsychological tests and MRI. Data were analysed according to three levels: (i) the relationship between neural structures, cognition, behaviour and hallucinations in behavioural variant frontotemporal dementia; (ii) the impact of the C9orf72 expansion; and (iii) hallucination subtype on expression of hallucinations. Basic and complex attentional (including divided attention and working memory) and visual function measures differed between groups (all P < 0.001) with hallucinators demonstrating poorer performance, along with evidence of structural changes centred on the prefrontal cortex, caudate and cerebellum (corrected for False Discovery Rate at P < 0.05 with a cluster threshold of 100 contiguous voxels). Attentional processes were also implicated in C9orf72 carriers with hallucinations with structural changes selectively involving the thalamus. Patients with visual hallucinations in isolation showed a similar pattern with emphasis on cerebellar atrophy. Our findings provided novel insights that attentional and visual function subsystems and related distributed brain structures are implicated in the generation of hallucinations in behavioural variant frontotemporal dementia, that dissociate across C9orf72, sporadic behavioural variant frontotemporal dementia and for the visual subtype of hallucinations. This loading on attentional and working memory measures is in line with current mechanistic models of hallucinations that frequently suggest a failure of integration of cognitive and perceptual processes. We therefore propose a novel cognitive and neural model for hallucination predisposition in behavioural variant frontotemporal dementia that aligns with a transdiagnostic model for hallucinations across neurodegeneration and psychiatry.

Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results.

GRN mutations cause progranulin haploinsufficiency, which eventually leads to frontotemporal dementia (FTD-GRN). PR006 is an investigational gene therapy delivering the granulin gene (GRN) using an adeno-associated virus serotype 9 (AAV9) vector. In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates. We initiated a first-in-human phase 1/2 open-label trial. Here we report results of a pre-specified interim analysis triggered with the last treated patient of the low-dose cohort (n = 6) reaching the 12-month follow-up timepoint. We also include preliminary data from the mid-dose cohort (n = 7). Primary endpoints were safety, immunogenicity and change in progranulin levels in cerebrospinal fluid (CSF) and blood. Secondary endpoints were Clinical Dementia Rating (CDR) plus National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) rating scale and levels of neurofilament light chain (NfL). One-time administration of PR006 into the cisterna magna was generally safe and well tolerated. All patients developed treatment-emergent anti-AAV9 antibodies in the CSF, but none developed anti-progranulin antibodies. CSF pleocytosis was the most common PR006-related adverse event. Twelve serious adverse events occurred, mostly unrelated to PR006. Deep vein thrombosis developed in three patients. There was one death (unrelated) occurring 18 months after treatment. CSF progranulin increased after PR006 treatment in all patients; blood progranulin increased in most patients but only transiently. NfL levels transiently increased after PR006 treatment, likely reflecting dorsal root ganglia toxicity. Progression rates, based on the CDR scale, were within the broad ranges reported for patients with FTD. These data provide preliminary insights into the safety and bioactivity of PR006. Longer follow-up and additional studies are needed to confirm the safety and potential efficacy of PR006. ClinicalTrials.gov identifier: NCT04408625 .

Disrupted social perception in frontotemporal dementia and Alzheimer's disease - Associated cognitive processes and clinical implications.

BACKGROUND: Social perception refers to the ability to adapt and update one's behaviour in accordance with the current context and provides the foundation for many complex social and emotional interactions. Alterations in social cognition are a hallmark of the behavioural variant of frontotemporal dementia (bvFTD), yet the capacity for social perception in this syndrome remains unclear. METHODS: We examined social perception in 18 bvFTD and 13 Alzheimer's disease (AD) patients, in comparison with 17 healthy older controls, using a social perception task derived from the Dewey Story Test. Participants also completed a comprehensive neuropsychological battery and carers provided ratings of behavioural and neuropsychiatric changes. RESULTS: Overall, bvFTD and AD performance diverged significantly from control ratings on the social perception task, however, no significant difference was found between patient groups. Standardised values relative to the mean control rating revealed considerable variability within the patient groups in terms of the direction of deviation, i.e., over- or under-rating the vignettes relative to healthy controls (range z-scores = -1.79 to +1.63). Greater deviation from control ratings was associated with more pronounced memory (p = .007) and behavioural (p = .009) disturbances in bvFTD; whilst social perception performance correlated exclusively with verbal fluency in AD (p = .003). CONCLUSIONS: Social perception is comparably disrupted in bvFTD and AD, yet likely reflects the differential breakdown of distinct cognitive processes in each dementia syndrome. Our findings have important clinical implications for the development of targeted interventions to manage disease-specific changes in social perception in dementia.

Exploring graded profiles of hippocampal atrophy along the anterior-posterior axis in semantic dementia and Alzheimer's disease.

Mounting evidence indicates marked hippocampal degeneration in semantic dementia (SD) however, the spatial distribution of hippocampal atrophy profiles in this syndrome remains unclear. Using a recently developed parcellation approach, we extracted hippocampal volumes from four distinct subregions running from anterior to posterior along the longitudinal axis (anterior, intermediate rostral, intermediate caudal, and posterior). Volumetric differences in hippocampal subregions were compared between 21 SD, 24 matched Alzheimer's disease (AD), and 27 healthy older Control participants. Despite comparable overall hippocampal volume loss, SD and AD groups diverged in terms of the magnitude of atrophy along the anterior-posterior axis of the hippocampus. Global hippocampal atrophy was observed in AD, with no discernible gradation or lateralisation. In contrast, SD patients displayed graded bilateral hippocampal atrophy, most pronounced on the left-hand side, and concentrated in anterior relative to posterior subregions. Finally, we found preliminary evidence that disease-specific vulnerability along the anterior-posterior axis of the hippocampus was associated with canonical clinical features of these syndromes.

Establishing the link between motivational disturbances and behavioural rigidity in frontotemporal dementia.

BACKGROUND: Rigid and inflexible behaviours are common in frontotemporal dementia (FTD), manifesting in compulsive pursuit of specific interests, routines, and rituals. Paradoxically, these changes occur alongside profound motivational disturbances including apathy and anhedonia. While posited to be related, no study to date has explored the link between motivational changes and behavioural rigidity in FTD. METHODS: Carer ratings for 71 FTD participants (26 semantic dementia [SD], 45 behavioural variant [bvFTD]) were obtained on the Dimensional Apathy Scale (apathy), the Snaith-Hamilton Pleasure Scale (hedonic tone) and the Cambridge Behavioural Inventory-Revised (CBI-R; behavioural changes). A rigidity index was created from existing items on the CBI-R. Whole-brain voxel-based morphometry was used to explore associations between rigidity and grey matter intensity in the combined FTD group. RESULTS: Behavioural rigidity was significantly related to apathy severity (r = 0.57) and decreased hedonic tone (r = -0.36) in the combined FTD group. Multiple linear regression revealed a significant diagnosis × hedonic tone interaction (ß = -1.40), whereby lower hedonic tone predicted rigidity in SD (r = -0.65) but not in bvFTD (r = -0.18). In contrast, the relationship between rigidity and apathy did not differ between the groups (ß = -0.42). At the neural level, rigidity correlated with degeneration of predominantly right-sided frontostriatal structures including, notably, the nucleus accumbens. CONCLUSIONS: As the first study to demonstrate a link between motivational changes and behavioural rigidity in FTD, our findings have important clinical implications. By identifying candidate mechanisms of behavioural rigidity, our findings can inform targeted interventions to manage inflexible patterns of thought and behaviour in daily life.

Late-onset epilepsy with cognitive symptoms: Comparison of cognitive and imaging profiles with probable Alzheimer's disease.

OBJECTIVE: We aimed to (i) compare the clinical, neuropsychological, and neuroimaging characteristics of unprovoked late-onset epilepsy (LOE) patients with cognitive symptoms against probable Alzheimer's disease (AD) patients; (ii) clarify how neurodegeneration and other processes could be implicated in the cognitive symptoms of unprovoked LOE patients; and (iii) characterize the longitudinal trajectory of unprovoked LOE patients with cognitive symptoms. METHODS: Twenty-six unprovoked LOE patients with cognitive symptoms and 26 probable AD were retrospectively recruited from epilepsy and memory clinics at a single tertiary referral center. The patients underwent comprehensive clinical, neuropsychological, and 18Fluorodeoxyglucose PET-CT assessments. All LOE patients had clinical follow-up and a subset of 17 patients had repeat neuropsychological assessments. RESULTS: At baseline, 18% of LOE patients with cognitive symptoms had dementia-range cognitive impairment and one received a diagnosis of probable AD. Compared with the probable AD group, the LOE group did not perform significantly better in global measures of cognition (total ACE-III), neuropsychological tests for fluency, working memory, language, attention, or executive function, but performed better in naming, memory, and visuospatial ability. The commonest patterns of cognitive impairment in the LOE group were frontal and left temporal, whereas all AD patients exhibited parietotemporal patterns. The AD group had more 18Fluorodeoxyglucose PET-CT hypometabolism in the parietal and occipital, but not the temporal and frontal lobes. During the 3.0 ± 3.2 years follow-up, improved seizure frequency in the LOE group covaried with improved total ACE-III score, there was no further conversion to probable AD and no group-level cognitive decline. CONCLUSION: Unprovoked LOE patients with cognitive symptoms had varying severities of cognitive impairment, and different patterns of cognitive and imaging abnormalities compared with AD patients. They were rarely diagnosed with probable AD at presentation or follow-up. Cognitive outcome in LOE may be related to seizure control. Cerebral small vessel disease may play a role in LOE-associated cognitive impairment.

Hemispheric contributions toward interoception and emotion recognition in left-vs right-semantic dementia.

BACKGROUND: The hemispheric contributions toward interoception, the perception of internal bodily cues, and emotion recognition remains unclear. Semantic dementia cases with either left-dominant (i.e., left-SD) or right-dominant (i.e., right-SD) anterior temporal lobe atrophy experience emotion recognition difficulties, however, little is known about interoception in these syndromes. Here, we hypothesised that right-SD would show worse interoception and emotion recognition due to right-dominant atrophy. METHODS: Thirty-five participants (8 left-SD; 6 right-SD; 21 controls) completed a monitoring task. Participants pressed a button when they: (1) felt their heartbeat, without pulse measurement (Interoception); or (2) heard a recorded heartbeat (Exteroception-control). Simultaneous ECG was recorded. Accuracy was calculated by comparing the event frequency (i.e., heartbeat or sound) to response frequency. Emotion recognition was assessed via the Facial Affect Selection Task. Voxel-based morphometry analyses identified neural correlates of interoception and emotion recognition. RESULTS: Right-SD showed worse interoception than controls and left-SD (both p's < 0.001). Both patient groups showed worse emotion recognition than controls (right-SD: p < .001; left-SD: p = .018), and right-SD showed worse emotion recognition than left-SD (p = .003). Regression analyses revealed that worse emotion recognition was predicted by right-SD (p = .002), left-SD (p = .005), and impaired interoception (p = .004). Interoception and emotion were associated with the integrity of right-lateralised structures including the insula, temporal pole, thalamus, superior temporal gyrus, and hippocampus. CONCLUSION: Our study provides the first evidence for impaired interoception in right-SD, suggesting that impaired emotion recognition in this syndrome is driven by inaccurate internal monitoring. Further we identified a common neurobiological basis for interoception and emotion in the right hemisphere.

Pearls & Oy-sters: Huntington Disease Presenting as Primary Progressive Aphasia: A Case of Semantics.

We present a case of semantic variant primary progressive aphasia as the presenting feature in a patient with Huntington disease (HD). The patient initially developed progressive language impairment including impaired naming and object knowledge and single-word comprehension and then developed chorea and behavioral changes. An MRI of the brain showed left anterior temporal lobe and hippocampal atrophy. A neurologic FDG PET/CT showed reduced metabolism in the head of the left caudate nucleus. Huntingtin gene testing revealed an expansion of 39 CAG repeats in 1 allele. This case outlines the substantial overlap between the clinical presentation of HD and frontotemporal lobar degeneration syndromes and provides commentary on the investigation of these neurodegenerative diseases.

Error profiles of facial emotion recognition in frontotemporal dementia and Alzheimer's disease.

OBJECTIVES: To identify the patterns of errors in facial emotion recognition in frontotemporal dementia (FTD) subtypes compared with Alzheimer's disease (AD) and healthy controls. DESIGN: Retrospective analysis. SETTING: Participants were recruited from FRONTIER, the frontotemporal dementia research group at the University of Sydney, Australia. PARTICIPANTS: A total of 356 participants (behavioral-variant FTD (bvFTD): 62, semantic dementia (SD)-left: 29, SD-right: 14, progressive non-fluent aphasia (PNFA): 21, AD: 76, controls: 90) were included. MEASUREMENTS: Facial emotion recognition was assessed using the Facial Affect Selection Task, a word-face matching task measuring recognition of the six basic emotions (anger, disgust, fear, happiness, sadness, and surprise), as well as neutral emotion, portrayed by black and white faces. RESULTS: Overall, all clinical groups performed significantly worse than controls with the exception of the PNFA subgroup (p = .051). The SD-right group scored worse than all other clinical groups (all p values < .027) and the bvFTD subgroup performed worse than the PNFA group (p < .001). The most frequent errors were in response to the facial emotions disgust (26.1%) and fear (22.9%). The primary error response to each target emotion was identified; patterns of errors were similar across all clinical groups. CONCLUSIONS: Facial emotion recognition is impaired in FTD and AD compared to healthy controls. Within FTD, bvFTD and SD-right are particularly impaired. Dementia groups cannot be distinguished based on error responses alone. Implications for future clinical diagnosis and research are discussed.

Mapping behavioural, cognitive and affective transdiagnostic dimensions in frontotemporal dementia.

Two common clinical variants of frontotemporal dementia are the behavioural variant frontotemporal dementia, presenting with behavioural and personality changes attributable to prefrontal atrophy, and semantic dementia, displaying early semantic dysfunction primarily due to anterior temporal degeneration. Despite representing independent diagnostic entities, mounting evidence indicates overlapping cognitive-behavioural profiles in these syndromes, particularly with disease progression. Why such overlap occurs remains unclear. Understanding the nature of this overlap, however, is essential to improve early diagnosis, characterization and management of those affected. Here, we explored common cognitive-behavioural and neural mechanisms contributing to heterogeneous frontotemporal dementia presentations, irrespective of clinical diagnosis. This transdiagnostic approach allowed us to ascertain whether symptoms not currently considered core to these two syndromes are present in a significant proportion of cases and to explore the neural basis of clinical heterogeneity. Sixty-two frontotemporal dementia patients (31 behavioural variant frontotemporal dementia and 31 semantic dementia) underwent comprehensive neuropsychological, behavioural and structural neuroimaging assessments. Orthogonally rotated principal component analysis of neuropsychological and behavioural data uncovered eight statistically independent factors explaining the majority of cognitive-behavioural performance variation in behavioural variant frontotemporal dementia and semantic dementia. These factors included Behavioural changes, Semantic dysfunction, General Cognition, Executive function, Initiation, Disinhibition, Visuospatial function and Affective changes. Marked individual-level overlap between behavioural variant frontotemporal dementia and semantic dementia was evident on the Behavioural changes, General Cognition, Initiation, Disinhibition and Affective changes factors. Compared to behavioural variant frontotemporal dementia, semantic dementia patients displayed disproportionate impairment on the Semantic dysfunction factor, whereas greater impairment on Executive and Visuospatial function factors was noted in behavioural variant frontotemporal dementia. Both patient groups showed comparable magnitude of atrophy to frontal regions, whereas severe temporal lobe atrophy was characteristic of semantic dementia. Whole-brain voxel-based morphometry correlations with emergent factors revealed associations between fronto-insular and striatal grey matter changes with Behavioural, Executive and Initiation factor performance, bilateral temporal atrophy with Semantic dysfunction factor scores, parietal-subcortical regions with General Cognitive performance and ventral temporal atrophy associated with Visuospatial factor scores. Together, these findings indicate that cognitive-behavioural overlap (i) occurs systematically in frontotemporal dementia; (ii) varies in a graded manner between individuals and (iii) is associated with degeneration of different neural systems. Our findings suggest that phenotypic heterogeneity in frontotemporal dementia syndromes can be captured along continuous, multidimensional spectra of cognitive-behavioural changes. This has implications for the diagnosis of both syndromes amidst overlapping features as well as the design of symptomatic treatments applicable to multiple syndromes.

Distinct hypothalamic involvement in the amyotrophic lateral sclerosis-frontotemporal dementia spectrum.

BACKGROUND: Hypothalamic dysregulation plays an established role in eating abnormalities in behavioural variant frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis (ALS). Its contribution to cognitive and behavioural impairments, however, remains unexplored. METHODS: Correlation between hypothalamic subregion atrophy and cognitive and behavioural impairments was examined in a large sample of 211 participants (52 pure ALS, 42 mixed ALS-FTD, 59 bvFTD, and 58 age- and education- matched healthy controls). RESULTS: Graded variation in hypothalamic involvement but relative sparing of the inferior tuberal region was evident across all patient groups. Bilateral anterior inferior, anterior superior, and posterior hypothalamic subregions were selectively implicated in memory, fluency and processing speed impairments in addition to apathy and abnormal eating habits, taking into account disease duration, age, sex, total intracranial volume, and acquisition parameters (all p ≤ .001). CONCLUSIONS: These findings revealed that subdivisions of the hypothalamus are differentially affected in the ALS-FTD spectrum and contribute to canonical cognitive and behavioural disturbances beyond eating abnormalities. The anterior superior and superior tuberal subregions containing the paraventricular nucleus (housing oxytocin-producing neurons) displayed the greatest volume loss in bvFTD and ALS-FTD, and ALS, respectively. Importantly, the inferior tuberal subregion housing the arcuate nucleus (containing different groups of neuroendocrine neurons) was selectively preserved across the ALS-FTD spectrum, supporting pathophysiological findings of discrete neuropeptide expression abnormalities that may underlie the pathogenesis of autonomic and metabolic abnormalities and potentially certain cognitive and behavioural symptom manifestations, representing avenues for more refined symptomatic treatment targets.

Olfactory Bulb Integrity in Frontotemporal Dementia and Alzheimer's Disease.

BACKGROUND: Olfactory dysfunction is highly prevalent in dementia syndromes, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). The structural integrity of the olfactory bulb (OB) is thought to play a critical role in odor detection and identification, but no MRI study has measured OB volume in FTD, or measured OB volume longitudinally in AD. OBJECTIVE: To measure OB volume in FTD and AD patients longitudinally using MRI. METHODS: This study measured OB volumes using MRI in patients diagnosed with behavioral-variant FTD (n = 55), semantic dementia (n = 34), progressive non-fluent aphasia (n = 30), AD (n = 50), and healthy age-matched controls (n = 55) at their first visit to a dementia research clinic ('baseline'). Imaging data in patients 12-months later were analyzed where available (n = 84) for longitudinal assessment. Volumes of subcortical and cortical olfactory regions ('olfactory network') were obtained via surface-based morphometry. RESULTS: Results revealed that in AD and FTD at baseline, OB volumes were similar to controls, whereas volumes of olfactory network regions were significantly reduced in all patient groups except in progressive non-fluent aphasia. Longitudinal data revealed that OB volume became significantly reduced (10-25% volume reduction) in all dementia groups with disease progression. CONCLUSION: Olfactory dysfunction is common in patients diagnosed with AD or FTD, but our results indicate that there is no detectable volume loss to the OBs upon first presentation to the clinic. Our findings indicate that the OBs become detectably atrophied later in the disease process. OB atrophy indicates the potential usefulness for OBs to be targeted in interventions to improve olfactory function.

Plasma Oxytocin Is Not Associated with Social Cognition or Behavior in Frontotemporal Dementia and Alzheimer's Disease Syndromes.

INTRODUCTION: Changes in social behavior and emotion processing are common in frontotemporal dementia (FTD) and semantic dementia (SD), and less so in Alzheimer's disease (AD). Recent research has investigated oxytocin as a potential treatment for these symptoms; however, whether plasma oxytocin is associated with social-emotional symptoms of dementia remains underexplored. METHODS: Thirty behavioral-variant FTD (bvFTD), 28 SD, 39 AD, and 24 controls underwent blood sampling to measure oxytocin. Participants completed an emotion processing battery. Carers completed the Cambridge Behavioral Inventory and the Neuropsychiatric Inventory. RESULTS: Patients with bvFTD were severely impaired in emotion processing and behavioral ratings, with milder impairment in SD and AD. No difference in plasma oxytocin was observed between groups (p = 0.632). No significant associations were found between oxytocin and social behavior or emotion processing (r values between -0.241 and 0.227, all p values >0.099). CONCLUSION: Our results indicate that plasma oxytocin is not reduced in dementia and is unrelated to social, emotional, and behavioral features. We noted high interindividual variability in our data; hence, future investigations should consider methodological influences such as serum versus saliva and diurnal variation on oxytocin function. These results demonstrate that current measurement measures of plasma oxytocin have limited utility in determining the role of oxytocin in FTD. Alternative oxytocin measures may prove more sensitive and should be considered when conducting clinical trials.

Thalamic and Cerebellar Regional Involvement across the ALS-FTD Spectrum and the Effect of C9orf72.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of the same disease spectrum. While thalamic−cerebellar degeneration has been observed in C9orf72 expansion carriers, the exact subregions involved across the clinical phenotypes of the ALS−FTD spectrum remain unclear. Using MRIs from 58 bvFTD, 41 ALS−FTD and 52 ALS patients compared to 57 controls, we aimed to delineate thalamic and cerebellar subregional changes across the ALS−FTD spectrum and to contrast these profiles between cases with and without C9orf72 expansions. Thalamic involvement was evident across all ALS−FTD clinical phenotypes, with the laterodorsal nucleus commonly affected across all groups (values below the 2.5th control percentile). The mediodorsal nucleus was disproportionately affected in bvFTD and ALS−FTD but not in ALS. Cerebellar changes were only observed in bvFTD and ALS−FTD predominantly in the superior−posterior region. Comparison of genetic versus sporadic cases revealed significantly lower volumes exclusively in the pulvinar in C9orf72 expansion carriers compared to non-carriers, irrespective of clinical syndrome. Overall, bvFTD showed significant correlations between thalamic subregions, level of cognitive dysfunction and severity of behavioural symptoms. Notably, strong associations were evident between mediodorsal nucleus atrophy and severity of behavioural changes in C9orf72-bvFTD (r = −0.9, p < 0.0005). Our findings reveal distinct thalamic and cerebellar atrophy profiles across the ALS−FTD spectrum, with differential impacts on behaviour and cognition, and point to a unique contribution of C9orf72 expansions in the clinical profiles of these patients.

Schizotypal traits across the amyotrophic lateral sclerosis-frontotemporal dementia spectrum: pathomechanistic insights.

BACKGROUND: Psychiatric presentations similar to that observed in primary psychiatric disorders are well described across the amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum. Despite this, schizotypal personality traits associated with increased risks of clinical psychosis development and poor psychosocial outcomes have never been examined. The current study aimed to provide the first exploration of schizotypal traits and its neural underpinnings in the ALS-FTD spectrum to gain insights into a broader spectrum of psychiatric overlap with psychiatric disorders. METHODS: Schizotypal traits were assessed using the targeted Schizotypal Personality Questionnaire in 99 participants (35 behavioural variant FTD, 10 ALS-FTD and 37 ALS patients, and 17 age-, sex- and education-matched healthy controls). Voxel-based morphometry analysis of whole-brain grey matter volume was conducted. RESULTS: Relative to controls, pervasive schizotypal personality traits across positive and negative schizotypy and disorganised thought disorders were identified in behavioural variant FTD, ALS (with the exception of negative schizotypy) and ALS-FTDALS-FTD patients (all p < .013), suggesting the presence of a wide spectrum of subclinical schizotypal symptoms beyond classic psychotic symptoms. Atrophy in frontal, anterior cingulate and insular cortices, and caudate and thalamus was involved in positive schizotypy, while integrity of the cerebellum was associated with disorganised thought disorder traits. CONCLUSIONS: The frontal-striatal-limbic regions underpinning manifestation of schizotypy in the ALS-FTDALS-FTD spectrum are similar to that established in previous schizophrenia research. This finding expands the concept of a psychiatric overlap in ALS-FTD and schizophrenia, and suggests potentially common underlying mechanisms involving disruptions to frontal-striatal-limbic networks, warranting a transdiagnostic approach for future investigations.

Try to see it my way - Examining the relationship between visual perspective taking and theory of mind in frontotemporal dementia.

The behavioural variant of frontotemporal dementia (bvFTD) is characterised by pronounced alterations in social functioning, including the understanding of others' thoughts and feelings via theory of mind. The emergence of such impairments in other social disorders such as autism and schizophrenia is suggested to reflect an inability to imagine the other person's visual perspective of the world. To our knowledge, relationships between visual perspective taking and theory of mind have not previously been explored in bvFTD. Here, we sought to examine the capacity for visual perspective taking and theory of mind in bvFTD, and to establish their inter-relationships and underlying neural correlates. Fifteen bvFTD patients and 15 healthy Controls completed a comprehensive battery of perspective taking measures, comprising Level 1 ('what') and Level 2 ('how') visual perspective taking tasks, a cartoon task capturing theory of mind, and a questionnaire assessing subjective perspective taking in daily life. Compared with Controls, bvFTD patients displayed significant impairments across all perspective taking measures. These perspective taking impairments, however, were not correlated with one another in bvFTD. Region-of-interest voxel-based morphometry analyses suggested distinct neural correlates for visual perspective taking (inferior frontal gyrus) versus theory of mind (medial prefrontal cortex, precuneus), which appeared to partially overlap with those implicated in subjective perspective taking (inferior frontal gyrus, precuneus, temporoparietal junction). Despite pervasive impairments in all aspects of perspective taking in bvFTD, these did not appear to relate to one another at the behavioural or neural level in our study. Future large-scale studies manipulating discrete aspects of the tasks will help to clarify the neurocognitive mechanisms of, and relationships between, visual perspective taking and theory of mind in bvFTD, along with their real-world implications.

The Role of Oxytocin in Social Circuits and Social Behavior in Dementia.

Administration of intranasal oxytocin has been found to improve social cognition in a number of brain conditions, including autism spectrum disorder and schizophrenia. Whether this approach is relevant in dementias is currently unknown, particularly in frontotemporal dementia, a younger-onset dementia characterized clinically by marked changes in social cognition and behavior and focal atrophy of the frontal and temporal lobes. This chapter provides an overview of the deficits in social cognition in frontotemporal dementia and reviews the emerging evidence of intranasal oxytocin administration as a potential treatment option for these deficits. Future research directions will also be discussed.

Cognitive and Neural Mechanisms of Social Communication Dysfunction in Primary Progressive Aphasia.

Mounting evidence suggests that, in parallel with well-defined changes in language, primary progressive aphasia (PPA) syndromes display co-occurring social cognitive impairments. Here, we explored multidimensional profiles of carer-rated social communication using the La Trobe Communication Questionnaire (LCQ) in 11 semantic dementia (SD), 12 logopenic progressive aphasia (LPA) and 9 progressive non-fluent aphasia (PNFA) cases and contrasted their performance with 19 Alzheimer's disease (AD) cases, 26 behavioural variant frontotemporal dementia (bvFTD) cases and 31 healthy older controls. Relative to the controls, the majority of patient groups displayed significant overall social communication difficulties, with common and unique profiles of impairment evident on the LCQ subscales. Correlation analyses revealed a differential impact of social communication disturbances on functional outcomes in patient and carer well-being, most pronounced for SD and bvFTD. Finally, voxel-based morphometry analyses based on a structural brain MRI pointed to the degradation of a distributed brain network in mediating social communication dysfunction in dementia. Our findings suggest that social communication difficulties are an important feature of PPA, with significant implications for patient function and carer well-being. The origins of these changes are likely to be multifactorial, reflecting the breakdown of fronto-thalamic brain circuits specialised in the integration of complex information.

Factors That Influence Non-Motor Impairment Across the ALS-FTD Spectrum: Impact of Phenotype, Sex, Age, Onset and Disease Stage.

Objective: This study aimed to establish (1) the pattern and severity of neuropsychiatric symptoms and other non-motor symptoms of sleep and mood, across ALS phenotypes in comparison to bvFTD and (2) the contribution of non-modifiable factors including age, sex and disease state to the severity of symptoms experienced by ALS patients. Methods: Consecutive participants were recruited to the study and underwent a detailed clinical, cognitive, behavioral and neuroimaging assessment. Neuropsychiatric and other non-motor symptoms were determined using the Cambridge Behavioral Inventory, the CBI-R. The scores were converted to define impairment in terms of mild, moderate and severe symptoms for each subscale. Rate, severity and contribution of King's staging and modifiable factors were also determined and a regression model identified predictors of symptom severity. Results: In total, 250 participants (115 ALS, 98 bvFTD, and 37 ALS-FTD patients) were recruited. A similar pattern of neuropsychiatric symptom severity was identified (apathy, disinhibition and stereotypic behavior) for all behavioral phenotypes of ALS compared to bvFTD (all p > 0.05). Neuropsychiatric symptoms were also present in cases defined as ALSpure and the cognitive phenotype of ALS (ALSci) although they occurred less frequently and were at the milder end of the spectrum. Disordered sleep and disrupted mood were common across all phenotypes (all p < 0.05). The severity of sleep dysfunction was influenced by both sex and age (all p < 0.05). Neuropsychiatric symptoms, sleep and mood disorders were common early in the disease process and deteriorated in line with progression on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; all p < 0.05). Diagnostic phenotype, disease duration and global cognition scores were the strongest predictors of non-motor and neuropsychiatric impairments. Conclusion: The current findings reveal strikingly similar patterns of changes across the subgroups of ALS and bvFTD, supporting the concept of the ALS-FTD spectrum. The findings further highlight the impact of non-motor and neuropsychiatric symptoms in patients with ALS, that are often as severe as that seen in ALS-FTD and bvFTD. This study advances understanding across the ALS-FTD spectrum that may accelerate the early identification of patient needs, to ensure prompt recognition of symptoms and thereby to improve clinical awareness, patient care and management.