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.

Heterogeneity of cortical pTDP-43 inclusion morphologies in amyotrophic lateral sclerosis.

BACKGROUND: Despite the presence of significant cortical pTDP-43 inclusions of heterogeneous morphologies in patients diagnosed with amyotrophic lateral sclerosis (ALS), pathological subclassification is routinely performed in the minority of patients with concomitant frontotemporal dementia (FTD). OBJECTIVE: In order to improve current understanding of the presence and relevance of pathological pTDP-43 subtypes in ALS, the present study examined the pattern of cortical pTDP-43 aggregates in 61 ALS cases without FTD. RESULTS: Based on the presence, morphology and composition of pTDP-43 pathology, three distinct ALS-TDP subtypes were delineated: (1) A predominant pattern of pTDP-43 granulofilamentous neuronal inclusions (GFNIs) and grains that were immuno-negative for p62 was identified in 18% of cases designated ALS-TDP type E; (2) neuronal cytoplasmic inclusions (NCIs) that were immuno-positive for both pTDP-43 and p62 were observed in 67% of cases assigned ALS-TDP type B; and (3) scarce cortical pTDP-43 and p62 aggregates were identified in 15% of cases coined ALS-TDP type SC (scarce cortical). Quantitative analyses revealed a significantly greater burden of pTDP-43 GFNI and grains in ALS-TDP type E. Principal component analysis demonstrated significant relationships between GFNIs, grains and ALS-TDP subtypes to support the distinction of subtypes E and B. No significant difference in age at death or disease duration was found between ALS-TDP subgroups to suggest that these subtypes represent earlier or later stages of the same disease process. Instead, a significantly higher ALS-TDP stage, indicating greater topographical spread of pTDP-43, was identified in ALS-TDP type E. Alzheimer's disease neuropathological change (ABC score ≥ intermediate) and Lewy body disease (Braak stage ≥ IV) was more prevalent in the ALS-TDP type SC cohort, which also demonstrated a significantly lower overall cognitive score. CONCLUSION: In summary, the present study demonstrates that ALS-TDP does not represent a single homogenous neuropathology. We propose the subclassification of ALS-TDP into three distinct subtypes using standard immuno-stains for pTDP-43 and p62 in the motor cortex, which is routinely sampled and evaluated for diagnostic neuropathological characterisation of ALS. We propose that future studies specify both clinicopathological group and pTDP-43 subtype to advance current understanding of the pathogenesis of clinical phenotypes in pTDP-43 proteinopathies, which will have significant relevance to the development of targeted therapies for this heterogeneous disorder.

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.

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.

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.

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.

Tackling clinical heterogeneity across the amyotrophic lateral sclerosis-frontotemporal dementia spectrum using a transdiagnostic approach.

The disease syndromes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) display considerable clinical, genetic and pathological overlap, yet mounting evidence indicates substantial differences in progression and survival. To date, there has been limited examination of how profiles of brain atrophy might differ between clinical phenotypes. Here, we address this longstanding gap in the literature by assessing cortical and subcortical grey and white matter volumes on structural MRI in a large cohort of 209 participants. Cognitive and behavioural changes were assessed using the Addenbrooke's Cognitive Examination and the Cambridge Behavioural Inventory. Relative to 58 controls, behavioural variant FTD (n = 58) and ALS-FTD (n = 41) patients displayed extensive atrophy of frontoinsular, cingulate, temporal and motor cortices, with marked subcortical atrophy targeting the hippocampus, amygdala, thalamus and striatum, with atrophy further extended to the brainstem, pons and cerebellum in the latter group. At the other end of the spectrum, pure-ALS patients (n = 52) displayed considerable frontoparietal atrophy, including right insular and motor cortices and pons and brainstem regions. Subcortical regions included the bilateral pallidum and putamen, but to a lesser degree than in the ALS-FTD and behavioural variant FTD groups. Across the spectrum the most affected region in all three groups was the insula, and specifically the anterior part (76-90% lower than controls). Direct comparison of the patient groups revealed disproportionate temporal atrophy and widespread subcortical involvement in ALS-FTD relative to pure-ALS. In contrast, pure-ALS displayed significantly greater parietal atrophy. Both behavioural variant FTD and ALS-FTD were characterized by volume decrease in the frontal lobes relative to pure-ALS. The motor cortex and insula emerged as differentiating structures between clinical syndromes, with bilateral motor cortex atrophy more pronounced in ALS-FTD compared with pure-ALS, and greater left motor cortex and insula atrophy relative to behavioural variant FTD. Taking a transdiagnostic approach, we found significant associations between abnormal behaviour and volume loss in a predominantly frontoinsular network involving the amygdala, striatum and thalamus. Our findings demonstrate the presence of distinct atrophy profiles across the ALS-FTD spectrum, with key structures including the motor cortex and insula. Notably, our results point to subcortical involvement in the origin of behavioural disturbances, potentially accounting for the marked phenotypic variability typically observed across the spectrum.

Neural mechanisms of psychosis vulnerability and perceptual abnormalities in the ALS-FTD spectrum.

OBJECTIVE: The aims of this study were to (i) explore psychotic experiences across the entire amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum from a clinical and genetic perspective, (ii) determine the rate of abnormal perceptual experiences across the five sensory modalities and (iii) explore the neurobiological factors that lead to psychosis vulnerability in ALS-FTD. METHODS: In a prospective case-controlled study design, 100 participants were enrolled including ALS (n = 37, 24% satisfied criteria for ALS-Plus), ALS-FTD (n = 11), bvFTD (n = 27) and healthy controls (n = 25). Psychotic experiences, perceptual abnormalities and psychosocial factors were determined by means of the clinical interview and carer and patient reports. Voxel-based morphometry analyses determined atrophy patterns in patients experiencing psychosis-like experiences and other perceptual abnormalities. RESULTS: The rates of psychotic experiences and abnormalities of perception in each sensory modality were high across the entire ALS-FTD continuum. The rate was highest in those with C9orf72 expansions. Rates were also high in patients with pure ALS including psychosis measured by carer-based reports (18%) and self-report measures of psychotic-like experiences (21%). In an ENTER regression model, social anxiety and ACE-III scores were the best predictors of psychosis proneness, accounting for 44% of the score variance. Psychosis-like experiences and perceptual abnormalities were associated with a predominantly frontal and temporal pattern of atrophy that extended to the cerebellum and centred on the anterior thalamus. INTERPRETATION: The model for psychosis proneness in ALS-FTD likely includes complex interactions between cognitive, social and neurobiological factors that determine vulnerability to psychosis and that may have relevance for individualised patient management.

Phenotypic variability in ALS-FTD and effect on survival.

OBJECTIVE: To determine if survival and cognitive profile is affected by initial presentation in amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) (motor vs cognitive), we compared survival patterns in ALS-FTD based on initial phenotypic presentation and their cognitive profile compared to behavioral variant FTD (bvFTD). METHODS: Cognitive/behavioral profiles were examined in 98 patients (59 ALS-FTD and 39 bvFTD). The initial presentation of ALS-FTD was categorized into either motor or cognitive. Survival was calculated from initial symptom onset. MRI brain atrophy patterns were examined using a validated visual rating scale. RESULTS: In the ALS-FTD group, 41 (69%) patients were categorized as having an initial cognitive presentation and 18 (31%) a motor presentation. Patients with motor presentation experienced a significantly shorter median survival of 2.7 years compared to 4.4 years (p < 0.001) in those with a cognitive presentation. No differences between motor vs cognitive onset ALS-FTD were found on cognitive testing. When compared to bvFTD, ALS-FTD-cognitive presentation was characterized by reduced language function (p < 0.001), verbal fluency (p = 0.001), and naming (p = 0.007). Both motor and cognitive onset ALS-FTD showed reduced emotion processing (p = 0.01) and exhibited greater motor cortex and dorsal lateral prefrontal cortex atrophy than bvFTD. Increased motor cortex atrophy was associated with 1.5-fold reduction in survival. CONCLUSIONS: Initial motor presentation in ALS-FTD leads to faster progression than in those with a cognitive presentation, despite similar overall cognitive deficits. These findings suggest that disease progression in ALS-FTD may be critically linked to physiologic and motor changes.

COG-01 Phenotypic variation in ALS-FTD and effect on survival.

Background: Within the Amyotrophic Lateral Sclerosis (ALS)-Frontotemporal dementia (FTD) spectrum there is considerable heterogeneity in clinical presentation and survival.Objectives: The current study aimed to examine how initial symptoms (motor compared to cognitive) may affect survival, with specific focus on structural cognitive and behavioural differences between ALS-FTD and bvFTD cohorts.Methods: Cognitive and behavioural profiles were examined in 98 patients (59 ALS-FTD and 39 bvFTD patients). The initial presentation of ALS-FTD was categorized into either motor or cognitive, based on symptoms combined with carer reports. Survival was calculated from initial symptom onset. Brain atrophy patterns on MRI were examined using a verified visual rating scale.Results: In the ALS-FTD group, 69% were categorized as having an initial cognitive presentation and 31% a motor presentation. Those patients with motor presentation of ALS-FTD experienced a significantly shorter survival of 33 months, compared to 63 months (p<0.007) in those with a cognitive presentation of ALS-FTD. On cognitive testing there were no differences between motor versus cognitive onset ALS-FTD. When compared to bvFTD, ALS-FTD, particularly the cognitive presentation, was characterized by reduced language function (p<0.001), verbal fluency (p = 0.001), and naming (p = 0.007). Both cognitive and motor presentation ALS-FTD had poorer emotion processing (p = 0.01) compared to bvFTD. On structural imaging analyses both motor and cognitive onset ALS-FTD patients had greater motor cortex and dorsal lateral prefrontal cortex atrophy compared to bvFTD patients. Increased motor cortex atrophy was associated with 1.5-fold reduction in survival.Discussion and conclusions: In ALS-FTD those with an initial motor presentation have a much faster progression than those with a cognitive presentation, despite having similar overall cognitive impairment, suggesting that disease progression in ALS-FTD may be critically linked to physiological and motor changes. Survival is also associated with motor cortex atrophy which is increased in ALS-FTD.These results provide further suggestions in relation to the categorization of clinical trial patients into fast and slow progressors.

Frontotemporal dementia.

Frontotemporal dementia (FTD) is the second commonest cause of young onset dementia. Our understanding of FTD and its related syndromes has advanced significantly in recent years. Among the most prominent areas of progress is the overlap between FTD, MND, and other neurodegenerative conditions at a clinicopathologic and genetic level. In parallel major advances in neuroimaging techniques, the discovery of new genetic mutations as well as the development of potential biomarkers may serve to further expand knowledge of the biologic processes at play in FTD and may in turn propel research toward identifying curative and preventative pharmacologic therapies. The aim of this chapter is to discuss the clinical, pathologic, and genetic complexities of FTD and related disorders.

Neural networks associated with body composition in frontotemporal dementia.

BACKGROUND: Frontotemporal dementia (FTD) is associated with complex changes in eating behavior and metabolism, which potentially affect disease pathogenesis and survival. It is currently not known if body composition changes and changes in fat deposition also exist in FTD, the relationship of these changes in eating behavior and appetite, and whether these changes are centrally mediated. METHODS: Body composition was measured in 28 people with behavioral-variant frontotemporal dementia (bvFTD), 16 with Alzheimer's disease (AD), and 19 healthy controls, using dual energy x-ray absorptiometry. Changes in body composition were correlated to brain grey matter atrophy using voxel-based morphometry on high-resolution magnetic resonance imaging. RESULTS: Behavioral-variant FTD was characterized by changes in body composition, with increased total fat mass, visceral adipose tissue area (VAT area), and android: gynoid ratio compared to control and AD participants (all P values < 0.05). Changes in body composition correlated to abnormal eating behavior and behavioral change (P < 0.01) and functional decline (P < 0.01). Changes in body composition also correlated to grey matter atrophy involving a distributed neural network that included the hippocampus, amygdala, nucleus accumbens, insula, cingulate, and cerebellum - structures known to be central to autonomic control - as well as the thalamus, putamen, accumbens, and caudate, which are involved in reward processing. CONCLUSIONS: Changes in body composition and fat deposition extend the clinical phenomenology in bvFTD beyond cognition and behavior, with changes associated with changes in reward and autonomic processing suggesting that these deficits may be central in FTD.

Psychiatric disorders in C9orf72 kindreds: Study of 1,414 family members.

OBJECTIVE: The aim of this study was to determine in a systematic manner if the C9orf72 phenotype might extend beyond frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) to include psychiatric disease. METHODS: A validated semistructured family history interview was conducted in a large cohort of patients with FTD and ALS (n = 89), with and without the C9orf72 expansion (n = 29 and n = 60, respectively), encompassing 1,414 first- and second-degree relatives. Statistical analyses used both the hazard ratio (HR) and the relative risk ratio to determine the risk profiles within families. RESULTS: A significant HR of 4.9 (95% confidence interval [CI]: 1.9-13.9, p = 0.003) confirmed a higher probability of developing schizophrenia for relatives of C9orf72 carriers compared with noncarriers. In addition, 8 relatives of C9orf72 carriers experienced an episode of late-onset psychosis unrelated to schizophrenia, in comparison to one noncarrier (HR = 17.9, 95% CI: 2.2-143.2, p = 0.007). The probability of suicide was also significantly higher for family members of C9orf72 carriers (HR = 2.7, 95% CI: 1.2-6.2, p = 0.02). An HR of 2.7 (95% CI: 1.1-6.9, p = 0.03) indicated a higher probability of autism spectrum disorder (ASD) in family members of C9orf72 carriers, and this risk extended to FTD. Furthermore, there was a positive association between psychosis in probands and mental health disorders, including ASD in their family members (p = 0.04). CONCLUSION: Overall, the results from this study suggest that a psychiatric phenotype exists within C9orf72 kindreds. Further studies should attempt to delineate the risk of psychiatric disorders in C9orf72 kindreds to aid in clinical decision making, particularly regarding genetic counseling, through collaborations between neurology and psychiatry.

The neural correlates and clinical characteristics of psychosis in the frontotemporal dementia continuum and the C9orf72 expansion.

OBJECTIVE: This present study aims to address the gap in the literature regarding the severity and underlying neural correlates of psychotic symptoms in frontotemporal dementia with and without the C9orf72 gene expansion. METHODS: Fifty-six patients with behavioural variant frontotemporal dementia (20 with concomitant amyotrophic lateral sclerosis) and 23 healthy controls underwent neuropsychological assessments, detailed clinical interview for assessment of psychosis symptoms, brain MRI and genetic testing. Carers underwent a clinical interview based upon the neuropsychiatric inventory. Patients were assessed at ForeFront, the Frontotemporal Dementia Research Group at Neuroscience Research Australia or at the Brain and Mind Centre, between January 2008 and December 2013. An index of psychosis was calculated, taking into account the degree and severity of psychosis in each case. Voxel-based morphometry analyses were used to explore relationships between the psychosis index and grey matter changes. RESULTS: Thirty-four percent of frontotemporal dementia patients showed psychotic features. C9orf72 expansion cases were more likely to exhibit psychotic symptoms than non-carriers (64% vs. 26%; p = 0.006), which were also more severe (psychotic index 23.1 vs. 8.1; p = 0.002). Delusions comprised persecutory, somatic, jealous and grandiose types and were present in 57% of C9orf72 carriers and 19% of non-carriers (p = 0.006). Auditory, visual or tactile hallucinations were present in 36% of C9orf72 carriers and 17% of non-carriers (p = 0.13). Increased psychotic symptoms in C9orf72 expansion carriers correlated with atrophy in a distributed cortical and subcortical network that included discrete regions of the frontal, temporal and occipital cortices, as well as the thalamus, striatum and cerebellum. CONCLUSIONS: This study underlines the need to consider and assess for psychotic symptoms in the frontotemporal dementia-amyotrophic lateral sclerosis continuum particularly in those with C9orf72 gene expansions. The network of brain regions identified in this study is strikingly similar to that identified in other psychotic disorders such as schizophrenia, which suggests that treatment strategies in psychiatry may be beneficial for the management of psychotic symptoms in frontotemporal dementia.

Neuronal network disintegration: common pathways linking neurodegenerative diseases.

Neurodegeneration refers to a heterogeneous group of brain disorders that progressively evolve. It has been increasingly appreciated that many neurodegenerative conditions overlap at multiple levels and therefore traditional clinicopathological correlation approaches to better classify a disease have met with limited success. Neuronal network disintegration is fundamental to neurodegeneration, and concepts based around such a concept may better explain the overlap between their clinical and pathological phenotypes. In this Review, promoters of overlap in neurodegeneration incorporating behavioural, cognitive, metabolic, motor, and extrapyramidal presentations will be critically appraised. In addition, evidence that may support the existence of large-scale networks that might be contributing to phenotypic differentiation will be considered across a neurodegenerative spectrum. Disintegration of neuronal networks through different pathological processes, such as prion-like spread, may provide a better paradigm of disease and thereby facilitate the identification of novel therapies for neurodegeneration.