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.

Examining the presence and nature of delusions in Alzheimer's disease and frontotemporal dementia syndromes.

OBJECTIVES: Abnormal beliefs and delusions have been reported in some people with dementia, however, the prevalence of delusions, and their neurocognitive basis has been underexplored. This study aimed to examine the presence, severity, content and neural correlates of delusions in a large, well-characterised cohort of dementia patients using a transdiagnostic, cross-sectional approach. METHODS: Four-hundred and eighty-seven people with dementia were recruited: 102 Alzheimer's disease, 136 behavioural-variant frontotemporal dementia, 154 primary progressive aphasia, 29 motor neurone disease, 46 corticobasal syndrome, 20 progressive supranuclear palsy. All patients underwent neuropsychological assessment and brain magnetic resonance imaging, and the Neuropsychiatric Inventory was conducted with an informant, by an experienced clinician. RESULTS: In our cohort, 48/487 patients (10.8%) had delusions. A diagnosis of behavioural-variant frontotemporal dementia (18.4%) and Alzheimer's disease (11.8%) were associated with increased risk of delusions. A positive gene mutation was observed in 11/27 people with delusions. Individuals with frequent delusions performed worse on the Addenbrooke's Cognitive Examination (p = 0.035), particularly on the orientation/attention (p = 0.022) and memory (p = 0.013) subtests. Voxel-based morphometry analyses found that increased delusional psychopathology was associated with reduced integrity of the right middle frontal gyrus, right planum temporale and left anterior temporal pole. CONCLUSION: Our results demonstrate that delusions are relatively common in dementia and uncover a unique cognitive and neural profile associated with the manifestation of delusions. Clinically, delusions may lead to delayed or misdiagnosis. Our results shed light on how to identify individuals at risk of neuropsychiatric features of dementia, a crucial first step to enable targeted symptom management.

Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders.

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

Frontal variant of Alzheimer's disease masquerading as behavioural-variant frontotemporal dementia: a case study comparison.

The current clinical diagnostic criteria for Alzheimer's disease (AD) recognize an atypical, non-amnestic presentation of AD, characterized by prominent executive dysfunction. Increasing evidence, however, indicates that the clinical phenotype of this so-called "frontal-variant" of AD (fv-AD) includes behavioral symptoms and deficits in social cognition, together with disproportionate frontal lobe atrophy. As these features resemble those characteristic of behavioral-variant frontotemporal dementia (bvFTD), differential diagnosis can be challenging. Here, we report a case of fv-AD who met clinical diagnostic criteria bvFTD, but had in vivo amyloid neuroimaging evidence of AD pathology. We compare this case against two individuals who were clinically diagnosed with bvFTD and early-onset AD, with in vivo amyloid neuroimaging confirmation of pathology. We highlight the challenges in differential diagnosis by contrasting their behavioral, cognitive and structural neuroimaging findings.

Energy expenditure in frontotemporal dementia: a behavioural and imaging study.

SEE FINGER DOI101093/AWW312 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Abnormal eating behaviour and metabolic parameters including insulin resistance, dyslipidaemia and body mass index are increasingly recognized as important components of neurodegenerative disease and may contribute to survival. It has previously been established that behavioural variant frontotemporal dementia is associated with abnormal eating behaviour characterized by increased sweet preference. In this study, it was hypothesized that behavioural variant frontotemporal dementia might also be associated with altered energy expenditure. A cohort of 19 patients with behavioural variant frontotemporal dementia, 13 with Alzheimer's disease and 16 (age- and sex-matched) healthy control subjects were studied using Actiheart devices (CamNtech) to assess resting and stressed heart rate. Actiheart devices were fitted for 7 days to measure sleeping heart rate, activity levels, and resting, active and total energy expenditure. Using high resolution structural magnetic resonance imaging the neural correlates of increased resting heart rate were investigated including cortical thickness and region of interest analyses. In behavioural variant frontotemporal dementia, resting (P = 0.001), stressed (P = 0.037) and sleeping heart rate (P = 0.038) were increased compared to control subjects, and resting heart rate (P = 0.020) compared to Alzheimer disease patients. Behavioural variant frontotemporal dementia was associated with decreased activity levels compared to controls (P = 0.002) and increased resting energy expenditure (P = 0.045) and total energy expenditure (P = 0.035). Increased resting heart rate correlated with behavioural (Cambridge Behavioural Inventory) and cognitive measures (Addenbrooke's Cognitive Examination). Increased resting heart rate in behavioural variant frontotemporal dementia correlated with atrophy involving the mesial temporal cortex, insula, and amygdala, regions previously suggested to be involved exclusively in social and emotion processing in frontotemporal dementia. These neural correlates overlap the network involved in eating behaviour in frontotemporal dementia, suggesting a complex interaction between eating behaviour, autonomic function and energy homeostasis. As such the present study suggests that increased heart rate and autonomic changes are prevalent in behavioural variant frontotemporal dementia, and are associated with changes in energy expenditure. An understanding of these changes and neural correlates may have potential relevance to disease progression and prognosis.

On the right side? A longitudinal study of left- versus right-lateralized semantic dementia.

The typical presentation of semantic dementia is associated with marked, left predominant anterior temporal lobe atrophy and with changes in language. About 30% of individuals, however, present with predominant right anterior temporal lobe atrophy, usually accompanied by behavioural changes and prosopagnosia. Here, we aimed to establish whether these initially distinct clinical presentations evolve into a similar syndrome at the neural and behavioural level. Thirty-one patients who presented with predominant anterior temporal lobe atrophy were included. Based on imaging, patients were categorized as either predominant left (n = 22) or right (n = 9) semantic dementia. Thirty-three Alzheimer's disease patients and 25 healthy controls were included for comparison. Participants completed the Addenbrooke's Cognitive Examination, a Face and Emotion Processing Battery and the Cambridge Behavioural Inventory, and underwent magnetic resonance imaging annually. Longitudinal neuroimaging analyses showed greater right temporal pole atrophy in left semantic dementia than Alzheimer's disease, whereas right semantic dementia showed greater orbitofrontal and left temporal lobe atrophy than Alzheimer's disease. Importantly, direct comparisons between semantic dementia groups revealed that over time, left semantic dementia showed progressive thinning in the right temporal pole, whereas right semantic dementia showed thinning in the orbitofrontal cortex and anterior cingulate. Behaviourally, longitudinal analyses revealed that general cognition declined in all patients. In contrast, patients with left and right semantic dementia showed greater emotion recognition decline than Alzheimer's disease. In addition, left semantic dementia showed greater motivation loss than Alzheimer's disease. Correlational analyses revealed that emotion recognition was associated with right temporal pole, right medial orbitofrontal and right fusiform integrity, while changes in motivation were associated with right temporal pole cortical thinning. While left and right semantic dementia show distinct profiles at presentation, both phenotypes develop deficits in emotion recognition and behaviour. These findings highlight the pervasive socio-emotional deficits in frontotemporal dementia, even in patients with an initial language presentation. These changes reflect right anterior temporal and orbitofrontal cortex degeneration, underscoring the role of these regions in social cognition and behaviour.

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.

Cognitive and Behavioral Symptoms in ALSFTD: Detection, Differentiation, and Progression.

Brief screening tools that detect and differentiate patients with amyotrophic lateral sclerosis and frontotemporal dementia (ALSFTD) from those more subtle cognitive or behavioral symptoms (ALS plus) and motor symptoms only (ALS pure) is pertinent in a clinical setting. The utility of 2 validated and data-driven tests (Mini-Addenbrooke's Cognitive Examination [M-ACE] and Motor Neuron Disease Behavioral Scale [MiND-B]) was investigated in 70 ALS patients (24 ALSFTD, 19 ALS plus, and 27 ALS pure). More than 90% of patients with ALSFTD scored at or below the cutoff on the M-ACE, whereas this was seen in only about 20% of ALS patients without dementia. The MiND-B differentiated between ALS pure and ALS plus diagnostic categories. Rasch modeling of M-ACE and MiND-B items revealed early cognitive (fluency, memory recall) and behavioral (apathy) symptoms in ALSFTD. The combined use of the M-ACE and MiND-B detects patients with ALSFTD, differentiates along the ALS continuum, and offers insight into the progression of nonmotor symptomatology in ALSFTD.

Tracking the progression of social cognition in neurodegenerative disorders.

BACKGROUND AND PURPOSE: Behavioural-variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) patients experience behavioural and emotion recognition alterations, yet understanding of how socioemotional processing is affected with disease progression is minimal. Additionally, evidence suggests that bvFTD patients with limited brain atrophy on neuroimaging at presentation (bvFTD-la) have a more benign course than those with marked atrophy (bvFTD-ma). Longitudinal investigation of these patients, however, is lacking. METHODS: We investigated general cognition, emotion recognition and sarcasm detection in 20 bvFTD (8 with limited brain atrophy) and 17 AD patients longitudinally and used mixed models analyses to determine the level and rates of decline across groups over time. RESULTS: At baseline, all patient groups performed worse than controls on general cognition and emotion recognition measures. The bvFTD-ma group showed significant impairment on the sarcasm detection task compared with controls. Longitudinally, an overall effect of time was present for general cognition (p<0.001); however, the rate of decline did not differ across groups. Trends for interactions between time and diagnosis were observed for both emotion recognition tasks (p=0.055; p=0.062), with the bvFTD-ma group declining more rapidly than AD or bvFTD-la groups. On the sarcasm detection task, the bvFTD-ma and AD patients declined, whereas bvFTD-la patients remained stable over time (p=0.002). CONCLUSIONS: Tasks of sarcasm detection represent a clinically useful tool to differentiate between bvFTD and AD at baseline. Furthermore, tasks of socioemotional functioning can track progression within bvFTD and identify bvFTD patients more likely to show a faster rate of decline.

A systematic review of causes of sudden and severe headache (Thunderclap Headache): should lists be evidence based?

BACKGROUND: There are many potential causes of sudden and severe headache (thunderclap headache), the most important of which is aneurysmal subarachnoid haemorrhage. Published academic reviews report a wide range of causes. We sought to create a definitive list of causes, other than aneurysmal subarachnoid haemorrhage, using a systematic review. METHODS: Systematic Review of EMBASE and MEDLINE databases using pre-defined search criteria up to September 2009. We extracted data from any original research paper or case report describing a case of someone presenting with a sudden and severe headache, and summarized the published causes. RESULTS: Our search identified over 21,000 titles, of which 1224 articles were scrutinized in full. 213 articles described 2345 people with sudden and severe headache, and we identified 6 English language academic review articles. A total of 119 causes were identified, of which 46 (38%) were not mentioned in published academic review articles. Using capture-recapture analysis, we estimate that our search was 98% complete. There is only one population-based estimate of the incidence of sudden and severe headache at 43 cases per 100,000. In cohort studies, the most common causes identified were primary headaches or headaches of uncertain cause. Vasoconstriction syndromes are commonly mentioned in case reports or case series. The most common cause not mentioned in academic reviews was pneumocephalus. 70 non-English language articles were identified but these did not contain additional causes. CONCLUSIONS: There are over 100 different published causes of sudden and severe headache, other than aneurysmal subarachnoid haemorrhage. We have now made a definitive list of causes for future reference which we intend to maintain. There is a need for an up to date population based description of cause of sudden and severe headache as the modern epidemiology of thunderclap headache may require updating in the light of research on cerebral vasoconstriction syndromes.

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.

Recurrence risk of congenital malformations in infants exposed to antiepileptic drugs in utero.

PURPOSE: Use of antiepileptic drugs in pregnancy is associated with congenital malformations and developmental delay. Previous studies have suggested that women who have had one child with a congenital malformation are at increased risk of having other children with malformations. We sought to confirm the magnitude of risk in a large cohort drawn from the United Kingdom Epilepsy and Pregnancy Register. METHODS: The United Kingdom Epilepsy and Pregnancy Register is a prospective, observational registration and follow-up study set up to determine the relative safety of antiepileptic drugs in pregnancy. We have extracted data for those women who prospectively registered more than one pregnancy and calculated the recurrence risks for fetal malformations. KEY FINDINGS: Outcome data were available for 1,534 pregnancies born to 719 mothers. For women whose first child had a congenital malformation there was a 16.8% risk of having another child with a congenital malformation, compared with 9.8% for women whose first child did not have a malformation (relative risk 1.73, 95% confidence interval [CI] 1.01-2.96). The risk for recurrence was 50% for women who had had two previous children with a congenital malformation. There was a trend toward a higher risk for recurrent malformations in pregnancies exposed to valproate (21.9%, relative risk 1.47, 95% CI 0.68-3.20) and topiramate (50%, relative risk 4.50, 95% CI 0.97-20.82), but not for other drugs such as carbamazepine and lamotrigine. Recurrence risks were also higher for pregnancies exposed to polytherapy regimens and for those where the dose of antiepileptic drug treatment had been increased after the first pregnancy. SIGNIFICANCE: Women who have had a child with a malformation are at increased risk of having other children with malformations. This is in keeping with previous reports that have suggested that genetic influences may be one of the factors determining the teratogenic risk of antiepileptic drugs.

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.

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.

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.

Illness Cognitions in ALS: New Insights Into Clinical Management of Behavioural Symptoms.

Timely management of frontotemporal dysfunction associated with amyotrophic lateral sclerosis (ALS) has important prognostic and therapeutic implications. However, there remains a paucity of research on best practise recommendations to guide the development of interventions for cognitive and behavioural symptoms as part of ALS care. Accordingly, a focus on illness perceptions may provide a preliminary framework for managing cognitive and behavioural symptoms. The aim of the present study was to explore the nature of illness perceptions among ALS patients with cognitive and behavioural symptoms. A total of 39 patients were recruited from a specialised ALS clinic. Factor analysis showed three independent and clinically interpretable factors corresponding to "cognitive and emotion related ALS perceptions," "cognitive- specific ALS perceptions" and "ALS coherence". Of these factors, greater perceived cognitive and emotional impacts of ALS were associated with an approximate 4-fold increased risk of behavioural changes (p < 0.05). Greater perceived cognitive and emotional impacts of ALS was also associated with more rapid disease progression (p < 0.001). As such, timely provision of intervention addressing perceptions about the impact of ALS on functioning as well as associated emotional distress may optimise clinical management of cognitive and behavioural symptoms of ALS.