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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.

Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease typically presenting with bulbar or limb weakness. There is increasing evidence that amyotrophic lateral sclerosis is a multisystem disease with early and frequent impacts on cognition, behaviour, sleep, pain and fatigue. Dysfunction of normal physiological and metabolic processes also appears common. Evidence from pre-symptomatic studies and large epidemiological cohorts examining risk factors for the future development of amyotrophic lateral sclerosis have reported a high prevalence of changes in behaviour and mental health before the emergence of motor weakness. This suggests that changes beyond the motor system are underway at an early stage with dysfunction across brain networks regulating a variety of cognitive, behavioural and other homeostatic processes. The full impact of non-motor dysfunction continues to be established but there is now sufficient evidence that the presence of non-motor symptoms impacts overall survival in amyotrophic lateral sclerosis, and with up to 80% reporting non-motor symptoms, there is an urgent need to develop more robust therapeutic approaches. This review provides a contemporary overview of the pathobiology of non-motor dysfunction, offering readers a practical approach with regard to assessment and management. We review the current evidence for pharmacological and non-pharmacological treatment of non-motor dysfunction in amyotrophic lateral sclerosis and highlight the need to further integrate non-motor dysfunction as an important outcome measure for future clinical trial design.

Aims: To determine the underlying cellular changes and clinical correlates associated with pathology of the hypothalamus in amyotrophic lateral sclerosis (ALS), as hypothalamic atrophy occurs in the preclinical phase of the disease. Methods: The hypothalamus was pathologically examined in nine patients with amyotrophic lateral sclerosis in comparison to eight healthy control subjects. The severity of regional atrophy (paraventricular nucleus: PVN, fornix and total hypothalamus) and peptidergic neuronal loss (oxytocin, vasopressin, cocaine- and amphetamine-regulating transcript: CART, and orexin) was correlated with changes in eating behaviour, sleep function, cognition, behaviour and disease progression. Results: Tar DNA-binding protein 43 (TDP-43) inclusions were present in the hypothalamus of all patients with amyotrophic lateral sclerosis. When compared to controls, there was atrophy of the hypothalamus (average 21% atrophy, p = 0.004), PVN (average 30% atrophy p = 0.014) and a loss of paraventricular oxytocin-producing neurons (average 49% loss p = 0.02) and lateral hypothalamic orexin-producing neurons (average 37% loss, significance p = 0.02). Factor analysis identified strong relationships between abnormal eating behaviour, hypothalamic atrophy and loss of orexin-producing neurons. With increasing disease progression, abnormal sleep behaviour and cognition associated with atrophy of the fornix. Conclusions: Substantial loss of hypothalamic oxytocin-producing neurons occurs in ALS, with regional atrophy and the loss of orexin neurons relating to abnormal eating behaviour in ALS. Oxytocin- and orexin neurons display TDP43 inclusions. Our study points to significant pathology in the hypothalamus that may play a key role in metabolic and pathogenic changes in ALS. (Less)

ObjectiveTo 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).MethodsCognitive/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.ResultsIn 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.ConclusionsInitial 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.

Two common clinical variants of frontotemporal dementia (FTD) are the behavioural variant (bvFTD) presenting with behavioural and personality changes attributable to prefrontal atrophy, and semantic dementia (SD) 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, characterisation, and management of those affected. Here, we explored common cognitive-behavioural and neural mechanisms contributing to heterogeneous FTD 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 explore the neural basis of clinical heterogeneity. Sixty-two FTD patients (31 bvFTD, 31 SD) 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 bvFTD and SD. These factors included Behavioural changes, Semantic dysfunction, General Cognition, Executive function, Initiation, Disinhibition, Visuospatial function, and Affective changes. Marked individual-level overlap between bvFTD and SD was evident on the Behavioural changes, General Cognition, Initiation, Disinhibition, and Affective changes factors. Compared to bvFTD, SD patients displayed disproportionate impairment on the Semantic dysfunction factor, whereas greater impairment on Executive and Visuospatial function factors was noted in bvFTD. Both patient groups showed comparable magnitude of atrophy to frontal regions, whereas severe temporal lobe atrophy was characteristic of SD. 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 FTD, (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 FTD 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.

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., Ahmed et al.’s findings demonstrate the presence of distinct atrophy profiles across the ALS–FTD spectrum, with key structures including the motor cortex and insula. Subcortical involvement is likely the origin of behavioural disturbances, potentially accounting for the marked phenotypic variability typically observed across the ALS-FTD spectrum., Graphical Abstract Graphical Abstract

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.

Introduction: A spectrum of non-motor manifestations in amyotrophic lateral sclerosis (ALS) patients has been increasingly recognized, with cognitive and behavioral impairments the most prominent. Evidence suggests that ALS overlaps on a pathological, genetic, and clinical level with frontotemporal dementia (FTD), thereby suggesting a frontotemporal spectrum disorder (ALS-FTSD). Cognitive impairment has been reported in up to 75% of ALS patients, whilst the rate of behavioral dysfunction ranges up to 50%.Areas covered: The present review explores the current understanding of cognitive and behavioral changes in ALS with a particular emphasis on its implications on prognosis and survival.Expert commentary: Further longitudinal studies are needed to clarify the evolution of cognitive impairment in ALS and how this may ultimately influence survival. Improving understanding of cognitive changes has important implications toward the capacity of patients in making critical medical decisions. There is a need to develop a universally accepted and validated cognitive assessment tool to be administered in a multidisciplinary clinic that is efficient and sensitive, as well as being integrated into the design and analysis of future ALS drug trials. In addition, revision of the ALS diagnostic criteria is critically needed that should accommodate cognitive and behavioral symptoms in addition to motor manifestations.

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

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

Objective Late onset, unprovoked epilepsy patients with cognitive impairment can have complex pathophysiology.1 Our objective was to study the characteristics and contributors of cognitive impairment in this group; and how patients with dementia could be differentiated from late onset epilepsy patients. Methods Twenty-six patients with epilepsy, onset after 50 years of age, with new cognitive complaints and 26 patients with clinically diagnosed Alzheimer’s Disease (AD) were recruited. These participants had comprehensive neuropsychological and neuroimaging assessments. A subset of 17 participants from the Epilepsy group underwent longitudinal neuropsychological assessment. Results In the Epilepsy group, the neuropsychological profile of cognitive impairment was consistent with the foci and severity of seizure activity in 46% of participants; subcortical microvascular change in 15%; mood disturbance in 15%; medication in 15%; alcohol in 4% and AD in 4%. Compared with the Epilepsy group, the AD group had a lower Addenbrookes Cognitive Examination III (ACE-III) score (79.3±10.8 versus 87.5±6.5, p=0.01); specifically in the attention, memory and visuospatial subdomains (p=0.004, p=0.002 and p=0.02) but not fluency and language subdomains (p>0.05); and lower scores on additional assessments of naming, visuospatial and executive function (p≤ 0.001). The AD group had more abnormal metabolism in the temporal, parietal and occipital lobes than the Epilepsy group (p=0.02, p=0.006 and p=0.005). Conclusion Patients with late onset epilepsy and cognitive complaints rarely have dementia diagnosed at their first neuropsychological assessment and tend to have milder cognitive impairment than patients with AD. The two groups can be differentiated by their neuropsychological and FDG-PET profiles. Reference Sen A, Capelli V, Husain M. Cognition and dementia in older patients with epilepsy. Brain 2018;141(6):1592–1608.

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.

Objective: Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder which includes cognitive and behavioral symptoms akin to frontotemporal dementia (FTD). Despite the necessity of caregiver intervention to assist with the management of cognitive and behavioral symptoms, there has been a lack of research on the topic. A focus on caregiver coping may offer a promising foundation to guide the development of interventions as part of ALS care. Accordingly, the aim of the present study was to examine the relationships between caregiver coping, psychological morbidity and burden of care in the context of ALS cognitive and behavioral symptoms. Methods: Fifty-five patient-caregiver dyads were recruited from specialized ALS and FTD clinics. Specific coping strategies were examined using the COPE Inventory/Brief COPE and psychological morbidity and burden were assessed using the Depression, Anxiety, and Stress Scale–21 and Zarit Burden Interview. The relationship between coping, psychological morbidity and burden of care were analyzed using univariate and multivariate methods. Results: High-burden caregivers were more likely to be caring for patients with a diagnosis of ALS-FTD (p =.0001). Caregivers used problem-focused strategies (particularly planning) more frequently (M = 71.4, SD = 15.3) compared to emotion-focused (M = 60.8, SD = 12.3) and dysfunctional coping strategies (M = 42.2, SD = 8.6). A diagnosis of ALS-FTD (p=.0001) and problem-focused strategies (p=.024) emerged as significant predictors of caregiver burden. Caregiver anxiety, depression and stress were not predictive of caregiver burden (p=.151). Conclusions: Timely provision of caregiver support optimizing problem-focused coping strategies as part of multidisciplinary ALS care, particularly for caregivers of ALS-FTD patients may mitigate caregiver burden.

We thank Dr. Abe for his interest in our study1 that investigated survival in patients with amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Specific comparison of motor and cognitive presentations in ALS-FTD established that patients with a motor onset of their disease had reduced survival—which was associated with increased motor cortex atrophy—suggesting that survival may be mediated by motor function and other critical physiologic aspects.

Funder: Royal Australasian College of Physicians; Id: http://dx.doi.org/10.13039/501100001232, Funder: MND Research Institute of Australia; Id: http://dx.doi.org/10.13039/100008714, Funder: Australian Research Council Future Fellowship; Id: http://dx.doi.org/10.13039/501100000923, OBJECTIVE: Alterations in eating behaviour are one of the diagnostic features of behavioural variant frontotemporal dementia (bvFTD). It is hypothesised that underlying brain network disturbances and atrophy to key structures may affect macronutrient preference in bvFTD. We aimed to establish whether a preference for dietary fat exists in bvFTD, its association with cognitive symptoms and the underlying neural mechanisms driving these changes. METHODS: Using a test meal paradigm, adapted from the obesity literature, with variable fat content (low 20%, medium 40% and high 60%), preference for fat in 20 bvFTD was compared to 16 Alzheimer's disease (AD) and 13 control participants. MRI brain scans were analysed to determine the neural correlates of fat preference. RESULTS: Behavioural variant FTD patients preferred the high-fat meal compared to both AD (U = 61.5; p = 0.001) and controls (U = 41.5; p = 0.001), with 85% of bvFTD participants consistently rating the high-fat content meal as their preferred option. This increased preference for the high-fat meal was associated with total behavioural change (Cambridge Behavioural Inventory: rs = 0.462; p = 0.001), as well as overall functional decline (Frontotemporal Dementia Rating Scale: rs = -0.420; p = 0.03). A preference for high-fat content in bvFTD was associated with atrophy in an extended brain network including frontopolar, anterior cingulate, insular cortices, putamen and amygdala extending into lateral temporal, posteromedial parietal and occipital cortices. CONCLUSIONS: Increased preference for fat content is associated with many of the canonical features of bvFTD. These findings offer new insights into markers of disease progression and pathogenesis, providing potential treatment targets.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are well-recognised as an extended disease spectrum. This study hypothesised that cortical hyperexcitability, an early pathophysiological abnormality in ALS, would distinguish cognitive phenotypes, as a surrogate marker of pathological disease burden. 61 patients with ALS, matched for disease duration (pure motor ALS, n = 39; ALS with coexistent FTD, ALS-FTD, n = 12; ALS with cognitive/behavioural abnormalities not meeting FTD criteria, ALS-Cog, n = 10) and 30 age-matched healthy controls. Cognitive function on the Addenbrooke’s cognitive examination (ACE) scale, behavioural function on the motor neuron disease behavior scale (MiND-B) and cortical excitability using transcranial magnetic stimulation (TMS) were documented. Cortical resting motor threshold (RMT), lower threshold indicating hyperexcitability, was lower in ALS-FTD (50.2 ± 6.9) compared to controls (64.3 ± 12.6, p

Frontotemporal dementia (FTD) has traditionally been regarded as a disease of cognition and behavior, but emerging evidence suggests that the disease also affects body functions including changes in eating behavior and metabolism, autonomic function, sleep behavior, and sexual function. Central to these changes are potentially complex neural networks involving the hypothalamus, with hypothalamic atrophy shown in behavioral variant FTD. The physiological changes found in FTD are reviewed and the key neural networks and neuroendocrine changes mediating these changes in function discussed, including the ability to use these changes as biomarkers to aid in disease diagnosis, monitoring disease progression, and as potential treatment targets.

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder. While initially pathophysiology was thought to be restricted to motor deficits, it is increasingly recognized that patients develop prominent changes in weight and eating behavior that result from and mediate the underlying neurodegenerative process. These changes include alterations in metabolism, lipid levels, and insulin resistance. Emerging research suggests that these alterations may be mediated through changes in the hypothalamic function, with atrophy of the hypothalamus shown in both ALS patients and also presymptomatic genetic at-risk patients. This chapter reviews the evidence for hypothalamic involvement in ALS, including melanocortin pathways and potential treatment targets.

After decades of research, large-scale clinical trials in patients diagnosed with frontotemporal lobar degeneration (FTLD) are now underway across multiple centres worldwide. As such, refining the determinants of survival in FTLD represents a timely and important challenge. Specifically, disease outcome measures need greater clarity of definition to enable accurate tracking of therapeutic interventions in both clinical and research settings. Multiple factors potentially determine survival, including the clinical phenotype at presentation; radiological patterns of atrophy including markers on both structural and functional imaging; metabolic factors including eating behaviour and lipid metabolism; biomarkers including both serum and cerebrospinal fluid markers of underlying pathology; as well as genetic factors, including both dominantly inherited genes, but also genetic modifiers. The present review synthesises the effect of these factors on disease survival across the syndromes of frontotemporal dementia, with comparison to amyotrophic lateral sclerosis, progressive supranuclear palsy and corticobasal syndrome. A pathway is presented that outlines the utility of these varied survival factors for future clinical trials and drug development. Given the complexity of the FTLD spectrum, it seems unlikely that any single factor may predict overall survival in individual patients, further suggesting that a precision medicine approach will need to be developed in predicting disease survival in FTLD, to enhance drug target development and future clinical trial methodologies.

Objective Physiological changes potentially influence disease progression and survival along the Amyotrophic Lateral Sclerosis (ALS)‐Frontotemporal dementia (FTD) spectrum. The peripheral peptides that regulate eating and metabolism may provide diagnostic, metabolic, and progression biomarkers. The current study aimed to examine the relationships and biomarker potential of hormonal peptides. Methods One hundred and twenty‐seven participants (36 ALS, 26 ALS‐ cognitive, patients with additional cognitive behavioral features, and 35 behavioral variant FTD (bvFTD) and 30 controls) underwent fasting blood analyses of leptin, ghrelin, neuropeptide Y (NPY), peptide YY (PYY), and insulin levels. Relationships between endocrine measures, cognition, eating behaviors, and body mass index (BMI) were investigated. Biomarker potential was evaluated using multinomial logistic regression for diagnosis and correlation to disease duration. Results Compared to controls, ALS and ALS‐cognitive had higher NPY levels and bvFTD had lower NPY levels, while leptin levels were increased in all patient groups. All groups had increased insulin levels and a state of insulin resistance compared to controls. Lower NPY levels correlated with increasing eating behavioral change and BMI, while leptin levels correlated with BMI. On multinomial logistic regression, NPY and leptin levels were found to differentiate between diagnosis. Reduced Neuropeptide Y levels correlated with increasing disease duration, suggesting it may be useful as a potential marker of disease progression. Interpretation ALS‐FTD is characterized by changes in NPY and leptin levels that may impact on the underlying regional neurodegeneration as they were predictive of diagnosis and disease duration, offering the potential as biomarkers and for the development of interventional treatments.

BACKGROUND AND PURPOSE Predicting the course of behavioural variant frontotemporal dementia (bvFTD) remains a major clinical challenge. This study aimed to identify factors that predict survival and clinical progression in bvFTD. METHODS Consecutive patients with clinically probable bvFTD were prospectively followed up over an 8-year period. Baseline neuropsychological variables, presence of a known pathogenic frontotemporal dementia gene mutation and a systematic visual magnetic resonance imaging assessment at baseline were examined as candidate predictors using multivariate modelling. RESULTS After screening 121 cases, the study cohort consisted of 75 patients with probable bvFTD, with a mean age of 60.8 ± 8.5 years, followed up for a mean duration of 7.2 ± 3.5 years from symptom onset. Median survival time from disease onset was 10.8 years and median survival, prior to transition to nursing home, was 8.9 years. A total of 25 of the 75 patients died during the study follow-up period. Survival without dependence was predicted by shorter disease duration at presentation (hazard ratio, 0.49, P = 0.001), greater atrophy in the anterior cingulate cortex (hazard ratio, 1.75, P = 0.047), older age (hazard ratio, 1.07, P = 0.026) and a higher burden of behavioural symptoms (hazard ratio, 1.04, P = 0.015). In terms of disease progression, presence of a known pathogenic frontotemporal dementia mutation (β = 0.46, P

Mounting evidence suggests an association between cerebellar atrophy and cognitive impairment in the main frontotemporal dementia syndromes. In contrast, whether cerebellar atrophy is present in the motor syndromes associated with frontotemporal lobar degeneration (corticobasal syndrome and progressive supranuclear palsy) and the extent of its contribution to their cognitive profile remain poorly understood. The current study aimed to comprehensively chart profiles of cognitive impairment in relation to cerebellar atrophy in 49 dementia patients (corticobasal syndrome = 33; progressive supranuclear palsy = 16) compared to 33 age-, sex- and education-matched healthy controls. Relative to controls, corticobasal syndrome and progressive supranuclear palsy patients demonstrated characteristic cognitive impairment, spanning the majority of cognitive domains including attention and processing speed, language, working memory, and executive function with relative preservation of verbal and nonverbal memory. Voxel-based morphometry analysis revealed largely overlapping patterns of cerebellar atrophy in corticobasal syndrome and progressive supranuclear palsy relative to controls, primarily involving bilateral Crus II extending into adjacent lobules VIIb and VIIIa. After controlling for overall cerebral atrophy and disease duration, exploratory voxel-wise general linear model analysis revealed distinct cerebellar subregions differentially implicated across cognitive domains in each patient group. In corticobasal syndrome, reduction in grey matter intensity in the left Crus I was significantly correlated with executive dysfunction. In progressive supranuclear palsy, integrity of the vermis and adjacent right lobules I–IV was significantly associated with language performance. These results are consistent with the well-established role of Crus I in executive functions and provide further supporting evidence for vermal involvement in cognitive processing. The current study presents the first detailed exploration of the role of cerebellar atrophy in cognitive deficits in corticobasal syndrome and progressive supranuclear palsy, offering insights into the cerebellum’s contribution to cognitive processing even in neurodegenerative syndromes characterized by motor impairment., Voxel-based morphometry analysis revealed that cerebellar atrophy in the left Crus I was correlated with executive dysfunction in corticobasal syndrome, whereas the vermis and adjacent right lobules I–IV were associated with language performance in progressive supranuclear palsy, demonstrating cerebellar contributions to cognition even in neurodegenerative syndromes characterized by motor impairment., Graphical Abstract Graphical Abstract

Adult-onset leukodystrophies and genetic leukoencephalopathies comprise a diverse group of neurodegenerative disorders of white matter with a wide age of onset and phenotypic spectrum. Patients with white matter abnormalities detected on MRI often present a diagnostic challenge to both general and specialist neurologists. Patients typically present with a progressive syndrome including various combinations of cognitive impairment, movement disorders, ataxia and upper motor neuron signs. There are a number of important and treatable acquired causes for this imaging and clinical presentation. There are also a very large number of genetic causes which due to their relative rarity and sometimes variable and overlapping presentations can be difficult to diagnose. In this review, we provide a structured approach to the diagnosis of inherited disorders of white matter in adults. We describe clinical and radiological clues to aid diagnosis, and we present an overview of both common and rare genetic white matter disorders. We provide advice on testing for acquired causes, on excluding small vessel disease mimics, and detailed advice on metabolic and genetic testing available to the practising neurologist. Common genetic leukoencephalopathies discussed in detail includeCSF1R,AARS2, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and mitochondrial and metabolic disorders.

ObjectiveThe 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.MethodsA 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.ResultsA 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).ConclusionOverall, 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 effects of neurodegenerative syndromes extend beyond cognitive function to involve key physiological processes, including eating and metabolism, autonomic nervous system function, sleep, and motor function. Changes in these physiological processes are present in several conditions, including frontotemporal dementia, amyotrophic lateral sclerosis, Alzheimer disease and the parkinsonian plus conditions. Key neural structures that mediate physiological changes across these conditions include neuroendocrine and hypothalamic pathways, reward pathways, motor systems and the autonomic nervous system. In this Review, we highlight the key changes in physiological processing in neurodegenerative syndromes and the similarities in these changes between different progressive neurodegenerative brain conditions. The changes and similarities between disorders might provide novel insights into the human neural correlates of physiological functioning. Given the evidence that physiological changes can arise early in the neurodegenerative process, these changes could provide biomarkers to aid in the early diagnosis of neurodegenerative diseases and in treatment trials.

BACKGROUND Patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) exhibit changes in eating behavior that could potentially affect lipid levels. OBJECTIVE This study aimed to document changes in lipid metabolism across the ALS-FTD spectrum to identify potential relationships to eating behavior (including fat intake), cognitive change, body mass index (BMI), and effect on survival. METHODS One hundred and twenty-eight participants were recruited: 37 ALS patients, 15 ALS patients with cognitive and behavioral change (ALS-Plus), 13 ALS-FTD, 31 behavioral variant FTD, and 32 healthy controls. Fasting total cholesterol, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL) and triglyceride levels were measured and correlated to eating behavior (caloric, fat intake), cognitive change, and BMI; effect on survival was examined using cox regression analyses. RESULTS There was a spectrum of lipid changes from ALS to FTD with increased triglyceride (p

Sleep disorders in amyotrophic lateral sclerosis (ALS) present a significant challenge to the management of patients. Issues include the maintenance of adequate ventilatory status through techniques such as non-invasive ventilation, which has the ability to modulate survival and improve patient quality of life. Here, a multidisciplinary approach to the management of these disorders is reviewed, from concepts about the underlying neurobiological basis, through to current management approaches and future directions for research.

Frontotemporal dementia (FTD) is a common cause of early onset dementia with behavioral variant FTD (bvFTD) being the most common form. bvFTD is characterized clinically by behavioral and personality changes, eating abnormalities, and pathologically, by systemic lipid dysregulation that impacts on survival. As lipoprotein metabolism is at the core of lipid dysregulation, here, we analyzed the composition, both proteins and lipids, of the two major lipoprotein classes in blood - high density lipoproteins (HDLs) and low density lipoproteins (LDLs). Fasted plasmas from bvFTD and Alzheimer's disease (AD) patients and controls were fractionated using fast protein liquid chromatography (FPLC) and samples analyzed by lipid assays, ELISA and western blotting. We found that apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II) levels in HDLs were decreased in bvFTD compared to controls, whereas apolipoprotein B (apoB) levels in LDLs were unaltered. We also found that cholesterol and triglyceride levels in FPLC fractions were altered in bvFTD compared to controls. The apoB:apoA-I ratio and the standard lipid ratios were significantly increased in bvFTD compared to AD and controls. Furthermore, we found that plasma apolipoprotein C-I and paraoxonase 1 levels were significantly altered in bvFTD and AD, respectively, compared controls. This study represents the first apolipoprotein analysis of bvFTD, and our results suggest altered HDL function and elevated cardiovascular disease risk in bvFTD.

Amyotrophic lateral sclerosis (ALS) is a disease of paradoxes. Patients usually have little or no medical history and tend to be fit and athletic,1 2 yet undergo a rapid, unrelenting decline. Patients predominantly present with progressive weakness, with involvement of cortical motor neurons and as the disease progresses, patients develop denervation, muscle atrophy, decreased muscle mass and decreased free fat mass, all of which would be expected to decrease energy expenditure.3 Yet patients with ALS are consistently hypermetabolic, with increased resting energy expenditure evident in up to 50% of patients.4 Several variables have been hypothesised to contribute to this hypermetabolic state, including uncontrolled fasciculations, increased respiratory work and mitochondrial dysfunction,4 yet the exact mechanism remains to be elucidated. In their JNNP paper Steyn and colleagues5 aim to …

Objectives:The Addenbrooke’s Cognitive Examination (ACE) is a common cognitive screening test for dementia. Here, we examined the relationship between the most recent version (ACE-III) and its predecessor (ACE-R), determined ACE-III cutoff scores for the detection of dementia, and explored its relationship with functional ability.Methods:Study 1 included 199 dementia patients and 52 healthy controls who completed the ACE-III and ACE-R. ACE-III total and domain scores were regressed on their corresponding ACE-R values to obtain conversion formulae. Study 2 included 331 mixed dementia patients and 87 controls to establish the optimal ACE-III cutoff scores for the detection of dementia using receiver operator curve analysis. Study 3 included 194 dementia patients and their carers to investigate the relationship between ACE-III total score and functional ability.Results:Study 1: ACE-III and ACE-R scores differed by ≤1 point overall, the magnitude varying according to dementia type. Study 2: a new lower bound cutoff ACE-III score of 84/100 to detect dementia was identified (compared with 82 for the ACE-R). The upper bound cutoff score of 88/100 was retained. Study 3: ACE-III scores were significantly related to functional ability on the Clinical Dementia Rating Scale across all dementia syndromes, except for semantic dementia.Conclusions:This study represents one of the largest and most clinically diverse investigations of the ACE-III. Our results demonstrate that the ACE-III is an acceptable alternative to the ACE-R. In addition, ACE-III performance has broader clinical implications in that it relates to carer reports of functional impairment in most common dementias. (JINS, 2018,24, 854–863)

To investigate whether primary lateral sclerosis (PLS) represents part of the amyotrophic lateral sclerosis–frontotemporal dementia (ALS–FTD) spectrum of diseases. Comprehensive assessment was taken on 21 patients with PLS and results were compared to patients diagnosed with pure motor ALS (n = 27) and ALS–FTD (n = 12). Clinical features, Addenbrooke’s Cognitive Examination (ACE) scores, Motor Neuron Disease Behaviour (Mind-B) scores, motor disability on the ALS functional rating scale (ALSFRS) and survival times were documented. Motor cortex excitability was evaluated using transcranial magnetic stimulation (TMS). Global cognition was impaired in PLS (mean total ACE score 82.5 ± 13.6), similar to ALS–FTD (mean total ACE score 76.3 ± 7.7, p > 0.05) while behavioural impairments were not prominent. TMS revealed that resting motor threshold (RMT) was significantly higher in PLS (75.5 ± 6.2) compared ALS–FTD (50.1 ± 7.2, p

Background: Apathy is the most commonly reported behavioural change in amyotrophic lateral sclerosis (ALS). However, the degree to which it affects prognosis and overlaps with depression in this population is unknown. The present study examined the relationship between level of apathy, mortality and survival time and whether apathy was linked to specific symptom clusters of depression. Methods: A cohort of 76 consecutive ALS patients attending specialised multidisciplinary clinics were classified according to level of apathy. The effect of clinical factors and apathy on survival time were analysed using univariate and multivariate methods. Results: The majority of patients with moderate-severe apathy died during the study (P = 0.003) and had a median survival time of 21.7 months, considerably shorter than patients with mild apathy (46.9 months) and no apathy (51.9 months) (P = 0.0001). Apathy remained a significant predictor of survival even after controlling for clinical factors and symptom duration at the time of study entry (hazard ratio 3.8, 95% confidence interval 1.9-7.5, P = 0.0001). Depression with demoralisation was not associated with level of apathy (P = 0.172) whereas depression with anhedonia was more common in patients with apathy than in those without apathy (P = 0.006). Conclusions: The presence of severe apathy is an independent, negative prognostic factor in ALS.

Behavioral variant frontotemporal dementia (bvFTD) is the most prevalent form of FTD syndromes. bvFTD is characterized clinically by changes in behavior and cognition and pathologically by focal brain atrophy and concomitant loss of lipids. bvFTD is further characterized by eating abnormalities that result in dyslipidemia. Although dyslipidemia is apparent in bvFTD, very little is known about global lipid changes in bvFTD and lipid dysregulation underlying bvFTD. Here, we undertook a comprehensive lipidomics analysis of blood plasma from patients with bvFTD, patients with Alzheimer’s disease (AD) and controls, using liquid chromatography-tandem mass spectrometry, with the aim of understanding lipid dysregulation in bvFTD. In our analysis, we detected all four major classes of lipids (glycerolipids, phospholipids, sphingolipids, sterols), 17 subclasses of lipids, and 3,225 putative individual lipid species in total, as well as a group of dietary lipids. We found that the levels of numerous lipid species were significantly altered in bvFTD compared to AD and control. We found that the total abundance of triglyceride (TG) increased significantly in bvFTD, whereas phosphatidylserine and phosphatidylglycerol decreased significantly in bvFTD. These results suggest manifestation of hypertriglyceridemia and hypoalphalipoproteinemia in bvFTD. We also identified five lipid molecules—TG (16:0/16:0/16:0), diglyceride (18:1/22:0), phosphatidylcholine (32:0), phosphatidylserine (41:5), and sphingomyelin (36:4)—that could potentially be used for developing biomarkers for bvFTD. Furthermore, an analysis of plant lipids revealed significant decreases in monogalactosyldiacylglycerol and sitosteryl ester in bvFTD, indicating altered eating behavior in bvFTD. This study represents the first lipidomics analysis of bvFTD and has provided new insights into an unrecognized perturbed pathology in bvFTD, providing evidence in support of considerable lipid dysregulation in bvFTD.

Objectives: Apathy is the most common behavioral symptom of amyotrophic lateral sclerosis (ALS). Despite its known impact on caregiver wellbeing, apathy is typically considered a unitary construct making assessment and targeting treatment problematic. The aim of this study was to explore the relationship between caregiver burden and the behavioral, cognitive, and emotional symptoms of apathy in ALS. Methods: Fifty-one ALS patient-caregiver dyads from an ALS/frontotemporal dementia Clinic were assessed with the Apathy Evaluation Scale which measured the cognitive, behavioral, emotional, and nonspecific symptoms of apathy as well as the Zarit Burden Interview, a measure of perceived burden among caregivers of cognitively impaired older adults. The relationship between apathy and caregiver burden were analyzed using univariate and multivariate methods. Results: Apathy was identified in 18% of ALS patients. Greater behavioral (p = 0.011) and nonspecific (p = 0.010) symptoms of apathy exhibited by patients were reported by caregivers with higher levels of burden compared to caregivers with lower levels of burden. Of the cognitive, behavioral, emotional, and nonspecific symptoms of apathy, only the behavioral symptoms explained a significant amount of variance in caregiver burden (p = 0.031). Conclusions: Apathy, specifically the behavioral symptoms of apathy was associated with higher burden of care among ALS caregivers, highlighting the importance of multidimensional assessment of apathy and provision of behavior management support as part of ALS care.

Apathy is one of the most common behavioural symptoms of amyotrophic lateral sclerosis (ALS), yet there are few studies that have investigated the relationship between apathy and quality of life (QOL) as they are experienced by the patient. A cohort of 60 ALS patients were evaluated using the Apathy Evaluation Scale which measured cognitive, behavioural, emotional and non-specific symptoms of apathy combined with the Personal Wellbeing Index, a multidimensional measure of QOL. The relationship between patient-rated apathy and QOL scores, controlling for potential clinical and psychological confounders were analysed using univariate and multivariate methods. Apathy was identified in 30% of ALS patients. Patients with apathy reported higher levels of depression (p = 0.0001). Compared to non-apathetic patients, patients with apathy had lower overall QOL (p = 0.001), most pronounced in the domains related to achievements in life (p = 0.001) and community-connectedness (p = 0.0001). Of the cognitive, behavioural, emotional and non-specific manifestations of apathy, only the emotional symptoms explained a significant amount of variance in achievements in life (p = 0.003) and community-connectedness (p = 0.001). As such, emotional manifestations of apathy may underlie worse QOL in ALS patients presenting with behavioural impairment. Patient-reported outcomes, particularly those assessing psychosocial functioning may be important for demonstrating the efficacy of interventions designed to improve QOL in ALS patients with behavioural impairment.

IntroductionWith approximately 200 procedures performed in the last year at our centre, worthwhile clinical lessons continue to emerge in the practice of endovascular clot retrieval (ECR) for acute stroke. This case demonstrates the value of considered clinical appraisal in a dynamic, information-rich setting. A 68 year-old man with established vertebrobasilar atherosclerotic disease developed capricious, blood pressure-sensitive neurological deficits after successful ECR for a basilar artery stroke, inviting the possibility of further intervention in the form of intracranial stenting. We avoided pursuing this course of action in favour of a more measured approach, entailing the provision of vasopressor support over the following week.MethodFollowing ECR, our patient was admitted to the intensive care unit for continuous blood pressure monitoring and close observation of his neurological deficits with serial NIHSS (National Institutes of Health Stroke Scale) scoring. Systolic blood pressures were maintained between 140–160 mmHg using vasopressor support, with the aim of allowing time for recovery of vascular autoregulation and collateralization.ResultsOver six days, the patient developed moderate left upper and lower limb weakness. An MRI performed on Day 5 revealed limited interval infarction of the right hemipons and cerebellum, with complete re-occlusion of the mid-basilar arterial segment. He left the ICU with a NIHSS score of 7, and was living independently at 90-day follow-up (Modified Rankin Score 1).ConclusionThe ultimately favourable net outcome for our patient clearly illustrates the imperative to remain within the boundaries of evidence-based practice in this bold and rapidly evolving discipline.

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

BACKGROUND AND PURPOSE: Transverse sinus venous stent placement has been shown to lower intracranial pressure in patients with venogenic pseudotumor cerebri and to reverse, or at least stabilize, its symptoms and signs. There have been no studies comparing the cost of venous stenting with the time-honored treatment for pseudotumor cerebri–CSF shunting. The purpose of this study was to compare the cost of trasverse sinus stenting versus CSF shunting for the treatment of pseudotumor cerebri. MATERIALS AND METHODS: This work was a retrospective cost analysis of individual resource use in 86 adults who were stented for pseudotumor cerebri during a 12-year period compared with resource use in 110 children who were shunted for hydrocephalus during a 3-year period. RESULTS: There was no significant difference between the cost of inserting an initial venous stent ($13,863 ± 4890) versus inserting an initial CSF shunt ($15,797 ± 5442) ( P = .6337) or between inserting an additional venous stent ($9421 ± 69) versus revising a CSF shunt ($10,470 ± 1245) ( P = .4996). There were far fewer additional venous stent insertions per patient than there were subsequent CSF shunt revisions; 87% of stents placed required just 1 stent procedure, whereas only 45% of shunts required 1 shunt procedure. The main cause of the cost difference was the need for repeated revisions of the shunts, especially when they became infected—24 instances of a total 143 shunt procedures (16.8%) at an average cost of $84,729, approximately 5 times the cost of an initial shunt insertion. CONCLUSIONS: Venous stenting costs significantly less per 100 procedures than does CSF shunting, due largely to the high cost of treating shunt infections and the need for repeated shunt revisions.

We describe 2 patients with inexorably progressive pseudotumor syndrome (intracranial hypertension without mass lesion or ventriculomegaly) both initially misdiagnosed as having idiopathic intracranial hypertension and who were eventually found to have spinal leptomeningeal lymphoma. Neither had, at any time, any clinical signs of a spinal cord or root lesion. We discuss the possible implications of these observations regarding the diagnosis and mechanism of the pseudotumor syndrome.

Background Invasive fungal sinusitis is a rare condition that usually occurs in immunocompromised patients and often presents as an orbital apex syndrome. It is frequently misdiagnosed on presentation and is almost always lethal without early treatment. Design Retrospective case series of 14 consecutive patients with biopsy-proven invasive fungal sinusitis from four tertiary hospitals. Participants Fourteen patients (10 men and 4 women; age range 46–82 years). Methods Retrospective chart review of all patients presenting with invasive fungal sinusitis between 1994 and 2010 at each hospital, with a close analysis of the tempo of the disease to identify any potential window of opportunity for treatment. Main Outcome Measures Demographic data, background medical history (including predisposing factors), symptoms, signs, radiological findings, histopathological findings, treatment approach and subsequent clinical course were recorded and analysed. Results Only one patient was correctly diagnosed at presentation. Only two patients were not diabetic or immunocompromised. The tempo was acute in two patients, subacute in nine patients and chronic in three patients. In the subacute and chronic cases, there was about 1 week of opportunity for treatment, from the time there was a complete orbital apex syndrome, and still a chance for saving the patient, to the time there was central nervous system invasion, which was invariably fatal. Only two patients survived – both had orbital exenteration, as well as antifungal drug treatment. Conclusions Invasive fungal sinusitis can, rarely, occur in healthy individuals and should be suspected as a possible cause of a progressive orbital apex syndrome.

Introduction Patients diagnosed with amyotrophic lateral sclerosis (ALS) generally have a limited medical history and a normal body mass index, raising the possibility of a premorbid ALS phenotype. Methods The prevalence of cardiometabolic factors was analyzed in 58 ALS patients via comprehensive cardiovascular assessments and compared with Australian population norms. Results ALS patients had good cardiac fitness and no reported cardiovascular events. Average blood pressure, heart rate, PR interval, and corrected QT interval were in the normal range. There were significantly fewer obese women in the ALS cohort (13.6%, P

Objective:To report the outcome of posterior semicircular canal occlusion surgery for intractable benign positional vertigo, regarding vertigo cure rate and hearing and balance outcomes.Methods:Retrospective review of 53 patients presenting with benign positional vertigo, unresponsive to repositioning manoeuvres, who eventually underwent posterior canal occlusion, over a 20 year period.Results:From 1991 to 2011, 5364 benign positional vertigo patients were treated in our balance disorders clinic; 53 of those who failed to respond to repositioning underwent posterior canal occlusion. All 53 were cured of their benign positional vertigo. Nine suffered some symptomatic permanent hearing loss (>20 dB at low and >25 dB at high frequencies). Ten patients suffered caloric vestibular function deterioration, with mild but permanent subjective imbalance in five; a further 10 patients with no post-operative caloric test changes also had some permanent imbalance. Benign positional vertigo later developed in the operated ear lateral canal in two patients and in the opposite ear posterior canal in eight patients. Two patients needed bilateral sequential posterior canal occlusion.Conclusion:Posterior canal occlusion is a highly effective treatment for intractable benign positional vertigo, with what is probably an acceptable risk to hearing and balance: five of six patients will have no hearing problem and nine of 10 no balance problem after surgery.

We reviewed retrospectively the outcomes of interventional endovascular treatment of direct or dural (indirect) carotid cavernous fistulas in 24 consecutive patients requiring endovascular treatment at Royal Prince Alfred Hospital between 1994 and 2009. Data was collected from each patient’s neurological, ophthalmological and radiological reports. Of the 12 patients with direct fistulas all had signs of orbital and ocular venous congestion and ophthalmoplegia; nine also had reduced vision ranging from 6/9 to nil perception of light, two had normal vision and one was unconscious. Nine of the 12 direct fistulas were embolized transarterially, two transvenously, one by a combination of both approaches and all were successfully closed. After treatment, seven of the nine patients with reduced vision had complete or nearly complete restoration of vision, while two who presented with nil perception of light (one in both eyes) had no recovery of vision. In contrast, seven of the 12 patients with dural fistulas had ophthalmoplegia, three had reduced vision, down to 6/24 and one did not have any sign of venous congestion. Vision recovered in all three patients after embolization of the dural fistula. Dural fistulas were embolized transvenously in 11 and transarterially in one patient. Apart from ophthalmoplegia, all other ocular signs and symptoms rapidly resolved after closure of the fistula in each of the 24 patients. The diagnosis was delayed by being missed either during the first admission or at the first specialist consultation in three of the 12 patients with direct fistulas, and in seven of the 12 patients with dural fistulas. One patient with a direct and another with a dural fistula had limited cerebral infarctions during embolization. In this series, endovascular interventional treatment of carotid cavenous fistulas restored visual loss in 10 of 12 patients with visual loss. The two who did not recover had presented with nil perception of light, one after a delay in diagnosis of 6 weeks. Some degree of ophthalmoplegia tended to remain. This emphasizes the need for early diagnosis and treatment before visual loss or ophthalmoplegia becomes severe.

BACKGROUND AND PURPOSE: Transverse sinus stenosis is common in patients with IIH. While the role of transverse sinus stenosis in IIH pathogenesis remains controversial, modeling studies suggest that stent placement within a transverse sinus stenosis with a significant pressure gradient should decrease cerebral venous pressure, improve CSF resorption in the venous system, and thereby reduce intracranial (CSF) pressure, improving the symptoms of IIH and reducing papilledema. We aimed to determine if IIH could be reliably treated by stent placement in transverse sinus stenosis. MATERIALS AND METHODS: We reviewed the clinical, venographic, and intracranial pressure data before and after stent placement in transverse sinus stenosis in 52 of our own patients with IIH unresponsive to maximum acceptable medical treatment, treated since 2001 and followed between 2 months and 9 years. RESULTS: Before stent placement, the mean superior sagittal sinus pressure was 34 mm Hg (462 mm H20) with a mean transverse sinus stenosis gradient of 20 mm Hg. The mean lumbar CSF pressure before stent placement was 322 mm H2O. In all 52 patients, stent placement immediately eliminated the TSS pressure gradient, rapidly improved IIH symptoms, and abolished papilledema. In 6 patients, symptom relapse (headache) was associated with increased venous pressure and recurrent stenosis adjacent to the previous stent. In these cases, placement of another stent again removed the transverse sinus stenosis pressure gradient and improved symptoms. Of the 52 patients, 49 have been cured of all IIH symptoms. CONCLUSIONS: These findings indicate a role for transverse sinus stent placement in the management of selected patients with IIH.

IntroductionPatients with Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) exhibit changes in eating behaviour that could potentially affect lipid levels and body composition. This study aimed to document changes in lipid metabolism and body composition across the ALS-FTD spectrum to identify potential relationships to eating behaviour (including fat intake), cognitive change, body mass index (BMI) and effect on survival.MethodsOne hundred and twenty eight participants were recruited: 37 ALS patients, 15 ALS patients with cognitive and behavioural change (ALS-Plus), and 13 ALS-FTD, 31 behavioural variant FTD, and 32 healthy controls. Fasting total cholesterol, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL) and triglyceride levels were measured and correlated to eating behaviour (caloric, fat intake), cognitive change, and BMI; effect on survival was examined using cox regression analyses. In a cohort of 60 patients, changes in body composition and fat deposition was examined using Dual energy X-ray absorptiometry scans (DEXA), a technique used in obesity research.ResultsThere was a spectrum of lipid changes from ALS to FTD with increased triglyceride (pConclusionA spectrum of changes in lipid metabolism and body composition has been identified in ALS-FTD, with total cholesterol levels found to potentially impact on survival. These changes were mediated by changes in fat intake, and BMI, and may also be mediated by the neurodegenerative process, offering the potential to modify these factors to slow disease progression and improve survival.

Background Primary lateral sclerosis (PLS), a rare upper motor neuron disorder, remains a debated entity as an upper motor neuron extreme form of amyotrophic lateral sclerosis (ALS) or a distinct disease. It is now well established that ALS and frontotemporal dementia (FTD) lie on two ends of the frontal neurodegenerative spectrum. While early descriptions of PLS excluded cognitive dysfunction, there is accumulating evidence of varying degrees of frontal lobe deficits accompanying structural and functional changes in the brain in PLS. Methodology This study examined the neurophysiological features using transcranial magnetic stimulation (TMS) and neuropsychological profile in a cohort of patients (n = 21) with PLS. Clinical, neuropsychological and TMS findings in PLS patients were compared with two distinct cohorts of patients who had pure ALS (n = 27) and ALSFTD (n = 12). Multivariable regression analysis was used to examine independent predictors of global cognitive function on the Addenbrooke’s cognitive examination (ACE) score and motor disability on the ALS functional rating scale (ALSFRS). Kaplan Meier curves were used to determine survival times for the three groups. Results Mean age in PLS was 60.9 ± 10.4, 47.6% of patients were males and 95% had limb onset disease. The mean survival time was longest in PLS (217.43 ± 22.4 months) and shortest in ALSFTD (38.54 ± 4.5 months). In addition to prominent upper motor neuron (UMN) dysfunction, ACE score was impaired in PLS (mean total ACE score 82.5 ± 13.6), lying intermediately between pure ALS (mean total ACE score 93.4 ± 3.9) and ALSFTD (mean total ACE score 76.3 ± 7.7). Behavioural impairments were not prominent in PLS as indicated by a higher total Motor Neuron Disease Behaviour (MiND-B) score than ALSFTD (PLS 32.1 ± 5.6, ALSFTD 22.4 ± 6.8, p = 0.005). In terms of cortical function, resting motor threshold (RMT) was significantly higher in PLS (93.2 ± 11.7, p RMT predicted higher global cognition score on the ACE ( β = 0.57, p = 0.001), independent of motor progression and clinical upper motor neuron dysfunction. Average SICI predicted motor disability ( β = 0.5, p = 0.008), on the ALS functional rating scale (ALSFRS), independent of disease duration and upper motor neuron score across the three groups. Conclusions There is a distinctive cognitive profile in PLS which resembles ALSFTD, without the behavioural disturbances typical of the FTD spectrum disorders. Cortical motor neuronal hyperexcitability was associated with poorer global cognitive function, independent of motor disease progression, while dysfunction of inhibitory interneuronal circuits predicted motor disability, across ALS, ALSFTD and PLS. Overall, these findings make a strong case for PLS being on the ALS FTD spectrum and suggest that cortical excitability contributes to neuropsychological and motor dysfunction by distinct pathophysiological mechanisms.

To contrast the relationships of hormonal eating peptides and hypothalamic volumes to eating behavior and metabolic changes (body mass index [BMI]) in behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA).Seventy-five patients with dementia (19 bvFTD, 26 svPPA, and 30 Alzheimer disease dementia) and 23 controls underwent fasting blood analyses of leptin, ghrelin, cholecystokinin, peptide tyrosine tyrosine (PYY), and agouti-related peptide (AgRP) levels. On brain MRI anterior, posterior, and total hypothalamic volumes were measured. Relationships between endocrine measures, hypothalamic volumes, eating behaviors, and BMI were investigated.Levels of AgRP were higher in patients with bvFTD (69 ± 89 pg/mL) and svPPA (62 ± 81 pg/mL) compared with controls (23 ± 19 pg/mL, p0.01). No differences were found for leptin, oxytocin, cholecystokinin, ghrelin, and PYY levels. Patients with bvFTD and svPPA had higher scores on questionnaires measuring eating behaviors. Atrophy of the posterior and total hypothalamus was observed in the bvFTD group only. Linear regression modeling revealed that leptin and AgRP levels predicted BMI.Eating abnormalities are multifactorial in FTD. In bvFTD, they are in part related to hypothalamic degeneration, with potential disintegration of the network connections between the hypothalamus and orbitofrontal cortex/reward pathways. In svPPA, although hypothalamic volumes are preserved, this group experiences elevated AgRP levels similar to bvFTD, which predicts BMI in both groups. This finding highlights the potential key role of AgRP in eating and metabolic changes and provides a potential target for treatment to modify disease progression.