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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 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.

Caregivers of patients diagnosed with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) often experience distressing symptoms related to their caregiving role. This review evaluates the existing literature on coping and their relationship to ALS and FTD caregiver psychological wellbeing. Published articles were identified via a systematic search of four databases (Cinahl Complete, Medline, Embase and PsycINFO). Overall, problem-focused coping strategies such as active coping and planning was used most often by ALS and FTD caregivers. Positive emotion-focused coping strategies such as acceptance were also frequently used by FTD caregivers. In contrast, dysfunctional coping strategies such as self-oriented reactions including self-blame, denial and self-preoccupation appeared to be the most salient coping strategy negatively impacting on caregiver psychological wellbeing. Six different coping measures were used and their psychometric properties were typically under-reported or satisfactory at best when reported. While coping is as an important aspect of caregivers’ experience, it remains unclear how the temporal dimensions of the coping process as well as stressor specificity influences psychological adaptation, and consequently, development of targeted caregiver intervention. The need for future studies to define the coping process more clearly in order to capture the unique stressors encountered by ALS and FTD caregivers throughout the different disease stages is emphasised.

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. National Health and Medical Research Council of Australia program (#1037746 and #1132524) and dementia team (#1095127) grants and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Program (#CE110001021). Dr E.M. Devenney is supported by a MNDRIA post-doctoral fellowship. Dr S. Tu is supported by a NHMRC post-doctoral fellowship (APP1121859). Dr R.M. Ahmed is supported by a NHMRC post-doctoral fellowship. Prof G.M. Halliday is a NHMRC Leadership Fellow (#1176607). Prof M.C. Kiernan received funding support from NHMRC Partnership Grant (#1153439) and Practitioner Fellowship (#115609). Prof O. Piguet is supported by a NHMRC Leadership Fellowship (GNT2008020). Dr M. Bocchetta is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). Dr M. Bocchetta’s work was also supported by the UK Dementia Research Institute which receives its funding from DRI ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. Dr M. Bocchetta acknowledges the support of NVIDIA Corporation with the donation of the Titan V GPU used for part of the analyses in this research. Prof J. D Rohrer is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH).

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)

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.

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

OBJECTIVES Almost 10% of people with dementia experience a younger-onset of disease (before 65 years). Changes in behaviour are common, as are delays in diagnosis and limited access to appropriate support and services. This study aimed to explore the specific behaviour support needs of families living with younger-onset dementia. METHODS Seventy-one families of people with younger-onset dementia were surveyed to understand the experience of family carers regarding difficult-to-manage behaviour changes, confidence in identifying and implementing behaviour support strategies, use of specific behaviour support strategies, and use of formal and informal support services regarding behaviour changes. RESULTS Survey responses were received from family members of people living with behavioural variant frontotemporal dementia (n = 28), semantic dementia (n = 17), and Alzheimer's disease (n = 23). Over 90% of family carers reported difficult-to-manage behaviours which fell into four main domains: (1) aggression, (2) compulsive behaviour, (3) disinhibition and inappropriate social behaviour, and (4) apathy. A range of preventative and responsive strategies, with an emphasis on de-escalation strategies were identified and carers reported variable confidence in managing behaviour changes or in accessing formal support strategies. CONCLUSIONS Difficult-to-manage behaviour changes in community-dwelling people with younger-onset dementia are common. The existing agency of families should be recognised and built upon with better access to specific behaviour support services to increase competence and confidence in providing behaviour support and ultimately improve quality of life for them and their family member with dementia.

BACKGROUND AND PURPOSE Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a multisystem disorder with 30%-50% of patients exhibiting cognitive impairment. The pathophysiological mechanisms of cognitive dysfunction are probably multifactorial although hypoventilation secondary to respiratory dysfunction may contribute to cognitive decline. The current study aimed to identify the relationship between respiratory function in ALS patients and the presence and degree of cognitive impairment. METHODS Amyotrophic lateral sclerosis patients were prospectively recruited from a multidisciplinary ALS clinic. Baseline clinical assessments including respiratory function as assessed by spirometry were recorded with forced vital capacity (FVC) ≤ 75% considered to be reduced respiratory function. Cognitive testing was performed utilizing the Addenbrooke's Cognitive Examination (ACE) and the Mini-Mental State Examination (MMSE). RESULTS From a cohort of 100 ALS patients, 48% were categorized as having impaired respiratory function (FVC = 58.24% ± 2.15%) whilst 52% had normal function (88.65% ± 1.27%). Compared to the group with normal respiratory function (ACE 90.68 ± 0.89, MMSE 28.22 ± 0.21), patients with respiratory dysfunction had significantly reduced cognitive function (ACE 86.83 ± 1.5, P = 0.025; MMSE 26.29 ± 0.45, P = 0.029). Furthermore, subscores demonstrated significant differences between the groups with respect to domains in memory (P = 0.003) and attention (P = 0.05) with a trend observed in fluency (P = 0.082). There was a significant correlation between patient baseline FVC and ACE scores as well as between FVC and memory and fluency subscores (P

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.

Objective The Motor Neuron Disease Behavioural Scale (MiND-B) is a clinically validated tool that was developed to detect behavioural dysfunction in patients with amyotrophic lateral sclerosis (ALS). The current study aimed to evaluate behavioural impairment using MiND-B, as well as cognitive dysfunction in ALS patients, and to determine their prognostic implications. Method Patients with a clinical diagnosis of ALS were prospectively recruited from a specialised multidisciplinary ALS clinic. Patients underwent behavioural assessment with the Motor Neuron Disease Behavioural Scale (MiND-B) and cognitive evaluation using the Addenbrooke’s Cognitive Examination (ACE). Primary outcome measure was selected as survival time, defined by time from assessment to time of death or censor date. Univariate assessment of survival effect was carried out using Kaplan-Meier survival analysis followed by cox regression analysis to assess the effect of MiND-B and ACE scores on survival time. Results A total of 134 patients were included in the study. MiND-B testing determined that 59% were classified as having behavioural dysfunction, with deficits associated with a significantly shorter survival time (HR 2.53, p = 0.003, 95% CI 1.3–4.6). Furthermore, regression analysis demonstrated that for every 1-point reduction in the MiND-B score, risk of death increased by 3%. ACE testing established that 33% of the cohort had evidence of cognitive dysfunction. Patients with cognitive dysfunction on ACE testing had a significantly shorter survival time than patients without cognitive impairment (HR 2.0, p = 0.042, 95% CI 1.04–3.3). Conclusion The presence of behavioural and cognitive impairments in ALS patients was associated with poor survival. The MiND-B and ACE inventories are simple and efficient clinical tools that can be administered in the multidisciplinary ALS clinic, that aid in the prognostication of this patient population.

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 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

OBJECTIVE The loss of autobiographical memories (ABM) is a pervasive feature of neurodegenerative diseases. Studies to date have not investigated ABM retrieval in amyotrophic lateral sclerosis (ALS), a multisystem disorder that may be associated with cognitive dysfunction and dementia. METHOD The integrity of autobiographical memory was evaluated in 22 ALS patients compared with 28 age-matched controls using the Autobiographical Interview (AI), a semistructured interview assessing autobiographical events from discrete time periods across the life span. RESULTS ABM retrieval was preserved in ALS and remained rich in detail for personal events in recent (last 12-months) and remote (teenage years) time epochs. ABM retrieval was positively correlated with months since ALS symptom onset, with a greater number of contextual details being recalled as ALS progressed. A shift in how ABMs were perceived in ALS patients became apparent, with more recurrent reflection of recent life, which was also weighted with greater personal importance. CONCLUSION The preservation of ABM in ALS has clinical implications for the use of life review as a therapeutic tool in a multidisciplinary care setting. (PsycINFO Database Record

It is increasingly recognized that metabolic factors influenced by eating behavior, may affect disease progression in neurodegeneration. In frontotemporal dementia (FTD), which shares a significant overlap with Amyotrophic lateral sclerosis (ALS), patients are well known to develop changes in eating behavior. Whether patients with pure ALS and those with cognitive and behavioral changes associated with ALS also develop similar changes is not known. The current study aimed to examine caloric intake, eating behavioral changes, body mass index, and using cox regression analyses survival across the spectrum of 118 ALS-FTD patients (29 pure ALS, 12 ALS-plus and 21 ALS-FTD, 56 behavioral variant FTD), compared with 25 control subjects. The current study found contrary to previous assumptions eating changes are not restricted to FTD, but a spectrum of eating behavioral changes occur in ALS, present in those with pure ALS and worsening as patients develop cognitive changes. ALS patients with cognitive impairment exhibited changes in food preference, with caloric intake and BMI increasing with the development of cognitive/behavioral changes. Both pure ALS and those with cognitive impairment demonstrated increased saturated fat intake. Survival analyses over the mean patient follow-up period of 6.9 years indicated that increasing eating behavioral changes were associated with an improved survival (threefold decrease risk of dying). Changes in eating behavior and metabolism occur in ALS in association with increasing cognitive impairment, perhaps exerting a protective survival influence. These changes provide insights into the common neural networks controlling eating and metabolism in FTD and ALS and provide potential targets to modify disease prognosis and progression.

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.

Background and aims: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) represent a disease spectrum. Caregiver burden in subtypes of FTD has not yet been directly compared with those patients who have co-existent FTD and ALS (ALSFTD). Method: Perceived caregiver burden was evaluated using the short Zarit Burden Interview (ZBI) in patients with behavioral-variant FTD (bvFTD, n = 21), semantic dementia (SD, n = 18), and ALSFTD (n = 15) at the initial clinical presentation and follow-up assessments. The Mini-Addenbrooke’s Cognitive Examination (M-ACE) and the Motor Neuron Disease Behaviour Scale (MiND-B) were also used. Linear mixed effects models examined longitudinal changes on the ZBI, M-ACE, and MiND-B across groups. Results: Burden at baseline was highest for the bvFTD group. Longitudinally, perceived burden increased for the SD and ALSFTD groups whereas in bvFTD, the level of burden which was high at baseline and remained high with disease progression. The severity of abnormal behaviors at baseline, as assessed by the MiND-B, correlated with baseline levels of caregiver burden and further accounted for 23% of the variance in caregiver burden at clinical follow-up. Conclusions: The trajectory of perceived burden differs across the FTD-ALS spectrum, with SD and ALSFTD caregivers demonstrating an increased burden that develops over time, compared to a persistently high level for bvFTD caregivers, evident throughout the disease course. The evolution of burden in these three syndromes likely reflects the initial presentation and clinical characterization that develops with time. Psycho-education programs for caregivers, which provide better coping strategies for challenging behaviors, may reduce levels of burden experienced with disease 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.

BACKGROUND: Behavioural/functional disturbances, characteristic of frontotemporal dementia (FTD), are also a feature of amyotrophic lateral sclerosis (ALS) and patients with combined ALS and FTD (FTD-ALS). AIM OF THE STUDY: To investigate the progression of behavioural disturbances in ALS and FTD using the frontotemporal dementia functional rating scale (FTDFRS). METHODS: Patients with ALS, FTD-ALS, and FTD were recruited from specialist clinics. Baseline assessments included the FTDFRS and the amyotrophic lateral sclerosis functional rating scale – revised (ALSFRS-R). Baseline assessments were included, as were longitudinal assessments in a proportion of patients. RESULTS: In total, 21 ALS, 12 FTD-ALS and 14 behavioural variant FTD (bvFTD) patients were included in the study. Moderate or severe behavioural disturbance was common in ALS patients at baseline (47.6%), although less frequent than in bvFTD patients; FTDALS patients displayed intermediate impairment. The ALSFRS-R showed the opposite pattern and did not correlate with the FTDFRS. During the follow-up period, significant (p

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.

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

Objective:Recognizing depressive symptoms in patients with amyotrophic lateral sclerosis (ALS) remains problematic given the potential overlap with the normal psychological responses to a terminal illness. Understanding mental health and disease-related risk factors for depression is key to identifying psychological morbidity. The present study aimed to determine the prevalence of depressive symptoms in ALS and to explore mental health and disease-related risk factors for depression.Method:Structured medical and psychiatric history questionnaires and a validated depression scale (Depression, Anxiety, Stress Scale–21) were completed by 27 ALS patients (60% female; 59% limb onset; age 65.11 ± SE 2.21) prior to their initial review at a multidisciplinary clinic. Physical function was assessed with the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS–R).Results:At the time of initial assessment, 44% of patients had a previous psychiatric history, although the majority (62%) reported no symptoms of depression. The mean ALSFRS–R score was 37.78 ± SE 1.22, with an average diagnostic interval of 16.04 ± SE 2.39 months. Logistic regression analysis revealed that the length of the diagnostic interval alone predicted depressive symptoms (χ2(3, n = 26) = 9.21, Odds Ratio (OR) = 1.12, p < 0.05.Significance of Results:The illness experiences of ALS patients rather than established mental health risk factors influence the manifestation of depressive symptoms in the early stages of the disease, with clinical implications for the assessment and treatment of psychological morbidity. Patients with lengthy diagnostic intervals may be prime targets for psychological assessment and intervention, especially in the absence of ALS-specific tests and biomarkers.

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

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.

IntroductionMotor neuron disease (MND) is increasingly recognised as a multisystems disorder with 30–50% of patients having mild to moderate cognitive impairment. Mechanisms of cognitive dysfunction in MND are multifactorial but chronic hypoxia secondary to respiratory dysfunction may contribute to cognitive decline in patients.ObjectivesThe current study aimed to identify the relationship between respiratory function in MND patients and the presence and degree of cognitive impairment.MethodsMND patients were prospectively recruited from a multidisciplinary MND clinic. Patients meeting the criteria for frontotemporal dementia were excluded. Baseline clinical assessments including respiratory function as assessed by spirometry were recorded with FVC ≤ 75% considered to have reduced respiratory function. Cognitive testing was performed utilising the Addenbrooke’s Cognitive Examination (ACE).ResultsFrom a cohort of 100 MND patients 48% were categorised as having impaired respiratory function whilst 52% had normal function. Compared to the group with normal respiratory function (ACE: 86.83±1.5), patients with respiratory dysfunction had significantly reduced cognitive function (ACE: 90.68±0.89, P=0.025). Subscores demonstrated significant differences between the groups with respect to domains in memory, attention with a trend observed in fluency. There was a significant correlation between FVC and ACE scores as well as between FVC and memory and fluency subscores (PConclusionMND patients with respiratory compromise were more likely to develop reduced cognitive function. In addition to improving physical function, it remains plausible that non-invasive ventilation may alter the progression of cognitive impairment in MND patients, thereby potentially improving their overall quality of life and carer burden.

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

To establish the frequency, severity, relationship to bulbar symptoms, and neural correlates of syntactic comprehension deficits across the frontotemporal dementia–amyotrophic lateral sclerosis (FTD-ALS) disease spectrum. In total, 85 participants were included in the study; 20 amyotrophic lateral sclerosis (ALS), 15 FTD-ALS, 27 progressive nonfluent aphasia (PNFA), and 23 controls. Syntactic comprehension was evaluated in ALS, FTD-ALS, PNFA, and controls using the Test for Reception of Grammar. Voxel-based morphometry examined neuroanatomical correlates of performance. Syntactic comprehension deficits were detected in 25% of ALS (p = 0.011), 92.9% of FTD-ALS (p < 0.001), and 81.5% of PNFA (p < 0.001) patients. FTD-ALS was disproportionately impaired compared to PNFA. Impaired Test for Reception of Grammar performance was frequent in ALS with early bulbar involvement but did not correlate with bulbar impairment overall. Left peri-insular atrophy correlated with syntactic comprehension deficits. Syntactic comprehension deficits are frequent in FTD-ALS, more severe than in PNFA, and related to left peri-insular atrophy. A significant minority of ALS patients are impaired, but the relationship between bulbar symptoms and syntactic impairment is not understood.

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.

Objective: To investigate, and establish neuroanatomical correlates of, semantic deficits in amyotrophic lateral sclerosis (ALS) and amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD), compared to semantic dementia (SD) and controls. Methods: Semantic deficits were evaluated using a naming and semantic knowledge composite score, comprising of verbal and non-verbal neuropsychological measures of single-word processing (confrontational naming, comprehension, and semantic association) from the Sydney Language Battery (SYDBAT) and Addenbrooke’s Cognitive Examination - Revised (ACE-R). Voxel-based morphometry (VBM) analysis was conducted using the region of interest approach. Results: In total, 84 participants were recruited from a multidisciplinary research clinic in Sydney. Participants included 17 patients with ALS, 19 patients with ALS-FTD, 22 patients with SD and 26 age- and education- matched healthy controls. Significant semantic deficits were observed in ALS and ALS-FTD compared to controls. The severity of semantic deficits varied across the clinical phenotypes; ALS patients were less impaired than ALS-FTD patients, who in turn were not as impaired as SD patients. Anterior temporal lobe atrophy significantly correlated with semantic deficits. Conclusion: Semantic impairment is a feature of ALS and ALS-FTD, and reflects the severity of temporal lobe pathology.

Weight loss and catabolic changes are increasingly recognized as factors that influence outcomes in patients with amyotrophic lateral sclerosis (ALS). An association between disease progression and low BMI has been reported in ALS; however, it remains unknown whether low BMI occurs across all forms of ALS and whether BMI changes with the development of cognitive impairment across the spectrum between ALS and frontotemporal dementia (FTD). One hundred and three ALS patients (56 limb predominant, 18 bulbar predominant, 13 ALS plus, 16 ALSFTD) were recruited and compared to 19 behavioral variant FTD (bvFTD) patients and a group of age-matched healthy controls. BMI was measured at the initial clinical visit. Patients were characterized as underweight, normal, overweight or obese, based on the current World Health Organization (WHO) guidelines. Limb and bulbar ALS patients had significantly lower BMI than ALS plus, ALSFTD, and bvFTD patient groups. When BMI was categorized using WHO guidelines the majority of the limb and bulbar ALS patients were either underweight or normal weight, whilst the majority of the ALS plus, ALSFTD and bvFTD patients were either overweight or obese. On follow-up BMI assessment the limb and bulbar groups tended to decline whilst ALS plus, ALSFTD and bvFTD groups remained stable or increased. BMI is significantly higher in ALS individuals with cognitive deficits. The present findings have prognostic implications for disease progression and may help delineate the metabolic profile across the ALSFTD spectrum.

Motor neuron disease (MND) and frontotemporal dementia (FTD) share clinical, genetic, and pathological features. Executive and behavioural disturbances are now recognised in MND, but non-executive cognitive impairments such as language dysfunction – a characteristic clinical feature of FTD – have not been explored to our knowledge. The present study investigated language in MND using tools specifically designed for use in different FTD phenotypes, including semantic dementia (SD) and progressive non-fluent aphasia (PNFA). Specifically, semantic deficits were assessed and compared to SD, whereas ability to interpret grammar was compared to PNFA. The study was performed in two parts. In part A, the Sydney language battery was used to assess aspects of semantic knowledge such as object naming, and results were compared to SD. In part B, interpretation of grammar was assessed using the test of reception of grammar (TROG), and results were compared to PNFA. Voxel-based morphometry was used to correlate patterns of cortical atrophy with performance on language measures. In total, 84 participants were included in part A (17 MND, 19 FTD-MND, 22 SD, and 26 controls) and 71 participants in part B (18 MND, 16 FTD-MND, 28 PNFA, and 9 controls). Part A demonstrated semantic deficits in MND and FTD-MND. For example, MND and FTD-MND were impaired on object naming (MND 25 ± 2.9, FTD-MND 17.1 ± 6.6, SD 5.4 ± 3.9, and controls 27 ± 1.9; p