Syntactic comprehension deficits across the FTD-ALS continuum

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

The Impact of Apathy in Amyotrophic Lateral Sclerosis

Motor neurone disease/amyotrophic lateral sclerosis (MND/ALS) is established as a multisystem neurodegenerative disorder which includes a broad spectrum of cognitive and behavioural symptoms similar to those with behavioural variant frontotemporal dementia (FTD). Behavioural symptoms include perseveration, disinhibition and most commonly apathy. This thesis examined the impact of apathy in ALS, and specifically, its relationship to clinical, patient and caregiver outcomes. Initial studies designed to elucidate the clinical significance of apathy demonstrated that nearly half of patients presenting at a specialised ALS clinic exhibited apathy of varying levels of severity. Patients with moderate to severe apathy had a considerably shorter survival time than those with no apathy and mild apathy, even after taking into account clinical confounders. Comprehensive multidimensional assessment of apathy revealed that patients with apathy had lower quality of life (QOL), most pronounced in the achievements in life and community-connectedness domains compared to non-apathetic patients. Of the cognitive, behavioural and emotional symptoms of apathy, only the emotional symptoms were predictive of achievements in life and community-connectedness. For caregivers, higher levels of cognitive, behavioural and emotional symptoms of apathy were reported by high-burden compared to low-burden caregivers. Only the behavioural symptoms of apathy were associated with greater caregiver burden. In conclusion, the importance of assessing apathy and its severity as part of routine clinical practice is of prognostic and therapeutic importance. In particular, moderate to severe apathy at presentation may be indicative of more aggressive disease which warrants prompt intervention and support for patients and their caregivers. Psychological interventions designed to specifically target the emotional symptoms of apathy may be of particular value for improving patients’ QOL. For caregivers, strategies to manage behavioural deficits associated with apathy, including their own reactions towards these behaviours may mitigate caregiver burden

Development of patient decision support tools for motor neuron disease using stakeholder consultation : a study protocol

Introduction: Motor neuron disease (MND) is a terminal, progressive, multisystem disorder. Well-timed decisions are key to effective symptom management. To date, there are few published decision support tools, also known as decision aids, to guide patients in making ongoing choices for symptom management and quality of life. This protocol is to develop and validate decision support tools for patients and families to use in conjunction with health professionals in MND multidisciplinary care. The tools will inform patients and families of the benefits and risks of each option, as well as the consequences of accepting or declining treatment. Methods and analysis: The study is being conducted from June 2015 to May 2016, using a modified Delphi process. A 2-stage, 7-step process will be used to develop the tools, based on existing literature and stakeholder feedback. The first stage will be to develop the decision support tools, while the second stage will be to validate both the tools and the process used to develop them. Participants will form expert panels, to provide feedback on which the development and validation of the tools will be based. Participants will be drawn from patients with MND, family carers and health professionals, support association workers, peak body representatives, and MND and patient decision-making researchers. Ethics and dissemination: Ethical approval for the study has been granted by Macquarie University Human Research Ethics Committee (HREC), approval number 5201500658. Knowledge translation will be conducted via publications, seminar and conference presentations to patients and families, health professionals and researchers.7 page(s

A longer diagnostic interval is a risk for depression in amyotrophic lateral sclerosis

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

Loss of the metabolism and sleep regulating neuronal populations expressing orexin and oxytocin in the hypothalamus in amyotrophic lateral sclerosis

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

Problem-focused coping underlying lower caregiver burden in ALS-FTD: Implications for caregiver intervention

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

Neuropsychiatric changes precede classic motor symptoms in ALS and do not affect survival

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 5 159; bulbar onset 5 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 5 219). Cox proportional hazard regression models were used for the survival analysis (n 5 115 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 (x2, 3.447, p 5 0.328, 22 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

Semantic deficits in amyotrophic lateral sclerosis

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

A novel tool to detect behavioural symptoms in ALS

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