Studies on the impact of assistive communication devices on the quality of life of patients with amyotrophic lateral sclerosis

Tese de doutoramento, Ciências Biomédicas (Neurociências), Universidade de Lisboa, Faculdade de Medicina, 2016Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disease with rapid and generalized degeneration of motor neurons. Patients with ALS experiment a relentless decline in functions that affect performance of most activities of daily living (ADL), such as speaking, eating, walking or writing. For this reason, dependence on caregivers grows as the disease progresses. Management of the respiratory system is one of the main concerns of medical support, since respiratory failure is the most common cause of death in ALS. Due to increasing muscle weakness, most patients experience dramatic decrease of speech intelligibility and difficulties in using upper limbs (UL) for writing. There is growing evidence that mild cognitive impairment is common in ALS, but most patients are self-conscious of their difficulties in communicating and, in very severe stages, locked-in syndrome can occur. When no other resources than speech and writing are used to assist communication, patients are deprived of expressing needs or feelings, making decisions and keeping social relationships. Further, caregivers feel increased dependence due to difficulties in communication with others and get frustrated about difficulties in understanding partners’ needs. Support for communication is then very important to improve quality of life of both patients and caregivers; however, this has been poorly investigated in ALS. Assistive communication devices (ACD) can support patients by providing a diversity of tools for communication, as they progressively lose speech. ALS, in common with other degenerative conditions, introduces an additional challenge for the field of ACD: as the disease progresses, technologies must adapt to different conditions of the user. In early stages, patients may need speech synthesis in a mobile device, if dysarthria is one of the initial symptoms, or keyboard modifications, as weakness in UL increases. When upper limbs’ dysfunction is high, different input technologies may be adapted to capture voluntary control (for example, eye-tracking devices). Despite the enormous advances in the field of Assistive Technologies, in the last decade, difficulties in clinical support for the use of assistive communication devices (ACD) persist. Among the main reasons for these difficulties are lack of assessment tools to evaluate communication needs and determine proper input devices and to indicate changes over disease progression, and absence of clinical evidence that ACD has relevant impact on the quality of life of affected patients. For this set of reasons, support with communication tools is delayed to stages where patients are severely disabled. Often in these stages, patients face additional clinical complications and increased dependence on their caregivers’ decisions, which increase the difficulty in adaptation to new communication tools. This thesis addresses the role of assistive technologies in the quality of life of early-affected patients with ALS. Also, it includes the study of assessment tools that can improve longitudinal evaluation of communication needs of patients with ALS. We longitudinally evaluated a group of 30 patients with bulbar-onset ALS and 17 caregivers, during 2 to 29 months. Patients were assessed during their regular clinical appointments, in the Hospital de Santa Maria-Centro Hospitalar Lisboa_Norte. Evaluation of patients was based on validated instruments for assessing the Quality of Life (QoL) of patients and caregivers, and on methodologies for recording communication and measuring its performance (including speech, handwriting and typing). We tested the impact of early support with ACD on the QoL of patients with ALS, using a randomized, prospective, longitudinal design. Patients were able to learn and improve their skills to use communication tools based on electronic assistive devices. We found a positive impact of ACD in psychological and wellbeing domains of quality of life in patients, as well as in the support and psychological domains in caregivers. We also studied performance of communication (words per minute) using UL. Performance in handwriting may decline faster than performance in typing, supporting the idea that the use of touchscreen-based ACD supports communication for longer than handwriting. From longitudinal recordings of speech and typing activity we could observe that ACD can support tools to detect early markers of bulbar and UL dysfunction in ALS. Methodologies that were used in this research for recording and assessing function in communication can be replicated in the home environment and form part of the original contributions of this research. Implementation of remote monitoring tools in daily use of ACD, based on these methodologies, is discussed. Considering those patients who receive late support for the use of ACD, lack of time or daily support to learn how to control complex input devices may hinder its use. We developed a novel device to explore the detection and control of various residual movements, based on sensors of accelerometry, electromyography and force, as input signals for communication. The aim of this input device was to develop a tool to explore new communication channels in patients with generalized muscle weakness. This research contributed with novel tools from the Engineering field to the study of assistive communication in patients with ALS. Methodologies that were developed in this work can be further applied to the study of the impact of ACD in other neurodegenerative diseases that affect speech and motor control of UL

Voice banking for people living with motor neurone disease: Views and expectations

Background: More than 80% of people living with MND (plwMND) develop difficulties with their speech, affecting communication, self-identity and quality of life. Most plwMND eventually use an augmentative and alternative communication device (AAC) to communicate. Some AAC devices provide a synthesized voice for speech, however these voices are often viewed as impersonal and a factor in AAC acceptance. Voice banking creates an approximation of the person's own voice that can be used in AAC and is argued to go some way to preserve a person's identity when natural voice is lost, but there has been little supporting research. // Aims: To understand what plwMND consider when deciding whether or not to bank their voice, what their expectations are, and the expectations of significant communication partners. // Methods: Semi-structured interviews were undertaken with plwMND who had either decided to bank their voice or had decided not to. Thematic analysis was used to provide a qualitative analysis of the data. // Procedures: Participants were an opportunistic sample of plwMND within England recruited via an open advert distributed by the MND Association (MNDA). // Outcomes and Results: Twelve plwMND were interviewed with nine significant others. Nine participants had decided to bank their voice and three decided not to. The data suggest ‘preserving identity’ is the overarching motivation in decision making for voice banking. Participants who decided to voice bank considered it would help to maintain their identity and preserve their social and work networks. Participants deciding not to bank their voice highlighted it could not replace their natural voice or preserve their identity. However, few in either group showed an awareness of how a voice bank is used in AAC, and how communication using AAC is significantly different to natural speech. // Conclusions and Implications: This research is the first study of its kind to examine the considerations for decision making around voice banking for plwMND. Preserving identity is central to decision making when considering whether or not to voice bank. However, the reality of using AAC and voice banking for communication is poorly understood. Professionals have a role to provide plwMND with more information about voice banking in the wider context of using AAC for communication. It may be that the process of voice banking itself is seen as a positive act for plwMND, independent of how it is used later. Further research with associated professionals and stakeholders is indicated

Nature of language impairment in motor neurone disease

Background: Language impairment associated with Motor Neurone Disease (MND) has been documented since the late 19th century, yet little is understood about the pervasiveness or nature of these deficits. The common clinical view among healthcare professionals is that communication difficulties can be attributed solely to the motor speech disorder dysarthria. Recent literature raises the possibility of more central processing deficits. Impairments in naming ability and comprehension of complex grammatical constructs have been frequently reported in some patients with MND. However, there is now growing evidence of spelling impairment, which could suggest the contribution of a more phonologically based deficit. In addition, the close relationship between MND and frontotemporal dementia (FTD) raises questions about the connection between the language impairments seen in MND patients and those documented in patients with the primary progressive aphasia (PPA) syndromes associated with FTD. Aims: This thesis examines the nature of speech and language deficits in people with MND and the extent to which expressive communication impairment can occur above and beyond dysarthria. In particular, the study explores: i) to what extent these language impairments can be attributed to deficits in working memory, executive functioning and/or disease severity; ii) what spelling errors can reveal about the integrity of lexical, phonological and orthographic processing; iii) whether similar patterns of impairment can be seen in PPA syndromes; iv) the relationship between language impairment and bulbar onset; and v) the impact these findings have on clinical management of MND patients. Methods: MND patients from across Scotland with changes in speech and/or language were tested using a neuropsychological battery of experimental and standardised tests of naming, spelling, syntactic comprehension, prosody and phonological and orthographical awareness. Patients were also screened for levels of dysarthria, executive functioning and working memory deficits, and results compared to those of matched controls. Findings: As a group, MND participants performed significantly worse than matched controls on measures of naming, spelling, orthographical awareness, grammatical comprehension, affective prosody and verbal fluency, but not working memory. However, based on patterns of individual impairment, of which spelling impairment formed a distinctive marker, the patient group divided into dichotomous subgroups, with 44% of participants categorised as ‘linguistically impaired’, while the remainder displayed little to no impairment. Those participants identified as linguistically impaired did not differ significantly from other MND participants on measures of disease severity, disease duration or dysarthria severity, although significantly more bulbar onset than limb onset participants were linguistically impaired. Spelling error patterns were suggestive of deficits at both a lexical and sublexical level, and were comparable to those reported in PPA literature. These findings suggest that dysarthria may be masking linguistic deficits in almost half of dysarthric MND patients, and highlight the importance of multidimensional assessment of language for effective clinical management

Modélisations de maladies des motoneurones en utilisant le poisson zébré

Les paraplégies spastiques familiales (PSF) sont un groupe de maladie neurodégénératives hétérogènes affectant les neurones moteurs supérieurs et causant une faiblesse musculaire progressive des membres inférieurs entrainant des problèmes de marche. Plus de 60 gènes ont été lies à cette maladie, leur nombre augmentant régulièrement. La sclérose latérale amyotrophique (SLA) est une maladie neurodégénérative à déclenchement tardif qui affecte les neurones moteurs supérieurs et inférieurs, entrainant une atrophie musculaire accompagnée de spasticité. La mort, causée par une insuffisance respiratoire survient dans les 2 à 5 ans après le début de la maladie. Ces deux maladies de neurones moteurs, bien que différentes, ont des gènes et des mécanismes pathologiques en commun. Ainsi, accroitre notre connaissance de leurs similarités et de leurs différences pourra nous aider à mieux comprendre chacune individuellement. Pour étudier ces deux maladies, nous avons utilisé des modèles de poisson zébré précédemment caractérisés et en avons développé de nouveaux pour approfondir nos connaissances sur les mécanismes physiopathologiques. Dans la première partie de cette thèse, nous avons identifié le stress du réticulum endoplasmique (RE) comme un nouveau mécanisme pathologique induit par la perte de fonction de spastin, un gène impliqué dans la PSF, et avons montré que des modulateurs du stress du RE sont capables de renverser le phénotype locomoteur. Nous avons aussi identifié un nouveau gène causatif de la PSF, CAPN1 (SPG76), et avons validé in vivo la pathogénicité de sa perte de fonction en identifiant une désorganisation des réseaux de microtubules comme phénotype principal. Dans la deuxième partie de cette thèse, nous avons généré plusieurs nouveaux modèles de poisson zébré de la SLA. Deux lignées transgéniques exprimant la protéine humaine de type sauvage ou mutante sous le contrôle d’un promoteur inductible nous ont permis de reproduire des résultats obtenus précédemment par l’injection d’ARNm et d’identifier des changements transcriptomiques similaires à ceux obtenus récemment avec des modèles de souris. Nous ii avons aussi généré deux nouvelles lignées en introduisant des mutations ponctuelles liées à la SLA dans les gènes tardbp et fus du poisson zébré en utilisant la technologie CRISPR/Cas9. Ces résultats soulignent la valeur du poisson zébré comme modèle pour étudier les maladies des neurones moteurs et leurs mécanismes physiopathologiques, et suggèrent de nouvelles approches thérapeutiques.Hereditary spastic paraplegias (HSP) are a group of heterogeneous neurodegenerative diseases affecting upper motor neurons, causing progressive gait dysfunction and more than 60 genes have been linked to this disease. On the other hand, amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disorder that affects both upper and lower motor neurons, leading to muscle atrophy with spasticity and death in two to five years due to respiratory failure. These two motor neuron disorders, while separate, share common genes and pathological mechanisms and as such, increasing our knowledge about their similarities and differences can help us have a better understanding of each of them individually. In order to study these two diseases, we used previously characterized zebrafish models and developed new ones to deepen our understanding of the pathophysiological mechanisms of HSP and ALS. In the first part of this thesis, we identified ER stress as a new pathological mechanism at play in HSP due to spastin loss-of-function and showed that ER stress modulators are able to rescue the locomotor phenotype. We also identified a new gene causative of HSP, CAPN1 (SPG76), provided in vivo validation of its loss-of-function pathogenicity and identified microtubule networks disorganization as one of the main defects. In the second part of this thesis, we generated several new zebrafish models to study ALS. Two transgenic lines expressing either a wild-type or a mutant TDP-43 protein under the control of an inducible promoter allowed us to recapitulate previous findings obtained with mRNA injections and identify transcriptomic changes due to the mutant protein that are in line with recent transcriptomic data obtained in mouse models. We also generated two new lines with knock-in of ALS-causative point mutations in the tardbp and fus zebrafish endogenous genes using the CRISPR/Cas9 technology. These results underscore the value of the zebrafish model to study motor neuron disorders and their pathophysiological mechanisms as well as open new therapeutic avenues

The prevalence and perceptions of hearing loss in individuals diagnosed with adult onset motor neuron disease (MND).

Although it is well-known that motor neuron disease (MND) primarily affects motor neurons, the involvement of sensory pathways in the disease is currently receiving more attention. There is a dearth of information regarding the atypical effects of MND, resulting in limited understanding of the vulnerability of for example the auditory system. The presence of hearing loss negatively impacts on participation across all communicative contexts, stripping individuals of autonomy and self-worth, ultimately resulting in withdrawal and isolation. These factors form the foundation for individual desire to pursue life-prolonging measures. Hearing loss, combined with dysarthria and the use of augmentative and alternative communicative strategies, implies that individuals with MND require additional support to meet their daily communicative needs. This descriptive, exploratory study aimed to identify the prevalence of hearing loss in eight individuals with adult onset MND. In addition, perceptions relating to the implications of auditory impairment and value of auditory diagnosis were explored. An evaluation of auditory function was performed on eight individuals with a neurologist confirmed diagnosis of MND. Auditory function was assessed using a comprehensive audiological test battery including both objective and subjective measures. Perceptions related to auditory impairment were determined using the Hearing Handicap Inventory for Adults (HHIA) and the Hearing Experience Questionnaire. Both individuals with MND and their primary caregivers completed the Hearing Experience Questionnaire. The results of the study indicate that a high frequency sensorineural hearing loss was identified in six participants. Auditory handicap, as measured by the Hearing Handicap Inventory for Adults, was reported in four participants, with social handicaps reported more than emotional handicaps. Individuals with MND and their caregivers identified communication as the most important functional skill. Interestingly, the caregivers related more to the threats auditory impairment than individuals with MND. The nature of hearing loss identified in this study mimics the pattern of a presbycustic (age-related) hearing loss. It is postulated that hearing loss may arise during disease course. Participants‘ limited understanding of the devastating consequences of hearing loss on quality of life highlights the need for inclusion of an audiologist as part of the multidisciplinary management team in MND. Audiological assessment, management, counseling and education will serve to guide the process of sensory regulation and limit psychosocial threats posed by MND. This will in turn promote enhanced quality of life and maintenance of individual autonomy

Characterization of Mouse and Human Astrocytes in Amyotrophic Lateral Sclerosis: Effects of Oxidative Stress and Blockade of the Metabotropic Glutamate Receptor 5

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder due to upper and lower motor neuron (MNs) death. Recognized as a non-cell-autonomous disease, ALS is also characterized by damage and degeneration of glial cells, such as astrocytes, microglia, and oligodendrocytes. Astrocytes acquire a reactive and toxic phenotype defined by an abnormal proliferation and by the release of neurotoxic factors. Recent studies reported that the uptake of [18F]-fluorodeoxyglucose (FDG) is increased in the spinal cord (SC) and decreased in the motor cortex (MC) of patients with ALS, suggesting that the disease might differently affect the two nervous districts with different time sequence or with different mechanisms. Here we show that MC and SC astrocytes harvested from newborn B6SJL-Tg (SOD1G93A) 1Gur (SOD1G93A) mice could play different roles in the pathogenesis of the disease. Spectrophotometric and cytofluorimetric analyses showed an increase in redox stress, a decrease in antioxidant capacity, and a relative mitochondria respiratory uncoupling in MC SOD1G93A astrocytes. By contrast, SC mutated cells showed a higher endurance against oxidative damage, through the increase in antioxidant defense and a preserved respiratory function. Thus, SOD1G93A mutation differently impaired MC and SC astrocyte biology in a very early stage of life. One major cause for MN degeneration in ALS is represented by glutamate-mediated excitotoxicity, due to the alteration of glutamate transmission mechanisms, including glutamate receptor function. In this context, the Group I metabotropic glutamate receptor 5 (mGluR5) has been proposed to play an important role in ALS, since it is largely overexpressed during disease progression and is involved in the altered neuronal and glial cellular processes. My research group previously demonstrated that mGluR5 produces abnormal glutamate release in the spinal cord of the SOD1G93A mouse model of ALS and that halving its expression has a positive impact on in-vivo disease progression, including motor neuron survival, astrogliosis, and microgliosis. They also investigated the consequences of reducing the mGluR5 expression in SOD1G93A mice on the reactive phenotype of spinal cord astrocytes cultured from late symptomatic (120 days old) SOD1G93A mice. Also in this model, reducing the mGluR5 expression ameliorated the astrocyte phenotype. UNIVERSITY OF GENOVA 8 Here, I translated this study to human astrocytes derived from healthy donors and ALS patients. We investigated the in-vitro pharmacological treatment effect of chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP), a negative allosteric modulator of mGluR5 on i-astrocytes differentiated from the inducible neural progenitor cells (iNPCs) obtained from the skin fibroblast (i-astrocytes) of two ALS patients and two healthy donors. The overexpression of anti-glial fibrillary acid protein (GFAP), S100 calcium-binding protein \u3b2 (S100\u3b2), and Complement component 3 (C3), three markers of astrogliosis, was reduced in CTEP-treated i-astrocytes. The same positive effect was obtained in the case of NLR family pyrin domain containing 3 (NLRP3) and nuclear factor erythroid 2-related factor 2 (NRF2), markers strictly related to inflammation and oxidative stress respectively, which are upregulated in ALS astrocytes. In-vitro pharmacological treatment with CTEP also reduced the expression of mGluR5 in mutated i-astrocytes. In addition, the CTEP treatment caused a decrement in antioxidant enzymatic activity such as malondialdehyde (MDA), glucose-6-phosphate dehydrogenase (G6PD), Glutathione reductase (GR), Glutathione peroxidase (GP), and catalase compared to the untreated samples, suggesting that the drug could cause a reduction of oxidative stress. Altogether, these results indicate that reduction of mGluR5 activation has a positive impact on i-astrocytes in ALS patients supporting the idea that the in-vivo amelioration of the disease progression, registered after mGluR5 genetical or pharmacological silencing, involve an astrocyte phenotype improvement also in humans. As a whole, mGluR5 may represent a potential therapeutic target to preserve MNs from death, also by modulating the reactive astroglial phenotype in ALS

Home-Based Music Therapy to Support Bulbar and Respiratory Functions of Persons with Early and Mid-Stage Amyotrophic Lateral Sclerosis—Protocol and Results from a Feasibility Study

Respiratory failure, malnutrition, aspiration pneumonia, and dehydration are the precursors to mortality in ALS. Loss of natural communication is considered one of the worst aspects of ALS. This first study to test the feasibility of a music therapy protocol for bulbar and respiratory rehabilitation in ALS employs a mixed-methods case study series design with repeated measures. Newly diagnosed patients meeting the inclusion criteria were invited to participate, until the desired sample size (n = 8) was achieved. The protocol was delivered to participants in their homes twice weekly for six weeks. Individualised exercise sets for independent practice were provided. Feasibility data (recruitment, retention, adherence, tolerability, self-motivation and personal impressions) were collected. Bulbar and respiratory changes were objectively measured. Results. A high recruitment rate (100%), a high retention rate (87.5%) and high mean adherence to treatment (95.4%) provide evidence for the feasibility of the study protocol. The treatment was well tolerated. Mean adherence to the suggested independent exercise routine was 53%. The outcome measurements to evaluate the therapy-induced change in bulbar and respiratory functions were defined. Findings suggest that the protocol is safe to use in early- and mid-stage ALS and that music therapy was beneficial for the participants’ bulbar and respiratory functions. Mean trends suggesting that these functions were sustained or improved during the treatment period were observed for most outcome parameters: Maximal Inspiratory Pressure, Maximal Expiratory Pressure, Peak Expiratory Flow, the Center for Neurologic Study—Bulbar Function Scale speech and swallowing subscales, Maximum Phonation Time, Maximum Repetition Rate—Alternating, Maximum Repetition Rate—Sequential, Jitter, Shimmer, NHR, Speaking rate, Speech–pause ratio, Pause frequency, hypernasality level, Time-to-Laryngeal Vestibule Closure, Maximum Pharyngeal Constriction Area, Peak Position of the Hyoid Bone, Total Pharyngeal Residue C24area. Conclusion. The suggested design and protocol are feasible for a larger study, with some modifications, including aerodynamic measure of nasalance, abbreviated voice sampling and psychological screening