A standardised, multilingual, Mini Linguistic State Examination (MLSE) for classifying and monitoring Primary Progressive Aphasia
Lead Research Organisation:
St George's, University of London
Department Name: Molecular & Clinical Sci Research Inst
Abstract
Dementia is a complex and multifaceted clinical state, which shows marked variations in the biological mechanisms and molecular structure of brain pathology, and in the effects that these pathologies have on brain function. Importantly, not all people with dementia are suffering from Alzheimer's disease (though this remains the commonest underlying pathology), and not all experience forgetfulness as the first sign of mental difficulty.
One type of dementia presentation that has been extensively studied over recent years is one that begins with selective difficulty understanding and/or producing speech and language - a pattern known as primary progressive aphasia (PPA). Because language is such a complex mental ability, and relies on a number of widely distributed brain areas, PPA can take a variety of forms. Currently, three distinct patterns are recognised. Some patients experience a reduced ability to appreciate the meaning of words or objects ('semantic dementia'), while in others the problems lie in the production of words and sentences ('progressive nonfluent aphasia'). A third group displays milder problems, along with a striking inability to repeat spoken sentences ('logopenic progressive aphasia').
At the level of pathology these three dementia syndromes are far from distinct, making their biological basis difficult to determine during life. Improved understanding should lead to the development of disease specific treatments, but because of their relative rarity (less than 5% of cases of dementia begin with PPA), clinical trials will necessitate large scale, international collaborations, and these will inevitably include patients who speak languages other than English. Such a diversity of language communities will obviously present problems in the context of a condition that primarily affects language itself. The principal aim of this project, therefore, is to lay the foundations of a common descriptive currency, in which the three types of PPA can be described, and patients' abilities quantified on the same scale, regardless of the language in which they are assessed.
To achieve this, we will develop a brief language assessment instrument, which will allow the three PPA syndromes to be distinguished from one another on a common set of criteria and monitored over time using equivalent levels of severity. In view of the worldwide impact and importance of the Mini Mental State Examination (MMSE) in defining and quantifying dementia more generally, this brief language test will be given the title of the Mini Linguistic State Examination (or 'MLSE'). The instrument is intended to be comprehensive yet brief, and capable of being administered by clinicians without special expertise in language assessment.
It would be unrealistic to try to develop versions of the MLSE for all the world's major languages at once, so we will concentrate on two European languages: English and Italian, the native languages of around 360 million and 60 million people, respectively. We will ensure that the same classifications emerge from the MLSE as are currently recognized by expert clinicians by validating the test against expert clinical opinion, and against the patterns of aphasia suffered by patients following a stroke. We will also look for validation in the MR imaging appearances that are known to be associated with each variant. When English and Italian versions of the instrument have been fully developed and validated, we will gather additional data from populations of patients with movement related neurodegenerative disorders (such as Parkinson's disease) in order to gain deeper insights into the effects of these groups of disorders on the brain, and to identify ways in which sufferers' quality of life can be improved through rehabilitation.
One type of dementia presentation that has been extensively studied over recent years is one that begins with selective difficulty understanding and/or producing speech and language - a pattern known as primary progressive aphasia (PPA). Because language is such a complex mental ability, and relies on a number of widely distributed brain areas, PPA can take a variety of forms. Currently, three distinct patterns are recognised. Some patients experience a reduced ability to appreciate the meaning of words or objects ('semantic dementia'), while in others the problems lie in the production of words and sentences ('progressive nonfluent aphasia'). A third group displays milder problems, along with a striking inability to repeat spoken sentences ('logopenic progressive aphasia').
At the level of pathology these three dementia syndromes are far from distinct, making their biological basis difficult to determine during life. Improved understanding should lead to the development of disease specific treatments, but because of their relative rarity (less than 5% of cases of dementia begin with PPA), clinical trials will necessitate large scale, international collaborations, and these will inevitably include patients who speak languages other than English. Such a diversity of language communities will obviously present problems in the context of a condition that primarily affects language itself. The principal aim of this project, therefore, is to lay the foundations of a common descriptive currency, in which the three types of PPA can be described, and patients' abilities quantified on the same scale, regardless of the language in which they are assessed.
To achieve this, we will develop a brief language assessment instrument, which will allow the three PPA syndromes to be distinguished from one another on a common set of criteria and monitored over time using equivalent levels of severity. In view of the worldwide impact and importance of the Mini Mental State Examination (MMSE) in defining and quantifying dementia more generally, this brief language test will be given the title of the Mini Linguistic State Examination (or 'MLSE'). The instrument is intended to be comprehensive yet brief, and capable of being administered by clinicians without special expertise in language assessment.
It would be unrealistic to try to develop versions of the MLSE for all the world's major languages at once, so we will concentrate on two European languages: English and Italian, the native languages of around 360 million and 60 million people, respectively. We will ensure that the same classifications emerge from the MLSE as are currently recognized by expert clinicians by validating the test against expert clinical opinion, and against the patterns of aphasia suffered by patients following a stroke. We will also look for validation in the MR imaging appearances that are known to be associated with each variant. When English and Italian versions of the instrument have been fully developed and validated, we will gather additional data from populations of patients with movement related neurodegenerative disorders (such as Parkinson's disease) in order to gain deeper insights into the effects of these groups of disorders on the brain, and to identify ways in which sufferers' quality of life can be improved through rehabilitation.
Technical Summary
Primary progressive aphasia (PPA) is an uncommon clinical manifestation of Alzheimer's, tau- and TDP-43-positive neuropathologies. Three clinical syndromes are recognised: semantic dementia (SD) (progressive loss of word and concept knowledge in association with bilateral anterior temporal atrophy); progressive nonfluent aphasia (PNFA) (distorted speech output with largely preserved comprehension, and cortical atrophy focused on left inferior frontal and insular regions); and logopenic progressive aphasia (LPA) (difficulties with word-finding and sentence repetition, in the presence of atrophy in left posterior cortical regions). The syndromes result from different combinations of dysfunction in fundamental components of the language system: speech fluency, word retrieval, appreciation of word and object meaning, use of grammar, and reading/writing. Syndromes and pathologies are probabilistically related, allowing the latter to be predicted in up to 70% of cases. In light of PPA's relative rarity, increased recognition and coordination of large patient cohorts across multiple sites will be required to study disease biology and clinico-pathological correlations, and enable clinical trials of potential treatments. Progress in both endeavours will benefit from a common method of extracting relevant clinical information from large numbers of individuals. The development of a brief, language specific clinical instrument that can classify patients into one of the three main subtypes of PPA, and to characterise the features of atypical variants, is the central aim of this project. The language battery, based on patterns of impairment across components of language competence, will provide a unified clinical diagnostic standard. Simultaneous development in English and Italian will catalyse and inform the creation of equivalent versions in other major languages of the world, providing a common descriptive clinical currency for the sharing of larger data sets.
Planned Impact
The outputs of this project will have multiple users outside the immediate community of neurodegenerative disease researchers. Important beneficiaries and impacts will include:
1) Pharmaceutical and biotechnology industries and clinical trials organizations, for whom the MLSE will provide a fully validated method of assessing outcomes in trials of treatments for either symptom alleviation or disease modification in frontotemporal dementia. The availability of parallel versions of the test in multiple languages will remove a major obstacle to the design of robust clinical trials involving international consortia. Opportunities for engagement with this sector will arise as soon as validation of the instrument has been completed and accepted for publication, and will continue for as long as treatments for the non-Alzheimer dementias remain an active goal of biomedical research. Although the applicants propose that the test should be freely usable for clinical purposes and in the interests of academic research, the IP (ownership of which would be shared among the Institutions involved in its development) would be subject to licensing for commercial use.
2) The use of machine learning methods in test data analysis, will stimulate interest from the computer and software industries, as well as computer science academics working in the healthcare and health informatics field. Individuals from these groups will be keen to engage in data sharing arrangements, and to benefit from the expertise of the investigators and researchers involved in the project. The involvement as project partner of Prof Chesi, who already has a high profile in both academic and industrial sectors, will greatly facilitate the recognition and uptake of collaborative opportunities during the lifetime of the project and within five to ten years after its completion.
3) Globalisation has provided an increasing number of opportunities for cooperation and collaboration with bioscientists working in developing nations, and the momentum that will be created by the need for parallel versions will immediately engage the academic and clinical communities in these countries, allowing them to interact and share information and expertise more widely. This will contribute to achieving the goals of global healthcare, and help to consolidate existing academic collaborations, foster fresh links, and facilitate industry involvement with increasing numbers of healthcare organisations worldwide.
4) The question of the true prevalence of young onset dementia syndromes such as frontotemporal dementia has not been fully and unequivocally resolved, though the problem is known to be more widespread and have greater socioeconomic impacts than had previously been recognized. An instrument that is sensitive to language changes characteristic of the two commonest causes of dementia before age 65, and to progression of mild abnormalities at 12 month follow-up would be a uniquely valuable tool in any investigation of the incidence and prevalence of such conditions. Accurate information would, in turn, inform health service policy, influence the importance given to young onset dementia research by charitable and public sector grant awarding bodies, and contribute over the longer term to an understanding of young onset dementia syndromes by the wider public.
5) Finally, the generic skills imparted to the research staff employed on this project would include not only those relevant to research (i.e. theory and technique, scientific data and project management) but also to the skills involved in collaboration across national boundaries (communication with other linguistic and cultural groups), which the effects of globalisation will render increasingly important to individual and national competitiveness.
1) Pharmaceutical and biotechnology industries and clinical trials organizations, for whom the MLSE will provide a fully validated method of assessing outcomes in trials of treatments for either symptom alleviation or disease modification in frontotemporal dementia. The availability of parallel versions of the test in multiple languages will remove a major obstacle to the design of robust clinical trials involving international consortia. Opportunities for engagement with this sector will arise as soon as validation of the instrument has been completed and accepted for publication, and will continue for as long as treatments for the non-Alzheimer dementias remain an active goal of biomedical research. Although the applicants propose that the test should be freely usable for clinical purposes and in the interests of academic research, the IP (ownership of which would be shared among the Institutions involved in its development) would be subject to licensing for commercial use.
2) The use of machine learning methods in test data analysis, will stimulate interest from the computer and software industries, as well as computer science academics working in the healthcare and health informatics field. Individuals from these groups will be keen to engage in data sharing arrangements, and to benefit from the expertise of the investigators and researchers involved in the project. The involvement as project partner of Prof Chesi, who already has a high profile in both academic and industrial sectors, will greatly facilitate the recognition and uptake of collaborative opportunities during the lifetime of the project and within five to ten years after its completion.
3) Globalisation has provided an increasing number of opportunities for cooperation and collaboration with bioscientists working in developing nations, and the momentum that will be created by the need for parallel versions will immediately engage the academic and clinical communities in these countries, allowing them to interact and share information and expertise more widely. This will contribute to achieving the goals of global healthcare, and help to consolidate existing academic collaborations, foster fresh links, and facilitate industry involvement with increasing numbers of healthcare organisations worldwide.
4) The question of the true prevalence of young onset dementia syndromes such as frontotemporal dementia has not been fully and unequivocally resolved, though the problem is known to be more widespread and have greater socioeconomic impacts than had previously been recognized. An instrument that is sensitive to language changes characteristic of the two commonest causes of dementia before age 65, and to progression of mild abnormalities at 12 month follow-up would be a uniquely valuable tool in any investigation of the incidence and prevalence of such conditions. Accurate information would, in turn, inform health service policy, influence the importance given to young onset dementia research by charitable and public sector grant awarding bodies, and contribute over the longer term to an understanding of young onset dementia syndromes by the wider public.
5) Finally, the generic skills imparted to the research staff employed on this project would include not only those relevant to research (i.e. theory and technique, scientific data and project management) but also to the skills involved in collaboration across national boundaries (communication with other linguistic and cultural groups), which the effects of globalisation will render increasingly important to individual and national competitiveness.
Organisations
- St George's, University of London (Lead Research Organisation)
- Universidade de São Paulo (Collaboration)
- National and Kapodistrian University of Athens (Collaboration)
- San Carlos University Hospital (Collaboration)
- Hokkaido University (Collaboration)
- Prince of Wales Hospital Shatin (Collaboration)
- National University of Mar del Plata (Collaboration)
- National Centre for Scientific Research (NCSR) Demokritos (Collaboration)
- University of Cambridge (Project Partner)
- University of Salerno (Project Partner)
- Istituto Universitario di Studi Superiori di Pavia (Project Partner)
Publications
Patel N
(2021)
A 'Mini Linguistic State Examination' to Classify Primary Progressive Aphasia
in SSRN Electronic Journal
Patel N
(2022)
A 'Mini Linguistic State Examination' to classify primary progressive aphasia.
in Brain communications
Peterson K
(2021)
Language Disorder in Progressive Supranuclear Palsy and Corticobasal Syndrome: Neural Correlates and Detection by the MLSE Screening Tool
in Frontiers in Aging Neuroscience
Peterson KA
(2021)
Language impairment in progressive supranuclear palsy and corticobasal syndrome.
in Journal of neurology
Garcia Reitboeck P
(2017)
Neuromyelitis optica: Application of computer diagnostics to historical case reports.
in Journal of the history of the neurosciences
Patel N
(2019)
Perioperative Cerebral Microbleeds After Adult Cardiac Surgery.
in Stroke
Catricalà E
(2017)
SAND: a Screening for Aphasia in NeuroDegeneration. Development and normative data
in Neurological Sciences
Battista P
(2018)
Screening for Aphasia in NeuroDegeneration for the Diagnosis of Patients with Primary Progressive Aphasia: Clinical Validity and Psychometric Properties.
in Dementia and geriatric cognitive disorders
Matias-Guiu JA
(2021)
Spanish Version of the Mini-Linguistic State Examination for the Diagnosis of Primary Progressive Aphasia.
in Journal of Alzheimer's disease : JAD
Catricalà E
(2019)
The language profile of progressive supranuclear palsy.
in Cortex; a journal devoted to the study of the nervous system and behavior
Title | Longitudinal digital speech samples from AD patients |
Description | Transcripts of speech samples collected annually from members of the OPTIMA cohort in Oxford. |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2017 |
Provided To Others? | No |
Impact | Analysis in progress; a set of transcription conventions and methods for comparison and error reduction were produced (publication in progress) |
Title | Mini Language State Examination (MLSE) |
Description | A brief battery covering the principal domains of language processing, designed to classify and monitor progression, in a standardised and reproducible fashion, patients with primary progressive aphasia syndromes |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2011 |
Provided To Others? | Yes |
Impact | A grant proposal is in progress in collaboration with the University of Oxford to fund a formal validation of the instrument across the English speaking world and to obtain normative data for it. The application will be submitted to Alzheimer's Research UK in January 2012. |
Description | Argentinian Spanish adaptation of the MLSE |
Organisation | National University of Mar del Plata |
Country | Argentina |
Sector | Academic/University |
PI Contribution | Development and dissemination of the MLSE instrument at international conferences |
Collaborator Contribution | The MLSE collaborators were contacted by n Argentinian researcher interested in adapting the MLSE for use in Argentinian population of patients with primary progressive aphasia. |
Impact | The Argentinian group will participate in an application to fund an international consortium of researchers to create a structured shareable database of PPA patients described using profiles generated by the MLSE. |
Start Year | 2019 |
Description | Cross linguistic analysis of AD speech in English and Greek |
Organisation | National Centre for Scientific Research (NCSR) Demokritos |
Country | Greece |
Sector | Academic/University |
PI Contribution | Data sharing of the OPITMA transcripts used in three of the Cognitive Archaeology papers. |
Collaborator Contribution | Inclusion of SGUL as partners on a successful H2020 consortium application; employment of one postdoctoral research fellow and a research assistant. |
Impact | The collaboration is multidisciplinary, involving neuroscience and neurology (SGUL) in collaboration with European centres with expertise in data science, machine learning, computer science, and software development. There is a separate arm exploring the applicability of the iASiS platform to big data in non small cell lung cancer. |
Start Year | 2017 |
Description | Development of MLSE versions in languages other than English and Italian |
Organisation | National Centre for Scientific Research (NCSR) Demokritos |
Country | Greece |
Sector | Academic/University |
PI Contribution | Application for a featured research session entitled 'Cross-Cultural and Cross-Linguistic Aspects of Cognitive Assessment in Dementia' at the 2018 Alzheimer's Association International Conference (AAIC) in Chicago. |
Collaborator Contribution | Submission of abstracts to the session proposal. |
Impact | Nil yet. |
Start Year | 2018 |
Description | Development of MLSE versions in languages other than English and Italian |
Organisation | National University of Mar del Plata |
Country | Argentina |
Sector | Academic/University |
PI Contribution | Application for a featured research session entitled 'Cross-Cultural and Cross-Linguistic Aspects of Cognitive Assessment in Dementia' at the 2018 Alzheimer's Association International Conference (AAIC) in Chicago. |
Collaborator Contribution | Submission of abstracts to the session proposal. |
Impact | Nil yet. |
Start Year | 2018 |
Description | Development of MLSE versions in languages other than English and Italian |
Organisation | National and Kapodistrian University of Athens |
Country | Greece |
Sector | Academic/University |
PI Contribution | Application for a featured research session entitled 'Cross-Cultural and Cross-Linguistic Aspects of Cognitive Assessment in Dementia' at the 2018 Alzheimer's Association International Conference (AAIC) in Chicago. |
Collaborator Contribution | Submission of abstracts to the session proposal. |
Impact | Nil yet. |
Start Year | 2018 |
Description | Development of MLSE versions in languages other than English and Italian |
Organisation | Prince of Wales Hospital Shatin |
Country | Hong Kong |
Sector | Hospitals |
PI Contribution | Application for a featured research session entitled 'Cross-Cultural and Cross-Linguistic Aspects of Cognitive Assessment in Dementia' at the 2018 Alzheimer's Association International Conference (AAIC) in Chicago. |
Collaborator Contribution | Submission of abstracts to the session proposal. |
Impact | Nil yet. |
Start Year | 2018 |
Description | Japanese adaptation of the MLSE |
Organisation | Hokkaido University |
Country | Japan |
Sector | Academic/University |
PI Contribution | Development and dissemination of the MLSE instrument. |
Collaborator Contribution | A consortium of Japanese researchers interested in primary progressive aphasia contacted the MLSE research collaborators to discuss adaptation of the test for use in a Japanese speaking population. |
Impact | The Japanese consortium will form part of a multidisciplinary application to fund an international consortium of neurologists, speech therapists, and neuropscyhologists to assemble a shareable, structured database of PPA cases described using profiles generated by the MLSE. |
Start Year | 2020 |
Description | Japanese adaptation of the MLSE |
Organisation | Hokkaido University |
Country | Japan |
Sector | Academic/University |
PI Contribution | Development and dissemination of the MLSE instrument. |
Collaborator Contribution | A consortium of Japanese researchers interested in primary progressive aphasia contacted the MLSE research collaborators to discuss adaptation of the test for use in a Japanese speaking population. |
Impact | The Japanese consortium will form part of a multidisciplinary application to fund an international consortium of neurologists, speech therapists, and neuropscyhologists to assemble a shareable, structured database of PPA cases described using profiles generated by the MLSE. |
Start Year | 2020 |
Description | Portuguese adaptation of the MLSE |
Organisation | Universidade de São Paulo |
Department | Department of Neurology, Psychiatry and Medical Psychology |
Country | Brazil |
Sector | Academic/University |
PI Contribution | Development and dissemination of the MLSE instrument at international conferences |
Collaborator Contribution | The MLSE collaborators were contacted by a Brazilian researcher interested in adapting the MLSE for use in a Portuguese speaking population of patients with primary progressive aphasia. |
Impact | The Brazilian group will participate in an application to fund an international consortium of researchers to create a structured shareable database of PPA patients described using profiles generated by the MLSE. |
Start Year | 2021 |
Description | Spanish adaptation of the MLSE |
Organisation | San Carlos University Hospital |
Country | Spain |
Sector | Hospitals |
PI Contribution | Development and dissemination of the MLSE instrument at international conferences |
Collaborator Contribution | The MLSE collaborators were contacted by a Spanish researcher interested in adapting the MLSE for use in a Castilian Spanish speaking population of patients with primary progressive aphasia. |
Impact | The Spanish group will participate in an application to fund an international consortium of researchers to create a structured shareable database of PPA patients described using profiles generated by the MLSE. |
Start Year | 2020 |
Description | |
IP Reference | |
Protection | Protection not required |
Year Protection Granted | |
Licensed | Yes |
Impact | The MLSE has been adapted for use in the USA, Spain and Latin America |
Title | Electronic Mini Linguistic State Examination (eMLSE) |
Description | Displays the scoring pages of the MLSE on a handheld device and the stimuli on a desktop computer screen. Automatically calculates and displays scores for each patient. |
Type Of Technology | Webtool/Application |
Year Produced | 2023 |
Impact | Too early for any actual impact, but there is a great deal of interest in the instrument both within the UK and among the MLSE's overseas collaborators. |
Title | Novoic Ltd. |
Description | Online platform for assessment of cognitive status based on a recording of narrative speech. |
Type Of Technology | Webtool/Application |
Year Produced | 2019 |
Impact | Private equity has been invested and formal trials of the product are about to be launched. The MLSE will be used as a clinical reference point to assist with data interpretation. |
URL | http://novoic.com |
Description | Australian National Dementia Conference - keynote address |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited to deliver keynote address at the annual Australian Dementia Conference in Melbourne: the largest national conference on dementia in Australia. |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.informa.com.au/event/conference/national-dementia-conference/ |
Description | Inaugural lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I delivered my inaugural lecture as Professor of Neurology at St George's, University of London. It was published on YouTube, where it has been viewed 216 times at the date this entry was submitted. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.youtube.com/watch?v=mYYBGHGc4k8 |