Publications by authors named "Orla Hardiman"

315 Publications

Patterns of Language Impairment in Early Amyotrophic Lateral Sclerosis.

Neurol Clin Pract 2021 Oct;11(5):e634-e644

Academic Unit of Neurology (MP-G, BD, SO, LM, EC, MH, AV, OH, NP), Trinity Biomedical Sciences Institute, Trinity College Dublin; and Department of Psychology (MP-G, BD, SO, LM, EC, NP), Beaumont Hospital, Dublin, Ireland.

Objective: To investigate the incidence and nature of language change and its relationship to executive dysfunction in a population-based incident amyotrophic lateral sclerosis (ALS) sample, with the hypothesis that patterns of frontotemporal involvement in early ALS extend beyond areas of executive control to regions associated with language processing.

Methods: One hundred seventeen population-based incident ALS cases without dementia and 100 controls matched by age, sex, and education were included in the study. A detailed assessment of language processing including lexical processing, word spelling, word reading, word naming, semantic processing, and syntactic/grammatical processing was undertaken. Executive domains of phonemic verbal fluency, working memory, problem-solving, cognitive flexibility, and social cognition were also evaluated.

Results: Language processing was impaired in this incident cohort of individuals with ALS, with deficits in the domains of word naming, orthographic processing, and syntactic/grammatical processing. Conversely, phonological lexical processing and semantic processing were spared. Although executive dysfunction accounted in part for impairments in grammatical and orthographic lexical processing, word spelling, reading, and naming, primary language deficits were also present.

Conclusions: Language impairment is characteristic of ALS at early stages of the disease and can develop independently of executive dysfunction, reflecting selective patterns of frontotemporal involvement at disease onset. Language change is therefore an important component of the frontotemporal syndrome associated with ALS.
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http://dx.doi.org/10.1212/CPJ.0000000000001006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610537PMC
October 2021

Resting-state EEG reveals four subphenotypes of amyotrophic lateral sclerosis.

Brain 2021 Nov 17. Epub 2021 Nov 17.

Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, University of Dublin, Ireland.

Amyotrophic lateral sclerosis (ALS) is a devastating disease characterised primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. ALS is both clinically and biologically heterogeneous. Subgrouping is currently undertaken using clinical parameters, such as site of symptom onset (bulbar or spinal), burden of disease (based on the modified El Escorial Research Criteria) and genomics in those with familial disease. However, with the exception of genomics, these subcategories do not take into account underlying disease pathobiology, and are not fully predictive of disease course or prognosis. Recently, we have shown that resting-state EEG can reliably and quantitatively capture abnormal patterns of motor and cognitive network disruption in ALS. These network disruptions have been identified across multiple frequency bands, and using measures of neural activity (spectral power) and connectivity (co-modulation of activity by amplitude envelope correlation and synchrony by imaginary coherence) on source-localised brain oscillations from high-density EEG. Using data-driven methods (similarity network fusion and spectral clustering), we have now undertaken a clustering analysis to identify disease subphenotypes and to determine whether different patterns of disruption are predictive of disease outcome. We show that ALS patients (N = 95) can be subgrouped into four phenotypes with distinct neurophysiological profiles. These clusters are characterised by varying degrees of disruption in the somatomotor (α-band synchrony), frontotemporal (β-band neural activity and γl-band synchrony) and frontoparietal (γl-band co-modulation) networks, which reliably correlate with distinct clinical profiles and different disease trajectories. Using an in-depth stability analysis, we show that these clusters are statistically reproducible and robust, remain stable after re-assessment using a follow-up EEG session, and continue to predict the clinical trajectory and disease outcome. Our data demonstrate that novel phenotyping using neuroelectric signal analysis can distinguish disease subtypes based exclusively on different patterns of network disturbances. These patterns may reflect underlying disease neurobiology. The identification of ALS subtypes based on profiles of differential impairment in neuronal networks has clear potential in future stratification for clinical trials. Advanced network profiling in ALS can also underpin new therapeutic strategies that are based on principles of neurobiology and designed to modulate network disruption.
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http://dx.doi.org/10.1093/brain/awab322DOI Listing
November 2021

expression quantitative trait loci in amyotrophic lateral sclerosis are differentially expressed.

Brain Commun 2021 7;3(4):fcab236. Epub 2021 Oct 7.

Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience King's College London, 5 Cutcombe Road, London SE5 9RT, UK.

Evidence indicates that common variants found in genome-wide association studies increase risk of disease through gene regulation via expression Quantitative Trait Loci. Using multiple genome-wide methods, we examined if Single Nucleotide Polymorphisms increase risk of Amyotrophic Lateral Sclerosis through expression Quantitative Trait Loci, and whether expression Quantitative Trait Loci expression is consistent across people who had Amyotrophic Lateral Sclerosis and those who did not. In combining public expression Quantitative Trait Loci data with Amyotrophic Lateral Sclerosis genome-wide association studies, we used Summary-data-based Mendelian Randomization to confirm that was the only gene that was genome-wide significant in mediating Amyotrophic Lateral Sclerosis risk via expression Quantitative Trait Loci (Summary-data-based Mendelian Randomization beta = 0.20, standard error = 0.04, -value = 4.29 × 10). Using motor cortex, we tested whether expression Quantitative Trait Loci showed significant differences in expression between Amyotrophic Lateral Sclerosis ( = 76) and controls ( = 25), genome-wide. Of 20 757 genes analysed, the two most significant expression Quantitative Trait Loci to show differential in expression between Amyotrophic Lateral Sclerosis and controls involve two known Amyotrophic Lateral Sclerosis genes ( and ). -acting expression Quantitative Trait Loci downstream of the gene showed significant differences in expression between Amyotrophic Lateral Sclerosis and controls (top expression Quantitative Trait Loci beta = 0.34, standard error = 0.063, -value = 4.54 × 10). These expression Quantitative Trait Loci also significantly modified Amyotrophic Lateral Sclerosis survival (number of samples = 4265, hazard ratio = 1.11, 95% confidence interval = 1.05-1.17, -value = 2.06 × 10) and act as an Amyotrophic Lateral Sclerosis trans-expression Quantitative Trait Loci hotspot for a wider network of genes enriched for function and Amyotrophic Lateral Sclerosis pathways. Using gene-set analyses, we found the genes that correlate with this trans-expression Quantitative Trait Loci hotspot significantly increase risk of Amyotrophic Lateral Sclerosis (beta = 0.247, standard deviation = 0.017, = 0.001) and schizophrenia (beta = 0.263, standard deviation = 0.008, -value = 1.18 × 10), a disease that genetically correlates with Amyotrophic Lateral Sclerosis. In summary, expression Quantitative Trait Loci are a major factor in Amyotrophic Lateral Sclerosis, not only influencing disease risk but are differentially expressed in Amyotrophic Lateral Sclerosis. expression Quantitative Trait Loci show distinct expression profiles in Amyotrophic Lateral Sclerosis that correlate with a wider network of genes that also confer risk of the disease and modify the disease's duration.
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http://dx.doi.org/10.1093/braincomms/fcab236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545614PMC
October 2021

Propagation patterns in motor neuron diseases: Individual and phenotype-associated disease-burden trajectories across the UMN-LMN spectrum of MNDs.

Neurobiol Aging 2021 Oct 8;109:78-87. Epub 2021 Oct 8.

Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, Ireland; Pitié-Salpêtrière University Hospital, Sorbonne University, Paris, France. Electronic address:

Motor neuron diseases encompass a divergent group of conditions with considerable differences in clinical manifestations, survival, and genetic vulnerability. One of the key aspects of clinical heterogeneity is the preferential involvement of upper (UMN) and lower motor neurons (LMN). While longitudinal imaging patters are relatively well characterized in ALS, progressive cortical changes in UMN,- and LMN-predominant conditions are seldom evaluated. Accordingly, the objective of this study is the juxtaposition of longitudinal trajectories in 3 motor neuron phenotypes; a UMN-predominant syndrome (PLS), a mixed UMN-LMN condition (ALS), and a lower motor neuron condition (poliomyelitis survivors). A standardized imaging protocol was implemented in a prospective, multi-timepoint longitudinal study with a uniform follow-up interval of 4 months. Forty-five poliomyelitis survivors, 61 patients with amyotrophic lateral sclerosis (ALS), and 23 patients with primary lateral sclerosis (PLS) were included. Cortical thickness alterations were evaluated in a dual analysis pipeline, using standard cortical thickness analyses, and a z-score-based individualized approach. Our results indicate that PLS patients exhibit rapidly progressive cortical thinning primarily in motor regions; ALS patients show cortical atrophy in both motor and extra-motor regions, while poliomyelitis survivors exhibit cortical thickness gains in a number of cerebral regions. Our findings suggest that dynamic cortical changes in motor neuron diseases may depend on relative UMN and/or LMN involvement, and increased cortical thickness in LMN-predominant conditions may represent compensatory, adaptive processes.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.031DOI Listing
October 2021

Correlations between measures of ALS respiratory function: is there an alternative to FVC?

Amyotroph Lateral Scler Frontotemporal Degener 2021 11 30;22(7-8):495-504. Epub 2021 Sep 30.

Academic Unit of Neurology, Trinity College Dublin, Dublin, Ireland.

An ongoing longitudinal study in six European sites includes a 3-monthly assessment of forced vital capacity (FVC), slow vital capacity (SVC), peak cough flow (PCF), and Sniff nasal inspiratory pressure (SNIP). The aim of this interim analysis was to assess the potential for SNIP to be a surrogate for aerosol generating procedures given COVID-19 related restrictions. : This was a prospective observational study. Patients attending six study sites with King's Stage 2 or 3 ALS completed baseline FVC/SVC/SNIP/PCF and repeated assessments 3 monthly. Data were collected from March 2018 to March 2020, after which a COVID-19 related study suspension was imposed. Correlations between the measures were calculated. A Bayesian multiple outcomes random-effects model was constructed to investigate rates of decline across measures. : In total, 270 cases and 828 assessments were included (Mean age 65.2 ± 15.4 years; 32.6% Female; 60% Kings stage 2; 81.1% spinal onset). FVC and SVC were the most closely correlated outcomes (0.95). SNIP showed the least correlation with other metrics 0.53 (FVC), 0.54 (SVC), 0.60 (PCF). All four measures significantly declined over time. SNIP in the bulbar onset group showed the fastest rate of decline. : SNIP was not well correlated with FVC and SVC, probably because it examines a different aspect of respiratory function. Respiratory measures declined over time, but differentially according to the site of onset. SNIP is not a surrogate for FVC and SVC, but is a complementary measure, declining linearly and differentiating spinal and bulbar onset patients.
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http://dx.doi.org/10.1080/21678421.2021.1908362DOI Listing
November 2021

Pathological neural networks and artificial neural networks in ALS: diagnostic classification based on pathognomonic neuroimaging features.

J Neurol 2021 Sep 28. Epub 2021 Sep 28.

Computational Neuroimaging Group, Trinity Biomedical Sciences Institute, Trinity College Dublin, Room 5.43, Pearse Street, Dublin 2, Ireland.

The description of group-level, genotype- and phenotype-associated imaging traits is academically important, but the practical demands of clinical neurology centre on the accurate classification of individual patients into clinically relevant diagnostic, prognostic and phenotypic categories. Similarly, pharmaceutical trials require the precision stratification of participants based on quantitative measures. A single-centre study was conducted with a uniform imaging protocol to test the accuracy of an artificial neural network classification scheme on a cohort of 378 participants composed of patients with ALS, healthy subjects and disease controls. A comprehensive panel of cerebral volumetric measures, cortical indices and white matter integrity values were systematically retrieved from each participant and fed into a multilayer perceptron model. Data were partitioned into training and testing and receiver-operating characteristic curves were generated for the three study-groups. Area under the curve values were 0.930 for patients with ALS, 0.958 for disease controls, and 0.931 for healthy controls relying on all input imaging variables. The ranking of variables by classification importance revealed that white matter metrics were far more relevant than grey matter indices to classify single subjects. The model was further tested in a subset of patients scanned within 6 weeks of their diagnosis and an AUC of 0.915 was achieved. Our study indicates that individual subjects may be accurately categorised into diagnostic groups in an observer-independent classification framework based on multiparametric, spatially registered radiology data. The development and validation of viable computational models to interpret single imaging datasets are urgently required for a variety of clinical and clinical trial applications.
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http://dx.doi.org/10.1007/s00415-021-10801-5DOI Listing
September 2021

A Road Map for Remote Digital Health Technology for Motor Neuron Disease.

J Med Internet Res 2021 09 22;23(9):e28766. Epub 2021 Sep 22.

Department of Neuroscience, Sheffield Institute for Translational Neuroscien, University of Sheffield, Sheffield, United Kingdom.

Despite recent and potent technological advances, the real-world implementation of remote digital health technology in the care and monitoring of patients with motor neuron disease has not yet been realized. Digital health technology may increase the accessibility to and personalization of care, whereas remote biosensors could optimize the collection of vital clinical parameters, irrespective of patients' ability to visit the clinic. To facilitate the wide-scale adoption of digital health care technology and to align current initiatives, we outline a road map that will identify clinically relevant digital parameters; mediate the development of benefit-to-burden criteria for innovative technology; and direct the validation, harmonization, and adoption of digital health care technology in real-world settings. We define two key end products of the road map: (1) a set of reliable digital parameters to capture data collected under free-living conditions that reflect patient-centric measures and facilitate clinical decision making and (2) an integrated, open-source system that provides personalized feedback to patients, health care providers, clinical researchers, and caregivers and is linked to a flexible and adaptable platform that integrates patient data in real time. Given the ever-changing care needs of patients and the relentless progression rate of motor neuron disease, the adoption of digital health care technology will significantly benefit the delivery of care and accelerate the development of effective treatments.
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http://dx.doi.org/10.2196/28766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495582PMC
September 2021

Imaging data indicate cerebral reorganisation in poliomyelitis survivors: Possible compensation for longstanding lower motor neuron pathology.

Data Brief 2021 Oct 21;38:107316. Epub 2021 Aug 21.

Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, Ireland.

A standardised, single-centre cross-sectional imaging protocol was utilised to investigate cortical grey matter and cerebral white matter alterations in 36 poliomyelitis survivors in contrast to healthy individuals and patients with amyotrophic lateral sclerosis (ALS) as a 'disease-control' group. [1] T1-weighted imaging and 32-direction diffusion tensor imaging data were obtained on a 3 Tesla Philips Achieva MRI system, using an IR-SPGR sequence and SE-EPI sequence respectively. Raw region-of-interest data and percentage change with respect to reference estimated marginal mean values are presented for grey and white matter metrics in key anatomical regions. Poliomyelitis survivors exhibit no frank grey or white matter degeneration. To the contrary, increased partial volumes can be detected in the brainstem, cerebellum and occipital lobes compared to healthy individuals. Higher fractional anisotropy was also noted in the corticospinal tracts, cerebellum, bilateral mesial temporal lobes and inferior frontal brain regions in poliomyelitis survivors in contrast to controls. Anatomical patterns of superior integrity metrics in polio survivors were concordant with anatomical regions of focal degeneration in ALS. Our imaging data indicate cortical and white matter reorganisation in polio survivors, which may be interpreted as compensatory adaptation to severe lower motor neuron injury acquired in infancy.
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http://dx.doi.org/10.1016/j.dib.2021.107316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397913PMC
October 2021

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

JAMA Neurol 2021 Oct;78(10):1236-1248

Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.

Objective: To identify the genetic variants associated with juvenile ALS.

Design, Setting, And Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.

Main Outcomes And Measures: De novo variants present only in the index case and not in unaffected family members.

Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.

Conclusions And Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.
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http://dx.doi.org/10.1001/jamaneurol.2021.2598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406220PMC
October 2021

Informal Caregivers in Amyotrophic Lateral Sclerosis: A Multi-Centre, Exploratory Study of Burden and Difficulties.

Brain Sci 2021 Aug 20;11(8). Epub 2021 Aug 20.

Academic Unit of Neurology, School of Medicine, Trinity College Dublin, D02 PN40 Dublin, Ireland.

Amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND) is a systemic and fatal neurodegenerative condition for which there is currently no cure. Informal caregivers play a vital role in supporting the person with ALS, and it is essential to support their wellbeing. This multi-centre, mixed methods descriptive exploratory study describes the complexity of burden and self-defined difficulties as described by the caregivers themselves. Quantitative and qualitative data were collected during face-to-face interviews with informal caregivers from centres in the Netherlands, England, and Ireland. Standardised measures assessed burden, quality of life, and psychological distress; furthermore, an open-ended question was asked about difficult aspects of caregiving. Most caregivers were female, spouse/partners, and lived with the person with ALS for whom they provided care. Significant differences between national cohorts were identified for burden, quality of life, and anxiety. Among the difficulties described were the practical issues associated with the caregiver role and emotional factors such as witnessing a patient's health decline, relationship change, and their own distress. The mixed-methods approach allows for a more nuanced understanding of the burden and difficulties experienced. It is important to generate an evidence base to support the psychosocial wellbeing and brain health of informal caregivers.
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http://dx.doi.org/10.3390/brainsci11081094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394559PMC
August 2021

Medical therapies for amyotrophic lateral sclerosis-related respiratory decline: an appraisal of needs, opportunities and obstacles.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Aug 14:1-10. Epub 2021 Aug 14.

Neurological Institute of New York, Columbia University, New York, NY, USA.

A roundtable convened in July 2020 examined issues concerning respiratory support in amyotrophic lateral sclerosis (ALS), with reference to the potential for an early-phase orally administered medication that might either postpone the introduction of noninvasive ventilation (NIV) and/or enhance the benefits to be gained from it. Attention was also given to the impact of the COVID-19 pandemic on usual practice in the assessment and management of ALS-related respiratory difficulties. Implementation of NIV marks a step-change in clinical status for patients and a major increase in burden for caregivers. All means to ease this transition should be explored: an oral therapy that supported respiratory function and patients' independence and sense of well-being would aid discussions to facilitate the eventual successful introduction of NIV. Assessment of a candidate oral therapy that might support respiratory function in ALS patients would be aided by the development of improved patient-reported outcome measures for robust quantification of treatment effect and quality of life. Such instruments could also be used to monitor patients' status during the COVID-19 pandemic, averting some of the risks of face-to-face assessment plus the patient burden and costs of traditional methods. Several oral candidate therapies have recently failed to meet their primary endpoints in clinical trials. However, understanding of the underlying physiology and appropriate trial design have grown and will inform future developments in this field.
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http://dx.doi.org/10.1080/21678421.2021.1920981DOI Listing
August 2021

FRONTotemporal dementia Incidence European Research Study-FRONTIERS: Rationale and design.

Alzheimers Dement 2021 Aug 2. Epub 2021 Aug 2.

Center for Neurodegenerative Diseases and the Aging Brain, Pia Fondazione di Culto e Religione, Cardinale Giovanni Panico, University of Bari-Aldo Moro, Bari, Italy.

Introduction: The incidence of Frontotemporal Lobar Degeneration (FTLD)-related disorders and their characteristics are not well known. The "FRONTotemporal dementia Incidence European Research Study" (FRONTIERS) is designed to fill this gap.

Methods: FRONTIERS is a European prospective, observational population study based on multinational registries. FRONTIERS comprises 11 tertiary referral centers across Europe with long-lasting experience in FTLD-related disorders and comprehensive regional referral networks, enabling incidence estimation over well-defined geographical areas.

Endpoints: The primary endpoints are (1) the incidence of FTLD-related disorders across Europe; (2) geographic trends of FTLD-related disorders; (3) the distribution of FTLD phenotypes in different populations and ethnicities in Europe; (4) inheritance of FTLD-related disorders, including the frequencies of monogenic FTLD as compared to overall disease burden; and (5) implementation of data banking for clinical and biological material.

Expected Impacts: FRONTIERS will improve the understanding of FTLD-related disorders and their epidemiology, promoting appropriate public health service policies and treatment strategies.
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http://dx.doi.org/10.1002/alz.12414DOI Listing
August 2021

Innovating Clinical Trials for Amyotrophic Lateral Sclerosis: Challenging the Established Order.

Neurology 2021 09 27;97(11):528-536. Epub 2021 Jul 27.

From the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.

Development of effective treatments for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology, and methodologic design challenges. We have evaluated 2 major themes in the design of pivotal, phase 3 clinical trials for ALS-(1) patient selection and (2) analytical strategy-and discussed potential solutions with the European Medicines Agency. Several design considerations were assessed using data from 5 placebo-controlled clinical trials (n = 988), 4 population-based cohorts (n = 5,100), and 2,436 placebo-allocated patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework that naturally adapts the trial duration when inaccurate assumptions are made at the design stage, such as enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria, and minimizing exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve as a blueprint for future clinical trials in this population.
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http://dx.doi.org/10.1212/WNL.0000000000012545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456357PMC
September 2021

Evaluation and categorisation of individual patients based on white matter profiles: Single-patient diffusion data interpretation in neurodegeneration.

J Neurol Sci 2021 09 21;428:117584. Epub 2021 Jul 21.

Computational Neuroimaging Group, Trinity College Dublin, Dublin, Ireland; Pitié-Salpêtrière University Hospital, Sorbonne University, Paris, France. Electronic address:

The majority of radiology studies in neurodegenerative conditions infer group-level imaging traits from group comparisons. While this strategy is helpful to define phenotype-specific imaging signatures for academic use, the meaningful interpretation of single scans of individual subjects is more important in everyday clinical practice. Accordingly, we present a computational method to evaluate individual subject diffusion tensor data to highlight white matter integrity alterations. Fifty white matter tracts were quantitatively evaluated in 132 patients with amyotrophic lateral sclerosis (ALS) with respect to normative values from 100 healthy subjects. Fractional anisotropy and radial diffusivity alterations were assessed individually in each patient. The approach was validated against standard tract-based spatial statistics and further scrutinised by the assessment of 78 additional data sets with a blinded diagnosis. Our z-score-based approach readily detected white matter degeneration in individual ALS patients and helped to categorise single subjects with a 'blinded diagnosis' as likely 'ALS' or 'control'. The group-level inferences from the z-score-based approach were analogous to the standard TBSS output maps. The benefit of the z-score-based strategy is that it enables the interpretation of single DTI datasets as well as the comparison of study groups. Outputs can be summarised either visually by highlighting the affected tracts, or, listing the affected tracts in a text file with reference to normative data, making it particularly useful for clinical applications. While individual diffusion data cannot be visually appraised, our approach provides a viable framework for single-subject imaging data interpretation.
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http://dx.doi.org/10.1016/j.jns.2021.117584DOI Listing
September 2021

Genotype-associated cerebellar profiles in ALS: focal cerebellar pathology and cerebro-cerebellar connectivity alterations.

J Neurol Neurosurg Psychiatry 2021 Nov 24;92(11):1197-1205. Epub 2021 Jun 24.

Computational Neuroimaging Group, Trinity College Dublin, Dublin, Ireland.

Objective: Cerebellar disease burden and cerebro-cerebellar connectivity alterations are poorly characterised in amyotrophic lateral sclerosis (ALS) despite the likely contribution of cerebellar pathology to the clinical heterogeneity of the condition.

Methods: A prospective imaging study has been undertaken with 271 participants to systematically evaluate cerebellar grey and white matter alterations, cerebellar peduncle integrity and cerebro-cerebellar connectivity in ALS. Participants were stratified into four groups: (1) patients testing positive for GGGGCC repeat expansions in , (2) patients carrying an intermediate-length repeat expansion in , (3) patients without established ALS-associated mutations and (4) healthy controls. Additionally, the cerebellar profile of a single patient with ALS who had an allele length of 62 was evaluated. Cortical thickness, grey matter and white matter volumes were calculated in each cerebellar lobule complemented by morphometric analyses to characterise genotype-associated atrophy patterns. A Bayesian segmentation algorithm was used for superior cerebellar peduncle volumetry. White matter diffusivity parameters were appraised both within the cerebellum and in the cerebellar peduncles. Cerebro-cerebellar connectivity was assessed using deterministic tractography.

Results: Cerebellar pathology was confined to lobules I-V of the anterior lobe in patients with sporadic ALS in contrast to the considerable posterior lobe and vermis disease burden identified in mutation carriers. Patients with intermediate expansions did not exhibit significant cerebellar pathology.

Conclusions: Focal rather than global cerebellar degeneration characterises ALS. Pathognomonic ALS symptoms which are typically attributed to other anatomical regions, such as dysarthria, dysphagia, pseudobulbar affect, eye movement abnormalities and cognitive deficits, may be modulated, exacerbated or partially driven by cerebellar changes in ALS.
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http://dx.doi.org/10.1136/jnnp-2021-326854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522463PMC
November 2021

Prediction of caregiver quality of life in amyotrophic lateral sclerosis using explainable machine learning.

Sci Rep 2021 06 10;11(1):12237. Epub 2021 Jun 10.

School of Computer Science, University College Dublin, Dublin 4, Ireland.

Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative, fatal and currently incurable disease. People with ALS need support from informal caregivers due to the motor and cognitive decline caused by the disease. This study aims to identify caregivers whose quality of life (QoL) may be impacted as a result of caring for a person with ALS. In this study, we worked towards the identification of the predictors of a caregiver's QoL in addition to the development of a model for clinical use to alert clinicians when a caregiver is at risk of experiencing low QoL. The data were collected through the Irish ALS Registry and via interviews on several topics with 90 patient and caregiver pairs at three time-points. The McGill QoL questionnaire was used to assess caregiver QoL-the MQoL Single Item Score measures the overall QoL and was selected as the outcome of interest in this work. The caregiver's existential QoL and burden, as well as the patient's depression and employment before the onset of symptoms were the features that had the highest impact in predicting caregiver quality of life. A small subset of features that could be easy to collect was used to develop a second model to use it in a clinical setting. The most predictive features for that model were the weekly caregiving duties, age and health of the caregiver, as well as the patient's physical functioning and age of onset.
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http://dx.doi.org/10.1038/s41598-021-91632-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192926PMC
June 2021

The patient's perspective of remote respiratory assessments during the COVID-19 pandemic.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Jun 7:1-5. Epub 2021 Jun 7.

Department of Physiotherapy, Beaumont Hospital, Dublin, Ireland.

Forced vital capacity (FVC) is an essential respiratory measurement for assessment and monitoring of patients with Amyotrophic Lateral Sclerosis (ALS). Our clinic rapidly implemented remote assessment of FVC after COVID-19 related restrictions on respiratory testing were imposed, using mini-spirometers and video consultation. We sought to evaluate the patient's experiences of performing remote respiratory assessments to guide future development and optimisation of the service. Twenty-five patients completed surveys. The mean age was 65.2 years and average time from diagnosis was 17.04 (2-99) months. Seventy-two percent ( = 18) required help from a caregiver to perform the tests. Ninety-two percent ( = 23) of patients reported that overall, they were satisfied and were happy to continue with remote respiratory assessment. Reducing the number of clinic visits for review and assessment was valued by 92% ( = 23) and reducing the risk associated with COVID-19 was valued by 96% ( = 24). The highest frequency reported as acceptable for performing the remote breathing assessments was monthly (60%,  = 15), followed by every second month (28%,  = 7). Remote respiratory testing is viewed positively by patients. These technologies used in combination with video-consultations and other novel forms of remote monitoring implemented in response to the COVID-19 crisis will continue to be valuable tools for clinical care in future. However, further evaluation of the validity of remote respiratory assessment is required.
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http://dx.doi.org/10.1080/21678421.2021.1920982DOI Listing
June 2021

Pathophysiology and Treatment of Non-motor Dysfunction in Amyotrophic Lateral Sclerosis.

CNS Drugs 2021 05 15;35(5):483-505. Epub 2021 May 15.

Brain and Mind Centre, The University of Sydney, 94 Mallett Street, Camperdown, NSW, Australia.

Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease typically presenting with bulbar or limb weakness. There is increasing evidence that amyotrophic lateral sclerosis is a multisystem disease with early and frequent impacts on cognition, behaviour, sleep, pain and fatigue. Dysfunction of normal physiological and metabolic processes also appears common. Evidence from pre-symptomatic studies and large epidemiological cohorts examining risk factors for the future development of amyotrophic lateral sclerosis have reported a high prevalence of changes in behaviour and mental health before the emergence of motor weakness. This suggests that changes beyond the motor system are underway at an early stage with dysfunction across brain networks regulating a variety of cognitive, behavioural and other homeostatic processes. The full impact of non-motor dysfunction continues to be established but there is now sufficient evidence that the presence of non-motor symptoms impacts overall survival in amyotrophic lateral sclerosis, and with up to 80% reporting non-motor symptoms, there is an urgent need to develop more robust therapeutic approaches. This review provides a contemporary overview of the pathobiology of non-motor dysfunction, offering readers a practical approach with regard to assessment and management. We review the current evidence for pharmacological and non-pharmacological treatment of non-motor dysfunction in amyotrophic lateral sclerosis and highlight the need to further integrate non-motor dysfunction as an important outcome measure for future clinical trial design.
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http://dx.doi.org/10.1007/s40263-021-00820-1DOI Listing
May 2021

Infratentorial pathology in frontotemporal dementia: cerebellar grey and white matter alterations in FTD phenotypes.

J Neurol 2021 Dec 13;268(12):4687-4697. Epub 2021 May 13.

Computational Neuroimaging Group, Trinity Biomedical Sciences Institute, Trinity College Dublin, Peter Bede, Room 5.43, Pearse Street, Dublin 2, Ireland.

The contribution of cerebellar pathology to cognitive and behavioural manifestations is increasingly recognised, but the cerebellar profiles of FTD phenotypes are relatively poorly characterised. A prospective, single-centre imaging study has been undertaken with a high-resolution structural and diffusion tensor protocol to systematically evaluate cerebellar grey and white matter alterations in behavioural-variant FTD(bvFTD), non-fluent variant primary progressive aphasia(nfvPPA), semantic-variant primary progressive aphasia(svPPA), C9orf72-positive ALS-FTD(C9 + ALSFTD) and C9orf72-negative ALS-FTD(C9-ALSFTD). Cerebellar cortical thickness and complementary morphometric analyses were carried out to appraise atrophy patterns controlling for demographic variables. White matter integrity was assessed in a study-specific white matter skeleton, evaluating three diffusivity metrics: fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD). Significant cortical thickness reductions were identified in: lobule VII and crus I in bvFTD; lobule VI VII, crus I and II in nfvPPA; and lobule VII, crus I and II in svPPA; lobule IV, VI, VII and Crus I and II in C9 + ALSFTD. Morphometry revealed volume reductions in lobule V in all groups; in addition to lobule VIII in C9 + ALSFTD; lobule VI, VIII and vermis in C9-ALSFTD; lobule V, VII and vermis in bvFTD; and lobule V, VI, VIII and vermis in nfvPPA. Widespread white matter alterations were demonstrated by significant fractional anisotropy, axial diffusivity and radial diffusivity changes in each FTD phenotype that were more focal in those with C9 + ALSFTD and svPPA. Our findings indicate that FTD subtypes are associated with phenotype-specific cerebellar signatures with the selective involvement of specific lobules instead of global cerebellar atrophy.
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http://dx.doi.org/10.1007/s00415-021-10575-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563547PMC
December 2021

Cognitive network hyperactivation and motor cortex decline correlate with ALS prognosis.

Neurobiol Aging 2021 08 10;104:57-70. Epub 2021 Mar 10.

Academic Unit of Neurology, Trinity College Dublin, the University of Dublin, Dublin 2, Ireland.

We aimed to quantitatively characterize progressive brain network disruption in Amyotrophic Lateral Sclerosis (ALS) during cognition using the mismatch negativity (MMN), an electrophysiological index of attention switching. We measured the MMN using 128-channel EEG longitudinally (2-5 timepoints) in 60 ALS patients and cross-sectionally in 62 healthy controls. Using dipole fitting and linearly constrained minimum variance beamforming we investigated cortical source activity changes over time. In ALS, the inferior frontal gyri (IFG) show significantly lower baseline activity compared to controls. The right IFG and both superior temporal gyri (STG) become progressively hyperactive longitudinally. By contrast, the left motor and dorsolateral prefrontal cortices are initially hyperactive, declining progressively. Baseline motor hyperactivity correlates with cognitive disinhibition, and lower baseline IFG activities correlate with motor decline rate, while left dorsolateral prefrontal activity predicted cognitive and behavioural impairment. Shorter survival correlates with reduced baseline IFG and STG activity and later STG hyperactivation. Source-resolved EEG facilitates quantitative characterization of symptom-associated and symptom-preceding motor and cognitive-behavioral cortical network decline in ALS.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.03.002DOI Listing
August 2021

Development and Psychometric Evaluation of Alternate Short Forms of the Action Naming Test.

Arch Clin Neuropsychol 2021 Apr 5. Epub 2021 Apr 5.

Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.

Objective: The action naming test (ANT) is a confrontation naming task used to assess the ability to name action words. This study aimed to create two short forms of the ANT and assess their equivalence, reliability, and comparability to the long form.

Methods: In total, 100 healthy adults (31 females and 69 males), aged 34-89 years (M = 64 and SD = 10.4) were recruited. Short forms were developed using a split-half procedure.

Results: No significant differences were observed between short forms on mean performance and distribution of scores for correct spontaneous responses, responses after semantic cue and total correct responses after cueing, but a higher number of accurate responses were prompted after phonemic cueing for Form A. Significant strong correlations between short forms and with the full form were encountered, although a weak correlation was found between short forms on performance after semantic cueing. IQ and age were significant predictors of action word retrieval. Whereas IQ also predicted post-cueing performance in all ANT forms, age predicted performance only for Form B.

Conclusion: The two ANT short forms are equivalent when considering total spontaneous responses and total correct responses after cueing, but semantic and phonemic cues evoked different responses on the two forms. The two short forms were also affected differently by demographics. When the psychometric equivalence of Forms A and B was examined, the strict conditions for parallel forms were not met for all performance indices. Therefore, these newly developed short versions should be considered as alternate forms.
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http://dx.doi.org/10.1093/arclin/acab013DOI Listing
April 2021

Noninvasive ventilation use by patients enrolled in VITALITY-ALS.

Amyotroph Lateral Scler Frontotemporal Degener 2021 11 1;22(7-8):486-494. Epub 2021 Apr 1.

St. Joseph's Hospital and Medical Cente, Barrow Neurological Institute, Phoenix, AZ, USA.

To evaluate the prescribing practices of noninvasive ventilation (NIV) and patient compliance during VITALITY-ALS. VITALITY-ALS enrolled patients with a slow vital capacity (SVC) ≥70% of predicted who were not using NIV at screening. Physicians prescribed NIV without restriction following randomization. Reason(s) for NIV prescription, dates prescribed and initiated, and compliance were recorded. Compliance was recorded as prescribed but never initiated, used ≥2 h/24 h, used ≥4 h/24 h, or used ≥22 h/24 h. In addition to other outcome measures, SVC and the revised ALS functional rating scale (ALSFRS-R) were performed at all visits. Patients were followed up to 56 weeks. 565 patients were randomized and dosed with placebo or in VITALITY-ALS; 195 (34.5%) were prescribed NIV: of these, 78.5% used it for ≥2 h/24 h, 71.3% for ≥4 h/24 h, and 11.8% for ≥22 h/24 h. The three most common reasons NIV was prescribed were decline in vital capacity, respiratory symptoms, and sleep-related symptoms. During the trial, 179/565 (31.7%) patients had a decline of SVC below 50%; of these patients, 122/179 (68.2%) were prescribed NIV. Reasons for prescribing NIV were different for patients from North America compared with Europe. Despite allowing for NIV initiation at any point following randomization in VITALITY-ALS, only slightly more than two out of three patients whose SVC fell below 50% were prescribed NIV; this was similar in Europe and in North America. Underutilization of NIV could influence survival outcomes in patients with ALS including those involved in clinical trials.
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http://dx.doi.org/10.1080/21678421.2021.1904993DOI Listing
November 2021

Increased cerebral integrity metrics in poliomyelitis survivors: putative adaptation to longstanding lower motor neuron degeneration.

J Neurol Sci 2021 May 21;424:117361. Epub 2021 Feb 21.

Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, Ireland. Electronic address:

Background: Post-polio syndrome (PPS) has been traditionally considered a slowly progressive condition that affects poliomyelitis survivors decades after their initial infection. Cerebral changes in poliomyelitis survivors are poorly characterised and the few existing studies are strikingly conflicting.

Objective: The overarching aim of this study is the comprehensive characterisation of cerebral grey and white matter alterations in poliomyelitis survivors with reference to healthy- and disease-controls using quantitative imaging metrics.

Methods: Thirty-six poliomyelitis survivors, 88 patients with ALS and 117 healthy individuals were recruited in a prospective, single-centre neuroimaging study using uniform MRI acquisition parameters. All participants underwent standardised clinical assessments, T1-weighted structural and diffusion tensor imaging. Whole-brain and region-of-interest morphometric analyses were undertaken to evaluate patterns of grey matter changes. Tract-based spatial statistics were performed to evaluate diffusivity alterations in a study-specific whiter matter skeleton.

Results: In contrast to healthy controls, poliomyelitis survivors exhibited increased grey matter partial volumes in the brainstem, cerebellum and occipital lobe, accompanied by increased FA in the corticospinal tracts, cerebellum, bilateral mesial temporal lobes and inferior frontal tracts. Polio survivors exhibited increased integrity metrics in the same anatomical regions where ALS patients showed degenerative changes.

Conclusions: Our findings indicate considerable cortical and white matter reorganisation in poliomyelitis survivors which may be interpreted as compensatory, adaptive change in response to severe lower motor neuron injury in infancy.
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http://dx.doi.org/10.1016/j.jns.2021.117361DOI Listing
May 2021

Discrete choice experiment for eliciting preference for health services for patients with ALS and their informal caregivers.

BMC Health Serv Res 2021 Mar 9;21(1):213. Epub 2021 Mar 9.

Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.

Background: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative condition with a mean life expectancy of 3 years from first symptom. Understanding the factors that are important to both patients and their caregivers has the potential to enhance service delivery and engagement, and improve efficiency. The Discrete Choice Experiment (DCE) is a stated preferences method which asks service users to make trade-offs for various attributes of health services. This method is used to quantify preferences and shows the relative importance of the attributes in the experiment, to the service user.

Methods: A DCE with nine choice sets was developed to measure the preferences for health services of ALS patients and their caregivers and the relative importance of various aspects of care, such as timing of care, availability of services, and decision making. The DCE was presented to patients with ALS, and their caregivers, recruited from a national multidisciplinary clinic. A random effects probit model was applied to estimate the impact of each attribute on a participant's choice.

Results: Patients demonstrated the strongest preferences about timing of receiving information about ALS. A strong preference was also placed on seeing the hospice care team later rather than early on in the illness. Patients also indicated their willingness to consider the use of communication devices. Grouping by stage of disease, patients who were in earlier stages of disease showed a strong preference for receipt of extensive information about ALS at the time of diagnosis. Caregivers showed a strong preference for engagement with healthcare professionals, an attribute that was not prioritised by patients.

Conclusions: The DCE method can be useful in uncovering priorities of patients and caregivers with ALS. Patients and caregivers have different priorities relating to health services and the provision of care in ALS, and patient preferences differ based on the stage and duration of their illness. Multidisciplinary teams must calibrate the delivery of care in the context of the differing expectations, needs and priorities of the patient/caregiver dyad.
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http://dx.doi.org/10.1186/s12913-021-06191-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941893PMC
March 2021

Extra-motor manifestations in post-polio syndrome (PPS): fatigue, cognitive symptoms and radiological features.

Neurol Sci 2021 Nov 26;42(11):4569-4581. Epub 2021 Feb 26.

Computational Neuroimaging Group, Trinity Biomedical Sciences Institute, Trinity College Dublin, Room 5.43, Pearse Street, Dublin 2, Ireland.

Background: There is a paucity of cerebral neuroimaging studies in post-polio syndrome (PPS), despite the severity of neurological and neuropsychological sequelae associated with the condition. Fatigue, poor concentration, limited exercise tolerance, paraesthesia and progressive weakness are frequently reported, but the radiological underpinnings of these symptoms are poorly characterised.

Objective: The aim of this study is to evaluate cortical and subcortical alterations in a cohort of adult polio survivors to explore the anatomical substrate of extra-motor manifestations.

Methods: Thirty-six patients with post-polio syndrome, a disease-control group with amyotrophic lateral sclerosis patients and a cohort of healthy individuals were included in a prospective neuroimaging study with a standardised clinical and radiological protocol. Validated clinical instruments were utilised to assess mood, cognitive and behavioural domains and specific aspects of fatigue. Cortical thickness analyses, subcortical volumetry, brainstem segmentation and region-of-interest (ROI) white matter analyses were undertaken to assess regional grey and white matter alterations.

Results: A high proportion of PPS patients exhibited apathy, verbal fluency deficits and reported self-perceived fatigue. On ROI analyses, cortical atrophy was limited to the cingulate gyrus, and the temporal pole and subcortical atrophy were only detected in the left nucleus accumbens. No FA reductions were noted to indicate white matter degeneration in any of the lobes.

Conclusions: Despite the high incidence of extra-motor manifestations in PPS, only limited cortical, subcortical and white matter degeneration was identified. Our findings suggest that non-structural causes, such as polypharmacy and poor sleep, may contribute to the complex symptomatology of post-polio syndrome.
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http://dx.doi.org/10.1007/s10072-021-05130-4DOI Listing
November 2021

Cognitive reserve in amyotrophic lateral sclerosis (ALS): a population-based longitudinal study.

J Neurol Neurosurg Psychiatry 2021 May 9;92(5):460-465. Epub 2021 Feb 9.

Department of Psychology, Beaumont Hospital, Dublin 9, Ireland.

Background: Amyotrophic lateral sclerosis (ALS) is often associated with cognitive and/or behavioural impairment. Cognitive reserve (CR) may play a protective role in offsetting cognitive impairment. This study examined the relationship between CR and longitudinal change in cognition in an Irish ALS cohort.

Methods: Longitudinal neuropsychological assessment was carried out on 189 patients over 16 months using the Edinburgh cognitive and behavioural ALS screen (ECAS) and an additional battery of neuropsychological tests. CR was measured by combining education, occupation and physical activity data. Joint longitudinal and time-to-event models were fitted to investigate the associations between CR, performance at baseline and decline over time while controlling for non-random drop-out.

Results: CR was a significant predictor of baseline neuropsychological performance, with high CR patients performing better than those with medium or low CR. Better cognitive performance in high CR individuals was maintained longitudinally for ECAS, social cognition, executive functioning and confrontational naming. Patients displayed little cognitive decline over the course of the study, despite controlling for non-random drop-out.

Conclusions: These findings suggest that CR plays a role in the presentation of cognitive impairment at diagnosis but is not protective against cognitive decline. However, further research is needed to examine the interaction between CR and other objective correlates of cognitive impairment in ALS.
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http://dx.doi.org/10.1136/jnnp-2020-324992DOI Listing
May 2021

Cross-reactive probes on Illumina DNA methylation arrays: a large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies.

NAR Genom Bioinform 2020 Dec 17;2(4):lqaa105. Epub 2020 Dec 17.

Department of Neurology, UMC Utrecht Brain Center, 3584 CG, Utrecht, the Netherlands.

Illumina DNA methylation arrays are a widely used tool for performing genome-wide DNA methylation analyses. However, measurements obtained from these arrays may be affected by technical artefacts that result in spurious associations if left unchecked. Cross-reactivity represents one of the major challenges, meaning that probes may map to multiple regions in the genome. Although several studies have reported on this issue, few studies have empirically examined the impact of cross-reactivity in an epigenome-wide association study (EWAS). In this paper, we report on cross-reactivity issues that we discovered in a large EWAS on the presence of the repeat expansion in ALS patients. Specifically, we found that that the majority of the significant probes inadvertently cross-hybridized to the locus. Importantly, these probes were not flagged as cross-reactive in previous studies, leading to novel insights into the extent to which cross-reactivity can impact EWAS. Our findings are particularly relevant for epigenetic studies into diseases associated with repeat expansions and other types of structural variation. More generally however, considering that most spurious associations were not excluded based on pre-defined sets of cross-reactive probes, we believe that the presented data-driven flag and consider approach is relevant for any type of EWAS.
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http://dx.doi.org/10.1093/nargab/lqaa105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745769PMC
December 2020

Extra-motor cerebral changes and manifestations in primary lateral sclerosis.

Brain Imaging Behav 2021 Oct 7;15(5):2283-2296. Epub 2021 Jan 7.

Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland.

Primary lateral sclerosis (PLS) is classically considered a 'pure' upper motor neuron disorder. Motor cortex atrophy and pyramidal tract degeneration are thought to be pathognomonic of PLS, but extra-motor cerebral changes are poorly characterized. In a prospective neuroimaging study, forty PLS patients were systematically evaluated with a standardised imaging, genetic and clinical protocol. Patients were screened for ALS and HSP associated mutations, as well as C9orf72 hexanucleotide repeats. Clinical assessment included composite reflex scores, spasticity scales, functional rating scales, and screening for cognitive and behavioural deficits. The neuroimaging protocol evaluated cortical atrophy patterns, subcortical grey matter changes and white matter alterations in whole-brain and region-of-interest analyses. PLS patients tested negative for known ALS- and HSP-associated mutations and C9orf72 repeat expansions. Voxel-wise analyses revealed anterior cingulate, dorsolateral prefrontal, insular, opercular, orbitofrontal and bilateral mesial temporal grey matter changes and white matter alterations in the fornix, brainstem, temporal lobes, and cerebellum. Significant thalamus, caudate, hippocampus, putamen and accumbens nucleus volume reductions were also identified. Extra-motor clinical manifestations were dominated by verbal fluency deficits, language deficits, apathy and pseudobulbar affect. Our clinical and radiological evaluation confirms considerable extra-motor changes in a population-based cohort of PLS patients. Our data suggest that PLS should no longer be considered a neurodegenerative disorder selectively affecting the pyramidal system. PLS is associated with widespread extra-motor changes and manifestations which should be carefully considered in the multidisciplinary management of this low-incidence condition.
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http://dx.doi.org/10.1007/s11682-020-00421-4DOI Listing
October 2021

Cortical progression patterns in individual ALS patients across multiple timepoints: a mosaic-based approach for clinical use.

J Neurol 2021 May 5;268(5):1913-1926. Epub 2021 Jan 5.

Computational Neuroimaging Group, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.

Introduction: The majority of imaging studies in ALS infer group-level imaging signatures from group comparisons, as opposed to estimating disease burden in individual patients. In a condition with considerable clinical heterogeneity, the characterisation of individual patterns of pathology is hugely relevant. In this study, we evaluate a strategy to track progressive cortical involvement in single patients by using subject-specific reference cohorts.

Methods: We have interrogated a multi-timepoint longitudinal dataset of 61 ALS patients to demonstrate the utility of estimating cortical disease burden and the expansion of cerebral atrophy over time. We contrast our strategy to the gold-standard approach to gauge the advantages and drawbacks of our method. We modelled the evolution of cortical integrity in a conditional growth model, in which we accounted for age, gender, disability, symptom duration, education and handedness. We hypothesised that the variance associated with demographic variables will be successfully eliminated in our approach.

Results: In our model, the only covariate which modulated the expansion of atrophy was motor disability as measured by the ALSFRS-r (t(153) = - 2.533, p = 0.0123). Using the standard approach, age also significantly influenced progression of CT change (t(153) = - 2.151, p = 0.033) demonstrating the validity and potential clinical utility of our approach.

Conclusion: Our strategy of estimating the extent of cortical atrophy in individual patients with ALS successfully corrects for demographic factors and captures relevant cortical changes associated with clinical disability. Our approach provides a framework to interpret single T1-weighted images in ALS and offers an opportunity to track cortical propagation patterns both at individual subject level and at cohort level.
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http://dx.doi.org/10.1007/s00415-020-10368-7DOI Listing
May 2021
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