Clinical audit research and evaluation of motor neuron disease (CARE-MND): a national electronic platform for prospective, longitudinal monitoring of MND in Scotland

Leighton, Danielle; Newton, Judith; Colville, Shuna; Bethell, Andrew; Craig, Gillian; Cunningham, Laura; Flett, Moira; Fraser, Dianne; Hatrick, Janice; Lennox, Helen; Marshall, Laura; McAleer, Dympna; McEleney, Alison; Millar, Kitty; Silver, Ann; Stephenson, Laura; Stewart, Susan D.; Storey, Dorothy; Stott, Gill; Thornton, Carol A.; Webber, Carolyn; Gordon, H.; Melchiorre, Giulia; Sherlock, Laura; Beswick, Emily; Buchanan, David; Abrahams, Sharon; Bateman, Anthony; Preston, Jenny; Duncan, Callum W.; Davenport, Richard; Gorrie, George; Morrison, Ian; Swingler, Robert; Chandran, Siddharthan; Pal, Suvankar

doi:10.1080/21678421.2019.1582673

Cited by 22 publications

(23 citation statements)

References 32 publications

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“…We studied people with MND (pwMND) registered on the CARE-MND platform, a population-based, prospective database of patients in Scotland diagnosed with MND 17 18. Since 2015, a major update of the register has taken place.…”

Section: Methodsmentioning

confidence: 99%

Relationship between neuropsychiatric disorders and cognitive and behavioural change in MND

McHutchison

Leighton

McIntosh

et al. 2019

J Neurol Neurosurg Psychiatry

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Contributors: C.A.M. contributed to the conception of the project, carried out the data analysis and drafted the manuscript. D.J.L. collected data included in the analysis and along with S.C. and S.P. was involved in the update of the CARE-MND platform. A.M., S.P. and S.A. contributed to the conception of the project and provided input on the statistical analysis. E.M.C., J.W., and M.P. conducted the C9orf72 screening. The manuscript was reviewed by all authors. Word count:-Abstract = 250 -Main text = 3789 -References = 43 -Tables = 6 -Figures = 2 -Supplementary files = 7 tables and 2 figuresObjective: In this population-based study, we aimed to determine whether neuropsychiatric history, medication or family history of neuropsychiatric disorders predicted cognitive and/or behavioural impairment in motor neurone disease (MND). Methods:People with MND (pwMND) on the Scottish CARE-MND register, diagnosed from January 2015-January 2018, with cognitive and/or behavioural data measured using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) were included. Data was extracted on patient neuropsychiatric, medication and family history of neuropsychiatric disorders.We identified patients with cognitive (MNDci, MNDcbi or MND-FTD) and behavioural (MNDbi, MNDcbi or MND-FTD) impairment. Results: Data were available for 305 pwMND (mean age at diagnosis=62.26 years, SD=11.40), of which 60 (19.7%) had a neuropsychiatric disorder. A family history of neuropsychiatric disorders was present in 36/231 (15.58%) of patients. Patient premorbid mood disorders were associated with increased apathy (OR=2.78, 95%CI=1.083 to 7.169). A family history of any neuropsychiatric disorder was associated with poorer visuospatial scores, MNDbi (OR=3.14, 95%CI=1.09 to 8.99) and MND-FTD (OR=5.08, 95%CI=1.26 to 20.40). A family history of mood disorders was associated with poorer overall cognition (exp(b)=0.725, p=0.026), language, verbal fluency and visuospatial scores, and MND-FTD (OR=7.57, 95%CI=1.55 to 46.87). A family history of neurotic disorders was associated with poorer language (exp(b)=0.362, p<0.001), visuospatial scores (exp(b)=0.625, p<0.009) and MND-FTD (OR=13.75, 95%CI=1.71 to 110.86). Conclusions:Neuropsychiatric disorders in patients and their families are associated with cognitive and behavioural changes post-MND diagnosis, with many occurring independently of MND-FTD and C9orf72 status. These findings support an overlap between MND, FTD and neuropsychiatric disorders, particularly mood disorders.

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Section: Methodsmentioning

confidence: 99%

Relationship between neuropsychiatric disorders and cognitive and behavioural change in MND

McHutchison

Leighton

McIntosh

et al. 2019

J Neurol Neurosurg Psychiatry

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“…All clinical data were collected as part of Scottish Motor Neurone Disease Register (SMNDR) and Care Audit Research and Evaluation for Motor Neurone Disease (CARE-MND) platform (ethics approval from Scotland A Research Ethics Committee 10/MRE00/78 and 15/SS/0216). Additionally, all cases had corresponding whole-genome sequencing and diagnostic repeat prime PCR, demonstrating pathogenic repeat lengths in the C9orf72 locus [53]. The use of human tissue for postmortem studies has been reviewed and approved by the Edinburgh Brain Bank ethics committee and the Academic and Clinical Central Office for Research and Development medical research ethics committee, in line with the Human Tissue (Scotland) Act 2006.…”

Section: Post-mortem Case Identificationmentioning

confidence: 99%

Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis

et al. 2021

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Axonal dysfunction is a common phenotype in neurodegenerative disorders, including in amyotrophic lateral sclerosis (ALS), where the key pathological cell-type, the motor neuron (MN), has an axon extending up to a metre long. The maintenance of axonal function is a highly energy-demanding process, raising the question of whether MN cellular energetics is perturbed in ALS, and whether its recovery promotes axonal rescue. To address this, we undertook cellular and molecular interrogation of multiple patient-derived induced pluripotent stem cell lines and patient autopsy samples harbouring the most common ALS causing mutation, C9orf72. Using paired mutant and isogenic expansion-corrected controls, we show that C9orf72 MNs have shorter axons, impaired fast axonal transport of mitochondrial cargo, and altered mitochondrial bioenergetic function. RNAseq revealed reduced gene expression of mitochondrially encoded electron transport chain transcripts, with neuropathological analysis of C9orf72-ALS post-mortem tissue importantly confirming selective dysregulation of the mitochondrially encoded transcripts in ventral horn spinal MNs, but not in corresponding dorsal horn sensory neurons, with findings reflected at the protein level. Mitochondrial DNA copy number was unaltered, both in vitro and in human post-mortem tissue. Genetic manipulation of mitochondrial biogenesis in C9orf72 MNs corrected the bioenergetic deficit and also rescued the axonal length and transport phenotypes. Collectively, our data show that loss of mitochondrial function is a key mediator of axonal dysfunction in C9orf72-ALS, and that boosting MN bioenergetics is sufficient to restore axonal homeostasis, opening new potential therapeutic strategies for ALS that target mitochondrial function.

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“…Participants were drawn from the Clinical Audit Research and Evaluation of MND (CARE-MND) platform, a prospectively maintained population-based register comprising longitudinal clinical, and research data for all pwALS in Scotland [5]. We extracted clinical characteristics of people with definite, probable or possible ALS [6].…”

Section: Dear Sirsmentioning

confidence: 99%

Riluzole prescribing, uptake and treatment discontinuation in people with amyotrophic lateral sclerosis in Scotland

et al. 2020

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Clinical audit research and evaluation of motor neuron disease (CARE-MND): a national electronic platform for prospective, longitudinal monitoring of MND in Scotland

Cited by 22 publications

References 32 publications

Relationship between neuropsychiatric disorders and cognitive and behavioural change in MND

Relationship between neuropsychiatric disorders and cognitive and behavioural change in MND

Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis

Riluzole prescribing, uptake and treatment discontinuation in people with amyotrophic lateral sclerosis in Scotland

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