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1.
Acta Neuropathol ; 139(1): 45-61, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31456032

RESUMO

Apart from amyloid ß deposition and tau neurofibrillary tangles, Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal loss and astrocytosis in the cerebral cortex. The goal of this study is to investigate genetic factors associated with the neuronal proportion in health and disease. To identify cell-autonomous genetic variants associated with neuronal proportion in cortical tissues, we inferred cellular population structure from bulk RNA-Seq derived from 1536 individuals. We identified the variant rs1990621 located in the TMEM106B gene region as significantly associated with neuronal proportion (p value = 6.40 × 10-07) and replicated this finding in an independent dataset (p value = 7.41 × 10-04) surpassing the genome-wide threshold in the meta-analysis (p value = 9.42 × 10-09). This variant is in high LD with the TMEM106B non-synonymous variant p.T185S (rs3173615; r2 = 0.98) which was previously identified as a protective variant for frontotemporal lobar degeneration (FTLD). We stratified the samples by disease status, and discovered that this variant modulates neuronal proportion not only in AD cases, but also several neurodegenerative diseases and in elderly cognitively healthy controls. Furthermore, we did not find a significant association in younger controls or schizophrenia patients, suggesting that this variant might increase neuronal survival or confer resilience to the neurodegenerative process. The single variant and gene-based analyses also identified an overall genetic association between neuronal proportion, AD and FTLD risk. These results suggest that common pathways are implicated in these neurodegenerative diseases, that implicate neuronal survival. In summary, we identified a protective variant in the TMEM106B gene that may have a neuronal protection effect against general aging, independent of disease status, which could help elucidate the relationship between aging and neuronal survival in the presence or absence of neurodegenerative disorders. Our findings suggest that TMEM106B could be a potential target for neuronal protection therapies to ameliorate cognitive and functional deficits.


Assuntos
Envelhecimento/genética , Encéfalo , Predisposição Genética para Doença/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Doenças Neurodegenerativas/genética , Neurônios , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Humanos , Masculino , Neurônios/metabolismo , Neurônios/patologia , Polimorfismo de Nucleotídeo Único
2.
Neurodegener Dis ; 20(4): 147-152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33902047

RESUMO

INTRODUCTION: Saliva problems are common and distressing for people with motor neuron disease (pwMND). Despite clinical guidelines for assessment and treatment, management of saliva problems has received little research attention. OBJECTIVE: We aimed to investigate the prevalence of saliva problems in pwMND, their association with clinical factors, and their management practice using a highly curated population-based register for motor neuron disease (MND) with 99% case ascertainment. METHODS: We conducted an analysis of pwMND diagnosed between January 2015 and October 2019 using the Scottish MND Register (CARE-MND [Clinical, Audit, Research, and Evaluation of MND]). The association between clinical factors and saliva problems was investigated using univariate and multivariable logistic regression; results are reported as odds ratio (OR) and 95% confidence intervals. A survey of health-care professionals involved in the care of pwMND was performed to contextualize the findings. RESULTS: 939 pwMND were included. Prevalence of saliva problems was 31.3% (294). Bulbar onset (OR 9.46 [4.7, 19.2]; p < 0.001) but not age, sex, time to diagnosis, or MND subtype were independently associated with the presence of saliva problems in multivariable regression, and 52.7% (155) of those with saliva problems received pharmacological management. The most commonly used medications were hyoscine, amitriptyline, carbocisteine, glycopyrrolate, and atropine. Evidence base (8, 72.7%) and local guidelines (10, 90.9%) were cited as the most important factors influencing treatment decision by survey respondents (n = 11). CONCLUSION: Saliva problems are common and associated with bulbar onset MND. A substantial proportion of pwMND with saliva problems did not receive recommended treatments. Future research is required to determine the relative efficacy of individual pharmacological treatments.


Assuntos
Esclerose Lateral Amiotrófica , Doença dos Neurônios Motores , Humanos , Doença dos Neurônios Motores/epidemiologia , Doença dos Neurônios Motores/terapia , Prevalência , Saliva , Escócia/epidemiologia
3.
Pract Neurol ; 20(2): 168-174, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32001663

RESUMO

A 74-year-old woman developed bilateral leg weakness, with fluctuating cognitive and systemic symptoms that progressed despite treatment. Her diagnosis was confirmed at autopsy. Her case was discussed at the Edinburgh Clinical Neurology Course 2019 Clinicopathological Conference.


Assuntos
Progressão da Doença , Linfoma de Células B/diagnóstico por imagem , Debilidade Muscular/diagnóstico por imagem , Paraplegia/diagnóstico por imagem , Idoso , Evolução Fatal , Feminino , Humanos , Extremidade Inferior/patologia , Linfoma de Células B/sangue , Linfoma de Células B/complicações , Debilidade Muscular/sangue , Debilidade Muscular/etiologia , Paraplegia/sangue , Paraplegia/etiologia , Fatores de Tempo
4.
Pract Neurol ; 19(2): 143-146, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30190285

RESUMO

The prime purpose of the clinicopathological conference (CPC) is education, delivered ideally in an entertaining and engaging manner. This article tackles both how to organise a CPC (more challenging than it might appear) and how to survive as a CPC discussant (always challenging). The patient at the heart of the CPC will have had a challenging and difficult illness. The reanalysis of the clinical presentation by the discussant, a re-exploration of their clinical journey, is the key to the educational value of the CPC rather than the ultimate diagnosis. A well-delivered CPC is the pinnacle of educational events in neurology, and this article highlights some useful tips on both sides of the divide.


Assuntos
Patologistas , Patologia Clínica , Autopsia , Humanos , Ensino
5.
Pract Neurol ; 19(1): 43-48, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30305378

RESUMO

Rhabdomyolysis is the combination of symptoms (myalgia, weakness and muscle swelling) and a substantial rise in serum creatine kinase (CK) >50 000 IU/L; there are many causes, but here we specifically address exertional rhabdomyolysis. The consequences of this condition can be severe, including acute kidney injury and requirement for higher level care with organ support. Most patients have 'physiological' exertional rhabdomyolysis with no underlying disease; they do not need investigation and should be advised to return to normal activities in a graded fashion. Rarely, exertional rhabdomyolysis may be the initial presentation of underlying muscle disease, and we review how to identify this much smaller group of patients, who do require investigation.


Assuntos
Exercício Físico , Rabdomiólise , Humanos , Rabdomiólise/diagnóstico , Rabdomiólise/etiologia , Rabdomiólise/terapia
6.
Pract Neurol ; 19(2): 147-155, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30425126

RESUMO

A 65-year-old man presented with transient neurological symptoms, followed by rapid cognitive decline, myoclonus and fevers. He had evidence of scleritis and an arthropathy. This paper reports the clinicopathological conference discussed at the Association of British Neurologists Annual Meeting 2017.


Assuntos
Disfunção Cognitiva/patologia , Mioclonia/patologia , Esclerite/patologia , Vasculite/patologia , Idoso , Disfunção Cognitiva/diagnóstico , Humanos , Artropatias/diagnóstico , Artropatias/patologia , Masculino , Mioclonia/diagnóstico , Recidiva , Esclerite/diagnóstico , Vasculite/diagnóstico
7.
Int J Geriatr Psychiatry ; 33(1): 151-158, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28247480

RESUMO

OBJECTIVE: Apathy is a prominent and disabling symptom in Parkinson's disease (PD) and is a multidimensional behaviour, but which dimensions are specifically affected is unclear. Therefore, the aim of this preliminary study was to determine the psychometric properties of the Dimensional Apathy Scale (DAS) and explore the multidimensional profile of apathy in PD patients. METHODS: Thirty-four PD patients, with 30 of their informants/carers, and 34 healthy controls, with 30 of their informants, completed the DAS, Apathy Evaluation Scale and the Geriatric Depression Scale Short Form. Motor staging and independent living status were recorded. RESULTS: Comparative group analyses revealed that PD patients were significantly more apathetic on self-rated executive (p = 0.01) and initiation (p = 0.03) dimensions than controls, where only executive apathy was significantly higher in ratings of patients' informants/carers compared with controls' informants (p = 0.02). A third of patients were impaired on at least one apathy dimension. Additionally, patients with apathy tended to have more impaired activities of daily living, while none of the apathy dimensions related to motor disability. CONCLUSION: Our findings show the DAS is a valid and reliable multidimensional apathy tool for use in PD. PD is characterised by an executive apathy profile as determined by informants/carers, although patients described both executive and initiation apathy. This indicates a lack of motivation for planning, organisation and attention and lack of initiation of thoughts or behaviours. Further research is needed to determine the cognitive underpinnings of this emerging apathy profile and the clinical impact in PD. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Apatia , Doença de Parkinson/psicologia , Escalas de Graduação Psiquiátrica/normas , Atividades Cotidianas/psicologia , Idoso , Idoso de 80 Anos ou mais , Atenção , Estudos de Casos e Controles , Função Executiva/fisiologia , Feminino , Avaliação Geriátrica/métodos , Humanos , Vida Independente/psicologia , Masculino , Pessoa de Meia-Idade , Motivação , Psicometria/métodos
11.
Arch Biochem Biophys ; 597: 1-11, 2016 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-27013205

RESUMO

Recent findings suggest that the senile plaques in Alzheimer's disease may contain soluble amyloid-ß peptide (Aß) fibril precursors along with insoluble fibrils. These soluble Aß species, including oligomers and protofibrils, have been well-studied in vitro and are formed via non-covalent self-assembly of Aß monomers. While both 40- and 42-residue forms of Aß are observed in the human body, the majority of the Aß aggregation work has been conducted on Aß42 or Aß40 separately, with relatively few investigations of mixtures. In order to study the effect of different combinations of Aß40 and Aß42 on protofibril formation, mixtures of either dry solid peptide, or purified Aß40 and Aß42 monomer solutions were mixed together and protofibril/monomer distributions were quantified. Increases in the Aß42/Aß40 ratio increased protofibril formation but the presence of Aß40 in the mixed Aß solutions had a significant negative impact on protofibril formation compared to equivalent solutions of pure Aß42. Protofibril size was less affected, but ß-sheet structure increased with protofibrils formed from higher Aß42/Aß40 ratio solutions. Direct measurement of Aß42/Aß40 ratios by C-terminal-selective ELISA found very little Aß40 incorporated into protofibrils. The cumulative data emphasizes the critical importance of Aß42, yet establishes Aß40 as a regulator of Aß42 aggregation.


Assuntos
Peptídeos beta-Amiloides/química , Fragmentos de Peptídeos/química , Agregados Proteicos , Humanos , Estrutura Secundária de Proteína
12.
Pract Neurol ; 16(5): 409-11, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27234850

RESUMO

Foreign accent syndrome (FAS) is a rare disorder where the affected person speaks in an accent that the listener perceives as foreign. Although most cases have left hemisphere lesions, some may be functional. We describe a case of functional FAS and present a video of her speech. We identify characteristics that help to distinguish functional from structural cases. These include preceding motor disturbances causing the maladaptive speech response, inconsistencies in accent production, the adoption of unusual mannerisms in speech and the speech disturbances being transient and reversible. We conclude that FAS is a complex disorder encompassing both functional and structural causes.


Assuntos
Transtornos da Articulação , Fala , Feminino , Humanos , Idioma , Pessoa de Meia-Idade , Síndrome
13.
BMC Med Educ ; 14: 225, 2014 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-25335431

RESUMO

BACKGROUND: Medical students perceive neurology to be a difficult subject, a phenomenon described as "neurophobia". Studies investigating student attitudes towards neurology have so far been limited by small sample sizes as a consequence of being conducted within a single medical school or region. We aimed to conduct the first national survey of the perception of neurology among UK medical students. METHODS: A 24 question online survey was designed and distributed in the form of a web-link to all UK medical schools. Responses were collected for 10 weeks with reminders sent at 3 and 6 weeks. A prize-draw of £300 was offered upon completion of the survey. RESULTS: 2877 medical students from 25 of 31 medical schools responded. Students found neurology to be significantly more difficult than other specialties and were least comfortable drawing up a neurological differential diagnosis compared to other specialties (p < 0.0001 for neurology vs. each of the other specialties). Neuroanatomy was regarded as the most important factor contributing to neurology being perceived as difficult. CONCLUSIONS: The findings of the first national survey addressing this issue are consistent with previous research. The perception of neurology remains unchanged, in contrast to the rapidly changing demands of neurological care in an ageing population. Neurological examination and formulating a differential diagnosis are important skills in any medical specialty, and combatting "neurophobia" in medical students is therefore essential.


Assuntos
Escolha da Profissão , Educação de Graduação em Medicina/estatística & dados numéricos , Neurologia/educação , Estudantes de Medicina/estatística & dados numéricos , Inquéritos e Questionários , Adulto , Estudos Transversais , Educação de Graduação em Medicina/métodos , Avaliação Educacional , Feminino , Humanos , Masculino , Percepção , Vigilância da População , Faculdades de Medicina/estatística & dados numéricos , Estudantes de Medicina/psicologia , Reino Unido
14.
J Neurol ; 271(8): 5256-5266, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38852112

RESUMO

BACKGROUND: Using the Clinical Audit Research and Evaluation of Motor Neuron Disease (CARE-MND) database and the Scottish Regenerative Neurology Tissue Bank, we aimed to outline the genetic epidemiology and phenotypes of an incident cohort of people with MND (pwMND) to gain a realistic impression of the genetic landscape and genotype-phenotype associations. METHODS: Phenotypic markers were identified from the CARE-MND platform. Sequence analysis of 48 genes was undertaken. Variants were classified using a structured evidence-based approach. Samples were also tested for C9orf72 hexanucleotide expansions using repeat-prime PCR methodology. RESULTS: 339 pwMND donated a DNA sample: 44 (13.0%) fulfilled criteria for having a pathogenic variant/repeat expansion, 53.5% of those with a family history of MND and 9.3% of those without. The majority (30 (8.8%)) had a pathogenic C9orf72 repeat expansion, including two with intermediate expansions. Having a C9orf72 expansion was associated with a significantly lower Edinburgh Cognitive and Behavioural ALS Screen ALS-Specific score (p = 0.0005). The known pathogenic SOD1 variant p.(Ile114Thr), frequently observed in the Scottish population, was detected in 9 (2.7%) of total cases but in 17.9% of familial cases. Rare variants were detected in FUS and NEK1. One individual carried both a C9orf72 expansion and SOD1 variant. CONCLUSIONS: Our results provide an accurate summary of MND demographics and genetic epidemiology. We recommend early genetic testing of people with cognitive impairment to ensure that C9orf72 carriers are given the best opportunity for informed treatment planning. Scotland is enriched for the SOD1 p.(Ile114Thr) variant and this has significant implications with regards to future genetically-targeted treatments.


Assuntos
Proteína C9orf72 , Doença dos Neurônios Motores , Fenótipo , Humanos , Escócia/epidemiologia , Doença dos Neurônios Motores/genética , Doença dos Neurônios Motores/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Proteína C9orf72/genética , Genótipo , Adulto , Expansão das Repetições de DNA/genética , Estudos de Coortes , Idoso de 80 Anos ou mais , Superóxido Dismutase-1/genética
15.
J Int Neuropsychol Soc ; 19(9): 986-94, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23953916

RESUMO

Letter fluency deficits are commonly detected in non-demented Parkinson's disease (PD) patients but the underlying cause remains uncertain. We investigated the role of slowed processing speed and executive dysfunction. Eighteen nondemented PD participants and nineteen controls were compared on letter fluency using a fluency index (Fi); the average time to "think" of each word, a measure independent of motor speed. Video analyses produced thinking times to switch between word clusters and generate a word within a cluster. Correlational and regression analyses were undertaken with tests of processing speed and executive functioning. The PD group exhibited significantly longer fluency indices than controls across all components. Performance on tests of executive functioning explained a significant proportion of variance whereas performance in processing speed tests did not. Moreover, PD participants with an executive functioning impairment showed significantly worse switching fluency indices only compared with Controls and PD participants without executive dysfunction. PD participants with executive dysfunction exhibited a disproportionate impairment in the time taken to switch between clusters than to think of words within clusters. Executive functioning contributed to fluency performance more than processing speed. Cognitive heterogeneity and motor slowing, may mask the profile of cognitive dysfunction in neurodegenerative disease.


Assuntos
Transtornos Cognitivos/etiologia , Função Executiva/fisiologia , Transtornos da Linguagem/etiologia , Doença de Parkinson/complicações , Idoso , Análise de Variância , Estudos de Casos e Controles , Transtornos Cognitivos/diagnóstico , Feminino , Humanos , Transtornos da Linguagem/diagnóstico , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fonética , Semântica , Comportamento Verbal , Vocabulário
16.
17.
J Neurol ; 270(3): 1702-1712, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36515702

RESUMO

BACKGROUND: We investigated the phenotypes and genotypes of a cohort of 'long-surviving' individuals with motor neuron disease (MND) to identify potential targets for prognostication. METHODS: Patients were recruited via the Clinical Audit Research and Evaluation for MND (CARE-MND) platform, which hosts the Scottish MND Register. Long survival was defined as > 8 years from diagnosis. 11 phenotypic variables were analysed. Whole genome sequencing (WGS) was performed and variants within 49 MND-associated genes examined. Each individual was screened for C9orf72 repeat expansions. Data from ancestry-matched Scottish populations (the Lothian Birth Cohorts) were used as controls. RESULTS: 58 long survivors were identified. Median survival from diagnosis was 15.5 years. Long survivors were significantly younger at onset and diagnosis than incident patients and had a significantly longer diagnostic delay. 42% had the MND subtype of primary lateral sclerosis (PLS). WGS was performed in 46 individuals: 14 (30.4%) had a potentially pathogenic variant. 4 carried the known SOD1 p.(Ile114Thr) variant. Significant variants in FIG4, hnRNPA2B1, SETX, SQSTM1, TAF15, and VAPB were detected. 2 individuals had a variant in the SPAST gene suggesting phenotypic overlap with hereditary spastic paraplegia (HSP). No long survivors had pathogenic C9orf72 repeat expansions. CONCLUSIONS: Long survivors are characterised by younger age at onset, increased prevalence of PLS and longer diagnostic delay. Genetic analysis in this cohort has improved our understanding of the phenotypes associated with the SOD1 variant p.(Ile114Thr). Our findings confirm that pathogenic expansion of C9orf72 is likely a poor prognostic marker. Genetic screening using targeted MND and/or HSP panels should be considered in those with long survival, or early-onset slowly progressive disease, to improve diagnostic accuracy and aid prognostication.


Assuntos
Esclerose Lateral Amiotrófica , Doença dos Neurônios Motores , Paraplegia Espástica Hereditária , Humanos , Proteína C9orf72/genética , Diagnóstico Tardio , Superóxido Dismutase-1/genética , Doença dos Neurônios Motores/epidemiologia , Doença dos Neurônios Motores/genética , Genótipo , Fenótipo , Paraplegia Espástica Hereditária/genética , Esclerose Lateral Amiotrófica/genética , Espastina/genética , DNA Helicases/genética , RNA Helicases/genética , Enzimas Multifuncionais/genética
18.
J Neurol Neurosurg Psychiatry ; 83(1): 86-8, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21949107

RESUMO

BACKGROUND AND PURPOSE: People with one or more first degree relative affected (FDRA) by aneurysmal subarachnoid haemorrhage (aSAH) are at a higher lifetime risk of an aSAH than those without a family history. Screening may be worthwhile for people with two or more FDRA by aSAH. Little is known about the characteristics of people with a family history of aSAH who undergo screening in clinical practice. METHODS: Observational analysis of consecutive attendances at an intracranial aneurysm screening clinic. RESULTS: Of 96 adults seen, 19 did not have a family history of aSAH and 77 had one or more FDRA by aSAH: 35 had two or more FDRA, 21 had one FDRA plus one or more affected second degree relative and 21 had one FDRA only. In these three respective groups, 29 (83%), 15 (71%) and five (24%) adults underwent screening, of whom six (21%), two (13%) and one (20%) had an aneurysm detected (p=0.5). Of the nine patients with aneurysms, four underwent treatment. Considering other risk factors, adults with two or more FDRA were more likely to be hypertensive (OR 3.3, 95% CI 1.0 to 10.8; p=0.046) but were no more likely to smoke or drink to excess than adults with one FDRA. Adults who underwent screening were more likely to be hypertensive and drink alcohol to excess (both p=0.03), but were no more likely to smoke than those who were not screened. CONCLUSIONS: In clinical practice, people undergoing intracranial aneurysm screening had stronger family histories of aSAH and they were also more likely to have modifiable risk factors for aSAH.


Assuntos
Aneurisma Intracraniano/diagnóstico , Hemorragia Subaracnóidea/diagnóstico , Adolescente , Adulto , Alcoolismo/complicações , Família , Feminino , Humanos , Hipertensão/complicações , Aneurisma Intracraniano/etiologia , Aneurisma Intracraniano/genética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fumar/efeitos adversos , Hemorragia Subaracnóidea/etiologia , Hemorragia Subaracnóidea/genética , Adulto Jovem
20.
Clin Med (Lond) ; 11(5): 476-8, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22034711

RESUMO

Autoimmune limbic encephalitis is an increasingly recognised cause of cognitive decline and confusion. The typical presentation is with subacute cognitive decline, behavioural disturbance and seizures. Magnetic resonance imaging may show characteristic changes in the medial temporal regions. The diagnosis is confirmed by identification of elevated voltage-gated potassium channel antibody (VGKC-Ab) titres. It is a highly treatable condition, often responding well to intravenous immunoglobulin or steroids. Recognition of autoimmune limbic encephalitis is sometimes delayed--usually because the diagnosis has not been considered--which can result in long-term neurological consequences.


Assuntos
Doenças Autoimunes do Sistema Nervoso/diagnóstico , Encefalite Límbica/diagnóstico , Encefalite Límbica/imunologia , Autoanticorpos/análise , Transtornos Cognitivos/imunologia , Diagnóstico Diferencial , Progressão da Doença , Epilepsia Tônico-Clônica/imunologia , Evolução Fatal , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Canais de Potássio de Abertura Dependente da Tensão da Membrana/imunologia , Prognóstico
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