RESUMO
BACKGROUND: Next-generation sequencing has enhanced our understanding of amyotrophic lateral sclerosis (ALS) and its genetic epidemiology. Outside the research setting, testing is often restricted to those who report a family history. The aim of this study was to explore the added benefit of offering routine genetic testing to all patients in a regional ALS centre. METHODS: C9ORF72 expansion testing and exome sequencing was offered to consecutive patients (150 with ALS and 12 with primary lateral sclerosis [PLS]) attending the Oxford Motor Neuron Disease Clinic within a defined time period. RESULTS: A total of 17 (11.3%) highly penetrant pathogenic variants in C9ORF72, SOD1, TARDBP, FUS and TBK1 were detected, of which 10 were also found through standard clinical genetic testing pathways. The systematic approach resulted in five additional diagnoses of a C9ORF72 expansion (number needed to test [NNT] = 28), and two further missense variants in TARDBP and SOD1 (NNT = 69). Additionally, 3 patients were found to carry pathogenic risk variants in NEK1, and 13 patients harboured common missense variants in CFAP410 and KIF5A, also associated with an increased risk of ALS. We report two novel non-coding loss-of-function splice variants in TBK1 and OPTN. No relevant variants were found in the PLS patients. Patients were offered double-blinded participation, but >80% requested disclosure of the results. CONCLUSIONS: This study provides evidence that expanding genetic testing to all patients with a clinical diagnosis of ALS enhances the potential for recruitment to clinical trials, but will have direct resource implications for genetic counselling.
Assuntos
Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/genética , Superóxido Dismutase-1/genética , Proteína C9orf72/genética , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Cinesinas/genéticaRESUMO
Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative syndrome. In up to 20% of cases, a family history is observed. Although Mendelian disease gene variants are found in apparently sporadic ALS, genetic testing is usually restricted to those with a family history or younger patients with sporadic disease. With the advent of therapies targeting genetic ALS, it is important that everyone treatable is identified. We therefore sought to determine the probability of a clinically actionable ALS genetic test result by age of onset, globally, but using the UK as an exemplar. Blood-derived DNA was sequenced for ALS genes, and the probability of a clinically actionable genetic test result estimated. For a UK subset, age- and sex-specific population incidence rates were used to determine the number of such results missed by restricting testing by age of onset according to UK's National Genomic Test Directory criteria. There were 6274 people with sporadic ALS, 1551 from the UK. The proportion with a clinically actionable genetic test result ranged between 0.21 [95% confidence interval (CI) 0.18-0.25] in the youngest age group to 0.15 (95% CI 0.13-0.17) in the oldest age group for a full gene panel. For the UK, the equivalent proportions were 0.23 (95% CI 0.13-0.33) in the youngest age group to 0.17 (95% CI 0.13-0.21) in the oldest age group. By limiting testing in those without a family history to people with onset below 40 years, 115 of 117 (98% of all, 95% CI 96%-101%) clinically actionable test results were missed. There is a significant probability of a clinically actionable genetic test result in people with apparently sporadic ALS at all ages. Although some countries limit testing by age, doing so results in a significant number of missed pathogenic test results. Age of onset and family history should not be a barrier to genetic testing in ALS.
Assuntos
Esclerose Lateral Amiotrófica , Masculino , Feminino , Humanos , Esclerose Lateral Amiotrófica/genética , Testes Genéticos , IncidênciaRESUMO
INTRODUCTION: Amyotrophic lateral sclerosis (ALS) has a reported incidence of 1-2/100,000 person-years. It is estimated that there are 5000 people with ALS in the UK at any one time; however, the true figure and geographical distribution, are unknown. In this study, we describe the establishment of a population register for England, Wales, and Northern Ireland and report-estimated incidence. Methods: People with a diagnosis of ALS given by a consultant neurologist and whose postcode of residence is within England, Wales, or Northern Ireland were eligible. The catchment area was based on six data contributors that had been participating since 2016. All centres included in this analysis were in England, and therefore Wales and Northern Ireland are not included in this report. Crude age- and sex-specific incidence rates were estimated using population census records for the relevant postcodes from Office of National Statistics census data. These rates were standardized to the UK population structure using direct standardization. Results: There were 232 people in the database with a date of diagnosis between 2017 and 2018, when missing data were imputed there were an estimated 287-301 people. The denominator population of the catchment area is 7,251,845 according to 2011 UK census data. Age- and sex-adjusted incidence for complete cases was 1.61/100,000 person-years (95% confidence interval 1.58, 1.63), and for imputed datasets was 2.072/100,000 person-years (95% CI 2.072, 2.073). Discussion: We found incidence in this previously unreported area of the UK to be similar to other published estimates. As the MND Register for England, Wales, and Northern Ireland grows we will update incidence estimates and report on further analyses.
Assuntos
Esclerose Lateral Amiotrófica , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Masculino , Irlanda do Norte/epidemiologia , País de Gales/epidemiologiaRESUMO
RATIONALE AND OBJECTIVES: Healthy aging is associated with pervasive declines in cognitive, motor, and sensory functioning. There are, however, substantial individual differences in behavioral performance among older adults. Several lines of animal research link age-related reductions of gamma-aminobutyric acid (GABA), the brain's primary inhibitory neurotransmitter, to age-related cognitive, motor, and sensory decline. Our study used proton magnetic resonance spectroscopy (MRS) at 3T to explore whether occipital GABA declines with age in humans and whether individual differences in occipital GABA are linked to individual differences in fluid processing ability. MATERIALS AND METHODS: We used a MEGA-PRESS sequence that combines frequency spectral editing with a point-resolved spectroscopy sequence to quantify GABA. Spectra were obtained from a 30â¯×â¯30â¯×â¯25 mm voxel placed in the occipital cortex of 20 young adults (mean age 20.7 years) and 18 older adults (mean age 76.5 years). Participants also performed 11 fluid processing tasks outside the scanner, the results of which were z-scored and averaged to calculate a summary measure of fluid processing ability. Regression analysis was employed to determine the relationship between GABA concentrations in the occipital cortex and a summary measure of fluid processing ability. RESULTS: Occipital GABA was significantly lower in older participants compared to the younger participants. We also observed a significant positive relationship between occipital GABA and fluid processing ability. In fact, higher GABA was associated with better task performance in 10 of the 11 tasks. CONCLUSION: These findings suggest that GABA levels decline with age in humans and are associated with declines in fluid processing ability.
Assuntos
Envelhecimento , Cognição/fisiologia , Espectroscopia de Ressonância Magnética/métodos , Lobo Occipital , Ácido gama-Aminobutírico/metabolismo , Idoso , Envelhecimento/fisiologia , Envelhecimento/psicologia , Feminino , Humanos , Masculino , Lobo Occipital/diagnóstico por imagem , Lobo Occipital/metabolismo , Adulto JovemRESUMO
BACKGROUND: The identification of blood-based biomarkers specific to the diagnosis of amyotrophic lateral sclerosis (ALS) is an active field of academic and clinical research. While inheritance studies have advanced the field, a majority of patients do not have a known genetic link to the disease, making direct sequence-based genetic testing for ALS difficult. The ability to detect biofluid-based epigenetic changes in ALS would expand the relevance of using genomic information for disease diagnosis. METHODS: Assessing differences in chromosomal conformations (i.e. how they are positioned in 3-dimensions) represents one approach for assessing epigenetic changes. In this study, we used an industrial platform, EpiSwitch™, to compare the genomic architecture of healthy and diseased patient samples (blood and tissue) to discover a chromosomal conformation signature (CCS) with diagnostic potential in ALS. A three-step biomarker selection process yielded a distinct CCS for ALS, comprised of conformation changes in eight genomic loci and detectable in blood. FINDINGS: We applied the ALS CCS to determine a diagnosis for 74 unblinded patient samples and subsequently conducted a blinded diagnostic study of 16 samples. Sensitivity and specificity for ALS detection in the 74 unblinded patient samples were 83â33% (CI 51â59 to 97â91%) and 76â92% (46â19 to 94â96%), respectively. In the blinded cohort, sensitivity reached 87â50% (CI 47â35 to 99â68%) and specificity was 75â0% (34â91 to 96â81%). INTERPRETATIONS: The sensitivity and specificity values achieved using the ALS CCS identified and validated in this study provide an indication that the detection of chromosome conformation signatures is a promising approach to disease diagnosis and can potentially augment current strategies for diagnosing ALS. FUND: This research was funded by Oxford BioDynamics and Innovate UK. Work in the Oxford MND Care and Research Centre is supported by grants from the Motor Neurone Disease Association and the Medical Research Council. Additional support was provided by the Northeast ALS Consortium (NEALS).
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Biomarcadores/sangue , Cromossomos Humanos/química , Ensaios de Triagem em Larga Escala/métodos , Adulto , Idoso , Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/genética , Estudos de Coortes , Epigênese Genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Conformação Molecular , Sensibilidade e EspecificidadeRESUMO
While many aspects of cognition have been investigated in relation to skilled music training, surprisingly little work has examined the connection between music training and attentional abilities. The present study investigated the performance of skilled musicians on cognitively demanding sustained attention tasks, measuring both temporal and visual discrimination over a prolonged duration. Participants with extensive formal music training were found to have superior performance on a temporal discrimination task, but not a visual discrimination task, compared to participants with no music training. In addition, no differences were found between groups in vigilance decrement in either type of task. Although no differences were evident in vigilance per se, the results indicate that performance in an attention-demanding temporal discrimination task was superior in individuals with extensive music training. We speculate that this basic cognitive ability may contribute to advantages that musicians show in other cognitive measures.
Assuntos
Atenção/fisiologia , Discriminação Psicológica/fisiologia , Música , Desempenho Psicomotor/fisiologia , Percepção do Tempo/fisiologia , Percepção Visual/fisiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto JovemRESUMO
The aim of this study is to use functional magnetic resonance imaging (fMRI) to prospectively examine pre-treatment predictors of post-treatment fatigue and cognitive dysfunction in women treated with adjuvant chemotherapy for breast cancer. Fatigue and cognitive dysfunction often co-occur in women treated for breast cancer. We hypothesized that pre-treatment factors, unrelated to chemotherapy per se, might increase vulnerability to post-treatment fatigue and cognitive dysfunction. Patients treated with (n = 28) or without chemotherapy (n = 37) and healthy controls (n = 32) were scanned coincident with pre- and one-month post-chemotherapy during a verbal working memory task (VWMT) and assessed for fatigue, worry, and cognitive dysfunction. fMRI activity measures in the frontoparietal executive network were used in multiple linear regression to predict post-treatment fatigue and cognitive function. The chemotherapy group reported greater pre-treatment fatigue than controls and showed compromised neural response, characterized by higher spatial variance in executive network activity, than the non-chemotherapy group. Also, the chemotherapy group reported greater post-treatment fatigue than the other groups. Linear regression indicated that pre-treatment spatial variance in executive network activation predicted post-treatment fatigue severity and cognitive complaints, while treatment group, age, hemoglobin, worry, and mean executive network activity levels did not predict these outcomes. Pre-treatment neural inefficiency (indexed by high spatial variance) in the executive network, which supports attention and working memory, was a better predictor of post-treatment cognitive and fatigue complaints than exposure to chemotherapy per se. This executive network compromise could be a pre-treatment neuromarker of risk, indicating patients most likely to benefit from early intervention for fatigue and cognitive dysfunction.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/psicologia , Transtornos Cognitivos/induzido quimicamente , Fadiga/induzido quimicamente , Imageamento por Ressonância Magnética/métodos , Biomarcadores/metabolismo , Neoplasias da Mama/metabolismo , Quimioterapia Adjuvante/efeitos adversos , Cognição/efeitos dos fármacos , Transtornos Cognitivos/diagnóstico , Fadiga/diagnóstico , Feminino , Humanos , Estudos Longitudinais , Memória de Curto Prazo/efeitos dos fármacos , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos ProspectivosRESUMO
UNLABELLED: [Correction Notice: An Erratum for this article was reported in Vol 33(3) of Health Psychology (see record 2014-07787-001). The name of author Misook Jung was misspelled as Mi Sook Jung. All versions of this article have been corrected.] OBJECTIVE: Altered cognitive function has been associated with breast cancer treatment, particularly adjuvant chemotherapy, but the underlying neuropsychological mechanisms are not yet understood. Recent research indicates that compromised attention and working memory can exist before adjuvant treatment, implicating psychological distress, such as worry, as a possible contributor to observed alterations in cognitive function. We hypothesized that worry associated with breast cancer diagnosis might influence neurocognitive responses before any adjuvant therapy. DESIGN: Fifty women, 25 due to receive chemotherapy and 25 due to receive radiation therapy, participated in the study. Women performed a verbal working memory task during functional magnetic resonance imaging scanning to assess neurocognitive responses before any adjuvant treatment and to test the relationship of such responses with self-reports of worry. RESULTS: Although prechemotherapy participants showed significantly higher levels of worry compared with preradiation participants, higher worry, across both groups, was related to altered brain function. Specifically, increased worry was associated with reduced demand-related deactivation in default-mode regions, such as the precuneus/posterior cingulate. Reduced demand-related deactivation was critically related to worse behavioral performance, which was partially mediated by worry. CONCLUSION: Worry appears to be a significant contributor to neurocognitive dysfunction independent of adjuvant treatment for breast cancer. These results suggest that alterations in cognitive function may develop before any chemotherapy treatment and that worry about cancer diagnosis may contribute to reports of "chemo brain" during treatment. Psychological interventions aimed at mitigating worry may help to alleviate cognitive dysfunction associated with life-threatening illness such as breast cancer.
Assuntos
Ansiedade/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/psicologia , Transtornos Cognitivos/etiologia , Adulto , Idoso , Encéfalo/fisiopatologia , Quimioterapia Adjuvante , Feminino , Humanos , Imageamento por Ressonância Magnética , Memória de Curto Prazo/fisiologia , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Previous articles have reported that bilingualism is associated with a substantial delay in the onset of both Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). The present study reports results from 74 MCI patients and 75 AD patients; approximately half of the patients in each group were bilingual. All patients were interviewed to obtain details of their language use, onset of their condition, and lifestyle habits. Patients performed three executive function (EF) tests from the D-KEFS battery (Trails, Color-Word Interference, Verbal Fluency) on 3 occasions over a period of approximately 1 year. Results replicated the finding that bilingual patients are several years older than comparable monolinguals at both age of symptom onset and date of first clinic visit. This result could not be attributed to language group differences in such lifestyle variables as diet, smoking, alcohol consumption, physical activity, or social activity. On the first testing occasion, performance on the EF tasks was generally comparable between the language groups, contesting arguments that bilinguals wait longer before attending the clinic. Finally, EF performance tended to decline over the 3 sessions, but no differences were found between monolinguals and bilinguals in the rate of decline.
Assuntos
Doença de Alzheimer/epidemiologia , Disfunção Cognitiva/epidemiologia , Função Executiva , Multilinguismo , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
Despite concern about cognitive decline in old age, few studies document the types and frequency of memory errors older adults make in everyday life. In the present study, 105 healthy older adults completed the Everyday Memory Questionnaire (EMQ; Sunderland, Harris, & Baddeley, 1983 , Journal of Verbal Learning and Verbal Behavior, 22, 341), indicating what memory errors they had experienced in the last 24 hours, the Memory Self-Efficacy Questionnaire (MSEQ; West, Thorn, & Bagwell, 2003 , Psychology and Aging, 18, 111), and other neuropsychological and cognitive tasks. EMQ and MSEQ scores were unrelated and made separate contributions to variance on the Mini Mental State Exam (MMSE; Folstein, Folstein, & McHugh, 1975 , Journal of Psychiatric Research, 12, 189), suggesting separate constructs. Tip-of-the-tongue errors were the most commonly reported, and the EMQ Faces/Places and New Things subscales were most strongly related to MMSE. These findings may help training programs target memory errors commonly experienced by older adults, and suggest which types of memory errors could indicate cognitive declines of clinical concern.
Assuntos
Envelhecimento/psicologia , Cognição , Transtornos da Memória/psicologia , Memória , Autoeficácia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Autorrelato , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: Previous reports have found that lifelong bilingualism is associated with a delay in the onset of dementia, including Dementia of the Alzheimer's Type (DAT). Because amnestic mild cognitive impairment (aMCI) is often a transition stage between normal aging and DAT, our aim in this paper was to establish whether this delay in symptom onset for bilinguals would also be seen in the onset of symptoms of aMCI and whether this delay would be consistent in different subtypes of aMCI. METHOD: We examined the effect of bilingualism on the age of diagnosis in individuals with single- or multiple-domain aMCI who were administered a battery of neuropsychological tests and questionnaires about their language and social background. RESULTS: Our results showed an interaction between aMCI type and language history. Only individuals diagnosed with single-domain aMCI demonstrated a later age of diagnosis for bilinguals (M = 79.4 years) than monolinguals (M = 74.9 years). DISCUSSION: This preliminary evidence suggests that the early protective advantage of bilingualism may be specific to single-domain aMCI, which is the type of aMCI most specifically associated with progression to DAT.
Assuntos
Envelhecimento/fisiologia , Amnésia/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Multilinguismo , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/classificação , Humanos , Testes NeuropsicológicosRESUMO
Interference from competing material at retrieval is a major cause of memory failure. We tested the hypothesis that such interference can be overcome by suppressing competing responses. In a three-phase task, participants in the critical interference condition first performed a vowel-counting task (Phase 1) that included pairs of orthographically similar words (e.g., allergy and analogy). After a delay, participants were asked to solve word fragments (e.g., a _ l _ _ gy) that resembled both words in a pair they had seen, but could be completed only by one of these words (Phase 2). We then measured the consequence of having successfully resolved interference in Phase 2 by asking participants to read a list of words, including rejected competitor words (i.e., the word in each pair that could not be used to solve the word fragments), as quickly as possible (Phase 3). Participants in the interference condition were slower to name the competitor words than participants in conditions that did not require interference resolution. These results constitute direct evidence for the role of active suppression in resolving interference during memory retrieval.