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BACKGROUND: Cognitive and behavioural dysfunction may occur in people with motor neuron disease (MND), with some studies suggesting an association with the C9ORF72 repeat expansion. Their onset and progression, however, is poorly understood. We explored how cognition and behaviour change over time, and whether demographic, clinical and genetic factors impact these changes. METHODS: Participants with MND were recruited through the Phenotype-Genotype-Biomarker study. Every 3-6 months, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was used to assess amyotrophic lateral sclerosis (ALS) specific (executive functioning, verbal fluency, language) and ALS non-specific (memory, visuospatial) functions. Informants reported on behaviour symptoms via semi-structured interview. RESULTS: Participants with neuropsychological data at ≥3 visits were included (n=237, mean age=59, 60% male), of which 18 (8%) were C9ORF72 positive. Baseline cognitive impairment was apparent in 18 (8%), typically in ALS specific domains, and associated with lower education, but not C9ORF72 status. Cognition, on average, remained stable over time, with two exceptions: (1) C9ORF72 carriers declined in all ECAS domains, (2) 8%-9% of participants with baseline cognitive impairment further declined, primarily in the ALS non-specific domain, which was associated with less education. Behavioural symptoms were uncommon. CONCLUSIONS: In this study, cognitive dysfunction was less common than previously reported and remained stable over time for most. However, cognition declines longitudinally in a small subset, which is not entirely related to C9ORF72 status. Our findings raise questions about the timing of cognitive impairment in MND, and whether it arises during early clinically manifest disease or even prior to motor manifestations.
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Esclerose Lateral Amiotrófica , Disfunção Cognitiva , Doença dos Neurônios Motores , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Esclerose Lateral Amiotrófica/diagnóstico , Proteína C9orf72/genética , Doença dos Neurônios Motores/genética , Doença dos Neurônios Motores/complicações , Disfunção Cognitiva/genética , Disfunção Cognitiva/complicações , Cognição/fisiologia , Testes NeuropsicológicosRESUMO
OBJECTIVE: 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 neuron disease (MND). METHODS: People with MND (pwMND) on the Scottish Clinical, Audit, Research and Evaluation of MND (CARE-MND) register, diagnosed from January 2015 to January 2018, with cognitive and/or behavioural data measured using the Edinburgh Cognitive and Behavioural ALS Screen were included. Data were extracted on patient neuropsychiatric, medication and family history of neuropsychiatric disorders. We identified patients with cognitive impairment (motor neuron disease with cognitive impairment (MNDci)), behavioural impairment (motor neuron disease with behavioural impairment (MNDbi), both (motor neuron disease with cognitive and behavioural impairment (MNDcbi)) or motor neuron disease-frontotemporal dementia (MND-FTD). 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). CONCLUSION: 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, frontotemporal dementia and neuropsychiatric disorders, particularly mood disorders.
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Disfunção Cognitiva/complicações , Demência Frontotemporal/psicologia , Transtornos Mentais/complicações , Transtornos Mentais/psicologia , Doença dos Neurônios Motores/psicologia , Idoso , Bases de Dados Factuais , Feminino , Demência Frontotemporal/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/complicações , Estudos Retrospectivos , EscóciaRESUMO
OBJECTIVE: Many studies examining stroke outcomes focus on more severe strokes or have short follow-up periods, so the long-term outcomes post-minor ischaemic stroke are unclear. METHODS: We recruited participants from inpatient and outpatient services with a lacunar or minor cortical ischaemic stroke (National Institutes of Health Stroke Scale score <8) and assessed current and premorbid cognitive functioning (Addenbrooke's Cognitive Examination-Revised (ACE-R), National Adult Reading Test (NART)), physical functioning (Timed Get Up and Go (TUG), 9-Hole Peg Test (9HPT)), dependency (modified Rankin Scale (mRS)), depression (Beck's Depression Inventory) in-person and remotely (Stroke Impact Scale). RESULTS: We followed up 224/264 participants at 3 years (mean age at index stroke=67, 126 (56%) men, 25 non-contactable, 15 declined): 66/151 (44%) had cognitive impairment, mean ACE-R 88 (SD 9, range 54-100/100), 61/156 (39%) had depression and 26/223 (12%) were dependent (mRS=3-5). Cognitive impairment at 3 years affected all ACE-R subdomains and was associated with ACE-R 1 year (ß=1.054, p<0.001) and NART (ß=1.023, p<0.05). Poor physical function was associated with stroke severity (TUG, ß=1.064, p<0.01) and recurrent stroke (9HPT, ß=1.130, p<0.05 right, ß=1.214, p<0.05 left). Higher ACE-R scores were associated with faster TUG (ß=-0.279, p<0.05) and 9HPT (right ß=-0.257, p<0.05; left ß=-0.302, p=0.05) and inversely with dependency (mRS=3-5, OR 0.88, 95% CI 0.80 to 0.97). We adjusted analyses for demographic, stroke and known risk factors. In-person and remote assessments were highly correlated. CONCLUSIONS: Cognitive, physical impairments and depression are common and interrelated 3 years after minor stroke. Cognitive and physical impairments require rehabilitation after minor stroke and argue for better integration of stroke and dementia services.
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Atividades Cotidianas , Isquemia Encefálica/fisiopatologia , Cognição , Desempenho Físico Funcional , Acidente Vascular Cerebral Lacunar/fisiopatologia , Idoso , Isquemia Encefálica/psicologia , Córtex Cerebral/irrigação sanguínea , Depressão/psicologia , Feminino , Seguimentos , Humanos , Masculino , Infarto do Miocárdio/epidemiologia , Recidiva , Índice de Gravidade de Doença , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/psicologia , Acidente Vascular Cerebral Lacunar/psicologiaRESUMO
BACKGROUND: Stroke is the second most common cause of death, and a common cause of dependency and dementia. Adult vascular risk factors and socioeconomic status (SES) are associated with increased risk, but less is known about early life risk factors, such as education, childhood SES, or intelligence (IQ). METHODS: We comprehensively searched Medline, PsycINFO, and EMBASE from inception to November 2015. We included all studies reporting data on >50 strokes examining childhood/premorbid IQ, SES, and education. Two reviewers independently screened full texts and extracted and cross-checked data, including available risk factor adjustments. We meta-analyzed stroke risk using hazard ratios (HR), odds ratios (OR), and mean differences (MD). We tested effects of study and participant characteristics in sensitivity analyses and meta-regression, and assessed heterogeneity and publication bias. RESULTS: We identified 90 studies examining stroke risk and education (79), SES (10), or IQ (nine) including approximately 164,683 stroke and over 5 million stroke-free participants. Stroke risk increased with lower education (OR = 1.35, 95% CI = 1.24, 1.48), SES (OR = 1.28, 95% CI = 1.12, 1.46), and IQ (HR = 1.17, 95% CI = 1.00, 1.37) in studies reporting point estimates, with similar associations for MD. We found minimal publication bias. Between-study heterogeneity was partly explained by participant age and case ascertainment method. CONCLUSIONS: Education, childhood SES, and intelligence have modest but important associations with lifetime stroke, and hence dementia, risks. Future studies distinguishing between the individual and combined effects of education, childhood SES and intelligence are needed to determine the independent contribution of each factor to stroke risk. See video abstract at, http://links.lww.com/EDE/B210.
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Escolaridade , Inteligência , Fatores Socioeconômicos , Acidente Vascular Cerebral/epidemiologia , Fatores Etários , Idoso , Criança , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Medição de Risco , Acidente Vascular Cerebral/diagnóstico , Análise de Sobrevida , Reino UnidoRESUMO
Background: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used. Methods: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845 ) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75 ECD , plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated. Findings: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40pg/ml and >100pg/ml correspond to future ALSFRS-R slopes of â¼0.5 and 1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields â¼25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75 ECD , and plasma miR-181ab is more limited. Interpretation: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency. Funding: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242). Research in Context: Evidence Before This Study: The phenotypic heterogeneity of ALS poses a challenge for clinical trials, making it more difficult to discern therapeutic effects of investigational agents amidst the noise of natural variability. Prognostic markers are important tools to help mitigate this issue. A host of clinical markers and putative biomarkers have been proposed to have prognostic value, but their relative utility, especially when considered jointly, and the practical implications of their use, have not been well defined.Added Value of This Study: Using a trial-like population from a natural history study, in which clinical trial-grade phenotypic data and multi-modal biomarker data were collected, we show that a subset of clinical factors, encapsulated by the ENCALS predictive model score, and serum neurofilament light chain (NfL) are the most powerful prognostic markers when considering either ALSFRS-R functional decline or permanent assisted ventilation (PAV)/tracheostomy-free survival. Importantly, serum NfL adds prognostic value even after adjusting for the ENCALS score, yielding an additional sample size saving of â¼27% in a hypothetical future clinical trial. While serum phosphorylated neurofilament heavy chain (pNfH), urinary p75 ECD , and plasma miR-181ab each holds some prognostic value, when considered together with the ENCALS score and serum NfL, only p75 ECD may yield additional but modest sample size saving. Implication of All Available Evidence: Blood NfL is a validated biomarker for multiple contexts-of-use. As a prognostic marker, it should be used together with clinical predictors, such as the ENCALS predictive model score, in all ongoing and future ALS clinical trials. The utility of urinary p75 ECD and plasma miR-181ab is less clear. Serum pNfH, as well as serum uric acid, albumin, creatinine, and C-reactive protein (CRP), provide no additional prognostic information.
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BACKGROUND AND OBJECTIVES: The severity of white matter hyperintensities (WMH) at presentation with stroke is associated with poststroke dementia and dependency. However, WMH can decrease or increase after stroke; prediction of cognitive decline is imprecise; and there are few data assessing longitudinal interrelationships among changing WMH, cognition, and function after stroke, despite the clinical importance. METHODS: We recruited patients within 3 months of a minor ischemic stroke, defined as NIH Stroke Scale (NIHSS) score <8 and not expected to result in a modified Rankin Scale (mRS) score >2. Participants repeated MRI at 1 year and cognitive and mRS assessments at 1 and 3 years. We ran longitudinal mixed-effects models assessing change in Addenbrooke's Cognitive Examination-Revised (ACE-R) and mRS scores. For mRS score, we assessed longitudinal WMH volumes (cube root; percentage intracranial volume [ICV]), adjusting for age, NIHSS score, ACE-R, stroke subtype, and time to assessment. For ACE-R score, we additionally adjusted for ICV, mRS, premorbid IQ, and vascular risk factors. We then used a multivariate model to jointly assess changing cognition/mRS score, adjusted for prognostic variables, using all available data. RESULTS: We recruited 264 patients; mean age was 66.9 (SD 11.8) years; 41.7% were female; and median mRS score was 1 (interquartile range 1-2). One year after stroke, normalized WMH volumes were associated more strongly with 1-year ACE-R score (ß = -0.259, 95% CI -0.407 to -0.111 more WMH per 1-point ACE-R decrease, p = 0.001) compared to subacute WMH volumes and ACE-R score (ß = 0.105, 95% CI -0.265 to 0.054, p = 0.195). Three-year mRS score was associated with 3-year ACE-R score (ß = -0.272, 95% CI -0.429 to -0.115, p = 0.001). Combined change in baseline-1-year jointly assessed ACE-R/mRS scores was associated with fluctuating WMH volumes (F = 9.3, p = 0.03). DISCUSSION: After stroke, fluctuating WMH mean that 1-year, but not baseline, WMH volumes are associated strongly with contemporaneous cognitive scores. Covarying longitudinal decline in cognition and independence after stroke, central to dementia diagnosis, is associated with increasing WMH volumes.
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Disfunção Cognitiva , Acidente Vascular Cerebral , Substância Branca , Idoso , Cognição , Disfunção Cognitiva/complicações , Disfunção Cognitiva/etiologia , Progressão da Doença , Feminino , Humanos , Imageamento por Ressonância Magnética , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico por imagem , Substância Branca/diagnóstico por imagemRESUMO
Considering premorbid or "peak" adult intelligence (IQ) is important when examining post-stroke cognition. The stability of estimated premorbid IQ and its relationship to current cognitive ability in stroke is unknown. We investigated changes in estimated premorbid IQ and current cognitive ability up to three years post-stroke. Minor stroke patients (NIHSS < 8) were assessed at one to three months, one and three years' post-stroke. The National Adult Reading Test (NART) and Addenbrooke's Cognitive Examination-Revised (ACE-R) were used to estimate premorbid IQ (NART IQ) and current cognitive ability respectively at each time-point. Baseline demographics, vascular and stroke characteristics were included. Of the 264 patients recruited (mean age 66), 158 (60%), 151 (57%), and 153 (58%) completed cognitive testing at each time-point respectively. NART IQ initially increased (mean difference (MD) = 1.32, 95% CI = 0.54 to 2.13, p < 0.001) before decreasing (MD = -4.269, 95% CI = -5.12 to -3.41, p < 0.001). ACE-R scores initially remained stable (MD = 0.29, 95% CI = -0.49 to 1.07, p > 0.05) before decreasing (MD = -1.05, 95% CI = -2.08 to -0.01, p < 0.05). Adjusting for baseline variables did not change the relationship between NART IQ and ACE-R with time. Increases in NART IQ were associated with more education. For ACE-R, older age was associated with declines, and higher NART IQ and more education was associated with increases. Across 3 years, we observed fluctuations in estimated premorbid IQ and minor changes in current cognitive ability. Future research should aim to identify variables associated with these changes. However, studies of post-stroke cognition should account for premorbid IQ.
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BACKGROUND: Depression after stroke is common and is associated with poorer recovery. Risk factors such as gender, age and stroke severity are established, but it is unclear whether factors from earlier in life might also contribute. METHODS: We searched MEDLINE, PsycINFO, EMBASE and meta-analysed all available evidence on childhood (premorbid) IQ, socioeconomic status (SES), education and stroke in adulthood. We included all studies reporting data on >50 patients, calculating overall odds ratios (OR), mean difference, correlation, 95% confidence intervals (CI) and 95% predictive intervals (PI) using random effects methods. We quality assessed all studies, performed sensitivity analyses, assessed heterogeneity and publication bias. RESULTS: We identified 33 studies including 2,664 participants with post-stroke depression and 5,460 without (314 participants not classified). Low education (< = 8 years) was associated with post-stroke depression in studies which defined depression as score of mild and above on a depression rating scale (OR 1.47 95% CI 1.10-1.97, p<0.01) but not in studies where depression was defined as severe depressive symptoms or a clinical diagnosis of major depression (OR 1.04 95% CI 0.90-1.31, p = 0.60). Low education was not associated with an increased risk for post-stroke depression in studies that adjusted for age and sex (OR 0.86 95% CI 0.50-1.48 p = 0.58). Those with post-stroke depression had fewer years of education than those without post-stroke depression (MD 0.68 95% CI 0.05-1.31 p = 0.04). Few studies adjusted for vascular risk factors or stroke severity. Heterogeneity between studies was moderate and was partly explained by severity of depression. In the one study identified premorbid IQ did not differ between those with post-stroke depression (mean IQ 10.1.8 SD 9.8) vs those without (mean IQ 104 SD 10.1). There were no studies that examined childhood socioeconomic status and risk of post-stroke depression. CONCLUSIONS: Having less education is associated with an increased risk of post-stroke depressive symptoms but with large confidence intervals and heterogeneity. Future studies should explore the relationship between early and late life risk factors to improve risk identification and to target prevention and treatment strategies.
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Desenvolvimento Infantil , Cognição , Depressão , Acidente Vascular Cerebral , Criança , Pré-Escolar , Depressão/etiologia , Depressão/fisiopatologia , Feminino , Humanos , Masculino , Fatores Sexuais , Fatores Socioeconômicos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologiaRESUMO
OBJECTIVE: Cerebrovascular disease (CVD) causes subclinical brain vascular lesions detected using neuroimaging and childhood factors may increase later CVD risk. METHODS: We searched MEDLINE, PsycINFO, and EMBASE, and meta-analyzed all available evidence on childhood (premorbid) IQ, socioeconomic status (SES), education, and subclinical CVD in later life. Overall odds ratios (OR), mean difference or correlation, and 95% confidence intervals (CIs) were calculated using random effects methods. RESULTS: We identified 30 relevant studies (n = 22,890). Lower childhood IQ and lower childhood SES were associated with more white matter hyperintensities (WMH) (IQ: n = 1,512, r = -0.07, 95% CI -0.12 to -0.02, p = 0.007; SES: n = 243, deep WMH r = -0.18, periventricular WMH r = -0.146). Fewer years of education were associated with several CVD markers (n = 15,439, OR = 1.17, 95% CI 1.05 to 1.31, p = 0.003). No studies assessed early life factors combined. CONCLUSIONS: Childhood IQ, SES, and education are associated with increased risk of CVD on neuroimaging in later life. Further studies are required to provide further evidence and thereby inform policy.