RESUMO
BACKGROUND: Research involving multimorbid older patients is gaining momentum. However, little is known about how to plan a randomised controlled trial (RCT) involving this group of patients. An evidence-based approach to the challenges of a recruitment process could guide researchers and help prevent underpowered trials. AIM: To define the number of multimorbid older patients that need to be identified and the number of eligible patients that need to be invited to achieve the desired recruitment number to a RCT. METHOD: We used recruitment data from the GerMoT trial, a RCT comparing proactive outpatient care based on Comprehensive Geriatric Assessment with usual care. Multimorbid older patients with high healthcare utilisation were recruited to the trial. RESULTS: Of the 1212 patients identified in a database as meeting the inclusion criteria 838 (70%) could be invited to participate in the trial. The rest could not be invited for a variety of reasons; 162 had moved out of area or into nursing homes and 86 had died before they could be contacted. 113 could not be reached. 450 (54%) of the invited patients agreed to participate. CONCLUSIONS: In our study, we have shown that it is possible to achieve a good consent rate despite older participants with multimorbidity. This can be used when planning an RCT for this patient group, who are often excluded from clinical trials. Our results are specific to a context that provides similar abilities to identify and recruit patients as can be seen in Sweden.
Assuntos
Multimorbidade , Casas de Saúde , Humanos , Idoso , Avaliação Geriátrica , Bases de Dados Factuais , HospitaisRESUMO
INTRODUCTION: We estimated the age-specific duration of the preclinical, prodromal, and dementia stages of Alzheimer's disease (AD) and the influence of sex, setting, apolipoprotein E (APOE) genotype, and cerebrospinal fluid tau on disease duration. METHODS: We performed multistate modeling in a combined sample of 6 cohorts (n = 3268) with death as the end stage and estimated the preclinical, prodromal, and dementia stage duration. RESULTS: The overall AD duration varied between 24 years (age 60) and 15 years (age 80). For individuals presenting with preclinical AD, age 70, the estimated preclinical AD duration was 10 years, prodromal AD 4 years, and dementia 6 years. Male sex, clinical setting, APOE ε4 allele carriership, and abnormal cerebrospinal fluid tau were associated with a shorter duration, and these effects depended on disease stage. DISCUSSION: Estimates of AD disease duration become more accurate if age, sex, setting, APOE, and cerebrospinal fluid tau are taken into account. This will be relevant for clinical practice and trial design.
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Doença de Alzheimer , Amiloide , Apolipoproteína E4/genética , Disfunção Cognitiva/patologia , Progressão da Doença , Sintomas Prodrômicos , Idoso , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Biomarcadores/líquido cefalorraquidiano , Feminino , Genótipo , Humanos , Estudos Longitudinais , Masculino , Tomografia por Emissão de Pósitrons , Fatores Sexuais , Fatores de Tempo , Proteínas tau/líquido cefalorraquidianoRESUMO
INTRODUCTION: We aimed to determine the added value of cerebrospinal fluid (CSF) to clinical and imaging tests to predict progression from mild cognitive impairment (MCI) to any type of dementia. METHODS: The risk of progression to dementia was estimated using two logistic regression models based on 250 MCI participants: the first included standard clinical measures (demographic, clinical, and imaging test information) without CSF biomarkers, and the second included standard clinical measures with CSF biomarkers. RESULTS: Adding CSF improved predictive accuracy with 0.11 (scale from 0-1). Of all participants, 136 (54%) had a change in risk score of 0.10 or higher (which was considered clinically relevant), of whom in 101, it was in agreement with their dementia status at follow-up. DISCUSSION: An individual person's risk of progression from MCI to dementia can be improved by relying on CSF biomarkers in addition to recommended clinical and imaging tests for usual care.
Assuntos
Disfunção Cognitiva/líquido cefalorraquidiano , Demência/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Demência/diagnóstico por imagem , Progressão da Doença , Escolaridade , Feminino , Seguimentos , Humanos , Modelos Logísticos , Imageamento por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Lobo Temporal/diagnóstico por imagemRESUMO
Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered.
Assuntos
Doença de Alzheimer/epidemiologia , Disfunção Cognitiva/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Biomarcadores/metabolismo , Disfunção Cognitiva/etiologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Prevalência , Prognóstico , Análise de SobrevidaRESUMO
We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aß42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.
Assuntos
Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Padrões de Prática Médica , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Atrofia , Biomarcadores/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/patologia , Europa (Continente) , Fluordesoxiglucose F18 , Internet , Imageamento por Ressonância Magnética , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Inquéritos e Questionários , Proteínas tau/líquido cefalorraquidianoRESUMO
BACKGROUND: Activities of daily living (ADL) are an essential part of the diagnostic criteria for Alzheimer's disease (AD). A decline in ADL affects independent living and has a strong negative impact on caregiver burden. Functional response to cholinesterase inhibitor (ChEI) treatment and factors that might influence this response in naturalistic AD patients need investigating. The aim of this study was to identify the socio-demographic and clinical factors that affect the functional response after 6 months of ChEI therapy. METHODS: This prospective, non-randomised, multicentre study in a routine clinical setting included 784 AD patients treated with donepezil, rivastigmine or galantamine. At baseline and after 6 months of treatment, patients were assessed using several rating scales, including the Instrumental Activities of Daily Living (IADL) scale, Physical Self-Maintenance Scale (PSMS) and Mini-Mental State Examination (MMSE). Demographic and clinical characteristics were investigated at baseline. The functional response and the relationships of potential predictors were analysed using general linear models. RESULTS: After 6 months of ChEI treatment, 49% and 74% of patients showed improvement/no change in IADL and in PSMS score, respectively. The improved/unchanged patients exhibited better cognitive status at baseline; regarding improved/unchanged PSMS, patients were younger and used fewer anti-depressants. A more positive functional response to ChEI was observed in younger individuals or among those having the interaction effect of better preserved cognition and lower ADL ability. Patients with fewer concomitant medications or those using NSAIDs/acetylsalicylic acid showed a better PSMS response. CONCLUSIONS: Critical characteristics that may influence the functional response to ChEI in AD were identified. Some predictors differed from those previously shown to affect cognitive response, e.g., lower cognitive ability and older age predicted better cognitive but worse functional response.
Assuntos
Atividades Cotidianas/psicologia , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Cognição , Pessoas com Deficiência , Donepezila , Feminino , Galantamina/uso terapêutico , Humanos , Indanos/uso terapêutico , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fenilcarbamatos/uso terapêutico , Piperidinas/uso terapêutico , Rivastigmina , Resultado do TratamentoRESUMO
In untreated patients with Alzheimer disease (AD) the functional ability is gradually lost. What happens to the patients after continuous long-term cholinesterase inhibitor (ChEI) treatment is less investigated. The objective of this study was to describe the longitudinal functional outcome and analyze factors affecting the outcome in ChEI-treated patients. In an open, 3-year, nonrandomized, prospective, multicenter study in a routine clinical setting, 790 patients were treated with either donepezil, rivastigmine, or galantamine. At baseline and every 6 months, they were assessed with several rating scales including Instrumental Activities of Daily Living (IADL), Physical Self-Maintenance Scale (PSMS), and Mini-Mental State Examination (MMSE). A faster functional decline was associated with lower cognitive ability at baseline, older age, and the interaction of higher education and longer time in the study. The patients residing with a spouse or relative showed slower deterioration in IADL score. A higher mean dose of ChEI, regardless of drug agent, was also related to slower instrumental ADL decline. Prediction models for longitudinal functional outcome were provided. AD severity at baseline is a key factor in obtaining reliable clinical prognoses of the long-term ADL ability. The dosage of ChEI treatment could possibly lead to a different functional outcome.
Assuntos
Atividades Cotidianas , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/administração & dosagem , Idoso , Inibidores da Colinesterase/uso terapêutico , Progressão da Doença , Donepezila , Relação Dose-Resposta a Droga , Feminino , Galantamina/administração & dosagem , Humanos , Indanos/administração & dosagem , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Fenilcarbamatos/administração & dosagem , Piperidinas/administração & dosagem , Rivastigmina , Resultado do TratamentoRESUMO
BACKGROUND: Alzheimer's disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Abeta(42) and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group. METHODS: Patients with SCI, naMCI, aMCI, and neurologically healthy controls were recruited from 20 memory clinics across Europe, between January, 2003, and June, 2005, into this prospective cohort study. A CSF AD profile was defined as an abnormal ratio of Abeta(42):tau. Patients were assessed annually up to 3 years. Outcome measures were changes in memory, overall cognition, mini-mental state examination (MMSE) score, daily function, and progression to AD-type dementia. FINDINGS: The CSF AD profile was more common in patients with SCI (31 of 60 [52%]), naMCI (25 of 37 [68%]), and aMCI (56 of 71 [79%]) than in healthy controls (28 of 89 [31%]). The profile was associated with cognitive decline in patients with naMCI (memory, MMSE, and daily function) and in patients with aMCI (MMSE and daily function). In patients with aMCI, a CSF AD profile was predictive of AD-type dementia (OR 26.8, 95% CI 1.6-456.4). INTERPRETATION: AD is a common cause of SCI, naMCI, and aMCI and is associated with cognitive decline in patients with naMCI or aMCI. Patients with SCI might be in the early stages of AD, and cognitive decline might become apparent only after longer follow-up. FUNDING: European Commission; Ana Aslan International Foundation.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Transtornos Cognitivos/líquido cefalorraquidiano , Transtornos Cognitivos/diagnóstico , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/análise , Biomarcadores/análise , Biomarcadores/líquido cefalorraquidiano , Transtornos Cognitivos/fisiopatologia , Estudos de Coortes , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fragmentos de Peptídeos/análise , Valor Preditivo dos Testes , Prevalência , Prognóstico , Estudos Prospectivos , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Proteínas tau/análiseRESUMO
BACKGROUND: The objective was to identify separate cognitive domains in the standard assessment tools (MMSE, ADAS-Cog) and analyze the process of decline within domains during three years in Alzheimer's disease (AD) patients with donepezil treatment. METHOD: AD patients (n = 421) were recruited from a clinical multi-centre study program in Sweden. Patients were assessed every six months during three years. All patients received donepezil starting directly after study entry. After dropouts, 158 patients remained for analyses over three years. Data for the other patients were analysed until they dropped out (4 groups based on length in study). RESULTS: Factor analyses of all items suggested that there were three intercorrelated factors: a General, a Memory and a Spatial factor for which we constructed corresponding domains. Overall there was a cognitive improvement at six months followed by a linear drop over time for the three domains. Some group and domain differences were identified. Patients who remained longer in the study had better initial performance and a slower deterioration rate. The early dropouts showed no improvement at six months and many dropped out due to side effects. The other groups displayed a performance improvement at six months that was less pronounced in the Memory domain. Before dropping out, deterioration accelerated, particularly in the Spatial domain. CONCLUSION: The course of illness in the three domains was heterogeneous among the patients. We were not able to identify any clinically relevant correlates of this heterogeneity. As an aid we constructed three algorithms corresponding to the cognitive domains, which can be used to characterize patients initially, identify rapid decliners and follow the course of the disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Cognição/efeitos dos fármacos , Indanos/uso terapêutico , Piperidinas/uso terapêutico , Idoso , Algoritmos , Doença de Alzheimer/psicologia , Análise de Variância , Apolipoproteínas E/genética , Donepezila , Análise Fatorial , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Nootrópicos/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Biomarker-based risk predictions of dementia in people with mild cognitive impairment are highly relevant for care planning and to select patients for treatment when disease-modifying drugs become available. We aimed to establish robust prediction models of disease progression in people at risk of dementia. METHODS: In this modelling study, we included people with mild cognitive impairment (MCI) from single-centre and multicentre cohorts in Europe and North America: the European Medical Information Framework for Alzheimer's Disease (EMIF-AD; n=883), Alzheimer's Disease Neuroimaging Initiative (ADNI; n=829), Amsterdam Dementia Cohort (ADC; n=666), and the Swedish BioFINDER study (n=233). Inclusion criteria were a baseline diagnosis of MCI, at least 6 months of follow-up, and availability of a baseline Mini-Mental State Examination (MMSE) and MRI or CSF biomarker assessment. The primary endpoint was clinical progression to any type of dementia. We evaluated performance of previously developed risk prediction models-a demographics model, a hippocampal volume model, and a CSF biomarkers model-by evaluating them across cohorts, incorporating different biomarker measurement methods, and determining prognostic performance with Harrell's C statistic. We then updated the models by re-estimating parameters with and without centre-specific effects and evaluated model calibration by comparing observed and expected survival. Finally, we constructed a model combining markers for amyloid deposition, tauopathy, and neurodegeneration (ATN), in accordance with the National Institute on Aging and Alzheimer's Association research framework. FINDINGS: We included all 2611 individuals with MCI in the four cohorts, 1007 (39%) of whom progressed to dementia. The validated demographics model (Harrell's C 0·62, 95% CI 0·59-0·65), validated hippocampal volume model (0·67, 0·62-0·72), and updated CSF biomarkers model (0·72, 0·68-0·74) had adequate prognostic performance across cohorts and were well calibrated. The newly constructed ATN model had the highest performance (0·74, 0·71-0·76). INTERPRETATION: We generated risk models that are robust across cohorts, which adds to their potential clinical applicability. The models could aid clinicians in the interpretation of CSF biomarker and hippocampal volume results in individuals with MCI, and help research and clinical settings to prepare for a future of precision medicine in Alzheimer's disease. Future research should focus on the clinical utility of the models, particularly if their use affects participants' understanding, emotional wellbeing, and behaviour. FUNDING: ZonMW-Memorabel.
Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Hipocampo/patologia , Imageamento por Ressonância Magnética , Fragmentos de Peptídeos/líquido cefalorraquidiano , Modelos de Riscos Proporcionais , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/patologia , Disfunção Cognitiva/patologia , Progressão da Doença , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Degeneração Neural , Neuroimagem , América do Norte/epidemiologia , Tamanho do Órgão , Fosforilação , Prognóstico , Processamento de Proteína Pós-Traducional , Proteínas tau/químicaRESUMO
BACKGROUND/AIMS: To build and analyze regression models predicting (1) the long-term cognitive outcome in donepezil-treated patients with Alzheimer's disease, and (2) the short-term (6 months) cognitive impact of treatment depending on cognitive severity at baseline. METHODS: The Swedish Alzheimer Treatment Study (SATS) is an open-label, non-randomized, 3-year, multicentre study in a routine clinical setting. A total of 435 patients, mostly in the mild and moderate stages of Alzheimer's disease, received the cholinesterase inhibitor donepezil. They were assessed with the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at baseline and every 6 months for a total period of 3 years. Regression models were fitted from the actual scores at different intervals for the prediction of the cognitive outcome. RESULTS: The ADAS-cog and MMSE scores during the 3-year treatment period could be predicted with a high degree of explanation using regression models (p < 0.001). Moreover, there was a significant relation between the mean cognitive change after 6 months of treatment and the baseline scores on MMSE (p < 0.01) and ADAS-cog (p < 0.001), respectively. CONCLUSION: Statistical models can be used to predict cognitive outcome in donepezil-treated cohorts of AD patients. These models can be clinically valuable, for example when assessing the efficacy of new therapies when added to cholinesterase inhibitor treatment.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Transtornos Cognitivos/tratamento farmacológico , Indanos/administração & dosagem , Modelos Estatísticos , Nootrópicos/administração & dosagem , Piperidinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Transtornos Cognitivos/fisiopatologia , Donepezila , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento , Valor Preditivo dos Testes , Escalas de Graduação Psiquiátrica , Análise de Regressão , Índice de Gravidade de DoençaRESUMO
Upon publication of this article [1], it was noticed that there were some inconsistencies in Tables 1, 2 and 3. Some of the superscript letters were incorrectly assigned. Please see below the correct tables.
RESUMO
BACKGROUND: Whether age at onset influences Alzheimer's disease (AD) progression and the effectiveness of cholinesterase inhibitor (ChEI) therapy is not clear. We aimed to compare longitudinal cognitive and global outcomes in ChEI-treated patients with early-onset Alzheimer's disease (EOAD) versus late-onset Alzheimer's disease (LOAD) in clinical practice. METHODS: This 3-year, prospective, observational, multicentre study included 1017 participants with mild to moderate AD; 143 had EOAD (age at onset < 65 years) and 874 had LOAD (age at onset ≥ 65 years). At baseline and semi-annually, patients were assessed using cognitive, global and activities of daily living (ADL) scales, and the dose of ChEI was recorded. Potential predictors of decline were analysed using mixed-effects models. RESULTS: Six-month response to ChEI therapy and long-term prognosis in cognitive and global performance were similar between the age-at-onset groups. However, deterioration was significantly faster when using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) over 3 years in participants with EOAD than in those with LOAD; hence, prediction models for the mean ADAS-Cog trajectories are presented. The younger cohort had a larger proportion of homozygote apolipoprotein E (APOE) ε4 allele carriers than the older cohort; however, APOE genotype was not a significant predictor of cognitive impairment in the multivariate models. A slower rate of cognitive progression was related to initiation of ChEIs at an earlier stage of AD, higher ChEI dose and fewer years of education in both groups. In LOAD, male sex, better instrumental ADL ability and no antipsychotic drug use were additional protective characteristics. The older patients received a lower ChEI dose than the younger individuals during most of the study period. CONCLUSIONS: Although the participants with EOAD showed a faster decline in ADAS-Cog, had a longer duration of AD before diagnosis, and had a higher frequency of two APOE ε4 alleles than those with LOAD, the cognitive and global responses to ChEI treatment and the longitudinal outcomes after 3 years were similar between the age-at-onset groups. A higher mean dose of ChEI and better cognitive status at the start of therapy were independent protective factors in both groups, stressing the importance of early treatment in adequate doses for all patients with AD.
Assuntos
Atividades Cotidianas/psicologia , Doença de Alzheimer , Inibidores da Colinesterase/uso terapêutico , Transtornos Cognitivos/etiologia , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Apolipoproteínas E/genética , Feminino , Humanos , Estudos Longitudinais , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Testes Neuropsicológicos , Avaliação de Resultados em Cuidados de Saúde , Fatores de TempoRESUMO
BACKGROUND/AIMS: Whether age at onset influences functional deterioration in Alzheimer disease (AD) is unclear. We, therefore, investigated risk factors for progression in activities of daily living (ADL) and nursing home placement (NHP) in cholinesterase inhibitor (ChEI)-treated patients with early-onset AD (EOAD) versus late-onset AD (LOAD). METHODS: This 3-year, prospective, observational, multicenter study included 1,017 participants with mild-to-moderate AD; 143 had EOAD (onset <65 years) and 874 LOAD (onset ≥65 years). Possible sociodemographic and clinical factors that could affect functional outcome and NHP were analyzed using mixed-effects models and logistic regression, respectively. RESULTS: Younger individuals exhibited longer illness duration before AD diagnosis, whereas 6-month functional response to ChEI therapy, 3-year changes in ADL capacities, time from diagnosis to NHP, and survival time in nursing homes were similar between the groups. In LOAD, a higher ChEI dose, no antidepressant use, and lower education level were protective factors for slower instrumental ADL (IADL) decline. In EOAD, antihypertensives/cardiac therapy implied faster IADL progression but lower risk of NHP. CONCLUSION: This study highlights the clinical importance of an earlier diagnosis and treatment initiation and the need for functional evaluations in EOAD. Despite the age differences between EOAD and LOAD, a similar need for nursing homes was observed.
RESUMO
BACKGROUND: Cerebrovascular disease (CVD) and amyloid-ß (Aß) often coexist, but their influence on neurodegeneration and cognition in predementia stages remains unclear. We investigated the association between CVD and Aß on neurodegenerative markers and cognition in patients without dementia. METHODS: We included 271 memory clinic patients with subjective or objective cognitive deficits but without dementia from the BioBank Alzheimer Center Limburg cohort (n = 99) and the LeARN (n = 50) and DESCRIPA (n = 122) multicenter studies. CSF Aß1-42 and white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) scans were used as measures of Aß and CVD, respectively. Individuals were classified into four groups based on the presence (+) or absence (-) of Aß and WMH. We investigated differences in phosphorylated tau, total tau (t-tau), and medial temporal lobe atrophy (MTA) between groups using general linear models. We examined cognitive decline and progression to dementia using linear mixed models and Cox proportional hazards models. All analyses were adjusted for study and demographics. RESULTS: MTA and t-tau were elevated in the Aß - WMH+, Aß + WMH-, and Aß + WMH+ groups. MTA was most severe in the Aß + WMH+ group compared with the groups with a single pathology. Both WMH and Aß were associated with cognitive decline, but having both pathologies simultaneously was not associated with faster decline. CONCLUSIONS: In the present study, we found an additive association of Aß and CVD pathology with baseline MTA but not with cognitive decline. Because our findings may have implications for diagnosis and prognosis of memory clinic patients and for future scientific research, they should be validated in a larger sample with longer follow-up.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Transtornos Cerebrovasculares/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Demência/diagnóstico por imagem , Idoso , Apolipoproteínas E/genética , Atrofia , Biomarcadores/líquido cefalorraquidiano , Encéfalo/metabolismo , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Estudos de Coortes , Demência/genética , Demência/metabolismo , Progressão da Doença , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Fosforilação , Proteínas tau/metabolismoRESUMO
BACKGROUND: Lifestyle factors have been associated with the risk of dementia, but the association with Alzheimer's disease (AD) remains unclear. OBJECTIVE: To examine the association between later life lifestyle factors and AD biomarkers (i.e., amyloid-ß 1-42 (Aß42) and tau in cerebrospinal fluid (CSF), and hippocampal volume) in individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). In addition, to examine the effect of later life lifestyle factors on developing AD-type dementia in individuals with MCI. METHODS: We selected individuals with SCD (nâ=â111) and MCI (nâ=â353) from the DESCRIPA and Kuopio Longitudinal MCI studies. CSF Aß42 and tau concentrations were assessed with ELISA assay and hippocampal volume with multi-atlas segmentation. Lifestyle was assessed by clinical interview at baseline for: social activity, physical activity, cognitive activity, smoking, alcohol consumption, and sleep. We performed logistic and Cox regression analyses adjusted for study site, age, gender, education, and diagnosis. Prediction for AD-type dementia was performed in individuals with MCI only. RESULTS: Later life lifestyle factors were not associated with AD biomarkers or with conversion to AD-type dementia. AD biomarkers were strongly associated with conversion to AD-type dementia, but these relations were not modulated by lifestyle factors. Apolipoprotein E (APOE) genotype did not influence the results. CONCLUSIONS: Later life lifestyle factors had no impact on key AD biomarkers in individuals with SCD and MCI or on conversion to AD-type dementia in MCI.
Assuntos
Transtornos Cognitivos/líquido cefalorraquidiano , Transtornos Cognitivos/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Estilo de Vida , Fatores Etários , Idoso , Consumo de Bebidas Alcoólicas/líquido cefalorraquidiano , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/patologia , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/patologia , Apolipoproteínas E/genética , Cognição , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/patologia , Autoavaliação Diagnóstica , Progressão da Doença , Escolaridade , Exercício Físico , Feminino , Seguimentos , Hipocampo/patologia , Humanos , Estudos Longitudinais , Masculino , Tamanho do Órgão , Fatores Sexuais , Sono , Fumar/líquido cefalorraquidiano , Fumar/epidemiologia , Fumar/patologia , Comportamento SocialRESUMO
We investigated whether dementia risk factors were associated with prodromal Alzheimer's disease (AD) according to the International Working Group-2 and National Institute of Aging-Alzheimer's Association criteria, and with cognitive decline. A total of 1394 subjects with mild cognitive impairment from 14 different studies were classified according to these research criteria, based on cognitive performance and biomarkers. We compared the frequency of 10 risk factors between the subgroups, and used Cox-regression to examine the effect of risk factors on cognitive decline. Depression, obesity, and hypercholesterolemia occurred more often in individuals with low-AD-likelihood, compared with those with a high-AD-likelihood. Only alcohol use increased the risk of cognitive decline, regardless of AD pathology. These results suggest that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairment. Future studies should validate these findings and determine whether risk factors might be of influence at an earlier stage (i.e., preclinical) of AD.
Assuntos
Doença de Alzheimer/etiologia , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Biomarcadores , Cognição , Disfunção Cognitiva/etiologia , Depressão , Progressão da Doença , Feminino , Humanos , Hipercolesterolemia , Masculino , Pessoa de Meia-Idade , Obesidade , Modelos de Riscos Proporcionais , Fatores de RiscoRESUMO
Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aß42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aß42 levels inversely correlated to VV/TIV in the whole study population (Aß42: râ=â-0.28; pâ<â0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: râ=â-0.15; p-tau: râ=â-0.13; both pâ<â0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF Aß42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aß42 levels.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Ventrículos Cerebrais/diagnóstico por imagem , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Idoso , Algoritmos , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Área Sob a Curva , Atrofia , Biomarcadores/líquido cefalorraquidiano , Feminino , Hipocampo/diagnóstico por imagem , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Reconhecimento Automatizado de Padrão , Fragmentos de Peptídeos/líquido cefalorraquidiano , Curva ROC , Proteínas tau/líquido cefalorraquidianoRESUMO
BACKGROUND: There is an increasing interest in cognitive and functional outcomes in the respective stages of Alzheimer's disease (AD) and in novel therapies particularly for the milder phases of AD. Our aim was to describe and compare various aspects of disease progression in patients with mild versus moderate AD in routine clinical practice of cholinesterase inhibitor (ChEI) therapy. METHODS: This 3-year, prospective, observational, multicentre study included 1021 participants. Of these, 734 had mild AD (Mini-Mental State Examination (MMSE) score, 20-26) and 287 had moderate AD (MMSE score, 10-19) at the start of ChEI treatment. At baseline and every 6 months, patients were assessed using cognitive, global, instrumental and basic activities of daily living (ADL) scales. Potential predictors of deterioration in moderate AD were analysed using mixed-effects models. RESULTS: The change from baseline between participants with mild and moderate stages of AD after 3 years of ChEI therapy differed significantly on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and basic ADL, but not using the MMSE and instrumental ADL scales. Protective independent factors for better cognitive long-term outcome in the group with moderate AD were older age, higher instrumental ADL ability, no antipsychotics, usage of non-steroidal anti-inflammatory drugs/acetylsalicylic acid, living with family member, lower education and a higher mean dose of ChEI. Apolipoprotein E genotype did not influence the rates of disease progression or the longitudinal outcomes. Prediction models were provided for moderate AD. CONCLUSIONS: More sensitive cognitive measures, such as the ADAS-cog scale, are required to detect a possibly faster deterioration among the participants with moderate AD. This study highlighted the clinical importance of instrumental ADL evaluations in patients at a mild stage of AD, and the importance of optimizing the ChEI dose even for individuals with moderate AD. Solitary living was a risk factor for faster cognitive decline, and probably expanded the need for formal care in the group with moderate AD. The patients with more advanced AD and presumably more pronounced neuroinflammation might have additional cognitive benefits from longer-term treatment with anti-inflammatory drugs.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Inibidores da Colinesterase/uso terapêutico , Cognição/efeitos dos fármacos , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Donepezila , Feminino , Galantamina/uso terapêutico , Humanos , Indanos/uso terapêutico , Masculino , Entrevista Psiquiátrica Padronizada , Piperidinas/uso terapêutico , Estudos Prospectivos , Rivastigmina/uso terapêutico , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Epigenetic dysregulation has been associated with cognitive decline and Alzheimer's disease. The present study investigated associations between common SNPs in genes regulating DNA methylation and age-related changes in cognitive decline in two independent prospective cohorts of patients suffering from mild cognitive impairment. An association between the rs1187120 SNP in DNMT3A and annual decline in cognitive functioning was discovered and replicated, suggesting that DNMT3A moderates cognitive decline in subjects with mild cognitive impairment.