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Objective: To assess the role of brief neuropsychological assessments in prediction and identification of Alzheimer's disease (AD) pathology and progression to AD dementia. Method: Adults (N = 255; range = 40-81 years) with self-reported cognitive decline underwent baseline and 2-year follow-up clinical assessment, including a brief neuropsychological screening and lumbar puncture. Five different mild cognitive impairment (MCI) algorithms were applied on baseline cognitive test results: one conventional, three amnestic (lenient, stringent, multidomain), and one comprehensive criterion. We compared predictive and diagnostic accuracy of these MCI criteria by performing logistic regression analyses and calculating diagnostic accuracy measures for 2-year outcomes of (1) clinical diagnosis of AD dementia and (2) cerebrospinal fluid biomarkers in the Alzheimer's continuum. Results: The lenient amnestic MCI criterion showed the largest effect size for predicting progression to AD dementia (OR = 13.762, 99% CI = 1.969-96.194, p = .001) and AD biomarkers (OR = 4.855, 99% CI = 1.974-11.924, p < .001) after 2 years. This criterion was sensitive for progression to dementia (sensitivity = 92.0%, specificity = 54.8%, positive likelihood ratio [LR+] = 2.03, LR- = 0.15) and showed the highest overall diagnostic accuracy for AD biomarkers (sensitivity = 72.7%, specificity = 59.1%, LR+ = 1.78, negative likelihood ratio [LR-] = 0.46). The multidomain amnestic MCI criterion produced the highest specificity for dementia (sensitivity = 76.0%, specificity = 73.0%, LR+ = 2.82, LR- = 0.33) and AD biomarkers (sensitivity = 46.8% specificity = 70.9% LR+ = 1.61, LR- = 0.75). Conclusions: Defining MCI using a brief neuropsychological battery provided limited accuracy for progression to AD dementia and cerebrospinal fluid Aß. The lenient amnestic MCI criterion identified the highest number of individuals who progressed to clinical AD or showed biomarker pathology, but this approach included a substantial number of false positives. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Assuntos
Doença de Alzheimer/psicologia , Demência/psicologia , Testes Neuropsicológicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/psicologia , Demência/patologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Background and Purpose- Cerebral small vessel disease is characterized by a wide range of focal and global brain changes. We used a magnetic resonance imaging segmentation tool to quantify multiple types of small vessel disease-related brain changes and examined their individual and combined predictive value on cognitive and functional abilities. Methods- Magnetic resonance imaging scans of 560 older individuals from LADIS (Leukoaraiosis and Disability Study) were analyzed using automated atlas- and convolutional neural network-based segmentation methods yielding volumetric measures of white matter hyperintensities, lacunes, enlarged perivascular spaces, chronic cortical infarcts, and global and regional brain atrophy. The subjects were followed up with annual neuropsychological examinations for 3 years and evaluation of instrumental activities of daily living for 7 years. Results- The strongest predictors of cognitive performance and functional outcome over time were the total volumes of white matter hyperintensities, gray matter, and hippocampi (P<0.001 for global cognitive function, processing speed, executive functions, and memory and P<0.001 for poor functional outcome). Volumes of lacunes, enlarged perivascular spaces, and cortical infarcts were significantly associated with part of the outcome measures, but their contribution was weaker. In a multivariable linear mixed model, volumes of white matter hyperintensities, lacunes, gray matter, and hippocampi remained as independent predictors of cognitive impairment. A combined measure of these markers based on Z scores strongly predicted cognitive and functional outcomes (P<0.001) even above the contribution of the individual brain changes. Conclusions- Global burden of small vessel disease-related brain changes as quantified by an image segmentation tool is a powerful predictor of long-term cognitive decline and functional disability. A combined measure of white matter hyperintensities, lacunar, gray matter, and hippocampal volumes could be used as an imaging marker associated with vascular cognitive impairment.
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Encéfalo , Doenças de Pequenos Vasos Cerebrais , Disfunção Cognitiva , Efeitos Psicossociais da Doença , Imageamento por Ressonância Magnética , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/fisiopatologia , Cognição , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Masculino , Valor Preditivo dos TestesRESUMO
Age-related white matter lesions (WML) are a risk factor for stroke, cognitive decline, and dementia. Different requirements are imposed on methods for the assessment of WML in clinical settings and for research purposes, but reliability analysis is of major importance. In this study, WML assessment with three different methods was evaluated. In the Gothenburg mild cognitive impairment study, MRI scans from 152 participants were used to assess WML with the Fazekas visual rating scale on T2 images, a manual volumetric method on FLAIR images, and FreeSurfer volumetry on T1 images. Reliability was acceptable for all three methods. For low WML volumes (2/3 of the patients), reliability was overall lower and nonsignificant for the manual volumetric method. Unreliability in the assessment of patients with low WML with manual volumetry may mainly be due to intensity variation in the FLAIR sequence used; hence, intensity standardization and normalization methods must be used for more accurate assessments. The FreeSurfer segmentations resulted in smaller WML volumes than the volumes acquired with the manual method and showed deviations from visible hypointensities in the T1 images, which quite likely reduces validity.
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Age-related white matter changes have been associated with cognitive functioning, even though their role is not fully understood. This work aimed to test a 3-factor model of the neuropsychological assessment battery and evaluate how the model fit the data longitudinally. Confirmatory factor analysis (CFA) was used to investigate the dimensions of a structured set of neuropsychological tests administered to a multicenter, international sample of independent older adults (LADIS study). Six hundred and thirty-eight older adults completed baseline neuropsychological, clinical, functional and motor assessments, which were repeated each year for a 3-year follow-up. CFA provided support for a 3-factor model. These factors involve the dimensions of executive functions, memory functions, and speed and motor control abilities. Performance decreased in most neuropsychological measures. Results showed that executive functioning, memory and speed of motor abilities are valid latent variables of neuropsychological performance among older adults, and that this structure is relatively consistent longitudinally, even though performance decreases with time.
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Envelhecimento/psicologia , Análise Fatorial , Testes Neuropsicológicos , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Função Executiva , Feminino , Humanos , Estudos Longitudinais , Masculino , Memória , Pessoa de Meia-Idade , Fibras Nervosas Mielinizadas/patologia , Desempenho PsicomotorRESUMO
BACKGROUND/AIMS: Demyelination and axonal degeneration are the hallmarks of established white matter lesions (WML). The neurochemistry of ongoing WML is only partially known. We explored cerebrospinal fluid (CSF) substances as markers of brain tissue damage in relation to progression of WML rated on magnetic resonance imaging. METHODS: CSF from elderly individuals with WML was analyzed for amyloid markers, total τ, hyperphosphorylated τ, neurofilament protein light subunit, sulfatide and CSF/serum-albumin ratio. After 3 years, a follow-up magnetic resonance imaging was performed. Progression of WML was rated using the Rotterdam Progression Scale (RPS). RESULTS: 37 subjects (age 73.6 ± 4.6 years) were included. Subjects with more pronounced progression (RPS > 2; n = 15) had lower mean sulfatide concentration at baseline as compared to subjects with no or minimal progression (RPS 0-2; n = 22) according to univariate analyses (p = 0.009). Sulfatide was the only biomarker that predicted the RPS score according to regression analysis, explaining 18.9% of the total variance (r = 0.38, p = 0.015). CONCLUSION: The correlation of CSF sulfatide levels and RPS scores may reflect a remyelination response to the demyelination process associated with WML. Furthermore, the results strengthen the notion that WML pathology is different from that of Alzheimer's disease.
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Encéfalo/patologia , Sulfoglicoesfingolipídeos/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores , Demência Vascular/líquido cefalorraquidiano , Demência Vascular/psicologia , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/psicologia , Progressão da Doença , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Leucoaraiose/líquido cefalorraquidiano , Leucoaraiose/psicologia , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Degeneração Neural/patologia , Degeneração Neural/psicologia , Países Baixos/epidemiologia , Testes Neuropsicológicos , Valor Preditivo dos Testes , Fatores Socioeconômicos , Proteínas tau/líquido cefalorraquidianoRESUMO
The objective of the present study was to evaluate a Monte Carlo feature selection (MCFS) and rough set Rosetta pipeline for generating rule-based models as a tool for comprehensive risk estimates for future Alzheimer's disease (AD) in individual patients with mild cognitive impairment (MCI). Risk estimates were generated on the basis of age, gender, Mini-Mental State Examination scores, apolipoprotein E (APOE) genotype and the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phospho-tau(181) (P-tau) and the 42 amino acid form of amyloid ß (Aß42) in two sets of longitudinally followed MCI patients (n = 217 in total). The predictive model was created in Rosetta, evaluated with the standard tenfold cross-validation approach and tested on an external set. Features were ranked and selected by the MCFS algorithm. Using the combined pipeline of MCFS and Rosetta, it was possible to predict AD among patients with MCI with an area under the receiver operating characteristics curve of 0.92. Risk estimates were produced for the individual patients and showed good correlation with actual diagnosis in cross validation, and on an external dataset from a new study. Analysis of the importance of attributes showed that the biochemical CSF markers contributed the most to the predictions, and that added value was gained by combining several biochemical markers. Despite a correlation with the biochemical markers, the genetic marker APOE ε4 did not contribute to the predictive power of the model.
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Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/psicologia , Progressão da Doença , Método de Monte Carlo , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Valor Preditivo dos Testes , Proteínas tau/líquido cefalorraquidianoRESUMO
BACKGROUND: The study aimed to evaluate the Cognitive Assessment Battery (CAB) in a specialist clinic setting in order to find out if it if it could be a supplement to the Mini-mental State Examination (MMSE) and distinguish between normal aging, mild cognitive impairment (MCI) and dementia, as well as MCI of different severities. METHODS: CAB consists of six short tests covering the cognitive domains of speed/attention, episodic memory, visuospatial functions, language and executive functions. It takes about 20 minutes to carry out and provides a quick overview of the patient's cognitive profile. Three groups were compared: healthy controls (N = 41), MCI (N = 83) and mild dementia (N = 28). RESULTS: CAB distinguished very clearly between controls and MCI as well as MCI and dementia. On further analysis CAB also distinguished between MCI of different severities. It also showed to have good sensitivity and specificity for identifying more severe MCI. CONCLUSIONS: CAB seems to be a useful supplement to MMSE and a screening instrument for MCI and dementia with good sensitivity and specificity.
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Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Demência/diagnóstico , Testes de Inteligência , Transtornos da Memória/diagnóstico , Competência Mental , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/complicações , Demência/etiologia , Demência/psicologia , Escolaridade , Função Executiva , Feminino , Humanos , Testes de Inteligência/normas , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/psicologia , Memória Episódica , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
Linear molecular motors translocate along polymeric tracks using discrete steps. The step length is usually measured using constant-force single molecule experiments in which the polymer is tethered to a force-clamped microsphere. During the enzymatic cycle the motor shortens the tether contour length. Experimental conditions influence the achievable step length resolution, and ideally experiments should be conducted with high clamp-force using slow motors linked to small beads via stiff short tethers. We focus on the limitations that the polymer-track flexibility, the thermal motion of the microsphere, and the motor kinetics pose for step-length measurement in a typical optical tweezers experiment. An expression for the signal/noise ratio in a constant-force, worm-like chain tethered particle, single-molecule experiment is developed. The signal/noise ratio is related to the Fourier transform of the pairwise distance distribution, commonly used to determine step length from a time-series. Monte Carlo simulations verify the proposed theory for experimental parameter values typically encountered with molecular motors (polymerases and helicases) translocating along single- or double-stranded nucleic acids. The predictions are consistent with recent experimental results for double-stranded DNA tethers. Our results map favorable experimental conditions for observing single motor steps on various substrates but indicate that principal resolution limits are set by thermal fluctuations.
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Simulação por Computador , Modelos Teóricos , Biopolímeros/química , DNA/química , Cinética , Microesferas , Método de Monte Carlo , RNA/químicaRESUMO
BACKGROUND: The Alzheimer's Disease Assessment Scale (ADAS) is often used in international multicenter trials. Use across countries presupposes correct translation and adaptation of the scale, and maintenance of its psychometric properties. OBJECTIVES: To compare the various translations of the ADAS used in Western Europe, to design internationally harmonized translations and to validate these. SETTING: International cooperative study in eight European countries. METHODS: An inventory was made of existing versions of the ADAS-Cog used in eight European countries, and adaptations were made. The concurrent validity of the harmonized versions of the ADAS was tested in 283 patients with probable or possible Alzheimer's disease. The Nurses Observation Scale for Geriatrics (NOSGER), CAMCOG-R and MMSE was used to assess concordance between cognitive and behavioral measures. RESULTS: Differences between the versions mainly involved object naming, items for verbal memory, such as the number of trials allowed, the imagery value of the words selected as targets or distractors, and the number of parallel versions. These differences were eliminated by adapting and harmonizing the various versions of the ADAS-Cog. Thereafter, only small differences between the different countries were found, and patterns of correlation between ADAS-Cog, and the NOSGER, CAMCOG-R and MMSE were consistent. CONCLUSIONS: The study underlines the need to use harmonized versions of instruments for rating dementia in multinational studies. The findings indicate that the harmonization of the ADAS-Cog was successful.