RESUMO
We aimed to characterize the cognitive profile of post-acute COVID-19 syndrome (PACS) patients with cognitive complaints, exploring the influence of biological and psychological factors. Participants with confirmed SARS-CoV-2 infection and cognitive complaints ≥ 8 weeks post-acute phase were included. A comprehensive neuropsychological battery (NPS) and health questionnaires were administered at inclusion and at 1, 3 and 6 months. Blood samples were collected at each visit, MRI scan at baseline and at 6 months, and, optionally, cerebrospinal fluid. Cognitive features were analyzed in relation to clinical, neuroimaging, and biochemical markers at inclusion and follow-up. Forty-nine participants, with a mean time from symptom onset of 10.4 months, showed attention-executive function (69%) and verbal memory (39%) impairment. Apathy (64%), moderate-severe anxiety (57%), and severe fatigue (35%) were prevalent. Visual memory (8%) correlated with total gray matter (GM) and subcortical GM volume. Neuronal damage and inflammation markers were within normal limits. Over time, cognitive test scores, depression, apathy, anxiety scores, MRI indexes, and fluid biomarkers remained stable, although fewer participants (50% vs. 75.5%; p = 0.012) exhibited abnormal cognitive evaluations at follow-up. Altered attention/executive and verbal memory, common in PACS, persisted in most subjects without association with structural abnormalities, elevated cytokines, or neuronal damage markers.
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Biomarcadores , COVID-19 , Cognição , Imageamento por Ressonância Magnética , Neuroimagem , Testes Neuropsicológicos , Síndrome de COVID-19 Pós-Aguda , Humanos , Masculino , COVID-19/psicologia , COVID-19/diagnóstico por imagem , COVID-19/complicações , Feminino , Biomarcadores/sangue , Pessoa de Meia-Idade , Neuroimagem/métodos , Adulto , Imageamento por Ressonância Magnética/métodos , SARS-CoV-2/isolamento & purificação , Idoso , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/sangue , AnsiedadeRESUMO
BACKGROUND: Anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis is an autoimmune disorder that can be treated with immunotherapy, but the symptoms that remain after treatment have not been well described. We aimed to characterise the clinical features of patients with anti-LGI1 encephalitis for 1 year starting within the first year after initial immunotherapy. METHODS: For this prospective cohort study, we recruited patients with anti-LGI1 encephalitis as soon as possible after they had received conventional immunotherapy for initial symptoms; patients were recruited from 21 hospitals in Spain. Patients were excluded if they had an interval of more than 1 year since initial immunotherapy, had pre-existing neurodegenerative or psychiatric disorders, or were unable to travel to Hospital Clínic de Barcelona (Barcelona, Spain). Patients visited Hospital Clínic de Barcelona on three occasions-the first at study entry (visit 1), the second 6 months later (visit 2), and the third 12 months after the initial visit (visit 3). They underwent neuropsychiatric and videopolysomnography assessments at each visit. Healthy participants who were matched for age and sex and recruited from Hospital Clínic de Barcelona underwent the same investigations at study entry and at 12 months. Cross-sectional comparisons of clinical features between groups were done with conditional logistic regression, and binary logistic regression was used to assess associations between cognitive outcomes at 12 months and clinical features before initial immunotherapy and at study entry. FINDINGS: Between May 1, 2019, and Sept 30, 2022, 42 participants agreed to be included in this study. 24 (57%) participants had anti-LGI1 encephalitis (mean age 63 years [SD 12]; 13 [54%] were female and 11 [46%] were male) and 18 (43%) were healthy individuals (mean age 62 years [10]; 11 [61%] were female and seven [39%] were male). At visit 1 (median 88 days [IQR 67-155] from initiation of immunotherapy), all 24 patients had one or more symptoms; 20 (83%) patients had cognitive deficits, 20 (83%) had psychiatric symptoms, 14 (58%) had insomnia, 12 (50%) had rapid eye movement (REM)-sleep behaviour disorder, nine (38%) had faciobrachial dystonic seizures, and seven (29%) had focal onset seizures. Faciobrachial dystonic seizures were unnoticed in four (17%) of 24 patients and focal onset seizures were unnoticed in five (21%) patients. At visit 1, videopolysomnography showed that 19 (79%) patients, but no healthy participants, had disrupted sleep structure (p=0·013); 15 (63%) patients and four (22%) healthy participants had excessive fragmentary myoclonus (p=0·039), and nine (38%) patients, but no healthy participants, had myokymic discharges (p=0·0051). These clinical and videopolysomnographic features led to additional immunotherapy in 15 (63%) of 24 patients, which resulted in improvement of these features in all 15 individuals. However, at visit 3, 13 (65%) of 20 patients continued to have cognitive deficits. Persistent cognitive deficits at visit 3 were associated with no use of rituximab before visit 1 (odds ratio [OR] 4·0, 95% CI 1·5-10·7; p=0·0015), REM sleep without atonia at visit 1 (2·2, 1·2-4·2; p=0·043), and presence of LGI1 antibodies in serum at visit 1 (11·0, 1·1-106·4; p=0·038). INTERPRETATION: Unsuspected but ongoing clinical and videopolysomnography alterations are common in patients with anti-LGI1 encephalitis during the first year or more after initial immunotherapy. Recognising these alterations is important as they are treatable, can be used as outcome measures in clinical trials, and might influence cognitive outcome. FUNDING: Fundació La Caixa.
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Encefalite , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Autoanticorpos , Estudos Transversais , Encefalite/imunologia , Encefalite/terapia , Peptídeos e Proteínas de Sinalização Intracelular , Leucina/uso terapêutico , Estudos Prospectivos , Estudos Retrospectivos , Convulsões/tratamento farmacológico , Sono , Espanha , Imunoterapia , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/terapiaRESUMO
BACKGROUND AND OBJECTIVE: Alzheimer's disease (AD) and frontotemporal dementia (FTD) show different patterns of cortical thickness (CTh) loss compared with healthy controls (HC), even though there is relevant heterogeneity between individuals suffering from each of these diseases. Thus, we developed CTh models to study individual variability in AD, FTD, and HC. METHODS: We used the baseline CTh measures of 379 participants obtained from the structural MRI processed with FreeSurfer. A total of 169 AD patients (63 ± 9 years, 65 men), 88 FTD patients (64 ± 9 years, 43 men), and 122 HC (62 ± 10 years, 47 men) were studied. We fitted region-wise temporal models of CTh using Support Vector Regression. Then, we studied associations of individual deviations from the model with cerebrospinal fluid levels of neurofilament light chain (NfL) and 14-3-3 protein and Mini-Mental State Examination (MMSE). Furthermore, we used real longitudinal data from 144 participants to test model predictivity. RESULTS: We defined CTh spatiotemporal models for each group with a reliable fit. Individual deviation correlated with MMSE for AD and with NfL for FTD. AD patients with higher deviations from the trend presented higher MMSE values. In FTD, lower NfL levels were associated with higher deviations from the CTh prediction. For AD and HC, we could predict longitudinal visits with the presented model trained with baseline data. For FTD, the longitudinal visits had more variability. CONCLUSION: We highlight the value of CTh models for studying AD and FTD longitudinal changes and variability and their relationships with cognitive features and biomarkers.
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Doença de Alzheimer , Demência Frontotemporal , Masculino , Humanos , Doença de Alzheimer/diagnóstico , Demência Frontotemporal/diagnóstico por imagem , Imageamento por Ressonância Magnética , Testes de Estado Mental e Demência , Biomarcadores/líquido cefalorraquidianoRESUMO
OBJECTIVE: Self-perceived cognitive functioning, considered highly relevant in the context of aging and dementia, is assessed in numerous ways-hindering the comparison of findings across studies and settings. Therefore, the present study aimed to link item-level self-report questionnaire data from international aging studies. METHOD: We harmonized secondary data from 24 studies and 40 different questionnaires with item response theory (IRT) techniques using a graded response model with a Bayesian estimator. We compared item information curves to identify items with high measurement precision at different levels of the self-perceived cognitive functioning latent trait. Data from 53,030 neuropsychologically intact older adults were included, from 13 English language and 11 non-English (or mixed) language studies. RESULTS: We successfully linked all questionnaires and demonstrated that a single-factor structure was reasonable for the latent trait. Items that made the greatest contribution to measurement precision (i.e., "top items") assessed general and specific memory problems and aspects of executive functioning, attention, language, calculation, and visuospatial skills. These top items originated from distinct questionnaires and varied in format, range, time frames, response options, and whether they captured ability and/or change. CONCLUSIONS: This was the first study to calibrate self-perceived cognitive functioning data of geographically diverse older adults. The resulting item scores are on the same metric, facilitating joint or pooled analyses across international studies. Results may lead to the development of new self-perceived cognitive functioning questionnaires guided by psychometric properties, content, and other important features of items in our item bank. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
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Cognição , Disfunção Cognitiva , Humanos , Idoso , Teorema de Bayes , Disfunção Cognitiva/diagnóstico , Inquéritos e Questionários , Autorrelato , PsicometriaRESUMO
OBJECTIVE: Subtle decline in memory is thought to arise in the preclinical phase of Alzheimer's disease (AD). However, detecting these initial cognitive difficulties cross-sectionally has been challenging, and the exact nature of the decline is still debated. Accelerated long-term forgetting (ALF) has been recently suggested as one of the earliest and most sensitive indicators of memory dysfunction in subjects at risk of developing AD. The objective of this study was to design and validate the 1-week memory battery (1WMB) for assessing episodic memory and ALF in cognitively unimpaired individuals. METHOD: The 1WMB is unique in that it assesses multimodal memory and measures recall at both short delay (20 min) and at long term (1 week). Forty-five cognitively unimpaired subjects were assessed with 1WMB and standardized neuropsychological tests. Subjective cognitive decline (SCD), levels of anxiety and depression, and cognitive reserve were also measured. RESULTS: The tests of 1WMB showed a high internal consistency, and concurrent validity was observed with standard tests of episodic memory and executive functions. The analysis revealed a greater loss of information at 1 week compared to short-term forgetting (20 min). Performance in the 1WMB was affected by age and educational level, but was not associated with levels of anxiety and depression. Unlike standard tests, performance in the 1WMB correlated with measures of SCD. CONCLUSION: Our findings indicate that the 1WMB has good psychometric properties, and future studies are needed to explore its potential usefulness to assess cognitively unimpaired subjects at increased risk of developing AD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
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Doença de Alzheimer , Disfunção Cognitiva , Memória Episódica , Humanos , Testes Neuropsicológicos , Doença de Alzheimer/psicologia , Rememoração Mental , Função Executiva , Transtornos da Memória/diagnóstico , Transtornos da Memória/etiologia , Transtornos da Memória/psicologiaRESUMO
Alzheimer's disease (AD) and frontotemporal dementia (FTD) are common causes of dementia with partly overlapping, symptoms and brain signatures. There is a need to establish an accurate diagnosis and to obtain markers for disease tracking. We combined unsupervised and supervised machine learning to discriminate between AD and FTD using brain magnetic resonance imaging (MRI). We included baseline 3T-T1 MRI data from 339 subjects: 99 healthy controls (CTR), 153 AD and 87 FTD patients; and 2-year follow-up data from 114 subjects. We obtained subcortical gray matter volumes and cortical thickness measures using FreeSurfer. We used dimensionality reduction to obtain a single feature that was later used in a support vector machine for classification. Discrimination patterns were obtained with the contribution of each region to the single feature. Our algorithm differentiated CTR versus AD and CTR versus FTD at the cross-sectional level with 83.3% and 82.1% of accuracy. These increased up to 90.0% and 88.0% with longitudinal data. When we studied the classification between AD versus FTD we obtained an accuracy of 63.3% at the cross-sectional level and 75.0% for longitudinal data. The AD versus FTD versus CTR classification has reached an accuracy of 60.7%, and 71.3% for cross-sectional and longitudinal data respectively. Disease discrimination brain maps are in concordance with previous results obtained with classical approaches. By using a single feature, we were capable to classify CTR, AD, and FTD with good accuracy, considering the inherent overlap between diseases. Importantly, the algorithm can be used with cross-sectional and longitudinal data.
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Doença de Alzheimer , Demência Frontotemporal , Humanos , Doença de Alzheimer/patologia , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/patologia , Estudos Transversais , Imageamento por Ressonância Magnética/métodos , Aprendizado de MáquinaRESUMO
OBJECTIVE: This research aims to study structural brain changes in patients with persistent olfactory dysfunctions after coronavirus disease 2019 (COVID-19). METHODS: COVID-19 patients were evaluated using T1-weighted and diffusion tensor imaging (DTI) on a 3T MRI scanner, 9.94 ± 3.83 months after COVID-19 diagnosis. Gray matter (GM) voxel-based morphometry was performed using FSL-VBM. Voxelwise statistical analysis of the fractional anisotropy, mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity was carried out with the tract-based spatial statistics in the olfactory system. The smell identification test (UPSIT) was used to classify patients as normal olfaction or olfactory dysfunction groups. Intergroup comparisons between GM and DTI measures were computed, as well as correlations with the UPSIT scores. RESULTS: Forty-eight COVID-19 patients were included in the study. Twenty-three were classified as olfactory dysfunction, and 25 as normal olfaction. The olfactory dysfunction group had lower GM volume in a cluster involving the left amygdala, insular cortex, parahippocampal gyrus, frontal superior and inferior orbital gyri, gyrus rectus, olfactory cortex, caudate, and putamen. This group also showed higher MD values in the genu of the corpus callosum, the orbitofrontal area, the anterior thalamic radiation, and the forceps minor; and higher RD values in the anterior corona radiata, the genu of the corpus callosum, and uncinate fasciculus compared with the normal olfaction group. The UPSIT scores for the whole sample were negatively associated with both MD and RD values (p-value ≤0.05 FWE-corrected). INTERPRETATION: There is decreased GM volume and increased MD in olfactory-related regions explaining prolonged olfactory deficits in post-acute COVID-19 patients.
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COVID-19 , Transtornos do Olfato , Humanos , Olfato , Imagem de Tensor de Difusão/métodos , Teste para COVID-19 , COVID-19/complicações , COVID-19/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Transtornos do Olfato/diagnóstico por imagem , Transtornos do Olfato/etiologiaRESUMO
OBJECTIVES: Early- and late-onset Alzheimer's disease (EOAD and LOAD) share the same neuropathological traits but show distinct cognitive features. We aimed to explore baseline and longitudinal outcomes of global and domain-specific cognitive function in a well characterized cohort of patients with a biomarker-based diagnosis. METHODS: In this retrospective cohort study, 195 participants were included and classified according to their age, clinical status, and CSF AD biomarker profile: 89 EOAD, 37 LOAD, 46 young healthy controls (age ≤ 65 years), and 23 old healthy controls (>65 years). All subjects underwent clinical and neuropsychological assessment, neuroimaging, APOE genotyping and lumbar puncture. RESULTS: We found distinct neuropsychological profiles between EOAD and LOAD at the time of diagnosis. Both groups showed similar performances on memory and language domains, but the EOAD patients displayed worsened deficits in visual perception, praxis, and executive tasks (p < 0.05). Longitudinally, cognitive decline in EOAD was more pronounced than LOAD in the global outcomes at the expense of these non-amnestic domains. We found that years of education significantly influenced the decline in most of the neuropsychological tests. Besides, the APOE ε4 status showed a significant effect on the decline of memory-related tasks within the EOAD cohort (p < 0.05). INTERPRETATION: Age of onset is a main factor shaping the cognitive trajectories in AD patients, with younger age driving to a steeper decline of the non-memory domains. Years of education are related to a transversal decline in all cognitive domains and APOE ε4 status to a specific decline in memory performance in EOAD.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Doença de Alzheimer/patologia , Estudos Retrospectivos , Idade de Início , Disfunção Cognitiva/etiologia , Testes NeuropsicológicosRESUMO
Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aß42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g., CSF Aß positivity; odds ratio [OR] = 0.67 [95% CI, 0.55-0.78], ß = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19-0.77], ß = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27-0.96], ß = -0.68, p = 0.04) in cognitively normal participants, 60-80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE ε4 genotype background may modulate Aß and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.
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Doença de Alzheimer , Amiloidose , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquidiano , Suscetibilidade a Doenças , Endofenótipos , Humanos , Pessoa de Meia-Idade , Fragmentos de Peptídeos/genética , Tomografia por Emissão de Pósitrons , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genéticaRESUMO
INTRODUCTION: The evidence for characteristics of persons with subjective cognitive decline (SCD) associated with amyloid positivity is limited. METHODS: In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, domain-specific complaints, concerns, feelings of worse performance) demographics, setting, apolipoprotein E gene (APOE) ε4 carriership, and neuropsychiatric symptoms with amyloid positivity. RESULTS: Between cohorts, amyloid positivity in 70-year-olds varied from 10% to 76%. Only older age, clinical setting, and APOE ε4 carriership showed univariate associations with increased amyloid positivity. After adjusting for these, lower education was also associated with increased amyloid positivity. Only within a research setting, informant-confirmed complaints, memory complaints, attention/concentration complaints, and no depressive symptoms were associated with increased amyloid positivity. Feelings of worse performance were associated with less amyloid positivity at younger ages and more at older ages. DISCUSSION: Next to age, setting, and APOE ε4 carriership, SCD-specific characteristics may facilitate the identification of amyloid-positive individuals.
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Amiloidose , Disfunção Cognitiva , Humanos , Amiloide , Proteínas Amiloidogênicas , Apolipoproteína E4/genética , Biomarcadores , Encéfalo/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/psicologia , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives. METHODS: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD. RESULTS: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046). CONCLUSIONS: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.
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INTRODUCTION: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. METHODS: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. RESULTS: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. DISCUSSION: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
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Doença de Alzheimer , Peptídeos beta-Amiloides/sangue , Biomarcadores/sangue , Proteínas Sanguíneas , Proteômica , Proteínas tau/sangue , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Apolipoproteína E4/sangue , Apolipoproteína E4/genética , Disfunção Cognitiva/sangue , Disfunção Cognitiva/patologia , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: We studied a sample of cognitively unimpaired individuals, with and without subjective cognitive decline (SCD), in order to investigate accelerated long-term forgetting (ALF) and to explore the relationships between objective and subjective cognitive performance and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. METHODS: Fifty-two individuals were included and SCD was quantified through the Subjective Cognitive Decline Questionnaire (SCD-Q), using its validated cutoff to classify participants as Low SCD-Q (n = 21) or High SCD-Q (n = 31). These groups were further subdivided according to the presence or absence of abnormal levels of CSF Aß42 . Objective cognitive performance was assessed with the Ancient Farming Equipment Test (AFE-T), a new highly-demanding test that calls for acquisition and retention of novel object/name pairs and allows measuring ALF over a 6-month period. RESULTS: The High SCD-Q group showed a significantly higher free forgetting rate at 3 months compared to the Low SCD-Q (F [1,44] = 4.72; p < 0.05). When stratifying by amyloid status, High SCD-Q/Aß+ showed a significantly lower performance than High SCD-Q/Aß-on the final free and cued learning scores (F [1,27] = 6.44, p < 0.05 and F [1,27] = 7.51, p < 0.05, respectively), the 1-week free and cued recall (F [1,24] = 4.49; p < 0.05 and F [1,24] = 7.10; p < 0.01, respectively), the 1-week cued forgetting rate (F [1,24] = 5.13; p < 0.05), and the 3-month cued recall (F [1,24] = 4.27; p < 0.05). Linear regression analyses showed that higher SCD-Q scores were associated with higher forgetting rates on the AFE-T (ß = -0.212; p < 0.05). CONCLUSIONS: It is possible to detect ALF in individuals with high SCD ratings, appearing especially in those with abnormal CSF Aß42 levels. Both in research and the clinical field, there is an increasing need of using more demanding cognitive measures, such as the AFE-T, for identifying and tracking the earliest cognitive changes in these populations.
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Doença de Alzheimer , Disfunção Cognitiva , Peptídeos beta-Amiloides , Biomarcadores , Humanos , Testes NeuropsicológicosRESUMO
Accelerated long-term forgetting (ALF) refers to a rapid loss of information over days or weeks despite normal acquisition/encoding. Notwithstanding its potential relevance as a presymptomatic marker of cognitive dysfunction, no study has addressed the relationship between ALF and Alzheimer's disease (AD) biomarkers. We examined ALF in APOE É4 carriers versus noncarriers, and its relationships with AD cerebrospinal fluid (CSF) biomarkers. We found ALF over three months in APOE É4 carriers (F(1,19) = 5.60; P < 0.05; Cohen's d = 1.08), and this performance was associated with abnormal levels of the CSF Aß42 /ptau ratio (r = -.614; P < 0.01). Our findings indicate that ALF is detectable in at-risk individuals, and that there is a relationship between ALF and the pathophysiological processes underlying AD.
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Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/genética , Idoso , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/fisiopatologia , Demência/líquido cefalorraquidiano , Demência/diagnóstico , Demência/genética , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos , Fatores de Tempo , Proteínas tau/líquido cefalorraquidianoRESUMO
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aß) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aß42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aß38 and CSF-Aß40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aß and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
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Doença de Alzheimer , Idoso , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Biomarcadores , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fragmentos de Peptídeos , Proteínas tau/genéticaRESUMO
BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. OBJECTIVE: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. METHODS: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). RESULTS: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E É4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. CONCLUSIONS: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.
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Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Idoso , Doença de Alzheimer/genética , Biomarcadores/sangue , Feminino , Expressão Gênica , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: There is increasing evidence that AD progression differs by sex. OBJECTIVE: The aim of this work was to determine sex differences in the association of baseline levels of cerebrospinal fluid (CSF) biomarkers (Aß42, p-tau, YKL-40, sTREM2) with longitudinal brain changes in cognitively unimpaired (CU) older adults. METHODS: This pilot study included 36 CU subjects (age 66.5±5.5, 12 male) scanned twice, two years apart. Using a voxel-wise analysis, we determined the sex differences in the association maps between CSF biomarkers and atrophy rates. RESULTS: We did not find differences related to Aß42. We found a greater impact of the rest of CSF biomarkers in areas of the Papez circuit in women versus men. Men showed greater involvement in lateral parietal and paracentral areas. DISCUSSION: Results suggest an early differential progression of brain atrophy between sexes. Further research will elucidate whether the mechanisms responsible for sex-specific atrophy patterns are biological and/or environmental.
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Peptídeos beta-Amiloides/líquido cefalorraquidiano , Encéfalo/patologia , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/patologia , Atrofia , Biomarcadores/líquido cefalorraquidiano , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Projetos Piloto , Caracteres SexuaisRESUMO
We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E É4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.
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Doença de Alzheimer/sangue , Biomarcadores/sangue , Proteínas Sanguíneas/análise , Angiopatia Amiloide Cerebral/sangue , Proteômica , Idoso , Doença de Alzheimer/diagnóstico por imagem , Apolipoproteína E4/genética , Carga Corporal (Radioterapia) , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Curva ROC , Proteínas tau/líquido cefalorraquidianoRESUMO
INTRODUCTION: Synaptic damage, axonal neurodegeneration, and neuroinflammation are common features in Alzheimer's disease (AD), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD). METHODS: Unicentric cohort of 353 participants included healthy control (HC) subjects, AD continuum stages, genetic AD and FTD, and FTD and CJD. We measured cerebrospinal fluid neurofilament light (NF-L), neurogranin (Ng), 14-3-3, and YKL-40 proteins. RESULTS: Biomarkers showed differences in HC subjects versus AD, FTD, and CJD. Disease groups differed between them except AD versus FTD for YKL-40. Only NF-L differed between all stages within the AD continuum. AD and FTD symptomatic mutation carriers presented differences with respect to HC subjects. Applying the AT(N) system, 96% subjects were positive for neurodegeneration if 14-3-3 was used, 94% if NF-L was used, 62% if Ng was used, and 53% if YKL-40 was used. DISCUSSION: Biomarkers of synapse and neurodegeneration differentiate HC subjects from neurodegenerative dementias and between AD, FTD, and CJD. NF-L and 14-3-3 performed similar to total tau when AT(N) system was applied.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Axônios/patologia , Biomarcadores/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquidiano , Demência Frontotemporal/líquido cefalorraquidiano , Inflamação , Idoso , Estudos de Casos e Controles , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Neurogranina/líquido cefalorraquidianoRESUMO
BACKGROUND: There is epidemiological evidence of an association between the metabolic syndrome (MetS), a cluster of cardiovascular risk factors related to central adiposity and insulin resistance, and cognitive impairment and dementia. On the other hand, there is evidence for a beneficial effect of physical activity on cognitive outcomes in older adult populations. In a cross-sectional study, we evaluated the relationship between aerobic physical activity and cognition in a cohort of overweight/obese older adults with MetS at risk for dementia. Cognitive function was assessed in a subsample of 82 subjects (men 55-75 y; women 60-75 y), with MetS and a BMI ≥27 to < 40 kg/m2 enrolled in the PREDIMED-PLUS study, a trial of diet and exercise in individuals with MetS with outcomes of cardiovascular prevention. Domain Z scores were calculated for the different cognitive domains. Aerobic physical activity was determined with the Rapid Assessment of Physical Activity questionnaire. RESULTS: Adjusted covariance analyses revealed that, compared to sedentary participants, those physically active obtained higher scores in mean global cognitive scores, with mean adjusted difference 0.254 (95% CI 0.032 to 0.477, p = 0.026) and frontal composites, with mean adjusted difference 0.375 (95% CI 0.110 to 0.639, p = 0.006). CONCLUSIONS: Our findings indicate that aerobic physical activity is associated with better global cognition and frontal function in overweight/obese older individuals with MetS, suggesting that physical activity could be a therapeutic strategy to reduce the risk of developing cognitive impairment or dementia in this population.