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1.
Medicine (Baltimore) ; 100(7): e24837, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33607852

RESUMO

ABSTRACT: Dysautonomia is common in patients with Parkinson disease (PD) since disease early phase. Scales for Outcomes in Parkinson's disease - Autonomic (SCOPA-AUT) is a well-designed scale assessing the autonomic dysfunctions of PD patients. Our objectives were to examine the autonomic dysfunction in PD and scan without evidence of dopaminergic deficit (SWEDD) patients and to assess the correlation of autonomic dysfunctions with cerebrospinal fluid (CSF) biomarkers.An analysis of the Parkinson's Progression Markers Initiative (PPMI) data including 414 PD patients, 60 SWEDD patients, and 170 healthy controls (HCs) with baseline CSF biomarker measurements and SCOPA-AUT assessments was presented. Autonomic symptoms including gastrointestinal, urinary, cardiovascular, pupillomotor, thermoregulatory and sexual dysfunctions were assessed by SCOPA-AUT scales. Spearman correlation test was used to examine the correlations between CSF measurements and each section of SCOPA-AUT scales in HCs and subjects with PD or SWEDD.More severe autonomic dysfunctions were observed in patients with SWEDD than those with PD (P < .001). Specifically, patients with PD have lower scores on the urinary scale [4 (0-17) vs 5 (1-18)], pupillomotor scale [0 (0-3) vs 0 (0-3)], thermoregulatory scale [0 (0-4) vs 1.5 (0-10)] and sexual scale [1 (0-6) vs 2 (0-6)] compared with SWEDD patients. Thermoregulatory dysfunction scores were found correlated with CSF α-syn levels in SWEDD group, and gastrointestinal dysfunction scores were correlated with CSF Abeta1-42 in PD group. Additionally, urinary dysfunction scores were correlated with CSF total tau and tau phosphorylated at threonine 181(p-tau181) levels in both HCs and PD patients.


Assuntos
Biomarcadores/líquido cefalorraquidiano , Dopamina/deficiência , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Sistema Nervoso Autônomo/fisiopatologia , Doenças do Sistema Nervoso Autônomo/líquido cefalorraquidiano , Doenças do Sistema Nervoso Autônomo/diagnóstico , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Regulação da Temperatura Corporal/fisiologia , Estudos de Casos e Controles , Feminino , Gastroenteropatias/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/fisiopatologia , Disautonomias Primárias/etiologia , Índice de Gravidade de Doença , Inquéritos e Questionários , Doenças Urológicas/metabolismo
2.
Neurology ; 95(19): e2648-e2657, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913020

RESUMO

OBJECTIVE: To investigate the association between discordant ß-amyloid (Aß) PET and CSF biomarkers at baseline and the emergence of tau pathology 5 years later. METHODS: We included 730 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants without dementia (282 cognitively normal, 448 mild cognitive impairment) with baseline [18F]florbetapir PET and CSF Aß42 available. Aß CSF/PET status was determined at baseline using established cutoffs. Longitudinal data were available for [18F]florbetapir (Aß) PET (baseline to 4.3 ± 1.9 years), CSF (p)tau (baseline to 2.0 ± 0.1 years), cognition (baseline to 4.3 ± 2.0 years), and [18F]flortaucipir (tau) PET (measured 5.2 ± 1.2 years after baseline to 1.6 ± 0.7 years later). We used linear mixed modeling to study the association between Aß CSF/PET status and tau pathology measured in CSF or using PET. We calculated the proportion of CSF+/PET- participants who during follow-up (1) progressed to Aß CSF+/PET+ or (2) became tau-positive based on [18F]flortaucipir PET. RESULTS: Aß CSF+/PET+ (n = 318) participants had elevated CSF (p)tau levels and worse cognitive performance at baseline, while CSF+/PET- (n = 80) participants were overall similar to the CSF-/PET- (N = 306) group. Five years after baseline, [18F]flortaucipir PET uptake in the CSF+/PET- group (1.20 ± 0.13) did not differ from CSF-/PET- (1.18 ± 0.08, p = 0.69), but was substantially lower than CSF+/PET+ (1.48 ± 0.44, p < 0.001). Of the CSF+/PET- participants, 21/64 (33%) progressed to Aß CSF+/PET+, whereas only one (3%, difference p < 0.05) became tau-positive based on [18F]flortaucipir PET. CONCLUSIONS: Aß load detectable by both CSF and PET seems to precede substantial tau deposition. Compared to participants with abnormal Aß levels on both PET and CSF, the CSF+/PET- group has a distinctly better prognosis.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Fragmentos de Peptídeos/líquido cefalorraquidiano , Placa Amiloide/diagnóstico por imagem , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Encéfalo/metabolismo , Carbolinas , Estudos de Casos e Controles , Disfunção Cognitiva/fisiopatologia , Meios de Contraste , Progressão da Doença , Etilenoglicóis , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Modelos de Riscos Proporcionais , Compostos Radiofarmacêuticos
3.
Neurology ; 95(19): e2658-e2665, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913021

RESUMO

OBJECTIVE: To determine whether treatment with escitalopram compared with placebo would lower CSF ß-amyloid 42 (Aß42) levels. RATIONALE: Serotonin signaling suppresses Aß42 in animal models of Alzheimer disease (AD) and young healthy humans. In a prospective study in older adults, we examined dose and treatment duration effects of escitalopram. METHODS: Using lumbar punctures to sample CSF levels before and after a course of escitalopram treatment, cognitively normal older adults (n = 114) were assigned to placebo, 20 mg escitalopram × 2 weeks, 20 mg escitalopram × 8 weeks, or 30 mg escitalopram × 8 weeks; CSF sampled pretreatment and posttreatment and within-subject percent change in Aß42 was used as the primary outcome in subsequent analyses. RESULTS: An overall 9.4% greater reduction in CSF Aß42 was found in escitalopram-treated compared with placebo-treated groups (p < 0.001, 95% confidence interval [CI] 4.9%-14.2%, d = 0.81). Positive baseline Aß status (CSF Aß42 levels <250 pg/mL) was associated with smaller Aß42 reduction (p = 0.006, 95% CI -16.7% to 0.5%, d = -0.52) compared with negative baseline amyloid status (CSF Aß42 levels >250 pg/mL). CONCLUSIONS: Short-term longitudinal doses of escitalopram decreased CSF Aß42 in cognitively normal older adults, the target group for AD prevention. CLINICALTRIALSGOV IDENTIFIER: NCT02161458. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for cognitively normal older adults, escitalopram decreases CSF Aß42.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Citalopram/administração & dosagem , Duração da Terapia , Fragmentos de Peptídeos/líquido cefalorraquidiano , Inibidores de Captação de Serotonina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/efeitos dos fármacos , Citalopram/farmacologia , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/efeitos dos fármacos , Estudos Prospectivos , Inibidores de Captação de Serotonina/farmacologia
4.
BMC Med Genet ; 21(1): 181, 2020 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-32919460

RESUMO

BACKGROUND: The complement component (3b/4b) receptor 1 gene (CR1) gene has been proved to affect the susceptibility of Alzheimer's disease (AD) in different ethnic and districts groups. However, the effect of CR1 genetic variants on amyloid ß (Aß) metabolism of AD human is still unclear. Hence, the aim of this study was to investigate genetic influences of CR1 gene on Aß metabolism. METHODS: All data of AD patients and normal controls (NC) were obtained from alzheimer's disease neuroimaging initiative database (ADNI) database. In order to assess the effect of each single nucleotide polymorphism (SNP) of CR1 on Aß metabolism, the PLINK software was used to conduct the quality control procedures to enroll appropriate SNPs. Moreover, the correlation between CR1 genotypes and Aß metabolism in all participants were estimated with multiple linear regression models. RESULTS: After quality control procedures, a total of 329 samples and 83 SNPs were enrolled in our study. Moreover, our results identified five SNPs (rs10494884, rs11118322, rs1323721, rs17259045 and rs41308433), which were linked to Aß accumulation in brain. In further analyses, rs17259045 was found to decrease Aß accumulation among AD patients. Additionally, our study revealed the genetic variants in rs12567945 could increase CSF Aß42 in NC population. CONCLUSIONS: Our study had revealed several novel SNPs in CR1 genes which might be involved in the progression of AD via regulating Aß accumulation. These findings will provide a new basis for the diagnosis and treatment AD.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Neuroimagem/métodos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Polimorfismo de Nucleotídeo Único , Receptores de Complemento 3b/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Feminino , Genótipo , Humanos , Masculino , Fragmentos de Peptídeos/metabolismo
5.
J Med Chem ; 63(15): 8216-8230, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32786237

RESUMO

Herein, we disclose three structurally differentiated γ-secretase modulators (GSMs) based on an oxadiazine scaffold. The analogues from series I potently inhibit the generation of Aß42 in vitro when the substituents at 3 and 4 positions of the oxadiazine moiety adopt an α orientation (cf. 11). To address the concern around potential reactivity of the exocyclic double bond present in series I toward nucleophilic attack, compounds containing either an endocyclic double bond, such as 20 (series II), or devoid of an olefinic moiety, such as 27 (series III), were designed and validated as novel GSMs. Compound 11 and azepine 20 exhibit robust lowering of CSF Aß42 in rats treated with a 30 mg/kg oral dose.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Alcenos/química , Alcenos/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Sítios de Ligação/fisiologia , Células HEK293 , Humanos , Oxidiazóis/química , Oxidiazóis/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/líquido cefalorraquidiano , Ratos , Relação Estrutura-Atividade
6.
Neurology ; 95(17): e2378-e2388, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-32788242

RESUMO

OBJECTIVE: To evaluate sex differences in CSF biomarkers, taking the potential modifying role of clinical disease stage and APOE ε4 genotype into account. METHOD: We included participants (n = 1,801) with probable Alzheimer disease (AD) dementia (n = 937), mild cognitive impairment (MCI; n = 437), and subjective cognitive decline (SCD; n = 427). Main outcomes were CSF ß-amyloid1-42 (Aß42), total tau (t-Tau), and tau phosphorylated at threonine 181 (p-Tau) levels. Age-corrected 3-way interactions between sex, disease stage (i.e., syndrome diagnosis at baseline), and APOE ε4 were tested with linear regression analyses for each outcome measure. In case of significant interactions (p < 0.05), sex differences were further evaluated by stratifying analyses for clinical disease stage and APOE ε4 genotype, including age as a covariate. RESULTS: Three-way interactions were significant for t-Tau (p < 0.001) and p-Tau (p < 0.01) but not Aß42. In APOE ε4 carriers, women showed higher p-Tau concentrations than men in SCD (Cohen d [95% confidence interval]: t-Tau = 0.52 [0.19-0.84], p < 0.001; p-Tau = 0.44 [0.11-0.77] p = 0.004) and MCI (Cohen d [95% CI]: t-Tau = 0.54 [0.28-0.80], p < 0.001; p-Tau = 0.52 [0.26-0.77], p < 0.001) but not in AD dementia. In APOE ε4 noncarriers, women showed higher p-Tau concentrations in MCI (Cohen d [95% CI]: t-Tau = 0.49 [0.17-0.80], p = 0.002; p-Tau = 0.47 [0.16-0.78], p = 0.003) and AD dementia (Cohen d [95% CI]: t-Tau = 0.42 [0.19-0.65], p < 0.001; p-Tau = 0.38 [0.15-0.61] p = 0.002) but not in SCD. CONCLUSIONS: Within APOE ε4 carriers, sex differences in CSF p-Tau are more evident in early disease stages, whereas for APOE ε4 noncarriers, sex differences are more evident in advanced disease stages. These findings suggest that the effect of APOE ε4 on sex differences in CSF biomarkers depends on disease stage in AD.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Progressão da Doença , Feminino , Genótipo , Heterozigoto , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Caracteres Sexuais , Proteínas tau/líquido cefalorraquidiano
7.
Neurology ; 95(9): e1134-e1143, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32636322

RESUMO

OBJECTIVE: To determine the nature and extent of minor neuropsychological deficits in patients with subjective cognitive decline (SCD) and their association with CSF biomarkers of Alzheimer disease (AD). METHOD: We analyzed data from n = 449 cognitively normal participants (n = 209 healthy controls, n = 240 patients with SCD) from an interim data release of the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE). An extensive neuropsychological test battery was applied at baseline for which we established a latent, 5 cognitive domain factor structure comprising learning and memory, executive functions, language abilities, working memory, and visuospatial functions. We compared groups in terms of global and domain-specific performance and correlated performance with different CSF markers of AD pathology. RESULTS: We observed worse performance (Cohen d = ≈0.25-0.5, adjusted for age, sex differences with analysis of covariance) in global performance, memory, executive functions, and language abilities for the SCD group compared to healthy controls. In addition, worse performance in these domains was moderately (r = ≈0.3) associated with lower CSF ß-amyloid42/40 and CSF ß-amyloid42/phosphorylated tau181 in the whole sample and specifically in the SCD subgroup. CONCLUSIONS: Within the spectrum of clinically unimpaired (i.e., before mild cognitive impairment) cognitive performance, SCD is associated with minor deficits in memory, executive function, and language abilities. The association of these subtle cognitive deficits with AD CSF biomarkers speaks to their validity and potential use for the early detection of underlying preclinical AD.


Assuntos
Disfunção Cognitiva/psicologia , Função Executiva , Idioma , Aprendizagem , Memória de Curto Prazo , Navegação Espacial , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Estudos de Casos e Controles , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/fisiopatologia , Autoavaliação Diagnóstica , Análise Fatorial , Feminino , Humanos , Testes de Linguagem , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Proteínas tau/líquido cefalorraquidiano
8.
Neurology ; 95(6): e662-e670, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32636325

RESUMO

OBJECTIVE: Early biomarkers for dementia with Lewy bodies (DLB) are lacking. To determine whether EEG differentiates the prodromal phase of DLB from other causes of mild cognitive impairment (MCI) and whether EEG is predictive for time to conversion from MCI to DLB, we compared EEGs and clinical follow-up of patients with MCI due to DLB with those of patients with MCI due to Alzheimer disease (MCI-AD). METHODS: We compared 37 patients with MCI who developed DLB during follow-up or had an abnormal 123I-PF-CIT SPECT scan (MCI-DLB) with 67 age-matched patients with MCI-AD. EEGs were assessed visually with a score of increasing abnormality (range 1-5). We performed fast Fourier transform to analyze the power spectrum. With survival analyses, EEG characteristics were related to time to progression to dementia. RESULTS: The visual EEG score was higher in MCI-DLB (score >2 in 60%) compared to MCI-AD (score >2 in 8%, p < 0.001). We found frontal intermittent delta activity in 22% of MCI-DLB, not in MCI-AD. Patients with MCI-DLB had a lower peak frequency (7.5 [6.0-9.9] Hz vs 8.8 [6.8-10.2] in MCI-AD, p < 0.001) and more slow-wave activity. Several individual EEG measures showed good performance to discriminate MCI-DLB from MCI-AD (areas under the curve up to 0.94). In MCI-DLB, high visual EEG score, diffuse abnormalities, and low α2 power were related to time to progression to dementia (hazard ratios 4.1, 9.9, 5.1, respectively). CONCLUSIONS: Profound EEG abnormalities are already present in the prodromal stage of DLB and have diagnostic and prognostic value. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that EEG abnormalities are more common in MCI-DLB than MCI-AD.


Assuntos
Eletroencefalografia , Doença por Corpos de Lewy/diagnóstico , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Diagnóstico Diferencial , Progressão da Doença , Diagnóstico Precoce , Feminino , Seguimentos , Análise de Fourier , Humanos , Radioisótopos do Iodo , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/fisiopatologia , Masculino , Pessoa de Meia-Idade , Países Baixos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Estudos Prospectivos , Compostos Radiofarmacêuticos , Avaliação de Sintomas , Fatores de Tempo , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos , Proteínas tau/líquido cefalorraquidiano
10.
Neurology ; 95(1): e46-e58, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32522798

RESUMO

OBJECTIVE: To investigate the relationship between the ATN classification system (amyloid, tau, neurodegeneration) and risk of dementia and cognitive decline in individuals with subjective cognitive decline (SCD). METHODS: We classified 693 participants with SCD (60 ± 9 years, 41% women, Mini-Mental State Examination score 28 ± 2) from the Amsterdam Dementia Cohort and Subjective Cognitive Impairment Cohort (SCIENCe) project according to the ATN model, as determined by amyloid PET or CSF ß-amyloid (A), CSF p-tau (T), and MRI-based medial temporal lobe atrophy (N). All underwent extensive neuropsychological assessment. For 342 participants, follow-up was available (3 ± 2 years). As a control population, we included 124 participants without SCD. RESULTS: Fifty-six (n = 385) participants had normal Alzheimer disease (AD) biomarkers (A-T-N-), 27% (n = 186) had non-AD pathologic change (A-T-N+, A-T+N-, A-T+N+), 18% (n = 122) fell within the Alzheimer continuum (A+T-N-, A+T-N+, A+T+N-, A+T+N+). ATN profiles were unevenly distributed, with A-T+N+, A+T-N+, and A+T+N+ containing very few participants. Cox regression showed that compared to A-T-N-, participants in A+ profiles had a higher risk of dementia with a dose-response pattern for number of biomarkers affected. Linear mixed models showed participants in A+ profiles showed a steeper decline on tests addressing memory, attention, language, and executive functions. In the control group, there was no association between ATN and cognition. CONCLUSIONS: Among individuals presenting with SCD at a memory clinic, those with a biomarker profile A-T+N+, A+T-N-, A+T+N-, and A+T+N+ were at increased risk of dementia, and showed steeper cognitive decline compared to A-T-N- individuals. These results suggest a future where biomarker results could be used for individualized risk profiling in cognitively normal individuals presenting at a memory clinic.


Assuntos
Doença de Alzheimer , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/classificação , Progressão da Doença , Idoso , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Neural/patologia , Proteínas tau/líquido cefalorraquidiano
11.
Neurology ; 95(3): e256-e267, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32591471

RESUMO

OBJECTIVE: We studied interrelationships between CSF biomarkers and associations with APOE ε4 genotype, demographic variables, vascular variables, and clinical diagnosis in Olmsted County, Minnesota. METHODS: We included 774 Mayo Clinic Study of Aging participants (693 cognitively unimpaired [CU]; 71 with mild cognitive impairment [MCI]). CSF ß-amyloid 42 (Aß42), total tau (t-tau), and hyperphosphorylated tau (p-tau) were analyzed using Aß42 CSF, t-tau CSF, and p-tau (181P) CSF electrochemiluminescence immunoassays. Bivariate mixture models were used to evaluate latent classes. We used linear regression models to evaluate independent associations of APOE ε4, demographic factors, cardiovascular risk, and diagnosis with CSF biomarker levels. Results were weighted back to the Olmsted County population. RESULTS: Interrelationships between CSF Aß42 and p-tau/t-tau were consistent with 2 latent classes in the general population. In subgroup 1 (n = 547 [71%]), we found a strong positive correlation between Aß42 and p-tau (ρ = 0.81), while the correlation was much smaller in group 2 (ρ = 0.26, n = 227 [29%]). Group 2 was associated with older age, APOE ε4 genotype, a diagnosis of MCI, and elevated amyloid PET. Overall, APOE ε4 genotype and MCI were associated with Aß42, while age was associated with p-tau/t-tau. There were no associations with sex, education, or vascular risk. CONCLUSION: We hypothesize the population without dementia can be subdivided into participants with and without biological Alzheimer disease (AD) based on the combination of CSF Aß42 and p-tau/t-tau (represented also by the p-tau/t-tau/Aß42 ratio). In those without biological AD, common factors such as CSF dynamics may cause a positive correlation between CSF Aß42 and p-tau/t-tau, while AD leads to dissociation of these proteins.


Assuntos
Envelhecimento/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Medicina Baseada em Evidências/métodos , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons/métodos , Punção Espinal/métodos , Proteínas tau/líquido cefalorraquidiano
12.
BMC Neurol ; 20(1): 174, 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32384876

RESUMO

BACKGROUND: Cognitive impairment (CI) with mixed vascular and neurodegenerative pathologies after stroke is common. The role of amyloid pathology in post-stroke CI is unclear. We hypothesize that amyloid deposition, measured with Flutemetamol (18F-Flut) positron emission tomography (PET), is common in seven-year stroke survivors diagnosed with CI and, further, that quantitatively assessed 18F-Flut-PET uptake after 7 years correlates with amyloid-ß peptide (Aß42) levels in cerebrospinal fluid (CSF) at 1 year, and with measures of neurodegeneration and cognition at 7 years post-stroke. METHODS: 208 patients with first-ever stroke or transient Ischemic Attack (TIA) without pre-existing CI were included during 2007 and 2008. At one- and seven-years post-stroke, cognitive status was assessed, and categorized into dementia, mild cognitive impairment or normal. Etiologic sub-classification was based on magnetic resonance imaging (MRI) findings, CSF biomarkers and clinical cognitive profile. At 7 years, patients were offered 18F-Flut-PET, and amyloid-positivity was assessed visually and semi-quantitatively. The associations between 18F-Flut-PET standardized uptake value ratios (SUVr) and measures of neurodegeneration (medial temporal lobe atrophy (MTLA), global cortical atrophy (GCA)) and cognition (Mini-Mental State Exam (MMSE), Trail-making test A (TMT-A)) and CSF Aß42 levels were assessed using linear regression. RESULTS: In total, 111 patients completed 7-year follow-up, and 26 patients agreed to PET imaging, of whom 13 had CSF biomarkers from 1 year. Thirteen out of 26 patients were diagnosed with CI 7 years post-stroke, but only one had visually assessed amyloid positivity. CSF Aß42 levels at 1 year, MTA grade, GCA scale, MMSE score or TMT-A at 7 years did not correlate with 18F-Flut-PET SUVr in this cohort. CONCLUSIONS: Amyloid binding was not common in 7-year stroke survivors diagnosed with CI. Quantitatively assessed, cortical amyloid deposition did not correlate with other measures related to neurodegeneration or cognition. Therefore, amyloid pathology may not be a key mediator of neurodegeneration 7 years post-stroke. TRIAL REGISTRATION: Clinicaltrials.gov (NCT00506818). July 23, 2007. Inclusion from February 2007, randomization and intervention from May 2007 and trial registration in July 2007.


Assuntos
Amiloide/metabolismo , Compostos de Anilina , Benzotiazóis , Disfunção Cognitiva/etiologia , Tomografia por Emissão de Pósitrons , Acidente Vascular Cerebral/complicações , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Amiloidose , Atrofia/complicações , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/metabolismo , Estudos de Coortes , Demência/complicações , Feminino , Seguimentos , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/metabolismo
13.
Nature ; 581(7806): 71-76, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32376954

RESUMO

Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-ß or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRß7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-ß and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.


Assuntos
Apolipoproteína E4/genética , Barreira Hematoencefálica/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Capilares/patologia , Ciclofilina A/líquido cefalorraquidiano , Ciclofilina A/metabolismo , Feminino , Heterozigoto , Hipocampo/irrigação sanguínea , Humanos , Masculino , Metaloproteinase 9 da Matriz/líquido cefalorraquidiano , Metaloproteinase 9 da Matriz/metabolismo , Giro Para-Hipocampal/irrigação sanguínea , Pericitos/patologia , Tomografia por Emissão de Pósitrons , Receptor beta de Fator de Crescimento Derivado de Plaquetas/líquido cefalorraquidiano , Lobo Temporal/irrigação sanguínea , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/metabolismo
14.
PLoS One ; 15(5): e0232785, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469871

RESUMO

BACKGROUND: Alzheimer's disease (AD) pathology precedes symptoms and its detection can identify at-risk individuals who may benefit from early treatment. Since the retinal nerve fiber layer (RNFL) is depleted in established AD, we tested whether its thickness can predict whether cognitively healthy (CH) individuals have a normal or pathological cerebrospinal fluid (CSF) Aß42 (A) and tau (T) ratio. METHODS: As part of an ongoing longitudinal study, we enrolled CH individuals, excluding those with cognitive impairment and significant ocular pathology. We classified the CH group into two sub-groups, normal (CH-NAT, n = 16) or pathological (CH-PAT, n = 27), using a logistic regression model from the CSF AT ratio that identified >85% of patients with a clinically probable AD diagnosis. Spectral-domain optical coherence tomography (OCT) was acquired for RNFL, ganglion cell-inner plexiform layer (GC-IPL), and macular thickness. Group differences were tested using mixed model repeated measures and a classification model derived using multiple logistic regression. RESULTS: Mean age (± standard deviation) in the CH-PAT group (n = 27; 75.2 ± 8.4 years) was similar (p = 0.50) to the CH-NAT group (n = 16; 74.1 ± 7.9 years). Mean RNFL (standard error) was thinner in the CH-PAT group by 9.8 (2.7) µm; p < 0.001. RNFL thickness classified CH-NAT vs. CH-PAT with 87% sensitivity and 56.3% specificity. CONCLUSIONS: Our retinal data predict which individuals have CSF biomarkers of AD pathology before cognitive deficits are detectable with 87% sensitivity. Such results from easy-to-acquire, objective and non-invasive measurements of the RNFL merit further study of OCT technology to monitor or screen for early AD pathology.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Disfunção Cognitiva/genética , Proteínas tau/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Amiloidose/líquido cefalorraquidiano , Amiloidose/diagnóstico por imagem , Amiloidose/genética , Amiloidose/patologia , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/metabolismo , Fibras Nervosas/patologia , Disco Óptico/diagnóstico por imagem , Disco Óptico/metabolismo , Disco Óptico/patologia , Retina/diagnóstico por imagem , Retina/metabolismo , Retina/patologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica , Proteínas tau/líquido cefalorraquidiano
15.
Neurology ; 94(21): e2233-e2244, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32398359

RESUMO

OBJECTIVE: To compare different ß-amyloid (Aß), tau, and neurodegeneration (AT[N]) variants within the Swedish BioFINDER studies. METHODS: A total of 490 participants were classified into AT(N) groups. These include 53 cognitively unimpaired (CU) and 48 cognitively impaired (CI) participants (14 mild cognitive impairment [MCI] and 34 Alzheimer disease [AD] dementia) from BioFINDER-1 and 389 participants from BioFINDER-2 (245 CU and 144 CI [138 MCI and 6 AD dementia]). Biomarkers for A were CSF Aß42 and amyloid-PET ([18F]flutemetamol); for T, CSF phosphorylated tau (p-tau) and tau PET ([18F]flortaucipir); and for (N), hippocampal volume, temporal cortical thickness, and CSF neurofilament light (NfL). Binarization of biomarkers was achieved using cutoffs defined in other cohorts. The relationship between different AT(N) combinations and cognitive trajectories (longitudinal Mini-Mental State Examination scores) was examined using linear mixed modeling and coefficient of variation. RESULTS: Among CU participants, A-T-(N)- or A+T-(N)- variants were most common. However, more T+ cases were seen using p-tau than tau PET. Among CI participants, A+T+(N)+ was more common; however, more (N)+ cases were seen for MRI measures relative to CSF NfL. Tau PET best predicted longitudinal cognitive decline in CI and p-tau in CU participants. Among CI participants, continuous T (especially tau PET) and (N) measures improved the prediction of cognitive decline compared to binary measures. CONCLUSIONS: Our findings show that different AT(N) variants are not interchangeable, and that optimal variants differ by clinical stage. In some cases, dichotomizing biomarkers may result in loss of important prognostic information.


Assuntos
Doença de Alzheimer/classificação , Doença de Alzheimer/epidemiologia , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/epidemiologia , Degeneração Neural/epidemiologia , Proteínas tau/metabolismo , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Compostos de Anilina/metabolismo , Benzotiazóis/metabolismo , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Carbolinas/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes de Estado Mental e Demência/estatística & dados numéricos , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Suécia/epidemiologia , Proteínas tau/líquido cefalorraquidiano
16.
Ann Neurol ; 88(1): 183-194, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32468646

RESUMO

OBJECTIVE: Preclinical evidence with nilotinib, a US Food and Drug Administration (FDA)-approved drug for leukemia, indicates improvement in Alzheimer's disease phenotypes. We investigated whether nilotinib is safe, and detectable in cerebrospinal fluid, and alters biomarkers and clinical decline in Alzheimer's disease. METHODS: This single-center, phase 2, randomized, double-blind, placebo-controlled study investigated the safety, tolerability, and pharmacokinetics of nilotinib, and measured biomarkers in participants with mild to moderate dementia due to Alzheimer's disease. The diagnosis was supported by cerebrospinal fluid or amyloid positron emission tomography biomarkers. Nilotinib 150 mg versus matching placebo was taken orally once daily for 26 weeks followed by nilotinib 300 mg versus placebo for another 26 weeks. RESULTS: Of the 37 individuals enrolled, 27 were women and the mean (SD) age was 70.7 (6.48) years. Nilotinib was well-tolerated, although more adverse events, particularly mood swings, were noted with the 300 mg dose. In the nilotinib group, central nervous system (CNS) amyloid burden was significantly reduced in the frontal lobe compared to the placebo group. Cerebrospinal fluid Aß40 was reduced at 6 months and Aß42 was reduced at 12 months in the nilotinib group compared to the placebo. Hippocampal volume loss was attenuated (-27%) at 12 months and phospho-tau-181 was reduced at 6 months and 12 months in the nilotinib group. INTERPRETATION: Nilotinib is safe and achieves pharmacologically relevant cerebrospinal fluid concentrations. Biomarkers of disease were altered in response to nilotinib treatment. These data support a larger, longer, multicenter study to determine the safety and efficacy of nilotinib in Alzheimer's disease. ANN NEUROL 2020 ANN NEUROL 2020;88:183-194.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Proteínas Tirosina Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Resultado do Tratamento , Proteínas tau/líquido cefalorraquidiano
17.
PLoS One ; 15(4): e0231765, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298384

RESUMO

Non-invasive biomarkers will enable widespread screening and early diagnosis of Alzheimer's disease (AD). We hypothesized that the considerable loss of brain tissue in AD will result in detection of brain lipid components in urine, and that these will change in concert with CSF and brain biomarkers of AD. We examined urine dicarboxylic acids (DCA) of carbon length 3-10 to reflect products of oxidative damage and energy generation or balance that may account for changes in brain function in AD. Mean C4-C5 DCAs were lower and mean C7-C10 DCAs were higher in the urine from AD compared to cognitively healthy (CH) individuals. Moreover, mean C4-C5 DCAs were lower and mean C7-C9 were higher in urine from CH individuals with abnormal compared to normal CSF amyloid and Tau levels; i.e., the apparent urine changes in AD also appeared to be present in CH individuals that have CSF risk factors of early AD pathology. In examining the relationship between urine DCAs and AD biomarkers, we found short chain DCAs positively correlated with CSF Aß42, while C7-C10 DCAs negatively correlated with CSF Aß42 and positively correlated with CSF Tau levels. Furthermore, we found a negative correlation of C7-C10 DCAs with hippocampal volume (p < 0.01), which was not found in the occipital volume. Urine measures of DCAs have an 82% ability to predict cognitively healthy participants with normal CSF amyloid/Tau. These data suggest that urine measures of increased lipoxidation and dysfunctional energy balance reflect early AD pathology from brain and CSF biomarkers. Measures of urine DCAs may contribute to personalized healthcare by indicating AD pathology and may be utilized to explore population wellness or monitor the efficacy of therapies in clinical trials.


Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Ácidos Dicarboxílicos/urina , Hipocampo/patologia , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Doenças Assintomáticas , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/urina , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/diagnóstico por imagem , Ácidos Dicarboxílicos/química , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Imagem por Ressonância Magnética , Masculino , Análise Multivariada , Fatores de Risco
18.
Neurobiol Aging ; 91: 5-14, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32305782

RESUMO

This study investigated the relationship between white matter hyperintensities (WMH) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. Subjects included 180 controls, 107 individuals with a significant memory concern, 320 individuals with early mild cognitive impairment, 171 individuals with late mild cognitive impairment, and 151 individuals with AD, with 3T MRI and CSF Aß1-42, total tau (t-tau), and phosphorylated tau (p-tau) data. Multiple linear regression models assessed the relationship between WMH and CSF Aß1-42, t-tau, and p-tau. Directionally, a higher WMH burden was associated with lower CSF Aß1-42 within each diagnostic group, with no evidence for a difference in the slope of the association across diagnostic groups (p = 0.4). Pooling all participants, this association was statistically significant after adjustment for t-tau, p-tau, age, diagnostic group, and APOE-ε4 status (p < 0.001). Age was the strongest predictor of WMH (partial R2~16%) compared with CSF Aß1-42 (partial R2~5%). There was no evidence for an association with WMH and either t-tau or p-tau. These data are supportive of a link between amyloid burden and presumed vascular pathology.


Assuntos
Envelhecimento/líquido cefalorraquidiano , Envelhecimento/patologia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Substância Branca/metabolismo , Substância Branca/patologia , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Biomarcadores/líquido cefalorraquidiano , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/diagnóstico , Transtornos Cerebrovasculares/patologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/patologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Substância Branca/diagnóstico por imagem
19.
Brain ; 143(3): 993-1009, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32203580

RESUMO

Alzheimer's disease neurodegeneration is thought to spread across anatomically and functionally connected brain regions. However, the precise sequence of spread remains ambiguous. The prevailing model used to guide in vivo human neuroimaging and non-human animal research assumes that Alzheimer's degeneration starts in the entorhinal cortices, before spreading to the temporoparietal cortex. Challenging this model, we previously provided evidence that in vivo markers of neurodegeneration within the nucleus basalis of Meynert (NbM), a subregion of the basal forebrain heavily populated by cortically projecting cholinergic neurons, precedes and predicts entorhinal degeneration. There have been few systematic attempts at directly comparing staging models using in vivo longitudinal biomarker data, and none to our knowledge testing if comparative evidence generalizes across independent samples. Here we addressed the sequence of pathological staging in Alzheimer's disease using two independent samples of the Alzheimer's Disease Neuroimaging Initiative (n1 = 284; n2 = 553) with harmonized CSF assays of amyloid-ß and hyperphosphorylated tau (pTau), and longitudinal structural MRI data over 2 years. We derived measures of grey matter degeneration in a priori NbM and the entorhinal cortical regions of interest. To examine the spreading of degeneration, we used a predictive modelling strategy that tests whether baseline grey matter volume in a seed region accounts for longitudinal change in a target region. We demonstrated that predictive spread favoured the NbM→entorhinal over the entorhinal→NbM model. This evidence generalized across the independent samples. We also showed that CSF concentrations of pTau/amyloid-ß moderated the observed predictive relationship, consistent with evidence in rodent models of an underlying trans-synaptic mechanism of pathophysiological spread. The moderating effect of CSF was robust to additional factors, including clinical diagnosis. We then applied our predictive modelling strategy to an exploratory whole-brain voxel-wise analysis to examine the spatial specificity of the NbM→entorhinal model. We found that smaller baseline NbM volumes predicted greater degeneration in localized regions of the entorhinal and perirhinal cortices. By contrast, smaller baseline entorhinal volumes predicted degeneration in the medial temporal cortex, recapitulating a prior influential staging model. Our findings suggest that degeneration of the basal forebrain cholinergic projection system is a robust and reliable upstream event of entorhinal and neocortical degeneration, calling into question a prevailing view of Alzheimer's disease pathogenesis.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Prosencéfalo Basal/patologia , Progressão da Doença , Degeneração Neural/patologia , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Núcleo Basal de Meynert/patologia , Biomarcadores , Bases de Dados Factuais , Córtex Entorrinal/patologia , Feminino , Substância Cinzenta/patologia , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Neuroimagem , Fosforilação
20.
Neurobiol Aging ; 90: 119-124, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32169356

RESUMO

Young-onset Parkinson's disease (YOPD) is a relevant condition whose neurobiology is questioned if different from those of typical late-onset Parkinson's disease (LOPD). Here, we explored whether the clinical-biochemical profile of Parkinson's disease (PD) could be affected by the age-of-onset (AO), as a possible result of a distinct neurodegenerative process. A panel of fluid biomarkers (CSF lactate, 42-amyloid-ß peptide, total and 181-phosphorylated tau; serum uric acid) and the standard scores for motor and nonmotor signs were assessed in 76 idiopathic PD patients (genetic cases excluded; YOPD, AO ≤ 50, n = 44; LOPD, AO > 50, n = 32) and 75 sex/age-matched controls, adjusting the models for the main confounding factors. In PD, AO directly correlated to either CSF lactate and tau proteins or the nonmotor symptoms scale score. Specifically, a younger AO was associated with lower levels of biomarkers and minor burden of nonmotor symptoms. Our findings indicate that clinical-biochemical features of idiopathic PD may vary depending on the AO, accounting for different profiles in YOPD and LOPD whose recognition is fundamental for further pathophysiological implications and clinical applications.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Lactatos/líquido cefalorraquidiano , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Adulto , Fatores Etários , Idade de Início , Idoso , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Humanos , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , Medicina de Precisão , Ácido Úrico/sangue
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