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1.
Nat Commun ; 11(1): 6252, 2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-33288742

RESUMO

Biomarkers have revolutionized scientific research on neurodegenerative diseases, in particular Alzheimer's disease, transformed drug trial design, and are also increasingly improving patient management in clinical practice. A few key cerebrospinal fluid biomarkers have been robustly associated with neurodegenerative diseases. Several novel biomarkers are very promising, especially blood-based markers. However, many biomarker findings have had low reproducibility despite initial promising results. In this perspective, we identify possible sources for low reproducibility of studies on fluid biomarkers for neurodegenerative diseases, with a focus on Alzheimer's disease. We suggest guidelines for researchers and journal editors, with the aim to improve reproducibility of findings.


Assuntos
Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Humanos , Doenças Neurodegenerativas/diagnóstico , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano
2.
Nat Commun ; 11(1): 6024, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33247134

RESUMO

The availability of blood-based assays detecting Alzheimer's disease (AD) pathology should greatly accelerate AD therapeutic development and improve clinical care. This is especially true for markers that capture the risk of decline in pre-symptomatic stages of AD, as this would allow one to focus interventions on participants maximally at risk and at a stage prior to widespread synapse loss and neurodegeneration. Here we quantify plasma concentrations of an N-terminal fragment of tau (NT1) in a large, well-characterized cohort of clinically normal elderly who were followed longitudinally. Plasma NT1 levels at study entry (when all participants were unimpaired) were highly predictive of future cognitive decline, pathological tau accumulation, neurodegeneration, and transition to a diagnosis of MCI/AD. These predictive effects were particularly strong in participants with even modestly elevated brain ß-amyloid burden at study entry, suggesting plasma NT1 levels capture very early cognitive, pathologic and neurodegenerative changes along the AD trajectory.


Assuntos
Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico , Degeneração Neural/sangue , Degeneração Neural/complicações , Proteínas tau/sangue , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/sangue , Disfunção Cognitiva/complicações , Disfunção Cognitiva/fisiopatologia , Feminino , Substância Cinzenta/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Memória Episódica , Degeneração Neural/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano
3.
Sci Rep ; 10(1): 15886, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985583

RESUMO

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia. Its cleaved fragments, soluble TREM2 (sTREM2), can be measured in the cerebrospinal fluid (CSF). Previous studies indicate higher CSF sTREM2 in symptomatic AD; however most of these studies have included biomarker positive AD cases and biomarker negative controls. The aim of the study was to explore potential differences in the CSF level of sTREM2 and factors associated with an increased sTREM2 level in patients diagnosed with mild cognitive impairment (MCI) or dementia due to AD compared with cognitively unimpaired controls as judged by clinical symptoms and biomarker category (AT). We included 299 memory clinic patients, 62 (20.7%) with AD-MCI and 237 (79.3%) with AD dementia, and 113 cognitively unimpaired controls. CSF measures of the core biomarkers were applied to determine AT status. CSF sTREM2 was analyzed by ELISA. Patients presented with comparable CSF sTREM2 levels as the cognitively unimpaired (9.6 ng/ml [SD 4.7] versus 8.8 ng/ml [SD 3.6], p = 0.27). We found that CSF sTREM2 associated with age-related neuroinflammation and tauopathy irrespectively of amyloid ß, APOE ε4 status or gender. The findings were similar in both symptomatic and non-symptomatic individuals.


Assuntos
Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/diagnóstico , Glicoproteínas de Membrana/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Imunológicos , Proteínas tau/líquido cefalorraquidiano
4.
Neurology ; 95(22): e3026-e3035, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32973122

RESUMO

OBJECTIVE: To investigate whether tau phosphorylated at Thr217 (p-tau T217) assay in CSF can distinguish patients with Alzheimer disease (AD) from patients with other dementias and healthy controls. METHODS: We developed and validated a novel Simoa immunoassay to detect p-tau T217 in CSF. There was a total of 190 participants from 3 cohorts with AD (n = 77) and other neurodegenerative diseases (n = 69) as well as healthy participants (n = 44). RESULTS: The p-tau T217 assay (cutoff 242 pg/mL) identified patients with AD with accuracy of 90%, with 78% positive predictive value (PPV), 97% negative predictive value (NPV), 93% sensitivity, and 88% specificity, compared favorably with p-tau T181 ELISA (52 pg/mL), showing 78% accuracy, 58% PPV, 98% NPV, 71% specificity, and 97% sensitivity. The assay distinguished patients with AD from age-matched healthy controls (cutoff 163 pg/mL, 98% sensitivity, 93% specificity), similarly to p-tau T181 ELISA (cutoff 60 pg/mL, 96% sensitivity, 86% specificity). In patients with AD, we found a strong correlation between p-tau T217 and p-tau T181, total tau and ß-amyloid 40, but not ß-amyloid 42. CONCLUSIONS: This study demonstrates that p-tau T217 displayed better diagnostic accuracy than p-tau T181. The data suggest that the new p-tau T217 assay has potential as an AD diagnostic test in clinical evaluation. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a CSF immunoassay for p-tau T217 distinguishes patients with AD from patients with other dementias and healthy controls.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Imunoensaio/normas , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/diagnóstico , Tauopatias/líquido cefalorraquidiano , Tauopatias/diagnóstico , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Afasia Primária Progressiva/líquido cefalorraquidiano , Afasia Primária Progressiva/diagnóstico , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Demência Frontotemporal/líquido cefalorraquidiano , Demência Frontotemporal/diagnóstico , Humanos , Imunoensaio/métodos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Paralisia Supranuclear Progressiva/líquido cefalorraquidiano , Paralisia Supranuclear Progressiva/diagnóstico
5.
Neurology ; 95(23): e3104-e3116, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-32873693

RESUMO

OBJECTIVE: To determine the ordering of changes in Alzheimer disease (AD) biomarkers among cognitively normal individuals. METHODS: Cross-sectional data, including CSF analytes, molecular imaging of cerebral fibrillar ß-amyloid (Aß) with PET using the [11C] benzothiazole tracer Pittsburgh compound B (PiB), MRI-based brain structures, and clinical/cognitive outcomes harmonized from 8 studies, collectively involving 3,284 cognitively normal individuals 18 to 101 years of age, were analyzed. The age at which each marker exhibited an accelerated change (called the change point) was estimated and compared across the markers. RESULTS: Accelerated changes in CSF Aß1-42 (Aß42) occurred at 48.28 years of age and in Aß42/Aß40 ratio at 46.02 years, followed by PiB mean cortical standardized uptake value ratio (SUVR) with a change point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change point at ≈60 years, similar to those for MRI hippocampal volume and cortical thickness. The change point for a cognitive composite occurred at 62.41 years. The change points for CSF Aß42 and Aß42/Aß40 ratio, albeit not significantly different from that for PiB SUVR, occurred significantly earlier than that for CSF Tau, Ptau, MRI markers, and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other. CONCLUSIONS: Our findings support the hypothesized early changes of amyloid in preclinical AD and suggest that changes in neuronal injury and neurodegeneration markers occur close in time to cognitive decline.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral , Disfunção Cognitiva , Proteínas tau/líquido cefalorraquidiano , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Compostos de Anilina , Biomarcadores/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Estudos Transversais , Feminino , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Sintomas Prodrômicos , Tiazóis , Adulto Jovem
6.
Biochim Biophys Acta Proteins Proteom ; 1868(12): 140537, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32896673

RESUMO

The diagnosis of Alzheimer's disease (AD) relies on the presence of amyloidosis and tauopathy, as reflected in cerebrospinal fluid (CSF), independently from the clinical stage. Recently, CSF d-serine has been proposed as a possible new AD biomarker, reflecting dysfunctional activation of neuronal glutamatergic N-methyl-d-aspartate receptor (NMDAR). In this study, we measured blood serum and CSF concentration of two NMDAR modulators, such as d-serine and d-aspartate, in a cohort of drug-free subjects encompassing the whole AD clinical spectrum. In addition, we also analyzed d-serine levels in a cohort of post-mortem AD and control cortex samples. We reported unaltered serum and CSF concentrations of d-serine and d-aspartate in AD patients both during the AD progression and compared to non-demented controls. Accordingly, no correlation was detected between serum or CSF d-serine content and mini-mental state examination or Clinical Dementia Rating. Similarly, cortical d-serine levels were also unaltered in post-mortem samples of AD patients. Overall, our results failed to confirm previous findings indicating the CSF d-serine as a novel biomarker for AD.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Biomarcadores , Serina/sangue , Serina/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Ácido Aspártico/sangue , Ácido Aspártico/líquido cefalorraquidiano , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Humanos , Masculino , Especificidade de Órgãos , Período Pós-Parto , Prognóstico , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano
7.
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
8.
Neurology ; 95(23): e3093-e3103, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-32989109

RESUMO

OBJECTIVE: To determine whether vascular risk and Alzheimer disease (AD) biomarkers have independent or synergistic effects on cognitive decline and whether vascular risk is associated with the accumulation of AD pathology as measured by change in biomarkers over time. METHODS: At baseline, participants (n = 168) were cognitively normal and primarily middle-aged (mean 56.4 years, SD 10.9 years) and had both vascular risk factor status and proximal CSF biomarkers available. Baseline vascular risk was quantified with a composite vascular risk score reflecting the presence or absence of hypertension, hypercholesterolemia, diabetes, current smoking, and obesity. CSF biomarkers of ß-amyloid (Aß)1-42, total tau (t-tau), and phosphorylated tau (p-tau) were used to create dichotomous high and low AD biomarker groups (based on Aß1-42 and tau). Linear mixed-effects models were used to examine change in a cognitive composite score (mean follow-up 13.9 years) and change in CSF biomarkers (mean follow-up 4.2 years). RESULTS: There was no evidence of a synergistic relationship between the vascular risk score and CSF AD biomarkers and cognitive decline. Instead, the vascular risk score (estimate -0.022, 95% confidence interval [CI] -0.043 to -0.002, p = 0.03) and AD biomarkers (estimate -0.060, 95% CI -0.096 to -0.024, p = 0.001) were independently and additively associated with cognitive decline. In addition, the vascular risk score was unrelated to levels of or rate of change in CSF Aß1-42, t-tau, or p-tau. CONCLUSIONS: The results of this observational cohort study suggest that vascular risk and biomarkers of AD pathology, when measured in midlife, act along independent pathways and underscore the importance of accounting for multiple risk factors for identifying cognitively normal individuals at the greatest risk of cognitive decline.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Doenças Cardiovasculares , Disfunção Cognitiva , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/fisiopatologia , Biomarcadores/líquido cefalorraquidiano , Doenças Cardiovasculares/líquido cefalorraquidiano , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/fisiopatologia , Diabetes Mellitus/epidemiologia , Feminino , Seguimentos , Humanos , Hipercolesterolemia/epidemiologia , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Fatores de Risco , Fumar/epidemiologia
9.
Neurology ; 95(15): e2065-e2074, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-32737076

RESUMO

OBJECTIVE: To evaluate the hypothesis that proximity to parental age at onset (AAO) in sporadic Alzheimer disease (AD) is associated with greater AD and neural injury biomarker alterations during midlife and to assess the role of nonmodifiable and modifiable factors. METHODS: This observational study included 290 cognitively unimpaired (CU) participants with a family history (FH) of clinically diagnosed sporadic AD (age 49-73 years) from the Alzheimer's and Families (ALFA) study. [18F]flutemetamol-PET standardized uptake value ratios, CSF ß-amyloid42/40 ratio, and phosphorylated tau were used as AD biomarkers. Hippocampal volumes and CSF total tau were used as neural injury biomarkers. Mental and vascular health proxies were calculated. In multiple regression models, we assessed the effect of proximity to parental AAO and its interaction with age on AD and neural injury biomarkers. Then, we evaluated the effects of FH load (number of parents affected), sex, APOE ε4, education, and vascular and mental health. RESULTS: Proximity to parental AAO was associated with ß-amyloid, but not with neural injury biomarkers, and interacted with sex and age, showing that women and older participants had increased ß-amyloid. FH load and APOE ε4 showed independent contributions to ß-amyloid load. Education and vascular and mental health proxies were not associated with AD biomarkers. However, lower mental health proxies were associated with decreased hippocampal volumes with age. CONCLUSION: The identification of the earliest biomarker changes and modifiable factors to be targeted in early interventions is crucial for AD prevention. Proximity to parental AAO may offer a timeline for detection of incipient ß-amyloid changes in women. In risk-enriched middle-aged cohorts, mental health may be a target for early interventions. CLINICALTRIALSGOV IDENTIFIER: NCT02485730. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in CU adults with FH of sporadic AD, proximity to parental AAO was associated with ß-amyloid but not with neural injury biomarkers.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Diagnóstico Precoce , Saúde da Família/estatística & dados numéricos , Proteínas tau/líquido cefalorraquidiano , Idade de Início , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Biomarcadores , Feminino , Genótipo , Hipocampo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Fatores de Risco , Fatores Sexuais
10.
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
11.
Ann Neurol ; 88(5): 878-892, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32829532

RESUMO

OBJECTIVE: There is an urgent need for sensitive, widely available, blood-based screening tests to identify presymptomatic individuals destined to develop Alzheimer's disease (AD). We investigated whether tau detected in plasma by our in-house NT1 assay is specifically altered in AD, and when applied to patients with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) can serve to predict progression to AD dementia. The predictive value of NT1 versus tau measured using assays from Quanterix and Roche, and the specificity of NT1 for AD versus a nonspecific marker of neurodegeneration (neurofilament light [NfL]) were also examined. METHODS: NT1 tau and NfL were measured in plasma from prospectively followed patients with SCD or MCI who remained cognitively stable, converted to AD dementia, or converted to non-AD dementias, and in cognitively unimpaired participants. Tau was measured using Quanterix and Roche assays in baseline subjects with SCD and MCI. RESULTS: Plasma NT1 tau was specifically elevated in AD, but not in non-AD dementia compared with controls, whereas NfL was increased in both AD and non-AD dementias. Baseline specimens from individuals who had SCD or MCI revealed that NT1 tau, but not tau measured using Quanterix or Roche assays, is elevated in subjects who progress to AD dementia. As expected, baseline plasma NfL is elevated in those who progress to AD and non-AD dementias. INTERPRETATION: Plasma NT1 tau is a specific marker of AD, which is elevated early in disease and may prove useful as a first round screen to identify individuals at risk of developing AD. ANN NEUROL 2020;88:878-892.


Assuntos
Doença de Alzheimer/sangue , Biomarcadores/sangue , Marcadores Genéticos , Proteínas tau/sangue , Idade de Início , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/sangue , Disfunção Cognitiva/genética , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/genética , Proteínas de Neurofilamentos/sangue , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genética
13.
Brain ; 143(7): 2295-2311, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32666090

RESUMO

Under the ATN framework, CSF analytes provide evidence of the presence or absence of Alzheimer's disease pathological hallmarks: amyloid plaques (A), phosphorylated tau (T), and accompanying neurodegeneration (N). Still, differences in CSF levels across amnestic and non-amnestic variants or due to co-occurring pathologies might lead to misdiagnoses. We assess the diagnostic accuracy of CSF markers for amyloid, tau, and neurodegeneration in an autopsy cohort of 118 Alzheimer's disease patients (98 amnestic; 20 non-amnestic) and 64 frontotemporal lobar degeneration patients (five amnestic; 59 non-amnestic). We calculated between-group differences in CSF concentrations of amyloid-ß1-42 peptide, tau protein phosphorylated at threonine 181, total tau, and the ratio of phosphorylated tau to amyloid-ß1-42. Results show that non-amnestic Alzheimer's disease patients were less likely to be correctly classified under the ATN framework using independent, published biomarker cut-offs for positivity. Amyloid-ß1-42 did not differ between amnestic and non-amnestic Alzheimer's disease, and receiver operating characteristic curve analyses indicated that amyloid-ß1-42 was equally effective in discriminating both groups from frontotemporal lobar degeneration. However, CSF concentrations of phosphorylated tau, total tau, and the ratio of phosphorylated tau to amyloid-ß1-42 were significantly lower in non-amnestic compared to amnestic Alzheimer's disease patients. Receiver operating characteristic curve analyses for these markers showed reduced area under the curve when discriminating non-amnestic Alzheimer's disease from frontotemporal lobar degeneration, compared to discrimination of amnestic Alzheimer's disease from frontotemporal lobar degeneration. In addition, the ATN framework was relatively insensitive to frontotemporal lobar degeneration, and these patients were likely to be classified as having normal biomarkers or biomarkers suggestive of primary Alzheimer's disease pathology. We conclude that amyloid-ß1-42 maintains high sensitivity to A status, although with lower specificity, and this single biomarker provides better sensitivity to non-amnestic Alzheimer's disease than either the ATN framework or the phosphorylated-tau/amyloid-ß1-42 ratio. In contrast, T and N status biomarkers differed between amnestic and non-amnestic Alzheimer's disease; standard cut-offs for phosphorylated tau and total tau may thus result in misclassifications for non-amnestic Alzheimer's disease patients. Consideration of clinical syndrome may help improve the accuracy of ATN designations for identifying true non-amnestic Alzheimer's disease.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Degeneração Lobar Frontotemporal/líquido cefalorraquidiano , Degeneração Lobar Frontotemporal/diagnóstico , Idoso , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Feminino , Degeneração Lobar Frontotemporal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Neural/patologia , Sensibilidade e Especificidade , Proteínas tau/líquido cefalorraquidiano
14.
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
15.
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
16.
Ann Neurol ; 88(3): 574-587, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32542885

RESUMO

OBJECTIVE: We analyzed the longitudinal profile of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in early Parkinson's disease (PD) compared with healthy controls (HCs) and tested baseline CSF biomarkers for prediction of clinical decline in PD. METHODS: Amyloid-ß 1 to 42 (Aß42 ), total tau (t-tau) and phosphorylated tau (p-tau) at the threonine 181 position were measured using the high-precision Roche Elecsys electrochemiluminescence immunoassay in all available CSF samples from longitudinally studied patients with PD (n = 416) and HCs (n = 192) followed for up to 3 years in the Parkinson's Progression Markers Initiative (PPMI). Longitudinal CSF and clinical data were analyzed with linear-mixed effects models. RESULTS: We found patients with PD had lower CSF t-tau (median = 157.7 pg/mL; range = 80.9-467.0); p-tau (median = 13.4 pg/mL; range = 8.0-40.1), and Aß42 (median = 846.2 pg/mL; range = 238.8-3,707.0) than HCs at baseline (CSF t-tau median = 173.5 pg/mL; range = 82.0-580.8; p-tau median = 15.4 pg/mL; range = 8.1-73.6; and Aß42 median = 926.5 pg/mL; range = 239.1-3,297.0; p < 0.05-0.001) and a moderate-to-strong correlation among these biomarkers in both patients with PD and HCs (Rho = 0.50-0.97; p < 0.001). Of the patients with PD, 31.5% had pathologically low levels of CSF Aß42 at baseline and these patients with PD had lower p-tau levels (median = 10.8 pg/mL; range = 8.0-32.8) compared with 27.7% of HCs with pathologically low CSF Aß42 (CSF p-tau median = 12.8 pg/mL; range 8.2-73.6; p < 0.03). In longitudinal CSF analysis, we found patients with PD had greater decline in CSF Aß42 (mean difference = -41.83 pg/mL; p = 0.03) and CSF p-tau (mean difference = -0.38 pg/mL; p = 0.03) at year 3 compared with HCs. Baseline CSF Aß42 values predicted small but measurable decline on cognitive, autonomic, and motor function in early PD. INTERPRETATION: Our data suggest baseline CSF AD biomarkers may have prognostic value in early PD and that the dynamic change of these markers, although modest over a 3-year period, suggest biomarker profiles in PD may deviate from healthy aging. ANN NEUROL 2020;88:574-587.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença de Parkinson , Estudos Prospectivos
17.
Neurology ; 95(10): 445-449, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32586897

RESUMO

Here, we report a case of COVID-19-related acute necrotizing encephalopathy where SARS-CoV-2 RNA was found in CSF 19 days after symptom onset after testing negative twice. Although monocytes and protein levels in CSF were only marginally increased, and our patient never experienced a hyperinflammatory state, her neurologic function deteriorated into coma. MRI of the brain showed pathologic signal symmetrically in central thalami, subinsular regions, medial temporal lobes, and brain stem. Extremely high concentrations of the neuronal injury markers neurofilament light and tau, as well as an astrocytic activation marker, glial fibrillary acidic protein, were measured in CSF. Neuronal rescue proteins and other pathways were elevated in the in-depth proteomics analysis. The patient received IV immunoglobulins and plasma exchange. Her neurologic status improved, and she was extubated 4 weeks after symptom onset. This case report highlights the neurotropism of SARS-CoV-2 in selected patients and emphasizes the importance of repeated lumbar punctures and CSF analyses in patients with suspected COVID-19 and neurologic symptoms.


Assuntos
Encéfalo/diagnóstico por imagem , Infecções por Coronavirus/líquido cefalorraquidiano , Leucoencefalite Hemorrágica Aguda/líquido cefalorraquidiano , Pneumonia Viral/líquido cefalorraquidiano , RNA Viral/líquido cefalorraquidiano , Aciclovir/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/genética , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Feminino , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Interleucina-6/líquido cefalorraquidiano , Leucoencefalite Hemorrágica Aguda/diagnóstico por imagem , Leucoencefalite Hemorrágica Aguda/fisiopatologia , Leucoencefalite Hemorrágica Aguda/terapia , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Pandemias , Troca Plasmática , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Reação em Cadeia da Polimerase em Tempo Real , Tomografia Computadorizada por Raios X , Tropismo Viral , Proteínas tau/líquido cefalorraquidiano
18.
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
19.
Psychiatry Res Neuroimaging ; 302: 111099, 2020 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-32505903

RESUMO

Cholinergic dysfunction is central in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). The electroencephalography-based acetylcholine index (EEG-Ach index) has been proposed as a biomarker of cholinergic dysfunction. However, it is unclear how the EEG-Ach index relates to amyloid-beta pathology and neurodegeneration. We investigated the association between the EEG-Ach index and cerebrospinal fluid (CSF) amyloid-beta, CSF total tau, cortical thickness, and hippocampal volume from magnetic resonance imaging (MRI), and cognition. A total of 127 patients with different neurodegenerative diseases were studied. The EEG-Ach index was calculated from quantitative EEG using statistical pattern recognition. The EEG-Ach index was associated with hippocampal volume and cortical thickness in frontal, temporal, and occipital cortices. Cross-sectional sub-analyses based on a small sample suggests that the EEG-Ach index increases the closest to AD dementia, downstream to amyloid-beta pathology, CSF total tau, and hippocampal volume. We conclude that cholinergic dysfunction correlates with atrophy in brain areas important for AD pathogenesis, and this association is more prominent in the dementia stage. These results together with previous studies from this project suggest that the EEG-Ach index may be a useful biomarker for cholinergic dysfunction, with value for differential diagnosis of dementia and monitoring patients at the dementia stage.


Assuntos
Doença de Alzheimer/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Eletroencefalografia , Hipocampo/diagnóstico por imagem , Doença por Corpos de Lewy/fisiopatologia , Acetilcolina , 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 , Atrofia , Biomarcadores/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Córtex Cerebral/patologia , Antagonistas Colinérgicos , Cognição , Estudos Transversais , Diagnóstico Diferencial , Feminino , Hipocampo/patologia , Humanos , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/patologia , Imagem por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Tamanho do Órgão , Escopolamina , Proteínas tau/líquido cefalorraquidiano
20.
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
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