An examination of a novel multipanel of CSF biomarkers in the Alzheimer's disease clinical and pathological continuum

Hulle, Carol Van; Jonaitis, Erin M.; Betthauser, Tobey J.; Batrla, Richard; Wild, Norbert; Kollmorgen, Gwendlyn; Andréasson, Ulf; Okonkwo, Ozioma C.; Bendlin, Barbara B.; Asthana, Sanjay; Carlsson, Cynthia M.; Johnson, Sterling C.; Zetterberg, Henrik; Blennow, Kaj

doi:10.1002/alz.12204

Cited by 93 publications

(138 citation statements)

References 47 publications

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“…Os níveis de sTREM2 não variam entre portadores e não portadores de variantes raras do gene Trem2 segundo Suárez-Calvet et al 34 , entretanto, os autores observaram um aumento de sTREM2-LCR na p.R47H e p.H157Y, diminuição na p.L211P, e valores iguais na p.R62H. Também não há diferença nas concentrações de sTREM2 em LCR entre portadores e não portadores de APOE ε4 18,36,28,41 . Foi demonstrado que a variante de risco rs7232 do gene MS4A6A está associada aos níveis de sTREM2 36 .…”

Section: Trem2unclassified

“…O estudo de Milà-alomà et al 59 demonstrou o aumento do GFAP ao longo da idade em indivíduos tanto Aβ-negativos quanto positivos na pré-clínica, porém está mais pronunciado nos Aβ-positivo 53 . Em indivíduos sintomáticos (CCL e demência) com perfil positivo DA (definido pela razão p-tau/Aβ42), os níveis de GFAP mostraram-se mais elevados em relação aos de perfil negativo 18 .…”

Section: Gfapunclassified

“…A proteína B S100 ligante de cálcio (S100B) é uma das proteínas solúveis mais abundantes no cérebro. Ela é expressa primariamente em astrócitos e encontrasse aumentada na DA 61,18,57 , mas também em outras doenças, como a demência vascular, como demonstrado por Llorens et al 57 , não havendo diferença significante de S100B entre ambas, e o marcadores sendo incapaz de distingui-las 57 . No estudo de Van Hulle et al 18 , os níveis de S100B em LCR se mostrou mais alto no grupo com perfil de DA (determinado pela razão p-tau/Aβ42) em indivíduos com comprometimento cognitivo (CCL e demência), enquanto não houve diferença em indivíduos sem comprometimento cognitivo 18 .…”

Section: S100bunclassified

“…Ela é expressa primariamente em astrócitos e encontrasse aumentada na DA 61,18,57 , mas também em outras doenças, como a demência vascular, como demonstrado por Llorens et al 57 , não havendo diferença significante de S100B entre ambas, e o marcadores sendo incapaz de distingui-las 57 . No estudo de Van Hulle et al 18 , os níveis de S100B em LCR se mostrou mais alto no grupo com perfil de DA (determinado pela razão p-tau/Aβ42) em indivíduos com comprometimento cognitivo (CCL e demência), enquanto não houve diferença em indivíduos sem comprometimento cognitivo 18 . O mesmo estudo apresentou fraca correlação de S100B com t-tau e neurofilamento leve 18 , contudo, no trabalho de Teitsdottir et al 61 , foi demonstrada correlação mais forte de S100B com esses marcadores, mas não com Aβ42.…”

Section: S100bunclassified

“…No estudo de Van Hulle et al 18 , os níveis de S100B em LCR se mostrou mais alto no grupo com perfil de DA (determinado pela razão p-tau/Aβ42) em indivíduos com comprometimento cognitivo (CCL e demência), enquanto não houve diferença em indivíduos sem comprometimento cognitivo 18 . O mesmo estudo apresentou fraca correlação de S100B com t-tau e neurofilamento leve 18 , contudo, no trabalho de Teitsdottir et al 61 , foi demonstrada correlação mais forte de S100B com esses marcadores, mas não com Aβ42. Também no estudo de Teitsdottir et al 61 foi demonstrada má capacidade de S100B em LCR para diferenciar indivíduos com perfil de DA dos não-DA (AUC = 0,61), definido pela razão t-tau/ Aβ42 61 .…”

Section: S100bunclassified

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Biomarcadores gliais da doença de Alzheimer

Bittencourt

Müller

2021

CBR

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Introdução: A neuroinflamação associada às células gliais é um elemento importante do processo patológico da doença de Alzheimer (DA). Este estudo apresenta uma revisão dos marcadores gliais quitinase 3-like 1 (YKL-40), do receptor desencadeado expresso nas células mieloides 2 (Triggering receptor expressed on myeloid cells 2 -TREM2), da proteína acídica fibrilar glial (GFAP) e da proteína B S100 ligante de cálcio (S100B). Métodos: Nesta revisão são analisados os marcadores gliais YKL-40, TREM2, GFAP e S100B presentes em sangue e/ou líquido cefalorraquidiano (LCR), a partir de estudos publicados até 2020 nos bancos de dados do PubMed, Medline e Periódicos Capes. Resultados: Foram recuperados 233 documentos, dentre os quais foram incluídos 60. Todos os marcadores se encontram aumentados na DA em LCR -YKL-40 e TREM2 solúvel (sTREM2), já na fase pré-clínica -, e em sangue, e estão correlacionados ao declínio cognitivo. No entanto, nenhum dos marcadores analisados apresentou grande potencial para o diagnóstico diferencial. Além da proteína TREM2 solúvel no LCR, no sangue também se pode identificar alteração nos níveis do RNAm de TREM2. GFAP sanguíneo mostra ser o melhor em distinguir controles de pacientes com Alzheimer. Há evidências de um efeito protetivo da ativação glial em reação ao acúmulo amiloide. Conclusão: Os marcadores gliais no geral têm pouca utilidade para o diagnóstico diferencial, mas podem auxiliar no prognóstico e como biomarcadores inespecíficos para doenças neurodegenerativas.

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Section: Trem2unclassified

Section: Gfapunclassified

Section: S100bunclassified

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Biomarcadores gliais da doença de Alzheimer

Bittencourt

Müller

2021

CBR

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Biomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease

et al. 2022

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IMPORTANCEThere is currently no consensus as to which biomarkers best predict longitudinal tau accumulation at different clinical stages of Alzheimer disease (AD).OBJECTIVE To describe longitudinal [ 18 F]RO948 tau positron emission tomography (PET) findings across the clinical continuum of AD and determine which biomarker combinations showed the strongest associations with longitudinal tau PET and best optimized clinical trial enrichment. DESIGN, SETTING, AND PARTICIPANTSThis longitudinal cohort study consecutively enrolled amyloid-β (Aβ)-negative cognitively unimpaired (CU) participants, Aβ-positive CU individuals, Aβ-positive individuals with mild cognitive impairment (MCI), and individuals with AD dementia between September 2017 and November 2020 from the Swedish BioFINDER-2 (discovery cohort) and BioFINDER-1 (validation cohort) studies.EXPOSURES Baseline plasma and cerebrospinal fluid Aβ42/Aβ40, tau phosphorylated at threonine-217 (p-tau217), p-tau181 and neurofilament light, magnetic resonance imaging, amyloid PET ([ 18 F]flutemetamol), and tau PET ([ 18 F]RO948 in the BioFINDER-2 study; [ 18 F]flortaucipir in the BioFINDER-1 study). MAIN OUTCOMES AND MEASURESBaseline tau PET standardized uptake value ratio (SUVR) and annual percent change in tau PET SUVR across regions of interest derived using a data-driven approach combining clustering and event-based modeling. Regression models were used to examine associations between individual biomarkers and longitudinal tau PET and to identify which combinations best predicted longitudinal tau PET. These combinations were then entered in a power analysis to examine how their use as an enrichment strategy would affect sample size in a simulated clinical trial. RESULTSOf 343 participants, the mean (SD) age was 72.56 (7.24) years, and 157 (51.1%) were female. The clustering/event-based modeling-based approach identified 5 regions of interest (stages). In Aβ-positive CU individuals, the largest annual increase in tau PET SUVR was seen in stage I (entorhinal cortex, hippocampus, and amygdala; 4.04% [95% CI, 2.67%-5.32%]). In Aβ-positive individuals with MCI and with AD dementia, the greatest increases were seen in stages II (temporal cortical regions; 4.45% [95% CI, 3.41%-5.49%]) and IV (certain frontal regions; 5.22% [95% CI, 3.95%-6.49%]), respectively. In Aβ-negative CU individuals and those with MCI, modest change was seen in stage I (1.38% [95% CI, 0.78%-1.99%] and 1.80% [95% CI, 0.76%-2.84%], respectively). When looking at individual predictors and longitudinal tau PET in the stages that showed most change, plasma p-tau217 (R 2 = 0.27, P < .005), tau PET (stage I baseline SUVR; R 2 = 0.13, P < .05) and amyloid PET (R 2 = 0.10, P < .05) were significantly associated with longitudinal tau PET in stage I in Aβ-positive CU individuals. In Aβ-positive individuals with MCI, plasma p-tau217 (R 2 = 0.24, P < .005) and tau PET (stage II baseline SUVR; R 2 = 0.44, P < .001) were significantly associated with longitudinal tau PET in stage II. Findings were replicated in BioFI...

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Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers

et al. 2023

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ImportanceAlzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression.ObjectiveTo evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals.Design, Setting, and ParticipantsThis prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aβ-positive participants were included in the main analyses.ExposuresBaseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort.Main Outcomes and MeasuresThe primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion.ResultsAmong 171 Aβ-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P &lt; .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time.Conclusions and RelevanceIn this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.

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An examination of a novel multipanel of CSF biomarkers in the Alzheimer's disease clinical and pathological continuum

Cited by 93 publications

References 47 publications

Biomarcadores gliais da doença de Alzheimer

Biomarcadores gliais da doença de Alzheimer

Biomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease

Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers

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