Objective subtle cognitive decline and plasma phosphorylated tau181: Early markers of Alzheimer's disease‐related declines

Thomas, Kelsey R.; Bangen, Katherine J.; Edmonds, Emily C.; Weigand, Alexandra J.; Walker, Kayla S.; Bondi, Mark W.; Galasko, Douglas; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1002/dad2.12238

Cited by 16 publications

(30 citation statements)

References 57 publications

(136 reference statements)

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“…To our knowledge, ours is the first study to examine tau PET in participants with Obj-SCD defined using sensitive neuropsychological scores. However, the results of our study are in line with prior work showing a 4-year trajectory of medial temporal lobe atrophy [ 3 ] and accelerated increases in plasma p-tau181 over time [ 24 ]. We had previously speculated that tau deposition was likely to precede neurodegeneration and was associated with the early cognitive changes observed in Obj-SCD [ 3 ].…”

Section: Discussionsupporting

confidence: 92%

“…Participants were considered to have Obj-SCD based on the following actuarial neuropsychological criteria: performed > 1 SD below the age-/education-/sex-adjusted mean on (a) 1 impaired total test score in 2 different cognitive domains (memory, language, attention/executive), (b) 2 impaired neuropsychological process scores from the Rey Auditory Verbal Learning Test (AVLT), or (c) 1 impaired total test score and 1 impaired process score [ 3 , 4 , 24 ]. The total test scores involved six neuropsychological test scores and, specifically, included two memory [AVLT delayed free recall correct responses and AVLT recognition discrimination (hits minus false positives)], two language measures [30-item Boston Naming Test total correct or Multilingual Naming Test total correct and Animal Fluency total score], and two attention/executive functioning measures [Trail Making Test Parts A and B times to completion].…”

Section: Methodsmentioning

confidence: 99%

“…Objective subtle cognitive decline (Obj-SCD), not to be confused with subjective cognitive decline, uses both sensitive neuropsychological total scores and process/error scores, which capture how efficiently a neuropsychological test is performed and the types of errors that are produced. Obj-SCD status has been associated with faster progression to MCI/dementia, declines in everyday functioning, faster β-amyloid (Aβ) accumulation, faster increases in plasma p-tau181 levels, faster entorhinal cortex atrophy, and altered cerebral blood flow and functional MRI patterns [3,4,[22][23][24][25]. However, the relationship between Obj-SCD and tau PET is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Tau levels are higher in objective subtle cognitive decline but not subjective memory complaint

Thomas

Weigand²,

Edwards³

et al. 2022

Alz Res Therapy

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Background The 2018 NIA-AA Alzheimer’s Disease (AD) Research Framework states that subtle cognitive decline in cognitively unimpaired individuals can be measured by subjective reports or evidence of objective decline on neuropsychological measures. Both subjective memory complaint (SMC) and objective subtle cognitive decline (Obj-SCD) have been shown to be associated with future cognitive decline and AD biomarkers. We examined whether there are differences in tau PET levels between (a) SMC− vs. SMC+ participants, (b) Obj-SCD− vs. Obj-SCD+ participants, and (c) participants with overlapping vs. discrepant SMC and Obj-SCD classifications. Methods Cognitively unimpaired participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 236) were classified at baseline as positive or negative for SMC (SMC− n = 77; SMC+ n = 159) based on the first 12 items of the Cognitive Change Index and/or classified as positive or negative for Obj-SCD (Obj-SCD− n = 173; Obj-SCD+ n = 63) based on previously defined neuropsychological criteria. Analyses of covariance, adjusting for age, sex, APOE ε4 carrier status, and pulse pressure, examined the group differences in tau PET (AV-1451) using a composite standardized uptake variable ratio (SUVR) for regions consistent with Braak stage III/IV. The chi-squared tests examined the tau positivity rates across the groups. Results Obj-SCD+ participants had higher tau continuous SUVR levels (p = .035, ηp2 = .019) and higher rates of tau positivity (15.8% Obj-SCD− vs. 30.2% Obj-SCD+) than Obj-SCD− participants. Neither tau levels (p = .381, ηp2 = .003) nor rates of tau positivity (18.2% SMC− and 20.1% SMC+) differed between the SMC groups. There was very little agreement between SMC and Obj-SCD classifications (42%; κ = 0.008, p = .862). Participants who were Obj-SCD+ without SMC had the highest tau PET levels and differed from participants who were SMC+ without Obj-SCD (p = .022). Tau levels in participants with both SMC and Obj-SCD did not differ from those with only Obj-SCD (p = .216). Tau positivity rates across the SMC-/Obj-SCD−, SMC+/Obj-SCD−, SMC−/Obj-SCD+, and SMC+/Obj-SCD+ groups were 10.5%, 18.1%, 40.0%, and 25.6%, respectively. Conclusion Participants with Obj-SCD had a greater tau PET burden than those without Obj-SCD, but SMC was not associated with higher tau levels. The combination of SMC and Obj-SCD did not have higher tau levels than Obj-SCD alone. Findings add to the evidence that the Obj-SCD classification is associated with AD biomarkers and faster cognitive decline in ADNI participants, but further work is needed to validate this approach in more representative/diverse cohorts.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tau levels are higher in objective subtle cognitive decline but not subjective memory complaint

Thomas

Weigand²,

Edwards³

et al. 2022

Alz Res Therapy

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“…In the present study, we chose to use one set size (i.e. 3) for the sake of comparability of findings along the disease continuum, particularly considering our aim of anticipating the MCI stages [ 9 , 23 , 63 , 83 , 84 ].…”

Section: Discussionmentioning

confidence: 99%

Memory markers in the continuum of the Alzheimer’s clinical syndrome

et al. 2022

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Background The individual and complementary value of the Visual Short-Term Memory Binding Test (VSTMBT) and the Free and Cued Selective Reminding Test (FCSRT) as markers to trace the AD continuum was investigated. It was hypothesised that the VSTMBT would be an early indicator while the FCSRT would inform on imminent progression. Methods Healthy older adults (n=70) and patients with mild cognitive impairment (MCI) (n=80) were recruited and followed up between 2012 and 2017. Participants with at least two assessment points entered the study. Using baseline and follow-up assessments four groups were defined: Older adults who were healthy (HOA), with very mild cognitive but not functional impairment (eMCI), and with MCI who did and did not convert to dementia (MCI converters and non-converters). Results Only the VSTMBT predicted group membership in the very early stages (HOA vs eMCI). As the disease progressed, the FCSRT became a strong predictor excluding the VSTMB from the models. Their complementary value was high during the mid-prodromal stages and decreased in stages closer to dementia. Discussion The study supports the notion that neuropsychological assessment for AD needs to abandon the notion of one-size-fits-all. A memory toolkit for AD needs to consider tools that are early indicators and tools that suggest imminent progression. The VSTMBT and the FSCRT are such tools.

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“…BB-Aβ42 and BB-Aβ42/40 ratios can also be used in combination with other markers including GFAP, p-tau, or APP to indicate the presence of amyloid pathology [ 13 , 16 , 22 , 31 , 60 ]. Furthermore, BB-tau and BB-p-tau were shown to be useful biomarkers for progression to cognitive decline, for predicting progression to AD or for diagnosing AD [ 3 , 7 , 13 , 15 , 20 – 22 , 26 , 30 , 31 , 34 , 38 , 47 , 57 , 60 ]. Furthermore, p-Tau (p-tau 217, p-tau 181, p-tau231) in plasma and CSF have been shown to correlate with amyloid pathology [ 3 , 4 , 18 , 43 ].…”

Section: Introductionmentioning

confidence: 99%

Blood-based Aβ42 increases in the earliest pre-pathological stage before decreasing with progressive amyloid pathology in preclinical models and human subjects: opening new avenues for prevention

et al. 2022

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Blood-based (BB) biomarkers for Aβ and tau can indicate pathological processes in the brain, in the early pathological, even pre-symptomatic stages in Alzheimer’s disease. However, the relation between BB biomarkers and AD-related processes in the brain in the earliest pre-pathology stage before amyloid pathology develops, and their relation with total brain concentrations of Aβ and tau, is poorly understood. This stage presents a critical window for the earliest prevention of AD. Preclinical models with well-defined temporal progression to robust amyloid and tau pathology provide a unique opportunity to study this relation and were used here to study the link between BB biomarkers with AD-related processes in pre- and pathological stages. We performed a cross-sectional study at different ages assessing the link between BB concentrations and AD-related processes in the brain. This was complemented with a longitudinal analysis and with analysis of age-related changes in a small cohort of human subjects. We found that BB-tau concentrations increased in serum, correlating with progressive development of tau pathology and with increasing tau aggregates and p-tau concentrations in brain in TauP301S mice (PS19) developing tauopathy. BB-Aβ42 concentrations in serum decreased between 4.5 and 9 months of age, correlating with the progressive development of robust amyloid pathology in APP/PS1 (5xFAD) mice, in line with previous findings. Most importantly, BB-Aβ42 concentrations significantly increased between 1.5 and 4.5 months, i.e., in the earliest pre-pathological stage, before robust amyloid pathology develops in the brain, indicating biphasic BB-Aβ42 dynamics. Furthermore, increasing BB-Aβ42 in the pre-pathological phase, strongly correlated with increasing Aβ42 concentrations in brain. Our subsequent longitudinal analysis of BB-Aβ42 in 5xFAD mice, confirmed biphasic BB-Aβ42, with an initial increase, before decreasing with progressive robust pathology. Furthermore, in human samples, BB-Aβ42 concentrations were significantly higher in old (> 60 years) compared to young (< 50 years) subjects, as well as to age-matched AD patients, further supporting age-dependent increase of Aβ42 concentrations in the earliest pre-pathological phase, before amyloid pathology. Also BB-Aβ40 concentrations were found to increase in the earliest pre-pathological phase both in preclinical models and human subjects, while subsequent significantly decreasing concentrations in the pathological phase were characteristic for BB-Aβ42. Together our data indicate that BB biomarkers reflect pathological processes in brain of preclinical models with amyloid and tau pathology, both in the pathological and pre-pathological phase. Our data indicate a biphasic pattern of BB-Aβ42 in preclinical models and a human cohort. And most importantly, we here show that BB-Aβ increased and correlated with increasing concentrations of Aβ in the brain, in the earliest pre-pathological stage in a preclinical model. Our data thereby identify a novel critical window for prevention, using BB-Aβ as marker for accumulating Aβ in the brain, in the earliest pre-pathological stage, opening new avenues for personalized early preventive strategies against AD, even before amyloid pathology develops.

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Objective subtle cognitive decline and plasma phosphorylated tau181: Early markers of Alzheimer's disease‐related declines

Cited by 16 publications

References 57 publications

Tau levels are higher in objective subtle cognitive decline but not subjective memory complaint

Tau levels are higher in objective subtle cognitive decline but not subjective memory complaint

Memory markers in the continuum of the Alzheimer’s clinical syndrome

Blood-based Aβ42 increases in the earliest pre-pathological stage before decreasing with progressive amyloid pathology in preclinical models and human subjects: opening new avenues for prevention

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