Longitudinal plasma phosphorylated tau 181 tracks disease progression in Alzheimer’s disease

Chen, Shi-Dong; Huang, Yu‐Yuan; Shen, Xue‐Ning; Guo, Yu; Tan, Lan; Dong, Qiang; Yu, Jin‐Tai; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1038/s41398-021-01476-7

Cited by 57 publications

(58 citation statements)

References 27 publications

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“…However, we should keep in mind that the axonal neurodegeneration indicated by the total tau protein is higher in AD than in NABD. As ptau181 is an established marker of disease progression in AD patients ( 24 ), we were surprised to find that it failed to correlate in our cohort suffering from longitudinal cognitive decline. The possible reasons for this might be our small sample and heterogeneous cohort involving early-onset and late-onset AD patients.…”

Section: Discussionmentioning

confidence: 66%

Cerebrospinal Fluid Total Tau Protein Correlates With Longitudinal, Progressing Cognitive Dysfunction in Anti-Neural Autoantibody-Associated Dementia and Alzheimer’s Dementia: A Case–Control Study

et al. 2022

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BackgroundNeural autoantibody-associated dementia (NABD) is an increasing phenomenon in memory clinics with a high impact on later therapy. Biomarkers are lacking that differentiate this type of dementia from neurodegenerative dementia such as Alzheimer’s dementia (AD). Our aim is to analyze neurodegeneration markers and their relationship to progressing cognitive dysfunction in NABD and AD to test for tools differentiating these two forms of dementia prior to neural autoantibody testing.MethodsIn our retrospective, observational study, we investigated 14 patients with dementia and serum and/or cerebrospinal fluid (CSF) neural autoantibodies as well as 14 patients with AD by relying on recent CSF and clinical criteria for AD. Patient files were checked for psychopathology, neuropsychological test performance, autoimmune indicators, CSF, and MRI results.ResultsOur patient groups did not differ in their psychopathology, autoimmune indicators, or MRI profile. The progression of cognitive dysfunction [as measured by the difference in Mini-Mental State Examination (MMSE) scores since disease onset, and the yearly progression rate (MMSE loss/per year)] did not vary significantly between groups. Total tau protein was significantly higher in AD patients than NABD patients revealing no signs of Alzheimer’s disease pathology in their CSF (p < 0.05). Total tau protein levels in CSF correlated with cognitive decline since disease onset (r = 0.38, p < 0.05) and yearly progression rates (r = 0.56, p < 0.005) in all patients.DiscussionOur results suggest that the progression of cognitive dysfunction as defined by MMSE does not seem to be an appropriate biomarker for distinguishing NABD from AD. However, the total tau protein level in CSF might be a relevant molecular biomarker that can indicate disease pathology and/or progression in both known AD and NABD, which is often accompanied by axonal degeneration. Total tau protein may be an additional diagnostic tool with which to differentiate anti-neural-associated dementia from AD if further research confirms these proof-of-concept findings in larger patient cohorts.

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Section: Discussionmentioning

confidence: 66%

Cerebrospinal Fluid Total Tau Protein Correlates With Longitudinal, Progressing Cognitive Dysfunction in Anti-Neural Autoantibody-Associated Dementia and Alzheimer’s Dementia: A Case–Control Study

et al. 2022

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“…Due to long time intervals between plasma samples and tau PET scans in the vast majority of participants, survival analyses were not conducted for tau PET conversion. Additionally in a recent study by our team, we observed that plasma p-tau181 increased on the single patient level over time as the disease progressed [ 32 ]. It was also confirmed that plasma p-tau181 was longitudinally correlated with AD-related CSF and PET neuroimaging biomarkers, both in the whole population or in subgroups defined by ATN classifications and cognitive status [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally in a recent study by our team, we observed that plasma p-tau181 increased on the single patient level over time as the disease progressed [ 32 ]. It was also confirmed that plasma p-tau181 was longitudinally correlated with AD-related CSF and PET neuroimaging biomarkers, both in the whole population or in subgroups defined by ATN classifications and cognitive status [ 32 ]. Together, these findings supported the effectiveness of plasma p-tau181 in monitoring pathological changes during the course of AD.…”

Section: Discussionmentioning

confidence: 99%

Plasma phosphorylated-tau181 as a predictive biomarker for Alzheimer’s amyloid, tau and FDG PET status

et al. 2021

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Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer’s diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could serve as a marker for Alzheimer’s pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET were included from ADNI. Cross-sectional relationships of plasma p-tau181 with PET biomarkers were tested. Longitudinally, we further investigated whether different p-tau181 levels at baseline predicted different progression of Alzheimer’s pathological changes in the brain. We found plasma p-tau181 significantly correlated with brain amyloid (Spearman ρ = 0.45, P < 0.0001), tau (0.25, P = 0.0003), and FDG PET uptakes (−0.37, P < 0.0001), and increased along the Alzheimer’s continuum. Individually, plasma p-tau181 could detect abnormal amyloid, tau pathologies and hypometabolism in the brain, similar with or even better than clinical indicators. The diagnostic accuracy of plasma p-tau181 elevated significantly when combined with clinical information (AUC = 0.814 for amyloid PET, 0.773 for tau PET, and 0.708 for FDG PET). Relationships of plasma p-tau181 with brain pathologies were partly or entirely mediated by the corresponding CSF biomarkers. Besides, individuals with abnormal plasma p-tau181 level (>18.85 pg/ml) at baseline had a higher risk of pathological progression in brain amyloid (HR: 2.32, 95%CI 1.32–4.08) and FDG PET (3.21, 95%CI 2.06–5.01) status. Plasma p-tau181 may be a sensitive screening test for detecting brain pathologies, and serve as a predictive biomarker for Alzheimer’s pathophysiology.

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“…In addition to neuropathological changes displayed in AD patient brains, clinical changes such as cognitive impairment are well characterized among AD patients. AD patient scores on the Mini-Mental State Exam (MMSE) are associated with both tau burden and NR2B-associated synaptic alterations [ 8 , 9 , 18 , 43 , 52 , 54 , 74 ]. Accordingly, we investigated the relationship between CK2 and cognitive function.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of CK2 mitigates Alzheimer’s tau pathology by preventing NR2B synaptic mislocalization

Marshall

McBride

Changolkar

et al. 2022

acta neuropathol commun

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Alzheimer’s disease (AD) is a neurodegenerative disorder that exhibits pathological changes in both tau and synaptic function. AD patients display increases in hyperphosphorylated tau and synaptic activity. Previous studies have individually identified the role of NR2B subunit-containing NMDA receptors in AD related synaptic dysfunction and aggregated tau without reconciling the conflicting differences and implications of NR2B expression. Inhibition of extrasynaptically located NR2B mitigates tau pathology in AD models, whereas the inhibition of synaptic NR2B replicates tau-associated hyperactivity. This suggests that a simultaneous increase in extrasynaptic NR2B and decrease in synaptic NR2B may be responsible for tau pathology and synaptic dysfunction, respectively. The synaptic location of NR2B is regulated by casein kinase 2 (CK2), which is highly expressed in AD patients. Here, we used patient brains diagnosed with AD, corticobasal degeneration, progressive supranuclear palsy or Pick’s disease to characterize CK2 expression across these diverse tauopathies. Human derived material was also utilized in conjunction with cultured hippocampal neurons in order to investigate AD-induced changes in NR2B location. We further assessed the therapeutic effect of CK2 inhibition on NR2B synaptic distribution and tau pathology. We found that aberrant expression of CK2, and synaptically translocated NR2B, is unique to AD patients compared to other tauopathies. Increased CK2 was also observed in AD-tau treated neurons in addition to the mislocalization of NR2B receptors. Tau burden was alleviated in vitro by correcting synaptic:extrasynaptic NR2B function. Restoring NR2B physiological expression patterns with CK2 inhibition and inhibiting the function of excessive extrasynaptic NR2B with Memantine both mitigated tau accumulation in vitro. However, the combined pharmacological treatment promoted the aggregation of tau. Our data suggests that the synaptic:extrasynaptic balance of NR2B function regulates AD-tau pathogenesis, and that the inhibition of CK2, and concomitant prevention of NR2B mislocalization, may be a useful therapeutic tool for AD patients.

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Longitudinal plasma phosphorylated tau 181 tracks disease progression in Alzheimer’s disease

Cited by 57 publications

References 27 publications

Cerebrospinal Fluid Total Tau Protein Correlates With Longitudinal, Progressing Cognitive Dysfunction in Anti-Neural Autoantibody-Associated Dementia and Alzheimer’s Dementia: A Case–Control Study

Cerebrospinal Fluid Total Tau Protein Correlates With Longitudinal, Progressing Cognitive Dysfunction in Anti-Neural Autoantibody-Associated Dementia and Alzheimer’s Dementia: A Case–Control Study

Plasma phosphorylated-tau181 as a predictive biomarker for Alzheimer’s amyloid, tau and FDG PET status

Inhibition of CK2 mitigates Alzheimer’s tau pathology by preventing NR2B synaptic mislocalization

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