Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study

Thijssen, Elisabeth H.; Joie, Renaud La; Strom, Amelia; Fonseca, Corrina; Iaccarino, Leonardo; Wolf, Amy; Spina, Salvatore; Allen, Isabel Elaine; Cobigo, Yann; Heuer, Hilary W.; VandeVrede, Lawren; Proctor, Nicholas K.; Lago, Argentina Lario; Baker, Suzanne L.; Sivasankaran, Rajeev; Kieloch, Agnieszka; Kinhikar, Arvind G.; Yu, Lu; Valentin, Marie‐Anne; Jeromin, Andreas; Zetterberg, Henrik; Hansson, Oskar; Mattsson‐Carlgren, Niklas; Graham, Danielle; Blennow, Kaj; Kramer, Joel H.; Grinberg, Lea T.; Seeley, William W.; Rosen, Howard J.; Boeve, Bradley F.; Miller, Bruce L.; Teunissen, Charlotte E.; Rabinovici, Gil D.; Rojas, Julio C.; Dage, Jeffrey L.; Boxer, Adam L.; investigators, Treatment for Frontotemporal Lobar Degeneration

doi:10.1016/s1474-4422(21)00214-3

Cited by 309 publications

(384 citation statements)

References 46 publications

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“…These are obtained through a metabolomic and lipidomic analysis that provides diagnosis with a reliability of more than 90% even three years before the onset of the first symptoms. In this sense, plasma biomarkers such as phosphorylated tau 181, phosphorylated tau 127, P231, Total tau and Nfl have demonstrated their potential in the diagnosis of AD, ptau127 being the marker with the highest diagnostic accuracy [ 80 , 81 , 82 , 83 ]. Likewise, it has been shown that lower levels of serotonin, phenylalanine, lysine, phosphatidylcholine, acylcarnitine and proline are associated with greater progression of AD [ 84 ].…”

Section: Resultsmentioning

confidence: 99%

Current Understanding of the Physiopathology, Diagnosis and Therapeutic Approach to Alzheimer’s Disease

et al. 2021

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Alzheimer’s disease (AD) is the most common cause of dementia. It is characterized by cognitive decline and progressive memory loss. The aim of this review was to update the state of knowledge on the pathophysiological mechanisms, diagnostic methods and therapeutic approach to AD. Currently, the amyloid cascade hypothesis remains the leading theory in the pathophysiology of AD. This hypothesis states that amyloid-β (Aβ) deposition triggers a chemical cascade of events leading to the development of AD dementia. The antemortem diagnosis of AD is still based on clinical parameters. Diagnostic procedures in AD include fluid-based biomarkers such as those present in cerebrospinal fluid and plasma or diagnostic imaging methods. Currently, the therapeutic armory available focuses on symptom control and is based on four pillars: pharmacological treatment where acetylcholinesterase inhibitors stand out; pharmacological treatment under investigation which includes drugs focused on the control of Aβ pathology and tau hyperphosphorylation; treatment focusing on risk factors such as diabetes; or nonpharmacological treatments aimed at preventing development of the disease or treating symptoms through occupational therapy or psychological help. AD remains a largely unknown disease. Further research is needed to identify new biomarkers and therapies that can prevent progression of the pathology.

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Section: Resultsmentioning

confidence: 99%

Current Understanding of the Physiopathology, Diagnosis and Therapeutic Approach to Alzheimer’s Disease

et al. 2021

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“…Converging evidence indicates that Aβ initially accumulates in the medial frontal cortex and medial parietal cortex, which are both elements of the default-mode network (DMN). In contrast, tau is initially deposited in the medial temporal lobe memory system, spreading from the entorhinal cortex to the hippocampus and parahippocampal cortex, and then to other brain regions [ 75 , 76 ]. Insufficient mitochondrial function and bioenergy output of mitochondrial in AD patients may lead to a reduction in cellular energy levels, concomitant leakage of electrons promotes the formation of reactive oxygen species (ROS), which can damage proteins, membrane lipids and nucleic acids.…”

Section: Mitophagy In Chronic Diseases Of the Nervous Systemmentioning

confidence: 99%

Mitophagy in neurological disorders

Zhang

Dai

2021

J Neuroinflammation

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Selective autophagy is an evolutionarily conserved mechanism that removes excess protein aggregates and damaged intracellular components. Most eukaryotic cells, including neurons, rely on proficient mitophagy responses to fine-tune the mitochondrial number and preserve energy metabolism. In some circumstances (such as the presence of pathogenic protein oligopolymers and protein mutations), dysfunctional mitophagy leads to nerve degeneration, with age-dependent intracellular accumulation of protein aggregates and dysfunctional organelles, leading to neurodegenerative disease. However, when pathogenic protein oligopolymers, protein mutations, stress, or injury are present, mitophagy prevents the accumulation of damaged mitochondria. Accordingly, mitophagy mediates neuroprotective effects in some forms of neurodegenerative disease (e.g., Alzheimer's disease, Parkinson’s disease, Huntington's disease, and Amyotrophic lateral sclerosis) and acute brain damage (e.g., stroke, hypoxic–ischemic brain injury, epilepsy, and traumatic brain injury). The complex interplay between mitophagy and neurological disorders suggests that targeting mitophagy might be applicable for the treatment of neurodegenerative diseases and acute brain injury. However, due to the complexity of the mitophagy mechanism, mitophagy can be both harmful and beneficial, and future efforts should focus on maximizing its benefits. Here, we discuss the impact of mitophagy on neurological disorders, emphasizing the contrast between the positive and negative effects of mitophagy.

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“…The CSF levels of Aβ 42 , τ T and τ P-181 were measured in duplicate by commercially available ELISA kits (Innotest β-amyloid 1-42, hTau antigen and phospho-tau 181; Fujirebio, Gent, Belgium) according to the manufacturer's instructions. We chose to measure τ P-181 , as in neurodegenerative disorder research and clinical practice, tau phosphorylated at threonine 181 (τ P-181 ) is the most commonly measured form of phosphorylated tau as a biomarker in the CSF [24] and, recently, in plasma [25]. Additionally, to better evaluate the τ P-181 levels, the ratio of τ P-181 to τ T (τ P-181 /τ T ) was calculated [26].…”

Section: Measurements Of Csf and Plasma Biomarkersmentioning

confidence: 99%

Genotyping and Plasma/Cerebrospinal Fluid Profiling of a Cohort of Frontotemporal Dementia–Amyotrophic Lateral Sclerosis Patients

et al. 2021

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Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of the same pathophysiological spectrum and have common genetic and cerebrospinal fluid (CSF) biomarkers. Our aim here was to identify causative gene variants in a cohort of Greek patients with FTD, ALS and FTD-ALS, to measure levels of CSF biomarkers and to investigate genotype-phenotype/CSF biomarker associations. In this cohort of 130 patients (56 FTD, 58 ALS and 16 FTD-ALS), we performed C9orf72 hexanucleotide repeat expansion analysis, whole exome sequencing and measurement of “classical” (Aβ42, total tau and phospho-tau) and novel (TDP-43) CSF biomarkers and plasma progranulin. Through these analyses, we identified 14 patients with C9orf72 repeat expansion and 11 patients with causative variants in other genes (three in TARDBP, three in GRN, three in VCP, one in FUS, one in SOD1). In ALS patients, we found that levels of phospho-tau were lower in C9orf72 repeat expansion and MAPT c.855C>T (p.Asp285Asp) carriers compared to non-carriers. Additionally, carriers of rare C9orf72 and APP variants had lower levels of total tau and Aβ42, respectively. Plasma progranulin levels were decreased in patients carrying GRN pathogenic variants. This study expands the genotypic and phenotypic spectrum of FTD/ALS and offers insights in possible genotypic/CSF biomarker associations.

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Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study

Cited by 309 publications

References 46 publications

Current Understanding of the Physiopathology, Diagnosis and Therapeutic Approach to Alzheimer’s Disease

Current Understanding of the Physiopathology, Diagnosis and Therapeutic Approach to Alzheimer’s Disease

Mitophagy in neurological disorders

Genotyping and Plasma/Cerebrospinal Fluid Profiling of a Cohort of Frontotemporal Dementia–Amyotrophic Lateral Sclerosis Patients

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