Transthyretin as a potential CSF biomarker for Alzheimer’s disease and dementia with Lewy bodies: effects of treatment with cholinesterase inhibitors

Schultz, Kristofer; Nilsson, Karin; Nielsen, Jonas Ellegaard; Lindquist, Suzanne G.; Hjermind, Lena E.; Andersen, Birgitte; Wallin, Anders; Nilsson, Carol L.; Petersén, Åsa

doi:10.1111/j.1468-1331.2009.02841.x

Cited by 23 publications

(15 citation statements)

References 31 publications

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“…It is thought that TTR has a “neuroprotective” role in AD, via the prevention of formation of A β fibrils. Despite TTR proteins having a strong linkage with DLB-type pathology, the study by Schultz et al [72] did not find any correlation between CSF concentrations of TTR and clinical presentation of DLB.…”

Section: Methodsmentioning

confidence: 95%

Cerebrospinal Fluid Biomarkers for Dementia with Lewy Bodies

Mukaetova‐Ladinska

Monteith

Perry

2010

International Journal of Alzheimer's Disease

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More than 750,000 of the UK population suffer from some form of cognitive impairment and dementia. Of these, 5–20% will have Dementia with Lewy Bodies (DLB). Clinico-pathological studies have shown that it is the low frequency of DLB clinical core features that makes the DLB diagnosis hardly recognisable during life, and easily misdiagnosed for other forms of dementia. This has an impact on the treatment and long-term care of the affected subjects. Having a biochemical test, based on quantification of a specific DLB biomarker within Cerebrospinal Fluid (CSF) could be an effective diagnostic method to improve the differential diagnosis. Although some of the investigated DLB CSF biomarkers are well within the clinical criteria for sensitivity and specificity (>90%), they all seem to be confounded by the contradictory data for each of the major groups of biomarkers (α-synuclein, tau and amyloid proteins). However, a combination of CSF measures appear to emerge, that may well be able to differentiate DLB from other dementias: α-synuclein reduction in early DLB, a correlation between CSF α-synuclein and Aβ42 measures (characteristic for DLB only), and t-tau and p-tau181 profile (differentiating AD from DLB).

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Section: Methodsmentioning

confidence: 95%

Cerebrospinal Fluid Biomarkers for Dementia with Lewy Bodies

Mukaetova‐Ladinska

Monteith

Perry

2010

International Journal of Alzheimer's Disease

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“…The sequestering agent TTR has been found to be the major A␤-binding protein in the CSF (Schwarzman et al, 1994;Carro et al, 2002) and represents a potential biomarker for AD (Schultz et al, 2010). The interaction of A␤ with TTR strongly depends on the quaternary structure of TTR (Du and Murphy, 2010).…”

Section: Discussionmentioning

confidence: 99%

Neurotoxicity and Memory Deficits Induced by Soluble Low-Molecular-Weight Amyloid- 1-42 Oligomers Are Revealed In Vivo by Using a Novel Animal Model

Brouillette¹,

Caillierez²,

Zommer³

et al. 2012

Journal of Neuroscience

164

141

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Neuronal and synaptic degeneration are the best pathological correlates for memory decline in Alzheimer's disease (AD). Although the accumulation of soluble low-molecular-weight amyloid-␤ (A␤) oligomers has been suggested to trigger neurodegeneration in AD, animal models overexpressing or infused with A␤ lack neuronal loss at the onset of memory deficits. Using a novel in vivo approach, we found that repeated hippocampal injections of small soluble A␤ 1-42 oligomers in awake, freely moving mice were able to induce marked neuronal loss, tau hyperphosphorylation, and deficits in hippocampus-dependent memory. The neurotoxicity of small A␤ 1-42 species was observed in vivo as well as in vitro in association with increased caspase-3 activity and reduced levels of the NMDA receptor subunit NR2B. We found that the sequestering agent transthyretin is able to bind the toxic A␤ 1-42 species and attenuated the loss of neurons and memory deficits. Our novel mouse model provides evidence that small, soluble A␤ 1-42 oligomers are able to induce extensive neuronal loss in vivo and initiate a cascade of events that mimic the key neuropathological hallmarks of AD.

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“…However, results in the literature are conflicting on TTR concentrations and quantitative proportions of the cysteine oxidations [6-12]. Thus, some studies indicate that TTR concentrations in CSF are altered in AD [13,14] and decrease during AD progression [15-17]. In contrast, CSF-TTR is reported to increase during normal aging [18].…”

Section: Introductionmentioning

confidence: 99%

Distinct transthyretin oxidation isoform profile in spinal fluid from patients with Alzheimer’s disease and mild cognitive impairment

et al. 2014

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BackgroundTransthyretin (TTR), an abundant protein in cerebrospinal fluid (CSF), contains a free, oxidation-prone cysteine residue that gives rise to TTR isoforms. These isoforms may reflect conditions in vivo. Since increased oxidative stress has been linked to neurodegenerative disorders such as Alzheimer’s disease (AD) it is of interest to characterize CSF-TTR isoform distribution in AD patients and controls. Here, TTR isoforms are profiled directly from CSF by an optimized immunoaffinity-mass spectrometry method in 76 samples from patients with AD (n = 37), mild cognitive impairment (MCI, n = 17)), and normal pressure hydrocephalus (NPH, n = 15), as well as healthy controls (HC, n = 7). Fractions of three specific oxidative modifications (S-cysteinylation, S-cysteinylglycinylation, and S-glutathionylation) were quantitated relative to the total TTR protein. Results were correlated with diagnostic information and with levels of CSF AD biomarkers tau, phosphorylated tau, and amyloid β1-42 peptide.ResultsPreliminary data highlighted the high risk of artifactual TTR modification due to ex vivo oxidation and thus the samples for this study were all collected using strict and uniform guidelines. The results show that TTR is significantly more modified on Cys(10) in the AD and MCI groups than in controls (NPH and HC) (p ≤ 0.0012). Furthermore, the NPH group, while having normal TTR isoform distribution, had significantly decreased amyloid β peptide but normal tau values. No obvious correlations between levels of routine CSF biomarkers for AD and the degree of TTR modification were found.ConclusionsAD and MCI patients display a significantly higher fraction of oxidatively modified TTR in CSF than the control groups of NPH patients and HC. Quantitation of CSF-TTR isoforms thus may provide diagnostic information in patients with dementia symptoms but this should be explored in larger studies including prospective studies of MCI patients. The development of methods for simple, robust, and reproducible inhibition of in vitro oxidation during CSF sampling and sample handling is highly warranted. In addition to the diagnostic information the possibility of using TTR as a CSF oxymeter is of potential value in studies monitoring disease activity and developing new drugs for neurodegenerative diseases.

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Transthyretin as a potential CSF biomarker for Alzheimer’s disease and dementia with Lewy bodies: effects of treatment with cholinesterase inhibitors

Abstract: Significant reductions in CSF TTR were found after cholinesterase inhibitor treatment in patients with AD compared to untreated individuals. CSF TTR was unaltered in patients with DLB and had no relationship to depression in the present cohort with dementias.

Cited by 23 publications

References 31 publications

Cerebrospinal Fluid Biomarkers for Dementia with Lewy Bodies

Cerebrospinal Fluid Biomarkers for Dementia with Lewy Bodies

Neurotoxicity and Memory Deficits Induced by Soluble Low-Molecular-Weight Amyloid- 1-42 Oligomers Are Revealed In Vivo by Using a Novel Animal Model

Distinct transthyretin oxidation isoform profile in spinal fluid from patients with Alzheimer’s disease and mild cognitive impairment

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