Phosphorylated tau 231, memory decline and medial temporal atrophy in normal elders

Glodzik, Lidia; Santi, Susan De; Tsui, Wai; Mosconi, Lisa; Zinkowski, Raymond; Pirraglia, Elizabeth; Wang, Hui‐Yu; Li, Yang; Rich, Kenneth; Zetterberg, Henrik; Blennow, Kaj; Mehta, Pankaj; Leon, Mony J. de

doi:10.1016/j.neurobiolaging.2009.12.026

Cited by 47 publications

(36 citation statements)

References 38 publications

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“…The evidence for the benefit of CSF biomarkers in AD research is highly compelling as many studies have shown the utility of the AD signature (low Aβ 42 together with high T-tau and P-tau) for AD diagnosis and have demonstrated its use as a predictor of disease progression [56,59,60,62,103,111,112]. Indeed, the high sensitivity/specificity of the AD signature could lead to its development as the “gold standard” in early/prodromal AD diagnostics.…”

Section: Discussionmentioning

confidence: 99%

Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer's disease

Blennow

Dubois

Fagan³

et al. 2014

Alzheimer's & Dementia

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Several potential disease-modifying drugs for Alzheimer’s disease (AD) have failed to show any effect on disease progression in clinical trials, conceivably because the AD subjects are already too advanced to derive clinical benefit from treatment and because diagnosis based on clinical criteria alone introduces a high misdiagnosis rate. Thus, well-validated biomarkers for early detection and accurate diagnosis are crucial. Low cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ1-42) peptide, in combination with high total tau and phosphorylated tau, are sensitive and specific biomarkers highly predictive of progression to AD dementia in patients with mild cognitive impairment. However, interlaboratory variations in the results seen with currently available immunoassays are of concern. Recent worldwide standardization efforts and quality control programs include standard operating procedures for both preanalytical (e.g., lumbar puncture and sample handling) and analytical (e.g., preparation of calibration curve) procedures. Efforts are also ongoing to develop highly reproducible assays on fully automated instruments. These global standardization and harmonization measures will provide the basis for the generalized international application of CSF bio-markers for both clinical trials and routine clinical diagnosis of AD.

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Section: Discussionmentioning

confidence: 99%

Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer's disease

Blennow

Dubois

Fagan³

et al. 2014

Alzheimer's & Dementia

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385

304

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“…However, limited data are available on combined CSF and imaging biomarkers in cognitively normal populations, and these offer inconsistent results. While some studies have found that decreased CSF Aβ42 is associated with cognitive decline among normal older adults [27–30], others could not confirm these observations [31, 32]. Prior work by Palmqvist and colleagues.…”

Section: Discussionmentioning

confidence: 99%

Alzheimer’s Disease Biomarkers and Future Decline in Cognitive Normal Older Adults

Dumurgier

Hanseeuw

Hatling

et al. 2017

JAD

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Background Identifying older adults at risk of cognitive decline represents a challenge as Alzheimer’s disease (AD) modifying therapies move towards preclinical stages. Objective To investigate the relationship between AD biomarkers and subsequent change in cognition in a cohort of cognitively intact older adults. Methods 84 cognitively normal subjects (mean age 72.0 years, 59% women) were recruited through the Massachusetts Alzheimer’s Disease Research Center and the Harvard Aging Brain Study and followed over 3 years. Measurements of beta-amyloid 1-42 (Ab42), total Tau (t-Tau) and Tau phosphorylated at threonine 181 (p-Tau181) in the CSF at study entry were available in all cases. Baseline brain MRI, FDG-PET and PiB-PET data were available in the majority of participants. Relationship between baseline AD biomarkers and longitudinal change in cognition was assessed using Cox proportional hazard regression and linear mixed models. Results 14% participants increased their global Clinical Dementia Rating (CDR) score from 0 to 0.5 during follow-up. A CDR score increase was associated with higher baseline CSF t-Tau and p-Tau181, higher global cortical PiB retention and lower hippocampal volume. The combination of high CSF t-Tau and low Aβ42 or low hippocampal volume was more strongly related to cognitive outcome than each single biomarker. Higher CSF t-Tau was the only biomarker associated with subsequent decline in MMSE score. Conclusions Baseline CSF t-Tau and p-Tau181, in vivo amyloid load and hippocampal volume were all independently associated with future decline in cognition. The discriminatory ability of these biomarkers to predict risk of cognitive decline, however, was only modest.

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“…Interestingly, Pittsburgh Compound B (PiB) retention was found in thalami and striatum both by us (Mosconi et al ., 2010) and others (Klunk et al ., 2008; Koivunen et al ., 2008; Scholl et al ., 2009) in subjects at risk or with AD. Even though these amyloid deposits are not believed to be related to cell loss (Klunk et al ., 2008) and the relationships between amyloid burden and atrophy are less consistent than relationships between neurofibrally pathology and atrophy (Josephs et al ., 2008; Fagan et al ., 2009; Driscoll et al ., 2010; Glodzik et al ., 2010), a recent report demonstrated an association between PiB retention and gray matter atrophy on a region by region basis (Chetelat et al ., 2010). Since CSF Aβ42 correlates with PiB retention in subjects without dementia (Fagan et al ., 2006), we speculate that the observed correlations between CSF Aβ42/Aβ40 and GM may reflect a subtle regional atrophy.…”

Section: Discussionmentioning

confidence: 99%

“…This, we speculate, corroborates the utility of tau to Aβ42 ratio concept. As in our previous work we used Aβ42/Aβ40 ratio instead of Aβ42 alone (Brys et al ., 2008; Glodzik et al ., 2010). In our experience ratio better reflects possible AD, since the concentration of Aβ42 is determined not only by ongoing pathology but also by the total CSF Aβ peptide concentration which is individually different (Wiltfang et al ., 2007).…”

Section: Discussionmentioning

confidence: 99%

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Alzheimer's disease markers, hypertension, and gray matter damage in normal elderly

Glodzik¹,

Mosconi²,

Tsui³

et al. 2012

Neurobiology of Aging

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It is not well known whether Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers are associated with brain damage in cognitively normal elderly. The combined influence of CSF biomarkers and hypertension (HTN) on the gray matter (GM) is also not well described. 115 cognitively healthy subjects (mean age 62.6±9.5, 62% women) received clinical assessment, a high resolution MRI and a lumbar puncture. The CSF levels of total tau (t-tau), hyperphosphorylated tau (p-tau231), amyloid beta (Aβ42/Aβ40), p-tau231/Aβ42 and t-tau/Aβ42 were dichotomized as ‘high’ and ‘low’ based on accepted cut-off values. Statistical parametric mapping was used to examine MRI scans for regional GM density, studied as a function of the CSF markers, HTN and combination of both. Global and medial temporal lobe (MTL) GM was also assessed. Voxel based morphometry revealed that higher t-tau was associated with lower GM density in the precunei. Subjects with higher p-tau231 and p-tau231/Aβ42 had less GM in temporal lobes. Low Aβ42/Aβ40 was related to less GM in the thalami, caudate and midbrain. Subjects with hypertension showed more GM atrophy in the cerebellum, occipital and frontal regions. Simultaneous presence of elevated CSF AD biomarkers and HTN was associated with more GM atrophy than either marker individually, but no interaction effects were identified. In conclusion, in normal elderly CSF tau markers were associated predominantly with lower GM estimates in structures typically affected early in the AD process. In this presymptomatic stage when no cognitive impairment is present, AD pathology and HTN have additive effects on gray matter damage.

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Phosphorylated tau 231, memory decline and medial temporal atrophy in normal elders

Cited by 47 publications

References 38 publications

Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer's disease

Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer's disease

Alzheimer’s Disease Biomarkers and Future Decline in Cognitive Normal Older Adults

Alzheimer's disease markers, hypertension, and gray matter damage in normal elderly

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