Longitudinal cerebrospinal fluid tau load increases in mild cognitive impairment

Leon, Mony J. de; Segal, S.; Tarshish, Chaim; DeSanti, Susan; Zinkowski, Raymond; Mehta, Pankaj; Convit, Antonio; Caraos, Conrad; Rusinek, Henry; Tsui, Wai; Louis, L.A. Saint; DeBernardis, John F.; Kerkman, Daniel J.; Qadri, Firdausi; Gary, Anthony T.; Lesbre, P; Wısnıewskı, Thomas; Poirier, John T.; Davies, Peter

doi:10.1016/s0304-3940(02)01038-8

Cited by 65 publications

(42 citation statements)

References 18 publications

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“…Most of these issues remain unexplored. Recently, we published evidence in support of the hypothesis that tau was diluted in the CSF [12]. While this factor was not examined in the present study, a more recent study showed that correction for ventricular enlargement associated with AD can improve the performance of a longitudinally collected IsoP [15].…”

Section: Discussionmentioning

confidence: 62%

“…However, unlike IsoP which demonstrates elevated rates of change, neither Total tau nor P-tau, nor Aβ42 analytes show meaningful evidence for longitudinal change [12].…”

Section: Discussionmentioning

confidence: 80%

“…We simply offer that the failed progression effects for the biomarkers relates to complex and confounding variables, such as, brain analyte production across stages of disease, analyte dilution in the CSF [12], clearance kinetics, and environmental factors. Most of these issues remain unexplored.…”

Section: Discussionmentioning

confidence: 99%

“…■ Key words Alzheimer's disease · CSF biomarkers · longitudinal · isoprostane dinal changes related to disease progression [10][11][12]. This limits the use of these biomarkers in monitoring the course of AD and possibly for evaluating therapeutic interventions.…”

Section: Introductionmentioning

confidence: 99%

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Longitudinal CSF isoprostane and MRI atrophy in the progression to AD

Leon

Mosconi

et al. 2007

J Neurol

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Very little data exist to evaluate the value of longitudinal CSF biological markers for Alzheimer's disease (AD). Most studies indicate that tau and amyloid beta markers do not reflect disease progression. We now report on a longitudinal, three-time point, CSF Isoprostane (IsoP) and quantitative MRI study that examined 11 normal elderly (NL) volunteers and 6 Mild Cognitive Impairment (MCI) patients. After 4 years, all 6 MCI patients declined to AD and 2 of the NL subjects declined to MCI. At baseline and longitudinally, the MCI patients showed reduced delayed memory, increased IsoP levels, and reduced medial temporal lobe gray matter concentrations as compared to NL. A group comprised of all decliners to AD or to MCI (n = 8) was distinguished at baseline from the stable NL controls (n = 9) by IsoP with 100% accuracy.Moreover, both at baseline and longitudinally, the IsoP measures significantly improved the diagnostic and predictive outcomes of conventional memory testing and quantitative MRI measurements. These data indicate that IsoP is potentially useful for both the early detection of AD-related pathology and for monitoring the course of AD.

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Section: Discussionmentioning

confidence: 62%

“…However, unlike IsoP which demonstrates elevated rates of change, neither Total tau nor P-tau, nor Aβ42 analytes show meaningful evidence for longitudinal change [12].…”

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Longitudinal CSF isoprostane and MRI atrophy in the progression to AD

Leon

Mosconi

et al. 2007

J Neurol

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“…Brain volume quantification with MRI has nothing analogous to daily turnover of a soluble protein with inevitable diurnal variation. 39 Lower physiologic variation in brain volume may translate into stronger correlations between MRI and clinical indices of disease progression over many subjects. Another possible explanation is that MRI measures at a fixed point in time reflect cumulative damage while t-tau reflects recent or transient damage; e.g., t-tau levels become elevated immediately after acute brain injury.…”

Section: Results Patient Characteristicsmentioning

confidence: 99%

MRI and CSF biomarkers in normal, MCI, and AD subjects

et al. 2009

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Objective: To investigate the relationship between baseline MRI and CSF biomarkers and subsequent change in continuous measures of cognitive and functional abilities in cognitively normal (CN) subjects and patients with amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD) and to examine the ability of these biomarkers to predict time to conversion from aMCI to AD. Methods:Data from the Alzheimer's Disease Neuroimaging Initiative, which consists of CN, aMCI, and AD cohorts with both CSF and MRI, were used. Baseline CSF (t-tau, A␤ 1-42 , and p-tau 181P ) and MRI scans were obtained in 399 subjects (109 CN, 192 aMCI, 98 AD). Structural Abnormality Index (STAND) scores, which reflect the degree of AD-like features in MRI, were computed for each subject. Results:Change on continuous measures of cognitive and functional performance was modeled as average Clinical Dementia Rating-sum of boxes and Mini-Mental State Examination scores over a 2-year period. STAND was a better predictor of subsequent cognitive/functional change than CSF biomarkers. Single-predictor Cox proportional hazard models for time to conversion from aMCI to AD showed that STAND and log (t-tau/A␤ 1-42 ) were both predictive of future conversion. The age-adjusted hazard ratio for an interquartile change (95% confidence interval) of STAND was 2.6 (1.7, 4.2) and log (t-tau/A␤ 1-42 ) was 2.0 (1.1, 3.4). Both MRI and CSF provided information about future cognitive change even after adjusting for baseline cognitive performance.Conclusions: MRI and CSF provide complimentary predictive information about time to conversion from amnestic mild cognitive impairment to Alzheimer disease and combination of the 2 provides better prediction than either source alone. However, we found that MRI was a slightly better predictor of future clinical/functional decline than the CSF biomarkers tested. Given that degenerative pathologic changes in Alzheimer disease (AD) occur before clinical symptoms, 1 it would be useful to have diagnostic indicators of the underlying biology to complement clinical assessment in evaluating the risk of future clinical decline. Two core biochemical and imaging biomarkers, CSF and structural MRI, reflect different aspects of the pathology of AD. Two promising CSF biomarkers for AD are total tau (t-tau) and A␤ 1-42 . 2-6We have also included analyses of phospho-tau 181P (p-tau 181P ) since it reflects phosphorylated tau and has been postulated to closely mirror neurofibrillary tangle (NFT) formation.

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Correlation of Cerebrospinal Fluid Levels of Tau Protein Phosphorylated at Threonine 231 With Rates of Hippocampal Atrophy in Alzheimer Disease

Hampel

Bürger²,

Pruessner³

et al. 2005

Arch Neurol

157

108

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Background: The microtubule-associated tau protein abnormally phosphorylated at threonine 231 (p-tau 231) has been investigated as a potential marker of Alzheimer disease. Levels of cerebrospinal fluid (CSF) p-tau 231 vary across patients with Alzheimer disease. We hypothesized that these variations partially reflect differences in the degree of neuronal damage and therefore may be used to predict structural disease progression. Objective: To investigate whether CSF p-tau 231 levels correlate with rates of hippocampal atrophy as an in vivo marker of regional neuronal loss. Design and Patients: We measured hippocampal volumes on the basis of serial magnetic resonance image examinations in 22 patients with Alzheimer disease. In addition, we determined CSF p-tau 231 levels at baseline. Results: Levels of CSF p-tau 231 were significantly correlated with baseline hippocampal volumes (PϽ.001) and rates of hippocampal atrophy (left hippocampus, PϽ.001; right hippocampus, P=.02), independent of disease duration and severity. Conclusion: These findings suggest that variations in ptau 231 levels may be used to predict progression of brain atrophy in patients with Alzheimer disease.

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Longitudinal cerebrospinal fluid tau load increases in mild cognitive impairment

Cited by 65 publications

References 18 publications

Longitudinal CSF isoprostane and MRI atrophy in the progression to AD

Longitudinal CSF isoprostane and MRI atrophy in the progression to AD

MRI and CSF biomarkers in normal, MCI, and AD subjects

Correlation of Cerebrospinal Fluid Levels of Tau Protein Phosphorylated at Threonine 231 With Rates of Hippocampal Atrophy in Alzheimer Disease

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