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- Buerger, Katharina, et al.
(författare)
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CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease.
- 2006
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 129:Pt 11, s. 3035-41
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Tidskriftsartikel (refereegranskat)abstract
- Hyperphosphorylated tau protein (P-tau) in CSF is a core biomarker candidate of Alzheimer's disease. Hyperphosphorylation of tau is thought to lead to neurofibrillary changes, a neuropathological hallmark of this type of dementia. Currently, the question is unresolved whether CSF levels of P-tau reflect neurofibrillary changes within the brain of a patient with the illness. Twenty-six patients were included with intra-vitam CSF as well as post-mortem neuropathological data. In the CSF, P-tau phosphorylated at threonine 231 (P-tau231P) was analysed. Post-mortem, scores of neurofibrillary tangles (NFT) and neuritic plaques (NP) were assessed in frontal, temporal, parietal and hippocampal cortical areas. In the same cortical regions, load of hyperphosphorylated tau protein (HP-tau load) was determined. Concentrations of P-tau231P were measured in frontal cortex homogenates. We found significant correlations between CSF P-tau231P concentrations and scores of NFTs and HP-tau load in all neocortical regions studied. The score of NPs was correlated with CSF P-tau231P only within the frontal cortex. There was a correlation between P-tau231P in CSF and brain homogenates. These findings indicate that CSF P-tau231P may serve as an in vivo surrogate biomarker of neurofibrillary pathology in Alzheimer's disease.
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| 5. |
- Glodzik, Lidia, et al.
(författare)
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Alzheimer's disease markers, hypertension, and gray matter damage in normal elderly.
- 2012
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 33:7, s. 1215-1227
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Tidskriftsartikel (refereegranskat)abstract
- 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. One hundred fifteen cognitively healthy subjects (mean age 62.6 ± 9.5%, 62% women) received clinical assessment, a high resolution magnetic resonance imaging (MRI), and a lumbar puncture. The CSF levels of total tau (t-tau), hyperphosphorylated tau (p-tau(231)), amyloid beta (Aβ42/Aβ40), p-tau(231)/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-tau(231) and p-tau(231)/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 biomarkers and HTN have additive effects on gray matter damage.
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| 6. |
- Glodzik, Lidia, et al.
(författare)
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Phosphorylated tau 231, memory decline and medial temporal atrophy in normal elders.
- 2011
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 32:12, s. 2131-41
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Tidskriftsartikel (refereegranskat)abstract
- Little is known whether cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) can predict both memory decline and associated longitudinal medial temporal lobe (MTL) gray matter (GM) reductions in cognitively healthy individuals. Fifty-seven normal elderly subjects received comprehensive evaluation at baseline and 2 years later. The baseline phosphorylated tau(231) (p-tau(231)), total tau, the amyloid beta (Aβ) Aβ42/Aβ40, t-tau/Aβ42 and p-tau(231)/Aβ42 ratios were examined as predictors of memory change and reductions in the global and MTL GM, determined from T1-weighted MRI. Twenty out of 57 participants experienced reduced memory performance at follow-up. The group with decreased memory performance showed higher baseline p-tau(231) (Z=-2.2, p=0.03), lower Aβ42/Aβ40 (t=-2.2 [55], p=0.04) and greater longitudinal MTL GM reductions (t([52])=-2.70, p=0.01). Higher baseline p-tau(231) was also associated with the absolute decrease in memory scores (rho=-0.30, p=0.02) and with longitudinal MTL GM reduction (F([2,52])=4.4, p=0.04, age corrected). Our results indicate that in normal individuals, elevated p-tau(231), a marker of neurofibrillary pathology is related to both a decrease in declarative memory and progressive atrophy of the MTL, suggesting its diagnostic potential in preclinical stage.
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| 7. |
- Glodzik-Sobanska, Lidia, et al.
(författare)
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The effects of normal aging and ApoE genotype on the levels of CSF biomarkers for Alzheimer's disease.
- 2009
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 30:5, s. 672-81
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Tidskriftsartikel (refereegranskat)abstract
- While cerebrospinal fluid (CSF) biomarkers are of use in the prediction and diagnosis of Alzheimer's disease our understanding of the background effects of age and the ApoE genotype is limited. Seventy-eight community-based normal volunteers (mean age 60+/-10 years, range 36-86) were examined to determine the relationships between CSF measures of total tau (T-tau), hyperphosphorylated tau (P-tau 231), amyloid beta (Abeta42/Abeta40 ratio), and isoprostane (IP) with age and ApoE genotype. The results showed that age by epsilon4 genotype interactions were found for P-tau231 (beta=1.82; p<0.05) and IP (beta=1.6; p<0.05). T-tau CSF concentration increased with age. The increasing CSF concentrations of P-tau and IP in epsilon4 carriers suggest that early tauopathy and oxidative stress may be related to the increased risk for AD. The data also suggest that T-tau changes are more age dependent than Abeta changes. The evidence that P-tau231 and IP are the earliest markers for the neuronal damage related to AD awaits longitudinal study.
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| 8. |
- Hampel, Harald, et al.
(författare)
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Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study.
- 2004
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Ingår i: Archives of general psychiatry. - : American Medical Association (AMA). - 0003-990X. ; 61:1, s. 95-102
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Abnormal hyperphosphorylation of the microtubule-associated protein tau and its incorporation into neurofibrillary tangles are major hallmarks of the pathogenesis of Alzheimer disease (AD). Different tau phosphoepitopes can be sensitively detected in cerebrospinal fluid (CSF). OBJECTIVE: To compare the diagnostic accuracy of CSF concentrations of tau proteins phosphorylated at 3 pathophysiologically important epitopes (p-tau) to discriminate among patients with AD, nondemented control subjects, and patients with other dementias. DESIGN AND SETTING: Cross-sectional, bicenter, memory clinic-based studies. PARTICIPANTS: One hundred sixty-one patients with a clinical diagnosis of AD, frontotemporal dementia, dementia with Lewy bodies, or vascular dementia and 45 nondemented controls (N = 206). MAIN OUTCOME MEASURES: Levels of tau protein phosphorylated at threonine 231 (p-tau231), threonine 181 (p-tau181), and serine 199 (p-tau199). The CSF p-tau protein levels were measured using 3 different enzyme-linked immunosorbent assays. RESULTS: The mean CSF levels of the studied p-tau proteins were significantly elevated in patients with AD compared with the other groups. Applied as single markers, p-tau231and p-tau181 reached specificity levels greater than 75% between AD and the combined non-AD group when sensitivity was set at 85% or greater. Statistical differences between the assay performances are presented. Particularly, discrimination between AD and dementia with Lewy bodies was maximized using p-tau181at a sensitivity of 94% and a specificity of 64%, and p-tau231 maximized group separation between AD and frontotemporal dementia with a sensitivity of 88% and a specificity of 92%. Combinations of the 3 markers did not add discriminative power compared with the application as single markers. CONCLUSIONS: The p-tau proteins in CSF come closest to fulfilling the criteria of a biological marker of AD. There is a tendency for p-tau proteins to perform differently in the discrimination of primary dementia disorders from AD.
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| 9. |
- Mosconi, Lisa, et al.
(författare)
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Oxidative Stress and Amyloid-Beta Pathology in Normal Individuals with A Maternal History of Alzheimer's.
- 2010
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Ingår i: Biological psychiatry. - : Elsevier BV. - 1873-2402 .- 0006-3223. ; 68:10, s. 913-921
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:: Epidemiology and imaging studies showed that cognitively normal (NL) individuals with a maternal history (MH) of late-onset Alzheimer's disease (LOAD) might be at increased risk for Alzheimer's disease (AD) compared with NL with a paternal history (PH) and NL with a negative family history of LOAD (NH). With a panel of cerebrospinal fluid (CSF) markers, this study examined whether NL MH showed evidence for AD pathology compared with PH and NH. METHODS:: Fifty-nine 40-80-year-old NL subjects were examined, including 23 MH and 14 PH whose parents had a clinician-certified diagnosis of LOAD and 22 NH. All subjects completed clinical neuropsychological examinations and a lumbar puncture to measure CSF levels of amyloid-beta (Abeta(40), Abeta(42), Abeta(42/40)), total and hyperphosphorylated tau (T-Tau and P-Tau(231); markers of axonal degeneration and neurofibrillary tangles, respectively), and F(2)-isoprostanes (IsoP) (a marker of oxidative stress). RESULTS:: Groups were comparable for demographic and neuropsychological measures. The MH subjects showed higher IsoP and reduced Abeta(42/40) CSF levels compared with NH and with PH (p values
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| 10. |
- Spiegel, Jonathan, et al.
(författare)
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Greater Specificity for Cerebrospinal Fluid P-tau231 over P-tau181 in the Differentiation of Healthy Controls from Alzheimer's Disease.
- 2016
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 49:1, s. 93-100
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) measures of phosphorylated-tau (P-tau) 231 and P-tau181 are two biomarkers for the identification of tau pathology as related to Alzheimer's disease (AD). While both are pathologically validated, their relative diagnostic performances are not well known. This cross-sectional diagnostic study of 87 normal (NL) subjects and 28 AD subjects compared CSF P-tau231 with CSF P-tau181. Logistic regression modeling demonstrated that the P-tau231 was superior to the P-tau181 in the diagnostic classifications. At a fixed 85% sensitivity cutoff, the ROC analysis shows that P-tau231 has greater overall specificity than P-tau181. While both P-tau analytes demonstrated equivalent negative predictive accuracies, P-tau231 yielded significantly fewer false positives. Moreover, P-tau231, but not P-tau181, demonstrated sensitivity to the E4 genotype. A postmortem validation with 9 AD subjects confirmed the superiority of the CSF P-tau231 specificity. This study suggests that P-tau231 has the potential to improve the CSF tau biomarker diagnosis of AD.
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