BRAIN_CSF biomarker profile in cognitively normal subjects.pdf (original) (raw)
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Biological Psychiatry, 2004
Background: Cerebrospinal fluid (CSF) measures of -amyloid 1-42 and tau are linked with the known neuropathology of Alzheimer's disease (AD). Numerous lines of evidence have also suggested that individuals with at least one APOE ε4 allele on chromosome 19 are at increased risk of developing AD. We tested these CSF markers in groups of subjects with AD and healthy older control subjects, using the absence or presence of the APOE ε4 allele as a predictive variable in the search for possible prognostic biomarkers of AD. Methods: We assessed the levels of -amyloid 1-42 and total tau in the CSF of 292 subjects (142 control subjects and 150 subjects with mild-to-moderate AD), who were research participants at the National Institute of Mental Health. The group of control subjects was enriched with a high percentage of subjects with a positive family history of AD. All subjects underwent extensive global cognitive testing. Results: When divided according to the absence or presence of the APOE ε4 allele, the control subjects with at least one ε4 allele had significantly lower CSF -amyloid 1-42 but not tau levels than control subjects without an APOE ε4 allele (p Ͻ .01). As expected, the AD patients had lower levels of CSF -amyloid 1-42 and higher CSF tau levels than the normal control group (p Ͻ .01). Conclusions: The association of APOE ε4 allele and lower, more AD-like levels of CSF -amyloid 1-42 in older control subjects is consistent with previous studies showing possible neuroimaging and cognitive abnormalities with ε4 carriers and suggests that CSF -amyloid 1-42 decreases might represent an early biomarker of AD. Longitudinal follow-up is of course required to verify whether this biomarker is indeed predictive of clinical conversion to AD.
Stability of CSF β-Amyloid1–42 and Tau Levels by APOE Genotype in Alzheimer Patients
Dementia and Geriatric Cognitive Disorders, 2006
Background: Cerebrospinal fluid (CSF) measures of β-amyloid1–42 and tau differ between patients with Alzheimer’s Disease (AD) and elderly normal controls. The effect of time and APOE genotype on these biomarkers continues to be elucidated. Methods: We assessed CSF β-amyloid1–42 and tau in 20 mild-to-moderate AD patients, 11 APOE Ε4+ and 9 APOE Ε4–, over a mean time of 3.8 years (range 1–11.1 years). Results: Over the period measured, CSF β-amyloid1–42 levels were lower in APOE Ε4+ compared to APOE Ε4– patients, and the levels decreased over time. Tau levels were stable over time and did not show an effect of APOE allele. Conclusions: While this is a limited clinical sample, the further decrease in CSF β-amyloid1–42 (i.e., more abnormal) combined with the CSF tau stability over a mean period of almost 4 years suggests that β-amyloid1–42 and tau maintain their potential usefulness as diagnostic biomarkers over time. These findings should be taken into account if CSF β-amyloid1–42 and ...
Neurobiology of Aging, 2006
We prospectively evaluated the diagnostic accuracy of cerebrospinal fluid (CSF)--amyloid 1-42 (A 42 ), -total-tau (tau) and -phosphorylatedtau 181 (p-tau 181 ) as measured by sandwich ELISAs in the clinical routine of a community state hospital to discriminate between patients with Alzheimer's disease (AD), healthy controls (HC), non-AD-dementias, a group composed of various psychiatric disorders (non-AD-dementias, mental diseases) and an age-matched random sample (RS) (total N = 219).
Alzheimer's & Dementia, 2012
In Alzheimer's disease (AD), the cerebral pathological changes begin many years before the clinical manifestation of the disease. Biomarkers for AD, such as the cerebrospinal fluid (CSF) concentrations of amyloid-,81-42 (A,Bl-42) and tau phosphorylated at threonine 181 (pTau181), may reflect these cerebral changes relatively early. Accordingly, cognitively healthy subjects at risk for AD often have altered CSF concentrations of A,Bl-42 and pTau181. In this study, we assessed the effects and interaction of two strong risk factors for AD, aging and the presence of the APOEc4 allele, on the CSF A,Bl-42 and pTau181 concentrations in 280 adults with normal cognition across the lifespan. For comparison, we further included 152 patients with probable AD. We found significant effects of age on the CSF A,Bl-42 and pTau181, and of the APOEc4 genotype on the A,Bl-42 levels in the cognitively normal participants. Carrying the APOEc4 allele was associated with a significant decrease of the A,Bl-42 concentrations in middle-aged and older participants. In the group of participants with AD, the A,Bl-42 levels were significantly lower in the APOEc4 carriers compared to the non-carriers. These findings demonstrate significant age effects on the CSF A,B 1 _ 42 and pTau181 across lifespan. They also suggest that the decrease of A,Bl-42, but not the increase ofpTaul81 CSF levels is accelerated by the APOEc4 genotype in middle-aged and older adults with normal cognition. of cerebrospinal fluid (CSF) A.B 1 -4 2 and pTau concentrations can already be detected in asymptomatic older subjects at risk for AD [1 ,2], and predict cognitive decline in cognitively healthy older adults and in subjects with mild cognitive impairment . The presence of the apolipoprotein c4 (APOEc4) allele is a well-established genetic risk factor for AD. Carrying the APOEc4 allele may accelerate the pathophysiological process [7) and lower the age of clinical onset of the disease . Some postmortem studies [I 0,11 ], but not all , have found associations of the APOEc4 genotype with higher levels of amyloid plaque deposition and neurofibrillary pathology. Studies on the associations of CSF biomarker levels with
Journal of Alzheimer's disease : JAD, 2010
In Alzheimer's disease (AD), the cerebral pathological changes begin many years before the clinical manifestation of the disease. Biomarkers for AD, such as the cerebrospinal fluid (CSF) concentrations of amyloid-β1-42 (Aβ1-42) and tau phosphorylated at threonine 181 (pTau181), may reflect these cerebral changes relatively early. Accordingly, cognitively healthy subjects at risk for AD often have altered CSF concentrations of Aβ1-42 and pTau181. In this study, we assessed the effects and interaction of two strong risk factors for AD, aging and the presence of the APOEε4 allele, on the CSF Aβ1-42 and pTau181 concentrations in 280 adults with normal cognition across the lifespan. For comparison, we further included 152 patients with probable AD. We found significant effects of age on the CSF Aβ1-42 and pTau181, and of the APOEε4 genotype on the Aβ1-42 levels in the cognitively normal participants. Carrying the APOEε4 allele was associated with a significant decrease of the Aβ1-42 ...
Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects
Brain : a journal of neurology, 2015
In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal ...
Journal of Neurology, Neurosurgery & Psychiatry, 1998
Biochemical markers for Alzheimer's disease would be of great value, especially to help in diagnosis early in the course of the disease. A pronounced increase in CSF tau protein (CSF-tau) is found in most patients with Alzheimer's disease. However, the specificity has to be further studied, as an increase in CSF-tau has also been found in other dementias, especially in vascular dementia. As most previous CSF studies have been based on selected inpatients, it was considered of special interest to examine the diagnostic potential of CSF-tau in a community population based sample of consecutive patients with dementia. Such patient material has been examined at the Piteå River Valley Hospital in Northern Sweden since 1986, and includes all those with memory disturbances in the community. The aim was also to study if an increase in CSF-tau is found early in the disease process, and whether CSF-tau changes during the progression of disease. Community population based sample of 75 demented patients (43 with Alzheimer's disease, 21 with vascular dementia, and 11 with mixed Alzheimer's disease/vascular dementia), 18 healthy subjects, and 18 neurological controls. A follow up investigation (including analysis of a new CSF sample) was performed in all patients after about one year. Concentrations of total (both normal tau and PHF-tau) tau in CSF, clinical measures (duration and severity of dementia), and apoE polymorphism. CSF-tau was markedly increased in Alzheimer's disease, 41/43 (95%) patients had values above the cut off level (mean+2 SD) in controls (306 pg/ml). High CSF-tau concentrations were also found in most patients with vascular dementia, preferentially in patients with vascular dementia without progressive leukoaraiosis on CT, whereas patients with vascular dementia with progressive leukoaraiosis had normal CSF-tau. Concentrations of CSF-tau were stable at one year follow up in both patients with Alzheimer's disease and patients with vascular dementia, and there was no correlation between CSF-tau and either duration or severity of dementia. The findings confirm the high sensitivity of CSF-tau for the diagnosis of Alzheimer's disease, but high CSF-tau was also found in vascular dementia, resulting in a lower specificity. However, high CSF-tau is preferentially found in patients with vascular dementia without progressive leukoaraiosis, which may constitute a group with concomitant Alzheimer's disease pathology. High CSF-tau may be present during the whole course of the disease in Alzheimer's disease. Possibly, therefore, the same high CSF-tau concentrations may be present before the onset of clinical dementia. Follow up studies on such patients will tell whether analysis of CSF-tau is useful as a biochemical marker for early Alzheimer's disease.
Neurobiology of Aging, 2009
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 (Aβ42/Aβ40 ratio), and isoprostane (IP) with age and ApoE genotype. The results showed that age by ε4 genotype interactions were found for P-tau231 (β = 1.82; p < 0.05) and IP (β = 1.6; p < 0.05). T-tau CSF concentration increased with age. The increasing CSF concentrations of P-tau and IP in ε4 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 Aβ changes. The evidence that P-tau231 and IP are the earliest markers for the neuronal damage related to AD awaits longitudinal study.
Cerebrospinal fluid tau and amyloid-β1-42 in patients with dementia
Brain : a journal of neurology, 2015
Progressive cognitive decline in combination with a cerebrospinal fluid biomarker pattern of low levels of amyloid-β1-42 and high levels of total tau and phosphorylated tau is typical of Alzheimer's disease. However, several neurodegenerative disorders may overlap with Alzheimer's disease both in regards to clinical symptoms and neuropathology. In a uniquely large cohort of dementia patients, we examined the associations of cerebrospinal fluid biomarkers for Alzheimer's disease molecular pathology with clinical dementia diagnoses and disease severity. We cross-referenced the Swedish Dementia Registry with the clinical laboratory database at the Sahlgrenska University Hospital. The final data set consisted of 5676 unique subjects with a clinical dementia diagnosis and a complete set of measurements for cerebrospinal fluid amyloid-β1-42, total tau and phosphorylated tau. In cluster analysis, disregarding clinical diagnosis, the optimal natural separation of this data set w...