Longitudinal Changes of CSF Biomarkers in Alzheimer's Disease
Authors: Seppälä, Toni T. | Koivisto, Anne M. | Hartikainen, Päivi | Helisalmi, Seppo | Soininen, Hilkka | Herukka, Sanna-Kaisa
Article Type: Research Article
Abstract: Longitudinal changes of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have been studied, but there are few consistent conclusions and even less is known about their variation during the different stages of the disease. We hypothesized that changes in CSF biomarker values would correlate with the progression of the cognitive decline in AD. One hundred and thirty-one memory clinic patients [56 AD, 57 mild cognitive impairment (MCI), 10 other neurological disorders, eight unimpaired subjects] underwent a clinical follow-up with repeated Mini-Mental Status Examination (MMSE) tests and two lumbar punctures with a median interval of 3 years. Levels of CSF …amyloid-β (Aβ)42 , tau, and p-tau-181 were measured using commercially available ELISA. Twenty-one of the MCI subjects progressed to AD, whereas 26 subjects remained stable and 56 subjects had AD already at the baseline. The subjects displaying the most rapid MMSE decline rate had the lowest baseline Aβ42 , highest tau, and highest p-tau-181 CSF concentrations. An annual decrease of 2.20 pg/ml/year in the CSF p-tau-181 concentration was seen in AD-AD patients (p = 0.001). The difference was significant compared to stable MCI-MCI (increase of 1.24 pg/ml/year, p = 0.001) and cognitively healthy (increase of 0.84 pg/ml/year, p = 0.013) subjects (p for group difference 0.004). The decrease rate of p-tau-181 correlated with the MMSE decrease rate in AD subjects (r = 0.579, p < 0.001). The CSF Aβ42 level decreased in the AD-AD group (decrease 11.9 pg/ml/year, p < 0.001). Concentrations of hyperphosphorylated tau decline in the late stages of the AD process. The decrease of p-tau-181 appears to correlate with cognitive functioning and probably reflects neuronal loss. More longitudinal studies of CSF biomarker dynamics are needed, especially in patients during the preclinical stage of the disease. Show more
Keywords: Alzheimer's disease, amyloid, biomarker, cerebrospinal fluid, CSF, longitudinal, mild cognitive impairment, tau
DOI: 10.3233/JAD-2011-101911
Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 583-594, 2011
Amyloid-β and Tau Dynamics in Human Brain Interstitial Fluid in Patients with Suspected Normal Pressure Hydrocephalus
Authors: Herukka, Sanna-Kaisa | Rummukainen, Jaana | Ihalainen, Jouni | von und zu Fraunberg, Mikael | Koivisto, Anne M. | Nerg, Ossi | Puli, Lakshman K. | Seppälä, Toni T. | Zetterberg, Henrik | Pyykkö, Okko T. | Helisalmi, Seppo | Tanila, Heikki | Alafuzoff, Irina | Hiltunen, Mikko | Rinne, Jaakko | Soininen, Hilkka | Jääskeläinen, Juha E. | Leinonen, Ville
Article Type: Research Article
Abstract: Background: Amyloid-β (Aβ1 - 42 ), total tau (T-tau), and phosphorylated tau (P-tau181 ) in the cerebrospinal fluid (CSF) are the most promising biomarkers of Alzheimer’s disease (AD). Still, little is known about the dynamics of these molecules in the living brain. In a transgenic mouse brain, soluble Aβ decreases with increasing age and advanced Aβ pathology as seen similarly in CSF. Objective: To assess the relationship between AD-related pathological changes in human brain tissue, ventricular and lumbar CSF, and brain interstitial fluid (ISF). Methods: Altogether 11 patients with suspected idiopathic normal pressure hydrocephalus underwent frontal cortical brain biopsy, 24-h intraventricular pressure …monitoring, and a microdialysis procedure. AD-related biomarkers were analyzed from brain tissue, CSF, and ISF. Results: ISF T-tau levels decreased strongly within the first 12 h, then plateauing until the end of the experiment. Aβ1 - 42 and P-tau181 remained stable during the experiment (n = 3). T-tau and P-tau were higher in the ISF than in ventricular or lumbar CSF, while Aβ1 - 42 levels were within similar range in both CSF and ISF samples. ISF P-tau correlated with the ventricular CSF T-tau (r = 0.70, p = 0.017) and P-tau181 (r = 0.64, p = 0.034). Five patients with amyloid pathology in the brain biopsy tended to reveal lower ISF Aβ1 - 42 levels than those six without amyloid pathology. Conclusions: This is the first study to report ISF Aβ and tau levels in the human brain without significant brain injury. The set-up used enables sampling from the brain ISF for at least 24 h without causing adverse effects due to the microdialysis procedure to follow the dynamics of the key molecules in AD pathogenesis in the living brain at various stages of the disease. Show more
Keywords: Alzheimer’s disease, amyloid-β, biomarkers, normal pressure hydrocephalus, tau
DOI: 10.3233/JAD-142862
Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 261-269, 2015