In this longitudinal study we investigated change over time in cerebrospinal fluid (CSF) levels of amyloid-beta 40 and 42 (Aβ40 and Aβ42), total tau (tau), tau phosphorylated at threonine 181 (ptau-181), isoprostane, neurofilaments heavy (NfH) and light (NfL). Twenty-four nondemented subjects, 62 mild cognitive impairment (MCI) and 68 Alzheimer's disease (AD) patients underwent 2 lumbar punctures, with minimum interval of 6, and a mean ± SD of 24 ± 13 months. Linear mixed models were used to assess change over time. Amyloid-beta 42, tau, and tau phosphorylated at threonine 181, differentiated between diagnosis groups (p < 0.05), whereas isoprostane, neurofilaments heavy, and NfL did not. In contrast, effects of follow-up time were only found for nonspecific CSF biomarkers: levels of NfL decreased, and levels of isoprostane, amyloid-beta 40, and tau increased over time (p < 0.05). Isoprostane showed the largest increase. In addition, increase in isoprostane was associated with progression of mild cognitive impairment to AD, and with cognitive decline as reflected by change in Mini Mental State Examination (MMSE). Contrary to AD-specific markers, nonspecific CSF biomarkers, most notably isoprostane, showed change over time. These markers could potentially be used to monitor disease progression in AD.
Major efforts are under way to investigate therapeutic strategies that have the potential to slow progression of Alzheimer's disease (AD). To evaluate the effect of these interventions, biological markers are needed that reflect progression of AD pathology.
The major pathological hallmarks of AD are senile plaques, containing beta-amyloid and neurofibrillary tangles with microtubule-associated tau protein (McKhann et al., 1984). Cerebrospinal fluid (CSF) biomarkers amyloid-beta 1–42 (Aβ42), total tau (tau), and tau phosphorylated at threonine 181 (ptau-181) reflect the neuropathology of AD and are useful as diagnostic markers for AD (Blennow and Hampel, 2003). Several studies evaluated whether these markers could also be used as markers to monitor disease progression, but until now these biomarkers showed little effect in longitudinal settings (Blennow et al., 2007, Bouwman et al., 2007, Buchhave et al., 2009, Li et al., 2007, Mollenhauer et al., 2005 and Zhou et al., 2009).
The specific biomarkers, amyloid-beta 42 (Aβ42), total tau (tau) and ptau-181, seem less suitable as biomarkers for monitoring of disease progression. Amyloid plaque deposition and tau tangle formation are early processes in AD, that may show little or no change later on (Jack et al., 2010). Other, more general and thus less specific disease processes are increasingly considered to play a major role in advanced stages of the disease (Jack et al., 2010). Oxidative stress damage is a process of neurotoxicity due to free radical-mediated damage to cellular membranes, which probably also occurs in advanced stages of AD (Quinn et al., 2004). Isoprostane, an oxidative stress marker, therefore, could be a useful marker to monitor AD. In fact, a few small studies have shown increase over time in isoprostane (de Leon et al., 2007, Montine et al., 2005 and Quinn et al., 2004). Neurofilaments are released from damaged neurons. CSF levels of neurofilaments have been shown to reflect the degree of neuronal degeneration and axonal loss in several neurological diseases (de Jong et al., 2007 and Petzold, 2005). Few cross-sectional studies have shown increased levels of neurofilaments in AD (Norgren et al., 2003 and Pijnenburg et al., 2007), and possibly changes in the levels of neurofilaments also reflect progression of the disease. Furthermore, we hypothesized that CSF amyloid-beta n-40 (Aβ40) could be a biomarker for disease progression, because Aβ40 has been associated with solid, less diffuse, types of amyloid plaques, that generally develop in later stages of AD (Iwatsubo et al., 1994 and Kumar-Singh, 2008).
We aimed to assess longitudinal effects of CSF biomarkers, in order to identify biomarkers that are useful to monitor disease progression. Our panel of 7 CSF biomarkers included Aβ42, tau and ptau-181, and several less specific CSF biomarkers, isoprostane, neurofilaments heavy (NfH), neurofilaments light (NfL), and Aβ40. We evaluated changes in CSF biomarker levels over time, and associations of change in CSF biomarker levels with change in Mini Mental State Examination (MMSE), in a large cohort of AD and mild cognitive impairment (MCI) patients and nondemented subjects.
