CSF markers in Alzheimer disease patients are not related to the different degree of cognitive impairment Alessandro Stefani a,b, ⁎ , Alessandro Martorana a,b , Sergio Bernardini d , Marta Panella b , Flavio Mercati c , Antonio Orlacchio a,b , Mariangela Pierantozzi b a IRCCS-Fondazione S. Lucia, Roma, Italy b Clinica Neurologica, Università di Roma Tor Vergata, Roma, Italy c Dipartimento di Fisica, Università di Roma la Sapienza, Italy d Dipartimento di Medicina di Laboratorio, Policlinico di Tor Vergata, Università di Roma Tor Vergata, Roma, Italy Received 2 May 2006; received in revised form 18 September 2006; accepted 19 September 2006 Available online 9 November 2006 Abstract Standard markers in cerebrospinal fluid (CSF), as soluble amyloid beta 1–42 (Aβ1–42) and total tau protein (t-tau), may contribute to dementia subtypes diagnostic accuracy. Yet, their sensitivity to assess the different degree of cognitive deficit is not fully clarified. Our study analyses Aβ1–42 and t-tau CSF levels in different cohorts of Alzheimer's disease (AD) patients, distinguished as early AD (mild cognitively impaired subjects recently converted to AD), mild AD (MMSE b 23; ≥ 18), and moderately advanced AD (MMSE b 18). The control group was represented by age-matched patients affected by depressive pseudo-dementia. Reduced Aβ1–42 and increased t-tau CSF levels were confirmed as hallmarks of AD at any disease stage. In early AD patients, Aβ1–42 levels were already significantly low, if compared to the control group (336 vs 867 ng/L; p b 0.0001). On the contrary, Aβ1–42 levels did not differ between AD subgroups, and in particular between mild to moderate AD. A significant progressive increase of t-tau concentration was found when comparing early AD (269 ng/L) to more advanced AD stages (468 ng/L and 495 ng/L for mild and moderate AD, respectively). Our findings confirm that the impairment of amyloidogenic cascade is an early, even pre-clinical process, but suggest that soluble Aβ1– 42 concentration has a negligible correlation with the clinical progression. Conversely, t-tau concentration correlates with the transition towards marked cognitive impairment. © 2006 Elsevier B.V. All rights reserved. Keywords: Alzheimer's disease; Beta-amyloid; Tau protein; Stage markers; Pseudo-dementia; MMSE 1. Introduction Alzheimer's disease (AD) is the most common form of dementia in the elderly, affecting N 20% of individuals over 80 years of age. Newly designed trials are under evaluation and promise to ameliorate the on-going symptomatic treatment with acetylcholine-esterase inhibitors [1]. The implementation of these new therapies on AD patients would require, however, an unequivocal diagnosis in the early phases of the disease and, more importantly, the availability of reliable biomarkers capable of monitoring progression and degree of cognitive impairment as well as potential efficacy of any therapy regimen. In other words, it would be important to identify biomarkers of various stages in the disease and not simply biomarkers of the disease, in order to validate therapies as the cognitive impairment worsens. So far, diagnostic criteria of AD, as established, for instance, by the NINCDS-ARDRA group [2], have a clinical diagnostic accuracy of 80–90% and benefit from neuro- radiological and neuro-physiological evidence [3]. In addition, several groups already use biochemical titres in the cerebro- spinal fluid (CSF): an elevated tau/Aβ1–42 ratio together with a peculiarly low soluble Aβ1–42 level and a specific increase of phosphorylated tau iso-forms characterizes AD vs non-AD Journal of the Neurological Sciences 251 (2006) 124 – 128 www.elsevier.com/locate/jns ⁎ Corresponding author. Dipartimento Neuroscienze, Università di Roma Tor Vergata, Via Montpellier 1, 00133 Rome Italy. Fax: +39620903118. E-mail address: stefani@uniroma2.it (A. Stefani). 0022-510X/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2006.09.014