| Research Abstract |
WE have three major purposes in the development of reliable biological markers in Alzheimer's discase (AD). First, it is necessary to identify specific biological markers that distinguish AD from non-AD dementing desorders of the elderly so that more accurate assays can be developed for the reliable diagnosis of AD.Second, we need biological markers that enable us to detect AD as early as possible so that AD patients obtain maximum benefit from therapy. Finally, the biological markers can be used to monitor the response of patients to potential neuroprotective drugs. Therefore, there is a compelling need to develop biological markers for AD that have adequate sensitivity and specificity to confirm the antemortem diagnosis of AD and identify appropriate patients as early as possible for emerging therapcutic interventions.
In 1993, Vandermeeien et al.reported the presence of micro-tubule-associated-protein tau in cerebrospinal fluid (CSF) of AD and non-AD subjects (13). This provocative s
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tudy prompted other research groups to examine the CSF-tau levels in AD for its potential diagnostic use. To date, a series of studies from several independent groups have reached the same conclusion that CSF-tau levels are significantly increased in subjects with AD compared with patients with other neurological discases and controls (5.7-9.14). We have extended our initial study (5) by quantitating CSF-tau levels using an ELISA from 97 AD patients (mean age : 74), 12 patients with Parkinson's discase (PD,mean age : 67), 12 patients with motor neuron discase (MND,mean age : 66), 10 patients with non-acute cerebrovascular discase (CDV,mean age : 67), 27 patients with other miscellaneous neurological discases (OTHERS,mean age : 55), and 15 normal control subjects without evidence of any neuropsychiatric discase (NORMAL,mean age : 56). The OTHERS group included subjects with the following clinical diagnoses : meningoencephalitis (n=5), epilepsy (n=4), multiple selerosis (n=3), normal pressure hydrocephalus (n=2), Bell's palsy (n=2), Gerstmann-Strauser-Scheinker discase (n=2), Creutzfeldt-Jacob discase (n=1), cerebellitis (n=1), polymyositis (n=1), chronic inflammatory demyclinating polyradiculoneuropathy (n=1), dementia due to vitamin B<@D212@>D2 deficiency (n=1), transverse myelitis (n=1), and systemic lupus erythematosus encephalitis (n=1). After obtaining informed consent, CSF was taken by routine lumbar puncture and centrifuged at 1500 rpm for 10 min., aliquoted, and stored at-80ﾟC until analysis. CSF-tau levels were quantitated by a commercial sandwich ELISA (Innogenetics, Belgium). The CSF-tau levels are significantly increased in AD (95.6(]SY.+-。[)105.3pg/mL) compared with those in PD (19.0(]SY.+-。[)9.0), MND (26.1(]SY.+-。[)21.1), CDV (26.0(]SY.+-。[)40.2), OTHERS(31.5(]SY.+-。[)31.1), and NORMAL(32.(]SY.+-。[)7(]SY.+-。[)43.2). Notably, it is important to point out that an increased CSF-tau level found in AD patients inespective of age at onset, racial background, ApoE,alpha<@D21@>D2-antichy-motrypsin, and presenilin-1 polymorphism, and clinical severity of dementia. Receiver Operating Characteristics analysis indicated that the CSF-tau determination had a diagnostic specificity of 75% and sensitivity of 93.8%. Furthermore, when the CSF-tau was taken in combination with CSF-Abeta, the diagnostic specificity and sensitivity have been improved to 86.8% and 94.8%, respectively (6). However, it should be noted that the elevated CSF-tau levels were also detected not only in certain acute neurological conditions (5,10), i.e., meningo-encephalitis, hypoxic brain injury, vitamin B<@D212@>D2 deficiency, AIDS and Creutzfeld-Jacob disease, but also in some chronic neurodegenerative diseases including diffuse Lewy body disease and frontotemporal dementia (1). This might suggest that it would
We reported an elevated CFS-tau level in two patients with very mild memory impairment who subsequently progressed to meet the diagnostic criteria for AD on follow-up, suggesting much higher clinical utility of CSF-tau for the early detection of the disease (11). Indeed, we showed that CSF-tau might be used as a predictor of dementia in patients with CDR0.5 (3). Recently, Galasko et al.have reported a similar observation (6). A future direction related to this issue is whether CSF-tau increases before the onset of AD symptoms. Results from two separate CSF samples obtained from the same AD patient during 2-year follow-up showed that CSF-tau levels continued to be abnormal as the disease progressed (2). In the future, multiple CSF samplings from the same patient obtained at periodic intervals spanning all stages of AD may yield powerful new strategics for monitoring the progression of AD and its response to novel therapeutic agents (12). Less
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