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Osteoarthritis and Rheumatoid Arthritis: Will New Data Clarify the Risk:Benefit Ratio of Cyclooxygenase‐2 Inhibitors?

To the Editor: Alzheimer’s disease (AD) most commonly begins with insidious memory failure and later progresses to more-generalized cognitive deficits and dementia, but memory complaints also are quite common even in normal elderly people. Therefore, it is of particular importance to establish an accurate and objective laboratory test to distinguish normal elderly people from subjects with mild cognitive impairment (MCI) who are likely to develop AD so that clinicians can make decisions on instituting therapies. Fifty consecutive individuals complaining of memory dysfunction were evaluated by the Japanese version of the Wechsler Memory ScaleFRevised (WMS-R). As described previously, the WMS-R has been validated for clinical use in the Japanese language. Subjects were functioning fairly well in the community and were neither psychoactive drug users nor excessive alcohol drinkers. Depression also was excluded by using the Geriatric Depression Scale. Thyroid function tests and vitamin B12 and folic acid levels were all within normal range. Serological test for syphilis was negative in all subjects. Global cognitive function was assessed using the MiniMental State Examination (MMSE). Because delayed episodic memory was found to be most severely impaired in MCI, scores of logical memory II, visual reproduction II, verbal paired associates II, and visual paired associates II in the WMS-R subscales were summed and expressed as ‘‘delayed recall score’’ after adjustment for age. The diagnosis of amnestic MCI was made based essentially on the following published criteria: complaint of defective memory function by patient or informant, normal activities of daily living, normal general cognitive function, abnormal memory function in the WMS-R as revealed by delayed recall score of 1.5 standard deviations (SDs) or more below age-matched control subjects, and absence of dementia. All values were expressed as mean 7SD. As a result, 28 individuals (mean age571.175.5) fulfilled the criteria, and the other 22 subjects (mean age568.578.5) were judged as having no cognitive impairment (NCI). Education did not differ significantly between the MCI (mean511.77 2.0 years) and the NCI (mean5 10.671.7 years) groups. The MMSE scores were 26.171.5 in the MCI group and 28.072.0 in the NCI group (P5.003). Cerebrospinal fluid (CSF) tau protein (CSF-tau) and CSF amyloid-b1–42 peptide (CSF-Ab1–42) were quantitated as described previously. Regional cerebral blood flow in the posterior cingulate cortex (rCBFpc) was measured on (I)iodoamphetamine– single positron emission computed tomography (IMPSPECT) images according to previously described methods. Figure 1 shows receiver operating characteristic curves with an area under the curve (AUC) of 0.93 for the CSF-tau, AUC of 0.72 for the rCBFpc, and AUC of 0.72 for the CSFAb1–42 (Po.05). The CSF-tau levels were significantly higher in the amnestic MCI group than in the NCI group (524.77238.6 vs 201.5789.6 pg/mL, Po.0001). The rCBFpc was significantly lower in the amnestic MCI group than in the NCI group (0.9170.12 vs 1.0070.08, P5.005), but there was no significant difference in CSFAb1–42 levels between the two comparison groups. For the distinction between amnestic MCI and NCI, the cutoff level of 341.0 pg/mL of the CSF-tau yielded a sensitivity of 83.3% and a specificity of 95.0%. To our knowledge, no study has ever described a relationship between delayed memory function and biomarkers such as CSF-tau and IMP-SPECT images in the same patient population of amnestic MCI. Despite a moderately invasive technique, CSF-tau appears to be the most appropriate indicator to support a differential diagnosis between MCI and normal elderly people. This study also demonstrates that amnestic MCI is not merely an age-associated condition, but appears to be a more pathological state that is associated with abundant neuron death, as revealed by elevated CSF-tau levels. In previous studies, it was demonstrated that CSF-tau alone or in combination with IMP-SPECT was highly predictive of developing AD in MCI subjects. Taking these results into consideration, we argue for clinical trials for early and