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PATIENTS SHOW SIGNIFICANT DISTURBANCE IN WATER INFLUX INTO CSF SPACE, STRONGLY SUPPORTING BETA-AMYLOID CLEARANCE HYPOTHESIS

      Background

      Recent studies on cerebrospinal fluid (CSF) homeostasis emphasize the importance of water influx through the peri-capillary (Virchow-Robin) space for both CSF production and reabsorption (Oreskovic and Klarica hypothesis). CSF influx through the water channel aquaporin-4 (AQP-4) is likely to play a role as the brain's equivalent of lymphatic drainage, and is believed to be critical for proper b -amyloid clearance. Using mice genetically modified for precursor protein (APP) overproduction (APP overproduction Alzheimer disease model) and [17O]H 2 O JJ vicinal coupling proton exchange (JJVCPE) MRI imaging, we discovered that APP overproduction alone was not sufficient to form senile plaque. An additional condition is necessary: a significant reduction of water influx into the CSF space, the condition which presumably represents a significant disturbance in b -amyloid clearance.

      Methods

      Six young volunteers (young control, 21-24 years old), seven senior volunteers (senior control, 60-78 years old, MMSE ≧ 26), and six Alzheimer's disease (AD) patients (study group, 59-84 years old, MMSE: 13-19) were included in this study. All AD patients were diagnosed by experienced neurologists based on DSM-IV criteria. CSF dynamics were analyzed using positron emission tomography (PET) following an intravenous injection of 1,000 MBq [15O]H2O synthesized on-site.

      Results

      Water influx into CSF space in AD patients expressed as influx ratio (0.761 ± 0.009) was significantly reduced (p < 0.001) compared to young controls (1.329 ± 0.218). Senior controls showed a large range of influx ratio (0.599-1.442) suggesting that reduction in water influx into CSF represents one of the “aging” processes.

      Conclusions

      Reduction in water influx into the CSF and clearance rate of b -amyloid is the necessary, if not sufficient, factor in the pathogenesis of AD. Cohort studies for assessing dynamical indices of the balance between production and clearance of b -amyloid in various patient populations, including mild cognitive impairment (MCI) patients, will be critical for our proper understanding of the pathogenesis of AD.