Concentrations of free 3-methoxy-4-hydroxyphenylglycol in the plasma and cerebrospinal fluid are highly correlated, but concentrations in the cerebrospinal fluid are always higher than those in plasma, even when large amounts of the catecholamine metabolite are derived from a tumor of the adrenal medulla. This is explained by considering the plasma and cerebrospinal fluid as a two-compartment system in which the rate constants for entry into and exit from the cerebrospinal fluid compartment are similar. 3-Methoxy-4-hydroxyphenylglycol that is synthesized, but not catabolized, in the central nervous system maintains cerebrospinal fluid levels at an increment over those in plasma. This increment can be used to provide the best available index of formation of 3-methoxy-4-hydroxyphenylglycol in the central nervous system.

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Introduction ‐ This study evaluates the activity of SDZ ENA 713, a centrally‐selective acetylcholinesterase (AChE) inhibitor, in the cerebral spinal fluid (CSF) of patients with Alzheimer's disease (AD), and its relationship to central and peripheral pharmacokinetic parameters. Methods ‐ Eighteen AD patients were enrolled in this open‐label, multiple‐dose study. Patients were titrated in 1 mg bid/week increments to target doses of 1, 2, 3, 4, 5, or 6 mg bid SDZ ENA 713. After patients had been maintained at their target dose for at least 3 days, continuous CSF samples were obtained via a lumbar catheter for 12.5 h, beginning 0.5 h prior to the final dose of SDZ ENA 713. Results ‐ Dose‐dependent inhibition of CSF AChE was significantly correlated (P<0.05) with plasma drug and metabolite concentrations. The 6 mg bid treatment group showed a maximum mean inhibition of 62% at 5.6 h post‐dose. Conclusion ‐ Rapid, sustained, dose‐dependent inhibition of CSF AChE suggests that SDZ ENA 713 has therapeutic potential in AD patients.

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MHPG is formed from norepinephrine metabolized throughout the body; its levels in plasma reflect total norepinephrine metabolism. Over half of the MHPG, is converted to VMA. Less than 20% of MHPG is derived from brain norepinephrine and urinary excretion of this metabolite cannot be used as a measure of brain norepinephrine metabolism. Because unconjugated MHPG is readily diffusable, there is a free exchange of this metabolite among plasma, cerebrospinal fluid, and nerve tissues (including brain and spinal cord). The CSF MHPG levels, after appropriately correction for the plasma contribution of the metabolite, reflect its rate of formation in the central nervous system.

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SUMMARY Cerebral glucose metabolic rate (CMRGlu), measured by positron emission tomography, was bilaterally and symmetrically reduced in two patients with autosomal dominant Alzheimer's disease. Supramarginal gyri and temporal lobes were most severely affected. An isolated reduction of CMRGlu in the left supramarginal gyrus was observed in one asymptomatic at-risk subject.

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