Reduction of plasma 24S-hydroxycholesterol (cerebrosterol) levels using high-dosage simvastatin in patients with hypercholesterolemia: evidence that simvastatin affects cholesterol metabolism in the human brain.

Abstract

BACKGROUND:

Previous studies have shown that patients with early onset of Alzheimer disease and vascular dementia have higher levels of circulating brain-derived 24S-hydroxycholesterol (cerebrosterol). Two recent epidemiological studies indicated that treatment with inhibitors of cholesterol synthesis (statins) reduces the incidence of Alzheimer disease.

OBJECTIVE:

To test the hypothesis that treatment with high-dosage simvastatin reduces circulating levels of 24S-hydroxycholesterol.

DESIGN:

Prospective, 24-week treatment trial for lowering of cholesterol levels. We conducted assessments at baseline, week 6, and week 24.

SETTING:

An academic outpatient clinical study.

PATIENTS:

Eighteen patients who met the criteria for hypercholesterolemia.

INTERVENTION:

Treatment with 80 mg/d of simvastatin at night.

MAIN OUTCOME MEASURES:

Plasma lipoprotein levels were measured enzymatically; lathosterol, by means of gas chromatography; and 24S-hydroxycholesterol, by means of gas chromatography-mass spectrometry.

RESULTS:

Simvastatin reduced total plasma cholesterol levels by 36% and 35% after 6 and 24 weeks, respectively (P<.001). Lathosterol levels were reduced by 74% and 72%, respectively, and the ratio of lathosterol to cholesterol, an indicator of whole-body cholesterol synthesis, was reduced by 60% and 61%, respectively (P<.001). Plasma 24S-hydroxycholesterol levels were lowered by 45% and 53%, respectively (P<.001). The ratio of 24S-hydroxycholesterol to cholesterol also decreased significantly (-12% [P=.01] and -23% [P<.002], respectively). The further reduction of 24S-hydroxycholesterol levels and its ratio to cholesterol from weeks 6 to 24 was also significant (P=.02 for both).

CONCLUSIONS:

The greater reduction of plasma concentrations of 24S-hydroxycholesterol compared with cholesterol indicates that simvastatin in a dosage of 80 mg/d reduces cholesterol turnover in the brain. The present results might describe a possible mechanism of how long-term treatment with statins could reduce the incidence of Alzheimer disease.

• Authors: Sandra Locatelli, Dieter Lütjohann, Hartmut H J Schmidt, Carsten Otto, Ulrike Beisiegel, Klaus von Bergmann
• Journal: Archives of neurology (Arch Neurol) Vol. 59 Issue 2 Pg. 213-6 (Feb 2002) ISSN: 0003-9942 [Print] United States
• PMID: 11843691 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticholesteremic Agents
• Hydroxycholesterols
• 24-hydroxycholesterol
• Cholesterol
• Simvastatin

Topics

• Administration, Oral
• Adult
• Aged
• Alzheimer Disease (physiopathology, prevention & control)
• Anticholesteremic Agents (pharmacology)
• Brain (metabolism)
• Cholesterol (metabolism)
• Female
• Humans
• Hydroxycholesterols (blood)
• Hypercholesterolemia (drug therapy, pathology)
• Male
• Middle Aged
• Prospective Studies
• Simvastatin (pharmacology)