Estrogen and cerebral blood flow: a mechanism to explain the impact of estrogen on the incidence and treatment of Alzheimer's disease.

摘要

OBJECTIVE: Women are three times as likely to develop late-onset Alzheimer's Disease (AD) as are age-matched men. In the perimenopausal period, women typically have profound hypoestrogenism associated with vasomotor episodes. The pattern of AD development in women resembles the hormonal changes that occur in the perimenopausal period; the risk of AD is lower in menopausal women taking estrogen replacement therapy (ERT), and ERT is associated with clinical improvement in AD patients. Further, ERT has been shown to augment the therapeutic benefits of medications designed to treat AD. To understand better the relationship between ERT, hot flushes and AD, a pilot study was conducted at UCLA-Harbor Medical Center. PATIENTS AND METHODS: Twelve healthy menopausal women experiencing daily hot flushes and not on ERT were recruited to participate in a clinical study. Each patient underwent regional cerebral blood flow (CBF) measurement using single-photon emission computed tomography (SPECT) at baseline and during a hot flush episode. Patients were then randomized to receive either 0.625 mg or 1.25 mg conjugated equine estrogens (CEE) daily. During the sixth week of ERT, each patient had a repeat SPECT study. Baseline SPECT data were compared with ERT data. RESULTS: Baseline examinations demonstrated CBF patterns commonly seen in patients with Alzheimer's disease. There was a global improvement in CBF associated with ERT, an average gain of 22% over baseline. Improvements were most dramatic in the temporal and parietal regions of the brain. The cortical CBF demonstrated a mean increase of 9.2 mL/100 g/min (P < .01). CONCLUSIONS: CBF is diminished in hypoestrogenic women, with regional patterns resembling those of patients with mild to moderate AD. Cerebral circulation tends to be further compromised during hot flush episodes. This mechanism could be the initiating event in the metabolic process that results in dementia of the Alzheimer's type, and thus serve as the link between hypoestrogenism and neurodegenerative diseases. In this study, ERT reversed these detrimental blood flow changes back to a normal pattern after only 6 weeks of CEE therapy. With improved blood flow, the brain is protected from the metabolic injury associated with hypoxia. The study is currently being repeated with a larger population.