Deep Brain Stimulation for Treatment of Severe Alzheimer's Disease: Study Protocol of a Prospective, Self-control Phase I Trial

This study is a prospective, self-control, phase I trial, which will be performed in Department of Neurosurgery, Chinese PLA General Hospital (Beijing, China). Six patients with severe Alzheimer's disease will be included in this study and receive continuous bilateral deep brain stimulation of the fornix.

BACKGROUND With the prolongation of life expectancy of the world population, Alzheimer's disease (AD) has become one of the major diseases that influence the quality of life in the aging population. The latest data have shown that there are approximately 24 million AD victims and the number increases in fold every 20 years. With global population aging, there is an increasing number of population who are at the risk of AD. Epidemiological studies in China have shown that the incidence of AD increases with aging and it is about 5% in people aged over 65 years and about 20% in people aged over 85 years. AD has been reported to greatly affect patient's quality of life. However, there is currently no effective method to hinder, postpone or treat AD. Cholinesterase inhibitors (Donepezil, Galantamine and Rivastigmine) and N-methyl-D-asparate receptor antagonist Memantine are the commonly used drugs. But the curative effects are not identified. Therefore, there is an urgent need to investigate a novel treatment method of AD.

Deep brain stimulation is hopeful in the treatment of AD. There is clinical evidence that deep brain stimulation can effectively postpone, hinder and even reverse the progression of AD. The clinical data also shows that selective atrophy of cholinergic neurons of the nucleus basalis of Meynert (NBM) is one of characteristics of AD. In 1985, Turnbull et al., were the first to report the role of deep brain stimulation of the NBM in AD patients. They detected cortical glucose metabolic activity using FDG-PRT and found that the cortical glucose metabolic activity in the frontal lobe, temporal lobe, parietal lobe, and occipital lobe of the right hemisphere (not stimulated) of AD patients was decreased by 21%, 24%, 10%, and 7.5%, respectively. By contrast, cortical glucose metabolic activity in the left hemisphere was decreased by 12%, 4%, 0 and -1.5% respectively. Although there were no improvements in clinical symptoms, study findings suggest that deep brain stimulation of the NBM is safe and leads to strong pathophysiologic response. Laxton et al. performed deep brain stimulation of the hypothalamus and fornix in six patients with mild AD. At 6 and 12 months after deep brain stimulation, Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) evaluations showed that patient's cognitive was improved. In the same case cohort, Smith et al. investigated cerebral glucose metabolism and found that deep brain metabolism increased cerebral glucose metabolism mainly through two orthogonal networks: a frontal-temporal-parietal-striatal- thalamic network and a frontal-temporal-parietal-occipital-hippocampal network. Fontaine et al. performed deep brain stimulation in one AD patients presenting with mild cognitive disorder. Twelve months after deep brain stimulation, cerebral glucose metabolism was slightly increased in the cerebrum, in particular in bilateral middle temporal gyri; in addition, cognitive function was improved as confirmed by MMSE and ADAS-Cog evaluations.

Deep brain stimulation for treatment of AD is internationally in its infancy. Only exploratory studies involving a few cases have been reported. Similar reports are not reported in China. Global doctors eager to understand the exact effects and possible complications and risks of deep brain stimulation in the treatment of AD. AD patients are also looking forward to the effectiveness of this therapy in reducing their sufferings.

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