Alzheimer Disease Clinical Trial
Official title:
Deep Brain Stimulation for Treatment of Severe Alzheimer's Disease: Study Protocol of a Prospective, Self-control Phase I Trial
To investigate the safety of deep brain stimulation in the treatment of severe Alzheimer's disease (AD); to investigate the effectiveness of deep brain stimulation in the treatment of severe AD, i.e., effects of deep brain stimulation on cognitive function in patients with severe AD and dementia grading; to investigate the effects of deep brain stimulation on cerebral glucose metabolism in patients with severe AD.
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.
Adverse events
1. At 6 months after surgery, radiological examination of the implants will be performed
to determine that the stimulation system is not impaired.
2. Deep brain stimulation parameters: frequency, amplitude and pulse width
3. After deep brain stimulation, follow-up evaluation will be performed once every 6
months. Deep brain stimulation-related complications, such as dyskinesia, dysarthria,
gait disorder, eye apraxia, depression, apathy and hypomania. Corresponding treatment
methods will be administered. All these will be reported to the principal investigator
and Institutional Review Board within 24 hours.
Data management According to the trial design, a table will be formulated for data
collection. Collected data will be input into an electronic database by professional staff
using a double-data entry strategy. Information accuracy will be checked when all recruited
patients are followed up. The database will be locked by the researcher in charge and will
not be altered. All information relating to this trial will be preserved by Department of
Neurosurgery, Chinese PLA General Hospital of China. The electronic database will be fully
disclosed to a professional statistician for statistical analysis.
Statistical analysis All data will be statistically analyzed by a statistician blinded to
randomization using SPSS 18.0 software. The successive normally distributed variables will
be expressed as the mean ± SD. The non-normally distributed variables will be expressed as
median and quartile. Classification variables will be expressed as count and percentage. A
paired t-test or Wilcoxon Matched-Pairs Signed-Rank Test will be used to compare the
continuous variables of the primary and secondary outcome measures at each time point. The
chi-square test or Fisher's exact test will be used to compare the classification variables.
A P level of <0.05 will be accepted as statistically significant.
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