Rationale for DBS in Alzheimer's Disease
It is increasingly recognized that the pathological process in Alzheimer's disease causes focal synaptic dysfunction, the consequences of which produce widespread disturbances in the function of circuits and networks involved in cognition and memory. This notion is supported by the striking regional deficits in brain glucose utilization, impairments of the brain's default mode network, and aberrations in structural and functional brain connectivity characteristic of Alzheimer's disease. These disruptions are implicated in the pathogenesis of cognitive impairment. Thus malfunction in one diseased area interferes secondarily with other areas less affected but whose function is nevertheless disrupted because it is linked in the network. In contrast to recent therapeutic trials, a different approach is proposed: modulating the brain circuit dysfunction to improve function. As DBS has been used to modulate the activity of motor circuits in Parkinson's disease and other disorders it may be possible to use this same approach to modulate activity in dysfunctional cognitive neural circuits in Alzheimer's disease.
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Clinical Results
The effect of DBS was measured using ADAS-cog-13, CDR-SB, and brain glucose metabolism as measured by FDG-PET with SPM analysis method. Increasing evidence exists that neuronal glucose metabolism is a main player in the complex processes involved with memory formation and retrieval. ADAS-cog-13 is used to assess a patient's cognitive status and CDR-SB assesses both cognitive and functional performance. The subgroup of interest in this analysis is ADvance patients aged 65 or older with mild AD. The subgroup includes 30 patients, with 15 in each arm. The ADvance trial was not powered to achieve statistical significance in clinical measures.
On glucose metabolism, patients in the DBSf treatment arm increased in five pre-specified brain regions of interest at 12 months whereas patients in the placebo group declined. Treated patients increased between 20.4% and 22.5% in the five regions, while the placebo group declined by 0.2% to 1.4%. This change was statistically significant at 6 months (p = 0.03), and the metabolism increase observed in the treatment group was maintained at 12 months.
On the ADAS Cog-13, patients in the placebo group worsened by an average of 7.8 at one year, whereas the worsening was 3.7 in the DBSf treatment arm. The trend toward slowing of clinical decline was not statistically significant (p = 0.12).
