Deep Brain Stimulation for Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is the most common type of dementia and as an age-related disease is increasing in prevalence as life expectancy has raised worldwide. In 2016 there were about 43.8 million individuals affected by dementia. This figure has more than doubled in the last 30 years (Nichols et al., 2019) and it is estimated that by the year 2050, one in every 85 persons will be affected by AD (Brookmeyer, Johnson, Ziegler‐Graham, and Arrighi, 2007). Dementia is tremendously debilitating for affected individuals and places a huge burden on their families and caregivers. Alzheimer's disease has been known for a long time and scientific efforts to understand disease pathophysiology have been massive. Pathological hallmarks of the disease are accumulation of amyloid-β peptide in extracellular space, presence of intracellular tangles of the protein tau, and also neuritic plaques formation (Thakur, Kamboj, Goswami, and Ahuja, 2018). Neuronal cell degeneration in AD is widely distributed in the brain and is seen particularly in the hippocampus, entorhinal cortex, amygdala, deep subcortical nuclei such as the cholinergic basal nuclei, serotonergic dorsal raphe, and noradrenergic locus coeruleus. Moreover, their cortical association regions of the frontal, temporal and parietal cortices are shown to be affected (Kumar and Singh, 2015). The cholinergic hypothesis of AD is among the oldest explanations of disease pathophysiology. The key points of physiological abnormalities in AD are the expression of cholinergic receptors, acetylcholine release, and choline transport. Cholinesterase inhibitors are among the AD treatment front line (Blake, Terry, Plagenhoef, Constantinidis, and Liu, 2017). Even though amyloid-β accumulation is a hallmark of the disease and several therapeutic strategies such as promoting amyloid clearance, preventing amyloid aggregation, amyloid based immunotherapy, and modulation of secretase enzyme were available but none were successful in demonstrating efficacy to cure or reverse the disease in clinical trials (Anand, Gill, and Mahdi, 2014). The network disturbance hypothesis is also an important debate in the understanding of AD pathophysiology. Fornix as a part of the Papez circuit is shown to have disease-related atrophy and neuronal micro structural impairments, and myelin break down (Mielke et al., 2012). Positron emission tomography (PET) imaging illustrates reduced glucose metabolism in various cortical areas in AD, including the medial temporal and parietal lobe (Jakobs, Lee, and Lozano, 2019). AD neurodegeneration also propagates frontal neural networks and involves the entorhinal cortex to limbic structures, comprising of ventral striatum and nucleus accumbens (Sachdev, Zhuang, Braidy, and Wen, 2013). Current clinical management of Alzheimer's disease solely comprises of four cholinesterase inhibitors and memantine as the US food and Drug Administration has approved (Anand et al., 2014). Several neurosurgical approaches including Stereotactic implantation of stem cells, vagal nerve stimulation ventriculoperitoneal shunt for amyloid clearance and transposition of omentum to treat hypoperfusion; but no clinical benefits were indicated (Jakobs et al., 2019). Deep Brain Stimulation (DBS) is a neuromodulation technique to stimulate neuronal circuits locally and also distantly through neuronal cell projections; thus the approach is very effective in diseases with circuit involvement. Parkinson’s disease, Obsessivecompulsive disorder, Tourette syndrome, and major depression are the most prominent diseases that have established clinical benefit from DBS (Hardenacke, Shubina, et al., 2013).