Steven D Targum
Alzheimer’s disease affects over five million people in the USA. Currently available drug treatments can only temporarily slow the progression of symptoms, and most recent clinical drug trials have been disappointing.
In 2012, Functional Neuromodulation initiated a clinical trial employing the novel strategy of utilising deep brain stimulation to enhance the activity of neuronal circuitry and improve memory function in early Alzheimer’s disease. The Advance study is a 12-month, double-blind, randomised, and controlled feasibility study to evaluate the safety, efficacy and tolerability of DBS-f in patients with mild Alzheimer’s.
Deep brain stimulation involves implanting indwelling electrodes within specific brain circuits to modulate neuronal activity to either suppress pathological activity or drive underactive output based upon the specific clinical needs of the disorder. Deep brain stimulation can modulate the neuronal activity of an entire interconnected brain network because the deep brain stimulation current acts locally at the site of application and remotely via anatomically connected areas.
Deep brain stimulation is currently approved by the US Food and Drug Administration (FDA) to treat Parkinson’s disease, essential tremor and dystonia. It has also been used to treat epilepsy, treatment resistant depression, bipolar disorder, anorexia nervosa, obsessive-compulsive disorder, Tourette’s syndrome, addiction and pain. It is now available in most major medical centres and more than 100,000 patients have been treated to date with over 8,000 new patients implanted each year.
The neurosurgical procedure necessary for deep brain stimulation electrode implantation is well established. The electrodes are connected to a pulse generator implanted in the chest and programmed to deliver continuous stimulation. The level of stimulation can be adjusted to modulate the activity of neuronal circuits up or down, based upon specific needs, in order to optimise the desired clinical outcome and minimise unwanted side effects. Alzheimer’s disease is a logical focus for deep brain stimulation treatment because its proposed mechanism of action of stimulating neuronal network activity may relate to the underlying etiology of Alzheimer’s disease. The pathological processes leading to Alzheimer’s disease include the accumulation of beta amyloid protein, the deposition of amyloid plaque and the disruption of neural network activity, a loss of synaptic function, and eventual neuronal death.
Neuroimaging has identified the topography of dysfunctional brain areas and has shown volumetric structural changes, particularly in the entorhinal cortex and hippocampus that predate the obvious cognitive symptoms seen in Alzheimer’s disease. In fact, the hippocampus is one of the first areas affected in Alzheimer’s disease. The fornix is a large axonal bundle that operates as a major inflow and output pathway from the hippocampus and medial temporal lobe. From animal studies, it is known that experimental lesions of the fornix can produce memory deficits. Therefore, the fornix is an important stimulation target for Alzheimer’s disease.
It is possible that DBS-f may modulate cortical circuits in mild Alzheimer’s disease and sustain cognitive function.
The DBS-f treatment for early Alzheimer’s disease is supported from results of a small, open-label trial conducted in Toronto by Andres Lozano et al. Six Alzheimer’s disease patients received DBS-f implants and were treated for 12 months. Follow-up positron emission tomography (PET) scan studies over the next year showed increased cortical glucose utilisation (posterior cingulate cortex and the precuneus) that were correlated with improved cognitive measures in some of these patients.
Furthermore, electromagnetic tomography (sLORETA) revealed that deep brain stimulation drove neural activity in the “memory circuit” including the entorhinal and hippocampal areas, and activated other areas including the anterior, temporal, and parietal cortical regions. The increases in glucose metabolism associated with DBS-f were more extensive and sustained than the cerebral metabolic effects observed with cholinesterase inhibitors. Furthermore, there were no serious adverse events observed in this small study.
In the Advance study, 20 patients with early Alzheimer’s disease were randomly assigned (1:1) to either DBS-f activation shortly after surgery or after 12 months. The first 12 months are double-blind after which every patient is eligible for active DBS-f treatment for the next 12 months. Comprehensive safety, clinical, cognitive and neuroimaging assessments are performed, including serial PET scans of glucose metabolism and magnetic resonance scans of hippocampal volumes and fornix white matter integrity.
Advance is currently being conducted at Toronto Western Hospital (Toronto, Canada), Johns Hopkins (Baltimore, USA), Banner Alzheimer’s Institute (Phoenix, USA), University of Florida (Gainesville, USA), and the University of Pennsylvania (Philadelphia, USA), and Butler and Rhode Island Hospitals/Brown University (Providence, USA).
Of course, in the Advance study the potential benefits of deep brain stimulation must be considered alongside its risks. Following implantation, there have been occasional intraoperative events such as cerebral haemorrhage or stroke. There can also be ongoing complications related to the hardware, such as breakage, malfunction, and infection that can occur in 5% to 10% of deep brain stimulation patients. Finally, stimulation-related adverse effects (such as paresthesias, dysarthria, and motor contractions) can occur but are usually reversible if stimulation is reduced or stopped.
The Advance trial builds on evidence supporting the role of neural network dysfunction in the pathology of Alzheimer’s disease and represents a novel circuitry-based approach to treatment.
Steven D Targum is the chief medical officer of Functional Neuromodulation