31 Alzheimer’s Disease: Epidemiology, Pathophysiology and Surgery
Abstract
Deep brain stimulation of the fornices is a promising surgical therapy for the treatment of Alzheimer’s disease that aims to modulate dysfunctional neural networks and delay disease progression. Data from a recent Phase II clinical trial found fornix DBS to be safe and associated with better cognitive outcomes in patients older than 65 years. Further studies need to be conducted to assess the significance of clinical response and optimal patient population for treatment.
31.1 Epidemiology
Alzheimer’s disease is the most common age-related neurodegenerative disease, accounting for over 80% of the global incidence of dementia. 1 Currently, within the United States the Alzheimer’s disease patient population includes approximately 200,000 individuals younger than 65 years and more than 5 million people 65 years-of-age or older. 2 Age is the predominant risk factor for Alzheimer’s disease, with a doubling of disease incidence seen every 5-years after age 65. The resulting risk of diagnosis exceeds 1 in 3 for those older than 85 years. Based on current population demographics, the World Health Organization estimates that the global prevalence of disease will more than triple by 2050, surpassing 115 million cases. 1
31.2 Pathophysiology
Since 1907, when Alois Alzheimer first described amyloid plaques and neurofibrillary tangles as the neuropathological hallmarks of his eponymous disease, these pathological hallmarks have come to highlight the central theme in Alzheimer’s disease pathophysiology – an abnormal accumulation of misfolded proteins that leads to cellular dysfunction, synaptic loss, and neural network failure. Currently, a unifying model of Alzheimer’s disease pathogenesis remains elusive, but within the past two decades, multiple lines of investigation implicate amyloid-β and tau, the components of amyloid plaques and neurofibrillary tangles respectively, as the seminal agents of disease pathogenesis and cellular injury. 3 On a macroscopic level, disease progression occurs as a consequence of progressive synaptic dysfunction that increasingly disrupts the activity of neural networks involved with memory, executive function, and language. Evidence of these disturbances is reflected by the incremental decline of regional glucose metabolism as well as structural and functional degradation of neural connectivity visualized through positron emission tomography (PET) and investigative magnetic resonance imaging (MRI) sequences. 4 , 5
31.3 Treatments
31.3.1 Deep Brain Stimulation (DBS)
DBS has emerged as a promising surgical therapy for Alzheimer’s disease, aiming to modulate the activity of dysfunctional neural networks by directly driving electrical activity and increasing neural circuit viability through trophic effects associated with stimulation. 6 Two DBS targets have been described for Alzheimer’s disease. One of these, the nucleus basalis of Meynert (nBM), we will discuss only briefly due to limited literature data. The nBM is the primary relay of cholinergic projections to the neocortex and medial temporal lobes. DBS of the nBM for Alzheimer’s disease has been described in 7 patients across 2 studies, and has been shown to increase subsequent global cerebral glucose metabolism in 4 patients at follow-up under 12 months. 7 , 8
The other DBS target is the fornix, the principle output tract of the hippocampus and projection path within the circuit of Papez. Early studies with fornix DBS in rodents and epilepsy patients demonstrated improved memory of test subjects. 6 , 9 In patients with mild Alzheimer’s disease, fornix DBS was recently evaluated by the ADvance trial, a phase II clinical study that yielded mixed results. 10 In ADvance, 42 patients underwent bilateral fornix DBS in a double-blinded fashion. Global cerebral glucose metabolism was statistically greater in patients receiving stimulation versus the sham group at 6-months, but did not remain statistically significant at 12 months. 10 On post-hoc analysis, age was found to be a significant discriminate of response with patients older than 65-years having improved clinical and metabolic outcomes in contrast to patients younger than 65 years who tended to have worse results with stimulation. 10 This age discrepancy has been found across other Alzheimer’s disease studies, including multiple drug trials, suggesting that younger patients may represent a different disease phenotype. 11
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