This research aimed to investigate novel cerebrovascular therapies for neurodegenerative diseases, with a particular focus on epilepsy and Alzheimer’s Disease.
Background: Epilepsy is one of the most common neurological conditions worldwide,
affecting roughly 50 million people. Of those diagnosed with epilepsy 30-40% do not
respond to pharmacological treatment and rely on surgical or dietary interventions to
attempt to control their seizures. These interventions are not appropriate for all patients,
and there are a number of risks associated with uncontrolled seizures, including increased risk of injury and sudden death.
Alzheimer’s disease (AD) is the most common cause of dementia, with approximately 50
million people currently diagnosed, and this number expected to double every 5 years.
Current treatments focus on symptom management, targeting acetylcholine or glutamate
levels within the brain to improve cognitive function, though they are not able to alter the
disease course. The newest treatments (lecanemab and donanemab) target amyloid
plaques, reducing levels within the brain and slowing cognitive decline, though they are only effective for patients early in the disease course, and are not available on the NHS.
Blood flow is known to be altered in both epilepsy and AD. Epileptic seizures result in
significant alterations to the cerebral blood flow, resulting in post-ictal hypoxia, which is
postulated to contribute to continuing epileptogenesis. Cerebrovascular alterations are also identified in over 50% of clinically diagnosed AD cases with blood flow alterations likely occurring even before cognitive symptoms develop. As such, therapies that target cerebral blood flow could provide breakthroughs in treatment for both epilepsy and AD patients.
Cooling for the reduction of neuronal seizure activity has been considered as a potential
therapy for epilepsy patients for many years, however, the impact of cooling on
haemodynamic activity has not been thoroughly investigated. The difficulties of creating a
cooling device suitable for translation into patients have also prevented progression of this therapeutic approach, but new technological advances have allowed reconsideration of cooling as a therapy. Research into increasing blood flow in AD has identified positive effects of hyperbaric oxygen treatment, increasing cerebral blood flow and potentially decreasing cognitive deficits. This treatment requires patients to travel to clinics, while an in home gas treatment could reduce the disruption for patients. Carbogen gas (95% O2, 5% CO2) combines the positive impact of oxygen, with the vasodilatory effects of CO2, potentially increasing the benefit that could be gained from breathing pure oxygen in a standard environment.
Aims: 1) To investigate the impact of cortical cooling on neural and haemodynamic activity induced by 4-AP seizures.
2) To test a novel cooling implant, investigating the impact of its cooling on 4-AP induced seizure activity.
3) To investigate carbogen gas as a potential therapy for Alzheimer’s disease.
Cooling was investigated using an anaesthetised 4-AP model of seizures, with cooling being supplied by either a skull-attached chamber over a thinned cranial window, or a novel cooling device positioned within a craniotomy. Carbogen treatment was applied in the APP/PSEN1 mouse model of AD for 1 hour a day over 2 months.
Results: Cooling from both a skull-attached chamber and novel cooling implant was capable of reducing neuronal activity induced by 4-AP. Cooling from a skull-attached chamber altered the haemodynamic activity during 4-AP induced seizures, with a novel finding showing differing impact of cooling in the middle cerebral artery (MCA), compared to the surrounding cortical tissue. Cooling to 25°C with the novel cooling implant was sufficient to reduce neuronal activity, compared to cooling to 10°C being required with the skull attached chamber. Carbogen gas treatment did not affect amyloid plaque load, but there was a lesser plaque burden in cortex surrounding major branches of the MCA. This novel finding suggests an important role of blood flow in amyloid accumulation.
Conclusions: These results provide novel insights into the impact of cooling on both neural and haemodynamic activity. They also demonstrate how cooling can be converted into a feasible therapeutic device for patients with drug resistant epilepsy. They show a novel finding supporting the role of blood flow in the clearance of amyloid plaques in an AD model. Finally, they demonstrate the importance of cerebrovascular approaches to novel therapies for neurodegenerative diseases.
