In the March 27 JAMA Neurology online, scientists led by Matti Sillanpää, University of Turku, Finland, report that some middle-aged adults who had developed epilepsy as children had more amyloid plaques in their brains than controls of the same age. This was just as true when the disease was in remission as when patients were still experiencing seizures. ApoE4 allele carriers were especially vulnerable. The results yield new insights about the long-term consequences of childhood epilepsy, and help explain why it may lead to cognitive disorders such as Alzheimer’s disease (AD).
“There’s been a lot of research into the mechanisms by which β-amyloid deposition and tau aggregation might promote seizures,” said Zachary Miller, University of California, San Francisco, who was not involved in the research. This study suggests the relationship goes two ways, he said. “Seizure activity itself may make a person vulnerable to the disease.” Miller found the paper exciting because it supports the notion that early life differences shape the susceptibility to neurodegenerative disease later on.
Amyloid in Epilepsy: PiB uptake is higher in people who had epilepsy as children than in controls (orange scale). In ApoE4 carriers, the increase was more widely distributed (blue scale). [© 2017 American Medical Association. All rights reserved.]
Previous studies have reported a greater incidence of dementia and AD in people with epilepsy (see Breteler et al., 1991; Breteler et al., 1995). Vice versa, AD patients have an increased risk of seizures (Amatniek et al., 2006). How might the two disorders be related? In the 1990s, researchers analyzed brain tissue surgically removed from people with otherwise unmanageable temporal lobe epilepsy. They found unusually high levels of amyloid precursor protein and of amyloid plaques (see Sheng et al., 1994; Mackenzie and Miller, 1994). It was unclear if the amyloid deposits were limited to epileptic loci, or if they occurred more generally throughout the brain, since there was no way to measure brain amyloid in living people at that time.
To address this, first author Juho Joutsa, now at Massachusetts General Hospital in Charlestown, took advantage of amyloid PET scanning. He measured uptake of the ligand Pittsburgh compound B (PiB) in 41 middle-aged patients who had developed epilepsy beginning around 5 years old and 46 age-matched controls from the Turku Adult Childhood Onset Epilepsy (TACOE) study. Patients had struggled with epilepsy for 17 years on average and had been followed clinically for about 50 years. Most were in remission, but some still had active seizures.
On visual inspection of the scans, nine epilepsy patients (22 percent) were PiB-positive, compared to just three (7 percent) of the controls. The areas of PiB uptake did not correspond to epileptic foci but were distributed across the brain. PiB standard uptake value ratios did not associate with age at onset, duration of active epilepsy, or how long the participant had been taking epilepsy drugs. People in remission, who had stopped treatment decades ago, were among those with more amyloid.
At a group level, semi-quantitative analysis indicated that epilepsy patients who carried an ApoE4 allele had higher PiB SUVRs in the prefrontal cortex (1.66) and whole cortex (1.53) than did ApoE4-positive controls (1.40 and 1.36 respectively). Regions where PiB bound included those involved in the default mode network, an area susceptible to Aβ deposition. “That might tell us there are similar things going on in epilepsy and in AD,” Joutsa told Alzforum. He does not know why some epilepsy patients accumulate amyloid so young while others don’t, but assumes there are contributing factors not captured in this study. A larger, possibly more homogenous cohort might help figure that out, he said.
That the epilepsy-related plaques turn up in the default mode network, an area of the brain known to be active when the mind wanders, is intriguing, said Marcus Raichle, Washington University in St. Louis. “When I saw this picture, I was stunned,” he told Alzforum (see image above). “That’s an area that we know to be vulnerable to amyloid in AD.” He wondered how epilepsy enhances susceptibility in that region.
Raichle was also struck that amyloid sticks around even in people whose epilepsy is controlled or in remission. Previous studies in AD patients and in animal models of the disease report that increased neuronal activity leads to more Aβ production and seizures (see Dec 2005 news; Sep 2007 news). That could mean a brain that has experienced epilepsy at some point is made marginally more active even once the seizures stop, he said.
Among people with active epilepsy, ApoE4 allele carriers deposited more amyloid than noncarriers (see image above). The ApoE4 allele mostly affected people with idiopathic disease, which scientists believe has a strong genetic basis, rather than “cryptogenic” epilepsy, which has less clear origins. Idiopathic patients could have additional genetic risk factors that make them more vulnerable to neuronal stress or faulty neuron repair, or that impair Aβ clearance, Joutsa said. ApoE itself has been linked to all these phenomena. Most recently, researchers led by Thomas Südhof, Stanford University, reported that ApoE has a differential effect on APP expression in human neurons, with the E4 allele driving APP protein levels up the most (see Jan 2017 news).
Together, the results suggest that people with epilepsy deposit Aβ at a younger age than the general population, carrying amyloid loads typical of people 10 years older, the authors wrote. Joutsa is unsure whether this predisposes patients to AD, but plans to follow this cohort to find out, ideally with longitudinal PiB-PET scanning.
Another recent paper from Sillanpää and the TACOE study group reported that older epilepsy patients with ongoing seizures perform worse on tests of language, semantics, and visuomotor function (Karrasch et al., 2017). These scientists also found more brain atrophy and network abnormalities in patients with active epilepsy (see Garcia-Ramos et al., 2017).—Gwyneth Dickey Zakaib
- Paper Alert: Synaptic Activity Increases Aβ Release
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