Epileptic activity in Alzheimer's disease: causes and clinical relevance

Abstract

Epileptic activity is frequently associated with Alzheimer’s disease; this association has therapeutic implications, because epileptic activity can occur at early disease stages and might contribute to pathogenesis. In clinical practice, seizures in patients with Alzheimer’s disease can easily go unrecognised because they usually present as non-motor seizures, and can overlap with other symptoms of the disease. In patients with Alzheimer’s disease, seizures can hasten cognitive decline, highlighting the clinical relevance of early recognition and treatment. Some evidence indicates that subclinical epileptiform activity in patients with Alzheimer’s disease, detected by extended neurophysiological monitoring, can also lead to accelerated cognitive decline. Treatment of clinical seizures in patients with Alzheimer’s disease with select antiepileptic drugs (AEDs), in low doses, is usually well tolerated and efficacious. Moreover, studies in mouse models of Alzheimer’s disease suggest that certain classes of AEDs that reduce network hyperexcitability have disease-modifying properties. These AEDs target mechanisms of epileptogenesis involving amyloid β and tau. Clinical trials targeting network hyperexcitability in patients with Alzheimer’s disease will identify whether AEDs or related strategies could improve their cognitive symptoms or slow decline.

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…The gist of the cumulative data is that (1) hallmarks of aging promote amyloidogenic APP processing and Tau pathology, (2) Aβ and Tau accumulations accelerate hallmarks of aging, and (3) there is no common linear pathway to synaptic dysfunction and neuronal death in AD. For indepth information on the roles of different hallmarks of brain aging in AD and related dementias, we refer the reader to the following review articles: oxidative stress (Texel and Mattson, 2011), mitochondrial dysfunction (Mattson et al, 2008; DuBoff et al, 2013), impaired autophagy (Nixon, 2013; Kerr et al, 2017), impaired DNA repair (Madabhushi et al, 2014; Leandro et al, 2015), aberrant neuronal network excitability (Palop and Mucke, 2016; Vossel et al, 2017), impaired adaptive stress response signaling (Stranahan and Mattson, 2012), dysregulated neuronal Ca 2+ homeostasis (Bezprozvanny and Mattson, 2008; Stutzmann and Mattson, 2011), impaired energy metabolism (Dauncey, 2014), neuroinflammation (Heppner et al, 2015), and stem cell deficits (Lazarov et al, 2010). Due to space limitations, in this section we describe one specific example of how oxidative damage, impaired autophagy, Ca 2+ dyshomeostasis, and aberrant neuronal network activity can interact reciprocally with Aβ pathology to cause synaptic dysfunction and neuronal death in AD.…”

Aging and the Epidemiology of Epilepsy

“…Seizures lower the pathologic threshold for the development of cognitive impairment and early dementia in AD. Seizures also contribute to cognitive decline in the earliest stages of AD progression [36]. However, the underlying mechanisms remain to be determined.…”

Brain regional synchronous activity predicts tauopathy in 3×TgAD mice

“…Previous studies have shown that several lines of mice expressing the P301L hTau mutation in neurons, including 3 × TgAD mice, exhibit age-dependent accumulation of pathological hyper-phosphorylated hTau in neurons in the Hip and anatomically associated regions of the cerebral cortex (Cook et al, 2015; Kashiwaya et al, 2013; Liu et al, 2010; Vossel et al, 2017). We therefore immunostained coronal brain sections from mice used for the fMRI analysis with an antibody that specifically binds to hTau (P301L mutant hTau in 3 × TgAD mice) or with an Aβ antibody to determine the potential contributions of these two neuropatho-logical AD features to brain regional synchronous activity indicated by ReHo.…”

“…In addition to increased incidence of seizures in AD patients (Vossel et al, 2017), a recent study revealed subclinical hippocampal seizures and spikes during sleep in AD patients (Lam et al, 2017). Studies of AD mouse models with cerebral Aβ and/or tau pathologies have demonstrated increased incidence of spontaneous or induced seizures, EEG evidence of global seizure-like activity, and increased excitability of hippocampal and entorhinal cortex projection neurons measured using intracellular electrodes (García-Cabrero et al, 2013; Kam et al, 2016; Kazim et al, 2017).…”

“…Previous studies have shown that anticonvulsant drugs (Mark et al, 1995b) and a ketone ester (Kashiwaya et al, 2013) can mitigate Aβ and tau pathologies and protect neurons against degeneration in experimental models of AD. Anticonvulsants are prescribed to AD patients with seizures (Vossel et al, 2017), and preclinical studies in AD animal models suggest that interventions that suppress neuronal hyperexcitability also have potential for slowing the neurodegenerative process and cognitive decline (Kashiwaya et al, 2013; Liu et al, 2010; Qing et al, 2008; Sanchez et al, 2012). Abnormal synchronous activity of neuronal circuits prone to tau pathology discerned by ReHo may provide a new diagnostic tool and a means for monitoring disease progression and treatment responses of patients with cognitive impairment.…”