Alzheimer’s Disease and Epilepsy: A Perspective on the Opportunities for Overlapping Therapeutic Innovation

Lehmann, L.; Lo, Alexandria; Knox, Kevin M.; Barker‐Haliski, Melissa

doi:10.1007/s11064-021-03332-y

Cited by 40 publications

(53 citation statements)

References 132 publications

(244 reference statements)

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“…Furthermore, it appears that ASMs (including LEV) do elicit such a positive effect on cognition even with chronic treatment in LOEU patients without AD ( 238 ), especially in patients diagnosed with focal seizures. Although the amount of randomized case-control studies remains too low for further conclusions ( 231 ), preclinical results of antiepileptic treatments in AD are promising [reviewed by ( 27 ), and ( 239 )]. They suggest decreases in excess neuronal activity ( 61 , 240 ), improved cognitive functions ( 240 – 242 ), reduced amyloid plaque load in some cases ( 242 ), or a rescue from the depletion of neuronal stem cells due to network hyperactivity [( 241 ), see ( 27 ) for a review].…”

Section: Methodological Considerations Diagnostic Hurdles and Treatme...mentioning

confidence: 99%

Sleep: The Tip of the Iceberg in the Bidirectional Link Between Alzheimer's Disease and Epilepsy

et al. 2022

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The observation that a pathophysiological link might exist between Alzheimer's disease (AD) and epilepsy dates back to the identification of the first cases of the pathology itself and is now strongly supported by an ever-increasing mountain of literature. An overwhelming majority of data suggests not only a higher prevalence of epilepsy in Alzheimer's disease compared to healthy aging, but also that AD patients with a comorbid epileptic syndrome, even subclinical, have a steeper cognitive decline. Moreover, clinical and preclinical investigations have revealed a marked sleep-related increase in the frequency of epileptic activities. This characteristic might provide clues to the pathophysiological pathways underlying this comorbidity. Furthermore, the preferential sleep-related occurrence of epileptic events opens up the possibility that they might hasten cognitive decline by interfering with the delicately orchestrated synchrony of oscillatory activities implicated in sleep-related memory consolidation. Therefore, we scrutinized the literature for mechanisms that might promote sleep-related epileptic activity in AD and, possibly dementia onset in epilepsy, and we also aimed to determine to what degree and through which processes such events might alter the progression of AD. Finally, we discuss the implications for patient care and try to identify a common basis for methodological considerations for future research and clinical practice.

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Section: Methodological Considerations Diagnostic Hurdles and Treatme...mentioning

confidence: 99%

Sleep: The Tip of the Iceberg in the Bidirectional Link Between Alzheimer's Disease and Epilepsy

et al. 2022

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“…On the other hand, epilepsy is a chronic disease with a cumulative incidence of 3% worldwide. Many factors increase the risk of developing epilepsy: congenital disorders ( 5 ), infections ( 8 ), trauma ( 9 ), tumors ( 10 ), vascular accidents ( 11 ), and neurodegenerative diseases ( 12 , 13 ). The incidence of focal seizures increases significantly in individuals aged 65+ ( 14 ), resulting in a higher socioeconomic impact for this group vs. younger individuals ( 15 ).…”

Section: Epilepsy and Seizuresmentioning

confidence: 99%

“…The incidence of focal seizures increases significantly in individuals aged 65+ ( 14 ), resulting in a higher socioeconomic impact for this group vs. younger individuals ( 15 ). Epilepsy in older adults can arise secondary to other disorders; ~10–20% of cases of epilepsy syndromes are comorbid with neurodegenerative diseases, such as Alzheimer's Disease (AD) ( 13 , 16 ). Despite this, the epileptic syndromes most frequently studied in preclinical practice generally favor disease or symptoms that occur in infant or adolescent stages of neurodevelopment, ( 17 , 18 ).…”

Section: Epilepsy and Seizuresmentioning

confidence: 99%

Can Old Animals Reveal New Targets? The Aging and Degenerating Brain as a New Precision Medicine Opportunity for Epilepsy

et al. 2022

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Older people represent the fastest growing group with epilepsy diagnosis. For example, cerebrovascular disease may underlie roughly 30–50% of epilepsy in older adults and seizures are also an underrecognized comorbidity of Alzheimer's disease (AD). As a result, up to 10% of nursing home residents may take antiseizure medicines (ASMs). Despite the greater incidence of epilepsy in older individuals and increased risk of comorbid seizures in people with AD, aged animals with seizures are strikingly underrepresented in epilepsy drug discovery practice. Increased integration of aged animals into preclinical epilepsy drug discovery could better inform the potential tolerability and pharmacokinetic interactions in aged individuals as the global population becomes increasingly older. Quite simply, the ASMs on the market today were brought forth based on efficacy in young adult, neurologically intact rodents; preclinical information concerning the efficacy and safety of promising ASMs is not routinely evaluated in aged animals. Integrating aged animals more often into basic epilepsy research may also uncover novel treatments for hyperexcitability. For example, cannabidiol and fenfluramine demonstrated clear efficacy in syndrome-specific pediatric models that led to a paradigm shift in the perceived value of pediatric models for ASM discovery practice; aged rodents with seizures or rodents with aging-related neuropathology represent an untapped resource that could similarly change epilepsy drug discovery. This review, therefore, summarizes how aged rodent models have thus far been used for epilepsy research, what studies have been conducted to assess ASM efficacy in aged rodent seizure and epilepsy models, and lastly to identify remaining gaps to engage aging-related neurological disease models for ASM discovery, which may simultaneously reveal novel mechanisms associated with epilepsy.

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“…The increased glutamatergic tone has been linked to glutamate-glutamine cycle disturbances, which lead to increased extracellular glutamate and decreased GABA levels [36,88,89]. In AD animal models the glutamatergic Nmethyl-D-aspartate receptors (AMPARs) activation increases beta-secretase activity, promotes the formation of amyloid plaques [90][91][92], tau hyperphosphorylation [11] and cell death [88]. GABAergic dysfunction has gained increasing attention in recent years.…”

Section: Role Of Neurotransmitters In Epiletogenesismentioning

confidence: 99%

“…AD impacts the number and function of voltage-dependent sodium (Na + ), calcium (Ca + ) and potassium (K + ) ion channels [11]. These ion channels contribute both to the generation and maintenance of epileptic seizures and AD pathophysiology as they can also increase glutamate-mediated excitotoxicity and neuronal hyperexcitability [90][91][92]. Intracellular calcium, in particular, must be tightly regulated for the excitatory-inhibitory balance.…”

Section: Ion Channel Disruptionsmentioning

confidence: 99%

Mechanisms Involved in Epileptogenesis in Alzheimer’s Disease and Their Therapeutic Implications

Altuna¹,

Olmedo²,

Carmona‐Iragui³

et al. 2022

Preprint

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Epilepsy and Alzheimer's disease (AD) incidence increase with age. There are reciprocal relationships between epilepsy and AD. Epilepsy is a risk factor for AD and, in turn, AD is an independent risk factor for developing epilepsy in old age and abnormal AD biomarkers in PET and or CSF are frequently found in late onset epilepsies of unknown etiology. Accordingly, epilepsy and AD share pathophysiological processes including neuronal hyperexcitability and an early excitatory-inhibitory dysregulation leading to dysfunction in the inhibitory GABAergic and excitatory glutamatergic systems. Moreover, both β-amyloid and tau protein aggregates, the anatomopathological hallmarks of AD, have proepileptic effects. Finally, these aggregates have been found in the resection material of refractory temporal lobe epilepsies suggesting that epilepsy leads to amyloid and tau aggregates. Some epileptic syndromes, such as medial temporal lobe epilepsy share structural and functional neuroimaging findings with AD, leading to overlapping symptomatology such as episodic memory deficits and toxic synergistic effects. In this respect, the existence of epileptiform activity and electroclinical seizures in AD appears to accelerate progression of cognitive decline and the presence of cognitive decline is much more prevalent in epileptic patients than in elderly without epilepsy. Notwithstanding their clinical significance, the diagnosis of clinical seizures in AD is a challenge. Most are focal and manifest with altered level of consciousness without motor symptoms, and are often interpreted as cognitive fluctuations. Finally, despite the frequent association of epilepsy and AD dementia, there is a lack of clinical trials to guide the use of antiseizure medications (ASM). There is also a potential role for ASMs to be used as disease-modifying drugs in AD.

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Alzheimer’s Disease and Epilepsy: A Perspective on the Opportunities for Overlapping Therapeutic Innovation

Cited by 40 publications

References 132 publications

Sleep: The Tip of the Iceberg in the Bidirectional Link Between Alzheimer's Disease and Epilepsy

Sleep: The Tip of the Iceberg in the Bidirectional Link Between Alzheimer's Disease and Epilepsy

Can Old Animals Reveal New Targets? The Aging and Degenerating Brain as a New Precision Medicine Opportunity for Epilepsy

Mechanisms Involved in Epileptogenesis in Alzheimer’s Disease and Their Therapeutic Implications

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