Association between white matter hyperintensities, cortical volumes, and late-onset epilepsy

Johnson, Emily L.; Krauss, Gregory L.; Lee, Alexandra K.; Schneider, Andrea L.C.; Kucharska‐Newton, Anna; Huang, Juebin; Jack, Clifford R.; Gottesman, Rebecca F.

doi:10.1212/wnl.0000000000007010

Cited by 33 publications

(35 citation statements)

References 36 publications

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“…We observed declines even prior to the onset of seizures on the test of executive function (DSST), which is associated with small vessel disease 35 . Vascular risk factors such as hypertension and diabetes are also associated with LOE, 8 as are white matter hyperintensities (a marker of cerebral small vessel disease) 27 . Vascular dementia is a leading cause of cognitive decline, and microvascular disease affecting subcortical networks could explain some of our findings 35 .…”

Section: Discussionmentioning

confidence: 60%

“…To identify incident cases, we included only participants with at least 2 years of seizure‐free claims data prior to the first seizure‐related code, and participants with the first seizure‐related code at age 67 or later (to allow for 2 years of seizure‐free claims following Medicare eligibility at age 65). This and similar definitions have been used previously in claims‐based research 4,5,8,27 and have been validated with chart review 26 . We excluded individuals with <2 years of FFS coverage or gaps in coverage.…”

Section: Methodsmentioning

confidence: 99%

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Late‐onset epilepsy and 25‐year cognitive change: The Atherosclerosis Risk in Communities (ARIC) study

et al. 2020

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Objective: To define the association between late-onset epilepsy (LOE) and 25-year change in cognitive performance. Methods: The Atherosclerosis Risk in Communities (ARIC) study is a multicenter longitudinal cohort study with participants from four U.S. communities. From linked Medicare claims, we identified cases of LOE, defined as ≥2 seizure-related diagnostic codes starting at age ≥67. The ARIC cohort underwent evaluation with in-person visits at intervals of 3-15 years. Cognition was evaluated 4 times over >25 years (including before the onset of seizures) using the Delayed Word Recall Test (DWRT), Digit Symbol Substitution Test (DSST), and Word Fluency Test (WFT); a global z-score was also calculated. We compared the longitudinal cognitive changes of participants with and without LOE, adjusting for demographics and LOE risk factors. Results: From 8033 ARIC participants with midlife cognitive testing and Medicare claims data available (4523 [56%] female, 1392 [17%] Black), we identified 585 cases of LOE. The rate of cognitive decline was increased on all measures in the participants who developed LOE compared to those without LOE. On the measure of global cognition, participants with LOE declined by −0.43 z-score points more over 25 years than did participants without epilepsy (95% confidence interval [CI] −0.59 to −0.27). Prior to the onset of seizures, cognitive decline was more rapid on the DWRT, DSST, and global z-scores in those who would later develop LOE than it was in non-LOE participants. Results were similar after excluding data from participants with dementia. Significance: Global cognition, verbal memory, executive function, and word fluency declined faster over time in persons developing LOE than without LOE. Declines in cognition preceding LOE suggest these are linked; it will be important to investigate causes for midlife cognitive declines associated with LOE.

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Section: Discussionmentioning

confidence: 60%

Section: Methodsmentioning

confidence: 99%

Late‐onset epilepsy and 25‐year cognitive change: The Atherosclerosis Risk in Communities (ARIC) study

et al. 2020

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“…However, little research has investigated the association between vascular risk factors and GABA disturbances [ 265 ]. Interestingly, the presence of early-life white matter hyperintensities predicts the incidence of late-onset epilepsy, suggesting a link between cerebrovascular disease and neural network disturbances [ 266 ]. Moreover, hyperhomocysteinemia, a shared risk factor for AD and cerebrovascular disease, is known to reduce GABA A mediated neurotransmission—as homocysteine antagonizes GABA A receptors [ 267 ].…”

Section: Mechanisms Linking Gaba Dysfunction and Memory Impairment In Admentioning

confidence: 99%

GABAergic dysfunction, neural network hyperactivity and memory impairments in human aging and Alzheimer’s disease

Jiménez-Baladó

Eich

2021

Seminars in Cell & Developmental Biology

108

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In this review, we focus on the potential role of the γ-aminobutyric acidergic (GABAergic) system in age-related episodic memory impairments in humans, with a particular focus on Alzheimer’s disease (AD). Well-established animal models have shown that GABA plays a central role in regulating and synchronizing neuronal signaling in the hippocampus, a brain area critical for episodic memory that undergoes early and significant morphologic and functional changes in the course of AD. Neuroimaging research in humans has documented hyperactivity in the hippocampus and losses of resting state functional connectivity in the Default Mode Network, a network that itself prominently includes the hippocampus—presaging episodic memory decline in individuals at-risk for AD. Apolipoprotein ε4, the highest genetic risk factor for AD, is associated with GABAergic dysfunction in animal models, and episodic memory impairments in humans. In combination, these findings suggest that GABA may be the linchpin in a complex system of factors that eventually leads to the principal clinical hallmark of AD: episodic memory loss. Here, we will review the current state of literature supporting this hypothesis. First, we will focus on the molecular and cellular basis of the GABAergic system and its role in memory and cognition. Next, we report the evidence of GABA dysregulations in AD and normal aging, both in animal models and human studies. Finally, we outline a model of GABAergic dysfunction based on the results of functional neuroimaging studies in humans, which have shown hippocampal hyperactivity to episodic memory tasks concurrent with and even preceding AD diagnosis, along with factors that may modulate this association.

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“…T2 white matter hyperintensities, which are associated with higher risk of late-onset epilepsy, may also be an informative biomarker. 46 Functional magnetic resonance imaging. Functional magnetic resonance imaging (fMRI) tasks that activate episodic memory circuitry reveal increased hippocampal activation that predicts impending MTL failure and cognitive decline in patients in the mild cognitive impairment (MCI) stage of AD.…”

Section: Imagingmentioning

confidence: 99%

“…T2 white matter hyperintensities, which are associated with higher risk of late-onset epilepsy, may also be an informative biomarker. 46 …”

Section: Introductionmentioning

confidence: 99%

Night Watch on the Titanic: Detecting Early Signs of Epileptogenesis in Alzheimer Disease

Lam

Noebels

2020

Epilepsy Curr

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Aberrant cortical network excitability is an inextricable feature of Alzheimer disease (AD) that can negatively impact memory and accelerate cognitive decline. Surface electroencephalogram spikes and intracranial recordings of nocturnal silent seizures in human AD, coupled with the abnormal neural synchrony that precedes development of behavioral seizures in mouse AD models, build the case for epileptogenesis as an early therapeutic target for AD. Since most individuals with AD do not develop overt seizures, leveraging functional biomarkers of epilepsy risk to stratify a heterogeneous AD patient population for treatment is research priority for successful clinical trial design. Who will benefit from antiseizure interventions, which one, and when should it begin?

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Association between white matter hyperintensities, cortical volumes, and late-onset epilepsy

Cited by 33 publications

References 36 publications

Late‐onset epilepsy and 25‐year cognitive change: The Atherosclerosis Risk in Communities (ARIC) study

Late‐onset epilepsy and 25‐year cognitive change: The Atherosclerosis Risk in Communities (ARIC) study

GABAergic dysfunction, neural network hyperactivity and memory impairments in human aging and Alzheimer’s disease

Night Watch on the Titanic: Detecting Early Signs of Epileptogenesis in Alzheimer Disease

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