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Open Access Publications from the University of California

About

The Department of Neurology, University of California, Davis is composed of a diverse faculty engaged in research on neurological disorders and fundamental neuroscience. Areas of strength in the department are in neurological therapeutics, epilepsy, cognitive neuroscience, dementias, neuromuscular disorders, Huntington's disease and multiple sclerosis.

Faculty in the Department of Neurology are situated on the UC Davis medical campus in Sacramento (in the Lawrence J. Ellison Ambulatory Care Center and at the M.I.N.D. Institute); at the UC Davis Center for Neuroscience and at the Center for Mind and Brain in Davis; and at the Department of Veterans Affairs Northern California Health Care System in Martinez.

Michael A. Rogawski, Chair
University of California, Davis
4860 Y Street, Suite 3700
Sacramento CA 95817

Department of Neurology, UC Davis School of Medicine

There are 1376 publications in this collection, published between 1991 and 2024.
Recent Work (5)

Epilepsy-Associated Dysfunction in the Voltage-Gated Neuronal Sodium Channel SCN1A

Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel subunit (NaV1.1) are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of four GEFS+ alleles and one SMEI allele using whole-cell patch-clamp analysis of heterologously expressed recombinant human SCN1A. One previously reported GEFS+ mutation (I1656M) and an additional novel allele (R1657C), both affecting residues in a voltage-sensing S4 segment, exhibited a similar depolarizing shift in the voltage dependence of activation. Additionally, R1657C showed a 50% reduction in current density and accelerated recovery from slow inactivation. Unlike three other GEFS+ alleles that we recently characterized, neither R1657C nor I1656M gave rise to a persistent, noninactivating current. In contrast, two other GEFS+ mutations (A1685V and V1353L) and L986F, an SMEI-associated allele, exhibited complete loss of function. In conclusion, our data provide evidence for a wide spectrum of sodium channel dysfunction in familial epilepsy and demonstrate that both GEFS+ and SMEI can be associated with nonfunctional SCN1A alleles.

What Clinical Observations on the Epidemiology of Antiepileptic Drug Intractability Tell Us About the Mechanisms of Pharmacoresistance

In the past several years, there have been important advances in the clinical epidemiology of antiepileptic drug resistance, as reviewed by Mohanraj and Brodie. It would appear that by and large, intractability is independent of the choice of antiepileptic drug (AED). Many patients will become seizure free on the first agent tried, irrespective of which one their physician decides to pick. Nonresponders to the first drug are in a different category: it is likely that they will continue to have seizures no matter which medicine or combination of medicines is tried. This simple clinical observation puts important constraints on the possible biological mechanisms for pharmacoresistance. In this essay, I consider the implications of the new clinical research for studies on the neurobiological mechanisms of AED intractability.

New Molecular Targets for Antiepileptic Drugs: alpha2delta, SV2A and Kv7/KCNQ/M Potassium Channels

Many currently prescribed antiepileptic drugs (AEDs) act via voltage-gated sodium channels, through effects on -aminobutyric acid–mediated inhibition, or via voltage-gated calcium channels. Some newer AEDs do not act via these traditional mechanisms. The molecular targets for several of these nontraditional AEDs have been defined using cellular electrophysiology and molecular approaches. Here, we describe three of these targets: 2, auxiliary subunits of voltage-gated calcium channels through which the gabapentinoids gabapentin and pregabalin exert their anticonvulsant and analgesic actions; SV2A, a ubiquitous synaptic vesicle glycoprotein that may prepare vesicles for fusion and serves as the target for levetiracetam and its analog brivaracetam (which is currently in late-stage clinical development); and Kv7/KCNQ/M potassium channels that mediate the M-current, which acts a brake on repetitive firing and burst generation and serves as the target for the investigational AEDs retigabine and ICA-105665. Functionally, all of the new targets modulate neurotransmitter output at synapses, focusing attention on presynaptic terminals as critical sites of action for AEDs.

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Open Access Policy Deposits (1373)

Neuropsychological Test Performance and MRI Markers of Dementia Risk

Background

To use neuropsychological assessments for studying the underlying disease processes contributing to dementia, it is crucial that they correspond to magnetic resonance imaging (MRI)-based measures of dementia, regardless of educational level.

Methods

French 3-City Dijon MRI study cohort members (n=1782) with assessments of white matter lesion volume (WMLV), hippocampal volume (HCV), and cerebrospinal fluid volume (CSFV), and 6 waves of neuropsychological assessments over 11 years, including Mini-Mental State Examination (MMSE), plus 5 other tests combined using a Z-score or item-response theory (IRT-cognition) comprised the study cohort. We evaluated, testing interactions, whether education modified associations of MRI markers with intercept or rate of change of MMSE, Z-score composite, or IRT-cognition.

Results

In linear models, education modified the associations of WMLV and CSFV with MMSE and CSFV and Z-score composite. In mixed models, education modified the associations of WMLV and CSFV with level of MMSE and the association of HCV with slope of MMSE. Education also modified the association with CSFV and slope of Z-score composite decline. There was no evidence that education modified associations between MRI measures and level or slope of IRT-cognition.

Conclusions

Longitudinal analysis of correctly scaled neuropsychological assessments may provide unbiased proxies for MRI-based measures of dementia risk.

High Altitude as a Risk Factor for the Development of Nonarteritic Anterior Ischemic Optic Neuropathy

Background

Episodic high-altitude exposure leads to optic disc edema and retinopathy. It is uncertain whether high-altitude exposure is a risk factor for nonarteritic anterior ischemic optic neuropathy (NAION).

Methods

We performed a single-center, retrospective, cross-sectional case study of 5 patients with high-altitude-associated NAION (HA-NAION) from April 2014 to April 2019. Main study parameters included known vascular risk factors for NAION, evolution of visual acuity, visual field, optic disc, and macula measurements.

Results

We studied 5 eyes of 5 patients with HA-NAION that occurred at 7,000-9,000 ft above sea level, 28 patients with classic NAION that developed at sea level (normal altitude NAION or NA-NAION), and 40 controls. All 5 patients with HA-NAION had clinically confirmed NAION by a neuro-ophthalmologist within 3-21 days of onset and comprehensive follow-up evaluations (average follow-up of 23 months). Other than high-altitude exposure, 4 of 5 patients had undiagnosed obstructive sleep apnea (OSA, apnea-hypopnea index 5.4-22.2) and 1 had systemic vascular risk factors. All patients had disc-at-risk in the contralateral eye. The best-corrected distance visual acuity was 20/20 to 20/70 (median logMAR 0) at presentation and 20/70 to counting finger (median logMAR 0) at ≥6 months. Automated static perimetry revealed average mean deviation of -18.6 dB at presentation and -22.1 dB at ≥6 months. The average retinal nerve fiber layer was 244 µm (80-348 µm) at onset and 59 µm (55-80 µm) at ≥6 months. The average ganglion cell complex thickness was 50 µm (43-54 µm) at onset and 52 µm (50-55 µm) at ≥6 months. The patients with OSA were started on home continuous positive airway pressure treatment. Visual outcomes were similar in patients with HA-NAION and NA-NAION. - After addressing all NAION risk factors, no new events occurred in the HA-NAION group within 2-8 years with or without repeat high-altitude exposure.

Conclusions

NAION can occur under high-altitude conditions. HA-NAION is associated with relatively younger age at onset, disc-at-risk, and OSA. These patients exhibit a relatively progressive course of vision loss after initial onset and severe thinning of optic nerves on optical coherence tomography. Treatment for OSA is recommended, especially with repeated high-altitude exposure.

Episodic memory performance in a multi-ethnic longitudinal study of 13,037 elderly

Age-related changes in memory are not uniform, even in the absence of dementia. Characterization of non-disease associated cognitive changes is crucial to gain a more complete understanding of brain aging. Episodic memory was investigated in 13,037 ethnically diverse elderly (ages 72 to 85 years) with two to 15 years of follow-up, and with known dementia status, age, sex, education, and APOE genotypes. Adjusted trajectories of episodic memory performance over time were estimated using Latent Class Mixed Models. Analysis was conducted using two samples at baseline evaluation: i) non-cognitively impaired individuals, and ii) all individuals regardless of dementia status. We calculated the age-specific annual incidence rates of dementia in the non-demented elderly (n = 10,220). Two major episodic memory trajectories were estimated: 1) Stable-consisting of individuals exhibiting a constant or improved memory function, and 2) Decliner-consisting of individuals whose memory function declined. The majority of the study participants maintain their memory performance over time. Compared to those with Stable trajectory, individuals characterized as Decliners were more likely to have non-white ethnic background, fewer years of education, a higher frequency of ε4 allele at APOE gene and five times more likely to develop dementia. The steepest decline in episodic memory was observed in Caribbean-Hispanics compared to non-Hispanic whites (p = 4.3 x 10(-15)). The highest incident rates of dementia were observed in the oldest age group, among those of Caribbean-Hispanics ancestry and among Decliners who exhibited rates five times higher than those with Stable trajectories (11 per 100 person-years versus 3 per 100 person-years. Age, education, ethnic background and APOE genotype influence the maintenance of episodic memory. Declining memory is one of the strongest predictors of incident dementia.

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