Na,K-ATPase alpha isoforms at the blood-cerebrospinal fluid-trigeminal nerve and blood-retina interfaces in the rat

Background: Cerebrospinal fluid (CSF) sodium concentration increases during migraine attacks, and both CSF and vitreous humor sodium increase in the rat migraine model. The Na,K-ATPase is a probable source of these sodium fluxes. Since Na,K-ATPase isoforms have different locations and physiological roles, our objective was to establish which alpha isoforms are present at sites where sodium homeostasis is disrupted. Methods: Specific Na,K-ATPase alpha isoforms were identified in rat tissues by immunohistochemistry at the blood-CSF barrier at the choroid plexus, at the blood-CSF-trigeminal barrier at the meninges, at the blood-retina barrier, and at the blood-aqueous barrier at the ciliary body. Calcitonin gene-related peptide (CGRP), occludin, or von Willibrand factor (vWF) were co-localized with Na,K-ATPase to identify trigeminal nociceptor fibers, tight junctions, and capillary endothelial cells respectively. Results: The Na,K-ATPase alpha-2 isoform is located on capillaries and intensely at nociceptive trigeminal nerve fibers at the meningeal blood-CSF-trigeminal barrier. Alpha-1 and −3 are lightly expressed on the trigeminal nerve fibers but not at capillaries. Alpha-2 is expressed at the blood-retina barriers and, with alpha-1, at the ciliary body blood aqueous barrier. Intense apical membrane alpha-1 was associated with moderate cytoplasmic alpha-2 expression at the choroid plexus blood-CSF barrier. Conclusion: Na,K-ATPase alpha isoforms are present at the meningeal, choroid plexus, and retinal barriers. Alpha-2 predominates at the capillary endothelial cells in the meninges and retinal ganglion cell layer

Measures of Resting State EEG Rhythms for Clinical Trials in Alzheimer’s Disease:Recommendations of an Expert Panel

The Electrophysiology Professional Interest Area (EPIA) and Global Brain Consortium endorsed recommendations on candidate electroencephalography (EEG) measures for Alzheimer's disease (AD) clinical trials. The Panel reviewed the field literature. As most consistent findings, AD patients with mild cognitive impairment and dementia showed abnormalities in peak frequency, power, and "interrelatedness" at posterior alpha (8-12Hz) and widespread delta (<4Hz) and theta (4-8Hz) rhythms in relation to disease progression and interventions. The following consensus statements were subscribed: (1) Standardization of instructions to patients, resting state EEG (rsEEG) recording methods, and selection of artifact-free rsEEG periods are needed; (2) power density and "interrelatedness" rsEEG measures (e.g., directed transfer function, phase lag index, linear lagged connectivity, etc.) at delta, theta, and alpha frequency bands may be use for stratification of AD patients and monitoring of disease progression and intervention; and (3) international multisectoral initiatives are mandatory for regulatory purposes

Compromised Behavior and Gamma Power During Working Memory in Cognitively Healthy Individuals With Abnormal CSF Amyloid/Tau.

Research shows that gamma activity changes in Alzheimer\u27s disease (AD), revealing synaptic pathology and potential therapeutic applications. We aim to explore whether cognitive challenge combined with quantitative EEG (qEEG) can unmask abnormal gamma frequency power in healthy individuals at high risk of developing AD. We analyzed low (30-50 Hz) and high gamma (50-80 Hz) power over six brain regions at EEG sensor level (frontal/central/parietal/left temporal/right temporal/occipital) in a dataset collected from an aging cohort during N-back working memory (WM) testing at two different load conditions

Human cerebrospinal fluid fatty acid levels differ between supernatant fluid and brain-derived nanoparticle fractions, and are altered in Alzheimer's disease.

Although saturated (SAFA), monounsaturated (MUFA), and polyunsaturated (PUFA) fatty acids are important structural components of neuronal membranes and precursors of signaling molecules, knowledge of their metabolism in Alzheimer's disease (AD) is limited. Based on recent discovery that lipids in cerebrospinal fluid (CSF) are distributed in both brain-derived nanoparticles (NP) and supernatant fluid (SF), we hypothesized that fatty acid (FA) abundance and distribution into these compartments is altered in early AD pathology.We assayed the FA composition and abundance in CSF fractions from cognitively healthy (CH), mild cognitive impairment (MCI), and AD study participants using gas chromatography-mass spectrometry. In the SF fraction, concentration of docosahexaenoic acid [DHA, (C22:6n-3)] was less in AD compared with CH, while alpha linolenic acid [α-LNA, (C18:3n-3)] was lower in MCI compared with CH. In the NP fraction, levels of SAFAs (C15:0, C16:0) and a MUFA (C15:1) differentiated CH from MCI, while two MUFAs (C15:1, C19:1) and four PUFAs (C20:2n-6, C20:3n-3, C22:4n-6, C22:5n-3) were higher in AD compared with CH. Levels of even-chain free SAFA and total free FA levels were higher in AD, levels of odd-chain free SAFAs, MUFAs, n-3 PUFAs, and total PUFA, were lower in AD compared with CH. Free n-6 PUFA levels were similar in all three groups.FA metabolism is compartmentalized differently in NP versus SF fractions of CSF, and altered FA levels reflect the importance of abnormal metabolism and oxidative pathways in AD. Depleted DHA in CSF fractions in AD is consistent with the importance of n-3 PUFAs in cognitive function, and suggests that disturbed PUFA metabolism contributes to AD pathology. This study of FA levels in CSF fractions from different cognitive stages shows potential AD biomarkers, and provides further insight into cell membrane dysfunctions, including mechanisms leading to amyloid production

Alpha desynchronization during simple working memory unmasks pathological aging in cognitively healthy individuals.

Our aim is to explore if cognitive challenge combined with objective physiology can reveal abnormal frontal alpha event-related desynchronization (ERD), in early Alzheimer's disease (AD). We used quantitative electroencephalography (qEEG) to investigate brain activities during N-back working memory (WM) processing at two different load conditions (N = 0 or 2) in an aging cohort. We studied 60-100 year old participants, with normal cognition, and who fits one of two subgroups from cerebrospinal fluid (CSF) proteins: cognitively healthy (CH) with normal amyloid/tau ratio (CH-NAT, n = 10) or pathological amyloid/tau ratio (CH-PAT, n = 14). We recorded behavioral performances, and analyzed alpha power and alpha spectral entropy (SE) at three occasions: during the resting state, and at event-related desynchronization (ERD) [250 ~ 750 ms] during 0-back and 2-back. During 0-back WM testing, the behavioral performance was similar between the two groups, however, qEEG notably differentiated CH-PATs from CH-NATs on the simple, 0-back testing: Alpha ERD decreased from baseline only in the parietal region in CH-NATs, while it decreased in all brain regions in CH-PATs. Alpha SE did not change in CH-NATs, but was increased from baseline in the CH-PATs in frontal and left lateral regions (p<0.01), and was higher in the frontal region (p<0.01) of CH-PATs compared to CH-NATs. The alpha ERD and SE analyses suggest there is frontal lobe dysfunction during WM processing in the CH-PAT stage. Additional power and correlations with behavioral performance were also explored. This study provide pilot information to further evaluate whether this biomarker has clinical significance

Alpha desynchronization during Stroop test unmasks cognitively healthy individuals with abnormal CSF Amyloid/Tau.

Synaptic dysfunctions precede cognitive decline in Alzheimer\u27s disease by decades, affect executive functions, and can be detected by quantitative electroencephalography (qEEG). We used quantitative electroencephalography combined with Stroop testing to identify changes of inhibitory controls in cognitively healthy individuals with an abnormal versus normal ratio of cerebrospinal fluid (CSF) amyloid/total-tau. We studied two groups of participants (60-94 years) with either normal (CH-NAT or controls, n = 20) or abnormal (CH-PAT, n = 21) CSF amyloid/tau ratio. We compared: alpha event-related desynchronization (ERD), alpha spectral entropy (SE), and their relationships with estimated cognitive reserve. CH-PATs had more negative occipital alpha ERD, and higher frontal and occipital alpha SE during low load congruent trials, indicating hyperactivity. CH-PATs demonstrated fewer frontal SE changes with higher load, incongruent Stroop testing. Correlations of alpha ERD with estimated cognitive reserve were significant in CH-PATs but not in CH-NATs. These results suggested compensatory hyperactivity in CH-PATs compared to CH-NATs. We did not find differences in alpha ERD comparisons with individual CSF amyloid(A), p-tau(T), total-tau(N) biomarkers

Modulation of neuronal activity and plasma membrane properties with low-power millimeter waves in organotypic cortical slices

As millimeter waves (MMWs) are being increasingly used in communications and military applications, their potential effects on biological tissue has become an important issue for scientific inquiry. Specifically, several MMW effects on the whole-nerve activity were reported, but the underlying neuronal changes remain unexplored. This study used slices of cortical tissue to evaluate the MMW effects on individual pyramidal neurons under conditions mimicking their in vivo environment. The applied levels of MMW power are three orders of magnitude below the existing safe limit for human exposure of 1 mW cm^(−2). Surprisingly, even at these low power levels, MMWs were able to produce considerable changes in neuronal firing rate and plasma membrane properties. At the power density approaching 1 µW cm^(−2), 1 min of MMW exposure reduced the firing rate to one third of the pre-exposure level in four out of eight examined neurons. The width of the action potentials was narrowed by MMW exposure to 17% of the baseline value and the membrane input resistance decreased to 54% of the baseline value across all neurons. These effects were short lasting (2 min or less) and were accompanied by MMW-induced heating of the bath solution at 3 °C. Comparison of these results with previously published data on the effects of general bath heating of 10 °C indicated that MMW-induced effects cannot be fully attributed to heating and may involve specific MMW absorption by the tissue. Blocking of the intracellular Ca^(2+)-mediated signaling did not significantly alter the MMW-induced neuronal responses suggesting that MMWs interacted directly with the neuronal plasma membrane. The presented results constitute the first demonstration of direct real-time monitoring of the impact of MMWs on nervous tissue at a microscopic scale. Implication of these findings for the therapeutic modulation of neuronal excitability is discussed