Higher sodium in older individuals or after stroke/reperfusion, but not in migraine or Alzheimer's disease - a study in different preclinical models.

Sodium serves as one of the primary cations in the central nervous system, playing a crucial role in maintaining normal brain function. In this study, we investigated alterations in sodium concentrations in the brain and/or cerebrospinal fluid across multiple models, including an aging model, a stroke model, a nitroglycerin (NTG)-induced rat migraine model, a familial hemiplegic migraine type 2 (FHM2) mouse model, and a transgenic mouse model of Alzheimer's disease (AD). Our results reveal that older rats exhibited higher sodium concentrations in cerebrospinal fluid (CSF), plasma, and various brain regions compared to their younger counterparts. Additionally, findings from the stroke model demonstrated a significant increase in sodium in the ischemic/reperfused region, accompanied by a decrease in potassium and an elevated sodium/potassium ratio. However, we did not detect significant changes in sodium in the NTG-induced rat migraine model or the FHM2 mouse model. Furthermore, AD transgenic mice showed no significant differences in sodium levels compared to wild-type mice in CSF, plasma, or the hippocampus. These results underscore the nuanced regulation of sodium homeostasis in various neurological conditions and aging, providing valuable insights into potential mechanisms underlying these alterations.

Disrupted brain functional connectivity as early signature in cognitively healthy individuals with pathological CSF amyloid/tau.

Alterations in functional connectivity (FC) have been observed in individuals with Alzheimer's disease (AD) with elevated amyloid (Aß) and tau. However, it is not yet known whether directed FC is already influenced by Aß and tau load in cognitively healthy (CH) individuals. A 21-channel electroencephalogram (EEG) was used from 46 CHs classified based on cerebrospinal fluid (CSF) Aß tau ratio: pathological (CH-PAT) or normal (CH-NAT). Directed FC was estimated with Partial Directed Coherence in frontal, temporal, parietal, central, and occipital regions. We also examined the correlations between directed FC and various functional metrics, including neuropsychology, cognitive reserve, MRI volumetrics, and heart rate variability between both groups. Compared to CH-NATs, the CH-PATs showed decreased FC from the temporal regions, indicating a loss of relative functional importance of the temporal regions. In addition, frontal regions showed enhanced FC in the CH-PATs compared to CH-NATs, suggesting neural compensation for the damage caused by the pathology. Moreover, CH-PATs showed greater FC in the frontal and occipital regions than CH-NATs. Our findings provide a useful and non-invasive method for EEG-based analysis to identify alterations in brain connectivity in CHs with a pathological versus normal CSF Aß/tau.

Parallel electrophysiological abnormalities due to COVID-19 infection and to Alzheimer's disease and related dementia.

Many coronavirus disease 2019 (COVID-19) positive individuals exhibit abnormal electroencephalographic (EEG) activity reflecting "brain fog" and mild cognitive impairments even months after the acute phase of infection. Resting-state EEG abnormalities include EEG slowing (reduced alpha rhythm; increased slow waves) and epileptiform activity. An expert panel conducted a systematic review to present compelling evidence that cognitive deficits due to COVID-19 and to Alzheimer's disease and related dementia (ADRD) are driven by overlapping pathologies and neurophysiological abnormalities. EEG abnormalities seen in COVID-19 patients resemble those observed in early stages of neurodegenerative diseases, particularly ADRD. It is proposed that similar EEG abnormalities in Long COVID and ADRD are due to parallel neuroinflammation, astrocyte reactivity, hypoxia, and neurovascular injury. These neurophysiological abnormalities underpinning cognitive decline in COVID-19 can be detected by routine EEG exams. Future research will explore the value of EEG monitoring of COVID-19 patients for predicting long-term outcomes and monitoring efficacy of therapeutic interventions. HIGHLIGHTS: Abnormal intrinsic electrophysiological brain activity, such as slowing of EEG, reduced alpha wave, and epileptiform are characteristic findings in COVID-19 patients. EEG abnormalities have the potential as neural biomarkers to identify neurological complications at the early stage of the disease, to assist clinical assessment, and to assess cognitive decline risk in Long COVID patients. Similar slowing of intrinsic brain activity to that of COVID-19 patients is typically seen in patients with mild cognitive impairments, ADRD. Evidence presented supports the idea that cognitive deficits in Long COVID and ADRD are driven by overlapping neurophysiological abnormalities resulting, at least in part, from neuroinflammatory mechanisms and astrocyte reactivity. Identifying common biological mechanisms in Long COVID-19 and ADRD can highlight critical pathologies underlying brain disorders and cognitive decline. It elucidates research questions regarding cognitive EEG and mild cognitive impairment in Long COVID that have not yet been adequately investigated.

Associations of Plasma Glutamatergic Metabolites with Alpha Desynchronization during Cognitive Interference and Working Memory Tasks in Asymptomatic Alzheimer's Disease.

Electroencephalogram (EEG) studies have suggested compensatory brain overactivation in cognitively healthy (CH) older adults with pathological beta-amyloid(Aß42)/tau ratios during working memory and interference processing. However, the association between glutamatergic metabolites and brain activation proxied by EEG signals has not been thoroughly investigated. We aim to determine the involvement of these metabolites in EEG signaling. We focused on CH older adults classified under (1) normal CSF Aß42/tau ratios (CH-NATs) and (2) pathological Aß42/tau ratios (CH-PATs). We measured plasma glutamine, glutamate, pyroglutamate, and γ-aminobutyric acid concentrations using tandem mass spectrometry and conducted a correlational analysis with alpha frequency event-related desynchronization (ERD). Under the N-back working memory paradigm, CH-NATs presented negative correlations (r = ~-0.74--0.96, p = 0.0001-0.0414) between pyroglutamate and alpha ERD but positive correlations (r = ~0.82-0.95, p = 0.0003-0.0119) between glutamine and alpha ERD. Under Stroop interference testing, CH-NATs generated negative correlations between glutamine and left temporal alpha ERD (r = -0.96, p = 0.037 and r = -0.97, p = 0.027). Our study demonstrated that glutamine and pyroglutamate levels were associated with EEG activity only in CH-NATs. These results suggest cognitively healthy adults with amyloid/tau pathology experience subtle metabolic dysfunction that may influence EEG signaling during cognitive challenge. A longitudinal follow-up study with a larger sample size is needed to validate these pilot studies.

Choriocapillaris and Retinal Vascular Alterations in Presymptomatic Alzheimer's Disease.

Purpose: To compare optical coherence tomography angiography (OCTA) retina metrics between cognitively healthy subjects with pathological versus normal cerebrospinal fluid (CSF) Aß42/tau ratios. Methods: Swept-source OCTA scans were collected using the Zeiss PLEX Elite 9000 and analyzed on 23 cognitively healthy (CH) subjects who had previously undergone CSF analysis. Thirteen subjects had a pathological Aß42/tau (PAT) ratio of <2.7132, indicative of presymptomatic Alzheimer's disease (AD), and 10 had a normal Aß42/tau (NAT) ratio of ≥2.7132. OCTA en face images of the superficial vascular complex (SVC) and deep vascular complex were binarized and skeletonized to quantify the perfusion density (PD), vessel length density (VLD), and fractal dimension (FrD). The foveal avascular zone (FAZ) area was calculated using the SVC slab. Choriocapillaris flow deficits (CCFDs) were computed from the en face OCTA slab of the CC. The above parameters were compared between CH-PATs and CH-NATs. Results: Compared to CH-NATs, CH-PATs showed significantly decreased PD, VLD, and FrD in the SVC, with a significantly increased FAZ area and CCFDs. Conclusions: Swept-source OCTA analysis of the SVC and CC suggests a significant vascular loss at the CH stage of pre-AD that might be an indicator of a neurodegenerative process initiated by the impaired clearance of Aß42 in the blood vessel wall and by phosphorylated tau accumulation in the perivascular spaces, a process that most likely mirrors that in the brain. If confirmed in larger longitudinal studies, OCTA retinal and inner choroidal metrics may be important biomarkers for assessing presymptomatic AD.

Practice makes imperfect: stronger implicit interference with practice in individuals at high risk of developing Alzheimer's disease.

Early screening to determine patient risk of developing Alzheimer's will allow better interventions and planning but necessitates accessible methods such as behavioral biomarkers. Previously, we showed that cognitively healthy older individuals whose cerebrospinal fluid amyloid/tau ratio indicates high risk of cognitive decline experienced implicit interference during a high-effort task, signaling early changes in attention. To further investigate attention's effect on implicit interference, we analyzed two experiments completed sequentially by the same high- and low-risk individuals. We hypothesized that if attention modulates interference, practice would affect the influence of implicit distractors. Indeed, while both groups experienced a strong practice effect, the association between practice and interference effects diverged between groups: stronger practice effects correlated with more implicit interference in high-risk participants, but less interference in low-risk individuals. Furthermore, low-risk individuals showed a positive correlation between implicit interference and EEG low-range alpha event-related desynchronization when switching from high- to low-load tasks. This suggests that lower attention on the task was correlated with stronger interference, a typical phenomenon in the younger population. These results demonstrate how attention impacts implicit interference and highlight early differences in perception between high- and low-risk individuals.

Resting heart rate (variability) and cognition relationships reveal cognitively healthy individuals with pathological amyloid/tau ratio.

Introduction: Resting heart rate (HR) and heart rate variability (HRV) have been linked with cognition in the general population and in older individuals. The knowledge of this aspect of heart-brain relationship is relatively absent in older individuals with early Alzheimer's disease (AD) pathology. This study explores relationships of the HR, HRV, and cognition in cognitively healthy individuals with pathological amyloid/tau ratio (CH-PATs) in cerebral spinal fluid (CSF) compared to those with normal ratio (CH-NATs). Methods: We examined therelationshipsbetween1) resting HR and Mini-Mental State Examination (MMSE); 2) resting HR and brain processing during Stroop interference; and 3) resting vagally mediated HRV (vmHRV) and task switching performance. Results: Our studies showed that compared to CH-NATs, those CH-PATs with higher resting HR presented with lower MMSE, and less brain activation during interference processing. In addition, resting vmHRV was significantly correlated with task switching accuracy in CH-NATs, but not in CH-PATs. Discussion: Thesethreedifferenttestsindicatedysfunctionalheart-brainconnections in CH-PATs, suggesting a potential cardio-cerebral dysfunctional integration.

Practice makes imperfect: stronger implicit interference with practice in individuals at high risk of developing Alzheimer's disease.

Early screening to determine patient risk of developing Alzheimer's will allow better interventions and planning but necessitates accessible methods such as behavioral biomarkers. Previously, we showed that cognitively healthy older individuals whose cerebrospinal fluid amyloid / tau ratio indicates high risk of cognitive decline experienced implicit interference during a high-effort task, signaling early changes in attention. To further investigate attention's effect on implicit interference, we analyzed two experiments completed sequentially by the same high- and low-risk individuals. We hypothesized that if attention modulates interference, practice would affect the influence of implicit distractors. Indeed, while both groups experienced a strong practice effect, the association between practice and interference effects diverged between groups: stronger practice effects correlated with more implicit interference in high-risk participants, but less interference in low-risk individuals. Furthermore, low-risk individuals showed a positive correlation between implicit interference and EEG low-range alpha event-related desynchronization when switching from high- to low-load tasks. These results demonstrate how attention impacts implicit interference and highlight early differences in cognition between high- and low-risk individuals.

The connection between heart rate variability (HRV), neurological health, and cognition: A literature review.

The heart and brain have bi-directional influences on each other, including autonomic regulation and hemodynamic connections. Heart rate variability (HRV) measures variation in beat-to-beat intervals. New findings about disorganized sinus rhythm (erratic rhythm, quantified as heart rate fragmentation, HRF) are discussed and suggest overestimation of autonomic activities in HRV changes, especially during aging or cardiovascular events. When excluding HRF, HRV is regulated via the central autonomic network (CAN). HRV acts as a proxy of autonomic activity and is associated with executive functions, decision-making, and emotional regulation in our health and wellbeing. Abnormal changes of HRV (e.g., decreased vagal functioning) are observed in various neurological conditions including mild cognitive impairments, dementia, mild traumatic brain injury, migraine, COVID-19, stroke, epilepsy, and psychological conditions (e.g., anxiety, stress, and schizophrenia). Efforts are needed to improve the dynamic and intriguing heart-brain interactions.

Stronger implicit interference in cognitively healthy older participants with higher risk of Alzheimer's disease.

Introduction: Abnormal cerebrospinal fluid amyloid beta (Aß)42 and tau levels have been revealed decades before symptoms onset in Alzheimer's disease (AD); however, the examination is usually invasive and inaccessible to most people. We thus aimed to develop a non-invasive behavioral test that targets early potential cognitive changes to gauge cognitive decline. Specifically, we hypothesized that older cognitive healthy participants would exhibit comparable performance when the task was explicit and relied on conscious cognition. However, when the task was implicit, the performance of participants at high and low risks for AD would bifurcate. That is, early changes in unconscious cognition could be linked to cognitive health. Methods: We measured implicit interference elicited by an imperceptible distractor in cognitively healthy elderly participants with normal (low risk) and pathological (high risk) Aß42/total tau ratio. Participants were required to perform a Stroop task (word-naming or color-naming on an ink-semantics inconsistent word) with a visually masked distractor presented prior to the target task. Results: We found that, under a high-effort task (i.e., color-naming in the Stroop task), high-risk participants suffered interference when the imperceptible distractor and the subsequent target were incongruent in the responses they triggered. Their reaction times were slowed down by approximately 4%. This implicit interference was not found in the low-risk participants. Discussion: These findings indicate that weakened inhibition of distracting implicit information can be a potential behavioral biomarker of early identification of AD pathology. Our study thus offers a new experimental paradigm to reveal early pathological aging by assessing how individuals respond to subperceptual threshold visual stimuli.

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

Synaptic dysfunctions precede cognitive decline in Alzheimer's 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.

Are there consistent abnormalities in event-related EEG oscillations in patients with Alzheimer's disease compared to other diseases belonging to dementia?

Cerebrospinal and structural-molecular neuroimaging in-vivo biomarkers are recommended for diagnostic purposes in Alzheimer's disease (AD) and other dementias; however, they do not explain the effects of AD neuropathology on neurophysiological mechanisms underpinning cognitive processes. Here, an Expert Panel from the Electrophysiology Professional Interest Area of the Alzheimer's Association reviewed the field literature and reached consensus on the event-related electroencephalographic oscillations (EROs) that show consistent abnormalities in patients with significant cognitive deficits due to Alzheimer's, Parkinson's (PD), Lewy body (LBD), and cerebrovascular diseases. Converging evidence from oddball paradigms showed that, as compared to cognitively unimpaired (CU) older adults, AD patients had lower amplitude in widespread delta (>4 Hz) and theta (4-7 Hz) phase-locked EROs as a function of disease severity. Similar effects were also observed in PD, LBD, and/or cerebrovascular cognitive impairment patients. Non-phase-locked alpha (8-12 Hz) and beta (13-30 Hz) oscillations were abnormally reduced (event-related desynchronization, ERD) in AD patients relative to CU. However, studies on patients with other dementias remain lacking. Delta and theta phase-locked EROs during oddball tasks may be useful neurophysiological biomarkers of cognitive systems at work in heuristic and intervention clinical trials performed in AD patients, but more research is needed regarding their potential role for other dementias.

Task switching reveals abnormal brain-heart electrophysiological signatures in cognitively healthy individuals with abnormal CSF amyloid/tau, a pilot study.

Electroencephalographic (EEG) alpha oscillations have been related to heart rate variability (HRV) and both change in Alzheimer's disease (AD). We explored if task switching reveals altered alpha power and HRV in cognitively healthy individuals with AD pathology in cerebrospinal fluid (CSF) and whether HRV improves the AD pathology classification by alpha power alone. We compared low and high alpha event-related desynchronization (ERD) and HRV parameters during task switch testing between two groups of cognitively healthy participants classified by CSF amyloid/tau ratio: normal (CH-NAT, n = 19) or pathological (CH-PAT, n = 27). For the task switching paradigm, participants were required to name the color or word for each colored word stimulus, with two sequential stimuli per trial. Trials include color (cC) or word (wW) repeats with low load repeating, and word (cW) or color switch (wC) for high load switching. HRV was assessed for RR interval, standard deviation of RR-intervals (SDNN) and root mean squared successive differences (RMSSD) in time domain, and low frequency (LF), high frequency (HF), and LF/HF ratio in frequency domain. Results showed that CH-PATs compared to CH-NATs presented: 1) increased (less negative) low alpha ERD during low load repeat trials and lower word switch cost (low alpha: p = 0.008, Cohen's d = -0.83, 95% confidence interval -1.44 to -0.22, and high alpha: p = 0.019, Cohen's d = -0.73, 95% confidence interval -1.34 to -0.13); 2) decreasing HRV from rest to task, suggesting hyper-activated sympatho-vagal responses. 3) CH-PATs classification by alpha ERD was improved by supplementing HRV signatures, supporting a potentially compromised brain-heart interoceptive regulation in CH-PATs. Further experiments are needed to validate these findings for clinical significance.

Plasma Lipolysis and Changes in Plasma and Cerebrospinal Fluid Signaling Lipids Reveal Abnormal Lipid Metabolism in Chronic Migraine.

BACKGROUND: Lipids are a primary storage form of energy and the source of inflammatory and pain signaling molecules, yet knowledge of their importance in chronic migraine (CM) pathology is incomplete. We aim to determine if plasma and cerebrospinal fluid (CSF) lipid metabolism are associated with CM pathology. METHODS: We obtained plasma and CSF from healthy controls (CT, n = 10) or CM subjects (n = 15) diagnosed using the International Headache Society criteria. We measured unesterified fatty acid (UFA) and esterified fatty acids (EFAs) using gas chromatography-mass spectrometry. Glycerophospholipids (GP) and sphingolipid (SP) levels were determined using LC-MS/MS, and phospholipase A2 (PLA2) activity was determined using fluorescent substrates. RESULTS: Unesterified fatty acid levels were significantly higher in CM plasma but not in CSF. Unesterified levels of five saturated fatty acids (SAFAs), eight monounsaturated fatty acids (MUFAs), five ω-3 polyunsaturated fatty acids (PUFAs), and five ω-6 PUFAs are higher in CM plasma. Esterified levels of three SAFAs, eight MUFAs, five ω-3 PUFAs, and three ω-6 PUFAs, are higher in CM plasma. The ratios C20:4n-6/homo-γ-C20:3n-6 representative of delta-5-desaturases (D5D) and the elongase ratio are lower in esterified and unesterified CM plasma, respectively. In the CSF, the esterified D5D index is lower in CM. While PLA2 activity was similar, the plasma UFA to EFA ratio is higher in CM. Of all plasma GP/SPs detected, only ceramide levels are lower (p = 0.0003) in CM (0.26 ± 0.07%) compared to CT (0.48 ± 0.06%). The GP/SP proportion of platelet-activating factor (PAF) is significantly lower in CM CSF. CONCLUSIONS: Plasma and CSF lipid changes are consistent with abnormal lipid metabolism in CM. Since plasma UFAs correspond to diet or adipose tissue levels, higher plasma fatty acids and UFA/EFA ratios suggest enhanced adipose lipolysis in CM. Differences in plasma and CSF desaturases and elongases suggest altered lipid metabolism in CM. A lower plasma ceramide level suggests reduced de novo synthesis or reduced sphingomyelin hydrolysis. Changes in CSF PAF suggest differences in brain lipid signaling pathways in CM. Together, this pilot study shows lipid metabolic abnormality in CM corresponding to altered energy homeostasis. We propose that controlling plasma lipolysis, desaturases, elongases, and lipid signaling pathways may relieve CM symptoms.

EEG measures for clinical research in major vascular cognitive impairment: recommendations by an expert panel.

Vascular contribution to cognitive impairment (VCI) and dementia is related to etiologies that may affect the neurophysiological mechanisms regulating brain arousal and generating electroencephalographic (EEG) activity. A multidisciplinary expert panel reviewed the clinical literature and reached consensus about the EEG measures consistently found as abnormal in VCI patients with dementia. As compared to cognitively unimpaired individuals, those VCI patients showed (1) smaller amplitude of resting state alpha (8-12 Hz) rhythms dominant in posterior regions; (2) widespread increases in amplitude of delta (< 4 Hz) and theta (4-8 Hz) rhythms; and (3) delayed N200/P300 peak latencies in averaged event-related potentials, especially during the detection of auditory rare target stimuli requiring participants' responses in "oddball" paradigms. The expert panel formulated the following recommendations: (1) the above EEG measures are not specific for VCI and should not be used for its diagnosis; (2) they may be considered as "neural synchronization" biomarkers to enlighten the relationships between features of the VCI-related cerebrovascular lesions and abnormalities in neurophysiological brain mechanisms; and (3) they may be tested in future clinical trials as prognostic biomarkers and endpoints of interventions aimed at normalizing background brain excitability and vigilance in wakefulness.

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 (8-12 Hz) and widespread delta (< 4 Hz) and theta (4-8 Hz) 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.

Evidence that blood-CSF barrier transport, but not inflammatory biomarkers, change in migraine, while CSF sVCAM1 associates with migraine frequency and CSF fibrinogen.

OBJECTIVE: Our objective is to explore whether blood-cerebrospinal fluid (CSF) barrier biomarkers differ in episodic migraine (EM) or chronic migraine (CM) from controls. BACKGROUND: Reports of blood-brain barrier and blood-cerebrospinal fluid barrier (BCSFB) disruption in migraine vary. Our hypothesis is that investigation of biomarkers associated with blood, CSF, brain, cell adhesion, and inflammation will help elucidate migraine pathophysiology. METHODS: We recruited 14 control volunteers without headache disorders and 42 individuals with EM or CM as classified using the International Classification of Headache Disorders, 3rd edition, criteria in a cross-sectional study located at our Pasadena and Stanford headache research centers in California. Blood and lumbar CSF samples were collected once from those diagnosed with CM or those with EM during two states: during a typical migraine, before rescue therapy, with at least 6/10 level of pain (ictal); and when migraine free for at least 48 h (interictal). The average number of headaches per month over the previous year was estimated by those with EM; this enabled comparison of biomarker changes between controls and three headache frequency groups: <2 per month, 2-14 per month, and CM. Blood and CSF biomarkers were determined using antibody-based methods. RESULTS: Antimigraine medication was only taken by the EM and CM groups. Compared to controls, the migraine group had significantly higher mean CSF-blood quotients of albumin (Qalb : mean ± standard deviation (SD): 5.6 ± 2.3 vs. 4.1 ± 1.9) and fibrinogen (Qfib mean ± SD: 1615 ± 99.0 vs. 86.1 ± 55.0). Mean CSF but not plasma soluble vascular cell adhesion molecule-1 (sVCAM-1) levels were significantly higher in those with more frequent migraine: (4.5 ng/mL ± 1.1 in those with <2 headache days a month; 5.5 ± 1.9 with 2-14 days a month; and 7.1 ± 2.9 in CM), while the Qfib ratio was inversely related to headache frequency. We did not find any difference in individuals with EM or CM from controls for CSF cell count, total protein, matrix metalloproteinase-9, soluble platelet-derived growth factor receptor ß, tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-6, IL-8, IL-10, or C-reactive protein. CONCLUSIONS: The higher Qalb and Qfib ratios may indicate that the transport of these blood-derived proteins is disturbed at the BCSFB in persons with migraine. These changes most likely occur at the choroid plexus epithelium, as there are no signs of typical endothelial barrier disruption. The most striking finding in this hypothesis-generating study of migraine pathophysiology is that sVCAM-1 levels in CSF may be a biomarker of higher frequency of migraine and CM. An effect from migraine medications cannot be excluded, but there is no known mechanism to suggest they have a role in altering the CSF biomarkers.

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's 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 (N = 0 or 2). Cognitively healthy (CH) study participants (≥60 years old) of both sexes were divided into two subgroups: normal amyloid/tau ratios (CH-NAT, n = 10) or pathological amyloid/tau (CH-PAT, n = 14) in cerebrospinal fluid (CSF). During low load (0-back) challenge, low gamma is higher in CH-PATs than CH-NATs over frontal and central regions (p = 0.014∼0.032, effect size (Cohen's d) = 0.95∼1.11). However, during high load (2-back) challenge, low gamma is lower in CH-PATs compared to CH-NATs over the left temporal region (p = 0.045, Cohen's d = -0.96), and high gamma is lower over the parietal region (p = 0.035, Cohen's d = -1.02). Overall, our studies show a medium to large negative effect size across the scalp (Cohen's d = -0.51∼-1.02). In addition, low gamma during 2-back is positively correlated with 0-back accuracy over all regions except the occipital region only in CH-NATs (r = 0.69∼0.77, p = 0.0098∼0.027); high gamma during 2-back correlated positively with 0-back accuracy over all regions in CH-NATs (r = 0.68∼0.78, p = 0.007∼0.030); high gamma during 2-back negatively correlated with 0-back response time over parietal, right temporal, and occipital regions in CH-NATs (r = -0.70∼-0.66, p = 0.025∼0.037). We interpret these preliminary results to show: (1) gamma power is compromised in AD-biomarker positive individuals, who are otherwise cognitively healthy (CH-PATs); (2) gamma is associated with WM performance in normal aging (CH-NATs) (most significantly in the frontoparietal region). Our pilot findings encourage further investigations in combining cognitive challenges and qEEG in developing neurophysiology-based markers for identifying individuals in the prodromal stage, to help improving our understanding of AD pathophysiology and the contributions of low- and high-frequency gamma oscillations in cognitive functions.

Correction: Retinal nerve fiber layer thickness predicts CSF amyloid/tau before cognitive decline.

[This corrects the article DOI: 10.1371/journal.pone.0232785.].

Retinal nerve fiber layer thickness predicts CSF amyloid/tau before cognitive decline.

BACKGROUND: Alzheimer's disease (AD) pathology precedes symptoms and its detection can identify at-risk individuals who may benefit from early treatment. Since the retinal nerve fiber layer (RNFL) is depleted in established AD, we tested whether its thickness can predict whether cognitively healthy (CH) individuals have a normal or pathological cerebrospinal fluid (CSF) Aß42 (A) and tau (T) ratio. METHODS: As part of an ongoing longitudinal study, we enrolled CH individuals, excluding those with cognitive impairment and significant ocular pathology. We classified the CH group into two sub-groups, normal (CH-NAT, n = 16) or pathological (CH-PAT, n = 27), using a logistic regression model from the CSF AT ratio that identified >85% of patients with a clinically probable AD diagnosis. Spectral-domain optical coherence tomography (OCT) was acquired for RNFL, ganglion cell-inner plexiform layer (GC-IPL), and macular thickness. Group differences were tested using mixed model repeated measures and a classification model derived using multiple logistic regression. RESULTS: Mean age (± standard deviation) in the CH-PAT group (n = 27; 75.2 ± 8.4 years) was similar (p = 0.50) to the CH-NAT group (n = 16; 74.1 ± 7.9 years). Mean RNFL (standard error) was thinner in the CH-PAT group by 9.8 (2.7) µm; p < 0.001. RNFL thickness classified CH-NAT vs. CH-PAT with 87% sensitivity and 56.3% specificity. CONCLUSIONS: Our retinal data predict which individuals have CSF biomarkers of AD pathology before cognitive deficits are detectable with 87% sensitivity. Such results from easy-to-acquire, objective and non-invasive measurements of the RNFL merit further study of OCT technology to monitor or screen for early AD pathology.