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Abstract: Background: Stroop task is used to evaluate inhibition, a core executive function. Alpha Event‐Related Desynchronization (ERD) from analysis of electroencephalogram (EEG) during Stroop task reflects brain interference processing. We previously reported different relationships between heart rate variability (HRV) and alpha ERD during Stroop task. However, HRV proxied autonomic function can be confounded by increasing erratic rhythm with age, quantified by heart rate fragmentation (HRF). The knowledge of HRF is limited in a Cognitively Healthy (CH) cohort. To fill this gap, we studied these measurements in CH participants who underwent a Stroop task. Method: We studied HRF in an established EEG dataset during Stroop task from CH participants when their CSF amyloid/tau ratio were normal (≥2.71, CH‐NATs) or pathological (

Alterations in functional connectivity (FC) have been observed in individuals with Alzheimers disease (AD) with elevated amyloid (Aβ) and tau. However, it is not yet known whether directed FC is already influenced by Aβ and tau load in cognitively healthy (CH) individuals. A 21-channel electroencephalogram (EEG) was used from 46 CHs classified based on cerebrospinal fluid (CSF) Aβ 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 Aβ/tau.

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.

BACKGROUND: Alzheimers 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.

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

ImportanceHigher dietary intake of the essential fatty acid docosahexaenoic (DHA) has been associated with better cognitive performance in several epidemiological studies. Animal and in vitro studies also indicate that DHA prevents amyloid deposition in the brain.ObjectiveTo determine the association between serum DHA levels, cerebral amyloidosis, and the volumes of brain areas affected by Alzheimer disease.Design, settings, and participantsCross-sectional analysis of serum DHA levels together with measures of amyloid deposition (Pittsburgh Compound B index), brain volumes, and neuropsychological testing scores from 61 participants in the Aging Brain Study. The study was conducted between June 2008 and May 2013, and the data were analyzed between October 2015 and April 2016. Linear models were adjusted for age, sex, years of education, and apolipoprotein E status.Main outcomes and measuresSerum DHA levels with cerebral amyloidosis measured using PIB PET.ResultsSamples were available from 61 Aging Brain Study participants (41 women and 20 men) who underwent amyloid PET imaging. The mean (SD) age of the participants was 77 (6) years and ranged from 67 to 88 years. Serum DHA levels (percentage of total fatty acids) were 23% lower in participants with cerebral amyloidosis than those without (0.97 vs 1.25, P = .007) and were inversely correlated with brain amyloid load (r = -0.32, P = .01) independent of age, sex, apolipoprotein E genotype, and years of education. Moreover, greater serum DHA levels were positively associated with brain volume in several subregions affected by AD, in particular the left subiculum (r = 0.38, P = .005) and the left entorhinal volumes (r = 0.51, P = .001). Serum DHA levels were also associated with nonverbal memory scores (r = 0.28, P = .03).Conclusions and relevanceIn this study, serum DHA levels were associated with pathogenesis of cerebral amyloidosis and with preservation of entorhinal and hippocampal volumes. These findings suggest an important role for DHA metabolism in brain amyloid deposition during the preclinical or early symptomatic stages of Alzheimer disease.

Background: Disrupted brain connectivity precedes cognitive impairment in Alzheimer's disease (AD), affects self‐regulation and executive functions, and can be revealed by quantitative electroencephalography (qEEG). Neuroimaging research on AD progression has demonstrated structural and functional abnormalities in specific brain regions and connections. However, little is known about the changes in directional functional connectivity in pre‐symptomatic AD. We aim to explore the information flow in pre‐symptomatic AD during cognitive flexibility challenge. Method: During a task‐switching challenge, 21‐head channel EEG was recorded from 55 cognitively healthy individuals classified into two groups (9 were excluded from artifacts or suboptimal performance): with an abnormal (CH‐PAT, n = 27) versus normal (CH‐NAT or controls, n = 19) ratio of cerebrospinal fluid (CSF) amyloid/total‐tau. In the task‐switching paradigm, each trial included two stimuli, and participants were required to either name the ink color or read the word when color words were printed in different colors of ink. Only correctly responded trials were analyzed. Directed functional connectivity between brain regions was estimated with Partial Directed Coherence (PDC) in frontal, central, parietal, temporal, and occipital regions in alpha frequency band (8‐12 Hz) during word‐color trials. Two‐sided t‐tests were conducted, with p<0.05 considered the level for significance. No multiple comparison correction was used for this exploratory study. Result: Pilot analysis shows significant differences between CH‐PATs and CH‐NATs: CH‐PATs has shown decreased information flow from the temporal and occipital regions compared to CH‐NATs with p‐values of 0.001 and 0.04, respectively. In addition, frontal brain regions have shown enhanced information flow in the CH‐PATs compared to CH‐NATs (p = 0.02) (Figs 1&2). Moreover, greater information flow between the medio‐frontal cortex and occipital regions was observed in CH‐PATS than CH‐NATS (Fig 1). Conclusion: Compared to CH‐NATs, the enhanced connectivity in frontal regions in CH‐PATs suggests that their frontal brain regions are compensating for the damage caused by the amyloid/tau pathology. The decreased information flow from temporal and occipital regions in CH‐PATs may indicate a loss of relative functional importance of these regions. Our exploratory findings provide a novel and alternative approach for connectivity‐based analysis to identify the effects of amyloid/tau pathology in CH participants. [ABSTRACT FROM AUTHOR]

Background: Non‐invasive molecules related to AD imaging biomarkers can reveal disease mechanisms and may help in the mass screening of an aging population. Our study aims to determine if urine dicarboxylic acids (DCA) that changed in AD are coupled with brain volume changes. Method: Study participants (> 65 years) were recruited in an ongoing HMRI Brain aging study, and MRI data were acquired and analyzed using NeuroQuant. The data were normalized to the intracranial volume (icv). DCAs were quantified using gas chromatography/mass spectrometry. We compared DCA and icv‐normalized brain region volumes in two ways: first, we used descriptive statistics to obtain the median (Q2) for short‐chain DCAs (C4+C5), medium‐chain DCAs (C7+C8+C9) and the ratio of short to medium chain DCAs ((C4+C5)/(C7+C8+C9)). Brain regions were then sorted to correspond to less than (Q2). Differences were determined using two‐sample t‐tests and Wilcoxon rank‐sum tests with adjustment for multiple comparisons using FDR. Secondly, icv‐normalized brain regions and T1 hypo‐intensity were compared with DCA levels using a two‐tailed student's t‐test. Result: There was no significant difference in the DCA levels of participants with low (icvQ2) (Fig.1A). In contrast, C4+C5 levels were higher, while C7+C8+C9 were lower in participants with higher whole brain volumes (WBV) (Fig. 1B). In addition, hippocampal volumes were greater when participants had a higher urine C4+C5 and lower C7+C8+C9. We identified 19 other icv‐normalized brain regions that were bigger when urine C4+C5 levels were high. In addition, participants with higher white matter hypo‐intensities had lower urine C4+C5 and a higher C7+C8+C9 DCA levels (Table 1). Conclusion: These data suggest that urine lipid composition is linked to icv‐normalized brain volumes. Higher mitochondrial‐associated lipids reflected larger brain volumes, while oxidized lipids indicated lower brain volumes. Thus, urine lipid levels can be used as surrogate biomarkers in clinical trials targeting brain volume changes. We will use a bigger sample size normalized for ApoE genotype, age, and sex to further examine lipids and brain volumes in participants with different cognitive states. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) impacts brain regions associated with memory and executive function in early stages. The Stroop task is used to evaluate inhibition, a common factor for executive functioning. Alpha Event‐Related Desynchronization (ERD) from electroencephalogram (EEG) analysis evaluates brain activation during a task. Also of interest is cardiovascular function such as heart rate (HR) and blood pressure (BP) as it relates to cognitive functioning in AD progression. However, the combined analysis of functional EEG with HR and BP have not been thoroughly reported in a Cognitively Healthy (CH) cohort. To fill this gap, we studied these measurements in CH participants who underwent a Stroop task. Method: We previously reported Stroop alpha ERD of CH participants when their cerebrospinal fluid amyloid/tau ratio were normal (≥2.71, CH‐NATs) or pathological (<2.71, CH‐PATs). Their heart rate (HRmax, HRmin, and HRmax‐HRmin) were analyzed from 5‐minute electrocardiogram (ECG) during resting or Stroop testing. Using a second cohort, including 22 CH‐NATs and 15 CH‐PATs, we analyzed alpha ERD while participants completed a Stroop task on a computer wearing a dry electroencephalogram (EEG) headset with 19 head sensors, which were correlated with HR and BP collected pre‐ and post‐task using an automatic blood pressure monitor. Result: HRmax and HRmax‐HRmin from rest to task were significantly increased in CH‐PATs but not CH‐NATs, while HRmin significantly increased in CH‐NATs (Fig. 1). Frontal alpha ERD during incongruent trials were positively correlated with pre‐(R2 = 0.43, p = 0.008) and post‐(R2 = 0.42, p = 0.009) task HR in CH‐PATs but not CH‐NATs. Pre‐test diastolic BP correlated positively with central alpha ERD during congruent trials in CH‐NATs (R2 = 0.20, p = 0.039) but not CH‐PATs (Fig. 2). Conclusion: These pilot results suggest 1) from resting to task, CH‐NATs presented greater HRmin, while CH‐PATs presented greater HRmax and HRmax‐HRmin; 2) HR is positively correlated with alpha ERD in CH‐PATs such that higher HR related to less brain activation (less negative alpha ERD). Higher pre‐task diastolic BP related to less brain activation in CH‐NATs. Although a larger sample is needed, these results support a potential application of non‐invasive EEG and ECG to identify those at higher risk of cognitive decline. [ABSTRACT FROM AUTHOR]

Background: The CSF amyloid to tau ratio can isolate cognitively healthy participants into normal Aβ42/tau (CH‐NAT) or a pathological Aβ42/tau (CH‐PAT) with a low or high risk of cognitive decline, respectively. We aim to determine if plasma Aβ42/tau ratios can differentiate CH‐NAT from CH‐PAT participants. Method: Study participants (> 65 years of age) were recruited, and demographic, neurological, and neuropsychological data were obtained in an ongoing HMRI Brain Aging study. Overnight fasting plasma and CSF were collected within a month of examination, and the levels of Aβ38, Aβ40, Aβ42 (MSD 6E10 kit), and total tau were quantified using the MSD electrochemiluminescence platform. Differences in fluid biomarker levels and the plasma ratios (n = 55) and CSF ratios (Aβ42/Aβ40, n = 41, Aβ42/tau, n = 55) were determined using nonparametric student t‐test and correlations using a Spearman test. Result: Aβ40 and Aβ42 levels were higher (15‐18‐fold, and 10‐14‐fold, respectively), while tau levels are 8‐13‐fold higher in CSF than in plasma. Plasma and CSF Aβ40 were not distinct in CH‐NAT compared with CH‐PAT. In contrast, Aβ42 levels were 30.9% lower in CH‐PAT (16.3 ± 18.3 pg/ml) compared with CH‐NAT plasma (23.6 ± 26.4 pg/mL) (p < 0.05). CSF Aβ42 levels in CH‐PAT (171.6 ± 124.6 pg/mL) were lower by 47.6% compared with CH‐NAT (327.6 ± 182.6 pg/ml) (p < 0.0001). The Aβ42/Aβ40 ratio was significantly lower in both plasma and CSF (Table 1A). Similarly, the Aβ42/tau ratio was significantly lower in plasma and CSF (Table 1B). Individually, plasma levels of Aβ42 and tau did not correlate with CSF levels. However, the ratio of Aβ42 to total tau in plasma significantly correlated with the CSF ratios (Spearman r = 0.36, p = 0.0071). Finally, CSF Aβ42/Aβ40 ratio correlated with Aβ42/tau ratio for all samples, CH (n = 100) and MCI (n = 35) (Fig. 1). Conclusion: While not as robust as CSF ratios, plasma Aβ42/Aβ40 and Aβ42/tau ratios can isolate cognitively healthy participants with lower risk from participants with a higher risk of cognitive decline. Thus, plasma represents a less invasive medium for the biomarker classification of aging participants. [ABSTRACT FROM AUTHOR]

Disturbances in the brain's capacity to meet its energy demand increase the risk of synaptic loss, neurodegeneration, and cognitive decline. Nutritional and metabolic interventions that target metabolic pathways combined with diagnostics to identify deficits in cerebral bioenergetics may therefore offer novel therapeutic potential for Alzheimer's disease (AD) prevention and management. Many diet‐derived natural bioactive components can govern cellular energy metabolism but their effects on brain aging are not clear. This review examines how nutritional metabolism can regulate brain bioenergetics and mitigate AD risk. We focus on leading mechanisms of cerebral bioenergetic breakdown in the aging brain at the cellular level, as well as the putative causes and consequences of disturbed bioenergetics, particularly at the blood‐brain barrier with implications for nutrient brain delivery and nutritional interventions. Novel therapeutic nutrition approaches including diet patterns are provided, integrating studies of the gut microbiome, neuroimaging, and other biomarkers to guide future personalized nutritional interventions. [ABSTRACT FROM AUTHOR]

Date Presented 03/22/24 This scoping review, spanning peer-reviewed and gray literature, summarizes interventions for health equity in children with disabilities and additional marginalized identities. Results from 31 articles inform approaches for promoting health parity. Primary Author and Speaker: Christie Cyktor Contributing Authors: Amy Houtrow, Jessica Jarvis, Ateh Fonteh, Helina Mengesha [ABSTRACT FROM AUTHOR]

Background: Growing need exists to link volumetric brain analysis to functional cognitive performance in early prediction of Alzheimer's disease. Method: In cognitively healthy older adults (N = 40; M age = 71.7±7.7 years), we established amyloid/tau ratios from cerebrospinal fluid, thus finding a small group with pathological amyloid/tau ratios (PAT, n = 11) and normal ratio (NAT, n = 29). Approximately 40% of the PAT group were expected to convert to mild cognitive impairment within 4 years. It was hypothesized that reduced performance on the California Verbal Learning Test‐II (CVLT‐II) Short Delay Free (SDFR) and Cued Recall (SDCR) task would be associated with smaller hippocampal and temporal lobe volume (obtained via NeuroQuant). Result: Hippocampal total, left, and right percentiles were found to be negatively associated with SDFR in the PAT group, r(38) = ‐.67*, ‐.66*, and ‐.63*, but not in the NAT group, r(38) = ‐.21, ‐.04, and ‐.35, such that a larger hippocampus was associated with fewer remembered words after a short delay on a list learning task in those with pathological amyloid/tau ratios. Temporal lobe volume was also found to be negatively associated with SDFR and SDCR in the PAT group, r(38) = ‐.67* and ‐.69*, but not in the NAT group, r(38) = ‐.36 and ‐.34, such that a larger temporal lobe was associated with fewer remembered words after a short delay on a list learning task (even when cued) in those with smaller amyloid/tau ratios. Two hierarchical multiple regression analyses, one including amyloid/tau ratio and the other including amyloid only, found that age and sex associate with ∼20.4% variance of the performance on the CVLT‐II SDFR task while temporal lobe volume increased associative value by 16.1% in the former [F (1, 35) = 8.871, p <.05] and by 15.4% in the latter [F (1, 35) = 8.430, p <.05]. Conclusion: Our findings suggest there may be early compensation in brain structures among cognitively healthy individuals whose CSF biomarker suggest increased risk for the development of symptomatic Alzheimer's disease, such that hippocampi and temporal lobes increase in size during early pre‐Alzheimer's stages despite reduced performance on memory tasks. [ABSTRACT FROM AUTHOR]

Background: Alpha oscillations during task switching reveals general attention (low alpha) and higher executive attentional control (high alpha). Alpha oscillations have been related to heart rate variability (HRV), both change in Alzheimer's disease (AD). We aim to explore if task switching challenge with quantitative electroencephalography (qEEG) can reveal abnormal alpha power and HRV in individuals with high risk of AD, and we predict HRV improves qEEG's detection of high AD risk. Method: We compared alpha power during task switching testing between two groups of cognitively healthy participants (52‐91 years) based on different cerebrospinal fluid (CSF) amyloid/tau ratio: normal (CH‐NAT, n=19) or pathological amyloid/tau ratio (CH‐PAT, n=27). Participants were required to name the color or word of a colored word for each stimulus, with two sequential stimuli per trial. Alpha event‐related desynchronization (ERD) was analyzed during low load, repeat trials (color‐color or word‐word) and high load, switch trials (color‐word or word‐color). HRV was assessed from 5‐minute ECG recording during rest or task, including: standard deviation of RR‐intervals (SDNN), root mean squared of successive differences (RMSSD) in the time domain, as well as high (HF) and low frequency (LF) in the frequency domain. We trained a binary classifier to predict the CH‐PATs using a 30 random split of training (80%) and testing (20%) data and two‐layer, fully connected neural network after identifying significant qEEG and HRV features. Result: We found that low alpha power was less negative in CH‐PATs than CH‐NATs (Central: ‐0.18±0.66 vs. ‐0.72±0.72, p=0.011, Cohen's d=0.79; Parietal: ‐0.25±0.75 vs. ‐0.83±0.92, p=0.024, Cohen's d=0.70) (Fig. 1). Furthermore, we observed significant HR and LF changes from resting to task state only in CH‐PATs, but not in CH‐NATs (Fig. 2). After identifying brain features and heart features, we explored the HRV effect on brain features' test accuracy. Conclusion: These results suggest: 1) low alpha power during task switching challenge differs between CH‐PATs and CH‐NATs; 2) HRV suggests hyperactive autonomic regulations from resting to task in CH‐PATs, but not CH‐NATs. qEEG reveals interaction of brain and heart features in early AD pathology that may help early diagnosis and monitoring of novel therapies. [ABSTRACT FROM AUTHOR]

Background: The health benefits of odd‐chain saturated fatty acids (ocSAFA) have recently been recognized. We previously showed decreased unesterified ocSAFA in cerebrospinal fluid (CSF) of AD compared to MCI and cognitively healthy (CH). However, changes in ocSAFA relative to even‐chain saturated fatty acids (ecSAFA) have not been determined in other biofluids. Therefore, we aim to determine if levels of ocSAFA and ecSAFA may reveal AD pathology in urine. Methods: We used neuropsychology and CSF measures of Ab42 and T‐tau to classify groups of elderly subjects as cognitively healthy (CH) with negative Ab42 (CH‐Ab‐), cognitively healthy with positive Ab42 (CH‐Ab+), MCI, and AD. We collected urine after an overnight fast and quantified unesterified fatty acids (UFA) and esterified fatty acids (EFA) using gas chromatography coupled with negative‐ion chemical ionization mass spectrometry. For data normalization, we measured ocSAFA species (C15:0, C17:0, C19:0) and ecSAFA species (14:0, C16:0, C18:0, C20:0, C22:0, C24:0) as a proportion of the sum of all UFA or EFA > C14:0 in urine. We calculated group differences using ordinary ANOVA with Tukey's multiple comparison tests. Results: Urine unesterified C15:0 levels were significantly higher in AD than in MCI and CT (p = 0.0016). Similarly, esterified levels of ocSAFA were higher in AD than in MCI and CT (p<0.0001). Although Aβ42 levels in CH‐Aβ+ and AD are not significantly different, unesterified C15:0, esterified C17:0, C19:0, and total esterified ocSAFA were significantly higher in AD urine than in CH‐Aβ+. Urinary unesterified ecSAFA levels did not change in AD compared with CH and MCI. In contrast, esterified ecSAFA decreased in AD compared to CH. While esterified C16:0 decreased, esterified C18:0 increased in AD urine compared to CH and MCI. These changes result in a significant decrease in the C18:0/C16:0 ratio in AD (Fig. 1). The ratio of esterified ocSAFA to ocSAFA was higher in AD than CH and MCI (p<0.0001) (Fig. 2). Conclusions: These studies suggest that urine saturated fatty acids can reveal AD‐associated pathology. Therefore, measurement of urine fatty acids can be used to monitor AD‐linked biochemical pathways or to monitor therapies targeting saturated fatty acid metabolism in AD. [ABSTRACT FROM AUTHOR]

Background: Age related atrophy occurs in Alzheimer's disease and related dementia (ADRD). Although atrophy was reported in early stage as mild cognitive impairment (MCI), the knowledge about earlier changes is limited. To fill this knowledge, we explored the age‐related atrophy in our pilot MRI database when participants at different stages of ADRD. Method: MRI data are analyzed using NeuroQuant. We studied MRI data in cognitively healthy (CH, n=74) individuals when their cerebrospinal fluid (CSF) amyloid/tau ratios were normal (CH‐NATs, n=18) or pathological (CH‐PATs, n=41), in participants with impaired or MCI (n=9), and Alzheimer's disease (AD, n=6), and other dementia (OD, n=6). We explored age, gender‐corrected norm percentiles for atrophy analysis in age‐related structures – (including hippocampal occupancy score (HOC, percent of hippocampi volume relative to inferior lateral ventricle volume), hippocampi, entorhinal cortex, and inferior lateral ventricles) and whole brain, cerebral white matter. We compared the data between CH, MCI, AD, and OD, compared between CH‐NATs and CH‐PATs, and compared between CH with cerebrospinal fluid (CSF) amyloid pathology (ChA+, n=15) and CH without CSF pathology (ChA‐T‐N‐, n=13) based on CSF Aβ42, phosphor‐tau (p‐tau), and total tau (t‐tau). Bonferroni correction was used for Multiple comparisons. Result: Analysis of MRIs collected at HMRI show neuro‐quantitative data in CH participants compared to MCI, AD, or OD, and MCI to AD and OD. Compared to CH, MCI have decreased HOC and larger superior lateral ventricle (Table 1, Figure 1), AD have decreased HOC, hippocampi, whole brain, and cerebral white matter, and larger lateral ventricles, OD have similar changes except hippocampi (no change). No significant changes observed between MCI and AD or OD. No significant changes were observed between CH‐NATs and CH‐PATs, or between ChA+ and ChA‐T‐N‐. Conclusion: Despite sample size limitation, these results suggest: 1) norm percentile is sensitive to age‐related atrophy at impaired stages, consistent with known changes; Whole brain volume decreases in AD and OD, only AD observed decreased hippocampal atrophy; 2) No apparent age‐related changes were observed in CH stage. Overall, MRI age‐ and gender‐corrected norm percentile for age‐related atrophy analysis is informative in individuals as early as MCI stage. [ABSTRACT FROM AUTHOR]

Background: Both resting heart rate variability (HRV) and resting heart rate (HR) are regulated by the central autonomic network linking prefrontal cortex with cardiac regulation. To better understand the interactions between the heart and cognition we determined the relationships between resting HR/HRV and cognitive function. Method: We compared and correlated resting HR with Mini‐Mental State Exam (MMSE) in cognitively healthy (CH, n=137) individuals when their CSF amyloid/tau ratios were normal (CH‐NATs, n=51) or pathological (CH‐PATs, n=68), in participants with mild cognitive impairment (MCI, n=54), and Alzheimer's disease (AD, n=42). We also compared and correlated HRV with behavioral performance (accuracy and response time) or alpha event‐related desynchronization (ERD) during Stroop (interference) or task switching testing between subsets of CH‐NATs and CH‐PATs. Cognitive tasks include: 1) Stroop during low load (congruent trials) and high load (incongruent trials); 2) task switching during low load, repeat trials (color‐color or word‐word) and high load, switch trials (color‐word or word‐color). HRV was assessed from 5‐minute resting ECG recording, including: HR and root mean squared of successive differences (RMSSD) that reflect vagal activities. Result: No differences of resting HR or HRV were observed between CH‐NATs, CH‐PATs, MCI, and AD. Interestingly, resting HR negatively correlated with MMSE only in CH‐PATs (r=‐0.57, p=0.002), but not in CH‐NATs (r=0.07, p=0.71), CH (r=‐0.09, p=0.57), MCI (r=‐0.14, p=0.41), or AD (r=‐0.11, p=0.59) (Fig 1). For Stroop interference testing, resting HR (preceding task) positively correlated with frontal alpha ERD during high load trails (r=0.78, p=0.017) in CH‐PATs, but not in CH‐NATs (Fig 2). For task switch testing, resting RMSSD positively correlated with accuracy during switch trials (r=0.64, p=0.004) in CH‐NATs, but not in CH‐PATs (Fig 3). Conclusion: These results suggest: 1) resting HR is linked with cognition in CH‐PATs; 2) resting HR is related to inhibitory control in CH‐PATs: higher HR linked with less negative alpha ERD (less activation); 3) resting HRV predicts task switching performance in CH‐NATs: higher RMSSD linked with higher accuracy. Overall, resting HR and HRV potentially reflect cognition and executive functions that differentiate CH‐NATs and CH‐PATs, suggesting different cerebral‐cardiovascular integration in these two populations. [ABSTRACT FROM AUTHOR]

Background: Framingham, or cardiovascular (CVD) risk score, as a composite score can accurately predict long‐term CVD risk in the general population. General lipid profiles contribute to CVD risk and Alzheimer's disease (AD) with inconsistent reports: both high and low triglyceride or body mass index (BMI) have been linked with AD risk. However, the knowledge of their contribution to early AD is limited. To study the changes of CVD risk score and lipid in early AD, we explored the CVD risk score and lipid profile risk factors in our aging cohort. Method: We compared estimated CVD risk score (Erisk) between cognitively healthy (CH, n=137) individuals, in participants with mild cognitive impairment (MCI, n=54), AD (n=42), and other dementia (OD) (n=23). We also compared lipid profile risk factors (BMI, triglyceride, cholesterol, high‐density lipoprotein (HDL) cholesterol, low‐density lipoprotein (LDL) cholesterol, and very low‐density lipoprotein (VLDL) cholesterol). Furthermore, we compared those risk factors in CH participants subgroups with different status of CSF amyloid (A), phospho‐tau (T), and total‐tau (N): between those with AD risk (A+T±N±: ChA+) and those without (ChA‐T‐N‐). Bonferroni correction was used for multiple comparisons. Result: Erisk and lipid profiles were not different between CH, MCI, AD, or OD. We observed lower triglyceride and VLDL cholesterol, and marginally lower BMI, in ChA+ group than in ChA‐T‐N‐ group (p<0.008, Fig 1). Conclusion: These pilot results suggest that CH participants with amyloid pathology presented with lower triglyceride and VLDL cholesterol values, and marginally lower BMI. Although these data need to be confirmed in a larger population, our study supports the concept that lower levels of triglycerides, VLDL cholesterol, or BMI may be linked to amyloid pathology in the CH stage. Further studies examining related factors and pathways that contribute to amyloid pathology such as APOE genotype and VLDL‐receptor expression are needed to fully understand the implications of our findings. [ABSTRACT FROM AUTHOR]

Background: The entorhinal cortex (ERC) area in the brain is affected early in AD, particularly among APOE4 carriers. We previously reported a positive association between plasma phospholipid docosahexaenoic acid (DHA) levels and the ERC thickness in the Aging Brain Program. We hypothesize that increases in plasma DHA after high‐dose DHA supplementation protects against thinning of the ERC when started before cognitive impairment including in APOE4 carriers, and that ERC thickness can be a useful marker for DHA supplementation efficacy. Method: We examined the effect of DHA treatment and association of plasma DHA species on the changes in the ERC area in the DHA Brain Delivery Pilot Trial (NCT02541929). T1‐weighted MRI scans were collected at 3T and FreeSurfer software was used to segment the ERC thickness. Total DHA, DHA in phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and phosphatidylethanolamine (PE) were measured in plasma together with Red blood cell (RBC) DHA levels before and after randomization to 2 grams of triglyceride DHA per day vs placebo over 6 months (n=28). Participants were all cognitively normal, consumed less than 200 mg of DHA per day, and were stratified by APOE4 genotype before randomization. Result: DHA treatment, adjusted for APOE4, was associated with a significant increase in ERC area thickness compared with placebo (mean group difference in ERC change (95% CI) 0.161 (0.003, 0.319), p=0.046). Among DHA subspecies measured, greater increase in plasma PC DHA levels after supplementation was significantly correlated with greater ERC area (mean ERC change per SD of PC DHA=0.103, p=0.011). The association persisted after adjusting for APOE4 status (mean ERC change per SD of PC DHA=0.109, p=0.007), indicating that the effect was independent of APOE4 status. Conclusion: These preliminary findings support a protective effect of high dose DHA in preserving the ERC thickness, including among APOE4 carriers. This finding supports early intervention, before the onset of cognitive impairment, with high dose DHA supplementation in individuals at risk of cognitive decline. PREVENTE4 trial (NCT03613844) is ongoing to help understand whether high dose DHA can prevent cognitive decline in individuals at increased risk of AD. HNY is supported by AA NIRG‐15‐361854, R01AG054434, R21AG056518, ADDF GC‐201711‐2014197. [ABSTRACT FROM AUTHOR]

Background: We previously identified urine dicarboxylic acids (DCA) of carbon length 4‐9 as candidate biomarkers of probable Alzheimer's disease (AD) and energy dysregulation, and found their levels correlated with hippocampal volume. Our aim was to evaluate these initial findings in a second cohort. Method: Study participants (> 65 years) were classified clinically as cognitively healthy (CH, n=188) or with probable AD (n=66) based on Uniform Data System‐3 of the National Alzheimer's Coordinating Center criteria. Cerebrospinal fluid (CSF) amyloid ß42 (A) and phospho‐ tau (T) levels were measured by validated immunoassay. Urine was collected in a "spot" sample after a 12 h overnight fast; target DCAs were detected using gas chromatography coupled with negative ion chemical ionization mass spectrometry and each DCA was normalized to deuterated internal standards and to a percent of total fatty acids. Result: The mean of short‐chain DCA's (C4‐C5) were higher in CH (44.38% ±17.79) compared to AD individuals (34.79% ±12.39) (p=0.0002), while the long‐chain DCA's (C7‐C9) were lower for CH (34.70% ±16.88) when compared to AD individuals (45.22% ±15.11) (p<0.0001). DCA levels in the subset of CH participants with A+/T+ were in a transition to the levels of the AD group and C4‐C5 and C7‐C9 differed from those with A‐/T‐ biomarkers (p=0.0001). Combining results into a ratio of short‐ to long‐chain DCAs distinguished the A‐/T‐ (2.330 ±2.144) from the A+/T+ group (1.178 ±0.946); p<0.0001. ROC curve of the DCA ratio between CH‐NAT and AD is 82%. Study participant clinical and DCA groups were not significantly correlated with the common confounders of age, sex, education or ApoE genotype. Conclusion: Our data extends our initial finding that urine DCA measures have potential as biomarkers of AD pathology, including for cognitively healthy individuals who are positive for CSF AT biomarkers. We propose that measurement of urine DCAs provides a new approach to screen for metabolic fluctuations in early AD and to monitor the effect of novel therapies in clinical trials. While studies are needed, including with other populations, varied clinical classifications, simplified chemistry, this data supports DCA biomarkers for widespread screening since the necessary urine sample is available from everyone. [ABSTRACT FROM AUTHOR]

Background: The association between neurochemical pathways and Electroencephalogram (EEG) signals has not been fully explored. We previously showed alpha desynchronization during interference testing decreased in preclinical Alzheimer's disease. We aim to explore how neurochemical dysfunction corresponds to alpha desynchronization. Method: Elderly participants were classified clinically as cognitively healthy (CH, n=14) using the Uniform Data System‐3. Cerebrospinal fluid amyloid ß42 and tau levels were measured by immunoassays, and CH was subdivided into participants with normal Ab42/tau (CH‐NAT, n=6) or pathological Ab42/tau (CH‐PAT, n=8). Plasma neurotransmitters and amino levels were measured using a LC/MS method. EEG was recorded during Stroop interference testing for alpha desynchronization (reflect brain activities), where participants were asked to respond to each colored word for the color of the ink, when color and word matches (congruent) or does not match (incongruent). We compared the relationships of alpha desynchronization at brain regions (frontal‐F, central‐C, parietal‐P, left temporal‐LT, right temporal‐RT, occipital‐O) and neurochemicals between the two groups. Result: Plasma diaminobutyric acid (DABA) levels negatively correlated with alpha desynchronization in CH‐NAT (FCP: r=‐0.98∼‐0.88, p=0.005∼0.049) but not in CH‐PATs. Similarly, plasma melatonin negatively correlated with alpha desynchronization during congruent trials in CH‐NAT (P: r=‐1, p=0.003) but not in CH‐PATs. For incongruent trials, citrulline levels positively correlated with EEG recordings in CH‐NATs (C,LT: r=0.86∼0.92, p=0.013∼0.003), while an opposite trend was observed in CH‐PATs (r=‐0.69∼‐0.78, p=0.057∼0.022). Glutamine and histidine negatively correlated with alpha desynchronization during incongruent recordings in the CH‐NAT but not in CH‐PAT state. Plasma adrenaline positively correlated with alpha desynchronization during incongruent recordings in the CH‐NAT (C,LT) but not in CH‐PATs. Homocysteine levels negatively correlated with alpha power in CH‐PATs (F,C,P,RT: r=‐0.84∼‐0.74, p=0.010∼0.034), but not in CH‐NATs. Conclusion: Our exploratory studies show different association of plasma neurochemical levels with alpha desynchronization. The most significant changes for our small sample size were observed for neurotransmitter metabolites (DABA, glutamine, adrenaline) and antioxidants (homocysteine). Validation of these data using a larger sample size is ongoing. These studies will provide a rationale for modulating neurochemical plasma levels to prevent early AD cognitive deficits and motivate EEG use to monitor the efficacy of these early interventions. [ABSTRACT FROM AUTHOR]

Background: It is not clear whether triglyceride DHA‐based formulations (TG‐DHA) can sufficiently enrich brain DHA. Animal studies suggest that phosphatidylcholine (PC) and lyso‐phosphatidylcholine (LPC) lipids might be preferred brain DHA substrates. The goal of this study is to assess the effect of high‐dose TG‐DHA supplementation on DHA‐containing PC (PC‐DHA) and LPC (LPC‐DHA) lipid species in plasma and total cerebrospinal fluid (CSF) DHA as a surrogate for brain DHA incorporation. Method: We conducted a randomized clinical trial stratified by DHA treatment (n=14) and placebo (n=14) status in non‐demented older participants (CDR ≤ 0.5, age ³ 55 years old). Participants were provided 2,040 mg DHA daily in the form of TG‐DHA for six months. Plasma and CSF were obtained at baseline and after supplementation. Participants were also stratified by ApoE ε4 status, an allele known to increase Alzheimer's disease (AD) risk. PC and LPC lipid species from plasma and CSF were isolated and examined by LC/MS‐MS. Total fatty acids in CSF were measured via GC/MS‐MS. Result: Among all participants, PC‐DHA represented 39% of total DHA in plasma, while LPC‐DHA represented 1.8% of total DHA. PC‐DHA increased by 69% and 19% in plasma and CSF, respectively, following supplementation compared to placebo (p<0.0001 for both). Plasma LPC‐DHA increased by 140% in the treatment group compared to placebo (p<0.0001). Increases in plasma PC‐DHA and LPC‐DHA were both significantly correlated to changes in total DHA in CSF (R=0.8 and 0.57, respectively, p<0.003 for both). A trend toward greater increases in PC‐DHA in non‐ApoE ε4 carriers compared to carriers were also observed. Conclusion: Our data indicate that high‐dose TG‐DHA supplementation effectively increases DHA phospholipid incorporation in plasma and CSF. We acknowledge that CSF may not exactly reflect brain lipid uptake but provides useful information on brain DHA bioavailability. Our findings support that high‐dose TG DHA supplementation are brain penetrant and can help answer whether enriching brain DHA can slow down cognitive decline in patients at risk of AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) is commonly characterized by the accumulation of beta‐amyloid plaques in the brain causing neuroinflammation and cognitive decline. Risk for developing AD is associated with the ε4 allele of Apolipoprotein E (ApoE), a cholesterol carrier involved in lipid transport and brain injury repair. Docosahexaenoic Acid (DHA), an omega‐3 polyunsaturated fatty acid, has been shown to decrease ß‐amyloid production and prevent inflammation. The aim of our study is to determine whether DHA incorporation can account for the differences in the efficacy of DHA intervention in carriers of the ApoE ε4 allele (APOE ε4) compared with noncarriers (non‐APOE ε4). Method: We supplied APOE ε4 (n = 15) and non‐APOE ε4 (n = 16) cognitively healthy (CDR ≤ 0.5) participants above the age of 55 with 2 g/day of daily fish oil supplements, for six months. Participants were randomized into either DHA‐treatment or placebo groups. We isolated red blood cells (RBCs) from participants at baseline (T0) and after six months (T6) and used LC/MS‐MS analyses to quantify phospholipid species. We isolated 44 phosphatidylcholine (PC) species and examined changes in DHA contents after supplementation. Result: We found no significant differences in total PC across treatment groups nor between APOE ε4 and non‐APOE ε4 participants. Acyl DHA‐containing PC species (PC38a:6 and PC40a:6) increased significantly between T0 and T6 (p < 0.02 for all) non‐APOE ε4 participants. In contrast, no significant differences were seen between APOE ε4 carriers after DHA supplementation. No significant differences were found in plasmalogen PC‐DHA (PC40p:6) for any group. The ratio of PC‐DHA to PC‐containing arachidonic acid (C20:4n‐6), an omega‐6 fatty acid known to favor neurodegeneration, was significantly higher (p = 0.0008) for non‐carriers but not for ε4 carriers. Conclusion: Our data shows that dietary supplementation gives specific incorporation of DHA into acyl‐PC species in RBCs of non‐APOE ε4 carriers but not for ε4 carriers. We propose that the increased risk of AD pathology of ε4 carriers may be due to the inefficient incorporation and transport of DHA. Alternative means are needed to enhance DHA incorporation and transport into blood cells of ε4 carriers to effectively combat cognitive decline even at its earliest stages. [ABSTRACT FROM AUTHOR]

Background: In addition to the amyloid hypothesis, it is accepted that neurotransmitter and energy dyshomeostasis may underlie AD pathology. Glutamate (Glu) is one of the most common excitatory neurotransmitters and is the precursor of glutamine (Gln) and pyroglutamine (PGln). Glu signaling intersects with lipid metabolism via neuronal phospholipase A2 activation and the regulation of adiposity. Lipids are a major storage form of energy that is critical to AD pathology. We propose that disturbance in Glu metabolism may interfere with how the brain regulates lipid storage in adipose tissue and its utilization by tissues, and this process can contribute to early AD pathology. Consequently, the aim of our study is to quantify plasma Glu and its metabolites and determine their interaction with lipid metabolism in a pre‐symptomatic AD cohort. Methods: We collected fasting blood samples from cognitively healthy (CH) study participants with normal cerebrospinal fluid amyloid/ tau ratio (CH‐NAT, n = 36) or with pathological amyloid/tau ratio (CH‐PAT, n = 34), and from AD participants (n = 26). The concentrations of Glu, Gln, and PGln were measured using liquid chromatography‐tandem mass spectrometry. Blood lipids were measured in a clinical laboratory (HMH, Pasadena) and CSF measures of Aβ42 and total tau were determined using an ELISA. Results: Blood plasma Glu but not Gln and PGln positively correlated with CSF Aβ42/T‐tau ratio, in CH and CH‐NAT (p = 0.02) but not in CH‐PAT (p > 0.05) or AD (p = 0.99) participants. Blood plasma Glu also positively correlated with mean diastolic pressure (p = 0.02), BMI (p = 0.001), plasma triglycerides (p < 0.0001), and VLDL‐cholesterol (p < 0.0001), and negatively correlated with HDL‐cholesterol (p = 0.0003), in all CH study participants. Glu did not correlate with BMI but correlated strongly with VLDL‐cholesterol in CH‐NAT. In contrast, Glu correlated with BMI but not with VLDL‐cholesterol in CH‐PAT. Conclusions: These data show the differential regulation of blood glutamate metabolism, CSF amyloid/tau, and plasma lipids in pre‐symptomatic AD compared with cognitively healthy participants. We propose that glutamate metabolism and the brain‐adipose interface may be involved in regulating cognitive function and improving its homeostasis may prevent the decline from cognitively healthy to pre‐symptomatic or AD pathology in elderly populations. [ABSTRACT FROM AUTHOR]