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 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

Waterpipe Smoke Exposure and Arterial Plaque Formation: Effects and Mechanisms Related to Sex, Autonomic Nervous System Changes and Endothelial Permeability in a Mouse Model of Atherosclerosis

Chronic inhalation exposure to particulate matter (PM) has been well documented to increase the risk of developing and dying from cardiovascular disease (CVD). This risk, however, has been studied mostly in ambient PM and cigarette tobacco. Waterpipes have been used for centuries to smoke tobacco and have recently increased in popularity worldwide, but its cardiovascular toxicity has not been widely studied. Therefore, I aimed to begin to fill this gap by studying the effects of long-term waterpipe smoke (WPS) inhalation on disease progression in an atherosclerosis prone mouse model (ApoE-/- mice).Methods: Male and female ApoE-/- mice underwent nose-only exposure to WPS for 2 hours per day, 4 days per week for either 8 or 20 weeks. In the 8-week exposure, an additional group exposed to charcoal denuded WPS (dWPS) was included to study the importance of volatile and PM components on cardiovascular toxicity. Atherosclerosis progression was measured by histological assessment of intima-media thickness in the aortic arch, brachiocephalic, left carotid and left subclavian arteries. Inflammation and endothelial permeability were assessed in plasma, as well as tissue expression of biomarkers and extravasation of Evan’s blue dye (EBD), which was injected just prior to euthanasia. Heart rate variability (HRV) was assessed daily throughout the study as a proxy for autonomic nervous system perturbations associated with CVD. Results: Intima-media thickness was altered mainly in the aortic arch as increased thickness in male ApoE-/- mice but decreased in the female mice after 5 months of WPS exposure. EBD extravasation was increased after only 2 months of WPS exposure in male mice. Inflammation marker, C-reactive protein, was decreased in female mice after 2 months of WPS inhalation. No significant changes were found in other markers of permeability or inflammation. HRV indicated sex-dependent effects, where WPS induced dampening of vagally mediated responses in females. In males, WPS increased vagal stimulation of the heart in a transient manner, seen only on the days of exposure, and not on the non-exposure days of each week. Conclusions: In summary, despite differences from the initial hypotheses, this dissertation presents results that WPS exposure is able to induce cardiovascular toxicity as assessed by heart rate variability, and that WPS can influence the progression of atherosclerosis differently between male and female mice

Heart rate variability changes during task shifting testing in pre‐symptomatic Alzheimer’s disease

Background. Early detection of Alzheimer’s disease (AD) is vital to begin and monitor treatments. However, as AD pathology begins long before the onset of symptoms, early detection is difficult. Previous studies have suggested differences in the cardiac and autonomic nervous systems (ANS) in AD patients, providing a possible non‐invasive marker of disease onset. The goal of this study is to compare heart rate variability (HRV) measures, representative of cardiac and ANS function, at rest as well as during cognitive testing to assess the use of HRV as a possible marker of pre‐symptomatic AD. Method. All participants are cognitively healthy (CH) separated into two subgroups based on ratios of amyloid/tau proteins in cerebrospinal fluid (CSF): normal (CH‐NAT, n=22) and pathological (CH‐PAT, n=36), which represents pre‐symptomatic AD. Heart rate variability (HRV) was assessed during 5‐minute intervals at rest and during Task Shifting testing. Participants were required to name the color or word of a colored word for each stimulus by pressing a button, with two sequential stimuli per trial. The trial could be switching (color‐word or word‐color) or repeat (color‐color or word‐word). ECG traces from subgroups of CH‐NATs (n=8) and CH‐PATs (n=13) were initially screened to remove ectopic beats, followed by identification of normal RR‐intervals (NN). HRV was analyzed as standard deviation of NN (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 to assess changes to autonomic, and particularly parasympathetic, input to the heart. Result. Comparing HRV changes assessed during rest and the task shifting testing in each individual, differences became apparent between CH‐NAT and CH‐PAT groups. In the CH‐NAT group, little to no change in SDNN and RMSSD occurred during cognitive testing from rest. The CH‐PAT group however showed a 20 percent drop in both SDNN and RMSSD during testing, indicating an imbalance of the ANS. Conclusion. This study provides a new approach and technique using HRV to non‐invasively differentiate between normal and pre‐symptomatic AD in cognitively healthy people

Heart rate variability changes during task shifting testing in pre‐symptomatic Alzheimer’s disease

Background. Early detection of Alzheimer’s disease (AD) is vital to begin and monitor treatments. However, as AD pathology begins long before the onset of symptoms, early detection is difficult. Previous studies have suggested differences in the cardiac and autonomic nervous systems (ANS) in AD patients, providing a possible non‐invasive marker of disease onset. The goal of this study is to compare heart rate variability (HRV) measures, representative of cardiac and ANS function, at rest as well as during cognitive testing to assess the use of HRV as a possible marker of pre‐symptomatic AD. Method. All participants are cognitively healthy (CH) separated into two subgroups based on ratios of amyloid/tau proteins in cerebrospinal fluid (CSF): normal (CH‐NAT, n=22) and pathological (CH‐PAT, n=36), which represents pre‐symptomatic AD. Heart rate variability (HRV) was assessed during 5‐minute intervals at rest and during Task Shifting testing. Participants were required to name the color or word of a colored word for each stimulus by pressing a button, with two sequential stimuli per trial. The trial could be switching (color‐word or word‐color) or repeat (color‐color or word‐word). ECG traces from subgroups of CH‐NATs (n=8) and CH‐PATs (n=13) were initially screened to remove ectopic beats, followed by identification of normal RR‐intervals (NN). HRV was analyzed as standard deviation of NN (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 to assess changes to autonomic, and particularly parasympathetic, input to the heart. Result. Comparing HRV changes assessed during rest and the task shifting testing in each individual, differences became apparent between CH‐NAT and CH‐PAT groups. In the CH‐NAT group, little to no change in SDNN and RMSSD occurred during cognitive testing from rest. The CH‐PAT group however showed a 20 percent drop in both SDNN and RMSSD during testing, indicating an imbalance of the ANS. Conclusion. This study provides a new approach and technique using HRV to non‐invasively differentiate between normal and pre‐symptomatic AD in cognitively healthy people

Heart rate and blood pressure decreases after a motor task in pre‐symptomatic AD

Background. Understanding how cardiovascular health affects the early Alzheimer’s disease (AD) pathology is challenging because several variables can contribute to significant changes in blood pressure (BP) and heart rate (HR). Previous studies have suggested an association between Alzheimer's disease and HR. Little association is known about pre‐symptomatic AD. We aim to explore the HR and BP changes before and after a motor task in a cognitive healthy population. Method. Participants (age ranged 61‐95 years old) were recruited from the local community, including cognitively healthy (CH) individuals who were further subdivided based on cerebrospinal fluid (CSF) classification: those with a normal amyloid/tau ratio (CH‐NAT, n = 11) or a pathological amyloid/tau ratio (CH‐PAT, n = 8). Two groups were age, gender, BMI, and education matched. Participants were asked to use a steering wheel to follow a moving line presented on the monitor. Practice session were followed by three task‐identical sessions, 90 seconds per session. Each session consisted of 3 repeated blocks, 30 seconds per block: bump, trail, and bump & trail. Systolic pressure (SP), diastolic pressure (DP), pulse pressure (PP), and HR were measured before and after completing the whole task. Result. No differences in BP and HR were found between CH‐NATs and CH‐PATs. We found a significant decrease in SP for both CH‐NATs (pre‐task 135.2±24.2, post‐task 127.2±18.8, reduced by 8±9.7, p = 0.0208) and CH‐PATs (pre‐task: 146.1±20.6, post‐task: 134.8±19.6, reduced by 11.3±5.2, p = 0.0004). Furthermore, CH‐PATs have a significant drop in HR (pre‐task: 71.4±10.7, post‐task: 66.3±8.2, reduced by 5.1±4.1 beats, p = 0.0098) compared to CH‐NATs (pre‐task: 70.8±11.8, post‐task: 69.2±13.3, reduced by 1.5±6.2 beats, p = 0.4302). CH‐PATs has decreased HR*SP (pre‐task: 10464±2375.6, post‐task: 8941.1±1843.1, reduced by 1522.9±775.8, p = 0.0009), compared to CH‐NATs (pre‐task: 9537.2±2098.3, post‐task: 8765.2±1769.2, reduced by 772.0±1153.5, p=0.0507). No significant change was found in DP for either CH‐NATs or CH‐PATs. Conclusion. Pre‐symptomatic AD participants have a significant drop of HR, SP, and SP*HR compared to CH‐NATs, indicating reduced sympathetic responses after motor task. These changes in HR and SP may provide evidence of compromised cardiovascular health and autonomic regulation in pre‐symptomatic AD

Heart rate and blood pressure decreases after a motor task in pre‐symptomatic AD

Background. Understanding how cardiovascular health affects the early Alzheimer’s disease (AD) pathology is challenging because several variables can contribute to significant changes in blood pressure (BP) and heart rate (HR). Previous studies have suggested an association between Alzheimer's disease and HR. Little association is known about pre‐symptomatic AD. We aim to explore the HR and BP changes before and after a motor task in a cognitive healthy population. Method. Participants (age ranged 61‐95 years old) were recruited from the local community, including cognitively healthy (CH) individuals who were further subdivided based on cerebrospinal fluid (CSF) classification: those with a normal amyloid/tau ratio (CH‐NAT, n = 11) or a pathological amyloid/tau ratio (CH‐PAT, n = 8). Two groups were age, gender, BMI, and education matched. Participants were asked to use a steering wheel to follow a moving line presented on the monitor. Practice session were followed by three task‐identical sessions, 90 seconds per session. Each session consisted of 3 repeated blocks, 30 seconds per block: bump, trail, and bump & trail. Systolic pressure (SP), diastolic pressure (DP), pulse pressure (PP), and HR were measured before and after completing the whole task. Result. No differences in BP and HR were found between CH‐NATs and CH‐PATs. We found a significant decrease in SP for both CH‐NATs (pre‐task 135.2±24.2, post‐task 127.2±18.8, reduced by 8±9.7, p = 0.0208) and CH‐PATs (pre‐task: 146.1±20.6, post‐task: 134.8±19.6, reduced by 11.3±5.2, p = 0.0004). Furthermore, CH‐PATs have a significant drop in HR (pre‐task: 71.4±10.7, post‐task: 66.3±8.2, reduced by 5.1±4.1 beats, p = 0.0098) compared to CH‐NATs (pre‐task: 70.8±11.8, post‐task: 69.2±13.3, reduced by 1.5±6.2 beats, p = 0.4302). CH‐PATs has decreased HR*SP (pre‐task: 10464±2375.6, post‐task: 8941.1±1843.1, reduced by 1522.9±775.8, p = 0.0009), compared to CH‐NATs (pre‐task: 9537.2±2098.3, post‐task: 8765.2±1769.2, reduced by 772.0±1153.5, p=0.0507). No significant change was found in DP for either CH‐NATs or CH‐PATs. Conclusion. Pre‐symptomatic AD participants have a significant drop of HR, SP, and SP*HR compared to CH‐NATs, indicating reduced sympathetic responses after motor task. These changes in HR and SP may provide evidence of compromised cardiovascular health and autonomic regulation in pre‐symptomatic AD

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 Alzheimers 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, Cohens d = -0.83, 95% confidence interval -1.44 to -0.22, and high alpha: p = 0.019, Cohens 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

A study of alpha desynchronization, heart rate, and MRI during stroop testing unmasks pre‐symptomatic Alzheimer’s disease

Background. Alzheimer’s disease (AD) studies suggested the need to detect pre‐symptomatic stage, when cognitive challenges reveal changes of alpha power (brain hyperactivity). Heart rate (HR) regulates brain oxygen supply, is regulated by the brain (eg. hippocampus and amygdala), and correlated with resting state alpha power. We aimed to compare alpha power, HR, and hippocampal and amygdala volume between pre‐symptomatic AD and normal, aging individuals. Method. We employed quantitative electroencephalography (qEEG) to monitor brain activity during resting and during Stroop interference testing. Cognitively healthy (CH) study participants (demographically matched) were recruited from the local community, consisting of two subgroups based on cerebrospinal fluid (CSF) proteins: with normal amyloid/tau ratio (CH‐NAT, n=20) or pathological amyloid/tau ratio (CH‐PAT, equals pre‐symptomatic AD, n=21). Cognition was assessed using Montreal Cognitive Assessment (MoCA) and Mini‐Mental State Examination‐7 (MMSE‐7). Participants were presented a series of colored words and asked to respond to each word for the color of the ink, including low load (congruent trials, when color matches the word) and high load (incongruent trials, when color does not match the word). Comparisons between two groups include: alpha desynchronization and alpha spectral entropy (SE), as well as the relationships of alpha desynchronization, HR after Stroop testing, and hippocampal and amygdala volumes (1.5T MRI, demographically balanced subgroups). Result. No alpha differences were found during the resting state. Occipital alpha desynchronization of CH‐PATs was more negative than in that of CH‐NATs (p=0.024) during the congruent trials (Figure 1), indicating hyperactivity during low load. CH‐PATs had higher alpha SE during congruent trials (p=0.042 frontal, p=0.039 occipital), and lower frontal SE change from congruent to incongruent trials (p=0.012) (Figure 2), supporting reduced functional reserve. Alpha desynchronization positively correlated with HR in CH‐PATs but not CH‐NATs; alpha desynchronization correlated with hippocampal or amygdala differently between CH‐NATs and CH‐PATs (Figure 4). Multiple spectral frequencies revealed correlations in MMSE‐7 & MoCA that differed between CH‐NATs and CH‐PATs. Conclusion. These results suggest that hyper‐excitability during low load challenge and limited brain reserve is manifest with increasing interference load in pre‐symptomatic AD. We also find brain‐heart coupling is altered in pre‐symptomatic AD

A study of alpha desynchronization, heart rate, and MRI during stroop testing unmasks pre‐symptomatic Alzheimer’s disease

Background. Alzheimer’s disease (AD) studies suggested the need to detect pre‐symptomatic stage, when cognitive challenges reveal changes of alpha power (brain hyperactivity). Heart rate (HR) regulates brain oxygen supply, is regulated by the brain (eg. hippocampus and amygdala), and correlated with resting state alpha power. We aimed to compare alpha power, HR, and hippocampal and amygdala volume between pre‐symptomatic AD and normal, aging individuals. Method. We employed quantitative electroencephalography (qEEG) to monitor brain activity during resting and during Stroop interference testing. Cognitively healthy (CH) study participants (demographically matched) were recruited from the local community, consisting of two subgroups based on cerebrospinal fluid (CSF) proteins: with normal amyloid/tau ratio (CH‐NAT, n=20) or pathological amyloid/tau ratio (CH‐PAT, equals pre‐symptomatic AD, n=21). Cognition was assessed using Montreal Cognitive Assessment (MoCA) and Mini‐Mental State Examination‐7 (MMSE‐7). Participants were presented a series of colored words and asked to respond to each word for the color of the ink, including low load (congruent trials, when color matches the word) and high load (incongruent trials, when color does not match the word). Comparisons between two groups include: alpha desynchronization and alpha spectral entropy (SE), as well as the relationships of alpha desynchronization, HR after Stroop testing, and hippocampal and amygdala volumes (1.5T MRI, demographically balanced subgroups). Result. No alpha differences were found during the resting state. Occipital alpha desynchronization of CH‐PATs was more negative than in that of CH‐NATs (p=0.024) during the congruent trials (Figure 1), indicating hyperactivity during low load. CH‐PATs had higher alpha SE during congruent trials (p=0.042 frontal, p=0.039 occipital), and lower frontal SE change from congruent to incongruent trials (p=0.012) (Figure 2), supporting reduced functional reserve. Alpha desynchronization positively correlated with HR in CH‐PATs but not CH‐NATs; alpha desynchronization correlated with hippocampal or amygdala differently between CH‐NATs and CH‐PATs (Figure 4). Multiple spectral frequencies revealed correlations in MMSE‐7 & MoCA that differed between CH‐NATs and CH‐PATs. Conclusion. These results suggest that hyper‐excitability during low load challenge and limited brain reserve is manifest with increasing interference load in pre‐symptomatic AD. We also find brain‐heart coupling is altered in pre‐symptomatic AD