Blood Pressure Variability and Plasma Biomarkers of Neuronal Injury and Alzheimer's Disease: A Clinic-Based Study of Patients with Diseases Along the Heart-Brain Axis.

 Higher blood pressure variability (BPV) predisposes to cognitive decline. To investigate underlying mechanisms, we measured 24-h ambulatory BPV, nocturnal dipping and orthostatic hypotension in 518 participants with vascular cognitive impairment, carotid occlusive disease, heart failure, or reference participants. We determined cross-sectional associations between BPV indices and plasma biomarkers of neuronal injury (neurofilament light chain) and Alzheimer's disease (phosphorylated-tau-181 and Aß42/Aß40). None of the BPV indices were significantly associated with any of the biomarkers. Hence, in patients with diseases along the heart-brain axis, we found no evidence for an association between BPV and selected markers of neuronal injury or Alzheimer's disease.

Serum Neurofilament Light and Postoperative Delirium in Cardiac Surgery: A Preplanned Secondary Analysis of a Prospective Observational Study.

BACKGROUND: Impaired cognition is a major predisposing factor for postoperative delirium, but it is not systematically assessed. Anesthesia and surgery may cause postoperative delirium by affecting brain integrity. Neurofilament light in serum reflects axonal injury. Studies evaluating the perioperative course of neurofilament light in cardiac surgery have shown conflicting results. The authors hypothesized that postoperative serum neurofilament light values would be higher in delirious patients, and that baseline concentrations would be correlated with patients' cognitive status and would identify patients at risk of postoperative delirium. METHODS: This preplanned secondary analysis included 220 patients undergoing elective cardiac surgery with cardiopulmonary bypass. A preoperative cognitive z score was calculated after a neuropsychological evaluation. Quantification of serum neurofilament light was performed by the Simoa (Quanterix, USA) technique before anesthesia, 2 h after surgery, on postoperative days 1, 2, and 5. Postoperative delirium was assessed using the Confusion Assessment Method for Intensive Care Unit, the Confusion Assessment Method, and a chart review. RESULTS: A total of 65 of 220 (29.5%) patients developed postoperative delirium. Delirious patients were older (median [25th percentile, 75th percentile], 74 [64, 79] vs. 67 [59, 74] yr; P < 0.001) and had lower cognitive z scores (-0.52 ± 1.14 vs. 0.21 ± 0.84; P < 0.001). Postoperative neurofilament light concentrations increased in all patients up to day 5, but did not predict delirium when preoperative concentrations were considered. Baseline neurofilament light values were significantly higher in patients who experienced delirium. They were influenced by age, cognitive z score, renal function, and history of diabetes mellitus. Baselines values were significantly correlated with cognitive z scores (r, 0.49; P < 0.001) and were independently associated with delirium whenever the patient's cognitive status was not considered (hazard ratio, 3.34 [95% CI, 1.07 to 10.4]). CONCLUSIONS: Cardiac surgery is associated with axonal injury, because neurofilament light concentrations increased postoperatively in all patients. However, only baseline neurofilament light values predicted postoperative delirium. Baseline concentrations were correlated with poorer cognitive scores, and they independently predicted postoperative delirium whenever patient's cognitive status was undetermined.

The Hierarchy of Coupled Sleep Oscillations Reverses with Aging in Humans.

A well orchestrated coupling hierarchy of slow waves and spindles during slow-wave sleep supports memory consolidation. In old age, the duration of slow-wave sleep and the number of coupling events decrease. The coupling hierarchy deteriorates, predicting memory loss and brain atrophy. Here, we investigate the dynamics of this physiological change in slow wave-spindle coupling in a frontocentral electroencephalography position in a large sample (N = 340; 237 females, 103 males) spanning most of the human life span (age range, 15-83 years). We find that, instead of changing abruptly, spindles gradually shift from being driven by slow waves to driving slow waves with age, reversing the coupling hierarchy typically seen in younger brains. Reversal was stronger the lower the slow-wave frequency, and starts around midlife (age range, ∼40-48 years), with an established reversed hierarchy between 56 and 83 years of age. Notably, coupling strength remains unaffected by age. In older adults, deteriorating slow wave-spindle coupling, measured using the phase slope index (PSI) and the number of coupling events, is associated with blood plasma glial fibrillary acidic protein levels, a marker for astrocyte activation. Data-driven models suggest that decreased sleep time and higher age lead to fewer coupling events, paralleled by increased astrocyte activation. Counterintuitively, astrocyte activation is associated with a backshift of the coupling hierarchy (PSI) toward a "younger" status along with increased coupling occurrence and strength, potentially suggesting compensatory processes. As the changes in coupling hierarchy occur gradually starting at midlife, we suggest there exists a sizable window of opportunity for early interventions to counteract undesirable trajectories associated with neurodegeneration.SIGNIFICANCE STATEMENT Evidence accumulates that sleep disturbances and cognitive decline are bidirectionally and causally linked, forming a vicious cycle. Improving sleep quality could break this cycle. One marker for sleep quality is a clear hierarchical structure of sleep oscillations. Previous studies showed that sleep oscillations decouple in old age. Here, we show that, rather, the hierarchical structure gradually shifts across the human life span and reverses in old age, while coupling strength remains unchanged. This shift is associated with markers for astrocyte activation in old age. The shifting hierarchy resembles brain maturation, plateau, and wear processes. This study furthers our comprehension of this important neurophysiological process and its dynamic evolution across the human life span.

Acoustic stimulation during sleep predicts long-lasting increases in memory performance and beneficial amyloid response in older adults.

BACKGROUND: Sleep and neurodegeneration are assumed to be locked in a bi-directional vicious cycle. Improving sleep could break this cycle and help to prevent neurodegeneration. We tested multi-night phase-locked acoustic stimulation (PLAS) during slow wave sleep (SWS) as a non-invasive method to improve SWS, memory performance and plasma amyloid levels. METHODS: 32 healthy older adults (agemean: 68.9) completed a between-subject sham-controlled three-night intervention, preceded by a sham-PLAS baseline night. RESULTS: PLAS induced increases in sleep-associated spectral-power bands as well as a 24% increase in slow wave-coupled spindles, known to support memory consolidation. There was no significant group-difference in memory performance or amyloid-beta between the intervention and control group. However, the magnitude of PLAS-induced physiological responses were associated with memory performance up to 3 months post intervention and beneficial changes in plasma amyloid. Results were exclusive to the intervention group. DISCUSSION: Multi-night PLAS is associated with long-lasting benefits in memory and metabolite clearance in older adults, rendering PLAS a promising tool to build upon and develop long-term protocols for the prevention of cognitive decline.

Biomarkers of Tuberculous Meningitis and Pediatric Human Immunodeficiency Virus on the African Continent.

Biomarkers in body fluids are helpful objective tools in diagnosis, prognosis and monitoring of (therapeutic) responses of many neurological diseases. Cerebrospinal fluid (CSF) biomarkers are part of the diagnostic toolbox for infectious neurological diseases. Tuberculous meningitis (TBM) and Human immunodeficiency virus (HIV), are important burdens of disease in Africa and can negatively affect brain health. Two thirds of the world's population of people living with HIV reside in sub-Saharan Africa and 25% of the global burden of tuberculosis (TB) is carried by the African continent. Neuroinflammation and damage of specific neuronal cell types are key constituents in the pathophysiology of these central nervous system (CNS) diseases, and important potential sources of circulating biomarkers. In this review, we summarize current research in the use of biomarkers in TBM and pediatric HIV as case demonstrations for high prevalence neurological diseases in Africa. Inflammatory molecules, primarily when detected in CSF, appear to have diagnostic value in these diseases, especially when measured as profiles. Brain injury molecules, such as S100, Neuron specific enolase and glial fibrillary acidic protein may have prognostic value in TBM, but more studies are needed. There is a need for more cost-economic and high sensitivity technologies to drive further biomarker discoveries and translate into healthcare improvements for these important healthcare problems in a globally fair way.

Cerebrospinal fluid collection: An informative animation video for patients and caregivers.

Daily clinical practice has shown that patients are often hesitant to undergo a lumbar puncture (LP) because of unfamiliarity with the awaiting procedure and/or unrealistic ideas concerning post-LP complications. In light of increased number of LPs in diagnostic and research settings, our institute has developed an educational video for patients and caregivers in which we inform them about and prepare them for the LP procedure. This video was based on the latest literature and was developed with the help of communication experts, medical doctors, and two separate patient panels.

Fatigue in patients with multiple sclerosis: is it related to pro- and anti-inflammatory cytokines?

OBJECTIVE: To investigate the pathophysiological role of pro- and anti-inflammatory cytokines in primary multiple sclerosis-related fatigue. METHODS: Fatigued and non-fatigued patients with multiple sclerosis (MS) were recruited and their cytokine profiles compared. Patients with secondary fatigue were excluded. Fatigue was assessed with the self-reported Checklist Individual Strength (CIS20r), subscale fatigue. A CIS20r fatigue cut-off score of 35 was applied to differentiate between non-fatigued (CIS20r fatigue ≤34) and fatigued (CIS20r fatigue ≥35) patients with MS. Blood was collected to determine the serum concentrations of pro-inflammatory cytokines (IL-1ß, IL-2, IL-6, IL-8, IL-12p70, IL-17, TNFα, and IFN-γ) and anti-inflammatory cytokines (IL-4, IL-5, IL-10, and IL-13). We controlled for the confounding effect of age, gender, duration of MS, disease severity, type of MS, and use of immunomodulatory drugs. RESULTS: Similar cytokine levels were observed between MS patients with (n = 21) and without fatigue (n = 14). Adjusted multiple regression analyses showed a single significant positive relationship, that of IL-6 with CIS20r fatigue score. The explained variance of the IL-6 model was 21.1%, once adjusted for the confounding effect of age. CONCLUSION: The pro-inflammatory cytokine interleukin-6 (IL-6) may play a role in the pathophysiology of primary fatigue in patients with MS. TRIAL REGISTRATIONS: ISRCTN69520623, ISRCTN58583714, and ISRCTN82353628.