Is Lumbar Puncture Needed? - Noninvasive Assessment of ICP Facilitates Decision Making in Patients with Suspected Idiopathic Intracranial Hypertension.

PURPOSE: Idiopathic intracranial hypertension (IIH) usually occurs in obese women of childbearing age. Typical symptoms are headache and sight impairment. Lumbar puncture (LP) is routinely used for both diagnosis and therapy (via cerebrospinal fluid drainage) of IIH. In this study, noninvasively assessed intracranial pressure (nICP) was compared to LP pressure (LPP) in order to clarify its feasibility for the diagnosis of IIH. MATERIALS AND METHODS: nICP was calculated using continuous signals of arterial blood pressure and cerebral blood flow velocity in the middle cerebral artery, a method which has been introduced recently. In 26 patients (f = 24, m = 2; age: 33 ±â€Š11 years), nICP was assessed one hour prior to LPP. If LPP was > 20 cmH2O, lumbar drainage was performed, LPP was measured again, and also nICP was reassessed. RESULTS: In total, LPP and nICP correlated with R = 0.85 (p < 0.001; N = 38). The mean difference of nICP-LPP was 0.45 ±â€Š4.93 cmH2O. The capability of nICP to diagnose increased LPP (LPP > 20 cmH2O) was assessed by ROC analysis. The optimal cutoff for nICP was close to 20 cmH2O with both a sensitivity and specificity of 0.92. Presuming 20 cmH2O as a critical threshold for the indication of lumbar drainage, the clinical implications would coincide in both methods in 35 of 38 cases. CONCLUSION: The TCD-based nICP assessment seems to be suitable for a pre-diagnosis of increased LPP and might eliminated the need for painful lumbar puncture if low nICP is detected.

Noninvasive Intracranial Pressure Assessment in Patients with Suspected Idiopathic Intracranial Hypertension.

INTRODUCTION: Idiopathic intracranial hypertension (IIH) usually occurs in obese women of childbearing age. Typical symptoms are headache and sight disorders. Besides ophthalmoscopy, lumbar puncture is used for both diagnosis and therapy of IIH. In this study, noninvasively-assessed intracranial pressure (nICP) was compared to lumbar pressure (LP) to clarify its suitability for diagnosis of IIH. METHODS: nICP was calculated using continuous signals of arterial blood pressure and cerebral blood flow velocity, a method previously introduced by the authors. In thirteen patients (f = 11, m = 2; age: 36 ± 10 years), nICP was assessed 1 h prior to LP. If LP was >20 cmH2O (~15 mmHg), lumbar drainage was performed, LP was measured again, and nICP was reassessed. RESULTS: In six patients, LP and nICP were compared after lumbar drainage. In three patients, assessment of nICP versus LP was repeated. In total, LP and nICP correlated with R = 0.82 (p < 0.001; N = 22). Mean difference of ICP-nICP was 0.8 ± 3.7 mmHg. Presuming 15 mmHg as critical threshold for indication of lumbar drainage in 20 of 22 cases, the clinical implications would have been the same in both methods. CONCLUSION: TCD-based ICP assessment seems to be a promising method for pre-diagnosis of increased LP and might prevent the need for lumbar puncture if nICP is low.

Ultrasound and dynamic functional imaging in vascular cognitive impairment and Alzheimer's disease.

BACKGROUND: The vascular contributions to neurodegeneration and neuroinflammation may be assessed by magnetic resonance imaging (MRI) and ultrasonography (US). This review summarises the methodology for these widely available, safe and relatively low cost tools and analyses recent work highlighting their potential utility as biomarkers for differentiating subtypes of cognitive impairment and dementia, tracking disease progression and evaluating response to treatment in various neurocognitive disorders. METHODS: At the 9th International Congress on Vascular Dementia (Ljubljana, Slovenia, October 2015) a writing group of experts was formed to review the evidence on the utility of US and arterial spin labelling (ASL) as neurophysiological markers of normal ageing, vascular cognitive impairment (VCI) and Alzheimer's disease (AD). Original articles, systematic literature reviews, guidelines and expert opinions published until September 2016 were critically analysed to summarise existing evidence, indicate gaps in current knowledge and, when appropriate, suggest standards of use for the most widely used US and ASL applications. RESULTS: Cerebral hypoperfusion has been linked to cognitive decline either as a risk or an aggravating factor. Hypoperfusion as a consequence of microangiopathy, macroangiopathy or cardiac dysfunction can promote or accelerate neurodegeneration, blood-brain barrier disruption and neuroinflammation. US can evaluate the cerebrovascular tree for pathological structure and functional changes contributing to cerebral hypoperfusion. Microvascular pathology and hypoperfusion at the level of capillaries and small arterioles can also be assessed by ASL, an MRI signal. Despite increasing evidence supporting the utility of these methods in detection of microvascular pathology, cerebral hypoperfusion, neurovascular unit dysfunction and, most importantly, disease progression, incomplete standardisation and missing validated cut-off values limit their use in daily routine. CONCLUSIONS: US and ASL are promising tools with excellent temporal resolution, which will have a significant impact on our understanding of the vascular contributions to VCI and AD and may also be relevant for assessing future prevention and therapeutic strategies for these conditions. Our work provides recommendations regarding the use of non-invasive imaging techniques to investigate the functional consequences of vascular burden in dementia.

Immunomodulation by fish-oil containing lipid emulsions in murine acute respiratory distress syndrome.

INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a major cause of mortality in intensive care units. Patients with ARDS often require parenteral nutrition with lipid emulsions as essential components. Besides being an energy supply, these lipid emulsions might display differential modulatory effects on lung integrity and inflammation. METHODS: In a pre-emptive strategy, we investigated the impact of three different intravenously infused lipid emulsions on lung morphology, leukocyte invasion, protein leakage and cytokines in a murine model of ARDS. Mice received an infusion of normal saline solution, a pure long-chain triglycerides (LCT) emulsion, a medium-chain triglycerides (MCT) containing mixed emulsion (LCT/MCT), or a fish oil (FO) containing mixed emulsion (LCT/MCT/FO) before lipopolysaccharide (LPS) challenge. RESULTS: Mice pre-infused with fish oil-containing lipid emulsion showed decreased leukocyte invasion, protein leakage, myeloperoxidase activity, and cytokine production in their alveolar space after LPS challenge compared to mice receiving LCT or LCT/MCT. In line with these findings, lung morphology assessed by histological staining after LPS-induced lung injury improved faster in the LCT/MCT/FO group. Concerning the above mentioned parameters, no significant difference was observed between mice infused with LCT or the combination of LCT and MCT. CONCLUSION: Fish oil-containing lipid emulsions might exert anti-inflammatory and pro-resolving effects in the murine model of acute lung injury. Partial replacement of n-6 fatty acids with n-3 fatty acids may thus be of benefit for critically ill patients at risk for ARDS which require parenteral nutrition.

Case management-based post-stroke care for patients with acute stroke and TIA (SOS-Care): a prospective cohort study.

BACKGROUND: The high incidence of stroke recurrence necessitates effective post-stroke care. This study investigates the effectiveness of a case management-based post-stroke care program in patients with acute stroke and TIA. METHODS: In this prospective cohort study, patients with TIA, ischemic stroke or intracerebral hemorrhage were enrolled into a 12-month case management-based program (SOS-Care) along with conventional care. Control patients received only conventional care. The program included home and phone consultations by case managers, focusing on education, medical and social needs and guideline-based secondary prevention. The primary outcome was the composite of stroke recurrence and vascular death after 12 months. Secondary outcomes included vascular risk factor control at 12 months. RESULTS: From 11/2011 to 12/2020, 1109 patients (17.9% TIA, 77.5% ischemic stroke, 4.6% intracerebral hemorrhage) were enrolled. After 85 (7.7%) dropouts, 925 SOS-Care patients remained for comparative analysis with 99 controls. Baseline characteristics were similar, except for fewer males and less frequent history of dyslipidemia in post-stroke care. At 12 months, post-stroke care was associated with a reduction in the composite endpoint compared to controls (4.9 vs. 14.1%; HR 0.30, 95% CI 0.16-0.56, p < 0.001), with consistent results in ischemic stroke patients alone (HR 0.32, 95% CI 0.17-0.61, p < 0.001). Post-stroke care more frequently achieved treatment goals for hypertension, dyslipidemia, diabetes, BMI and adherence to secondary prevention medication (p < 0.05). CONCLUSIONS: Case management-based post-stroke care may effectively mitigate the risk of vascular events in unselected stroke patients. These findings could guide future randomized trials investigating the efficacy of case management-based models in post-stroke care.

Effects of anti-inflammatory vagus nerve stimulation on the cerebral microcirculation in endotoxinemic rats.

BACKGROUND: In sepsis syndromes the severity of the inflammation triggers microvascular dysfunction and early organ failure. We studied the effects of anti-inflammatory vagus nerve stimulation on the cerebral microcirculatory integrity in an endotoxinemic rat model. METHODS: In both control and endotoxinemic (5 mg/kg lipopolysaccharide i.v.) rats, the effect of cervical bilateral vagotomy with or without left-sided distal vagus nerve stimulation were compared to non-vagotomized, nonstimulated group (sham). Neurovascular coupling was analyzed by electrical forepaw stimulation, EEG, and cortical laser-Doppler flow recording. Resting cerebral blood flow, evoked potentials and hemodynamic responses, were obtained over a period of 4.5 hours. Regulation of the nitric oxide system (iNOS expression and nitrite/nitrate measurements), cytokines (IFN-γ, TNF-α, IL-6, IL-10), hypoxic and apoptosis signaling molecules (HIF-2α, Bax) were measured at the end of experiments. RESULTS: In endotoxinemic rats, vagus nerve stimulation tended to increase anti-inflammatory cytokine levels and resulted in a stabile hemodynamic response (28 ± 13%; versus baseline). Vagotomized animals incurred a pro-inflammatory response (7 ± 4%; P < 0.0001 versus baseline) and produced more HIF-2α than vagotomized vagus nerve stimulated (VNS) animals. Evoked potential amplitudes were stabilized in VNS (15 ± 7 µV; n.s. versus baseline) as compared to vagotomised rats (8 ± 5 µV; P < 0.001 versus baseline). However, no effects were observed on apoptosis markers or nitric oxide levels. CONCLUSIONS: Vagus nerve stimulation in endotoxinemic rats had a positive effect on neurovascular coupling and stabilized evoked potentials.

Early neurovascular uncoupling in the brain during community acquired pneumonia.

INTRODUCTION: Sepsis leads to microcirculatory dysfunction and therefore a disturbed neurovascular coupling in the brain. To investigate if the dysfunction is also present in less severe inflammatory diseases we studied the neurovascular coupling in patients suffering from community acquired pneumonia. METHODS: Patients were investigated in the acute phase of pneumonia and after recovery. The neurovascular coupling was investigated with a simultaneous electroencephalogram (EEG)-Doppler technique applying a visual stimulation paradigm. Resting EEG frequencies, visual evoked potentials as well as resting and stimulated hemodynamic responses were obtained. Disease severity was characterized by laboratory and cognitive parameters as well as related scoring systems. Data were compared to a control group. RESULTS: Whereas visually evoked potentials (VEP) remained stable a significant slowing and therefore uncoupling of the hemodynamic responses were found in the acute phase of pneumonia (Rate time: control group: 3.6 ± 2.5 vs. acute pneumonia: 1.6 ± 2.4 s; P < 0.0005). In the initial investigation, patients who deteriorated showed a decreased hemodynamic response as compared with those who recovered (gain: recovered: 15% ± 4% vs. deteriorated: 9% ± 3%, P < 0.05; control: 14% ± 5%). After recovery the coupling normalized. CONCLUSIONS: Our study underlines the role of an early microcirculatory dysfunction in inflammatory syndromes that become evident in pre-septic conditions with a gradual decline according to disease severity.

Functional transcranial Doppler: presymptomatic changes in Fabry disease.

BACKGROUND AND AIM: Cerebrovascular disease may progress asymptomatically in the early stages of Fabry disease (FD). Our aim was to test whether functional transcranial Doppler (fTCD) could provide useful data in the evaluation of these presymptomatic FD patients. METHODS: A cohort of 12 adult FD patients from families with the classical phenotype of the disease was evaluated with fTCD in the posterior cerebral artery. RESULTS: Compared to healthy controls, resting blood velocities were significantly lower in the FD cohort (p = 0.032 for systolic, p = 0.021 for diastolic). FTCD suggested a disturbed neurovascular coupling in the visual cortex of FD patients, with lower gain (p = 0.007) and rate time (p = 0.019). Men had a significantly higher attenuation (p = 0.013) and lower natural frequency (p = 0.046) than the heterozygous women. CONCLUSION: These data are the first to suggest that patients with FD may develop cortical vascular dysfunction in the territory of the posterior circulation, early in the natural history of the disease. If the present findings are confirmed in larger, prospective studies, fTCD will be useful for assessing stroke risk in as yet asymptomatic FD patients, improving preventive therapeutic management.

Autonomic dysfunction affects cerebral neurovascular coupling.

OBJECTIVE: Autonomic failure (AF) affects the peripheral vascular system, but little is known about its influence on cerebrovascular regulation. Patients with familial amyloidotic polyneuropathy (FAP) were studied as a model for AF. METHODS: Ten mild (FAPm), 10 severe (FAPs) autonomic dysfunction FAP patients, and 15 healthy controls were monitored in supine and sitting positions for arterial blood pressure (ABP) and heart rate (HR) with arterial volume clamping, and for blood flow velocity (BFV) in posterior (PCA) and contralateral middle cerebral arteries (MCA) with transcranial Doppler. Analysis included resting BFV, cerebrovascular resistance parameters (cerebrovascular resistance index, CVRi; resistance area product, RAP; and critical closing pressure, CrCP), and neurovascular coupling through visually evoked BFV responses in PCA (gain, rate time, attenuation, and natural frequency). RESULTS: In non-stimulation conditions, in each position, there were no significant differences between the groups, regarding HR, BP, resting BFV, and vascular resistance parameters. Sitting ABP was higher than in supine in the three groups, although only significantly in controls. Mean BFV was lower in sitting in all the groups, lacking statistical significance only in FAPs PCA. CVRi and CrCP increased with sitting in all the groups, while RAP increased in controls but decreased in FAPm and FAPs. In visual stimulation conditions, FAPs comparing to controls had a significant decrease of natural frequency, in supine and sitting, and of rate time and gain in sitting position. INTERPRETATION: These results demonstrate that cerebrovascular regulation is affected in FAP subjects with AF, and that it worsens with orthostasis.

Association of history of cerebrovascular disease with severity of COVID-19.

OBJECTIVE: To determine whether a history of cerebrovascular disease (CVD) increases risk of severe coronavirus disease 2019 (COVID-19). METHODS: In a retrospective multicenter study, we retrieved individual data from in-patients treated March 1 to April 15, 2020 from COVID-19 registries of three hospitals in Saxony, Germany. We also performed a systematic review and meta-analysis following PRISMA recommendations using PubMed, EMBASE, Cochrane Library databases and bibliographies of identified papers (last search on April 11, 2020) and pooled data with those deriving from our multicenter study. Of 3762 records identified, 11 eligible observational studies of laboratory-confirmed COVID-19 patients were included in quantitative data synthesis. Risk ratios (RR) of severe COVID-19 according to history of CVD were pooled using DerSimonian and Laird random effects model. Between-study heterogeneity was assessed using Cochran's Q and I2-statistics. Severity of COVID-19 according to definitions applied in included studies was the main outcome. Sensitivity analyses were conducted for clusters of studies with equal definitions of severity. RESULTS: Pooled analysis included data from 1906 laboratory-confirmed COVID-19 patients (43.9% females, median age ranging from 39 to 76 years). Patients with previous CVD had higher risk of severe COVID-19 than those without [RR 2.07, 95% confidence interval (CI) 1.52-2.81; p < 0.0001]. This association was also observed in clusters of studies that defined severe manifestation of the disease by clinical parameters (RR 1.44, 95% CI 1.22-1.71; p < 0.0001), necessity of intensive care (RR 2.79, 95% CI 1.83-4.24; p < 0.0001) and in-hospital death (RR 2.18, 95% CI 1.75-2.7; p < 0.0001). CONCLUSION: A history of CVD might constitute an important risk factor of unfavorable clinical course of COVID-19  suggesting a need of tailored infection prevention and clinical management strategies for this population at risk.

Ethnic influences on neurovascular coupling: a pilot study in whites and Asians.

BACKGROUND AND PURPOSE: An ethnic extraintracranial difference in atherosclerosis has been well reported, whereas the potential mechanism remains unclear. We aimed to investigate neurovascular coupling in healthy whites and Asians. METHODS: Twenty volunteers of each ethnicity were recruited to perform a functional transcranial Doppler examination with standardized checkerboard patterns as visual stimulation (3 x 4, 6 x 8, and 12 x 16 checks subtending a visual field section of 18 degrees x 24 degrees , flicker rate 1 Hz). Hemodynamic responses in both posterior cerebral arteries were evaluated with a control system approach. RESULTS: The rate time, that is, the initial speed of flow velocity adaptation, was significantly lower in Asians leading to an approximately 2-second delayed hemodynamic adaptation. The other hemodynamic parameters and the dependency of hemodynamic responses in regard to the complexity degree of the stimulus were similar between groups. CONCLUSIONS: The constellation suggests a greater initial mismatch between functionally increased metabolic demand of neurons and adjusted cerebral blood flow in Asians.

Effect of smoking cessation on visually evoked cerebral blood flow response in healthy volunteers.

BACKGROUND/AIMS: In our previous study, impaired visually evoked flow velocity response was demonstrated in young chronic smokers. Our aim was to study whether impaired cerebrovascular reactivity is reversible 6-18 months after smoking cessation. METHODS: Flow velocity changes, evoked by visual stimulus, were recorded in the posterior cerebral arteries in 15 smokers, 15 former smokers and 15 nonsmokers. The stimulation protocol consisted of 10 cycles with a resting phase of 20 s (baseline) and a stimulating phase of 40 s for each cycle. Relative changes of flow velocity were expressed in relation to baseline. Breath holding index, visual evoked potential and intima-media thickness were also examined. RESULTS: Repeated measures ANOVA revealed marked difference in the flow velocity time courses between the 3 groups (p < 0.01). The flow response was significantly worse in former smokers than in nonsmokers (p < 0.002), however, no significant difference was found between former and current smokers (p = 0.0556). CONCLUSION: This is the first transcranial Doppler study demonstrating long-term impairment of visually evoked cerebrovascular response after smoking cessation. These findings indicate that the impairment of neurovascular coupling caused by smoking is due to structural changes of the vessels, rather than acute effect of smoking.

Effect of ApoE epsilon4 allele on visual evoked potentials and resultant flow coupling in patients with Alzheimer.

The apolipoprotein E epsilon4 (ApoE epsilon4) allele is a strong susceptibility factor for Alzheimer disease, which promotes neurodegeneration and cerebrovascular dysfunction. To address this issue in more detail, we simultaneously obtained visual evoked potentials and resultant hemodynamic responses in newly diagnosed Alzheimer patients without signs of vascular lesions on a cerebral magnetic resonance imaging (MRI) scan. Patients were grouped according to ApoE genotype (n = 19 ApoE epsilon4 carrier and n = 12 noncarrier). ApoE epsilon4 carrier had significantly longer peak latencies and a trend to higher interpeak latencies of late potential components. Potential amplitudes and hemodynamic responses were similar in both groups. At the incidental stage of disease process, it appears that the ApoE epsilon4 allele mainly promotes neuronal dysfunction rather than aggravates neurovascular dysfunction. Studies with larger patient samples are warranted to corroborate the first findings.

Natalizumab and regulation of cerebral blood flow: results from an observational study.

BACKGROUND: Natalizumab inhibits adherence of leukocytes to the cerebral endothelium. Since leukocytes play a role in regulating vascular tone, natalizumab may also affect cerebral vasoregulation. The aim of this observational study was to investigate whether neurovascular coupling and cerebral autoregulation are altered following routine clinical infusion of natalizumab in patients with relapsing-remitting multiple sclerosis. METHODS: In 18 patients receiving regular infusion of 300 mg natalizumab, neurovascular coupling to visual stimulation and dynamic cerebral autoregulation (phase and gain of 0.1-Hz oscillations) were measured by transcranial Doppler ultrasound (before, and 2 h and 2 days after the infusion). A repeated examination 28 days after infusion served as a control situation. RESULTS: Neurovascular coupling was altered 2 h and 2 days after infusion with an overshooting initial hemodynamic response. After 28 days, neurovascular coupling was similar to values before the infusion. Dynamic cerebral autoregulation, cerebral blood flow velocity and pulsatility index in the middle and posterior cerebral artery were unaltered. CONCLUSION: Natalizumab infusion is associated with a temporarily increased initial hyperemia to functional activation. Such a hyperreactivity suggests an increased bioavailability of nitric oxide during functional activation.

Effects of inducible nitric oxide synthase inhibition or norepinephrine on the neurovascular coupling in an endotoxic rat shock model.

INTRODUCTION: The inducible nitric oxide synthase (iNOS) plays a crucial role in early sepsis-related microcirculatory dysfunction. Compared to a catecholamine therapy we tested effects of a specific iNOS-inhibitor (1400W) on the microcirculatory function in the brain. METHODS: Seventy SD-rats (280-310 g) were divided into 1 control and 6 sepsis groups. Sepsis groups received 1 or 5 mg/kg lipopolysaccharide (LPS) intravenously to induce a moderate or severe sepsis syndrome. Thirty minutes later rats were further randomized into subgroups receiving moderate volume therapy alone or additionally continuous norepinephrine (NE) or 1400W infusion. Separately, effects of 1400W on neurofunctional parameters were investigated in 3 rats without sepsis induction. Performing electric forepaw-stimulation evoked potentials (N2-P1 amplitude, P1-latency) and local hemodynamic responses were recorded with surface electrodes and laser Doppler over the somatosensory cortex at baseline and repeatedly after LPS administration. Cytokine levels (tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL6), interferon-gamma (IFNgamma)) and cell destruction markers (neuron-specific enolase (NSE), S-100 calcium binding protein B (S100B)) were obtained at the end of experiments. RESULTS: During sepsis progression resting cerebral blood flow increased and functionally activated hemodynamic responses decreased in a dose-dependent manner. Whereas 1400W and NE improved blood pressure, only 1400W stabilized resting flow levels. However, both regimens were ineffective on the functionally coupled flow responses and destruction markers were similar between groups. CONCLUSIONS: NE and 1400W appeared to be ineffective in mitigating the effects of sepsis on the neurovascular coupling. Other regimens are needed to protect the cerebral microcirculation under septic conditions.

The neurovascular coupling bears properties of a feedforward and feedback regulative mechanism.

Temporal profiles of mediators involved in the neurovascular coupling bear feedforward and feedback characteristics, which are supported by mathematical modeling of evoked hemodynamic responses. However, cerebral autoregulation was expressed as a feedback control system. Therefore, question of overdetermination of the neurovascular coupling model arises. Addressing this issue, we analyzed both models for their appropriateness in describing the neurovascular coupling. Visually evoked flow velocities were recorded from healthy volunteers (aged 24.7 +/- 1.6 SD; 9 females, 11 males) with transcranial Doppler in the posterior cerebral artery. Control system parameters of the two models were specified according to the least-square-fitting technique. Mean square errors between measured and modeled curves and Akaike's information criterion (AIC) supported the feedforward-feedback model. Mean square differences decreased from 27.2 +/- 37.9 to 2.3 +/- 2 and the AIC from 2.7 +/- 0.6 %(2) to 2 +/- 0.3 %(2). The feedforward element increased the accuracy of the control system model in describing the fast initial response. Biologically, the parameter decreases the initial mismatch between the fast neuronal but slow vascular response because of visual activation.

Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation.

The cellular mechanisms underlying functional hyperemia--the coupling of neuronal activation to cerebral blood vessel responses--are not yet known. Here we show in rat cortical slices that the dilation of arterioles triggered by neuronal activity is dependent on glutamate-mediated [Ca(2+)](i) oscillations in astrocytes. Inhibition of these Ca(2+) responses resulted in the impairment of activity-dependent vasodilation, whereas selective activation--by patch pipette--of single astrocytes that were in contact with arterioles triggered vessel relaxation. We also found that a cyclooxygenase product is centrally involved in this astrocyte-mediated control of arterioles. In vivo blockade of glutamate-mediated [Ca(2+)](i) elevations in astrocytes reduced the blood flow increase in the somatosensory cortex during contralateral forepaw stimulation. Taken together, our findings show that neuron-to-astrocyte signaling is a key mechanism in functional hyperemia.

The role of neutrophil granulocytes in immune-to-brain communication.

Immune-to-brain communication has been studied in a variety of experimental models. Crucial insights into signalling and mechanisms were previously revealed in studies investigating fever induction pathways. The scientific community has primarily focused on neuronal and humoral pathways in the manifestation of this response. Emerging evidence has now shown that immune-to-brain signalling via immune cells is pivotal for normal brain function and brain pathology. The present manuscript aims to provide a brief overview on the current understanding of how immune cells signal to the brain. Insights are summarized on the potential physiological significance of some immune cells signalling from the periphery to the brain. A particular focus is laid on the role of neutrophil granulocytes. As such, IL-1ß expressing neutrophil granulocytes have been shown to transfer inflammatory information to the brain and contribute to prolonged behavioural changes due to septic encephalopathy in rats during severe systemic inflammation induced by the bacterial component and TLR4 agonist lipopolysaccharide. Modulation of immune cell recruitment to the brain is discussed by various confounding factors including sleep, exercise, the nutritional status e.g. obesity, leptin and omega 3 fatty acids, and psychological or inflammatory stressors. The physiological significance of immune cell mediated communication between the immune system and the brain is highlighted by the fact that systemic inflammatory insults can exacerbate ongoing brain pathologies via immune cell trafficking. New insights into mechanisms and mediators of immune cell mediated immune-to-brain communication are important for the development of new therapeutic strategies and the better understanding of existing ones. Abbreviations: ACTH: adrenocorticotropic hormone; BBB: blood-brain barrier; BBI: blood-brain interface; CD: cluster of differentiation; CINC: cytokine-induced neutrophil chemoattractant; CRH: corticotropin releasing hormone; CVOs: circumventricular organs; CXCR: chemokine receptor; DAPI: 40:6-diamidino-2-phenylindole dilactate; DHA: docosahexaenoid acid; ICAM: intracellular adhesion molecule; IL: interleukin; i.p.: intraperitoneal; i.v.: intravenous; KC: keratinocytes-derived chemokine; LPS: lipopolysaccharide; MIP: macrophage inflammatory protein; MS: multiple sclerosis; NFκB: nuclear factor kappa B; NF-IL6: nuclear factor IL-6; PCTR: protectin conjugates in tissue regeneration; PG: prostaglandin; p.i.: post injection; PVN: paraventricular nucleus; ra: receptor antagonist; STAT3: signal transducer and activator of transcription 3; TIMP: tissue inhibitors of metalloproteinases; TLR: toll-like receptor; TNFα: tumor necrosis factor alpha.

Effects of initiation and acute withdrawal of statins on the neurovascular coupling mechanism in healthy, normocholesterolemic humans.

BACKGROUND AND PURPOSE: Recent clinical trials imply increased risk of vascular events after statin withdrawal. There is evidence that this observation relates to an impaired nitric oxide system. The present analysis investigates the effect of initiation and withdrawal of statin therapy on resting and functionally activated cerebral hemodynamics in healthy young volunteers. METHODS: Sixteen healthy students (aged 23.7+/-3.3 years, 10 male) were subjected to a placebo-controlled, double-blind crossover study with a washout phase between blocks of 4 weeks. In the verum group, 20 mg pravastatin was taken for 2 weeks followed by 40 mg for 4 weeks. Withdrawal effects were investigated the day after discontinuation. Total cholesterol levels, blood pressure, resting and evoked hemodynamic responses due to a visual stimulation task in the posterior cerebral artery were obtained at baseline and then weekly and the day after discontinuation. RESULTS: In the verum group, cholesterol levels significantly decreased after 2 weeks (from 183+/-30 to 150+/-28 mg/dL; P<0.001) and then remained nearly stable (147+/-21 mg/dL after 6 weeks). Blood pressure, resting and evoked hemodynamic responses remained constant throughout the study. The day after statin withdrawal, evoked flow velocity responses were significantly lower (11+/-4% versus 13+/-5% at baseline; P<0.01) indicating inappropriate blood supply of active neurons. CONCLUSIONS: Reduction in evoked flow velocity responses reflects reduced nitric oxide bioavailability and therefore supports molecular findings of acute statin withdrawal. Questions arise if the present data might give a link to reports of increased vascular events in patients at vascular risk after acute statin withdrawal.

Interplay of cerebral autoregulation and neurovascular coupling evaluated by functional TCD in different orthostatic conditions.

BACKGROUND: Adequate cerebral blood flow (CBF) is mainly governed by neurovascular coupling (NC) which adapts local CBF to underlying cortical activity,and cerebral autoregulation (CA)that tends to maintain constant CBF despite changes in arterial blood pressure (BP). Since it was suggested that resistance vessels play an important role in both mechanisms, we investigated the irregulative interplay by performing a functional transcranial Doppler(f-TCD) test under different orthostatic conditions. METHODS: Fifteen healthy volunteers performed a visual reading test stimulation task after stabilized in sitting, supine and upright position on a tilt table. Simultaneously, BP and heart rate (HR) were recorded by a photoplethysmographic method and CBF velocity was measured with TCD in left posterior cerebral artery, and, as a reference, also in right middle cerebral artery. Evoked flow velocity (FV) responses were evaluated by a control system approach for systolic and diastolic data. Parameters studied were baseline FV with eyes closed, stable FV under stimulation (gain), oscillatory feature (natural frequency) and damping (attenuation) of the control system model, rate time, and also systolic and diastolic BP and HR. ANOVA test was used for comparing the values of variables in different postural settings, inferring statistical significance at a p < 0,05 level. RESULTS: Although there was a significant variation on the different orthostatic conditions in systolic (p = 0,027) and diastolic (p = 0,001) BP and HR (p = 0,0001), there was no significant change in the basal or evoked CBF velocities. CONCLUSIONS: An intact CA compensates the different orthostatic conditions completely thus allowing an independent regulation of NC according to the metabolic needs of cortical stimulation.