Neuroprotection of Cholinergic Neurons with a Tau Aggregation Inhibitor and Rivastigmine in an Alzheimer's-like Tauopathy Mouse Model.

Basal forebrain cholinergic dysfunction, most likely linked with tau protein aggregation, is a characteristic feature of Alzheimer's disease (AD). Recent evidence suggests that tau protein is a putative target for the treatment of dementia, and the tau aggregation inhibitor, hydromethylthionine mesylate (HMTM), has emerged as a potential disease-modifying treatment. However, its efficacy was diminished in patients already receiving approved acetylcholinesterase inhibitors. In this study, we ask whether this negative interaction can also be mimicked in experimental tau models of AD and whether the underlying mechanism can be understood. From a previous age profiling study, 6-month-old line 1 (L1) tau transgenic mice were characterized by a severe reduction in several cholinergic markers. We therefore assessed whether long-term pre-exposure with the acetylcholinesterase inhibitor rivastigmine alone and in conjunction with the tau aggregation inhibitor HMTM can reverse cholinergic deficits in L1. Rivastigmine and HMTM, and combinations of the two compounds were administered orally for 11 weeks to both L1 and wild-type mice. The brains were sectioned with a focus on the basal forebrain, motor cortex and hippocampus. Immunohistochemical staining and quantification of choline acetyltransferase (ChAT), tyrosine kinase A (TrkA)-positive neurons and relative optical intensity (ROI) for vesicular acetylcholine transporter (VAChT), and acetylcholinesterase (AChE) reactivity confirmed reversal of the diminished cholinergic phenotype of interneurons (nucleus accumbens, striatum) and projection neurons (medial septum, nucleus basalis magnocellularis) by HMTM, to a greater extent than by rivastigmine alone in L1 mice. Combined administration did not yield additivity but, in most proxies, led to antagonistic effects in which rivastigmine decreased the benefits shown with HMTM alone. Local markers (VAChT and AChE) in target structures of the basal forebrain, motor cortex and hippocampal CA3 seemed to be normalized by HMTM, but not by rivastigmine or the combination of both drugs. HMTM, which was developed as a tau aggregation inhibitor, strongly decreased the tau load in L1 mice, however, not in combination with rivastigmine. Taken together, these data confirm a cholinergic phenotype in L1 tau transgenic mice that resembles the deficits observed in AD patients. This phenotype is reversible by HMTM, but at the same time appears to be subject to a homeostatic regulation induced by chronic pre-treatment with an acetylcholinesterase inhibitor, which interferes with the efficacy of HMTM. The strongest phenotypic reversal coincided with a normalization of the tau load in the cortex and hippocampus of L1, suggesting that tau accumulation underpins the loss of cholinergic markers in the basal forebrain and its projection targets.

Exaggerated pressor response to static squats in Parkinson's disease (PD) and healthy subjects is likely an individual trait, not influenced by whole body vibration (WBV).

BACKGROUND: Reduced muscle strength is one symptom of Parkinson's disease (PD). Strength can be increased by strength training, which may cause exaggerated blood pressure (BP) rise. It is believed that exercises performed on vibrating platform can strengthen leg muscles without excessive BP increase. OBJECTIVE: To measure the pressor response to static exercises performed during whole body vibration in PD patients. METHODS: Twenty-four aged PD patients and twelve healthy young volunteers participated in the study. PD subjects performed six repetitions of deep-, semi-squat, and calves at vibration frequency of 30 Hz. Each 30 s exercise was followed by 30 s rest. The young volunteers performed two sessions of above-mentioned exercises with and without vibration. BP was measured continuously. RESULTS: In PD patients, the highest BP values were observed during deep squat; systolic blood pressure rose 10 mmHg in 'weak responders', and 50 mmHg in 'strong responders'. This difference correlated with the rise in pulse pressure suggesting indirectly the role of stoke volume in individual response. In healthy subjects pressor response was also individually differentiated and not influenced by vibration. CONCLUSION: Deep and semi squat can evoke a strong cardiovascular response in some PD and healthy subjects. Low-magnitude vibrations likely did not affect pressor response.

The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain.

The elderly population is growing worldwide, with important health and socioeconomic implications. Clinical and experimental studies on aging have uncovered numerous changes in the brain, such as decreased neurogenesis, increased synaptic defects, greater metabolic stress, and enhanced inflammation. These changes are associated with cognitive decline and neurobehavioral deficits. Although aging is not a disease, it is a significant risk factor for functional worsening, affective impairment, disease exaggeration, dementia, and general disease susceptibility. Conversely, life events related to mental stress and trauma can also lead to accelerated age-associated disorders and dementia. Here, we review human studies and studies on mice and rats, such as those modeling human neurodegenerative diseases, that have helped elucidate (1) the dynamics and mechanisms underlying the biological and pathological aging of the main projecting systems in the brain (glutamatergic, cholinergic, and dopaminergic) and (2) the effect of defective glutamatergic, cholinergic, and dopaminergic projection on disabilities associated with aging and neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Detailed knowledge of the mechanisms of age-related diseases can be an important element in the development of effective ways of treatment. In this context, we briefly analyze which adverse changes associated with neurodegenerative diseases in the cholinergic, glutaminergic and dopaminergic systems could be targeted by therapeutic strategies developed as a result of our better understanding of these damaging mechanisms.

Device for Controlling Stimulus Self-Application During Autonomic Nervous System Tests.

Assessment of autonomic nervous system (ANS) functioning may be performed non-invasively using autonomic tests which are based on evaluation of response of cardiovascular system to the applied stimuli, such as increased air pressure during Valsalva maneuver, skeletal muscle contraction during static handgrip or deep slow breathing. The cardiovascular response depends, besides ANS reaction and test protocol, also on the way stimulus is self-applied by the test subject. We present a versatile device for controlling stimulus self-application during three ANS tests: Valsalva maneuver, static handgrip, and deep breathing. It integrates two different gauges and a pace setter for breathing into one device. The core of the device is a linear LED display which, using green, yellow, and red diodes, informs the subject about the correctness of self-application of respective stimulus. The settings of the device can be adjusted to the needs of the protocol chosen. The device can record the duration of mouth air pressure or the force produced by the subject during ANS tests, which assures correctness of the tests, thus allowing to track individual variability changes in the response to the test. The device was verified during ANS tests and its use was intuitive for patients, reducing the time needed for training before tests and decreasing the effort of the physician.

Tau Oligomers Neurotoxicity.

Although the mechanisms of toxic activity of tau are not fully recognized, it is supposed that the tau toxicity is related rather not to insoluble tau aggregates but to its intermediate forms. It seems that neurofibrillar tangles (NFTs) themselves, despite being composed of toxic tau, are probably neither necessary nor sufficient for tau-induced neuronal dysfunction and toxicity. Tau oligomers (TauOs) formed during the early stages of tau aggregation are the pathological forms that play a key role in eliciting the loss of neurons and behavioral impairments in several neurodegenerative disorders called tauopathies. They can be found in tauopathic diseases, the most common of which is Alzheimer's disease (AD). Evidence of co-occurrence of b-amyloid, α-synuclein, and tau into their most toxic forms, i.e., oligomers, suggests that these species interact and influence each other's aggregation in several tauopathies. The mechanism responsible for oligomeric tau neurotoxicity is a subject of intensive investigation. In this review, we summarize the most recent literature on the damaging effect of TauOs on the stability of the genome and the function of the nucleus, energy production and mitochondrial function, cell signaling and synaptic plasticity, the microtubule assembly, neuronal cytoskeleton and axonal transport, and the effectiveness of the protein degradation system.

BDNF as a Promising Therapeutic Agent in Parkinson's Disease.

Brain-derived neurotrophic factor (BDNF) promotes neuroprotection and neuroregeneration. In animal models of Parkinson's disease (PD), BDNF enhances the survival of dopaminergic neurons, improves dopaminergic neurotransmission and motor performance. Pharmacological therapies of PD are symptom-targeting, and their effectiveness decreases with the progression of the disease; therefore, new therapeutical approaches are needed. Since, in both PD patients and animal PD models, decreased level of BDNF was found in the nigrostriatal pathway, it has been hypothesized that BDNF may serve as a therapeutic agent. Direct delivery of exogenous BDNF into the patient's brain did not relieve the symptoms of disease, nor did attempts to enhance BDNF expression with gene therapy. Physical training was neuroprotective in animal models of PD. This effect is mediated, at least partly, by BDNF. Animal studies revealed that physical activity increases BDNF and tropomyosin receptor kinase B (TrkB) expression, leading to inhibition of neurodegeneration through induction of transcription factors and expression of genes related to neuronal proliferation, survival, and inflammatory response. This review focuses on the evidence that increasing BDNF level due to gene modulation or physical exercise has a neuroprotective effect and could be considered as adjunctive therapy in PD.

Exercise-Induced Neuroprotection and Recovery of Motor Function in Animal Models of Parkinson's Disease.

Parkinson's disease (PD) is manifested by progressive motor, autonomic, and cognitive disturbances. Dopamine (DA) synthesizing neurons in the substantia nigra (SN) degenerate, causing a decline in DA level in the striatum that leads to the characteristic movement disorders. A disease-modifying therapy to arrest PD progression remains unattainable with current pharmacotherapies, most of which cause severe side effects and lose their efficacy with time. For this reason, there is a need to seek new therapies supporting the pharmacological treatment of PD. Motor therapy is recommended for pharmacologically treated PD patients as it alleviates the symptoms. Molecular mechanisms behind the beneficial effects of motor therapy are unknown, nor is it known whether such therapy may be neuroprotective in PD patients. Due to obvious limitations, human studies are unlikely to answer these questions; therefore, the use of animal models of PD seems indispensable. Motor therapy in animal models of PD characterized by the loss of dopaminergic neurons has neuroprotective and neuroregenerative effects, and the completeness of neuronal protection may depend on (i) degree of neuronal loss, (ii) duration and intensity of exercise, and (iii) time elapsed between insult and commencing of training. As the physical activity is neuroprotective for dopaminergic neurons, the question arises what is the mechanism of this protective action. A current hypothesis assumes a central role of neurotrophic factors in the neuroprotection of dopaminergic neurons, even though it is still not clear whether increased DA level in the nigrostriatal axis results from neurogenesis of dopaminergic neurons in the SN, recovery of the phenotype of dopaminergic neurons, increased sprouting of the residual dopaminergic axons in the striatum, or generation of local striatal neurons from inhibitory interneurons. In the present review, we discuss studies describing the influence of physical exercise on the PD-like changes manifested in animal models of the disease and focus our interest on the current state of knowledge on the mechanism of neuroprotection induced by physical activity as a supportive therapy in PD.

Impaired hemodynamic response to tilt, handgrip and Valsalva manoeuvre in patients with takotsubo syndrome.

PURPOSE: Long-term ß-adrenolytics treatment in takotsubo syndrome (TTS) patients is based on the premise, that TTS is strongly associated with sympathetic nervous system overactivity. The aim of the study was to establish hemodynamic response to tilt, handgrip and Valsalva manoeuvre in patients with takotsubo syndrome compared to healthy subjects (CONTROL) and patients after ST Elevation Myocardial Infarction (STEMI). MATERIAL AND METHOD: Echocardiographic examination was performed at rest, ECG and continuously non-invasively measured arterial blood pressure were used for evaluation of hemodynamic responses to Valsalva manoeuvre, static handgrip (HG) followed by post-exercise ischemia, and tilt. Ten healthy women, 20 with TTS and 20 after STEMI, mean age 64 ±â€¯8.5 years, participated in the study. RESULTS: Pressor response to Valsalva manoeuvre and tilt in TTS group was diminished in comparison to CONTROL and close to that of STEMI. During HG, increase of SBP was the lowest in TTS group. Data indirectly suggest that it was due to deficient stroke volume in TTS and STEMI patients during these manoeuvres; though echocardiographic findings at rest did not reveal any significant differences between groups. CONCLUSIONS: Our data show that despite apparent resolution of the immediate effects of TTS, impaired response to cardiovascular challenge, similar to that in STEMI patients, persisted. As the manoeuvres applied mimic daily life situations, causes of impairment should be searched for and potential health risk evaluated.

Neuroplasticity and Neuroprotective Effect of Treadmill Training in the Chronic Mouse Model of Parkinson's Disease.

Physical training confers protection to dopaminergic neurons in rodent models of parkinsonism produced by neurotoxins. The sparing effect of physical training on dopaminergic neurons can be tested with training applied during chronic MPTP treatment, while the neurorestorative effect when training is applied after completing such treatment. In this study, the effect of the onset of training respective to chronic MPTP treatment was specifically addressed. Three groups of mice were injected with 10 doses of MPTP (12.5 mg/kg/injection) over 5 weeks. The first group remained sedentary; the second one underwent early onset training, which started 1 week before commencing MPTP treatment, continued throughout 5 weeks of treatment and 4 weeks thereafter; the third group underwent late-onset training of the same length and intensity as the former group, except that it started immediately after the end of MPTP treatment. Two groups served as controls: a saline-injected group that remained sedentary and saline-injected group, which underwent the same training as the early and late-onset training groups. Both early and late-onset physical training saved almost all nigral and VTA dopaminergic neurons, prevented inflammatory response, and increased the BDNF and GDNF levels to a similar extent. From these results one may conclude that early and late-onset training schedules were equipotent in their neuroprotective effect and that the mechanism of neuroprotection was similar. The sparing effect of early onset training may be satisfactorily explained by assuming that the increased level of BDNF and GDNF prevented the degeneration of dopaminergic neurons. To explain a similar number of dopaminergic neurons detected at the end of the early and late-onset training, one should additionally assume that the former training schedule induced neurogenesis. Results of this study support the view that physical activity may be neuroprotective even at a more advanced stage of PD and justify starting physical activity at any point of the disease.

Body position classification for cardiorespiratory measurement.

Heart activity, or at least heart rate variability, is associated with body position. Our previous studies have confirmed that impedance pneumography may be used to record respiratory function, but the calibration coefficients for this method depend on position. Data were collected from 24 students (12 male, 12 female), who alternated positions between lying (on front, back, and right side), sitting and standing. Signals from an attached iPhone's internal sensors (accelerometer, gyroscope, magnetometer) were recorded and attitude relative to gravity was calculated. The signals were subsequently segmented and marked. Five algorithms were trained and cross-validated for different sensor combinations. Without differentiation of sitting and standing, 100% accuracy was achieved using all algorithms. The classifier best differentiating these two states was based on random forests, with overall accuracy of 90%. Simple methods based on a proposed hybrid classifier were tested for online measurement without the need for signal segmentation, with 99% accuracy. The prospect of the algorithms' use in long-term studies (particularly cardiorespiratory monitoring) was assessed.

Assessment of calibration methods on impedance pneumography accuracy.

The aim was to assess accuracy of tidal volumes (TV) calculated by impedance pneumography (IP), reproducibility of calibration coefficients (CC) between IP and pneumotachometry (PNT), and their relationship with body posture, breathing rate and depth. Fourteen students performed three sessions of 18 series: normal and deep breathing at 6, 10, 15 breaths/min rates, while supine, sitting and standing; 18 CC were calculated for every session. Session 2 was performed 2 months after session 1, session 3 1-3 days after session 2. TV were calculated using full or limited set of CC from current session, in case of sessions 2 and 3 also using CC from session 1 and 2, respectively. When using full set of CC from current session, IP underestimated TV by -3.2%. Using CC from session 2 for session 3 measurements caused decrease of relative difference: -3.9%, from session 1 for session 2: -5.3%; for limited set of CC: -5.0%. The body posture had significant effect on CC. The highest accuracy was obtained when all factors influencing CC were considered. The application of CC related only to body posture may result in shortening of calibration and moderate accuracy loss. Using CC from previous session compromises accuracy moderately.

In aged men, central vessel transmural pressure is reduced by brief Valsalva manoeuvre during strength exercise.

A brief Valsalva manoeuvre, lasting 2-3 s, performed by young healthy men during strength exercise reduces transmural pressure acting on intrathoracic arteries. In this study, we sought to verify this finding in older men. Twenty normotensive, prehypertensive and moderately hypertensive otherwise healthy men 46-69 years old performed knee extensions combined with inspiration or with brief Valsalva manoeuvre performed at 10, 20 and 40 mmHg mouth pressure. Same respiratory manoeuvres were also performed at rest. Non-invasively measured blood pressure, knee angle, respiratory airflow and mouth pressure were continuously registered. In comparison to inspiration, estimated transmural pressure acting on thoracic arteries changed slightly and insignificantly during brief Valsalva manoeuvre at 10 and 20 mmHg mouth pressure. At 40 mmHg mouth pressure, transmural pressure declined at rest (-8·8 ± 11·4 mmHg) and during knee extension (-12·1 ± 11·9 mmHg). This decline ensued, as peak systolic pressure increase caused by this manoeuvre, was distinctly <40 mmHg. Only a main effect of mouth pressure was revealed (P<0·001) and neither exercise nor interaction between these factors, what suggests that transmural pressure decline, depended mainly on intrathoracic pressure developed during brief Valsalva manoeuvre. Resting blood pressure did not influence the effect of brief Valsalva manoeuvre on transmural pressure.

Early hemodynamic response to the tilt test in patients with syncope.

INTRODUCTION: Our aim was to evaluate the differences in the early hemodynamic response to the tilt test (HUTT) in patients with and without syncope using impedance cardiography (ICG). MATERIAL AND METHODS: One hundred twenty-six patients (72 female/48 male; 37 ±17 years) were divided into a group with syncope (HUTT(+), n = 45 patients) and a group without syncope (HUTT(-), n = 81 patients). ECG and ICG signals were continuously recorded during the whole examination, allowing the calculation of heart rate (HR), stroke volume (SV), and cardiac output (CO) for every beat. The hemodynamic parameters (averaged over 1 min) were analyzed at the following points of the HUTT: the last minute of resting, the period immediately after the tilt (0 min), 1 min and 5 min after the maneuver. The absolute changes of HR, SV and CO were calculated for 0, 1, and 5 min after the maneuver in relation to the values at rest (ΔHR, ΔSV, ΔCO). Also, the percentage changes were calculated (HRi, SVi, COi). RESULTS: There were no differences between the groups in absolute and percentage changes of hemodynamic parameters immediately after and 1 min after tilting. Significant differences between the HUTT(+) and HUTT(-) groups were observed in the 5(th) min of tilting: for ΔSV (-27.2 ±21.2 ml vs. -9.7 ±27.2 ml; p = 0.03), ΔCO (-1.78 ±1.62 l/min vs. -0.34 ±2.48 l/min; p = 0.032), COi (-30 ±28% vs. -0.2 ±58%; p = 0.034). CONCLUSIONS: In the 5(th) min the decrease of hemodynamic parameters (ΔSV, ΔCO, COi) was significantly more pronounced in HUTT(+) patients in comparison to the HUTT(-) group.

Impedance cardiography: recent advancements.

The aim of this paper is the presentation of recent advancements in impedance cardiography regarding methodical approach, applied equipment and clinical or research implementations. The review is limited to the papers which were published over last 17 months (dated 2011 and 2012) in well recognised scientific journals.

Effects of a brief Valsalva manoeuvre on hemodynamic response to strength exercises.

Strength training is a recommended measure against loss of strength and muscle mass because of age- or illness-induced inactivity. Strength exercises may impose heavy cardiovascular load by increasing heart rate and blood pressure. To increase strength efficiently, a heavy load has to be applied; this, however, leads to a spontaneous Valsalva manoeuvre, which additionally raises blood pressure. Avoidance of this manoeuvre is recommended. If the additional rise in arterial blood pressure caused by Valsalva manoeuvre is smaller than intrathoracic or intracranial pressures during this manoeuvre, Valsalva manoeuvre may actually protect arteries located in the thorax and in the brain by diminishing transmural pressure acting across these vessels. Effect of controlled breathing or brief Valsalva manoeuvre on arterial pressure at rest and during knee extension against 15-repetition maximum resistance was evaluated. In 12 healthy young men blood pressure was measured continuously and non-invasively, knee angle, speed of respiratory air or mouth pressure (MP) were continuously registered. Each combination of respiratory and exercise manoeuvres was repeated six times, for every of last three repetitions peak and trough systolic and diastolic pressure were determined. Strength exercises elevated peak pressures more than trough pressures, systolic more than diastolic. Valsalva manoeuvre increased only peak systolic and peak diastolic pressure. This increase was in average lesser than MP, thus rendering an argument in favour of protective role of brief Valsalva manoeuvre because of decline in transmural pressure acting on thoracic and possibly cerebral arteries. However, there was strong individual variability, and in few instances, arterial pressure increased because of brief Valsalva manoeuvre more than MP; thus in some subjects, the manoeuvre might enhance transmural pressure acting on thorax arteries.

Holter-type impedance cardiography device. A system for continuous and non-invasive monitoring of cardiac haemodynamics.

Impedance cardiography (ICG) enables the non-invasive, reproducible, beat-to-beat estimation of stroke volume (SV) changes, and the measurement of the absolute values of the ejection time (ET) and pre-ejection period (PEP), which allows the indirect evaluation of cardiac contractility. The miniaturised, Holter-type impedance cardiography device with built-in one channel of ECG called ReoMonitor, was constructed. The system allows the long-term, beat-to-beat, automatic evaluation of SV, ET, PEP and heart rate. The measurements obtained by ReoMonitor were verified using on echocardiographic method in supine and tilted positions. A high correlation coefficient (r=0.83) was calculated between the measurements collected using both methods. Speech or vigorous movement distinctly lowered the percentage of properly recognised cardiac cycles (during daytime: 20-80%, during the night: 75-90%). However, during exercise testing on a cycloergometer the quality of recordings was good. The following clinical applications of a system are presented: a) evaluation of hemodynamical abnormalities caused by arrhythmia events, b) vasovagal syncope diagnosis, and c) optimisation of atrio-ventricular delay during dual-chamber pacing.