Christian Lange-Asschenfeldt

Alzheimer’s disease, cerebrovascular dysfunction and the benefits of exercise: From vessels to neurons

Exercise training promotes extensive cardiovascular changes and adaptive mechanisms in both the peripheral and cerebral vasculature, such as improved organ blood flow, induction of antioxidant pathways, and enhanced angiogenesis and vascular regeneration. Clinical studies have demonstrated a reduction of morbidity and mortality from cardiovascular disease among exercising individuals. However, evidence from recent large clinical trials also suggests a substantial reduction of dementia risk - particularly regarding Alzheimers disease (AD) - with regular exercise. Enhanced neurogenesis and improved synaptic plasticity have been implicated in this beneficial effect. However, recent research has revealed that vascular and specifically endothelial dysfunction is essentially involved in the disease process and profoundly aggravates underlying neurodegeneration. Moreover, vascular risk factors (VRFs) are probably determinants of incidence and course of AD. In this review, we emphasize the interconnection between AD and VRFs and the impact of cerebrovascular and endothelial dysfunction on AD pathophysiology. Furthermore, we describe the molecular mechanisms of the beneficial effects of exercise on the vasculature such as activation of the vascular nitric oxide (NO)/endothelial NO synthase (eNOS) pathway, upregulation of antioxidant enzymes, and angiogenesis. Finally, recent prospective clinical studies dealing with the effect of exercise on the risk of incident AD are briefly reviewed. We conclude that, next to upholding neuronal plasticity, regular exercise may counteract AD pathophysiology by building a vascular reserve.

Epidemiology, Symptoms, and Treatment Characteristics of Hyponatremic Psychiatric Inpatients

Abstract Hyponatremia is a common phenomenon in psychiatry occurring as an adverse effect to drugs or following polydipsia. We performed a retrospective in-depth analysis of hyponatremia cases in a large unselected population of psychiatric inpatients. During a 3-year period, all cases of hyponatremia were identified among patients admitted to a large psychiatric state and university hospital by the institution’s electronic laboratory database. Demographic, treatment-related, and laboratory data were obtained by consecutive chart review, respectively. Hyponatremia occurred in 347 (4.9%) of 7113 cases, of which the majority (78%) displayed only a mild manifestation. Symptoms were recorded in 28.8% of cases, already occurred in mild forms, and comprised gait impairment (45%, including falls), confusion (30%), sedation (26%), and dyspepsia (41%). Age, female sex, nonpsychiatric drug polypharmacy—particularly with thiazides and/or angiotensin-converting enzyme inhibitors—and diagnosis of a mood disorder were associated with more severe hyponatremia, respectively. The proportion of hyponatremic patients treated with venlafaxine, trazodone, carbamazepine, oxcarbazepine, and first-generation antipsychotics, respectively, was significantly higher in the hyponatremia sample than in the normonatremic population. This was, surprisingly, not the case with selective serotonin reuptake inhibitors or any other antidepressant drug class. We found prescription with second-generation antipsychotics to be significantly associated with less severe hyponatremia. Hyponatremia may be mainly attributed to the syndrome of inappropriate antidiuretic hormone secretion, as indicated by decreased serum osmolarity in our sample. Besides old age and female sex, treatment with certain drugs—rather than whole drug classes—carries a substantially increased risk.

Hippocampal synaptic depression following spatial learning in a complex maze

Activity-dependent alteration in synaptic efficacy is referred to as synaptic plasticity and is the believed hallmark of any learning process. Here we employed a recently validated complex maze for spatial training and investigated the impact of repeated and extensive training on basal synaptic transmission of the hippocampal Schaffer collateral-CA1 synaptic connection in vitro. In the present experiments, male CD-1 mice were trained in a complex maze for eight consecutive days five times a day. Subsequently, input-output functions of field excitatory postsynaptic potentials (fEPSPs) recorded in the CA1 area following stimulation of the Schaffer collateral-commissural fiber pathway were analyzed in acute hippocampal slices. We found a marked right shift of the fEPSP response in trained compared to untrained animals while fiber volley size remained unchanged. The findings provide evidence for a direct implication of homosynaptic hippocampal long-term depression in a spatial learning paradigm.

Can an early weight management program (WMP) prevent olanzapine (OLZ)-induced disturbances in body weight, blood glucose and lipid metabolism? Twenty-four- and 48-week results from a 6-month randomized trial.

Abstract Objectives. This study was designed to investigate whether a preventive weight management program (WMP) reduces weight gain during olanzapine (OLZ) treatment. Moreover, we examined the effects of intervention on metabolic parameters. Methods. Patients (N = 100) with schizophrenia or schizoaffective disorder (DSM-IV) who had commenced treatment with OLZ were recruited. Following a run-in period of 4 weeks, 74 patients who had gained at least 1.5 kg body weight were randomized to receive either 12 bi-weekly WMP sessions (prevention group (PG), n = 36), or usual care (control group (CG), n = 38). Anthropometric and metabolic parameters were assessed after the 24-week intervention phase and a 24-week follow-up. Results. Forty-two percent of 74 participants (PG: 36.1%, CG: 47.4%) finished the 24-week intervention phase while 34% of them (PG: 30.6%, CG: 36.8%) completed the 48-week study. There was no significant difference in weight gain between groups (PG: + 3.4 ± 4.2 kg vs. CG: + 4.5 ± 6.1 kg, P = 0.184) after 24 weeks. Nevertheless, PG showed a significantly smaller increase in waist circumference than CG (PG: + 4.6 ± 8.3 cm, CG: + 10.1 ± 7.3 cm, P = 0.019) after 48 weeks. Furthermore, PG showed a significantly smaller increase in fasting glucose (P = 0.031) and 2-h glucose after oral glucose load (P = 0.018) than CG. Conclusions. These results suggest that preventive WMP may reduce the risk of abdominal obesity and deterioration of glucose metabolism in OLZ-treated patients.

Transient reduction of spontaneous neuronal network activity by sublethal amyloid β (1–42) peptide concentrations

Soluble amyloid β1–42 (Aβ1–42) peptide has recently been assigned a key role in early Alzheimer’s disease (AD) pathophysiology accounting for synaptic dysfunction before amyloid plaque formation and neurodegeneration can occur. Following sublethal Aβ1–42 administration, we observed an acute but transient reduction of the spike and burst rate of spontaneously active cortical networks cultured on microelectrode arrays. This simple experimental system appears suitable for future long-term pharmacological and genetic studies of Aβ1–42 signaling, thus providing a valuable new tool in AD research.

An Ultrasensitive Assay for Diagnosis of Alzheimer's Disease

Alzheimers disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia. Aging is among the most significant risk factors. Today, AD can be diagnosed with certainty only post mortem, detecting insoluble beta-amyloid peptide (Abeta) aggregates in the patients brain tissue. We have developed an ultrasensitive assay for early and non-invasive diagnosis of AD. This highly specific and sensitive assay uses fluorescence correlation spectroscopy (FCS) and is sensitive enough to detect even single aggregates in body fluids of AD patients. We investigate the correlation of aggregated Abeta concentrations in body fluids with clinical symptoms of AD.

Multielectrode array analysis of cerebrospinal fluid in Alzheimer’s disease versus mild cognitive impairment: A potential diagnostic and treatment biomarker

Pathological cerebrospinal fluid (CSF) alterations like changes in amyloid-β1-42 and tau protein concentration are typical in Alzheimers disease (AD). However, it remains unclear, if the composition of known or unknown pathological factors in native CSF has a functional significance in AD. In this pilot study, we used multielectrode array (MEA) neurochips to determine whether CSF of individuals with AD (AD-CSF) may have distinct neurofunctional properties that may distinguish it from that of individuals with mild cognitive impairment (MCI) - a differential diagnosis of high clinical importance. MEAs are neuronal cultures coupled to a multisite electrical recording system with the ability to reflect pharmacological or toxicological alterations on the functional level of whole neuronal networks. Collective rhythmical electrical activity was substantially enhanced after exposure to CSF of cognitively healthy subjects (controls) and of MCI individuals (MCI-CSF) alike. However, this activity increment was significantly reduced when MEAs were exposed to AD-CSF compared to MCI-CSF. Moreover, following AD-CSF exposure, networks showed significantly enhanced burst durations and less synchronous bursting, respectively. Thus, AD-CSF and MCI-CSF could be distinguished by characteristic changes of the network firing pattern on MEAs. When data of MCI individuals and AD patients were pooled, the network suppression correlated significantly with the degree of cognitive decline. The findings of this pilot study may set the stage for a unique and straightforward diagnostic bioassay of AD with particular value in the differential diagnosis to MCI and as a much needed biomarker for clinical trials.

Multimodal gain control at the hippocampal Schaffer collateral-CA1 synapse.

Information processing at central nervous system synapses is shaped by long-lasting modifications, such as long-term potentiation and short-lived and putatively synapse-specific modifications by various forms of short-term plasticity, such as facilitation, potentiation, and depression. Using an extracellular paired-pulse facilitation (PPF) protocol at the Schaffer collateral-CA1 (SC) connection in acute hippocampal slices in mice, we extend previous reports of optimal signal gain at intermediate interpulse intervals obtained at single SC synapses to the network level. Moreover, maximum signal gain changed when the input intensity was altered. We found further that facilitation decreased with increasing stimulus amplitude and duration in an exact exponential fashion when varied at a fixed interpulse interval. Variation of these intensity parameters accounted for significant changes in PPF adding a spatial dimension to time-based synaptic filter characteristics. Thus, this synapse functions as an amplitude window discriminator with a low-level aperture in combination with a band-pass frequency filter. By providing mathematical functions for the characteristic presynaptic parameters frequency, stimulus amplitude, and pulse duration at the network level our results lay ground for future studies on pharmacologically, genetically, or otherwise altered animal models.

Pharmacotherapy of generalized anxiety disorder: focus and update on pregabalin

Generalized anxiety disorder (GAD) is one of the most common psychiatric disorders and clinically characterized by both psychological anxiety and somatic symptoms (muscular tension and autonomic symptoms). Next to serotonergic antidepressants, the Ca2+ channel α2δ ligand pregabalin is an approved first-line treatment of GAD in many countries. Pregabalin is considered effective against psychological and somatic anxiety symptoms alike. However, occurrence of discontinuation syndromes and a growing number of reports regarding abuse or dependence during the last years are concerns, particularly in patients with a history of addictive behavior. Here we review key issues of GAD and the pharmacology and pharmacokinetics of pregabalin. Above all, we evaluate evidence from available randomized placebo-controlled as well as head-to-head clinical trials with other drugs regarding its efficacy and safety in the GAD treatment.

Attention and CERAD test performances in cognitively impaired elderly subjects

Attention plays a fundamental role in cognitive performance and is closely interrelated with all major cognitive domains. In this retrospective study, we correlated different measures of attention with standard cognitive parameters in 85 cognitively impaired elderly individuals presenting with cognitive complaints to a memory clinic.