Pawel Kermer

Enhanced Detection of Paroxysmal Atrial Fibrillation by Early and Prolonged Continuous Holter Monitoring in Patients With Cerebral Ischemia Presenting in Sinus Rhythm

Background and Purpose Diagnosis of paroxysmal atrial fibrillation is difficult but highly relevant in patients presenting with cerebral ischemia yet free from atrial fibrillation on admission. Early initiation and prolongation of continuous Holter monitoring may improve diagnostic yield compared with the standard of care including a 24-hour Holter recording. Methods— In the observational Find-AF trial (ISRCTN 46104198), consecutive patients presenting with symptoms of cerebral ischemia were included. Patients free from atrial fibrillation at presentation received 7-day Holter monitoring. Results— Two hundred eighty-one patients were prospectively included. Forty-four (15.7%) had atrial fibrillation documented by routine electrocardiogram on admission. All remaining patients received Holter monitors at a median of 5.5 hours after presentation. In those 224 patients who received Holter monitors but had no previously known paroxysmal atrial fibrillation, the detection rate with early and prolonged (7 days) Holter monitoring (12.5%) was significantly higher than for any 24-hour (mean of 7 intervals: 4.8%, P=0.015) or any 48-hour monitoring interval (mean of 6 intervals: 6.4%, P=0.023). Of those 28 patients with new atrial fibrillation on Holter monitoring, 15 (6.7%) had been discharged without therapeutic anticoagulation after routine clinical care (ie, with data from 24-hour Holter monitoring only). Detection rates were 43.8% or 6.3% for short supraventricular runs of ≥10 beats or prolonged episodes (<5 hours) of atrial fibrillation, respectively. Diagnostic yield appeared to be only slightly and not significantly increased during the first 3 days after the index event. Conclusions— Prolongation of Holter monitoring in patients with symptoms of cerebral ischemic events increases the rate of detection of paroxysmal atrial fibrillation up to Day 7, leading to a relevant change in therapy in a substantial number of patients. Early initiation of monitoring does not appear to be crucial. Hence, prolonged Holter monitoring (≥7 days) should be considered for all patients with unexplained cerebral ischemia.

Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7

The spinocerebellar ataxias type 1 (SCA1), 2 (SCA2), 3 (SCA3), 6 (SCA6) and 7 (SCA7) are genetically defined autosomal dominantly inherited progressive cerebellar ataxias (ADCAs). They belong to the group of CAG-repeat or polyglutamine diseases and share pathologically expanded and meiotically unstable glutamine-encoding CAG-repeats at distinct gene loci encoding elongated polyglutamine stretches in the disease proteins. In recent years, progress has been made in the understanding of the pathogenesis of these currently incurable diseases: Identification of underlying genetic mechanisms made it possible to classify the different ADCAs and to define their clinical and pathological features. Furthermore, advances in molecular biology yielded new insights into the physiological and pathophysiological role of the gene products of SCA1, SCA2, SCA3, SCA6 and SCA7 (i.e. ataxin-1, ataxin-2, ataxin-3, α-1A subunit of the P/Q type voltage-dependent calcium channel, ataxin-7). In the present review we summarize our current knowledge about the polyglutamine ataxias SCA1, SCA2, SCA3, SCA6 and SCA7 and compare their clinical and electrophysiological features, genetic and molecular biological background, as well as their brain pathologies. Furthermore, we provide an overview of the structure, interactions and functions of the different disease proteins. On the basis of these comprehensive data, similarities, differences and possible disease mechanisms are discussed.

Neuronal death after brain injury

Abstract Neuronal damage in the central nervous system leads to primary cell death, induced directly by the trauma, and delayed secondary death of neurons, the latter depending on environmental changes, lack of metabolic and trophic supply, and altered gene transcription. While primary death of neurons occurring within a short time after trauma is not a realistic target for therapy, secondary cell death might be prevented by new neuroprotective strategies. Although there are increasing data concerning cell rescue after ischemic and traumatic brain injury through the last decade, the mechanisms that underlie secondary death of neurons following lesion are still incompletely understood and are now the subject of a more detailed investigation. In this review, we want to give an overview on what is known about the molecular mechanisms of delayed ischemic and traumatic neuronal death in vivo and about promising neuroprotective treatment strategies that might be of future clinical relevance or have already entered clinical trials.

α-Synuclein and its disease-related mutants interact differentially with the microtubule protein tau and associate with the actin cytoskeleton

alpha-Synuclein is a primarily neuronal protein that is enriched at the pre-synapse. alpha-Synuclein and the microtubule binding protein tau have been implicated in neurodegenerative diseases. alpha-Synuclein is known to associate with phospholipid vesicles, regulates dopamine metabolism and exhibits chaperone activity, but its main role remains largely unknown. Furthermore, knowledge on its interactions and post-translational modifications is essential for a molecular understanding of alpha-synucleinopathies. We investigated alpha-synuclein mutations, causative for autosomal dominant forms of Parkinsons disease (A30P, A53T and E46K), and phosphorylation mutants at serine 129 (S129A and S129D) using fluorescently labelled alpha-synuclein, actin and tau. The investigation of colocalization, and protein-protein interactions by Förster resonance energy transfer and fluorescence lifetime imaging showed that alpha-synuclein associates with the actin cytoskeleton and interacts with tau. The A30P mutation and cytoskeletal destabilization decreased this interaction. Given the concurrent loss of membrane binding by this mutation, we propose a membrane-bound functional complex with tau that might involve the actin cytoskeleton.

Neuronal Apoptosis in Neurodegenerative Diseases: From Basic Research to Clinical Application

In recent years, the investigation of erroneous regulation of apoptotic mechanisms during acute and chronic injury of neuronal cells has gained increasing attention. Besides acute neuronal trauma and ischemia, chronic neurodegenerative diseases like Alzheimer’s, Huntington’s, Parkinson’s and Lou-Gehrig’s disease (amyotrophic lateral sclerosis) are of particular interest. The present article will provide an overview of basic apoptotic mechanisms, the contribution of neuronal apoptosis to the above-mentioned disorders, potential clinical applications and their limitations and the possible implications for future studies regarding these neurodegenerative diseases.

Contribution of caspase-8 to apoptosis of axotomized rat retinal ganglion cells in vivo

We have investigated the role of caspase-8 and its mode of activation during apoptosis of adult rat retinal ganglion cells (RGCs) in vivo. Retinal pro-caspase-8 expression was almost completely restricted to RGCs. Although caspase-8 is known to be involved in death-receptor-dependent apoptosis, measurable caspase-8 activity or even RGC death could be induced by neither tumor necrosis factor-alpha nor Fas ligand injections into unlesioned eyes. However, substantial caspase-8 activation could be detected after optic nerve transection as shown by a fluorogenic activity assay and Western blot analysis. Intravitreal injection of caspase-8 inhibitors significantly attenuated degeneration of RGCs and reduced the number of RGCs showing caspase-3 activation. A late peak of caspase-8 activity and additive protective effects of caspase-8 and -9 inhibition on axotomized RGCs place caspase-8 in our model rather late in the apoptosis cascade, possibly after the onset of mitochondrial dysfunction.

Bag1 is a regulator and marker of neuronal differentiation

Bag 1 acts as a co-chaperone for Hsp70/Hsc70. We report here that stable over-expression of Bag1 in immortalized neuronal CSM14.1 cells prevents death following serum deprivation. Bag1 over-expression slowed the proliferative rate of CSM14.1 cells, resulted in increased levels of phospo-MAP kinases and accelerated neuronal differentiation. Immunocytochemistry revealed mostly nuclear localization of Bag1 protein in these cells. However, during differentiation in vitro, Bag1 protein shifted from predominantly nuclear to mostly cytosolic in CSM14.1 cells. To explore in vivo parallels of these findings, we investigated Bag1 expression in the developing mouse nervous system using immunohistochemical methods. Early in brain development, Bag1 was found in nuclei of neuronal precursor cells, whereas cytosolic Bag1 staining was observed mainly after completion of neuronal precursor migration and differentiation. Taken together, these findings raise the possibility that the Bag1 protein is expressed early in neurogenesis in vivo and is capable of modulating neuronal cell survival and differentiation at least in part from a nuclear location.

BAG1 promotes axonal outgrowth and regeneration in vivo via Raf-1 and reduction of ROCK activity.

Improved survival of injured neurons and the inhibition of repulsive environmental signalling are prerequisites for functional regeneration. BAG1 (Bcl-2-associated athanogene-1) is an Hsp70/Hsc70-binding protein, which has been shown to suppress apoptosis and enhance neuronal differentiation. We investigated BAG1 as a therapeutic molecule in the lesioned visual system in vivo. Using an adeno-associated viral vector, BAG1 (AAV.BAG1) was expressed in retinal ganglion cells (RGC) and then tested in models of optic nerve axotomy and optic nerve crush. BAG1 significantly increased RGC survival as compared to adeno-associated viral vector enhanced green fluorescent protein (AAV.EGFP) treated controls and this was independently confirmed in transgenic mice over-expressing BAG1 in neurons. The numbers and lengths of regenerating axons after optic nerve crush were also significantly increased in the AAV.BAG1 group. In pRGC cultures, BAG1-over-expression resulted in a approximately 3-fold increase in neurite length and growth cone surface. Interestingly, BAG1 induced an intracellular translocation of Raf-1 and ROCK2 and ROCK activity was decreased in a Raf-1-dependent manner by BAG1-over-expression. In summary, we show that BAG1 acts in a dual role by inhibition of lesion-induced apoptosis and interaction with the inhibitory ROCK signalling cascade. BAG1 is therefore a promising molecule to be further examined as a putative therapeutic tool in neurorestorative strategies.

Transthoracic Echocardiography to Rule Out Paroxysmal Atrial Fibrillation as a Cause of Stroke or Transient Ischemic Attack

Background and Purpose— We assessed whether echocardiography can predict paroxysmal atrial fibrillation (PAF) in patients with cerebral ischemia presenting in sinus rhythm. Methods— Within the prospective Find-AF cohort, 193 consecutive patients with cerebral ischemia and sinus rhythm on presentation had evaluation of echocardiographic parameters of left atrial size and function. PAF was diagnosed by 7-day Holter monitoring. Results— In 26 patients with PAF, late diastolic Doppler (A) and tissue Doppler (a′) velocities were lower whereas left atrial diameter, left atrial volume index (LAVI), LAVI/A, and LAVI/a′ were larger (P<0.05 for all) than they were in 167 patients without PAF. In multivariate models A, a′, LAVI/A, and LAVI/a′ predicted the presence of PAF. Area under the receiver operating characteristic curve to diagnose PAF was highest for LAVI/a′ (0.813 [0.738; 0.889]). A previously suggested cut-off of LAVI/a′ <2.3 had 92% sensitivity, 55.8% specificity, and 98% negative predictive value for PAF. Conclusions— LAVI/a′ <2.3 can effectively rule out PAF in patients with cerebral ischemia.

Aggregopathy in Neurodegenerative Diseases: Mechanisms and Therapeutic Implication

Many neurodegenerative diseases such as Parkinson’s, Alzheimer’s, Huntington’s and Lou Gehrig’s disease are associated with the misfolding and aggregation of proteins. While the relevance of these aggregates for neuronal degeneration and their impact on cellular function is still a matter of debate, several experimental therapeutic approaches have been aimed at interfering with protein aggregation. In this review, we want to summarize the current understanding of aggregate formation and toxicity in neurodegenerative diseases with an emphasis on Parkinson’s disease. Furthermore, we will discuss current treatment strategies in these diseases targeting aggregate formation and concurrent neuronal cell death in these diseases.