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Zempel H.,German Center for Neurodegenerative Diseases | Mandelkow E.,German Center for Neurodegenerative Diseases | Mandelkow E.,Max Planck Institute for Neurological Research
Trends in Neurosciences | Year: 2014

Tau is a microtubule-associated-protein that is sorted into neuronal axons in physiological conditions. In Alzheimer disease (AD) and other tauopathies, Tau sorting mechanisms fail and Tau becomes missorted into the somatodendritic compartment. In AD, aberrant amyloid-β (Aβ) production might trigger Tau missorting. The physiological axonal sorting of Tau depends on the developmental stage of the neuron, the phosphorylation state of Tau and the microtubule cytoskeleton. Disease-associated missorting of Tau is connected to increased phosphorylation and aggregation of Tau, and impaired microtubule interactions. Disease-causing mechanisms involve impaired transport, aberrant kinase activation, non-physiological interactions of Tau, and prion-like spreading. In this review we focus on the physiological and pathological (mis)sorting of Tau, the underlying mechanisms, and effects in disease. © 2014 Elsevier Ltd.

Heiss W.-D.,Max Planck Institute for Neurological Research
International Journal of Stroke | Year: 2010

The 'penumbra' is a concept coined in animal experiments suggesting that functionally impaired tissue can survive and recover if sufficient reperfusion is re-established within a limited time period, which depends on the level of residual flow. In an ischaemic territory, irreversible damage progresses over time from the centre of the most severe flow reduction to the periphery with less disturbed perfusion. This centrifugal progression of irreversible tissue damage is characterised by a complex cascade of interconnected electrophysiological, molecular, metabolic and perfusion disturbances. Waves of depolarisations, the peri infarct spreading depressions, inducing activation of ion pumps and liberation of excitatory transmitters play an important role in the drastically increased metabolic demand during reduced oxygen supply causing hypoxic tissue changes and lactacidosis, which further damage the tissue. Positron emission tomography allows the quantification of regional cerebral blood flow, the regional metabolic rate for oxygen and the regional oxygen extraction fraction, which can be used to identify regions with a critical reduction in these physiologic variables as indicators of penumbra and irreversible damage within ischaemic territories in animal models and patients with stroke. These positron emission tomography methods require arterial blood sampling and due to the complex logistics involved, are limited for routine application. Therefore, newer tracers were developed for the noninvasive detection of irreversible tissue damage (flumazenil) and of hypoxic tissue changes (fluoromisonidazole). As a widely applicable clinical tool, diffusion/perfusion-weighted magnetic resonance imaging is used; the 'mismatch' between perfusion and diffusion changes serves as a surrogate marker of the penumbra. However, in comparative studies of magnetic resonance imaging and positron emission tomography, diffusion-weighted imaging showed a high false-positive rate of irreversible damage, and the perfusion-weighted-diffusion-weighted mismatch overestimated the penumbra as defined by positron emission tomography. Advanced analytical procedures of magnetic resonance imaging data may improve the reliability of these surrogate markers but should be validated with quantitative procedures. © 2010 The Authors. Journal compilation © 2010 World Stroke Organization.

Heiss W.-D.,Max Planck Institute for Neurological Research
Neuroscience Bulletin | Year: 2014

Cerebrovascular diseases are caused by interruption or significant impairment of the blood supply to the brain, which leads to a cascade of metabolic and molecular alterations resulting in functional disturbance and morphological damage. These pathophysiological changes can be assessed by positron emission tomography (PET), which permits the regional measurement of physiological parameters and imaging of the distribution of molecular markers. PET has broadened our understanding of the flow and metabolic thresholds critical for the maintenance of brain function and morphology: in this application, PET has been essential in the transfer of the concept of the penumbra (tissue with perfusion below the functional threshold but above the threshold for the preservation of morphology) to clinical stroke and thereby has had great impact on developing treatment strategies. Radioligands for receptors can be used as early markers of irreversible neuronal damage and thereby can predict the size of the final infarcts; this is also important for decisions concerning invasive therapy in large (“malignant”) infarctions. With PET investigations, the reserve capacity of blood supply to the brain can be tested in obstructive arteriosclerosis of the supplying arteries, and this again is essential for planning interventions. The effect of a stroke on the surrounding and contralateral primarily unaffected tissue can be investigated, and these results help to understand the symptoms caused by disturbances in functional networks. Chronic cerebrovascular disease causes vascular cognitive disorders, including vascular dementia. PET permits the detection of the metabolic disturbances responsible for cognitive impairment and dementia, and can differentiate vascular dementia from degenerative diseases. It may also help to understand the importance of neuroinflammation after stroke and its interaction with amyloid deposition in the development of dementia. Although the clinical application of PET investigations is limited, this technology had and still has a great impact on research into cerebrovascular diseases. © 2014, Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg.

Heiss W.-D.,Max Planck Institute for Neurological Research
European Journal of Neurology | Year: 2012

Advances in resuscitation and critical care management have resulted in the survival of many patients despite severe brain damage. These patients may remain in coma or in vegetative state. The probability of recovery of conscious function is dependent on the extent of structural brain damage, which is difficult to assess by clinical, laboratory or functional tests. Positron emission tomography (PET) of 18F-fluordeoxyglucose (FDG) can be used to investigate metabolic and functional impairment of the brain. In acute vegetative state (AVS, duration<1month), overall glucose utilization was significantly reduced in comparison with age-matched controls. In a few cases with locked-in syndrome, cortical metabolism was in the normal range. 11C-Flumazenil (FMZ) measures the density of benzodiazepine receptors (BZRs) and thereby furnishes an estimate of neuronal integrity. PET with this tracer demonstrated a considerable reduction in BZRs in cortical areas, but indicated that the cerebellum was spared from neuronal loss. The comparison of FDG- and FMZ-PET findings in AVS demonstrates that alterations of cerebral glucose consumption do not represent mere functional inactivation, but also irreversible structural damage. In some cases with minimally conscious state, auditory stimuli with emotional valence induced more brain activation (investigated by H215O-PET) than meaningless noise; such studies can be used to detect residual cortical function. To improve prognostication of chances for recovery, a combination of functional activation studies and assessment of the extent of neuronal damage might be the optimal procedure and should be tested in larger cohorts of patients with comatose states of different severity. © 2011 The Author(s). European Journal of Neurology © 2011 EFNS.

Heiss W.-D.,Max Planck Institute for Neurological Research
Annals of the New York Academy of Sciences | Year: 2012

An ischemic penumbra has the potential for functional recovery provided that local blood flow can be reestablished, but irreversible damage will develop without sufficient reperfusion, depending on the interaction of severity and duration of ischemia. With acute flows below the threshold required for maintenance of basic housekeeping, injury in the core is established within a few minutes. During the subacute phase, the irreversible damage expands into the penumbra: multiple electrical and biological signals are triggered by periinfarct, spreading depression-like depolarizations leading to hypoxia and stepwise increase in lactate. Usually within 6 to 8 hours, all the penumbra are converted into irreversible infarcts. In a delayed phase, secondary phenomena may cause additional tissue damage: disruption of the tight junctions results in vasogenic edema, leading to increase of water content and damage expansion. Neutrophils and cytokinins cause secondary inflammation, inducing further damage in periinfarct regions and connecting fiber tracts. Multimodal imaging might be able to differentiate among the tissue compartments affected by acute, subacute, or delayed ischemic damage, and thereby might provide the basis for phase-specific treatment strategies. © 2012 New York Academy of Sciences.

Wessel J.R.,University of California at San Diego | Wessel J.R.,Max Planck Institute for Neurological Research
Frontiers in Human Neuroscience | Year: 2012

From its discovery in the early 1990s until this day, the error-related negativity (ERN) remains the most widely investigated electrophysiological index of cortical error processing. When researchers began addressing the electrophysiology of subjective error awareness more than a decade ago, the role of the ERN, alongside the subsequently occurring error positivity (Pe), was an obvious locus of attention. However, the first two studies explicitly addressing the role of error-related event-related brain potentials (ERPs) would already set the tone for what still remains a controversy today: in contrast to the clear-cut findings that link the amplitude of the Pe to error awareness, the association between ERN amplitude and error awareness is vastly unclear. An initial study reported significant differences in ERN amplitude with respect to subjective error awareness, whereas the second failed to report this result, leading to a myriad of follow-up studies that seemed to back up or contradict either view. Here, I review those studies that explicitly dealt with the role of the error-related ERPs in subjective error awareness, and try to explain the differences in reported effects of error awareness on ERN amplitude. From the point of view presented here, different findings between studies can be explained by disparities in experimental design and data analysis, specifically with respect to the quantification of subjective error awareness. Based on the review of these results, I will then try to embed the error-related negativity into a widely known model of the implementation of access consciousness in the brain, the global neuronal workspace (GNW) model, and speculate as the ERN's potential role in such a framework. At last, I will outline future challenges in the investigation of the cortical electrophysiology of error awareness, and offer some suggestions on how they could potentially be addressed. © 2012 Wessel.

Hossmann K.-A.,Max Planck Institute for Neurological Research
Journal of Cerebral Blood Flow and Metabolism | Year: 2012

Brain injury after focal ischemia evolves along two basically different pathophysiologies, depending on the severity of the primary flow reduction and the dynamics of postischemic recirculation. In permanent and gradually reversed focal ischemia as after thromboembolic occlusion, primary core injury is irreversible but the expansion of the core into the penumbra can be alleviated by hemodynamic and molecular interventions. Such alleviation can only be achieved within 3 hours after the onset of ischemia because untreated core injury expands to near maximum size during this interval. In promptly reversed transient ischemia as after mechanical vascular occlusion, primary core injury may recover but a secondary delayed injury evolves after a free interval of as long as 6 to 12 hours. This injury can be alleviated throughout the free interval but the longer window is without clinical relevance because transient mechanical vascular occlusion is not a model of naturally occurring stroke. As this difference is widely ignored in stroke research, most clinical trials have been designed with a far too long therapeutic window, which explains their failure. Transient mechanical vascular occlusion models should, therefore, be eliminated from the repertoire of preclinical stroke research. © 2012 ISCBFM All rights reserved.

Ullsperger M.,Max Planck Institute for Neurological Research
Brain structure & function | Year: 2010

To detect erroneous action outcomes is necessary for flexible adjustments and therefore a prerequisite of adaptive, goal-directed behavior. While performance monitoring has been studied intensively over two decades and a vast amount of knowledge on its functional neuroanatomy has been gathered, much less is known about conscious error perception, often referred to as error awareness. Here, we review and discuss the conditions under which error awareness occurs, its neural correlates and underlying functional neuroanatomy. We focus specifically on the anterior insula, which has been shown to be (a) reliably activated during performance monitoring and (b) modulated by error awareness. Anterior insular activity appears to be closely related to autonomic responses associated with consciously perceived errors, although the causality and directions of these relationships still needs to be unraveled. We discuss the role of the anterior insula in generating versus perceiving autonomic responses and as a key player in balancing effortful task-related and resting-state activity. We suggest that errors elicit reactions highly reminiscent of an orienting response and may thus induce the autonomic arousal needed to recruit the required mental and physical resources. We discuss the role of norepinephrine activity in eliciting sufficiently strong central and autonomic nervous responses enabling the necessary adaptation as well as conscious error perception.

Morgan M.J.,Max Planck Institute for Neurological Research
Vision Research | Year: 2012

Prolonged inspection of moving stimuli causes stationary stimuli to appear moving in the opposite direction to the adapting stimulus (the Waterfall effect). It has been claimed that distracting the viewer's attention from the adapting stimulus by a secondary task reduces the strength of adaptation. However, the method used to show the effect of distraction (the duration of the aftereffect) is potentially susceptible to bias. The experiments reported here show no effect in genuinely naïve subjects, or in experienced observers using a variety of cancellation procedures to measure the effect. © 2012 Elsevier Ltd.

Heiss W.-D.,Max Planck Institute for Neurological Research
Cerebrovascular Diseases | Year: 2011

The concept of the ischemic penumbra was formulated 30 years ago based on experiments in animal models showing functional impairment and electrophysiological disturbances with decreasing flow to the brain below defined values (the threshold for function) and irreversible tissue damage with the blood supply further decreased (the threshold for infarction). The perfusion range between these thresholds was termed 'penumbra', and restitution of flow above the functional threshold was able to reverse the deficits without permanent damage. However, in further experiments, the dependency of the development of irreversible lesions on the interaction of the severity and duration of critically reduced blood flow was established - proving that the lower the flow, the shorter the time for efficient reperfusion. Therefore, infarction develops from the core of ischemia to the areas of less severe hypoperfusion. The propagation of irreversible tissue damage is characterized by a complex cascade of interconnected electrophysiological, molecular, metabolic and perfusional disturbances. Waves of depolarizations, the peri-infarct spreading depression-like depolarizations, inducing activation of ion pumps and liberation of excitatory transmitters, have dramatic consequences as drastically increased metabolic demand cannot be satisfied in regions with critically reduced blood supply. The translation of experimental concept into the basis for efficient treatment of stroke requires non-invasive methods by which regional flow and energy metabolism can be repeatedly investigated to demonstrate penumbra tissue that can benefit from therapeutic interventions. Positron emission tomography (PET) allows the quantification of regional cerebral blood flow, the regional metabolic rate for oxygen and the regional oxygen extraction fraction. From these variables, clear definitions of irreversible tissue damage and critically perfused but potentially salvageable tissue (i.e. the penumbra) can be achieved in animal models and stroke patients. Additionally, further tracers can be used for early detection of irreversible tissue damage, e.g. by the central benzodiazepine receptor ligand flumazenil. However, PET is a research tool and its complex logistics limit clinical routine applications. As a widely applicable clinical tool,perfusion/diffusion-weighted (PW/DW) MRI is used, and the 'mismatch' between the PW and the DW abnormalities serve as an indicator of the penumbra. However, comparative studies of PW/DW-MRI and PET have pointed to an overestimation of the core of irreversible infarction as well as of the penumbra by MRI modalities. Some of these discrepancies can be explained by unselective application of relative perfusionthresholds, which might be improved by more complex analytical procedures. Heterogeneity of the MRI signatures used for the definition of the mismatch are also responsible for disappointing results in the application of PW/DW-MRI for the selection of patients for clinical trials. As long as a validation of the mismatch selection paradigm is lacking, its use as a surrogate marker of outcome is limited. Copyright © 2011 S. Karger AG, Basel.

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