All Articles

J. Leigh Leasure^1,2*, Rebecca West¹

Exercise has long been considered a useful means by which to maintain brain health and treat brain diseases. Yet many of the neural benefits of exercise, such as enhanced hippocampal neurogenesis, take weeks to manifest. Moreover, the brains most in need of the restorative effects of exercise are often paired with bodies that can tolerate very little physical activity, such as those deconditioned by stroke. It would therefore be of great utility to pinpoint ways in which the brain benefits of exercise could be augmented without adding additional exercise time. Exercise represents a significant challenge to the brain because of the heat produced by exercising muscles, but physical activity in the cold attenuates this physiological burden. Using a rat model of voluntary exercise, we recently tested the hypothesis that exercise in cold ambient temperature (4.5°C) would stimulate hippocampal neurogenesis more effectively than exercise at room temperature. We found that, compared to animals that ran at room temperature, animals that exercised in the cold ran a shorter distance and for less total time. Nonetheless, they had more significantly more newly generated neurons in the hippocampal dentate gyrus, indicating that running in the cold may be an effective means by which to maximize brain exercise benefits, yet minimize exercise time.

Exercise is increasingly becoming accepted as “medicine” for diseases of both brain and body1. For the brain, exercise offers chemical, cellular and structural benefits, including enhanced generation of new neurons, glia and blood vessels2-5, increased expression of neurotrophins (such as brain-derived neurotrophic factor (BDNF)6,7), dendritic remodeling8,9 and stabilization of stress responses10 and inflammatory signaling11. These mechanisms of action directly counteract those present in disease states. For example, the depressed brain is characterized by decreased synaptic plasticity, hippocampal neurogenesis and BDNF12, all of which can be reversed by exercise.

Riikka-Liisa Uronen, Henri J. Huttunen^*

In Alzheimer’s disease (AD), loss of neurons and synapses parallels the formation of neurofibrillary tangles, protein aggregates mainly composed of hyperphosphorylated and aggregated Tau protein. Tau is mostly a cytosolic protein but can also be secreted by neurons. Cell-to-cell transfer of misfolded Tau protein plays a key role in the spread of neurofibrillary pathology between brain regions in AD and other tauopathies. Advances in genome-wide technologies have identified a large number of genetic risk factors for late-onset AD (LOAD). Currently, it remains unknown if genetic factors influence disease risk or progression rate by altering cell-to-cell propagation of Tau. Several LOAD risk genes are functionally associated with endocytic trafficking providing a potential link to Tau secretion and uptake. Recently, a LOAD risk gene FRMD4A was shown to regulate Tau secretion via a pathway linked to presynaptic vesicle machinery and polarity signaling. Tau release is linked to neuronal activity, and genetic factors that affect presynaptic vesicle release in the aging brain may also influence disease progression in AD and other tauopathies. In this mini review, we summarize the recent literature with a focus on the role of FRMD4A-cytohesin-Arf6 pathway and presynaptic vesicle machinery in the secretion of Tau.

Gabriele C Saretzki

Telomerase is best known for its canonical function in telomere maintenance. However, a growing number of non-telomeric functions have been described. Several groups have found the telomerase protein TERT to persist in adult brain neurons. A protective role for the telomerase protein TERT had been demonstrated in cultivated mouse neurons during brain development, against excitotoxic stresses from N-methyl-D-aspartate (NMDA) and glutamate and agents known to be involved in neurodegenerative diseases such as beta amyloid peptides and hyperphosphorylated tau. In contrast, lack of telomerase and TERT protein increase oxidative stress and decrease neuronal survival. Research on telomerase and TERT protein in human neurodegenerative diseases is a relatively new field. However, there is emerging evidence of a beneficial role of telomerase in human brains and animal models of neurodegenerative diseases that suggests to explore the possibility of using telomerase activators as neuroprotective agents to combat brain ageing and to ameliorate neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. The current mini-review summarises the knowledge about this developing novel area of brain research.

Alejandra N. Martinez¹, Mario T. Philipp^1,2

This review addresses the role that substance P (SP) and its preferred receptor neurokinin-1 (NK1R) play in neuroinflammation associated with select bacterial, viral, parasitic, and neurodegenerative diseases of the central nervous system. The SP/NK1R complex is a key player in the interaction between the immune and nervous systems. A common effect of this interaction is inflammation. For this reason and because of the predominance in the human brain of the NK1R, its antagonists are attractive potential therapeutic agents. Preventing the deleterious effects of SP through the use of NK1R antagonists has been shown to be a promising therapeutic strategy, as these antagonists are selective, potent, and safe. Here we evaluate their utility in the treatment of different neuroinfectious and neuroinflammatory diseases, as a novel approach to clinical management of CNS inflammation.

Bernd Krone

The sporadic forms of motor neuron diseases seem to depend on a multitude of factors that are, however, largely speculative. A main endogenous factor is seen in the enhanced expression of human endogenous retroviruses (HERVs). It is supposed that this is affecting the biogenesis of neuromelanin, in particular in the locus coeruleus. An altered neuromelanin with increased storage of metals and of precursors for toxins from food, respectively, might be of central importance. A hypothesis is described that is able to explain a number of observations and to understand roles and interactions of different factors. Toxins affecting the excitatory system are formed apparently within altered neuromelanin. Moreover, neuromelanin loaded with metal is also a microenvironment where pathological variants of proteins such as of alpha-synuclein are generated. Familial and toxin related forms of the diseases merge in formation and deposition of aberrant proteins and in a failure to destroy superoxide, thus increasing the harm from oxidative and nitrosative stress. This view might give some rational to revive investigations in methods for stabilization of storage and cautious squeezing out of metals and toxicants from neuromelanin, relying eventually on melatonin, iron chelators and chloroquine, respectively.

Nathalie Khoury, Kevin B. Koronowski and Miguel A. Perez-Pinzon*

In the absence of effective neuroprotective agents in the clinic, ischemic and pharmacological preconditioning are gaining increased interest in the field of cerebral ischemia. Our lab recently reported that resveratrol preconditioning affords tolerance against a focal cerebral ischemic insult in mice that can last for at least 14 days in vivo making it the longest window of ischemic tolerance discovered to date by a single administration of a pharmacological agent. The mechanism behind this novel extended window of ischemic tolerance remains elusive. In the below commentary we discuss potential mechanisms that could explain this novel extended window of ischemic tolerance in the context of previously identified windows and the known mechanisms behind them. We also draw parallels from the fields of hibernation and hypoxia-tolerance, which are chronic adaptations to severe conditions of hypoxia and ischemia known to be mediated by a form of metabolic depression. We also briefly discuss the importance of epigenetic modifications in maintaining this depressed state of metabolism.

Godinho C^1,2,3, Domingos J^1,3, Domingos J^1,3,4*

Healthcare professionals and pharmaceutical companies invest a great amount of time and effort in continuously creating electronic health solutions. These technology system developments may represent a step forward in care as ultimately it is not possible to manage what cannot be evaluated.

Yet, the use of future generations of technology depends on their specific design, fabrication, distribution, and, most importantly, patients adopting these new technologies as life companions. Data management and the use of artificial intelligence appear as new technological challenges. The overload, sharing and handling of information give rise to new legal, social, and ethical discussions in a field where there is a lack of universal criteria for data ownership, privacy and sharing.

Future technological progress requires much cooperation between multidisciplinary teams including sufficient sharing and benchmarking within open access frameworks.

Yoshio Matsuda

Jeffrey L. Neul^1,2, Alan K. Percy²

Kurt A. Jellinger

The aging brain is characterized by the simultaneous presence of multiple pathologies, and the prevalence of multi-morbidity increases with age. Large clinico-pathological correlative studies have shown that in brains of both cognitively intact and impaired aged subjects, the presence of a single disease is a rare finding, while most brains show neurodegenerative, cerebrovascular and other pathologies, which frequently have been missed clinically and may even be difficult to identify at postmortem examination. Since both clinical and autopsy studies differ in selection and classification criteria and in the applied evaluation methods, irrespective of the clinical symptoms, the reported frequency of cerebral pathologies varies considerably. The frequent co-occurrence of different pathologies indicates their mutual interaction in order to promote cognitive decline and other clinical symptoms. These facts have also implications for improvement of clinical diagnosis and prognosis, for the development of specific biomarkers, preventive strategies, and therapeutic targets for cerebral multi-morbidity.

Carl Marincowitz and Will Townend

Background: Head injury represents an extremely common presentation to Emergency Departments (ED), but not all patients present immediately after injury. There is evidence that clinical deterioration following head injury will usually occur within 24 hours. It is unclear whether this means that head injury patients that present in a delayed manner, especially after 24 hours, have a lower prevalence of significant traumatic injuries.

Methods: This is a commentary on a systematic review that we conducted with the aim of identifying all studies that assess the risk of significant injuries in delayed ED presentation head injury populations. We postulated that the risk of injury may be different in this group compared to patients that present immediately.

Results: Three studies were eligible for inclusion. They were all of poor methodological quality, and heterogeneity prevented meta-analysis. The reported prevalence of traumatic intra-cranial injury on CT was between 2.2% and 6.3%.

Conclusion: Available evidence suggests that head injury patients who present in a delayed fashion to the ED may have lower rates of intra-cranial injury compared to non-delayed head injury patients. However, the evidence is sparse and it is of too low quality to guide clinical practice. Further research is required to help the clinical risk assessment of this group.

Kurt A. Jellinger

Multiple system atrophy (MSA) is a fatal orphan neurodegenerative disorder that manifests with autonomic, parkinsonian, cerebellar, and pyramidal features. It is characterized by the accumulation of misfolded α-synuclein (αSyn) in oligodendroglia and neurons, affecting multiple parts of the central, autonomic and perípheral system. Both the etiology and pathogenesis of MSA are unknown, although a genetic component has been proposed. Accumulation of aberrant αSyn in oligodendrocytes, preceded by relocation of p25α protein from myelin into oligodendroglia, results in the formation of insoluble glial cytoplasmic inclusions (GCIs). These changes are associated with proteasomal, mitochondrial and lipid transport dysfunction, oxidative stress, reduced trophic transport, neuroinflammation and other noxious factors. Their interaction induces dysfunction of the oligodendroglial-myelin-axon-neuron complex, resulting in the system-specific pattern of neurodegeneration characterizing MSA as a synucleinopathy with oligodendroglio-neuronopathy. Propagation of modified toxic αSyn species from neurons to oligodendroglia by "prion-like" transfer and its spreading to associate neuronal pathways result in multi-system involvement. No reliable biomarkers are currently available for the clinical diagnosis and prognosis of MSA and neither effective neuroprotective nor disease-modifying therapies of MSA are available, although novel treatment strategies targeting αSyn are under discussion. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes to develop reliable diagnostic biomarkers and to deliver targets for effective treatment of this hitherto incurable disorder is urgently needed.

Mark Tommerdahl

Wolfgang H Jost

For years we have been injecting botulinum toxin relying mainly on our clinical experience and, in some cases, on the use of electromyography. Within that time some therapists introduced sonography for guidance and emphasize the advantages of this technique. Schramm et al., for example, pointed out the relevance of sonography for botulinum toxin treatment in cervical dystonia. Within a short time the importance of sonography has been well documented in this indication. Even assuming a critical distance, the significance of this technique has become largely indisputable.