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Anthocyanins, a flavonoid class of polyphenols, are water soluble dark colored natural pigments found in fruits and vegetables. Owing to their wide distribution in plant materials, dietary consumption of anthocyanins is high compared to other flavonoids. Anthocyanins, due to their multifaceted medicinal properties are the active components in many herbal folk medicines. As in vitro and in vivo results, animal models, and clinical trials in various cell lines suggest, anthocyanins possess antioxidant, antidiabetic, antihyperlipidemic, anti-inflammatory, anticarcinogenic, antiulcer, and preventive activities against cardiovascular diseases. Additionally, anthocyanins exhibit chemotherapeutic, cardioprotective, hepatoprotective, and neuroprotective activities. In the diet, anthocyanins are absorbed in the stomach and intestinal cells and rapidly detected in the plasma. These promising properties of anthocyanins may well provide health benefits against chronic diseases.

Background: Alzheimer's disease (AD) is currently incurable and a majority of investigational drugs have failed clinical trials. One explanation for this failure may be the invalidity of hypotheses focusing on amyloid to explain AD pathogenesis. Recently, hypotheses which are centered on synaptic and metabolic dysfunction are increasingly implicated in AD. Objective: Evaluate AD hypotheses by comparing neurotransmitter and metabolite marker concentrations in normal versus AD CSF. Methods: Meta-analysis allows for statistical comparison of pooled, existing cerebrospinal fluid (CSF) marker data extracted from multiple publications, to obtain a more reliable estimate of concentrations. This method also provides a unique opportunity to rapidly validate AD hypotheses using the resulting CSF concentration data. Hubmed, Pubmed and Google Scholar were comprehensively searched for published English articles, without date restrictions, for the keywords “AD”, “CSF”, and “human” plus markers selected for synaptic and metabolic pathways. Synaptic markers were acetylcholine, gamma-aminobutyric acid (GABA), glutamine, and glycine. Metabolic markers were glutathione, glucose, lactate, pyruvate, and 8 other amino acids. Only studies that measured markers in AD and controls (Ctl), provided means, standard errors/deviation, and subject numbers were included. Data were extracted by six authors and reviewed by two others for accuracy. Data were pooled using ratio of means (RoM of AD/Ctl) and random effects meta-analysis using Cochrane Collaboration’s Review Manager software. Results: Of the 435 identified publications, after exclusion and removal of duplicates, 35 articles were included comprising a total of 605 AD patients and 585 controls. The following markers of synaptic and metabolic pathways were significantly changed in AD/controls: acetylcholine (RoM 0.36, 95% CI 0.24-0.53, p Conclusion: This study provides proof of concept for the use of meta-analysis validation of AD hypotheses, specifically via robust evidence for the cholinergic hypothesis of AD. Our data disagree with the other synaptic hypotheses of glutamate excitotoxicity and GABAergic resistance to neurodegeneration, given observed unchanged glutamate levels and decreased GABA levels. With regards to metabolic hypotheses, the data supported upregulation of anaerobic glycolysis, pentose phosphate pathway (glutathione), and anaplerosis of the tricarboxylic acid cycle using glutamate. Future applications of meta-analysis indicate the possibility of further in silico evaluation and generation of novel hypotheses in the AD field.

Background:Despite increased neuronal death, senile plaques, and neurofibrillary tangles observed in patients suffering from Alzheimer’s disease (AD), the detailed mechanism of cell death in AD is still poorly understood.Method:We hypothesized that p38 kinase activates and then phosphorylates Bax, leading to its translocation to mitochondria in AD brains compared to controls. The aim of this study was to investigate the role of p38 kinase in phosphorylation and sub-cellular localization of pro-apoptotic Bax in the frontal cortex of the brains from AD and control subjects. Increased oxidative stress in AD individuals compared to control was evaluated by measuring the levels of carbonylated proteins and oxidized peroxiredoxin, an antioxidant enzyme. The relative amounts of p38 kinase and phospho-Bax in mitochondria in AD brains and controls were determined by immunoblot analysis using the respective antibody against each protein following immunoprecipitation.Results:Our results showed that the levels of oxidized peroxiredoxin-SO3and carbonylated proteins are significantly elevated in AD brains compared to controls, demonstrating the increased oxidative stress.Conclusion:The amount of phospho-p38 kinase is increased in AD brains and the activated p38 kinase appears to phosphorylate Thr residue(s) of Bax, which leads to its mitochondrial translocation, contributing to apoptosis and ultimately, neurodegeneration.

Background: The last two decades have seen a great advance in the data that supports the two current hypotheses in Alzheimer's disease field, the amyloid beta hypothesis and the tau hypothesis. Not surprisingly, Aβ and tau proteins are currently the major therapeutic research targets for AD treatment. Unfortunately, nothing but moderate success has emerged from such therapeutic approaches. With this in mind, we will discuss deep brain stimulation as a promising therapeutic strategy that aims to restore brain activity. Lastly, in the scope of cognitive deficit restoration, we will discuss the relevance of the limbic formation as a promising neuroanatomical target for deep brain stimulation. Methods: Immunohistochemistry for modified tau (phosphorylated at Ser199–202–Thr205 labelled by the antibody AT8) was performed on paraffin-embedded human brain sections providing a detailed characterization of NFT pathology. Results: Abnormally phosphorylated tau protein is the key common marker in several brain diseases such as Alzheimer's disease, Parkinson's disease, Pick Disease, Down syndrome and frontotemporal dementia and is capable of affecting synaptic events that are critical for memory formation. With this in mind, therapeutic strategies aiming to restore synaptic events could offer better outcomes. Conclusion: The humble success of current therapeutic strategies along with the lack of basic knowledge of the brain disease mechanisms calls for alternatives that benefit patients in the present moment. One of particular interest is the neurostimulation strategy that is already a well-established treatment for several movement disorders and when compared to current Alzheimer's therapeutic strategies, deep brain stimulation does not directly interfere with the normal protein function, therefore increasing the probability of success.

A method for the molecular mapping of formalin-fixed, paraffin-embedded human hippocampal tissue affected by Alzheimer's disease (AD) is presented. This approach utilizes imaging mass spectrometry (IMS) with matrix-assisted laser desorption/ionization (MALDI). The usefulness of this technique in comparing diseased versus nor mal tissue at the molecular level while continuing to maintain topological and morphological integrity is evident in the preliminary findings. The critical correlation of the deparaffination, washing, matrix deposition, and analysis steps in handling the tissue sections and how these steps impact the successful mapping of human hippocampal tissue is clearly demonstrated. By use of this technique we have been able to identify several differences between the hippocampal AD tissue and the control hippocampal tissue. From the observed peptide clip masses we present preliminary identifications of the amyloid-beta peptides known to be prominent in the brains of those with AD. We have obtained high-resolution mass spectra and mass images with 100μm spatial resolution. Future experiments will couple this work with MALDI LIFT experiments to enable top down proteomics of fresh frozen tissue, which is not possible with paraffin-embedded tissues.

We studied the brain distribution of amyloid-β (Aβ) and phosphorylated tau (τ) in 20 consecutive autopsy cases between the ages of 51 and 65, with no history of neurologic disease during life. We note that early accumulations of Aβ and τ occur in distinct neuroanatomical distributions. In the locus ceruleus and medial temporal lobe allocortex τ often occurs in the absence of diffuse Aβ and that Aβ occurs in the neocortex in the absence of τ. In those cases with both Aβ and τ were present in the sections, there was no overlap at the microanatomical or cellular level. APOE genotype was also assessed, showing no specific relationship with the presence or distribution of Aβ and τ, although the numbers of cases were limited. These findings indicate that the early appearances of hallmark proteins of Alzheimer’s disease are disconnected both in time and in space, suggesting that both are reactive phenomena with no mechanistic relationship in aging or preclinical disease.

Amyloid formation is the pathological hallmark of type 2 diabetes (T2D) and Alzheimer's disease (AD). These diseases are marked by extracellular amyloid deposits of islet amyloid polypeptide (IAPP) in the pancreas and amyloid β (Aβ) in the brain. Since IAPP may enter the brain and disparate amyloids can cross-seed each other to augment amyloid formation, we hypothesized that pancreatic derived IAPP may enter the brain to augment misfolding of Aβ in AD. The corollaries for validity of this hypothesis are that IAPP [1] enters the brain, [2] augments Aβ misfolding, [3] associates with Aβ plaques, and most importantly [4] plasma levels correlate with AD diagnosis. We demonstrate the first 3 corollaries that: (1) IAPP is present in the brain in human cerebrospinal fluid (CSF), (2) synthetic IAPP promoted oligomerization of Aβ in vitro, and (3) endogenous IAPP localized to Aβ oligomers and plaques. For the 4th corollary, we did not observe correlation of peripheral IAPP levels with AD pathology in either an African American cohort or AD transgenic mice. In the African American cohort, with increased risk for both T2D and AD, peripheral IAPP levels were not significantly different in samples with no disease, T2D, AD, or both T2D and AD. In the Tg2576 AD mouse model, IAPP plasma levels were not significantly elevated at an age where the mice exhibit the glucose intolerance of pre-diabetes. Based on this negative data, it appears unlikely that peripheral IAPP cross-seeds or "infects" Aβ pathology in AD brain. However, we provide novel and additional data which demonstrate that IAPP protein is present in astrocytes in murine brain and secreted from primary cultured astrocytes. This preliminary report suggests a potential and novel association between brain derived IAPP and AD, however whether astrocytic derived IAPP cross-seeds Aβ in the brain requires further research.

This study aimed to show that the rat model of sporadic Alzheimer's disease (sAD) generated by the intracerebroventricular (icv) injection of a sub-diabetogenic dose of streptozotocin (icvSTZ) is characterized by brain mitochondrial abnormalities. Three-month-old male Wistar rats were investigated 5 weeks after a single bilateral icv injection of STZ (3 mg/ Kg) or vehicle. icvSTZ administration induced a decrease in brain weight and cognitive decline, without affecting blood glucose levels. icvSTZ administration also resulted in a significant increase in hippocampal amyloid beta peptide 1-42 (Aβ(1-42)) levels as well as in cortical and hippocampal hyperphosphorylated tau protein levels. Brain mitochondria from icvSTZ rats revealed deficits in their function, as shown by a decrease in mitochondrial transmembrane potential, repolarization level, ATP content, respiratory state 3, respiratory control ratio and ADP/O index and an increase in lag phase of repolarization. Mitochondria from icvSTZ rats also displayed a decrease in pyruvate and α-ketoglutarate dehydrogenases and cytochrome c oxidase activities and an increase in the susceptibility to calcium-induced mitochondrial permeability transition. An increase in hydrogen peroxide and lipid peroxidation levels and a reduction in glutathione content were also observed in mitochondria from icvSTZ rats. These results demonstrate that the insulin-resistant brain state that characterizes this rat model of sAD is accompanied by the occurrence of mitochondrial abnormalities reinforcing the validity of this animal model to study sAD pathogenesis and potential therapies.

Despite over one hundred years of intense effort studying Alzheimer's disease (AD), we still do not understand its cause(s) and this adversely affects our ability to develop strongly effective treatments and means to prevent it. This is because our research efforts are not aligned to decipher this age-related disorder that, well after its discovery, has become a major cause of death throughout the world. We are therefore recommending a process to analyze some of the principal factors that hinder our progress in this field of research. Recognizing these barriers - and acting on such a recognition by seeking to resolve them experimentally and garnering societal support to do so - will constitute critical steps towards establishing strategies that will lead to a sorely needed paradigm shift in AD research, and ultimately to the prevention and the effective treatment of this devastating condition. This will probably also spur progress in many related neuropsychiatric disorders, and in that sense act as a seminal endeavor with far-reaching consequences. In order to accomplish this complex task, the biomedical community must acknowledge and come to a consensus about the factors that limit our progress, and then work together to generate new algorithms to tackle these fundamental issues rationally, effectively and deliberately.

Alzheimers disease (AD) is a devastating disorder that leads to memory loss and dementia. Neurodegeneration of cholinergic neurons in the septum and other basal forebrain areas is evident in early stages of AD. Glutamatergic neurons are also affected early in AD. In these stages, amyloid-β-peptide (Aβ) plaques are present in the hippocampus and other cortices but not in the basal forebrain, which includes the septum. We postulate that early deposition of hippocampal Aβ damages the axon terminals of cholinergic and glutamatergic septo-hippocampal neurons, leading to their degeneration. To determine the mechanisms underlying septal degeneration, fibrillar Aβ1-40 was injected into the Cornu Ammonis (CA1) hippocampal region of rats. Controls were injected with reverse peptide Aβ40-1. A 16% reduction in NeuN+ cells was observed around the injection sites when compared to controls (p < 0.05) one week after injections. Stereology was used to estimate the number of choline acetyl transferase (ChAT), glutamate and glutamic acid decarboxylase 67 (GAD67) immunoreactive septal neurons. Medial septal ChAT and glutamate immunoreactive neurons were reduced 38% and 26%, respectively by hippocampal injections of Aβ1-40 peptide in relation to controls. In contrast, the number of GAD67 inmunoreactive neurons was not significantly reduced. Apoptotic cells were detected in the medial septal region of Aβ1-40 treated animals but not in controls. These results indicate that limited Aβ-induced hippocampal lesions lead to an overall damage of vulnerable septal neuronal populations, most likely by Aβ interaction with septo-hippocampal axon terminals. Thus, axon terminals constitute an important target for novel therapeutics dedicated to control Aβ-induced toxicity.

Mitochondria fulfill a number of essential cellular functions, being recognized that the strict regulation of the structure, function and turnover of these organelles is an immutable control node for the maintenance of neuronal integrity and homeostasis. Many lines of evidence posit that mitochondria constitute a convergence point of preconditioning - a paradigm that affords robust brain tolerance in the face of neurodegenerative insults. Indeed, it has been described that preconditioning activates an adaptive reprogramming of mitochondrial biology in response to a noxious stress-stimulus, which in turn will contribute to augment both mitochondrial and neuronal tolerance. Mitochondrial reactive species (ROS), mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels and mitochondrial permeability transition pore have been identified as specific mitochondrial mediators and targets of the adaptive program underlying preconditioning. Recent studies further link mitochondrial biogenesis, dynamics and mitophagy to preconditioning, thereby representing novel mechanisms by which preconditioning may mediate brain tolerance. The present review summarizes the current views on how mitochondrial biology is linked to preconditioning-induced neuroprotection. A better understanding of the mitochondrial mechanisms underlying preconditioning will help in the development of novel therapeutic approaches with the primary goal of modulating mitochondria to enhance brain tolerance against neurodegenerative events.

Mitochondrial dynamics play a crucial role in the pathobiology underlying Alzheimer’s disease (AD) and Parkinson’s disease (PD). Although a complete scientific understanding of these devastating conditions has yet to be realized, alterations in mitochondrial fission and fusion, and in the protein complexes that orchestrate mitochondrial fission and fusion, have been well established in AD- and PD-related neurodegeneration. Whether fission/fusion disruption in the brain is a causal agent in neuronal demise or a product of some other upstream disturbance is still a matter of debate; however, in both AD and PD, the potential for successful therapeutic amelioration of degeneration via mitochondrial protection is high. We here discuss the role of mitochondrial dynamics in AD and PD and assess the need for their therapeutic exploitation.

Parkinson's disease (PD) is a progressive, age-related movement disorder, whose neuropathology is character- ized by degeneration of the afferent pigmented neurons of the substantia nigra. Also associated with PD neuropathology are disrupted iron homeostasis, oxidative stress, and intracellular deposition of alpha-synuclein protein in Lewy bodies. Here we review oxidative stress mechanisms in Parkinson's disease, with emphasis on the relationship between oxidative stress and alpha-synuclein gene expression.

Oxidative stress occurs early in the progression of Alzheimer disease, significantly before the development of the pathologic hallmarks, neurofibrillary tangles and senile plaques. All classes of macromolecules (sugar, lipids, proteins, and nucleic acids) are affected by oxidative stress leading, inevitably, to neuronal dysfunction. Extensive data from the literature support the notion that mitochondrial and metal abnormalities are key sources of oxidative stress in Alzheimer disease. Furthermore, it has been suggested that in the initial stages of the development of Alzheimer disease, amyloid-beta deposition and hyperphosphorylated tau function as compensatory responses to ensure that neuronal cells do not succumb to oxidative damage. However, during the progression of the disease, the antioxidant activity of both agents is either overwhelmed or, according to others, evolves into pro-oxidant activity resulting in the exacerbation of reactive species production.

Although cellular RNA should be subject to the same oxidative insults as DNA and other cellular macromolecules, oxidative damage to RNA has not been a major focus in investigating the magnitude and the biological consequences of the free radical damage. However, because RNA is mostly single-stranded and its bases are not protected by hydrogen bonding and are less protected by specific proteins, RNA may be more susceptible to oxidative insults than DNA. Thereafter, oxidative damage to protein-coding RNA or non-coding RNA will potentially cause errors in proteins or dysregulation of gene expression. While less lethal than mutations in genome, such non-acutely lethal insults to cells might be associated with underlying mechanisms of several human diseases, especially chronic degeneration. Recently, oxidative RNA damage has been described in several neurodegenerative diseases including Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and prion diseases. Of particular interest, oxidative RNA damage is a feature in vulnerable neurons at the very earliest-stages of these diseases, suggesting that RNA oxidation may actively contribute to the onset or to the development of disease. Mechanistically speaking, an increasing body of evidence suggests that the detrimental effects of oxidative RNA damage to protein synthesis are attenuated, at least in part, by the existence of mechanisms that avoid the incorporation of the damaged ribonucleotides into the translational machinery. Further investigations toward understanding of the consequences and processing mechanisms related to oxidative RNA damage may provide significant insights into the pathogenesis and therapeutic strategies for neurodegenerative and other degenerative diseases.

There is considerable evidence showing that oxidative damage is one of the earliest neuronal and pathological changes of Alzheimer disease and many, if not all, of the etiological and pathological causes of the disease are related, directly or indirectly, to free radical production and oxidative damage. Here we summarize the current body of knowledge suggestive that oxidative damage is, if not the key factor, certainly a major factor in Alzheimer disease. As such, therapeutic modalities encompassing antioxidants may be an effective approach to the treatment of neurodegenerative diseases and delay the aging process.

Osteopontin (OPN) is a glycophosphoprotein expressed by several cell types and has pro-adhesive, chemotactic, and cytokine-like properties. OPN is involved in a number of physiologic and pathologic events including angiogenesis, apoptosis, inflammation, oxidative stress, remyelination, wound healing, bone remodeling, cell migration and tumorigenesis. Since these functions of OPN, and the events that it regulates, are involved with neurodegeneration, we examined whether OPN was differentially expressed in the hippocampus of the Alzheimer's disease (AD) compared with age-matched (59-93 years) control brain. We report for the first time the immunocytochemical localization of OPN in the cytoplasm of pyramidal neurons. In AD brains, there was a significant 41 % increase in the expression of neuron OPN compared with age-matched control brain. No staining of other neuronal cell types was observed. Additionally, there was a significant positive correlation between OPN staining intensity and both amyloid-beta load (r(2) = 0.25; P < 0.05; n = 20) and aging (r(2) = 0.32; P < 0.01; n = 20) among all control and AD subjects. Controlling for age indicated that OPN expression was significantly influenced by amyloid-beta load, but not age. While the functional consequences of this amyloid-beta associated increase in OPN expression are unclear, it is notable that OPN is primarily localized to those neurons that are known to be vulnerable to AD-related neurite loss, degeneration and death. Given that the induction of OPN expression (and amyloid-beta generation) is associated with remodeling and tumorigenesis, our results suggest that OPN may play a role in the aberrant re-entry of neurons into the cell cycle and/or neuronal remyelination in AD.

The complex nature and genesis of oxidative damage in Alzheimer disease can be partly answered by mitochondrial and redox-active metal abnormalities. By releasing high levels of hydrogen peroxide, dysfunctional mitochondria propagate a series of interactions between redox-active metals and oxidative response elements. In the initial phase of disease development, amyloid-beta deposition and hyperphosphorylated tau may function as compensatory responses and downstream adaptations to ensure that neuronal cells do not succumb to oxidative injuries. However, during the progression of the disease, the antioxidant activity of both agents evolves into pro-oxidant activity representing a typical gain-of-function transformation, which can result from an increase in reactive species and a decrease in clearance mechanisms.

Elevated plasma homocysteine is an independent risk factor for the development of Alzheimer disease, however, the precise mechanisms underlying this are unclear. In this article, we expound on a novel hypothesis depicting the involvement of homocysteine in a vicious circle involving iron dysregulation and oxidative stress designated as the ferric cycle (Dwyer et al., 2004). Moreover, we suspect that the development of a critical heme deficiency in vulnerable neurons is an additional consequence of ferric cycle activity. Oxidative stress and heme deficiency are consistent with many pathological changes found in Alzheimer disease including mitochondrial abnormalities and impaired energy metabolism, cell cycle and cell signaling abnormalities, neuritic pathology, and other features of the disease involving alterations in iron homeostasis such as the abnormal expression of heme oxygenase-1 and iron response protein 2. Based on the ferric cycle concept, we have developed a model of Alzheimer disease development and progression, which offers an explanation for why sporadic Alzheimer disease is different than normal aging and why familial Alzheimer disease and sporadic Alzheimer disease could have different etiologies but a common end-stage.

In recent years, Alzheimer disease (AD) has received great attention as an incurable and fatal disease that threatens the lives of aging individuals. Debates regarding areas of research and treatment designs have made headlines as scientists in the field question ongoing work. Despite these academic quarrels, significant insights concerning the cellular and molecular basis of AD have illuminated the potential causes and consequences of AD pathogenesis in the human brain. Additionally, assigning relationships among scientific evidence is difficult due to the nature of the disease. It is crucial to note that all findings do not constitute causality as AD has many stages of progression, and therefore a particular finding may reflect disease epiphenomenon. Determining the primary causes of disease are even more problematic when considering that a succinct timeline in which a normal aging brain develops AD-like changes due to a single cause may not be appropriate, as increasing lines of evidence indicate that multiple factors likely contribute to the clinical manifestation of AD. Implications for therapeutic strategies are dramatically affected by viewing AD as a multi-factorial disease state, one specific treatment may not be able to prevent or reverse AD if this is indeed the case. In this regard, the current focus on individual therapeutic targets may prove to be ineffective in the successful treatment of AD; however, if taken in combination, these singular therapies may likely result in the global suppression of AD. In this review, the scientific basis for common AD therapeutics as well as the efficacy of these treatments will be discussed.

Based on epidemiological and observational studies, estrogen and hormone-replacement therapy were until recently viewed as major factors in the prevention of Alzheimer's disease (AD). However, a recent randomized clinical trial revealed that hormone replacement therapy using estrogen plus progestin may actually exacerbate the incidence of dementia when administered to elderly women. These contradictory reports have cast grave doubt on the role of estrogen in disease pathogenesis and led us to consider an alternate hypothesis that would be consistent with both observations. Specifically, we suspect that hormones of the hypothalamic pituitary gonadal axis such as gonadotropins, that are regulated by estrogen (or in males by testosterone), are involved in the pathogenesis of Alzheimer's disease. One such gonadotropin, luteinizing hormone (LH), is significantly elevated in both the sera and brain tissue of patients with AD and leads to an increased production of amyloid-beta. Importantly, a key role in disease pathogenesis is further supported by the fact that the distribution of neuronal receptors for LH parallels those populations of neurons that degenerate during the course of the disease. That gonadotropins, not estrogen nor testosterone, mediate disease pathogenesis has led to a paradigm shift, not only for the treatment of AD but a wide variety of other age-related diseases. Therefore, the effects of agents that abolish LH, such as leuprolide acetate, which are currently being evaluated in Phase II clinical trials for the treatment of AD, are eagerly anticipated.

Protein aggregation and misfolding are two of the pathological hallmarks that are common to many neurodegenerative diseases including Alzheimer disease, Parkinson disease and Huntington disease. While it has generally been assumed that protein aggregation is responsible for neurodegeneration in these disorders, we suspect that protein aggregation, rather than being a major killer of neurons, is, in fact, an attempt to protect neurons from stressful, disease-causing conditions. In this review, we weigh the evidence of whether amyloids, aggregates and neuronal inclusions are good or bad news for neurons.

Oxidative damage is shown to affect every class of biological macromolecule in Alzheimer disease. Disruptions in iron and copper homeostasis are understood as being key players in neurodegenerative disease pathogenesis. Metal homeostasis as it pertains to alterations in brain function in neurodegenerative diseases is reviewed here with its relations to oxidative stress. While there is substantial documented evidence for alterations in transition metal metabolism, redox-activity and localization, it is also important to note that alterations in specific copper- and iron-containing metalloenzymes also contribute to the neurodegenerative process. Understanding these changes offers the opportunity to identify pathways where modification of the disease process can offer effective clinical intervention, from gene therapy to pharmaceuticals with antioxidant and chelating properties.

The age-related neurodegenerative diseases exemplified by Alzheimerhyp;s disease (AD), Lewy body diseases such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntingtonhyp;s disease are characterized by the deposition of abnormal forms of specific proteins in the brain. Although several factors appear to underlie the pathological depositions, the cause of neuronal death in each disease appears to be multifactorial. In this regard, evidence in each case for a role of oxidative stress is provided by the finding that the pathological deposits are immunoreactive to antibodies recognizing protein side-chains modified either directly by reactive oxygen or nitrogen species, or by products of lipid peroxidation or glycoxidation. Although the source(s) of increased oxidative damage are not entirely clear, the findings of increased localization of redox-active transition metals in the brain regions most affected is consistent with their contribution to oxidative stress. It is tempting to speculate that free radical oxygen chemistry plays a pathogenetic role in all these neurodegenerative conditions, though it is as yet undetermined what types of oxidative damage occur early in pathogenesis, and what types are secondary manifestations of dying neurons. Delineation of the profile of oxidative damage in each disease will provide clues to how the specific neuronal populations are differentially affected by the individual disease conditions.

This special issue gives a framework of an international effort, to critically and constructively overview the clinical and pathological aspects of Lyme neuroborreliosis and show directions for future practice and research. The issue in the diagnosis and treatment of Lyme neuroorreliosis is assessed followed by a comprehensive analysis of the involvement of connective tissue and associated clinical manifestations. A critical review shows that both the meningovascular and meningoencephalitic forms, which define chronic or late neurosyphilis also occur in Lyme neuroborreliosis. Clinical and pathological confir-mation of these tertiary forms and detection of Borrelia burgdorferi in association with tertiary brain lesions were reported by many authors. These observations indicate that similarly to Treponema pallidum, Borrelia burgdorferi infection is directly involved in the late or chronic manifestations of Lyme neuroborreliosis. Chronic or late Lyme neuroborreliosis both refer to tertiary neuroborreliosis, therefore, the use of these terms as different entities is not justified and may lead to confusion. A critical assessment of clinical trials will guide the design of future clinical studies and a detailed analysis of various factors influencing PCR detection of Borrelia specific DNA would be precious to improve the sensitivity of this potentially important diagnostic tool. An update on the virulence determinants of Borrelia burgdorferi and the pathomechanisms involved in Lyme disease is discussed followed by a review showing the importance of co-infections in the diagnosis and treatment of Lyme disease. Evidence for an infectious origin of various neuro-psychiatric symptoms of tick-borne diseases and various psychiatric disorders are also discussed. The involvement of immune system reactions, chronic inflammation, genetic and environmental factors are also considered. Finally an update on the perspectives on Lyme Borreliosis in Canada closes the special issue. The majority of authors are internationally recognized neurologists and scientists with extensive experience and complementary expertise in clinical and/or basic research on Lyme disease. The exchange of knowledge at an international level and between experts in various branches of medicine and in basic research is the way to advance faster in this new, promising and important field of medicine. The aim of this special issue is to contribute to this process. This approach motivated the authors at the annual meeting of the German Borreliosis Society (Deutsche Borreliose-Gesells-chaft, DBG) in 2011 at Wuppertal, Germany to initiate and realize this special issue. This issue is dedicated to the memory of Mark A. Smith whose untimely death has left a void for those looking to novel ideas to solve chronic diseases.