EPMA Journal

Golubnitschaja, Olga

doi: 10.1007/s13167-010-0030-5pmid: 23199059

Current figures: About 300 million Diabetics frequently affected by Poly-Neuropathy as secondary complication, 18 million patients with Alzheimer’s disease also diagnosed as Diabetes Type 3, neurodegenerative eye diseases with leading causes of blindness—diabetic retinopathy and estimated 67 million glaucoma patients worldwide, millions of patients with Parkinson’s disease, Multiple Sclerosis, Epilepsy, Cerebral Palsy and Dementia in the elderly—altogether dramatically affect life quality, social and economical indexes of populations around the globe. Optimistic versus Pessimistic Prognosis depends much on diagnostic, preventive and treatment approaches which healthcare will preferably adopt in the near future. Without innovation in healthcare, neurodegenerative disorders can reach more than 30% of global disease burden till 2020. In contrast, effective utilisation of advanced early/predictive diagnostics, preventive and personalised medical approaches could enable a significant portion of population to reach the 100-year age limit remaining vibrant in excellent physical and mental health as actively contributing members of society.

Tasker, R.; Adams-Marriott, Amber; Shaw, Christopher

doi: 10.1007/s13167-010-0019-0pmid: 23199060

Mental and neurological disorders are increasingly prevalent and constitute a major societal and economic burden worldwide. Many of these diseases and disorders are characterized by progressive deterioration over time, that ultimately results in identifiable symptoms that in turn dictate therapy. Disease-specific symptoms, however, often occur late in the degenerative process. A better understanding of presymptomatic events could allow for the development of new diagnostics and earlier interventions that could slow or stop the disease process. Such studies of progressive neurodegeneration require the use of animal models that are characterized by delayed or slowly developing disease phenotype(s). This brief review describes several examples of such animal models that have recently been developed with relevance to various neurological diseases and disorders, and delineates the potential of such models to aid in predictive diagnosis, early intervention and disease prevention.

Mozaffarieh, Maneli; Fraenkl, Stefan; Konieczka, Katarzyna; Flammer, Josef

doi: 10.1007/s13167-010-0018-1pmid: 23199061

Glaucoma is a major cause of vision loss worldwide with nearly 8 million people bilaterally blind from the disease. This number is estimated to increase over the next 10 years. The key to preventing blindness from glaucoma is effective diagnosis and treatment. The classical glaucoma treatment focuses on intraocular pressure (IOP) reduction. Better knowledge of the pathogenesis has opened up additional therapeutical approaches often called non-IOP lowering treatment. Whilst most of these new avenues of treatment are still in the experimental phase, others are already used by some physicians. These new therapeutic approaches allow a more personalised patient treatment. Non-IOP lowering treatment includes improvements of ocular blood flow, particularly blood flow regulation. This can be achieved by improving the regulation of ocular blood flow (improving autoregulation) by drugs such as carbonic anhydrase inhibitors, magnesium or calcium channel blockers. It can also be improved by decreasing blood pressure over-dips. Blood pressure can be increased by an increase in salt intake or in rare cases by treatment with fludrocortisone. Experimentally, glaucomatous optic neuropathy can be prevented by inhibition of astrocyte activation, either by blockage of epidermal growth factor receptor or by counteracting Endothelin. Glaucomatous optic neuropathy can also be prevented by nitric oxide-2 synthase inhibition. Suppression of matrix metalloproteinase-9 inhibits apoptosis of retinal ganglion cells and tissue remodelling. Upregulation of heat shock proteins protects the retinal ganglion cells and the optic nerve head. Reduction of oxidative stress especially at the level of mitochondria also seems to be protective. This can be achieved by gingko, dark chocolate, polyphenolic flavonoids occurring in tea, coffee or red wine and anthocyanosides found in bilberries as well as by ubiquinone and melatonin. This review describes the individual mechanisms which may be targeted by non-IOP lowering treatment based on our pathogenic scheme.

Golubnitschaja, Olga; Yeghiazaryan, Kristina; Flammer, Josef

doi: 10.1007/s13167-010-0031-4pmid: 23199062

Prediction and prevention of glaucoma. Neurodegenerative eye disease glaucoma is the second leading cause of blindness with estimated 67 million patients worldwide. Molecular pathomechanisms of glaucoma demonstrate both a considerable overlap with and remarkable particularities compared to other neurodegenerative disorders e.g. Alzheimer’s disease. Identification of pathology-specific biomarker-sets is essential to develop advanced diagnostic approaches and personalised patients’ treatment. Subcellular imaging and expression patterns in blood as the reliable platform for early/predictive glaucoma diagnosis. Following key pathways are affected in glaucoma pathology: stress response, apoptosis and DNA-repair, adhesion, blood-brain-barrier-breakdown, tissue remodelling, transcription regulation, multidrug resistance and energy metabolism.

Hasler, Pascal; Flammer, Josef

doi: 10.1007/s13167-010-0017-2pmid: 23199063

Age-related macular degeneration (AMD) is an ophthalmologic disease which usually affects older adults and represents the leading cause of legal blindness in Europe and the United States of America. The pathogenesis of AMD is complex and, nowadays, the treatments are targeting more the late form of the disease. Age and genetic make-up are the most important risk factors identified to date. There are undoubtedly environmental and other risk factors involved and the adverse effect of smoking is well established. New treatments for AMD have emerged with improved prognostic outcome. This remarkable advances in our understanding of the genetic and biological foundations of this disease were derived from a recent convergence of scientific and clinical data. In the near future we will have several therapeutic options for treatment of AMD at different stages and therefore personalising more and more the treatment.

Fraenkl, Stephan; Mozaffarieh, Maneli; Flammer, Josef

doi: 10.1007/s13167-010-0025-2pmid: 21258633

A retinal vein occlusion (RVO) is a sight threatening disease. It can be divided into central vein occlusion and branch retinal vein occlusion. The pathogenesis of the condition remains to be solved. Mechanical compression of the vessel wall or thrombotic occlusion of the vessel lumen, sometimes combined with rheological disorders, are often assumed pathomechanisms. Accordingly, the therapy relies either on mechanical decompression, lyses of thrombi or improvement of rheology. A number of observations however, such as the relationship of RVO to atherosclerotic risk factors, spontaneous reversibility particularly in young patients, rest flow observed in angiography, occlusion despite anticoagulation or thrombocytopenia and finally the positive effect of anti-VEGF therapy are not explained by the present pathogenetic concept. As a new concept we propose a local venous constriction induced by vasoconstrictive molecules diffusing from neighbouring diseased arteries and/or from other neighbouring (hypoxic) tissues. Recognizing these postulated conditions might lead to an earlier identification of impending vein occlusions as well as to a treatment more tailored to the risk factor constellation of the particular patient.

Yeghiazaryan, Kristina; Flammer, Josef; Golubnitschaja, Olga

doi: 10.1007/s13167-010-0032-3pmid: 23199064

Paradigm change from late interventional approach to predictive diagnostics followed by targeted prevention before manifest pathology, presents innovative concept for advanced healthcare. Preselection of healthy but pathology-predisposed individuals is the primary task in the overall action. Vasospasm is a frequent syndrome defined as an inappropriate constriction or insufficient dilatation in microcirculation. Vasospastic individuals are considered as healthy subpopulation predisposed to several pathologies including neurodegeneration. Clinical observations, subcellular imaging and “gene hunting”-investigations provide evidence for vasospasm as predisposition to glaucoma; development of further related pathologies cannot be excluded. Predictive molecular-profiling in blood can specify individual predisposition for effective prevention.

Mandel, Silvia; Morelli, Micaela; Halperin, Ilan; Korczyn, Amos

doi: 10.1007/s13167-010-0036-zpmid: 23199065

Neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease (AD) are considered disorders of multifactorial origin, inevitably progressive and having a long preclinical period. Therefore, the availability of biological markers or biomarkers (BMs) for early disease diagnosis will impact the management of AD and PD in several dimensions; it will 1) help to capture high-risk individuals before symptoms develop, a stage where prevention efforts might be expected to have their greatest impact; 2) provide a measure of disease progression that can be evaluated objectively, while clinical measures are much less accurate; 3) help to discriminate between true AD or PD and other causes of a similar clinical syndrome; 4) delineate pathophysiological processes responsible for the disease; 5) determine the clinical efficacy of novel, disease-modifying (neuroprotective) strategies. In the long run the availability of reliable BMs will significantly advance the research and therapeutics of AD and PD.

Grossman, Iris; Lutz, Michael; Crenshaw, Donna; Saunders, Ann; Burns, Daniel; Roses, Allen

doi: 10.1007/s13167-010-0024-3pmid: 21124753

Alzheimer’s disease (AD) presents one of the leading healthcare challenges of the 21st century, with a projected worldwide prevalence of >107 million cases by 2025. While biomarkers have been identified, which may correlate with disease progression or subtype for the purpose of disease monitoring or differential diagnosis, a biomarker for reliable prediction of late onset disease risk has not been available until now. This deficiency in reliable predictive biomarkers, coupled with the devastating nature of the disease, places AD at a high priority for focus by predictive, preventive and personalized medicine. Recent data, discovered using phylogenetic analysis, suggest that a variable length poly-T sequence polymorphism in the TOMM40 gene, adjacent to the APOE gene, is predictive of risk of AD age-of-onset when coupled with a subject’s current age. This finding offers hope for reliable assignment of disease risk within a 5-7 year window, and is expected to guide enrichment of clinical trials in order to speed development of preventative medicines.

Gozes, Illana

doi: 10.1007/s13167-010-0029-ypmid: 23199066

Microtubules are key cytoskeletal elements found in all eukaryotic cells. The microtubule shaft is composed of the heterodimer protein, tubulin and decorated with multiple microtubule associated protein, regulating microtubule function. Tau (tubulin associated unit) or MAPT (microtubule associated protein tau), among the first microtubule associated proteins to be identified, was implicated in microtubule initiation as well as assembly, with increased expression in neurons and specific association with axonal microtubules. Alzheimer’s disease (AD) is the most prevalent tauopathy, exhibiting tau-neurofibrillary tangles associated with cognitive dysfunction. AD is also characterized by β-amyloid plaques. An abundance of tau inclusions, in the absence of β-amyloid deposits, can be found in Pick’s disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and other diseases, collectively described as tauopathies. The increase in tau pathology in AD correlates with the associated cognitive decline. The current manuscript touches on the variability as well as common denominators of the various tau pathologies coupled to new approaches/current innovation in treatment of tauopathies in favor of advanced technologies in predictive diagnostics, targeted preventive and personalized medicine (PPPM).