Neurodegenerative Krankheiten

 

Neurodegenerative disease is a condition in which cells of the brain and spinal cord are lost. The brain and spinal cord are composed of neurons that do different functions such as controlling movements, processing sensory information, and making decisions. Aside from a small number of neural stem cells that are created daily, cells of the brain and spinal cord are not readily regenerated en mass, so excessive damage can be devastating. Neurodegenerative diseases result from deterioration of neurons which over time will lead to neurodegeneration and disabilities resulting from this. They are crudely divided into two groups according to phenotypic effects, although these are not mutually exclusive:

1. conditions causing problems with movements, such as ataxia
2. conditions affecting memory and conditions related to dementia

Neurodegenerative diseases can result from stroke, heat stress, head and spinal cord trauma (blunt or infectious pathology), and bleeding that occurs in the brain, the pressure from which eventually causes the death of one or more neurons.

Many times neuronal death begins long before the patient will ever experience any symptoms. It can be months or years before any effect is felt. Symptoms are noticed when lots of cells have died and certain parts of the brain have been weakened to the point that they can no longer function properly.

SCIENTIFIC PAPERS

Dirks, S. J., E. D. Paunovich, et al. (2003). "The patient with Parkinson's disease." Quintessence Int 34(5): 379-93.

ABSTRACT: Parkinson's disease is an idiopathic, slowly progressive disorder of the central nervous system characterized by resting tremor, muscular rigidity, slow and decreased movement (bradykinesia), and postural instability. In the United States, Parkinson's disease is the fourth most common neurodegenerative disorder in the elderly, affecting an estimated half a million people. Oral health care providers can expect to be called upon to care for patients with this progressively debilitating disease. To provide competent care to patients with Parkinson's disease, clinicians must understand the disease, its treatment, and its impact on the patient's ability to undergo and respond to dental care.

Meske, V., F. Albert, et al. (1999). "Culture of autopsy-derived fibroblasts as a tool to study systemic alterations in human neurodegenerative disorders such as Alzheimer's disease--methodological investigations." J Neural Transm 106(5-6): 537-48.

ABSTRACT: The present study was undertaken in order to analyse the possibility of culturing post mortem derived human fibroblasts. The combination of post mortem fibroblasts with the autopsy proven and histopathologically staged brain will allow the correlative investigation of dynamic biochemical processes which are systemically underlying or accompanying a neurological and/or psychiatric disorder. These studies are limited in autopsy brain or are uncertain when the neuropathological status is lacking, i.e. when fibroblasts were obtained from living patients. Our examinations of human autopsy fibroblast and those under experimentally controlled post mortem conditions with rats clearly demonstrate that autopsy-derived fibroblasts can be reliably cultured. The cells grown displayed typical morphological and staining characteristics as well as pharmacological responsiveness. Even cells obtained from a 99 years old individual or an individual with a post mortem delay of 48 hours grew in our culture system.

Perry, V. H. (2004). "The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease." Brain Behav Immun 18(5): 407-13.

ABSTRACT:  Systemic inflammation is associated with sickness behaviour and signals pass from the blood to the brain via macrophage populations associated with the brain, the perivascular macrophages and the microglia. The amplitude, or gain, of this transduction process is critically dependent on the state of activation of these macrophages. In chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, or prion disease the pathology is associated with a highly atypical inflammatory response, characterised by the activation of the macrophage populations in the brain: the cells are primed. Recent evidence suggests that systemic inflammation may impact on local inflammation in the diseased brain leading to exaggerated synthesis of inflammatory cytokines and other mediators in the brain, which may in turn influence behaviour. These interactions suggest that systemic infections, or indeed any systemic challenge that promotes a systemic inflammatory response, may contribute to the outcome or progression of chronic neurodegenerative disease.

Perry, V. H., T. A. Newman, et al. (2003). "The impact of systemic infection on the progression of neurodegenerative disease." Nat Rev Neurosci 4(2): 103-12.

Smith, T. S. and J. P. Bennett, Jr. (1997). "Mitochondrial toxins in models of neurodegenerative diseases. I: In vivo brain hydroxyl radical production during systemic MPTP treatment or following microdialysis infusion of methylpyridinium or azide ions." Brain Res 765(2): 183-8.

ABSTRACT: Mitochondrial electron transport chain (ETC) function is selectively reduced in multiple tissues, including brain, from patients with Parkinson's disease (PD) and Alzheimer's disease (AD). The ETC defects are specific to each illness, involve complex I in PD and complex IV in AD, are transferable with mitochondrial DNA (mtDNA) and lead to increased production of reactive oxygen species (ROS) in mtDNA-deficient clonal neuronal cells hybridized with mtDNA ('cybrids') from PD or AD patients. C57BL/6 mice treated with MPTP developed elevated tissue hydroxyl radical ('OH) levels in striatum and ventral midbrain but not cerebellum. In brain microdialysis in awake rats, striatal 'OH output increased 3-5-fold after infusion of methylpyridinium ion (MPP+), a complex I inhibitor, or sodium azide, a complex IV inhibitor. Elevated 'OH after MPP+ was blocked stereospecifically by infusion of the nitric oxide synthase (NOS) inhibitor nitro-L-arginine or by the NMDA channel blocker MK801. Neither NOS inhibition nor NMDA blockade altered azide-induced 'OH production. ETC inhibition in vivo increases production of toxic 'OH, but the underlying mechanisms vary as a function of which ETC complex is inhibited. These results support the concept of developing oxygen free radical scavengers for both AD and PD and further suggest that inhibition of NOS and blockade of NMDA receptor function may alter progression of idiopathic PD.

Tanke, H. J. (2007). "Genomics and proteomics: the potential role of oral diagnostics." Ann N Y Acad Sci1098: 330-4.

ABSTRACT: Advances in genomics and proteomics increasingly contribute to the understanding of signal transduction pathways that control growth, differentiation, and death of cells. Since defects in these processes may result in the expression of inherited and or acquired disease, the identification of candidate disease genes and modifier genes by parallel use of genotyping together with an integrated study of gene expression and metabolite levels is instrumental for future health care. This approach, called systems biology, aims to recognize early onset of disease, institute preventive treatment, and identify new molecular targets for novel drugs in cancer, cardiovascular and metabolomic disease (e.g., diabetes), and neurodegenerative disorders. Gene interaction networks have recently been demonstrated, in which hub genes, that is, genes that show the highest level of interactions with other genes, play a special role. Hub genes, often chromatin regulators, may act as modifier genes (genes that modify the effect of other genes) in multiple mechanistically unrelated genetic diseases in humans. In addition, it has been shown that small metabolites such as hormones and cytokines, or proteins/enzymes such as C reactive protein (C-RP) and matrix metaloproteinase (MMP), reflect disease status in case of oral cancer, asthma, or periodontal and cardiac disease. Many of these molecular targets, as well as pathogen-specific DNA and RNA sequences, can be measured in oral fluids, providing a unique opportunity to develop novel noninvasive diagnostic tests. Efforts so far concentrate on the use of lab-on-a-chip technology in combination with novel reporters and microsensor arrays to measure multianalytes in oral fluids. Handheld devices that perform sensitive detection of multiple analytes in oral fluid will be obtainable in the near future.

Van Den Heuvel, A. G., J. Van der Grond, et al. (1997). "Differentiation between portal-systemic encephalopathy and neurodegenerative disorders in patients with Wilson disease: H-1 MR spectroscopy." Radiology 203(2): 539-43.

ABSTRACT: PURPOSE: To investigate the extent to which neurodegeneration and metabolic changes caused by portosystemic shunting occur in Wilson disease. MATERIALS AND METHODS: Twenty-two adult patients with biochemically proved Wilson disease underwent magnetic resonance (MR) imaging, hydrogen-1 MR spectroscopy, neurologic and psychometric testing, and ultrasound evaluation of the liver. In addition, 13 age-matched adult control subjects underwent MR imaging and H-1 MR spectroscopy. For MR spectroscopy, the authors used a single-voxel technique with a repetition time of 2,000 msec and an echo time of 31 msec. The volume of interest included the right and left globi pallidus, which are the most common sites of lesions in Wilson disease. RESULTS: N-acetylaspartate-creatine and choline-creatine ratios were decreased in patients with Wilson disease versus control subjects (P < .001 for N-acetylaspartate-creatine ratio, P < .05 for choline-creatine ratio). Also, patients with Wilson disease and portosystemic shunting had lower myo-inositol-creatine ratios than did patients with Wilson disease and no portosystemic shunting (P < .05). CONCLUSION: Reductions in N-acetylaspartate indicate neuronal loss consistent with the neurodegenerative pattern associated with Wilson disease. In addition, H-1 MR spectroscopy shows metabolic abnormality in the brain, as decreased myoinositol, caused by portosystemic shunting.

Widera, D., W. D. Grimm, et al. (2007). "Highly efficient neural differentiation of human somatic stem cells, isolated by minimally invasive periodontal surgery." Stem Cells Dev 16(3): 447-60.

ABSTRACT: Neural stem cells (NSCs) are potential sources for cell therapy of neurodegenerative diseases and for drug screening. Despite their potential benefits, ethical and practical considerations limit the application of NSCs derived from human embryonic stem cells (ES) or adult brain tissue. Thus, alternative sources are required to satisfy the criteria of ready accessibility, rapid expansion in chemically defined media and reliable induction to a neuronal fate. We isolated somatic stem cells from the human periodontium that were collected during minimally invasive periodontal access flap surgery as part of guided tissue regeneration therapy. These cells could be propagated as neurospheres in serum-free medium, which underscores their cranial neural crest cell origin. Culture in the presence of epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2) under serum-free conditions resulted in large numbers of nestin-positive/Sox-2-positive NSCs. These periodontium-derived (pd) NSCs are highly proliferative and migrate in response to chemokines that have been described as inducing NSC migration. We used immunocytochemical techniques and RT-PCR analysis to assess neural differentiation after treatment of the expanded cells with a novel induction medium. Adherence to substrate, growth factor deprivation, and retinoic acid treatment led to the acquisition of neuronal morphology and stable expression of markers of neuronal differentiation by more than 90% of the cells. Thus, our novel method might provide nearly limitless numbers of neuronal precursors from a readily accessible autologous adult human source, which could be used as a platform for further experimental studies and has potential therapeutic implications.