Alternative Treatment for Parkinson Disease

The Parkinson's-Reversing Breakthrough

The Parkinson's Breakthrough Program entails the most effective and natural strategies people can use to heal the root cause of Parkinson's Disease. It is a digital manual aimed at showing the users the most effective method for overcoming Parkinson's without high-priced prescription drugs riddled with harmful side effects.The program was not created to be a quick fix. In fact, like different programs, it is tasking. Yet, you will not have to spend a lot of time dealing with it. The system requires your full attention, perseverance, and discipline. For the period of its usage, you will have the opportunity to use to eat some food ingredients that will detoxify you.The methods employed in this book are natural ones that have been proven by many specialists. The users will be privy to what to do and what not to do to treat the underlying root cause of their Parkinson's and the way they can reverse the symptoms naturally and effectively. The system comes with bonus E-books- Lessons from The Miracle Doctors, Mind Control in the USA', and 10 Deadly Health Myths of The 21st Century. The book is in a digital format (PDF) and has been created at a very affordable price. More here...

The ParkinsonsReversing Breakthrough Summary

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Striatonigral Degeneration

Striatonigral degeneration is a slowly progressive degenerative disease of middle age that greatly resembles Parkinson's disease. Rigidity, akinesia, and postural Progressive supranuclear palsy (PSP). A 65-year-old man presented with a 6-year history of difficulty walking and frequent falls, inability to look up or down, difficulty speaking and swallowing, and declining memory. Family history was not contributory. On examination, he was not able to articulate words, but was able to follow simple commands. The vertical and horizontal eye movements were severely restricted. The muscle tone was increased in the neck, trunk, and extremities, but strength was good. No tremor was noted. He needed assistance to rise from a chair and ambulate. The gait was slow and shuffling. Tendon reflexes were brisk, plantar reflexes were flexor, and the vestibulo-ocular reflex was present. He died at age 66 following a 7-year clinical course. Midbrain shows degeneration of the substantia nigra (HE)....

Postencephalitic Parkinsonism

This disease has been reported among survivors of the epidemic of von Economo encephalitis lethargica that occurred in Europe in 1915 and in the United States in 1918. The parkinsonism developed many years following the encephalitis and afflicted young adults and children. It presented with parkinsonian features, extra-ocular muscle palsy, and oculogyric spasm, which is a tonic conjugate deviation of the eyes lasting minutes or hours. Grossly, the substantia nigra and locus ceruleus are depigmented. The histology is characterized by (a) lympho-plasmacytic perivascular infiltrations, particularly severe in the brainstem (b) neuronal losses and gliosis in the substantia nigra, locus ceruleus, and brain-stem (c) the presence of argyrophilic, tau-positive neurofibrillary tangles in neurons of the brainstem, hippocampus, frontal, temporal, and insular cortex and (d) the presence of tau-positive cytoplasmic inclusions in astrocytes.

Pet And Complications Of Longterm Levodopa Therapy

De la Fuente-Fernandez et al. (99), using FDOPA PET, studied 15 patients who had a stable response to L-dopa and 52 with MFs . Patients with MF had further decreases in stri-atal FDOPA uptake compared with those who had a stable response to L-dopa. As expected, patients with MF had a more prolonged disease course than the stable subjects, and the fluctuators had an earlier age of disease onset. This decrement in FDOPA Ki persisted even after adjustment for disease course and matching the two groups. However, there was significant FDOPA Ki overlap between the groups. This finding was interpreted as a suggestion of increased DA turnover in the fluctuators (99). This was confirmed by a longitudinal study with RAC PET, in which eight patients with early PD and a good response to L-dopa after an average of 1.5 yr of treatment were evaluated (Fig. 4). The subjects had the first scan washed-out of medications and two additional scans 1 h and 4 h after a single oral dose of L-dopa. After...

Treatment of Parkinsons disease

Dyskinesia comprises involuntary writhing movement of the face and limbs that may be biphasic (occurring at the start and end of motor response) or develop at the time of the maximum plasma levodopa concentration. They respond initially to reducing the dose of levodopa but at the cost of bradykinesia and as time passes there is progressively less scope to obtain benefit without unwanted effects. End-of-dose deterioration is managed by increasing the frequency of dosing with levodopa (e.g. to 2-3-hourly), but this tends to result in the appearance, or worsening of the dyskinesia. The motor response then becomes more brittle with abrupt swings between hyper- and hypomobility (the on-off phenomenon). Despite their unpredicatable nature over the course of a single day, these changes are in fact dose-related, an effect that becomes apparent only when the response is related to total medication taken over a week. Various strategies have been devised to overcome these problems. Controlled...

Druginduced Parkinsonism

The classical antipsychotic (see p. 380) drugs block dopamine receptors and their antipsychotic activity relates closely to this action, which notably involves the D2-receptor, the principal target in Parkinson's disease. It comes as no surprise, therefore, that these drugs can induce a state whose clinical features are very similar to those of idiopathic Parkinson's disease. The piperazine phenothiazines, e.g. trifluoperazine, and the butyrophenones, e.g. haloperidol, are most commonly involved. In one series14 of 95 new cases of parkinsonism referred to a department of geriatric medicine, 51 were associated with prescribed drugs and half of these required hospital admission. After withdrawal of the offending drug most cases resolved completely in 7 weeks. But One old lady who had received trifluoperazine (for a minor fright and anxiety) for 5 weeks, took 36 weeks to recover from the drug-induced parkinsonism but never managed to get home again. When drug-induced parkinsonism is...

Diseases with Akinetic Rigidity Idiopathic Parkinsons Disease

Lewy Body Pathology

Idiopathic Parkinson's disease (iPD), the most common movement disorder and a major cause of neurologic Akinetic-rigid form Parkinson's disease Progressive supranuclear palsy Dementia with parkinsonism linked to chromosome 17 Striatonigral degeneration Corticobasal degeneration Postencephalitic parkinsonism Parkinsonism-dementia complex of Guam disability in the elderly, may affect individuals of 40 to 60 years of age, but it is seen primarily in those in their sixth decade. The annual incidence is 7 to 10 per 100,000 population, and this figure increases with age. A slight male preponderance is noted. About 1 to 3 of the population over the age of 65 years is afflicted. A rare juvenile form has an onset between 20 and 40 years of age. The disease occurs sporadically, but a considerable number of familial incidences have been identified. Both environmental and genetic etiologies are considered. The role of environmental factors is suggested by the clinical resemblance of iPD to the...

Micronutrients Parkinsons

In Parkinson's disease high doses of vitamin B6, iron, and manganese should be avoided. High doses of vitamin B6 may decrease the effectiveness of of L-dopa therapy, and high doses of iron and manganese can aggravate the disease. Parkinson disease, and low body stores of these B vit

Activation And Regional Cbf Patterns In Normal Individuals And In Pd

It is hypothesized that the BG function by activating parts of the cortex into similar frequencies, thereby facilitating the performance of a motor or cognitive action. This pattern of activation, referred to as focused attention, would be the physiological substrate for the harmonic performance of movement. In PD, the imbalance between direct and indirect pathways as a consequence of dopamine deficiency leads to overactivation of BG output nuclei and subsequent failure to achieve the state of focused attention (10). Several reports have addressed the changes in CBF and 18F-FDG uptake during different tasks in PD patients. In an inhaled C15O2 CBF PET study, Playford et al. (14) evaluated six PD patients and six controls at rest during the execution of freely chosen movements and with programmed repetitive forward movement of a joystick. For the free-selection task, both groups had similar increases in blood flow in left sensorimotor and bilateral premotor cortices. However, PD...

Energy Metabolism In Pd

Although the etiology of PD is unknown, the possibility of an underlying defect in mitochondrial metabolism has been addressed in several biochemical studies (76). There is evidence of reduced complex I activity in the substantia nigra in PD, and Gu et al. have suggested that a mitochondrial DNA abnormality may underlie this complex I defect in at least a subgroup of PD patients (77). Studies in other tissues, however, have produced conflicting results, perhaps in part because biochemical studies involve removal of mitochondria from their natural milieu, with consequent mechanical disruption and a loss of normal control mechanisms. In contrast, MRS provides the potential to study mitochondrial metabolism in vivo. for mitochondrial disease (78). Penn et al. have used 31P-MRS to investigate energy metabolism in muscle in patients with PD. The Pi PCr ratio was significantly increased in PD, suggesting a small, generalized mitochondrial defect (79). Further studies are needed to determine...

Pet Studies In Familial Pd

A family history of parkinsonism is present in 5-10 of individuals with PD. Currently, at least 10 loci and 5 genes with both autosomal-recessive and autosomal-dominant patterns of inheritance recognized. A genetic component for PD is plausible even for sporadic cases because asymptomatic twins of PD individuals show decreased putaminal FDOPA uptake (85). Of utmost importance in the understanding of sporadic PD is the concept that a number of the recently described mutations result in impaired function of ubiquitin proteasomal function, a mechanism that is related to the clearance of cellular proteins (86).

Parkinsonism Dementia Complex of Guam

This disease occurs among the Chamorro tribe of Guam. It presents with parkinsonian features and progressive dementia, and it may be associated with ALS (see the section, Motor Neuron Diseases). Grossly, the brain is atrophic, and the substantia nigra and locus ceruleus are discolored. The histology is characterized by neuronal losses that are particularly severe in the hippocampus, temporal and frontal cortex, hypothalamus, substantia nigra, and locus ceruleus. Variable neuronal losses are present in the thalamus and basal ganglia. Tauimmunopositive neurofibrillary tangles are evident in the remaining neurons of affected areas. Neuritic plaques and neuropil threads are inconspicuous.

Mrs In Parkinsonism

Several studies that used 1H-MRS in PD have been reported, reviewed by Davie (62) and systematically by Clarke and Lowry (63). A large multicenter study of 151 patients with PD showed no significant difference in either NAA Cr or NAA Cho ratios between controls and patients who were not taking levodopa (64). Other groups (65-67) have reported similar results. Similarly, in a small study using absolute metabolite quantitation, NAA, Cr, and Cho concentrations in PD did not differ significantly from those in controls (68). Although no significant difference was observed in the NAA Cr ratio in levodopa-treated patients with PD, Ellis et al. reported reduced NAA Cr in drug-naive PD patients compared with both the treated PD group and with the control group (69). These authors suggested that the reduced ratio in PD might reflect a functional abnormality of neurons in the putamen that can be reversed with levodopa treatment. Clarke and Lowry have reported a significant decrease in the NAA...

Functional Mri In Pd

Motor activation studies provide a means to investigate the regional cerebral mechanisms involved in motor control in normal subjects and in patients with disorders affecting these control systems. Typical fMRI experiments involve measurement of regional blood oxygen level-dependent signal increases associated with specific activation paradigms. These signal changes occur as a result of the increased local cerebral blood flow and altered oxyhemoglobin concentration associated with neuronal activation. Functional MRI experiments have extended our knowledge of disordered motor control systems, based on the extensive previous experience obtained with PET motor activation studies in control subjects and in patients with PD. PET studies have suggested that cortical motor areas, such as the supplementary motor area (SMA), seem to be underactive in akinetic parkinsonian patients (84,85), whereas other motor areas, such as the parietal and lateral premotor cortex and the cerebellum, appear to...

Parkinsons Disease

In a study of 52 subjects with Parkinson's disease (PD) (28 men and 24 women), using DXA (Norland XR-26) to measure total body BMC, bone mineral content was found to be significantly decreased when compared to controls (78). The z-score for men with PD averaged -0.47 and for women, -0.84. In this same study, metacarpal radiogrammetry did not reveal any significant differences between PD patients and controls. A brief report in abstract form from Turc et al. (79) noted that in 19 men with PD BMD in the PA spine as measured with DXA was significantly reduced in comparison to age-matched controls. BMD averaged 0.965 0.146 g cm2 in the PD subjects and 1.063 0.146 g cm2 in the controls. Although femoral bone density was also reduced in the PD subjects, the difference from age-matched controls was not significant.

Diet Parkinsons

A low-protein diet can be beneficial in Parkinson's disease.1 L-dopa is one of several amino acids that compete for uptake into the brain from the bloodstream. During L-dopa therapy, restricting dietary protein reduces competition from other amino acids and allows more L-dopa to enter the brain. One limitation of L-dopa therapy is that its beneficial effects unpredictably wax and wane through the day. Protein restriction can reduce these daily fluctuations and make L-dopa therapy more effective, particularly if most of the daily protein is eaten with the evening meal.1 Free-radical damage (see pp. 115) appears to play a role in Parkinson's disease. Diets high in natural anti-oxidants (such as vitamins E and C and carote-noids) may reduce risk of Parkinson's disease or slow down its progression.2,3

Alternative Nonneural Stem Cell Sources

Somatic stem cells have been claimed to possess a broad differentiation potential, and several studies over the past 5 yr have suggested that stem cells from tissues outside of the brain are also capable of generating neurons (92). Such stem cells may be considered alternatives in PD, and this chapter describes two potential sources bone marrow-derived cells (93-95) and umbilical cord stem cells (96). Other potential sources include adult multipotent progenitor cells derived from bone marrow (97) and skin-derived stem cells (98), but only a few studies on these cell sources have been published to date. A recent study suggested that engineered human bone marrow cells could be suitable for autologous transplantation in PD (94). In this study, human bone marrow cells transfected with the Notch intracellular domain protein and treated with neurotrophic factors differentiated into TH-expressing neurons. Transplantation of these TH-expressing neurons into the striatum of 6-OHDA-lesioned...

Pros And Cons With Sources Currently Available

Although DAergic neurons can be generated in large numbers from neural precursors under special conditions (25), they are still not a realistic option as donor cells for transplantation in PD. Limitations in long-term propagation of the cells and difficulties in achieving stable DAergic differentiation continue to be major problems. As mentioned in the DAergic Differentiation by Epigenetic Factors section, the efficiency of DAergic differentiation decreases with time in midbrain neural precursors after proliferation for extended periods in vitro (30). Furthermore, although expanded precursors The risk that undifferentiated cells are included among transplanted human ES-derived DAergic neurons is a major issue. Obviously, this can lead to the formation of lethal teratomas in the host brain. Chromosomal aberrations identified in mid-term cultured human ES cells are a cause for concern (122). This suggests that long-term propagation of human ES cells can lead to abnormalities in the...

Imaging Blood Flow And Metabolism

Striatal glucose metabolism and perfusion are generally found to be normal in PD (6-10), although some studies have demonstrated an asymmetry of striatal metabolism (11). Interestingly, atypical parkinsonian disorder has been differentiated from idiopathic PD by the appearance of striatal metabolic abnormalities in the atypical group (12), which may provide a useful adjunct to routine clinical examination. Many studies have shown more global cortical hypometabolism or hypoperfusion or a loss of posterior parietal metabolism with a pattern similar to that observed in Alzheimer's, and other neurodegenerative diseases (8,9,1318). Others have used the differences in regional metabolism or rCBF to discriminate between PD and MSA (10,19) or PSP (20). Studies of blood flow and glucose metabolism in patients with pure Lewy body disease with no features of Alzheimer's disease have consistently shown biparietal, bitemporal hypometabolism, a pattern that was once...

Multimodality And Multitracer Studies

Glucose metabolism has been studied in parkinsonian disorders with 18F FDG and PET, and the data combined with striatal 18F fluorodopa uptake measurements to give an improved diagnostic indicator, and a better understanding of the underlying disease processes (19,51,59,201). However, it should be noted that the improvement was relatively small over the good predictive capabilities of 18F fluorodopa by itself in these patient groups. Some studies have used the complementary information coming from structural MRI and functional 18F FDG PET in distinguishing between control subjects and patients with MSA (53,202-205), in whom both focal MRI hypointensities, changes in striatal and midbrain size, and reduced glucose metabolism occurred on the side contralateral to clinical symptoms. Magnetic resonance spectroscopy adds an important new probe to complement functional PET and SPECT imaging studies (204). Other studies have combined data from MRI and postsynaptic dopamine receptor...

Whole Bone Marrow Transplants In An Hd Model

The disease is caused by an expansion of trinucleotide (cytosine-adenine-guanine CAG ) repeats on the IT15 locus of chromosome 4 (47) that codes for the huntingtin protein. Although the gene encoding huntingtin is expressed ubiquitously, selective degeneration occurs, causing GABAergic neuronal loss in the corpus striatum (caudate nucleus, putamen, and globus pallidus). To date, neither curative nor neuroprotective therapies are available to stop disease progression. However, positive results from fetal neural transplants in patients with Parkinson's disease have demonstrated the potential clinical value for this type of therapy (48,49). Recently, intracerebral transplantation of fetal neuroblasts from the striata primordia has been conducted in some HD patients, and beneficial results of this procedure have also been reported (50,51). Nevertheless, the use of primary immature neurons or precursors in transplantation has some limitations owing to the heterogeneity...

Fetal Neural Transplantation

Promising laboratory findings in animal models of Parkinson's disease (PD) and Huntington's disease (HD), which were treated with neural transplantation strategies, have formed the scientific basis for clinical trials (2,5). More than 350 PD, HD, and stroke patients have already received intracerebral neural transplantation. However, these patients have demonstrated variable degrees of clinical improvement, owing partly to the low viability of the grafts (2,6-11). Because graft survival is greatly altered by the host immune response, cells that can avoid immunosurveillance, particularly autologous cells (e.g., the transplant recipient's adrenal or stem cells), may limit graft rejection (12-18). Fetal cells persist as the most widely studied graft source for transplantation. Unfortunately, many logistical and ethical issues hinder the use of primary fetal cells in the clinic. Thus, a primary research endeavor in cell transplantation has concentrated on searching for a nonprimary fetal...

Postsynaptic Da Function

Altered postsynaptic DA function in PD has also been investigated with a number of PET radioligands. It is known that dopaminergic transmission is facilitated mainly by D1 and D2 receptors in the striatum. Striatal D1 receptor binding is usually measured with 11C SCH23390 and remains normal in early PD patients who are not on drug therapy (33). However, D1 binding seems to be reduced by 10 if a patient receives treatment with levodopa for several years (34). Striatal D2 receptor binding is most often estimated using 11C raclopride (RAC) and is mildly elevated in early phases of PD, untreated with antiparkinsonian medications (34-36). The elevation is particularly pronounced in the putamen. This upregulation is reversed with DA replacement therapy at more advanced stage (37) . Striatal D2 binding remains unchanged in the putamen but reduced by 16 in the caudate after continued medical treatment (34). Because RAC has a low affinity to D2 receptors, PET imaging with this tracer has been...

Potential Complications After Transplantation

Complications related to the intrastriatal transplantation of human embryonic mesencephalic tissue are usually mild and transient as reported by most of clinical trials with PD. All patients have bilateral dyskinesias before grafting that are greatly decreased a few months after the surgery because of concurrent reduction in dopaminergic drugs. However, as the number of graft recipients increases, dyskinesias in the absence of or with only minimal amounts of dopaminergic medication have been reported after the surgery. One study examined five patients during the course of 1-3 yr after unilateral implantation in the caudate and putamen (100). There was a moderate increase in FDOPA uptake in the grafted putamen along with a different degree of bilateral improvement in motor skills. Delayed asymmetrical dyskinesias were observed in three patients on the side contralateral to the graft. It was speculated that this might reflect increased presynaptic storage and release of DA induced by...

Encouraging Human Experience With Pig Transplants

An Food and Drug Administration-approved US clinical phase I study is being conducted using neural xenotransplantation in 12 PD patients (18,19). This safety trial is focused on the unilateral transplantation of fetal pig mesencephalic neural cells into the putamen and caudate. Six patients received continuous systemic cyclosporine. An interim report at 12 mo listed no evidence of serious adverse events. Cultures were negative for bacterial and viral contamination, and no porcine endogenous retrovirus DNA sequences were found. As assessed by magnetic resonance imaging, the cannula tracts were localized within the putamen and caudate without noticeable tissue trauma. In the medication-off state, total Unified Parkinson's Disease Rating Scale scores improved by 19 (p 0.01), with three patients improving over 30 and two patients exhibiting improved gait. 18F-Levodopa positron emission tomography failed to show changes on the transplanted side. Histological analysis of the graft in a...

Therapeutic Potential Of Embryonic Stem Cells

Most of the enthusiasm relating to embryonic stem (ES) cells results directly from the perceived need for cell replacement therapy for a host of degenerative diseases. Indeed, disorders of organ failure are not reversible, and organ transplantation cannot meet the needs of an ever-aging population. Primary pump failure in the heart, alcoholic or viral liver failure, P-cell-deficient type 1 diabetes, and Parkinson's disease (PD) are frequently cited as examples of monocellular deficiency states that might be amenable

Presynaptic Da Function

18F fluorodopa (FDOPA) is the radioligand used mostly for quantifying the nigrostriatal dopaminergic dysfunction in PD. This tracer measures the rate of FDOPA decarboxylation and subsequent storage in the dopaminergic nerve terminals. FDOPA uptake is estimated by using a striatal occipital ratio (SOR striatal occipital - 1) (9,10) or influx constant (K ) computed from dynamic data (11-13). It has been established that FDOPA uptake is reduced in the posterior putamen but relatively preserved in the caudate nucleus and anterior putamen in early stages of PD (13-16). FDOPA uptake is decreased in both putamen (60 ) and caudate (40 ) in patients with advanced PD (Fig. 1). This has been valuable in discriminating PD from normal controls and also in early differential diagnosis of PD from other atypical parkinsonisms. More importantly, FDOPA uptake indices in putamen and caudate have been consistently shown to correlate negatively with the severity of motor symptoms in PD. FDOPA binding is...

Encapsulated Cell Lines And Neural Stem Cells

Lated chromaffin cells, a significant decrease in drug-induced rotations was seen which was maintained for the 9-mo study period (77). PC12 cells are a cell line derived from a tumor of the rat adrenal medulla that, when differentiated, will produce dopamine. Using encapsulation techniques, PC12 cells were transplanted into the striatum of parkinsonian monkeys. PC12-trans-planted animals performed better at contralateral reaching tasks than did animals transplanted with empty capsules or animals transplanted with encapsulated bovine chromaffin cells (76). Two other research groups found that encapsulated PC12 cells produced measurable levels of dopamine, and 18F-DOPA uptake could be seen within the areas of the transplanted capsules. However, there was no clear evidence of striatal reinnervation or sprouting of dopamine nerve terminals, suggesting that the PC12 cells within the capsules merely dispense dopamine and do not make functional connections with the host environment (78)....

Synthesis And The Availability Of The Evidence

One potentially valuable finding reported by Olanow and colleagues (3) was that the post hoc analysis of the data revealed significant transplant benefits in patients with lower UPDRS motor (off) scores. The effect was only evident for the four-grafts-per-side group, and the authors were careful to point out that this finding reflects failure of transplanted patients to deteriorate, rather than improvement in parkinsonian features. The effect was only evident when compared to the control group (n 6) with milder scores. In a later review, Olanow (30) suggested that, Post hoc analysis demonstrated significant improvements with transplantation in patients with milder disease, but no age-related benefits were detected. The notion that patients with milder PD benefit more from transplantation than those with a more advanced form is an appealing hypothesis. Unfortunately, inspection of the evidence (3) does not appear to support this hypothesis. Both Graph A (mild) and Graph B (advanced)...

Sertoli Cells Is There A Role In Transplantation

PD is a progressive neurodegenerative disease characterized by a selective and severe loss of dopaminergic neurons in the substantia nigra. The most common therapy for PD is the administration of levodopa (L-dopa). Although quite effective in the early disease stages, L-dopa does not stop disease progression, and debilitating side effects manifest over several years. Transplantation of fetal dopaminergic neurons into the striatum of PD patients has been under clinical investigation for nearly two decades and has been met with generally encouraging results (26). As already mentioned, however, the limited availability and ethical issues concerning the use of human fetal tissue precludes this approach from widespread practice. Therefore, there is a great deal of interest in developing the use of fetal dopaminergic tissue transplants from other species. Based largely on the successful demonstration that Sertoli cells promote the survival of discordant islet cell grafts to reverse diabetes...

Fetal Vm Tissue Transplants

Striatum Tissue

By 3-6 mo after transplantation, many parkinsonian monkeys were less behaviorally impaired than nontransplanted monkeys (17,50-52,55, 63,65,68,71-73). In unilaterally dopamine-depleted monkeys, the fetal neural tissue transplants had improved voluntary reaching tasks and exhibited less drug-induced rotations (65,68,72). In a bilaterally dopamine-depleted monkey with motor impairments severe enough to require constant monitoring, the fetal VM grafts stimulated such improvement that the animal was considered nearly normal in behavior and regained the ability to feed without assistance (63). However, in that same study, another severely parkinsonian monkey showed no improvement, even at 7-mo post-transplant (63). Upon examination of the VM graft of this animal, few surviving dopamine neurons of graft origin were found, whereas numerous cells survived in the animal that had improved (63). Despite the large numbers of animals that benefited from the VM transplants, some did not improve...

58. Emerich D.f. Hemendinger R. And Halberstadt C.r. The Testicular-derived Sertoli Cell Cellular Immunoscience To

H., Deacon, T. W., et al. (1996) Xenotransplantation of porcine fetal ventral mesencephalon in a rat model of Parkinson's disease functional recovery and graft morphology. Exp. Neurol. 140, 1-13. 15. Nakao, N. (1995) Overexpressing Cu Zn superoxide dismutase enhances survival of transplanted neurons in a rat model of Parkinson's disease. Nature Med. 1, 226-231. 18. Deacon, T., Schumacher, J., Dinsmore, J., et al. (1997) Histological evidence of fetal pig neural survival after transplantation into a patient with Parkinson's disease. Nat. Med. 3, 350-353. 19. Schumacher, J. M., Ellias, S. A., Palmer, E. P., et al. (2000) Transplantation of embryonic porcine mesencephalic tissue in patients with PD. Neurology 14, 1042-1050. 20. Fink, J. S., Schumacher, J. M., Ellias, S. L., et al. (2000) Porcine xenografts in Parkinson's disease and Huntington's disease patients preliminary results. Cell Transplant. 9, 273-278.

Potential Clinical Applications Of Bmscs In Neurologic Injury And Disease

Cell replacement mechanisms are self-evident. Although the prevention of pathologic processes is the ultimate goal, replacing lost CNS tissues with autologous grafts is an ideal alternative for conditions in which these measures are not available. Parkinson's disease (PD) is the classic example of a disease in which a specific cell population becomes dysfunctional and dies by a process that is poorly understood and not yet preventable. Moreover, there is longstanding experimental and clinical evidence that supports the idea that replacement of dopaminergic neurons can ameliorate functional disabilities. Thus, BMSC-derived dopaminergic neurons could have significant therapeutic potential. Whether the BMSCs are induced to undergo neural differentiation prior to transplantation, rather than naturally in situ, will need to be carefully evaluated, but cell replacement strategies using BMSCs hold major promise. Indeed, Huntington's disease, spinocerebellar ataxia, stroke, traumatic brain...

Neural Transplantation Of Primary Fetal Striatal Tissue

Dissection Ganglionic Eminences

The relatively focal loss of medium spiny GABAergic projection neurons in the striatum presents an opportunity to explore neural transplantation as a strategy for cell replacement and circuit reconstruction. The medium spiny neurons of the caudate nucleus and putamen form part of a complex circuitry of parallel feedback loops involving discrete areas of cortex and subcortical structures. The medium spiny neurons receive major inputs from the cerebral cortex, thalamus, and substantia nigra pars compacta, and their primary outputs occur via GABAergic projections to the globus pallidus and the substantia nigra pars reticulata. Experimental studies conducted in animals over the past two decades have established that striatal neurons that are lost through a lesion can be functionally replaced by transplantation of the homologous population of fetal neurons. To achieve this, the developing fetal striatum is dissected, dissociated using enzymatic digestion of the tissue or diced into small...

Transplantation Of Nt2n Cells In Stroke Patients

Additional challenges in the field of neural transplantation include demonstration of graft viability and functional effects. A subsequent clinical report evaluated the function of NT2N-transplanted cells using positron emission tomography (PET) (64). Uptake of fluorodeoxyglucose (FDG) was measured at baseline and at 6 and 12 months after transplantation of NT2N neurons. At 6-mo posttransplantation, 7 of 11 patients showed more than 10 increase in FDG uptake in the area of cell implantation this increase correlated with clinical improvement, as measured by stroke scale values. In a recent study that reported the first postmortem brain in an NT2N-transplanted patient at 2 yr posttransplantation (65), histological examination revealed neurofilament immunoreactive neurons resembling those seen in NT2N neurons in vitro. The observed NT2N cell graft survival in this patient suggests that these transplanted cells mediated functional outcome. The PET and histological data from transplanted...

Adrenal Medulla Tissue Transplants

Early transplant protocols used a two-step method for transplanting adrenal tissue. First, a cavity was created in the brain at the transplant site using a small amount of sterile gelatin foam. This cavity was thought to set the stage for the transplant, as it was found that the brain releases neurotrophic factors during the first few days following damage (36,37). The adrenal tissue would then be transplanted into a site that was enriched with neurotrophins and blood vessels to increase graft survival. One study found that adrenal grafts placed into the striatum alleviated some motor impairments seen in hemiparkinsonian monkeys approx 3 mo after transplantation (38). Monkeys showed improvement in reaching with their contralateral limb and had decreased apomorphine-induced rotations. As the post-transplant time increased, the improvements began to reverse (38,39). At 6 mo, the transplanted monkeys were sacrificed, and no tyrosine hydroxylase-positive donor cells were found. In a...

Bone Marrow As A Source Of Cells For Brain Repair

BMSCs have been recently tested in models of Parkinson's disease. Because of its defined pathogenesis, this disease has been considered a good target for cell replacement therapy. Transplantation of BMSCs in the corpus striatum of the mouse model of Parkinson's disease has shown that BMSCs express the dopaminergic synthetic enzyme tyrosine hydroxylase and induce behavioral recovery in this model (27). Additionally, it is possible to engineer BMSCs to overexpress specific genes, thereby increasing their therapeutic efficiency. Given that the standard treatment for Parkinson's disease (3,4-dihydroxyphenylalanine l-dopa ) has limited long-term benefit, therapy with transduced cells may provide a constant and well-tolerated source of the lacking compounds. Investigators have examined the possibility of using several different pro 6-hydroxy-dopamine (Parkinson's) MPTP mice (Parkinson's)

Imaging Pathophysiology Of Pd

In vitro and in vivo studies in humans have demonstrated that idiopathic PD is preceded by early degeneration of DA neurons in the ventrolateral substantia nigra pars compacta projecting to the posterior and dorsal putamen (5-8). With disease progression, nigrostriatal projections to more anterior and ventral putamen areas begin to decrease, with late loss of projections to the caudate nucleus. This leads to widespread decline Motor symptoms in PD patients develop after a preclinical period and evolve from unilateral to bilateral involvement. A clinical diagnosis is made if the patient shows at least two of the four cardinal signs of PD with a good response to levodopa treatment. A variable degree of cognitive impairment in frontal function is also present during advanced stages of the disease. The severity of the overall symptoms is evaluated objectively by standardized ratings such as Unified Parkinson's Disease Rating Scale (UPDRS). PET imaging has provided important insight into...

Medical And Surgical Treatments Of Pd

PET imaging markers described above provide important functional basis for introducing effective interventions and directly assessing their therapeutic efficacy. Imaging evaluation is absolutely necessary because clinical observation is most likely to be insensitive to incremental improvement in the brain function. This can be performed by measuring longitudinal changes in functional indices in PD patients before and after the treatment. The patients should be off dopaminertic medications for at least 12 h before PET scanning to minimize any confounding effects. In recent years, many imaging studies have demonstrated an association between relative regional changes in brain function induced by treatment and corresponding clinical performance. It has been reported that impaired rCBF activations in regions involved in simple motor tasks can be restored by levodopa infusion and DBS of the internal globus pallidus (GPi) (60,61). UPDRS motor ratings are improved by more than 34 and rCBF...

Quantitative Estimation Of Regional Brain Iron With

Schwab And England Score

The adult brain has a very high iron content, particularly in the basal ganglia. Direct postmortem measurements have shown nonheme brain iron to be very low throughout the brain at birth but to increase gradually in most parts of the brain during the first two decades of life (35). Brain iron concentration is maximal in the globus pallidus, substantia nigra, red nucleus, caudate, and putamen. Abnormally elevated iron levels are evident in various neurodegenerative disorders, including PD, in which increased iron in the substantia nigra has been reported (36,37). Laser microprobe studies indicate that iron normally accumulates within neuromelanin granules of nigral neurons and that iron levels within these granules are significantly increased in PD (38). Extended X-ray absorption fine-structure experiments have shown that ferritin is the only storage protein detectable in both control and parkinsonian brain, with increased loading of ferritin with iron in PD (39). Although ferritin in...

Evaluation With Multiple Imaging Markers

To establish whether the transplantation fully restores the cerebral brain function in PD patients, it is necessary to evaluate its efficacy by multitracer PET imaging. Previous studies have documented both striatal and frontal reductions in presyn-aptic DA function and their relationships with motor and cognitive impairment ( 15,29). The capacity to release endogenous DA in these areas has also been proven by measuring reduction in postsynaptic D2 receptor binding induced by pharmacological challenges (39). The successful DA transplantation should maximally increase and sustain the levels of these parameters of dopaminergic function postoperatively. PET FDG or H2 15O activation studies are ideal to investigate the graft-mediated recovery of metabolic or blood flow function and its role in improving motor and cognitive impairment in patients with PD. The best way is likely to involve acquiring presynaptic DA imaging, FDG, and rCBF activation data in the same patients before and after...

Summary And Conclusions

At present, conventional MRI shows no convincing structural changes in PD itself, but it may be useful in helping to distinguish PD from other neurodegenerative parkinsonian syndromes and from the occasional case of parkinsonism secondary to a focal brain lesion. MRS also may provide useful information in distinguishing PD from disorders such as MSA. opments to provide relevant information. Novel pulse sequences may provide more information regarding substantia nigra pathology in PD. The use of MR as a tool to measure regional iron concentrations should provide more information regarding the relationship between iron accumulation and parkinsonian symptoms. MRS provides a sensitive tool for the researcher to investigate in vivo the possible contribution of abnormalities in brain energy metabolism to the pathogenesis of PD. MRS also allows the assessment of other metabolite changes in PD, for example, providing for the evaluation of the potential importance of changes in regional brain...

Imaging The Dopaminergic System

Dihydroxyphenylalanine ( 18F fluorodopa) as a measure of the integrity of dopamine neurons (43,44). 18F fluorodopa measures changes in aromatic L-amino decarboxylase activity, which is dependent on the availability of striatal dopaminergic nerve terminals and is proportional to the number of dopamine neurons in the substantia nigra (45). Quantitative parameters associated with 18F fluorodopa uptake, such as the striatal-to-background uptake ratio, and the influx rate constant, have been shown to be useful indicators of dopaminergic degeneration in PD and other syndromes (4667). Indeed, 18F fluorodopa and PET are often regarded as the gold standard in the detection of dopamine neuronal loss (68), although the contributions from SPECT imaging, and other direct measures of the dopaminergic binding sites, both pre- and postsynaptic, are increasing (55,56,69-71). The analysis of 18F fluorodopa PET studies is known to have a number of serious potential problems. 18F fluorodopa is...

Alternative Sources Of Da Tissue

Fully differentiated DA neurons (98). These DA neurons caused gradual and sustained behavioral recovery of DA-mediated motor asymmetry. Parallel increase in DAT binding was seen in the grafted striatum (equal to 75-90 of the intact side) and correlated with the number of neurons counted at postmortem in the graft. In contrast, there was much less DAT activity in sham controls. These findings demonstrate that transplanted embryonic stem cells can develop spontaneously into DA neurons to restore cerebral function and behavior in an animal model of PD. Other types of substitute DA cells and DA neurons cultivated from human embryonic cells are currently under investigation and may become available in the near future (74,107). A new therapy closely related to DA transplantation is the use of genetic manipulation to normalize DA production and delivery in the brain. This pioneering development has been actively tested in animal models of PD (108,109). However, clinical trials of these cell...

Imaging Other Neurotransmitter Systems

Although most imaging studies have investigated the effects of parkinsonian disorders on the dopaminergic system, neuropathology and biochemical studies suggest that serotonin neurons also are affected by the disease process (214). The integrity of serotonin neurons in the midbrain region can be studied using the SPECT tracer 123I P-CIT (215,216). Although this radioligand is more commonly associated with measurements of the dopamine transporter, it also binds with high affinity to the serotonin transporter. However, owing to the high concentration of dopamine transporters in the striatum, imaging of the serotonergic system with this tracer is limited to the midbrain (217). Despite these technical difficulties, studies suggest that dopamine and serotonin transporters are differentially affected in PD, and serotonin transporters in the midbrain region may not be affected in relatively early stages of PD (218,219). In later stages of the disease, serotonin transporters are reduced in...

Imaging Of Da Transporter

PET imaging with DAT radioligands may be used as molecular markers to assess striatal presynaptic function in PD patients after DA cell transplantation. This has been demonstrated in a unilateral rat model of neurotransplantation with 11C CFT and microPET scanner (91). Parkinsonian lesions were created by injecting 6-hydroxydopamine. DAT binding in the lesioned striatum was reduced to 15 to 35 of the unoperated side. After grafting with non-DA cells from dorsal mesencephalon, the binding remained to levels observed before transplantation and rats had no behavioral recovery. In contrast, after DA neuronal transplantation, behavioral recovery occurred only after the specific DAT binding had increased to 75 to 85 of the intact side. DAT radioligand has also been used to investigate the role of implanting DA neurons in the clinical manifestation of levodopa-induced dyskinesia in a rat model of PD (92). Dys-kinesia was induced gradually during the course of 1 mo with a low dose of levodopa...

Imaging Of Postsynaptic Da Receptors

Of striatocortical functional systems in patients treated with fetal cell implantation. It is reported that recovery of movement-related cortical function has been delayed in PD after striatal dopaminergic grafting (96). The cortical activation was still impaired at 6.5 mo after transplantation, although motor symptoms and mean striatal DA storage capacity had significantly improved. At 18 mo after surgery, there was further significant clinical improvement without any more increase in striatal FDOPA uptake. The surgery significantly improved rostral supplementary motor and dorsal prefrontal cortical activation during performance of joystick movements, in agreement with the results of subthalamic nucleus DBS (63,65). These data suggest that it is not enough for the graft to simply deliver DA and that functional integration of the grafted neurons within the host brain is necessary to produce substantial clinical recovery in PD.

Abstract

Developing dopaminergic (DAergic) neurons that originate from aborted human embryos have been implanted into the brains of patients with Parkinson's disease (PD) and, in some cases, have successfully restored function. However, there are insufficient numbers of cells available to allow this therapy to become widely used. The limited amount of tissue from embryos may be circumvented by the use of cell lines that can be expanded in vitro for banking, then differentiated into DAergic neurons just prior to implantation into patients. Today, there are four main sources for such cell lines with future potential for banking and cell therapy for PD human embryonic stem cells, human neural stem cells, human genetically immortalized stem progenitor cells, and human adult-derived non-neural stem cells, such as bone marrow-derived stem cells. Currently, it is not possible to utilize these cell sources therapeutically for PD. The primary reasons are because it has not been feasible to effectively...

Conclusion

In the last 20 yr, neural transplants in the parkinsonian primate model have provided knowledge about immunorejection in the brain, donor age and neurogenesis, transplant location, optimal tissue choices, and tissue alternatives. At present, fetal VM tissue transplanted into the caudate of a dopamine-depleted monkey can replenish the nigrostriatal dopamine system at least to a level that produces significant motor improvements for most behaviors in a certain number of animals. Fortunately, innovative technologies provoke new questions that lead researchers and patients to find even better treatments, if not cures. NSC may be one of those treatments. In parkinsonian primates, NSC migrate to the site of neuropathology and provide trophic support to partially restore the striatal dopamine system. The effects on motor impairments, and the extent of differentiation to replace lost cells, are currently being investigated. It is an exciting new field, where the parkinsonian primate model...

Xenogenic Tissue

Studies of the ability of porcine tissue to achieve brain repair have been conducted predominantly in PD models. Primary tissue grafts have been shown to integrate into the host environment, but even with cyclosporine, a slow rejection process ensues, and finding ways to overcome the issue of graft rejection is the subject of much investigation. Primary porcine ventral mesencephalic (VM) tissue grafted into cortically lesioned neonate brains survived and integrated with the host brain and sent out long axonal projections, thus showing porcine tissue's capable response to rat axonal guidance factors (119). Similar findings have been reported after placing porcine VM tissue into the lesioned cortex of adult rats (120) and into the striatum in animal models of HD and PD (172). There has been good functional improvement with grafts placed in the striatum of a 6-hydroxydopamine-lesioned rat model, according to compensation on the amphetamine rotation test (121). In these studies,...

Summary

Tegmentum Tumor Mri

At present, conventional magnetic resonance imaging (MRI) shows no convincing structural changes in Parkinson's disease (PD) itself, but it may be useful in helping to distinguish PD from other neurodegenerative parkinsonian syndromes. Magnetic resonance spectroscopy (MRS) also may provide useful information in distinguishing PD from disorders such as multiple system atrophy. The general field of MRI and MRS is evolving rapidly, and a number of new developments may provide relevant information. Novel pulse sequences, for instance, may provide more information regarding substantia nigra pathology in PD. The use of MR technologies to measure regional concentrations of brain iron should provide more information regarding the relationship between iron accumulation and parkinsonian symptoms. MRS provides a sensitive tool to investigate the possible contribution of abnormal brain energy metabolism to the pathogenesis of PD. MRS also allows the assessment of other metabolite changes in PD,...

The Dopamine System

In the CNS, dopamine (DA) is synthesized by neurons of the pars compacta of the substantia nigra (SNc) and the ventral tegmental area (VTA) in the midbrain. The aromatic amino acid tyrosine is converted to DA by means of two reactions the first one, involving tyrosine-hydroxylase, the rate-limiting enzyme in this pathway, converts tyrosine into l-3,4-dihydroxyphenylalanine (L-dopa). The second reaction is mediated by aromatic L-amino acid decarboxylase (AADC) and transforms L-dopa into DA, which constitutes approx 80 of all catecholamines (CAs) in the brain (3). Whereas AADC is not thought to be rate limiting for DA synthesis in the normal brain, the situation may be different in PD. DA is packaged via the vesicular monoamine transporter (VMAT2) in synaptic vesicles in concentrations up to 1000 times higher than in cytosol, until release from dopaminergic terminals after an action potential. The membrane dopamine transporter (DAT) is responsible for DA reuptake into presynaptic...

H111111111

Fluorodopa uptake measured by PET correlates well with tyrosine hydroxylase cell counts in the substantia nigra (courtesy of E. G. McGeer and UBC-TRIUMF PET group). Several studies addressed the issue of FDOPA PET in the diagnosis and, above all, its potential in the differential diagnosis of parkinsonian syndromes in clinical practice. Brooks and colleagues (63) used FDOPA and S- 11C -nomifensine, a DA reuptake blocker, to detect distinctive alterations in IPD compared with parkinsonism-dominant MSA (MSA-P) and pure autonomic failure patients and controls. Direct comparison between IPD and MSA-P disclosed a homogeneous reduction of striatal FDOPA Ki in MSA patients, in contrast with the rostrocaudal gradient in IPD (63). More recently, IPD was compared with MSA-P by means of FDOPA, RAC, and 18F-FDG PET as well as 3D-MRI volumetry. FDOPA had similar Ki values in both conditions and some MSA patients displayed the rostrocaudal gradient typical of IPD. However, unlike IPD, MSA...

Conclusions

With PET, it has become possible to understand the spectrum of changes that take place in cortical and subcortical structures in the course of PD, as well as in related diseases presenting with parkinsonism. The investigation of CBF and metabolism has disclosed patterns of activation in distant sites that previously could be only inferred by means of neuroana-tomical and neuropathological studies. Biochemical alterations at the receptor level are now visualized in vivo, and the use of radioligands aimed at different parts of the nigrostriatal synapse makes possible a better understanding of DA metabolism, such as progression of dopaminergic cell loss and adaptive mechanisms in these and other neurotransmitter systems.

Pet Radioligands

One of the earliest discoveries using 11C-P-CFT was that more than more than 70 destruction of dopaminergic cells was required to produce parkinsonian symptoms in monkeys (47). 11C-P-CFT can reliably discriminate between changes in DAT distribution caused by PD and PSP (48). It may also be used to detect dopaminergic cell loss in early PD (49). (P-CBT) was developed to study the role of the halogenated site in DAT selectivity of cocaine analogs (58). Its radioactively brominated form (76Br-P-CBT) reaches peak concentration in the striatum in about 60 min and remains there for about 4 h, with a striatal-to-cerebellar activity ratio between 17 and 22 (58). In a study of 18 patients with PD, 76Br-P-CBT demonstrated reduction of DAT density better than 18fluorodopa but was not able to stratify disease severity (59).

Discussion

Fig. 4. (previous page) P-galactosidase histochemistry reveals significant engraftment throughout the brains of single-MAPC-injected chimeric mice. P-Gal activity is undetectable in MAPC-injected, nonchimeric mouse hippocampus (A). (Granule and pyramidal cell layers, and hilus are delineated with superimposed dashed lines for comparison with chimeric hippocampus (B), in which X-gal labeling is strikingly dense.) MAPC-derived cells were found in every area of the brain examined. Their widespread distribution is shown in each of the (numbered) layers of the cortex (C), in the neuronal and fiber tracts (*) of the striatum (D), in the cells of the medial septal nucleus (E), and in the substantia nigra (F). Higher power examination of the hippocampus reveals increased MAPC-derived cells in neuronal layers, such as the stratum granulosum and hilus (G). MAPC contribution to the cerebellum was also very extensive, with increased histochemical density in the granule and Purkinje cell layers...

Outcome Measures

There are now a variety of standardized scales available for the measurement of functional changes in patients with neurological disorders (25). Leading researchers recognized that the progress of cellular therapies for neurological disorders would be enhanced if research groups used similar assessment procedures. Langston and colleagues (25) constructed the Core Assessment Program for Intracerebral Transplantation (CAPIT) to guide research in the field. The CAPIT-PD contains a battery of functional assessments for PD, including the commonly used United Parkinson's Disease Rating Scale (UPDRS) (25). The CAPIT-PD protocol specifies not only pre-and postgrafting of the tests but also the conditions ( on or off' medication) to conduct the tests. In addition, pre- and postoperative assessment of levels of dopaminergic activity are determined using 18F-fluorodopa positron emission tomography (PET) scans. There are more recent developments of the CAPIT-PD protocol, as well as protocols for...

Stem Cells

Several immortalized neural cell lines have been examined in transplantation studies. The oncogene must be sufficiently downregulated in the differentiating neural cells, to allow the differentiation programs to proceed and to avoid tumor formation after grafting. Ideally, proliferation should end, and differentiation should be initiated, before the cells are harvested for transplantation. Another option is to rely on the oncogene being spontaneously downregulated in conjunction with graft surgery. V-myc has been reported to be downregulated following intracerebral transplantation (52,61), but detection of v-myc mRNA is still possible using reverse transcriptase-polymerase chain reaction (62). This degree of downregulation is unlikely to be sufficient to meet the level of safety required in clinical trials. Nevertheless, in experimental animals, cell lines generated by the constitutive expression of immortalizing oncogenes have been shown as nontumori-genic (63). Following...

Spect Radioligands

In diagnosis and evaluation of PD, multiple studies have demonstrated 123I-FP-P-CIT's ability to reveal reduced DAT density, perhaps more effectively than 123I-P-CIT (33-35). Like its progenitor, 123I-FP-P-CIT is also able to detect bilateral decreases in striatal DAT density in PD patients with minimal or unilateral symptoms (36). However, there is still some disagreement about whether striatal DAT density as measured by 123I-FP-P-CIT correlates with the stage of PD or the severity of PD symptoms (32,37,38). 99mTechnetium-TRODAT-1 has shown some promise in evaluating PD. Uptake of 99mTc-TRODAT-1 in the posterior putamen was significantly reduced in a controlled study of 42 patients with PD (43). In another study of 34 patients with PD, putaminal uptake of 99mTc-TRODAT-1 was significantly correlated with Hoehn and Yahr stage in addition, bilaterally decreased putaminal uptake could be identified in patients with Stage I disease (44). 99mTechnetium-TRODAT-1 has also been reported to be...

Organic Aciduria

Marked widening of the operculae is found on MRI in patients with glutaric acidemia type 1. White matter changes have been reported in approx half of patients with organic acidurias (128). Abnormal high signal intensity on T2-weighted images is seen in the basal ganglia and periventricular white matter in approx two thirds of children. Abnormal high signal on T2-weighted images may be seen in the dentate nucleus, substantia nigra, and the pontine medial lemniscus (129). Features seen on MRI in adult-onset cases have been described as a diffuse leu-koencephalopathy.

Imaging With Fdopa

Animal models of parkinsonism induced with a neurotoxin (MPTP) have played an important role in the development of cell transplantation surgery (73,74). This has been performed mainly in primates and mice to provide controlled striatal lesions to test various aspects of transplantation strategy. The functional restoration of the DA innervation of striatum has been investigated in MPTP-lesioned Gottingen minipigs after grafting of fetal pig mesencephalic neurons (75). Pigs received bilateral Since early 1990s, many studies in PD patients have been performed to evaluate the safety and efficacy of fetal nigral transplantation into the striatum. This has evolved from unilateral transplantation (77-80) to bilateral transplantation ( 81-83) for a more complete functional recovery. Patients received transplants in caudate and putamen and exhibited significant clinical benefits along with increased FDOPA uptake in the grafted areas. Doses of medications often were reduced, resulting in the...

Clinical Studies

FDOPA was first used to visualize the nigrostriatal system in humans in the early 1980s (49). Studies in parkinsonism have been conducted since that time, when it was first used in MPTP-exposed individuals (50) and PD patients (51). After image acquisition, FDOPA uptake is usually calculated using multiple-timepoint graphical analysis (52-53). The typical finding in idiopathic PD (IPD) is an asymmetric FDOPA uptake with relative sparing of the caudate compared to putamen (39), corresponding to the preferential cell loss in the ventrolateral tier of the SNc (54). FDOPA may also identify subclinical deficits of DA production in individuals at genetic (55) or environmental (50) risk for PD. Of the cardinal signs of PD, the one that has the best correlation with striatal FDOPA is bradykinesia, as rated by the Purdue pegboard and modified Columbia scores (56).

Experimental therapeutics

For most drugs the dynamic effect and hence therapeutic potential can be investigated only in patients, e.g. drugs for parkinsonism and antimicrobials. These two groups of subjects for drug testing are complementary, not mutually exclusive in drug development. Introduction of novel agents into both groups poses ethical and scientific problems (see below).

Some Common Design Configurations

This is the most common clinical trial design for confirmatory therapeutic (Phase 3) trials. Subjects are randomised, to one of two or more treatment 'arms'. These treatments will include the investigational drug at one or more doses, and one or more control treatments such as placebo and or an active comparator. Parallel group designs are particularly useful in conditions that fluctuate over a short-term basis, e.g. migraine or irritable bowel syndrome, but are also used in chronic stable diseases such as Parkinson's disease and forms of cancer. The particular advantages of the parallel group design are simplicity, the ability to approximate more closely the likely conditions of use, and the avoidance of 'carry-over effects' (see below).

Atrioventricular Connections

Describing (abnormal) accessory AV pathways, which usually are called bundles of Kent (Cobb et al. 1968). In Kent's paper, a muscular connection between the right atrium and the right ventricle is described that crosses the annulus fibrosis, and a histological section is shown as well. This observation prompted Mines (1914) to accurately predict the re-entrant pathway of the tachycardia in what we now call the Wolff-Parkinson-White (WPW) syndrome, unknown at thetime(seeSect. 5.2). Infact, whatKentdescribedwas notanaccessorybundle consisting of ordinary muscle, but a node-like structure which is a remnant of an extensive AV ring of specialized tissue present in the embryo. In rare cases, the accessory pathway consists of such specialized cells (Becker et al. 1978). As argued by Anderson and Becker (1981) there are indeed good scientific reasons for discontinuing the use of'Kent bundle' the most important being that Kent did not describe connections in terms of morphology we know today...

Atrioventricular Reentrant Tachycardia

This was written 16 years before Wolff, Parkinson and White (1930) described the clinical syndrome that now bears their name, 18 years before Holzmann and Scherf (1932) ascribed the abnormal ECG in these patients to pre-excitation of the ventricles via an accessory AV bundle, 19 years before Wolferth and Wood (1933) published diagrams showing the pathway for orthodromic and antidromic re-entry, and 53 years before the first studies in patients employing intraoperative mapping and programmed stimulation during cardiac catheterization proved Mines' predictions to be correct (Durrer and Roos 1967 Burchell et al. 1967 Durrer et al. 1967). It is remarkable that none of these papers quotes Mines. As already mentioned in Sect. 3.1), Kent did not describe the usual accessory pathway. For Mines, what was important was that a human heart had been described with multiple connections between atria and ventricles, thereby providing and anatomical substrate for re-entrant excitation.

Treatment Of Dependence

In 1976 a too-clever 23-year-old addict seeking to manufacture his own pethidine 'took a synthetic shortcut and injected himself with what was later with his help proved to be two closely related byproducts one was MPTP (methylphenyltetra-hydropyridine).8'9 Three days later he developed a severe parkinsonian syndrome that responded to levodopa. MPTP selectively destroys melanin-containing cells in the substantia nigra. Further such cases have occurred from use of supposed synthetic heroin. MPTP has since been used in experimental research on parkinsonism. What the future holds for individuals and for society in this area can only be imagined.

Glutamate Is Potentially Toxic To Neurons Excitotoxicity

Despite its physiological role as a neurotransmitter, glutamate can be lethal to neurons upon intense exposure (4). Overactivation of glutamate receptors has been implicated in neuronal degeneration and loss in such acute conditions as hypoxia-ischemia, hypoglycemia, head injury, stroke, and prolonged epileptic seizures, as well as in chronic neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and acquired immunodeficiency syndrome (AIDS) dementia (4). In most instances, neuronal cell loss is attributable to excitotoxicity, a term derived from its mediation by excitatory amino acid receptors.

Clinical Features

A combination of cerebellar dysfunction, parkinsonian features, and autonomic failure characterize the clinical picture. In some patients, cerebellar, and in others, par-kinsonian symptoms predominate. The Shy-Drager syndrome may occur with either one. Ataxia of gait is usually the presenting cerebellar symptom, followed by ataxia of limbs, dysarthria, and ocular signs such as nystagmus, ocular dysmetria, fixation instability, and jerky pursuit movements. The parkinsonian features include rigidity, bradykinesia-akinesia, postural instability, hypokinetic dysarthria, and tremor. The autonomic failure consists of orthostatic hypotension, bladder dysfunction (urinary frequency, urgency, retention), bowel dysfunction (constipation), and sexual (male erectile) dysfunction. Spasticity, hyper-reflexia, sleep disorder, respiratory stridor, and hypoventilation add to the syndrome. The course averages from 6 to 10 years. MRI demonstrates cerebellar atrophy and

Fascicular Paralysis of the Oculomotor Nerve

Due to the separation of the third nerve fascicles as they leave their nuclear complex, pass through the red nucleus, substantia nigra, and the pyramidal tracts to exit the brain-stem into the interpeduncular fossa, damage in this region often results in incomplete paralysis. The pupil may be spared, or an isolated paralysis of elevation may be found. Even patterns of isolated superior or inferior divisional palsies of the third nerve can arise from disease located within

Use in Prevention and Therapy

Abnormalities in the acetylcholine system in the brain may produce motor disturbances. Therefore, choline and lecithin supplements may benefit people with Parkinson disease, Huntington disease, and other nervous disorders characterized by abnormal movements.7 Choline and lecithin may also be beneficial in reducing tardive dyskinesia associated with antipsychotic drug use.1

Other Sleep Disorders

Described as 'crawling', 'aching', 'tingling' and is partially or completely relieved with leg motion, returning after movement ceases. Most if not all patients with this complaint also have periodic limb movements disorder (PLMD), which may occur independently of RLS. These periodic limb movements consist of highly stereotyped movements, usually of the legs, that occur repeatedly (typically every 20-40 seconds) during the night. They may wake the patient, in which case there may be a complaint of daytime sleepiness or occasionally insomnia, but often only awaken the sleeping partner, who is usually kicked. RLS and PLMS are considered to be movement disorders and may respond to formulations of levodopa but dopamine agonists, e.g. ropinirole, and other treatments such as gabapentin are under investigation

Note On Pathophysiology

Parkinson's disease9 affects about 1 in 200 of the elderly population. In broad terms, it is caused by degeneration of the substantia nigra10 in the midbrain, and consequent loss of dopamine-containing neurons in the nigrostriatal pathway (see Fig. 19.3, p. 382). There is no known cure but drug treatment can, if properly managed, dramatically improve quality of life in this progressive disease. Two balanced systems are important in the extrapyramidal control of motor activity at the level of the corpus striatum and substantia nigra in one the neurotransmitter is acetylcholine in the other it is a dopamine. In Parkinson's disease there is degenerative loss of nigrostriatal dopaminergic neurons and the symptoms and signs of the disease are due to dopamine depletion. Certain drugs also produce the features of Parkinson's disease (see below) and the general term 'parkinsonism' is used to cover both the disease and the drug-induced states. The symptom triad of the disease is bradykinesia,...

Objectives of therapy

(a) replenish neuronal dopamine by supplying levodopa, which is its natural precursor administration of dopamine itself is ineffective as it does not cross the blood-brain barrier 11 Saltzman E W 1996 Living with Parkinson's disease. New England Journal of Medicine 334 114-116. Both approaches are effective in therapy and may usefully be combined. It therefore comes as no surprise that drugs which prolong the action of acetylcholine (anticholinesterases) or drugs which deplete dopamine stores (reserpine) or block dopamine receptors (antipsychotics, e.g. chlorpromazine) will exacerbate the symptoms of parkinsonism or induce a parkinson-like state. Other parts of the brain in which dopaminergic systems are involved include the medulla (induction of vomiting), the hypothalamus (suppression of prolactin secretion) and certain paths to the cerebral cortex. Different effects of dopaminergic drugs can be explained by activation of these systems, namely emesis, suppression of lactation...

Chronic orthostatic hypotension

Autonomic failure and secondary to parkinsonism and diabetes. The clinical features can be mimicked by saline depletion. The two conditions are clearly separated by measurement of plasma levels of noradrenaline (supine and erect) and renin. These are elevated in saline depletion, but depressed in most causes of hypotension due to autonomic failure.

Myoclonus Epilepsy with Ragged Red Fibers

The pathology consists of (a)neuronal degenerations and gliosis in the dentate nuclei and cortex of the cerebellum, inferior olivary nuclei, red nucleus, substantia nigra, globus pallidus, and Clarke nucleus of the spinal cord (b) demyelination of the superior cerebellar peduncles and posterior columns and spinocerebellar tracts of the spinal cord and (c) ragged-red fiber myopathy.

Causes Of Atrial Fibrillation

Ondas Delta

Wolff-Parkinson-White Syndrome Another cause of AF is the Wolff-Parkinson-White (WPW) syndrome. In patients with this condition, AF may be life-threatening. In addition to the AV node, patients with WPW have an accessory pathway that provides an alternate route for electrical communication between the atria and ventricles, leading to preexcitation, that is, early ventricular depolarization that begins prior to normal AV nodal conduction. A portion of ventricular activation occurs over the accessory pathway, with the remaining occurring normally through the His-Purkinje system. This preexcitation is recognized on the ECG as a delta wave, or early up-slurring of the R wave, which both widens the QRS complex and shortens the PR interval, which represents the normal AV nodal conduction time (Figure 3-2). Some patients with the ECG abnormalities of WPW syndrome are asymptomatic others have recurrent tachyarrhythmias. Most of the tachycardia is caused by paroxysmal supraventricular...

Adrenergic Neuron Blocking Drugs

Reserpine is an alkaloid from plants of the genus Rauivolfia, used in medicine since ancient times in southern Asia, particularly for insanity more recently, reserpine was extensively used in psychiatry but is now obsolete. Reserpine depletes adrenergic nerves of noradrenaline primarily by blocking amine storage within vesicles present in the nerve ending, so reducing stores of releasable transmitter. Its antihypertensive action is due chiefly to peripheral action, but it enters the CNS and depletes catecholamine stores there too this explains the sedation, depression and parkinsonian (extrapyramidal) side effects that can accompany its use. The effects on catecholamine storage persist for days to weeks after it is withdrawn.

Mitochondria Aging and Human Disease

The identification of nuclear-encoded mitochondrial genes is yielding new insights into the interaction of both genomes in mitochondrial function. Some of the nuclear genes shown to influence mitochondrial function include frataxin (47), adenine nucleotide transporter 1 (ANT1) (48), TWINKLE (49), and SURF1 (50). An area of active investigation and debate is the relationship of mitochondrial dysfunction to common, sporadic, age-related neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). AD affects memory, judgment, and other higher cognitive functions. The neuropathological hallmarks of AD include neurofibrillary tangles and amyloid containing plaques. Oxidative damage in AD has been reported (51), and reduced cytochrome oxidase (COX) activity has been described in AD brains (52,53). PD presents with bradykinesia, rigidity, and tremor in the sixth to eighth decades. Pathologically, there is selective loss of dopaminergic neurons in the substania...

Calcineurin In Cell Proliferation And Adhesionrelated Phenomena

Another factor that might be envisaged is genomic mutations. Mutations in the exons as well as introns of the tau gene have been reported in cases of familial dementia and Parkinson's disease. Mutations in the exons seem to affect the ability of tau to promote microtubule assembly (Hasegawa et al. 1998). Nonetheless, this abnormal phosphorylation state has been attributed to the generation of an imbalance between protein kinases and phosphatases, engendered by a reduction in the levels of phosphatases (Iqbal and Grundke-Iqbal, 1996). More specifically, the high state of tau phosphorylation has been related to calcineurin dysfunction. This is suggested by the findings of Kayyali et al. (1997) that calcineurin A-a (- -) knock-out mice show hyperphosphorylation of tau. The abnormal tau accumulates, and these mice also exhibit cytoskeletal changes that might affect neuronal function.

Porcine Embryonic GABAergic Cell Transplants

Historically, transplantation of fetal neurons and glia have been demonstrated to survive, integrate, and reduce functional deficits in animal models of Parkinson's disease and Huntington's disease (296, 297). In addition, surgical implants in humans have been successfully performed in pilot studies (298). An FDA-approved safety and feasibility study of transplantation of embryonic porcine lateral ganglionic eminence cells (NeuroCellTMFE, Diacrin, Inc.) into epileptogenic tissue in patients with surgically amenable temporal or frontal lobe onset seizures was initiated (198). Before transplantation, the cells were treated with anti-MHC I monoclonal antibodies, thus removing the need for treatment with the immunosuppressant cyclosporine. Preliminary evaluation in three patients with medically refractory partial-onset seizures have shown that the procedure is safe and well tolerated.

Neurodegenerative Diseases And Apoptosis

Oxidative Decarboxylierung

Neuronal apoptosis is a process that naturally occurs during development of the brain, as more neurons than needed are originally produced and those which are not correctly connected will die in order to set the proper number of neurons to form a functional network. Neuronal death underlies the symptoms of many human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis. Neurological symptoms will depend of which neuronal population is targeted. The identification of specific genetic and environmental factors responsible for these diseases has bolstered evidence for a shared pathway of neuronal death or apoptosis (reviewed in Mattson 2000 Fadeel and Orrenius 2005 Krantic et al., 2005), which main mechanisms and signalings are depicted in Fig. 2. disease, Parkinson's disease, amyotrophic lateral sclerosis (reviewed in Langley and Ratan 2004). The generation of deleterious oxidants is mostly attributed to metabolism, a...

Allotransplantation In

Ssri Binding Portion Pet

The EBMT has recently updated data on the outcome of 209 allogeneic transplants from their registry (13) (Table 1). There were 163 men (78 ) and 46 women (22 ), with a median age of 42 yr (range, 22-64 yr). The median interval between diagnosis and transplantation was 45 mo (range, 5-198 mo) and at diagnosis, 76 of patients studied were in stages B or C 22 of patients had received one conventional line of therapy, 28 two lines, and 50 three lines. These lines included fludarabine for 44 of 209 patients (21 ), chlorambucil in 30 of 209 patients (14 ), and 32 of 209 (15 ) received ChOP. At transplantation, 172 patients were evaluated for response to therapy 19 of 172 patients (11 ) were in CR, 78 of 172 (45 ) in PR, and 75 of 172 (44 ) in PD. Ninety patients (43 ) received BM, 115 PBSCs (55 ), and 4 BM and PBPCs (2 ). One hundred and sixty-six patients (83 ) received an allotransplant from HLA-identical sibling donors, 6 from syngeneic donors (3 ), 16 (8 ) from matched and mismatched...

Reentry of excitation

Intraatrial Reentrant Tachycardia

Geometric factors - When a thin bundle of fibres inserts into a larger muscle mass - for example, the Purkinje fibre-ventricular muscle junction ( junction ) - the insertion point can be the site for unidirectional block of conduction.57 Such block has not been observed in normal fibres, even though the anterograde junctional conduction delay may be longer than in the retrograde direction. With reduced Na+ channel availability, however, anterograde block may occur at the junction whereas retrograde conduction remains possible.58 More recent studies indicate that the Purkinje fibre-muscle junction is better represented by a three dimensional model of overlying two dimensional sheets of fibres, rather than terminal Purkinje fibres inserting into a three dimensional ventricular muscle mass.59 If so, activation of the ventricular muscle layer occurs only at specific junctional sites otherwise, a considerable resistive barrier exists between the two cell layers.57 It follows that reasons...

Molecular Basis For The Side Effects Of Anticholinergics

Some of the cyclic groups in anticholin-ergics are pharmacophoric moieties for other types of activities. For example, the compounds containing a phenothiazine nucleus exhibit central depressing and antihistaminic side effects. These side effects are of advantage in the treatment of Parkinson's syndrome. The side effects of certain drugs that result from their anticholinergic activities are prominent among some analgesics (e.g., meperidine), antihistamines (e.g., promethazine), psychosedatives (e.g., benactizine), and psychotomimetics (e.g., dexoxodrol).

Distribution of Cannabinoid Receptors within the CNS

Results obtained in autoradiographic studies with rat brain and spinal cord indicate that the distribution pattern of specific binding sites for cannabinoids within the CNS is heterogeneous, unlike that for any other known receptor type and consistent with the known ability of cannabinoid receptor agonists to impair cognition and memory, to alter motor function and movement and to relieve pain (Herkenham et al., 1990, 1991b). The highest concentrations of cannabinoid binding sites in rat brain (4-6.4pmol mg protein) are in the substantia nigra pars reticulata, the entopeduncular nucleus, the globus pallidus, the lateral caudate-putamen, the ependymal and subependymal zones at the centre of the olfactory bulb and the molecular layer of the cerebellum. Other areas of rat brain quite rich in cannabinoid binding sites (2-4pmol mg protein) include the hippocampus, cerebral cortex, intrabulbar anterior commissure, nucleus accumbens and septum. Among the areas of rat brain less densely...

Meningothelial Tumors Meningiomas Grades

Paraparesis Parasagittal

Macrosection of the tumor (HE). B. The tumor fills the posterior part of the third ventricle (LFB-CV). C. Small seeding tumorous nodule in subarachnoid space consists of small cells with round-to-oval hyperchromatic nuclei (HE). D. The cells immunoreact for synaptophysin. E. Small tumorous nodules in the substantia nigra (HE). Pineoblastoma in an adult male. A. Macrosection of the tumor (HE). B. The tumor fills the posterior part of the third ventricle (LFB-CV). C. Small seeding tumorous nodule in subarachnoid space consists of small cells with round-to-oval hyperchromatic nuclei (HE). D. The cells immunoreact for synaptophysin. E. Small tumorous nodules in the substantia nigra (HE).

Corroborative Results From Genetic And Pharmacological Inactivation Of Parp

Death during ischemia and validated targeting PARP for neuroprotection. In one rodent model of MPTP-induced Parkinson's disease, dopamine neurons in the substantia nigra in PARP-- mice could survive MPTP toxicity while most of those neurons in the wild-type littermates were degenerated.109 Indeed, PARP inhibitors offered effective neuroprotection in MPTP-treated mice.110 In other rodent models of traumatic brain injuries, PARP inhibition significantly ameliorated neural damage and PARP gene deletion offered significant functional benefit in motor skills and learning.811 PARP activation mediated ischemia-reperfusion injury was also found in other organs, e.g., in heart and muscle, suggesting a general role for PARP in free radical-elicited necrotic cell death.111112 PARP-- mice or hearts prepared from them were spared of myocardium and preserved myocardial functions after being subject to ischemia.113-115 Although the in vitro cardioprotective effects of PARP inactivation could largely...

With cogwheel phenomenon

Fig. 21.5 a Testing of the muscle tone around the elbow joint by passive manipulation during maximal relaxation of the muscles. b Diagram of important pathological findings the pocketknife phenomenon (fading of resistance when under steady pressure), and cogwheeling (joint rigidity with repeated, brief, and uniform increases in tonus over the entire range of motion of the joint) in case of muscle rigidity in Parkinson's disease

Imaging dopamine metabolism with PET

Dopamine is a chemical messenger produced within the nerve cells that is essential for the transmission of the nerve impulse and hence involved in a wide range of important functions, including movement, cognition and behaviour. Dysfunctions in the central nervous dopamine system can lead to diseases such as Parkinson's and schizophrenia. Alterations in the levels of this neurotransmitter have also been implicated in a variety of behavioural problems such as attention deficit and hyperactivity.

Stem Cells and Regenerative Medicine

Advances in medicine and medical technology have resulted in a tremendous improvement in health and welfare. However, we are still faced with various diseases that are difficult to treat using contemporary medicine. For organ failures (heart failure, renal failure, liver failure) and neurodegenerative diseases (Parkinson's and Alzheimer's disease), there is at present no effective treatment other than the transplantation of organs from human donors or cells from a fetus. In the case of transplantation, there are many problems such as immunological rejection, infectious diseases, and a lack of donors, and the development of a novel treatment method has been desired. During the past decade, regenerative medicine has appeared as a key technology for the next generation of medical care 6-12 . Cell therapy and organ repair using stem cells have become very attractive in regenerative medicine.

Arylpiperidines with an Oxygen Substituentat C Reversal of the ester in meperidine gives MPPP iVmethyl4phenyl4

Propionoxypiperidine, 121) and increases analgesic activity 5- to 10-fold (see Ref. 405). First described in 1943 (433), this compound took on new significance in the late 1970s when the drug began appearing as a designer drug (a compound with a minor structural change that was prepared in attempts to evade laws regulating controlled substances) and sold on the streets as a heroin substitute. During the synthesis of MPPP in clandestine drug laboratories, however, dehydration occurred during the acylation of the 4-phenyl-4-piperi-dol, resulting in the formation of MPTP (N-methy 1-4-pheny 1-1,2,3,6-tetr ahydr opyr idine, 122 see Fig. 7.25). People who took the contaminated drug exhibited symptoms of parkinsonism, even in subjects in their twenties (434). The neurotoxic effects of MPTP are thought to be attributable to its metabolism to MPP+ (123, N-methyl-4-phenylpyridinium) by monoamine oxidase and destruction of dopaminergic neurons, resulting in the parkin-sonism-like symptoms (see...

Genetic Studies in Aging Brain

Another successful method to delineate potential causal susceptibility genes is linkage analysis using a genome-scan approach. A current strategy is to employ markers termed microsatellite markers comprised of polymorphisms that likely represent random genetic variations 84 . Microsatellite maps have been generated that span the entire genome 86 , and several studies have used linkage-based approaches to find candidate genes in age-related paradigms, including AD and Parkinson's disease (PD) 87-89 . Genome-wide linkage studies of aging cohorts have also been performed for macular degeneration of the eye 90-92 . Comparative studies across phyla have also been utilized to identify genetic changes associated with the aging process 93 , 94 . Moreover, employing animal models to study senescence avoids some of the aforementioned confounds of evaluating genes associated with aging in humans.

Caloric Restriction

There are many theories on aging, and one of the most widely accepted is the gradual age-related accumulation of irreparable and irreversible cellular and molecular damage. One environmental manipulation that can alter the aging process is caloric restriction (CR). For example, the lifespan of rodents can be increased by approximately 50 when CR is initiated in young adulthood and maintained throughout life 95 . CR also decreases the incidence of systemic age-related diseases, including cancer, cardiovascular disease, and diabetes in a variety of animal models 96, 97 , making dietary restriction a plausible and relatively inexpensive preventive therapy to consider for aging human populations. CR also has profound behavioral and attentional effects 98 . Moreover, CR in rodents increases neurogenesis in the dentate gyrus 95, 99 and partially attenuates the effects of ischemia 100, 101 and of (MPTP) poisoning within substantia nigra dopaminergic neurons 95, 102 . Thus, CR is an ideal...

Targeted Drug Delivery

Brain morphology has been observed following treatment with such biomaterials in animal models of Parkinson's, Alzheimer's and Huntington's disease (Popovic et al., 2006). Aptamers are also widely studied modes of drug delivery. Aptamers are oligonucleotide ligands that are selected for high affinity binding to molecular targets.

Biological Considerations

If a polymorphism is due to multiple mutations at the same position, the frequency of the derived state will be higher. Unfortunately, LD with nearby polymorphisms will be lower, thus decreasing the likelihood that susceptibility loci will be detected through association with a mapped marker. Pritchard 58 shows that susceptibility alleles can reach appreciable frequencies by recurrent mutation essentially mutation balances weak selection against the deleterious allele. Interestingly, such independent mutations in the same gene, detected by family-based linkage analysis, can provide very strong evidence for disease causation (e.g., DJ1 and early-onset parkinsonism 59 ).

Neuroaxonal Dystrophy with Brain Iron Deposition

Axonal Spheroids Lfb Stain

Neuroaxonal dystrophy with brain iron deposition or Hallervorden-Spatz disease is caused by mutations in the pantothenate kinase gene (PANK2) located on chromosome 20. The disease can occur from infancy through adulthood. Extrapyramidal symptoms and signs are in the foreground of the clinical picture dystonic posturing, choreoathetotic movements, rigidity, and dysarthric speech. The movement disorders are associated with progressive mental deterioration. Specific diagnostic tests are not available. T2-weighted MRI is useful to show bilateral hypointensity (iron deposits) with a central hyperintense area (necrosis) in the globus palli-dus and in the reticular zone of the substantia nigra. Pathology Grossly, the brain shows bilateral softening and rusty discoloration of the globus pallidus. The histology is characterized by necrosis of the globus pal-lidus, iron-containing pigments in the globus pallidus and reticular zone of the substantia nigra, and the presence of axonal spheroids in...

Genetics Of Panic Disorder And The Htr1a1019 Polymorphism

Two complete genome-wide linkage scans for PD liability genes have been published (Crowe, Goedken, Samuelson, Wilson, & Nelson, 2001 Knowles et al., 1998). Although none of the findings reached a level of statistical confidence according to stringent criteria, a region suggestive of a susceptibility locus for PD on chromosome 7p15 was independently identified in both studies. Crowe and colleagues (2001) detected the highest lod score of 2.23 at the D7S2846 locus, located at 57.8 cM on chromosome 7, in a region that lies within 15 cM from the D7S435 locus reported by Knowles and colleagues (1998). Linkage to numerous other markers over a substantial proportion of the human genome had previously been excluded under various parametric models in different sets of pedigrees (for a review, see Lesch, 2003). Some of the conflicting results of linkage analyses in PD may be ascribed to methodological differences in family ascertainment, phenotype definition, diagnostic assessment, and...

General Properties of AVV and LVV

The ability of a viral vector to transduce remote neurones via retrograde transport may have major implications for its use in experimental neuroscience. This feature is heavily dependent on the properties of the viral particle, but could also be influenced by the phenotype of the targeted neurones. There has been some controversy regarding the ability of the conventional AVV (serotype 5) to transduce neurones retrogradely, but this issue has been recently resolved by a number of studies. For example, through the use of AVV with the Rous sarcoma virus long terminal repeat as the promoter, retrograde transduction was obtained after microinjections into the caudate putamen (49). Trans-fected cells (predominantly dopaminergic) were found in substantia nigra compacta that was 2 mm from the site of injection, ruling out viral diffusion as the method of transfec-tion. Nashimura et al. (50) achieved retrograde transfection through intrahippocampal AVV injections using a modified chicken...

Studies With Apoptosis Inhibitors

Several studies have employed caspase inhibitors of either biological (viral or cellular caspase inhibitors) or chemical origin (peptide inhibitors). Application of broad-spectrum caspase inhibitors such as zVAD-fmk and BAF has been shown to prevent or delay neuronal cell death in response to ischemic, traumatic or excitotoxic neuron death, as well as in animal models of Parkinson's Disease. These compound binds irreversibly to the catalytic site of caspases, forming a covalent inhibitor enzyme complex. In addition, other cysteine proteases such as calpains and cathepsins may also be inhibited by these compounds, thus aggravating interpretation of the involvement of type I versus type II apoptosis in these experiments. Moreover, many of these inhibitors also inhibit the formation and secretion of interleukin-1p, and may therefore exhibit potent anti-inflammatory effects. Protective effects have also been observed with more specific inhibitor of executioner caspases such as zDEVD.fmk....

P2X Glial Signalling and Plasticity Responses

Taken together these data indicate the strict links between purinergic signalling and glial mediated CNS inflammatory responses. The purinergic mediated release of inflammatory cytokines from microglial cells is of particular relevance taking into account the suggested role of cytokines in different CNS pathologies. Cytokine mediated inflammation mechanisms were suggested as pathogenic mechanisms in multiple sclerosis, Alzheimer's and Parkinson's disease.103 The availability of specific purinergic agonists antagonists and the definition of the P2X receptors role in controlling the inflammatory cascade is providing important data for planning new therapeutic strategies for neurodegenerative diseases.

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