A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson's disease

Adenosine A(2A) receptors, abundantly expressed on striatal medium spiny neurons, appear to activate signaling cascades implicated in the regulation of coexpressed ionotropic glutamatergic receptors. To evaluate the contribution of adenosinergic mechanisms to the pathogenesis of the response alterations induced by dopaminergic treatment, we studied the ability of the selective adenosine A(2A) receptor antagonist KW-6002 to prevent as well as palliate these syndromes in rodent and primate models of Parkinson's disease. In rats, KW-6002 reversed the shortened motor response produced by chronic levodopa treatment while reducing levodopa-induced hyperphosphorylation at S845 residues on AMPA receptor GluR1 subunits. In primates, KW-6002 evidenced modest antiparkinsonian activity when given alone. Once-daily coadministration of KW-6002 with apomorphine prevented the development of dyskinesias, which appeared in control animals 7-10 days after initiating apomorphine treatment. Animals initially given apomorphine plus KW-6002 for 3 weeks did not begin to manifest apomorphine-induced dyskinesias until 10-12 days after discontinuing the A(2A) antagonist. These results suggest that KW-6002 can attenuate the induction as well as the expression of motor response alterations to chronic dopaminergic stimulation in parkinsonian animals, possibly by blocking A(2A) receptor-stimulated signaling pathways. Our findings strengthen the rationale for developing A(2A) antagonists as an early treatment strategy for Parkinson's disease.     

Mapping of rat brain using the Synuclein-1 monoclonal antibody reveals somatodendritic expression of alpha-synuclein in populations of neurons homologous to those vulnerable to Lewy body formation in human synucleopathies

The neuronal protein alpha-synuclein has been implicated in the pathogenesis of Parkinson disease and other neurodegenerative diseases. Although many studies report that alpha-synuclein expression is restricted to neuronal presynaptic terminals, this protein aggregates in Lewy bodies in somata that are typically distant from their axon terminals. Few studies have addressed this paradox and there has been no compelling explanation proposed for the apparent discrepancy between the locus of neuronal alpha-synuclein expression and the loci of Lewy bodies in the majority of Parkinson disease cases. We explored this issue by extensively characterizing the monoclonal antibody Synuclein-1 (Syn-1) and using this highly selective antibody to map the distribution of alpha-synuclein throughout rat brain and in human substantia nigra (SN). Additionally, alpha-synuclein expression in rat SN detected by 2 polyclonal antibodies against alpha-synuclein was compared with that detected by the Syn-1 antibody. In contrast with many previous reports, alpha-synuclein was detected by Syn-1 in neuronal somata and dendrites in restricted brain regions, as well as more ubiquitously in axons and terminals. The strongest alpha-synuclein neuronal expression in rat was found in brainstem and cortical regions that are homologous to regions prone to Lewy body formation in humans. The Syn-1 antibody labeled abundant somatodendritic alpha-synuclein in both rat and human SN, a major locus of Lewy body formation and neurodegeneration in Parkinson disease. By contrast, very few immunoreactive somata in the rat SN were labeled by the 2 polyclonal antibodies. We explore possible explanations for the differences in conflicting reports of patterns of alpha-synuclein expression in brain, including differences among antibodies.     

Regulation of matrix metalloproteinase (matrixin) genes in blood vessels: a multi-step recruitment model for pathological remodelling

Matrix metalloproteinases (MMPs; matrixins) are a family of structurally related enzymes that collectively promote turnover of all components of the extracellular matrix. Matrix turnover is required for vascular repair, but, if excessive, leads to pathologies that include aneurysm formation and atherosclerotic plaque instability. We review the positive and negative regulation of metalloproteinase gene induction. We propose that multiple steps of gene induction recruit a wider spectrum of MMPs, which may ultimately lead to a transition from matrix turnover to matrix destruction. Studying the detailed mechanisms involved may suggest possibilities for intervening selectively against pathological MMP induction.     

Dopaminergic modulation of cortical function in patients with Parkinson's disease

Patients with idiopathic Parkinson's disease suffer not only from classic motor symptoms, but from deficits in cognitive function, primarily those subserved by the prefrontal cortex as well. The aim of the current study was to investigate the modulatory effects of dopaminergic therapy on neural systems subserving working memory and motor function in patients with Parkinson's disease. Ten patients with stage I and II Parkinson's disease were studied with functional magnetic resonance imaging, during a relatively hypodopaminergic state (ie, 12 hours after a last dose of dopamimetic treatment), and again during a dopamine-replete state. Functional magnetic resonance imaging was performed under three conditions: a working memory task, a cued sensorimotor task and rest. Consistent with prior data, the cortical motor regions activated during the motor task showed greater activation during the dopamine-replete state; however, the cortical regions subserving working memory displayed greater activation during the hypodopaminergic state. Interestingly, the increase in cortical activation during the working memory task in the hypodopaminergic state positively correlated with errors in task performance, and the increased activation in the cortical motor regions during the dopamine-replete state was positively correlated with improvement in motor function. These results support evidence from basic research that dopamine modulates cortical networks subserving working memory and motor function via two distinct mechanisms: nigrostriatal projections facilitate motor function indirectly via thalamic projections to motor cortices, whereas the mesocortical dopaminergic system facilitates working memory function via direct inputs to prefrontal cortex. The results are also consistent with evidence that the hypodopaminergic state is associated with decreased efficiency of prefrontal cortical information processing and that dopaminergic therapy improves the physiological efficiency of this region.     

A retrospective study of neuroradiological abnormalities detected on structural magnetic resonance imaging of the brain in elderly patients with cognitive impairment

BACKGROUND: The aim of the study was to investigate the relationship between neuroradiological and clinical diagnosis in patients presenting with cognitive impairment, and also the relationship between the neuroradiological abnormalities and cognitive function as assessed by the Mini-Mental State Examination (MMSE) score. METHODS: One hundred and four elderly subjects (65 years and over) with cognitive impairment, referred to secondary hospital services and who had brain magnetic resonance imaging (MRI) scans as part of routine clinical investigations, were studied by review of their MRI scans using a standardized procedure and by examination of the case notes. RESULTS: In patients with a clinical diagnosis of senile dementia Alzheimer-type (SDAT), the diagnosis was reviewed in 11.1%. In patients with vascular dementia, the diagnosis was reviewed in 62. 5%. In patients without a firm clinical diagnosis, radiological features compatible with SDAT were seen in 44.4% and with vascular dementia in 27.0%. Only 2/104 patients showed a significant focal lesion on MRI. Of the variables studied (age, sex, degree of hippocampal atrophy, extent of T2 hyper-intensities, and enlargement of the sulcal and ventricular cerebrospinal fluid (CSF) spaces) only hippocampal atrophy predicted the MMSE score ( p < 0.002). CONCLUSION: MRI brain scanning has an important role in aiding and refining the clinical diagnosis of cognitive impairment/dementia in the elderly.     

The content,integrity, and efficacy of a nurse coaching intervention in type 2 diabetes

PURPOSE: The purpose of this study was to systematically evaluate the content, integrity, and efficacy of a nurse coaching intervention provided after diabetes education that focused on dietary and exercise lifestyle change in persons with type 2 diabetes. METHODS: A multimethod design incorporated an interpretive approach to examine the content and integrity of the intervention and a multiple-baseline, single-subject method to determine the preliminary efficacy of the intervention. RESULTS: The primary strategies of the nurse coaching intervention consisted of facilitating lifestyle change through educational reinforcement, psychosocial support, and motivational guidance. Aggregate quantitative outcomes revealed a modest increase in health-promoting behaviors and a decrease in fasting blood glucose, indicating a trend toward physiologic adaptation. Participants demonstrated a significant increase in integration reflective of psychosocial adaptation. CONCLUSIONS: Providing individualized nursing care after diabetes education may improve health outcomes and the quality of life of persons newly diagnosed with type 2 diabetes. This multimethod design is a cost-effective approach for preliminary evaluation of complex and/or novel interventions.     

Final Adult Height and its Relationship to Blood Glucose Control and Microvascular Complications in IDDM

The effect of longitudinal blood glucose control on final adult height was evaluated in 181 subjects (94 women and 87 men) with IDDM. Diabetes onset was at a median age of 6.9 years with an interquartile range of 4.7 years. Longitudinal glycated haemoglobin values were determined over a mean period of 6.6 ± 2.6 years during their growth phase. Serial eye and joint examinations and urinary albumin excretion rates were performed with final assessment being carried out at a mean age of 21.1 ± 3.0 years. The mean adult height standard deviation score of the whole group was ?0.22 ± 1.15 and was reduced compared to the mean height of the general population and to the mean height of the subjects' parents and siblings. There was an inverse correlation with mean longitudinal glycated haemoglobin and final adult height (p<0.01). There was also an inverse relationship between adult height and the severity of eye, kidney, and joint complications, but when controlled by glycated haemoglobin, this relationship only remained significant for eye complications. Final adult height is reduced in subjects with early onset IDDM who remain in poor blood glucose control during their growth period.