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There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers. [ABSTRACT FROM AUTHOR]

The article reports on the results of research which was conducted in an effort to determine whether the use of external focus instructions would reduce postural instability in individuals with idiopathic Parkinson Disease. Researchers asked fourteen participants with the disease to balance on an unstable surface (inflated rubber disk) and focus on reducing movements to their feet or the disk. Researchers found that subtle wording distinctions that direct attention to movements are capable of reducing postural instability in standing patients with Parkinson Disease.

Extending the 2002 stress-appraisal model of Chappell and Reid, we examined the relationships between caregiver stressors (e.g., cognitive impairment and functional dependency of the recipient), appraisal (informal hours of caregiving), and protective factors (e.g., social support, self-esteem, and quality of the caregiver-recipient relationship) associated with the burden and quality of life of Parkinson's disease caregivers. There were 136 caregivers (M = 64.59 years) who completed an online survey. Using structural equation modeling, we found that the extended stress-appraisal model of Chappell and Reid provided a good fit to the data (χ² = 67.87, df 55, p > .05; χ²/df = 1.23, Comparative Fit Index = 0.98, Root Mean Square Error of Approximation = 0.04). This study provides an important contribution to a growing field of research that applies theoretical models to investigate the stressors, appraisals, and protective factors that impact caregiver well-being. [ABSTRACT FROM AUTHOR]

Presents a summary of an article entitled `The Use of Marching Music to Affect Motor Block Characteristics in Parkinsonian Gait,' by T. Blahut, R. Crossen, S. Park, R. Rashleger and M. Moore.

Failed storage capacity, leading to pulsatile delivery of dopamine (DA) in the striatum, is used to explain the emergence of ‘wearing off’ and dyskinaesia in Parkinsons disease. In this study, we show that surviving DA neurons in 6-OHDA lesioned rats sprout to re-innervate the striatum, and maintain terminal density until ∼60% of neurons are lost. We demonstrate that DA terminal density correlates with baseline striatal DA concentration ([DA]). Electrochemical and synaptosome studies in 6-OHDA lesioned rats and primates suggest that impaired striatal DA re-uptake and increased DA release from medial forebrain bundle fibres contribute to maintaining striatal DA levels. In lesioned rats where terminal density fell by 60% or more, l-DOPA administration increased striatal DA levels markedly. The striatal [DA] produced by l-DOPA directly correlated with the extent of dyskinaesia, suggesting that dyskinaesia was related to high striatal [DA]. While sprouting and decreased dopamine uptake transporter function would be expected to contribute to the marked increase in l-DOPA induced [DA], the increased [DA] was most marked when DAergic fibres were >60% denervated, suggesting that other release sites, such as serotonergic fibres might be contributing. In conclusion, the extent of dyskinaesia was directly proportional to the extent of DA terminal denervation and levels of extra-synaptic striatal DA. We propose that sprouting of DA terminals and decreased dopamine uptake transporter function prevent the appearance of Parkinsonian symptoms until about 60% loss of nigral neurons, but also contribute to dysregulated striatal DA release that is responsible for the emergence of dyskinaesia and ‘wearing off’. [ABSTRACT FROM AUTHOR]

To study the effect of disease duration on the clinical, neuropsychological and [18F]-deoxyglucose (FDG) PET findings in patients with mixed type multiple system atrophy (MSA), this study included 16 controls and 37 mixed-type MSA patients with a shorter than a 3-year history of cerebellar or parkinsonian symptoms. We classified the patients into three groups according to the duration of parkinsonian or cerebellar symptoms (Group I = ≤1 year; II = 13–24 months; III = 25–36 months). We performed UPDRS, international cooperative ataxia rating scale (ICARS), and a neuropsychological test battery. We compared the FDG PET findings of each group of patients with controls. Group I patients frequently had memory and frontal executive dysfunction. They showed hypometabolism in the frontal cortex, anterior cerebellar hemisphere and vermis. They had parkinsonian motor deficits, but no basal ganglia hypometabolism. Group II and III patients frequently had multiple domain cognitive impairments, and showed hypometabolism in the frontal and parieto-temporal cortices. Hypometabolism of the bilateral caudate and the left posterolateral putamen was observed in Group II, and whole striatum in Group III. In summary, the cortical hypometabolism begins in the frontal cortex and spreads to the parieto-temporal cortex in MSA. This spreading pattern coincides with the progressive cognitive decline. Early caudate hypometabolism may also contribute to the cognitive impairment. Parkinsonian motor deficits precede putaminal hypometabolism that begins in its posterolateral part. Cerebellar hypometabolism occurs early in the clinical courses and seems to be a relevant metabolic descriptor of cerebellar deficits. [ABSTRACT FROM AUTHOR]

Presents an abstract of the study `How big is the pool of symptomatic but clinically undiagnosed parkinsonism?,' by J. Meara, P. Hobson, W. Mutch and S. Bisarya, presented during the spring meeting of the British Geriatrics Society on April 6 to 8, 1995.