Genetic dissection of familial Parkinson's disease

In the past few years, the genetic contribution to Parkinson's disease (PD) has gained major attention and has resulted in the identification of the first mutant gene, called alpha-synuclein, involved in the pathogenesis of autosomal-dominant PD. alpha-Synuclein is a major component of Lewy bodies, which are a neuropathological feature of PD. Furthermore, deletions in the parkin gene have been identified as the primary cause in rare forms of autosomal-recessive juvenile PD. The elucidation of polygenic changes in the dopamine pathway, mitochondrial dysfunction, and metabolism of xenobiotics is now technically possible by means of association and genotype studies. The increasing knowledge of the pathogenesis of PD at a molecular level will have important implications for the development of individual therapeutic strategies to prevent disease progression.     

Parkinson's disease, pesticides, and glutathione transferase polymorphisms

BACKGROUND: Parkinson's disease is thought to be secondary to the presence of neurotoxins, and pesticides have been implicated as possible causative agents. Glutathione transferases (GST) metabolise xenobiotics, including pesticides. Therefore, we investigated the role of GST polymorphisms in the pathogenesis of idiopathic Parkinson's disease. METHODS: We genotyped by PCR polymorphisms in four GST classes (GSTM1, GSTT1, GSTP1, and GSTZ1) in 95 Parkinson's disease patients and 95 controls. We asked all patients for information about pesticide exposure. FINDINGS: The distribution of the GSTP1 genotypes differed significantly between patients and controls who had been exposed to pesticides (controls vs patients: AA 14 [54%] of 26 vs seven [18%] of 39; AB 11 [42%] of 26 vs 22 [56%] of 39; BB 1 [4%] of 26 vs six [15%] of 39; AC 0 vs four [10%] of 39, p=0.009). No association was found with any of the other GST polymorphisms. Pesticide exposure and a positive family history were risk factors for Parkinson's disease. INTERPRETATION: GSTP1-1, which is expressed in the blood-brain barrier, may influence response to neurotoxins and explain the susceptibility of some people to the parkinsonism-inducing effects of pesticides.     

Genetic polymorphisms as risk factors for coronary artery disease

The acute myocardial infarction is a multi factor disease, and various risk factors participate in its occurrence and progression. Recently, many investigators have paid their attention to the genetic polymorphisms as new risk factors for coronary artery disease. These include the polymorphisms or mutations of the gene which relates to hypertension, diabetes, the platelet function, the property of the blood vessel, the blood coagulation fibrinogenolysis system, and serum lipids. The tendency toward the occurrence and progression of coronary artery disease might be decided genetically by combining these genetic polymorphisms.     

Genetic and environmental risk factors for Parkinson's disease in a Chinese population

An epidemiological study of the environmental and genetic factors as well as the possible interplay between them was conducted among 215 patients with Parkinson's disease and 313 controls in a Chinese population in Hong Kong. In univariate analysis, a regular tea drinking habit was found to be a protective factor, which had not been reported before. Smoking (a protective factor), family history, duration of pesticide exposure (in years) in farming and pesticide exposure during farming in women (both risk factors) have been reported previously. In multivariate analysis, current smoking reached borderline significance at the 5% level and the variables, years exposed to pesticides and family history were significant at the 10% level. By contrast with the common occurrence of polymorphism of the CYP2D6 gene (a gene involved with xenobiotic metabolism) in white people, it is very rare in China and is not thought to be a significant factor contributing to Parkinson's disease in Chinese people.     

S-methylation in Parkinson's disease

We report thiolmethyltransferase (TMT) activity in RBC membrane preparations from patients with Parkinson's disease (PD), normal controls, and patients with symptomatic parkinsonism. Unlike previous reports, our report found no significant decrease in TMT activity in PD patients compared with normal controls. Low S-methylation capacity does not appear to be a risk factor for PD in Japanese patients.     

Dementia in Parkinson's disease

The occurrence of dementia in patients with Parkinson's disease was studied in a Parkinsonian population consisting of all traceable patients residing in a defined area. The prevalence of dementia was found to be 29 per cent in 444 patients studied. The frequency of dementia increased with advancing age and the patients showing signs of clinical arteriosclerosis were more often demented than the patients without arteriosclerosis. There was, however, an evident association between the stage of the disease and the frequency of dementia. The most severely disabled patients displayed dementia more often than the mildly affected, both among the patients with and without arteriosclerosis. The demented patients showed significantly more severe rigidity and hypokinesia when compared with the non-demented. Increasing severity of rigidity and hypolinesia, in particular was found to have a positive correlation with the degree of dementia. The association between dementia and the degree of motor involvement is considered to suggest the role of subcortical structures in the patholophysiology of dementia in Parkinson's disease.     

Sleep benefit in Parkinson's disease

Sleep benefit (SB) In Parkinson's disease (PD) is not well characterized. To determine SB frequency, as well as to characterize and correlate it with other disease variables, we evaluated prospectively a consecutive series of 312 PD patients by means of a structured questionnaire: 55% reported having SB and 35% reported that awakening was their best time of the day. Because of SB, 21% of the entire population were able to skip or delay medication. The mean duration of the phenomenon was 85.4 +/- 67 min. Patients with SB were significantly older (p < 0.0002), had disease longer (p < 0.05), and were often men (chi 2 = 3.5, df 1, p = 0.05). Patients with SB took sleep medication with similar frequency as those without SB. There were no differences in hours of sleep or sleep latency. Sleep problems such as nightmares or somnambulism, but not the number of sleep awakenings, were similar in both groups. In conclusion, SB is a frequent phenomenon, especially in men, elderly patients, and patients with longer disease duration. SB enables the morning L-dopa dose to be postponed in approximately 50% of patients.     

Pharyngo-esophageal dysphagia in Parkinson's disease

The radiologic characteristics of pharyngoesophageal (PE) dysfunction in Parkinson's disease (PD) are not well established, partly because most previous studies have examined only small numbers of patients. We administered a dynamic videofluoroscopic swallowing function study to 71 patients with idiopathic PD. Using the Hoehn and Yahr disease severity scale, patients were subdivided into those with mild/moderate disease, subgroup I (n = 38), and advanced PD disease, subgroup II (n = 33). From pharyngeal ingestion to gastric emptying, bolus transport was normal in only 2 patients. The most common abnormalities occurring during pharyngeal ingestion included impaired motility, vallecular and pyriform sinus stasis, supraglottic and glottic aspiration, and deficient epiglottic positioning and range of motion. Esophageal abnormalities were multiple but most commonly included delayed transport, stasis, bolus redirection, and tertiary contractions. Typical aberrations of lower esophageal sphincter (LES) function included an open or delayed opening of the LES and gastro-esophageal reflux. A pathogenesis linking PE with the pathology of PD is proposed.     

Memory disturbances in Parkinson's disease

Disturbances in memory belong to the most frequent cognitive impairments in Parkinson patients. This review treats problematical aspects in the clinical diagnosis of these memory disturbances, which are particularly evident in free recall, immediate reproduction, the chronological sequencing of events and the initiation of meaningful strategies. These selective impairments are discussed within a theoretical frame of reference. Finally, considering the time demands and work loading in contemporary psychological practice, recommendations are given for economical and multidimensional routine diagnostic testing.     

Genetics of Parkinson's disease

For the past 40 years, research into Parkinson's disease (PD) has been predominantly the province of epidemiologists interested in pursuing the connection between the disease and environmental factors such as viral infection or neurotoxins. Hereditary influences were actually discounted because of a high monozygotic twin discordance rate found in studies that were later shown to be inadequate and inconclusive. There has recently been a resurgence of interest in investigating hereditary factors in PD when it became more and more apparent that a positive family history was a major risk factor for the disease. Meanwhile, it also became increasingly apparent from neuropathological studies that the common, idiopathic form of Parkinson's disease had, in fact, a pathological correlate, i.e., the existence of Lewy bodies, an eosinophilic cytoplasmic inclusion body, distributed diffusely throughout the substantia nigra, hypothalamus, hippocampus, autonomic ganglia and olfactory tracts. Although candidate gene approaches to linkage in PD families have not been rewarding, a genome wide scan mapped PD to 4q21-23 in one large family with PD with diffuse Lewy bodies, where a candidate gene, alpha-synuclein, resides. This gene encodes a presynaptic protein of which a peptide fragment is known to be a constituent of Alzheimer's disease plaques. The identification of a missense mutation in the alpha-synuclein gene in four independent PD families suggests that at least some fraction of familial PD with diffuse Lewy bodies is the result of an abnormal protein that interferes with normal protein degradation leading to the development of inclusions and ultimately neuronal cell death. There may be common pathogenetic mechanisms involved in alpha-synuclein mutations in PD and beta-amyloid and presenilin gene mutations in Alzheimer's disease.     

Auditory event-related potentials in Parkinson's disease

We studied 49 patients with Parkinson's disease (PD) by a neuropsychological battery examining the temporo-spatial orientation, short-term memory, comprehension, non-verbal intelligence, long-term memory and anomia and the Auditory Event-Related Potentials. In the patients the latencies of the N100 and N200 waves were prolonged and the amplitude of the P300 wave was reduced compared with controls. No difference was found in the ERP of patients with and without cognitive deficits. Equally, no correlation was found between the ERP, the cognitive impairment, the length or the severity of the disease evaluated by Hoehn-Yahr's and Webster's scales.     

Variable memory profiles in Parkinson's disease

Thirty-nine patients with Parkinson's disease (PD) were categorized into one of three subgroups using discriminant function analysis and three key indices from the California Verbal Learning Test (CVLT). Patients were classified as having one of three memory profiles: (a) a normal memory profile; (b) a memory profile often observed in patients with Huntington's disease (HD); or (c) a memory profile often observed in patients with Alzheimer's disease (AD). Twenty of the patients with PD were classified as having a normal profile, 10 as having an HD profile, and 9 as having an AD profile. The three subgroups did not differ on measures of global cognitive functioning, letter fluency, confrontation naming, or visuo-construction, suggesting that the patients with PD with an AD memory profile were not experiencing AD, per se. These results demonstrate that the memory deficits associated with PD can be similar to those found in patients with either HD or AD, and argues against the notion that the behavioral manifestations of PD are homogeneous.