Phillip D. Swanson

DNA deletion associated with hereditary neuropathy with liability to pressure palsies

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that causes episodes of focal demyelinating neuropathy following minor trauma to peripheral nerves. We assign the HNPP locus to chromosome 17p11.2 and demonstrate the presence of a large interstitial deletion associated with this disorder in three unrelated pedigrees. De novo deletion is documented in one pedigree. The deleted region appears uniform in all pedigrees and includes the gene for peripheral myelin protein 22 (PMP-22), suggesting that underexpression of PMP-22 may cause HNPP. The deletion in HNPP spans approximately 1.5 Mb and includes all markers that are known to map within the Charcot-Marie-Tooth neuropathy type 1A (CMT1A) duplication. Furthermore, the breakpoints in HNPP and CMT1A map to the same intervals in 17p11.2, suggesting that these genetic disorders may be the result of reciprocal products of unequal crossover.

Parkinson’s disease risks associated with dietary iron, manganese, and other nutrient intakes

Background: Dietary influences on oxidative stress have been thought to play important role in the etiology of PD. Objective: To examine associations of PD with dietary nutrients, including minerals, vitamins, and fats. Methods: A population-based case-control study was conducted among newly diagnosed case (n = 250) and control subjects (n = 388) identified between 1992 and 2002 from enrollees of the Group Health Cooperative health maintenance organization in western Washington state. Controls were frequency matched to cases on sex and age. In-person interviews elicited data on food frequency habits during most of adult life. Nutrient intakes were calculated and analyzed by adjusting each person’s nutrient intake by their total energy intake (the nutrient density technique). Results: Subjects with an iron intake in the highest quartile compared with those in the lowest quartile had an increased risk of PD (odds ratio = 1.7, 95% CI: 1.0, 2.7, trend p = 0.016). There was an apparent joint effect of iron and manganese; dietary intake above median levels of both together conferred a nearly doubled risk compared with lower intakes of each nutrient (odds ratio = 1.9, 95% CI: 1.2, 2.9). No strong associations were found for either antioxidants or fats. Conclusion: A high intake of iron, especially in combination with high manganese intake, may be related to risk for PD.

Biochemical abnormalities in Huntington's chorea brains

The enzymes glutamic acid decarboxylase, choline acetylase, and succinate dehydrogenase were reduced by 74 to 93 percent in striatum of brains from three patients who died with long-standing Huntingtons chorea. Little change was found in acetylcholinesterase or monoamine oxidase activities. In an early case of this disease in a fourth patient, there were no enzymatic changes. A high-molecular-weight soluble protein was present in the striatum of the advanced cases but membrane protein patterns did not differ from those of controls.

Dietary factors in Parkinson's disease: The role of food groups and specific foods

The association between self‐reported past food intake and Parkinsons disease (PD) was investigated in a case‐control study of men and women aged 40–89 years.

A genetic polymorphism of MAO-B modifies the association of cigarette smoking and Parkinson's disease

In a population-based case-control study, we found a reversal of the association of cigarette smoking with Parkinsons disease (PD) in relation to the monoamine oxidase B intron 13 genetic polymorphism. A reduced PD risk related to pack-years of smoking was detected for persons with the G allele, whereas an opposite effect was found among persons with the A allele. These results indicate an unexplained interaction between cigarette smoking and this genetic polymorphism.

Neural transplantation in Huntington disease: Long-term grafts in two patients

Objective: Clinical trials of fetal neural tissue transplantation for Huntington disease (HD) have been conducted with variable clinical results. However, no long-term analysis of graft survival and integration has been published. Here, we report the pathologic findings in two patients with HD who died 74 and 79 months after transplantation. Methods: Methods used were pathologic examination, histochemistry, and immunohistochemistry. Results: Neostriatum from both patients showed typical neuropathologic changes of advanced HD. Surviving grafts were identified in both patients (6/6 sites and 7/8 sites, respectively) as well-demarcated nests within host neostriatum with associated needle tracts. Grafted neurons adopted either dominant calbindin/parvalbumin or calretinin immunoreactivity (IR). Few neurofilament, MAP-2, DARPP-32, tyrosine hydroxylase, or calbindin IR processes traversed the host parenchyma-graft interface despite minimal junctional gliosis. Immunohistochemistry for CD68 showed microgliosis that was more pronounced in host striatum than graft. Scattered CD45 and CD3 IR cells were present within grafts and host parenchyma. No ubiquitin IR neuronal intranuclear inclusions were identified in graft neurons, although these were prevalent in host cells. Conclusions: These two autopsies confirm previous findings of neuronal differentiation and survival of transplanted fetal tissue from the ganglionic eminence and also demonstrate viability of neurons from fetal transplants in human neostriatum for more than 6 years. Despite prolonged survival, these grafts had poor integration with host striatum that is likely responsible for lack of clear clinical improvement in these patients.

Association of a polymorphism in intron 13 of the monoamine oxidase B gene with Parkinson disease

Monoamine oxidase B (MAO-B) is an enzyme that has relevance for Parkinson disease (PD) because of its roles in catabolizing dopamine and potentially activating exogenous neurotoxicants. A polymorphism of the gene encoding MAO-B has been identified as a single base change (A or G) in intron 13 of the X chromosome. The A allele was previously associated with an approximately twofold risk of PD. The present study compared A and G allele frequencies between newly diagnosed idiopathic PD cases and a control group free of neurodegenerative diseases. All study subjects were Caucasian. Cases were 37 men and 25 women, age 37-80 years; controls were 50 men and 29 women, age 45-82 years. MAO-B genotype was determined by the allele-specific polymerase chain reaction on DNA extracted from peripheral lymphocytes. In complete contrast to previous studies, elevated risks were detected with the G allele. The age-adjusted odds ratio for the G allele in males was 1.87 ((95% confidence interval) 0.78-4.47). Among females the age-adjusted odds ratios were 5.00 ((95% confidence interval) 1.13-22.1) for the GA genotype and 5.60 ((95% confidence interval) 1.01-30.9) for the GG genotype. These findings, although of limited statistical precision, suggest that the G allele of this MAO-B polymorphism may relate to PD risk.

Uptake of calcium ions by synaptosomes from rat brain

Abstract Rat brain synaptosomes incubated in modified Krebs-Ringer media accumulated 45 Ca in amounts dependent upon the medium calcium concentration. At 37 °C, 45 Ca uptake was increased by 19% upon the application of electrical pulses. Uptake was effectively inhibited by ruthenium red, uncouplers of oxidative phosphorylation, antimycin A and rotenone, and fluorocitrate while oligomycin and ouabain increased 45 Ca uptake. Transfer to a medium low in Na + led to marked increase in 45 Ca uptake and this effect was also found in the presence of rotenone and arsenate. The results indicate the requirements of metabolic energy for a component of calcium uptake by synaptosomes. Effects of low Na + incubation and electrical stimulation may be due to events at the outer synaptosomal membrane though the possibility of direct effects at the mitochondrion have not been excluded.

Glutathione S-transferase M1, T1, and P1 polymorphisms and Parkinson's disease.

Oxidative stress is widely thought to contribute significantly to the pathogenesis Parkinsons disease (PD). Given the role of glutathione S-transferases (GSTs) in the conjugation of electrophiles and protection against reactive oxygen species, genes encoding the GSTs have been considered candidates for association studies of PD. We tested for associations between genotypes of GSTM1(homozygous deletion vs. non-deleted), GSTT1(homozygous deletion vs. non-deleted), and GSTP1 (Ile104Val and Ala113Val) and PD in a case-control study of 214 idiopathic PD cases and 330 age- and gender-matched, unrelated controls of Caucasian ethnicity. No significant associations with any of the GST genotypes were observed. However, there was a marginally significant difference in the distribution of GSTP1 104 genotypes between cases and controls (P=0.07), with an excess of Ile104Val heterozygotes found among cases (odds ratio (OR)=1.43; 95% Confidence Interval (CI): 0.98-2.08). This difference in the genotype distribution was strongest among smokers (OR for heterozygote=1.92; 95% CI: 1.12-3.29) versus non-smokers and among males (OR for heterozygote=1.99; 95% CI: 1.24-3.19) versus females. The distribution of GSTP1 Ile104Val and Ala113Val haplotypes did not differ between cases and controls. Taken together, these results suggest a potentially minor role of GSTP1 in PD, but do not give evidence for associations with either GSTM1 or GSTT1.

Occupational factors and risk of Parkinson's disease: A population-based case-control study.

BACKGROUND Parkinsons disease (PD) has been associated with various workplace factors, but the evidence is inconsistent. OBJECTIVE To estimate the risk of PD associated with various jobs and workplace exposures. METHODS We conducted a population-based, case-control study of 404 incident PD cases and 526 age and sex-matched controls, collecting self-reported work histories including job titles and exposures to various industrial toxicants. Relative risks of PD from these exposures were estimated with odds ratios (OR) and 95% confidence intervals (CI) using logistic regression. RESULTS Risk was not significantly affected by farming work, by metal work, or by exposure to pesticides, metals, or solvents. CONCLUSIONS These findings do not provide support for the hypothesis that workplace factors affect the risk of PD.