Genetic and pathological links between Parkinson's disease and the lysosomal disorder Sanfilippo syndrome.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder of unknown etiology. The characteristic α-synuclein aggregation of PD is also a feature of Sanfilippo syndrome, a storage disorder caused by α-N-acetylglucosaminidase (NAGLU) gene mutations. We explored genetic links between these disorders and studied the pathology of Sanfilippo syndrome to investigate a common pathway toward α-synuclein aggregation. METHODS: We typed the 2 single-nucleotide polymorphisms that tag the common haplotypes of NAGLU in 926 PD patients and 2308 controls and also stained cortical tissue from 2 cases of Sanfilippo A syndrome using the anti-α-synuclein antibody, Per7. RESULTS: Allelic analysis showed an association between rs2071046 and risk for PD (P 1.3 × 10(-3) ). Intracellular α-synuclein accumulation was observed in the cortical tissue of both Sanfilippo A syndrome cases. CONCLUSIONS: This study suggests a possible role of NAGLU in susceptibility to PD while extending evidence for α-synuclein aggregation in the brain in lysosomal storage disorders. Our findings support a mechanism involving lysosomal dysfunction more generally in the pathogenesis of PD.

Allelic variation of a functional polymorphism in the serotonin transporter gene and depression in Parkinson's disease.

A genetic susceptibility to depression in PD, acting via the serotonergic system, has been suggested. We examined the influence of allelic variation (L/S) in a functional polymorphism in the serotonin transporter (5-HTTLPR) gene upon mood in 108 PD patients and 82 controls. Using a logistic regression model we found no evidence for an association between 5-HTTLPR genotypes, or the presence of the S allele, and depression.

Executive dysfunction and attention contribute to gait interference in 'off' state Parkinson's Disease.

Motor and cognitive processes are required for successful 'real world' walking. We explored the specific contribution of motor function, executive function, and attention to functional gait performance in people with Parkinson's Disease (PD) when 'off' medication. Twenty-nine people with PD wearing an accelerometer were tested in their home whilst walking under four task conditions. Explanatory characteristics included age, motor function, executive function, sustained attention and divided attention. Repeated measures ANOVA compared gait speed under different task conditions. Multiple regression analysis explored the effect of characteristics on gait speed and gait interference (difference between dual and single task). Gait performance deteriorated under complex conditions (F=51.0, P<.001). Motor function and attention explained up to 65% variance in gait speed. Motor function, attention and executive function explained up to 66% variance in gait interference. Sustained attention explained up to 10% variance in gait speed; executive function explained up to 21% variance in gait interference and divided attention explained up to 22% variance in gait interference. Motor function, executive function and attention contribute to gait speed and gait interference in PD during a functional walking task whilst 'off' medication. When both executive function and attention are included as explanatory variables, attention discriminates gait performance more effectively. Whilst both contribute to functional gait, they are used selectively to optimise performance for different conditions and to meet complex task requirements.

Genetic variation of CHRNA4 does not modulate attention in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder, characterised by cognitive decline and attentional impairment. Recently, variation in CHRNA4 (rs1044396) has been shown to affect visual and auditory function, affecting speed and attention, in healthy adults. An association between CHRNA4 variation and PD has not been shown. To determine the link between CHRNA4 variation and attentional deficit in PD. A genotype-phenotype correlation between the common CHRNA4:rs1044396 variant and several baseline parameters of attention was carried out in a large cohort of PD cases (n=222) and controls (n=159). We identified significant associations to measures of attention in PD patients compared to controls. However, we found no significant link to CHRNA4:rs1044396 genotypes to baseline attention variables in PD or in controls. We conclude that CHRNA4:rs1044396 genotypes do not significantly influence the attentional deficit found in PD patients. Contrary to previous studies, we also found no significant influence in healthy age-matched controls.

Predicting the cost of Parkinson's disease.

The degenerative nature of Parkinson's disease (PD) suggests that it will lead to high levels of resource use. This study measures service use and costs for a representative community sample of PD patients and identifies cost predictors. Patients were identified from general practices and were interviewed twice, separated by a 12-month interval. Demographic and clinical data on patients were collected and 6-month costs were calculated. Regression analysis was used to identify significant baseline predictors of follow-up costs. The annual service costs (baseline and follow-up combined) were 13,804 pounds per person. Formal service costs accounted for 20% of this figure with informal care from families/friends accounting for 80%. The regression model explained 42% of total follow-up costs and significant predictors included gender (with men having higher costs), disability, and depression.

Clinical phenotype of subjects with Parkinson's disease and orthostatic hypotension: autonomic symptom and demographic comparison.

The objective of this study was to characterize the phenotypic associations of orthostatic hypotension (OH) in Parkinson's disease (PD). One hundred fifty-nine subjects with PD underwent assessment including autonomic symptom severity scoring, disease-specific rating scales, and measurement of postural blood pressure response. Symptoms of autonomic impairment weakly correlated with disease duration and severity. A posture and gait instability (PIGD) motor phenotype was associated with greater severity of autonomic symptoms. Eighty subjects (50.3%) had OH. These subjects were older, more likely to be male, and taking larger doses of dopaminergic medications than those without OH. There was no difference in disease severity or duration between those with and those without OH. Symptomatic dizziness did not distinguish between groups, although subjects with OH had more symptoms of generalized autonomic impairment than those without. Progressive autonomic involvement may be linked to disease progression in PD, particularly in patients with a PIGD phenotype, but dichotomization into groups with and without OH is a relatively insensitive method for demonstrating this. Longitudinal studies of changes in autonomic reflex abnormalities, autonomic symptom profiles, and motor severity might clarify these associations.

Orthostatic hypotension in Parkinson's disease: association with cognitive decline?

BACKGROUND: Orthostatic hypotension is common in Lewy body disorders and may be related to disease progression and the spread of Lewy body pathology. We therefore hypothesize that PD patients with orthostatic hypotension (OH) have a different cognitive profile compared to PD patients without OH. METHODS: This cross-sectional study included 175 PD patients. Blood pressure (BP) was measured with a validated digital blood pressure monitor and patients with a systolic BP drop of > or =20 mmHg or a systolic pressure of <90 mm Hg after standing were considered to have OH. Cognition was assessed using MMSE extended by a selection of computerized cognitive tests focusing on reaction time, sustained attention, working memory and episodic verbal and visual memory. RESULTS: Eighty-seven (49.7%) of the PD patients had OH. These patients were significantly more impaired in sustained attention and visual episodic memory compared to PD patients without OH. CONCLUSION: We conclude that there are differences in the neuropsychological performance of patients with PD and OH, supporting the hypothesis that OH might be a marker for disease progression and cognitive decline in PD.

Mitochondrial DNA haplogroup cluster UKJT reduces the risk of PD.

There is increasing evidence that genetic variants of mitochondrial DNA have an important role in the cause of idiopathic Parkinson's disease. We determined the mitochondrial DNA haplogroup of 455 Parkinson's disease cases, 185 Alzheimer's disease cases, and 447 healthy English control subjects. The UKJT haplogroup cluster was associated with a 22% reduction in population-attributable risk for Parkinson's disease. There was no association between individual haplogroups or the UKJT cluster and Alzheimer's disease, confirming that the association with Parkinson's disease was disease specific and not a general effect seen in all neurodegenerative diseases.