Michele L. Rajput

Course in Parkinson disease subtypes: A 39-year clinicopathologic study

Background: Individual variations in the course of Lewy body Parkinson disease (PD) are well known. Patients have been classified into different clinical subtypes to identify differences in the course among the subgroups. Several studies indicate that the outcome is more favorable in tremor dominant (TD) cases but others report no difference. A majority of progression studies are based on cross-sectional single point data or short-term clinical observations. The lack of longitudinally followed autopsy-confirmed PD cohort remains a major weakness in the literature. Biochemical studies of brain indicate most pronounced abnormalities in akinetic/rigid (AR) and the least in TD cases. We postulate that PD course in these subtypes is concordant with the biochemical findings. Objective: To compare the course in TD, mixed (MX), and AR subtypes of PD. Methods: Longitudinal clinical follow-up and autopsy studies were performed on 166 patients with PD over 39 years (1968–2006). Patients were classified into TD, AR, and MX based on the entire clinical course. Only the pathologically confirmed PD cases were included. Results: Sixty-six percent of cases had MX, 26% AR, and 8% TD profile. The age at onset was younger (p < 0.001) and progression to Hoehn & Yahr stage 4 was slower (p = 0.016) in the TD cases. Dementia was most common in AR (p = 0.039) and the least common in TD. In general, the course was most favorable in TD, followed by MX and AR subgroups. Conclusion: The three subtypes of Parkinson disease have different courses which are concordant with the differences in brain biochemical abnormalities.

Parkinsonism, Lrrk2 G2019S, and tau neuropathology.

Lrrk2 G2019S is predominantly associated with α-synuclein–immunopositive Lewy body pathology. We have identified Family SK where Lrrk2 G2019S segregates with slowly progressive parkinsonism and the affected proband has tau-immunopositive neurofibrillary tangle pathology. Thus α-synucleinopathy and tauopathy, the predominant pathologies associated with parkinsonism, may be alternate outcomes of the same underlying genetic cause. Intriguingly, we observe no evidence of a direct interaction between either the tau or α-synuclein protein with Lrrk2.

DNAJC13 mutations in Parkinson disease

A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case-control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA. A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation, of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch-German-Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows that the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions. In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor-sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2 and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.

A Randomized, Double-Blind Placebo-Controlled Trial of Iron in Restless Legs Syndrome

Background: Previous open-label trials have shown iron to be efficacious in the treatment of restless legs syndrome. We performed a randomized, double-blind, placebo-controlled trial of iron sulfate. Methods: Twenty-eight patients were randomized to receive either ferrous sulfate 325 mg b.i.d. or placebo for 12 weeks. The primary outcome measure was the dichotomous variable of improvement or no improvement in average quality of sleep as recorded by a visual analog scale nightly over a 2-week period, comparing a pretreatment 2-week baseline to weeks 13–14. Secondary outcome measures included a comparison of the quality of sleep as measured by a visual analog scale, effect of restless legs syndrome on life as a whole as measured by a different visual analog scale, and the percentage of nights patients were symptomatic. Results: No significant differences were noted between iron and placebo groups for both primary and secondary outcome measures. Responders taking iron did have a significant increase in their iron saturation compared to nonresponders taking iron. Conclusions: Iron sulfate does not appear to be an effective empiric treatment for restless legs syndrome.

Mirror aneurysms: a reflection on natural history

OBJECT Investigators conducting the International Study of Unruptured Intracranial Aneurysms, sponsored by the National Institutes of Health, sought to evaluate predictors of future hemorrhage in patients who had unruptured mirror aneurysms. These paired aneurysms in bilateral arterial positions mirror each other; their natural history is unknown. METHODS Centers in the US, Canada, and Europe enrolled patients for prospective assessment of unruptured intracranial aneurysms. Central radiological review confirmed the presence or absence of mirror aneurysms in patients without a history of prior subarachnoid hemorrhage (SAH) (Group 1). Outcome at 1 and 5 years and aneurysm characteristics are compared. RESULTS Of 3120 patients with aneurysms treated in 61 centers, 376 (12%) had mirror aneurysms, which are more common in women than men (82% [n = 308] vs 73% [n = 1992], respectively; p <0.001) and in patients with a family history of aneurysm or SAH (p <0.001). Compared with patients with nonmirror saccular aneurysms, a greater percentage of patients with mirror aneurysms had larger (>10 mm) aneurysms (mean maximum diameter 11.7 vs 10.4 mm, respectively; p <0.001). The most common distribution for mirror aneurysms was the middle cerebral artery (34% [126 patients]) followed by noncavernous internal carotid artery (32% [121]), posterior communicating artery (16% [60]), cavernous internal carotid artery (13% [48]), anterior cerebral artery/anterior communicating artery (3% [13]), and vertebrobasilar circulation (2% [8]). When these patients were compared with patients without mirror aneurysms, no statistically significant differences were found in age (mean age 54 years in both groups), blood pressure, smoking history, or cardiac disease. Aneurysm rupture rates were similar (3.0% for patients with mirror aneurysms vs 2.8% for those without). CONCLUSIONS Overall, patients with mirror aneurysms were more likely to be women, to report a family history of aneurysmal SAH, and to have larger aneurysms. The presence of a mirror aneurysm was not an independent predictor of future SAHs.

Alpha‐synuclein polymorphisms are associated with Parkinson's disease in a Saskatchewan population

Alpha‐synuclein gene (SNCA) mutations cause familial Parkinsonism but the role of SNCA variability in idiopathic Parkinsons disease (PD) remains incompletely defined. We report a study of SNCA genetic variation in 452 idiopathic PD cases and 245 controls. SNCA copy number mutations were not associated with early‐onset disease in this population. The minor allele “G” at rs356165 was associated with increased odds of PD (P = 0.013) and genetic variation in D4S3481 (Rep1) was associated with age of disease onset (P = 0.007). There was a trend toward association between variation at rs2583988 and rapid PD progression.

Clinical features at first visit and rapid disease progression in Parkinson's disease.

We report a retrospective multivariable analysis of the association between patient characteristics at first clinic visit and rapid disease progression in 1411 Parkinsons disease patients treated between 1985 and 2006. At first visit rapid progression was positively associated with age at onset > or = 70 years (OR=5.77), rigidity (OR=1.94), bradykinesia (OR=1.73), dementia (OR=2.61), and levodopa use (OR=1.74). Rapid progression was negatively associated with disease duration (OR=0.52), male sex (OR=0.49), and resting tremor at first visit (OR=0.44). Family history of movement disorders, while significant for univariable analysis, did not retain significance in multivariable analysis. This initial clinical profile may aid physicians in adjusting treatment and follow-up plans. Further prospective studies are needed to evaluate this relationship.

Phactr2 and Parkinson's disease

Attempts at replicating the first genome-wide association study (GWAS) in Parkinsons disease (PD) have not successfully identified genetic risk factors. The present study reevaluates data from the first GWAS and focuses on the SNP (rs11155313, located in the Phactr2 gene) with the lowest P-value in the Tier 2 patient-control series. We employed four case-control series to examine the nominated SNP rs11155313 and identified association in US (OR: 1.39, P=0.032), Canadian (OR: 1.41, P=0.014) and Irish (OR: 1.44, P=0.034) patient-control series, but not in the Norwegian series (OR: 1.15, P=0.27). When combining all four series the observed trend was statistically significant (OR: 1.30, P<0.001). This study shows that reappraisal of publicly available results of GWAS may help nominate new risk factors for PD.

SLC1A2 rs3794087 does not associate with essential tremor

A recent genome-wide association study of patients with essential tremor (ET) from Germany has nominated SLC1A2 rs3794087 as a novel risk factor for disease. This association was independently replicated in the Chinese population, albeit with an opposite direction of effect. To further define the role of SLC1A2 in ET, we genotyped rs3794087 in a North American series consisting of 1347 patients with ET and controls. Statistical analysis did not identify significant differences in genotype or allele frequencies between healthy controls and patients with ET (p > 0.36). These findings therefore do not support a role for SLC1A2 rs3794087 in susceptibility to ET in the North American population. Further studies in ethnically distinct populations of patients with ET are necessary to understand whether genetic variability in SLC1A2 affects disease risk for ET.

Baseline motor findings and Parkinson disease prognostic subtypes

Objective: To identify the significance of baseline motor features to the lifelong prognostic motor subtypes in a Parkinson disease (PD) cohort. Methods: In a previous study of 166 PD cases, we observed different prognosis in tremor-dominant, akinetic-rigid, and mixed subtypes. This study includes the same cases, but we excluded 10 cases with symptoms of ≥15 years duration at baseline. Relative severity of tremor, bradykinesia/akinesia, and rigidity at baseline were evaluated as predictors of the motor subtypes, which are known to have different prognosis. Results: The most common motor subtype was mixed, followed by akinetic-rigid and then the tremor-dominant. Seventy cases were not receiving antiparkinsonian drugs at baseline. The prognostic subtypes could be predicted at baseline in 85% of all and in 91% of the treatment-naive cases. Sensitivity, specificity, and positive predictive values were strong for the mixed and the akinetic-rigid but weak for the tremor-dominant subtype. Conclusions: Our data show that motor profile at baseline can predict prognosis in most PD cases. These findings can be incorporated into clinical practice.