The development of biomarkers for the diagnosis and monitoring disease progression in Parkinson's disease (PD) is of great importance since diagnosis based on clinical parameters has a considerable ...error rate. In this study, we utilized metabolomic profiling using high performance liquid chromatography coupled with electrochemical coulometric array detection (LCECA) to look for biomarkers in plasma useful for the diagnosis of PD. We examined 25 controls and 66 PD patients. We also measured 8-hydroxy-2-deoxyguanosine (8-OHdG) levels as a marker of oxidative damage to DNA. We initially examined the profiles of unmedicated PD subjects compared to controls to rule out confounding effects of symptomatic medications. We found a complete separation of the two groups. We then determined the variables, which played the greatest role in separating the two groups and applied them to PD subjects taking dopaminergic medications. Using these parameters, we achieved a complete separation of the PD patients from controls. 8-OHdG levels were significantly increased in PD patients, but overlapped controls. Two other markers of oxidative damage were measured in our LCECA profiles. Uric acid was significantly reduced while glutathione was significantly increased in PD patients. These findings show that metabolomic profiling with LCECA coulometric array has great promise for developing biomarkers for both the diagnosis, as well as monitoring disease progression in PD.
To evaluate the safety and efficacy of 60 Hz deep brain stimulation (DBS) of the globus pallidus internus (GPi) in 15 consecutive patients with primary dystonia.
We conducted a retrospective analysis ...of clinic charts relative to 15 consecutive patients with medically refractory primary dystonia who underwent stereotactic implantation of DBS leads within the GPi. Twelve had the DYT1 gene mutation. Frame-based MRI and intraoperative microelectrode recording were employed for targeting. All patients were treated exclusively with stimulation at 60 Hz from therapy outset. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) served as the primary measure of symptom severity at baseline and 1, 3, 6, and 12 months after treatment.
All patients tolerated DBS treatment well and showed a progressive median improvement of their BFMDRS motor subscores from 38% at 1 month to 89% at 1 year (p < 0.001, Wilcoxon rank sum test). The disability subscores were similarly improved. The clinical response to DBS allowed seven patients to completely discontinue their medications; six additional patients had reduced their medications by at least 50%. Surgical complications were limited to two superficial infections, which were treated successfully.
Stimulation of the internal globus pallidus at 60 Hz is safe and effective for treating medically refractory primary dystonia.
To compare the phenotype of primary-appearing dystonia due to variant ataxia-telangiectasia (A-T) with that of other dystonia ascertained for genetics research.
Movement disorder specialists examined ...20 Canadian Mennonite adult probands with primary-appearing dystonia, as well as relatives in 4 families with parent-child transmission of dystonia. We screened for the exon 43 c.6200 C>A (p. A2067D) ATM mutation and mutations in DYT1 and DYT6. Clinical features of the individuals with dystonia who were harboring ATM mutations were compared with those of individuals without mutations.
Genetic analysis revealed a homozygous founder mutation in ATM in 13 members from 3 of the families, and no one harbored DYT6 or DYT1 mutations. Dystonia in ATM families mimicked other forms of early-onset primary torsion dystonia, especially DYT6, with prominent cervical, cranial, and brachial involvement. Mean age at onset was markedly younger in the patients with variant A-T (n = 12) than in patients with other dystonia (n = 23), (12 years vs 40 years, p < 0.05). The patients with A-T were remarkable for the absence of notable cerebellar atrophy on MRI, lack of frank ataxia on examination, and absence of ocular telangiectasias at original presentation, as well as the presence of prominent myoclonus-dystonia in 2 patients. Many also developed malignancies.
Ataxia and telangiectasias may not be prominent features of patients with variant A-T treated for dystonia in adulthood, and variant A-T may mimic primary torsion dystonia and myoclonus-dystonia.
To test the hypothesis that there is familial aggregation of dystonia and other movement disorders in relatives of patients with musician's dystonia (MD) and to identify possible environmental ...triggers.
The families of 28 index patients with MD (14 with a reported positive family history of focal task-specific dystonia FTSD and 14 with no known family history FH-) underwent a standardized telephone screening interview using a modified version of the Beth Israel Dystonia Screen. Videotaped neurologic examinations were performed on all participants who screened positive and consensus diagnoses established. All patients were investigated for DYT1 dystonia and suitable families were tested for linkage to DYT7. All family members were administered questionnaires covering potential triggers of FTSD.
A diagnosis of dystonia was established in all 28 index patients and in 19/97 examined relatives (MD: n = 8, other FTSD: n = 9, other dystonias: n = 2), 5 of whom were members of FH- families. In 27 of the 47 affected individuals, additional forms of dystonia were seen; other movement disorders were observed in 23 patients. In total, 18 families were multiplex families with two to four affected members. Autosomal dominant inheritance was compatible in at least 12 families. The GAG deletion in DYT1 was absent in all patients. Linkage to DYT7 could be excluded in 1 of the 11 informative families. With respect to potential environmental triggers, there was no significant difference between patients with MD/FTSD compared to unaffected family members.
Our results suggest a genetic contribution to musician's dystonia with phenotypic variability including focal task-specific dystonia.
Olfactory dysfunction is an established nonmotor feature of idiopathic Parkinson disease (PD), which may precede disease onset. Olfaction is likely disturbed in patients with PD with leucine-rich ...repeat kinase (LRRK2) G2019S mutations, although the degree of impairment is debated. It is also unclear whether mutation carriers who have not yet manifested with PD have olfactory disturbances.
Thirty-one subjects with LRRK2 G2019S mutation-related PD (PD-manifesting carriers PD-MC), 30 subjects with PD without mutations (PD noncarriers PD-NC), 28 mutation carrier family members (nonmanifesting carriers NMC), and 46 controls completed the University of Pennsylvania Smell Identification Test (UPSIT). Generalized estimating equations were applied to determine whether olfactory score was associated with PD and LRRK2 mutation status.
As expected, having PD was associated with impaired olfaction regardless of LRRK2 mutation status. More importantly, however, impaired olfaction was increased overall in LRRK2 carriers both with and without PD, though the impairment was only present in a subset of NMCs. Compared to controls, the mean score was lower among NMC (difference = -3.518, p = 0.006), MC (difference = -7.677, p < 0.0001), and idiopathic PD (PD-NC) (difference = -13.810, p < 0.0001). Olfaction was better among MC (PD-MC) than non-LRRK2 PD (PD-NC) (difference = 6.13, p = 0.0012). Group differences from the continuous analysis were maintained in dichotomous analysis stratifying at 15th percentile for age and gender.
Olfaction is impaired in LRRK2 G2019S-mutation related PD, although less overall than other PD. Further, olfaction is impaired in a subset of LRRK2 NMC, suggesting that olfaction may be a marker for development of PD in this group, and that longitudinal studies are warranted.
To assess the cognitive phenotype of glucocerebrosidase (GBA) mutation carriers with early-onset Parkinson disease (PD).
We administered a neuropsychological battery and the University of ...Pennsylvania Smell Identification Test (UPSIT) to participants in the CORE-PD study who were tested for mutations in PARKIN, LRRK2, and GBA. Participants included 33 GBA mutation carriers and 60 noncarriers of any genetic mutation. Primary analyses were performed on 26 GBA heterozygous mutation carriers without additional mutations and 39 age- and PD duration-matched noncarriers. Five cognitive domains, psychomotor speed, attention, memory, visuospatial function, and executive function, were created from transformed z scores of individual neuropsychological tests. Clinical diagnoses (normal, mild cognitive impairment MCI, dementia) were assigned blind to genotype based on neuropsychological performance and functional impairment as assessed by the Clinical Dementia Rating (CDR) score. The association between GBA mutation status and neuropsychological performance, CDR, and clinical diagnoses was assessed.
Demographics, UPSIT, and Unified Parkinson's Disease Rating Scale-III performance did not differ between GBA carriers and noncarriers. GBA mutation carriers performed more poorly than noncarriers on the Mini-Mental State Examination (p = 0.035), and on the memory (p = 0.017) and visuospatial (p = 0.028) domains. The most prominent differences were observed in nonverbal memory performance (p < 0.001). Carriers were more likely to receive scores of 0.5 or higher on the CDR (p < 0.001), and a clinical diagnosis of either MCI or dementia (p = 0.004).
GBA mutation status may be an independent risk factor for cognitive impairment in patients with PD.
To determine whether reduced striatal D2 receptor binding reported in patients with idiopathic torsion dystonia is associated with the genotype, the authors used PET and 11C-raclopride to assess ...non-manifesting carriers of the DYT1 mutation. D2 receptor binding was reduced by approximately 15% in caudate and putamen (p < 0.005). These results suggest that striatal D2 binding reductions are a trait feature of the DYT1 genotype.
To determine whether changes in D(2) receptor availability are present in carriers of genetic mutations for primary dystonia.
Manifesting and nonmanifesting carriers of the DYT1 and DYT6 dystonia ...mutations were scanned with (11)C raclopride (RAC) and PET. Measures of D(2) receptor availability in the caudate nucleus and putamen were determined using an automated region-of-interest approach. Values from mutation carriers and healthy controls were compared using analysis of variance to assess the effects of genotype and phenotype. Additionally, voxel-based whole brain searches were conducted to detect group differences in extrastriatal regions.
Significant reductions in caudate and putamen D(2) receptor availability were evident in both groups of mutation carriers relative to healthy controls (p < 0.001). The changes were greater in DYT6 relative to DYT1 carriers (-38.0 +/- 3.0% vs -15.0 +/- 3.0%, p < 0.001). By contrast, there was no significant difference between manifesting and nonmanifesting carriers of either genotype. Voxel-based analysis confirmed these findings and additionally revealed reduced RAC binding in the ventrolateral thalamus of both groups of mutation carriers. As in the striatum, the thalamic binding reductions were more pronounced in DYT6 carriers and were not influenced by the presence of clinical manifestations.
Reduced D(2) receptor availability in carriers of dystonia genes is compatible with dysfunction or loss of D(2)-bearing neurons, increased synaptic dopamine levels, or both. These changes, which may be present to different degrees in the DYT1 and DYT6 genotypes, are likely to represent susceptibility factors for the development of clinical manifestations in mutation carriers.
► We compared sex differences in family history in 175 Jewish Parkinson disease (PD) subjects. ► Parents of PD daughters had an increased risk of parkinsonism (HR 2.59,
p
=
0.014). ► Adjusting for
...LRRK2 G2019S mutations, the increased risk among parents of PD women persisted (HR 2.19,
p
=
0.023). ► Even accounting for LRRK2 mutations, women with PD have a greater relative genetic load.
G2019S mutations in the
LRRK2 gene are responsible for up to 18% of PD in individuals of Jewish descent. While a male preponderance of Parkinson disease (PD) has been consistently reported, this gender difference is not noted in
LRRK2 G2019S mutation carriers. In order to test whether there is an increased genetic component in women of Jewish background in general, we examined family history of parkinsonism in 175 Jewish PD patients (82 female and 93 male) and assessed whether parkinsonism was more frequent in family members of women with PD in comparison with family members of men with PD, adjusting for
LRRK2 G2019S mutations in the proband. Using Cox proportional hazard models to evaluate the risk of parkinsonism among family members of PD subjects, having a daughter with PD compared with a son was associated with increased risk of parkinsonism in the parent (HR 2.59,
p
=
0.014) as was having a child with a
LRRK2 G2019S mutation (HR 3.19,
p
=
0.003). The increased risk among parents of women with PD persisted when adjusting for
LRRK2 status (HR 2.19,
p
=
0.023). Among individuals of Jewish descent, there is a relatively greater genetic load in women with PD, and this is not fully accounted for by the G2019S mutation. Further study that evaluates family information bias and assesses the role of glucocerebrosidase mutations is indicated.
To develop diagnostic testing guidelines for the DYT1 GAG deletion in the Ashkenazi Jewish (AJ) and non-Jewish (NJ) primary torsion dystonia (PTD) populations and to determine the range of dystonic ...features in affected DYT1 deletion carriers.
The authors screened 267 individuals with PTD; 170 were clinically ascertained for diagnosis and treatment, 87 were affected family members ascertained for genetic studies, and 10 were clinically and genetically ascertained and included in both groups. We used published primers and PCR amplification across the critical DYT1 region to determine GAG deletion status. Features of dystonia in clinically ascertained (affected) DYT1 GAG deletion carriers and noncarriers were compared to determine a classification scheme that optimized prediction of carriers. The authors assessed the range of clinical features in the genetically ascertained (affected) DYT1 deletion carriers and tested for differences between AJ and NJ patients.
The optimal algorithm for classification of clinically ascertained carriers was disease onset before age 24 years in a limb (misclassification, 16.5%; sensitivity, 95%; specificity, 80%). Although application of this classification scheme provided good separation in the AJ group (sensitivity, 96%; specificity, 88%), as well as in the group overall, it was less specific in discriminating NJ carriers from noncarriers (sensitivity, 94%; specificity, 69%). Using age 26 years as the cut-off and any site at onset gave a sensitivity of 100%, but specificity decreased to 54% (63% in AJ and 43% in NJ). Among genetically ascertained carriers, onset up to age 44 years occurred, although the great majority displayed early limb onset. There were no significant differences between AJ and NJ genetically ascertained carriers, except that a higher proportion of NJ carriers had onset in a leg, rather than an arm, and widespread disease.
Diagnostic DYT1 testing in conjunction with genetic counseling is recommended for patients with PTD with onset before age 26 years, as this single criterion detected 100% of clinically ascertained carriers, with specificities of 43% to 63%. Testing patients with onset after age 26 years also may be warranted in those having an affected relative with early onset, as the only carriers we observed with onset at age 26 or later were genetically ascertained relatives of individuals whose symptoms started before age 26 years.
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