DNAJC13 p.Asn855Ser mutation screening in Parkinson's disease and pathologically confirmed Lewy body disease patients.

BACKGROUND: Recently, a novel mutation in exon 24 of DNAJC13 gene (p.Asn855Ser, rs387907571) has been reported to cause autosomal dominant Parkinson's disease (PD) in a multi-incident Mennonite family. METHODS: In the present study the mutation containing exon of the DNAJC13 gene has been sequenced in a Caucasian series consisting of 1938 patients with clinical PD and 838 with pathologically diagnosed Lewy body disease (LBD). RESULTS: Our sequence analysis did not identify any coding variants in exon 24 of DNAJC13. Two previously described variants in intron 23 (rs200204728 and rs2369796) were observed. CONCLUSION: Our results indicate that the region surrounding the DNAJC13 p.Asn855Ser substitution is highly conserved and mutations in this exon are not a common cause of PD or LBD among Caucasian populations.

SNCA, MAPT, and GSK3B in Parkinson disease: a gene-gene interaction study.

BACKGROUND AND PURPOSE: Recent evidence suggests that variation in the SNCA, MAPT, and GSK3B genes interacts in affecting risk for Parkinson disease (PD). In the current study, we attempt to validate previously published findings, evaluating gene-gene interactions between SNCA, MAPT, and GSK3B in association with PD. METHODS: Three Caucasian PD patient-control series from the United States, Ireland, and Norway (combined n = 1020 patients and 1095 controls) were genotyped for SNCA rs356219, MAPT H1/H2-discriminating SNP rs1052553, and GSK3B rs334558 and rs6438552. RESULTS: Our findings indicate that as previously reported, the SNCA rs356219-G allele and MAPT rs1052553 (H1 haplotype) were both associated with an increased risk of PD, whilst contrary to previous reports, GSK3B variants were not. No pair-wise interaction was observed between SNCA, MAPT, and GSK3B; the risk effects of SNCA rs356219-G and MAPT rs1052553-H1 were seen in a similar manner across genotypes of other variants, with no evidence suggesting synergistic, antagonistic, or deferential effects. CONCLUSIONS: In the Caucasian patient-control series examined, risk for PD was influenced by variation in SNCA and MAPT but not GSK3B. Additionally, those three genes did not interact in determining disease risk.

Death-associated protein kinase 1 variation and Parkinson's disease.

BACKGROUND AND PURPOSE: Mutations of the LRRK2 gene are now recognized as major risk factors for Parkinson's disease. The Lrrk2 protein is a member of the ROCO family, which also includes Lrrk1 and Dapk1. Functional genetic variants of the DAPK1 gene (rs4877365 and rs4878104) have been previously associated with Alzheimer's disease. METHODS: Herein, we assessed the role of DAPK1 variants (rs4877365 and rs4878104) in risk of Parkinson's disease with Sequenom iPLEX genotyping, employing one Taiwanese series (391 patients with Parkinson's disease, 344 controls) and five separate Caucasian series' (combined sample size 1962 Parkinson's disease patients, 1900 controls). RESULTS: We observed no evidence of association for rs4877365 and rs4878104 and risk of Parkinson's disease in any of the individual series or in the combined Caucasian series under either an additive or recessive model. CONCLUSION: These specific DAPK1 intronic variants do not increase the risk of Parkinson's disease. However, further functional studies are required to elucidate the potential therapeutic implications with the dimerization of the Dapk1 and Lrrk2 proteins.

Association of the MAPT locus with Parkinson's disease.

BACKGROUND AND PURPOSE: Whilst an association between the tau gene (MAPT)-containing H1 haplotype and supranuclear gaze palsy (PSP) has long been recognized, the effect of H1 on risk for Parkinson's disease (PD) has remained more contentious. METHODS: Herein, we examined the association of H1 and PD in three Caucasian PD patient-control series from Ireland, Norway, and the US (combined: n = 2619), by genotyping two H1/H2 single nucleotide polymorphisms (SNPs) in MAPT (rs1052553) and in the Saitohin gene (rs62063857) and one H1-specific SNP (rs242557). RESULTS: We identified a significant association between H1/H2 and risk of PD (rs1052553 OR: 1.43, CI: 1.23-1.64; rs62063857 OR: 1.45, CI: 1.27-1.67), but no effect of the H1-specific SNP rs242557 (OR: 0.92, CI: 0.82-1.03). CONCLUSIONS: Our findings show that the H1 haplotype is a significant risk factor for PD. However, one H1-specific SNP (rs242557) previously implicated in PSP did not alter the risk of PD, indicating that distinct H1 sub-haplotypes probably drive the associations with PD and PSP.

Calbindin-1 association and Parkinson's disease.

BACKGROUND AND PURPOSE: Calcium levels have been proposed to play an important role in the selective vulnerability of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). Recently, an association was reported between the calcium buffer, calbindin (rs1805874) and risk of PD in a Japanese patient-control series. METHODS: We genotyped rs1805874 in four independent Caucasian patient-control series (1543 PD patients, 1771 controls). RESULTS: There was no evidence of an association between rs1805874 and disease risk in individual populations or in the combined series (odds ratio: 1.04, 95% CI: 0.82-1.31, P = 0.74). DISCUSSION: Our study shows there is no association between rs1805874 and risk for PD in four Caucasian populations. This suggests the effect of calbindin on PD risk displays population specificity.

Neuroimaging Advances in Deep Brain Stimulation: Review of Indications, Anatomy, and Brain Connectomics.

Deep brain stimulation is an established therapy for multiple brain disorders, with rapidly expanding potential indications. Neuroimaging has advanced the field of deep brain stimulation through improvements in delineation of anatomy, and, more recently, application of brain connectomics. Older lesion-derived, localizationist theories of these conditions have evolved to newer, network-based "circuitopathies," aided by the ability to directly assess these brain circuits in vivo through the use of advanced neuroimaging techniques, such as diffusion tractography and fMRI. In this review, we use a combination of ultra-high-field MR imaging and diffusion tractography to highlight relevant anatomy for the currently approved indications for deep brain stimulation in the United States: essential tremor, Parkinson disease, drug-resistant epilepsy, dystonia, and obsessive-compulsive disorder. We also review the literature regarding the use of fMRI and diffusion tractography in understanding the role of deep brain stimulation in these disorders, as well as their potential use in both surgical targeting and device programming.

GRN 3'UTR+78 C>T is not associated with risk for Parkinson's disease.

BACKGROUND AND PURPOSE: A single nucleotide polymorphism in the 3'-untranslated region of the progranulin gene (GRN; 3'UTR+78C>T; rs5848) was reported to alter the risk for frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). rs5848 is located within a micro-RNA binding site and affects the expression of GRN. METHODS: As FTLD-U patients often present with parkinsonism, we investigated the association of GRN rs5848 and risk of Parkinson's disease in two Caucasian patient-control series (n = 1413) from the US and Poland. RESULTS: No association was observed between rs5848 and susceptibility to Parkinson's disease (individual series and combined analysis). CONCLUSIONS: This finding shows that GRN rs5848 does not affect the risk of Parkinson's disease in the US and Polish populations.

Medications used to treat Parkinson's disease and the risk of gambling.

Recent case-series studies indicated that a medication used to treat Parkinson's disease (PD), in particular Pramipexole, is associated with gambling. A case-series study cannot test this hypothesis; therefore, we need to design a case-control or cohort study to test the aforementioned hypothesis. Typical of a case-control design, we sampled on the dependent variable, which we defined as incident gambling in PD. A research neurologist, who was kept uninformed of the case-control status, retrospectively measured the exposure of interest (i.e. medications used to treat PD) by using the medical database system of Mayo Clinic Jacksonville. Eleven patients with PD without history of gambling, but had newly developed gambling, were matched by age and sex to the control group of 37 PD patients without gambling at a ratio of one case to at least three controls. Disease duration, age, and sex did not differ between cases and controls. Combined therapy with Pramipexole and levodopa did not increase the risk of gambling as compared to monotherapy with Pramipexole (OR, 0.15; 95% CI, 0.01-1.26). Treatment with Pramipexole was associated with increased risk of gambling and this association approached significance (OR, 3.6; 95% CI, 0.9-14.9). Patients with PD who newly developed gambling behavior were more likely to have been taking Pramipexole than other anti-PD medication. However, the association between Pramipexole and gambling behavior is not necessarily etiologic.

Correlation of outcome to neurosurgical lesions: confirmation of a new method using data after microelectrode-guided pallidotomy.

The purpose of this study was the development of a new method to correlate functional surgery with outcome measures. Lesions following microelectrode guided globus pallidus internus (GPi) pallidotomy for Parkinson's disease are presented to demonstrate this new method in regard to clinical outcome. A clinical series of 26 patients with extensive neurological and neuropsychological data were studied. Three-month postoperative MRI lesion borders at the AC-PC plane were scaled to a standard size, and the lesions were stored in a virtual array with a cell size of one voxel. The average outcome measure for each voxel is presented graphically. Unified Parkinson's disease rating scale (UPDRS) motor scores improved more with posterolateral and centrally located GPi lesions than with anteromedial lesions. A correlation of lesion location to outcome was also visible for subscales of the UPDRS. The distributions were similar for the left and right sides, as well as for ipsi- and contralateral measurements. In general, verbal fluency decreased after lesioning the dominant hemisphere, and posterolateral lesions caused less impairment. This method enables associative analyses between brain area and outcome down to the size of a few voxels. This may be particularly helpful for planning and validating neurosurgical targets for various disorders.

Clinical and genetic features of families with frontotemporal dementia and parkinsonism linked to chromosome 17 with a P301S tau mutation.

In 9 patients with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with a P301S tau mutation, the predominant phenotype was frontotemporal dementia in 3 and parkinsonism in 6. Comparison of the tau genotype/haplotype carrying the mutation and the initial clinical sign showed association between H1/H1 and parkinsonism and between H1/H2 and personality change. Thus, the tau haplotype carrying the mutation and the tau genotype may be related to the clinical phenotype throughout the disease course.

Essential tremor: predictors of disease progression in a clinical cohort.

OBJECTIVES: To examine the utility of baseline factors to predict disease progression among a clinical cohort of patients diagnosed with essential tremor. MEASURES: Tremor Rating Scale (TRS). METHODS: A clinical series of 128 consecutive patients diagnosed with essential tremor was included for study. 45 (35%) patients had at least one follow-up exam (mean = 3.6 years). Baseline predictive factors examined included age, age at onset of symptoms, disease duration, sex, handedness, total tremor rating score, asymmetric tremor ratings, location of initial tremor onset, use of drugs for movement disorders, ETOH responsiveness of tremor, association of head or neck tremor, history of depression, familial history of essential tremor, Parkinson's disease, Alzheimer's disease and other movement disorders. RESULTS: On average, the TRS total score increased by <1 point per year before the first visit to the clinic and by about 2 points per year during the observed study period. The increase of 2 points per year during the observed study period represented an approximate 12% annual change from the mean TRS total score at the first clinic visit. Significant (p<0.05) predictive factors associated with increased tremor severity at the initial clinic visit included older age, longer disease duration, use of movement disorder drugs and the presence of voice tremor (r = 0.24, 0.27, 0.25, 0.19). The major factors associated with an increase in tremor severity from the initial clinic visit to the last follow up included asymmetrical tremor ratings, unilateral initial tremor onset and longer follow-up duration (r = 0.32, 0.31, 0.30). Multivariate regression analysis accounted for about 17-30% of the variance in tremor ratings (p<0.05). CONCLUSION: Essential tremor is a slow, progressive disease. The rate of disease progression and the factors associated with disease progression may vary throughout the disease course.

Concerning neuroprotective therapy for Parkinson's disease.

Studying potential neuroprotective therapy for Parkinson's disease is conceptually problematic because of the heterogenous nature of the Parkinson's syndrome and complexities in operational definitions for neuroprotection. The current literature concerning neuroprotection provides no convincing evidence of any treatment as definitively neuroprotective in Parkinson's disease. Recent clinical trials and novel trial designs are reviewed that may identify meaningful therapy, resulting in maintenance of neurological function and quality of life for persons with Parkinson's disease.

Clinical and pathologic features of families with LRRK2-associated Parkinson's disease.

The etiology for Parkinson's disease (PD) remains unknown. Genetic causes have been identified with several distinct mutations. Recently, 9 mutations involving a novel gene, leucine-rich repeat kinase 2 (LRRK2), have been identified as the cause of autosomal dominant PD in kindreds, with some of them previously linked to the PARK8 locus on chromosome 12. LRRK2 mutations are relatively common genetic causes of familial and sporadic PD. In addition, these mutations have been identified in diverse populations. The clinical and pathologic features of LRRK2-associated PD are indistinguishable from idiopathic PD; however, considerable clinical and pathologic variability exists even among kindreds. This short review highlights the clinical and pathologic features in LRRK2-associated parkinsonism.

Familial oculoleptomeningeal amyloidosis. Report of a new family with unusual features.

A family had a dominantly inherited amyloid angiopathy that involved the meninges of the brain and spinal cord, retina, vitreous humor, peripheral nerves, and systemic organs. Clinical features included hemiplegic migraine, periodic obtundation, psychosis, seizures, intracerebral hemorrhage, myelopathy, visual impairment, deafness, and peripheral neuropathy. Pathological findings consisted of amyloid deposition in the leptomeningeal and retinal vessels, in the vitreous humor, and in perivascular tissue throughout the body. Evaluation of the amyloid showed it to be a transthyretin (prealbumin). A brief course of plasmapheresis produced a short-lived decrease concentration in circulating transthyretin.

Oculoleptomeningeal amyloidosis associated with a new transthyretin variant Ser64.

BACKGROUND: A Canadian family with oculoleptomeningeal amyloidosis with both central and peripheral nervous system disorders was described in 1988. Death of affected family members resulted from recurrent cerebral hemorrhage. OBJECTIVE: To determine if oculoleptomeningeal amyloidosis is caused by a mutation in transthyretin (prealbumin). METHODS: DNA isolated from peripheral blood and archival tissues of affected members of the kindred was studied by direct DNA sequencing and restriction fragment length polymorphism analysis. RESULTS: Direct DNA sequencing identified a thymine-to-cytosine transition at the second base of codon 64, which resulted in a replacement of serine for phenylalanine. This mutation, which creates an additional HinfI site was detected by restriction fragment length polymorphism analysis in each affected individual. CONCLUSION: In this kindred, oculoleptomeningeal amyloidosis is related to a mutation in transthyretin (Phe64Ser).

Efficacy of levodopa therapy on motor function after posteroventral pallidotomy for Parkinson's disease.

We evaluated motor function in 41 consecutive PD patients undergoing unilateral MRI/microelectrode-guided posteroventral pallidotomy to determine whether the motor effects of levodopa therapy change after surgery. Total Unified Parkinson's Disease Rating Scale motor "off" and motor "on" subscores all improved and the rapidity of action, magnitude, and duration of motor response to levodopa therapy were all maintained after pallidotomy.

Cyanide-induced parkinsonism: a clinicopathologic report.

An 18-year-old man ingested 975 to 1,300 mg of potassium cyanide in a suicide attempt. He was treated and survived the poisoning episode, but then had severe parkinsonian syndrome, characterized primarily by akinesia and rigidity. He died 19 months after the drug overdose. At autopsy, major destructive changes were found in the globus pallidus and putamen, whereas the melanin-containing zone of substantia nigra was intact. This is the first clinicopathologic report of parkinsonism as a result of cyanide poisoning.

Thalamic stimulation for the treatment of midline tremors in essential tremor patients.

The authors prospectively collected unblinded data from 27 consecutive patients following thalamic stimulation. A significant reduction of midline tremor was achieved after unilateral surgery, but a staged contralateral surgery had an additional effect. A subgroup analysis showed significant beneficial effects for head, voice, tongue, and face tremor. The most frequent reversible side effects were disequilibrium, dysarthria, and paresthesias. We observed more pulse generator adjustments for speech problems in the bilaterally implanted group.

Levodopa and deprenyl treatment effects on peripheral indices of oxidant stress in Parkinson's disease.

The oxidant stress theory of Parkinson's disease (PD) hypothesizes that levodopa treatment may be potentially harmful and this is supported by studies demonstrating levodopa toxicity to cultured dopaminergic neurons. These in vitro experiments, however, lack the physiologic protective mechanisms present in vivo. Oxyradical damage to cell membranes liberates malondialdehyde, which we measured in the serum of 27 PD patients just before and after levodopa (with carbidopa) administration. We also measured plasma products of the two routes by which levodopa potentially generated oxyradicals: (1) 5-S-cysteinyl-dopa (derived from levodopa autoxidation), and (2) 3,4-dihydroxyphenylacetic acid (DOPAC), produced by monoamine oxidase (MAO) metabolism of dopamine. Following levodopa/carbidopa administration, both of these plasma products were markedly increased; however, the mean serum malondialdehyde concentration was unchanged and remained similar to the normal control group (N=15) value. Chronic treatment with the MAO-B inhibitor, deprenyl (N=16), was not associated with any differences in serum malondialdehyde or plasma 5-S-cysteinyl-dopa concentrations compared with those not treated with deprenyl (N=11). The post-levodopa rise of plasma DOPAC was only slightly attenuated with deprenyl therapy, consistent with a predominant MAO-A effect in the circulation and peripheral organs. Thus, in contrast to in vitro studies, we did not detect evidence of oxidative damage in the circulation following levodopa administration, despite marked increase in the products of dopamine oxidative metabolism.

Hereditary late-onset chorea without significant dementia: genetic evidence for substantial phenotypic variation in Huntington's disease.

We examined five individuals and obtained information concerning six other members from two unrelated families, nearly all of whom developed chorea after age 50 (one patient developed chorea at age 40). The severity of chorea progressed in all patients and became disabling in some individuals approximately 15 years after onset. Cognitive impairment was absent or minimal. All five examined patients were cognitively normal, even 10 to 30 years following the onset of chorea. Formal neuropsychometric testing demonstrated mild cognitive impairment in two individuals. Nevertheless, all patients were able to maintain employment or carry on with their usual household tasks until chorea was severe. One individual first became demented 30 years after the onset of chorea. Neuroimaging (with CT or MRI) in four patients failed to demonstrate significant caudate or putaminal atrophy 8 to 15 years following the onset of chorea. Three other family members (who were not available for examination) were said to have suffered chorea (without any mental decline) beginning after age 50, with subsequent survival of 20 years (in one) and 30 years (in two). Given this constellation of history and findings, three experienced neurologists and two medical geneticists concluded that these patients had a familial chorea syndrome distinct from Huntington's disease (HD). However, genetic analysis of the trinucleotide (CAG) repeat length associated with HD (in 4p16.3) determined repeat lengths of 44 and 46 in four patients tested (within the HD range). We conclude that these patients have HD and that such families represent further convincing examples of significant phenotypic variation for HD.