Stuttering is a speech disorder with disruption of verbal fluency which is occasionally present in patients with Parkinson's disease (PD). Long-term medical management of PD is frequently complicated ...by fluctuating motor functions and dyskinesias. High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment of motor fluctuations and is the most common surgical procedure in PD. Here we report the re-occurrence and aggravation of stuttering following STN-DBS in two male patients treated for advanced PD. In both patients the speech fluency improved considerably when the neurostimulator was turned off, indicating that stuttering aggravation was related to neurostimulation of the STN itself, its afferent or efferent projections and/or to structures localized in the immediate proximity. This report supports previous studies demonstrating that lesions of the basal ganglia-thalamocortical motor circuit, including the STN, is involved in the development of stuttering. In advanced PD STN-DBS is generally an effective and safe treatment. However, patients with PD and stuttering should be informed about the risk of aggravated symptoms following surgical therapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Parkinson’s disease (PD) and schizophrenia (SCZ) are heritable brain disorders that involve dysregulation of the dopaminergic system. Epidemiological studies have reported potential comorbidity ...between the disorders, and movement disturbances are common in patients with SCZ before treatment with antipsychotic drugs. Despite this, little is known about shared genetic etiology between the disorders.
We analyzed recent large genome-wide association studies on patients with SCZ (N = 77,096) and PD (N = 417,508) using a conditional/conjunctional false discovery rate (FDR) approach to evaluate overlap in common genetic variants and improve statistical power for genetic discovery. Using a variety of biological resources, we functionally characterized the identified genomic loci.
We observed genetic enrichment in PD conditional on associations with SCZ and vice versa, indicating polygenic overlap. We then leveraged this cross-trait enrichment using conditional FDR analysis and identified 9 novel PD risk loci and 1 novel SCZ locus at conditional FDR < .01. Furthermore, we identified 9 genomic loci jointly associated with PD and SCZ at conjunctional FDR < .05. There was an even distribution of antagonistic and agonistic effect directions among the shared loci, in line with the insignificant genetic correlation between the disorders. Of 67 genes mapped to the shared loci, 65 are expressed in the human brain and show cell type–specific expression profiles.
Altogether, the study increases understanding of the genetic architectures underlying SCZ and PD, indicating that common molecular genetic mechanisms may contribute to overlapping pathophysiological and clinical features between the disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background and objectives: Autosomal recessive spinocerebellar ataxia-13 (SCAR13) is an ultra-rare disorder characterized by slowly progressive cerebellar ataxia, cognitive deficiencies, and skeletal ...and oculomotor abnormalities. The objective of this case report is to expand the clinical and molecular spectrum of SCAR13. Methods: We investigated a consanguineous Pakistani family with four patients partially presenting with clinical features of SCAR13 using whole exome sequencing. Segregation analysis was performed by Sanger sequencing in all the available individuals of the family. Results: Patients presented with quadrupedal gait, delayed developmental milestones, non-progressive peripheral neuropathy, and cognitive impairment. Whole exome sequencing identified a novel pathogenic nonsense homozygous variant, Gly240*, in the gene GRM1 as a cause of SCAR13 that segregates with the recessive disease. Discussion: We report a novel homozygous nonsense variant in the GRM1 gene in four Pakistani patients presenting with clinical features that partially overlap with the already reported phenotype of SCAR13. In addition, the family presented quadrupedal gait and non-progressive symptoms, manifestations which have not been recognized previously. So far, only four variants in GRM1 have been reported, in families of Roma, Iranian, and Tunisian origins. The current study adds to the mutation spectrum of GRM1 and provides a rare presentation of SCAR13, the first from the Pakistani population.
Autosomal dominant parkinsonism has been attributed to pathogenic amino acid substitutions in leucine-rich repeat kinase 2 (LRRK2). By sequencing multiplex families consistent with a
PARK8 ...assignment, we identified a novel heterozygous
LRRK2 mutation. A referral sample of 248 affected probands from families with autosomal dominant parkinsonism was subsequently assessed; 7 (2.8%) were found to carry a heterozygous
LRRK2 6055G→A transition (G2019S). These seven patients originate from the United States, Norway, Ireland, and Poland. In samples of patients with idiopathic Parkinson disease (PD) from the same populations, further screening identified six more patients with
LRRK2 G2019S; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 have an
LRRK2 G2019S substitution, 7 with a diagnosis of PD. Of note, all patients share an ancestral haplotype indicative of a common founder, and, within families,
LRRK2 G2019S segregates with disease (multipoint LOD score 2.41). Penetrance is age dependent, increasing from 17% at age 50 years to 85% at age 70 years. In summary, our study demonstrates that
LRRK2 G2019S accounts for parkinsonism in several families within Europe and North America. Our work highlights the fact that a proportion of clinically typical, late-onset PD cases have a genetic basis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cognitive decline and dementia are common and debilitating non-motor phenotypic features of Parkinson's disease with a variable severity and time of onset. Common genetic variation of the ...Apolipoprotein E (
) and micro-tubule associated protein tau (
) loci have been linked to cognitive decline and dementia in Parkinson's disease, although studies have yielded mixed results. To further elucidate the influence of
and
variability on dementia in Parkinson's disease, we genotyped postmortem brain tissue samples of clinically and pathologically well-characterized Parkinson's donors and performed a survival analysis of time to dementia.
We included a total of 152 neuropathologically confirmed Parkinson's disease donors with or without clinical dementia during life. We genotyped known risk variants tagging the
ε4 allele and
H1/H2 inversion haplotype. Cox proportional hazards regression analyses adjusted for age at onset, sex and genetic principal components were performed to assess the association between the genetic variants and time from motor onset to onset of dementia.
We found that both the
ε4 allele (HR 1.82, 95 % CI 1.16-2.83,
= 0.009) and
H1-haplotype (HR 1.71, 95 % CI 1.06-2.78,
= 0.03) were associated with earlier development of dementia in patients with Parkinson's disease.
Our results provide further support for the importance of
ε4 and
H1-haplotype in the etiology of Parkinson's disease dementia, with potential future relevance for risk stratification and patient selection for clinical trials of therapies targeting cognitive decline in Parkinson's disease.
•Two coding variants in the glucocerebrosidase (GBA) gene were genotyped in Parkinson’s disease (PD) patients and controls.•We find an association between the low-frequency GBA variant E326K and ...PD.•Two independent association signals within the chromosome 1 SYT11-GBA locus observed in previous GWAS of PD were genotyped.•We find that the GBA variant E326K may fully account for the primary association signal observed at the chromosome 1 SYT11-GBA locus.
Coding variants in the GBA gene have been identified as the numerically most important genetic risk factors for Parkinson's disease (PD). In addition, genome-wide association studies (GWAS) have identified associations with PD in the SYT11-GBA region on chromosome 1q22, but the relationship to GBA coding variants have remained unclear. The aim of this study was to sequence the complete GBA gene in a clinical cohort and to investigate whether coding variants within the GBA gene may be driving reported association signals.
We analyzed high-throughput sequencing data of all coding exons of GBA in 366 patients with PD. The identified low-frequency coding variants were genotyped in three Scandinavian case-controls series (786 patients and 713 controls). Previously reported risk variants from two independent association signals within the SYT11-GBA locus on chromosome 1 were also genotyped in the same samples. We performed association analyses and evaluated linkage disequilibrium (LD) between the variants.
We identified six rare mutations (1.6%) and two low-frequency coding variants in GBA. E326K (rs2230288) was significantly more frequent in PD patients compared to controls (OR 1.65, p=0.03). There was no clear association of T369M (rs75548401) with disease (OR 1.43, p=0.24). Genotyping the two GWAS hits rs35749011 and rs114138760 in the same sample set, we replicated the association between rs35749011 and disease status (OR 1.67, p=0.03), while rs114138760 was found to have similar allele frequencies in patients and controls. Analyses revealed that E326K and rs35749011 are in very high LD (r2 0.95).
Our results confirm that the GBA variant E326K is a susceptibility allele for PD. The results suggest that E326K may fully account for the primary association signal observed at chromosome 1q22 in previous GWAS of PD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Less than 50% of stroke patients in Norway reach hospital within 4 h of symptom onset. Early prehospital identification of stroke and triage to the right level of care may result in more patients ...receiving acute treatment. Quality of communication between paramedics and the stroke centre directly affects prehospital on-scene time, emphasising this as a key factor to reduce prehospital delay. Prehospital stroke scales are developed for quick and easy identification of stroke, but have poor sensitivity and specificity compared to an in-hospital assessment with the National Institutes of Health Stroke Scale (NIHSS). The aim of the Paramedic Norwegian Acute Stroke Prehospital Project (ParaNASPP) is to assess whether a structured learning program, prehospital NIHSS and a mobile application facilitating communication with the stroke physician may improve triage of acute stroke patients.
A stepped wedge cluster randomised controlled intervention design will be used in this trial in Oslo, Norway. Paramedics at five ambulance stations will enrol adult patients with suspected stroke within 24 h of symptom onset. All paramedics will begin in a control phase with standard procedures. Through an e-learning program and practical training, a random and sequential switch to the intervention phase takes place. A mobile application for NIHSS scoring, including vital patient information for treatment decisions, transferring data from paramedics to the on-call stroke physician at the Stroke Unit at Oslo University Hospital, will be provided for the intervention. The primary outcome measure is positive predictive value (PPV) for prehospital identification of patients with acute stroke defined as the proportion of patients accepted for stroke evaluation and discharged with a final stroke diagnosis. One thousand three hundred patients provide a 50% surplus to the 808 patients needed for 80% power to detect a 10% increase in PPV.
Structured and digital communication using a common scale like NIHSS may result in increased probability for better identification of stroke patients and less stroke mimics delivered to a stroke team for acute diagnostics and treatment in our population.
ClinicalTrials.gov NCT04137874 . Registered on October 24, 2019.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Understanding the contribution of immune mechanisms to Parkinson’s disease pathogenesis is an important challenge, potentially of major therapeutic implications. To further elucidate the ...involvement of peripheral immune cells, we studied epigenome-wide DNA methylation in isolated populations of CD14
+
monocytes, CD19
+
B cells, CD4
+
T cells, and CD8
+
T cells from Parkinson’s disease patients and healthy control participants. We included 25 patients with a maximum five years of disease duration and 25 controls, and isolated four immune cell populations from each fresh blood sample. Epigenome-wide DNA methylation profiles were generated from 186 samples using the Illumina MethylationEpic array and association with disease status was tested using linear regression models. We identified six differentially methylated CpGs in CD14
+
monocytes and one in CD8 + T cells. Four differentially methylated regions were identified in monocytes, including a region upstream of
RAB32
, a gene that has been linked to
LRRK2
. Methylation upstream of
RAB32
correlated negatively with mRNA expression, and
RAB32
expression was upregulated in Parkinson’s disease both in our samples and in summary statistics from a previous study. Our epigenome-wide association study of early Parkinson’s disease provides evidence for methylation changes across different peripheral immune cell types, highlighting monocytes and the
RAB32
locus. The findings were predominantly cell-type-specific, demonstrating the value of isolating purified cell populations for genomic studies.
Lrrk2 and Lewy body disease Ross, Owen A.; Toft, Mathias; Whittle, Andrew J. ...
Annals of neurology,
February 2006, Volume:
59, Issue:
2
Journal Article
Peer reviewed
Objective
The Lrrk2 kinase domain G2019S substitution is the most common genetic basis of familial and sporadic parkinsonism. Patients harboring the G2019S substitution usually present with clinical ...Parkinson's disease.
Methods
Herein, we report that the most common neuropathology of G2019S‐associated Parkinson's disease is Lewy body disease.
Results
Lrrk2 G2019S was observed in approximately 2% (n = 8) of our Parkinson's disease/Lewy body disease cases (n = 405). The mutation was also found in one control subject and one Alzheimer's disease patient, reflecting reduced penetrance.
Interpretation
Therapeutic strategies targeted at modulating Lrrk2 kinase activity may be important to treat patients with genetically defined familial or typical sporadic Parkinson's disease. Ann Neurol 2006;59:388–393
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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