Mathias Toft

• Wang, Qin; Sobering, Andrew K.; Tirrito, Christian; Haghshenas, Sadegheh; Hjortshøj, Tina Duelund & Platzer, Konrad [Show all 58 contributors for this article] (2026). Biallelic inactivating variants in the chromatin remodeler DMAP1 cause a syndromic neurodevelopmental disorder. Journal of Clinical Investigation. ISSN 0021-9738. 136(15). doi: 10.1172/JCI198229. Full text in Research Archive Show summary

  Chromatin remodeling is a dynamic epigenetic process that alters chromatin structure to gauge gene accessibility, enabling precise spatiotemporal gene expression, with disruptions often underlying neurodevelopmental disorders (NDDs), although the mechanistic underpinning remains incompletely understood. Despite essential roles in chromatin remodeling processes such as DNA methylation and histone acetylation and deposition, DMAP1 has not been implicated in human disease. We identified 20 individuals from 16 families with a syndromic NDD carrying homozygous or compound heterozygous variants in DMAP1. Neural-specific knockdown of its Drosophila ortholog, dDMAP1, caused pupal lethality, structural defects in the mushroom body (MB), decreased dendrite length, abnormal social behavior and mechanical-induced seizures. Human reference DMAP1 could largely compensate for the loss of dDMAP1 in knockdown flies, whereas patient variants failed to restore or differentially rescued the phenotypes, confirming their pathogenicity with differing severity. Transcriptome profiling of dDMAP1-knockdown fly brains nominated Cbl and SF1 as downstream targets. Their overexpression rescued the aforementioned lethality and MB defects. Finally, a DNA methylation episignature was identified, leading to the molecular diagnosis of an additional patient. Our findings demonstrate that biallelic inactivating variants in DMAP1 cause a syndromic NDD, expanding the short list of recessive disease-causing genes within the epigenetic machinery.

• Vuong, Thuy My Thi; Ørstavik, Kristin; Steen, Unni; Toft, Mathias; Brunborg, Cathrine & Wekre, Lena Lande (2026). The EXPLAIN Study: Exploring Arthrogryposis Multiplex Congenita in Adults in Norway — A Description of Demographic, Medical, and Neurological Findings. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics (AJMG). ISSN 1552-4868. doi: 10.1002/ajmg.c.70017. Full text in Research Archive
• Staubo, Sara Cecilie; Størset, Elisabet; Toft, Mathias; Lie, Ingeborg Haugesag; Alvik, Kirsti Margrete Johansen & Pål, Jostad, [Show all 11 contributors for this article] (2026). Evaluating impulse control disorders in people with Parkinson’s disease: agreement and added value of patient and caregiver reports. Frontiers in Neurology. 17. doi: 10.3389/fneur.2026.1791205. Full text in Research Archive Show summary

  Background: People with Parkinson’s Disease (PD) treated with dopamine agonists are at increased risk for developing impaired impulse control behavior. It has been suggested that patients tend to underreport problems with impaired impulse control, indicating that caregiver evaluations may be a helpful supplement to clinical assessment.Objective: To examine the agreement between evaluations of impaired impulse control provided by people with PD treated with dopamine agonists and by their caregivers.Methods: People with PD and their caregivers independently completed the validated Questionnaire for Impulse-Compulsive Disorders in Parkinson’s Disease-Rating Scale (QUIP-RS) and the Impulse Control Disorders and Related Conditions (ICDRC) questionnaire. Patient and caregiver assessment were compared statistically for total scores and subscores on both questionnaires.Results: Overall, patient and caregiver assessment on both the QUIP-RS and ICDRC showed no consistent systematic differences. Patients reported a slightly higher total ICDRC score and higher combined subscores for punding and dopamine dysregulation syndrome compared to their caregivers. Further, patient evaluations showed a wider range of responses for hypersexuality (QUIP-RS and ICDRC) and for gambling (ICDRC).Conclusion: The assessment of impaired impulse control remains difficult, and our findings indicate that the role of caregiver evaluations is still uncertain.

• Akdeniz, Bayram Cevdet; Bahrami, Shahram; Hagen, Espen; Fuhrer, Julian; Fominykh, Vera & Shadrin, Alexey [Show all 108 contributors for this article] (2026). Polygenic Hazard Score for Predicting Age-associated Risk of Alzheimer’s Disease in European Populations: Development and Validation. medRxiv. doi: 10.1101/2025.07.28.25332293. Full text in Research Archive Show summary

  Abstract Objectives Polygenic hazard score (PHS) models can be used to predict the age-associated risk for complex diseases, including Alzheimer’s disease (AD). In this study, we present an improved PHS model for AD that incorporates a large number of genetic variants and demonstrates enhanced predictive accuracy for age of onset in European populations compared to alternative models. Methods We used the genotyped European Alzheimer & Dementia Biobank (EADB) sample (n=42,120) to develop and evaluate the performance of the PHS model. We developed a PHS model building on 720 genetic variants, including Apolipoprotein E ( APOE ) ε2 and ε4 alleles. We used Elastic Net-regularized Cox regression approach to develop the PHS model. Results The new PHS model (EADB720) improved prediction accuracy compared to alternative models in European populations, with the Odds Ratio OR80/20 from the highest quintile of risk (80th risk percentile and above) to the lowest quintile of risk (20th risk percentile and below) varying between 5.10 and 13.15 within the range of age of onset from 65 – 85 years. Our model also improved risk stratification across ε3/3 individuals of European ancestry (OR80/20 ranges from 1.95 to 3.52). It was also successfully validated in independent datasets (HUSK, DemGene and ADNI) by achieving OR80/20 up to 10.00 in each independent dataset. Conclusion Our EADB720 model significantly improves the accuracy of age-associated risk of AD across European populations (pval<0.03). Accurately predicting the age of onset of AD is of large clinical importance to implementing new AD medication and early intervention in clinical settings.

• Shen, Xueyi; Anirudhan, Jithu; Fatima, Ambrin; Plant, Estelle; Szemes, Tünde & Bouveret, Zélie [Show all 27 contributors for this article] (2025). Evidence That Dmrta2 Acts through Repression of Pax6 in Cortical Patterning and Identification of a Mutation Impairing DNA Recognition Associated with Microcephaly in Human. eNeuro. 12(6). doi: 10.1523/ENEURO.0377-24.2025. Full text in Research Archive
• Kulisevsky, Jaime; García-Ruíz, Pedro; Outeiro, Tiago Fleming; Gurevich, Tanya; Klivènyi, Péter & Laar, Teus Van [Show all 11 contributors for this article] (2025). Pharmacogenetics in advanced Parkinson’s disease. Journal of Neural Transmission. ISSN 0300-9564. 132(11), p. 1719–1726. doi: 10.1007/s00702-025-03057-0. Full text in Research Archive
• Bugge, Helge Fagerheim; Guterud, Mona; Larsen, Karianne; Toft, Mathias; Hov, Maren Ranhoff & Sandset, Else Charlotte (2025). Presenting symptoms and diagnostic accuracy of prehospital stroke scales for patients with suspected mild minor stroke. European Stroke Journal. ISSN 2396-9873. 11(1). doi: 10.1177/23969873251360592. Full text in Research Archive
• Argren, Maria Bengtson Argren; Engstrand, Helene; Husøy, Andreas Kattem; Kristoffersen, Espen Saxhaug; Toft, Mathias & Pripp, Are Hugo [Show all 8 contributors for this article] (2025). Prevalence of headache disorders in Norway: results from the population based PopHEAD study. The Journal of Headache and Pain. ISSN 1129-2369. 26(1). doi: 10.1186/s10194-025-02216-8. Full text in Research Archive Show summary

  Background Reliable and up-to-date prevalence estimates of headache disorders are essential for public health planning. Despite previous large-scale studies, there is a lack of validated and up-to-date population-representative prevalence estimates from Europe. Here, we aimed to estimate the one-year prevalence of the major headache disorders in Norway using a validated diagnostic tool. Methods PopHEAD is a population-based Norwegian cross-sectional study. A random sample of 28,753 individuals aged 18–70 years was invited to complete a digital version of the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, adapted and translated into Norwegian. Headache diagnoses were made using a standardized algorithm based on the International Classification of Headache Disorders (ICHD-3) criteria and validated by telephone interview in a sub-sample. Prevalence estimates were calculated as crude proportions with 95% confidence intervals and sequentially adjusted for age and sex, measurement error and selection bias. Associations with demographic variables were investigated. Results A total of 8,265 participants (3,344 men and 4,921 women; mean age 47.3 years) responded. The crude one-year prevalence was 29.6% for migraine (36.5% in women, 19.4% in men), 52.7% for tension-type headache (TTH) (51.4% in women, 54.6% in men), and 5.1% for probable medication-overuse headache (pMOH) (6.5% in women, 3.1% in men). After adjusting for age, sex, measurement error, and selection bias, the estimated prevalence was 20.3% for migraine, 47.9% for TTH, and 5.9% for pMOH. Migraine prevalence was highest among participants with low income and low education, while TTH prevalence was highest in participants with high socioeconomic status. pMOH prevalence was highest in participants aged 26–45 years and in participants with low education. Conclusion The PopHEAD study provides updated, validated and bias-adjusted prevalence estimates for migraine, TTH and pMOH in the Norwegian adult population. These data may inform health resource allocation for headache management in similar populations.

• Staubo, Sara Cecilie; Fuskevåg, Ole Martin; Toft, Mathias; Lie, Ingeborg Haugesag; Alvik, Kirsti Margrete Johansen & Jostad, Pål [Show all 13 contributors for this article] (2025). Impulse control and correlation to dopamine agonist serum concentrations in people with Parkinson's disease. Journal of Neurology. ISSN 0340-5354. 272(2). doi: 10.1007/s00415-024-12870-8. Full text in Research Archive
• Lie, Ingeborg Haugesag; Tan, Manuela; Andersen, Maren Stolp; Toft, Mathias & Pihlstrøm, Lasse (2025). Epigenome-wide association study, meta-analysis, and multiscore profiling of whole blood in Parkinson's disease. Annals of clinical and translational neurology. 12(4), p. 701–713. doi: 10.1002/acn3.52292. Full text in Research Archive
• Dalbro, Solveig Elisabeth Jacobsen; Elsais, Ahmed; Rydning, Siri Kristine Lynne; Toft, Mathias; Kerty, Emilia & Larsen, Stig (2025). Repeatability, reliability, and stability of eye movement measurements in Parkinson’s disease, cerebellar ataxia, and healthy adults. Frontiers in Neurology. 16. doi: 10.3389/fneur.2025.1556314. Full text in Research Archive
• Afridi, Tehseen Ullah Khan; Fatima, Ambrin; Satti, Humayoon Shafique; Akram, Zaineb; Yousafzai, Imran Khan & Naeem, Wajahat Bin [Show all 17 contributors for this article] (2024). Exome sequencing in four families with neurodevelopmental disorders: genotype–phenotype correlation and identification of novel disease-causing variants in VPS13B and RELN. Molecular Genetics and Genomics. ISSN 1617-4615. 299(1). doi: 10.1007/s00438-024-02149-y. Full text in Research Archive
• Kakar, Naseebullah; Mascarenhas, Selinda; Ali, Asmat; Azmatullah, NN; Haider, Syed M. Ijlal & Badiger, Vaishnavi Ashok [Show all 19 contributors for this article] (2024). Further evidence of biallelic NAV3 variants associated with recessive neurodevelopmental disorder with dysmorphism, developmental delay, intellectual disability, and behavioral abnormalities. Human Genetics. ISSN 0340-6717. doi: 10.1007/s00439-024-02718-6. Full text in Research Archive Show summary

  Neuron navigators (NAVs) are cytoskeleton-associated proteins well known for their role in axonal guidance, neuronal migration, and neurite growth necessary for neurodevelopment. Neuron navigator 3 (NAV3) is one of the three NAV proteins highly expressed in the embryonic and adult brain. However, the role of the NAV3 gene in human disease is not well-studied. Recently, five bi-allelic and three mono-allelic variants in NAV3 were reported in 12 individuals from eight unrelated families with neurodevelopmental disorder (NDD). Here, we report five patients from three unrelated consanguineous families segregating autosomal recessive NDD. Patients have symptoms of dysmorphism, intellectual disability, developmental delay, and behavioral abnormalities. Exome sequencing (ES) was performed on two affected individuals from one large family, and one affected individual from each of the other two families. ES revealed two homozygous nonsense c.6325C > T; p.(Gln2109Ter) and c.6577C > T; p.(Arg2193Ter) and a homozygous splice site (c.243 + 1G > T) variants in the NAV3 (NM_001024383.2). Analysis of single-cell sequencing datasets from embryonic and young adult human brains revealed that NAV3 is highly expressed in the excitatory neurons, inhibitory neurons, and microglia, consistent with its role in neurodevelopment. In conclusion, in this study, we further validate biallelic protein truncating variants in NAV3 as a cause of NDD, expanding the spectrum of pathogenic variants in this newly discovered NDD gene.

• Domenighetti, Cloé; Sugier, Pierre-Emmanuel; Sreelatha, Ashwin Ashok Kumar; Schulte, Claudia; Grover, Sandeep & Portugal, Berta [Show all 77 contributors for this article] (2024). Association of Body Mass Index and Parkinson Disease A Bidirectional Mendelian Randomization Study. Neurology. ISSN 0028-3878. 103(3). doi: 10.1212/WNL.0000000000209620. Full text in Research Archive
• Tan, Manuela; Lawton, Michael A.; Pollard, Miriam I.; Brown, Emmeline; Real, Raquel & Carrasco, Alejandro Martinez [Show all 40 contributors for this article] (2024). Genome-wide determinants of mortality and motor progression in Parkinson’s disease. NPJ Parkinson's Disease. 10(1). doi: 10.1038/s41531-024-00729-8. Full text in Research Archive Show summary

  There are 90 independent genome-wide significant genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1, ASNS, PDE5A, and XPO1. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD.

• Bahrami, Shahram; Nordengen, Kaja; Rokicki, Jaroslav; Shadrin, Alexey; Rahman, Mohammad Zillur & Smeland, Olav Bjerkehagen [Show all 17 contributors for this article] (2024). The genetic landscape of basal ganglia and implications for common brain disorders. Nature Communications. 15(1). doi: 10.1038/s41467-024-52583-0. Full text in Research Archive Show summary

  The basal ganglia are subcortical brain structures involved in motor control, cognition, and emotion regulation. We conducted univariate and multivariate genome-wide association analyses (GWAS) to explore the genetic architecture of basal ganglia volumes using brain scans obtained from 34,794 Europeans with replication in 4,808 white and generalization in 5,220 non-white Europeans. Our multivariate GWAS identified 72 genetic loci associated with basal ganglia volumes with a replication rate of 55.6% at P < 0.05 and 87.5% showed the same direction, revealing a distributed genetic architecture across basal ganglia structures. Of these, 50 loci were novel, including exonic regions of APOE, NBR1 and HLAA. We examined the genetic overlap between basal ganglia volumes and several neurological and psychiatric disorders. The strongest genetic overlap was between basal ganglia and Parkinson’s disease, as supported by robust LD-score regression-based genetic correlations. Mendelian randomization indicated genetic liability to larger striatal volume as potentially causal for Parkinson’s disease, in addition to a suggestive causal effect of greater genetic liability to Alzheimer’s disease on smaller accumbens. Functional analyses implicated neurogenesis, neuron differentiation and development in basal ganglia volumes. These results enhance our understanding of the genetic architecture and molecular associations of basal ganglia structure and their role in brain disorders.

• Sugier, Pierre-Emmanuel; Lucotte, Elise A.; Domenighetti, Cloé; Law, Matthew H.; Iles, Mark M. & Brown, Kevin [Show all 94 contributors for this article] (2023). Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers. Movement Disorders. ISSN 0885-3185. 38(4), p. 604–615. doi: 10.1002/mds.29337. Full text in Research Archive
• Yousaf, Hammad; Rehmat, Shagufta; Jameel, Muhammad; Ibrahim, Rabab; Hashmi, Sohana Nadeem & Makhdoom, Ehtisham Ul Haq [Show all 13 contributors for this article] (2023). A homozygous founder variant in PDE2A causes paroxysmal dyskinesia with intellectual disability. Clinical Genetics. ISSN 0009-9163. 104(3), p. 324–333. doi: 10.1111/cge.14386. Full text in Research Archive Show summary

  Intellectual developmental disorder with paroxysmal dyskinesia or seizures (IDDPADS, OMIM#619150) is an ultra-rare childhood-onset autosomal recessive movement disorder manifesting paroxysmal dyskinesia, global developmental delay, impaired cognition, progressive psychomotor deterioration and/or drug-refractory seizures. We investigated three consanguineous Pakistani families with six affected individuals presenting overlapping phenotypes partially consistent with the reported characteristics of IDDPADS. Whole exome sequencing identified a novel missense variant in Phosphodiesterase 2A (PDE2A): NM_002599.4: c.1514T > C p.(Phe505Ser) that segregated with the disease status of individuals in these families. Retrospectively, we performed haplotype analysis that revealed a 3.16 Mb shared haplotype at 11q13.4 among three families suggesting a founder effect in this region. Moreover, we also observed abnormal mitochondrial morphology in patient fibroblasts compared to controls. Belonging to diverse age groups (13 years-60 years), patients presented paroxysmal dyskinesia, developmental delay, cognitive abnormalities, speech impairment, and drug-refractory seizures with variable onset of disease (as early as 3 months of age to 7 years). Together with the previous reports, we observed that intellectual disability, progressive psychomotor deterioration, and drug-refractory seizures are consistent outcomes of the disease. However, permanent choreodystonia showed variability. We also noticed that the later onset of paroxysmal dyskinesia manifests severe attacks in terms of duration. Being the first report from Pakistan, we add to the clinical and mutation spectrum of PDE2A-related recessive disease raising the total number of patients from six to 12 and variants from five to six. Together, with our findings, the role of PDE2A is strengthened in critical physio-neurological processes.

• Tunold, Jon-Anders; Tan, Manuela; Koga, Shunsuke; Geut, Hanneke; Rozemuller, Annemieke J. M & Valentino, Rebecca [Show all 16 contributors for this article] (2023). Lysosomal polygenic risk is associated with the severity of neuropathology in Lewy body disease. Brain. ISSN 0006-8950. 146(10), p. 4077–4087. doi: 10.1093/brain/awad183. Full text in Research Archive Show summary

  Abstract Intraneuronal accumulation of misfolded α-synuclein is the pathological hallmark of Parkinson’s disease and dementia with Lewy bodies, often co-occurring with variable degrees of Alzheimer’s disease related neuropathology. Genetic association studies have successfully identified common variants associated with disease risk and phenotypic traits in Lewy body disease, yet little is known about the genetic contribution to neuropathological heterogeneity. Using summary statistics from Parkinson’s disease and Alzheimer’s disease genome-wide association studies, we calculated polygenic risk scores and investigated the relationship with Lewy, amyloid-β and tau pathology. Associations were nominated in neuropathologically defined samples with Lewy body disease from the Netherlands Brain Bank (n = 217) and followed up in an independent sample series from the Mayo Clinic Brain Bank (n = 394). We also generated stratified polygenic risk scores based on single-nucleotide polymorphisms annotated to eight functional pathways or cell types previously implicated in Parkinson’s disease and assessed for association with Lewy pathology in subgroups with and without significant Alzheimer’s disease co-pathology. In an ordinal logistic regression model, the Alzheimer’s disease polygenic risk score was associated with concomitant amyloid-β and tau pathology in both cohorts. Moreover, both cohorts showed a significant association between lysosomal pathway polygenic risk and Lewy pathology, which was more consistent than the association with a general Parkinson’s disease risk score and specific to the subset of samples without significant concomitant Alzheimer’s disease related neuropathology. Our findings provide proof of principle that the specific risk alleles a patient carries for Parkinson’s and Alzheimer’s disease also influence key aspects of the underlying neuropathology in Lewy body disease. The interrelations between genetic architecture and neuropathology are complex, as our results implicate lysosomal risk loci specifically in the subset of samples without Alzheimer’s disease co-pathology. Our findings hold promise that genetic profiling may help predict the vulnerability to specific neuropathologies in Lewy body disease, with potential relevance for the further development of precision medicine in these disorders.

• Saadi, Saadia Maryam; Cali, Elisa; Khalid, Lubaba Bintee; Yousaf, Hammad; Zafar, Ghazala & Khan, Haq Nawaz [Show all 18 contributors for this article] (2023). Genetic Investigation of Consanguineous Pakistani Families Segregating Rare Spinocerebellar Disorders. Genes. 14(7). doi: 10.3390/genes14071404. Full text in Research Archive Show summary

  Spinocerebellar disorders are a vast group of rare neurogenetic conditions, generally characterized by overlapping clinical symptoms including progressive cerebellar ataxia, spastic paraparesis, cognitive deficiencies, skeletal/muscular and ocular abnormalities. The objective of the present study is to identify the underlying genetic causes of the rare spinocerebellar disorders in the Pakistani population. Herein, nine consanguineous families presenting different spinocerebellar phenotypes have been investigated using whole exome sequencing. Sanger sequencing was performed for segregation analysis in all the available individuals of each family. The molecular analysis of these families identified six novel pathogenic/likely pathogenic variants; ZFYVE26: c.1093del, SACS: c.1201C&gt;T, BICD2: c.2156A&gt;T, ALS2: c.2171-3T&gt;G, ALS2: c.3145T&gt;A, and B4GALNT1: c.334_335dup, and three already reported pathogenic variants; FA2H: c.159_176del, APTX: c.689T&gt;G, and SETX: c.5308_5311del. The clinical features of all patients in each family are concurrent with the already reported cases. Hence, the current study expands the mutation spectrum of rare spinocerebellar disorders and implies the usefulness of next-generation sequencing in combination with clinical investigation for better diagnosis of these overlapping phenotypes.

• Cappelletti, Chiara; Henriksen, Sandra Pilar; Geut, Hanneke; Rozemuller, Annemieke J. M.; Berg, Wilma D. J. van de & Pihlstrøm, Lasse [Show all 7 contributors for this article] (2023). Transcriptomic profiling of Parkinson's disease brains reveals disease stage specific gene expression changes. Acta Neuropathologica. ISSN 0001-6322. 146, p. 227–244. doi: 10.1007/s00401-023-02597-7. Full text in Research Archive Show summary

  Parkinson´s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Aggravation of symptoms is mirrored by accumulation of protein aggregates mainly composed by alpha-synuclein in different brain regions, called Lewy bodies (LB). Previous studies have identifed several molecular mechanisms as autophagy and infammation playing a role in PD pathogenesis. Increased insights into mechanisms involved in early disease stages and driving the progression of the LB pathology are required for the development of disease-modifying strategies. Here, we aimed to elucidate disease stage-specifc transcriptomic changes in brain tissue of well-characterized PD and control donors. We collected frontal cortex samples from 84 donors and sequenced both the coding and non-coding RNAs. We categorized our samples into groups based on their degree of LB pathology aiming to recapitulate a central aspect of disease progression. Using an analytical pipeline that corrected for sex, age at death, RNA quality, cell composition and unknown sources of variation, we found major disease stage-specifc transcriptomic changes. Gene expression changes were most pronounced in donors at the disease stage when microscopic LB changes frst occur in the sampled brain region. Additionally, we identifed disease stage-specifc enrichment of brain specifc pathways and immune mechanisms. On the contrary, we showed that mitochondrial mechanisms are enriched throughout the disease course. Our data-driven approach also suggests a role for several poorly characterized lncRNAs in disease development and progression of PD. Finally, by combining genetic and epigenetic information, we highlighted two genes (MAP4K4 and PHYHIP) as candidate genes for future functional studies. Together our results indicate that transcriptomic dysregulation and associated functional changes are highly disease stagespecifc, which has major implications for the study of neurodegenerative disorders.

• Tunold, Jon-Anders; Tan, Manuela; Toft, Mathias; Ross, Owen; Berg, Wilma D.J. van de & Pihlstrøm, Lasse (2023). Lysosomal Polygenic Burden Drives Cognitive Decline in Parkinson's Disease with Low Alzheimer Risk. Movement Disorders. ISSN 0885-3185. doi: 10.1002/mds.29698. Full text in Research Archive Show summary

  Abstract Background Genetics influence cognitive progression in Parkinson's disease, possibly through mechanisms related to Lewy and Alzheimer's disease pathology. Lysosomal polygenic burden has recently been linked to more severe Lewy pathology post mortem. Objectives To assess the influence of lysosomal polygenic burden on cognitive progression in Parkinson's disease patients with low Alzheimer's disease risk. Methods Using Cox regression we assessed association between lysosomal polygenic scores and time to Montreal Cognitive Assessment score ≤ 21 in the Parkinson's Progression Markers Initiative cohort (n = 374), with replication in data from the Parkinson's Disease Biomarker Program (n = 777). Patients were stratified by Alzheimer's disease polygenic risk. Results The lysosomal polygenic score was associated with faster progression of cognitive decline in patients with low Alzheimer's disease risk in both datasets ( P  = 0.0032 and P  = 0.0054, respectively). Conclusion Our study supports complex interplay between genetics and neuropathology in Parkinson's disease‐related cognitive impairment, emphasizing the role of lysosomal polygenic burden. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

• Nordengen, Kaja; Cappelletti, Chiara; Bahrami, Shahram; Frei, Oleksandr; Pihlstrøm, Lasse & Henriksen, Sandra Pilar [Show all 11 contributors for this article] (2023). Pleiotropy with sex-specific traits reveals genetic aspects of sex differences in Parkinson’s disease. Brain. ISSN 0006-8950. 147(3), p. 858–870. doi: 10.1093/brain/awad297. Full text in Research Archive Show summary

  Parkinson’s disease is an age-related neurodegenerative disorder with a higher incidence in males than females. The causes for this sex difference are unknown. Genome-wide association studies (GWAS) have identified 90 Parkinson’s disease risk loci, but the genetic studies have not found sex-specific differences in allele frequency on autosomal chromosomes or sex chromosomes. Genetic variants, however, could exert sex-specific effects on gene function and regulation of gene expression. To identify genetic loci that might have sex-specific effects, we studied pleiotropy between Parkinson’s disease and sex-specific traits. Summary statistics from GWASs were acquired from large-scale consortia for Parkinson’s disease (n cases = 13 708; n controls = 95 282), age at menarche (n = 368 888 females) and age at menopause (n = 69 360 females). We applied the conditional/conjunctional false discovery rate (FDR) method to identify shared loci between Parkinson’s disease and these sex-specific traits. Next, we investigated sex-specific gene expression differences in the superior frontal cortex of both neuropathologically healthy individuals and Parkinson’s disease patients (n cases = 61; n controls = 23). To provide biological insights to the genetic pleiotropy, we performed sex-specific expression quantitative trait locus (eQTL) analysis and sex-specific age-related differential expression analysis for genes mapped to Parkinson’s disease risk loci. Through conditional/conjunctional FDR analysis we found 11 loci shared between Parkinson’s disease and the sex-specific traits age at menarche and age at menopause. Gene-set and pathway analysis of the genes mapped to these loci highlighted the importance of the immune response in determining an increased disease incidence in the male population. Moreover, we highlighted a total of nine genes whose expression or age-related expression in the human brain is influenced by genetic variants in a sex-specific manner. With these analyses we demonstrated that the lack of clear sex-specific differences in allele frequencies for Parkinson’s disease loci does not exclude a gen- etic contribution to differences in disease incidence. Moreover, further studies are needed to elucidate the role that the candidate genes identified here could have in determining a higher incidence of Parkinson’s disease in the male population.

• Andersen, Maren Stolp; Leikfoss, Ingvild Sørum; Brorson, Ina Skaara; Cappelletti, Chiara; Bettencourt, Conceicao & Toft, Mathias [Show all 7 contributors for this article] (2023). Epigenome-wide association study of peripheral immune cell populations in Parkinson’s disease. NPJ Parkinson's Disease. 9(1). doi: 10.1038/s41531-023-00594-x. Full text in Research Archive
• Staubo, Sara Cecilie; Fuskevåg, Ole Martin; Toft, Mathias; Lie, Ingeborg Haugesag; Alvik, Kirsti Margrete Johansen & Jostad, Pål [Show all 13 contributors for this article] (2023). Dopamine agonist serum concentrations and impulse control disorders in Parkinson's disease. European Journal of Neurology. ISSN 1351-5101. 31(2). doi: 10.1111/ene.16144. Full text in Research Archive Show summary

  Background and purpose: Impulse control disorders (ICDs) are common among Parkinson's disease patients using dopamine agonists. We wanted to determine whether ICD patients have higher dopamine agonist serum concentrations than those without any sign of ICD.<p> <p>Methods: Patients who used either pramipexole or ropinirole depot once daily were screened for ICDs using the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease–Rating Scale. Those who scored above the cut-off for one or more of the four defined ICDs (gambling, compulsive sexual behavior, compulsive shopping, and binge-eating) were compared in a case–control study to patients who scored zero points (no evidence of ICD) on the same items. They were examined clinically and evaluated using relevant scales. Three blood samples were taken on the same day: before daily dose, and then 6 and 12 h later. <p>Results: Forty-six patients were included: 19 ICD-positive and 27 controls. Ropinirole serum concentrations 6 h after daily intake (C_max) were higher in the case group compared to the control group, as was the daily ropinirole dosage. No differences were observed in serum concentrations, dosage or total drug exposure for pramipexole. Disease duration and length of dopamine agonist treatment was significantly longer among ICD patients for ropinirole, but not for pramipexole. <p>Conclusions: The use of pramipexole may in itself confer high ICD risk, whereas ICDs among ropinirole users depend more on serum concentration and drug exposure. The pharmacokinetic properties of ropinirole make it challenging to predict its effects on patients, which supports the need for therapeutic drug monitoring to reduce risk of ICD.

• Vollstedt, Eva-Juliane; Schaake, Susen; Lohmann, Katja; Padmanabhan, Shalini; Brice, Alexis & Lesage, Suzanne [Show all 134 contributors for this article] (2023). Embracing monogenic Parkinson's disease: The MJFF Global Genetic PD Cohort. Movement Disorders. ISSN 0885-3185. 38(2), p. 286–303. doi: 10.1002/mds.29288. Full text in Research Archive Show summary

  Background As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed. Results We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials.

• Guterud, Mona; Bugge, Helge Fagerheim; Røislien, Jo; Kramer-Johansen, Jo; Toft, Mathias & Ihle-Hansen, Hege Beathe [Show all 11 contributors for this article] (2023). Prehospital screening of acute stroke with the National Institutes of Health Stroke Scale (ParaNASPP): a stepped-wedge, cluster-randomised controlled trial. Lancet Neurology. ISSN 1474-4422. 22(9), p. 800–811. doi: 10.1016/S1474-4422(23)00237-5. Full text in Research Archive Show summary

  Background Timely treatment of acute stroke depends on early identification and triage. Improved methods for recognition of stroke in the prehospital setting are needed. We aimed to assess whether use of the National Institutes of Health Stroke Scale (NIHSS) by paramedics in the ambulance could improve communication with the hospital, augment triage, and enhance diagnostic accuracy of acute stroke. Methods The Paramedic Norwegian Acute Stroke Prehospital Project (ParaNASPP) was a stepped-wedge, single-blind, cluster-randomised controlled trial. Patients with suspected acute stroke, who were evaluated by paramedics from five ambulance stations in Oslo, Norway, were eligible for inclusion. The five ambulance stations (defined as clusters) all initially managed patients according to a standard stroke protocol (control group), with randomised sequential crossover of each station to the intervention group. The intervention consisted of supervised training on NIHSS scoring, a mobile application to aid scoring, and standardised communication with stroke physicians. Random allocation was done via a simple lottery draw by administrators at Oslo University Hospital, who were independent of the research team. Allocation concealment was not possible due to the nature of the intervention. The primary outcome was the positive predictive value (PPV) for prehospital identification of patients with a final discharge diagnosis of acute stroke, analysed by intention to treat. Prespecified secondary safety outcomes were median prehospital on-scene time and median door-to-needle time. This trial is registered with ClinicalTrials.gov, NCT04137874, and is completed. Findings Between June 3, 2019, and July 1, 2021, 935 patients were evaluated by paramedics for suspected acute stroke. 134 patients met exclusion criteria or did not consent to participate. The primary analysis included 447 patients in the intervention group and 354 in the control group. There was no difference in PPV for prehospital identification of patients with a final discharge diagnosis of acute stroke between the intervention group (48·1%, 95% CI 43·4–52·8) and control group (45·8%, 40·5–51·1), with an estimated percentage points difference between groups of 2·3 (95% CI –4·6 to 9·3; p=0·51). Median prehospital on-scene time increased by 5 min in the intervention group (29 min [IQR 23–36] vs 24 min [19–31]; p<0·0001), whereas median door-to-needle time was similar between groups (26 min [21–36] vs 27 min [20–36]; p=0·90). No prehospital deaths were reported in either group. Interpretation The intervention did not improve diagnostic accuracy in patients with suspected stroke. A general increase in prehospital time during the pandemic and the identification of smaller strokes that require more deliberation are possible explanations for the increased on-scene time. The ParaNASPP model is to be implemented in Norway from 2023, and will provide real-life data for further research.

• Pihlstrøm, Lasse; Shireby, Gemma; Geut, Hanneke; Henriksen, Sandra Pilar; Rozemuller, Annemieke J. M. & Tunold, Jon-Anders [Show all 13 contributors for this article] (2022). Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology. Nature Communications. 13, p. 1–10. doi: 10.1038/s41467-022-32619-z. Full text in Research Archive Show summary

  Abstract Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2 , SFMBT2 , AKAP6 and PHYHIP . Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.

• Yousaf, Hammad; Fatima, Ambrin; Ali, Zafar; Baig, Shahid M.; Toft, Mathias & Iqbal, Zafar (2022). A Novel Nonsense Variant in GRM1 Causes Autosomal Recessive Spinocerebellar Ataxia 13 in a Consanguineous Pakistani Family. Genes. 13(9). doi: 10.3390/genes13091667. Full text in Research Archive Show summary

  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.

• Domenighetti, Cloé; Sugier, Pierre-Emmanuel; Sreelatha, Ashwin Ashok Kumar; Schulte, Claudia; Grover, Sandeep & Mohamed, Océane [Show all 79 contributors for this article] (2022). Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study. Movement Disorders. ISSN 0885-3185. 37(4), p. 857–864. doi: 10.1002/mds.28902. Full text in Research Archive Show summary

  Background Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). Methods We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P-difference with women = 0.029). Conclusions Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society

• Grover, Sandeep; Sreelatha, Ashwin Ashok Kumar; Pihlstrøm, Lasse; Domenighetti, Cloé; Schulte, Claudia & Sugier, Pierre-Emmanuel [Show all 83 contributors for this article] (2022). Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence from the COURAGE-PD Consortium. Neurology. ISSN 0028-3878. 99(7), p. E698–E710. doi: 10.1212/WNL.0000000000200699. Full text in Research Archive Show summary

  Background and Objectives Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations. Methods A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC). Results The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance (p < 5 × 10−8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (p < 0.025): (rs34311866: β(SE)COURAGE = 0.477(0.203), pCOURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE)COURAGE+IPDGC = 0.720(0.122), pCOURAGE+IPDGC = 3.13 × 10−9) and a novel BST1 locus (rs4698412: β(SE)COURAGE+IPDGC = −0.526(0.096), pCOURAGE+IPDGC = 4.41 × 10−8). Discussion Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.

• Domenighetti, Cloé; Douillard, Venceslas; Sugier, Pierre-Emmanuel; Sreelatha, Ashwin Ashok Kumar; Schulte, Claudia & Grover, Sandeep [Show all 80 contributors for this article] (2022). The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited. Movement Disorders. ISSN 0885-3185. 37(9), p. 1929–1937. doi: 10.1002/mds.29133. Full text in Research Archive
• Bugge, Helge Fagerheim; Guterud, Mona; Røislien, Jo; Larsen, Karianne; Ihle-Hansen, Hege & Toft, Mathias [Show all 8 contributors for this article] (2022). National Institutes of Health Stroke Scale scores obtained using a mobile application compared to the conventional paper form: A randomised controlled validation study. BMJ Innovations. ISSN 2055-8074. 9(1), p. 57–63. doi: 10.1136/bmjinnov-2022-000968. Full text in Research Archive Show summary

  Background Prehospital delay contributes to treatment delay in acute stroke. Numerous prehospital stroke scales exist for stroke identification, but they lack the diagnostic accuracy of the in-hospital National Institutes of Health Stroke Scale (NIHSS). We have developed a mobile application to aid paramedics assessing prehospital NIHSS. This study explores agreement between NIHSS scores obtained using the Paramedic Norwegian Acute Stroke Prehospital Project (ParaNASPP) application compared with conventional assessment. Methods 25 physicians working with stroke were randomised to an application group or control. 20 unique videos portraying acute stroke symptoms were scored by both groups. 95% limits of agreement (LoA) were calculated using Bland-Altman’s method, comparing the groups to predefined scores, and each other. LoAs within ±3 NIHSS points were considered acceptable. Cohen’s kappa was calculated on dichotomised NIHSS scores. Results The ParaNASPP application group had 95% LoA of −2.33 to 2.71. The control group had LoA of −2.60 to 2.55. Direct comparison between the groups gave LoA of −3.12 to 3.55. When compared with the dichotomised predefined scores kappa was 0.93 in the application group and 0.89 in the control group. Kappa was 0.84 for direct comparison between the groups. Discussion There was very good agreement between the application and both the predefined score and the control group. Scores from the ParaNASPP application differ slightly more than our predefined goal when compared with the control group, but is well within when compared with the predefined NIHSS scores. We consider this acceptable and the ParaNASPP application validated for further clinical studies.

• Domenighetti, Cloé; Sugier, Pierre-Emmanuel; Sreelatha, Ashwin Ashok Kumar; Schulte, Claudia; Grover, Sandeep & Mohamed, Oceáne [Show all 79 contributors for this article] (2022). Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease. Journal of Parkinson's Disease. ISSN 1877-7171. 12(1), p. 267–282. doi: 10.3233/JPD-212851. Full text in Research Archive Show summary

  Background:Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective:To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods:We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results:We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion:Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

• Langmyhr, Margrete; Henriksen, Sandra Pilar; Cappelletti, Chiara; Berg, Wilma D. J. van de; Pihlstrøm, Lasse & Toft, Mathias (2021). Allele-specific expression of Parkinson’s disease susceptibility genes in human brain. Scientific Reports. 11(1). doi: 10.1038/s41598-020-79990-9. Full text in Research Archive Show summary

  Genome-wide association studies have identifed genetic variation in genomic loci associated with susceptibility to Parkinson’s disease (PD), the most common neurodegenerative movement disorder worldwide. We used allelic expression profling of genes located within PD-associated loci to identify cis-regulatory variation afecting gene expression. DNA and RNA were extracted from post-mortem superior frontal gyrus tissue and whole blood samples from PD patients and controls. The relative allelic expression of transcribed SNPs in 12 GWAS risk genes was analysed by real-time qPCR. Allele-specifc expression was identifed for 9 out of 12 genes tested (GBA, TMEM175, RAB7L1, NUCKS1, MCCC1, BCKDK, ZNF646, LZTS3, and WDHD1) in brain tissue samples. Three genes (GPNMB, STK39 and SIPA1L2) did not show signifcant allele-specifc efects. Allele-specifc efects were confrmed in whole blood for three genes (BCKDK, LZTS3 and MCCC1), whereas two genes (RAB7L1 and NUCKS1) showed brain-specifc allelic expression. Our study supports the hypothesis that changes to the cis-regulation of gene expression is a major mechanism behind a large proportion of genetic associations in PD. Interestingly, allele-specifc expression was also observed for coding variants believed to be causal variants (GBA and TMEM175), indicating that splicing and other regulatory mechanisms may be involved in disease development.

• Yu, Eric; Ambati, Aditya; Andersen, Maren Stolp; Krohn, Lynne; Estiar, Mehrdad A. & Saini, Prabhjyot [Show all 19 contributors for this article] (2021). Fine mapping of the HLA locus in Parkinson’s disease in Europeans. NPJ Parkinson's Disease. 7(84). doi: 10.1038/s41531-021-00231-5. Full text in Research Archive Show summary

  We fine mapped the leukocyte antigen (HLA) region in 13,770 Parkinson’s disease (PD) patients, 20,214 proxy-cases, and 490,861 controls of European origin. Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1*03:01, HLA-DQB1*03:02, HLA-DRB1*04:01, and HLA-DRB1*04:04. Haplotype analyses followed by amino acid analysis and conditional analyses suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1*04 subtypes—11V, 13H, and 33H (OR = 0.87, 95% CI: 0.83–0.90, p < 8.23 × 10−9 for all three variants). No other effects were present after adjustment for these amino acids. Our results suggest that specific HLA-DRB1 variants are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to the identification of new targets for therapeutics development.

• Berge-Seidl, Victoria; Pihlstrøm, Lasse & Toft, Mathias (2021). Integrative analysis identifies bHLH transcription factors as contributors to Parkinson’s disease risk mechanisms. Scientific Reports. 11:3502, p. 1–10. doi: 10.1038/s41598-021-83087-2. Full text in Research Archive Show summary

  Abstract Genome-wide association studies (GWAS) have identified multiple genetic risk signals for Parkinson’s disease (PD), however translation into underlying biological mechanisms remains scarce. Genomic functional annotations of neurons provide new resources that may be integrated into analyses of GWAS findings. Altered transcription factor binding plays an important role in human diseases. Insight into transcriptional networks involved in PD risk mechanisms may thus improve our understanding of pathogenesis. We analysed overlap between genome-wide association signals in PD and open chromatin in neurons across multiple brain regions, finding a significant enrichment in the superior temporal cortex. The involvement of transcriptional networks was explored in neurons of the superior temporal cortex based on the location of candidate transcription factor motifs identified by two de novo motif discovery methods. Analyses were performed in parallel, both finding that PD risk variants significantly overlap with open chromatin regions harboring motifs of basic Helix-Loop-Helix (bHLH) transcription factors. Our findings show that cortical neurons are likely mediators of genetic risk for PD. The concentration of PD risk variants at sites of open chromatin targeted by members of the bHLH transcription factor family points to an involvement of these transcriptional networks in PD risk mechanisms.

• Pham, Uyen Ha Gia; Skogseid, Inger Marie; Pripp, Are Hugo; Bøen, Erlend & Toft, Mathias (2021). Impulsivity in Parkinson’s disease patients treated with subthalamic nucleus deep brain stimulation—An exploratory study. PLOS ONE. 16(3), p. 1–13. doi: 10.1371/journal.pone.0248568. Full text in Research Archive Show summary

  Background: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a recognized treatment in Parkinson’s disease (PD). Knowledge is still limited regarding the possible impact of STN-DBS on personality traits and the personality characteristics of PD patients who undergo surgery. Methods: To assess personality traits in relation to STN-DBS we did an ancillary protocol as part of a prospective randomized study that compared two surgical strategies. Patients were assessed with the Temperament and Character Inventory (TCI), the Urgency, Premeditation, Perseverance and Sensation Seeking impulse behavior scale, the Eysenck Personality Questionnaire (EPQ) and the Toronto Alexithymia Scale preoperatively and after one year of STN-DBS. EPQ and TCI baseline scores were compared with mean scores of healthy reference populations. Results: After 12-months of STN-DBS, there was a significant decline in Persistence compared to baseline. Preoperatively, the STN-DBS patients had significantly lower Persistence and Self-Transcendence scores, and significantly higher scores on Novelty-Seeking, Self-Directedness, Cooperativeness and on Social Conformity than referenced populations. No difference was found in Neuroticism or Harm-Avoidance scores. The baseline prevalence of alexithymia was low and at 1-year follow-up there was no significant change in alexithymia scores. Conclusions: We found a higher baseline level of impulsivity in PD patients who underwent STN-DBS. After one year of STN-DBS, our results indicated that the treatment may affect the patients’ personality by increasing certain aspects of impulsivity. There was no effect on alexithymia. The preoperative personality profile of PD patients might influence the outcome of STN-DBS.

• Tunold, Jon-Anders; Geut, Hanneke; Rozemuller, J.M. Annemieke; Henriksen, Sandra Pilar; Toft, Mathias & Berg, Wilma D.J. van de [Show all 7 contributors for this article] (2021). APOE and MAPT are associated with dementia in neuropathologically confirmed Parkinson's disease. Frontiers in Neurology. 12:631145, p. 1–8. doi: 10.3389/fneur.2021.631145. Full text in Research Archive Show summary

  Introduction: 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 ( APOE ) and micro-tubule associated protein tau ( MAPT ) 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 APOE and MAPT 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. Methods: 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 APOE ε4 allele and MAPT 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. Results: We found that both the APOE ε4 allele (HR 1.82, 95 % CI 1.16–2.83, p = 0.009) and MAPT H1-haplotype (HR 1.71, 95 % CI 1.06–2.78, p = 0.03) were associated with earlier development of dementia in patients with Parkinson's disease. Conclusion: Our results provide further support for the importance of APOE ε4 and MAPT 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.

• Blauwendraat, Cornelis; Iwaki, Hirotaka; Makarious, Mary B.; Bandres-Ciga, Sara; Leonard, Hampton L. & Grenn, Francis P. [Show all 40 contributors for this article] (2021). Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease. Annals of Neurology. ISSN 0364-5134. 90(1), p. 35–42. doi: 10.1002/ana.26090. Full text in Research Archive
• Chen, Zhongbo; Zhang, David; Reynolds, Regina H.; Gustavsson, Emil Karl; García-Ruiz, Sonia & D’Sa, Karishma [Show all 154 contributors for this article] (2021). Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage. Nature Communications. 12(1), p. 1–13. doi: 10.1038/s41467-021-22262-5. Full text in Research Archive
• Bjerknes, Silje Kristin; Toft, Mathias; Brandt, Reidun; Rygvold, Trine Waage; Konglund, Ane & Dietrichs, Espen [Show all 8 contributors for this article] (2021). Subthalamic Nucleus Stimulation in Parkinson's Disease: 5-Year Extension Study of a Randomized Trial. Movement Disorders Clinical Practice. 9(1), p. 48–59. doi: 10.1002/mdc3.13348. Full text in Research Archive Show summary

  Background In Parkinson's disease (PD) long-term motor outcomes of subthalamic nucleus deep brain stimulation (STN-DBS) are well documented, while comprehensive reports on non-motor outcomes are fewer and less consistent. Objective To report motor and non-motor symptoms after 5-years of STN-DBS. Methods We performed an open 5-year extension study of a randomized trial that compared intraoperative verification versus mapping of STN using microelectrode recordings. Changes from preoperative to 5-years of STN-DBS were evaluated for motor and non-motor symptoms (MDS-UPDRS I-IV), sleep disturbances (PDSS), autonomic symptoms (Scopa-Aut), quality of life (PDQ-39) and cognition through a neuropsychological test battery. We evaluated whether any differences between the two randomization groups were still present, and assessed preoperative predictors of physical dependence after 5 years of treatment using logistic regression. Results We found lasting improvement of off-medication motor symptoms (total MDS-UPDRS III, bradykinetic-rigid symptoms and tremor), on-medication tremor, motor fluctuations, and sleep disturbances, but reduced performance across all cognitive domains, except verbal memory. Reduction of verbal fluency and executive function was most pronounced the first year and may thus be more directly related to the surgery than worsening in other domains. The group mapped with multiple microelectrode recordings had more improvement of bradykinetic-rigid symptoms and of PDQ-39 bodily discomfort sub-score, but also more reduction in word fluency. Older age was the most important factor associated with physical dependence after 5 years. Conclusion STN-DBS offers good long-term effects, including improved sleep, despite disease progression. STN-DBS surgery may negatively impact verbal fluency and executive function.

• Storm, Catherine S.; Kia, Demis A.; Almramhi, Mona M.; Bandres-Ciga, Sara; Finan, Chris & Noyce, Alastair J. [Show all 175 contributors for this article] (2021). Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome. Nature Communications. 12(1), p. 1–14. doi: 10.1038/s41467-021-26280-1. Full text in Research Archive
• Blauwendraat, Cornelis; Reed, Xylena; Krohn, Lynne; Heilbron, Karl; Bandres-Ciga, Sara & Tan, Manuela [Show all 62 contributors for this article] (2020). Genetic modifiers of risk and age at onset in GBA associated Parkinson's disease and Lewy body dementia. Brain. ISSN 0006-8950. 143(1), p. 234–248. doi: 10.1093/brain/awz350. Full text in Research Archive
• Krohn, Lynne; Wu, Richard Y. J.; Heilbron, Karl; Ruskey, Jennifer A.; Laurent, Sandra B. & Blauwendraat, Cornelis [Show all 50 contributors for this article] (2020). Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies. Annals of Neurology. ISSN 0364-5134. 87(4), p. 584–598. doi: 10.1002/ana.25687. Full text in Research Archive
• Iwaki, Hirotaka; Blauwendraat, Cornelis; Leonard, Hampton; Makarious, Mary B.; Kim, Jonggeol J. & Liu, Ganqiang [Show all 48 contributors for this article] (2020). Differences in the presentation and progression of Parkinson's disease by sex. Movement Disorders. ISSN 0885-3185. p. 1–14. doi: 10.1002/mds.28312. Full text in Research Archive
• Bjerknes, Silje Kristin; Skogseid, Inger Marie; Hauge, Tuva Jin; Dietrichs, Espen & Toft, Mathias (2020). Subthalamic deep brain stimulation improves sleep and excessive sweating in Parkinson’s disease. NPJ Parkinson's Disease. 6:29, p. 1–7. doi: 10.1038/s41531-020-00131-0. Full text in Research Archive Show summary

  Abstract Parkinson’s disease (PD) is a complex multisystem disorder with motor and non-motor symptoms (NMS). NMS may have an even greater impact on quality of life than motor symptoms. Subthalamic nucleus deep brain stimulation (STN-DBS) has been shown to improve motor fluctuations and quality of life, whereas the effects on different NMS have been less examined. Sleep disturbances and autonomic dysfunction are among the most prevalent NMS. We here report the efficacy of STN-DBS on sleep disturbances and autonomic dysfunction. In the parent trial, 60 patients were included in a single-center randomized prospective study, with MDS-UPDRS III and PDQ-39 as primary endpoints at 12 months of STN-DBS. Preplanned assessments at baseline and postoperatively at 3 and 12 months also included Parkinson’s Disease Sleep Scale (PDSS); Scopa-Aut; and MDS-UPDRS I, II, and IV. We found that STN-DBS had a significant and lasting positive effect on overall sleep quality, nocturnal motor symptoms and restlessness, and daytime dozing. Several aspects of autonomic dysfunction were also improved at 3 months postoperatively, although at 12 months only thermoregulation (sudomotor symptoms) remained significantly improved. We could not identify preoperative factors that predicted improvement in PDSS or Scopa-Aut. There was a close relationship between improved autonomic symptoms and improved quality of life after 1 year. NMS and especially sleep and autonomic dysfunction deserve more focus to improve patient outcomes further.

• Smeland, Olav Bjerkehagen; Shadrin, Alexey A.; Bahrami, Shahram; Broce, Iris J.; Tesli, Martin Steen & Frei, Oleksandr [Show all 22 contributors for this article] (2020). Genome-wide Association Analysis of Parkinson’s Disease and Schizophrenia Reveals Shared Genetic Architecture and Identifies Novel Risk Loci. Biological Psychiatry. ISSN 0006-3223. 89(3), p. 227–235. doi: 10.1016/j.biopsych.2020.01.026. Full text in Research Archive Show summary

  BACKGROUND:Parkinson’s disease (PD) and schizophrenia (SCZ) are heritable brain disorders that involvedysregulation of the dopaminergic system. Epidemiological studies have reported potential comorbidity between thedisorders, 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.METHODS: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 incommon genetic variants and improve statistical power for genetic discovery. Using a variety of biologicalresources, we functionally characterized the identified genomic loci.RESULTS:We observed genetic enrichment in PD conditional onassociations with SCZ and vice versa, indicatingpolygenic overlap. We then leveraged this cross-trait enrichment using conditional FDR analysis and identified 9 novel PDrisk loci and 1 novel SCZ locus at conditional FDR,.01. Furthermore, we identified 9 genomic loci jointly associated withPD and SCZ at conjunctional FDR,.05. There was an even distribution of antagonistic and agonistic effect directionsamong the shared loci, in line with the insignificant genetic correlation between the disorders. Of 67 genes mapped to theshared loci, 65 are expressed in the human brain and show cell type–specific expression profiles.CONCLUSIONS: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 clinicalfeatures between the disorders.

• Flengsrud, Karoline; Toft, Mathias & Dietrichs, Espen (2019). Essensiell tremor. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 139(8), p. 1–5. doi: 10.4045/tidsskr.18.0904. Full text in Research Archive Show summary

  Essensiell tremor rammer nesten 1 % av befolkningen og kan være svært hemmende. Fortsatt er mye uklart rundt patofysiologi, miljøfaktorer og genetiske årsaker. Sannsynligvis rommer diagnosen flere forskjellige tilstander. Vi gir her en oppdatert oversikt over essensiell tremor, medikamentell og nevrokirurgisk behandling samt gjennomgang av forslag til nye definisjoner for tremor generelt og essensiell tremor spesielt. Essensiell tremor er en av de vanligste nevrologiske sykdommene, med en anslått prevalens på nesten 1 % og økende med alder (1). Tradisjonelt ble essensiell tremor oppfattet som en monosymptomatisk sykdom med aksjonstremor, men uten andre nevrologiske symptomer. Vi vet nå at tilstanden kan være mer kompleks, med flere motoriske og ikke-motoriske symptomer (2). En oversikt over essensiell tremor ble publisert i Tidsskriftet i 2008 (3). Siden den gang er det blitt introdusert en ny sykdomsklassifikasjon, og vi har fått flere og bedre alternativer til nevrokirurgisk behandling. Vi gir her en oppdatert klinisk oversikt over tilstanden. Artikkelen bygger dels på forfatternes egne erfaringer, dels på litteratursøk i PubMed, der et skjønnsmessig utvalg av relevante artikler om diagnostikk, etiologi, patofysiologi, definisjon og behandling etter 2007 er inkludert.

• Iqbal, Zafar; Koht, Jeanette; Pihlstrøm, Lasse; Henriksen, Sandra Pilar; Cappelletti, Chiara & Russell, Michael Bjørn [Show all 9 contributors for this article] (2019). Missense mutations in DYT-TOR1A dystonia. Neurology: Genetics. 5:e343(4), p. 1–6. doi: 10.1212/NXG.0000000000000343. Full text in Research Archive Show summary

  DYT-TOR1A dystonia is caused by dominant mutations in the TOR1A gene, most frequently a heterozygous in-frame deletion in exon 5 (c.904_906delGAG; p.302/303delE).1 The most frequent phenotype has childhood onset in a limb, spreading to generalized dystonia within a few years. However, also mild focal forms and onset in the cervical and even cranial region have been described. Age at onset varies from 3 to 64 years,2 and penetrance is only 30%. Other in-frame deletions and point mutations in TOR1A have been associated with dystonia in a limited number of patients.3,4 Here, we report 2 new patients with missense mutations in TOR1A.

• Nalls, Mike A.; Blauwendraat, Cornelis; Vallerga, Costanza L.; Heilbron, Karl; Bandres-Ciga, Sara & Chang, Diana [Show all 51 contributors for this article] (2019). Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet Neurology. ISSN 1474-4422. 18(12), p. 1091–1102. doi: 10.1016/S1474-4422(19)30320-5. Full text in Research Archive
• Rongve, Arvid; Witoelar, Aree; Ruiz, Agustín; Athanasiu, Lavinia; Abdelnour, Carla & Clarimon, Jordi [Show all 40 contributors for this article] (2019). GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study. Scientific Reports. 9(7013). doi: 10.1038/s41598-019-43458-2. Full text in Research Archive Show summary

  Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10−8). One additional genetic locus previously linked to psychosis in Alzheimer’s disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10−6. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.

• Iwaki, Hirotaka; Blauwendraat, Cornelis; Leonard, Hampton L.; Kim, Jonggeol J.; Liu, Ganqiang & Maple-Grødem, Jodi [Show all 45 contributors for this article] (2019). Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts. Movement Disorders. ISSN 0885-3185. 34(12), p. 1839–1850. doi: 10.1002/mds.27845. Full text in Research Archive
• Fernandez-Santiago, Ruben; Martín-Flores, Núria; Antonelli, Francesca; Cerquera, Catalina; Moreno, Verónica & Bandres-Ciga, Sara [Show all 15 contributors for this article] (2019). SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson’s Disease. Movement Disorders. ISSN 0885-3185. 34(9), p. 1333–1344. doi: 10.1002/mds.27770. Full text in Research Archive
• Blauwendraat, Cornelis; Heilbron, Karl; Vallerga, Costanza L; Bandres-Ciga, Sara; Coelln, Rainer von & Pihlstrøm, Lasse [Show all 42 contributors for this article] (2019). Parkinson's disease age at onset genome-wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms. Movement Disorders. ISSN 0885-3185. 34(6), p. 866–875. doi: 10.1002/mds.27659. Full text in Research Archive
• Iwaki, Hirotaka; Blauwendraat, Cornelis; Leonard, Hampton L.; Liu, Ganqiang; Maple-Grødem, Jodi & Corvol, Jean-Christophe [Show all 41 contributors for this article] (2019). Genetic risk of Parkinson disease and progression: An analysis of 13 longitudinal cohorts. Neurology: Genetics. 5(4), p. 1–14. doi: 10.1212/NXG.0000000000000348. Full text in Research Archive Show summary

  Objective: To determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression. Methods: We evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed. Results: We confirmed the importance of GBA on phenotypes. GBA variants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69–6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04–20.60]). We also replicated previously reported associations of GBA variants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16–1.52] for the C allele of rs76904798) and an intronic variant in PMVK and the development of wearing-off effects (HR 1.66 [1.19–2.31] for the C allele of rs114138760). Age at onset was associated with TMEM175 variant p.M393T (−0.72 [−1.21 to −0.23] in years), the C allele of rs199347 (intronic region of GPNMB, 0.70 [0.27–1.14]), and G allele of rs1106180 (intronic region of CCDC62, 0.62 [0.21–1.03]). Conclusions: This study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.

• Puschmann, Andreas; Jimenez-Ferrer, Itzia; Lundblad-Andersson, Elin; Mårtensson, Emma; Hansson, Oskar & Odin, Per [Show all 26 contributors for this article] (2019). Low prevalence of known pathogenic mutations in dominant PD genes: A Swedish multicenter study. Parkinsonism & Related Disorders. ISSN 1353-8020. 66, p. 158–165. doi: 10.1016/j.parkreldis.2019.07.032. Full text in Research Archive
• Blauwendraat, Cornelis; Kia, Demis A.; Pihlstrøm, Lasse; Gan-Or, Ziv; Lesage, Suzanne & Gibbs, J. Raphael [Show all 22 contributors for this article] (2018). Insufficient evidence for pathogenicity of SNCA His50Gln (H50Q) in Parkinson's disease. Neurobiology of Aging. ISSN 0197-4580. 64, p. 159.e5–159.e8. doi: 10.1016/j.neurobiolaging.2017.12.012. Full text in Research Archive
• Bjørnaraa, Kari Anne; Pihlstrøm, Lasse; Dietrichs, Espen & Toft, Mathias (2018). Risk variants of the α-synuclein locus and REM sleep behavior disorder in Parkinson's disease: A genetic association study. BMC Neurology. 18(20), p. 1–5. doi: 10.1186/s12883-018-1023-6. Full text in Research Archive Show summary

  Background Parkinson’s disease is a heterogeneous disorder where genetic factors may underlie clinical variability. Rapid eye movement sleep behavior disorder (RBD) is a parasomnia strongly linked to synucleinopathies, including Parkinson’s disease. We hypothesized that SNCA variants conferring risk of Parkinson’s disease would also predispose to an RBD phenotype. Methods We assessed possible RBD (pRBD) status using the RBD screening questionnaire and investigated known susceptibility variants for Parkinson’s disease located in the α-synuclein (SNCA) and tau (MAPT) gene loci in 325 Parkinson’s disease patients. Associations between genetic risk variants and RBD were investigated by logistic regression, and an independent dataset of 382 patients from the Parkinson’s Progression Marker Initiative (PPMI) study was used for replication. Results pRBD was associated with rs3756063 located in the 5’ region of SNCA (two-sided p = 0.018, odds ratio 1.44). We replicated this finding in the PPMI dataset (one-sided p = 0.036, odds ratio 1.35) and meta-analyzed the results (two-sided p = 0.0032, odds ratio 1.40). The Parkinson’s disease risk variant in the 3′ region of SNCA and the MAPT variant showed no association with pRBD. Conclusions Our findings provide proof of principle that a largely stable, dichotomous clinical feature of Parkinson’s disease can be linked to a specific genetic susceptibility profile. Indirectly, it also supports the hypothesis of RBD as relevant marker for a distinct subtype of the disorder.

• Bjerknes, Silje Kristin; Toft, Mathias; Konglund, Ane; Pham, Uyen Ha Gia; Waage, Trine Rygvold & Pedersen, Lena [Show all 11 contributors for this article] (2018). Multiple microelectrode recordings in STN-DBS surgery for Parkinson's disease: a randomized study. Movement Disorders Clinical Practice. 5(3), p. 296–305. doi: 10.1002/mdc3.12621. Full text in Research Archive Show summary

  Background: Subthalamic nucleus deep brain stimulation improves motor symptoms and fluctuations in advanced Parkinson's disease, but the degree of clinical improvement depends on accurate anatomical electrode placement. Methods used to localize the sensory‐motor part of the nucleus vary substantially. Using microelectrode recordings, at least three inserted microelectrodes are needed to obtain a three‐dimensional map. Therefore, multiple simultaneously inserted microelectrodes should provide better guidance than single sequential microelectrodes. We aimed to compare the use of multiple simultaneous versus single sequential microelectrode recordings on efficacy and safety of subthalamic nucleus stimulation. Methods: Sixty patients were included in this double‐blind, randomized study, 30 in each group. Primary outcome measures were the difference from baseline to 12 months in the MDS‐UPDRS motor score (part III) in the off‐medication state and quality of life using the Parkinson's Disease Questionnaire‐39 (PDQ‐39) scores. Results: The mean reduction of the MDS‐UPDRS III off score was 35 (SD 12) in the group investigated with multiple simultaneous microelectrodes compared to 26 (SD 10) in the single sequential microelectrode group (p = 0.004). The PDQ‐39 Summary Index did not differ between the groups, but the domain scores activities of daily living and bodily discomfort improved significantly more in the multiple microelectrodes group. The frequency of serious adverse events did not differ significantly. Conclusions: After 12 months of subthalamic nucleus stimulation, the multiple microelectrodes group had a significantly greater improvement both in MDS‐UPDRS III off score and in two PDQ‐39 domains. Our results may support the use of multiple simultaneous microelectrode recordings.

• Kristiansen, Madeleine; Maple-Grødem, Jodi; Alves, Guido Werner; Arepalli, Sampath; Hernandez, Dena G & Iwaki, Hirotaka [Show all 11 contributors for this article] (2018). A paradoxical relationship between family history, onset age, and genetic risk in Parkinson's disease. Movement Disorders. ISSN 0885-3185. 34(2), p. 298–299. doi: 10.1002/mds.27555. Full text in Research Archive
• Blauwendraat, Cornelis; Reed, Xylena; Kia, Demis A.; Gan-Or, Ziv; Lesage, Suzanne & Pihlstrøm, Lasse [Show all 29 contributors for this article] (2018). Frequency of loss of function variants in LRRK2 in Parkinson disease. JAMA Neurology. ISSN 2168-6149. 75(11), p. 1416–1422. doi: 10.1001/jamaneurol.2018.1885. Full text in Research Archive
• Berge-Seidl, Victoria; Pihlstrøm, Lasse; Wszolek, Zbigniew K.; Ross, Owen A. & Toft, Mathias (2018). No evidence for DNM3 as genetic modifier of age at onset in idiopathic Parkinson's disease. Neurobiology of Aging. ISSN 0197-4580. 74, p. 1–5. doi: 10.1016/j.neurobiolaging.2018.09.022. Full text in Research Archive
• Pihlstrøm, Lasse; Blauwendraat, Cornelis; Cappelletti, Chiara; Berge-Seidl, Victoria; Langmyhr, Margrete & Henriksen, Sandra Pilar [Show all 12 contributors for this article] (2018). A comprehensive analysis of SNCA-related genetic risk in sporadic parkinson disease. Annals of Neurology. ISSN 0364-5134. 84(1), p. 117–129. doi: 10.1002/ana.25274. Full text in Research Archive
• Berge, Victoria; Pihlstrøm, Lasse; Maple-Grødem, Jodi; Forsgren, Lars; Linder, Jan & Larsen, Jan Petter [Show all 8 contributors for this article] (2017). The GBA variant E326K is associated with Parkinson's disease and explains a genome-wide association signal. Neuroscience Letters. ISSN 0304-3940. 658, p. 48–52. doi: 10.1016/j.neulet.2017.08.040. Full text in Research Archive Show summary

  Objective 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. Methods 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. Results 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). Conclusions 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.

• Iqbal, Zafar; Rydning, Siri Lynne; Wedding, Iselin Marie; Koht, Jeanette; Pihlstrøm, Lasse & Rengmark, Aina Sylvia Haugen [Show all 9 contributors for this article] (2017). Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia. PLOS ONE. 12:e0174667(3), p. 1–19. doi: 10.1371/journal.pone.0174667. Full text in Research Archive Show summary

  Hereditary ataxia and spastic paraplegia are heterogeneous monogenic neurodegenerative disorders. To date, a large number of individuals with such disorders remain undiagnosed. Here, we have assessed molecular diagnosis by gene panel sequencing in 105 early and late-onset hereditary ataxia and spastic paraplegia probands, in whom extensive previous investigations had failed to identify the genetic cause of disease. Pathogenic and likely-pathogenic variants were identified in 20 probands (19%) and variants of uncertain significance in ten probands (10%). Together these accounted for 30 probands (29%) and involved 18 different genes. Among several interesting findings, dominantly inherited KIF1A variants, p.(Val8Met) and p.(Ile27Thr) segregated in two independent families, both presenting with a pure spastic paraplegia phenotype. Two homozygous missense variants, p.(Gly4230Ser) and p.(Leu4221Val) were found in SACS in one consanguineous family, presenting with spastic ataxia and isolated cerebellar atrophy. The average disease duration in probands with pathogenic and likely-pathogenic variants was 31 years, ranging from 4 to 51 years. In conclusion, this study confirmed and expanded the clinical phenotypes associated with known disease genes. The results demonstrate that gene panel sequencing and similar sequencing approaches can serve as efficient diagnostic tools for different heterogeneous disorders. Early use of such strategies may help to reduce both costs and time of the diagnostic process.

• Rengmark, Aina Sylvia Haugen; Pihlstrøm, Lasse; Linder, Jan; Forsgren, Lars & Toft, Mathias (2016). Low frequency of GCH1 and TH mutations in Parkinson's disease. Parkinsonism & Related Disorders. ISSN 1353-8020. 29, p. 109–111. doi: 10.1016/j.parkreldis.2016.05.010. Full text in Research Archive
• Pihlstrøm, Lasse; Morset, Kristina Rebekka; Grimstad, Espen; Vitelli, Valeria & Toft, Mathias (2016). A cumulative genetic risk score predicts progression in Parkinson's disease. Movement Disorders. ISSN 0885-3185. 31(4), p. 487–490. doi: 10.1002/mds.26505. Full text in Research Archive
• Pihlstrøm, Lasse; Berge, Victoria; Rengmark, Aina Sylvia Haugen & Toft, Mathias (2015). Parkinson's disease correlates with promoter methylation in the α-synuclein gene. Movement Disorders. ISSN 0885-3185. 30(4), p. 577–580. doi: 10.1002/mds.26073. Full text in Research Archive
• Pihlstrøm, Lasse; Rengmark, Aina Sylvia Haugen; Bjørnarå, Kari Anne; Dizdar, Nil; Fardell, Camilla & Forsgren, Lars [Show all 13 contributors for this article] (2015). Fine mapping and resequencing of the PARK16 locus in Parkinson's disease. Journal of Human Genetics. ISSN 1434-5161. 60(7), p. 357–362. doi: 10.1038/jhg.2015.34. Full text in Research Archive
• Lill, Christina M.; Rengmark, Aina Sylvia Haugen; Pihlstrøm, Lasse; Fogh, Isabella; Shatunov, Aleksey & Sleiman, Patrick M. [Show all 51 contributors for this article] (2015). The role of TREM2 R47H as a risk factor for Alzheimer’s disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson’s disease. Alzheimer's & Dementia. ISSN 1552-5260. 11(12), p. 1407–1416. doi: 10.1016/j.jalz.2014.12.009. Full text in Research Archive
• Wang, Lisa; Aasly, Jan; Annesi, Grazia; Bardien, Soraya; Bozi, Maria & Brice, Alexis [Show all 55 contributors for this article] (2015). Large-scale assessment of polyglutamine repeat expansions in Parkinson disease. Neurology. ISSN 0028-3878. 85(15), p. 1283–1292. doi: 10.1212/WNL.0000000000002016. Full text in Research Archive
• Pham, Uyen Ha Gia; Solbakk, Anne-Kristin; Skogseid, Inger Marie; Toft, Mathias; Pripp, Are Hugo & Konglund, Ane [Show all 11 contributors for this article] (2015). Personality changes after deep brain stimulation in Parkinson's Disease. Parkinson's Disease. ISSN 2090-8083. 2015:490507. doi: 10.1155/2015/490507. Full text in Research Archive
• Pham, Uyen Ha Gia; Andersson, Stein; Toft, Mathias; Pripp, Are Hugo; Konglund, Ane & Dietrichs, Espen [Show all 10 contributors for this article] (2015). Self-Reported Executive Functioning in Everyday Life in Parkinson's Disease after Three Months of Subthalamic Deep Brain Stimulation. Parkinson's Disease. ISSN 2090-8083. 2015:461453. doi: 10.1155/2015/461453. Full text in Research Archive Show summary

  Objective . Studies on the effect of subthalamic deep brain stimulation (STN-DBS) on executive functioning in Parkinson’s disease (PD) are still controversial. In this study we compared self-reported daily executive functioning in PD patients before and after three months of STN-DBS. We also examined whether executive functioning in everyday life was associated with motor symptoms, apathy, and psychiatric symptoms. Method . 40 PD patients were examined with the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A), the Symptom Checklist 90-Revised (SCL-90-R), and the Apathy Evaluation Scale (AES-S). Results . PD patients reported significant improvement in daily life executive functioning after 3 months of STN-DBS. Anxiety scores significantly declined, while other psychiatric symptoms remained unchanged. The improvement of self-reported executive functioning did not correlate with motor improvement after STN-DBS. Apathy scores remained unchanged after surgery. Only preoperative depressed mood had predictive value to the improvement of executive function and appears to prevent potentially favorable outcomes from STN-DBS on some aspects of executive function. Conclusion . PD patients being screened for STN-DBS surgery should be evaluated with regard to self-reported executive functioning. Depressive symptoms in presurgical PD patients should be treated. Complementary information about daily life executive functioning in PD patients might enhance further treatment planning of STN-DBS.

• Bjørnarå, Kari Anne; Dietrichs, Espen & Toft, Mathias (2015). Longitudinal assessment of probable rapid eye movement sleep behaviour disorder in Parkinson's disease. European Journal of Neurology. ISSN 1351-5101. 22(8), p. 1242–1244. doi: 10.1111/ene.12723. Full text in Research Archive
• Toft, Mathias (2014). Advances in genetic diagnosis of neurological disorders. Acta Neurologica Scandinavica. ISSN 0001-6314. 129(198), p. 20–25. doi: 10.1111/ane.12232. Full text in Research Archive
• Pihlstrøm, Lasse; Rengmark, Aina Sylvia Haugen; Bjørnarå, Kari Anne & Toft, Mathias (2014). Effective variant detection by targeted deep sequencing of DNA pools: An example from parkinson's disease. Annals of Human Genetics. ISSN 0003-4800. 78(3), p. 243–252. doi: 10.1111/ahg.12060. Full text in Research Archive
• Bjerknes, Silje Kristin; Skogseid, Inger Marie; Sæhle, Terje; Dietrichs, Espen & Toft, Mathias (2014). Surgical site infections after deep brain stimulation surgery: Frequency, characteristics and management in a 10-year period. PLOS ONE. 9(8). doi: 10.1371/journal.pone.0105288. Full text in Research Archive
• Koht, Jeanette; Rengmark, Aina Sylvia Haugen; Opladen, Thomas; Bjørnarå, Kari Anne; Selberg, Tore & Tallaksen, Chantal [Show all 8 contributors for this article] (2014). Clinical and genetic studies in a family with a novel mutation in the sepiapterin reductase gene. Acta Neurologica Scandinavica. ISSN 0001-6314. 129(198), p. 7–12. doi: 10.1111/ane.12230. Full text in Research Archive
• Børretzen, Mari Naumann; Bjerknes, Silje Kristin; Sæhle, Terje; Skjelland, Mona; Skogseid, Inger Marie & Toft, Mathias [Show all 7 contributors for this article] (2014). Long-term follow-up of thalamic deep brain stimulation for essential tremor - patient satisfaction and mortality. BMC Neurology. 14(120). doi: 10.1186/1471-2377-14-120. Full text in Research Archive
• Bjørnarå, Kari Anne; Dietrichs, Espen & Toft, Mathias (2014). Clinical features associated with sleep disturbances in Parkinson's disease. Clinical neurology and neurosurgery (Dutch-Flemish ed. Print). ISSN 0303-8467. 124, p. 37–43. doi: 10.1016/j.clineuro.2014.06.027. Full text in Research Archive
• Lilleeng, Bård Flattun; Brønnick, Kolbjørn S; Toft, Mathias; Dietrichs, Espen & Larsen, Jan Petter (2014). Progression and survival in Parkinson's disease with subthalamic nucleus stimulation. Acta Neurologica Scandinavica. ISSN 0001-6314. 130(5), p. 292–298. doi: 10.1111/ane.12224. Full text in Research Archive
• Bjørnarå, Kari Anne; Dietrichs, Espen & Toft, Mathias (2013). REM sleep behavior disorder in Parkinson's disease - Is there a gender difference? Parkinsonism & Related Disorders. ISSN 1353-8020. 19(1), p. 120–122. doi: 10.1016/j.parkreldis.2012.05.027. Full text in Research Archive
• Pihlstrøm, Lasse; Axelsson, Gunnar; Bjørnarå, Kari Anne; Dizdar, Nil; Fardell, Camilla & Forsgren, Lars [Show all 14 contributors for this article] (2013). Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease. Neurobiology of Aging. ISSN 0197-4580. 34(6). doi: 10.1016/j.neurobiolaging.2012.10.019. Full text in Research Archive
• Karlsson, Magdalena Kauczynska; Sharma, Praveen; Aasly, Jan; Toft, Mathias; Skogar, Ørjan & Sæbø, Solve [Show all 7 contributors for this article] (2013). Found in transcription: Accurate Parkinson’s disease classification in peripheral blood. Journal of Parkinson's Disease. ISSN 1877-7171. 3(1), p. 19–29. doi: 10.3233/JPD-120159. Full text in Research Archive
• Toft, Mathias (2011). The Wilson films - MS Tremor. Movement Disorders. ISSN 0885-3185. 26(14), p. 2471–2472. doi: 10.1002/mds.24010. Full text in Research Archive Show summary

  Action tremor was for a long time considered to be a defining symptom of multiple sclerosis. The Wilson films include a short segment showing a female patient suffering from relatively severe action tremor. Tremor is the most common movement disorder in multiple sclerosis, and can be very disabling in some patients. Insights into the frequency and treatment of tremor in multiple sclerosis have changed since the Wilson films were taken, and are reviewed herein. (c) 2011 Movement Disorder Society

• Toft, Mathias & Dietrichs, Espen (2011). Aggravated stuttering following subthalamic deep brain stimulation in Parkinson's disease - two cases. BMC Neurology. 11. doi: 10.1186/1471-2377-11-44. Full text in Research Archive Show summary

  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.

• Pihlstrøm, Lasse & Toft, Mathias (2011). Parkinson’s Disease: What Remains of the ‘‘Missing Heritability’’? Movement Disorders. ISSN 0885-3185. 26(11), p. 1971–1973. doi: 10.1002/mds.23898. Full text in Research Archive

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• Haraldsen, Ira Hebold; Hatlestad-Hall, Christoffer; Marra, Camillo; Renvall, Hanna; Maestú, Fernando & Acosta-Hernández, Jorge [Show all 69 contributors for this article] (2023). Intelligent digital tools for screening of brain connectivity and dementia risk estimation in people affected by mild cognitive impairment: the AI-Mind clinical study protocol. Frontiers in Neurorobotics. 17. doi: 10.3389/fnbot.2023.1289406. Full text in Research Archive Show summary

  More than 10 million Europeans show signs of mild cognitive impairment (MCI), a transitional stage between normal brain aging and dementia stage memory disorder. The path MCI takes can be divergent; while some maintain stability or even revert to cognitive norms, alarmingly, up to half of the cases progress to dementia within 5 years. Current diagnostic practice lacks the necessary screening tools to identify those at risk of progression. The European patient experience often involves a long journey from the initial signs of MCI to the eventual diagnosis of dementia. The trajectory is far from ideal. Here, we introduce the AI-Mind project, a pioneering initiative with an innovative approach to early risk assessment through the implementation of advanced artificial intelligence (AI) on multimodal data. The cutting-edge AI-based tools developed in the project aim not only to accelerate the diagnostic process but also to deliver highly accurate predictions regarding an individual’s risk of developing dementia when prevention and intervention may still be possible. AI-Mind is a European Research and Innovation Action (RIA H2020-SC1-BHC-06-2020, No. 964220) financed between 2021 and 2026. First, the AI-Mind Connector identifies dysfunctional brain networks based on high-density magneto- and electroencephalography (M/EEG) recordings. Second, the AI-Mind Predictor predicts dementia risk using data from the Connector, enriched with computerized cognitive tests, genetic and protein biomarkers, as well as sociodemographic and clinical variables. AIMind is integrated within a network of major European initiatives, including The Virtual Brain, The Virtual Epileptic Patient, and EBRAINS AISBL service for sensitive data, HealthDataCloud, where big patient data are generated for advancing digital and virtual twin technology development. AI-Mind’s innovation lies not only in its early prediction of dementia risk, but it also enables a virtual laboratory scenario for hypothesis-driven personalized intervention research. This article introduces the background of the AI-Mind project and its clinical study protocol, setting the stage for future scientific contribution.

• Bugge, Helge Fagerheim; Guterud, Mona; Bache, Kristi Cecilie Grønvold; Braarud, Anne-Cathrine; Eriksen, Erik & Fremstad, Kjell Otto [Show all 15 contributors for this article] (2022). Paramedic Norwegian Acute Stroke Prehospital Project (ParaNASPP) study protocol: a stepped wedge randomised trial of stroke screening using the National Institutes of Health Stroke Scale in the ambulance. Trials. 23(1). doi: 10.1186/s13063-022-06006-4. Full text in Research Archive Show summary

  Background: 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. Methods: 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. Discussion: 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.

• Iqbal, Zafar & Toft, Mathias (2019). TMEM230 variants in Parkinson’s disease. Nature Genetics. ISSN 1061-4036. 51(3), p. 366–366. doi: 10.1038/s41588-019-0353-7. Full text in Research Archive
• Rongve, Arvid; Witoelar, Aree Widya; Ruiz, Agustín; Athanasiu, Lavinia; Abdelnour, Carla & Clarimon, Jordi [Show all 40 contributors for this article] (2019). Author Correction: GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study (Scientific Reports, (2019), 9, 1, (7013), 10.1038/s41598-019-43458-2). Scientific Reports. 9(1). doi: 10.1038/s41598-019-51827-0. Full text in Research Archive
• Toft, Mathias & Ross, Owen A. (2016). Exome variant mining in familial Parkinson disease will replication find the gold? JAMA Neurology. ISSN 2168-6149. 73(1), p. 21–22. doi: 10.1001/jamaneurol.2015.3536. Full text in Research Archive
• Iqbal, Zafar; Pihlstrøm, Lasse; Rengmark, Aina Sylvia Haugen; Henriksen, Sandra Pilar; Linder, Jan & Forsgren, Lars [Show all 7 contributors for this article] (2016). Rare variants in dementia genes and Parkinson's disease. European Journal of Human Genetics. ISSN 1018-4813. 24(12), p. 1661–1662. doi: 10.1038/ejhg.2016.79. Full text in Research Archive
• Iqbal, Zafar & Toft, Mathias (2015). CHCHD2 and Parkinson's disease. Lancet Neurology. ISSN 1474-4422. 14(7), p. 680–681. doi: 10.1016/S1474-4422(15)00096-4. Full text in Research Archive
• Pihlstrøm, Lasse & Toft, Mathias (2015). Cumulative genetic risk and age at onset in Parkinson's disease. Movement Disorders. ISSN 0885-3185. 30(12), p. 1712–1713. doi: 10.1002/mds.26366. Full text in Research Archive
• Toft, Mathias & Dietrichs, Espen (2014). Medication costs following subthalamic nucleus deep brain stimulation for Parkinson's disease. Movement Disorders. ISSN 0885-3185. 29(2), p. 275–276. doi: 10.1002/mds.25504. Full text in Research Archive
• Pihlstrøm, Lasse; Bjornara, KA; Dizdar, N; Fardell, C; Forsgren, L & Holmberg, B [Show all 12 contributors for this article] (2012). A Scandinavian multi-centre study replicates 11 susceptibility loci from genome-wide association studies in Parkinson's disease. European Journal of Neurology. ISSN 1351-5101. 19, p. 40–40. Full text in Research Archive
• Toft, Mathias & Dietrichs, Espen (2011). Levodopa-Responsive Parkinsonism in Probable Extrapontine Myelinolysis of the Mesencephalon. Movement Disorders. ISSN 0885-3185. 26(12), p. 2180–2181. doi: 10.1002/mds.23876. Full text in Research Archive
• Toft, Mathias (2011). International Consortium Identifies New Genetic Risk Factors for Parkinson's Disease. Movement Disorders. ISSN 0885-3185. 26(4), p. 606–606. doi: 10.1002/mds.23725. Full text in Research Archive

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