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4. Early downregulation of hsa-miR-144-3p in serum from drug-naïve Parkinson's disease patients

Author

Zago E., Dal Molin A., Dimitri G. M., Xumerle L., Pirazzini C., Bacalini M. G., Maturo M. G., Azevedo T., Spasov S., Gomez-Garre P., Perinan M. T., Jesus S., Baldelli L., Sambati L., Calandra Buonaura G., Garagnani P., Provini F., Cortelli P., Mir P., Trenkwalder C., Mollenhauer B., Franceschi C., Lio P., Nardini C., Adarmes-Gomez A., Bartoletti-Stella A., Bhatia K. P., Marta B. -T., Boninsegna C., Broli M., Dolores B. -R., Calandra-Buonaura G., Capellari S., Carrion-Claro M., Cilea R., Clayton R., Molin A. D., De Luca S., De Massis P., Doykov I., Escuela-Martin R., Fabbri G., Gabellini A., Giuliani C., Guaraldi P., Hagg S., Hallqvist J., Halsband C., Heywood W., Houlden H., Huertas I., Jylhava J., Labrador-Espinosa M. A., Licari C., Luchinat C., Macias D., Macri S., Magrinelli F., Rodriguez J. F. M., Massimo D., Mengozzi G., Meoni G., Mignani F., Milazzo M., Mills K., Nassetti S. A., Pedersen N. L., Perinan-Tocino M. T., Ravaioli F., Sala C., Scaglione C. L. M., Schade S., Schreglmann S., Strom S., Tejera-Parrado C., Tenori L., Turano P., Valzania F., Ortega R. V., Williams D., Apollo - University of Cambridge Repository, Zago E., Dal Molin A., Dimitri G.M., Xumerle L., Pirazzini C., Bacalini M.G., Maturo M.G., Azevedo T., Spasov S., Gomez-Garre P., Perinan M.T., Jesus S., Baldelli L., Sambati L., Calandra Buonaura G., Garagnani P., Provini F., Cortelli P., Mir P., Trenkwalder C., Mollenhauer B., Franceschi C., Lio P., Nardini C., Adarmes-Gomez A., Bartoletti-Stella A., Bhatia K.P., Marta B.-T., Boninsegna C., Broli M., Dolores B.-R., Calandra-Buonaura G., Capellari S., Carrion-Claro M., Cilea R., Clayton R., Molin A.D., De Luca S., De Massis P., Doykov I., Escuela-Martin R., Fabbri G., Gabellini A., Giuliani C., Guaraldi P., Hagg S., Hallqvist J., Halsband C., Heywood W., Houlden H., Huertas I., Jylhava J., Labrador-Espinosa M.A., Licari C., Luchinat C., Macias D., Macri S., Magrinelli F., Rodriguez J.F.M., Massimo D., Mengozzi G., Meoni G., Mignani F., Milazzo M., Mills K., Nassetti S.A., Pedersen N.L., Perinan-Tocino M.T., Ravaioli F., Sala C., Scaglione C.L.M., Schade S., Schreglmann S., Strom S., Tejera-Parrado C., Tenori L., Turano P., Valzania F., Ortega R.V., and Williams D.

Subjects
Male, Aging, Molecular biology, Science, Immunology, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Medical research, Humans, Parkinson, 030304 developmental biology, Aged, 0303 health sciences, Multidisciplinary, Biological techniques, Parkinson Disease, Middle Aged, 3. Good health, nervous system diseases, Computational biology and bioinformatics, MicroRNAs, Neurology, ageing, Medicine, Female, 030217 neurology & neurosurgery, Biomarkers
Abstract

Advanced age represents one of the major risk factors for Parkinson's Disease. Recent biomedical studies posit a role for microRNAs, also known to be remodelled during ageing. However, the relationship between microRNA remodelling and ageing in Parkinson's Disease, has not been fully elucidated. Therefore, the aim of the present study is to unravel the relevance of microRNAs as biomarkers of Parkinson's Disease within the ageing framework. We employed Next Generation Sequencing to profile serum microRNAs from samples informative for Parkinson's Disease (recently diagnosed, drug-naïve) and healthy ageing (centenarians) plus healthy controls, age-matched with Parkinson's Disease patients. Potential microRNA candidates markers, emerging from the combination of differential expression and network analyses, were further validated in an independent cohort including both drug-naïve and advanced Parkinson's Disease patients, and healthy siblings of Parkinson's Disease patients at higher genetic risk for developing the disease. While we did not find evidences of microRNAs co-regulated in Parkinson's Disease and ageing, we report that hsa-miR-144-3p is consistently down-regulated in early Parkinson's Disease patients. Moreover, interestingly, functional analysis revealed that hsa-miR-144-3p is involved in the regulation of coagulation, a process known to be altered in Parkinson's Disease. Our results consistently show the down-regulation of hsa-mir144-3p in early Parkinson's Disease, robustly confirmed across a variety of analytical and experimental analyses. These promising results ask for further research to unveil the functional details of the involvement of hsa-mir144-3p in Parkinson's Disease., This work was supported by the Horizon 2020 Framework Programme (Grant number 634821, PROPAG-AGING).

Published
2022

6. Unchanged gastric emptying and visceral perception in early Parkinson's disease after a high caloric test meal

Author

Epprecht, L, Schreglmann, S R, Goetze, O, Woitalla, D, Baumann, C R, Waldvogel, D, University of Zurich, and Schreglmann, S R

Subjects
2728 Neurology (clinical), 2808 Neurology, 610 Medicine & health, 10040 Clinic for Neurology
Abstract

Delayed gastric emptying (GE) is a frequent non-motor feature in Parkinson´s disease (PD). This prospective study (clinicaltrials.gov Identifier NCT01518751) investigated GE and visceral perception in early motor phase PD patients in comparison to age-matched and younger controls. In addition, the effect of Levodopa on GE was assessed in healthy aged controls. 16 PD patients (Hoehn & Yahr 2), 11 sex-/age-matched Ctrl1 and 10 young, male Ctrl2 subjects were subjected to a high caloric (428kcal) 13C-Sodium Octanoate breath test strictly OFF dopaminergic medication. Visceral appetite sensation was monitored using visual analogue scales (VAS). GE was similarly studied in 7 controls ON/OFF oral Levodopa. GE was not altered in PD patients compared to age-/sex-matched and younger controls (p=0.76). Subjective appetite perception was not altered in the PD group in comparison to Ctrl1, but was significantly higher in Ctrl2 subjects (p=0.02). 100mg oral Levodopa/25mg Benserazide significantly slowed GE by 18% among healthy controls (p=0.04). In early motor stage PD OFF dopaminergic medication, there was no GE slowing after a high caloric test meal. Levodopa, however, caused a robust GE slowing in healthy aged individuals. Our data indicate that clinically relevant GE slowing in early PD is related to the iatrogenic effect of dopamine treatment. Subjective appetite perception is not affected in this disease stage. This data add to the understanding of gastrointestinal symptoms in early motor stage PD and highlight the influence of dopaminergic medication.

Published
2021

10. Early downregulation of hsa-miR-144-3p in serum from drug-naïve Parkinson’s disease patients

Author

Zago, E., Dal Molin, A., Dimitri, G. M., Xumerle, L., Pirazzini, C., Bacalini, M. G., Maturo, M. G., Azevedo, T., Spasov, S., Gomez-Garre, P., Perinan, M. T., Jesus, S., Baldelli, L., Sambati, L., Calandra-Buonaura, G., Garagnani, P., Provini, F., Cortelli, P., Mir, P., Trenkwalder, C., Mollenhauer, B., Franceschi, C., Lio, P., Nardini, C., Adarmes-Gomez, A., Bartoletti-Stella, A., Bhatia, K. P., Marta, B. -T., Boninsegna, C., Broli, M., Dolores, B. -R., Capellari, S., Carrion-Claro, M., Cilea, R., Clayton, R., Molin, A. D., De Luca, S., De Massis, P., Doykov, I., Escuela-Martin, R., Fabbri, G., Gabellini, A., Giuliani, C., Guaraldi, P., Hagg, S., Hallqvist, J., Halsband, C., Heywood, W., Houlden, H., Huertas, I., Jylhava, J., Labrador-Espinosa, M. A., Licari, C., Luchinat, C., Macias, D., Macri, S., Magrinelli, F., Rodriguez, J. F. M., Massimo, D., Mengozzi, G., Meoni, G., Mignani, F., Milazzo, M., Mills, K., Nassetti, S. A., Pedersen, N. L., Perinan-Tocino, M. T., Ravaioli, F., Sala, C., Scaglione, C. L. M., Schade, S., Schreglmann, S., Strom, S., Tejera-Parrado, C., Tenori, L., Turano, P., Valzania, F., Ortega, R. V., and Williams, D.

Subjects
hsa‑miR‑144‑3p, serum, Parkinson’s disease patients
Published
2022

11. Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

Author

Storm, Catherine S., Kia, Demis A., Almramhi, Mona M., Bandres-Ciga, Sara, Finan, Chris, Noyce, A. J., Kaiyrzhanov, R., Middlehurst, B., Tan, M., Houlden, H., Morris, H. R., Plun-Favreau, H., Holmans, P., Hardy, J., Trabzuni, D., Quinn, J., Bubb, V., Mok, K. Y., Kinghorn, K. J., Lewis, P., Schreglmann, S. R., Lovering, R., R'Bibo, L., Manzoni, C., Rizig, M., Ryten, M., Guelfi, S., Escott-Price, V., Chelban, V., Foltynie, T., Williams, N., Morrison, K. E., Clarke, C., Harvey, K., Jacobs, B. M., Brice, Alexis, Danjou, F., Lesage, S., Corvol, J. C., Martinez, M., Schulte, C., Brockmann, K., Simón-Sánchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Schneider, S. A., Cookson, M. R., Blauwendraat, C., Craig, D. W., Billingsley, K., Makarious, M. B., Narendra, D. P., Faghri, F., Gibbs, J. R., Hernandez, D. G., Van Keuren-Jensen, K., Shulman, J. M., Iwaki, H., Leonard, H. L., Nalls, M. A., Robak, L., Bras, J., Guerreiro, R., Lubbe, S., Troycoco, T., Finkbeiner, S., Mencacci, N. E., Lungu, C., Singleton, A. B., Scholz, S. W., Reed, X., Uitti, R. J., Ross, O. A., Grenn, F. P., Moore, A., Alcalay, R. N., Wszolek, Z. K., Gan-Or, Z., Rouleau, G. A., Krohn, L., Mufti, K., van Hilten, J. J., Marinus, J., Adarmes-Gómez, A. D., Aguilar Barberà, Miquel, Álvarez Angulo, Iñaki, Alvarez, V., Barrero, F. J., Yarza, J. A. B., Bernal-Bernal, I., Blázquez Estrada, M, Bonilla-Toribio, M., Botía, J. A., Boungiorno, M. T., Buiza-Rueda, Dolores, Cámara, A., Carrillo, F., Carrión-Claro, M., Cerdan, D., Clarimón, Jordi, Compta, Y., Diez-Fairen, M., Dols-Icardo, Oriol, Duarte, J., Duran, R., Escamilla-Sevilla, F., Ezquerra, M., Feliz, C., Fernández, M., Fernández-Santiago, R., Garcia, C., García-Ruiz, P., Gómez-Garre, P., Heredia, M. J. G., Gonzalez-Aramburu, I., Pagola, A. G., Hoenicka, J., Infante, J., Jesús, S., Jimenez-Escrig, A., Kulisevsky, Jaime, Labrador-Espinosa, M. A., Lopez-Sendon, J. L., de Munain Arregui, A. L., Macias, D., Torres, I. M., Marín, J., Marti, M. J., Martínez-Castrillo, J. C., Méndez-del-Barrio, C., González, M. M., Mata, M., Mínguez, A., Mir, P., Rezola, E. M., Muñoz, E., Pagonabarraga, J., Pastor, P., Errazquin, F. P., Periñán-Tocino, T., Ruiz-Martínez, J., Ruz, C., Rodriguez, A. S., Sierra, M., Suarez-Sanmartin, E., Tabernero, C., Tartari, J. P., Tejera-Parrado, C., Tolosa, E., Valldeoriola, F., Vargas-González, L., Vela, Lydia, Vives, F., Zimprich, A., Pihlstrom, L., Toft, M., Taba, P., Koks, S., Hassin-Baer, S., Majamaa, K., Siitonen, A., Tienari, P., Okubadejo, N. U., Ojo, O. O., Shashkin, C., Zharkinbekova, N., Akhmetzhanov, V., Kaishybayeva, G., Karimova, A., Khaibullin, T., Lynch, T. L., Hingorani, Aroon, Wood, Nicholas W.., Universitat Autònoma de Barcelona, Rosetrees Trust, John Black Charitable Foundation, University College London, King Abdulaziz University, National Institute for Health Research (UK), Universidad de Cantabria, HUS Neurocenter, Department of Neurosciences, and Clinicum

Subjects
Aging, Science, Quantitative Trait Loci, General Physics and Astronomy, Neurodegenerative, 3124 Neurology and psychiatry, General Biochemistry, Genetics and Molecular Biology, Article, Cohort Studies, Risk Factors, Genetics research, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Aetiology, Multidisciplinary, Genome, Parkinson's Disease, Genome, Human, Prevention, 3112 Neurosciences, Neurosciences, Brain, Genetic Variation, Parkinson Disease, General Chemistry, Mendelian Randomization Analysis, International Parkinson’s Disease Genomics Consortium, Brain Disorders, Good Health and Well Being, Gene Expression Regulation, Neurology, 5.1 Pharmaceuticals, Case-Control Studies, Neurological, Disease Progression, Development of treatments and therapeutic interventions, Human, Biotechnology
Abstract

Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development., There is currently no disease-modifying treatment for Parkinson’s disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome.

Published
2021

12. FV 12. Non-invasive Suppression of Essential Tremor via Phase-Locked Disruption of its Temporal Coherence

Author

Schreglmann, S., primary, Wang, D., additional, Peach, R., additional, Li, J., additional, Zhang, X., additional, Latorre, A., additional, Rhodes, E., additional, Panella, E., additional, Boyden, E.S., additional, Barahona, M., additional, Santaniello, S., additional, Rothwell, J., additional, Bhatia, K., additional, and Grossman, N., additional

Published
2021
Full Text
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13. Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage

Author

Chen, Z., Zhang, D., Reynolds, R.H., Gustavsson, E.K., García-Ruiz, S., D'Sa, K., Fairbrother-Browne, A., Vandrovcova, J., Noyce, A.J., Kaiyrzhanov, R., Middlehurst, B., Kia, D.A., Tan, M., Morris, H.R., Plun-Favreau, H., Holmans, P., Trabzuni, D., Bras, J., Quinn, J., Mok, K.Y., Kinghorn, K.J., Billingsley, K., Wood, N.W., Lewis, P., Schreglmann, S., Guerreiro, Rita, Lovering, R., R'Bibo, L., Manzoni, C., Rizig, M., Guelfi, S., Escott-Price, V., Chelban, V., Foltynie, T., Williams, N., Brice, A., Danjou, F., Lesage, S., Corvol, Jean-Christophe, Martinez, M., Schulte, C., Brockmann, K., Simón-Sánchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Nicolas, A., Cookson, M. R, Bandres-Ciga, S., Blauwendraat, Cornelis, Craig, David W, Faghri, F., Gibbs, J.R., Hernandez, D.G., Van Keuren-Jensen, K., Shulman, J.M., Leonard, H.L., Nalls, M.A., Robak, L., Lubbe, S., Finkbeiner, S., Mencacci, N.E., Lungu, C., Singleton, A. B., Scholz, S.W., Reed, X., Alcalay, Roy N, Gan-Or, Z., Rouleau, G.A., Krohn, L., van Hilten, J.J., Marinus, J., Adarmes-Gómez, A.D, Aguilar Barberà, Miquel, Alvarez, Ignacio, Alvarez, V., Barrero, F. J, Yarza, J.A.B., Bernal-Bernal, I., Blazquez, M., Bonilla-Toribio, Marta, Botía, J., Boungiorno, M.T., Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, F., Carrión-Claro, M., Cerdan, D., Clarimón, Jordi, Compta, Yaroslau, Diez-Fairen, M., Dols Icardo, Oriol, Duarte, J., Duran, Raquel, Escamilla-Sevilla, F., Ezquerra, M., Feliz, C., Fernández, M., Fernández-Santiago, R., Garcia, C., García-Ruiz, P., Gómez-Garre, P., Heredia, M.J.G., Gonzalez-Aramburu, I., Pagola, A.G., Hoenicka, J., Infante, J., Jesús, S., Jimenez-Escrig, A., Kulisevsky, Jaime, Labrador-Espinosa, Miguel A, Lopez-Sendon, J.L., de Munain Arregui, A.L., Macias, D., Torres, I.M., Marín, J., Marti, M.J., Martínez-Castrillo, J.C., Méndez-del-Barrio, C., González, M.M., Mata, M., Mínguez, A., Mir, P., Rezola, E.M., Muñoz, E., Pagonabarraga Mora, Javier, Pastor, P., Errazquin, F.P., Periñán-Tocino, T., Ruiz-Martínez, J., Ruz, C., Rodriguez, A.S., Sierra, M., Suarez-Sanmartin, E., Tabernero, C., Tartari, J. P., Tejera-Parrado, C., Tolosa, E., Valldeoriola, F., Vargas-González, L., Vela, L., Vives, F., Zimprich, Alexander, Pihlstrom, L., Toft, M., Koks, S., Taba, P., Hassin-Baer, S., Hardy, J., Houlden, Henry, Gagliano Taliun, S. A., Ryten, M., Universitat Autònoma de Barcelona, Universidad de Cantabria, Lord Leonard and Lady Estelle Wolfson Foundation, Medical Research Council (UK), Dementia Research Institute (UK), Alzheimer Society, Alzheimer's Research UK, Wellcome Trust, Dolby Family Fund, National Institute for Health Research (UK), NIHR Biomedical Research Centre (UK), Agencia Estatal de Investigación (España), Fundación Séneca, and Gobierno de la Región de Murcia

Subjects
0301 basic medicine, Apolipoprotein E, Aging, Messenger, General Physics and Astronomy, Neurodegenerative, Alzheimer's Disease, Genome, Linkage Disequilibrium, Negative selection, 0302 clinical medicine, 2.1 Biological and endogenous factors, Aetiology, health care economics and organizations, Conserved Sequence, Phylogeny, Multidisciplinary, Brain, Neurodegenerative Diseases, Single Nucleotide, Alzheimer's disease, Phenotype, International Parkinson’s Disease Genomics Consortium, Neurological, Regression Analysis, Long Noncoding, DNA, Intergenic, RNA, Long Noncoding, Human, Biotechnology, Lineage (genetic), Science, 1.1 Normal biological development and functioning, Computational biology, Biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Chromosomes, 03 medical and health sciences, Apolipoproteins E, Underpinning research, Alzheimer Disease, Genetic variation, Genetics, Acquired Cognitive Impairment, Humans, RNA, Messenger, Polymorphism, Gene, Whole genome sequencing, Intergenic, Pair 19, Genome, Human, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Molecular Sequence Annotation, General Chemistry, DNA, Introns, Brain Disorders, 030104 developmental biology, Gene Ontology, RNA, Dementia, Chromosomes, Human, Pair 19, 030217 neurology & neurosurgery
Abstract

Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer’s disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease., Knowledge of genomic features specific to humans may be important for understanding disease. Here the authors demonstrate a potential role for these human-lineage-specific sequences in brain development and neurological disease.

Published
2021

14. Unchanged gastric emptying and visceral perception in early Parkinson's disease after a high caloric test meal

Author

Epprecht, L., Schreglmann, S., Goetze, O., Woitalla, D., Baumann, C., Waldvogel, D., Epprecht, L., Schreglmann, S., Goetze, O., Woitalla, D., Baumann, C., and Waldvogel, D.

Abstract

Delayed gastric emptying (GE) is a frequent non-motor feature in Parkinson´s disease (PD). This prospective study (clinicaltrials.gov Identifier NCT01518751) investigated GE and visceral perception in early motor phase PD patients in comparison to age-matched and younger controls. In addition, the effect of Levodopa on GE was assessed in healthy aged controls. 16 PD patients (Hoehn & Yahr 2), 11 sex-/age-matched Ctrl1 and 10 young, male Ctrl2 subjects were subjected to a high caloric (428kcal) 13C-Sodium Octanoate breath test strictly OFF dopaminergic medication. Visceral appetite sensation was monitored using visual analogue scales (VAS). GE was similarly studied in 7 controls ON/OFF oral Levodopa. GE was not altered in PD patients compared to age-/sex-matched and younger controls (p=0.76). Subjective appetite perception was not altered in the PD group in comparison to Ctrl1, but was significantly higher in Ctrl2 subjects (p=0.02). 100mg oral Levodopa/25mg Benserazide significantly slowed GE by 18% among healthy controls (p=0.04). In early motor stage PD OFF dopaminergic medication, there was no GE slowing after a high caloric test meal. Levodopa, however, caused a robust GE slowing in healthy aged individuals. Our data indicate that clinically relevant GE slowing in early PD is related to the iatrogenic effect of dopamine treatment. Subjective appetite perception is not affected in this disease stage. This data add to the understanding of gastrointestinal symptoms in early motor stage PD and highlight the influence of dopaminergic medication.

Published
2021

15. Non-invasive amelioration of essential tremor via phase-locked disruption of its temporal coherence

Author

Schreglmann, S, Wang, D, Peach, R, Li, J, Zhang, X, Latorre, A, Rhodes, E, Panella, E, Boyden, E, Barahona, M, Santaniello, S, Bhatia, K, Rothwell, J, and Grossman, N

Abstract

Aberrant neural oscillations hallmark numerous brain disorders. Here, we first report a method to track the phase of neural oscillations in real-time via endpoint-corrected Hilbert transform (ecHT) that mitigates the characteristic Gibbs distortion. We then used ecHT to show that the aberrant neural oscillation that hallmarks essential tremor (ET) syndrome, the most common adult movement disorder, can be noninvasively suppressed via electrical stimulation of the cerebellum phase-locked to the tremor. The tremor suppression is sustained after the end of the stimulation and can be phenomenologically predicted. Finally, using feature-based statistical-learning and neurophysiological-modelling we show that the suppression of ET is mechanistically attributed to a disruption of the temporal coherence of the oscillation via perturbation of the tremor generating a cascade of synchronous activity in the olivocerebellar loop. The suppression of aberrant neural oscillation via phase-locked driven disruption of temporal coherence may represent a powerful neuromodulatory strategy to treat brain disorders.

Published
2020

18. SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

Author

Fernandez-Santiago, R., Martin-Flores, N., Antonelli, F., Cerquera, C., Moreno, V., Bandres-Ciga, S., Manduchi, E., Tolosa, E., Singleton, A.B., Moore, J.H., Noyce, A.J., Kaiyrzhanov, R., Middlehurst, B., Kia, D.A., Tan, M., Houlden, H., Morris, H.R., Plun-Favreau, H., Holmans, P., Hardy, J., Trabzuni, D., Bras, J., Quinn, J., Mok, K.Y., Kinghorn, K.J., Billingsley, K., Wood, N.W., Lewis, P., Schreglmann, S., Guerreiro, R., Lovering, R., R'Bibo, L., Manzoni, C., Rizig, M., Ryten, M., Guelfi, S., Escott-Price, V., Chelban, V., Foltynie, T., Williams, N., Morrison, K.E., Clarke, C., Brice, A., Danjou, F., Lesage, S., Corvol, J.C., Martinez, M., Schulte, C., Brockmann, K., Simoon-Saanchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Nicolas, A., Cookson, M.R., Blauwendraat, C., Craig, D.W., Faghri, F., Gibbs, J.R., Hernandez, D.G., Keuren-Jensen, K. van, Shulman, J.M., Iwaki, H., Leonard, H.L., Nalls, M.A., Robak, L., Lubbe, S., Finkbeiner, S., Mencacci, N.E., Lungu, C., Scholz, S.W., Reed, X., Alcalay, R.N., Gan-Or, Z., Rouleau, G.A., Krohn, L., Hilten, J.J. van, Marinus, J., Adarmes-Goomez, A.D., Aguilar, I., Alvarez, I., Alvarez, V., Barrero, F.J., Yarza, J.A.B., Bernal-Bernal, I., Blazquez, M., Bonilla-Toribio, M., Botia, J.A., Boungiorno, M.T., Buiza-Rueda, D., Camara, A., Carrillo, F., Carrion-Claro, M., Cerdan, D., Clarimon, J., Compta, Y., Casa, B. de la, Diez-Fairen, M., Dols-Icardo, O., Duarte, J., Duran, R., Escamilla-Sevilla, F., Ezquerra, M., Feliz, C., Fernandez, M., Garcia, C., Garcia-Ruiz, P., Gomez-Garre, P., Heredia, M.J.G., Gonzalez-Aramburu, I., Pagola, A.G., Hoenicka, J., Infante, J., Jesus, S., Jimenez-Escrig, A., Kulisevsky, J., Labrador-Espinosa, M.A., Lopez-Sendon, J.L., Arregui, A.L.D., Macias, D., Torres, I.M., Marin, J., Marti, M.J., Martinez-Castrillo, C., Mendez-del-Barrio, C., Gonzalez, M.M., Mata, M., Minguez, A., Mir, P., Rezola, E.M., Munoz, E., Pagonabarraga, J., Pascual-Sedano, B., Pastor, P., Errazquin, F.P., Perinan-Tocino, T., Ruiz-Martinez, J., Ruz, C., Rodriguez, A.S., Sierra, M., Suarez-Sanmartin, E., Tabernero, C., Tartari, J.P., Tejera-Parrado, C., Valldeoriola, F., Vargas-Gonzalez, L., Vela, L., Vives, F., Zimprich, A., Pihlstrom, L., Toft, M., Koks, S., Taba, P., Hassin-Baer, S., Malagelada, C., Int Parkinson's Dis Genomics Conso, Fundació La Marató de TV3, Michael J. Fox Foundation for Parkinson's Research, National Institutes of Health (US), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), and Ministerio de Ciencia, Innovación y Universidades (España)

Subjects
0301 basic medicine, epistasis, Male, Parkinson's disease, very elderly, alpha-synuclein, Alpha‐synuclein, regulatory associated protein of mTOR, Cohort Studies, 0302 clinical medicine, single nucleotide polymorphism, genetics, Age of Onset, Genetics, Aged, 80 and over, Polymorphism, Single Nucleoti, biology, TOR Serine-Threonine Kinases, target of rapamycin kinase, fchsd1 gene, Age at onset, Chromosome Mapping, glycogen synthase kinase 3beta, Parkinson Disease, Middle Aged, cohort analysis, LRRK2, priority journal, Neurology, chromosomal mapping, neuromodulation, mTOR, alpha-Synuclein, Female, age at onset, Signal Transduction, onset age, Adult, MTOR protein, human, protein kinase LKB1, gene locus, Genotype, multifactor dimensionality reduction, SNP, Single-nucleotide polymorphism, rps6ka2 gene, Polymorphism, Single Nucleotide, Risk Assessment, Article, brain function, 03 medical and health sciences, alpha synuclein, medicine, Humans, controlled study, Genetic Predisposition to Disease, human, ddc:610, SNCA protein, human, gene, Mechanistic target of rapamycin, PI3K/AKT/mTOR pathway, mammalian target of rapamycin, Aged, RPTOR, Epistasis, Genetic, Odds ratio, medicine.disease, major clinical study, nervous system diseases, 030104 developmental biology, mTOR signaling, biology.protein, Epistasis, pathology, Neurology (clinical), genetic predisposition, 030217 neurology & neurosurgery
Abstract

Special Issue: Focused Ultrasound in Parkinson's Disease., [Background] Single nucleotide polymorphisms (SNPs) in the α‐synuclein (SNCA ) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine‐rich repeat kinase 2 (LRRK2)‐associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored., [Objectives] The mechanistic target of rapamycin (mTOR ) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO., [Methods] Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium., [Results] In the discovery series cohort, we found a 4‐loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P, [Conclusions] These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society, Funding Information; Fundació la Marató de TV3. Grant Number: 60510; Michael J. Fox Foundation for Parkinson's Research. Grant Numbers: Dyskinesia Challenge 2014, MJF_PPMI_10_001, PI044024; National Institutes of Health. Grant Number: LM010098; Secretaría de Estado de Investigación, Desarrollo e Innovación. Grant Number: SAF2014‐57160R and SAF2017‐88812R.

Published
2019

19. SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

Author

Martin-Flores, N, Antonelli, F, Cerquera, C, Moreno, V, Manduchi, E, Moore, JH, Noyce, AJ, Kaiyrzhanov, R, Middlehurst, B, Kia, DA, Tan, M, Houlden, H, Morris, HR, Plun-Favreau, H, Holmans, P, Hardy, J, Trabzuni, D, Bras, J, Quinn, J, Mok, KY, Kinghorn, KJ, Billingsley, K, Wood, NW, Lewis, P, Schreglmann, S, Guerreiro, R, Lovering, R, R'Bibo, L, Manzoni, C, Rizig, M, Ryten, M, Guelfi, S, Escott-Price, V, Chelban, V, Foltynie, T, Williams, N, Morrison, KE, Clarke, C, Brice, A, Danjou, F, Lesage, S, Corvol, JC, Martinez, M, Schulte, C, Brockmann, K, Simoon-Saanchez, J, Heutink, P, Rizzu, P, Sharma, M, Gasser, T, Nicolas, A, Cookson, MR, Bandres-Ciga, S, Blauwendraat, C, Craig, DW, Faghri, F, Gibbs, JR, Hernandez, DG, Van Keuren-Jensen, K, Shulman, JM, Iwaki, H, Leonard, HL, Nalls, MA, Robak, L, Lubbe, S, Finkbeiner, S, Mencacci, NE, Lungu, C, Singleton, AB, Scholz, SW, Reed, X, Alcalay, RN, Gan-Or, Z, Rouleau, GA, Krohn, L, van Hilten, JJ, Marinus, J, Adarmes-Goomez, AD, Aguilar, I, Alvarez, I, Alvarez, V, Barrero, FJ, Yarza, JAB, Bernal-Bernal, I, Blazquez, M, Bonilla-Toribio, M, Botia, JA, Boungiorno, MT, Buiza-Rueda, D, Camara, A, Carrillo, F, Carrion-Claro, M, Cerdan, D, Clarimon, J, Compta, Y, de la Casa, B, Diez-Fairen, M, Dols-Icardo, O, Duarte, J, Duran, R, Escamilla-Sevilla, F, Feliz, C, Fernandez, M, Fernandez-Santiago, R, Garcia, C, Garcia-Ruiz, P, Gomez-Garre, P, Heredia, MJG, Gonzalez-Aramburu, I, Pagola, AG, Hoenicka, J, Infante, J, Jesus, S, Jimenez-Escrig, A, Kulisevsky, J, Labrador-Espinosa, MA, Lopez-Sendon, JL, Arregui, ALD, Macias, D, Torres, IM, Marin, J, Marti, MJ, Martinez-Castrillo, C, Mendez-del-Barrio, C, Gonzalez, MM, Mata, M, Minguez, A, Mir, P, Rezola, EM, Munoz, E, Pagonabarraga, J, Pascual-Sedano, B, Pastor, P, Errazquin, FP, Perinan-Tocino, T, Ruiz-Martinez, J, Ruz, C, Rodriguez, AS, Sierra, M, Suarez-Sanmartin, E, Tabernero, C, Tartari, JP, Tejera-Parrado, C, Tolosa, E, Valldeoriola, F, Vargas-Gonzalez, L, Vela, L, Vives, F, Zimprich, A, Pihlstrom, L, Toft, M, Koks, S, Taba, P, Hassin-Baer, S, Ezquerra, M, Malagelada, C, and Int Parkinson's Dis Genomics Conso

Subjects
epistasis, alpha-synuclein, Parkinson's disease, mTOR, SNP, age at onset
Abstract

Background Single nucleotide polymorphisms (SNPs) in the alpha-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. Objectives The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. Methods Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. Results In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P < .001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P < .0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. Conclusions These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. (c) 2019 International Parkinson and Movement Disorder Society

Published
2019

20. Pyridostigmine bromide versus fludrocortisone in the treatment of orthostatic hypotension in Parkinson's disease - a randomized controlled trial

Author

Schreglmann, S R; https://orcid.org/0000-0002-4129-5808, Büchele, F, Sommerauer, M, Epprecht, L; https://orcid.org/0000-0002-0877-4698, Kägi, G, Hägele-Link, S, Götze, O, Zimmerli, L, Waldvogel, D, Baumann, C R, Schreglmann, S R; https://orcid.org/0000-0002-4129-5808, Büchele, F, Sommerauer, M, Epprecht, L; https://orcid.org/0000-0002-0877-4698, Kägi, G, Hägele-Link, S, Götze, O, Zimmerli, L, Waldvogel, D, and Baumann, C R

Published
2017

23. Unchanged gastric emptying and visceral perception in early Parkinson's disease after a high caloric test meal

Author

Epprecht, L, Schreglmann, S R, Goetze, O, Woitalla, D, Baumann, C R, Waldvogel, D, Epprecht, L, Schreglmann, S R, Goetze, O, Woitalla, D, Baumann, C R, and Waldvogel, D

Abstract

Delayed gastric emptying (GE) is a frequent non-motor feature in Parkinson´s disease (PD). This prospective study (clinicaltrials.gov Identifier NCT01518751) investigated GE and visceral perception in early motor phase PD patients in comparison to age-matched and younger controls. In addition, the effect of Levodopa on GE was assessed in healthy aged controls. 16 PD patients (Hoehn & Yahr 2), 11 sex-/age-matched Ctrl1 and 10 young, male Ctrl2 subjects were subjected to a high caloric (428 kcal) (13)C-Sodium Octanoate breath test strictly OFF dopaminergic medication. Visceral appetite sensation was monitored using visual analogue scales (VAS). GE was similarly studied in 7 controls ON/OFF oral Levodopa. GE was not altered in PD patients compared to age-/sex-matched and younger controls (p = 0.76). Subjective appetite perception was not altered in the PD group in comparison to Ctrl1, but was significantly higher in Ctrl2 subjects (p = 0.02). 100 mg oral Levodopa/25 mg Benserazide significantly slowed GE by 18% among healthy controls (p = 0.04). In early motor stage PD OFF dopaminergic medication, there was no GE slowing after a high caloric test meal. Levodopa, however, caused a robust GE slowing in healthy aged individuals. Our data indicate that clinically relevant GE slowing in early PD is related to the iatrogenic effect of dopamine treatment. Subjective appetite perception is not affected in this disease stage. This data add to the understanding of gastrointestinal symptoms in early motor stage PD and highlight the influence of dopaminergic medication.

Published
2015

28. Multifocal CNS demyelination after octreotide treatment for metastatic meningioma.

Author

Schreglmann, S. R., Jelčić, I., Taegtmeyer, A. B., Linnebank, M., and Weller, M.

Subjects
*SOMATOSTATIN receptors, *MENINGIOMA, *DEMYELINATION, *NEUROLOGICAL disorders, *OCTREOTIDE acetate, *PATIENTS, *THERAPEUTICS
Abstract

The article describes the case of a female patient with metastatic somatostatin receptor-positive meningioma who was diagnosed with multifocal central nervous system (CNS) demyelination after octreotide therapy. It discusses the findings of a magnetic resonance imaging (MRI) conducted on the patient. It concluded that there is a possible risk for autoimmune medicated focal demyelination by octreotide treatment in polyallergic patients.

Published
2013
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29. Unchanged gastric emptying and visceral perception in early Parkinson's disease after a high caloric test meal

Author

Epprecht, L., Schreglmann, S., Goetze, O., Woitalla, D., Baumann, C., Waldvogel, D., Epprecht, L., Schreglmann, S., Goetze, O., Woitalla, D., Baumann, C., and Waldvogel, D.

Abstract

Delayed gastric emptying (GE) is a frequent non-motor feature in Parkinson´s disease (PD). This prospective study (clinicaltrials.gov Identifier NCT01518751) investigated GE and visceral perception in early motor phase PD patients in comparison to age-matched and younger controls. In addition, the effect of Levodopa on GE was assessed in healthy aged controls. 16 PD patients (Hoehn & Yahr 2), 11 sex-/age-matched Ctrl1 and 10 young, male Ctrl2 subjects were subjected to a high caloric (428kcal) 13C-Sodium Octanoate breath test strictly OFF dopaminergic medication. Visceral appetite sensation was monitored using visual analogue scales (VAS). GE was similarly studied in 7 controls ON/OFF oral Levodopa. GE was not altered in PD patients compared to age-/sex-matched and younger controls (p=0.76). Subjective appetite perception was not altered in the PD group in comparison to Ctrl1, but was significantly higher in Ctrl2 subjects (p=0.02). 100mg oral Levodopa/25mg Benserazide significantly slowed GE by 18% among healthy controls (p=0.04). In early motor stage PD OFF dopaminergic medication, there was no GE slowing after a high caloric test meal. Levodopa, however, caused a robust GE slowing in healthy aged individuals. Our data indicate that clinically relevant GE slowing in early PD is related to the iatrogenic effect of dopamine treatment. Subjective appetite perception is not affected in this disease stage. This data add to the understanding of gastrointestinal symptoms in early motor stage PD and highlight the influence of dopaminergic medication.

30. A geroscience approach for Parkinson's disease: Conceptual framework and design of PROPAG-AGEING project

Author

Chiara Pirazzini, Tiago Azevedo, Luca Baldelli, Anna Bartoletti-Stella, Giovanna Calandra-Buonaura, Alessandra Dal Molin, Giovanna Maria Dimitri, Ivan Doykov, Pilar Gómez-Garre, Sara Hägg, Jenny Hällqvist, Claire Halsband, Wendy Heywood, Silvia Jesús, Juulia Jylhävä, Katarzyna Malgorzata Kwiatkowska, Miguel A. Labrador-Espinosa, Cristina Licari, Maria Giovanna Maturo, Giacomo Mengozzi, Gaia Meoni, Maddalena Milazzo, Maria Teresa Periñán-Tocino, Francesco Ravaioli, Claudia Sala, Luisa Sambati, Sebastian Schade, Sebastian Schreglmann, Simeon Spasov, Leonardo Tenori, Dylan Williams, Luciano Xumerle, Elisa Zago, Kailash P. Bhatia, Sabina Capellari, Pietro Cortelli, Paolo Garagnani, Henry Houlden, Pietro Liò, Claudio Luchinat, Massimo Delledonne, Kevin Mills, Pablo Mir, Brit Mollenhauer, Christine Nardini, Nancy L. Pedersen, Federica Provini, Stephen Strom, Claudia Trenkwalder, Paola Turano, Maria Giulia Bacalini, Claudio Franceschi, Astrid Adarmes-Gómez, Marta Bonilla-Toribio, Claudia Boninsegna, Marcella Broli, Dolores Buiza-Rueda, Mario Carrión-Claro, Rosalia Cilea, Robert Clayton, Silvia De Luca, Patrizia De Massis, Rocio Escuela-Martin, Giovanni Fabbri, Anna Gabellini, Cristina Giuliani, Pietro Guaraldi, Ismae Huertas, Daniel Macias, Stefania Macrì, Francesca Magrinelli, Juan Francisco Martín Rodríguez, Francesco Mignani, Stefania Alessandra Nassetti, Cesa Lorella Maria Scaglione, Cristina Tejera-Parrado, Franco Valzania, Rosario Vigo Ortega, Pirazzini C., Azevedo T., Baldelli L., Bartoletti-Stella A., Calandra Buonaura G., Dal Molin A., Dimitri G.M., Doykov I., Gomez-Garre P., Hagg S., Hallqvist J., Halsband C., Heywood W., Jesus S., Jylhava J., Kwiatkowska K.M., Labrador-Espinosa M.A., Licari C., Maturo M.G., Mengozzi G., Meoni G., Milazzo M., Perinan-Tocino M.T., Ravaioli F., Sala C., Sambati L., Schade S., Schreglmann S., Spasov S., Tenori L., Williams D., Xumerle L., Zago E., Bhatia K.P., Capellari S., Cortelli P., Garagnani P., Houlden H., Lio P., Luchinat C., Delledonne M., Mills K., Mir P., Mollenhauer B., Nardini C., Pedersen N.L., Provini F., Strom S., Trenkwalder C., Turano P., Bacalini M.G., Franceschi C., Adarmes-Gomez A., Bonilla-Toribio M., Boninsegna C., Broli M., Buiza-Rueda D., Carrion-Claro M., Cilea R., Clayton R., Molin A.D., De Luca S., De Massis P., Escuela-Martin R., Fabbri G., Gabellini A., Giuliani C., Guaraldi P., Huertas I., Macias D., Macri S., Magrinelli F., Rodriguez J.F.M., Mignani F., Nassetti S.A., Scaglione C.L.M., Tejera-Parrado C., Valzania F., and Ortega R.V.

Subjects
0301 basic medicine, Gerontology, Male, Aging, Parkinson's disease, Biomedical Research, Inflammaging, Neurodegeneration, Omics, Disease, Motor Activity, 03 medical and health sciences, 0302 clinical medicine, Omic, medicine, Humans, Metabolomics, Risk factor, Aged, Aged, 80 and over, Neurons, Geroscience, business.industry, Age Factors, Brain, Parkinson Disease, Genomics, medicine.disease, 3. Good health, Europe, 030104 developmental biology, Conceptual framework, Ageing, Geriatrics, Research Design, Case-Control Studies, Nerve Degeneration, Twin Studies as Topic, Female, Healthy ageing, Inflammation Mediators, business, 030217 neurology & neurosurgery, Motor disability, Developmental Biology, Signal Transduction
Abstract

Advanced age is the major risk factor for idiopathic Parkinson's disease (PD), but to date the biological relationship between PD and ageing remains elusive. Here we describe the rationale and the design of the H2020 funded project "PROPAG-AGEING", whose aim is to characterize the contribution of the ageing process to PD development. We summarize current evidences that support the existence of a continuum between ageing and PD and justify the use of a Geroscience approach to study PD. We focus in particular on the role of inflammaging, the chronic, low-grade inflammation characteristic of elderly physiology, which can propagate and transmit both locally and systemically. We then describe PROPAG-AGEING design, which is based on the multi-omic characterization of peripheral samples from clinically characterized drug-naive and advanced PD, PD discordant twins, healthy controls and "super-controls", i.e. centenarians, who never showed clinical signs of motor disability, and their offspring. Omic results are then validated in a large number of samples, including in vitro models of dopaminergic neurons and healthy siblings of PD patients, who are at higher risk of developing PD, with the final aim of identifying the molecular perturbations that can deviate the trajectories of healthy ageing towards PD development.

Published
2020

31. Pyridostigmine bromide versus fludrocortisone in the treatment of orthostatic hypotension in Parkinson's disease - a randomized controlled trial

Author

Sebastian R Schreglmann, Michael Sommerauer, O. Götze, Stefan Hägele-Link, Georg Kägi, Lorenz Epprecht, Fabian Büchele, Daniel Waldvogel, Christian R. Baumann, Lukas Zimmerli, University of Zurich, and Schreglmann, S R

Subjects
Male, Supine position, Supine hypertension, Fludrocortisone, Blood Pressure, 610 Medicine & health, 030204 cardiovascular system & hematology, law.invention, Hypotension, Orthostatic, 03 medical and health sciences, Orthostatic vital signs, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, Risk Factors, law, Humans, Medicine, Aged, Cross-Over Studies, business.industry, Repeated measures design, Parkinson Disease, Middle Aged, 3. Good health, 10040 Clinic for Neurology, Treatment Outcome, Blood pressure, 2728 Neurology (clinical), Neurology, Anesthesia, 2808 Neurology, Quality of Life, Female, Pyridostigmine Bromide, Cholinesterase Inhibitors, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Background and purpose Evidence for effective treatment options for orthostatic hypotension (OH) in Parkinson's disease (PD) is scarce. Elevation of cholinergic tone with pyridostigmine bromide has been reported as a way to improve blood pressure (bp) regulation in neurogenic hypotension without causing supine hypertension. Methods This was a double-centre, double-blind, randomized, active-control, crossover, phase II non-inferiority trial of pyridostigmine bromide for OH in PD (clinicaltrials.gov NCT01993680). Patients with confirmed OH were randomized to 14 days 3 × 60 mg/day pyridostigmine bromide or 1 × 0.2 mg/day fludrocortisone before crossover. Outcome was measured by peripheral and central bp monitoring during the Schellong manoeuvre and questionnaires. Results Thirteen participants were enrolled between April 2013 and April 2015 with nine participants completing each trial arm. Repeated measures comparison showed a significant 37% improvement with fludrocortisone for the primary outcome diastolic bp drop on orthostatic challenge (baseline 22.9 ± 13.6 vs. pyridostigmine bromide 22.1 ± 17.0 vs. fludrocortisone 14.0 ± 12.6 mmHg; P = 0.04), whilst pyridostigmine bromide had no effect. Fludrocortisone caused an 11% peripheral systolic supine bp rise (baseline 128.4 ± 12.8 vs. pyridostigmine bromide 130.4 ± 18.3 vs. fludrocortisone 143.2 ± 10.1 mmHg; P = 0.01) but no central mean arterial supine bp rise (baseline 107.2 ± 7.8 vs. pyridostigmine bromide 97.0 ± 12.0 vs. fludrocortisone 107.3 ± 6.3 mmHg; P = 0.047). Subjective OH severity, motor score and quality of life remained unchanged by both study interventions. Conclusions Pyridostigmine bromide is inferior to fludrocortisone in the treatment of OH in PD. This trial provides first objective evidence of the efficacy of 0.2 mg/day fludrocortisone for OH in PD, causing minor peripheral but no central supine hypertension. In addition to peripheral bp, future trials should include central bp measurements, known to correlate more closely with cardiovascular risk.

Published
2017
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32. Multifocal CNS demyelination after octreotide treatment for metastatic meningioma

Author

Michael Weller, Sebastian R Schreglmann, Anne B. Taegtmeyer, Ilijas Jelcic, Michael Linnebank, University of Zurich, and Schreglmann, S R

Subjects
Adult, Central Nervous System, Pathology, medicine.medical_specialty, Lung Neoplasms, Antineoplastic Agents, Hormonal, CNS demyelination, Neural Conduction, Octreotide, 610 Medicine & health, Meningioma, Acromegaly, otorhinolaryngologic diseases, Humans, Medicine, Receptors, Somatostatin, Neurologic Examination, business.industry, Somatostatin receptor, Metastatic Meningioma, General Medicine, medicine.disease, Combined Modality Therapy, 10040 Clinic for Neurology, 2746 Surgery, nervous system diseases, 2728 Neurology (clinical), Somatostatin, Evoked Potentials, Visual, Female, Surgery, Neurology (clinical), business, Demyelinating Diseases, Recurrent Meningioma, medicine.drug
Abstract

Octreotide (Sandostatin® Novartis, Berne, Switzerland) is a omatostatin analog approved for the treatment of acromegaly nd gastrointestinal syndromes of hormone hypersecretion in witzerland. Since somatostatin receptors (SSTR) are present on ost meningiomas, octreotide has been suggested as a salvage reatment for patients with recurrent meningioma with presence f somatostatin receptors confirmed by octreotide SPECT or PET tudies [1,2]. We report the case of a patient with metastatic omatostatin receptor-positive meningioma who developed mulifocal CNS demyelination after octreotide therapy.

Published
2013

33. Plasma proteomics identify biomarkers predicting Parkinson's disease up to 7 years before symptom onset.

Author

Hällqvist J, Bartl M, Dakna M, Schade S, Garagnani P, Bacalini MG, Pirazzini C, Bhatia K, Schreglmann S, Xylaki M, Weber S, Ernst M, Muntean ML, Sixel-Döring F, Franceschi C, Doykov I, Śpiewak J, Vinette H, Trenkwalder C, Heywood WE, Mills K, and Mollenhauer B

Subjects
Humans, Male, Female, Aged, Middle Aged, Machine Learning, REM Sleep Behavior Disorder blood, REM Sleep Behavior Disorder diagnosis, Case-Control Studies, Mass Spectrometry, Parkinson Disease blood, Parkinson Disease diagnosis, Biomarkers blood, Proteomics methods
Abstract

Parkinson's disease is increasingly prevalent. It progresses from the pre-motor stage (characterised by non-motor symptoms like REM sleep behaviour disorder), to the disabling motor stage. We need objective biomarkers for early/pre-motor disease stages to be able to intervene and slow the underlying neurodegenerative process. Here, we validate a targeted multiplexed mass spectrometry assay for blood samples from recently diagnosed motor Parkinson's patients (n = 99), pre-motor individuals with isolated REM sleep behaviour disorder (two cohorts: n = 18 and n = 54 longitudinally), and healthy controls (n = 36). Our machine-learning model accurately identifies all Parkinson patients and classifies 79% of the pre-motor individuals up to 7 years before motor onset by analysing the expression of eight proteins-Granulin precursor, Mannan-binding-lectin-serine-peptidase-2, Endoplasmatic-reticulum-chaperone-BiP, Prostaglaindin-H2-D-isomaerase, Interceullular-adhesion-molecule-1, Complement C3, Dickkopf-WNT-signalling pathway-inhibitor-3, and Plasma-protease-C1-inhibitor. Many of these biomarkers correlate with symptom severity. This specific blood panel indicates molecular events in early stages and could help identify at-risk participants for clinical trials aimed at slowing/preventing motor Parkinson's disease., (© 2024. The Author(s).)

Published
2024
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35. A geroscience approach for Parkinson's disease: Conceptual framework and design of PROPAG-AGEING project.

Author

Pirazzini C, Azevedo T, Baldelli L, Bartoletti-Stella A, Calandra-Buonaura G, Dal Molin A, Dimitri GM, Doykov I, Gómez-Garre P, Hägg S, Hällqvist J, Halsband C, Heywood W, Jesús S, Jylhävä J, Kwiatkowska KM, Labrador-Espinosa MA, Licari C, Maturo MG, Mengozzi G, Meoni G, Milazzo M, Periñán-Tocino MT, Ravaioli F, Sala C, Sambati L, Schade S, Schreglmann S, Spasov S, Tenori L, Williams D, Xumerle L, Zago E, Bhatia KP, Capellari S, Cortelli P, Garagnani P, Houlden H, Liò P, Luchinat C, Delledonne M, Mills K, Mir P, Mollenhauer B, Nardini C, Pedersen NL, Provini F, Strom S, Trenkwalder C, Turano P, Bacalini MG, and Franceschi C

Subjects
Aged, Aged, 80 and over, Female, Humans, Male, Age Factors, Case-Control Studies, Europe, Genomics, Metabolomics, Motor Activity, Nerve Degeneration, Research Design, Signal Transduction, Twin Studies as Topic, Aging genetics, Aging metabolism, Aging pathology, Biomedical Research, Brain metabolism, Brain pathology, Brain physiopathology, Geriatrics, Inflammation Mediators metabolism, Neurons metabolism, Neurons pathology, Parkinson Disease genetics, Parkinson Disease metabolism, Parkinson Disease pathology, Parkinson Disease physiopathology
Abstract

Advanced age is the major risk factor for idiopathic Parkinson's disease (PD), but to date the biological relationship between PD and ageing remains elusive. Here we describe the rationale and the design of the H2020 funded project "PROPAG-AGEING", whose aim is to characterize the contribution of the ageing process to PD development. We summarize current evidences that support the existence of a continuum between ageing and PD and justify the use of a Geroscience approach to study PD. We focus in particular on the role of inflammaging, the chronic, low-grade inflammation characteristic of elderly physiology, which can propagate and transmit both locally and systemically. We then describe PROPAG-AGEING design, which is based on the multi-omic characterization of peripheral samples from clinically characterized drug-naïve and advanced PD, PD discordant twins, healthy controls and "super-controls", i.e. centenarians, who never showed clinical signs of motor disability, and their offspring. Omic results are then validated in a large number of samples, including in vitro models of dopaminergic neurons and healthy siblings of PD patients, who are at higher risk of developing PD, with the final aim of identifying the molecular perturbations that can deviate the trajectories of healthy ageing towards PD development., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2021
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36. Syringomyelia-Associated Dystonia: Case Series, Literature Review, and Novel Insights.

Author

Mulroy E, Balint B, Latorre A, Schreglmann S, Menozzi E, and Bhatia KP

Abstract

Background: Syringomyelia has previously been suggested as a potential trigger of secondary dystonia. However, a definite causal relationship between the conditions remains to be established. We describe 4 cases of syrinx-associated dystonia, review past literature on the subject, and propose novel pathophysiological insights into this association., Methods: We reviewed demographic, clinical, and neuroradiological features in 4 cases of syrinx-associated dystonia. A retrospective review of previously published literature on the subject was also conducted., Results: Patients with syrinx-associated dystonia were younger than those with primary dystonia. None had sensory gestes. Syringomyelia frequently involved the cervical cord. Arnold-Chiari type 1 malformation was a common finding. Some patients responded to botulinum toxin and syrinx decompression., Conclusion: Further work is needed to clearly establish the correlation between syringomyelia and dystonia. However, plausibly, syrinx-related disruption of the dystonia network (through alterations in sensory inputs, loss of inhibition and cerebellar abnormalities) could explain the association.

Published
2019
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37. Role of α-synuclein in adult neurogenesis and neuronal maturation in the dentate gyrus.

Author

Winner B, Regensburger M, Schreglmann S, Boyer L, Prots I, Rockenstein E, Mante M, Zhao C, Winkler J, Masliah E, and Gage FH

Subjects
Aged, 80 and over, Animals, Cell Count, Dendrites pathology, Dendrites physiology, Dendritic Spines pathology, Dendritic Spines physiology, Dentate Gyrus cytology, Dentate Gyrus growth & development, Female, Fluorescent Antibody Technique, Genetic Vectors, Green Fluorescent Proteins, Humans, Immunohistochemistry, Lewy Body Disease pathology, Male, Mice, Mice, Knockout, Phosphodiesterase Inhibitors pharmacology, Retroviridae genetics, Rolipram pharmacology, beta-Synuclein physiology, Dentate Gyrus physiology, Neurogenesis physiology, Neurons physiology, alpha-Synuclein physiology
Abstract

α-Synuclein has been reported to be important in modulating brain plasticity and to be a key protein in neurodegenerative diseases, including Lewy body dementia (LBD). We investigated how α-synuclein levels modulate adult neurogenesis and the development of dendritic arborization and spines in the dentate gyrus, in which new neurons are constantly added. In the human hippocampus, levels of endogenous α-synuclein were increased in LBD, and the numbers of SOX2-positive cells were decreased. We investigated whether newly generated neurons were modulated by endogenous α-synuclein, and we found increased adult neurogenesis in α/β-synuclein knock-out mice. In contrast, overexpression of human wild-type α-synuclein (WTS) decreased the survival and dendritic development of newborn neurons. Endogenous α-synuclein expression levels increased the negative impact of WTS on dendrite development, suggesting a toxic effect of increasing amounts of α-synuclein. To attempt a rescue of the dendritic phenotype, we administered rolipram to activate the cAMP response element-binding protein pathway, which led to a partial rescue of neurite development. The current work provides novel insights into the role of α-synuclein in adult hippocampal neurogenesis.

Published
2012
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38. Transdermal rotigotine causes impulse control disorders in patients with restless legs syndrome.

Author

Schreglmann SR, Gantenbein AR, Eisele G, and Baumann CR

Subjects
Administration, Cutaneous, Aged, Aged, 80 and over, Disruptive, Impulse Control, and Conduct Disorders complications, Dopamine Agonists administration & dosage, Female, Humans, Longitudinal Studies, Male, Middle Aged, Restless Legs Syndrome complications, Retrospective Studies, Surveys and Questionnaires, Tetrahydronaphthalenes administration & dosage, Thiophenes administration & dosage, Disruptive, Impulse Control, and Conduct Disorders chemically induced, Disruptive, Impulse Control, and Conduct Disorders diagnosis, Dopamine Agonists adverse effects, Restless Legs Syndrome diagnosis, Tetrahydronaphthalenes adverse effects, Thiophenes adverse effects
Abstract

Introduction: Dopaminergic drugs are the mainstay of treatment for restless legs syndrome (RLS). We analyzed the frequency and clinical characteristics of impulse control disorders (ICD) in patients with RLS on transdermal rotigotine treatment., Methods: Retrospective case series at a university movement disorder clinic (n = 28, 17 women). Symptoms of ICD were assessed via detailed history taking and scoring with the Zurich Screening Questionnaire for ICD (ZICD) prior to and after initiation of treatment., Results: None of the patients had a history of ICD prior to treatment. Baseline mean scores for patients who did (8.0 ± 2.5) and did not (6.2 ± 2.7) develop ICD under treatment did not differ. Six male patients (21%) developed various symptoms of ICD (mean ZICD scores 20.7 ± 10.2) on rotigotine treatment (mean dose: 3.8 mg/d), including binge eating, hypersexuality, compulsive shopping, pathological gambling, and punding, equaling a prevalence rate of 21%. Also in the non-ICD group, ZICD scores increased (7.5 ± 2.8)., Conclusion: This is the first report of ICD in patients treated with transdermal rotigotine for RLS. In contrast to literature, even low doses of rotigotine (mean 3.8 mg/d) can cause ICD. Therefore every prescribing physician should be aware that ICD may emerge in both RLS and PD patients on any dopaminergic treatment, and should actively ask for such symptoms. The ZICD questionnaire not only replicated the findings of detailed history taking but also showed an increased tendency towards impulsive behaviour in subjects that did not develop ICD., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2012
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39. Bilateral vertebral artery occlusion with retrograde basilary flow in three cases of giant cell arteritis.

Author

Boettinger M, Sebastian S, Gamulescu MA, Grauer O, Ritzka M, Schuierer G, Bogdahn U, Steinbrecher A, and Schlachetzki F

Abstract

Vertebrobasilar ischaemia is a rare life-threatening complication in giant cell arteritis (GCA). We report three patients with bilateral vertebral artery occlusion. Neurovascular imaging, including CT-angiography, MR-angiography and colour-coded duplex sonography revealed flow reversal in the basilar artery as well as inflammation of the vertebral vessel wall. The first patient died from massive brainstem infarction, the other two patients survived the initial inflammatory phase of GCA. No stroke recurrence at 12 months' follow-up on warfarin and steroid treatment was observed. Bilateral distal vertebral artery occlusion and retrograde basilar artery flow persisted.Outcome in these patients is dependant on potent immunosuppression, concurrent atherosclerotic steno-occlusive disease and presence and/or rapid development of sufficient collateral pathways into the vertebrobasilar circulation. The identification of patients with high risk of ischaemia due to compromised vertebrobasilar flow may be important to select adjunct treatment to immunosuppression, such as anticoagulation in GCA.

Published
2009
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