34 results on '"Knudsen, Karoline"'
Search Results
2. Functional and 123I-MIBG scintigraphy assessment of cardiac adrenergic dysfunction in diabetes
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Rasmussen, Thorsten K., Borghammer, Per, Finnerup, Nanna B., Jensen, Troels S., Hansen, John, Knudsen, Karoline, Singer, Wolfgang, Lamotte, Guillaume, and Terkelsen, Astrid J.
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- 2024
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3. [18F]FEOBV positron emission tomography may not be a suitable method to measure parasympathetic denervation in patients with Parkinson's disease
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Horsager, Jacob, Okkels, Niels, Fedorova, Tatyana D., Knudsen, Karoline, Skjærbæk, Casper, Van Den Berge, Nathalie, Jacobsen, Jan, Munk, Ole Lajord, Danielsen, Erik Hvid, Bender, Dirk, Brooks, David J., and Borghammer, Per
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- 2022
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4. Healthy brain aging assessed with [18F]FDG and [11C]UCB-J PET
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Andersen, Katrine B., Hansen, Allan K., Knudsen, Karoline, Schacht, Anna Christina, Damholdt, Malene F., Brooks, David J., and Borghammer, Per
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- 2022
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5. Imaging progressive peripheral and central dysfunction in isolated REM sleep behaviour disorder after 3 years of follow-up
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Fedorova, Tatyana D., Knudsen, Karoline, Andersen, Katrine B., Horsager, Jacob, Skjærbæk, Casper, Beier, Christoph P., Sommerauer, Michael, Svendsen, Kristina B., Otto, Marit, and Borghammer, Per
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- 2022
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6. Cholinergic changes in Lewy body disease: implications for presentation, progression and subtypes
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Okkels, Niels, primary, Grothe, Michel J, additional, Taylor, John-Paul, additional, Hasselbalch, Steen Gregers, additional, Fedorova, Tatyana D, additional, Knudsen, Karoline, additional, van der Zee, Sygrid, additional, van Laar, Teus, additional, Bohnen, Nicolaas, additional, Borghammer, Per, additional, and Horsager, Jacob, additional
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- 2024
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7. Impaired cholinergic integrity of the colon and pancreas in dementia with Lewy bodies
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Instituto de Salud Carlos III, European Commission, Aase og Ejnar Danielsens Fond, Michael J. Fox Foundation for Parkinson's Research, Lundbeck Foundation, Grothe, Michel J. [0000-0003-2600-9022], Okkels, Niels, Horsager, Jacob, Fedorova, Tatyana D., Knudsen, Karoline, Skjærbæk, Casper, Andersen, Katrine B., Labrador-Espinosa, Miguel, Vestergård, Karsten, Mortensen, Janne, Klit, Henriette, Møller, Mette, Danielsen, Erik H., Johnsen, Erik L., Bekan, Goran, Hansen, Kim V., Munk, Ole L., Damholdt, Malene F., Kjeldsen, Pernille L., Hansen, Allan K., Gottrup, Hanne, Grothe, Michel J., Borghammer, Per, Instituto de Salud Carlos III, European Commission, Aase og Ejnar Danielsens Fond, Michael J. Fox Foundation for Parkinson's Research, Lundbeck Foundation, Grothe, Michel J. [0000-0003-2600-9022], Okkels, Niels, Horsager, Jacob, Fedorova, Tatyana D., Knudsen, Karoline, Skjærbæk, Casper, Andersen, Katrine B., Labrador-Espinosa, Miguel, Vestergård, Karsten, Mortensen, Janne, Klit, Henriette, Møller, Mette, Danielsen, Erik H., Johnsen, Erik L., Bekan, Goran, Hansen, Kim V., Munk, Ole L., Damholdt, Malene F., Kjeldsen, Pernille L., Hansen, Allan K., Gottrup, Hanne, Grothe, Michel J., and Borghammer, Per
- Abstract
Dementia with Lewy bodies is characterized by a high burden of autonomic dysfunction and Lewy pathology in peripheral organs and components of the sympathetic and parasympathetic nervous system. Parasympathetic terminals may be quantified with 18F-fluoroetoxybenzovesamicol, a PET tracer that binds to the vesicular acetylcholine transporter in cholinergic presynaptic terminals. Parasympathetic imaging may be useful for diagnostics, improving our understanding of autonomic dysfunction and for clarifying the spatiotemporal relationship of neuronal degeneration in prodromal disease. Therefore, we aimed to investigate the cholinergic parasympathetic integrity in peripheral organs and central autonomic regions of subjects with dementia with Lewy bodies and its association with subjective and objective measures of autonomic dysfunction. We hypothesized that organs with known parasympathetic innervation, especially the pancreas and colon, would have impaired cholinergic integrity. To achieve these aims, we conducted a cross-sectional comparison study including 23 newly diagnosed non-diabetic subjects with dementia with Lewy bodies (74 ± 6 years, 83% male) and 21 elderly control subjects (74 ± 6 years, 67% male). We obtained whole-body images to quantify PET uptake in peripheral organs and brain images to quantify PET uptake in regions of the brainstem and hypothalamus. Autonomic dysfunction was assessed with questionnaires and measurements of orthostatic blood pressure. Subjects with dementia with Lewy bodies displayed reduced cholinergic tracer uptake in the pancreas (32% reduction, P = 0.0003) and colon (19% reduction, P = 0.0048), but not in organs with little or no parasympathetic innervation. Tracer uptake in a region of the medulla oblongata overlapping the dorsal motor nucleus of the vagus correlated with autonomic symptoms (rs = −0.54, P = 0.0077) and changes in orthostatic blood pressure (rs = 0.76, P < 0.0001). Tracer uptake in the pedunculopontine region correlat
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- 2024
8. Dopaminergic Dysfunction Is More Symmetric in Dementia with Lewy Bodies Compared to Parkinson’s Disease
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Fedorova, Tatyana Dmitrievna, primary, Knudsen, Karoline, additional, Horsager, Jacob, additional, Hansen, Allan K., additional, Okkels, Niels, additional, Gottrup, Hanne, additional, Vang, Kim, additional, and Borghammer, Per, additional
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- 2023
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9. Impaired cholinergic integrity of the colon and pancreas in dementia with Lewy bodies.
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Okkels, Niels, Horsager, Jacob, Fedorova, Tatyana D, Knudsen, Karoline, Skjærbæk, Casper, Andersen, Katrine B, Labrador-Espinosa, Miguel, Vestergaard, Karsten, Mortensen, Janne K, Klit, Henriette, Møller, Mette, Danielsen, Erik H, Johnsen, Erik L, Bekan, Goran, Hansen, Kim V, Munk, Ole L, Damholdt, Malene F, Kjeldsen, Pernille L, Hansen, Allan K, and Gottrup, Hanne
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LEWY body dementia ,PARASYMPATHETIC nervous system ,ORTHOSTATIC intolerance ,PANCREAS ,COLON (Anatomy) ,DYSAUTONOMIA ,SYMPATHETIC nervous system - Abstract
Dementia with Lewy bodies is characterized by a high burden of autonomic dysfunction and Lewy pathology in peripheral organs and components of the sympathetic and parasympathetic nervous system. Parasympathetic terminals may be quantified with
18 F-fluoroetoxybenzovesamicol, a PET tracer that binds to the vesicular acetylcholine transporter in cholinergic presynaptic terminals. Parasympathetic imaging may be useful for diagnostics, improving our understanding of autonomic dysfunction and for clarifying the spatiotemporal relationship of neuronal degeneration in prodromal disease. Therefore, we aimed to investigate the cholinergic parasympathetic integrity in peripheral organs and central autonomic regions of subjects with dementia with Lewy bodies and its association with subjective and objective measures of autonomic dysfunction. We hypothesized that organs with known parasympathetic innervation, especially the pancreas and colon, would have impaired cholinergic integrity. To achieve these aims, we conducted a cross-sectional comparison study including 23 newly diagnosed non-diabetic subjects with dementia with Lewy bodies (74 ± 6 years, 83% male) and 21 elderly control subjects (74 ± 6 years, 67% male). We obtained whole-body images to quantify PET uptake in peripheral organs and brain images to quantify PET uptake in regions of the brainstem and hypothalamus. Autonomic dysfunction was assessed with questionnaires and measurements of orthostatic blood pressure. Subjects with dementia with Lewy bodies displayed reduced cholinergic tracer uptake in the pancreas (32% reduction, P = 0.0003) and colon (19% reduction, P = 0.0048), but not in organs with little or no parasympathetic innervation. Tracer uptake in a region of the medulla oblongata overlapping the dorsal motor nucleus of the vagus correlated with autonomic symptoms (rs = −0.54, P = 0.0077) and changes in orthostatic blood pressure (rs = 0.76, P < 0.0001). Tracer uptake in the pedunculopontine region correlated with autonomic symptoms (rs = −0.52, P = 0.0104) and a measure of non-motor symptoms (rs = −0.47, P = 0.0230). In conclusion, our findings provide the first imaging-based evidence of impaired cholinergic integrity of the pancreas and colon in dementia with Lewy bodies. The observed changes may reflect parasympathetic denervation, implying that this process is initiated well before the point of diagnosis. The findings also support that cholinergic denervation in the brainstem contributes to dysautonomia. [ABSTRACT FROM AUTHOR]- Published
- 2024
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10. Analysis of peripheral blood immune cells from people with Parkinson's disease
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Singh, Ankita, Ferreira, Sara A, Jeyaseelan, Tulieca, Knudsen, Karoline, Fedorova, Tatyana, Horsager, Jacob, Okkels, Niels, Skjaerbaek, Casper, Andersen, Katrine, Degn, Søren E, Lin, Lin, Borghammer, Per, and Romero-Ramos, Marina
- Abstract
A-synuclein pathology is associated to Parkinson’s disease (PD) neurodegeneration, which affects central and peripheral nervous systems. Accordingly, degenerative signs are observed in the midbrain and putamen, but also in the autonomic system, such as gut and heart denervation. In parallel to the neuronal event and linked to PD progression, adaptive and innate immune changes occur in the brain and periphery. The progression of these pathological events might be related to disease subtypes and might be associated to disease onset and evolution of the prion-like spreading of a-synuclein aggregation. Based on this, the existance of two PD subtypes have been hypothesized: brain-first and body-first. Particularly in the body-first, which is proposed to start in the digestive tube, the vagus nerve is affected very early. This is of relevance since the vagus nerve’s immunomodulatory role will be compromised early in this PD subtype, which might promote inflammation. Thus, we hypothesized a differential immune response in PD subtypes also influenced by sex, that might be of relevance for the disease progression. Here we have performed single-cell transcriptome and Adaptive Immune Receptor Repertoire sequencing analyses of the peripheral blood mononuclear cells from healthy controls (n=10) and PD patients: prodromal (iRBD) (n=10), de novo PD (4 years from diagnose, n=10). Our preliminary bioinformatic data analysis shows a significant change in the adaptive cell compartment.  
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- 2023
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11. Severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies
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Okkels, Niels, Horsager, Jacob, Labrador-Espinosa, Miguel, Kjeldsen, Pernille L., Damholdt, Malene F., Mortensen, Janne, Vestergård, Karsten, Knudsen, Karoline, Andersen, Katrine B., Fedorova, Tatyana D., Skjærbæk, Casper, Gottrup, Hanne, Hansen, Allan K., Grothe, Michel J., and Borghammer, Per
- Abstract
Cholinergic changes play a fundamental role in the natural history of Dementia with Lewy bodies and Lewy body disease in general. Despite important achievements in the field of cholinergic research, significant challenges remain. We conducted a study with four main objectives: First, to examine the integrity of cholinergic terminals in newly diagnosed Dementia with Lewy bodies. Second, to disentangle the cholinergic contribution to dementia by comparing cholinergic changes in Lewy body patients with and without dementia. Third, to investigate the in vivo relationship between cholinergic terminal loss and atrophy of cholinergic cell clusters in the basal forebrain at different stages of Lewy body disease. Fourth, to test whether any asymmetrical degeneration in cholinergic terminals would correlate with motor dysfunction and hypometabolism.To achieve these objectives, we conducted a comparative cross-sectional study of 25 newly diagnosed Dementia with Lewy bodies patients (age 74 ± 5 years, 84% male), 15 healthy control subjects (age 75 ± 6 years, 67% male), and 15 Parkinson’s disease patients without dementia (age 70 ± 7 years, 60% male). All participants underwent [18F]fluoroetoxybenzovesamicol PET and high-resolution structural MRI. In addition, we collected clinical [18F]fluorodeoxyglucose PET images. Brain images were normalized to standard space and regional tracer uptake and volumetric indices of basal forebrain degeneration were extracted.Patients with dementia showed spatially distinct reductions in cholinergic terminals across the cerebral cortex, limbic system, thalamus, and brainstem. Also, cholinergic terminal binding in cortical and limbic regions correlated quantitatively and spatially with atrophy of the basal forebrain. By contrast, patients without dementia showed decreased cholinergic terminal binding in the cerebral cortex despite preserved basal forebrain volumes. In patients with dementia, cholinergic terminal reductions were most severe in limbic regions and least severe in occipital regions compared to those without dementia. Interhemispheric asymmetry of cholinergic terminals correlated with asymmetry of brain metabolism and lateralized motor function.In conclusion, this study provides robust evidence for severe cholinergic terminal loss in newly diagnosed Dementia with Lewy bodies, which correlates with structural imaging measures of cholinergic basal forebrain degeneration. In patients without dementia, our findings suggest that loss of cholinergic terminal function occurs before neuronal cell degeneration. Moreover, the study supports that degeneration of the cholinergic system is important for brain metabolism and may be linked with degeneration in other transmitter systems. Our findings have implications for understanding how cholinergic system pathology contributes to the clinical features of Lewy body disease, changes in brain metabolism, and disease progression patterns.
- Published
- 2023
12. Thyroid [123I]MIBG uptake in Parkinson’s disease and diabetes mellitus
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Fedorova, Tatyana D., primary, Knudsen, Karoline, additional, Rasmussen, Thorsten K, additional, Horsager, Jacob, additional, Nahimi, Adjmal, additional, Skjærbæk, Casper, additional, Schaeffer, Eva, additional, Berg, Daniela, additional, Terkelsen, Astrid J., additional, and Borghammer, Per, additional
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- 2023
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13. Severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies
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Aase and Ejnar Danielsen Foundation, Instituto de Salud Carlos III, European Commission, Lundbeck Foundation, Michael J. Fox Foundation for Parkinson's Research, Okkels, Niels, Horsager, Jacob, Labrador, Miguel Ángel, Kjeldsen, Pernille L., Damholdt, Malene F., Mortensen, Janne, Vestergård, Karsten, Knudsen, Karoline, Andersen, Katrine B., Fedorova, Tatyana D., Skjærbæk, Casper, Gottrup, Hanne, Hansen, Allan K., Grothe, Michel J., Borghammer, Per, Aase and Ejnar Danielsen Foundation, Instituto de Salud Carlos III, European Commission, Lundbeck Foundation, Michael J. Fox Foundation for Parkinson's Research, Okkels, Niels, Horsager, Jacob, Labrador, Miguel Ángel, Kjeldsen, Pernille L., Damholdt, Malene F., Mortensen, Janne, Vestergård, Karsten, Knudsen, Karoline, Andersen, Katrine B., Fedorova, Tatyana D., Skjærbæk, Casper, Gottrup, Hanne, Hansen, Allan K., Grothe, Michel J., and Borghammer, Per
- Abstract
Cholinergic changes play a fundamental role in the natural history of dementia with Lewy bodies and Lewy body disease in general. Despite important achievements in the field of cholinergic research, significant challenges remain. We conducted a study with four main objectives: (i) to examine the integrity of cholinergic terminals in newly diagnosed dementia with Lewy bodies; (ii) to disentangle the cholinergic contribution to dementia by comparing cholinergic changes in Lewy body patients with and without dementia; (iii) to investigate the in vivo relationship between cholinergic terminal loss and atrophy of cholinergic cell clusters in the basal forebrain at different stages of Lewy body disease; and (iv) to test whether any asymmetrical degeneration in cholinergic terminals would correlate with motor dysfunction and hypometabolism. To achieve these objectives, we conducted a comparative cross-sectional study of 25 newly diagnosed dementia with Lewy bodies patients (age 74 ± 5 years, 84% male), 15 healthy control subjects (age 75 ± 6 years, 67% male) and 15 Parkinson's disease patients without dementia (age 70 ± 7 years, 60% male). All participants underwent 18F-fluoroetoxybenzovesamicol PET and high-resolution structural MRI. In addition, we collected clinical 18F-fluorodeoxyglucose PET images. Brain images were normalized to standard space and regional tracer uptake and volumetric indices of basal forebrain degeneration were extracted. Patients with dementia showed spatially distinct reductions in cholinergic terminals across the cerebral cortex, limbic system, thalamus and brainstem. Also, cholinergic terminal binding in cortical and limbic regions correlated quantitatively and spatially with atrophy of the basal forebrain. In contrast, patients without dementia showed decreased cholinergic terminal binding in the cerebral cortex despite preserved basal forebrain volumes. In patients with dementia, cholinergic terminal reductions were most severe in limbic regio
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- 2023
14. Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies.
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Rahayel, Shady, Tremblay, Christina, Vo, Andrew, Misic, Bratislav, Lehéricy, Stéphane, Arnulf, Isabelle, Vidailhet, Marie, Corvol, Jean-Christophe, Group, the ICEBERG Study, Gagnon, Jean-François, Postuma, Ronald B, Montplaisir, Jacques, Lewis, Simon, Matar, Elie, Martens, Kaylena Ehgoetz, Borghammer, Per, Knudsen, Karoline, Hansen, Allan K, Monchi, Oury, and Gan-Or, Ziv
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GENE ontology ,RAPID eye movement sleep ,CEREBRAL atrophy ,LEWY body dementia ,PARTIAL least squares regression ,ALZHEIMER'S disease - Abstract
Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49–87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41–88) years; 77% men] with T
1 -weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks. [ABSTRACT FROM AUTHOR]- Published
- 2023
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15. Disruption of Sleep Microarchitecture Is a Sensitive and Early Marker of Parkinson’s Disease
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Doppler, Christopher E.J., primary, Smit, Julia, additional, Hommelsen, Maximilian, additional, Seger, Aline, additional, Okkels, Niels, additional, Horsager, Jacob, additional, Kinnerup, Martin, additional, Hansen, Allan K., additional, Fedorova, Tatyana D., additional, Knudsen, Karoline, additional, Otto, Marit, additional, Nahimi, Adjmal, additional, Fink, Gereon R., additional, Borghammer, Per, additional, and Sommerauer, Michael, additional
- Published
- 2022
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16. Dopaminergic Dysfunction Is More Symmetric in Dementia with Lewy Bodies Compared to Parkinson's Disease
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Fedorova, Tatyana Dmitrievna, Knudsen, Karoline, Horsager, Jacob, Hansen, Allan K., Okkels, Niels, Gottrup, Hanne, Vang, Kim, and Borghammer, Per
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Dopamine/metabolism ,Cellular and Molecular Neuroscience ,Corpus Striatum/metabolism ,Lewy Bodies/metabolism ,Humans ,Neurology (clinical) ,Parkinson Disease/metabolism ,Lewy Body Disease/pathology ,Retrospective Studies - Abstract
Background:The α-syn Origin site and Connectome model (SOC) proposes that α-synucleinopathies can be divided into two categories: the asymmetrical brain-first, and more symmetrical body-first Lewy body disease. We have hypothesized that most patients with dementia with Lewy bodies (DLB) belong to the body-first subtype, whereas patients with Parkinson’s disease (PD) more often belong to the brain-first subtype.Objective:To compare asymmetry of striatal dopaminergic dysfunction in DLB and PD patients using [18F]-FE-PE2I positron emission tomography (PET).Methods:We analyzed [18F]-FE-PE2I PET data from 29 DLB patients and 76 PD patients who were identified retrospectively during a 5-year period at Dept. of Neurology, Aarhus University Hospital. Additionally, imaging data from 34 healthy controls was used for age-correction and visual comparison.Results:PD patients showed significantly more asymmetry in specific binding ratios between the most and least affected putamen (p Conclusion:Patients with DLB show significantly more symmetric striatal degeneration on average compared to PD patients. These results support the hypothesis that DLB patients may be more likely to conform to the body-first subtype characterized by a symmetrical spread of pathology, whereas PD patients may be more likely to conform to the brain-first subtype with more lateralized initial propagation of pathology.
- Published
- 2023
17. Intestinal Transit in Early Moderate Parkinson’s Disease Correlates with Probable RBD: Subclinical Esophageal Dysmotility Does Not Correlate
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Skjærbæk, Casper, primary, Knudsen, Karoline, additional, Kinnerup, Martin, additional, Hansen, Kim Vang, additional, and Borghammer, Per, additional
- Published
- 2022
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18. Alpha-Synuclein Strain Variability in Body-First and Brain-First Synucleinopathies
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Just, Mie Kristine, primary, Gram, Hjalte, additional, Theologidis, Vasileios, additional, Jensen, Poul Henning, additional, Nilsson, K. Peter R., additional, Lindgren, Mikael, additional, Knudsen, Karoline, additional, Borghammer, Per, additional, and Van Den Berge, Nathalie, additional
- Published
- 2022
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19. Clinical and imaging evidence of brain-first and body-first Parkinson's disease
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Horsager, Jacob, Knudsen, Karoline, Sommerauer, Michael, Horsager, Jacob, Knudsen, Karoline, and Sommerauer, Michael
- Abstract
Braak's hypothesis has been extremely influential over the last two decades. However, neuropathological and clinical evidence suggest that the model does not conform to all patients with Parkinson's disease (PD). To resolve this controversy, a new model was recently proposed; in brain-first PD, the initial alpha-synuclein pathology arise inside the central nervous system, likely rostral to the substantia nigra pars compacta, and spread via interconnected structures - eventually affecting the autonomic nervous system; in body-first PD, the initial pathological alpha-synuclein originates in the enteric nervous system with subsequent caudo-rostral propagation to the autonomic and central nervous system. By using REM-sleep behavior disorder (RBD) as a clinical identifier to distinguish between body-first PD (RBDpositive at motor symptom onset) and brain-first PD (RBD-negative at motor symptom onset), we explored the literature to evaluate clinical and imaging differences between these proposed subtypes. Body-first PD patients display: 1) a larger burden of autonomic symptoms -in particular orthostatic hypotension and constipation, 2) more frequent pathological alpha-synuclein in peripheral tissues, 3) more brainstem and autonomic nervous system involvement in imaging studies, 4) more symmetric striatal dopaminergic loss and motor symptoms, and 5) slightly more olfactory dysfunction. In contrast, only minor cortical metabolic alterations emerge before motor symptoms in body-first. Brain-first PD is characterized by the opposite clinical and imaging patterns. Patients with pathological LRRK2 genetic variants mostly resemble a brain-first PD profile whereas patients with GBA variants typically conform to a body-first profile. SNCA-variant carriers are equally distributed between both subtypes. Overall, the literature indicates that body-first and brain-first PD might be two distinguishable entities on some clinical and imaging markers.
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- 2022
20. Disruption of Sleep Microarchitecture Is a Sensitive and Early Marker of Parkinson's Disease
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Doppler, Christopher E. J., Smit, Julia, Hommelsen, Maximilian, Seger, Aline, Okkels, Niels, Horsager, Jacob, Kinnerup, Martin, Hansen, Allan K., Fedorova, Tatyana D., Knudsen, Karoline, Otto, Marit, Nahimi, Adjmal, Fink, Gereon R., Borghammer, Per, Sommerauer, Michael, Doppler, Christopher E. J., Smit, Julia, Hommelsen, Maximilian, Seger, Aline, Okkels, Niels, Horsager, Jacob, Kinnerup, Martin, Hansen, Allan K., Fedorova, Tatyana D., Knudsen, Karoline, Otto, Marit, Nahimi, Adjmal, Fink, Gereon R., Borghammer, Per, and Sommerauer, Michael
- Abstract
Background: Although sleep disturbances are highly prevalent in patients with Parkinson's disease, sleep macroarchitecture metrics show only minor changes. Objective: To assess alterations of the cyclic alternating pattern (CAP) as a critical feature of sleep microarchitecture in patients with prodromal, recent, and established Parkinson's disease. Methods: We evaluated overnight polysomnography for classic sleep macroarchitecture and CAP metrics in 68 patients at various disease stages and compared results to 22 age- and sex-matched controls. Results: Already at the prodromal stage, patients showed a significantly reduced CAP rate as a central characteristic of sleep microarchitecture. Temporal characteristics of CAP showed a gradual change over disease stages and correlated with motor performance. In contrast, the sleep macroarchitecture metrics did not differ between groups. Conclusion: Data suggest that alterations of sleep microarchitecture are an early and more sensitive characteristic of Parkinson's disease than changes in sleep macroarchitecture.
- Published
- 2022
21. Alpha-Synuclein Strain Variability in Body-First and Brain-First Synucleinopathies
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Just, Mie Kristine, Gram, Hjalte, Theologidis, Vasileios, Jensen, Poul Henning, Nilsson, Peter, Lindgren, Mikael, Knudsen, Karoline, Borghammer, Per, van den Berge, Nathalie, Just, Mie Kristine, Gram, Hjalte, Theologidis, Vasileios, Jensen, Poul Henning, Nilsson, Peter, Lindgren, Mikael, Knudsen, Karoline, Borghammer, Per, and van den Berge, Nathalie
- Abstract
Pathogenic alpha-synuclein (asyn) aggregates are a defining feature of neurodegenerative synucleinopathies, which include Parkinsons disease, Lewy body dementia, pure autonomic failure and multiple system atrophy. Early accurate differentiation between these synucleinopathies is challenging due to the highly heterogeneous clinical profile at early prodromal disease stages. Therefore, diagnosis is often made in late disease stages when a patient presents with a broad range of motor and non-motor symptoms easing the differentiation. Increasing data suggest the clinical heterogeneity seen in patients is explained by the presence of distinct asyn strains, which exhibit variable morphologies and pathological functions. Recently, asyn seed amplification assays (PMCA and RT-QuIC) and conformation-specific ligand assays have made promising progress in differentiating between synucleinopathies in prodromal and advanced disease stages. Importantly, the cellular environment is known to impact strain morphology. And, asyn aggregate pathology can propagate trans-synaptically along the brain-body axis, affecting multiple organs and propagating through multiple cell types. Here, we present our hypothesis that the changing cellular environments, an asyn seed may encounter during its brain-to-body or body-to-brain propagation, may influence the structure and thereby the function of the aggregate strains developing within the different cells. Additionally, we aim to review strain characteristics of the different synucleinopathies in clinical and preclinical studies. Future preclinical animal models of synucleinopathies should investigate if asyn strain morphology is altered during brain-to-body and body-to-brain spreading using these seeding amplification and conformation-specific assays. Such findings would greatly deepen our understanding of synucleinopathies and the potential link between strain and phenotypic variability, which may enable specific diagnosis of different synuclein, Funding Agencies|Lundbeck Foundation [R322-2019-2544, R276-2018-294]; Danish Parkinsons Association; Jascha Foundation - Lundbeck Foundation [R276-2018-294]; Bjarne Saxhofs Foundation; Jascha Foundation
- Published
- 2022
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22. Clinical and imaging evidence of brain-first and body-first Parkinson's disease
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Horsager, Jacob, primary, Knudsen, Karoline, additional, and Sommerauer, Michael, additional
- Published
- 2022
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23. Asymmetric Dopaminergic Dysfunction in Brain-First versus Body-First Parkinson’s Disease Subtypes
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Knudsen, Karoline, primary, Fedorova, Tatyana D., additional, Horsager, Jacob, additional, Andersen, Katrine B., additional, Skjærbæk, Casper, additional, Berg, Daniela, additional, Schaeffer, Eva, additional, Brooks, David J., additional, Pavese, Nicola, additional, Van Den Berge, Nathalie, additional, and Borghammer, Per, additional
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- 2021
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24. Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression.
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Rahayel, Shady, Tremblay, Christina, Vo, Andrew, Zheng, Ying Qiu, Lehéricy, Stéphane, Arnulf, Isabelle, Vidailhet, Marie, Corvol, Jean Christophe, Group, ICEBERG Study, Gagnon, Jean François, Postuma, Ronald B, Montplaisir, Jacques, Lewis, Simon, Matar, Elie, Martens, Kaylena Ehgoetz, Borghammer, Per, Knudsen, Karoline, Hansen, Allan, Monchi, Oury, and Misic, Bratislav
- Abstract
Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease, or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% men) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e., a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, p = 0.0007) and tissue deformation (r = 0.52, p = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function, and can be recreated using the dynamics of agent-based modelling, structural connectivity, and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
25. ARadionuclide imaging of the gut-brain axis in Parkinson’s disease.
- Author
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Horsager, Jacob, Knudsen, Karoline, and Borghammer, Per
- Published
- 2021
- Full Text
- View/download PDF
26. A Radionuclide imaging of the gut-brain axis in Parkinson’s disease.
- Author
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Horsager, Jacob, Knudsen, Karoline, and Borghammer, Per
- Published
- 2021
- Full Text
- View/download PDF
27. [18F]FEOBV positron emission tomography may not be a suitable method to measure parasympathetic denervation in patients with Parkinson's disease.
- Author
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Horsager, Jacob, Okkels, Niels, Fedorova, Tatyana D., Knudsen, Karoline, Skjærbæk, Casper, Van Den Berge, Nathalie, Jacobsen, Jan, Munk, Ole Lajord, Danielsen, Erik Hvid, Bender, Dirk, Brooks, David J., and Borghammer, Per
- Abstract
Introduction: The peripheral autonomic nervous system may be involved years before onset of motor symptoms in some patients with Parkinson's disease (PD). Specific imaging techniques to quantify the cholinergic nervous system in peripheral organs are an unmet need. We tested the hypothesis that patients with PD display decreased [18F]FEOBV uptake in peripheral organs - a sign of parasympathetic denervation.Methods: We included 15 PD patients and 15 age- and sex matched healthy controls for a 70 min whole-body dynamic positron emission tomography (PET) acquisition. Compartmental modelling was used for tracer kinetic analyses of adrenal gland, pancreas, myocardium, spleen, renal cortex, muscle and colon. Standard uptake values (SUV) at 60-70 min post injection were also extracted for these organs. Additionally, SUVs were also determined in the total colon, prostate, parotid and submandibular glands.Results: We found no statistically significant difference of [18F]FEOBV binding parameters in any organs between patients with PD and healthy controls, although trends were observed. The pancreas SUV showed a 14% reduction in patients (P = 0.021, not statistically significant after multiple comparison correction). We observed a trend towards lower SUVs in the pancreas, colon, adrenal gland, and myocardium of PD patients with versus without probable REM sleep behavior disorder.Conclusion: [18F]FEOBV PET may not be a sensitive marker for parasympathetic degeneration in patients with PD. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
28. Impaired cholinergic integrity of the colon and pancreas in dementia with Lewy bodies.
- Author
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Okkels N, Horsager J, Fedorova TD, Knudsen K, Skjærbæk C, Andersen KB, Labrador-Espinosa M, Vestergaard K, Mortensen JK, Klit H, Møller M, Danielsen EH, Johnsen EL, Bekan G, Hansen KV, Munk OL, Damholdt MF, Kjeldsen PL, Hansen AK, Gottrup H, Grothe MJ, and Borghammer P
- Subjects
- Humans, Male, Aged, Female, Cross-Sectional Studies, Pancreas pathology, Cholinergic Agents, Colon pathology, Lewy Body Disease diagnostic imaging, Lewy Body Disease pathology, Autonomic Nervous System Diseases diagnostic imaging, Autonomic Nervous System Diseases etiology
- Abstract
Dementia with Lewy bodies is characterized by a high burden of autonomic dysfunction and Lewy pathology in peripheral organs and components of the sympathetic and parasympathetic nervous system. Parasympathetic terminals may be quantified with 18F-fluoroetoxybenzovesamicol, a PET tracer that binds to the vesicular acetylcholine transporter in cholinergic presynaptic terminals. Parasympathetic imaging may be useful for diagnostics, improving our understanding of autonomic dysfunction and for clarifying the spatiotemporal relationship of neuronal degeneration in prodromal disease. Therefore, we aimed to investigate the cholinergic parasympathetic integrity in peripheral organs and central autonomic regions of subjects with dementia with Lewy bodies and its association with subjective and objective measures of autonomic dysfunction. We hypothesized that organs with known parasympathetic innervation, especially the pancreas and colon, would have impaired cholinergic integrity. To achieve these aims, we conducted a cross-sectional comparison study including 23 newly diagnosed non-diabetic subjects with dementia with Lewy bodies (74 ± 6 years, 83% male) and 21 elderly control subjects (74 ± 6 years, 67% male). We obtained whole-body images to quantify PET uptake in peripheral organs and brain images to quantify PET uptake in regions of the brainstem and hypothalamus. Autonomic dysfunction was assessed with questionnaires and measurements of orthostatic blood pressure. Subjects with dementia with Lewy bodies displayed reduced cholinergic tracer uptake in the pancreas (32% reduction, P = 0.0003) and colon (19% reduction, P = 0.0048), but not in organs with little or no parasympathetic innervation. Tracer uptake in a region of the medulla oblongata overlapping the dorsal motor nucleus of the vagus correlated with autonomic symptoms (rs = -0.54, P = 0.0077) and changes in orthostatic blood pressure (rs = 0.76, P < 0.0001). Tracer uptake in the pedunculopontine region correlated with autonomic symptoms (rs = -0.52, P = 0.0104) and a measure of non-motor symptoms (rs = -0.47, P = 0.0230). In conclusion, our findings provide the first imaging-based evidence of impaired cholinergic integrity of the pancreas and colon in dementia with Lewy bodies. The observed changes may reflect parasympathetic denervation, implying that this process is initiated well before the point of diagnosis. The findings also support that cholinergic denervation in the brainstem contributes to dysautonomia., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2024
- Full Text
- View/download PDF
29. Severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies.
- Author
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Okkels N, Horsager J, Labrador-Espinosa M, Kjeldsen PL, Damholdt MF, Mortensen J, Vestergård K, Knudsen K, Andersen KB, Fedorova TD, Skjærbæk C, Gottrup H, Hansen AK, Grothe MJ, and Borghammer P
- Subjects
- Humans, Male, Aged, Aged, 80 and over, Middle Aged, Female, Lewy Bodies metabolism, Cross-Sectional Studies, Cholinergic Agents, Atrophy pathology, Lewy Body Disease metabolism
- Abstract
Cholinergic changes play a fundamental role in the natural history of dementia with Lewy bodies and Lewy body disease in general. Despite important achievements in the field of cholinergic research, significant challenges remain. We conducted a study with four main objectives: (i) to examine the integrity of cholinergic terminals in newly diagnosed dementia with Lewy bodies; (ii) to disentangle the cholinergic contribution to dementia by comparing cholinergic changes in Lewy body patients with and without dementia; (iii) to investigate the in vivo relationship between cholinergic terminal loss and atrophy of cholinergic cell clusters in the basal forebrain at different stages of Lewy body disease; and (iv) to test whether any asymmetrical degeneration in cholinergic terminals would correlate with motor dysfunction and hypometabolism. To achieve these objectives, we conducted a comparative cross-sectional study of 25 newly diagnosed dementia with Lewy bodies patients (age 74 ± 5 years, 84% male), 15 healthy control subjects (age 75 ± 6 years, 67% male) and 15 Parkinson's disease patients without dementia (age 70 ± 7 years, 60% male). All participants underwent 18F-fluoroetoxybenzovesamicol PET and high-resolution structural MRI. In addition, we collected clinical 18F-fluorodeoxyglucose PET images. Brain images were normalized to standard space and regional tracer uptake and volumetric indices of basal forebrain degeneration were extracted. Patients with dementia showed spatially distinct reductions in cholinergic terminals across the cerebral cortex, limbic system, thalamus and brainstem. Also, cholinergic terminal binding in cortical and limbic regions correlated quantitatively and spatially with atrophy of the basal forebrain. In contrast, patients without dementia showed decreased cholinergic terminal binding in the cerebral cortex despite preserved basal forebrain volumes. In patients with dementia, cholinergic terminal reductions were most severe in limbic regions and least severe in occipital regions compared to those without dementia. Interhemispheric asymmetry of cholinergic terminals correlated with asymmetry of brain metabolism and lateralized motor function. In conclusion, this study provides robust evidence for severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies, which correlates with structural imaging measures of cholinergic basal forebrain degeneration. In patients without dementia, our findings suggest that loss of cholinergic terminal function occurs 'before' neuronal cell degeneration. Moreover, the study supports that degeneration of the cholinergic system is important for brain metabolism and may be linked with degeneration in other transmitter systems. Our findings have implications for understanding how cholinergic system pathology contributes to the clinical features of Lewy body disease, changes in brain metabolism and disease progression patterns., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
- Full Text
- View/download PDF
30. Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies.
- Author
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Rahayel S, Tremblay C, Vo A, Misic B, Lehéricy S, Arnulf I, Vidailhet M, Corvol JC, Gagnon JF, Postuma RB, Montplaisir J, Lewis S, Matar E, Ehgoetz Martens K, Borghammer P, Knudsen K, Hansen AK, Monchi O, Gan-Or Z, and Dagher A
- Subjects
- Male, Humans, Female, Cerebral Cortical Thinning pathology, Mitochondria metabolism, Atrophy pathology, Synucleinopathies diagnostic imaging, Synucleinopathies genetics, Alzheimer Disease pathology, REM Sleep Behavior Disorder diagnostic imaging, REM Sleep Behavior Disorder genetics, REM Sleep Behavior Disorder complications
- Abstract
Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49-87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41-88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2023
- Full Text
- View/download PDF
31. Thyroid [ 123 I]MIBG uptake in Parkinson's disease and diabetes mellitus.
- Author
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Fedorova TD, Knudsen K, Rasmussen TK, Horsager J, Nahimi A, Skjærbæk C, Schaeffer E, Berg D, Terkelsen AJ, and Borghammer P
- Abstract
Thyroid [
123 I]MIBG uptake is proposed as a tool for differentiating between Parkinson's disease (PD) and diabetes mellitus (DM) on [123 I]MIBG scintigraphies since both patient groups show decreased cardiac uptake. One study compared thyroid [123 I]MIBG uptake in DM and PD patients and reported reduced [123 I]MIBG uptake only in the PD group. Here, we investigated thyroid [123 I]MIBG uptake in patients with PD and DM and found severely reduced thyroid [123 I]MIBG uptake in DM. Larger studies are needed to substantiate whether DM patients are more or less likely to exhibit decreased thyroid MIBG uptake compared to controls and PD patients., Competing Interests: None, (© 2023 The Authors.)- Published
- 2023
- Full Text
- View/download PDF
32. Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression.
- Author
-
Rahayel S, Tremblay C, Vo A, Zheng YQ, Lehéricy S, Arnulf I, Vidailhet M, Corvol JC, Gagnon JF, Postuma RB, Montplaisir J, Lewis S, Matar E, Ehgoetz Martens K, Borghammer P, Knudsen K, Hansen A, Monchi O, Misic B, and Dagher A
- Subjects
- Aged, Atrophy pathology, Brain pathology, Cerebral Cortical Thinning, Female, Gene Expression, Humans, Male, alpha-Synuclein genetics, alpha-Synuclein metabolism, Neurodegenerative Diseases pathology, Prions metabolism, REM Sleep Behavior Disorder metabolism, Synucleinopathies diagnostic imaging, Synucleinopathies genetics
- Abstract
Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% male) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e. a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, P = 0.0007) and tissue deformation (r = 0.52, P = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function and can be recreated using the dynamics of agent-based modelling, structural connectivity and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
33. Radionuclide Imaging of the Gut-Brain Axis in Parkinson Disease.
- Author
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Horsager J, Knudsen K, and Borghammer P
- Published
- 2021
- Full Text
- View/download PDF
34. Regional locus coeruleus degeneration is uncoupled from noradrenergic terminal loss in Parkinson's disease.
- Author
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Doppler CEJ, Kinnerup MB, Brune C, Farrher E, Betts M, Fedorova TD, Schaldemose JL, Knudsen K, Ismail R, Seger AD, Hansen AK, Stær K, Fink GR, Brooks DJ, Nahimi A, Borghammer P, and Sommerauer M
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Magnetic Resonance Imaging methods, Male, Middle Aged, Multimodal Imaging methods, Positron-Emission Tomography methods, Locus Coeruleus diagnostic imaging, Locus Coeruleus metabolism, Norepinephrine Plasma Membrane Transport Proteins metabolism, Parkinson Disease diagnostic imaging, Parkinson Disease metabolism
- Abstract
Previous studies have reported substantial involvement of the noradrenergic system in Parkinson's disease. Neuromelanin-sensitive MRI sequences and PET tracers have become available to visualize the cell bodies in the locus coeruleus and the density of noradrenergic terminal transporters. Combining these methods, we investigated the relationship of neurodegeneration in these distinct compartments in Parkinson's disease. We examined 93 subjects (40 healthy controls and 53 Parkinson's disease patients) with neuromelanin-sensitive turbo spin-echo MRI and calculated locus coeruleus-to-pons signal contrasts. Voxels with the highest intensities were extracted from published locus coeruleus coordinates transformed to individual MRI. To also investigate a potential spatial pattern of locus coeruleus degeneration, we extracted the highest signal intensities from the rostral, middle, and caudal third of the locus coeruleus. Additionally, a study-specific probabilistic map of the locus coeruleus was created and used to extract mean MRI contrast from the entire locus coeruleus and each rostro-caudal subdivision. Locus coeruleus volumes were measured using manual segmentations. A subset of 73 subjects had 11C-MeNER PET to determine noradrenaline transporter density, and distribution volume ratios of noradrenaline transporter-rich regions were computed. Patients with Parkinson's disease showed reduced locus coeruleus MRI contrast independently of the selected method (voxel approaches: P < 0.0001, P < 0.001; probabilistic map: P < 0.05), specifically on the clinically-defined most affected side (P < 0.05), and reduced locus coeruleus volume (P < 0.0001). Reduced MRI contrast was confined to the middle and caudal locus coeruleus (voxel approach, rostral: P = 0.48, middle: P < 0.0001, and caudal: P < 0.05; probabilistic map, rostral: P = 0.90, middle: P < 0.01, and caudal: P < 0.05). The noradrenaline transporter density was lower in patients with Parkinson's diseasein all examined regions (group effect P < 0.0001). No significant correlation was observed between locus coeruleus MRI contrast and noradrenaline transporter density. In contrast, the individual ratios of noradrenaline transporter density and locus coeruleus MRI contrast were lower in Parkinson's disease patients in all examined regions (group effect P < 0.001). Our multimodal imaging approach revealed pronounced noradrenergic terminal loss relative to cellular locus coeruleus degeneration in Parkinson's disease; the latter followed a distinct spatial pattern with the middle-caudal portion being more affected than the rostral part. The data shed first light on the interaction between the axonal and cell body compartments and their differential susceptibility to neurodegeneration in Parkinson's disease, which may eventually direct research towards potential novel treatment approaches., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
- Full Text
- View/download PDF
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