Publications
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Pasquini J, Brooks DJ, Pavese N, 2021, The Cholinergic Brain in Parkinson's Disease, MOVEMENT DISORDERS CLINICAL PRACTICE, ISSN: 2330-1619
Binda KH, Lillethorup TP, Real CC, et al., 2021, Exercise protects synaptic density in a rat model of Parkinson's disease, EXPERIMENTAL NEUROLOGY, Vol: 342, ISSN: 0014-4886
Knudsen K, Fedorova TD, Horsager J, et al., 2021, Asymmetric Dopaminergic Dysfunction in Brain-First versus Body-First Parkinson's Disease Subtypes., J Parkinsons Dis
BACKGROUND: We have hypothesized that Parkinson's disease (PD) comprises two subtypes. Brain-first, where pathogenic α-synuclein initially forms unilaterally in one hemisphere leading to asymmetric nigrostriatal degeneration, and body-first with initial enteric pathology, which spreads through overlapping vagal innervation leading to more symmetric brainstem involvement and hence more symmetric nigrostriatal degeneration. Isolated REM sleep behaviour disorder has been identified as a strong marker of the body-first type. OBJECTIVE: To analyse striatal asymmetry in [18F]FDOPA PET and [123I]FP-CIT DaT SPECT data from iRBD patients, de novo PD patients with RBD (PD +RBD) and de novo PD patients without RBD (PD - RBD). These groups were defined as prodromal body-first, de novo body-first, and de novo brain-first, respectively. METHODS: We included [18F]FDOPA PET scans from 21 iRBD patients, 11 de novo PD +RBD, 22 de novo PD - RBD, and 18 controls subjects. Also, [123I]FP-CIT DaT SPECT data from iRBD and de novo PD patients with unknown RBD status from the PPPMI dataset was analysed. Lowest putamen specific binding ratio and putamen asymmetry index (AI) was defined. RESULTS: Nigrostriatal degeneration was significantly more symmetric in patients with RBD versus patients without RBD or with unknown RBD status in both FDOPA (p = 0.001) and DaT SPECT (p = 0.001) datasets. CONCLUSION: iRBD subjects and de novo PD +RBD patients present with significantly more symmetric nigrostriatal dopaminergic degeneration compared to de novo PD - RBD patients. The results support the hypothesis that body-first PD is characterized by more symmetric distribution most likely due to more symmetric propagation of pathogenic α-synuclein compared to brain-first PD.
Doppler CEJ, Kinnerup MB, Brune C, et al., 2021, Regional locus coeruleus degeneration is uncoupled from noradrenergic terminal loss in Parkinson's disease., Brain
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. Parkinson's disease patients 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, m
Pagano G, Molloy S, Bain PG, et al., 2021, Impulse control disorders are associated with lower ventral striatum dopamine D3 receptor availability in Parkinson's disease: A [11C]-PHNO PET study., Parkinsonism Relat Disord, Vol: 90, Pages: 52-56
INTRODUCTION: Reduced postsynaptic D3 dopaminergic receptor availability has been reported in the ventral striatum of pathological gamblers without Parkinson's disease (PD) and in patients with PD and impulse control disorders (ICD). However, a direct relationship between ventral striatum D3 dopaminergic receptors and the severity of ICD in PD patients has not yet been proven using a validated tool for ICD in PD, such as the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease-Rating Scale (QUIP-RS). In this pilot study, we investigated the relationship between ventral striatum D3 dopamine receptor availability and severity of impulse control disorder (ICD) in Parkinson's disease (PD). METHODS: Twelve patients were assessed with PET and the high affinity dopamine D3 receptor radioligand [11C]-PHNO. Severity of ICD was assessed with the QUIP-RS. RESULTS: We found that lower ventral striatum D3 receptor availability measured with [11C]-PHNO PET was associated with greater severity of ICD, as measured by the QUIP-RS score (rho = -0.625, p = 0.03). CONCLUSION: These findings suggest that the occurrence and severity of ICD in Parkinson's disease may be linked to reductions in ventral striatum dopamine D3 receptor availability. Further studies in larger cohort of patients need to be performed in order to confirm our findings and clarify whether lower ventral striatum D3 receptor may reflect a pharmacological downregulation to higher dopamine release in ventral striatum of patients with ICD or a patients' predisposition to ICD.
Eskildsen SF, Iranzo A, Stokholm MG, et al., 2021, Impaired cerebral microcirculation in isolated REM sleep behaviour disorder., Brain, Vol: 144, Pages: 1498-1508
During the prodromal period of Parkinson's disease and other α-synucleinopathy-related parkinsonisms, neurodegeneration is thought to progressively affect deep brain nuclei, such as the locus coeruleus, caudal raphe nucleus, substantia nigra, and the forebrain nucleus basalis of Meynert. Besides their involvement in the regulation of mood, sleep, behaviour, and memory functions, these nuclei also innervate parenchymal arterioles and capillaries throughout the cortex, possibly to ensure that oxygen supplies are adjusted according to the needs of neural activity. The aim of this study was to examine whether patients with isolated REM sleep behaviour disorder, a parasomnia considered to be a prodromal phenotype of α-synucleinopathies, reveal microvascular flow disturbances consistent with disrupted central blood flow control. We applied dynamic susceptibility contrast MRI to characterize the microscopic distribution of cerebral blood flow in the cortex of 20 polysomnographic-confirmed patients with isolated REM sleep behaviour disorder (17 males, age range: 54-77 years) and 25 healthy matched controls (25 males, age range: 58-76 years). Patients and controls were cognitively tested by Montreal Cognitive Assessment and Mini Mental State Examination. Results revealed profound hypoperfusion and microvascular flow disturbances throughout the cortex in patients compared to controls. In patients, the microvascular flow disturbances were seen in cortical areas associated with language comprehension, visual processing and recognition and were associated with impaired cognitive performance. We conclude that cortical blood flow abnormalities, possibly related to impaired neurogenic control, are present in patients with isolated REM sleep behaviour disorder and associated with cognitive dysfunction. We hypothesize that pharmacological restoration of perivascular neurotransmitter levels could help maintain cognitive function in patients with this prodromal phenotype of
Jost ST, Visser-Vandewalle V, Rizos A, et al., 2021, Non-motor predictors of 36-month quality of life after subthalamic stimulation in Parkinson disease, NPJ PARKINSONS DISEASE, Vol: 7
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- Citations: 2
Brooks DJ, 2021, Future Imaging in Dementia, SEMINARS IN NUCLEAR MEDICINE, Vol: 51, Pages: 303-308, ISSN: 0001-2998
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- Citations: 1
Kinnerup MB, Sommerauer M, Damholdt MF, et al., 2021, Preserved noradrenergic function in Parkinson's disease patients with rest tremor, NEUROBIOLOGY OF DISEASE, Vol: 152, ISSN: 0969-9961
Andersen KB, Hansen AK, Damholdt MF, et al., 2021, Reduced Synaptic Density in Patients with Lewy Body Dementia: An [C-11]UCB-J PET Imaging Study, MOVEMENT DISORDERS, ISSN: 0885-3185
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Farmen K, Nissen SK, Stokholm MG, et al., 2021, Monocyte markers correlate with immune and neuronal brain changes in REM sleep behavior disorder, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 118, ISSN: 0027-8424
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Femminella GD, Livingston NR, Raza S, et al., 2021, Does insulin resistance influence neurodegeneration in non-diabetic Alzheimer's subjects?, Alzheimers Research & Therapy, Vol: 13, Pages: 1-11, ISSN: 1758-9193
BackgroundType 2 diabetes is a risk factor for Alzheimer’s disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects.MethodsIn total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function.ResultsIn this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs.ConclusionsIn non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.
Thomsen MB, Ferreira SA, Schacht AC, et al., 2021, PET imaging reveals early and progressive dopaminergic deficits after intra-striatal injection of preformed alpha-synuclein fibrils in rats, NEUROBIOLOGY OF DISEASE, Vol: 149, ISSN: 0969-9961
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- Citations: 4
Brooks DJ, 2021, Imaging Familial and Sporadic Neurodegenerative Disorders Associated with Parkinsonism, NEUROTHERAPEUTICS, ISSN: 1933-7213
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- Citations: 2
Mullin S, Stokholm MG, Hughes D, et al., 2020, Brain Microglial Activation Increased in Glucocerebrosidase (GBA) Mutation Carriers without Parkinson's disease, MOVEMENT DISORDERS, Vol: 36, Pages: 774-779, ISSN: 0885-3185
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- Citations: 5
Edison P, Leng F, Hinz R, et al., 2020, Influence of microglial activation on structural and functional connectivity in mild cognitive impairment subjects: Development of new models and analysis methods/neuroinflammation, Alzheimer's and Dementia, ISSN: 1552-5260
Staer K, Iranzo A, Stokholm MG, et al., 2020, Cortical cholinergic dysfunction correlates with microglial activation in the substantia innominata in REM sleep behavior disorder, PARKINSONISM & RELATED DISORDERS, Vol: 81, Pages: 89-93, ISSN: 1353-8020
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- Citations: 1
Edison P, Femminella GD, van der Doef T, et al., 2020, Behavioural symptoms in Alzheimer's disease are associated with white matter lesions (WML) volume and are independent of atrophy and hypometabolism: Neuroimaging /Optimal..., Alzheimer's and Dementia, ISSN: 1552-5260
Edison P, Raza S, Femminella GD, et al., 2020, Relationship between spectral analysis, SUV and SUV Pons ratio as a measure of cerebral glucose metabolic rate in Alzheimer's Disease: Neuroimaging/multi-modal comparisons., Alzheimer's and Dementia, ISSN: 1552-5260
Edison P, Calsolaro V, Hinz R, et al., 2020, Microglial activation evaluated using flutriciclamide (11F-GE180) in subjects with cognitive impairment: Neuroimaging /Optimal neuroimaging measures for ..., Alzheimer's and Dementia, ISSN: 1552-5260
Leng F, Hinz R, Dani M, et al., 2020, Tau formation is associated with microglial activation in more widespread cortical areas than amyloid deposition: Multimodal neuroimaging comparison, Alzheimer's and Dementia, ISSN: 1552-5260
Chetelat G, Arbizu J, Barthel H, et al., 2020, Amyloid-PET and F-18-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias, LANCET NEUROLOGY, Vol: 19, Pages: 951-962, ISSN: 1474-4422
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- Citations: 34
Horsager J, Andersen KB, Knudsen K, et al., 2020, Brain-first versus body-first Parkinson's disease: a multimodal imaging case-control study, BRAIN, Vol: 143, Pages: 3077-3088, ISSN: 0006-8950
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- Citations: 54
Vibholm AK, Landau AM, Moller A, et al., 2020, NMDA receptor ion channel activation detected in vivo with [F-18]GE-179 PET after electrical stimulation of rat hippocampus, JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, Vol: 41, Pages: 1301-1312, ISSN: 0271-678X
Xu Z, Anderson KN, Saffari SE, et al., 2020, Progression of sleep disturbances in Parkinson's disease: a 5-year longitudinal study, JOURNAL OF NEUROLOGY, Vol: 268, Pages: 312-320, ISSN: 0340-5354
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- Citations: 5
Pasquini J, Ceravolo R, Brooks DJ, et al., 2020, Progressive loss of raphe nuclei serotonin transporter in early Parkinson's disease: A longitudinal I-123-FP-CIT SPECT study, PARKINSONISM & RELATED DISORDERS, Vol: 77, Pages: 170-175, ISSN: 1353-8020
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- Citations: 3
Edison P, Calsolaro V, Hinz R, et al., 2020, Microglial activation evaluated using Flutriciclamide (11F-GE180) in subjects with cognitive impairment, 2020 Alzheimer's Association International Conference
Edison P, Leng F, Hinz R, et al., 2020, Tau formation is associated with microglial activation in more widespread cortical areas than amyloid deposition does, 2020 Alzheimer's Association International Conference
Edison P, Femminella GD, Livingston NR, et al., 2020, Influence of cerebral glucose metabolic rate on cognitive function in Alzheimer's subjects, 2020 Alzheimer's Association International Conference
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