Publications
924 results found
O'Brien JT, Chouliaras L, Sultana J, et al., 2022, RENEWAL: REpurposing study to find NEW compounds with Activity for Lewy body dementia-an international Delphi consensus., Alzheimers Res Ther, Vol: 14
Drug repositioning and repurposing has proved useful in identifying new treatments for many diseases, which can then rapidly be brought into clinical practice. Currently, there are few effective pharmacological treatments for Lewy body dementia (which includes both dementia with Lewy bodies and Parkinson's disease dementia) apart from cholinesterase inhibitors. We reviewed several promising compounds that might potentially be disease-modifying agents for Lewy body dementia and then undertook an International Delphi consensus study to prioritise compounds. We identified ambroxol as the top ranked agent for repurposing and identified a further six agents from the classes of tyrosine kinase inhibitors, GLP-1 receptor agonists, and angiotensin receptor blockers that were rated by the majority of our expert panel as justifying a clinical trial. It would now be timely to take forward all these compounds to Phase II or III clinical trials in Lewy body dementia.
Horsager J, Okkels N, Fedorova TD, et al., 2022, [18F]FEOBV positron emission tomography may not be a suitable method to measure parasympathetic denervation in patients with Parkinson's disease, PARKINSONISM & RELATED DISORDERS, Vol: 104, Pages: 21-25, ISSN: 1353-8020
Andersen OM, Bøgh N, Landau AM, et al., 2022, A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency., Cell Rep Med, Vol: 3
The established causal genes in Alzheimer's disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease's initial preclinical phase. Mutations in SORL1, encoding the endosome recycling receptor SORLA, are found in 2%-3% of individuals with early-onset AD, and SORL1 haploinsufficiency appears to be causal for AD. To test whether SORL1 can function as an AD causal gene, we use CRISPR-Cas9-based gene editing to develop a model of SORL1 haploinsufficiency in Göttingen minipigs, taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young adult minipigs is found to phenocopy the preclinical in vivo profile of AD observed with APP, PSEN1, and PSEN2, resulting in elevated levels of β-amyloid (Aβ) and tau preceding amyloid plaque formation and neurodegeneration, as observed in humans. Our study provides functional support for the theory that SORL1 haploinsufficiency leads to endosome cytopathology with biofluid hallmarks of autosomal dominant AD.
Andersen KB, Hansen AK, Knudsen K, et al., 2022, Healthy brain aging assessed with [F-18]FDG and [C-11]UCB-J PET, NUCLEAR MEDICINE AND BIOLOGY, Vol: 112-113, Pages: 52-58, ISSN: 0969-8051
Venkataraman A, Mansur A, Rizzo G, et al., 2022, Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer’s Disease, Science Translational Medicine, Vol: 14, Pages: 1-11, ISSN: 1946-6234
Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). In this study, we quantified the in vivo expression of the endoplasmic reticulum stress marker, sigma 1 receptor (S1R), using [11C]SA4503 PET, the mitochondrial complex I (MC1) with [18F]BCPP-EF and the pre-synaptic vesicular protein SV2A with [11C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and cerebral blood flow (CBF) measured with magnetic resonance imaging (MRI) arterial spin labelling. Eight patients with AD were followed longitudinally to estimate the rate of change of the physiological and structural pathology markers with disease progression. The patients showed widespread increases in S1R (≤ 27%) and regional reduction in MC1 (≥ -28%) and SV2A (≥ -25%) radioligand binding, brain volume (≥ -23%), and CBF (≥ -26%). [18F]BCPP-EF PET MC1 binding (≥ -12%) and brain volumes (≥ -5%) showed progressive reductions over 12-18 months, suggesting that they both could be used as pharmacodynamic indicators in early-stage therapeutics trials. Associations of reduced MC1 and SV2A and increased S1R radioligand binding with reduced cognitive performance in AD, although exploratory, suggested a loss of metabolic functional reserve with disease. Our study thus provides in vivo evidence for widespread, clinically relevant cellular stress and bioenergetic abnormalities in early AD.
Lang AE, Siderowf AD, Macklin EA, et al., 2022, Trial of Cinpanemab in Early Parkinson's Disease, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 387, Pages: 408-420, ISSN: 0028-4793
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- Citations: 8
Lillethorup TP, Noer O, Alstrup AKO, et al., 2022, Spontaneous partial recovery of striatal dopaminergic uptake despite nigral cell loss in asymptomatic MPTP-lesioned female minipigs, NEUROTOXICOLOGY, Vol: 91, Pages: 166-176, ISSN: 0161-813X
Horsager J, Okkels N, Van Den Berge N, et al., 2022, In vivo vesicular acetylcholine transporter density in human peripheral organs: an [F-18] FEOBV PET/CT study, EJNMMI RESEARCH, Vol: 12, ISSN: 2191-219X
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- Citations: 1
Sigurdsson HP, Yarnall AJ, Galna B, et al., 2022, Gait-Related Metabolic Covariance Networks at Rest in Parkinson's Disease, MOVEMENT DISORDERS, Vol: 37, Pages: 1222-1234, ISSN: 0885-3185
Jansen WJ, Janssen O, Tijms BM, et al., 2022, Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum, JAMA NEUROLOGY, Vol: 79, Pages: 228-243, ISSN: 2168-6149
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- Citations: 14
Kjeldsen PL, Parbo P, Hansen KV, et al., 2022, Asymmetric amyloid deposition in preclinical Alzheimer’s disease: A PET study, Aging Brain, Vol: 2, Pages: 100048-100048, ISSN: 2589-9589
Madsen LS, Nielsen RB, Parbo P, et al., 2022, Capillary function progressively deteriorates in prodromal Alzheimer’s disease: A longitudinal MRI perfusion study, Aging Brain, Vol: 2, Pages: 100035-100035, ISSN: 2589-9589
Leng F, Hinz R, Gentleman S, et al., 2021, Neuroinflammation, functional connectivity and structural network integrity in the Alzheimer's spectrum, Alzheimer's & dementia : the journal of the Alzheimer's Association, Vol: 17
BACKGROUND: To investigate whether neuroinflammation and β-amyloid (Aβ) deposition influence brain structural and functional connectivity in Alzheimer's spectrum, we conducted a cross-sectional multimodal imaging study and interrogated the associations between imaging biomarkers of neuroinflammation, Aβ deposition, brain connectivity and cognition. METHOD: 58 participants (25 MCI, 16 AD dementia and 17 healthy controls) were recruited and scanned with 11 C-PBR28 and 18 F-flutemetamol PET, T1-weighted, diffusion tensor and resting-state functional MRI. Brain structural and functional connectivity were assessed by global white matter integrity and functional topology metrics, while neuroinflammation and Aβ deposition were evaluated by 11 C-PBR28 and 18 F-flutemetamol uptake, respectively. Changes of the biomarkers were compared between diagnostic groups and robust regression analyses at both voxel and regional level were performed on Aβ positive patients, who were considered to be representative of Alzheimer's continuum. RESULT: Increased 11 C-PBR28 and 18 F-flutemetamol uptake, decreased FA values, impaired small-worldness and local efficiency of functional network were observed in the AD cohort. In Aβ-positive patients, cortical 11 C-PBR28 uptake correlated with decreased structural integrity and network local efficiency independent of 18 F-flutemetamol uptake and cortical thickness. Network structural integrity and cortical thickness correlated with functional metrics, including small-worldness and local efficiency, which were all associated with cognition. CONCLUSION: Our findings suggest that cortical neuroinflammation may lead to disruption of structural and functional brain network independent of amyloid deposition and cortical atrophy, which in turn can lead to cognitive impairment in AD.
Venkataraman A, Bishop C, Mansur A, et al., 2021, Imaging synaptic microstructure and synaptic loss in vivo in early Alzheimer’s Disease, Publisher: Cold Spring Harbor Laboratory
Background Synaptic loss and neurite dystrophy are early events in Alzheimer’s Disease (AD). We aimed to characterise early synaptic microstructural changes in vivo.Methods MRI neurite orientation dispersion and density imaging (NODDI) and diffusion tensor imaging (DTI) were used to image cortical microstructure in both sporadic, late onset, amyloid PET positive AD patients and healthy controls (total n = 28). We derived NODDI measures of grey matter extracellular free water (FISO), neurite density (NDI) and orientation dispersion (ODI), which provides an index of neurite branching and orientation, as well as more conventional DTI measures of fractional anisotropy (FA), mean/axial/radial diffusivity (MD, AD, RD, respectively). We also performed [11C]UCB-J PET, which provides a specific measure of the density of pre-synaptic vesicular protein SV2A. Both sets of measures were compared to regional brain volumes.Results The AD patients showed expected relative decreases in regional brain volumes (range, -6 to - 23%) and regional [11C]UCB-J densities (range, -2 to -25%). Differences between AD and controls were greatest in the hippocampus. NODDI microstructural measures showed greater FISO (range, +26 to +44%) in AD, with little difference in NDI (range, -1 to +7%) and mild focal changes in ODI (range, -4 to +3%). Regionally greater FISO and lower [11C]UCB-J binding were correlated across grey matter in patients (most strongly in the caudate, r2 = 0.37, p = 0.001). FISO and DTI RD were strongly positively associated, particularly in the hippocampus (r2 = 0.98, p < 7.4 × 10−9). After 12-18 months we found a 5% increase in FISO in the temporal lobe, but little change across all ROIs in NDI and ODI. An exploratory analysis showed higher parietal lobe FISO was associated with lower language scores in people with AD.Conclusions We interpreted the increased extracellular free water as a possible consequence of glial activation. The dynamic range of disease
Doppler CEJ, Kinnerup MB, Brune C, et al., 2021, Regional locus coeruleus degeneration is uncoupled from noradrenergic terminal loss in Parkinson's disease, BRAIN, Vol: 144, Pages: 2732-2744, ISSN: 0006-8950
Vibholm AK, Dietz MJ, Beniczky S, et al., 2021, Activated N-methyl-D-aspartate receptor ion channels detected in focal epilepsy with [F-18]GE-179 positron emission tomography, EPILEPSIA, Vol: 62, Pages: 2899-2908, ISSN: 0013-9580
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- Citations: 1
, 2021, Abstracts of the MDS Virtual Congress 2021., Mov Disord, Vol: 36 Suppl 1, Pages: S1-S599
Pasquini J, Brooks DJ, Pavese N, 2021, The Cholinergic Brain in Parkinson's Disease, MOVEMENT DISORDERS CLINICAL PRACTICE, Vol: 8, Pages: 1012-1026, ISSN: 2330-1619
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- Citations: 10
Venkataraman A, Mansur A, Rizzo G, et al., 2021, Widespread cell stress and mitochondrial dysfunction in early Alzheimer’s Disease, Publisher: MedRxiv
Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). We quantified the in vivo density of the endoplasmic reticulum stress marker, the sigma 1 receptor (S1R) using [11C]SA4503 PET, as well as that of mitochondrial complex I (MC1) with [18F]BCPP-EF and the pre-synaptic vesicular protein SV2A with [11C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and brain perfusion (CBF) measured with MRI arterial spin labelling. 8 AD patients were followed longitudinally to estimate rates of change with disease progression over 12-18 months. The AD patients showed widespread increases in S1R (≤ 27%) and regional decreases in MC1 (≥ -28%), SV2A (≥ -25%), brain volume (≥ -23%), and CBF (≥ -26%). [18F]BCPP-EF PET MC1 density (≥ -12%) and brain volumes (≥ -5%) were further reduced at follow up in brain regions consistent with the differences between AD patients and controls at baseline. Exploratory analyses showing associations of MC1, SV2A and S1R density with cognitive changes at baseline and longitudinally with AD, but not in controls, suggested a loss of metabolic functional reserve with disease. Our study thus provides novel in vivo evidence for widespread cellular stress and bioenergetic abnormalities in early AD and that they may be clinically meaningful.
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 & RELATED DISORDERS, Vol: 90, Pages: 52-56, ISSN: 1353-8020
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- Citations: 3
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: 11
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
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- Citations: 8
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, Vol: 36, Pages: 2057-2065, ISSN: 0885-3185
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- Citations: 13
Eskildsen SF, Iranzo A, Stokholm MG, et al., 2021, Impaired cerebral microcirculation in isolated REM sleep behaviour disorder, BRAIN, Vol: 144, Pages: 1498-1508, ISSN: 0006-8950
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- Citations: 3
Brooks DJ, 2021, Future Imaging in Dementia, SEMINARS IN NUCLEAR MEDICINE, Vol: 51, Pages: 303-308, ISSN: 0001-2998
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- Citations: 2
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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- Citations: 11
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
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- Citations: 3
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: 17
Brooks DJ, 2021, Imaging Familial and Sporadic Neurodegenerative Disorders Associated with Parkinsonism, NEUROTHERAPEUTICS, Vol: 18, Pages: 753-771, ISSN: 1933-7213
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- Citations: 2
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