| 1. |
- Coenen, Mirthe, et al.
(författare)
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Spatial distributions of white matter hyperintensities on brain MRI: A pooled analysis of individual participant data from 11 memory clinic cohorts
- 2023
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Ingår i: NeuroImage. Clinical. - 2213-1582. ; 40
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as "unusual", but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns. METHODS: Individual participant data (N=3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented. RESULTS: WMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected. DISCUSSION: Aggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered.
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| 2. |
- Iderberg, Hanna, et al.
(författare)
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NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat.
- 2015
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 271:May 30, s. 335-350
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Tidskriftsartikel (refereegranskat)abstract
- L-DOPA is the gold-standard treatment for Parkinson's disease (PD), but induces troublesome dyskinesia after prolonged treatment. This is associated with the 'false neurotransmitter' conversion of L-DOPA to dopamine by serotonin neurons projecting from the raphe to the dorsal striatum. Reducing their activity by targeting pre-synaptic 5-HT1A receptors should thus be an attractive therapeutic strategy, but previous 5-HT1A agonists have yielded disappointing results. Here, we describe the activity of a novel, highly selective and potent 5-HT1A agonist, NLX-112 (also known as befiradol or F13640) in rat models relevant to PD and its associated affective disorders. NLX-112 (0.16mg/kgi.p.) potently and completely reversed haloperidol-induced catalepsy in intact rats and abolished L-DOPA-induced Abnormal Involuntary Movements (AIMs) in hemiparkinsonian rats, an effect that was reversed by the selective 5-HT1A antagonist, WAY100635. In microdialysis experiments, NLX-112 profoundly decreased striatal 5-HT extracellular levels, indicative of inhibition of serotonergic function. NLX-112 also blunted the L-DOPA-induced surge in dopamine levels on the lesioned side of the brain, an action that likely underlies its anti-dyskinetic effects. NLX-112 (0.16mg/kgi.p.) robustly induced rotations in hemiparkinsonian rats, suggesting that it has a motor facilitatory effect. Rotations were abolished by WAY100635 and were ipsilateral to the lesioned side, suggesting a predominant stimulation of the dopamine system on the non-lesioned side of the brain. NLX-112 also efficaciously reduced immobility time in the forced swim test (75% reduction at 0.16mg/kgi.p.) and eliminated stress-induced ultrasonic vocalization at 0.08mg/kgi.p., effects consistent with potential antidepressant- and anxiolytic-like properties. In other tests, NLX-112 (0.01-0.16mg/kgi.p.) did not impair the abilityof L-DOPA to rescue fore-paw akinesia in the cylinder test but decreased rotarod performance, probably due to induction of flat body posture and fore-paw treading which are typical of 5-HT1A agonists upon acute administration. However, upon repeated administration of NLX-112 (0.63mg/kgi.p., twice a day), flat body posture and fore-paw treading subsided within 4days of treatment. Taken together, these observations suggest that NLX-112 could exhibit a novel therapeutic profile, combining robust anti-dyskinetic properties without impairing the therapeutic properties of L-DOPA, and with additional beneficial effects on non-motor (affective) symptoms.
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| 3. |
- McCreary, D., et al.
(författare)
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Development and Validation of a Targeted Next-Generation Sequencing Gene Panel for Children With Neuroinflammation
- 2019
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Ingår i: Jama Network Open. - : American Medical Association (AMA). - 2574-3805. ; 2:10
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Neuroinflammatory disorders are a range of severe neurological disorders causing brain and spinal inflammation and are now increasingly recognized in the pediatric population. They are often characterized by marked genotypic and phenotypic heterogeneity, complicating diagnostic work in clinical practice and molecular diagnosis. OBJECTIVE To develop and evaluate a next-generation sequencing panel targeting genes causing neuroinflammation or mimicking neuroinflammation. DESIGN, SETTING, AND PARTICIPANTS Cohort study in which a total of 257 genes associated with monogenic neuroinflammation and/or cerebral vasculopathy, including monogenic noninflammatory diseases mimicking these entities, were selected. A customized enrichment capture array, the neuroinflammation gene panel (NIP), was created. Targeted high-coverage sequencing was applied to DNA samples taken from eligible patients referred to Great Ormond Street Hospital in London, United Kingdom, between January 1, 2017, and January 30, 2019, because of onset of disease early in life, family history, and/or complex neuroinflammatory phenotypes. MAIN OUTCOMES AND MEASURES The main outcome was the percentage of individuals with definitive molecular diagnoses, variant classification, and clinical phenotyping of patients with pathogenic variants identified using the NIP panel. The NIP panel was initially validated in 16 patients with known genetic diagnoses. RESULTS The NIP was both sensitive (95%) and specific (100%) for detection of known mutations, including gene deletions, copy number variants, small insertions and deletions, and somatic mosaicism with allele fraction as low as 3%. Prospective testing of 60 patients (30 [50%] male; median [range] age, 9.8 [0.8-20] years) presenting with heterogeneous neuroinflammatory phenotypes revealed at least 1 class 5 (clearly pathogenic) variant in 9 of 60 patients (15%); 18 of 60 patients (30%) had at least 1 class 4 (likely pathogenic) variant. Overall, a definitive molecular diagnosis was established in 12 of 60 patients (20%). CONCLUSIONS AND RELEVANCE The NIP was associated with molecular diagnosis in this cohort and complemented routine laboratory and radiological workup of patients with neuroinflammation. Unexpected genotype-phenotype associations in patients with pathogenic variants deviating from the classic phenotype were identified. Obtaining an accurate molecular diagnosis in a timely fashion informed patient management, including successful targeted treatment in some instances and early institution of hematopoietic stem cell transplantation in others.
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| 4. |
- Iderberg, Hanna, et al.
(författare)
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Activity of serotonin 5-HT1A receptor 'biased agonists' in rat models of Parkinson's disease and l-DOPA-induced dyskinesia.
- 2015
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Ingår i: Neuropharmacology. - : Elsevier BV. - 1873-7064 .- 0028-3908. ; 93, s. 52-67
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Tidskriftsartikel (refereegranskat)abstract
- Serotonin 5-HT1A receptor agonists reduce l-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease (PD). Here, we compared the effects of novel 5-HT1A receptor 'biased agonists' on LID in hemiparkinsonian rats. F13714 preferentially activates pre-synaptic 5-HT1A autoreceptors. F15599 preferentially activates cortical postsynaptic 5-HT1A heteroreceptors. The partial agonist, tandospirone, does not differentiate these receptor subpopulations. The drugs were also tested on rotational behavior, rotarod and cylinder test for evaluation of locomotor activity, motor coordination and forelimb akinesia. Finally, the effects of F13714 and F15599 on 5-HT, DA, glutamate, and GABA release were investigated by microdialysis. F13714 abolished l-DOPA-induced AIMs even at very low doses (0.02-0.04 mg/kg). This effect was reversed by the selective 5-HT1A receptor antagonist, WAY100635. F13714 also elicited ipsilateral rotations (which were blocked by WAY100635) and potentiated the rotational activity of a sub-threshold dose of l-DOPA (2 mg/kg). F13714 profoundly inhibited striatal 5-HT release on both sides of the brain, and slightly increased DA release on the intact side. F15599 inhibited the l-DOPA-induced AIMs only at a dose (0.16 mg/kg) that reduced 5-HT release. Tandospirone produced a modest attenuation of peak AIMs severity and did not elicit rotations. F13714, F15599 and tandospirone did not modify the action of l-DOPA in the cylinder test but impaired rotarod performance at the highest doses tested. Targeting 5-HT1A receptors with selective biased agonists exerts distinct effects in the rat model of PD and LID. Preferential activation of 5-HT1A autoreceptors could potentially translate to superior antidyskinetic and l-DOPA dose-sparing effects in PD patients.
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| 5. |
- Jones, Alfred J. H., et al.
(författare)
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Visualizing band structure hybridization and superlattice effects in twisted MoS2/WS2 heterobilayers
- 2022
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Ingår i: Current Opinion in Chemical Engineering. - : IOP Publishing Ltd. - 2211-3398. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- A mismatch of atomic registries between single-layer transition metal dichalcogenides (TMDs) in a two-dimensional (2D) van der Waals heterostructure produces a moire superlattice with a periodic potential, which can be fine-tuned by introducing a twist angle between the materials. This approach is promising both for controlling the interactions between the TMDs and for engineering their electronic band structures, yet direct observation of the changes to the electronic structure introduced with varying twist angle has so far been missing. Here, we probe heterobilayers comprised of single-layer MoS2 and WS2 with twist angles ranging from 2 degrees to 20 degrees and determine the twist angle-dependent evolution of the electronic band structure using micro-focused angle-resolved photoemission spectroscopy. We find strong interlayer hybridization between MoS2 and WS2 electronic states at the (Gamma) over bar -point of the Brillouin zone, leading to a shift of the valence band maximum in the heterostructure. Replicas of the hybridized states are observed at the center of twist angle-dependent moire mini Brillouin zones. We confirm that these replica features arise from the inherent moire potential by comparing our experimental observations with density functional theory calculations of the superlattice dispersion. Our direct visualization of these features underscores the potential of using twisted heterobilayer semiconductors to engineer hybrid electronic states and superlattices that alter the electronic and optical properties of 2D heterostructures for a wide range of twist angles.
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