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  • Anders, Silke, et al. (författare)
  • When seeing outweighs feeling : a role for prefrontal cortex in passive control of negative affect in blindsight
  • 2009
  • Ingår i: Brain. - Oxford : Oxford University Press. - 0006-8950 .- 1460-2156. ; 132:11, s. 3021-3031
  • Tidskriftsartikel (refereegranskat)abstract
    • Affective neuroscience has been strongly influenced by the viewthat a ‘feeling’ is the perception of somatic changesand has consequently often neglected the neural mechanisms thatunderlie the integration of somatic and other information inaffective experience. Here, we investigate affective processingby means of functional magnetic resonance imaging in nine corticallyblind patients. In these patients, unilateral postgeniculatelesions prevent primary cortical visual processing in part ofthe visual field which, as a result, becomes subjectively blind.Residual subcortical processing of visual information, however,is assumed to occur in the entire visual field. As we have reportedearlier, these patients show significant startle reflex potentiationwhen a threat-related visual stimulus is shown in their blindvisual field. Critically, this was associated with an increaseof brain activity in somatosensory-related areas, and an increasein experienced negative affect. Here, we investigated the patients’response when the visual stimulus was shown in the sighted visualfield, that is, when it was visible and cortically processed.Despite the fact that startle reflex potentiation was similarin the blind and sighted visual field, patients reported significantlyless negative affect during stimulation of the sighted visualfield. In other words, when the visual stimulus was visibleand received full cortical processing, the patients’ phenomenalexperience of affect did not closely reflect somatic changes.This decoupling of phenomenal affective experience and somaticchanges was associated with an increase of activity in the leftventrolateral prefrontal cortex and a decrease of affect-relatedsomatosensory activity. Moreover, patients who showed strongerleft ventrolateral prefrontal cortex activity tended to showa stronger decrease of affect-related somatosensory activity.Our findings show that similar affective somatic changes canbe associated with different phenomenal experiences of affect,depending on the depth of cortical processing. They are in linewith a model in which the left ventrolateral prefrontal cortexis a relay station that integrates information about subcorticallytriggered somatic responses and information resulting from in-depthcortical stimulus processing. Tentatively, we suggest that theobserved decoupling of somatic responses and experienced affect,and the reduction of negative phenomenal experience, can beexplained by a left ventrolateral prefrontal cortex-mediatedinhibition of affect-related somatosensory activity.
  • Benedet, Andreá L., et al. (författare)
  • Stage-specific links between plasma neurofilament light and imaging biomarkers of Alzheimer's disease
  • 2020
  • Ingår i: Brain. - : Oxford University Press. - 0006-8950. ; 143:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Neurofilament light (NfL) is a marker of neuroaxonal injury, a prominent feature of Alzheimer's disease. It remains uncertain, however, how it relates to amyloid and tau pathology or neurodegeneration across the Alzheimer's disease continuum. The aim of this study was to investigate how plasma NfL relates to amyloid and tau PET and MRI measures of brain atrophy in participants with and without cognitive impairment. We retrospectively examined the association between plasma NfL and MRI measures of grey/white matter volumes in the Alzheimer's Disease Neuroimaging Initiative [ADNI: n = 1149; 382 cognitively unimpaired control subjects and 767 cognitively impaired participants (mild cognitive impairment n = 420, Alzheimer's disease dementia n = 347)]. Longitudinal plasma NfL was measured using single molecule array (Simoa) technology. Cross-sectional associations between plasma NfL and PET amyloid and tau measures were independently assessed in two cohorts: ADNI [n = 198; 110 cognitively unimpaired, 88 cognitively impaired (MCI n = 67, Alzheimer's disease dementia n = 21), data accessed October 2018]; and Translational Biomarkers in Aging and Dementia [TRIAD, n = 116; 74 cognitively unimpaired, 42 cognitively impaired (MCI n = 16, Alzheimer's disease dementia n = 26), data obtained November 2017 to January 2019]. Associations between plasma NfL and imaging-derived measures were examined voxel-wise using linear regression (cross-sectional) and linear mixed effect models (longitudinal). Cross-sectional analyses in both cohorts showed that plasma NfL was associated with PET findings in brain regions typically affected by Alzheimer's disease; associations were specific to amyloid PET in cognitively unimpaired and tau PET in cognitively impaired (P < 0.05). Longitudinal analyses showed that NfL levels were associated with grey/white matter volume loss; grey matter atrophy in cognitively unimpaired was specific to APOE ϵ4 carriers (P < 0.05). These findings suggest that plasma NfL increases in response to amyloid-related neuronal injury in preclinical stages of Alzheimer's disease, but is related to tau-mediated neurodegeneration in symptomatic patients. As such, plasma NfL may a useful measure to monitor effects in disease-modifying drug trials.
  • Blomqvist, Anders, 1949-, et al. (författare)
  • Cytoarchitectonic and immunohistochemical characterization of a specific pain and temperature relay, the posterior portion of the ventral medial nucleus, in the human thalamus
  • 2000
  • Ingår i: Brain. - 0006-8950 .- 1460-2156. ; 123:3, s. 601-619
  • Tidskriftsartikel (refereegranskat)abstract
    • Previous studies in the macaque monkey have identified a thalamic nucleus, the posterior portion of the ventral medial nucleus (VMpo), as a dedicated lamina I spinothalamocortical relay for pain and temperature sensation. The dense plexus of calbindin-immunoreactive fibres that characterizes VMpo in primates enables its homologue to be identified in the human thalamus by immunohistochemical labelling for calbindin. We have now analysed in detail the cytoarchitectonic characteristics of VMpo and its relationship with immunoreactivity for calbindin, substance P and calcitonin gene-related peptide (CGRP) in the human thalamus. The area in the posterolateral thalamus in which dense calbindin-immunoreactive fibre terminations are present coincides nearly completely with a distinct region that contains small to medium-sized cells with round or oval shapes that are aggregated in clusters separated by cell sparse areas. This region, which we identify as VMpo, is located posteromedial to the ventral posterior lateral (VPL) and ventral posterior medial (VPM) nuclei, ventral to the anterior pulvinar and centre median nuclei, lateral to the limitans and parafascicular nuclei and dorsal to the medial geniculate nucleus. Calbindin-immunoreactive fibres enter VMpo from the spinal lemniscus and form large patches of dense terminal-like staining over clusters of VMpo neurons. A few of these clusters also display terminal-like substance P labelling. Small bursts of CGRP staining are intercalated between the calbindin-labelled clusters, but there is little or no overlap between these two markers. CGRP inmunoreactivity is also present over small, non-clustered neurons in the calbindin-negative area that separates VMpo from the VPL and VPM nuclei, which we denote as the posterior nucleus (Po). These observations provide a concise description of VMpo in the human thalamus. Further, they suggest that the lamina I spinothalamic tract fibres (represented by calbindin and probably also substance P immunoreactivity) and vagal-solitary-parabrachial afferents (represented by CGRP immunoreactivity) form closely related, but separate, termination fields that can be considered to represent different aspects of enteroceptive information regarding the physiological status of the tissues and organs of the body. The location of VMpo and the adjacent Po fits with clinical descriptions of the thalamic area from which pain, temperature and visceral sensations can be evoked by microstimulation, and where nociceptive and thermoreceptive neurons have been recorded in humans. It also corresponds to the area in which infarcts cause analgesia and thermoanaesthesia and can lead to the paradoxical development of central pain.
  • Brenner, David, et al. (författare)
  • Hot-spot KIF5A mutations cause familial ALS
  • 2018
  • Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 141, s. 688-697
  • Tidskriftsartikel (refereegranskat)abstract
    • Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 x 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p. Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 x 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.
  • Brinkmalm, Gunnar, et al. (författare)
  • Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer's brain
  • 2019
  • Ingår i: Brain. - 0006-8950 .- 1460-2156. ; 142:5, s. 1441-1457
  • Tidskriftsartikel (refereegranskat)abstract
    • The primary structure of canonical amyloid-β-protein was elucidated more than 30 years ago, yet the forms of amyloid-β that play a role in Alzheimer's disease pathogenesis remain poorly defined. Studies of Alzheimer's disease brain extracts suggest that amyloid-β, which migrates on sodium dodecyl sulphate polyacrylamide gel electrophoresis with a molecular weight of ∼7 kDa (7kDa-Aβ), is particularly toxic; however, the nature of this species has been controversial. Using sophisticated mass spectrometry and sensitive assays of disease-relevant toxicity we show that brain-derived bioactive 7kDa-Aβ contains a heterogeneous mixture of covalently cross-linked dimers in the absence of any other detectable proteins. The identification of amyloid-β dimers may open a new phase of Alzheimer's research and allow a better understanding of Alzheimer's disease, and how to monitor and treat this devastating disorder. Future studies investigating the bioactivity of individual dimers cross-linked at known sites will be critical to this effort. © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.
  • Brundin, Patrik, et al. (författare)
  • Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson's disease
  • 2000
  • Ingår i: Brain. - : Oxford University Press. - 1460-2156 .- 0006-8950. ; 123, s. 1380-1390
  • Tidskriftsartikel (refereegranskat)abstract
    • Five parkinsonian patients were transplanted bilaterally into the putamen and caudate nucleus with human embryonic mesencephalic tissue from between seven and nine donors. To increase graft survival, the lipid peroxidation inhibitor tirilazad mesylate was administered to the tissue before implantation and intravenously to the patients for 3 days thereafter. During the second postoperative year, the mean daily L-dopa dose was reduced by 54% and the UPDRS (Unified Parkinson's Disease Rating Scale) motor score in 'off' phase was reduced by a mean of 40%. At 10-23 months after grafting, PET showed a mean 61% increase of 6-L-[(18)F]fluorodopa uptake in the putamen, and 24% increase in the caudate nucleus, compared with preoperative values. No obvious differences in the pattern of motor recovery were observed between these and other previously studied cases with putamen grafts alone. The amount of mesencephalic tissue implanted in each putamen and caudate nucleus was 42 and 50% lower, respectively, compared with previously transplanted patients from our centre. Despite this reduction in grafted tissue, the magnitudes of symptomatic relief and graft survival were very similar. These findings suggest that tirilazad mesylate may improve survival of grafted dopamine neurons in patients, which is in agreement with observations in experimental animals.
  • Buerger, Katharina, et al. (författare)
  • CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease.
  • 2006
  • Ingår i: Brain. - 0006-8950 .- 1460-2156. ; 129:Pt 11, s. 3035-41
  • Tidskriftsartikel (refereegranskat)abstract
    • Hyperphosphorylated tau protein (P-tau) in CSF is a core biomarker candidate of Alzheimer's disease. Hyperphosphorylation of tau is thought to lead to neurofibrillary changes, a neuropathological hallmark of this type of dementia. Currently, the question is unresolved whether CSF levels of P-tau reflect neurofibrillary changes within the brain of a patient with the illness. Twenty-six patients were included with intra-vitam CSF as well as post-mortem neuropathological data. In the CSF, P-tau phosphorylated at threonine 231 (P-tau231P) was analysed. Post-mortem, scores of neurofibrillary tangles (NFT) and neuritic plaques (NP) were assessed in frontal, temporal, parietal and hippocampal cortical areas. In the same cortical regions, load of hyperphosphorylated tau protein (HP-tau load) was determined. Concentrations of P-tau231P were measured in frontal cortex homogenates. We found significant correlations between CSF P-tau231P concentrations and scores of NFTs and HP-tau load in all neocortical regions studied. The score of NPs was correlated with CSF P-tau231P only within the frontal cortex. There was a correlation between P-tau231P in CSF and brain homogenates. These findings indicate that CSF P-tau231P may serve as an in vivo surrogate biomarker of neurofibrillary pathology in Alzheimer's disease.
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