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1.	Acker, T, et al. (författare) Characterization of a putative tumor stem cell in malignant brain tumors 2004 Ingår i: ACTA NEUROPATHOLOGICA. - 0001-6322. ; 108:4, s. 354-354 Konferensbidrag (övrigt vetenskapligt/konstnärligt)
2.	Adori, Csaba, et al. (författare) Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system : new aspects on Alzheimer's disease 2015 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 129:4, s. 541-563 Tidskriftsartikel (refereegranskat)abstract Alzheimer's disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites. This is noteworthy since cortical and hypothalamic somatostatin content is reduced in neurodegenerative pathologies. Yet a possible role of a somatostatin signal deficit in the maintenance of noradrenergic projections remains unknown. Here, we deployed tissue microarrays, immunohistochemistry, quantitative morphometry and mRNA profiling in a cohort of Alzheimer's and age-matched control brains in combination with genetic models of somatostatin receptor deficiency to establish causality between defunct somatostatin signalling and noradrenergic neurodegeneration. In Alzheimer's disease, we found significantly reduced somatostatin protein expression in the temporal cortex, with aberrant clustering and bulging of tyrosine hydroxylase-immunoreactive afferents. As such, somatostatin receptor 2 (SSTR2) mRNA was highly expressed in the human LC, with its levels significantly decreasing from Braak stages III/IV and onwards, i.e., a process preceding advanced Alzheimer's pathology. The loss of SSTR2 transcripts in the LC neurons appeared selective, since tyrosine hydroxylase, dopamine beta-hydroxylase, galanin or galanin receptor 3 mRNAs remained unchanged. We modeled these pathogenic changes in Sstr2 (-/-) mice and, unlike in Sstr1 (-/-) or Sstr4 (-/-) genotypes, they showed selective, global and progressive degeneration of their central noradrenergic projections. However, neuronal perikarya in the LC were found intact until late adulthood (< 8 months) in Sstr2 (-/-) mice. In contrast, the noradrenergic neurons in the superior cervical ganglion lacked SSTR2 and, as expected, the sympathetic innervation of the head region did not show any signs of degeneration. Our results indicate that SSTR2-mediated signaling is integral to the maintenance of central noradrenergic projections at the system level, and that early loss of somatostatin receptor 2 function may be associated with the selective vulnerability of the noradrenergic system in Alzheimer's disease.
3.	Aguilar-Calvo, Patricia, et al. (författare) Shortening heparan sulfate chains prolongs survival and reduces parenchymal plaques in prion disease caused by mobile, ADAM10-cleaved prions 2020 Ingår i: Acta Neuropathologica. - : SPRINGER. - 0001-6322 .- 1432-0533. ; 139:3, s. 527-546 Tidskriftsartikel (refereegranskat)abstract Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1(+/-)) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography-mass spectrometry (LC-MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC-MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions.
4.	Alafuzoff, Irina, et al. (författare) Assessment of beta-amyloid deposits in human brain : a study of the BrainNet Europe Consortium 2009 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 117:3, s. 309-320 Tidskriftsartikel (refereegranskat)abstract beta-Amyloid (A-beta) related pathology shows a range of lesions which differ both qualitatively and quantitatively. Pathologists, to date, mainly focused on the assessment of both of these aspects but attempts to correlate the findings with clinical phenotypes are not convincing. It has been recently proposed in the same way as iota and alpha synuclein related lesions, also A-beta related pathology may follow a temporal evolution, i.e. distinct phases, characterized by a step-wise involvement of different brain-regions. Twenty-six independent observers reached an 81% absolute agreement while assessing the phase of A-beta, i.e. phase 1 = deposition of A-beta exclusively in neocortex, phase 2 = additionally in allocortex, phase 3 = additionally in diencephalon, phase 4 = additionally in brainstem, and phase 5 = additionally in cerebellum. These high agreement rates were reached when at least six brain regions were evaluated. Likewise, a high agreement (93%) was reached while assessing the absence/presence of cerebral amyloid angiopathy (CAA) and the type of CAA (74%) while examining the six brain regions. Of note, most of observers failed to detect capillary CAA when it was only mild and focal and thus instead of type 1, type 2 CAA was diagnosed. In conclusion, a reliable assessment of A-beta phase and presence/absence of CAA was achieved by a total of 26 observers who examined a standardized set of blocks taken from only six anatomical regions, applying commercially available reagents and by assessing them as instructed. Thus, one may consider rating of A-beta-phases as a diagnostic tool while analyzing subjects with suspected Alzheimer's disease (AD). Because most of these blocks are currently routinely sampled by the majority of laboratories, assessment of the A-beta phase in AD is feasible even in large scale retrospective studies.
5.	Alafuzoff, I, et al. (författare) Histopathological criteria for progressive dementia disorders : clinical-pathological correlation and classification by multivariate data analysis. 1987 Ingår i: Acta Neuropathologica. - 0001-6322 .- 1432-0533. ; 74:3, s. 209-25 Tidskriftsartikel (refereegranskat)abstract Autopsied brains from 55 patients with dementia between 59-95 years of age (mean age 77.9 +/- 8.1 years) and 19 non-demented individuals between 46-91 years of age (mean age 74.3 +/- 10.5 years) were examined to establish histopathological criteria for normal ageing, primary degenerative [Alzheimer's disease (AD)/senile dementia of Alzheimer type (SDAT)] and vascular (multi-infarct) dementia (MID) disorders. Senile/neuritic plaques, neurofibrillary tangles, microscopic infarcts and perivascular serum protein deposits were quantified in the frontal lobe (Brodmann area 10) and in the hippocampus. The demented patients were classified according to the DSM-III criteria into AD/SDAT and MID. Operationally defined histopathological criteria for dementias, based on the degree/amount of the histopathological changes seen in aged non-demented patients, were postulated. The demented patients were clearly separable into three histopathological types, namely AD/SDAT, MID and AD-MID, the dementia type where both the degenerative and the vascular changes are coexistent in greater extent than are seen in the non-demented individuals. Using general clinical, gross neuroanatomical and histopathological data three separate dementia classes, namely AD/SDAT, MID and AD-MID, were visualized in two-dimensional space by multivariate data analysis. This analysis revealed that the pathology in the AD-MID patients was not merely a linear combination of the pathology in AD/SDAT and MID, indicating that AD-MID might represent a dementia type of its own. The clinical diagnosis for AD/SDAT and MID was certain in only half of the AD/SDAT and one third of the MID cases when evaluated histopathologically and by multivariate data analysis. AD/SDAT, MID and AD-MID were histopathologically diagnosed in 49%, 24% and 27%, respectively, of all the dementia cases studied. Opposite correlation between the number of tangles, plaques and the patient age in non-demented and AD/SDAT cases were observed, indicating that the pathogenesis of tangles and plaques in the two groups of patients might be different and that AD/SDAT might not be a form of an exaggerated ageing process.
6.	Alafuzoff, Irina, et al. (författare) Inter-laboratory comparison of neuropathological assessments of beta-amyloid protein : a study of the BrainNet Europe consortium. 2008 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 115:5, s. 533-46 Tidskriftsartikel (refereegranskat)abstract Amyloid-beta-protein (Abeta) is generally assessed by neuropathologists in diagnostics. This BrainNet Europe ( http://www.brainnet-europe.org/ ) (15 centres and 26 participants) study was carried out to investigate the reliability of such an assessment. In the first part of this trial, tissue microarray sections were stained with the antibody of each centre's choice. Reflecting the reality, seven antibodies and a plethora of pretreatment strategies were used. Ninety-two percent of the stainings were of good/acceptable quality and the estimation of presence of Abeta aggregates yielded good results. However, a poor agreement was reached particularly regarding quantitative (density) and qualitative (diffuse/cored plaques) results. During a joint meeting, the clone 4G8 was determined to label best the fleecy/diffuse plaques, and thus, this clone and the formic acid pretreatment technique were selected for the second part of this study. Subsequently, all stained sections were of good/acceptable quality and again a high level of concordance of the dichotomized (presence/absence) assessment of plaques and CAA was achieved. However, even when only one antibody was used, the type of Abeta-aggregates (diffuse/cored), type of vessel and Vonsattel grade, were not reliably assigned. Furthermore, the quantification of lesions was far from reliable. In line with the first trial, the agreement while assessing density (some, moderate and many) was unimpressive. In conclusion, we can confirm the utility of immunohistochemical detection of Abeta-protein in diagnostics and research. It is noteworthy that to reach reproducible results a dichotomized assessment of Abeta-immunoreactivity rather than quantification and assignment of various types of lesions should be applied, particularly when comparing results obtained by different neuropathologists.
7.	Alafuzoff, Irina, et al. (författare) Staging/typing of Lewy body related alpha-synuclein pathology : a study of the BrainNet Europe Consortium 2009 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 117:6, s. 635-652 Tidskriftsartikel (refereegranskat)abstract When 22 members of the BrainNet Europe (BNE) consortium assessed 31 cases with alpha-synuclein (alphaS) immunoreactive (IR) pathology applying the consensus protocol described by McKeith and colleagues in 2005, the inter-observer agreement was 80%, being lowest in the limbic category (73%). When applying the staging protocol described by Braak and colleagues in 2003, agreement was only 65%, and in some cases as low as 36%. When modifications of these strategies, i.e., McKeith's protocol by Leverenz and colleagues from 2009, Braak's staging by Müller and colleagues from 2005 were applied then the agreement increased to 78 and 82%, respectively. In both of these modifications, a reduced number of anatomical regions/blocks are assessed and still in a substantial number of cases, the inter-observer agreement differed significantly. Over 80% agreement in both typing and staging of alphaS pathology could be achieved when applying a new protocol, jointly designed by the BNE consortium. The BNE-protocol assessing alphaS-IR lesions in nine blocks offered advantages over the previous modified protocols because the agreement between the 22 observers was over 80% in most cases. Furthermore, in the BNE-protocol, the alphaS pathology is assessed as being present or absent and thus the quality of staining and the assessment of the severity of alphaS-IR pathology do not alter the inter-observer agreement, contrary to other assessment strategies. To reach these high agreement rates an entity of amygdala-predominant category was incorporated. In conclusion, here we report a protocol for assessing alphaS pathology that can achieve a high inter-observer agreement for both the assignment to brainstem, limbic, neocortical and amygdala-predominant categories of synucleinopathy and the Braak stages.
8.	Anan, Intissar, et al. (författare) Colonic enteric nervous system in patients with familial amyloidotic neuropathy. 1999 Ingår i: Acta Neuropathologica. - 0001-6322 .- 1432-0533. ; 98:1, s. 48-54 Tidskriftsartikel (refereegranskat)abstract The colonic enteric nervous system was investigated in autopsy specimens from 12 patients with familial amyloidotic neuropathy (FAP) and 9 controls. The infiltration of amyloid deposits in the enteric nervous system was studied by double staining for amyloid and nerve elements. The myenteric plexus was immunostained for protein gene product (PGP) 9.5, vasoactive intestinal peptide (VIP), substance P and nitric oxide synthase (NOS). The immunostained nerve elements were quantified by computerised image analysis. Double staining revealed that there was no amyloid infiltration in the ganglia, or in the nerve fibres in the colonic enteric nervous system of FAP patients. The relative volume density of PGP 9.5-immunoreactive nerve fibres in both the circular and the longitudinal muscle layers in FAP patients did not differ significantly from that of controls. The relative volume density of VIP-immunoreactive nerve fibres in the circular muscle layer was significantly decreased in FAP patients compared with controls, but not in the longitudinal layer. The number of VIP-immunoreactive neurons/mm2 myenteric ganglia was significantly decreased in FAP patients. There were no statistical differences in the relative volume density for substance P- and NOS-immunoreactive nerve fibres between FAP patients and controls, nor was there any difference between FAP patients and controls regarding the number of NOS- and substance P-immunoreactive neurons/mm2 myenteric ganglia. It is concluded that the colonic enteric nervous system as a whole is intact and is not damaged by amyloid infiltration. The present observation of a reduction of VIP-immunoreactive nerve fibres and neurons in myenteric plexus of FAP patients might be one of the factors that contribute to the motility disorders seen in FAP patients.
9.	Anan, Intissar, et al. (författare) Comparison of amyloid deposits and infiltration of enteric nervous system in the upper with those in the lower gastrointestinal tract in patients with familial amyloidotic polyneuropathy. 2001 Ingår i: Acta Neuropathologica. - 0001-6322 .- 1432-0533. ; 102:3, s. 227-32 Tidskriftsartikel (refereegranskat)abstract Gastrointestinal (GI) complications in familial amyloidotic polyneuropathy (FAP) are invariably present during the course of the disease. The aim of this study was to investigate amyloid deposits in the myenteric plexus of the stomach and small intestine in FAP patients and compare the results with those of the colon. Six FAP patients were included in the study. The myenteric plexus and the number of macrophages (CD68) and blood vessels were immunostained and quantified by computerised image analysis. Double staining for amyloid and nerve elements was used to detect amyloid infiltration in the myenteric plexus. Amyloid was found predominantly in the walls of blood vessels, and was detected in the nerves of five FAP patients and in 18% of the examined ganglia of the myenteric plexus of the stomach. In the small intestine, 6% of examined ganglia showed amyloid deposits. In contrast, no deposits were found in the myenteric plexus of the colon. CD68-positive cells showed no difference in three parts of the GI tract. Most amyloid deposits were noted in the stomach, followed by the small intestine. There are significantly more blood vessels in the stomach and small intestine compared with the colon, and the amount of amyloid correlated with the number of blood vessels, and not with the amount of nerves and ganglia. The enteric nerve system is not a targeted organ for amyloid deposition in FAP.
10.	Andersson, Ulrika, et al. (författare) Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas 2004 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 108:2, s. 135-142 Tidskriftsartikel (refereegranskat)abstract Overexpression of epidermal growth factor receptor (EGFR, ErbB1) correlates with enhanced malignant potential of many human tumor types including glioblastoma multiforme. The significance of EGFR expression in meningiomas is, however, unclear. Reports regarding the other EGFR family members, ErbB2-4, in brain tumors are sparse. In this study, the expression of the EGFR family members was analyzed in relation to various parameters for the clinical importance of these receptors in 44 gliomas and 26 meningiomas. In gliomas, quantitative real-time reverse transcription (RT)-PCR revealed the highest EGFR mRNA expression in high-grade gliomas, while ErbB2 and ErbB3 mRNA were detected only in a few high-grade gliomas. In contrast, ErbB4 expression was most pronounced in low-grade gliomas. Immunohistochemistry showed significantly higher EGFR protein expression in high-grade gliomas compared to low-grade gliomas (P= 0.004). ErbB2 protein expression was mainly seen in high-grade gliomas. ErbB3 protein expression was low in all gliomas analyzed. ErbB4 protein expression was significantly higher in low-grade gliomas than in high-grade gliomas (P= 0.007). In meningiomas, quantitative real-time RT-PCR revealed expression of EGFR, ErbB2, and ErbB4 mRNA in the majority of the tumors. ErbB3 was detected in only one of the meningiomas analyzed. Immunohistochemistry demonstrated high ErbB2 protein expression in meningiomas. An intriguing observation in astrocytomas and oligodendrogliomas grade II, was a significantly decreased overall survival for patients with high EGFR protein expression (P= 0.04). The high ErbB4 expression in low-grade compared to high-grade gliomas might suggest that ErbB4 acts as a suppressor of malignant transformation in brain tumors, which is in line with previous studies in other tumor types.
11.	Ashton, Nicholas J., et al. (författare) Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology. 2021 Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 141:5, s. 709-724 Tidskriftsartikel (refereegranskat)abstract The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise in detecting Alzheimer's disease (AD) pathophysiology. Tau phosphorylated at threonine 231 (p-tau231) is one such biomarker in CSF but its usefulness as a blood biomarker is currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 which was validated in four independent cohorts (n=588) in different settings, including the full AD continuum and non-AD neurodegenerative disorders. Plasma p-tau231 was able to identify patients with AD and differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults with high accuracy (AUC=0.92-0.94). Plasma p-tau231 also distinguished AD patients from patients with non-AD neurodegenerative disorders (AUC=0.93), as well as from amyloid-β negative MCI patients (AUC=0.89). In a neuropathology cohort, plasma p-tau231 in samples taken on avergae 4.2years prior to post-mortem very accurately identified AD neuropathology in comparison to non-AD neurodegenerative disorders (AUC=0.99), this is despite all patients being given an AD dementia diagnosis during life. Plasma p-tau231 was highly correlated with CSF p-tau231, tau pathology as assessed by [18F]MK-6240 positron emission tomography (PET), and brain amyloidosis by [18F]AZD469 PET. Remarkably, the inflection point of plasma p-tau231, increasing as a function of continuous [18F]AZD469 amyloid-β PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-β PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-β PET quartiles 2-4, whereas CSF p-tau217 and plasma p-tau181 increased only at quartiles 3-4 and 4, respectively. Finally, plasma p-tau231 differentiated individuals across the entire Braak stage spectrum, including Braak staging from Braak 0 through Braak I-II, which was not observed for plasma p-tau181. To conclude, this novel plasma p-tau231 assay identifies the clinicalstages of ADand neuropathology equally well as plasma p-tau181, but increases earlier, already with subtle amyloid-β deposition, prior to the threshold for amyloid-β PET positivity has been attained, and also in response to early brain tau deposition. Thus, plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below PET threshold of amyloid-β positivity or apparent entorhinal tau deposition.
12.	Ata, A K, et al. (författare) Expression of various TGF-beta isoforms and type I receptor in necrotizing human brain lesions. 1997 Ingår i: Acta neuropathologica. - 0001-6322. ; 93:4, s. 326-33 Tidskriftsartikel (refereegranskat)abstract It is known that transforming growth factor beta (TGF-beta) is involved in the modulation of cell growth, differentiation, and repair following injury. We performed an immunohistochemical study of human brain autopsy and biopsy material for the expression of TGF-beta isoforms beta 1, beta 2 and beta 3, and TGF-beta receptor (T beta R) type I in different cells of necrotizing lesions such as infarction and abscess, and compared them with controls. Various cell types, both inside and in the proximity of lesions, showed immunoreactivity indicating the presence of all three isoforms. Significant values of immunoreaction for various TGF-beta s and T beta R-I were observed in cells such as astrocytes, macrophages, neurons, microvascular endothelial cells, and granulocytes. In the control cases, comprising biopsy material without necrotizing lesions, a prominent TGF-beta 2 immunoreactivity was observed in glial cells and neurons. TGF-beta 1 and TGF-beta 3 reactivity in controls, when compared with TGF-beta 2, was less. T beta R-I antiserum showed clear and distinct signals in the same type of cells as for TGF-beta s in the necrotizing lesions with varying values of significance. Our findings suggest that TGF-beta s and their receptor type I are involved in reactive processes around necrotizing human brain lesions like glial and macrophage responses, angiogenesis, and deposition of extracellular matrix.
13.	Ata, K A, et al. (författare) Expression of transforming growth factor-beta1, 2, 3 isoforms and type I and II receptors in acute focal cerebral ischemia: an immunohistochemical study in rat after transient and permanent occlusion of middle cerebral artery. 1999 Ingår i: Acta neuropathologica. - 0001-6322. ; 97:5, s. 447-55 Tidskriftsartikel (refereegranskat)abstract Transforming growth factor beta (TGF-beta) is involved in the modulation of cell growth, differentiation and repair following injury of various organs. Previous studies on human autopsy material have indicated that TGF-beta isoforms-beta1, -beta2 and -beta3, and TGF-beta receptor type I are expressed in various cells of necrotizing brain lesions like infarction and abscess. The present immunohistochemical study was designed to investigate changes that may occur with regard to TGF-beta and its receptors type I and II in a rat model of focal brain ischemia induced by transient or permanent occlusion of the middle cerebral artery. Our findings indicate that at days 1 and 3 following such transient and permanent ischemia there is an up-regulation of TGF-beta isoforms -beta1, -beta2 and -beta3, and TGF-beta receptor types I and II mainly in the perifocal neurons, reactive astroglial cells, endothelial cells and macrophages.
14.	Auer, R. N., et al. (författare) The distribution of hypoglycemic brain damage 1984 Ingår i: Acta Neuropathologica. - 0001-6322. ; 64:3, s. 177-191 Tidskriftsartikel (refereegranskat)abstract Rats were exposed to insulin-induced hypoglycemia resulting in periods of cerebral isoelectricity ranging from 10 to 60 min. After recovery with glucose, they were allowed to wake up and survive for 1 week. Control rats were recovered at the stage of EEG slowing. After sub-serial sectioning, the number and distribution of dying neurons was assessed in each brain region. Acid fuchsin was found to stain moribund neurons a brilliant red. Brains from control rats showed no dying neurons. From 10 to 60 min of cerebral isoelectricity, the number of dying neurons per brain correlated positively with the number of minutes of cerebral isoelectricity up to the maximum examined period of 60 min. Neuronal necrosis was found in the major brain regions vulnerable to several different insults. However, within each region the damage was not distributed as observed in ischemia. A superficial to deep gradient in the density of neuronal necrosis was seen in the cerebral cortex. More severe damage revealed a gradient in relation to the subjacent white matter as well. The caudatoputamen was involved more heavily near the white matter, and in more severely affected animals near the angle of the lateral ventricle. The hippocampus showed dense neuronal necrosis at the crest of the dentate gyrus and a gradient of increasing selective neuronal necrosis medially in CA1. The CA3 zone, while relatively resistant, showed neuronal necrosis in relation to the lateral ventricle in animals with hydrocephalus. Sharp demarcations between normal and damaged neuropil were found in the hippocampus. The periventricular amygdaloid nuclei showed damage closest to the lateral ventricles. The cerebellum was affected first near the foramina of Luschka, with damage occurring over the hemispheres in more severely affected animals. Purkinje cells were affected first, but basket cells were damaged as well. Rare necrotic neurons were seen in brain stem nuclei. The spinal cord showed necrosis of neurons in all areas of the gray matter. Infarction was not seen in this study. The possibility is discussed that a neurotoxic substance borne in the tissue fluid and cerebrospinal fluid (CSF) contributes to the pathogenesis of neuronal necrosis in hypoglycemic brain damage.
15.	Auer, R., et al. (författare) The dentate gyrus in hypoglycemia : Pathology implicating excititoxin-mediated neuronal necrosis 1985 Ingår i: Acta Neuropathologica. - 0001-6322. ; 67:3-4, s. 279-288 Tidskriftsartikel (refereegranskat)abstract A detailed light- and electron-microscopic study of the damage to the rat dentate gyrus in hypoglycemia was undertaken, in view of the previously advanced hypothesis that hypoglycemic nerve cell injury is mediated by a released neurotoxin. The distribution of neuronal necrosis showed a relationship to the subarachnoid cisterns. Electron microscopy of the dentate granule cells and their apical dendrites revealed dendrosomal, axon-sparing neuronal pathology. Dentate granule cells were affected first in the dendrites in the outer layer of the stratum moleculare, sparing axons of passage and terminal boutons. Subsequently, the neuronal perikarya were affected, and Wallerian degeneration of axons followed. Cell membrane abnormalities preceded the appearance of mitochondrial flocculent densities and degradation of the cytoskeleton, and are suggested to be early lethal changes. The observed early dendrotoxic changes, and the dendrosomal, axon-sparing nature of the lesion implicate an excitotoxin-mediated neuronal necrosis in hypoglycemia.
16.	Bell, Jeanne E, et al. (författare) Management of a twenty-first century brain bank : experience in the BrainNet Europe consortium. 2008 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 115:5, s. 497-507 Tidskriftsartikel (refereegranskat)abstract Collections of human postmortem brains gathered in brain banks have underpinned many significant developments in the understanding of central nervous system (CNS) disorders and continue to support current research. Unfortunately, the worldwide decline in postmortem examinations has had an adverse effect on research tissue procurement, particularly from control cases (non-diseased brains). Recruitment to brain donor programmes partially addresses this problem and has been successful for dementing and neurodegenerative conditions. However, the collection of brains from control subjects, particularly from younger individuals, and from CNS disorders of sudden onset, remains a problem. Brain banks need to adopt additional strategies to circumvent such shortages. The establishment of brain bank networks allows data on, and access to, control cases and unusual CNS disorders to be shared, providing a larger resource for potential users. For the brain banks themselves, inclusion in a network fosters the sharing of protocols and development of best practice and quality control. One aspect of this collective experience concerns brain bank management, excellence in which is a prerequisite not only for gaining the trust of potential donors and of society in general, but also for ensuring equitable distribution to researchers of high quality tissue samples. This review addresses the legal, ethical and governance issues, tissue quality, and health and safety aspects of brain bank management and data management in a network, as well as the needs of users, brain bank staffing, donor programs, funding issues and public relations. Recent developments in research methodology present new opportunities for researchers who use brain tissue samples, but will require brain banks to adopt more complex protocols for tissue collection, preparation and storage, with inevitable cost implications for the future.
17.	Bergstedt, Kerstin, et al. (författare) Initiation of protein synthesis and heat-shock protein-72 expression in the rat brain following severe insulin-induced hypoglycemia 1993 Ingår i: Acta Neuropathologica. - 0001-6322. ; 86:2, s. 145-153 Tidskriftsartikel (refereegranskat)abstract Following stress such as heat shock or transient cerebral ischemia, global brain protein synthesis initiation is depressed through modulation of eucaryotic initiation factor (eIF) activities, and modification of ribosomal subunits. Concomitantly, expression of a certain class of mRNA, heat-shock protein (HSP) mRNA, is induced. Here we report that the activity of eucaryotic initiation factor-2 (eIF-2), a protein that participates in the regulation of a rate-limiting initiation step of protein synthesis, transiently decreases following insulin-induced severe hypoglycemia in the rat brain neocortex. Expression of HSP 72, a 72-kDa HSP, in surviving neurons was seen at 1-7 days of recovery following 30 min of hypoglycemic coma, but not at 1 h and 6 h of recovery. In the neocortex, HSP 72 was first seen in layer IV, and later also in surviving neurons in layer II. In the CA1 region and in the crest of dentate gyrus, HSP 72 expression was evident in cells adjacent to irreversibly damaged neurons. In the CA3 region and the hilus of dentate gyrus, HSP 72 was expressed in a few scattered neurons. In septal nucleus, HSP 72 was expressed in a lateral to medial fashion over a period of 1-3 days of recovery. We conclude that severe insulin-induced hypoglycemia induces a stress response in neurons in the recovery phase, including inhibition of protein synthesis initiation, depression of eIF-2 activity, and a delayed and prolonged expression of HSP 72 in surviving neurons. The HSP 72 expression may be a protective response to injurious stress.
18.	Bevilacqua, Jorge A, et al. (författare) "Necklace" fibers, a new histological marker of late-onset MTM1-related centronuclear myopathy. 2009 Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 117:3, s. 283-91 Tidskriftsartikel (refereegranskat)abstract Mutations in the gene encoding the phosphoinositide phosphatase myotubularin 1 protein (MTM1) are usually associated with severe neonatal X-linked myotubular myopathy (XLMTM). However, mutations in MTM1 have also been recognized as the underlying cause of "atypical" forms of XLMTM in newborn boys, female infants, female manifesting carriers and adult men. We reviewed systematically the biopsies of a cohort of patients with an unclassified form of centronuclear myopathy (CNM) and identified four patients presenting a peculiar histological alteration in some muscle fibers that resembled a necklace ("necklace fibers"). We analyzed further the clinical and morphological features and performed a screening of the genes involved in CNM. Muscle biopsies in all four patients demonstrated 4-20% of fibers with internalized nuclei aligned in a basophilic ring (necklace) at 3 microm beneath the sarcolemma. Ultrastructurally, such necklaces consisted of myofibrils of smaller diameter, in oblique orientation, surrounded by mitochondria, sarcoplasmic reticulum and glycogen granules. In the four patients (three women and one man), myopathy developed in early childhood but was slowly progressive. All had mutations in the MTM1 gene. Two mutations have previously been reported (p.E404K and p.R241Q), while two are novel; a c.205_206delinsAACT frameshift change in exon 4 and a c.1234A>G mutation in exon 11 leading to an abnormal splicing and the deletion of nine amino acids in the catalytic domain of MTM1. Necklace fibers were seen neither in DNM2- or BIN1-related CNM nor in males with classical XLMTM. The presence of necklace fibers is useful as a marker to direct genetic analysis to MTM1 in CNM.
19.	Boza-Serrano, Antonio, et al. (författare) Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease 2019 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 138:2, s. 251-273 Tidskriftsartikel (refereegranskat)abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer’s disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.
20.	Boza-Serrano, A., et al. (författare) Galectin-3 is elevated in CSF and is associated with A beta deposits and tau aggregates in brain tissue in Alzheimer's disease 2022 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. Tidskriftsartikel (refereegranskat)abstract Galectin-3 (Gal-3) is a beta-galactosidase binding protein involved in microglial activation in the central nervous system (CNS). We previously demonstrated the crucial deleterious role of Gal-3 in microglial activation in Alzheimer's disease (AD). Under AD conditions, Gal-3 is primarily expressed by microglial cells clustered around A beta plaques in both human and mouse brain, and knocking out Gal-3 reduces AD pathology in AD-model mice. To further unravel the importance of Gal-3-associated inflammation in AD, we aimed to investigate the Gal-3 inflammatory response in the AD continuum. First, we measured Gal-3 levels in neocortical and hippocampal tissue from early-onset AD patients, including genetic and sporadic cases. We found that Gal-3 levels were significantly higher in both cortex and hippocampus in AD subjects. Immunohistochemistry revealed that Gal-3+ microglial cells were associated with amyloid plaques of a larger size and more irregular shape and with neurons containing tau-inclusions. We then analyzed the levels of Gal-3 in cerebrospinal fluid (CSF) from AD patients (n=119) compared to control individuals (n= 36). CSF Gal-3 levels were elevated in AD patients compared to controls and more strongly correlated with tau (p-Tau181 and t-tau) and synaptic markers (GAP-43 and neurogranin) than with amyloid-beta. Lastly, principal component analysis (PCA) of AD biomarkers revealed that CSF Gal-3 clustered and associated with other CSF neuroinflammatory markers, including sTREM-2, GFAP, and YKL-40. This neuroinflammatory component was more highly expressed in the CSF from amyloid-beta positive (A+), CSF p-Tau181 positive (T+), and biomarker neurodegeneration positive/negative (N+/-) (A + T +N+/-) groups compared to the A + T-N- group. Overall, Gal-3 stands out as a key pathological biomarker of AD pathology that is measurable in CSF and, therefore, a potential target for disease-modifying therapies involving the neuroinflammatory response.
21.	Boza-serrano, Antonio, et al. (författare) Galectin-3 is elevated in CSF and is associated with Aβ deposits and tau aggregates in brain tissue in Alzheimer’s disease 2022 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. Tidskriftsartikel (refereegranskat)abstract Galectin-3 (Gal-3) is a beta-galactosidase binding protein involved in microglial activation in the central nervous system(CNS). We previously demonstrated the crucial deleterious role of Gal-3 in microglial activation in Alzheimer’s disease(AD). Under AD conditions, Gal-3 is primarily expressed by microglial cells clustered around Aβ plaques in both humanand mouse brain, and knocking out Gal-3 reduces AD pathology in AD-model mice. To further unravel the importance ofGal-3-associated infammation in AD, we aimed to investigate the Gal-3 infammatory response in the AD continuum. First,we measured Gal-3 levels in neocortical and hippocampal tissue from early-onset AD patients, including genetic and sporadiccases. We found that Gal-3 levels were signifcantly higher in both cortex and hippocampus in AD subjects. Immunohistochemistry revealed that Gal-3+microglial cells were associated with amyloid plaques of a larger size and more irregularshape and with neurons containing tau-inclusions. We then analyzed the levels of Gal-3 in cerebrospinal fuid (CSF) fromAD patients (n=119) compared to control individuals (n=36). CSF Gal-3 levels were elevated in AD patients comparedto controls and more strongly correlated with tau (p-Tau181 and t-tau) and synaptic markers (GAP-43 and neurogranin)than with amyloid-β. Lastly, principal component analysis (PCA) of AD biomarkers revealed that CSF Gal-3 clustered andassociated with other CSF neuroinfammatory markers, including sTREM-2, GFAP, and YKL-40. This neuroinfammatory component was more highly expressed in the CSF from amyloid-β positive (A+), CSF p-Tau181 positive (T+), andbiomarker neurodegeneration positive/negative (N+/−) (A+T+N+/−) groups compared to the A+T−N− group. Overall,Gal-3 stands out as a key pathological biomarker of AD pathology that is measurable in CSF and, therefore, a potential targetfor disease-modifying therapies involving the neuroinfammatory response.
22.	Braak, Heiko, et al. (författare) Intraneuronal tau aggregation precedes diffuse plaque deposition, but amyloid-β changes occur before increases of tau in cerebrospinal fluid. 2013 Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 126:5, s. 631-641 Tidskriftsartikel (refereegranskat)abstract In comparison to the levels in age and gender-matched controls, reduced levels of pathological amyloid-β protein in cerebrospinal fluid routinely precede the onset of Alzheimer's disease-related symptoms by several years, whereas elevated soluble abnormal tau fractions (phosphorylated tau, total tau protein) in cerebrospinal fluid are detectable only with the onset and progression of clinical symptoms. This sequence of events in cerebrospinal fluid (amyloid-β changes detectable prior to abnormal tau changes) contrasts with that in which both proteins develop in the brain, where intraneuronal tau inclusions (pretangles, neurofibrillary tangles, neuropil threads) appear decades before the deposition of amyloid-β plaques (diffuse plaques, neuritic plaques). This viewpoint attempts to address questions arising in connection with this apparent sequential discrepancy-questions and issues for which there are currently no clear-cut answers.
23.	Büki, Andras, 1966-, et al. (författare) Peptidergic innervation of human cerebral blood vessels and saccular aneurysms 1999 Ingår i: Acta Neuropathologica. - : Springer. - 0001-6322 .- 1432-0533. ; 98:4, s. 383-388 Tidskriftsartikel (refereegranskat)abstract Peptidergic innervation of the human cerebral vasculature has not yet been described in detail and its role in the maintenance of cerebral autoregulation still needs to be established. Similarly, few data exist on the innervation of vascular malformations. The aim of this study was to clarify the peptidergic innervation patterns of human cerebral arteries of various sizes, and, for the first time, that of saccular aneurysms. Light microscopic study of whole-mount preparations of human cerebral arteries and aneurysm sacs resected either during tumor removal or after neck-clipping were carried out by means of silver-intensified light microscopic immunocytochemistry visualizing neuropeptide-Y, calcitonin gene-related peptide and substance P immunoreactivity. Systematic morphological investigations confirmed the presence of longitudinal fiber bundles on the adventitia and a network-like deeper peptidergic system at the adventitia-media border, while in smaller pial and intraparenchymal vessels, only sparse longitudinal immunopositive axons could be detected. The innervation pattern was totally absent in the wall of saccular aneurysms with the complete disappearance of peptidergic nerve fibers in some areas. To the best of our knowledge neither the disappearance of this network on small pial and intraparenchymal vessels, nor the absence of an innervation pattern in saccular aneurysms have been described before. Nonhomogeneous peptidergic innervation of the human cerebral vascular tree might be one of the factors responsible for the distinct autoregulatory properties of the capacitance and resistance vessels. Malfunction of this vasoregulatory system might lead to the impairment of autoregulation during pathological conditions such as subarachnoid hemorrhage.
24.	Cantoni, Claudia, et al. (författare) TREM2 regulates microglial cell activation in response to demyelination in vivo 2015 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 129:3, s. 429-447 Tidskriftsartikel (refereegranskat)abstract Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage.
25.	Carlsson, Lena, et al. (författare) Cytoskeletal derangements in hereditary myopathy with a desmin L345P mutation 2002 Ingår i: Acta Neuropathologica. - : Springer. - 0001-6322 .- 1432-0533. ; 104:5, s. 493-504 Tidskriftsartikel (refereegranskat)abstract Patients with abnormal accumulations of desmin have been described in myopathies with or without cardiac involvement. Desmin deposits were sometimes associated with abnormal aggregates of other cytoskeletal proteins. In the present study we present how the cytoskeletal organisation of desmin, nestin, synemin, paranemin, plectin and alphaB-crystallin is altered in skeletal muscles from a patient with a L345P mutation in the desmin gene. In general, accumulations of desmin together with synemin, nestin, plectin and alphaB-crystallin were present between myofibrils and beneath the sarcolemma. However, as the biopsy samples were very myopathic, large variability in fibre size and fibre maturation was seen, thus the myofibrillar content and the cytoskeletal organisation varied considerably. In cultured satellite cells from the patient, desmin aggregates were not observed in initial passages, but occurred over time in culture in the form of perinuclear, peripheral or cytoplasmic deposits. Nestin colocalised to the abnormal desmin deposits to a larger extent than did vimentin. alphaB-Crystallin was only present in cells with a disrupted desmin network. Plectin was altered in a subset of cells with a disrupted desmin network, whereas synemin and paranemin were not detected. We conclude that the L345P desmin mutation has a profound influence on the cytoskeletal organisation both in vivo and in vitro, which reflects the pathogenesis of the desmin myopathy.
26.	Casar-Borota, Olivera, et al. (författare) Bilateral atypical choroid plexus papillomas in cerebellopontine angles mimicking neurofibromatosis 2. 2006 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 111:5, s. 500-2 Tidskriftsartikel (refereegranskat)
27.	Chapuis, Julien, et al. (författare) Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism 2017 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 133:6, s. 955-966 Tidskriftsartikel (refereegranskat)abstract Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer’s disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the “post-GWAS” era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production.
28.	Cicognola, Claudia, et al. (författare) Novel tau fragments in cerebrospinal fluid : relation to tangle pathology and cognitive decline in Alzheimer’s disease 2019 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 137:2, s. 279-296 Tidskriftsartikel (refereegranskat)abstract Tau is an axonal microtubule-binding protein. Tau pathology in brain and increased tau concentration in the cerebrospinal fluid (CSF) are hallmarks of Alzheimer’s disease (AD). Most of tau in CSF is present as fragments. We immunoprecipitated tau from CSF and identified several endogenous peptides ending at amino acid (aa) 123 or 224 using high-resolution mass spectrometry. We raised neo-epitope-specific antibodies against tau fragments specifically ending at aa 123 and 224, respectively. With these antibodies, we performed immunohistochemistry on brain tissue and designed immunoassays measuring N-123, N-224, and x-224 tau. Immunoassays were applied to soluble brain fractions from pathologically confirmed subjects (81 AD patients, 33 controls), CSF from three cross-sectional and two longitudinal cohorts (a total of 133 AD, 38 MCI, 20 MCI-AD, 31 PSP, 15 CBS patients, and 91 controls), and neuronally- and peripherally-derived extracellular vesicles (NDEVs and PDEVs, respectively) in serum from four AD patients and four controls. Anti-tau 224 antibody stained neurofibrillary tangles and neuropil threads, while anti-tau 123 only showed weak cytoplasmic staining in AD. N-224 tau was lower in the AD soluble brain fraction compared to controls, while N-123 tau showed similar levels. N-224 tau was higher in AD compared to controls in all CSF cohorts (p < 0.001), but not N-123 tau. Decrease in cognitive performance and conversion from MCI to AD were associated with increased baseline CSF levels of N-224 tau (p < 0.0001). N-224 tau concentrations in PSP and CBS were significantly lower than in AD (p < 0.0001) and did not correlate to t-tau and p-tau. In a longitudinal cohort, CSF N-224 tau levels were stable over 6 months, with no significant effect of treatment with AChE inhibitors. N-224 tau was present in NDEVs, while N-123 tau showed comparable concentrations in both vesicle types. We suggest that N-123 tau is produced both in CNS and PNS and represents a general marker of tau metabolism, while N-224 tau is neuron-specific, present in the tangles, secreted in CSF, and upregulated in AD, suggesting a link between tau cleavage and propagation, tangle pathology, and cognitive decline.
29.	Clausen, Bettina Hjelm, et al. (författare) Cell therapy centered on IL-1Ra is neuroprotective in experimental stroke. 2016 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 131:5, s. 91-775 Tidskriftsartikel (refereegranskat)abstract Cell-based therapies are emerging as new promising treatments in stroke. However, their functional mechanism and therapeutic potential during early infarct maturation has so far received little attention. Here, we asked if cell-based delivery of the interleukin-1 receptor antagonist (IL-1Ra), a known neuroprotectant in stroke, can promote neuroprotection, by modulating the detrimental inflammatory response in the tissue at risk. We show by the use of IL-1Ra-overexpressing and IL-1Ra-deficient mice that IL-1Ra is neuroprotective in stroke. Characterization of the cellular and spatiotemporal production of IL-1Ra and IL-1α/β identifies microglia, not infiltrating leukocytes, as the major sources of IL-1Ra after experimental stroke, and shows IL-1Ra and IL-1β to be produced by segregated subsets of microglia with a small proportion of these cells co-expressing IL-1α. Reconstitution of whole body irradiated mice with IL-1Ra-producing bone marrow cells is associated with neuroprotection and recruitment of IL-1Ra-producing leukocytes after stroke. Neuroprotection is also achieved by therapeutic injection of IL-1Ra-producing bone marrow cells 30 min after stroke onset, additionally improving the functional outcome in two different stroke models. The IL-1Ra-producing bone marrow cells increase the number of IL-1Ra-producing microglia, reduce the availability of IL-1β, and modulate mitogen-activated protein kinase (MAPK) signaling in the ischemic cortex. The importance of these results is underlined by demonstration of IL-1Ra-producing cells in the human cortex early after ischemic stroke. Taken together, our results attribute distinct neuroprotective or neurotoxic functions to segregated subsets of microglia and suggest that treatment strategies increasing the production of IL-1Ra by infiltrating leukocytes or microglia may also be neuroprotective if applied early after stroke onset in patients.
30.	Coimbra, Cicero, et al. (författare) Diminished neuronal damage in the rat brain by late treatment with the antipyretic drug dipyrone or cooling following cerebral ischemia 1996 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 92:5, s. 447-453 Tidskriftsartikel (refereegranskat)abstract It has been shown that changes in body core temperature several hours after a transient ischemic insult affect neuronal survival. We report that body core temperature in normal rats fluctuates over a 24-h period, while in rats subjected to 10 min transient ischemia induced by occlusion of the common carotid arteries in combination with hypotension, body temperature persistently increases to above 38.5°C from 21 to 63 h following recirculation. The antipyretic drug dipyrone administered from 12 to 72 h recovery depresses body temperature to normothermic values and markedly diminishes neuronal damage in the neocortex and hippocampus when evaluated at 7 days of survival. Cooling the animals down to normothermic levels provided similar protection to that obtained with dipyrone treatment. These results suggest that hyperthermia occurring late during reperfusion aggravates delayed neuronal damage and can be effectively prevented by antipyretic drugs. The data imply that: (1) temperature-dependent processes occurring late during recovery are involved in delayed neuronal death, (2) inflammation may be an important factor in delayed neuronal death, (3) prostanoids and interleukins may contribute to this process (4) postischemic prolonged (days) temperature control is required for proper evaluation of drug therapy in brain ischemia models, and (5) fever in patients suffering brain ischemia should be impeded.
31.	Coimbra, Cicero, et al. (författare) Moderate hypothermia mitigates neuronal damage in the rat brain when initiated several hours following transient cerebral ischemia 1994 Ingår i: Acta Neuropathologica. - 0001-6322. ; 87:4, s. 325-331 Tidskriftsartikel (refereegranskat)abstract Intraischemic moderate hypothermia generally protects the brain against ischemic cell death, while hypothermia instigated several hours into the reperfusion phase is considered to be less effective. Here we report the effect of hypothermia (32.5°-33.5°C) of 5-h duration, initiated at 2, 6, 12, 24 and 36 h into the recirculation phase following 10 min of transient cerebral ischemia, on ischemic neuronal injury in the hippocampus and striatum of the rat. Hypothermia induced at 2 h, and 6 h postischemia reduces neuronal damage in the entire hippocampal CA1 region by approximately 50%. In the lateral CA1 region hypothermia induced at 12 h postischemia, significantly mitigates necrosis. When initiated at 2 h postischemia, but not later, protection was also observed in the striatum. Hypothermia induced 24 and 36 h postischemia was ineffective. A period of hypothermia of 5 h, initiated 2 h postischemia, was required for marked neuronal protection in the CA1 region, while 3.5-h hypothermia decreased neuronal damage by approximately 10% and 30 min hypothermia was ineffective. The clinical implications of the data are that extended period of hypothermia initiated long into the recovery phase following ischemia may prove beneficial. Hypothermia protects brain regions displaying rapid as well as delayed neuronal damage, and a minimal time of hypothermia is required for effective neuronal protection. Also, strict temperature control for up to 24 h postischemia may be required for proper assessment of the efficacy of cerebro-protective drugs.
32.	Crary, John F., et al. (författare) Primary age-related tauopathy (PART) : a common pathology associated with human aging 2014 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 128:6, s. 755-766 Tidskriftsartikel (refereegranskat)abstract We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (A beta) plaques. For these "NFT+/A beta-aEuroe brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of A beta accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
33.	De Roeck, A, et al. (författare) Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease 2017 Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 134:3, s. 475-487 Tidskriftsartikel (refereegranskat)
34.	Deming, Yuetiva, et al. (författare) Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers 2017 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 133:5, s. 839-856 Tidskriftsartikel (refereegranskat)abstract More than 20 genetic loci have been associated with risk for Alzheimer’s disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case–control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42 near GLIS1 on 1p32.3 (β = −0.059, P = 2.08 × 10−8) and within SERPINB1 on 6p25 (β = −0.025, P = 1.72 × 10−8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10−2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10−2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10−3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.
35.	Deming, Yuetiva, et al. (författare) Sex-specific genetic predictors of Alzheimer’s disease biomarkers 2018 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 136:6, s. 857-872 Tidskriftsartikel (refereegranskat)abstract Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer’s disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = − 0.03, p = 4.25 × 10−8; β = 0.03, p = 3.97 × 10−8) than males (β = − 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10−10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD’s genetic architecture.
36.	Diaz-Lucena, D., et al. (författare) TREM2 expression in the brain and biological fluids in prion diseases 2021 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 141, s. 841-859 Tidskriftsartikel (refereegranskat)abstract Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune cell surface receptor that regulates microglial function and is involved in the pathophysiology of several neurodegenerative diseases. Its soluble form (sTREM2) results from shedding of the TREM2 ectodomain. The role of TREM2 in prion diseases, a group of rapidly progressive dementias remains to be elucidated. In the present study, we analysed the expression of TREM2 and its main sheddase ADAM10 in the brain of sporadic Creutzfeldt-Jakob disease (sCJD) patients and evaluated the role of CSF and plasma sTREM2 as a potential diagnostic marker of prion disease. Our data indicate that, compared to controls, TREM2 is increased in sCJD patient brains at the mRNA and protein levels in a regional and subtype dependent fashion, and expressed in a subpopulation of microglia. In contrast, ADAM10 is increased at the protein, but not the mRNA level, with a restricted neuronal expression. Elevated CSF sTREM2 is found in sCJD, genetic CJD with mutations E200K and V210I in the prion protein gene (PRNP), and iatrogenic CJD, as compared to healthy controls (HC) (AUC = 0.78-0.90) and neurological controls (AUC = 0.73-0.85), while CSF sTREM2 is unchanged in fatal familial insomnia. sTREM2 in the CSF of cases with Alzheimer's disease, and multiple sclerosis was not significantly altered in our series. CSF sTREM2 concentrations in sCJD are PRNP codon 129 and subtype-related, correlate with CSF 14-3-3 positivity, total-tau and YKL-40, and increase with disease progression. In plasma, sTREM2 is increased in sCJD compared with HC (AUC = 0.80), displaying positive correlations with plasma total-tau, neurofilament light, and YKL-40. We conclude that comparative study of TREM2 in brain and biological fluids of prion diseases reveals TREM2 to be altered in human prion diseases with a potential value in target engagement, patient stratification, and disease monitoring.
37.	Dube, U, et al. (författare) Overlapping genetic architecture between Parkinson disease and melanoma 2020 Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 139:2, s. 347-364 Tidskriftsartikel (refereegranskat)
38.	Ekhtiari Bidhendi, Elaheh, et al. (författare) Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis 2018 Ingår i: Acta Neuropathologica. - : Springer. - 0001-6322 .- 1432-0533. ; 136:6, s. 939-953 Tidskriftsartikel (refereegranskat)abstract Motor neurons containing aggregates of superoxide dismutase 1 (SOD1) are hallmarks of amyotrophic lateral sclerosis (ALS) caused by mutations in the gene encoding SOD1. We have previously reported that two strains of mutant human (h) SOD1 aggregates (denoted A and B) can arise in hSOD1-transgenic models for ALS and that inoculation of such aggregates into the lumbar spinal cord of mice results in rostrally spreading, templated hSOD1 aggregation and premature fatal ALS-like disease. Here, we explored whether mutant hSOD1 aggregates with prion-like properties also exist in human ALS. Aggregate seeds were prepared from spinal cords from an ALS patient carrying the hSOD1G127Gfs7 truncation mutation and from mice transgenic for the same mutation. To separate from mono-, di- or any oligomeric hSOD1 species, the seed preparation protocol included ultracentrifugation through a density cushion. The core structure of hSOD1G127Gfs7 aggregates present in mice was strain A-like. Inoculation of the patient- or mouse-derived seeds into lumbar spinal cord of adult hSOD1-expressing mice induced strain A aggregation propagating along the neuraxis and premature fatal ALS-like disease (p < 0.0001). Inoculation of human or murine control seeds had no effect. The potencies of the ALS patient-derived seed preparations were high and disease was initiated in the transgenic mice by levels of hSOD1G127Gfs*7 aggregates much lower than those found in the motor system of patients carrying the mutation. The results suggest that prion-like growth and spread of hSOD1 aggregation could be the primary pathogenic mechanism, not only in hSOD1 transgenic rodent models, but also in human ALS.
39.	Elobeid, Adila, et al. (författare) Hyperphosphorylated tau in young and middle-aged subjects 2012 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 123:1, s. 97-104 Tidskriftsartikel (refereegranskat)abstract The brain tissue obtained from ninety-five cognitively unimpaired subjects, with ages ranging from 22 to 50 years upon death, were immunohistochemically assessed for neurodegenerative changes, i.e., hyperphosphorylated tau (HP tau) and beta-amyloid (A beta) pathology in predilection neuroanatomical areas. HP tau pathology was observed in the transentorhinal cortex and/or the locus coeruleus (LC) in 33% of the subjects, without any obvious risk factors known to alter the microtubule-associated protein. HP tau pathology was noted in the LC in 25 out of 83 subjects (30%), lacking concomitant cortical A beta or transentorhinal HP tau pathology. This observation was present even when assessing only one routine section of 7 mu m thickness. The recent suggestion of prion-like propagation of neurodegeneration and the finding of neurodegeneration being quite common in middle-aged persons is alarming. It is noteworthy, however, that a substantial number of neurologically unimpaired subjects even at a very old age display only sparse to modest extent of neurodegenerative pathology. Thus, only a subset of subjects with neurodegenerative changes early in life seem to progress to a symptomatic disease with ageing. This observation brings forth the notion that other, yet unknown modifying factors influence the progression of degeneration that leads to a symptomatic disorder. The known association between alterations in the LC and mood disorders, and the finding of the LC being frequently affected with HP tau pathology suggest that clinicopathological studies on young subjects both with or without mood disorders are warranted.
40.	Elovaara, I, et al. (författare) Upregulated expression of Fas and Fas ligand in brain through the spectrum of HIV-1 infection 1999 Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 98:4, s. 355-362 Tidskriftsartikel (refereegranskat)
41.	Eriksson, S H, et al. (författare) Widespread microdysgenesis in therapy-resistant epilepsy--a case report on post-mortem findings. 2002 Ingår i: Acta neuropathologica. - 0001-6322. ; 103:1, s. 74-7 Tidskriftsartikel (refereegranskat)abstract Microdysgenesis is a subtle malformation, which is often found in specimens from epilepsy surgery. It is, however, not clear whether the changes are focal or diffuse. A recent autopsy case offered an opportunity to investigate whether microdysgenesis found after temporal lobe surgery was focal or widespread in the brain. The entire brain of a 20-year-old patient who died suddenly and unexpectedly was examined histologically. Microdysgenesis had previously been diagnosed after a left temporal lobectomy performed because of therapy-resistant seizures. A light microscopic examination was performed on specimens stained with Luxol-fast blue-cresyl violet and polyclonal antibodies to glial fibrillary acidic protein. Widespread microdysgenesis with irregular nerve cell distribution in the cortex and an increased number of nerve cells in cortical layer I and in the white matter was found in the right temporal and parietal lobes and bilaterally in the frontal and occipital lobes. The post-mortem examination confirmed the previous diagnosis of microdysgenesis and showed that the changes were widespread in a patient who was operated on because of focal epilepsy.
42.	Fang, Z, et al. (författare) Intracellular calcium-binding protein S100A4 influences injury-induced migration of white matter astrocytes. 2006 Ingår i: Acta Neuropathol (Berl). - 0001-6322. ; 111:3, s. 213-9 Tidskriftsartikel (refereegranskat)
43.	Faustini, Gaia, et al. (författare) Synapsin III deficiency hampers α-synuclein aggregation, striatal synaptic damage and nigral cell loss in an AAV-based mouse model of Parkinson’s disease 2018 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 136:4, s. 621-639 Tidskriftsartikel (refereegranskat)abstract Parkinson’s disease (PD), the most common neurodegenerative movement disorder, is characterized by the progressive loss of nigral dopamine neurons. The deposition of fibrillary aggregated α-synuclein in Lewy bodies (LB), that is considered to play a causative role in the disease, constitutes another key neuropathological hallmark of PD. We have recently described that synapsin III (Syn III), a synaptic phosphoprotein that regulates dopamine release in cooperation with α-synuclein, is present in the α-synuclein insoluble fibrils composing the LB of patients affected by PD. Moreover, we observed that silencing of Syn III gene could prevent α-synuclein fibrillary aggregation in vitro. This evidence suggests that Syn III might be crucially involved in α-synuclein pathological deposition. To test this hypothesis, we studied whether mice knock-out (ko) for Syn III might be protected from α-synuclein aggregation and nigrostriatal neuron degeneration resulting from the unilateral injection of adeno-associated viral vectors (AAV)-mediating human wild-type (wt) α-synuclein overexpression (AAV-hαsyn). We found that Syn III ko mice injected with AAV-hαsyn did not develop fibrillary insoluble α-synuclein aggregates, showed reduced amount of α-synuclein oligomers detected by in situ proximity ligation assay (PLA) and lower levels of Ser129-phosphorylated α-synuclein. Moreover, the nigrostriatal neurons of Syn III ko mice were protected from both synaptic damage and degeneration triggered by the AAV-hαsyn injection. Our observations indicate that Syn III constitutes a crucial mediator of α-synuclein aggregation and toxicity and identify Syn III as a novel therapeutic target for PD.
44.	Ferrer, I, et al. (författare) Brain-derived neurotrophic factor reduces cortical cell death by ischemia after middle cerebral artery occlusion in the rat 2001 Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 101:3, s. 229-238 Tidskriftsartikel (refereegranskat)
45.	Fisher, Michael J., et al. (författare) Integrated molecular and clinical analysis of low-grade gliomas in children with neurofibromatosis type 1 (NF1) 2021 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 141:4, s. 605-617 Tidskriftsartikel (refereegranskat)abstract Low-grade gliomas (LGGs) are the most common childhood brain tumor in the general population and in individuals with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Surgical biopsy is rarely performed prior to treatment in the setting of NF1, resulting in a paucity of tumor genomic information. To define the molecular landscape of NF1-associated LGGs (NF1-LGG), we integrated clinical data, histological diagnoses, and multi-level genetic/genomic analyses on 70 individuals from 25 centers worldwide. Whereas, most tumors harbored bi-allelic NF1 inactivation as the only genetic abnormality, 11% had additional mutations. Moreover, tumors classified as non-pilocytic astrocytoma based on DNA methylation analysis were significantly more likely to harbor these additional mutations. The most common secondary alteration was FGFR1 mutation, which conferred an additional growth advantage in multiple complementary experimental murine Nf1 models. Taken together, this comprehensive characterization has important implications for the management of children with NF1-LGG, distinct from their sporadic counterparts.
46.	Forsberg, Karin, et al. (författare) Glial nuclear aggregates of superoxide dismutase-1 are regularly present in patients with amyotrophic lateral sclerosis 2011 Ingår i: Acta Neuropathologica. - : SpringerLink. - 0001-6322 .- 1432-0533. ; 121:5, s. 623-634 Tidskriftsartikel (refereegranskat)abstract The most common cause of amyotrophic lateral sclerosis (ALS) is mutations in superoxide dismutase-1 (SOD1). Since there is evidence for the involvement of non-neuronal cells in ALS we searched for signs of SOD1 abnormalities focusing on glia. Spinal cords from 9 ALS patients carrying SOD1 mutations, 51 patients with sporadic or familial ALS who lacked such mutations, and 46 controls were examined by immunohistochemistry. A set of anti-peptide antibodies with specificity for misfolded SOD1 species was used. Misfolded SOD1 in the form of granular aggregates was regularly detected in the nuclei of ventral horn astrocytes, microglia and oligodendrocytes in ALS patients carrying and as well as lacking SOD1 mutations. There was negligible staining in neurodegenerative and non-neurological controls. Misfolded SOD1 appeared occasionally also in nuclei of motoneurons of ALS patients. The results suggest that misfolded SOD1 present in glial and motoneuron nuclei may generally be involved in ALS pathogenesis.
47.	Forsberg, Karin, et al. (författare) Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation 2023 Ingår i: Acta Neuropathologica. - : Springer-Verlag New York. - 0001-6322 .- 1432-0533. ; 145:1, s. 13-28 Tidskriftsartikel (refereegranskat)abstract Mutations in the gene encoding the ubiquitously expressed free radical scavenging enzyme superoxide dismutase-1 (SOD1) are found in 2–6% of amyotrophic lateral sclerosis patients. The most frequent SOD1 mutation worldwide is D90A. Amyotrophic lateral sclerosis caused by this mutation has some unusual features: the heredity is usually recessive, the phenotype is stereotypic with slowly evolving motor symptoms beginning in the legs and may also include sensory, autonomic, and urinary bladder involvement. Furthermore, the mutant protein resembles the wild type, with normal content and enzymatic activity in the central nervous system. Here, we report neuropathological findings in nine patients homozygous for the D90A mutation. All nine had numerous small granular inclusions immunoreactive for misfolded SOD1 in motor neurons and glial nuclei in the spinal cord and brainstem. In addition to degeneration of the corticospinal tracts, all patients had degeneration of the dorsal columns. We also found intense gliosis in circumscribed cortical areas of the frontal and temporal lobes and in the insula. In these areas and in adjacent white matter, there were SOD1 staining neuropil threads. A few SOD1-immunopositive cytoplasmic neuronal inclusions were observed in cortical areas, as were glial nuclear inclusions. As suggested by the symptoms and signs and earlier neurophysiological and imaging investigations, the histopathology in patients homozygous for the D90A SOD1 extends beyond the motor system to include cognitive and sensory cortical areas. However, even in the patients that had a symptomatic disease duration of more than 2 or 3 decades and lived into their 70s or 80s, there were no SOD1-inclusion pathology and no typical dysfunction (apart from the musculature) in non-nervous organs. Thus, only specific parts of the CNS seem to be vulnerable to toxicity provoked by homozygously expressed mutant SOD1.
48.	Frisk, Jun Mei Hu, et al. (författare) DTYMK is essential for genome integrity and neuronal survival 2022 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 143, s. 245-262 Tidskriftsartikel (refereegranskat)abstract Nucleotide metabolism is a complex pathway regulating crucial cellular processes such as nucleic acid synthesis, DNA repair and proliferation. This study shows that impairment of the biosynthesis of one of the building blocks of DNA, dTTP, causes a severe, early-onset neurodegenerative disease. Here, we describe two unrelated children with bi-allelic variants in DTYMK, encoding dTMPK, which catalyzes the penultimate step in dTTP biosynthesis. The affected children show severe microcephaly and growth retardation with minimal neurodevelopment. Brain imaging revealed severe cerebral atrophy and disappearance of the basal ganglia. In cells of affected individuals, dTMPK enzyme activity was minimal, along with impaired DNA replication. In addition, we generated dtymk mutant zebrafish that replicate this phenotype of microcephaly, neuronal cell death and early lethality. An increase of ribonucleotide incorporation in the genome as well as impaired responses to DNA damage were observed in dtymk mutant zebrafish, providing novel pathophysiological insights. It is highly remarkable that this deficiency is viable as an essential component for DNA cannot be generated, since the metabolic pathway for dTTP synthesis is completely blocked. In summary, by combining genetic and biochemical approaches in multiple models we identified loss-of-function of DTYMK as the cause of a severe postnatal neurodegenerative disease and highlight the essential nature of dTTP synthesis in the maintenance of genome stability and neuronal survival.
49.	Fritschi, Sarah K., et al. (författare) A beta seeds resist inactivation by formaldehyde 2014 Ingår i: Acta Neuropathologica. - : Springer Verlag (Germany). - 0001-6322 .- 1432-0533. ; 128:4, s. 477-484 Tidskriftsartikel (refereegranskat)abstract Cerebral beta-amyloidosis can be exogenously induced by the intracerebral injection of brain extracts containing aggregated beta-amyloid (A beta) into young, pre-depositing A beta precursor protein- (APP) transgenic mice. Previous work has shown that the induction involves a prion-like seeding mechanism in which the seeding agent is aggregated A beta itself. Here we report that the beta-amyloid-inducing activity of Alzheimers disease (AD) brain tissue or aged APP-transgenic mouse brain tissue is preserved, albeit with reduced efficacy, after formaldehyde fixation. Moreover, spectral analysis with amyloid conformation-sensitive luminescent conjugated oligothiophene dyes reveals that the strain-like properties of aggregated A beta are maintained in fixed tissues. The resistance of A beta seeds to inactivation and structural modification by formaldehyde underscores their remarkable durability, which in turn may contribute to their persistence and spread within the body. The present findings can be exploited to establish the relationship between the molecular structure of A beta aggregates and the variable clinical features and disease progression of AD even in archived, formalin-fixed autopsy material.
50.	Gabery, Sanaz, et al. (författare) Changes in key hypothalamic neuropeptide populations in Huntington disease revealed by neuropathological analyses. 2010 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 120, s. 777-788 Tidskriftsartikel (refereegranskat)abstract Huntington disease (HD) is a fatal neurodegenerative disorder caused by expansion of a CAG repeat in the HD gene. Degeneration concentrating in the basal ganglia has been thought to account for the characteristic psychiatric symptoms, cognitive decline and motor dysfunction. However, the homeostatic control of emotions and metabolism are disturbed early in HD, and focused studies have identified a loss of orexin (hypocretin) neurons in the lateral hypothalamus in HD patients. There has been limited assessment of other hypothalamic cell populations that may be involved. In this study, we quantified the neuropeptide-expressing hypothalamic neurons known to regulate metabolism and emotion in patients with HD compared to healthy controls using unbiased stereological methods. We confirmed the loss of orexin-expressing neurons in HD and revealed substantial differences in the peptide expression of other neuronal populations in the same patients. Both oxytocin- and vasopressin-expressing neurons were decreased by 45 and 24%, respectively, while the number of cocaine- and amphetamine-regulated transcript (CART)-expressing neurons was increased by 30%. The increased expression of CART in the hypothalamus is consistent with a previous study showing increased CART levels in cerebrospinal fluid from HD patients. There was no difference in the numbers of neuropeptide Y-expressing neurons. These results show significant and specific alterations in the peptide expression of hypothalamic neurons known to regulate metabolism and emotion. They may be important in the development of psychiatric symptoms and metabolic disturbances in HD, and may provide potential targets for therapeutic interventions.

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