| 1. |
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| 2. |
- Alafuzoff, Irina, et al.
(författare)
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Beta-amyloid deposition in brains of subjects with diabetes
- 2009
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 35:1, s. 60-68
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Tidskriftsartikel (refereegranskat)abstract
- AIM:A causative association between diabetes mellitus (DM) and Alzheimer's disease (AD) has been suggested based on clinical and epidemiological studies. One hypothesis is that the link between DM and AD is related to the function of insulin-degrading enzyme (IDE), an enzyme that degrades not only insulin and pancreatic amylin but also beta-amyloid (Abeta). Thus, in diabetics, insulin and Abeta might compete for IDE and this might lead to an increase in Abeta. The objective of this study was to test the hypothesis that hyperinsulinaemia can elevate Abeta levels and thus contribute to AD pathology in humans.METHODS:Neuropathological examination was carried out employing conventional and immunohistochemical (IHC) methods of the brains obtained post mortem from 701 aged subjects.RESULTS:The loads of IHC/Abeta, silver stained neuritic plaques (NP) and neurofibrillary tangles (NFT) were significantly higher in subjects carrying the Apolipoprotein E e4 allele. In contrast, the loads of Abeta, NPs and NFT in the brains were not influenced by hyperglycaemia when comparing 134 diabetic with 567 non-diabetic subjects.CONCLUSIONS:We conclude that the hypothesis that hyperinsulinaemia would significantly elevate the Abeta load and thus increase the extent of AD pathology cannot be supported. Our result challenges the claim that DM is a direct risk factor of developing AD. Thus further studies on pathological lesions in demented diabetics should be conducted.
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| 3. |
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| 4. |
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| 5. |
- Baldo, B., et al.
(författare)
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SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease
- 2019
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 45:4, s. 361-379
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Metabolic dysfunction is involved in modulating the disease process in Huntington disease (HD) but the underlying mechanisms are not known. The aim of this study was to investigate if the metabolic regulators sirtuins are affected in HD. Methods: Quantitative real-time polymerase chain reactions were used to assess levels of SIRT1-3 and downstream targets in post mortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin (HTT) using recombinant adeno-associated viral vectors in mice. Results: We show that mRNA levels of the metabolic regulator SIRT1 are increased in the striatum and the cerebral cortex but not in the less affected cerebellum in post mortem HD brains. Levels of SIRT2 are only increased in the striatum and SIRT3 is not affected in HD. Interestingly, mRNA levels of SIRT1 are selectively increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets and reduced mRNA levels of orexin (hypocretin), prodynorphin and melanin-concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant HTT suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes in SIRT1 require more widespread expression of mutant HTT. Conclusions: We show that SIRT1 expression is increased in HD-affected brain regions and that metabolic pathways are altered in the HD hypothalamus.
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| 6. |
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| 7. |
- Bergh, Sofia, et al.
(författare)
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Effects of mutant huntingtin in oxytocin neurons on non-motor features of Huntington's disease
- 2023
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 49:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: Early non-motor features including anxiety, depression and altered social cognition are present in Huntington's disease (HD). The underlying neurobiological mechanisms are not known. Oxytocin (OXT) is involved in the regulation of emotion, social cognition and metabolism, and our previous work showed that the OXT system is affected early in HD. The aim of the study was to investigate the potential causal relationship between the selective expression of mutant huntingtin (mHTT) in OXT neurons and the development of non-motor features and neuropathology. Methods: To express mHTT only in OXT neurons, we used a novel flex-switch adeno-associated viral vector design to selectively express either mHTT or wild-type HTT in the paraventricular nucleus of the hypothalamus using OXT-Cre-recombinase mice. We also performed a mirror experiment to selectively delete mHTT in OXT neurons using the BACHD mouse model. Mice underwent a battery of behavioural tests to assess psychiatric and social behaviours 3 months post-injection or at 2 months of age, respectively. Post-mortem analyses were performed to assess the effects on the OXT system. Results: Our results show that selective expression of mHTT in OXT neurons was associated with the formation of mHTT inclusions and a 26% reduction of OXT-immunopositive neurons as well as increased anxiety-like behaviours compared with uninjected mice. However, selective deletion of mHTT from OXT neurons alone was not sufficient to alter the metabolic and psychiatric phenotype of the BACHD mice at this early time point. Conclusions: Our results indicate that mHTT expression can exert cell-autonomous toxic effects on OXT neurons without affecting the non-motor phenotype at early time points in mice.
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| 8. |
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| 9. |
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| 10. |
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| 11. |
- Cheong, Rachel Y., et al.
(författare)
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Effects of mutant huntingtin inactivation on Huntington disease-related behaviours in the BACHD mouse model
- 2021
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 47:4, s. 564-578
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Huntington disease (HD) is a fatal neurodegenerative disorder with no disease-modifying treatments approved so far. Ongoing clinical trials are attempting to reduce huntingtin (HTT) expression in the central nervous system (CNS) using different strategies. Yet, the distribution and timing of HTT-lowering therapies required for a beneficial clinical effect is less clear. Here, we investigated whether HD-related behaviours could be prevented by inactivating mutant HTT at different disease stages and to varying degrees in an experimental model. Methods: We generated mutant BACHD mice with either a widespread or circuit-specific inactivation of mutant HTT by using Cre recombinase (Cre) under the nestin promoter or the adenosine A2A receptor promoter respectively. We also simulated a clinical gene therapy scenario with allele-specific HTT targeting by injections of recombinant adeno-associated viral (rAAV) vectors expressing Cre into the striatum of adult BACHD mice. All mice were assessed using behavioural tests to investigate motor, metabolic and psychiatric outcome measures at 4–6 months of age. Results: While motor deficits, body weight changes, anxiety and depressive-like behaviours are present in BACHD mice, early widespread CNS inactivation during development significantly improves rotarod performance, body weight changes and depressive-like behaviour. However, conditional circuit-wide mutant HTT deletion from the indirect striatal pathway during development and focal striatal-specific deletion in adulthood failed to rescue any of the HD-related behaviours. Conclusions: Our results indicate that widespread targeting and the timing of interventions aimed at reducing mutant HTT are important factors to consider when developing disease-modifying therapies for HD.
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| 12. |
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| 13. |
- Craggs, L. J. L., et al.
(författare)
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Clusterin/Apolipoprotein J immunoreactivity is associated with white matter damage in cerebral small vessel diseases
- 2016
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 42:2, s. 194-209
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Tidskriftsartikel (refereegranskat)abstract
- AimBrain clusterin is known to be associated with the amyloid- deposits in Alzheimer's disease (AD). We assessed the distribution of clusterin immunoreactivity in cerebrovascular disorders, particularly focusing on white matter changes in small vessel diseases. MethodsPost-mortem brain tissues from the frontal or temporal lobes of a total of 70 subjects with various disorders including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral amyloid angiopathy (CAA) and AD were examined using immunohistochemistry and immunofluorescence. We further used immunogold electron microscopy to study clusterin immunoreactivity in extracellular deposits in CADASIL. ResultsImmunostaining with clusterin antibodies revealed strong localization in arterioles and capillaries, besides cortical neurones. We found that clusterin immunostaining was significantly increased in the frontal white matter of CADASIL and pontine autosomal dominant microangiopathy and leukoencephalopathy subjects. In addition, clusterin immunostaining correlated with white matter pathology severity scores. Immunostaining in axons ranged from fine punctate deposits in single axons to larger confluent areas with numerous swollen axon bulbs, similar to that observed with known axon damage markers such as non-phosphorylated neurofilament H and the amyloid precursor protein. Immunofluorescence and immunogold electron microscopy experiments showed that whereas clusterin immunoreactivity was closely associated with vascular amyloid- in CAA, it was lacking within the granular osmiophilic material immunolabelled by NOTCH3 extracelluar domain aggregates found in CADASIL. ConclusionsOur results suggest a wider role for clusterin associated with white matter damage in addition to its ability to chaperone proteins for clearance via the perivascular drainage pathways in several disease states.
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| 14. |
- Dahlrot, R. H., et al.
(författare)
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Prognostic value of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression in glioblastoma excluding nontumour cells from the analysis
- 2018
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 44:2, s. 172-184
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Tidskriftsartikel (refereegranskat)abstract
- Aims: It is important to predict response to treatment with temozolomide (TMZ) in glioblastoma (GBM) patients. Both MGMT protein expression and MGMT promoter methylation status have been reported to predict the response to TMZ. We investigated the prognostic value of quantified MGMT protein levels in tumour cells and the prognostic importance of combining information of MGMT protein level and MGMT promoter methylation status.Methods: MGMT protein expression was quantified in tumour cells in 171 GBMs from the population‐based Region of Southern Denmark (RSD)‐cohort using a double immunofluorescence approach. Pyrosequencing was performed in 157 patients. For validation we used GBM‐patients from a Nordic Study (NS) investigating the effect of radiotherapy and different TMZ schedules.Results: When divided at the median, patients with low expression of MGMT protein (AF‐low) had the best prognosis (HR = 1.5, P = 0.01). Similar results were observed in the subgroup of patients receiving the Stupp regimen (HR = 2.0, P = 0.001). In the NS‐cohort a trend towards superior survival (HR = 1.6, P = 0.08) was seen in patients with AF‐low. Including MGMT promoter methylation status, we found for both cohorts that patients with methylated MGMT promoter and AF‐low had the best outcome; median OS 23.1 and 20.0 months, respectively.Conclusion: Our data indicate that MGMT protein expression in tumour cells has an independent prognostic significance. Exclusion of nontumour cells contributed to a more exact analysis of tumour‐specific MGMT protein expression. This should be incorporated in future studies evaluating MGMT status before potential integration into clinical practice.
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| 15. |
- Dehghani, F., et al.
(författare)
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Inhibition of microglial and astrocytic inflammatory responses by the immunosuppressant mycophenolate mofetil
- 2010
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 36:7, s. 598-611
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Nucleotide depletion induced by the immunosuppressant mycophenolate mofetil (MMF) has been shown to exert neuroprotective effects. It remains unclear whether nucleotide depletion directly counteracts neuronal demise or whether it inhibits microglial or astrocytic activation, thereby resulting in indirect neuroprotection. Methods: Effects of MMF on isolated microglial cells, astrocyte/microglial cell co-cultures and isolated hippocampal neurones were analysed by immunocytochemistry, quantitative morphometry, and elisa. Results: We found that: (i) MMF suppressed lipopolysaccharide-induced microglial secretion of interleukin-1 beta, tumour necrosis factor-alpha and nitric oxide; (ii) MMF suppressed lipopolysaccharide-induced astrocytic production of tumour necrosis factor-alpha but not of nitric oxide; (iii) MMF strongly inhibited proliferation of both microglial cells and astrocytes; (iv) MMF did not protect isolated hippocampal neurones from excitotoxic injury; and (v) effects of MMF on glial cells were reversed after treatment with guanosine. Conclusions: Nucleotide depletion induced by MMF inhibits microglial and astrocytic activation. Microglial and astrocytic proliferation is suppressed by MMF-induced inhibition of the salvage pathway enzyme inosine monophosphate dehydrogenase. The previously observed neuroprotection after MMF treatment seems to be indirectly mediated, making this compound an interesting immunosuppressant in the treatment of acute central nervous system lesions.
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| 16. |
- Eide, P. K., et al.
(författare)
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Astrogliosis and impaired aquaporin-4 and dystrophin systems in idiopathic normal pressure hydrocephalus
- 2018
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846. ; 44:5, s. 474-490
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Idiopathic normal pressure hydrocephalus (iNPH) is one subtype of dementia that may improve following drainage of cerebrospinal fluid (CSF). This prospective observational study explored whether expression of the water channel aquaporin-4 (AQP4) and the anchoring molecule dystrophin 71 (Dp71) are altered at astrocytic perivascular endfeet and in adjacent neuropil of iNPH patient. Observations were related to measurements of pulsatile and static intracranial pressure (ICP). Methods: The study included iNPH patients undergoing overnight monitoring of the pulsatile/static ICP in whom a biopsy was taken from the frontal cerebral cortex during placement of the ICP sensor. Reference (Ref) biopsies were sampled from 13 patients who underwent brain surgery for epilepsy, tumours or cerebral aneurysms. The brain tissue specimens were examined by light microscopy, immunohistochemistry, densitometry and morphometry. Results: iNPH patients responding to surgery (n = 44) had elevated pulsatile ICP, indicative of impaired intracranial compliance. As compared to the Ref patients, the cortical biopsies of iNPH patients revealed prominent astrogliosis and reduced expression of AQP4 and Dp71 immunoreactivities in the astrocytic perivascular endfeet and in parts of the adjacent neuropil. There was a significant correlation between degree of astrogliosis and reduction of AQP4 and Dp71 at astrocytic perivascular endfeet. Conclusions: Idiopathic normal pressure hydrocephalus patients responding to CSF diversion present with abnormal pulsatile ICP, indicative of impaired intracranial compliance. A main histopathological finding was astrogliosis and reduction of AQP4 and of Dp71 in astrocytic perivascular endfeet. We propose that the altered AQP4 and Dp71 complex contributes to the subischaemia prevalent in the brain tissue of iNPH.
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| 17. |
- Ek Olofsson, H., et al.
(författare)
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A cortical microvascular structure in vascular dementia, Alzheimer's disease, frontotemporal lobar degeneration and nondemented controls : a sign of angiogenesis due to brain ischaemia?
- 2019
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 45:6, s. 557-569
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We observed a microvascular structure in the cerebral cortex that has not, to our knowledge, been previously described. We have termed the structure a ‘raspberry’, referring to its appearance under a bright-field microscope. We hypothesized that raspberries form through angiogenesis due to some form of brain ischaemia or hypoperfusion. The aims of this study were to quantify raspberry frequency within the cerebral cortex according to diagnosis (vascular dementia, Alzheimer's disease, frontotemporal lobar degeneration and nondemented controls) and brain regions (frontal, temporal, parietal and occipital cortices, regardless of diagnosis). Materials and methods: In each of 10 age-matched subjects per group, a 20-mm section of the cerebral cortex was examined in haematoxylin-and-eosin-stained sections of the frontal, temporal and parietal, and/or occipital lobes. Tests were performed to validate the haematoxylin-and-eosin-based identification of relative differences between the groups, and to investigate inter-rater variability. Results: Raspberry frequency was highest in subjects with vascular dementia, followed by those with frontotemporal lobar degeneration, Alzheimer's disease and last, nondemented controls. The frequency of raspberries in subjects with vascular dementia differed from that of all other groups at a statistically significant level. In the cerebral lobes, there was a statistically significant difference between the frontal and occipital cortices. Conclusions: We believe the results support the hypothesis that raspberries are a sign of angiogenesis in the adult brain. It is pertinent to discuss possible proangiogenic stimuli, including brain ischaemia (such as mild hypoperfusion due to a combination of small vessel disease and transient hypotension), neuroinflammation and protein pathology.
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| 18. |
- Espinosa-Oliva, Ana M., et al.
(författare)
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Inflammatory bowel disease induces pathological α-synuclein aggregation in the human gut and brain
- 2024
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Ingår i: Neuropathology and Applied Neurobiology. - 0305-1846. ; 50:1
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Tidskriftsartikel (refereegranskat)abstract
- Aims: According to Braak's hypothesis, it is plausible that Parkinson's disease (PD) originates in the enteric nervous system (ENS) and spreads to the brain through the vagus nerve. In this work, we studied whether inflammatory bowel diseases (IBDs) in humans can progress with the emergence of pathogenic α-synuclein (α-syn) in the gastrointestinal tract and midbrain dopaminergic neurons. Methods: We have analysed the gut and the ventral midbrain from subjects previously diagnosed with IBD and form a DSS-based rat model of gut inflammation in terms of α-syn pathology. Results: Our data support the existence of pathogenic α-syn in both the gut and the brain, thus reinforcing the potential role of the ENS as a contributing factor in PD aetiology. Additionally, we have analysed the effect of a DSS-based rat model of gut inflammation to demonstrate (i) the appearance of P-α-syn inclusions in both Auerbach's and Meissner's plexuses (gut), (ii) an increase in α-syn expression in the ventral mesencephalon (brain) and (iii) the degeneration of nigral dopaminergic neurons, which all are considered classical hallmarks in PD. Conclusion: These results strongly support the plausibility of Braak's hypothesis and emphasise the significance of peripheral inflammation and the gut-brain axis in initiating α-syn aggregation and transport to the substantia nigra, resulting in neurodegeneration.
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| 19. |
- Gabery, Sanaz, et al.
(författare)
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Loss of the metabolism and sleep regulating neuronal populations expressing orexin and oxytocin in the hypothalamus in amyotrophic lateral sclerosis
- 2021
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 47:7, s. 979-989
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To determine the underlying cellular changes and clinical correlates associated with pathology of the hypothalamus in amyotrophic lateral sclerosis (ALS), as hypothalamic atrophy occurs in the preclinical phase of the disease. Methods: The hypothalamus was pathologically examined in nine patients with amyotrophic lateral sclerosis in comparison to eight healthy control subjects. The severity of regional atrophy (paraventricular nucleus: PVN, fornix and total hypothalamus) and peptidergic neuronal loss (oxytocin, vasopressin, cocaine- and amphetamine-regulating transcript: CART, and orexin) was correlated with changes in eating behaviour, sleep function, cognition, behaviour and disease progression. Results: Tar DNA-binding protein 43 (TDP-43) inclusions were present in the hypothalamus of all patients with amyotrophic lateral sclerosis. When compared to controls, there was atrophy of the hypothalamus (average 21% atrophy, p = 0.004), PVN (average 30% atrophy p = 0.014) and a loss of paraventricular oxytocin-producing neurons (average 49% loss p = 0.02) and lateral hypothalamic orexin-producing neurons (average 37% loss, significance p = 0.02). Factor analysis identified strong relationships between abnormal eating behaviour, hypothalamic atrophy and loss of orexin-producing neurons. With increasing disease progression, abnormal sleep behaviour and cognition associated with atrophy of the fornix. Conclusions: Substantial loss of hypothalamic oxytocin-producing neurons occurs in ALS, with regional atrophy and the loss of orexin neurons relating to abnormal eating behaviour in ALS. Oxytocin- and orexin neurons display TDP43 inclusions. Our study points to significant pathology in the hypothalamus that may play a key role in metabolic and pathogenic changes in ALS.
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| 23. |
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| 24. |
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| 25. |
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| 26. |
- Hong, Xu, et al.
(författare)
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Memory deficits correlate with tau and spine pathology in P301S MAPT transgenic mice.
- 2014
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 40:7, s. 833-843
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Tidskriftsartikel (refereegranskat)abstract
- AIM: P301SMAPT transgenic mice (P301S mice) are a widely used model of frontotemporal dementia and parkinsonism linked to chromosome 17 with tau pathology (FTDP-17-tau). However, a systematic correlation between cognitive deficits and cellular tau pathology at different ages is still missing. Therefore, our study investigated memory deficits of P301S mice in relation to pathological tau species and dendritic spine pathology throughout adulthood. METHODS: We analysed P301S mice behaviourally with the novel open field, rotarod, and Morris water maze tests to measure deficits in locomotion, balance and cognition, respectively; immunohistochemically with different tau antibodies for specific tau species; and with Golgi staining for dendritic spine pathology. RESULTS: We confirmed the occurrence of locomotor deficits at an age of 5months and newly report memory deficits from 2.5months of age onwards. At this early age, MC1 and CP13, but not AT180 immunoreactivity, was prominent in the hippocampus of P301S mice. Neuronal cell loss in the hippocampus of P301S mice was not observed to occur till 6months of age. However, there was a significant reduction in the density of dendritic spines from young adulthood onwards in hippocampal pyramidal neurones. CONCLUSION: In P301S mice, memory deficits precede the onset of locomotor dysfunction and coincide with the appearance of conformationally changed, S202-phosphorylated tau and reduced spine density in the absence of neuronal cell loss in the hippocampus. Our finding provides insights into the toxic effects of different tau species in vivo and may facilitate the development of new therapies against neurodegenerative tauopathies. © 2014 British Neuropathological Society.
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| 27. |
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| 28. |
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| 30. |
- Karlsson, Christine, et al.
(författare)
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Genetic intratumour heterogeneity in high-grade brain tumours is associated with telomere-dependent mitotic instability.
- 2007
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Ingår i: Neuropathology & Applied Neurobiology. - : Wiley. - 1365-2990 .- 0305-1846. ; 33:4, s. 440-454
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) and other high-grade brain tumours are typically characterized by complex chromosome abnormalities and extensive intratumour cytogenetic heterogeneity. The mechanisms behind this diversity have been little explored. In this study, we analysed the pattern of chromosome segregation at mitosis in 20 brain tumours. We found an abnormal segregation of chromatids at mitosis through anaphase bridging (10-25% of anaphase cells) in all 10 GBMs. Anaphase bridging was also found in two medulloblastomas (7-15%), one anaplastic astrocytoma (17%) and one oligodendroglioma (6%). These tumours showed a relatively high degree of cytogenetic complexity and heterogeneity. In contrast, cell division abnormalities were not found in low-grade brain tumours with less complex karyotypes, including two pilocytic astrocytomas and two ependymomas. Further analysis of two GBMs by fluorescence in situ hybridization with telomeric repeat probes revealed excessive shortening of TTAGGG repeats, indicating dysfunctional protection of chromosome ends. In xenografts established from these GBMs, there was a gradual reduction in cytogenetic heterogeneity through successive passages as the proportion of abnormally short telomeres was reduced and the frequency of anaphase bridges decreased from >25% to 0. However, bridging could be reintroduced in late-passage xenograft cells by pharmacological induction of telomere shortening, using a small-molecule telomerase inhibitor. Telomere-dependent abnormal segregation of chromosomes at mitosis is thus a common phenomenon in high-grade brain tumours and may be one important factor behind cytogenetic intratumour diversity in GBM.
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| 31. |
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| 32. |
- Kovacs, Gabor G, et al.
(författare)
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Neuropathology of the hippocampus in FTLD-Tau with Pick bodies : A study of the BrainNet Europe Consortium
- 2013
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 39:2, s. 166-178
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Frontotemporal lobar degeneration with Pick bodies (Pick's disease) is characterized by the presence of tau immunoreactive spherical structures in the cytoplasm of neurons. In view of confusion about the molecular pathology of Pick's disease, we aimed to evaluate the spectrum of tau pathology and concomitant neurodegeneration-associated protein depositions in the characteristically affected hippocampus. Methods: We evaluated immunoreactivity for tau (AT8, 3R, 4R), α-synuclein, TDP43, p62, and ubiquitin in the hippocampus, entorhinal and temporal cortex in 66 archival cases diagnosed neuropathologically as Pick's disease. Results: Mean age at death was 68.2 years (range 49 to 96). Fifty-two (79%) brains showed 3R immunoreactive spherical inclusions in the granule cells of the dentate gyrus. These typical cases presented mainly with the behavioural variant of FTD, followed by progressive aphasia, mixed syndromes or early memory disturbance. α-Synuclein immunoreactivity was seen only in occasional spherical tau-positive inclusions, TDP-43 IR was absent, and 4R IR was present only as neurofibrillary tangles in pyramidal neurons. Aβ immunoreactivity was observed in 16 cases; however, the overall level of Alzheimer's disease-related alterations was mainly low or intermediate (n = 3). Furthermore, we identified six cases with unclassifiable tauopathy. Conclusions: 1) Pick's disease may occur also in elderly patients and is characterized by a relatively uniform pathology with 3R tau inclusions particularly in the granule cells of dentate gyrus; 2) even minor deviation from these morphological criteria suggests a different disorder; and 3) immunohistological revision of archival cases expands the spectrum of tauopathies that require further classification.
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| 33. |
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| 34. |
- Kuusisto, E, et al.
(författare)
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Use of p62/SQSTM1 antibodies for neuropathological diagnosis.
- 2008
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 34:2, s. 169-80
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Tidskriftsartikel (refereegranskat)abstract
- The demonstration of proteinaceous inclusions in the brain is the key step in the pathological diagnosis of degenerative dementias. The diversity of these diseases has necessitated the use of a panel of (immuno)stains to visualize all suspect pathologies, elevating diagnostic costs. Immunodetection of p62 (sequestosome 1), an abundant constituent in diverse pathological inclusions, holds the potential for a broad-specificity, high-contrast inclusion label. In the brain, pathological p62-positive aggregates comprise both cytoplasmic and nuclear types in neurones and glia, with abnormal tau, alpha-synuclein, TAR DNA-binding protein 43 or polyglutamine proteins as primary components. We therefore set out to evaluate the performance of p62 antibodies for diagnostic immunohistochemistry. We optimized the application conditions and compared the staining profiles of eight commercial p62 antibodies with each other and with reference immunostains, using 2-mm tissue multiarrays representing the major tauo- and synucleinopathies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). The lesions were best visualized using monoclonal antibodies, displaying most types of hallmark inclusions with excellent contrast. Expanding the list of p62-containing aggregates, we demonstrated p62 in tufted astrocytes, coiled bodies, astrocytic plaques, and variform neocortical inclusions and pathological processes in FTLD-U. Polyclonal antibodies exhibited lower sensitivities with variable background levels. We also noted more subtle p62-immunoreactive features lacking overt disease associations. Emphasizing the importance of proper antibody and epitope unmasking methods for maximum sensitivity, we recommend p62 immunodetection as a screening stain for diagnostic practice.
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| 35. |
- Leinonen, Ville, et al.
(författare)
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Post-mortem findings in 10 patients with presumed normal pressure hydrocephalus and review of the literature
- 2011
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 38:1, s. 72-86
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Neuropathological features of idiopathic normal pressure hydrocephalus (iNPH) are poorly characterized. Brain biopsy during life may help in the differential diagnosis of dementia but post-mortem validation of biopsy findings is scarce. Here we review and report brain biopsy and post-mortem neuropathological findings in patients with presumed NPH. Methods: We evaluated 10 patients initially investigated by intraventricular pressure monitoring and a frontal cortical biopsy for histological and immunohistochemical assessment as a diagnostic procedure for presumed NPH. Results: Out of the 10 patients, eight were shunted and seven benefited. Until death, six had developed severe and two mild cognitive impairment. One was cognitively unimpaired, and one was mentally retarded. Three subjects displayed Ab aggregates in their frontal cortical biopsy obtained at the initial procedure. One of these patients developed Alzheimer's disease during a follow-up time of nearly 10 years. One patient with cognitive impairment and NPH suffered from corticobasal degeneration. In six patients various vascular lesions were seen at the final neuropathological investigation. Five of them were cognitively impaired, and in four vascular lesions were seen sufficient in extent to be considered as causative regarding their symptoms. Conclusions: The frequent finding of vascular pathology in NPH is intriguing suggesting that vascular alterations might be causative of cognitive impairment in a notable number of patients with NPH and dementia. Brain biopsy can be used to detect Ab aggregates but neuropathological characteristics of iNPH as a distinct disease still need to be discovered.
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| 36. |
- Libard, Sylwia, et al.
(författare)
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Is islet amyloid polypeptide indeed expressed in the human brain?
- 2023
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Ingår i: Neuropathology and Applied Neurobiology. - : John Wiley & Sons. - 0305-1846 .- 1365-2990. ; 49:4
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Tidskriftsartikel (refereegranskat)abstract
- Aims This study aims to study the association between pancreatic islet amyloid polypeptide (IAPP) and Alzheimer's disease neuropathological change (ADNC) in brain biopsies obtained from subjects with idiopathic normal pressure hydrocephalus (iNPH) and in post-mortem (PM) brain samples obtained from aged individuals.Methods For the immunohistochemical (IHC) analyses, two IAPP antibodies (Abs), monoclonal and polyclonal, and Abs directed towards ADNC were applied.Results The iNPH cohort included 113 subjects. Amyloid-& beta; (A & beta;) was detected in 50% and hyperphosphorylated & tau; (HP & tau;) in 47% of the cases. Concomitant pathology was seen in 32%. The PM cohort included 77 subjects. A & beta; was detected in 69% and HP & tau; in 91% of the cases. Combined A & beta;/HP & tau; pathology was seen in 62%. Reactivity for the monoclonal IAPP was not detected in the brain tissue in either of the cohorts. Reactivity for the polyclonal IAPP was observed in all 77 PM brain samples.Conclusions There was no specific expression of IAPP in human brain tissue; hence, an association between IAPP and ADNC is not assessable. Of note, the observed reactivity of the polyclonal IAPP Ab was not reproduced with a specific monoclonal Ab; thus, we considered the observed staining with the polyclonal Ab to be unreliable. When using IHC, several pitfalls, especially the choice of an Ab, always need to be considered. Polyclonal Abs cross-react with other epitopes and proteins, thus leading to false-positive results. This seems to be the case for the polyclonal IAPP Abs in the human brain.
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| 37. |
- Manojlovic-Gacic, E, et al.
(författare)
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Invited Review: Pathology of pituitary neuroendocrine tumours : present status, modern diagnostic approach, controversies and future perspectives from a neuropathological and clinical standpoint
- 2020
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 46:2, s. 89-110
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Forskningsöversikt (refereegranskat)abstract
- Neuroendocrine tumours of the adenohypophysis have traditionally been designated as pituitary adenomas to underline their usually indolent growth and lack of metastatic potential. However, they may demonstrate a huge spectrum of growth patterns and endocrine disturbances, some of them significantly affecting health and quality of life. To predict tumour growth, risk of postoperative recurrence and response to medical therapy in patients with pituitary neuroendocrine tumours is challenging. A thorough histopathological and immunohistochemical diagnostic work-up is an obligatory part of a multidisciplinary effort to precisely define the tumour type and assess prognostic and predictive factors on an individual basis. In this review, we have summarized the current status in the pathology in pituitary neuroendocrine tumours based on the selection of references from the PubMed database. We have presented possible diagnostic approaches according to the current pituitary cell lineage-based classification. The importance of recognizing histological subtypes with potentially aggressive behaviour and identification of prognostic and predictive tissue biomarkers have been highlighted. Controversies related to particular subtypes of pituitary tumours and a still limited prognostic impact of the current classification indicate the need for further refinement. Multidisciplinary approach including clinical, pathological and molecular genetic characterization will be essential for improved personalized therapy and the search for novel therapeutic targets in patients with pituitary neuroendocrine tumours.
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| 38. |
- Martikainen, P., et al.
(författare)
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Brain pathology in three subjects from the same pedigree with presenilin-1 (PSEN1) P264L mutation
- 2010
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 36:1, s. 41-54
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Our goal was to assess pathological lesions with respect to type and distribution and to compare these results with the clinical presentation including symptoms and mode of progression in three members of the same pedigree with a P264L presenilin-1 gene mutation. METHODS: We used immunohistochemistry and a tissue microarray technique applied to post mortem brain tissue samples. RESULTS: All three subjects were demented, one subject displayed spastic paraparesis and two had Parkinsonism. All three cases displayed abundant cotton wool plaques composed of amyloid-beta42 but also containing other proteins, for example, hyperphosphorylated tau and in one case TAR DNA binding protein 43. The distribution of the pathology varied and seemed to some extent to be related to the clinical phenotype. An association was detected between neocortical/thalamic involvement and psychiatric symptoms, between striatal/amygdaloid involvement and Parkinsonism, and between brainstem involvement and spastic paraparesis. CONCLUSIONS: Subjects from the same pedigree carrying the same mutation display a clear variability in the type and distribution of pathology as well as in their clinical symptoms. These results emphasize that still unknown factors significantly alter the pathological and clinical phenotypes in genetically predetermined disease.
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| 39. |
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| 40. |
- Milosavljević, Filip, et al.
(författare)
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The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia
- 2023
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 49:1
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Tidskriftsartikel (refereegranskat)abstract
- Aims: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. Methods: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. Results: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. Conclusions: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.
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| 41. |
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| 42. |
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| 43. |
- Monoranu, Camelia Maria, et al.
(författare)
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pH measurement as quality control on human post mortem brain tissue : a study of the BrainNet Europe consortium
- 2009
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 35:3, s. 329-337
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Most brain diseases are complex entities. Although animal models or cell culture experiments mimic some disease aspects, human post mortem brain tissue remains essential to advance our understanding of brain diseases using biochemical and molecular techniques. Post mortem artefacts must be properly understood, standardized, and either eliminated or factored into such experiments. Here we examine the influence of several premortem and post mortem factors on pH, and discuss the role of pH as a biochemical marker for brain tissue quality. METHODS: We assessed brain tissue pH in 339 samples from 116 brains provided by 8 different European and 2 Australian brain bank centres. We correlated brain pH with tissue source, post mortem delay, age, gender, freezing method, storage duration, agonal state and brain ischaemia. RESULTS: Our results revealed that only prolonged agonal state and ischaemic brain damage influenced brain tissue pH next to repeated freeze/thaw cycles. CONCLUSIONS: pH measurement in brain tissue is a good indicator of premortem events in brain tissue and it signals limitations for post mortem investigations.
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| 44. |
- Nordborg, C, et al.
(författare)
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Oedema-related tissue damage after temporary and permanent occlusion of the middle cerebral artery
- 1994
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Ingår i: Neuropathology & Applied Neurobiology. - : Wiley. - 1365-2990 .- 0305-1846. ; 20:1, s. 56-65
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Tidskriftsartikel (refereegranskat)abstract
- Eleven adults spontaneously-hypertensive male rats (SHR) were studied 22 h or 7 days after a 2 h unilateral occlusion of the right middle cerebral artery (MCA). Another 11 SHR were studied after 24 h or 7 days of permanent MCA ligation. The brain infarcts were significantly larger (P < 0.05) after permanent occlusion than after a 2 h occlusion. More extensive and widespread vasogenic oedema, emanating from the infarcts, was visualized immunohistochemically in the temporarily-ligated animals and the relative number of astrocytes in their contralateral hemispheres was greater, thereby indicating that the vasogenic oedema influences the degree of gliosis. An immunopositivity for albumin but not for fibrinogen extended via the white matter into the ipsilateral thalamic nuclei, where cytolytic nerve cell damage, severely shrunken and karyorrhectic nerve cells as well as gliosis were found one week after permanent and temporary MCA ligation. The histological changes in the thalamus indicated a difference in timing between lateral and medial parts of the lesion as well as between temporarily- and permanently-ligated SHR. These findings together with the close spatial correlation with albumin immunoreactivity indicate that the spread of extravasated plasma constituents or degradation products with the oedema bulk flow from the infarct influences the timing, character and extent of thalamic lesions after cerebral infarction.
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| 45. |
- Oldfors Hedberg, Carola, 1969, et al.
(författare)
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Respiratory chain dysfunction in perifascicular muscle fibres in patients with dermatomyositis is associated with mitochondrial DNA depletion
- 2022
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 48:7
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Tidskriftsartikel (refereegranskat)abstract
- Aims Patients with dermatomyositis (DM) suffer from reduced aerobic metabolism contributing to impaired muscle function, which has been linked to cytochrome c oxidase (COX) deficiency in muscle tissue. This mitochondrial respiratory chain dysfunction is typically seen in perifascicular regions, which also show the most intense inflammatory reaction along with capillary loss and muscle fibre atrophy. The objective of this study was to investigate the pathobiology of the oxidative phosphorylation deficiency in DM. Methods Muscle biopsy specimens with perifascicular COX deficiency from five juveniles and seven adults with DM were investigated. We combined immunohistochemical analyses of subunits in the respiratory chain including complex I (subunit NDUFB8), complex II (succinate dehydrogenase, subunit SDHB) and complex IV (COX, subunit MTCO1) with in situ hybridisation, next generation deep sequencing and quantitative polymerase chain reaction (PCR). Results There was a profound deficiency of complexes I and IV in the perifascicular regions with enzyme histochemical COX deficiency, whereas succinate dehydrogenase activity and complex II were preserved. In situ hybridisation of mitochondrial RNA showed depletion of mitochondrial DNA (mtDNA) transcripts in the perifascicular regions. Analysis of mtDNA by next generation deep sequencing and quantitative PCR in affected muscle regions showed an overall reduction of mtDNA copy number particularly in the perifascicular regions. Conclusion The respiratory chain dysfunction in DM muscle is associated with mtDNA depletion causing deficiency of complexes I and IV, which are partially encoded by mtDNA, whereas complex II, which is entirely encoded by nuclear DNA, is preserved. The depletion of mtDNA indicates a perturbed replication of mtDNA explaining the muscle pathology and the disturbed aerobic metabolism.
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| 46. |
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| 47. |
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| 48. |
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| 49. |
- Petit, Géraldine, et al.
(författare)
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Review: The future of cell therapies and brain repair: Parkinson's disease leads the way.
- 2014
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Ingår i: Neuropathology & Applied Neurobiology. - : Wiley. - 1365-2990 .- 0305-1846. ; 40:1, s. 60-70
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Forskningsöversikt (refereegranskat)abstract
- During the past 40 years brain tissue grafting techniques have been used both to study fundamental neurobiological questions and to treat neurological diseases. Motor symptoms of Parkinson's disease are largely due to degeneration of midbrain dopamine neurones. Because the nigrostriatal pathology is relatively focused anatomically, Parkinson's disease is considered the ideal candidate for brain repair by neural grafting and dopamine neurone transplantation for it has led the way in the neural transplantation research field. In this mini-review, we briefly highlight four important areas of development. First, we describe marked functional benefits up to 18 years after transplantation surgery in patients with Parkinson's disease. This is proof-of-principle that, using optimal techniques and patient selection, grafted dopamine neurones can work in humans and the duration of the benefit exceeds placebo effects associated with surgery. Second, we describe that eventually protein aggregates containing α-synuclein, identical to Lewy bodies, develop inside foetal dopamine neurones transplanted to patients with Parkinson's disease. This gives clues about pathogenetic mechanisms operating in Parkinson's disease, and also raises the question whether neural graft function will eventually decline as the result of the disease process. Third, we describe new emerging sources of transplantable dopamine neurones derived from pluripotent stem cells or reprogrammed adult somatic cells. Fourth, we highlight an important European Union-funded multicentre clinical trial involving transplantation of foetal dopamine neurones in Parkinson's disease. We describe the design of this ongoing trial and how it can impact on the overall future of cell therapy in Parkinson's disease.
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| 50. |
- Qu, Mingqi, et al.
(författare)
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Molecular Genetic and Epigenetic analysis of NCX2/SLC8A2 at 19q13.3 in Human Gliomas
- 2010
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 36:3, s. 198-210
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Tidskriftsartikel (refereegranskat)abstract
- AimLoss of heterozygosity (LOH) at 19q13.3 is a common genetic change in human gliomas, indicating yet unknown glial-specific tumour suppressor genes in this chromosome region. NCX2/SLC8A2 located on chromosome 19q13.32 encodes a Na(+)/Ca(2+)exchanger, which contributes to intracellular Ca(2+)homeostasis. Its expression is restricted to brain, and it is neither present in other normal tissues nor in gliomas at any significant level. The aim of this study was to investigate if NCX2 might be a tumour suppressor gene involved in glioma.MethodsWe performed a systematic analysis of NCX2 in 42 human gliomas using microsatellite analysis for evaluation of LOH at 19q, DNA sequencing and DNA methylation analysis.ResultsExcept for three known intragenic SNPs, rs12459087, rs7259674, and rs8104926, no NCX2 sequence variations were detected in any of the tumour samples. Furthermore, a CpG island in the 5' promoter region of NCX2 was unmethylated. Interestingly, the CpG sites of three gene-body CpG islands located in exon 2, intron 2-3 and exon 3 and of a 5' CpG rich area relevant to so called CpG island shore of NCX2 were methylated in all 8 glioma samples and in 3 established glioma cell lines tested. Surprisingly, NCX2 could be activated by addition of the DNA methylation inhibitor 5-aza-2'-deoxycytidine to glioma cell lines in which NCX2 was completely silent.ConclusionResults indicate that DNA methylation may play a key role in the transcriptional silencing of NCX2.
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