| 1. |
- Lau, Heather H. C., et al.
(författare)
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The existence of A beta strains and their potential for driving phenotypic heterogeneity in Alzheimer's disease
- 2021
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Ingår i: Acta Neuropathologica. - : Springer. - 0001-6322 .- 1432-0533. ; 142:1, s. 17-39
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Forskningsöversikt (refereegranskat)abstract
- Reminiscent of the human prion diseases, there is considerable clinical and pathological variability in Alzheimer's disease, the most common human neurodegenerative condition. As in prion disorders, protein misfolding and aggregation is a hallmark feature of Alzheimer's disease, where the initiating event is thought to be the self-assembly of A beta peptide into aggregates that deposit in the central nervous system. Emerging evidence suggests that A beta, similar to the prion protein, can polymerize into a conformationally diverse spectrum of aggregate strains both in vitro and within the brain. Moreover, certain types of A beta aggregates exhibit key hallmarks of prion strains including divergent biochemical attributes and the ability to induce distinct pathological phenotypes when intracerebrally injected into mouse models. In this review, we discuss the evidence demonstrating that A beta can assemble into distinct strains of aggregates and how such strains may be primary drivers of the phenotypic heterogeneity in Alzheimer's disease.
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| 2. |
- Mohseni, Simin
(författare)
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Hypoglycemic neuropathy
- 2001
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Ingår i: Acta Neuropathologica. - 0001-6322 .- 1432-0533. ; 102:5, s. 413-421
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Forskningsöversikt (refereegranskat)abstract
- Hypoglycemia is a relatively common condition primarily affecting diabetic patients treated with insulin or other hypoglycemic drugs and insulinoma patients. Clinical experience and experimental studies show that hypoglycemia may cause alterations both in the central (CNS) and the peripheral (PNS) nervous system. Hypoglycemic effects on the CNS include various symptoms such as irritability and lack of concentration, disruption of cognitive functions, convulsions and unconsciousness. As for pathology, a loss of neurons has been noted, being more obvious in the cerebral cortex and the hippocampus than in the brain stem, cerebellum and spinal cord. Myelin damage and glial changes have also been observed in the CNS. The development of pathological changes in the brain has mainly been studied on autopsy material from patients who died in insulin coma and in animals exposed to a severe hypoglycemia and showing an isoelectric electroencephalogram. It has been suggested that hypoglycemic loss of neurons in the brain is related to excititoxic actions of aspartate on N-methyl-D-aspartate receptors. With respect to the PNS, scattered clinical observations in humans and experimental studies in animals show that hypoglycemia causes a distal axonopathy including both degenerative and regenerative events. In this respect, motor axons seem to be more vulnerable than sensory axons. Animal experiments show that a peripheral neuropathy may develop even in cases with a mild hypoglycemia compatible with a generally normal behavior. The cellular mechanisms behind the development of hypoglycemic. PNS alterations are unknown. To elucidate the pathophysiology of hypoglycemic neuropathy more basic research is needed.
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| 3. |
- Molinuevo, J. L., et al.
(författare)
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Current state of Alzheimer's fluid biomarkers
- 2018
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 136:6, s. 821-853
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Forskningsöversikt (refereegranskat)abstract
- Alzheimer's disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers A42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, -synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.
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| 4. |
- Neumann, Julia E., et al.
(författare)
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Medulloblastoma : experimental models and reality
- 2017
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 134:5, s. 679-689
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Forskningsöversikt (refereegranskat)abstract
- Medulloblastoma is the most frequent malignant brain tumor in childhood, but it may also affect infants, adolescents, and young adults. Recent advances in the understanding of the disease have shed light on molecular and clinical heterogeneity, which is now reflected in the updated WHO classification of brain tumors. At the same time, it is well accepted that preclinical research and clinical trials have to be subgroup-specific. Hence, valid models have to be generated specifically for every medulloblastoma subgroup to properly mimic molecular fingerprints, clinical features, and responsiveness to targeted therapies. This review summarizes the availability of experimental medulloblastoma models with a particular focus on how well these models reflect the actual disease subgroup. We further describe technical advantages and disadvantages of the models and finally point out how some models have successfully been used to introduce new drugs and why some medulloblastoma subgroups are extraordinary difficult to model.
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| 5. |
- Pekny, Milos, 1965, et al.
(författare)
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Astrocytes - a central element in neurological diseases.
- 2016
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 131:3, s. 323-345
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Forskningsöversikt (refereegranskat)abstract
- The neurone-centred view of the past disregarded or downplayed the role of astroglia as a primary component in the pathogenesis of neurological diseases. As this concept is changing, so is also the perceived role of astrocytes in the healthy and diseased brain and spinal cord. We have started to unravel the different signalling mechanisms that trigger specific molecular, morphological and functional changes in reactive astrocytes that are critical for repairing tissue and maintaining function in CNS pathologies, such as neurotrauma, stroke, or neurodegenerative diseases. An increasing body of evidence shows that the effects of astrogliosis on the neural tissue and its functions are not uniform or stereotypic, but vary in a context-specific manner from astrogliosis being an adaptive beneficial response under some circumstances to a maladaptive and deleterious process in another context. There is a growing support for the concept of astrocytopathies in which the disruption of normal astrocyte functions, astrodegeneration or dysfunctional/maladaptive astrogliosis are the primary cause or the main factor in neurological dysfunction and disease. This review describes the multiple roles of astrocytes in the healthy CNS, discusses the diversity of astroglial responses in neurological disorders and argues that targeting astrocytes may represent an effective therapeutic strategy for Alexander disease, neurotrauma, stroke, epilepsy and Alzheimer’s disease as well as other neurodegenerative diseases.
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| 6. |
- Tajsharghi, Homa, 1968, et al.
(författare)
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Myosinopathies: pathology and mechanisms.
- 2013
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 125:1, s. 3-18
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Forskningsöversikt (refereegranskat)abstract
- The myosin heavy chain (MyHC) is the molecular motor of muscle and forms the backbone of the sarcomere thick filaments. Different MyHC isoforms are of importance for the physiological properties of different muscle fiber types. Hereditary myosin myopathies have emerged as an important group of diseases with variable clinical and morphological expression depending on the mutated isoform and type and location of the mutation. Dominant mutations in developmental MyHC isoform genes (MYH3 and MYH8) are associated with distal arthrogryposis syndromes. Dominant or recessive mutations affecting the type IIa MyHC (MYH2) are associated with early-onset myopathies with variable muscle weakness and ophthalmoplegia as a consistent finding. Myopathies with scapuloperoneal, distal or limb-girdle muscle weakness including entities, such as myosin storage myopathy and Laing distal myopathy are the result of usually dominant mutations in the gene for slow/β cardiac MyHC (MYH7). Protein aggregation is part of the features in some of these myopathies. In myosin storage myopathy protein aggregates are formed by accumulation of myosin beneath the sarcolemma and between myofibrils. In vitro studies on the effects of different mutations associated with myosin storage myopathy and Laing distal myopathy indicate altered biochemical and biophysical properties of the light meromyosin, which is essential for thick filament assembly. Protein aggregates in the form of tubulofilamentous inclusions in association with vacuolated muscle fibers are present at late stage of dominant myosin IIa myopathy and sometimes in Laing distal myopathy. These protein aggregates exhibit features indicating defective degradation of misfolded proteins. In addition to protein aggregation and muscle fiber degeneration some of the myosin mutations cause functional impairment of the molecular motor adding to the pathogenesis of myosinopathies.
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