With reactive astrogliosis being established as one of the hallmarks of Alzheimer's disease (AD), there is high interest in developing novel positron emission tomography (PET) tracers to detect early ...astrocyte reactivity. BU99008, a novel astrocytic PET ligand targeting imidazoline-2 binding sites (I
BS) on astrocytes, might be a suitable candidate. Here we demonstrate for the first time that BU99008 could visualise reactive astrogliosis in postmortem AD brains and propose a multiple binding site Super-high-affinity (SH), High-affinity (HA) and Low-affinity (LA) model for BU99008, I
BS specific ligands (2-BFI and BU224) and deprenyl in AD and control (CN) brains. The proportion (%) and affinities of these sites varied significantly between the BU99008, 2-BFI, BU224 and deprenyl in AD and CN brains. Regional binding studies demonstrated significantly higher
H-BU99008 binding in AD brain regions compared to CN. Comparative autoradiography studies reinforced these findings, showing higher specific binding for
H-BU99008 than
H-Deprenyl in sporadic AD brain compared to CN, implying that they might have different targets. The data clearly shows that BU99008 could detect I
BS expressing reactive astrocytes with good selectivity and specificity and hence be a potential attractive clinical astrocytic PET tracer for gaining further insight into the role of reactive astrogliosis in AD.
Autosomal-dominant Alzheimer's disease (ADAD) may be associated with atypical amyloid beta deposits in the brain. In vivo amyloid imaging using
C-Pittsburgh compound B (PiB) tracer has shown ...differences in binding between brains from ADAD and sporadic Alzheimer's disease (sAD) patients. To gain further insight into the various pathological characteristics of these genetic variants, we performed large frozen hemisphere autoradiography and brain homogenate binding assays with
H-PiB,
H-MK6240-
H-THK5117, and
H-deprenyl for detection of amyloid fibrils, tau depositions, and activated astrocytes, respectively, in two AβPParc mutation carriers, one PSEN1ΔE9 mutation carrier, and three sAD cases. The results were compared with Abeta 40, Abeta 42, AT8, and GFAP immunostaining, respectively, as well as with Congo red and Bielschowsky. PiB showed a very low binding in AβPParc. A high binding was observed in PSEN1ΔE9 and in sAD tissues but with different binding patterns. Comparable
H-THK5117 and
H-deprenyl brain homogenate binding was observed for AβPParc, PSEN1ΔE9, and sAD, respectively. Some differences were observed between
H-MK6240 and
H-THK5117 in ADAD. A positive correlation between
H-deprenyl and
H-THK5117 binding was observed in AβPParc, while no such correlation was found in PSEN1ΔE9 and sAD. Our study demonstrates differences in the properties of the amyloid plaques between two genetic variants of AD and sAD. Despite the lack of measurable amyloid fibrils by PiB in the AβPParc cases, high regional tau and astrocyte binding was observed. The lack of correlation between
H-deprenyl and
H-THK5117 binding in PSEN1ΔE9 and sAD in contrast of the positive correlation observed in the AβPParc cases suggest differences in the pathological cascade between variants of AD that warrant further exploration in vivo.
Abstract Background Resolution is the final stage of the inflammatory response, when restoration of tissue occurs. Failure may lead to chronic inflammation, which is known as part of the pathology in ...the brain of individuals with Alzheimer's disease (AD). Methods Specialized pro-resolving mediators (SPMs), receptors, biosynthetic enzyme, and downstream effectors involved in resolution were analyzed in postmortem hippocampal tissue from AD patients and non-AD subjects. SPMs were analyzed in cerebrospinal fluid (CSF). Results SPMs and SPM receptors were detected in the human brain. Levels of the SPM lipoxin A4 (LXA4 ) were reduced in AD, both in the CSF and hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in AD brains. LXA4 and RvD1 levels in CSF correlated with Mini-Mental State Examination (MMSE) scores. Conclusions A resolution pathway exists in the brain and the alterations described herein strongly suggest a dysfunction of this pathway in AD. MMSE correlations suggest a connection with cognitive function in AD.
Background
Frontotemporal dementia (FTD) is a neurodegenerative disease, resulting in progressive problems in language and/or behaviour and is often diagnosed before 65 years of age. Ubiquitin ...positive protein aggregates in the brain are among the key pathologic hallmarks of frontotemporal lobar degeneration (FTLD) postmortem. The TANK-binding kinase 1 gene (
TBK1
) is on the list of genes that can contribute to the development of FTD as well as the related neurodegenerative disease amyotrophic lateral sclerosis (ALS).
Methods
In this study, using an array of clinical and neuropathological data combined with biochemical and proteomics assays, we analyze the
TBK1
splice-mutation (c.1340 + 1G > A) in a Swedish family with a history of FTD and ALS. We also explore the K63 ubiquitination landscape in post-mortem brain tissue and fibroblast cultures.
Results
The intronic (c.1340 + 1G > A) mutation in
TBK1
results in haploinsufficiency and affects the activity of the protein in symptomatic and pre-symptomatic mutation carriers.
Conclusion
Our results suggest that the mutation leads to a significant reduction of TBK1 activity and induce alterations in K63 ubiquitination profile of the cell already in the presymptomatic stages.
The objective of this study is to assess the frequency of autoantibodies against 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) in a single center myositis cohort and to analyze ...associations with statin exposure, clinical features, and outcome of disease course.
A total of 312 patients with idiopathic inflammatory myopathies (IIMs) followed at the rheumatology clinic, Karolinska University Hospital, were identified in the Euromyositis registry between 1988 and 2014 and were classified according to the 2017 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) criteria. Available serum samples were analyzed for anti-HMGCR autoantibodies by ELISA. Positive sera were confirmed by immunoprecipitation. Clinical data were extracted from Euromyositis registry and medical records. Muscle samples were examined by two pathologists blinded to the subjects' autoantibody status.
Of 312 patients, 13 (4.3%) were positive for anti-HMGCR. Two of the 13 (15%) anti-HMGCR-positive patients had histories of statin use versus 12 (4.2%) in the anti-HMGCR-negative group. In the anti-HMGCR-positive group, five (38%) had a clinical phenotype compatible with dermatomyositis. Muscle biopsies of patients with HMGCR autoantibodies showed findings consistent with immune-mediated necrotizing myopathy in all cases except for one. Five (38%) patients required treatment with intravenous immunoglobulin compared to seven (2.3%) without this antibody. At the last visit, seven patients had chronic, active disease course, and five of 13 patients were in remission, including three without treatment.
Patients with IIM related to anti-HMGCR autoantibodies may present with a wide range of symptoms, more than previously anticipated. When a broad approach to screening for these antibodies is applied, only a minority of patients was found to have previous statin exposure. The results of this study justify the addition of anti-HMGCR autoantibodies to routine diagnostic procedures in patients with myositis.
Idiopathic inflammatory myopathies (IIM) are rare autoimmune systemic diseases characterized by muscle weakness and the presence of muscle-infiltrating T cells. IIM represent a clinical challenge due ...to heterogeneity of symptoms and variability of response to immunosuppressive treatment. Here, we performed in-depth single-cell sequencing on muscle-infiltrating T cells and peripheral blood memory T cells in six patients with recently diagnosed IIM. We identified tissue resident memory T-cell (T
) signatures including the expression of HOBIT, XCL1 and CXCR6 in the muscle biopsies of all patients with IIM. Clonally expanded T-cell clones were mainly found among cytotoxic and T
implying their role in the disease pathogenesis. Finally, identical expanded T-cell clones persisting at follow-up in the muscle tissue of two patients suggest their involvement in disease chronicity. Our study reveals a muscle tissue resident memory T-cell signature in patients with IIM and a transcriptomic map to identify novel therapeutic targets in IIM.
Dual pathology in fragile X mental retardation 1 (
premutation carriers and fragile X-associated tremor/ataxia syndrome (FXTAS) patients is an emerging phenomenon. Although it includes atypical ...parkinsonism, neuropathological confirmation is very scarce. Here, we describe neuropathological findings for a female who suffered a severe parkinsonian syndrome with apraxia and supranuclear palsy. She died at the age of 50, six years after the initial diagnosis. Prominent neuronal loss was found in the pallidum, subthalamic nucleus, and tectum, but the loss of Purkinje cells was rather mild. Intranuclear inclusions containing ubiquitin and FMRpolyglycine, a pathological hallmark of FXTAS, were detected in neurons and astrocytes. However, this inclusion pathology was overshadowed by a very prominent four repeat tau accumulation in tufted astrocytes, oligodendroglial coiled bodies, thread structures, and neurons. This is, to best of our knowledge, the first report describing a pathologically confirmed progressive supranuclear palsy - corticobasal syndrome (PSP-CBS) variant case in a
premutation carrier.
(1) Background: Muscle protein synthesis in critically ill patients is, on average, normal despite dramatic muscle loss, but the variation is much larger than in controls. Here, we evaluate if this ...variation is due to 1) heterogeneity in synthesis rates, 2) morphological variation or infiltrating cells, or 3) heterogeneity in the synthesis of different protein fractions. (2) Methods: Muscle biopsies were taken from both legs of critically ill patients (n = 17). Mixed and mitochondrial protein synthesis rates and morphologies were evaluated in both legs. Synthesis rates of myosin and actin were determined in combined biopsies and compared with controls. (3) Results: Muscle protein synthesis rates had a large variability in the patients (1.4–10.8%/day). No differences in mixed and mitochondrial protein synthesis rates between both legs were observed. A microscopic examination revealed no morphological differences between the two legs or any infiltrating inflammatory cells. The synthesis rates for myosin were lower and for actin they were higher in the muscles of critically ill patients, compared with the controls. (4) Conclusions: The large variation in muscle protein synthesis rates in critically ill patients is not the result of heterogeneity in synthesis rates, nor due to infiltrating cells. There are differences in the synthesis rates of different proteins, but these do not explain the larger variations.
S-adenosylmethionine (SAM) is the predominant methyl group donor and has a large spectrum of target substrates. As such, it is essential for nearly all biological methylation reactions. SAM is ...synthesized by methionine adenosyltransferase from methionine and ATP in the cytoplasm and subsequently distributed throughout the different cellular compartments, including mitochondria, where methylation is mostly required for nucleic-acid modifications and respiratory-chain function. We report a syndrome in three families affected by reduced intra-mitochondrial methylation caused by recessive mutations in the gene encoding the only known mitochondrial SAM transporter, SLC25A26. Clinical findings ranged from neonatal mortality resulting from respiratory insufficiency and hydrops to childhood acute episodes of cardiopulmonary failure and slowly progressive muscle weakness. We show that SLC25A26 mutations cause various mitochondrial defects, including those affecting RNA stability, protein modification, mitochondrial translation, and the biosynthesis of CoQ10 and lipoic acid.
Oxidative stress has an important role in the pathological process of most neurodegenerative disorders, including Alzheimer's disease (AD). The glutaredoxin (Grx) and thioredoxin (Trx) systems are ...central in maintaining a reduced environment in the cell and thus render protection against oxidative stress. Here, we show that Trx1 and Grx1 were released to the cerebrospinal fluid in 120 cases examined, and that the levels of these proteins increased significantly in the early stages of AD in comparison to mild cognitive impairment (MCI). Trx1 and Grx1 levels correlated with the established AD biomarkers tau and phospho-tau (p-tau). Moreover, by determining the levels of Trx1 and Grx1, discrimination between MCI converters and patients with stable MCI were possible. By applying the protein levels of Trx1 together with conventional diagnostic markers (Mini-Mental State Examination, tau, and p-tau) to a stepwise regression model, MCI stable, MCI converter, mild AD, and moderate AD was correctly diagnosed in 32 out of 33 cases. In order to further evaluate the involvement of these systems in AD, the immunoreactivity of Trx1, Trx2, Grx1, and Grx2 were investigated and the expression pattern was shown to be altered in hippocampus tissue sections from AD patients compared to controls. In conclusion, we introduce members of the thioredoxin super family of proteins as promising early biomarkers in the diagnosis of AD, suggesting their potential involvement in the pathogenesis of the disease.
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