| 21. |
- Garcia-Reitboeck, P., et al.
(författare)
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Human Induced Pluripotent Stem Cell-Derived Microglia-Like Cells Harboring TREM2 Missense Mutations Show Specific Deficits in Phagocytosis
- 2018
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 24:9, s. 2300-2311
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Tidskriftsartikel (refereegranskat)abstract
- Dysfunction of microglia, the brain's immune cells, is linked to neurodegeneration. Homozygous missense mutations in TREM2 cause Nasu-Hakola disease (NHD), an early-onset dementia. To study the consequences of these TREM2 variants, we generated induced pluripotent stem cell-derived microglia-like cells (iPSC-MGLCs) from patients with NHD caused by homozygous T66M or W50C missense mutations. iPSC-MGLCs expressed microglial markers and secreted higher levels of TREM2 than primary macrophages. TREM2 expression and secretion were reduced in variant lines. LPS-mediated cytokine secretion was comparable between control and TREM2 variant iPSC-MGLCs, whereas survival was markedly reduced in cells harboring missense mutations when compared with controls. Furthermore, TREM2 missense mutations caused a marked impairment in the phagocytosis of apoptotic bodies, but not in Escherichia coli or zymosan substrates. Coupled with changes in apoptotic cell-induced cytokine release and migration, these data identify specific deficits in the ability of iPSC-MGLCs harboring TREM2 missense mutations to respond to specific pathogenic signals.
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| 22. |
- Georgiou, E., et al.
(författare)
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AAV9-mediated SH3TC2 gene replacement therapy targeted to Schwann cells for the treatment of CMT4C
- 2023
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Ingår i: Molecular Therapy. - 1525-0016. ; 31:11, s. 3290-3307
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Tidskriftsartikel (refereegranskat)abstract
- Type 4C Charcot-Marie-Tooth (CMT4C) demyelinating neuropathy is caused by autosomal recessive SH3TC2 gene mutations. SH3TC2 is highly expressed in myelinating Schwann cells. CMT4C is a childhood-onset progressive disease without effective treatment. Here, we generated a gene therapy for CMT4C mediated by an adeno-associated viral 9 vector (AAV9) to deliver the human SH3TC2 gene in the Sh3tc2-/mouse model of CMT4C. We used a minimal fragment of the myelin protein zero (Mpz) promoter (miniMpz), which was cloned and validated to achieve Schwann cell-targeted expression of SH3TC2. Following the demonstration of AAV9miniMpz.SH3TC2myc vector efficacy to re-establish SH3TC2 expression in the peripheral nervous system, we performed an early as well as a delayed treatment trial in Sh3tc2-/mice. We demonstrate both after early as well as following late treatment improvements in multiple motor performance tests and nerve conduction velocities. Moreover, treatment led to normalization of the organization of the nodes of Ranvier, which is typically deficient in CMT4C patients and bers, increased myelin thickness and reduced g-ratios at both time points of intervention. Taken together, our results provide a proof of concept for an effective and potentially translatable gene replacement therapy for CMT4C treatment.
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| 23. |
- Gibson, L. L., et al.
(författare)
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Plasma Neurofilament Light and p-tau181 and Risk of Psychosis in Parkinson's Disease
- 2022
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Ingår i: Journal of Parkinsons Disease. - : IOS Press. - 1877-7171 .- 1877-718X. ; 12:5, s. 1527-1538
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neuropsychiatric symptoms are common and important to people with Parkinson's disease (PD), but their etiology is poorly understood. Plasma neurofilament light (NfL) and p-tau181 are biomarkers of neuro-axonal degeneration and tau pathology respectively, which have yet to be explored in association with the affective and psychotic symptoms in PD. Objective: To investigate the relationship between plasma NfL and p-taul 81 with the affective and psychotic symptoms in PD. Methods: We assessed the baseline concentration of plasma NfL and p-taul 81 in a cohort of 108 patients with PD and 38 healthy controls. A subgroup of patients (n = 63) were assessed annually with clinical measures for up to 7 years. Psychotic symptoms were assessed using the Non-Motor Symptom Scale and affective symptoms were measured in the Hospital Anxiety and Depression Scale. Results: Baseline plasma NfL was a significant predictor of psychotic symptoms longitudinally across the study adjusted for age, Hoehn and Yahr stage, duration of follow up, duration of disease, baseline levodopa and dopamine agonist medication, and baseline cognition: (OR 8.15 [95% CI 1.40-47.4], p =0 .020). There was no association between NfL concentration and the cumulative prevalence of affective symptoms. Plasma p-taul 81 concentration was not associated with psychotic or affective symptoms. Conclusion: These findings suggest psychotic symptoms are associated with greater neurodegeneration in PD. Further studies are needed to explore NfL as a potential biomarker for psychosis in PD.
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| 24. |
- Gorgoraptis, N., et al.
(författare)
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In vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury
- 2019
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 11:508
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Tidskriftsartikel (refereegranskat)abstract
- Traumatic brain injury (TBI) can trigger progressive neurodegeneration, with tau pathology seen years after a single moderate-severe TBI. Identifying this type of posttraumatic pathology in vivo might help to understand the role of tau pathology in TBI pathophysiology. We used flortaucipir positron emission tomography (PET) to investigate whether tau pathology is present many years after a single TBI in humans. We examined PET data in relation to markers of neurodegeneration in the cerebrospinal fluid (CSF), structural magnetic resonance imaging measures, and cognitive performance. Cerebral flortaucipir binding was variable, with many participants with TBI showing increases in cortical and white matter regions. At the group level, flortaucipir binding was increased in the right occipital cortex in TBI when compared to healthy controls. Flortaucipir binding was associated with increased total tau, phosphorylated tau, and ubiquitin carboxyl-terminal hydrolase L1 CSF concentrations, as well as with reduced fractional anisotropy and white matter tissue density in TBI. Apolipoprotein E (APOE) epsilon 4 genotype affected the relationship between flortaucipir binding and time since injury, CSF beta amyloid 1-42 (A beta 42) concentration, white matter tissue density, and longitudinal Mini-Mental State Examination scores in TBI. The results demonstrate that tau PET is a promising approach to investigating progressive neurodegeneration associated with tauopathy after TBI.
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| 25. |
- Heller, C, et al.
(författare)
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Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia
- 2020
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Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 91:3, s. 263-270
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Tidskriftsartikel (refereegranskat)abstract
- There are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker.MethodsPlasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman’s correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures.ResultsPlasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, –61.3 to 54.6), MAPT mutations (12.7, –33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe.ConclusionsRaised GFAP concentrations appear to be unique to GRN-related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials.
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| 26. |
- Kapoor, M., et al.
(författare)
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Plasma neurofilament light chain concentration is increased and correlates with the severity of neuropathy in hereditary transthyretin amyloidosis
- 2019
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Ingår i: Journal of the Peripheral Nervous System. - : Wiley. - 1085-9489 .- 1529-8027. ; 24:4, s. 314-319
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary transthyretin amyloidosis (ATTRm) causes a disabling peripheral neuropathy as part of a multisystem disorder. The recent development of highly effective gene silencing therapies has highlighted the need for effective biomarkers of disease activity to guide the decision of when to start and stop treatment. In this study, we measured plasma neurofilament light chain (pNfL) concentration in 73 patients with ATTR and found that pNfL was significantly raised in ATTRm patients with peripheral neuropathy compared to healthy controls. Furthermore, pNFL correlated with disease severity as defined by established clinical outcome measures in patients for whom this information was available. These findings suggest a potential role of pNfL in monitoring disease activity and progression in ATTRm patients.
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| 27. |
- Keshavan, A., et al.
(författare)
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Concordance of csf measures of alzheimer’s pathology with amyloid pet status in a preclinical cohort: A comparison of lumipulse and established immunoassays
- 2021
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Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - : Wiley. - 2352-8729. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: We assessed the concordance of cerebrospinal fluid (CSF) amyloid beta (Aβ) and tau measured on the fully automated Lumipulse platform with presymptomatic Alzheimer’s disease (AD) pathology on amyloid positron emission tomography (PET). METHODS: In 72 individuals from the Insight 46 study, CSF Aβ40, Aβ42, total tau (t-tau), and phosphorylated tau at site 181 (p-tau181) were measured using Lumipulse, INNOTEST, and Meso Scale Discovery (MSD) assays and inter-platform Pearson correlations derived. Lumipulse Aβ42 measures were adjusted to incorporate standardization to certified reference materials. Logistic regressions and receiver operating characteristics analysis generated CSF cut-points optimizing concordance with18F florbetapir amyloid PET status (n = 63). RESULTS: Measurements of CSF Aβ, p-tau181, and their ratios correlated well across platforms (r 0.84 to 0.94, P < .0001); those of t-tau and t-tau/Aβ42 correlated moderately (r 0.57 to 0.79, P < .0001). The best concordance with amyloid PET (100% sensitivity and 94% specificity) was afforded by cut-points of 0.075 for Lumipulse Aβ42/Aβ40, 0.087 for MSD Aβ42/Aβ40 and 17.3 for Lumipulse Aβ42/p-tau181. DISCUSSION: The Lumipulse platform provides comparable sensitivity and specificity to established CSF immunoassays in identifying pre-symptomatic AD pathology. © 2020 The Authors.
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| 28. |
- Moens, T. G., et al.
(författare)
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Sense and antisense RNA are not toxic in Drosophila models of C9orf72-associated ALS/FTD
- 2018
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 135:3, s. 445-457
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Tidskriftsartikel (refereegranskat)abstract
- A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Neurodegeneration may occur via transcription of the repeats into inherently toxic repetitive sense and antisense RNA species, or via repeat-associated non-ATG initiated translation (RANT) of sense and antisense RNA into toxic dipeptide repeat proteins. We have previously demonstrated that regular interspersion of repeat RNA with stop codons prevents RANT (RNA-only models), allowing us to study the role of repeat RNA in isolation. Here we have created novel RNA-only Drosophila models, including the first models of antisense repeat toxicity, and flies expressing extremely large repeats, within the range observed in patients. We generated flies expressing similar to 100 repeat sense or antisense RNA either as part of a processed polyadenylated transcript or intronic sequence. We additionally created Drosophila expressing >1000 RNA-only repeats in the sense direction. When expressed in adult Drosophila neurons polyadenylated repeat RNA is largely cytoplasmic in localisation, whilst intronic repeat RNA forms intranuclear RNA foci, as does >1000 repeat RNA, thus allowing us to investigate both nuclear and cytoplasmic RNA toxicity. We confirmed that these RNA foci are capable of sequestering endogenous Drosophila RNA-binding proteins, and that the production of dipeptide proteins (poly-glycine-proline, and poly-glycine-arginine) is suppressed in our models. We find that neither cytoplasmic nor nuclear sense or antisense RNA are toxic when expressed in adult Drosophila neurons, suggesting they have a limited role in disease pathogenesis.
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| 29. |
- O'Connor, A., et al.
(författare)
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Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer's disease: a longitudinal cohort study
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26
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Tidskriftsartikel (refereegranskat)abstract
- Blood biomarkers have great potential to advance clinical care and accelerate trials in Alzheimer's disease (AD). Plasma phospho-tau181 (p-tau181) is a promising blood biomarker however, it is unknown if levels increase in presymptomatic AD. Therefore, we investigated the timing of p-tau181 changes using 153 blood samples from 70 individuals in a longitudinal study of familial AD (FAD). Plasma p-tau181 was measured, using an in-house single molecule array assay. We compared p-tau181 between symptomatic carriers, presymptomatic carriers, and non-carriers, adjusting for age and sex. We examined the relationship between p-tau181 and neurofilament light and estimated years to/from symptom onset (EYO), as well as years to/from actual onset in a symptomatic subgroup. In addition, we studied associations between p-tau181 and clinical severity, as well testing for differences between genetic subgroups. Twenty-four were presymptomatic carriers (mean baseline EYO -9.6 years) while 27 were non-carriers. Compared with non-carriers, plasma p-tau181 concentration was higher in both symptomatic (p < 0.001) and presymptomatic mutation carriers (p < 0.001). Plasma p-tau181 showed considerable intra-individual variability but individual values discriminated symptomatic (AUC 0.93 [95% CI 0.85-0.98]) and presymptomatic (EYO >= -7 years) (AUC 0.86 [95% CI 0.72-0.94]) carriers from non-carriers of the same age and sex. From a fitted model there was evidence (p = 0.050) that p-tau181 concentrations were higher in mutation carriers than non-carriers from 16 years prior to estimated symptom onset. Our finding that plasma p-tau181 concentration is increased in symptomatic and presymptomatic FAD suggests potential utility as an easily accessible biomarker of AD pathology.
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| 30. |
- Paterson, R. W., et al.
(författare)
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Do cerebrospinal fluid transfer methods affect measured amyloid β42, total tau, and phosphorylated tau in clinical practice?
- 2015
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Ingår i: Alzheimer's & Dementia. - : Elsevier Inc.. - 1552-5260 .- 1552-5279. ; 1:3, s. 380-384
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Cerebrospinal fluid (CSF) neurodegenerative markers are measured clinically to support a diagnosis of Alzheimer's disease. Several preanalytical factors may alter the CSF concentrations of amyloid β 1-42 (Aβ1-42) in particular with the potential to influence diagnosis. We aimed to determine whether routine handling of samples alters measured biomarker concentration compared with that of prompt delivery to the laboratory. Methods: Forty individuals with suspected neurodegenerative diseases underwent diagnostic lumbar punctures using a standardized technique. A sample of each patient's CSF was sent to the laboratory by four different delivery methods: (1) by courier at room temperature; (2) by courier, on ice; (3) using standard hospital portering; and (4) after quarantining for >24 hours. Aβ1-42, total tau (t-tau), and phosphorylated tau (p-tau) levels measured using standard enzyme-linked immunosorbent assay techniques were compared between transfer methods. Results: There were no significant differences in Aβ1-42, t-tau, or p-tau concentrations measured in samples transported via the different delivery methods despite significant differences in time taken to deliver samples. Discussion: When CSF is collected in appropriate tubes, transferred at room temperature, and processed within 24 hours, neurodegenerative markers can be reliably determined. © 2015 The Authors.
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