| 1. |
- Alagaratnam, Jasmini, et al.
(author)
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Correlation between cerebrospinal fluid and plasma neurofilament light protein in treated HIV infection: results from the COBRA study.
- 2022
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In: Journal of neurovirology. - : Springer Science and Business Media LLC. - 1538-2443 .- 1355-0284. ; 28:1, s. 54-63
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Journal article (peer-reviewed)abstract
- Cerebrospinal fluid (CSF) neurofilament light protein (NfL) is a marker of central nervous system neuro-axonal injury. A novel, ultra-sensitive assay can determine plasma NfL. In untreated people-with-HIV (PWH), CSF and plasma NfL are strongly correlated. We aimed to assess this correlation in PWH on suppressive antiretroviral treatment (ART) and lifestyle-similar HIV-negative individuals enrolled into the COmorBidity in Relation to AIDS (COBRA) study. Differences in paired CSF (sandwich ELISA, UmanDiagnostics) and plasma (Simoa digital immunoassay, Quanterix™) NfL between PWH and HIV-negative participants were tested using Wilcoxon's test; associations were assessed using Pearson's correlation. CSF and plasma NfL, standardised to Z-scores, were included as dependent variables in linear regression models to identify factors independently associated with values in PWH and HIV-negative participants. Overall, 132 PWH (all with plasma HIV RNA<50 copies/mL) and 79 HIV-negative participants were included. Neither CSF (median 570 vs 568pg/mL, p=0.37) nor plasma (median 10.7 vs 9.9pg/mL, p=0.15) NfL differed significantly between PWH and HIV-negative participants, respectively. CSF and plasma NfL correlated moderately, with no significant difference by HIV status (PWH: rho=0.52; HIV-negative participants: rho=0.47, p (interaction)=0.63). In multivariable regression analysis, higher CSF NfL Z-score was statistically significantly associated with older age and higher CSF protein, and higher plasma NfL Z-score with older age, higher serum creatinine and lower bodyweight. In conclusion, in PWH on ART, the correlation between CSF and plasma NfL is moderate and similar to that observed in lifestyle-similar HIV-negative individuals. Consideration of renal function and bodyweight may be required when utilising plasma NfL.
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| 2. |
- Alawode, Deborah O T, et al.
(author)
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Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer's disease.
- 2021
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In: Journal of internal medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 290:3, s. 583-601
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Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) is increasingly prevalent worldwide, and disease-modifying treatments may soon be at hand; hence now, more than ever, there is a need to develop techniques that allow earlier and more secure diagnosis. Current biomarker-based guidelines for AD diagnosis, which have replaced the historical symptom-based guidelines, rely heavily on neuroimaging and cerebrospinal fluid (CSF) sampling. Whilst these have greatly improved the diagnostic accuracy of AD pathophysiology, they are less practical for application in primary care, population-based and epidemiological settings, or where resources are limited. In contrast, blood is a more accessible and cost-effective source of biomarkers in AD. In this review paper, using the recently proposed amyloid, tau and neurodegeneration [AT(N)] criteria as a framework towards a biological definition of AD, we discuss recent advances in biofluid-based biomarkers, with a particular emphasis on those with potential to be translated into blood-based biomarkers. We provide an overview of the research conducted both in CSF and in blood to draw conclusions on biomarkers that show promise. Given the evidence collated in this review, plasma neurofilament light chain (N), and phosphorylated tau (p-tau; T) show particular potential for translation into clinical practice. However, p-tau requires more comparisons to be conducted between its various epitopes before conclusions can be made as to which one most robustly differentiates AD from non-AD dementias. Plasma amyloid beta (A) would prove invaluable as an early screening modality, but it requires very precise tests and robust pre-analytical protocols.
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| 3. |
- Ali, Muhammad, et al.
(author)
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Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk.
- 2022
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In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 17:5
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Journal article (peer-reviewed)abstract
- Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g., CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55-0.78], β = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19-0.77], β = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27-0.96], β = -0.68, p = 0.04) in cognitively normal participants, 60-80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE ε4 genotype background may modulate Aβ and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.
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| 4. |
- Alosco, Michael L, et al.
(author)
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Cerebrospinal fluid tau, Aβ, and sTREM2 in Former National Football League Players: Modeling the relationship between repetitive head impacts, microglial activation, and neurodegeneration.
- 2018
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In: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 14:9, s. 1159-1170
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Journal article (peer-reviewed)abstract
- Cerebrospinal fluid (CSF) protein analysis may facilitate detection and elucidate mechanisms of neurological consequences from repetitive head impacts (RHI), such as chronic traumatic encephalopathy. We examined CSF concentrations of total tau (t-tau), phosphorylated tau, and amyloid β1-42 and their association with RHI in former National Football League (NFL) players. The role of microglial activation (using sTREM2) was examined as a pathogenic mechanism of chronic traumatic encephalopathy.Sixty-eight former NFL players and 21 controls underwent lumbar puncture to quantify t-tau, p-tau181, amyloid β1-42, and sTREM2 in the CSF using immunoassays. The cumulative head impact index estimated RHI.No between-group differences for CSF analytes emerged. In the former NFL players, the cumulative head impact index predicted higher t-tau concentrations (P=.041), and higher sTREM2 levels were associated with higher t-tau concentrations (P=.009).In this sample of former NFL players, greater RHI and increased microglial activation were associated with higher CSF t-tau concentrations.
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| 5. |
- Altmann, Patrick, et al.
(author)
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Increased serum neurofilament light chain concentration indicates poor outcome in Guillain-Barré syndrome.
- 2020
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In: Journal of neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 17:1
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Journal article (peer-reviewed)abstract
- Guillain-Barré syndrome (GBS) is an autoimmune disease that results in demyelination and axonal damage. Five percent of patients die and 20% remain significantly disabled on recovery. Recovery is slow in most cases and eventual disability is difficult to predict, especially early in the disease. Blood or cerebrospinal fluid (CSF) biomarkers that could help identify patients at risk of poor outcome are required. We measured serum neurofilament light chain (sNfL) concentrations from blood taken upon admission and investigated a correlation between sNfL and clinical outcome.Baseline sNfL levels in 27 GBS patients were compared with a control group of 22 patients with diagnoses not suggestive of any axonal damage. Clinical outcome parameters for GBS patients included (i) the Hughes Functional Score (HFS) at admission, nadir, and discharge; (ii) the number of days hospitalised; and (iii) whether intensive care was necessary.The median sNfL concentration in our GBS sample on admission was 85.5pg/ml versus 9.1pg/ml in controls. A twofold increase in sNfL concentration at baseline was associated with an HFS increase of 0.6 at nadir and reduced the likelihood of discharge with favourable outcome by a factor of almost three. Higher sNfL levels upon admission correlated well with hospitalisation time (rs=0.69, p<0.0001), during which transfer to intensive care occurred more frequently at an odds ratio of 2.4. Patients with baseline sNfL levels below 85.5pg/ml had a 93% chance of being discharged with an unimpaired walking ability.sNfL levels measured at hospital admission correlated with clinical outcome in GBS patients. These results represent amounts of acute axonal damage and reflect mechanisms resulting in disability in GBS. Thus, sNfL may serve as a convenient blood-borne biomarker to personalise patient care by identifying those at higher risk of poor outcome.
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| 6. |
- Ashton, Nicholas J., et al.
(author)
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Plasma levels of soluble TREM2 and neurofilament light chain in TREM2 rare variant carriers.
- 2019
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In: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11:1
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Journal article (peer-reviewed)abstract
- Results from recent clinical studies suggest that cerebrospinal fluid (CSF) biomarkers that are indicative of Alzheimer's disease (AD) can be replicated in blood, e.g. amyloid-beta peptides (Aβ42 and Aβ40) and neurofilament light chain (NFL). Such data proposes that blood is a rich source of potential biomarkers reflecting central nervous system pathophysiology and should be fully explored for biomarkers that show promise in CSF. Recently, soluble fragments of the triggering receptor expressed on myeloid cells 2 (sTREM2) protein in CSF have been reported to be increased in prodromal AD and also in individuals with TREM2 rare genetic variants that increase the likelihood of developing dementia.In this study, we measured the levels of plasma sTREM2 and plasma NFL using the MesoScale Discovery and single molecule array platforms, respectively, in 48 confirmed TREM2 rare variant carriers and 49 non-carriers.Our results indicate that there are no changes in plasma sTREM2 and NFL concentrations between TREM2 rare variant carriers and non-carriers. Furthermore, plasma sTREM2 is not different between healthy controls, mild cognitive impairment (MCI) or AD.Concentrations of plasma sTREM2 do not mimic the recent changes found in CSF sTREM2.
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| 7. |
- Banerjee, Gargi, et al.
(author)
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Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy.
- 2020
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In: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 74:4, s. 1189-1201
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Journal article (peer-reviewed)abstract
- There is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-β (Aβ) cerebral amyloid angiopathy (CAA).To determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA.We performed a detailed comparison of CSF markers, comparing patients with CAA, Alzheimer's disease (AD), and control (CS) participants, recruited from the Biomarkers and Outcomes in CAA (BOCAA) study, and a Specialist Cognitive Disorders Service.We included 10 CAA, 20 AD, and 10 CS participants (mean age 68.6, 62.5, and 62.2 years, respectively). In unadjusted analyses, CAA patients had a distinctive CSF biomarker profile, with significantly lower (p<0.01) median concentrations of Aβ38, Aβ40, Aβ42, sAβPPα, and sAβPPβ. CAA patients had higher levels of neurofilament light (NFL) than the CS group (p<0.01), but there were no significant differences in CSF total tau, phospho-tau, soluble TREM2 (sTREM2), or neurogranin concentrations. AD patients had higher total tau, phospho-tau and neurogranin than CS and CAA groups. In age-adjusted analyses, differences for the CAA group remained for Aβ38, Aβ40, Aβ42, and sAβPPβ. Comparing CAA patients with amyloid-PET positive (n=5) and negative (n=5) scans, PET positive individuals had lower (p<0.05) concentrations of CSF Aβ42, and higher total tau, phospho-tau, NFL, and neurogranin concentrations, consistent with an "AD-like" profile.CAA has a characteristic biomarker profile, suggestive of a global, rather than selective, accumulation of amyloid species; we also provide evidence of different phenotypes according to amyloid-PET positivity. Further replication and validation of these preliminary findings in larger cohorts is needed.
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| 8. |
- Batzu, Lucia, et al.
(author)
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Plasma p-tau181, neurofilament light chain and association with cognition in Parkinson's disease.
- 2022
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In: NPJ Parkinson's disease. - : Springer Science and Business Media LLC. - 2373-8057. ; 8:1
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Journal article (peer-reviewed)abstract
- Early identification of cognitive impairment in Parkinson's disease (PD) has important clinical and research implications. The aim of our study was to investigate the role of plasma tau phosphorylated at amino acid 181 (p-tau181) and plasma neurofilament light chain (NfL) as biomarkers of cognition in PD. Baseline concentrations of plasma p-tau181 and NfL were measured in a cohort of 136 patients with PD and 63 healthy controls (HC). Forty-seven PD patients were followed up for up to 2 years. Cross-sectional and longitudinal associations between baseline plasma biomarkers and cognitive progression were investigated using linear regression and linear mixed effects models. At baseline, plasma p-tau181 concentration was significantly higher in PD subjects compared with HC (p=0.026). In PD patients, higher plasma NfL was associated with lower MMSE score at baseline, after adjusting for age, sex and education (p=0.027). Baseline plasma NfL also predicted MMSE decline over time in the PD group (p=0.020). No significant association between plasma p-tau181 concentration and baseline or longitudinal cognitive performance was found. While the role of p-tau181 as a diagnostic biomarker for PD and its relationship with cognition need further elucidation, plasma NfL may serve as a feasible, non-invasive biomarker of cognitive progression in PD.
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| 9. |
- Carroll, Antonia S., et al.
(author)
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Serum neurofilament light chain in hereditary transthyretin amyloidosis: validation in real-life practice
- 2024
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In: AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS. - 1350-6129 .- 1744-2818.
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Journal article (peer-reviewed)abstract
- Background: Neurofilament light chain (NfL) has emerged as a sensitive biomarker in hereditary transthyretin amyloid polyneuropathy (ATTRv-PN). We hypothesise that NfL can identify conversion of gene carriers to symptomatic disease, and guide treatment approaches. Methods: Serum NfL concentration was measured longitudinally (2015-2022) in 59 presymptomatic and symptomatic ATTR variant carriers. Correlations between NfL and demographics, biochemistry and staging scores were performed as well as longitudinal changes pre- and post-treatment, and in asymptomatic and symptomatic cohorts. Receiver-operating analyses were performed to determine cut-off values. Results: NfL levels correlated with examination scores (CMTNS, NIS and MRC; all p < .01) and increased with disease severity (PND and FAP; all p < .05). NfL was higher in symptomatic and sensorimotor converters, than asymptomatic or sensory converters irrespective of time (all p < .001). Symptomatic or sensorimotor converters were discriminated from asymptomatic patients by NfL concentrations >64.5 pg/ml (sensitivity= 91.9%, specificity = 88.5%), whereas asymptomatic patients could only be discriminated from sensory or sensorimotor converters or symptomatic individuals by a NfL concentration >88.9 pg/ml (sensitivity = 62.9%, specificity = 96.2%) However, an NfL increment of 17% over 6 months could discriminate asymptomatic from sensory or sensorimotor converters (sensitivity = 88.9%, specificity = 80.0%). NfL reduced with treatment by 36%/year and correlated with TTR suppression (r = 0.64, p = .008). Conclusions: This data validates the use of serum NfL to identify conversion to symptomatic disease in ATTRv-PN. NfL levels can guide assessment of disease progression and response to therapies.
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| 10. |
- Clarke, Mica T M, et al.
(author)
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CSF synaptic protein concentrations are raised in those with atypical Alzheimer's disease but not frontotemporal dementia.
- 2019
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In: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11
-
Journal article (peer-reviewed)abstract
- Increased CSF levels of a number of synaptic markers have been reported in Alzheimer's disease (AD), but little is known about their concentrations in frontotemporal dementia (FTD). We investigated this in three synaptic proteins, neurogranin, SNAP-25, and synaptotagmin-1.CSF samples were analysed from 66 patients with a disorder in the FTD spectrum and 19 healthy controls. Patients were stratified by their tau to Aβ42 ratio: those with a ratio of >1 considered as having likely AD pathology, i.e. an atypical form of AD ('AD biomarker' group [n=18]), and <1 as likely FTD pathology ('FTD biomarker' group [n=48]). A subgroup analysis compared those in the FTD group with likely tau (n=7) and TDP-43 (n=18) pathology. Concentrations of neurogranin were measured using two different ELISAs (Ng22 and Ng36), and concentrations of two SNAP-25 fragments (SNAP-25tot and SNAP-25aa40) and synaptotagmin-1 were measured via mass spectrometry.The AD biomarker group had significantly higher concentrations of all synaptic proteins compared to controls except for synaptotagmin-1 where there was only a trend to increased levels-Ng22, AD mean 232.2 (standard deviation 138.9) pg/ml, controls 137.6 (95.9); Ng36, 225.5 (148.8) pg/ml, 130.0 (80.9); SNAP-25tot, 71.4 (27.9) pM, 53.5 (11.7); SNAP-25aa40, 14.0 (6.3), 7.9 (2.3) pM; and synaptotagmin-1, 287.7 (156.0) pM, 238.3 (71.4). All synaptic measures were significantly higher in the atypical AD group than the FTD biomarker group except for Ng36 where there was only a trend to increased levels-Ng22, 114.0 (117.5); Ng36, 171.1 (75.2); SNAP-25tot, 49.2 (16.7); SNAP-25aa40, 8.2 (3.4); and synaptotagmin-1, 197.1 (78.9). No markers were higher in the FTD biomarker group than controls. No significant differences were seen in the subgroup analysis, but there was a trend to increased levels in those with likely tau pathology.No CSF synaptic proteins have been shown to be abnormal in those with likely FTD pathologically. Higher CSF synaptic protein concentrations of neurogranin, SNAP-25, and synaptotagmin-1 appear to be related to AD pathology.
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| 11. |
- Foiani, Martha S, et al.
(author)
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Plasma tau is increased in frontotemporal dementia.
- 2018
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In: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 89:8, s. 804-807
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Journal article (peer-reviewed)abstract
- Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder presenting clinically with personality change (behavioural variant FTD (bvFTD)) or language deficits (primary progressive aphasia (PPA)). About a third of FTD is familial with mutations inGRN,MAPTandC9orf72being the major genetic causes. Robust biomarkers of the underlying pathology are still lacking in FTD with no markers currently being able to distinguish those with tau and TDP-43 inclusions during life.This study used an ultrasensitive single molecule methodology to measure plasma tau concentrations in 176 participants: 71 with bvFTD, 83 with PPA and 22 healthy controls. The patient group included 36 with pathogenic mutations in eitherMAPT(n=12),GRN(n=9) orC9orf72(n=15). Group comparisons were performed between clinical and genetic groups and controls using a linear regression model with bias-corrected bootstrap CIs. Correlative analyses were performed to investigate associations with measures of disease severity and progression.Higher plasma tau concentrations were seen in bvFTD (mean 1.96 (SD 1.07) pg/mL) and PPA (2.65 (2.15) pg/mL) compared with controls (1.67 (0.50) pg/mL). Investigating the PPA group further showed significantly higher levels compared with controls in each of the PPA subtypes (non-fluent, semantic and logopenic variants, as well as a fourth group not meeting criteria for one of the three main variants). In the genetic groups, only theMAPTgroup had significantly increased concentrations (2.62 (1.39) pg/mL) compared with controls. No significant correlations were seen with cross-sectional or longitudinal brain volumes, serum neurofilament light chain concentrations or disease duration.Plasma tau levels are increased in FTD in all clinical groups, but in the genetic subtypes only inMAPTmutations, the group of patients who definitively have tau pathology at postmortem. Future studies will be required in pathologically confirmed cohorts to investigate this association further, and whether plasma tau will be helpful in differentiating patients with FTD with tau from those with other pathologies.
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| 12. |
- Gafson, Arie R, et al.
(author)
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Breaking the cycle: Reversal of flux in the tricarboxylic acid cycle by dimethyl fumarate.
- 2019
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In: Neurology(R) neuroimmunology & neuroinflammation. - 2332-7812. ; 6:3
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Journal article (peer-reviewed)abstract
- To infer molecular effectors of therapeutic effects and adverse events for dimethyl fumarate (DMF) in patients with relapsing-remitting MS (RRMS) using untargeted plasma metabolomics.Plasma from 27 patients with RRMS was collected at baseline and 6 weeks after initiating DMF. Patients were separated into discovery (n = 15) and validation cohorts (n = 12). Ten healthy controls were also recruited. Metabolomic profiling using ultra-high-performance liquid chromatography mass spectrometry (UPLC-MS) was performed on the discovery cohort and healthy controls at Metabolon Inc (Durham, NC). UPLC-MS was performed on the validation cohort at the National Phenome Centre (London, UK). Plasma neurofilament concentration (pNfL) was assayed using the Simoa platform (Quanterix, Lexington, MA). Time course and cross-sectional analyses were performed to identify pharmacodynamic changes in the metabolome secondary to DMF and relate these to adverse events.In the discovery cohort, tricarboxylic acid (TCA) cycle intermediates fumarate and succinate, and TCA cycle metabolites succinyl-carnitine and methyl succinyl-carnitine increased 6 weeks following treatment (q < 0.05). Methyl succinyl-carnitine increased in the validation cohort (q < 0.05). These changes were not observed in the control population. Increased succinyl-carnitine and methyl succinyl-carnitine were associated with adverse events from DMF (flushing and abdominal symptoms). pNfL concentration was higher in patients with RRMS than in controls and reduced over 15 months of treatment.TCA cycle intermediates and metabolites are increased in patients with RRMS treated with DMF. The results suggest reversal of flux through the succinate dehydrogenase complex. The contribution of succinyl-carnitine ester agonism at hydroxycarboxylic acid receptor 2 to both therapeutic effects and adverse events requires investigation.
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| 13. |
- Garcia-Moreno, Hector, et al.
(author)
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Tau and neurofilament light-chain as fluid biomarkers in spinocerebellar ataxia type 3
- 2022
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In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 29:8, s. 2439-2452
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Journal article (peer-reviewed)abstract
- BACKGROUND AND PURPOSE: Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures.METHODS: To evaluate total tau (t-tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and neurofilament light-chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD-1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t-tau and phosphorylated tau (p-tau181 ). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t-tau levels.RESULTS: Plasma t-tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non-Ataxia Signs was associated with t-tau in ataxic patients (p = 0.004). Pre-ataxic carriers showed higher cerebrospinal fluid t-tau and p-tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t-tau was elevated in MJDTg mice compared to wild-type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001).CONCLUSION: Our results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.
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| 14. |
- Garland, Patrick, et al.
(author)
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Neurofilament light predicts neurological outcome after subarachnoid haemorrhage.
- 2021
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In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 144:3, s. 761-768
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Journal article (peer-reviewed)abstract
- To improve outcome prediction following subarachnoid haemorrhage (SAH), we sought a biomarker integrating early brain injury and multiple secondary pathological processes in a prospective study of 42 non-traumatic SAH patients and 19 control individuals. Neurofilament light (NF-L) was elevated in CSF and serum following SAH. CSF and serum NF-L on Days 1-3 post-SAH strongly predicted modified Rankin score at 6 months, independent of World Federation of Neurosurgical Societies (WFNS) score. NF-L from Day 4 onwards also had a profound impact on outcome. To link NF-L to a SAH-specific pathological process, we investigated NF-L's relationship with extracellular haemoglobin. Most CSF haemoglobin was not complexed with haptoglobin, yet was able to be bound by exogenous haptoglobin i.e. haemoglobin was scavengeable. CSF scavengeable haemoglobin was strongly predictive of subsequent CSF NF-L. Next, we investigated NF-L efflux from the brain after SAH. Serum and CSF NF-L correlated positively. The serum/CSF NF-L ratio was lower in SAH versus control subjects, in keeping with glymphatic efflux dysfunction after SAH. CSF/serum albumin ratio was increased following SAH versus controls. The serum/CSF NF-L ratio correlated negatively with the CSF/serum albumin ratio, indicating that transfer of the two proteins across the blood-brain interface is dissociated. In summary, NF-L is a strong predictive marker for SAH clinical outcome, adding value to the WFNS score, and is a promising surrogate end point in clinical trials.
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| 15. |
- Gibson, Lucy L, et al.
(author)
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NMDA Receptor Antibodies and Neuropsychiatric Symptoms in Parkinson's Disease.
- 2023
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In: The Journal of neuropsychiatry and clinical neurosciences. - : American Psychiatric Association Publishing. - 1545-7222 .- 0895-0172. ; 35:3, s. 236-243
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Journal article (peer-reviewed)abstract
- N-methyl-d-aspartate receptor (NMDAR) encephalitis is an autoantibody-mediated neurological syndrome with prominent cognitive and neuropsychiatric symptoms. The clinical relevance of NMDAR antibodies outside the context of encephalitis was assessed in this study.Plasma from patients with Parkinson's disease (PD) (N=108) and healthy control subjects (N=89) was screened at baseline for immunoglobulin A (IgA), IgM, and IgG NMDAR antibodies, phosphorylated tau 181 (p-tau181), and the neuroaxonal injury marker neurofilament light (NfL). Clinical assessment of the patients included measures of cognition (Mini-Mental State Examination [MMSE]) and neuropsychiatric symptoms (Hospital Anxiety and Depression Scale; Non-Motor Symptoms Scale for Parkinson's Disease). A subgroup of patients (N=61) was followed annually for up to 6 years.Ten (9%) patients with PD tested positive for NMDAR antibodies (IgA, N=5; IgM, N=6; IgG, N=0), and three (3%) healthy control subjects had IgM NMDAR antibodies; IgA NMDAR antibodies were detected significantly more commonly among patients with PD than healthy control subjects (χ2=4.23, df=1, p=0.04). Age, gender, and disease duration were not associated with NMDAR antibody positivity. Longitudinally, antibody-positive patients had significantly greater decline in annual MMSE scores when the analyses were adjusted for education, age, disease duration, p-tau181, NfL, and follow-up duration (adjusted R2=0.26, p=0.01). Neuropsychiatric symptoms were not associated with antibody status, and no associations were seen between NMDAR antibodies and p-tau181 or NfL levels.NMDAR antibodies were associated with greater cognitive impairment over time in patients with PD, independent of other pathological biomarkers, suggesting a potential contribution of these antibodies to cognitive decline in PD.
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| 16. |
- Gisslén, Magnus, 1962, et al.
(author)
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CSF concentrations of soluble TREM2 as a marker of microglial activation in HIV-1 infection
- 2019
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In: Neurology-Neuroimmunology & Neuroinflammation. - : Ovid Technologies (Wolters Kluwer Health). - 2332-7812. ; 6:1
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Journal article (peer-reviewed)abstract
- Objective To explore changes in CSF sTREM2 concentrations in the evolving course of HIV-1 infection. In this retrospective cross-sectional study, we measured concentrations of the macrophage/ microglial activation marker sTREM2 in CSF samples from 121 HIV-1-infected adults and 11 HIV-negative controls and examined their correlations with other CSF and blood biomarkers of infection, inflammation, and neuronal injury. CSF sTREM2 increased with systemic and CNS HIV-1 disease severity, with the highest levels found in patients with HIV-associated dementia (HAD). In untreated HIV-1-infected patients without an HAD diagnosis, levels of CSF sTREM2 increased with decreasing CD4(+) T-cell counts. CSF concentrations of both sTREM2 and the neuronal injury marker neurofilament light protein (NFL) were significantly associated with age. CSF sTREM2 levels were also independently correlated with CSF NFL. Notably, this association was also observed in HIV-negative controls with normal CSF NFL. HIV-infected patients on suppressive antiretroviral treatment had CSF sTREM2 levels comparable to healthy controls. Elevations in CSF sTREM2 levels, an indicator of macrophage/microglial activation, are a common feature of untreated HIV-1 infection that increases with CD4(+) T-cell loss and reaches highest levels in HAD. The strong and independent association between CSF sTREM2 and CSF NFL suggests a linkage between microglial activation and neuronal injury in HIV-1 infection. CSF sTREM2 has the potential of being a useful biomarker of innate CNS immune activation in different stages of untreated and treated HIV-1 infection.
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| 17. |
- Graham, Neil Samuel Nyholm, et al.
(author)
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Multicentre longitudinal study of fluid and neuroimaging BIOmarkers of AXonal injury after traumatic brain injury: the BIO-AX-TBI study protocol.
- 2020
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In: BMJ open. - : BMJ. - 2044-6055. ; 10:11
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Journal article (peer-reviewed)abstract
- Traumatic brain injury (TBI) often results in persistent disability, due particularly to cognitive impairments. Outcomes remain difficult to predict but appear to relate to axonal injury. Several new approaches involving fluid and neuroimaging biomarkers show promise to sensitively quantify axonal injury. By assessing these longitudinally in a large cohort, we aim both to improve our understanding of the pathophysiology of TBI, and provide better tools to predict clinical outcome.BIOmarkers of AXonal injury after TBI is a prospective longitudinal study of fluid and neuroimaging biomarkers of axonal injury after moderate-to-severe TBI, currently being conducted across multiple European centres. We will provide a detailed characterisation of axonal injury after TBI, using fluid (such as plasma/microdialysate neurofilament light) and neuroimaging biomarkers (including diffusion tensor MRI), which will then be related to detailed clinical, cognitive and functional outcome measures. We aim to recruit at least 250 patients, including 40 with cerebral microdialysis performed, with serial assessments performed twice in the first 10 days after injury, subacutely at 10 days to 6weeks, at 6 and 12 months after injury.The relevant ethical approvals have been granted by the following ethics committees: in London, by the Camberwell St Giles Research Ethics Committee; in Policlinico (Milan), by the Comitato Etico Milano Area 2; in Niguarda (Milan), by the Comitato Etico Milano Area 3; in Careggi (Florence), by the Comitato Etico Regionale per la Sperimentazione Clinica della Regione Toscana, Sezione area vasta centro; in Trento, by the Trento Comitato Etico per le Sperimentazioni Cliniche, Azienda Provinciale per i Servizi Sanitari della Provincia autonoma di Trento; in Lausanne, by the Commission cantonale d'éthique de la recherche sur l'être humain; in Ljubljana, by the National Medical Ethics Committee at the Ministry of Health of the Republic of Slovenia. The study findings will be disseminated to patients, healthcare professionals, academics and policy-makers including through presentation at conferences and peer-reviewed publications. Data will be shared with approved researchers to provide further insights for patient benefit.NCT03534154.
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| 18. |
- Guerreiro, Rita, et al.
(author)
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Genetic Variants and Related Biomarkers in Sporadic Alzheimer's Disease.
- 2015
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In: Current genetic medicine reports. - : Springer Science and Business Media LLC. - 2167-4876. ; 3, s. 19-25
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Journal article (peer-reviewed)abstract
- From a neuropathological perspective, elderly patients who die with a clinical diagnosis of sporadic Alzheimer's disease (AD) are a heterogeneous group with several different pathologies contributing to the AD phenotype. This poses a challenge when searching for low effect size susceptibility genes for AD. Further, control groups may be contaminated by significant numbers of preclinical AD patients, which also reduces the power of genetic association studies. Here, we discuss how cerebrospinal fluid and imaging biomarkers can be used to increase the chance of finding novel susceptibility genes and as a means to study the functional consequences of risk alleles.
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| 19. |
- Hamilton, Calum Alexander, et al.
(author)
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Plasma biomarkers of neurodegeneration in mild cognitive impairment with Lewy bodies
- 2023
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In: PSYCHOLOGICAL MEDICINE. - 0033-2917 .- 1469-8978. ; 53:16, s. 7865-7873
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Journal article (peer-reviewed)abstract
- Background. Blood biomarkers of Alzheimer's disease (AD) may allow for the early detection of AD pathology in mild cognitive impairment (MCI) due to AD (MCI-AD) and as a co-pathology in MCI with Lewy bodies (MCI-LB). However not all cases of MCI-LB will feature AD pathology. Disease-general biomarkers of neurodegeneration, such as glial fibrillary acidic protein (GFAP) or neurofilament light (NfL), may therefore provide a useful supplement to AD biomarkers. We aimed to compare the relative utility of plasma A beta 42/40, p-tau181, GFAP and NfL in differentiating MCI-AD and MCI-LB from cognitively healthy older adults, and from one another.Methods. Plasma samples were analysed for 172 participants (31 healthy controls, 48 MCI-AD, 28 possible MCI-LB and 65 probable MCI-LB) at baseline, and a subset (n = 55) who provided repeated samples after >= 1 year. Samples were analysed with a Simoa 4-plex assay for A beta 42, A beta 40, GFAP and NfL, and incorporated previously-collected p-tau181 from this same cohort.Results. Probable MCI-LB had elevated GFAP (p < 0.001) and NfL (p = 0.012) relative to controls, but not significantly lower A beta 42/40 (p = 0.06). GFAP and p-tau181 were higher in MCI-AD than MCI-LB. GFAP discriminated all MCI subgroups, from controls (AUC of 0.75), but no plasma-based marker effectively differentiated MCI-AD from MCI-LB. NfL correlated with disease severity and increased with MCI progression over time (p = 0.011).Conclusion. Markers of AD and astrocytosis/neurodegeneration are elevated in MCI-LB. GFAP offered similar utility to p-tau181 in distinguishing MCI overall, and its subgroups, from healthy controls.
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| 20. |
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| 21. |
- Heslegrave, Amanda, et al.
(author)
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Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer's disease.
- 2016
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In: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 11
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Journal article (peer-reviewed)abstract
- The discovery that heterozygous missense mutations in the gene encoding triggering receptor expressed on myeloid cells 2 (TREM2) are risk factors for Alzheimer's disease (AD), with only the apolipoprotein E (APOE) ε4 gene allele conferring a higher risk, has led to increased interest in immune biology in the brain. TREM2 is expressed on microglia, the resident immune cells of the brain and has been linked to phagocytotic clearance of amyloid β (Aβ) plaques. Soluble TREM2 (sTREM2) has previously been measured in cerebrospinal fluid (CSF) by ELISA but in our hands commercial kits have proved unreliable, suggesting that other methods may be required. We developed a mass spectrometry method using selected reaction monitoring for the presence of a TREM2 peptide, which can be used to quantify levels of sTREM2 in CSF.
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| 22. |
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| 23. |
- James, Sarah-Naomi, et al.
(author)
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A population-based study of head injury, cognitive function and pathological markers.
- 2021
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In: Annals of clinical and translational neurology. - : Wiley. - 2328-9503. ; 8:4, s. 842-856
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Journal article (peer-reviewed)abstract
- To assess associations between head injury (HI) with loss of consciousness (LOC), ageing and markers of later-life cerebral pathology; and to explore whether those effects may help explain subtle cognitive deficits in dementia-free individuals.Participants (n=502, age=69-71) from the 1946 British Birth Cohort underwent cognitive testing (subtests of Preclinical Alzheimer Cognitive Composite), 18 F-florbetapir Aβ-PET and MR imaging. Measures include Aβ-PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) microstructure, Alzheimer's disease (AD)-related cortical thickness, and serum neurofilament light chain (NFL). LOC HI metrics include HI occurring: (i) >15years prior to the scan (ii) anytime up to age 71.Compared to those with no evidence of an LOC HI, only those reporting an LOC HI>15years prior (16%, n=80) performed worse on cognitive tests at age 69-71, taking into account premorbid cognition, particularly on the digit-symbol substitution test (DSST). Smaller brain volume (BV) and adverse NAWM microstructural integrity explained 30% and 16% of the relationship between HI and DSST, respectively. We found no evidence that LOC HI was associated with Aβ load, hippocampal volume, WMH volume, AD-related cortical thickness or NFL (all p>0.01).Having a LOC HI aged 50's and younger was linked with lower later-life cognitive function at age ~70 than expected. This may reflect a damaging but small impact of HI; explained in part by smaller BV and different microstructure pathways but not via pathology related to AD (amyloid, hippocampal volume, AD cortical thickness) or ongoing neurodegeneration (serum NFL).
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| 24. |
- Kagiava, Alexia, et al.
(author)
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AAV9-mediated Schwann cell-targeted gene therapy rescues a model of demyelinating neuropathy.
- 2021
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In: Gene therapy. - : Springer Science and Business Media LLC. - 1476-5462 .- 0969-7128. ; 28:10-11, s. 659-675
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Journal article (peer-reviewed)abstract
- Mutations in the GJB1 gene, encoding the gap junction (GJ) protein connexin32 (Cx32), cause X-linked Charcot-Marie-Tooth disease (CMT1X), an inherited demyelinating neuropathy. We developed a gene therapy approach for CMT1X using an AAV9 vector to deliver the GJB1/Cx32 gene under the myelin protein zero (Mpz) promoter for targeted expression in Schwann cells. Lumbar intrathecal injection of the AAV9-Mpz.GJB1 resulted in widespread biodistribution in the peripheral nervous system including lumbar roots, sciatic and femoral nerves, as well as in Cx32 expression in the paranodal non-compact myelin areas of myelinated fibers. A pre-, as well as post-onset treatment trial in Gjb1-null mice, demonstrated improved motor performance and sciatic nerve conduction velocities along with improved myelination and reduced inflammation in peripheral nerve tissues. Blood biomarker levels were also significantly ameliorated in treated mice. This study provides evidence that a clinically translatable AAV9-mediated gene therapy approach targeting Schwann cells could potentially treat CMT1X.
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| 25. |
- Kagiava, Alexia, et al.
(author)
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Gene replacement therapy in two Golgi-retained CMT1X mutants before and after the onset of demyelinating neuropathy
- 2023
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In: MOLECULAR THERAPY METHODS & CLINICAL DEVELOPMENT. - 2329-0501. ; 30, s. 377-393
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Journal article (peer-reviewed)abstract
- X-linked Charcot-Marie-Tooth disease type 1 (CMT1X) is a demyelinating neuropathy resulting from loss-of-function mu-tations affecting the GJB1/connexin 32 (Cx32) gene. We previ-ously showed functional and morphological improvement in Gjb1-null mice following AAV9-mediated delivery of human Cx32 driven by the myelin protein zero (Mpz) promoter in Schwann cells. However, CMT1X mutants may interfere with virally delivered wild-type (WT) Cx32. To confirm the efficacy of this vector also in the presence of CMT1X mutants, we deliv-ered AAV9-Mpz-GJB1 by lumbar intrathecal injection in R75W/Gjb1-null and N175D/Gjb1-null transgenic lines ex-pressing Golgi-retained mutations, before and after the onset of the neuropathy. Widespread expression of virally delivered Cx32 was demonstrated in both genotypes. Re-establishment of WT Cx32 function resulted in improved muscle strength and increased sciatic nerve motor conduction velocities in all treated groups from both mutant lines when treated before as well as after the onset of the neuropathy. Furthermore, morphological analysis showed improvement of myelination and reduction of inflammation in lumbar motor roots and pe-ripheral nerves. In conclusion, this study provides proof of principle for a clinically translatable gene therapy approach to treat CMT1X before and after the onset of the neuropathy, even in the presence of endogenously expressed Golgi-retained Cx32 mutants.
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