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| 2. |
- Altmann, Patrick, et al.
(författare)
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Serum neurofilament light chain withstands delayed freezing and repeated thawing.
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Serum neurofilament light chain (sNfL) and its ability to expose axonal damage in neurologic disorders have solicited a considerable amount of attention in blood biomarker research. Hence, with the proliferation of high-throughput assay technology, there is an imminent need to study the pre-analytical stability of this biomarker. We recruited 20 patients with common neurological diagnoses and 10 controls (i.e. patients without structural neurological disease). We investigated whether a variation in pre-analytical variables (delayed freezing up to 24h and repeated thawing/freezing for up to three cycles) affects the measured sNfL concentrations using state of the art Simoa technology. Advanced statistical methods were applied to expose any relevant changes in sNfL concentration due to different storing and processing conditions. We found that sNfL concentrations remained stable when samples were frozen within 24h (mean absolute difference 0.2pg/ml; intraindividual variation below 0.1%). Repeated thawing and re-freezing up to three times did not change measured sNfL concentration significantly, either (mean absolute difference 0.7pg/ml; intraindividual variation below 0.2%). We conclude that the soluble sNfL concentration is unaffected at 4-8°C when samples are frozen within 24h and single aliquots can be used up to three times. These observations should be considered for planning future studies.
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| 3. |
- Altmann, P., et al.
(författare)
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Seven day pre-analytical stability of serum and plasma neurofilament light chain
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Neurofilament light chain (NfL) has emerged as a biomarker of neuroaxonal damage in several neurologic conditions. With increasing availability of fourth-generation immunoassays detecting NfL in blood, aspects of pre-analytical stability of this biomarker remain unanswered. This study investigated NfL concentrations in serum and plasma samples of 32 patients with neurological diagnoses using state of the art Simoa technology. We tested the effect of delayed freezing of up to 7 days and statistically determined stability and validity of measured concentrations. We found concentrations of NfL in serum and plasma to remain stable at room temperature when processing of samples is delayed up to 7 days (serum: mean absolute difference 0.9 pg/mL, intraindividual variation 1.2%; plasma: mean absolute difference 0.5 pg/mL, intraindividual variation 1.3%). Consistency of these results was nearly perfect for serum and excellent for plasma (intraclass correlation coefficients 0.99 and 0.94, respectively). In conclusion, the soluble serum and plasma NfL concentration remains stable when unprocessed blood samples are stored up to 7 days at room temperature. This information is essential for ensuring reliable study protocols, for example, when shipment of fresh samples is needed.
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| 4. |
- Banote, Rakesh Kumar, et al.
(författare)
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Amyloid precursor protein-b facilitates cell adhesion during early development in zebrafish
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the biological function of amyloid beta (A beta) precursor protein (APP) beyond its role in Alzheimer's disease is emerging. Yet, its function during embryonic development is poorly understood. The zebrafish APP orthologue, Appb, is strongly expressed during early development but thus far has only been studied via morpholino-mediated knockdown. Zebrafish enables analysis of cellular processes in an ontogenic context, which is limited in many other vertebrates. We characterized zebrafish carrying a homozygous mutation that introduces a premature stop in exon 2 of the appb gene. We report that appb mutants are significantly smaller until 2 dpf and display perturbed enveloping layer (EVL) integrity and cell protrusions at the blastula stage. Moreover, appb mutants surviving beyond 48 hpf exhibited no behavioral defects at 6 dpf and developed into healthy and fertile adults. The expression of the app family member, appa, was also found to be altered in appb mutants. Taken together, we show that appb is involved in the initial development of zebrafish by supporting the integrity of the EVL, likely by mediating cell adhesion properties. The loss of Appb might then be compensated for by other app family members to maintain normal development.
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| 5. |
- Bark, Lovisa, et al.
(författare)
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Central nervous system biomarkers GFAp and NfL associate with post-acute cognitive impairment and fatigue following critical COVID-19.
- 2023
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Ingår i: Scientific reports. - : Springer Nature. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- A high proportion of patients with coronavirus disease 2019 (COVID-19) experience post-acute COVID-19, including neuropsychiatric symptoms. Objective signs of central nervous system (CNS) damage can be investigated using CNS biomarkers such as glial fibrillary acidic protein (GFAp), neurofilament light chain (NfL) and total tau (t-tau). We have examined whether CNS biomarkers can predict fatigue and cognitive impairment 3-6months after discharge from the intensive care unit (ICU) in critically ill COVID-19 patients. Fifty-seven COVID-19 patients admitted to the ICU were included with analysis of CNS biomarkers in blood at the ICU and at follow up. Cognitive dysfunction and fatigue were assessed with the Montreal Cognitive Assessment (MoCA) and the Multidimensional Fatigue inventory (MFI-20). Elevated GFAp at follow-up 3-6months after ICU discharge was associated to the development of mild cognitive dysfunction (p=0.01), especially in women (p=0.005). Patients who experienced different dimensions of fatigue at follow-up had significantly lower GFAp in both the ICU and at follow-up, specifically in general fatigue (p=0.009), physical fatigue (p=0.004), mental fatigue (p=0.001), and reduced motivation (p=0.001). Women showed a more pronounced decrease in GFAp compared to men, except for in mental fatigue where men showed a more pronounced GFAp decrease compared to women. NfL concentration at follow-up was lower in patients who experienced reduced motivation (p=0.004). Our findings suggest that GFAp and NfL are associated with neuropsychiatric outcome after critical COVID-19.Trial registration The study was registered à priori (clinicaltrials.gov: NCT04316884 registered on 2020-03-13 and NCT04474249 registered on 2020-06-29).
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| 6. |
- Behzadi, Arvin, et al.
(författare)
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Neurofilaments can differentiate ALS subgroups and ALS from common diagnostic mimics.
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Delayed diagnosis and misdiagnosis are frequent in people with amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease (MND). Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) are elevated in ALS patients. We retrospectively quantified cerebrospinal fluid (CSF) NFL, CSF pNFH and plasma NFL in stored samples that were collected at the diagnostic work-up of ALS patients (n=234), ALS mimics (n=44) and controls (n=9). We assessed the diagnostic performance, prognostication value and relationship to the site of onset and genotype. CSF NFL, CSF pNFH and plasma NFL levels were significantly increased in ALS patients compared to patients with neuropathies & myelopathies, patients with myopathies and controls. Furthermore, CSF pNFH and plasma NFL levels were significantly higher in ALS patients than in patients with other MNDs. Bulbar onset ALS patients had significantly higher plasma NFL levels than spinal onset ALS patients. ALS patients with C9orf72HREmutations had significantly higher plasma NFL levels than patients withSOD1mutations. Survival was negatively correlated with all three biomarkers. Receiver operating characteristics showed the highest area under the curve for CSF pNFH for differentiating ALS from ALS mimics and for plasma NFL for estimating ALS short and long survival. Allthree biomarkers have diagnostic value in differentiating ALS from clinically relevant ALS mimics. Plasma NFL levels can be used to differentiate between clinical and genetic ALS subgroups.
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| 7. |
- Bergström, Petra, et al.
(författare)
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Amyloid precursor protein expression and processing are differentially regulated during cortical neuron differentiation
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid precursor protein (APP) and its cleavage product amyloid beta (A beta) have been thoroughly studied in Alzheimer's disease. However, APP also appears to be important for neuronal development. Differentiation of induced pluripotent stem cells (iPSCs) towards cortical neurons enables in vitro mechanistic studies on human neuronal development. Here, we investigated expression and proteolytic processing of APP during differentiation of human iPSCs towards cortical neurons over a 100-day period. APP expression remained stable during neuronal differentiation, whereas APP processing changed. alpha-Cleaved soluble APP (sAPP alpha) was secreted early during differentiation, from neuronal progenitors, while beta-cleaved soluble APP (sAPP beta) was first secreted after deep-layer neurons had formed. Short A beta peptides, including A beta 1-15/16, peaked during the progenitor stage, while processing shifted towards longer peptides, such as A beta 1-40/42, when post-mitotic neurons appeared. This indicates that APP processing is regulated throughout differentiation of cortical neurons and that amyloidogenic APP processing, as reflected by A beta 1-40/42, is associated with mature neuronal phenotypes.
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| 8. |
- Byrne, L. M., et al.
(författare)
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Cerebrospinal fluid neurogranin and TREM2 in Huntington's disease
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Biomarkers of Huntington's disease (HD) in cerebrospinal fluid (CSF) could be of value in elucidating the biology of this genetic neurodegenerative disease, as well as in the development of novel therapeutics. Deranged synaptic and immune function have been reported in HD, and concentrations of the synaptic protein neurogranin and the microglial protein TREM2 are increased in other neurodegenerative diseases. We therefore used ELISAs to quantify neurogranin and TREM2 in CSF samples from HD mutation carriers and controls. CSF neurogranin concentration was not significantly altered in HD compared to controls, nor was it significantly associated with disease burden score, total functional capacity or motor score. An apparent increase in CSF TREM2 in manifest HD was determined to be due to increasing TREM2 with age. After age adjustment, there was no significant alteration of TREM2 in either HD group, nor any association with motor, functional or cognitive score, or brain volume quantified by MRI. Both analyses were well-powered, and sample size calculations indicated that several thousand samples per group would be needed to prove that disease-associated alterations do in fact exist. We conclude that neither neurogranin nor TREM2 is a useful biofluid biomarker for disease processes in Huntington's disease.
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| 9. |
- Chebli, Jasmine, et al.
(författare)
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The localization of amyloid precursor protein to ependymal cilia in vertebrates and its role in ciliogenesis and brain development in zebrafish
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid precursor protein (APP) is expressed in many tissues in human, mice and in zebrafish. In zebrafish, there are two orthologues, Appa and Appb. Interestingly, some cellular processes associated with APP overlap with cilia-mediated functions. Whereas the localization of APP to primary cilia of in vitro-cultured cells has been reported, we addressed the presence of APP in motile and in non-motile sensory cilia and its potential implication for ciliogenesis using zebrafish, mouse, and human samples. We report that Appa and Appb are expressed by ciliated cells and become localized at the membrane of cilia in the olfactory epithelium, otic vesicle and in the brain ventricles of zebrafish embryos. App in ependymal cilia persisted in adult zebrafish and was also detected in mouse and human brain. Finally, we found morphologically abnormal ependymal cilia and smaller brain ventricles in appa(-/-)appb(-/-) mutant zebrafish. Our findings demonstrate an evolutionary conserved localisation of APP to cilia and suggest a role of App in ciliogenesis and cilia-related functions.
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| 10. |
- Eckerström, Marie, 1981, et al.
(författare)
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Cognitive impairment without altered levels of cerebrospinal fluid biomarkers in patients with encephalitis caused by varicella-zoster virus: a pilot study.
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Varicella-zoster virus (VZV) is one of the most common agents causing viral infections of the central nervous system (CNS). VZV encephalitis is associated with severe neurological sequelae, despite antiviral treatment. Cognitive impairment has been reported and VZV has been associated with dementia. Our aim was to investigate the cognitive impairment and cerebrospinal fluid biomarkers in a follow-up study of patients with VZV encephalitis. Thirteen patients with VZV encephalitis, diagnosed by detection of VZV DNA in cerebrospinal fluid (CSF) by PCR and concomitant symptoms of encephalitis, were included. Neuropsychological assessment in parallel with a lumbar puncture to obtain CSF was performed 1.5-7years after acute disease. The CSF biomarkers neurofilament light chain (NFL), S100B, glial fibrillary acidic protein (GFAP), amyloid-β (Aβ) 40 and Aβ42, total tau (t-tau) and phosphorylated tau (p-tau) were analysed and compared to controls (n=24). Cognitive impairment was shown in the domains of executive functions and speed/attention and to a minor degree in the domains of learning/memory and language, indicated by a significantly poorer performance on seven neuropsychological test variables. No convincing evidence of alterations in concentrations of biomarkers in the CSF were shown. Our results indicate that patients with VZV encephalitis suffer from cognitive impairment long time after acute disease. Importantly, these impairments do not seem to be accompanied by biomarker evidence of ongoing neuronal or astrocytic injury/activation or induction of dementia-related brain pathologies by the infection.
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