| 1. |
- Lukkarinen, Heikki, et al.
(författare)
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Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus.
- 2021
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 80:4, s. 1629-1642
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Tidskriftsartikel (refereegranskat)abstract
- Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant.To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared.L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs.All biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R=0.87, T-tau R=0.83, P-tau R=0.92, NFL R=0.94, NRGN R=0.9; all p< 0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4.Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.
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| 2. |
- Chernyaeva, Larisa, et al.
(författare)
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Reduced binding of apoE4 to complement factor H promotes amyloid-β oligomerization and neuroinflammation
- 2023
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Ingår i: EMBO Reports. - 1469-221X. ; 24:7
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Tidskriftsartikel (refereegranskat)abstract
- The APOE4 variant of apolipoprotein E (apoE) is the most prevalent genetic risk allele associated with late-onset Alzheimer's disease (AD). ApoE interacts with complement regulator factor H (FH), but the role of this interaction in AD pathogenesis is unknown. Here we elucidate the mechanism by which isoform-specific binding of apoE to FH alters Aβ1-42-mediated neurotoxicity and clearance. Flow cytometry and transcriptomic analysis reveal that apoE and FH reduce binding of Aβ1-42 to complement receptor 3 (CR3) and subsequent phagocytosis by microglia which alters expression of genes involved in AD. Moreover, FH forms complement-resistant oligomers with apoE/Aβ1-42 complexes and the formation of these complexes is isoform specific with apoE2 and apoE3 showing higher affinity to FH than apoE4. These FH/apoE complexes reduce Aβ1-42 oligomerization and toxicity, and colocalize with complement activator C1q deposited on Aβ plaques in the brain. These findings provide an important mechanistic insight into AD pathogenesis and explain how the strongest genetic risk factor for AD predisposes for neuroinflammation in the early stages of the disease pathology.
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| 3. |
- Halonen, Jaana, et al.
(författare)
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Psychotropic medication before and after disability retirement by pre-retirement perceived work-related stress
- 2020
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Ingår i: European Journal of Public Health. - : Oxford University Press (OUP). - 1101-1262 .- 1464-360X. ; 30:1, s. 158-163
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Tidskriftsartikel (refereegranskat)abstract
- Background: Retirement has been associated with improved mental health, but it is unclear how much this is due to the removal of work-related stressors. We examined rates of psychotropic medication use before and after the transition to disability retirement due to mental, musculoskeletal and other causes by pre-retirement levels of perceived work stress (effort-reward imbalance, ERI). Methods: Register-based date and diagnosis of disability retirement of 2766 participants of the Finnish Public Sector study cohort were linked to survey data on ERI, socialand health-related covariates, and to national records on prescribed reimbursed psychotropic medication, measured as defined daily doses (DDDs). Follow-up for DDDs was 2–5 years before and after disability retirement. We assessed differences in the levels of DDDs before and after retirement among those with high vs. low level of pre-retirement ERI with repeated measures regression. Results: Those with high (vs. low) levels of ERI used slightly more psychotropic medication before disability retirement due to mental disorders [rate ratio (RR) 1.14, 95% confidence intervals (CI) 0.94–1.37], but after retirement this difference attenuated (RR 0.94, 95% CI 0.80–1.10, P for interaction 0.02). Such a change was not observed for the other causes of disability retirement. Conclusions: The level of psychotropic medication use over the transition to disability retirement due to mental, but not musculoskeletal or other, causes was modified by pre-retirement perceived work-related stress. This suggests that among people retiring due to mental disorders those who had stressful jobs benefit from retirement more than those with low levels of work-related stress.
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| 4. |
- Jansen, Iris E, et al.
(författare)
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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
- 2022
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n=8074; replication n=5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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| 5. |
- Kaipainen, Aku L, et al.
(författare)
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Cerebrospinal fluid dynamics in idiopathic intracranial hypertension : a literature review and validation of contemporary findings
- 2021
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Ingår i: Acta Neurochirurgica. - : Springer. - 0001-6268 .- 0942-0940. ; 163:12, s. 3353-3368
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Tidskriftsartikel (refereegranskat)abstract
- Background: Idiopathic intracranial hypertension (IIH) is a rare disease of unknown aetiology related possibly to disturbed cerebrospinal fluid (CSF) dynamics and characterised by elevated intracranial pressure (ICP) causing optic nerve atrophy if not timely treated. We studied CSF dynamics of the IIH patients based on the available literature and our well-defined cohort.Method: A literature review was performed from PubMed between 1980 and 2020 in compliance with the PRISMA guideline. Our study includes 59 patients with clinical, demographical, neuro-ophthalmological, radiological, outcome data, and lumbar CSF pressure measurements for suspicion of IIH; 39 patients had verified IIH while 20 patients did not according to Friedman’s criteria, hence referred to as symptomatic controls.Results: The literature review yielded 19 suitable studies; 452 IIH patients and 264 controls had undergone intraventricular or lumbar CSF pressure measurements. In our study, the mean CSF pressure, pulse amplitudes, power of respiratory waves (RESP), and the pressure constant (P0) were higher in IIH than symptomatic controls (p < 0.01). The mean CSF pressure was higher in IIH patients with psychiatric comorbidity than without (p < 0.05). In IIH patients without acetazolamide treatment, the RAP index and power of slow waves were also higher (p < 0.05). IIH patients with excess CSF around the optic nerves had lower relative pulse pressure coefficient (RPPC) and RESP than those without (p < 0.05).Conclusions: Our literature review revealed increased CSF pressure, resistance to CSF outflow and sagittal sinus pressure (SSP) as key findings in IIH. Our study confirmed significantly higher lumbar CSF pressure and increased CSF pressure waves and RAP index in IIH when excluding patients with acetazolamide treatment. In overall, the findings reflect decreased craniospinal compliance and potentially depleted cerebral autoregulation resulting from the increased CSF pressure in IIH. The increased slow waves in patients without acetazolamide may indicate issues in autoregulation, while increased P0 could reflect the increased SSP.
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| 6. |
- Leinonen, Ville, et al.
(författare)
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Comparison of particle number size distribution trends in ground measurements and climate models
- 2022
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Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 22:19, s. 12873-12905
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Tidskriftsartikel (refereegranskat)abstract
- Despite a large number of studies, out of all drivers of radiative forcing, the effect of aerosols has the largest uncertainty in global climate model radiative forcing estimates. There have been studies of aerosol optical properties in climate models, but the effects of particle number size distribution need a more thorough inspection. We investigated the trends and seasonality of particle number concentrations in nucleation, Aitken, and accumulation modes at 21 measurement sites in Europe and the Arctic. For 13 of those sites, with longer measurement time series, we compared the field observations with the results from five climate models, namely EC-Earth3, ECHAM-M7, ECHAM-SALSA, NorESM1.2, and UKESM1. This is the first extensive comparison of detailed aerosol size distribution trends between in situ observations from Europe and five earth system models (ESMs). We found that the trends of particle number concentrations were mostly consistent and decreasing in both measurements and models. However, for many sites, climate models showed weaker decreasing trends than the measurements. Seasonal variability in measured number concentrations, quantified by the ratio between maximum and minimum monthly number concentration, was typically stronger at northern measurement sites compared to other locations. Models had large differences in their seasonal representation, and they can be roughly divided into two categories: for EC-Earth and NorESM, the seasonal cycle was relatively similar for all sites, and for other models the pattern of seasonality varied between northern and southern sites. In addition, the variability in concentrations across sites varied between models, some having relatively similar concentrations for all sites, whereas others showed clear differences in concentrations between remote and urban sites. To conclude, although all of the model simulations had identical input data to describe anthropogenic mass emissions, trends in differently sized particles vary among the models due to assumptions in emission sizes and differences in how models treat size-dependent aerosol processes. The inter-model variability was largest in the accumulation mode, i.e. sizes which have implications for aerosol–cloud interactions. Our analysis also indicates that between models there is a large variation in efficiency of long-range transportation of aerosols to remote locations. The differences in model results are most likely due to the more complex effect of different processes instead of one specific feature (e.g. the representation of aerosol or emission size distributions). Hence, a more detailed characterization of microphysical processes and deposition processes affecting the long-range transport is needed to understand the model variability.
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| 7. |
- Lukkarinen, Heikki, et al.
(författare)
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Concordance of Alzheimer's Disease-Related Biomarkers Between Intraventricular and Lumbar Cerebrospinal Fluid in Idiopathic Normal Pressure Hydrocephalus.
- 2023
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 91:1, s. 305-319
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42), total tau (T-tau), and phosphorylated tau 181 (P-tau181) are widely used. However, concentration gradient of these biomarkers between intraventricular (V-CSF) and lumbar CSF (L-CSF) has been demonstrated in idiopathic normal pressure hydrocephalus (iNPH), potentially affecting clinical utility.Here we aim to provide conversion factors for clinical and research use between V-CSF and L-CSF.Altogether 138 iNPH patients participated. L-CSF samples were obtained prior to shunt surgery. Intraoperative V-CSF samples were obtained from 97 patients. Post-operative follow-up L- and V-CSF (shunt reservoir) samples of 41 patients were obtained 1-73 months after surgery and then after 3, 6, and 18 months. CSF concentrations of Aβ42, T-tau, and P-tau181 were analyzed using commercial ELISA assays.Preoperative L-CSF Aβ42, T-tau, and P-tau181 correlated to intraoperative V-CSF (ρ=0.34-0.55, p<0.001). Strong correlations were seen between postoperative L- and V-CSF for all biomarkers in every follow-up sampling point (ρs Aβ 42: 0.77-0.88, T-tau: 0.91-0.94, P-tau181: 0.94-0.96, p<0.0001). Regression equations were determined for intraoperative V- and preoperative L-CSF (Aβ 42: V-CSF=185+0.34*L-CSF, T-tau: Ln(V-CSF)=3.11+0.49*Ln(L-CSF), P-tau181: V-CSF=8.2+0.51*L-CSF), and for postoperative V- and L-CSF (Aβ 42: V-CSF=86.7+0.75*L-CSF, T-tau: V-CSF=86.9+0.62*L-CSF, P-tau181: V-CSF=2.6+0.74*L-CSF).Aβ 42, T-tau, and P-tau181 correlate linearly in-between V- and L-CSF, even stronger after CSF shunt surgery. Equations presented here, provide a novel tool to use V-CSF for diagnostic and prognostic entities relying on the L-CSF concentrations and can be applicable to clinical use when L-CSF samples are not available or less invasively obtained shunt reservoir samples should be interpreted.
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| 8. |
- Tommiska, Pihla, et al.
(författare)
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Finnish study of intraoperative irrigation versus drain alone after evacuation of chronic subdural haematoma (FINISH) : a study protocol for a multicentre randomised controlled trial
- 2020
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 10:6, s. 038275-038275
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Chronic subdural haematomas (CSDHs) are one of the most common neurosurgical conditions. The goal of surgery is to alleviate symptoms and minimise the risk of symptomatic recurrences. In the past, reoperation rates as high as 20%-30% were described for CSDH recurrences. However, following the introduction of subdural drainage, reoperation rates dropped to approximately 10%. The standard surgical technique includes burr-hole craniostomy, followed by intraoperative irrigation and placement of subdural drainage. Yet, the role of intraoperative irrigation has not been established. If there is no difference in recurrence rates between intraoperative irrigation and no irrigation, CSDH surgery could be carried out faster and more safely by omitting the step of irrigation. The aim of this multicentre randomised controlled trial is to study whether no intraoperative irrigation and subdural drainage results in non-inferior outcome compared with intraoperative irrigation and subdural drainage following burr-hole craniostomy of CSDH. METHODS AND ANALYSIS: This is a prospective, randomised, controlled, parallel group, non-inferiority multicentre trial comparing single burr-hole evacuation of CSDH with intraoperative irrigation and evacuation of CSDH without irrigation. In both groups, a passive subdural drain is used for 48 hours as a standard of treatment. The primary outcome is symptomatic CSDH recurrence requiring reoperation within 6 months. The predefined non-inferiority margin for the primary outcome is 7.5%. To achieve a 2.5% level of significance and 80% power, we will randomise 270 patients per group. Secondary outcomes include modified Rankin Scale, rate of mortality, duration of operation, length of hospital stay, adverse events and change in volume of CSDH. ETHICS AND DISSEMINATION: The study was approved by the institutional review board of the Helsinki and Uusimaa Hospital District (HUS/3035/2019 §238) and duly registered at ClinicalTrials.gov. We will disseminate the findings of this study through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT04203550.
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| 9. |
- Vogelezang, Suzanne, et al.
(författare)
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Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.
- 2020
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 16:10
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Tidskriftsartikel (refereegranskat)abstract
- The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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