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1.
Psychoneuroendocrinology ; 109: 104415, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31472432

RESUMO

Growth factors, such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), and neurotrophic factors, including brain-derived neurotophic factor (BDNF), have attracted attention in studies of the biological effects of long-term stress exposure due to their neuroprotective roles. This study investigated whether circulating levels of EGF, VEGF and BDNF were altered in individuals with stress-related exhaustion disorder. Forty patients diagnosed with exhaustion disorder and 40 healthy subjects (50% women) provided fasting blood samples for analysis of EGF, VEGF, and BDNF in plasma. We found significantly lower levels of EGF, VEGF, and BDNF in patients with ED compared to healthy controls. This pattern was seen in both male and female patients. Given the important roles of BDNF and VEGF for brain plasticity and neurogenesis, decreased levels after long-term stress exposure could indicate increased risk of neuronal damage and cognitive impairments in this patient group.

2.
Infect Dis (Lond) ; : 1-9, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31556765

RESUMO

Background: Despite suppressive antiretroviral therapy (ART), many HIV-infected individuals have low-level persistent immune activation in the central nervous system (CNS). There have been concerns regarding the CNS efficacy of tenofovir alafenamide fumarate (TAF) because of its low cerebrospinal fluid (CSF) concentrations and because it is a substrate of the active efflux transporter P-glycoprotein. Our aim was to investigate whether switching from emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) or abacavir (ABC)/lamivudine (3TC) to FTC/TAF would lead to changes in residual intrathecal immune activation, viral load, or neurocognitive function. Methods: Twenty HIV-1-infected neuro-asymptomatic adults (11 on ABC/3TC and 9 on FTC/TDF) were included in this prospective study. At baseline, all participants changed their nucleoside analogues to FTC/TAF without any other changes in their ART regimen. We performed lumbar punctures, venipunctures, and neurocognitive testing at baseline and after three and 12 months. Results: During follow-up, there were no significant changes in CSF or plasma HIV RNA, CSF neopterin, CSF ß2-microglobulin, IgG index, albumin ratio, CSF NFL, or neurocognitive function in assessed by Cogstate in any of the groups. Conclusion: This small pilot study indicates that switching to FTC/TAF from ABC/3TC or FTC/TDF has neither a positive, nor a negative effect on the HIV infection in the CNS.

3.
Alzheimers Res Ther ; 11(1): 82, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31521194

RESUMO

BACKGROUND: Increasing evidence implicates dysfunctional proteostasis and the involvement of the autophagic and endo-lysosomal system and the ubiquitin-proteasome system in neurodegenerative diseases. In Alzheimer's disease (AD), there is an accumulation of autophagic vacuoles within the neurons. In Parkinson's disease (PD), susceptibility has been linked to genes encoding proteins involved in autophagy and lysosomal function, as well as mutations causing lysosomal disorders. Furthermore, both diseases are characterized by the accumulation of protein aggregates. METHODS: Proteins associated with endocytosis, lysosomal function, and the ubiquitin-proteasome system were identified in the cerebrospinal fluid (CSF) and targeted by combining solid-phase extraction and parallel reaction monitoring mass spectrometry. In total, 50 peptides from 18 proteins were quantified in three cross-sectional cohorts including AD (N = 61), PD (N = 21), prodromal AD (N = 10), stable mild cognitive impairment (N = 15), and controls (N = 68). RESULTS: A pilot study, including subjects selected based on their AD CSF core biomarker concentrations, showed increased concentrations of several targeted proteins in subjects with core biomarker levels indicating AD pathology compared to controls. Next, in a clinically characterized cohort, lower concentrations in CSF of proteins in PD were found compared to subjects with prodromal AD. Further investigation in an additional clinical study again revealed lower concentrations in CSF of proteins in PD compared to controls and AD. CONCLUSION: In summary, significantly different peptide CSF concentrations were identified from proteins AP2B1, C9, CTSB, CTSF, GM2A, LAMP1, LAMP2, TCN2, and ubiquitin. Proteins found to have altered concentrations in more than one study were AP2B1, CTSB, CTSF, GM2A, LAMP2, and ubiquitin. Interestingly, given the genetic implication of lysosomal function in PD, we did identify the CSF concentrations of CTSB, CTSF, GM2A, and LAMP2 to be altered. However, we also found differences in proteins associated with endocytosis (AP2B1) and the ubiquitin-proteasome system (ubiquitin). No difference in any peptide CSF concentration was found in clinically characterized subjects with AD compared to controls. In conclusion, CSF analyses of subjects with PD suggest a general lysosomal dysfunction, which resonates well with recent genetic findings, while such changes are minor or absent in AD.

5.
Epilepsy Behav ; : 106520, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31526644

RESUMO

PURPOSE: The purpose of this study was to assess the incidence of acute symptomatic seizures and poststroke epilepsy (PSE) in a well-characterized cohort of patients treated with mechanical thrombectomy. In addition, we aimed to describe the dynamics of blood markers of brain injury in patients that developed PSE. METHODS: Participants of the prospective AnStroke Trial of anesthesia method during mechanical thrombectomy were included and acute symptomatic seizures and PSE ascertained by medical records review. Blood markers neurofilament light (NFL), tau, glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B), and neuron-specific enolase (NSE) were assessed. RESULTS: A total of 90 patients with acute anterior ischemic stroke were included. Median National Institutes of Health Stroke Scale (NIHSS) at admission to hospital was 18 (IQR 15-22). Recanalization was achieved in 90%. No patients had epilepsy prior to the ischemic stroke. Four patients (4.4%) had acute symptomatic seizures and four patients (4.4%) developed PSE during the follow-up time (to death or last medical records review) of 0-4.5 years (median follow-up 1070 days IQR 777-1306), resulting in a two-year estimated PSE risk of 5.3% (95%CI: 0.2-10.4%). Blood markers of brain injury (NFL, tau, GFAP, S100B, and NSE) were generally above the cohort median in patients that developed PSE. CONCLUSIONS: The incidence of PSE after mechanical thrombectomy was low in our cohort. All blood biomarkers displayed interesting sensitivity and specificity. However, the number of PSE cases was small and more studies are needed on risk factors for PSE after mechanical thrombectomy. The potential of blood markers of brain injury markers to contribute to assessment of PSE risk should be explored further. This article is part of the Special Issue "Seizures & Stroke".

6.
Artigo em Inglês | MEDLINE | ID: mdl-31529404

RESUMO

Imaging mass spectrometry (IMS) is a promising new chemical imaging modality that generates a large body of complex imaging data, which in turn can be approached using multivariate analysis approaches for image analysis and segmentation. Processing IMS raw data is critically important for proper data interpretation and has significant effects on the outcome of data analysis, in particular statistical modeling. Commonly, data processing methods are chosen based on rational motivations rather than comparative metrics, though no quantitative measures to assess and compare processing options have been suggested. We here present a data processing and analysis pipeline for IMS data interrogation, processing and ROI annotation, segmentation, and validation. This workflow includes (1) objective evaluation of processing methods for IMS datasets based on multivariate analysis using PCA. This was then followed by (2) ROI annotation and classification through region-based active contours (AC) segmentation based on the PCA component scores matrix. This provided class information for subsequent (3) OPLS-DA modeling to evaluate IMS data processing based on the quality metrics of their respective multivariate models and for robust quantification of ROI-specific signal localization. This workflow provides an unbiased strategy for sensitive annotation of anatomical regions of interest combined with quantitative comparison of processing procedures for multivariate analysis allowing robust ROI annotation and quantification of the associated molecular histology.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31508810

RESUMO

BACKGROUND: Mortality is high after an acute hip fracture (AHF) surgery. Are cognitive impairment and/or altered levels of Alzheimer's Disease (AD)-biomarkers in cerebrospinal fluid (CSF) predictors of mortality in AHF-patients, as retrospective studies indicate? METHODS: Prospective single-center study including 373 AHF-patients, operated in spinal anesthesia. Cognitive status was evaluated by Clinical Dementia Rating (CDR); CSF was analyzed for AD-biomarker concentrations (total tau (T-tau), phosphorylated tau (P-tau), amyloid beta ratio (Aß42/Aß40). CDR and biomarker levels were related to mortality up to one-year post-surgery, using univariate logistic regression analysis. RESULTS: Survival analyses showed that mortality was associated to the degree of dementia. In the entire patient cohort 30-, 90-, and 365-day mortality rates were 7.2%, 15.5%, and 25.5%, respectively, but only 2.7%, 5.5%, and 12.6%, for cognitively intact vs. 16.3%, 31.7%, and 42.3% for demented patients (OR=2.2-2.8 [CI=1.6-4.9]; p=0.0001). High CSF T-tau (OR=1.19 [CI=1.05-1.33]; p=0.004) and low Aß42/Aß40-ratio (OR=0.85 [CI=0.74-0.97]; p=0.017) were associated with increased 90-day mortality. Analysis of 4 subgroups (Cognitive impairment +/- and Biomarkers +/-) showed significant associations of dementia and CSF biomarker concentrations to mortality after an AHF. Even cognitively intact patients presenting with abnormal AD-biomarkers showed an increased 90-day mortality which, however, was statistically insignificant. CONCLUSIONS: Cognitive impairment and altered CSF biomarker concentrations indicative of AD pathology can predict increased mortality in patients with an AHF, and so probably even before clinical dementia diagnosis by early biomarker analysis; a notion that may have substantial clinical implications by improving perioperative treatment and postoperative rehabilitation.

8.
Alzheimers Dement ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31495601

RESUMO

INTRODUCTION: Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins. METHODS: 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid. RESULTS: A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization. DISCUSSION: The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.

9.
Brain ; 142(9): 2581-2589, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31497858

RESUMO

Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.

10.
Mult Scler Relat Disord ; 35: 228-232, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31404762

RESUMO

BACKGROUND: The prediction of disease activity in patients with a first demyelinating event suggestive of multiple sclerosis (MS) is of high clinical relevance. Cerebrospinal fluid (CSF) neurofilament light chain (NfL) has shown to have prognostic value in MS patients. In this work, we measured CSF NfL in patients at the first demyelinating event in order to find a cut-off value able to discriminate patients who will have disease activity from those who will remain stable during the follow-up. METHODS: We included CSF samples collected within 30 days after the onset of the first demyelinating event from 32 patients followed-up for 3.8 ±â€¯2.5 years. CSF NfL was measured with a newly developed in-house enzyme linked immunosorbent assay (ELISA). RESULTS: At the first demyelinating event, patients with subsequent disease activity had significantly higher baseline CSF NfL values compared to clinically and radiologically stable patients (median 812.5 pg/mL, range 205-2359 pg/mL vs 329.5 pg/mL, range 156-3492 pg/mL, p = 0.002). A CSF NfL cut-off value of 500 pg/mL significantly discriminated these two groups of patients with a 90% sensitivity and an 83.3% specificity. CONCLUSION: Our results confirm that CSF NfL is a prognostic marker in the very early phases of MS. The validation of a cut-off value of 500 pg/mL could provide clinicians with a dichotomous variable that can simplify the prognostic assessment of patients at the first demyelinating event.

11.
Sci Transl Med ; 11(505)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413141

RESUMO

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer's Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 × 10-15); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.

12.
BMC Geriatr ; 19(1): 224, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31426756

RESUMO

BACKGROUND: At present, we know relatively little about priorities and problems with topics that older adults experience when completing different examinations in longitudinal population-based studies. To examine these topics, research must be adapted to investigate the meanings, motivations, and interpretations of the individual participants themselves. Therefore, the present study aimed to explore older adults' motives, understandings and experiences regarding participating in the Gothenburg H70 Birth Cohort Studies (the H-70 study). METHODS: Focus group discussions were used. A total of thirty-eight persons, 19 women and 19 men participated in nine focus groups. A strategic sampling technique was used to ensure that the focus group participants represented the larger population. RESULTS: The results supported the overall theme: "It was well worth the effort," which summarized how the participants felt about the population health study. The following specific themes were also identified: an intense event, for the benefit of oneself and others, confidence in health research and the researcher, key decisions about test outcomes and the survey raising questions and providing few answers. CONCLUSIONS: Knowledge of priorities and problems with topics experienced by older adults completing different examinations when participating in longitudinal population-based studies is crucial for research to improve the health and wellbeing of older people. To date, older people's involvement in population-based cohort studies has largely been as research subjects. This study is a first step toward the participants taking a more active part by allowing them to share their experiences which can be used to improve the research procedures. This requires the participation of older adults in collaboration with the researchers, to ensure the quality of longitudinal studies of older adults. Therefore, our intention when it comes to future research will be to involve older adults-the target group-in the research procedure.

13.
J Alzheimers Dis ; 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31424403

RESUMO

BACKGROUND: Aberrant amyloid-ß (Aß) deposition in the brain occurs two decades prior to the manifestation of Alzheimer's disease (AD) clinical symptoms and therefore brain Aß load measured using PET serves as a gold standard biomarker for the early diagnosis of AD. However, the uneconomical nature of PET makes blood markers, that reflect brain Aß deposition, attractive candidates for investigation as surrogate markers. OBJECTIVE: Investigation of plasma Aß as a surrogate marker for brain Aß deposition in cognitively normal elderly individuals. METHODS: Plasma Aß40 and Aß42 concentrations were measured using the ultrasensitive Single Molecule Array (Simoa) assay in 95 cognitively normal elderly individuals, who have all undergone PET to assess brain Aß deposition. Based on the standard uptake value ratios (SUVR) obtained from PET imaging, using the tracer 18F-Florbetaben, plasma Aß was compared between 32 participants assessed to have low brain Aß load (Aß-, SUVR <1.35) and 63 assessed to have high brain Aß load (Aß+, SUVR ≥1.35). RESULTS: Plasma Aß42/Aß40 ratios were lower in the Aß+ group compared to the Aß-group. Plasma Aß40 and Aß42 levels were not significantly different between Aß-and Aß+ groups, although a trend of higher plasma Aß40 was observed in the Aß+ group. Additionally, plasma Aß42/Aß40 ratios along with the known AD risk factors, age and APOEɛ4 status, resulted in Aß+ participants being distinguished from Aß-participants based on an area under the receiver operating characteristic curve shown to be 78%. CONCLUSION: Plasma Aß ratios in this study are a potential biomarker for brain Aß deposition and therefore, for preclinical AD. However, this method to measure plasma Aß needs further development to increase the accuracy of this promising AD blood biomarker.

14.
J Neurol ; 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375988

RESUMO

BACKGROUND AND PURPOSE: Neurofilament light chain (NfL) is a marker of neuroaxonal damage. We aimed to study associations between serum NfL (sNfL) concentrations at different time points after ischemic stroke and outcomes. METHODS: We prospectively included ischemic stroke cases (n = 595, mean age 59 years, 64% males) and assessed outcomes by both the modified Rankin Scale (mRS) and the NIH stroke scale (NIHSS) at 3 months and by mRS at 2 years. In a subsample, long-term (7-year) outcomes were also assessed by both mRS and NIHSS. We used the ultrasensitive single-molecule array assay to measure sNfL in the acute phase (range 1-14, median 4 days), after 3 months and 7 years in cases and once in controls (n = 595). RESULTS: Acute-phase sNfL increased by the time to blood-draw and highest concentrations were observed at 3 months post-stroke. High sNfL associated to stroke severity and poor outcomes, and both associations were strongest for 3-month sNfL. After adjusting for age, previous stroke, stroke severity, and day of blood draw, 3-month sNfL was significantly associated to both outcomes at all time points (p < 0.01 throughout). For all main etiological subtypes, both acute phase and 3-month sNfL were significantly higher than in controls, but the dynamics of sNfL differed by stroke subtype. CONCLUSIONS: The results from this study inform on sNfL in ischemic stroke and subtypes over time, and show that sNfL predicts short- and long-term neurological and functional outcomes. Our findings suggest a potential utility of sNfL in ischemic stroke outcome prediction.

15.
Transl Psychiatry ; 9(1): 180, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371701

RESUMO

Anorexia nervosa (AN) is a severe psychiatric disorder with high mortality and, to a large extent, unknown pathophysiology. Structural brain differences, such as global or focal reductions in grey or white matter volumes, as well as enlargement of the sulci and the ventricles, have repeatedly been observed in individuals with AN. However, many of the documented aberrances normalize with weight recovery, even though some studies show enduring changes. To further explore whether AN is associated with neuronal damage, we analysed the levels of neurofilament light chain (NfL), a marker reflecting ongoing neuronal injury, in plasma samples from females with AN, females recovered from AN (AN-REC) and normal-weight age-matched female controls (CTRLS). We detected significantly increased plasma levels of NfL in AN vs CTRLS (medianAN = 15.6 pg/ml, IQRAN = 12.1-21.3, medianCTRL = 9.3 pg/ml, IQRCTRL = 6.4-12.9, and p < 0.0001), AN vs AN-REC (medianAN-REC = 11.1 pg/ml, IQRAN-REC = 8.6-15.5, and p < 0.0001), and AN-REC vs CTRLS (p = 0.004). The plasma levels of NfL are negatively associated with BMI overall samples (ß (±se) = -0.62 ± 0.087 and p = 6.9‧10-12). This indicates that AN is associated with neuronal damage that partially normalizes with weight recovery. Further studies are needed to determine which brain areas are affected, and potential long-term sequelae.

16.
J Alzheimers Dis ; 71(1): 281-290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31381510

RESUMO

BACKGROUND: Vascular risk factors promote cerebral small vessel disease and neuropathological changes, particularly in white matter where large-caliber axons are located. How Alzheimer's disease pathology influences the brain's vulnerability in this regard is not well understood. OBJECTIVE: Systemic vascular risk was assessed in relation to cerebrospinal fluid concentrations of neurofilament light, a biomarker of large-caliber axonal injury, evaluating for interactions by clinical and protein markers of Alzheimer's disease. METHODS: Among Alzheimer's Disease Neuroimaging Initiative participants with normal cognition (n = 117), mild cognitive impairment (n = 190), and Alzheimer's disease (n = 95), linear regression related vascular risk (as measured by the modified Framingham Stroke Risk Profile) to neurofilament light, adjusting for age, sex, education, and cognitive diagnosis. Interactions were assessed by cognitive diagnosis, and by cerebrospinal fluid markers of Aß42, hyperphosphorylated tau, and total tau. RESULTS: Vascular risk and neurofilament light were not related in the main effect model (p = 0.08). However, interactions emerged for total tau (p = 0.01) and hyperphosphorylated tau (p = 0.002) reflecting vascular risk becoming more associated with cerebrospinal fluid neurofilament light in the context of greater concentrations of tau biomarkers. An interaction also emerged for the Alzheimer's disease biomarker profiles (p = 0.046) where in comparison to the referent 'normal' biomarker group, individuals with abnormal levels of both Aß42 and total tau showed stronger associations between vascular risk and neurofilament light. CONCLUSION: Older adults may be more vulnerable to axonal injury in response to higher vascular risk burdens in the context of concomitant Alzheimer's disease pathology.

17.
Acta Neuropathol Commun ; 7(1): 120, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31349874

RESUMO

Soluble aggregates of amyloid-ß (Aß) have been associated with neuronal and synaptic loss in Alzheimer's disease (AD). However, despite significant recent progress, the mechanisms by which these aggregated species contribute to disease progression are not fully determined. As the analysis of human cerebrospinal fluid (CSF) provides an accessible window into the molecular changes associated with the disease progression, we characterised soluble aggregates present in CSF samples from individuals with AD, mild cognitive impairment (MCI) and healthy controls using a range of sensitive biophysical methods. We used super-resolution imaging and atomic force microscopy to characterise the size and structure of the aggregates present in CSF and correlate this with their ability to permeabilise lipid membranes and induce an inflammatory response. We found that these aggregates are extremely heterogeneous and exist in a range of sizes, varying both structurally and in their mechanisms of toxicity during the disease progression. A higher proportion of small aggregates of Aß that can cause membrane permeabilization are found in MCI CSF; in established AD, a higher proportion of the aggregates were larger and more prone to elicit a pro-inflammatory response in glial cells, while there was no detectable change in aggregate concentration. These results show that large aggregates, some longer than 100 nm, are present in the CSF of AD patients and suggest that different neurotoxic mechanisms are prevalent at different stages of AD.

18.
Mol Neurobiol ; 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31290061

RESUMO

The ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the main brain ß-secretase responsible for the amyloidogenic processing of the amyloid precursor protein (APP). Previous studies have suggested that cerebrospinal fluid (CSF) ß-secretase activity may be a candidate diagnostic biomarker for Alzheimer's disease (AD), but biochemical characterization of BACE1 protein in CSF is needed. CSF samples from 19 AD patients and 19 age-matched non-AD controls (n = 19) were classified according to their Aß42, total tau, and P-tau CSF biomarker levels. We found that ß-secretase activity was higher in the CSF of AD subjects than in that of the controls. We found that the majority of the ß-secretase activity in the CSF, measured using a peptide substrate homologous to the BACE1 cleavage site, was not inhibited by specific BACE1 inhibitors. We defined enzymatic activity attributable specifically to BACE1 as the activity that was blocked by the specific inhibitors, which is still higher in AD subjects. BACE1 protein levels were characterized by lectin binding, immunoprecipitation, blue native-PAGE, and western blotting using antibodies against specific protein domains. BACE1 was found to be present in human CSF as a mature form of ~ 70 kDa that probably comprised truncated and full-length species, and also as an immature form of ~ 50 kDa that retains the prodomain. CSF-BACE1 was found to assemble into hetero-complexes containing distinct species. Immunoblotting with an antibody against the C-terminus of BACE1 revealed significantly higher levels of the 70-kDa full-length BACE1, while the 50 kDa immature form remained unaltered. When the 70-kDa species was probed with an antibody against the N-terminus of BACE1 (which does not discriminate between truncated and full-length forms), no increase in immunoreactivity was observed, suggesting that truncated forms of BACE1 do not increase in AD. In conclusion, the complexity of BACE1 species in CSF has to be taken into consideration when determining BACE1 activity and protein levels in CSF as biomarkers of AD.

19.
Artigo em Inglês | MEDLINE | ID: mdl-31302732

RESUMO

Preclinical studies indicate a link between the kynurenine pathway and monocyte chemoattractant protein-1 (MCP-1), but there is a lack of clinical studies examining this further. We here perform a secondary analysis of kynurenine metabolites and MCP-1 in cerebrospinal fluid of 23 twins affected from schizophrenia, bipolar disorder or unaffected. We show an association between MCP-1 and kynurenic acid (KYNA), driven by unique environmental influences and a less pronounced association between MCP-1 and tryptophan. No association was detected between MCP-1 and quinolinic acid. Further studies on the mechanism behind the putative relationship between KYNA and MCP-1 are needed.

20.
JAMA Neurol ; 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31206160

RESUMO

Importance: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date. Objectives: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions. Data Sources: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC. Study Selection: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex. Data Extraction and Synthesis: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept. Main Outcome and Measure: The cNfL levels adjusted for age and sex across diagnoses. Results: Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes. Conclusions and Relevance: These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.

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