Publications by authors named "Birgitte Andersen"

123 Publications

Immediate post-procedural functional assessment of percutaneous coronary intervention: current evidence and future directions.

Eur Heart J 2021 Apr 5. Epub 2021 Apr 5.

The Lambe Institute for Translational Medicine and Curam, National University of Ireland, University Road, Galway H91 TK3, Ireland.

Percutaneous coronary intervention (PCI) guided by coronary physiology provides symptomatic benefit and improves patient outcomes. Nevertheless, over one-fourth of patients still experience recurrent angina or major adverse cardiac events following the index procedure. Coronary angiography, the current workhorse for evaluating PCI efficacy, has limited ability to identify suboptimal PCI results. Accumulating evidence supports the usefulness of immediate post-procedural functional assessment. This review discusses the incidence and possible mechanisms behind a suboptimal physiology immediately after PCI. Furthermore, we summarize the current evidence base supporting the usefulness of immediate post-PCI functional assessment for evaluating PCI effectiveness, guiding PCI optimization, and predicting clinical outcomes. Multiple observational studies and post hoc analyses of datasets from randomized trials demonstrated that higher post-PCI functional results are associated with better clinical outcomes as well as a reduced rate of residual angina and repeat revascularization. As such, post-PCI functional assessment is anticipated to impact patient management, secondary prevention, and resource utilization. Pre-PCI physiological guidance has been shown to improve clinical outcomes and reduce health care costs. Whether similar benefits can be achieved using post-PCI physiological assessment requires evaluation in randomized clinical outcome trials.
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http://dx.doi.org/10.1093/eurheartj/ehab186DOI Listing
April 2021

Comparison of the clinical impact of 2-[18F]FDG-PET and cerebrospinal fluid biomarkers in patients suspected of Alzheimer's disease.

PLoS One 2021 12;16(3):e0248413. Epub 2021 Mar 12.

Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: The two biomarkers 2-[18F]FDG-PET and cerebrospinal fluid biomarkers are both recommended to support the diagnosis of Alzheimer's disease. However, there is a lack of knowledge for the comparison of the two biomarkers in a routine clinical setting.

Objective: The aim was to compare the clinical impact of 2-[18F]FDG-PET and cerebrospinal fluid biomarkers on diagnosis, prognosis, and patient management in patients suspected of Alzheimer's disease.

Methods: Eighty-one patients clinically suspected of Alzheimer's disease were retrospectively included from the Copenhagen Memory Clinic. As part of the clinical work-up all patients had a standard diagnostic program examination including MRI and ancillary investigations with 2-[18F]FDG-PET and cerebrospinal fluid biomarkers. An incremental study design was used to evaluate the clinical impact of the biomarkers. First, the diagnostic evaluation was based on the standard diagnostic program, then the diagnostic evaluation was revised after addition of either cerebrospinal fluid biomarkers or 2-[18F]FDG-PET. At each diagnostic evaluation, two blinded dementia specialists made a consensus decision on diagnosis, prediction of disease course, and change in patient management. Confidence in the decision was measured on a visual analogue scale (0-100). After 6 months, the diagnostic evaluation was performed with addition of the other biomarker. A clinical follow-up after 12 months was used as reference for diagnosis and disease course.

Results: The two biomarkers had a similar clinical value across all diagnosis when added individually to the standard diagnostic program. However, for the correctly diagnosed patient with Alzheimer's disease cerebrospinal fluid biomarkers had a significantly higher impact on diagnostic confidence (mean scores±SD: 88±11 vs. 82±11, p = 0.046) and a significant reduction in the need for ancillary investigations (23 vs. 18 patients, p = 0.049) compared to 2-[18F]FDG-PET.

Conclusion: The two biomarkers had similar clinical impact on diagnosis, but cerebrospinal fluid biomarkers had a more significant value in corroborating the diagnosis of Alzheimer's disease compared to 2-[18F]FDG-PET.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248413PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954298PMC
March 2021

Laboratory-based investigation of the materials' water activity and pH relative to fungal growth in internally insulated solid masonry walls.

Indoor Air 2021 Jan 28. Epub 2021 Jan 28.

Department of Civil Engineering, Technical University of Denmark, Kongens Lyngby, Denmark.

This project investigated fungal growth conditions in artificially contaminated interfaces between solid masonry and adhesive mortar for internal insulation. The project comprised several laboratory experiments: test of three fungal decontamination methods; investigation of development of fungal growth in solid masonry walls fitted with five internal insulation systems; and investigation of volatile organic compounds (VOC) diffusion through materials and whole insulation systems. One aim was to examine whether the alkaline environment (pH > 9) in the adhesive mortars could prevent fungal growth despite the water activity (a ) in the interface exceeds the level (a  > 0.75) commonly considered critical for fungal growth. The findings indicate that do-it-yourself decontamination solutions were inadequate for removal of fungal growth, while professional solutions were successful. However, the choice of decontamination method was of minor importance in the case of application of internal insulation with high pH adhesive mortar, as the high pH adhesive mortars were found to inactivate existing growth and prevented spore germination during the experimental period. The three tested VOCs were capable of diffusing through most of the examined products and could potentially affect the indoor air quality.
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http://dx.doi.org/10.1111/ina.12796DOI Listing
January 2021

A Pilot Study on Baseline Fungi and Moisture Indicator Fungi in Danish Homes.

J Fungi (Basel) 2021 Jan 20;7(2). Epub 2021 Jan 20.

Wood and Biomaterials, Building and Construction, Danish Technological Institute, Gregersensvej 1, DK-2630 Taastrup, Denmark.

In many complaint cases regarding bad indoor environments, there is no evidence of visible fungal growth. To determine if the problems are fungi-related, dust sampling is the method of choice among building surveyors. However, there is a need to differentiate between species belonging to a normal, dry indoor environment and species belonging to a damp building envelope. The purposes of this pilot study were to examine which fungal species are present in problem-free Danish homes and to evaluate different detection and identification methods. Analyses showed that the fungal diversity outside was different from the diversity inside and that the composition of fungal species growing indoors was different compared to those found as spores, both indoors and outdoors. Common for most homes were , and sect. together with spp., and . . The results show that ITS sequencing of dust samples is adequate if supported by thorough building inspections and that food products play as large a role in the composition of the baseline spora as the outdoor air and surrounding vegetation. This pilot study provides a list of baseline fungal species found in Danish homes with a good indoor environment.
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http://dx.doi.org/10.3390/jof7020071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909426PMC
January 2021

FGF19 and FGF21 for the Treatment of NASH-Two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 From Mice to Human.

Front Endocrinol (Lausanne) 2020 22;11:601349. Epub 2020 Dec 22.

Liver Disease Research, Global Drug Discovery, Novo Nordisk A/S, Maaloev, Denmark.

FGF19 and FGF21 analogues are currently in clinical development for the potential treatment of NASH. In Phase 2 clinical trials analogues of FGF19 and FGF21 decrease hepatic steatosis with up to 70% (MRI-PDFF) after 12 weeks and as early as 12-16 weeks of treatment an improvement in NASH resolution and fibrosis has been observed. Therefore, this class of compounds is currently of great interest in the field of NASH. FGF19 and FGF21 belong to the endocrine FGF19 subfamily and both require the co-receptor beta-klotho for binding and signalling through the FGF receptors. FGF19 is expressed in the ileal enterocytes and is released into the enterohepatic circulation in response to bile acids stimuli and in the liver FGF19 inhibits hepatic bile acids synthesis by transcriptional regulation of Cyp7A1, which is the rate limiting enzyme. FGF21 is, on the other hand, highly expressed in the liver and is released in response to high glucose, high free-fatty acids and low amino-acid supply and regulates energy, glucose and lipid homeostasis by actions in the CNS and in the adipose tissue. FGF19 and FGF21 are differentially expressed, have distinct target tissues and separate physiological functions. It is therefore of peculiar interest to understand why treatment with both FGF19 and FGF21 analogues have strong beneficial effects on NASH parameters in mice and human and whether the mode of action is overlapping This review will highlight the physiological and pharmacological effects of FGF19 and FGF21. The potential mode of action behind the anti-steatotic, anti-inflammatory and anti-fibrotic effects of FGF19 and FGF21 will be discussed. Finally, development of drugs is always a risk benefit analysis and the human relevance of adverse effects observed in pre-clinical species as well as findings in humans will be discussed. The aim is to provide a comprehensive overview of the current understanding of this drug class for the potential treatment of NASH.
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http://dx.doi.org/10.3389/fendo.2020.601349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783467PMC
December 2020

The role of physical and cognitive function in performance of activities of daily living in patients with mild-to-moderate Alzheimer's disease - a cross-sectional study.

BMC Geriatr 2020 11 27;20(1):513. Epub 2020 Nov 27.

Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9 - section 8025, 2100, Copenhagen, Denmark.

Background: Several factors may play a role in the ability of patients with Alzheimer's disease to perform activities of daily living (ADL). The aim of this study was to examine the impact of different aspects of physical performance and cognitive functions on ADL in patients suffering from mild-to-moderate Alzheimer's disease.

Methods: We conducted secondary analyses on cross-sectional baseline data from the randomized controlled multicentre study "Preserving quality of life, physical health and functional ability in Alzheimer's Disease: The effect of physical exercise" (ADEX). In total, 185 AD patients (76 women and 109 men), with a mean age on 70,4 years, were included. Data from physical performance tests (Astrand cycle test, Timed up & Go (TUG), Sit to Stand test (STS)) and cognitive tests (Mini Mental Status Examination (MMSE), Symbol Digit Modalities Test (SDMT), Stroop Color and Word test (Stroop)) were used. Their associations with ADL, measured on the ADCS-ADL scale was assessed in multivariable regression analyses.

Results: SDMT and MMSE had significant, moderate correlations with total ADL (SDMT: r = 0.33, MMSE: r = 0.42) and instrumental ADL (SDMT: r = 0.31, MMSE: r = 0.42), but not with basic ADL. Adjusting for age and sex, the associations between SDMT and MMSE to total ADL and instrumental ADL persisted. No significant associations were found between Astrand, TUG, STS or Stroop and total ADL, basic ADL or instrumental ADL.

Conclusion: Total ADL and instrumental ADL are associated with cognitive functions, including executive function. No significant association between examined physical performance parameters and ADL functions was observed, and consequently does not support an impact of physical function on ADL functions in patients with mild-to-moderate Alzheimer's disease and relatively well-preserved physical function. Strategies aimed to improve cognition may be better suited to improve ADL function in patients with mild-to-moderate Alzheimer's disease.

Trial Registration: NCT01681602 . Registered 10 September 2012, retrospectively registered.
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http://dx.doi.org/10.1186/s12877-020-01926-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693499PMC
November 2020

Biomarker counseling, disclosure of diagnosis and follow-up in patients with mild cognitive impairment: A European Alzheimer's disease consortium survey.

Int J Geriatr Psychiatry 2021 02 16;36(2):324-333. Epub 2020 Sep 16.

Servicio de geriatria, Hospital Universitario Ramon y Cajal, Madrid, Spain.

Objectives: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI.

Methods: An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI.

Results: The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI.

Conclusions: The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning.
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http://dx.doi.org/10.1002/gps.5427DOI Listing
February 2021

Dietary Intervention Accelerates NASH Resolution Depending on Inflammatory Status with Minor Additive Effects on Hepatic Injury by Vitamin E Supplementation.

Antioxidants (Basel) 2020 Sep 1;9(9). Epub 2020 Sep 1.

Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870 Frederiksberg C, Denmark.

Despite the lack of effective pharmacotherapy against nonalcoholic steatohepatitis (NASH) and liver fibrosis, vitamin E (vitE) supplementation and lifestyle modifications are recommended for the management of NASH due to promising clinical results. We recently reported a positive effect of supplementation with 800 IU vitE and atorvastatin on NASH resolution in guinea pigs. In the present study, we investigated the effect of high-dose vitE therapy combined with dietary intervention against progressive NASH and advanced fibrosis in the guinea pig model. Sixty-six guinea pigs received either high-fat (HF) or standard guinea pig chow diet (Control) for 25 weeks. Prior to eight weeks of intervention, HF animals were allocated into groups; dietary intervention (Chow) or dietary intervention with 2000 IU/d vitE supplementation (CvitE). Both Chow and CvitE reduced dyslipidemia, hepatic lipid accumulation and liver weight ( < 0.05), while CvitE further decreased hepatocellular ballooning ( < 0.05). Subanalyses of individual responses within intervention groups showed significant correlation between the hepatic hallmarks of NASH and lipid accumulation vs. inflammatory state ( < 0.05). Collectively, our results indicate that individual differences in sensitivity towards intervention and inflammatory status determine the potential beneficial effect of dietary intervention and high-dose vitE supplementation. Moreover, the study suggests that inflammation is a primary target in NASH treatment.
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http://dx.doi.org/10.3390/antiox9090808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555643PMC
September 2020

FGF21 regulates hepatic metabolic pathways to improve steatosis and inflammation.

Endocr Connect 2020 Aug;9(8):755-768

Global Obesity and Liver Disease Research, Novo Nordisk A/S, Måløv, Denmark.

The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased dramatically worldwide and, subsequently, also the risk of developing non-alcoholic steatohepatitis (NASH), hepatic fibrosis, cirrhosis and cancer. Today, weight loss is the only available treatment, but administration of fibroblast growth factor 21 (FGF21) analogues have, in addition to weight loss, shown improvements on liver metabolic health but the mechanisms behind are not entirely clear. The aim of this study was to investigate the hepatic metabolic profile in response to FGF21 treatment. Diet-induced obese (DIO) mice were treated with s.c. administration of FGF21 or subjected to caloric restriction by switching from high fat diet (HFD) to chow to induce 20% weight loss and changes were compared to vehicle dosed DIO mice. Cumulative caloric intake was reduced by chow, while no differences were observed between FGF21 and vehicle dosed mice. The body weight loss in both treatment groups was associated with reduced body fat mass and hepatic triglycerides (TG), while hepatic cholesterol was slightly decreased by chow. Liver glycogen was decreased by FGF21 and increased by chow. The hepatic gene expression profiles suggest that FGF21 increased uptake of fatty acids and lipoproteins, channeled TGs toward the production of cholesterol and bile acid, reduced lipogenesis and increased hepatic glucose output. Furthermore, FGF21 appeared to reduce inflammation and regulate hepatic leptin receptor-a expression. In conclusion, FGF21 affected several metabolic pathways to reduce hepatic steatosis and improve hepatic health and markedly more genes than diet restriction (61 vs 16 out of 89 investigated genes).
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http://dx.doi.org/10.1530/EC-20-0152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424338PMC
August 2020

The autocrine role of FGF21 in cultured adipocytes.

Biochem J 2020 07;477(13):2477-2487

Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark.

Exposure to cold alters glucose and lipid metabolism of white and brown adipose tissue via activation of β-adrenergic receptor (ADRB). Fibroblast growth factor 21 (FGF21) has been shown to be locally released from adipose tissue upon activation of ADRBs and FGF21 increases glucose uptake in adipocytes. Therefore, FGF21 may play an autocrine role in inducing glucose uptake after β-adrenergic stimulation. To determine the putative autocrine role of FGF21, we stimulated three different types of adipocytes in vitro with Isoprenaline (Iso), an ADRB agonist, in the presence or absence of the FGF receptor (FGFR) inhibitor PD 173074. The three cell lines represent white (3T3-L1), beige (ME3) and brown (WT-1) adipocyte phenotypes, respectively. All three cells systems expressed β-klotho (KLB) and FGFR1 after differentiation and treatment with recombinant FGF21 increased glucose uptake in 3T3-L1 and WT-1 adipocytes, while no significant effect was observed in ME3. Oppositely, all three cell lines responded to Iso treatment and an increase in glucose uptake and lipolysis were observed. Interestingly, in response to the Iso treatment only the WT-1 adipocytes showed an increase in FGF21 in the medium. This was consistent with the observation that PD 173074 decreased Iso-induced glucose uptake in the WT-1 adipocytes. This suggests that FGF21 plays an autocrine role and increases glucose uptake after β-adrenergic stimulation of cultured brown WT-1 adipocytes.
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http://dx.doi.org/10.1042/BCJ20200220DOI Listing
July 2020

Physical Exercise May Increase Plasma Concentration of High-Density Lipoprotein-Cholesterol in Patients With Alzheimer's Disease.

Front Neurosci 2020 27;14:532. Epub 2020 May 27.

Danish Dementia Research Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Lifestyle factors have been shown to increase the risk of developing Alzheimer's disease (AD) later in life. Specifically, an unfavorable cholesterol profile, and insulin resistance are associated with increased risk of developing AD. One way to non-pharmacologically affect the levels of plasma lipids is by exercise, which has been shown to be beneficial in cognitively healthy individuals. In this randomized controlled trial y, we therefore aimed to clarify the effect of physical exercise on the lipid profile, insulin and glucose in patients with AD. In addition, we investigated the effect of apolipoproteinE genotype on total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and triglycerides (TG) in plasma from patients with AD. Plasma samples from 172 patients who underwent 16 weeks of moderate-to-high intensity exercise ( = 90) or treatment as usual ( = 82) were analyzed change from baseline for the levels of total cholesterol, LDL-C, HDL-C, TG, glucose, and insulin. In addition, we analyzed those from the exercise group who adhered to the protocol with an attendance of 2/3 or more of the exercise session and who followed the protocol of an intensity of 70% of the maximum heart rate. We found a significant increase in plasma HDL-C levels between the "high exercise sub-group" compared to control group. After intervention HDL-C was increased by 4.3% in the high-exercise group, and decreased by 0.7% in the control group, after adjustment for statin use. In conclusion, short term physical activity may be beneficial on the cholesterol profile in patients with AD.
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http://dx.doi.org/10.3389/fnins.2020.00532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269030PMC
May 2020

Cholinergic dysfunction, neurodegeneration, and amyloid-beta pathology in neurodegenerative diseases.

Psychiatry Res Neuroimaging 2020 08 17;302:111099. Epub 2020 May 17.

Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Cholinergic dysfunction is central in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). The electroencephalography-based acetylcholine index (EEG-Ach index) has been proposed as a biomarker of cholinergic dysfunction. However, it is unclear how the EEG-Ach index relates to amyloid-beta pathology and neurodegeneration. We investigated the association between the EEG-Ach index and cerebrospinal fluid (CSF) amyloid-beta, CSF total tau, cortical thickness, and hippocampal volume from magnetic resonance imaging (MRI), and cognition. A total of 127 patients with different neurodegenerative diseases were studied. The EEG-Ach index was calculated from quantitative EEG using statistical pattern recognition. The EEG-Ach index was associated with hippocampal volume and cortical thickness in frontal, temporal, and occipital cortices. Cross-sectional sub-analyses based on a small sample suggests that the EEG-Ach index increases the closest to AD dementia, downstream to amyloid-beta pathology, CSF total tau, and hippocampal volume. We conclude that cholinergic dysfunction correlates with atrophy in brain areas important for AD pathogenesis, and this association is more prominent in the dementia stage. These results together with previous studies from this project suggest that the EEG-Ach index may be a useful biomarker for cholinergic dysfunction, with value for differential diagnosis of dementia and monitoring patients at the dementia stage.
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http://dx.doi.org/10.1016/j.pscychresns.2020.111099DOI Listing
August 2020

Resting distal to aortic pressure ratio and fractional flow reserve discordance affects the diagnostic performance of quantitative flow ratio: Results from an individual patient data meta-analysis.

Catheter Cardiovasc Interv 2021 Apr 1;97(5):825-832. Epub 2020 Jun 1.

Department of Cardiology, Aarhus University Hospital, Skejby, Denmark.

Objective: To evaluate the diagnostic performance of quantitative flow ratio (QFR) related to fractional flow reserve (FFR) and resting distal-to-aortic pressure ratio (resting Pd/Pa) concordance.

Background: QFR is a method for computation of FFR based on standard coronary angiography. It is unclear how QFR is performed in patients with discordance between FFR and resting pressure ratios (distal-to-aortic pressure ratio [Pd/Pa]).

Materials And Methods: The main comparison was the diagnostic performance of QFR with FFR as reference stratified by correspondence between FFR and resting Pd/Pa. Secondary outcome measures included distribution of clinical or procedural characteristics stratified by FFR and resting Pd/Pa correspondence.

Results: Four prospective studies matched the inclusion criteria. Analysis was performed on patient level data reaching a total of 759 patients and 887 vessels with paired FFR, QFR, and resting Pd/Pa. Median FFR was 0.85 (IQR: 0.77-0.90). Diagnostic accuracy of QFR with FFR as reference was higher if FFR corresponded to resting Pd/Pa: accuracy 90% (95% CI: 88-92) versus 72% (95% CI: 64-80), p < .001, and sAUC 0.95 (95% CI: 0.92-0.96) versus 0.73 (95% CI: 0.69-0.77), p < .001. Resting Pd/Pa and FFR discordance were related to age, sex, hypertension, and lesion severity.

Conclusion: Diagnostic performance of QFR with FFR as reference is reduced for lesions with discordant FFR (≤0.80) and resting Pd/Pa (≤0.92) measurements.
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http://dx.doi.org/10.1002/ccd.28976DOI Listing
April 2021

Whole transcriptome analysis and validation of metabolic pathways in subcutaneous adipose tissues during FGF21-induced weight loss in non-human primates.

Sci Rep 2020 04 29;10(1):7287. Epub 2020 Apr 29.

Novo Nordisk Research Center Seattle, Inc, Seattle, WA, USA.

Fibroblast growth factor 21 (FGF21) induces weight loss in mouse, monkey, and human studies. In mice, FGF21 is thought to cause weight loss by stimulating thermogenesis, but whether FGF21 increases energy expenditure (EE) in primates is unclear. Here, we explore the transcriptional response and gene networks active in adipose tissue of rhesus macaques following FGF21-induced weight loss. Genes related to thermogenesis responded inconsistently to FGF21 treatment and weight loss. However, expression of gene modules involved in triglyceride (TG) synthesis and adipogenesis decreased, and this was associated with greater weight loss. Conversely, expression of innate immune cell markers was increased post-treatment and was associated with greater weight loss. A lipogenesis gene module associated with weight loss was evaluated by testing the function of member genes in mice. Overexpression of NRG4 reduced weight gain in diet-induced obese mice, while overexpression of ANGPTL8 resulted in elevated TG levels in lean mice. These observations provide evidence for a shifting balance of lipid storage and metabolism due to FGF21-induced weight loss in the non-human primate model, and do not fully recapitulate increased EE seen in rodent and in vitro studies. These discrepancies may reflect inter-species differences or complex interplay of FGF21 activity and counter-regulatory mechanisms.
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http://dx.doi.org/10.1038/s41598-020-64170-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190698PMC
April 2020

Changes in the left temporal microstate are a sign of cognitive decline in patients with Alzheimer's disease.

Brain Behav 2020 06 27;10(6):e01630. Epub 2020 Apr 27.

Department of Neurology, Danish Dementia Research Centre (DDRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Introduction: Large-scale brain networks are disrupted in the early stages of Alzheimer's disease (AD). Electroencephalography microstate analysis, a promising method for studying brain networks, parses EEG signals into topographies representing discrete, sequential network activations. Prior studies indicate that patients with AD show a pattern of global microstate disorganization. We investigated whether any specific microstate changes could be found in patients with AD and mild cognitive impairment (MCI) compared to healthy controls (HC).

Materials And Methods: Standard EEGs were obtained from 135 HC, 117 patients with MCI, and 117 patients with AD from six Nordic memory clinics. We parsed the data into four archetypal microstates.

Results: There was significantly increased duration, occurrence, and coverage of microstate A in patients with AD and MCI compared to HC. When looking at microstates in specific frequency bands, we found that microstate A was affected in delta (1-4 Hz), theta (4-8 Hz), and beta (13-30 Hz), while microstate D was affected only in the delta and theta bands. Microstate features were able to separate HC from AD with an accuracy of 69.8% and HC from MCI with an accuracy of 58.7%.

Conclusions: Further studies are needed to evaluate whether microstates represent a valuable disease classifier. Overall, patients with AD and MCI, as compared to HC, show specific microstate alterations, which are limited to specific frequency bands. These alterations suggest disruption of large-scale cortical networks in AD and MCI, which may be limited to specific frequency bands.
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http://dx.doi.org/10.1002/brb3.1630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303403PMC
June 2020

Human β-Defensin 2 Mediated Immune Modulation as Treatment for Experimental Colitis.

Front Immunol 2020 31;11:93. Epub 2020 Jan 31.

Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.

Defensins represents an integral part of the innate immune system serving to ward off potential pathogens and to protect the intestinal barrier from microbial encroachment. In addition to their antimicrobial activities, defensins in general, and human β-defensin 2 (hBD2) in particular, also exhibit immunomodulatory capabilities. In this report, we assessed the therapeutic efficacy of systemically administered recombinant hBD2 to ameliorate intestinal inflammation in three distinct animal models of inflammatory bowel disease; i.e., chemically induced mucosal injury (DSS), loss of mucosal tolerance (TNBS), and T-cell transfer into immunodeficient recipient mice. Treatment efficacy was confirmed in all tested models, where systemically administered hBD2 mitigated inflammation, improved disease activity index, and hindered colitis-induced body weight loss on par with anti-TNF-α and steroids. Treatment of lipopolysaccharide (LPS)-activated human peripheral blood mononuclear cells with rhBD2 confirmed the immunomodulatory capacity in the circulatory compartment. Subsequent analyzes revealed dendritic cells (DCs) as the main target population. Suppression of LPS-induced inflammation was dependent on chemokine receptor 2 (CCR2) expression. Mechanistically, hBD2 engaged with CCR2 on its DC target cell to decrease NF-κB, and increase CREB phosphorylation, hence curbing inflammation. To our knowledge, this is the first study showing efficacy of a systemically administered defensin in experimental disease.
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http://dx.doi.org/10.3389/fimmu.2020.00093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006816PMC
April 2021

A visual rating scale for cingulate island sign on 18F-FDG-PET to differentiate dementia with Lewy bodies and Alzheimer's disease.

J Neurol Sci 2020 Mar 24;410:116645. Epub 2019 Dec 24.

Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address:

Valid diagnosis of dementia with Lewy bodies (DLB) is essential to establish appropriate treatment and care. However, the diagnostic accuracy is complicated by clinical and pathological overlap with Alzheimer's disease (AD). Cingulate island sign (CIS), defined as sparing of posterior cingulate cortex (PCC) relative to precuneus and cuneus on 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET), is included in the revised diagnostic DLB criteria. There are no guidelines for the visual grading of CIS, although visual rating is a fast-applicable method in a clinical setting. The objective was to develop a robust visual CIS scale and evaluate the performance in differentiating DLB with and without amyloid beta pathology (Aβ+/-), and AD. 18F-FDG-PET scans from 35 DLB patients, 36 AD patients, and 23 healthy controls were rated according to a visual CIS scale based on specific reading criteria. The visual CIS scale was validated against a quantitative CIS ratio derived from a region of interest analysis of PCC, precuneus, and cuneus. DLB patients had a significantly higher visual CIS score compared to AD patients, and controls. A cut-off visual CIS score of 4 significantly differentiated DLB Aβ- patients from DLB Aβ+ patients. In conclusion, the visual CIS scale is clinically useful to differentiate DLB from AD. The degree of CIS may be related to Aβ pathology in DLB patients.
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http://dx.doi.org/10.1016/j.jns.2019.116645DOI Listing
March 2020

Fungal and chemical diversity in hay and wrapped haylage for equine feed.

Mycotoxin Res 2020 May 27;36(2):159-172. Epub 2019 Nov 27.

The Laminitis Clinic, Mead House, Dauntsey, Chippenham, Wiltshire, SN15 4JA, UK.

The presence of fungi and mycotoxins in silage (fermented maize) for cattle and other ruminants have been studied extensively compared to wrapped haylage (fermented grass) for horses and other monogastric animals. The purpose of this work was to examine the fungal diversity of wrapped haylage and conventional hay and to analyse the forage sample for fungal metabolites. Faeces samples were also analysed to study the fate of fungi and metabolites. Fungal diversity of the samples was determined by direct plating on DG18, V8 and MEA and chemical analyses were done using LC-MS/MS. The results show that Sordaria fimicola was common in both hay and haylage, while Penicillium spp. was prevalent in haylage and Aspergillus spp. in hay. Communiols were found in all types of samples together with gliocladic acid. Roquefortines and fumigaclavines were found in haylage with no visible fungal growth, but not in hay. In haylage hot spot samples, a series of Penicillium metabolites were detected: Andrastins, fumigaclavines, isofumigaclavines, marcfortines, mycophenolic acid, PR toxins, and roquefortines. Penicillium solitum was found repeatedly in haylage and haylage hot spot samples and viridicatols were detected in a hot spot sample, which has not been reported before. Even haylage with no visible fungal growth contained more metabolites than hay. Individually, the metabolites detected in haylage may, in high doses, be mutagenic, neurotoxic or immunosuppressive; but the synergistic effect of small doses may also have other or greater negative health effects on equines than on ruminants.
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http://dx.doi.org/10.1007/s12550-019-00377-5DOI Listing
May 2020

Microbiological quality of mink feed raw materials and feed production area.

Acta Vet Scand 2019 Nov 21;61(1):56. Epub 2019 Nov 21.

National Veterinary Institute, Technical University of Denmark, Kemitorvet, Building 202, 2800, Kgs. Lyngby, Denmark.

Background: The quality of mink feed and raw ingredients affect health and growth. The objectives of this study were to examine the microbiological quality of ready-to-eat mink feed and its raw ingredients, screen the plant part of the feed for mycotoxins, and determine the hygiene of the production environment in the feed processing facilities. The results of the study are important for identification of critical steps in the feed production and for formulation of recommendations for improvements of production processes to obtain better quality feed. Feed and swab samples were taken at three Danish mink feed producers October 2016 and May 2017, respectively. Viable counts, detection of methicillin-resistant Staphylococcus aureus (MRSA), influenza virus and filamentous fungi were performed together with qualitative chemical analyses for bioactive fungal metabolites and mycotoxins. Swab samples were analyzed for total viable counts.

Results: Viable counts varied between 7.2 × 10 and 9.3 × 10 cfu/g in raw ingredients and between 10 and 10 cfu/cm on different surfaces at the feed production facilities. A pork meat product, pork haemoglobin, pork liver and a poultry mix was found positive for MRSA, while monophasic Salmonella [4,5,12:i:-] was detected in a pork meat product. Neither MRSA nor Salmonella was detected in any ready-to-eat feed. Influenza A virus was not detected in any sample. Filamentous fungi were detected in all analysed samples of ready-to-eat feed while dihydro-demethyl-sterigmatocystin was found in almost 50% of all ready-to-eat feed samples and in 80% of the sugar beet pulp. Fumonisins and other Fusarium toxins were found especially in corn gluten meal and extruded barley and wheat.

Conclusions: Mink feed contained a cocktail of mycotoxins and bacteria, which may not per se cause clinical disease, but may affect organ function and animal performance and well-being.
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http://dx.doi.org/10.1186/s13028-019-0489-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873557PMC
November 2019

UCP1-independent glucose-lowering effect of leptin in type 1 diabetes: only in conditions of hypoleptinemia.

Am J Physiol Endocrinol Metab 2020 01 19;318(1):E72-E86. Epub 2019 Nov 19.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity - and thus also leptin levels - in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.
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http://dx.doi.org/10.1152/ajpendo.00253.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985793PMC
January 2020

[Use of capnography in the emergency department].

Ugeskr Laeger 2019 Sep;181(38)

In Denmark, capnography is routinely used in monitoring patients with artificial airways. Non-invasive capnography is occasionally used by prehospital providers, but not applied inside hospital walls. Multiple studies illustrate benefits from capnography in non-intubated patients. Non-invasive capnography may reveal altered ventilation in conditions such as opioid-induced respiratory depression and acute dyspnoea, during metabolic acidosis and among patients with seizures and cerebral damage. Implementation requires education, guidelines for inhospital use and financial investment.
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September 2019

Novel Inhibitory Function of the Lipase Propeptide and Three-Dimensional Structures of Its Complexes with the Enzyme.

ACS Omega 2019 Jun 7;4(6):9964-9975. Epub 2019 Jun 7.

York Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, U.K.

Many proteins are synthesized as precursors, with propeptides playing a variety of roles such as assisting in folding or preventing them from being active within the cell. While the precise role of the propeptide in fungal lipases is not completely understood, it was previously reported that mutations in the propeptide region of the lipase have an influence on the activity of the mature enzyme, stressing the importance of the amino acid composition of this region. We here report two structures of this enzyme in complex with its propeptide, which suggests that the latter plays a role in the correct maturation of the enzyme. Most importantly, we demonstrate that the propeptide shows inhibition of lipase activity in standard lipase assays and propose that an important role of the propeptide is to ensure that the enzyme is not active during its expression pathway in the original host.
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http://dx.doi.org/10.1021/acsomega.9b00612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648591PMC
June 2019

Oscillatory connectivity as a diagnostic marker of dementia due to Alzheimer's disease.

Clin Neurophysiol 2019 10 29;130(10):1889-1899. Epub 2019 Jul 29.

Department of Neurology, Danish Dementia Research Centre (DDRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Objective: Quantitative EEG power has not been as effective in discriminating between healthy aging and Alzheimer's disease as conventional biomarkers. But EEG coherence has shown promising results in small samples. The overall aim was to evaluate if EEG connectivity markers can discriminate between Alzheimer's disease, mild cognitive impairment, and healthy aging and to explore the early underlying changes in coherence.

Methods: EEGs were included in the analysis from 135 healthy controls, 117 patients with mild cognitive impairment, and 117 patients with Alzheimer's disease from six Nordic memory clinics. Principal component analysis was performed before multinomial regression.

Results: We found classification accuracies of above 95% based on coherence, imaginary part of coherence, and the weighted phase-lag index. The most prominent changes in coherence were decreased alpha coherence in Alzheimer's disease, which was correlated to the scores of the 10-word test in the Consortium to Establish a Registry for Alzheimer's Disease battery.

Conclusions: The diagnostic accuracies for EEG connectivity measures are higher than findings from studies investigating EEG power and conventional Alzheimer's disease biomarkers. Furthermore, decreased alpha coherence is one of the earliest changes in Alzheimer's disease and associated with memory function.

Significance: EEG connectivity measures may be useful supplementary diagnostic classifiers.
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http://dx.doi.org/10.1016/j.clinph.2019.07.016DOI Listing
October 2019

Letter by Westra et al Regarding Article, "Accuracy of Fractional Flow Reserve Derived From Coronary Angiography".

Circulation 2019 07 8;140(2):e94-e95. Epub 2019 Jul 8.

Department of Cardiology, Aarhus University Hospital, Denmark.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.038282DOI Listing
July 2019

Moderate- to high-intensity exercise does not modify cortical β-amyloid in Alzheimer's disease.

Alzheimers Dement (N Y) 2019 7;5:208-215. Epub 2019 Jun 7.

Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Introduction: Animal models of Alzheimer's disease show that exercise may modify β-amyloid (Aβ) deposition. We examined the effect of a 16-week exercise intervention on cortical Aβ in patients with mild-to-moderate Alzheimer's disease.

Methods: Thirty-six patients with Alzheimer's disease were randomized to either one hour of aerobic exercise three times weekly for 16 weeks or usual care. Pre and post intervention, 11Carbon-Pittsburgh compound B positron emission tomography was carried out to assess cortical Aβ, and quantified using standardized uptake value rations (SUVRs).

Results: The intervention showed no effect on follow-up SUVRs in a covariance analysis with group allocation, baseline intervention SUVR, age, sex, and baseline Mini-Mental State Examination as predictors. Change in SUVRs did not correlate with changes in measures of physical or aerobic fitness.

Discussion: The present findings do not support an effect of exercise on Aβ. However, the relatively short intervention period may account for a lack of efficacy. Further studies should test earlier and longer interventions.
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http://dx.doi.org/10.1016/j.trci.2019.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556817PMC
June 2019

Diagnostic performance of quantitative flow ratio in prospectively enrolled patients: An individual patient-data meta-analysis.

Catheter Cardiovasc Interv 2019 Nov 9;94(5):693-701. Epub 2019 Apr 9.

Department of Cardiology, Aarhus University Hospital, Skejby, Denmark.

Objectives: We aimed to provide robust performance estimates for quantitative flow ratio (QFR) in assessment of intermediary coronary lesions.

Background: Angiography-based functional lesion assessment by QFR may appear as a cost saving and safe approach to expand the use of physiology-guided percutaneous coronary interventions. QFR was proven feasible and showed good diagnostic performance in mid-sized off-line and on-line studies with fractional flow reserve (FFR) as reference standard.

Methods: We performed a collaborative individual patient-data meta-analysis of all available prospective studies with paired assessment of QFR and FFR using the CE-marked QFR application. The main outcome was agreement of QFR and FFR using a two-step analysis strategy with a multilevel mixed model accounting for study and center level variation.

Results: Of 16 studies identified, four studies had prospective enrollment and provided patient level data reaching a total of 819 patients and 969 vessels with paired FFR and QFR: FAVOR Pilot (n = 73); WIFI II (n = 170); FAVOR II China (n = 304) and FAVOR II Europe-Japan (n = 272). We found an overall agreement (mean difference 0.009 ± 0.068, I = 39.6) of QFR with FFR. The diagnostic performance was sensitivity 84% (95%CI: 77-90, I = 70.1), specificity 88% (95%CI: 84-91, I = 60.1); positive predictive value 80% (95%CI: 76-85, I = 33.4), and negative predictive value 95% (95%CI: 93-96, I = 75.9).

Conclusions: Diagnostic performance of QFR was good with FFR as reference in this meta-analysis of high quality studies. QFR could provide an easy, safe, and cost-effective solution for functional evaluation of coronary artery stenosis.
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http://dx.doi.org/10.1002/ccd.28283DOI Listing
November 2019

Impact of a clinical decision support tool on prediction of progression in early-stage dementia: a prospective validation study.

Alzheimers Res Ther 2019 03 20;11(1):25. Epub 2019 Mar 20.

Danish Dementia Research Centre, Neuroscience Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark.

Background: In clinical practice, it is often difficult to predict which patients with cognitive complaints or impairment will progress or remain stable. We assessed the impact of using a clinical decision support system, the PredictND tool, to predict progression in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) in memory clinics.

Methods: In this prospective multicenter study, we included 429 patients with SCD (n = 230) and MCI (n = 199) (female 54%, age 67 ± 9, MMSE 28 ± 2) and followed them for at least 12 months. Based on all available patient baseline data (demographics, cognitive tests, cerebrospinal fluid biomarkers, and MRI), the PredictND tool provides a comprehensive overview of the data and a classification defining the likelihood of progression. At baseline, a clinician defined an expected follow-up diagnosis and estimated the level of confidence in their prediction using a visual analogue scale (VAS, 0-100%), first without and subsequently with the PredictND tool. As outcome measure, we defined clinical progression as progression from SCD to MCI or dementia, and from MCI to dementia. Correspondence between the expected and the actual clinical progression at follow-up defined the prognostic accuracy.

Results: After a mean follow-up time of 1.7 ± 0.4 years, 21 (9%) SCD and 63 (32%) MCI had progressed. When using the PredictND tool, the overall prognostic accuracy was unaffected (0.4%, 95%CI - 3.0%; + 3.9%; p = 0.79). However, restricting the analysis to patients with more certain classifications (n = 203), we found an increase of 3% in the accuracy (95%CI - 0.6%; + 6.5%; p = 0.11). Furthermore, for this subgroup, the tool alone showed a statistically significant increase in the prognostic accuracy compared to the evaluation without tool (6.4%, 95%CI 2.1%; 10.7%; p = 0.004). Specifically, the negative predictive value was high. Moreover, confidence in the prediction increased significantly (∆VAS = 4%, p < .0001).

Conclusions: Adding the PredictND tool to the clinical evaluation increased clinicians' confidence. Furthermore, the results indicate that the tool has the potential to improve prediction of progression for patients with more certain classifications.
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http://dx.doi.org/10.1186/s13195-019-0482-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425602PMC
March 2019

Quantitative Electroencephalography Analyzed by Statistical Pattern Recognition as a Diagnostic and Prognostic Tool in Mild Cognitive Impairment: Results from a Nordic Multicenter Cohort Study.

Dement Geriatr Cogn Dis Extra 2018 Sep-Dec;8(3):426-438. Epub 2018 Nov 27.

Regional Dementia Research Centre, Department of Neurology, Zealand University Hospital, Roskilde, Denmark.

Aim: To examine diagnostic and prognostic potential of quantitative electroencephalography (qEEG) analyzed by the statistical pattern recognition (SPR) method in patients with cognitive impairment. We compared the differential diagnostic ability of SPR to visual EEG analysis. Correlation between SPR findings and cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers were evaluated.

Methods: It is a multicenter cohort study involving 129 patients, (mild cognitive impairment [MCI], AD, and healthy controls). Standardized EEG was performed at baseline. Patients were continuously clinically evaluated.

Results: Receiver Operating Characteristic curves showed a low discriminative ability of SPR and no ability to predict clinical progression in patients with MCI. Moderate correlation between SPR analysis and CSF AD biomarkers was found.

Conclusion: The diagnostic and prognostic abilities of qEEG were low. The SPR method was superior to the visual EEG analysis. The qEEG method correlates well to CSF AD biomarkers, suggesting association with pathology in AD.
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http://dx.doi.org/10.1159/000490788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323395PMC
November 2018

Impact of a Clinical Decision Support Tool on Dementia Diagnostics in Memory Clinics: The PredictND Validation Study.

Curr Alzheimer Res 2019 ;16(2):91-101

Department of Neurology, Danish Dementia Research Centre, University of Copenhagen, Rigshospitalet, Denmark.

Background: Determining the underlying etiology of dementia can be challenging. Computer- based Clinical Decision Support Systems (CDSS) have the potential to provide an objective comparison of data and assist clinicians.

Objectives: To assess the diagnostic impact of a CDSS, the PredictND tool, for differential diagnosis of dementia in memory clinics.

Methods: In this prospective multicenter study, we recruited 779 patients with either subjective cognitive decline (n=252), mild cognitive impairment (n=219) or any type of dementia (n=274) and followed them for minimum 12 months. Based on all available patient baseline data (demographics, neuropsychological tests, cerebrospinal fluid biomarkers, and MRI visual and computed ratings), the PredictND tool provides a comprehensive overview and analysis of the data with a likelihood index for five diagnostic groups; Alzheimer´s disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia and subjective cognitive decline. At baseline, a clinician defined an etiological diagnosis and confidence in the diagnosis, first without and subsequently with the PredictND tool. The follow-up diagnosis was used as the reference diagnosis.

Results: In total, 747 patients completed the follow-up visits (53% female, 69±10 years). The etiological diagnosis changed in 13% of all cases when using the PredictND tool, but the diagnostic accuracy did not change significantly. Confidence in the diagnosis, measured by a visual analogue scale (VAS, 0-100%) increased (ΔVAS=3.0%, p<0.0001), especially in correctly changed diagnoses (ΔVAS=7.2%, p=0.0011).

Conclusion: Adding the PredictND tool to the diagnostic evaluation affected the diagnosis and increased clinicians' confidence in the diagnosis indicating that CDSSs could aid clinicians in the differential diagnosis of dementia.
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http://dx.doi.org/10.2174/1567205016666190103152425DOI Listing
April 2020