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Background: There are few studies on validation of depression scales in the elderly in Latin America. This study aimed to assess the validity of Montgomery-Åsberg. Depression Rating Scale (MADRS) and Cornell Scale for Depression in Dementia (CSDD) in Brazilian elderly outpatients.Methods: A convenience sample of 95 outpatients was diagnosed for dementia and depression according to DSM-IV-TR, ICD-10, and PDC-dAD criteria. Receiver Operating Curves (ROC) were used to calculate the area under the curve (AUC) and to assess MADRS and CSDD cut-offs for each diagnostic criterion.Results: Dementia was diagnosed in 71 of 95 patients. Depression was diagnosed in 35, 30, and 51 patients by ICD-10, DSM-IV, and PDC-dAD, respectively. MADRS cut-off score of 10 correctly diagnosed 67.4% and 66.3% patients as depressed according to DSM-IV and ICD-10. A cut-off of 9 correctly identified 74.7% by PDC-dAD criteria; a CSDD cut-off score of 13 best recognized depression according to DSM-IV and ICD-10. A score of 11 diagnosed depression according to PDC-dAD, while MADRS = 9 recognized depression in dementia. CSDD was more efficient in showing depression in mild than in moderate/severe dementia according to DSM-IV/ICD-10. PDC-dAD behaved nicely for any severity stage.Conclusion: MADRS and CSDD cut-offs of 10 and 13 were the optimal ones to diagnose depression in elderly, respectively. CSDD cut-offs are higher than those found in other countries. Other Latin American studies are needed to compare results with our study. [ABSTRACT FROM AUTHOR]

Background: Spatial orientation is required for independent mobility in society. Deficits in spatial orientation can be an early symptom of Alzheimer's disease and other dementias, and there is a need for brief assessment tools to identify impairments., Objective: The aim of this study was to evaluate the construct and known-group validity of our newly developed Spatial Orientation Screening (SOS) questionnaire., Methods: We included 132 patients with subjective cognitive decline (n = 16), mild cognitive impairment (n = 32), or all-cause dementia (n = 84) from a memory clinic and a reference group of cognitively unimpaired older adults (n = 108). The patients and their next-of-kin answered the self- and proxy-rated versions of the 4-item SOS (0-8 points) and the 10-item Questionnaire of Everyday Navigational Ability (QuENA, 0-30 points). The patients also performed the Floor Maze Test (FMT) for performance-based spatial abilities., Results: Mean ages (SD) of the patient and reference groups were 68.6 (±7.6) years and 73.7 (±6.7) years, respectively. Construct validity between self-rated versions of the SOS and QuENA was satisfactory with r s  = 0.66, between the proxy-rated versions r s  = 0.61, and between the proxy-reported SOS and FMT r s  = 0.49 (all p < 0.001). Known-group validity was also acceptable, with significantly higher median (IQR) SOS self-reported scores in patients 1.0 (2.0) compared to the reference group 0.2 (0.5) points, (p < 0.001). Informants reported more severe impairments compared to the patients' self-reports on both SOS and QuENA (both p < 0.001)., Conclusions: The SOS had satisfactory validity for use as a screening instrument for assessment of spatial orientation in memory clinic patients., Competing Interests: Declaration of conflicting interestsKarin Persson reports work with Novo Nordisk NN6535-4730 trial outside the submitted work.Geir Selbæk has participated at advisory board meetings for Roche and Eisai concerning monoclonal antibody drugs for treatment of Alzheimer's disease.Anne Brita Knapskog has contributed to clinical trials for Roche (BN29553), Boehringer-Ingelheim (1346.0023), Novo Nordisk (NN6535-4730), and GSK (219867).Knut Engedal is an Editorial Board Member of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review.The remaining authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Sex differences in neuroinflammation could contribute to women's increased risk of Alzheimer's disease (AD), providing rationale for exploring sex-specific AD biomarkers. In AD, dysregulation of the kynurenine pathway (KP) contributes to neuroinflammation and there is some evidence of sex differences in KP metabolism. However, the sex-specific associations between KP metabolism and biomarkers of AD and neuroinflammation need to be explored further., Methods: Here we investigate sex differences in cerebrospinal fluid concentrations of seven KP metabolites and sex-specific associations with established AD biomarkers and neopterin, an indicator of neuroinflammation. This study included 311 patients with symptomatic AD and 105 age-matched cognitively unimpaired (CU) controls, followed for up to 5 years., Results: We found sex differences in KP metabolites in the AD group, with higher levels of most metabolites in men, while there were no sex differences in the CU group. In line with this, more KP metabolites were significantly altered in AD men compared to CU men, and there was a trend in the same direction in AD women. Furthermore, we found sex-specific associations between kynurenic acid and the kynurenic acid/quinolinic acid ratio with neopterin, but no sex differences in the associations between KP metabolites and clinical progression., Discussion: In our cohort, sex differences in KP metabolites were restricted to AD patients. Our results suggest that dysregulation of the KP due to increased inflammation could contribute to higher AD risk in women., (© 2024. The Author(s).)

Background/aims: The number of patients suffering from cognitive decline and dementia increases, and new possible treatments are being developed. Thus, the need for time efficient and cost-effective methods to facilitate an early diagnosis and prediction of future cognitive decline in patients with early cognitive symptoms is becoming increasingly important. The aim of this study was to evaluate whether an MRI based software, NeuroQuant® (NQ), producing volumetry of the hippocampus and whole brain volume (WBV) could predict: (1) conversion from subjective cognitive decline (SCD) at baseline to mild cognitive impairment (MCI) or dementia at follow-up, and from MCI at baseline to dementia at follow-up and (2) progression of cognitive and functional decline defined as an annual increase in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score., Methods: MRI was performed in 156 patients with SCD or MCI from the memory clinic at Oslo University Hospital (OUH) that had been assessed with NQ and had a clinical follow-up examination. Logistic and linear regression analyses were performed with hippocampus volume and WBV as independent variables, and conversion or progression as dependent variables, adjusting for demographic and other relevant covariates including Mini-Mental State Examination-Norwegian Revised Version score (MMSE-NR) and Apolipoprotein E ɛ4 ( APOE ɛ4) carrier status., Results: Hippocampus volume, but not WBV, was associated with conversion to MCI or dementia, but neither were associated with conversion when adjusting for MMSE-NR. Both hippocampus volume and WBV were associated with progression as measured by the annual change in CDR-SB score in both unadjusted and adjusted analyses., Conclusion: The results indicate that automated regional MRI volumetry of the hippocampus and WBV can be useful in predicting further cognitive decline in patients with early cognitive symptoms., Competing Interests: KP, TE, and A-BK report work with Roche BN29553 trial; KP and A-BK report work with Novo Nordisk NN6535-4730 trial; TE and A-BK report work with Boehringer-Ingelheim 1346.0023 trial; outside the submitted work. GS reports participation in advisory board meetings for Biogen and Roche regarding new disease-modifying therapies for Alzheimer’s disease. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Amland, Selbæk, Brækhus, Edwin, Engedal, Knapskog, Olsrud and Persson.)

Background and Aims: We have previously shown that systemic inflammation was associated with post-stroke cognitive impairment (PSCI). Because neopterin, kynurenine pathway (KP) metabolites, and B6 vitamers are linked to inflammation, in our study we investigated whether those biomarkers were associated with PSCI., Material and Methods: The Norwegian Cognitive Impairment After Stroke study is a prospective multicenter cohort study of patients with acute stroke recruited from May 2015 through March 2017. Plasma samples of 422 participants (59 % male) with ischemic stroke from the index hospital stay and 3 months post-stroke were available for analyses of neopterin, KP metabolites, and B6 vitamers using liquid chromatography-tandem mass spectrometry. Mixed linear regression analyses adjusted for age, sex, and creatinine, were used to assess whether there were associations between those biomarkers and cognitive outcomes, measured by the Montreal Cognitive Assessment scale (MoCA) at 3-, 18-, and 36-month follow-up., Results: Participants had a mean (SD) age of 72 (12) years, with a mean (SD) National Institutes of HealthStroke Scale score of 2.7 (3.6) at Day 1. Higher baseline values of quinolinic acid, PAr (i.e., an inflammatory marker based on vitamin B6 metabolites), and HKr (i.e., a marker of functional vitamin B6 status based on selected KP metabolites) were associated with lower MoCA score at 3, 18, and 36 months post-stroke (p < 0.01). Higher baseline concentrations of neopterin and 3-hydroxykynurenine were associated with lower MoCA scores at 18 and 36 months, and higher concentrations of xanthurenic acid were associated with higher MoCA score at 36 months (p < 0.01). At 3 months post-stroke, higher concentrations of neopterin and lower values of pyridoxal 5́-phosphate were associated with lower MoCA scores at 18- and 36-month follow-up, while lower concentrations of picolinic acid were associated with a lower MoCA score at 36 months (p < 0.01)., Conclusion: Biomarkers and metabolites of systemic inflammation, including biomarkers of cellular immune activation, indexes of vitamin B6 homeostasis, and several neuroactive metabolites of the KP pathway, were associated with PSCI., Trial Registration: ClinicalTrials.gov: NCT02650531., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: The aims were to compare the novel regional brain volumetric measures derived by the automatic software NeuroQuant (NQ) with clinically used visual rating scales of medial temporal lobe atrophy (MTA), global cortical atrophy-frontal (GCA-f), and posterior atrophy (PA) brain regions, assessing their diagnostic validity, and to explore if combining automatic and visual methods would increase diagnostic prediction accuracy., Methods: Brain magnetic resonance imaging (MRI) examinations from 86 patients with subjective and mild cognitive impairment (i.e., non-dementia, n = 41) and dementia (n = 45) from the Memory Clinic at Oslo University Hospital were assessed using NQ volumetry and with visual rating scales. Correlations, receiver operating characteristic analyses calculating area under the curves (AUCs) for diagnostic accuracy, and logistic regression analyses were performed., Results: The correlations between NQ volumetrics and visual ratings of corresponding regions were generally high between NQ hippocampi/temporal volumes and MTA (r = -0.72/-0.65) and between NQ frontal volume and GCA-f (r = -0.62) but lower between NQ parietal/occipital volumes and PA (r = -0.49/-0.37). AUCs of each region, separating non-dementia from dementia, were generally comparable between the two methods, except that NQ hippocampi volume did substantially better than visual MTA (AUC = 0.80 vs. 0.69). Combining both MRI methods increased only the explained variance of the diagnostic prediction substantially regarding the posterior brain region., Conclusions: The findings of this study encourage the use of regional automatic volumetry in locations lacking neuroradiologists with experience in the rating of atrophy typical of neurodegenerative diseases, and in primary care settings., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Introduction: The kynurenine pathway's (KP) malfunction is closely related to Alzheimer's disease (AD), for antagonistic kynurenic acid (KA) and agonistic quinolinic acid act on the N-methyl-D-aspartate receptor, a possible therapeutic target in treating AD., Methods: In our longitudinal case-control study, KP metabolites in the cerebrospinal fluid were analyzed in 311 patients with AD and 105 cognitively unimpaired controls., Results: Patients with AD exhibited higher concentrations of KA (β = 0.18, P < 0.01) and picolinic acid (β = 0.20, P < 0.01) than the controls. KA was positively associated with tau pathology (β = 0.29, P < 0.01), and a higher concentration of KA was associated with the slower progression of dementia., Discussion: The higher concentrations of neuroprotective metabolites KA and picolinic acid suggest that the activation of the KP's neuroprotective branch is an adaptive response in AD and may be a promising target for intervention and treatment. Highlights Patients with Alzheimer's disease (AD) exhibited higher concentrations of kynurenic acid and picolinic acid than controls. Higher concentrations of kynurenic acid were associated with slower progression of AD. Potential neurotoxic kynurenines were not increased among patients with AD. Activation of the kynurenine pathway's neuroprotective branch may be an adaptive response in AD., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The aim of this study was to assess the diagnostic validity of a deep learning-based method estimating brain age based on magnetic resonance imaging (MRI) and to compare it with volumetrics obtained using NeuroQuant (NQ) in a clinical cohort. Brain age prediction was performed on minimally processed MRI data using deep convolutional neural networks and an independent training set. The brain age gap (difference between chronological and biological age) was calculated, and volumetrics were performed in 110 patients with dementia (Alzheimer's disease, frontotemporal dementia (FTD), and dementia with Lewy bodies), and 122 with non-dementia (subjective and mild cognitive impairment). Area-under-the-curve (AUC) based on receiver operating characteristics and logistic regression analyses were performed. The mean age was 67.1 (9.5) years and 48.7% (113) were females. The dementia versus non-dementia sensitivity and specificity of the volumetric measures exceeded 80% and yielded higher AUCs compared to BAG. The explained variance of the prediction of diagnostic stage increased when BAG was added to the volumetrics. Further, BAG separated patients with FTD from other dementia etiologies with > 80% sensitivity and specificity. NQ volumetrics outperformed BAG in terms of diagnostic discriminatory power but the two methods provided complementary information, and BAG discriminated FTD from other dementia etiologies., (© 2023. Springer Nature Limited.)

Background: Currently, there are no disease-modifying pharmacological treatment options for dementia with Lewy bodies (DLB). The hallmark of DLB is pathological alpha-synuclein (aS) deposition. There are growing amounts of data suggesting that reduced aS clearance is caused by failure in endolysosomal and authophagic pathways, as well as and glucocerebrosidase (GCase) dysfunction and mutations in the GCase gene (GBA). The population's studies demonstrated that the incidence of GBA mutations is higher among Parkinson's disease (PD) patients, and carriers of such mutations have a higher risk of developing PD. The incidence of GBA mutations is even higher in DLB and a genome-wide association study (GWAS) confirmed the correlation between GBA mutations and DLB. In vivo experiments have shown that ambroxol (ABX) may increase GCase activity and GCase levels and therefore enhance aS autophagy-lysosome degradation pathways. Moreover, there is an emerging hypothesis that ABX may have an effect as a DLB modifying drug. The aims of the study "Ambroxol in new and early Dementia with Lewy Bodies (ANeED) are to investigate the tolerability, safety and effects of ABX in patients with DLB., Methods: This is a multicentre, phase IIa, double-blinded, randomised and placebo-controlled clinical trial, using a parallel arm design for 18 months' follow-up. The allocation ratio is 1:1 (treatment:placebo)., Discussion: The ANeED study is an ongoing clinical drug trial with ABX. The unique, but not fully understood mechanism of ABX on the enhancement of lysosomal aS clearance may be promising as a possible modifying treatment in DLB., Trial Registration: The clinical trial is registered in the international trials register - clinicaltrials.com (NCT0458825) and nationally at the Current Research Information System in Norway (CRISTIN 2235504)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chwiszczuk, Breitve, Kirsebom, Selnes, Fløvig, Knapskog, Skogseth, Hubbers, Holst-Larsen and Rongve.)

Introduction: Alzheimer's disease (AD) can be characterised in vivo by biomarkers reflecting amyloid-β (Aβ) and tau pathology. However, there is a need for biomarkers reflecting additional pathological pathways. Matrix metalloproteinases (MMPs) have recently been highlighted as candidate biomarkers for sex-specific mechanisms and progression in AD., Methods: In this cross-sectional study, we investigated nine MMPs and four tissue inhibitors of metalloproteinases (TIMPs) in the cerebrospinal fluid of 256 memory clinic patients with mild cognitive impairment or dementia due to AD and 100 cognitively unimpaired age-matched controls. We studied group differences in MMP/TIMP levels and examined the associations with established markers of Aβ and tau pathology as well as disease progression. Further, we studied sex-specific interactions., Results: MMP-10 and TIMP-2 levels differed significantly between the memory clinic patients and the cognitively unimpaired controls. Furthermore, MMP- and TIMP-levels were generally strongly associated with tau biomarkers, whereas only MMP-3 and TIMP-4 were associated with Aβ biomarkers; these associations were sex-specific. In terms of progression, we found a trend towards higher MMP-10 at baseline predicting more cognitive and functional decline over time exclusively in women., Conclusion: Our results support the use of MMPs/TIMPs as markers of sex differences and progression in AD. Our findings show sex-specific effects of MMP-3 and TIMP-4 on amyloid pathology. Further, this study highlights that the sex-specific effects of MMP-10 on cognitive and functional decline should be studied further if MMP-10 is to be used as a prognostic biomarker for AD., (© 2023. The Author(s).)

Background: Inflammation is proposed to be involved in the pathogenesis of poststroke cognitive impairment. The aim of this study was to investigate associations between concentrations of systemic inflammatory biomarkers after ischemic stroke and poststroke cognitive impairment., Methods: The Nor-COAST study (Norwegian Cognitive Impairment After Stroke) is a prospective observational multicenter cohort study, including patients hospitalized with acute stroke between 2015 and 2017. Inflammatory biomarkers, including the TCC (terminal C5b-9 complement complex) and 20 cytokines, were analyzed in plasma, collected at baseline, 3-, and 18 months poststroke, using ELISA and a multiplex assay. Global cognitive outcome was assessed with the Montreal Cognitive Assessment (MoCA) scale. We investigated the associations between plasma inflammatory biomarkers at baseline and MoCA score at 3-, 18-, and 36-month follow-ups; the associations between inflammatory biomarkers at 3 months and MoCA score at 18- and 36-month follow-ups; and the association between these biomarkers at 18 months and MoCA score at 36-month follow-up. We used mixed linear regression adjusted for age and sex., Results: We included 455 survivors of ischemic stroke. Higher concentrations of 7 baseline biomarkers were significantly associated with lower MoCA score at 36 months; TCC, IL (interleukin)-6, and MIP (macrophage inflammatory protein)-1α were associated with MoCA at 3, 18, and 36 months ( P <0.01). No biomarker at 3 months was significantly associated with MoCA score at either 18 or 36 months, whereas higher concentrations of 3 biomarkers at 18 months were associated with lower MoCA score at 36 months ( P <0.01). TCC at baseline and IL-6 and MIP-1α measured both at baseline and 18 months were particularly strongly associated with MoCA ( P <0.01)., Conclusions: Higher concentrations of plasma inflammatory biomarkers were associated with lower MoCA scores up to 36 months poststroke. This was most pronounced for inflammatory biomarkers measured in the acute phase following stroke., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02650531.

Background: Mobility impairments, in terms of gait and balance, are common in persons with dementia. To explore this relationship further, we examined the associations between mobility and cerebrospinal fluid (CSF) core biomarkers for Alzheimer's disease (AD)., Methods: In this cross-sectional study, we included 64 participants [two with subjective cognitive decline (SCD), 13 with mild cognitive impairment (MCI) and 49 with dementia] from a memory clinic. Mobility was examined using gait speed, Mini-Balance Evaluation Systems test (Mini-BESTest), Timed Up and Go (TUG), and TUG dual-task cost (TUG DTC). The CSF biomarkers included were amyloid-β 42 (Aβ 42 ), total-tau (t-tau), and phospho tau (p-tau 181 ). Associations between mobility and biomarkers were analyzed through correlations and multiple linear regression analyses adjusted for (1) age, sex, and comorbidity, and (2) SCD/MCI vs. dementia., Results: Aβ 42 was significantly correlated with each of the mobility outcomes. In the adjusted multiple regression analyses, Aβ 42 was significantly associated with Mini-BESTest and TUG in the fully adjusted model and with TUG DTC in step 1 of the adjusted model (adjusting for age, sex, and comorbidity). T-tau was only associated with TUG DTC in step 1 of the adjusted model. P-tau 181 was not associated with any of the mobility outcomes in any of the analyses., Conclusion: Better performance on mobility outcomes were associated with higher levels of CSF Aβ 42 . The association was strongest between Aβ 42 and Mini-BESTest, suggesting that dynamic balance might be closely related with AD-specific pathology., Competing Interests: A-BK, KP, and PB-W report work with Roche drug trial BN29553 and Novo Nordisk drug trial NN6535-4730 trial. A-BK report work with Boehringer-Ingelheim drug trial 1346.0023. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tangen, Sverdrup, Taraldsen, Persson, Engedal, Bekkhus-Wetterberg and Knapskog.)

BACKGROUNDThe kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation. Delirium (acute confusion) is a common complication of acute illness and is associated with increased risk of dementia and mortality. However, the molecular mechanisms underlying delirium, particularly in relation to the KP, remain elusive.METHODSWe undertook a multicenter observational study with 586 hospitalized patients (248 with delirium) and investigated associations between delirium and KP metabolites measured in cerebrospinal fluid (CSF) and serum by targeted metabolomics. We also explored associations between KP metabolites and markers of neuronal damage and 1-year mortality.RESULTSIn delirium, we found concentrations of the neurotoxic metabolite quinolinic acid in CSF (CSF-QA) (OR 2.26 [1.78, 2.87], P < 0.001) to be increased and also found increases in several other KP metabolites in serum and CSF. In addition, CSF-QA was associated with the neuronal damage marker neurofilament light chain (NfL) (β 0.43, P < 0.001) and was a strong predictor of 1-year mortality (HR 4.35 [2.93, 6.45] for CSF-QA ≥ 100 nmol/L, P < 0.001). The associations between CSF-QA and delirium, neuronal damage, and mortality remained highly significant following adjustment for confounders and multiple comparisons.CONCLUSIONOur data identified how systemic inflammation, neurotoxicity, and delirium are strongly linked via the KP and should inform future delirium prevention and treatment clinical trials that target enzymes of the KP.FUNDINGNorwegian Health Association and South-Eastern Norway Regional Health Authorities.

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., (© 2022. The Author(s).)

Purpose: The Norwegian Registry of Persons Assessed for Cognitive Symptoms (NorCog) was established to harmonise and improve the quality of diagnostic practice across clinics assessing persons with cognitive symptoms in Norwegian specialist healthcare units and to establish a large research cohort with extensive clinical data., Participants: The registry recruits patients who are referred for assessment of cognitive symptoms and suspected dementia at outpatient clinics in Norwegian specialist healthcare units. In total, 18 120 patients have been included in NorCog during the period of 2009-2021. The average age at inclusion was 73.7 years. About half of the patients (46%) were diagnosed with dementia at the baseline assessment, 35% with mild cognitive impairment and 13% with no or subjective cognitive impairment; 7% received other specified diagnoses such as mood disorders., Findings to Date: All patients have a detailed baseline characterisation involving lifestyle and demographic variables; activities of daily living; caregiver situation; medical history; medication; psychiatric, physical and neurological examinations; neurocognitive testing; blood laboratory work-up; and structural or functional brain imaging. Diagnoses are set according to standardised diagnostic criteria. The research biobank stores DNA and blood samples from 4000 patients as well as cerebrospinal fluid from 800 patients. Data from NorCog have been used in a wide range of research projects evaluating and validating dementia-related assessment tools, and identifying patient characteristics, symptoms, functioning and needs, as well as caregiver burden and requirement of available resources., Future Plans: The finish date of NorCog was originally in 2029. In 2021, the registry's legal basis was reformalised and NorCog got approval to collect and keep data for as long as is necessary to achieve the purpose of the registry. In 2022, the registry underwent major changes. Paper-based data collection was replaced with digital registration, and the number of variables collected was reduced. Future plans involve expanding the registry to include patients from primary care centres., Competing Interests: Competing interests: A-BK was the principal investigator of three drug trials (ROCHE BN29553, Boehringer-Ingelheim 1346.23 and Novo Nordisk NN6535-4730). KP was rater in the ROCHE BN29553 and Novo Nordisk NN6535-4730 trials, and IS was investigator in the Boehringer-Ingelheim 1346.23 trial., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Noradrenergic and dopaminergic neurons are involved in cognitive functions, relate to behavioral and psychological symptoms in dementia and are affected in Alzheimer's disease (AD). Amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N) hallmarks the AD neuropathology. Today, the AT(N) pathophysiology can be assessed through biomarkers. Previous studies report cerebrospinal fluid (CSF) catecholamine concentrations in AD patients without biomarker refinement. We explored if CSF catecholamines relate to AD clinical presentation or neuropathology as reflected by CSF biomarkers. CSF catecholamines were analyzed in AD patients at the mild cognitive impairment (MCI; n = 54) or dementia stage (n = 240) and in cognitively unimpaired (n = 113). CSF biomarkers determined AT status and indicated synaptic damage (neurogranin). The AD patients (n = 294) had higher CSF noradrenaline and adrenaline concentrations, but lower dopamine concentrations compared to the cognitively unimpaired (n = 113). AD patients in the MCI and dementia stage of the disease had similar CSF catecholamine concentrations. In the CSF neurogranin positively associated with noradrenaline and adrenaline but not with dopamine. Adjusted regression analyses including AT status, CSF neurogranin, age, gender, and APOEε4 status verified the findings. In restricted analyses comparing A+T+ patients to A-T- cognitively unimpaired, the findings for CSF adrenaline remained significant (p < 0.001) but not for CSF noradrenaline (p = 0.07) and CSF dopamine (p = 0.33). There were no differences between A+T+ and A-T- cognitively unimpaired. Thus, we find alterations in CSF catecholamines in symptomatic AD and the CSF adrenergic transmitters to increase simultaneously with synaptic damage as indexed by CSF neurogranin., (© 2022. The Author(s).)

Background: Vitamin D insufficiency has been suggested as a dementia risk factor., Objective: In this cross-sectional, explorative study we investigated whether levels of vitamin D in cerebrospinal fluid (CSF) are lower in patients with positive biomarkers of Alzheimer's disease (AD) compared to cognitively healthy controls and whether polymorphisms of the vitamin D receptor (VDR) gene, FokI, BsmI, ApaI, and TaqI, are associated with levels of vitamin D in CSF and cognition., Methods: We included 100 patients≥65 years assessed for cognitive impairment and 76 cognitively healthy controls. Levels of 25-hydroxyvitamin D (25(OH)D) in both serum and CSF, and VDR polymorphisms were analyzed., Results: The mean level of 25(OH)D in serum was 78.6 (SD 28.9) nmol/l. While serum levels of 25(OH)D were not significantly different between the groups, CSF levels of 25(OH)D were significantly lower in patients with positive AD core biomarkers (p = 0.001) compared to patients without such biomarkers. Individuals with the BsmI major homozygote genotype had significantly lower results on a 10-word delayed recall test (p = 0.044) and verbal fluency test (p = 0.013), and individuals with the TaqI major homozygote genotype had significantly lower results on a verbal fluency test (p = 0.030) compared to individuals with the corresponding minor homozygote genotype., Conclusion: Patients with positive AD core biomarkers have low CSF levels of 25(OH)D, despite sufficient serum levels. CSF levels of 25(OH)D do not seem to be affected by any of the four VDR gene polymorphisms. TaqI and BsmI major homozygote genotypes might be at increased risk for development of cognitive decline.

Background: Several studies have examined association between vitamin D levels in serum and cognition, but little is known of vitamin D levels in cerebrospinal fluid (CSF) and association with Alzheimer's disease (AD)., Objective: In this cross-sectional, explorative study we investigated possible associations of vitamin D in CSF with biomarkers for AD, amyloid-β, tau protein/phosphorylated tau protein in CSF, and with the cytokines IL-6, IL-8, and TNF-α in CSF in patients with cognitive impairment and cognitively healthy controls., Methods: We included 100 outpatients ≥65 years referred for assessment of cognitive impairment and 76 age- and sex-matched cognitively healthy controls. Levels of 25-hydroxyvitamin D (25(OH)D), amyloid-β, tau protein and phosphorylated tau protein, as well as IL-6, IL-8, and TNF-α, were analyzed in CSF in both groups., Results: Higher levels of 25(OH)D in CSF in all groups together were associated with lower levels of tau protein (p = 0.01) and phosphorylated tau protein (p = 0.005). We found no association between 25(OH)D levels in CSF and pathological levels of amyloid-β in CSF nor levels of IL-6 or TNF-α in CSF. Higher levels of 25(OH)D in CSF were associated with higher levels of IL-8 in CSF (p = 0.002). However, vitamin D explained only 6% of variance in IL-8. There was no significant difference between the patient groups and the control group regarding the association between 25(OH)D in CSF and any of the three cytokines in CSF., Conclusion: Participants with higher CSF levels of 25(OH)D exhibited reduced CSF levels of tau protein and phosphorylated tau protein.

Background: Patients with Alzheimer's disease (AD) show heterogeneity in clinical progression rate, and we have limited tools to predict prognosis. Amyloid burden from 18F-Flutemetamol positron emission tomography (PET), as measured by standardized uptake value ratios (SUVR), might provide prognostic information., Objective: We investigate whether 18F-Flutemetamol PET composite or regional SUVRs are associated with trajectories of clinical progression., Methods: This observational longitudinal study included 94 patients with clinical AD. PET images were semi-quantified with normalization to pons. Group-based trajectory modeling was applied to identify trajectory groups according to change in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) over time. Multinomial logistic regression models assessed the association of SUVRs with trajectory group membership., Results: Three trajectory groups were identified. In the regression models, neither composite nor regional SUVRs were associated with trajectory group membership., Conclusion: There were no associations between CDR progression and 18F-Flutemetamol PET-derived composite SUVRs or regional SUVRs in clinical AD.

Introduction: One pathological hallmark of Alzheimer's disease (AD) is atrophy of medial temporal brain regions that can be visualized on magnetic resonance imaging (MRI), but not all patients will have atrophy. The aim was to use MRI to categorize patients according to their hippocampal atrophy status and to present prevalence of the subtypes, difference in clinical symptomatology and progression, and factors associated with hippocampal subtypes., Methods: We included 215 patients with AD who had been assessed with the clinically available MRI software NeuroQuant (NQ; CorTechs labs/University of California, San Diego, CA, USA). NQ measures the hippocampus volume and calculates a normative percentile. Atrophy was regarded to be present if the percentile was ≤5. Demographics, cognitive measurements, AD phenotypes, apolipoprotein E status, and results from cerebrospinal fluid and amyloid positron emission tomography analyses were included as explanatory variables of the hippocampal subtypes., Results: Of all, 60% had no hippocampal atrophy. These patients were younger and less cognitively impaired concerning global measures, memory function, and abstraction but impaired concerning executive, visuospatial, and semantic fluency, and more of them had nonamnestic AD, compared to those with hippocampal atrophy. No difference in progression rate was observed between the two groups. In mild cognitive impairment patients, amyloid pathology was associated with the no hippocampal atrophy group., Conclusion: The results have clinical implications. Clinicians should be aware of the large proportion of AD patients presenting without atrophy of the hippocampus as measured with this clinical MRI method in the diagnostic set up and that nonamnestic phenotypes are more common in this group as compared to those with atrophy. Furthermore, the findings are relevant in clinical trials., (© 2022 S. Karger AG, Basel.)

Background: 18 F-flutemetamol positron emission tomography (PET) is used to assess cortical amyloid-β burden in patients with cognitive impairment to support a clinical diagnosis. Visual classification is the most widely used method in clinical practice although semi-quantification is beneficial to obtain an objective and continuous measure of the Aβ burden. The aims were: first to evaluate the correspondence between standardized uptake value ratios (SUVRs) from three different software, Centiloids and visual classification, second to estimate thresholds for supporting visual classification and last to assess differences in semi-quantitative measures between clinical diagnoses., Methods: This observational study included 195 patients with cognitive impairment who underwent 18 F-flutemetamol PET. PET images were semi-quantified with SyngoVia, CortexID suite, and PMOD. Receiver operating characteristics curves were used to compare visual classification with composite SUVR normalized to pons (SUVRpons) and cerebellar cortex (SUVRcer), and Centiloids. We explored correlations and differences between semi-quantitative measures as well as differences in SUVR between two clinical diagnosis groups: Alzheimer's disease-group and non-Alzheimer's disease-group., Results: PET images from 191 patients were semi-quantified with SyngoVia and CortexID and 86 PET-magnetic resonance imaging pairs with PMOD. All receiver operating characteristics curves showed a high area under the curve (>0.98). Thresholds for a visually positive PET was for SUVRcer: 1.87 (SyngoVia) and 1.64 (CortexID) and for SUVRpons: 0.54 (SyngoVia) and 0.55 (CortexID). The threshold on the Centiloid scale was 39.6 Centiloids. All semi-quantitative measures showed a very high correlation between different software and normalization methods. Composite SUVRcer was significantly different between SyngoVia and PMOD, SyngoVia and CortexID but not between PMOD and CortexID. Composite SUVRpons were significantly different between all three software. There were significant differences in the mean rank of SUVRpons, SUVRcer, and Centiloid between Alzheimer's disease-group and non-Alzheimer's disease-group., Conclusions: SUVR from different software performed equally well in discriminating visually positive and negative 18 F-Flutemetamol PET images. Thresholds should be considered software-specific and cautiously be applied across software without preceding validation to categorize scans as positive or negative. SUVR and Centiloid may be used alongside a thorough clinical evaluation to support a clinical diagnosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/qims-21-188). HLS has received consultancy fees from Siemens Healthineers. THE has been a rater in two clinical trials (Roche BN29553 and Boehringer-Ingelheim 1346.0023) outside the submitted work. ABK has been a national coordinator and principal investigator in three clinical trials (Roche BN29553, Boehringer-Ingelheim 1346.0023 and Novo Nordisk, EVOKE NN6535-4730) outside the submitted work. The other authors have no conflicts of interest to declare., (2022 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background: Neuroinflammation is a central component of Alzheimer's disease (AD) and correlates closely with amyloid pathology. Markers of inflammation such as cytokines, and amyloidogenic aggregates, so-called nanoplaques, are both promising biomarker candidates for AD. We have previously shown that there is a relationship between the levels of nanoplaques and cytokines in cerebrospinal fluid, but it is unknown whether this association extends to serum., Objective: Investigate in a naturalistic memory clinic cohort whether the associations between nanoplaques and cytokines in the cerebrospinal fluid extends to serum., Methods: We collected serum from 49 patients assessed for cognitive complaints at the Oslo University Hospital Memory Clinic (15 with clinical AD). We assessed the levels of serum nanoplaques with the novel Thioflavin-T fluorescence correlation spectroscopy (ThT-FCS) assay. Serum levels of nine cytokines (eotaxin-1, granulocyte colony-stimulating factor [G-CSF], interleukin [IL]-6, IL-7, IL-8, monocyte chemoattractant protein-1 (MCP-1), gamma induced protein 10 (IP-10), macrophage inflammatory protein [MIP]-1α, and MIP-1β) were quantified with a multiplex assay and read on a Luminex IS 200 instrument., Results: Serum nanoplaques were not increased in clinical AD patients compared to non-AD memory clinic patients and nanoplaques were not associated with any cytokines. The cytokines IL-8 and G-CSF were increased in patients with clinical AD compared to non-AD patients., Conclusion: In this small pilot study, serum nanoplaques were not associated with serum cytokines. Nanoplaque levels could not be used to separate clinical AD patients from non-AD patients in this unselected memory clinic cohort.

Background: Chronic low-grade inflammation is associated with both ischemic stroke and sedentary behaviour. The aim of this study was to investigate the predictive abilities of biomarkers of inflammation and immune modulation associated with sedentary behaviour for ischemic stroke recurrence and mortality in a stroke population., Methods: Patients admitted to hospital for acute stroke were recruited to the prospective multicentre cohort study, the Norwegian Cognitive Impairment After Stroke (Nor-COAST) study, from May 2015 until March 2017. Patients with ischemic stroke, blood samples available from the three-month follow-up, and no stroke recurrence before the three-month follow-up were included. Serum was analysed for C-reactive protein (CRP) with high-sensitive technique, and plasma for interleukin-6 (IL-6), neopterin, pyridoxic acid ratio index (PAr-index: 4-pyridoxic acid: [pyrioxal+pyridoxal-5'-phosphate]) and kynurenic acid (KA). Ischemic stroke recurrence and death were identified by the Norwegian Stroke Registry and the Cause of Death Registry until 31 December 2018., Results: The study included 354 patients, 57% male, mean age 73 (SD 11) years, mean observation time 2.5 (SD 0.6) years, and median National Institute of Health Stroke Scale of 0 (IQR 1) at three months. CRP was associated with mortality (HR 1.40, CI 1.01, 1.96, p = 0.046), and neopterin was associated with the combined endpoint (recurrent ischemic stroke or death) (HR 1.52, CI 1.06, 2.20, p = 0.023), adjusted for age, sex, prior cerebrovascular disease, modified Rankin Scale, and creatinine. When adding neopterin and KA to the same model, KA was negatively associated (HR 0.57, CI 0.33, 0.97, p = 0.038), and neopterin was positively associated (HR 1.61, CI 1.02, 2.54, p = 0.040) with mortality. Patients with cardioembolic stroke at baseline had higher levels of inflammation at three months., Conclusion: Neopterin might be a valuable prognostic biomarker in stroke patients. The use of KA as a measure of anti-inflammatory capacity should be investigated further., Trial Registration: The study was registered at Clinicaltrials.gov ( NCT02650531 ). First posted on 08/01/2016., (© 2021. The Author(s).)

Background: Sedentary behaviour is associated with disease, but the molecular mechanisms are not understood. Valid biomarkers with predictive and explanatory properties are required. Therefore, we have investigated traditional and novel biomarkers of inflammation and immune modulation and their association to objectively measured sedentary behaviour in an ischemic stroke population., Methods: Patients admitted to hospital with acute ischemic stroke were included in the multicentre Norwegian Cognitive Impairment After Stroke (Nor-COAST) study (n = 815). For this sub-study (n = 257), sedentary behaviour was registered 3 months after stroke using position transition data from the body-worn sensor, ActivPal®. Blood samples were analysed for high sensitive C-reactive protein (hsCRP), the cytokines interleukin-6 (IL-6) and 10 (IL-10), neopterin, tryptophan (Trp), kynurenine (kyn), kynurenic acid (KA), and three B6 vitamers, pyridoxal 5'-phosphate (PLP), pyridoxal (PL), and pyridoxic acid (PA). The kynurenine/tryptophan ratio (KTR) and the pyridoxic acid ratio index (PAr = PA: PL + PLP) were calculated., Results: Of the 815 patients included in the main study, 700 attended the three-month follow-up, and 257 fulfilled the inclusion criteria for this study. Sedentary time was significantly associated with levels of hsCRP, IL-6, neopterin, PAr-index, and KA adjusted for age, sex, waist circumference, and creatinine. In a fully adjusted model including all the significant biomarkers except hsCRP (because of missing values), sedentary time was independently positively associated with the PAr-index and negatively with KA. We did not find an association between sedentary behaviour, IL-10, and KTR., Conclusions: The PAr-index is known to capture several modes of inflammation and has previously shown predictive abilities for future stroke. This novel result indicates that the PAr-index could be a useful biomarker in future studies on sedentary behaviour and disease progression. KA is an important modulator of inflammation, and this finding opens new and exciting pathways to understand the hazards of sedentary behaviour., Trial Registration: The study was registered at Clinicaltrials.gov ( NCT02650531 ). First posted 08/01/2016., (© 2021. The Author(s).)

Introduction: Post-stroke cognitive impairment (PSCI) is common, but evidence on the impact of vascular risk factors is lacking. We explored the association between pre-stroke vascular risk factors and PSCI and studied the course of PSCI. Materials and Methods: Vascular risk factors were collected at baseline in stroke survivors ( n = 635). Cognitive assessments of attention, executive function, memory, language, and the Montreal Cognitive Assessment (MoCA) were performed at 3 and/or 18 months post-stroke. Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS). PSCI was measured with global z; MoCA z-score; and z-score of the four assessed cognitive domains. Mixed-effect linear regression was applied with global z, MoCA z-score, and z-scores of the cognitive domains as dependent variables. Independent variables were the vascular risk factors (hypertension, hypercholesterolemia, smoking, diabetes mellitus, atrial fibrillation, coronary heart disease, previous stroke), time, and the interaction between these. The analyses were adjusted for age, education, and sex. There were between 5 and 25% missing data for the variables for PSCI. Results: Mean age was 71.6 years (SD 11.7); 42% were females; and the mean NIHSS score at admittance was 3.8 (SD 4.8). Regardless of vascular risk factors, global z, MoCA, and all the assessed cognitive domains were impaired at 3 and 18 months, with MoCA being the most severely impaired. Atrial fibrillation (AF) was associated with poorer language at 18 months and coronary heart disease (CHD) with poorer MoCA at 18 months (LR = 12.80, p = 0.002, and LR = 8.32, p = 0.004, respectively). Previous stroke was associated with poorer global z and attention at 3 and 18 months (LR = 15.46, p < 0.001, and LR = 16.20, p < 0.001). In patients without AF, attention improved from 3 to 18 months, and in patients without CHD, executive function improved from 3 to 18 months (LR = 10.42, p < 0.001, and LR = 9.33, p = 0.009, respectively). Discussion: Our findings indicate that a focal stroke lesion might be related to pathophysiological processes leading to global cognitive impairment. The poorer prognosis of PSCI in patients with vascular risk factors emphasizes the need for further research on complex vascular risk factor interventions to prevent PSCI., Competing Interests: IS and A-BK have been investigators in the Boehringer Ingelheim drug trial 1346.0023, and A-BK has also been an investigator for Roche BN29553. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Aam, Gynnild, Munthe-Kaas, Saltvedt, Lydersen, Knapskog, Ihle-Hansen, Ellekjær, Eldholm and Fure.)

Objectives: Patients with dementia follow different trajectories of progression. We aimed to investigate which factors at the time of diagnosis could predict trajectory group membership., Design: Longitudinal observational study., Setting: Specialized memory clinic, Oslo University Hospital in Norway., Participants: Patients assessed at the memory clinic, between 12 January 2009 and 31 July 2016, who were registered in the Norwegian Registry of persons assessed for cognitive symptoms (NorCog) and diagnosed with dementia after the baseline examination period (n = 442). The patients were followed up to 3 years, with an average of 3.5 examinations., Measurements: Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), the Consortium to Establish a Registry of Alzheimer's disease (CERAD) 10-item word list delayed recall, the Clock Drawing Test, (CDT) Trail Making Test A (TMT-A), and Neuropsychiatric Inventory Questionnaire (NPI-Q). Based on changes in scores on the CDR-SB, we used group-based trajectory modeling (GBTM) to explore the presence of trajectory groups. Multinomial logistic regression was used to explore whether a set of baseline variables could predict trajectory group membership., Results: Three trajectory groups were identified, one with a slow progression rate and two with more-rapid progression. Rapid progression was associated with older age, lower cognitive function (MMSE and TMT-A), and more-pronounced neuropsychiatric symptoms (NPI-Q) at the time of diagnosis., Conclusions: Our findings demonstrate the heterogeneity of dementia progression and describe risk factors for rapid progression, emphasizing the need for individual follow-up regimes. For future intervention studies, our results may guide the selection of patients.

Background: Chronic brain pathology and pre-stroke cognitive impairment (PCI) is predictive of post-stroke dementia. The aim of the current study was to measure pre-stroke neurodegenerative and vascular disease burden found on brain MRI and to assess the association between pre-stroke imaging pathology and PCI, whilst also looking for potential sex differences., Methods: This prospective brain MRI cohort is part of the multicentre Norwegian cognitive impairment after stroke (Nor-COAST) study. Patients hospitalized with acute ischemic or hemorrhagic stroke were included from five participating stroke units. Visual rating scales were used to categorize baseline MRIs (N = 410) as vascular, neurodegenerative, mixed, or normal, based on the presence of pathological imaging findings. Pre-stroke cognition was assessed by interviews of patients or caregivers using the Global Deterioration Scale (GDS). Stroke severity was assessed with the National Institute of Health Stroke Scale (NIHSS). Univariate and multiple logistic regression analyses were performed to investigate the association between imaging markers, PCI, and sex., Results: Patients' (N = 410) mean (SD) age was 73.6 (±11) years; 182 (44%) participants were female, the mean (SD) NIHSS at admittance was 4.1 (±5). In 68% of the participants, at least one pathological imaging marker was found. Medial temporal lobe atrophy (MTA) was present in 30% of patients, white matter hyperintensities (WMH) in 38% of patients and lacunes in 35% of patients. PCI was found in 30% of the patients. PCI was associated with cerebrovascular pathology (OR 2.5; CI = 1.4 to 4.5, p = 0.001) and mixed pathology (OR 3.4; CI = 1.9 to 6.1, p = 0.001) but was not associated with neurodegeneration (OR 1.0; CI = 0.5 to 2.2; p = 0.973). Pathological MRI markers, including MTA and lacunes, were more prevalent among men, as was a history of clinical stroke prior to the index stroke. The OR of PCI for women was not significantly increased (OR 1.2; CI = 0.8 to 1.9; p = 0.3)., Conclusions: Pre-stroke chronic brain pathology is common in stroke patients, with a higher prevalence in men. Vascular pathology and mixed pathology are associated with PCI. There were no significant sex differences for the risk of PCI., Trial Registration: NCT02650531 , date of registration: 08.01.2016.

Background: The aggregation of amyloid β (Aβ) is central in the pathogenesis of Alzheimer's disease (AD). Recently it has been shown that specifically, larger, Thioflavin T-binding Aβ aggregates are associated with increased neuroinflammation and cytokine release. This study was aimed to quantify fibrillary amyloid aggregates, so-called nanoplaques, and investigate their relationship with cytokines in the cerebrospinal fluid (CSF)., Methods: CSF was collected from 111 patients assessed for cognitive complaints at the Oslo University Hospital Memory Clinic. The patients were grouped based on their amyloid status. The CSF nanoplaque concentration was quantified with the Thioflavin T-fluorescence correlation spectroscopy (ThT-FCS) assay. The levels of nine cytokines (eotaxin-1, granulocyte stimulating factor, interleukin [IL]-6, IL-7, IL-8, monocyte chemoattractant protein-1, gamma-induced protein 10, macrophage inflammatory protein [MIP]-1α, and MIP-1β) were quantified with a magnetic bead-based multiplex assay and read on a Luminex IS 200 instrument., Results: There were 49 amyloid-negative and 62 amyloid-positive patients in the cohort; none of the cytokines differed significantly between the amyloid groups. The increased nanoplaque levels were associated with levels of MIP-1β below the lower limit of quantification, and with decreased levels of MIP-1α and IL-8. The associations remained significant when adjusted for age, sex, cognitive function, apolipoprotein ε4 status and CSF core biomarker levels., Conclusion: The cytokine levels were not associated with amyloid status in this cohort. The nanoplaque levels were negatively associated with MIP-1β, MIP-1α and IL-8, which is in line with recent findings suggesting that the upregulation of some cytokine markers has a protective role and is negatively associated with AD progression.

Objectives: Neuropsychiatric symptoms (NPS) are associated with dementia severity and progression rate. NPS clusters have different neurobiological underpinnings; therefore, their effect on dementia progression may differ. Furthermore, little is known about whether individual comorbidities affect progression rate. We investigated the effect of NPS clusters and individual comorbidities on dementia progression., Methods: A memory clinic cohort with all-cause dementia (N = 442) was followed for up to 3 years from diagnosis. Previously, we found trajectory groups of dementia progression in this cohort: one with slow progression and two with rapid progression. In the present study, using principal component analysis, three symptom clusters of NPS were identified on the Neuropsychiatric Inventory Questionnaire (NPI-Q): agitation, affective and psychosis symptom clusters. Data regarding comorbidity were collected by linkage to the Norwegian Patient Registry. Multinomial logistic regression was applied to explore the association between NPS clusters and comorbidity with trajectory-group membership., Results: Adjusted for demographics, dementia aetiology, comorbidity and cognition, we found that, at the time of dementia diagnosis, for every point within the psychosis symptom cluster of the NPI-Q, the risk of rapid progression increased by 53%; for every point within the affective symptom cluster, the risk of rapid progression increased by 29%. A previous diagnosis of mental and behavioural disorders (excluding dementia) decreased the risk of rapid dementia progression by 65%., Conclusions: Psychosis and affective symptom clusters at the time of diagnosis were associated with rapid progression of dementia. Previous diagnoses of mental and behavioural disorders (excluding dementia) were associated with slow progression., (© 2021 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Alzheimer's disease is the most common cause of dementia globally. Its prevalence will increase considerably in the years to come, in pace with the increasing proportion of older people. No disease-modifying treatment is currently available. Measures to mitigate risk in mid-life may potentially prevent or postpone up to 40 % of dementia cases at group level.

Background: Studies regarding adequacy of secondary stroke prevention are limited. We report medication adherence, risk factor control and factors influencing vascular risk profile following ischaemic stroke., Methods: A total of 664 home-dwelling participants in the Norwegian Cognitive Impairment After Stroke study, a multicenter observational study, were evaluated 3 and 18 months poststroke. We assessed medication adherence by self-reporting (4-item Morisky Medication Adherence Scale) and medication persistence (defined as continuation of medication(s) prescribed at discharge), achievement of guideline-defined targets of blood pressure (BP) (<140/90 mmHg), low-density lipoprotein cholesterol (LDL-C) (<2.0 mmol L -1 ) and haemoglobin A1c (HbA1c) (≤53 mmol mol -1 ) and determinants of risk factor control., Results: At discharge, 97% were prescribed antithrombotics, 88% lipid-lowering drugs, 68% antihypertensives and 12% antidiabetic drugs. Persistence of users declined to 99%, 88%, 93% and 95%, respectively, at 18 months. After 3 and 18 months, 80% and 73% reported high adherence. After 3 and 18 months, 40.7% and 47.0% gained BP control, 48.4% and 44.6% achieved LDL-C control, and 69.2% and 69.5% of diabetic patients achieved HbA1c control. Advanced age was associated with increased LDL-C control (OR 1.03, 95% CI 1.01 to 1.06) and reduced BP control (OR 0.98, 0.96 to 0.99). Women had poorer LDL-C control (OR 0.60, 0.37 to 0.98). Polypharmacy was associated with increased LDL-C control (OR 1.29, 1.18 to 1.41) and reduced HbA1c control (OR 0.76, 0.60 to 0.98)., Conclusion: Risk factor control is suboptimal despite high medication persistence and adherence. Improved understanding of this complex clinical setting is needed for optimization of secondary preventive strategies., (© 2020 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Working memory training (WMT) effects may be modulated by mild cognitive impairment (MCI) subtypes, and variations in APOE -epsilon ( APOE -ε) and LMX1A genotypes. Sixty-one individuals (41 men/20 women, mean age 66 years) diagnosed with MCI (31 amnestic/30 non-amnestic) and genotyped for APOE -ε and LMX1A completed 4 weeks/20-25 sessions of WMT. Cognitive functions were assessed before, 4 weeks and 16 weeks after WMT. Except for Processing Speed, the non-amnestic MCI group (naMCI) outperformed the amnestic MCI (aMCI) group in all cognitive domains across all time-points. At 4 weeks, working memory function improved in both groups ( p < 0.0001), but at 16 weeks the effects only remained in the naMCI group. Better performance was found after training for the naMCI patients with LMX1A -AA genotype and for the APOE -ε4 carriers. Only the naMCI- APOE -ε4 group showed improved Executive Function at 16 weeks. WMT improved working memory and some non-trained cognitive functions in individuals with MCI. The naMCI group had greater training gain than aMCI group, especially in those with LMX1A -AA genotype and among APOE- ε4-carriers. Further research with larger sample sizes for the subgroups and longer follow-up evaluations is warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hernes, Flak, Løhaugen, Skranes, Hol, Madsen, Knapskog, Engvig, Pripp, Ulstein, Lona, Zhang and Chang.)

Background: Motor and cognitive impairments are frequently observed following stroke, but are often managed as distinct entities, and there is little evidence regarding how they are related. The aim of this study was to describe the prevalence of concurrent motor and cognitive impairments 3 months after stroke and to examine how motor performance was associated with memory, executive function and global cognition., Methods: The Norwegian Cognitive Impairment After Stroke (Nor-COAST) study is a prospective multicentre cohort study including patients hospitalized with acute stroke between May 2015 and March 2017. The National Institutes of Health Stroke Scale (NIHSS) was used to measure stroke severity at admission. Level of disability was assessed by the Modified Rankin Scale (mRS). Motor and cognitive functions were assessed 3 months post-stroke using the Montreal Cognitive Assessment (MoCA), Trail Making Test Part B (TMT-B), 10-Word List Recall (10WLR), Short Physical Performance Battery (SPPB), dual-task cost (DTC) and grip strength (Jamar®). Cut-offs were set according to current recommendations. Associations were examined using linear regression with cognitive tests as dependent variables and motor domains as covariates, adjusted for age, sex, education and stroke severity., Results: Of 567 participants included, 242 (43%) were women, mean (SD) age was 72.2 (11.7) years, 416 (75%) had an NIHSS score ≤ 4 and 475 (84%) had an mRS score of ≤2. Prevalence of concurrent motor and cognitive impairment ranged from 9.5% for DTC and 10WLR to 22.9% for grip strength and TMT-B. SPPB was associated with MoCA (regression coefficient B = 0.465, 95%CI [0.352, 0.578]), TMT-B (B = -9.494, 95%CI [- 11.726, - 7.925]) and 10WLR (B = 0.132, 95%CI [0.054, 0.211]). Grip strength was associated with MoCA (B = 0.075, 95%CI [0.039, 0.112]), TMT-B (B = -1.972, 95%CI [- 2.672, - 1.272]) and 10WLR (B = 0.041, 95%CI [0.016, 0.066]). Higher DTC was associated with more time needed to complete TMT-B (B = 0.475, 95%CI [0.075, 0.875]) but not with MoCA or 10WLR., Conclusion: Three months after suffering mainly minor strokes, 30-40% of participants had motor or cognitive impairments, while 20% had concurrent impairments. Motor performance was associated with memory, executive function and global cognition. The identification of concurrent impairments could be relevant for preventing functional decline., Trial Registration: ClinicalTrials.gov Identifier: NCT02650531 .

Accurate biomarkers of Alzheimer's disease (AD) are essential for early diagnosis and intervention. Available biomarkers are not sufficient to permit the monitoring of AD progression over time, and additional biomarkers are required. Measures of aggregated amyloid-β (Aβ) could be useful biomarkers for AD. Here, we investigate whether levels of Thioflavin-T (ThT) positive amyloid aggregates, i.e., nanoplaques, in cerebrospinal fluid (CSF) could serve as useful biomarkers for AD. One-hundred and eighteen memory clinic patients were AT(N) classified, and CSF nanoplaque concentrations were compared between patients on the "Alzheimer's continuum" (A+ patients) and patients with "Normal AD biomarkers" or "Non-AD pathologic change" (A- patients). CSF nanoplaque concentrations and sizes were quantified using the novel ThT-Fluorescence Correlation Spectroscopy (ThT-FCS) assay, and core biomarkers (Aβ 42 , total tau and phosphorylated tau) were determined by enzyme-linked immunosorbent assays. We investigated the association between nanoplaque concentrations and core biomarkers, and the diagnostic value of nanoplaque levels. Nanoplaque levels were increased in A+ patients compared to A- patients. Nanoplaque concentrations were negatively associated with Aβ 42 , but not related to total tau or phosphorylated tau measures. Quantification of nanoplaques did not improve the classification of patients on the Alzheimer's continuum compared to the core biomarkers alone. Dynamic changes in nanoplaques concentration and size throughout AD stages should be explored in longitudinal studies., Competing Interests: ABK and THE have worked on clinical trials for Roche (BN29553) and Boehringer-Ingelheim (1346.0023). AT, LT and VV have filed a patent application under the Patent Cooperation Treat (PCT) WO 2019/192969 A1 “Method for the Diagnosis of Amyloid-Associated Diseases.” The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Aksnes, Tiiman, Edwin, Terenius, Bogdanović, Vukojević and Knapskog.)

Background: Delirium is associated with an increased risk of incident dementia and accelerated progression of existing cognitive symptoms. Reciprocally, dementia increases the risk of delirium. Cerebrospinal fluid (CSF) concentration of the dendritic protein neurogranin has been shown to increase in early Alzheimer's disease (AD), likely reflecting synaptic dysfunction and/or degeneration., Objective: To elucidate the involvement of synaptic dysfunction in delirium pathophysiology, we tested the association between CSF neurogranin concentration and delirium in hip fracture patients with different AD-biomarker profiles, while comparing them to cognitively unimpaired older adults (CUA) and AD patients., Methods: The cohort included hip fracture patients with (n = 70) and without delirium (n = 58), CUA undergoing elective surgery (n = 127), and AD patients (n = 46). CSF was collected preoperatively and diagnostically in surgery and AD patients respectively. CSF neurogranin concentrations were analyzed in all samples with an in-house ELISA. Delirium was assessed pre-and postoperatively in hip fracture patients by trained investigators using the Confusion Assessment Method. Hip fracture patients were further stratified based on pre-fracture dementia status, delirium subtype, and AD fluid biomarkers., Results: No association was found between delirium and CSF neurogranin concentration (main analysis: delirium versus no delirium, p = 0.68). Hip fracture patients had lower CSF neurogranin concentration than AD patients (p = 0.001) and CUA (p = 0.035) in age-adjusted sensitivity analyses., Conclusion: The findings suggest that delirium is not associated with increased CSF neurogranin concentration in hip fracture patients, possibly due to advanced neurodegenerative disease and age and/or because synaptic degeneration is not an important pathophysiological process in delirium.

Introduction: The progression rate of Alzheimer's disease (AD) varies and might be affected by the triggering receptor expressed on myeloid cells (TREM2) activity. We explored if cerebrospinal fluid (CSF) soluble TREM2 (sTREM2), a proxy of microglial activity, is associated with clinical progression rate., Methods: Patients with clinical AD (N = 231) were followed for up to 3 years after diagnosis. Cognitively healthy controls (N = 42) were followed for 5 years. CSF sTREM2 was analyzed by enzyme-linked immunosorbent assay. Group-based trajectory modeling revealed distinct clinical progression groups., Results: Higher CSF sTREM2 was associated with slow clinical progression. The slow- and medium-progressing groups had higher CSF sTREM2 than the cognitively healthy, who had a similar level to patients with rapid clinical progression., Discussion: CSF sTREM2 levels were associated with clinical progression in AD, regardless of core biomarkers. This could be useful in assessing disease development in relation to patient care and clinical trial recruitment., Competing Interests: Dr. Edwin, Dr. Persson, and Dr. Knapskog report work with Roche BN29553; Dr. Edwin, Dr. Knapskog, and Dr. Saltvedt report work with Boehringer‐Ingelheim 1346.0023, outside the submitted work. Dr. Nilsson has received an honorarium from BioArctic, and has a collaboration with this company, outside the submitted work. The other authors declare no conflicts of interest., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Objectives: To estimate transition times from dementia diagnosis to nursing-home (NH) admission or death and to examine whether sex, education, marital status, level of cognitive impairment and dementia aetiology are associated with transition times., Design: Markov multistate survival analysis and flexible parametric models., Setting: Participants were recruited from the Norwegian Registry of Persons Assessed for Cognitive Symptoms (NorCog) in specialist healthcare between 2008 and 2017 and followed until August 2019, a maximum of 10.6 years follow-up time (mean 4.4 years, SD 2.2). Participants' address histories, emigration and vital status were retrieved from the National Population Registry from time of diagnosis and linked to NorCog clinical data., Participants: 2,938 home-dwelling persons with dementia, ages 40-97 years at time of diagnosis (mean 76.1, SD 8.5)., Results: During follow-up, 992 persons (34%) were admitted to nursing-homes (NHs) and 1,556 (53%) died. Approximately four years after diagnosis, the probability of living in a NH peaked at 19%; thereafter, the probability decreased due to mortality. Median elapsed time from dementia diagnosis to NH admission among those admitted to NHs was 2.28 years (IQR 2.32). The probability of NH admission was greater for women than men due to women´s lower mortality rate. Persons living alone, particularly men, had a higher probability of NH admission than cohabitants. Age, dementia aetiology and severity of cognitive impairment at time of diagnosis did not influence the probability of NH admission. Those with fewer than 10 years of education had a lower probability of NH admission than those with 10 years or more, and this was independent of the excess mortality in the less-educated group., Conclusion: Four years after diagnosis, half of the participants still lived at home, while NH residency peaked at 19%. Those with fewer than 10 years of education were less often admitted to NH., Competing Interests: The authors have declared that no competing interests exist.

Background and Purpose: Sedentary behaviour is a risk factor for vascular disease and stroke patients are more sedentary than their age-matched peers. The association with glucose levels, as a potential mediator, is unclear, and we have investigated the association between long-bout sedentary behaviour and long-term glucose levels in stroke survivors., Methods: This study uses data from the Norwegian Cognitive Impairment After Stroke study, a multicentre cohort study. The patients were recruited at hospital admission for acute stroke, and the follow-up was done at the outpatient clinic. Sedentary behaviour-being in a sitting or reclining position-was registered 3 months after stroke using position transition data from the body-worn sensor activPAL attached to the unaffected thigh. A MATLAB script was developed to extract activity data from 08:00 to 10:00 for 4 days and to categorise the data into four bout-length categories. The primary outcome was glycated haemoglobin (HbA1c), analysed at 3 months. Regression models were used to analyse the association between HbA1c and sedentary behaviour in the whole population and stratified based on a diagnosis of diabetes mellitus (DM). Age, body mass index and the use of antidiabetic drugs were added as covariates into the models., Results: From a total of 815 included patients, 379 patients fulfilled the inclusion criteria for this study. We found no association between time in sedentary behaviour and HbA1c in the whole stroke population. We found time in sedentary behaviour in bouts of ≥90 min to be associated with a higher HbA1c in patients with DM., Conclusion: Long-bout sedentary time is associated with a higher HbA1c in patients with DM 3 months after ischaemic stroke. Future research should investigate the benefit of breaking up sedentary time as a secondary preventive measure., Trial Registration Number: NCT02650531, https://clinicaltrials.gov/ct2/show/NCT02650531., Competing Interests: Competing interests: A-BK: principal investigator in two drug trials (Roche BN29553 and Boehringer-Ingelheim 1346-0023) at the memory clinic, Oslo University Hospital. Others: none declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia. Its cleaved fragments, soluble TREM2 (sTREM2), can be measured in the cerebrospinal fluid (CSF). Previous studies indicate higher CSF sTREM2 in symptomatic AD; however most of these studies have included biomarker positive AD cases and biomarker negative controls. The aim of the study was to explore potential differences in the CSF level of sTREM2 and factors associated with an increased sTREM2 level in patients diagnosed with mild cognitive impairment (MCI) or dementia due to AD compared with cognitively unimpaired controls as judged by clinical symptoms and biomarker category (AT). We included 299 memory clinic patients, 62 (20.7%) with AD-MCI and 237 (79.3%) with AD dementia, and 113 cognitively unimpaired controls. CSF measures of the core biomarkers were applied to determine AT status. CSF sTREM2 was analyzed by ELISA. Patients presented with comparable CSF sTREM2 levels as the cognitively unimpaired (9.6 ng/ml [SD 4.7] versus 8.8 ng/ml [SD 3.6], p = 0.27). We found that CSF sTREM2 associated with age-related neuroinflammation and tauopathy irrespectively of amyloid β, APOE ε4 status or gender. The findings were similar in both symptomatic and non-symptomatic individuals.

Background: Post-stroke cognitive impairment (PSCI) is common, but evidence of cognitive symptom profiles, course over time, and pathogenesis is scarce. We investigated the significance of time and etiologic stroke subtype for the probability of PSCI, severity, and cognitive profile. Methods: Stroke survivors ( n = 617) underwent cognitive assessments of attention, executive function, memory, language, perceptual-motor function, and the Montreal Cognitive Assessment (MoCA) after 3 and/or 18 months. PSCI was classified according to DSM-5 criteria. Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS). Stroke subtype was categorized as intracerebral hemorrhage (ICH), large artery disease (LAD), cardioembolic stroke (CE), small vessel disease (SVD), or un-/other determined strokes (UD). Mixed-effects logistic or linear regression was applied with PSCI, MoCA, and z-scores of the cognitive domains as dependent variables. Independent variables were time as well as stroke subtype, time, and interaction between these. The analyses were adjusted for age, education, and sex. The effects of time and stroke subtype were analyzed by likelihood ratio tests (LR). Results: Mean age was 72 years (SD 12), 42% were females, and mean NIHSS score at admittance was 3.8 (SD 4.8). Probability (95% CI) for PSCI after 3 and 18 months was 0.59 (0.51-0.66) and 0.51 (0.52-0.60), respectively and remained constant over time. Global measures and most cognitive domains were assessed as impaired for the entire stroke population and for most stroke subtypes. Executive function and language improved for the entire stroke population (LR) = 9.05, p = 0.003, and LR = 10.38, p = 0.001, respectively). After dividing the sample according to stroke subtypes, language improved for ICH patients (LR = 18.02, p = 0.003). No significant differences were found in the severity of impairment between stroke subtypes except for attention, which was impaired for LAD and CE in contrast to no impairment for SVD (LR = 56.58, p < 0.001). Conclusions: In this study including mainly minor strokes, PSCI is common for all subtypes, both early and long-term after stroke, while executive function and language improve over time. The findings might contribute to personalizing follow-up and offer new insights into underlying mechanisms. Further research is needed on underlying mechanisms, PSCI prevention and treatment, and relevance for rehabilitation., (Copyright © 2020 Aam, Einstad, Munthe-Kaas, Lydersen, Ihle-Hansen, Knapskog, Ellekjær, Seljeseth and Saltvedt.)

Introduction: Post-stroke neurocognitive disorder (NCD) is common; prevalence varies between studies, partially related to lack of consensus on how to identify cases. The aim was to compare the prevalence of post-stroke NCD using only cognitive assessment (model A), DSM-5 criteria (model B), and the Global Deterioration Scale (model C) and to determine agreement among the three models., Methods: In the Norwegian Cognitive Impairment After Stroke study, 599 patients were assessed 3 months after suffering a stroke., Results: The prevalence of mild NCD varied from 174 (29%) in model B to 83 (14%) in model C; prevalence of major NCD varied from 249 (42%) in model A to 68 (11%) in model C. Cohen's kappa and Cohen's quadratic weighted kappa showed fair to very good agreement among models; the poorest agreement was found for identification of mild NCD., Discussion: The findings indicate a need for international harmonization to classify post-stroke NCD., Competing Interests: The authors declare they have no competing interests. ABK and IS have been investigators in the drug trial Boehringer‐Ingelheim 1346.0023, and ABK has also been an investigator for Roche BN29553., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Background: Aggregation of amyloid-β (Aβ) is an early pathological event in Alzheimer's disease (AD). Consequently, measures of pathogenic aggregated Aβ are attractive biomarkers for AD. Here, we use a recently developed Thioflavin-T-Fluorescence Correlation Spectroscopy (ThT-FCS) assay to quantify structured ThT-responsive protein aggregates, so-called nanoplaques, in the cerebrospinal fluid (CSF)., Objective: The overall aim of this work was to assess whether ThT-FCS determined CSF nanoplaque levels could predict amyloid brain uptake as determined by 18F-Flutemetamol PET analysis. Further, we assess whether nanoplaque levels could predict clinical AD., Methods: Nanoplaque levels in the CSF from 54 memory clinic patients were compared between sub-groups classified by 18F-Flutemetamol PET as amyloid-positive or amyloid-negative, and by clinical assessment as AD or non-AD., Results: Nanoplaque levels did not differ between amyloid groups and could not predict brain amyloid uptake. However, nanoplaque levels were significantly increased in patients with clinical AD, and were significant predictors for AD when adjusting for age, sex, cognitive function, and apolipoprotein E (APOE) genotype., Conclusion: The concentration of nanoplaques in the CSF differentiates patients with clinical AD from non-AD patients.

Neurodegenerative diseases are highly debilitating illnesses and a growing cause of morbidity and mortality worldwide. Mitochondrial dysfunction and impairment of mitochondrial-specific autophagy, namely mitophagy, have emerged as important components of the cellular processes underlying neurodegeneration. Defective mitophagy has been highlighted as the cause of the accumulation of damaged mitochondria, which consequently leads to cellular dysfunction and/or death in neurodegenerative diseases. Here, we highlight the recent advances in the molecular mechanisms of mitochondrial homeostasis and mitophagy in neurodegenerative diseases. In particular, we evaluate how mitophagy is altered in Alzheimer's, Parkinson's, and Huntington's diseases, as well as in amyotrophic lateral sclerosis, and the potential of restoring mitophagy as a therapeutic intervention. We also discuss the interlinked connections between mitophagy and innate immunity (e.g., the involvement of Parkin, interferons and TRIM21) as well as the opportunity these pathways provide to develop combinational therapeutic strategies targeting them and related molecular mechanisms in such neurodegenerative diseases., Competing Interests: Declaration of interests E.F.F. has CRADA arrangements with ChromaDex and is consultant to Aladdin Healthcare Technologies and Vancouver Dementia Prevention Centre., (© 2020 Elsevier Inc. All rights reserved.)

Background: Delirium is a common and serious complication in geriatric patients. The pathophysiology of delirium is not known., Objective: The objective of the current study was to test the hypothesis that cerebrospinal fluid (CSF) levels of inflammatory markers at the time of spinal anesthesia for hip surgery are associated with delirium., Methods: In total 133 hip fracture patients and 125 cognitively healthy controls undergoing elective surgery, together with 73 Alzheimer's disease (AD) dementia patients, were recruited at Oslo University Hospital and Diakonhjemmet Hospital, Oslo, Norway. Delirium was evaluated daily in hip fracture patients by the Confusion Assessment Method (CAM). Depression was evaluated by Cornell Scale for Depression in Dementia (CSDD). Tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-8 (IL-8) levels were measured in CSF using a Mesoscale Discovery (MSD) immunoassay., Results: Hip fracture patients had significantly higher IL-8 levels (p < 0.001) compared to cognitively healthy controls or patients with stable AD dementia. Furthermore, preoperative IL-8 levels were significantly higher (p = 0.013) in hip fracture patients who developed delirium (incident delirium) after surgery as compared to patients with no delirium. However, subgroup analyses showed that IL-8 levels were only significantly higher in delirium patients without dementia (p = 0.006). In contrast, depression subgroup analysis showed that IL-8 concentration was significantly higher (p = 0.002) in delirium patients with depression. Both TNF-α and IL-1β were undetected in most patients., Conclusions: Our study suggests that IL-8 levels are associated with delirium onset and that underlying depression or dementia influences IL-8 levels.

Objective: Neuroinflammation may play an important role in the pathogenesis and progression of Alzheimer disease (AD). The aim of the present study was to detect whether increased inflammatory activity at baseline could predict cognitive and functional decline in patients with amnestic mild cognitive impairment (aMCI) or AD dementia after 2 years., Methods: Serum samples from 242 memory clinic patients with an aMCI (n=88) or AD dementia (n=154) were analyzed for C-reactive protein and for 14 other inflammatory markers [interleukin (IL)-1β, interleukin-1 receptor antagonist, IL-6, IL-10, IL-12p40, IL-17a, IL-18, IL-22, IL-33, tumor necrosis factor, cluster of differentiation 40 ligand, interferon-γ, chemokine ligand (CCL) 2, and CCL4] by bead-based multiplex immunoassay. Disease progression was measured by the annual increase in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and annual decrease in the score on the Mini-Mental State Examination (MMSE)., Results: No association between increased levels of the inflammatory markers and change on the CDR-SB or MMSE score was found, but there was a significant difference in baseline IL-6 and interleukin-1 receptor antagonist levels between aMCI and AD dementia groups., Conclusion: Increased levels of inflammatory markers were not associated with faster progression as measured by the annual change on the CDR-SB or MMSE score.

Background: Hip fracture represents a substantial acute inflammatory trauma, which may constitute a significant insult to the degenerating brain. Research suggests that an injury of this kind can affect memory and thinking in the future but it is unclear whether, and how, inflammatory trauma injures the brain. The impact of Acute SystematiC inflammation upon cerebRospinal fluId and blood BiomarkErs of brain inflammation and injury in Dementia: a study in acute hip fracture patients (ASCRIBED) explores this relationship, to understand the effect of inflammation on the progression of dementia., Methods: This protocol describes a multi-centre sample collection observational study. The study utilises the unique opportunity provided by hip fracture operations undertaken via spinal anaesthesia to collect cerebrospinal fluid (CSF) and blood, to investigate the impact of acute brain inflammation caused by hip fracture on the exacerbation of dementia. We will recruit 200 hip fracture patients with a diagnosis or evidence of dementia; and 200 hip fracture patients without dementia. We will also recruit 'Suitable informants', individuals in regular contact with the patient, to provide further proxy evidence of a patient's potential cognitive decline. We will compare these 400 samples with existing CSF and blood samples from a cohort of dementia patients who had not experienced a systemic inflammatory response due to injury. This will provide a comparison between patients with and without dementia who are suffering a systemic inflammatory response; with stable patients living with dementia., Discussion: We will test the hypothesis that hip fracture patients living with dementia show elevated markers of brain inflammation, as well as neuronal injury and Alzheimer-related plaque pathology, in comparison to (1) stable patients living with dementia and (2) hip fracture patients without dementia, as measured by biomarkers in CSF and blood. The findings will address the hypothesis that systemic inflammatory events can exacerbate underlying dementia and inform the search for new treatments targeting inflammation in dementia., Trial Registration: ISRCTN43803769 . Registered 11 May 2017.

Background: Alzheimer's disease (AD) remains a clinical diagnosis but biomarkers from cerebrospinal fluid (CSF) and more lately amyloid imaging with positron emission tomography (PET), are important to support a diagnosis of AD., Objective: To compare amyloid-β (Aβ) PET imaging with biomarkers in CSF and evaluate the prediction of Aβ PET on diagnosis in a memory clinic setting., Methods: We included 64 patients who had lumbar puncture and Aβ PET with 18F-Flutemetamol performed within 190 days. PET was binary classified (Flut+ or Flut-) and logistic regression analyses for correlation to each CSF biomarker; Aβ 42 (Aβ42), total tau (T-tau) and phosphorylated tau (P-tau), were performed. Cut-off values were assessed by receiver operating characteristic (ROC) curves. Logistic regression was performed for prediction of clinical AD diagnosis. We assessed the interrater agreement of PET classification as well as for diagnoses, which were made both with and without knowledge of PET results., Results: Thirty-two of the 34 patients (94%) in the Flut+ group and nine of the 30 patients (30%) in the Flut- group had a clinical AD diagnosis. There were significant differences in all CSF biomarkers in the Flut+ and Flut- groups. Aβ42 showed the highest correlation with 18F-Flutemetamol PET with a cut-off value of 706.5 pg/mL, corresponding to sensitivity of 88% and specificity of 87%. 18F-Flutemetamol PET was the best predictor of a clinical AD diagnosis. We found a very high interrater agreement for both PET classification and diagnosis., Conclusions: The present study showed an excellent correlation of Aβ42 in CSF and 18F-Flutemetamol PET and the presented cut-off value for Aβ42 yields high sensitivity and specificity for 18F-Flutemetamol PET. 18F-Flutemetamol PET was the best predictor of clinical AD diagnosis., Competing Interests: I have read the journal´s policy and the authors of this manuscript have the following competing interests: ABK is the principal investigator of, and THE is a rater, in two drug trials (ROCHE BN29553 and Boehringer-Ingelheim 1346-0023) conducted at the memory clinic, Oslo University Hospital.

Objective: We investigated if a 5-week computerized adaptive working memory training program (Cogmed ® ) of 20 to 25 sessions would be effective in improving the working memory capacity and other neuropsychological functions compared to a non-adaptive working memory training program (active-controlled) in adult patients with mild cognitive impairment (MCI)., Methods: This randomized double-blinded active control trial included 68 individuals aged 43 to 88 years, 45 men and 23 women, who were diagnosed with MCI at four Memory clinics. The study sample was randomized by block randomization to either adaptive or non-adaptive computerized working memory training. All participants completed the training, and were assessed with a comprehensive neuropsychological test battery before the intervention, and at 1 and 4 months after training., Results: Compared to the non-adaptive training group, the adaptive training group did not show significantly greater improvement on the main outcome of working memory performance at 1 and 4 months after training., Conclusion: No difference were found between the two types of training on the primary outcome of working memory, or on secondary outcomes of cognitive function domains, in this sample of MCI patients. Hence, the hypothesis that the adaptive training program would lead to greater improvements compared to the non-adaptive training program was not supported. Within group analyses was not performed due to the stringent RCT design.

Cortisol dysregulation has been reported in dementia and depression. Cortisol levels and its associates were investigated among older people living at home and in nursing homes, in a cross-sectional study. A sample of 650 older people, from the community (home and nursing homes) and specialized care (memory clinics and old age psychiatry wards), mean age 76.8 (SD = 10.3) (dementia n = 319, depression, n = 154, dementia plus depression n = 53, and reference group n = 124), was included. Assessment included the Mini Mental State Examination (MMSE), Cornell scale for depression in dementia, activities of daily living scales, and salivary cortisol. Number of drugs was registered. The results showed that the cortisol ratio was highest among patients with dementia and co-morbid depression in comparison to those with either depression or dementia and the reference group. Characteristics significantly associated with cortisol levels were higher MMSE score (in patients with dementia and co-morbid depression), male gender (in people with dementia), and number of medications (in the reference group). We conclude that the cortisol ratio was highest among patients with dementia and co-morbid depression in comparison to those with either depression or dementia and the reference group. The association of cortisol level with MMSE score among patients with dementia and depression could further indicate that increased stress is related to cognitive function.