Neopterin, kynurenine metabolites, and indexes related to vitamin B6 are associated with post-stroke cognitive impairment: The Nor-COAST study.

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.

Plasma Inflammatory Biomarkers Are Associated With Poststroke Cognitive Impairment: The Nor-COAST Study.

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.

Higher concentrations of kynurenic acid in CSF are associated with the slower clinical progression of Alzheimer's disease.

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 (ß = 0.18, P < 0.01) and picolinic acid (ß = 0.20, P < 0.01) than the controls. KA was positively associated with tau pathology (ß = 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.

Hippocampal Atrophy Subtypes of Alzheimer's Disease Using Automatic MRI in a Memory Clinic Cohort: Clinical Implications.

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.

Investigating novel biomarkers of immune activation and modulation in the context of sedentary behaviour: a multicentre prospective ischemic stroke cohort study.

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.

Neopterin and kynurenic acid as predictors of stroke recurrence and mortality: a multicentre prospective cohort study on biomarkers of inflammation measured three months after ischemic stroke.

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.

Neuropsychiatric symptoms and comorbidity: Associations with dementia progression rate in a memory clinic cohort.

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.

Trajectories and risk factors of dementia progression: a memory clinic cohort followed up to 3 years from diagnosis.

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.

Pre-stroke cognitive impairment is associated with vascular imaging pathology: a prospective observational study.

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.

Associations between post-stroke motor and cognitive function: a cross-sectional study.

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 .

Alzheimer's disease ­ diagnosis and treatment. / Alzheimers sykdom ­ diagnostikk og behandling.

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.

The Association Between Circulating Inflammatory Markers and the Progression of Alzheimer Disease in Norwegian Memory Clinic Patients With Mild Cognitive Impairment or Dementia.

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)-1ß, 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.

The Loss in Expectation of Life due to Early-Onset Mild Cognitive Impairment and Early-Onset Dementia in Norway.

INTRODUCTION: Whether patients with early-onset dementia have poorer or improved survival compared with those with a late onset largely depends on the survival measure. Survival estimates for early-onset mild cognitive impairment (MCI) diagnosis are particularly scarce. We aimed to estimate life expectancy (LE) in patients with early-onset dementia or early MCI, and loss in expectation of life (LEL) for these groups. Comparisons were made with the general Norwegian population and a subgroup of patients with late-onset dementia. METHODS: Early onset was defined as receiving a diagnosis of MCI or dementia before age 65 years. LE and LEL were predicted using flexible parametric survival models. Our study population was comprised of newly diagnosed (incident) cases (n = 4,906), aged 50-90 years at the time of diagnosis (672 were diagnosed before age 65 years, of which 291 were diagnosed with dementia), in the Norwegian register of persons assessed for cognitive symptoms (NorCog) between 2009 and 2017, and patients were followed up for mortality or censorship until January 2018. RESULTS: Among the early-onset patients, 8 and 23% died during follow-up, in the MCI and dementia groups, respectively. Both early-onset MCI and especially early-onset dementia were associated with lower LE than in the general Norwegian population; LE for 60-year-old women in 2016 was 26 years in the general population, 20 years in MCI patients, and 7 years in dementia patients. The corresponding LE at 80 years was 10, 6, and 5 years. Thus, LEL were particularly pronounced for patients with early dementia. The diagnosis-specific LE pattern in men was similar to that in women. DISCUSSION: Early-onset MCI was associated with substantial life years lost (5-6 years), but the loss was particularly pronounced for those with early-onset dementia, reducing the expected life length by 2 decades.

Study protocol: ASCRIBED: 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.

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.

Cortisol levels among older people with and without depression and dementia.

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.

The Norwegian Cognitive impairment after stroke study (Nor-COAST): study protocol of a multicentre, prospective cohort study.

BACKGROUND: Early and late onset post-stroke cognitive impairment (PCI) contributes substantially to disability following stroke, and is a high priority within stroke research. The aetiology for PCI is complex and related to the stroke itself, brain resilience, comorbid brain diseases, prestroke vulnerability and complications during the hospital stay. The aim of the Norwegian Cognitive Impairment After Stroke study (Nor-COAST) is to quantify and measure levels of cognitive impairments in a general Norwegian stroke population and to identify biological and clinical markers associated with prognosis for cognitive disorders following incident stroke. The study will be organised within five work packages: 1) Incidence and trajectories 2) Pathological mechanisms 3) Development of a risk score 4) Impact of physical activity and 5) Adherence to secondary prevention. METHODS: Nor-COAST is an ongoing multicentre (five participating hospitals), prospective, cohort study with consecutive inclusion during the acute phase and with follow-up at three and 18 months, and at three years. Inclusion criteria are stroke defined according to the WHO criteria. During the recruitment period from 18.05.2015 to 31.03.2017, 816 participants have been included. Cognitive impairment will be classified according to the DSM-5 criteria using a consensus group. Cognitive function is assessed by a standardised neuropsychological test battery, the Montreal Cognitive Assessment, Trail making A and B, ten-word immediate and delayed recall test, the Controlled Oral Word Association, Global Deterioration Scale and proxy based information by and the Ascertain Dementia 8 item informant questionnaire. Biomarkers include magnetic resonance imaging, routine blood samples and bio-banking. Clinical assessments include characteristics of the stroke, comorbidity, delirium, frailty and tests for cognitive and physical function, sensor based activity monitoring and adherence to secondary prophylaxis. DISCUSSION: Nor-COAST is the first Norwegian multicentre study to quantify burden of PCI that will provide reliable estimates in a general stroke population. A multidisciplinary approach aiming to identify biomarkers and clinical markers of overall prognosis will add new knowledge about risk profiles, including pre-stroke vulnerability and modifiable factors such as physical activity and secondary prophylaxis of relevance for clinical practice and later intervention studies. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02650531 . Retrospectively registered January 8, 2016. First participant included May 18, 2015.

Association between vascular comorbidity and progression of Alzheimer's disease: a two-year observational study in Norwegian memory clinics.

BACKGROUND: Vascular risk factors increase the risk of Alzheimer's disease (AD), but there is limited evidence on whether comorbid vascular conditions and risk factors have an impact on disease progression. The aim of this study was to examine the association between vascular disease and vascular risk factors and progression of AD. METHODS: In a longitudinal observational study in three Norwegian memory clinics, 282 AD patients (mean age 73.3 years, 54% female) were followed for mean 24 (16-37) months. Vascular risk factors and vascular diseases were registered at baseline, and the vascular burden was estimated by the Framingham Stroke Risk Profile (FSRP). Cerebral medical resonance images (MRIs) were assessed for white matter hyperintensities (WMH), lacunar and cortical infarcts. The associations between vascular comorbidity and progression of dementia as measured by annual change in Clinical Dementia Rating Sum of Boxes (CDR-SB) scores were analysed by multiple regression analyses, adjusted for age and sex. RESULTS: Hypertension occurred in 83%, hypercholesterolemia in 53%, diabetes in 9%, 41% were overweight, and 10% were smokers. One third had a history of vascular disease; 16% had heart disease and 15% had experienced a cerebrovascular event. MRI showed lacunar infarcts in 16%, WMH with Fazekas score 2 in 26%, and Fazekas score 3 in 33%. Neither the vascular risk factors and diseases, the FSRP score, nor cerebrovascular disease was associated with disease progression in AD. CONCLUSIONS: Although vascular risk factors and vascular diseases were prevalent, no impact on the progression of AD after 2 years was shown.

Comparison of automated volumetry of the hippocampus using NeuroQuant® and visual assessment of the medial temporal lobe in Alzheimer's disease.

Background Different clinically feasible methods for evaluation of medial temporal lobe atrophy exists and are useful in diagnostic work-up of Alzheimer's disease (AD). Purpose To compare the diagnostic properties of two clinically available magnetic resonance imaging (MRI)-based methods-an automated volumetric software, NeuroQuant® (NQ) (evaluation of hippocampus volume) and the Scheltens scale (visual evaluation of medial temporal lobe atrophy [MTA])-in patients with AD dementia, and subjective and mild cognitive impairment (non-dementia). Material and Methods MRIs from 56 patients (31 AD, 25 non-dementia) were assessed with both methods. Correlations between the methods were calculated and receiver operating curve (ROC) analyses that yield area under the curve (AUC) statistics were conducted. Results High correlations were found between the two MRI assessments for the total hippocampal volume measured with NQ and mean MTA score (-0.753, P < 0.001), for the right (-0.767, P < 0.001), and for the left (-0.675, P < 0.001) sides. The NQ total measure yielded somewhat higher AUC (0.88, "good") compared to the MTA mean measure (0.80, "good") in the comparison of patients with AD and non-dementia, but the accuracy was in favor of the MTA scale. Conclusion The two methods correlated highly and both methods reached equally "good" power.

Factors that influence the levels of cerebrospinal fluid biomarkers in memory clinic patients.

BACKGROUND: The cerebrospinal fluid (CSF) biomarkers amyloid ß (Aß), phospho tau (P-tau) and total tau (T-tau) are used increasingly to support a clinical diagnosis of Alzheimer's disease. The diagnostic power of these biomarkers has been reported to vary among different studies' results. The results are poorer when heterogeneous groups of patients have been included compared to studies where patients with Alzheimer's dementia (AD) and healthy controls have been studied. The aim of this study was to examine if age, APOE genotype and sex were associated with the levels of CSF biomarkers among patients referred to a memory clinic. METHODS: We included 257 patients from two memory clinics who had been assessed for dementia, including lumbar puncture. RESULTS: The mean age of the patients was 68.1 (SD: 8.0) years; 50.2% were women and 66.5% were APOE ε4 positive. Of these patients, 80.5% were diagnosed with AD or amnestic MCI. Both APOE ε4 and increasing age were associated with decreasing levels of Aß, but not the levels of the tau proteins. In multiple regression analyses, disease stage, defined as a MMSE ≥25 or <25, influenced factors associated with the CSF biomarkers. Among those with MMSE score ≥ 25, age, APOE ε4 genotype, and MMSE score, in addition to a diagnosis of AD, were associated with Aß level, with an explained variance of 0.43. When using P-tau or T-tau as a dependent variable, the presence of one or two APOE ε4 alleles, and MMSE score influenced the results, in addition to the diagnosis of AD. The explained variance was lower for P-tau (0.26) and for T-tau (0.32). Among those with MMSE <25, these variables explained very little of the variance. There were no gender differences. CONCLUSIONS: We found that factors in addition to a diagnosis of AD, were associated with the levels of CSF biomarkers. Among those with MMSE ≥25, lower levels of Aß were associated with several factors including increasing age. This is not reflected in clinical practice, where age-specific cutoffs exist only for T-tau. In this study, age was not associated with the levels of tau proteins.

Performance of Cerebrospinal Fluid Biomarkers of Alzheimer Disease in a Memory Clinic in Norway.

BACKGROUND: Although Alzheimer disease (AD) remains a clinical diagnosis, biomarkers are in use to support the diagnosis. Three cerebrospinal biomarkers, amyloid-ß (Aß), total tau (T-tau), and phospho tau (P-tau), reflect neuropathologic changes observed in AD patients. OBJECTIVE: The aim of this study was to explore the performance of the cerebrospinal fluid biomarkers used in a memory clinic setting. METHODS: We included 205 patients who had been through a standardized examination including lumbar puncture. Diagnoses were made blind to the results of the spinal fluid analyses. RESULTS: By combining low Aß and high T-tau or P-tau values, the sensitivity was 31.9% and the specificity was 92.5% when comparing patients with AD with other patients. In receiver operating characteristic analyses, the AUC for the Aß was 0.78 (SE=0.04; 95% CI, 0.7-0.85), for T-tau 0.80 (SE=0.03; 95% CI, 0.73-0.86), and for P-tau 0.76 (SE=0.04; 95% CI, 0.69-0.83). A significant difference was found between the sexes, with higher values of Aß among younger men (under 65 y of age) with AD [799.8 (SD=317.2) vs. 558.9 (SD=123.5) for women, P-value=0.003]. CONCLUSIONS: The present study found a lower performance of the biomarkers than reported previously.