Brief Intervention as a Method to Reduce Z-Hypnotic Use by Older Adults: Feasibility Case Series.

BACKGROUND: Z-hypnotics or z-drugs are commonly prescribed for insomnia and sleep difficulties in older adults. These drugs are associated with adverse events and dependence and are not recommended for long-term use. Despite evidence of older adults being more sensitive to a wide array of adverse events and clinical guidelines advocating limiting use, inappropriate use in this population is still prevalent. Previous intervention studies have focused mainly on prescriber information. Simple, individually focused intervention designs are less studied. Brief intervention (BI) is a simple, easily transferable method mainly used to treat patients at risk of alcohol overuse. OBJECTIVE: Our objective was to design and test the feasibility and acceptability of a BI intervention adapted to address individual, inappropriate use of z-hypnotics among older adults. This preparatory study aimed to optimize the intervention in advance of a quantitative randomized controlled trial investigating the treatment effect in a larger population. METHODS: This feasibility case series was conducted at Akershus University Hospital, Norway, in autumn 2021. We included 5 adults aged ≥65 years with long-term (≥4 weeks) use of z-hypnotics and 2 intervening physicians. Additionally, 2 study investigators contributed with process evaluation notes. The BI consists of information on the risk of inappropriate use and individualized advice on how to reduce use. The focus of the intervention is behavioral and aims, in cooperation with the patient and based on shared decision-making, to change patient behavior regarding sleep medication rather than physician-based detoxification and termination of z-hypnotic prescriptions. Qualitative and descriptive quantitative data were collected from intervening physicians, study investigators, and participants at baseline, immediately after the intervention, and at the 6-week follow-up. RESULTS: Data were obtained from 2 physicians, 2 study investigators, and 5 participants (4 women) with a median age of 84 years. The average time spent on the BI consultation was 15 minutes. All 5 participants completed the intervention without problems. The participants and 2 intervening physicians reported the intervention as acceptable and were satisfied with the delivery of the intervention. After the intervention, 2 participants stopped their use of z-hypnotics completely and participated in the follow-up interview. Study investigators identified logistical challenges regarding location and time requirements. Identified aspects that may improve the intervention and reduce dropouts included revising the intervention content, focusing on rebound insomnia, adding an information leaflet, and supporting the patient in the period between the intervention and follow-up. The notion that the intervention should best be located and conducted by the patient's own general practitioner was supported by the participants. CONCLUSIONS: We identified important aspects to improve the designed intervention and found that the BI is feasible and acceptable for incorporation into a larger randomized trial investigating the treatment effect of BI for reducing z-hypnotic use by older adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT03162081; http://tinyurl.com/rmzx6brn.

Mortality and health-related quality of life in older adults with long-term use of opioids, z-hypnotics or benzodiazepines: a prospective observational study at 5 years follow-up.

OBJECTIVES: Disease and medication use in older age is a consequence of age-related declining health. Multimorbidity followed by polypharmacy is common. Central nervous system depressing (CNSD) drugs such as opioids, benzodiazepines and z-hypnotics are not recommended for long-term use in older adults but are in use by many. We aimed to assess mortality and change in health-related quality of life (HRQoL) in older adults with long-term use of CNSDs. METHOD: A prospective observational study was conducted at Akershus University Hospital, Norway, 2017-2019, with follow-up in 2021-2022, including 246 participants aged 65-90. At 5-year follow-up, 78 (32%) participants had passed away. Mortality data were collected from patient electronic health records. Of the surviving 168 (68%), we collected further follow-up data from 38 (16%) participants. Follow-up included demographic and clinical data. The EuroQuol Group EQ-5D-5L questionnaire was used to measure HRQoL. Analysis include Cox regression model for survival data and linear mixed model for change in HRQoL over time. RESULTS: At follow-up, 78 (31.7%) were deceased. Mean survival time was 3.3 years. Total time for survival data was 4.7 years. Mortality was higher among participants with long-term use of CNSD (HR 1.9 95% CI (1.2 to 3.2), p=0.01). The multivariable analysis found being older (HR 1.1 95% CI (1.0 to 1.1), p=0.020) and male sex (HR 2.1 95% CI (1.2 to 3.5), p=0.008) to be associated with increased risk of mortality. According to the linear mixed model (n=38), there was no significant difference between surviving users and non-users in change in HRQoL EQ-5D-5L index from baseline to follow-up. CONCLUSION: Mortality was higher for long-term users of CNSDs at 5-year follow-up. Being older and male sex were associated with mortality. Among survivors, there was no significant difference between the groups in change of HRQoL over time. TRIAL REGISTRATION NUMBER: NCT03162081; 22 May 2017.

Delirium in acute stroke is associated with increased cognitive and psychiatric symptoms over time: The Nor-COAST study.

BACKGROUND: Delirium, an acute and fluctuating mental disturbance of attention, cognition, and consciousness, commonly occurs in acute stroke. Research on long-term outcomes of stroke patients experiencing delirium is limited, especially regarding cognitive and psychiatric symptoms. METHODS: As part of the Nor-COAST study, 373 patients were screened for delirium using the Confusion Assessment Method (CAM) in the acute phase of stroke. Patients were included in the mixed-model linear regression analyses if they had available data from the follow-ups at three, 18 or 36 months, totaling 334 (44.6 % women, mean (SD) age: 72.1 (12.5) years, 17 (5.1 %) diagnosed with delirium). Global cognition was measured using the Montreal Cognitive Assessment (MoCA). Psychiatric symptoms were measured using the Hospital Anxiety and Depression Scale (HADS) and the Neuropsychiatric Inventory-Questionnaire (NPI-Q). RESULTS: At three months, delirium was associated with a higher NPI-Q score (Mean (SD) 2.9 (3.6) vs 1.4 (2.2)). At 18 and 36 months, delirium was associated with a lower MoCA score (Mean (SD) 19.7 (6.6) vs 24.3 (5.0), and 20.6 (7.6) vs 24.6 (4.8)), higher HADS anxiety symptoms (5.0 (4.3) vs 3.3 (3.3), and 5.9 (4.1) vs 3.4 (3.6)), higher HADS depression symptoms (7.2 (4.7) vs 3.4 (3.3), and 6.6 (5.1) vs 3.7 (3.7)), and higher NPI-Q score (2.4 (4.4) vs 1.7 (2.3), 2.6 (4.5) vs 1.0 (1.9)). Delirium significantly predicted the psychiatric symptoms hallucinations and agitation. CONCLUSIONS: Patients with delirium in the acute phase of stroke may be particularly vulnerable to developing cognitive and psychiatric symptoms in the chronic phase.

Diagnostic accuracy of the Clock Drawing Test in screening for early post-stroke neurocognitive disorder: the Nor-COAST study.

BACKGROUND: Post-stroke neurocognitive disorder, though common, is often overlooked by clinicians. Moreover, although the Montreal Cognitive Assessment (MoCA) has proven to be a valid screening test for neurocognitive disorder, even more time saving tests would be preferred. In our study, we aimed to determine the diagnostic accuracy of the Clock Drawing Test (CDT) for post-stroke neurocognitive disorder and the association between the CDT and MoCA. METHODS: This study is part of the Norwegian Cognitive Impairment After Stroke study, a multicentre prospective cohort study following patients admitted with acute stroke. At the three-month follow-up, patients were classified with normal cognition, mild neurocognitive disorder, or major neurocognitive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Any neurocognitive disorder compromised both mild- and major neurocognitive disorder. The CDT at the three-month assessment was given scores ranging from 0 to 5. Patients able to complete the CDT and whose cognitive status could be classified were included in analyses. The CDT diagnostic accuracy for post-stroke neurocognitive disorder was identified using receiver operating characteristic curves, sensitivity, specificity, positive predictive value, and negative predictive value. The association between the MoCA and CDT was analysed with Spearman's rho. RESULTS: Of 554 participants, 238 (43.0%) were women. Mean (SD) age was 71.5 (11.8) years, while mean (SD) National Institutes of Health Stroke Scale score was 2.6 (3.7). The area under the receiver operating characteristic curve of the CDT for major neurocognitive disorder and any neurocognitive disorder was 0.73 (95% CI, 0.68-0.79) and 0.68 (95% CI, 0.63-0.72), respectively. A CDT cutoff of < 5 yielded 68% sensitivity and 60% specificity for any neurocognitive disorder and 78% sensitivity and 53% specificity for major neurocognitive disorder. Spearman's correlation coefficient between scores on the MoCA and CDT was 0.50 (95% CI, 0.44-0.57, p < .001). CONCLUSIONS: The CDT is not accurate enough to diagnose post-stroke neurocognitive disorder but shows acceptable accuracy in identifying major neurocognitive disorder. Performance on the CDT was associated with performance on MoCA; however, the CDT is inferior to MoCA in identifying post-stroke neurocognitive disorder. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02650531). Retrospectively registered January 8, 2016.

A Machine Learning Approach to Predict Post-stroke Fatigue. The Nor-COAST study.

OBJECTIVE: This study aimed to predict fatigue 18 months post-stroke by utilizing comprehensive data from the acute and sub-acute phases after stroke in a machine-learning set-up. DESIGN: A prospective multicenter cohort-study with 18-month follow-up. SETTING: Outpatient clinics at 3 university hospitals and 2 local hospitals. PARTICIPANTS: 474 participants with the diagnosis of acute stroke (mean ± SD age; 70.5 (11.3), 59% male; N=474). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary outcome, fatigue at 18 months, was assessed using the Fatigue Severity Scale (FSS-7). FSS-7≥5 was defined as fatigue. In total, 45 prediction variables were collected, at initial hospital-stay and 3-month post-stroke. RESULTS: The best performing model, random forest, predicted 69% of all subjects with fatigue correctly with a sensitivity of 0.69 (95% CI: 0.50, 0.86), a specificity of 0.74 (95% CI: 0.66, 0.83), and an Area under the Receiver Operator Characteristic curve of 0.79 (95% CI: 0.69, 0.87) in new unseen data. The proportion of subjects predicted to suffer from fatigue, who truly suffered from fatigue at 18-months was estimated to 0.41 (95% CI: 0.26, 0.57). The proportion of subjects predicted to be free from fatigue who truly did not have fatigue at 18-months was estimated to 0.90 (95% CI: 0.83, 0.96). CONCLUSIONS: Our findings indicate that the model has satisfactory ability to predict fatigue in the chronic phase post-stroke and may be applicable in clinical settings.

Self-reported cognitive and psychiatric symptoms at 3 months predict single-item measures of fatigue and daytime sleep 12 months after ischemic stroke.

Introduction: Post-stroke fatigue and increased need for daytime sleep are multidimensional and insufficiently understood sequelae. Our aim was to study the relationships of self-reported cognitive and psychiatric symptoms at 3 months with fatigue and daytime sleep at 12 months post-stroke. Methods: Ischemic stroke patients without reported history of dementia or depression completed postal surveys 3- and 12-months post-stroke. At 3 months, psychiatric symptoms were assessed with the Hospital Anxiety and Depression Scale (HADS), and self-reported changes in cognitive symptoms (concentration and memory) compared to pre-stroke were assessed using single-item measures. At 12 months, single-item questions about changes in self-reported difficulties sleeping at night, fatigue and daytime sleep were included. First, we studied whether self-reported cognitive and/or psychiatric symptoms at 3 months were associated with daytime sleep and fatigue at 12 months using multiple logistic regression. Second, we fitted 2 structural equation models (SEMs) predicting fatigue and 2 models predicting daytime sleep. We compared a model where only age, sex, stroke severity (National Institutes of Health Stroke Scale; NIHSS), and difficulties sleeping at night predicted fatigue and daytime sleep at 12 months to a model where mental distress (i.e., a latent variable built of cognitive and psychiatric symptoms) was included as an additional predictor of fatigue and daytime sleep at 12 months. Results: Of 156 patients (NIHSS within 24 hours after admission (mean ± SD) = 3.6 ± 4.3, age = 73.0 ± 10.8, 41% female) 37.9% reported increased daytime sleep and 50.0% fatigue at 12 months. Increased psychiatric symptoms and worsened cognitive symptoms were associated with fatigue and daytime sleep at 12 months, after controlling for NIHSS, age, sex, and difficulties sleeping at night. SEM models including mental distress as predictor showed adequate model fit across 3 fit measures (highest RMSEA = 0.063, lowest CFI and TLI, both 0.975). Models without mental distress were not supported. Conclusion: Self-reported cognitive and psychiatric symptoms at 3 months predict increased daytime sleep and fatigue at 12 months. This highlights the relevance of monitoring cognitive and psychiatric symptoms in the subacute phase post-stroke. However, future research using validated measures of self-reported symptoms are needed to further explore these relationships.

The relationship of acute delirium with cognitive and psychiatric symptoms after stroke: a longitudinal study.

OBJECTIVE: Delirium, a common complication after stroke, is often overlooked, and long-term consequences are poorly understood. This study aims to explore whether delirium in the acute phase of stroke predicts cognitive and psychiatric symptoms three, 18 and 36 months later. METHOD: As part of the Norwegian Cognitive Impairment After Stroke Study (Nor-COAST), 139 hospitalized stroke patients (49% women, mean (SD) age: 71.4 (13.4) years; mean (SD) National Institutes of Health Stroke Scale (NIHSS) 3.0 (4.0)) were screened for delirium with the Confusion Assessment Method (CAM). Global cognition was measured with the Montreal Cognitive Assessment (MoCA), while psychiatric symptoms were measured using the Hospital Anxiety and Depression Scale (HADS) and the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Data was analyzed using mixed-model linear regression, adjusting for age, gender, education, NIHSS score at baseline and premorbid dementia. RESULTS: Thirteen patients met the criteria for delirium. Patients with delirium had lower MoCA scores compared to non-delirious patients, with the largest between-group difference found at 18 months (Mean (SE): 20.8 (1.4) versus (25.1 (0.4)). Delirium was associated with higher NPI-Q scores at 3 months (Mean (SE): 2.4 (0.6) versus 0.8 (0.1)), and higher HADS anxiety scores at 18 and 36 months, with the largest difference found at 36 months (Mean (SE): 6.2 (1.3) versus 2.2 (0.3)). CONCLUSIONS: Suffering a delirium in the acute phase of stroke predicted more cognitive and psychiatric symptoms at follow-up, compared to non-delirious patients. Preventing and treating delirium may be important for decreasing the burden of post-stroke disability.

The effect of cognitive function and central nervous system depressant use on mortality-A prospective observational study of previously hospitalised older patients.

BACKGROUND: Older patients are often users of prolonged Central Nervous System Depressants (CNSD) (Z-hypnotics, benzodiazepines and opioids), which may be associated with reduced cognition. The long-term effects of CNSD use and reduced cognitive function in older patients are unclear. The aim of this study was to examine whether cognitive function and CNSD use at baseline hospitalisation were associated with all-cause mortality two years after discharge. METHODS: We conducted a prospective observational study, including baseline data (2017-2018) from previously hospitalised older patients (65-90 years), assessing all-cause mortality two years after discharge. We used logistic regression to assess the primary outcome, all-cause mortality two years after baseline hospitalisation. The primary predictors were cognitive function measured by The Mini Mental State Examination (MMSE) and prolonged CNSD use (continuous use ≥ 4 weeks). Adjustment variables: age, gender, education, the Hospital Anxiety and Depression Scale (HADS) and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G), using receiver operating characteristics (ROC) to compare the predictive power of the models. In a sub-analysis we used, the Neurobehavioural Cognitive State Examination (Cognistat) and the Clock Drawing Test. RESULTS: Two years after discharge, out of 246 baseline patients, 43 were deceased at follow-up, among these 27 (63%) were CNSD users, and 16 (36%) were non-users at baseline, (p = 0.002). In the multivariable models cognitive function (MMSE score) was a predictor of mortality (OR 0.81 (95% CI 0.69; 0.96), p = 0.014). CNSD use was associated with mortality (OR 2.71 (95% CI 1.06; 6.95), p = 0.038), with ROC AUC: 0.74-0.77 for these models. Results using Cognistat supported the findings. The Clock Drawing Test was not significant predictor of mortality. CONCLUSION: Two years after discharge from the hospital, older patients with reduced cognitive function and CNSD use during hospital stay had higher mortality. This underlines that inappropriate (prolonged and concurrent) use of CNSDs should be avoided by older patients, particularly in patients with reduced cognitive function. TRIAL REGISTRATION: NCT03162081, 22 May 2017.

The association between pain and central nervous system depressing medication among hospitalised Norwegian older adults.

OBJECTIVES: Central nervous system depressant medications (CNSD) including benzodiazepines, z-hypnotics and opioids are regularly prescribed for the older patient. These medications are linked to dependence and associated with severe side effects in some older patients. Consensus recommendations for this group suggest limiting their use. We have recently described a high proportion of long-term CNSD use and dependence among older in-hospital patients. In this study, we aim to investigate factors associated with pain intensity and presentation of pain among older adults with long-term use of CNSDs compared to non-users. METHODS: Two hundred and forty six elderly hospitalised patients were recruited consecutively in a cross-sectional study. Data was collected from patients and electronic health records (EHR). Independent variables were sex, age, education, emotional symptoms (hospital anxiety and depression scale [HADS]), cognitive function (Mini-mental State Examination test [MMSE]), comorbidity (cumulative illness rating score - geriatrics [CIRS-G]), loneliness (the six-item De Jong Gierveld Loneliness Scale) and prolonged (≥4 weeks) use of any CNSDs or prolonged use of opioids (≥4 weeks). All variables, including pain intensity, were collected at one time point consistent with the cross-sectional study design. Statistical analyses included descriptive statistics and linear regression models using the above mentioned variables and pain intensity (visual analogue scale for pain intensity [VAS] pain 0-100) as outcome. Additional information regarding pain presentation was extracted from the patients' EHR. RESULTS: Mean pain intensity VAS (SD) was 35.2 (30.4) and 18.1 (24.2) respectively, for patients with vs. without prolonged use of CNSDs. In the multivariable linear regression analysis, prolonged use of CNSDs and opioids were positively associated with pain intensity (VAS) (regression coefficient (95% CI) 20.7 (11.0; 30.3), p<0.001, and 19.8 (5.7; 33.8), p=0.006, respectively), while sex, age, education, MMSE, HADS, CIRS-G and loneliness scores were not. Pain related to back (23.2%) and lower extremities (23.2%) were most common pain sites, and those with one or more pain sites reported overall higher pain intensity compared to those with no reported pain sites (p<0.006). CONCLUSIONS: Prolonged use of CNSD medications as well as prolonged use of opioids are both positively associated with pain intensity. The results may have implications for treatment and long-term pain management for older patients.

The Relationship of Psychiatric Symptoms with Performance-Based and Self-Reported Cognitive Function After Ischemic Stroke.

OBJECTIVE: Findings on the relationship of psychiatric symptoms with performance-based and self-reported cognitive function post-stroke are inconclusive. We aimed to (1) study the relation of depression and anxiety to performance-based cognitive function and (2) explore a broader spectrum of psychiatric symptoms and their association with performance-based versus self-reported cognitive function. METHOD: Individuals with supratentorial ischemic stroke performed neuropsychological examination 3 months after stroke. For primary analyses, composite scores for memory and attention/executive function were calculated based on selected neuropsychological tests, and the Hospital Anxiety and Depression Scale (HADS) was used. Psychiatric symptoms and self-reported cognitive function for secondary aims were assessed using the Symptom-Checklist-90 - Revised (SCL-90-R). RESULTS: In a sample of 86 patients [mean (M) age: 64.6 ± 9.2; Mini-Mental State Examination (MMSE), 3-7 days post-stroke: M = 28.4 ± 1.7; National Institutes of Health Stroke Scale (NIHSS) after 3 months: M = 0.7 ± 1.6] depressive symptoms (HADS) were associated with poorer memory performance after controlling for age, sex, and education (p ≤ .01). In a subsample (n = 41; Age: M = 65.7 ± 8.1; MMSE: M = 28.4 ± 1.8; NIHSS: M = 1.0 ± 1.9), symptoms of phobic anxiety (SCL-90-R) were associated with poorer performance-based memory and attention/executive function, and symptoms of anxiety (SCL-90-R) with lower attention/executive function. Higher levels of self-reported cognitive difficulties were associated with higher scores in all psychiatric domains (p ≤ .05). CONCLUSION: Even in relatively well-functioning stroke patients, depressive symptoms are associated with poorer memory. The results also suggest that various psychiatric symptoms are more related to self-reported rather than to performance-based cognitive function. Screening for self-reported cognitive difficulties may not only help to identify patients with cognitive impairment, but also those who need psychological treatment.

"What should I do when I get home?" treatment plan discussion at discharge between specialist physicians and older in-patients: mixed method study.

BACKGROUND: During discharge from hospital, older patients and physicians discuss the plan for managing patients' health at home. If not followed at home, it can result in poor medication management, readmissions, or other adverse events. Comorbidities, polypharmacy and cognitive impairment may create challenges for older patients. We assessed discharge conversations between older in-patients and physicians for treatment plan activities and medication information, with emphasis on the role of cognitive function in the ongoing conversation. METHODS: We collected 11 videos of discharge consultations, medication lists, and self-reported demographic information from hospitalised patients ≥65 years at the Geriatric department in a general hospital. Mini Mental State Examination score < 25 was classified as low cognitive function. We used microanalysis of face-to-face dialogue to identify and characterise sequences of interaction focused on and distinguishing the treatment plan activities discussed. In addition to descriptive statistics, we used a paired-sample t-test and Mann-Whitney U test for non-parametric data. RESULTS: Patients' median age was 85 (range: 71-90);7 were females and 4 males. Median of 17 (range: 7 to 23) treatment plan activities were discussed. The proportions of the activities, grouped from a patient perspective, were: 0.40 my medications, 0.21 something the hospital will do for me, 0.18 someone I visit away from home, 0.12 daily routine and 0.09 someone coming to my home. Patients spoke less (mean 190.9 words, SD 133.9) during treatment plan activities compared to other topics (mean 759 words, SD 480.4), (p = .001). Patients used on average 9.2 (SD 3.1) medications; during the conversations, an average of 4.5 (SD 3.3) were discussed, and side effects discussed on average 1.2 (SD 2.1) times. During treatment plan discussions, patients with lower cognitive function were less responsive and spoke less (mean 116.5 words, SD 40.9), compared to patients with normal cognition (mean 233.4 words, SD 152.4), (p = .089). CONCLUSION: Physicians and geriatric patients discuss many activities during discharge conversations, mostly focusing on medication use without stating side effects. Cognitive function might play a role in how older patients respond. These results may be useful for an intervention to improve communication between physicians and older hospitalised patients.

Association between prescribed central nervous system depressant drugs, comorbidity and cognition among hospitalised older patients: a cross-sectional study.

OBJECTIVES: Central nervous system depressants (CNSDs) such as opioids, benzodiazepine and Z-hypnotics are commonly used. However, CNSDs may influence cognitive function, especially in older hospitalised patients with comorbidities. The aim was to examine the association between CNSD use and cognitive function in older patients. We assessed global and domain specific cognitive function, among hospitalised older patients, including covariates for comorbidity, anxiety and depression. DESIGN: Cross-sectional hospital-based study. SETTINGS: Data was collected consecutively from inpatients at somatic wards of a general university hospital. PARTICIPANTS: Older patients between 65 and 90 years with/without CNSD use for ≥4 weeks. OUTCOME MEASURES: The main outcome was cognitive function assessed by Cognistat. Secondary outcomes were routine clinical tests in the wards (mini-mental state examination (MMSE), trail making test (TMT) A and B, and clock drawing tests). Analyses were bivariate and multiple linear regression, adjusted for age, gender, and education. Covariates were comorbidity, depression and anxiety scores. RESULTS: The main result indicated that CNSD users (n=100) had (ß=-3.4, 95% CI 6.27 to -0.58, p=0.017) lower Cognistat score than non-users (n=146), adjusted for age, gender, education, anxiety and depression, but not significant when including covariate for comorbidity (ß= -2.50 - 5.45; -0.46, p=0.097). Comorbidity was associated with cognitive function (ß=-0.77, 95% CI -1.22 to -0.14, p=0.014). Cognistat subdimensions associated with CNSD use were language (p=0.017) and calculation (p=0.003). In clock drawing test, users had lower scores than non-users (ß=-0.80, 95% CI 1.24 to -0.36, p=0.004), but no significant difference was found with MMSE and TMT A or B. Z-hypnotics were associated with reduced cognitive function. CONCLUSION: Among older hospitalised patients, global cognition and specific cognitive functions were associated with long-term use of CNSD medication as well as with somatic comorbidity. TRIAL REGISTRATION NUMBER: NCT03162081, 22 May 2017.

Biomarkers in subtypes of mild cognitive impairment and subjective cognitive decline.

OBJECTIVES: Preclinical Alzheimers disease (AD) patients may or may not show cognitive impairment on testing. AD biomarkers are central to the identification of those at low, intermediate, or high risk of later dementia due to AD. We investigated biomarker distribution in those identified as subjective cognitive decline (SCD), amnestic (aMCI), and nonamnestic (naMCI) mild cognitive impairment (MCI) subtypes. In addition, the clinical groups were compared with controls on downstream neuroimaging markers. MATERIALS AND METHODS: Cerebrospinal fluid (CSF) amyloid-ß42 (A ß42) and total tau (t-tau), phosphorylated tau (p-tau), fluorodeoxyglucose (FDG), positron-emission tomography (PET), and MRI neuroimaging measures were collected from 116 memory clinic patients. They were characterized as SCD, aMCI, and naMCI according to comprehensive neuropsychological criteria. ANOVAs were used to assess differences when biomarkers were treated as continuous variables and chi square analyses were used to assess group differences in distribution of biomarkers. RESULTS: We did not find any between group differences in Aß42, nor in p-tau, but we observed elevated t-tau in aMCI and SCD relative to the naMCI group. Significantly lower cortical glucose metabolism (as measured by FDG PET) was found in aMCI relative to SCD and controls, and there was a trend for lower metabolism in naMCI. Significant thinner entorhinal cortex (ERC) was found in aMCI and SCD. As expected biomarkers were significantly more frequently pathological in aMCI than in naMCI and SCD, whereas the naMCI and SCD groups displayed similar pathological biomarker burden. CONCLUSIONS: aMCI cases show the most pathologic biomarker burden. Interestingly naMCI and SCD subjects show similar levels of pathological biomarkers albeit the former displayed neuropsychological deficits. That the latter group may represent a risk group is supported by our observation of both elevated CSF tau and thinner ERC relative to controls.

Detecting At-Risk Alzheimer's Disease Cases.

While APOEɛ4 is the major genetic risk factor for Alzheimer's disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aß42 (pAß) and APOEɛ4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pAß and APOEɛ4 frequency compared to NC. Also, NCFD had higher APOEɛ4 frequencies without increased fraction of pAß compared to NC, and cases recruited from memory clinics had higher fractions of pAß and APOEɛ4 frequency than self-referred. This study shows that memory clinic referrals are pAß enriched, whereas self-referred and NCFD cases more frequently are pAß negative but at risk (APOEɛ4 positive), suitable for primary intervention.

Cerebrospinal Fluid Levels of Amyloid Beta 1-43 Mirror 1-42 in Relation to Imaging Biomarkers of Alzheimer's Disease.

Introduction: Amyloid beta 1-43 (Aß43), with its additional C-terminal threonine residue, is hypothesized to play a role in early Alzheimer's disease pathology possibly different from that of amyloid beta 1-42 (Aß42). Cerebrospinal fluid (CSF) Aß43 has been suggested as a potential novel biomarker for predicting conversion from mild cognitive impairment (MCI) to dementia in Alzheimer's disease. However, the relationship between CSF Aß43 and established imaging biomarkers of Alzheimer's disease has never been assessed. Materials and Methods: In this observational study, CSF Aß43 was measured with ELISA in 89 subjects; 34 with subjective cognitive decline (SCD), 51 with MCI, and four with resolution of previous cognitive complaints. All subjects underwent structural MRI; 40 subjects on a 3T and 50 on a 1.5T scanner. Forty subjects, including 24 with SCD and 12 with MCI, underwent 18F-Flutemetamol PET. Seventy-eight subjects were assessed with 18F-fluorodeoxyglucose PET (21 SCD/7 MCI and 11 SCD/39 MCI on two different scanners). Ten subjects with SCD and 39 with MCI also underwent diffusion tensor imaging. Results: Cerebrospinal fluid Aß43 was both alone and together with p-tau a significant predictor of the distinction between SCD and MCI. There was a marked difference in CSF Aß43 between subjects with 18F-Flutemetamol PET scans visually interpreted as negative (37 pg/ml, n = 27) and positive (15 pg/ml, n = 9), p < 0.001. Both CSF Aß43 and Aß42 were negatively correlated with standardized uptake value ratios for all analyzed regions; CSF Aß43 average rho -0.73, Aß42 -0.74. Both CSF Aß peptides correlated significantly with hippocampal volume, inferior parietal and frontal cortical thickness and axial diffusivity in the corticospinal tract. There was a trend toward CSF Aß42 being better correlated with cortical glucose metabolism. None of the studied correlations between CSF Aß43/42 and imaging biomarkers were significantly different for the two Aß peptides when controlling for multiple testing. Conclusion: Cerebrospinal fluid Aß43 appears to be strongly correlated with cerebral amyloid deposits in the same way as Aß42, even in non-demented patients with only subjective cognitive complaints. Regarding imaging biomarkers, there is no evidence from the present study that CSF Aß43 performs better than the classical CSF biomarker Aß42 for distinguishing SCD and MCI.

Hippocampal complex atrophy in poststroke and mild cognitive impairment.

To investigate putative interacting or distinct pathways for hippocampal complex substructure (HCS) atrophy and cognitive affection in early-stage Alzheimer's disease (AD) and cerebrovascular disease (CVD), we recruited healthy controls, patients with mild cognitive impairment (MCI) and poststroke patients. HCSs were segmented, and quantitative white-matter hyperintensity (WMH) load and cerebrospinal fluid (CSF) amyloid-ß concentrations were determined. The WMH load was higher poststroke. All examined HCSs were smaller in amyloid-positive MCI than in controls, and the subicular regions were smaller poststroke. Memory was reduced in amyloid-positive MCI, and psychomotor speed and executive function were reduced in poststroke and amyloid-positive MCI. Size of several HCS correlated with WMH load poststroke and with CSF amyloid-ß concentrations in MCI. In poststroke and amyloid-positive MCI, neuropsychological function correlated with WMH load and hippocampal volume. There are similar patterns of HCS atrophy in CVD and early-stage AD, but different HCS associations with WMH and CSF biomarkers. WMHs add to hippocampal atrophy and the archetypal AD deficit delayed recall. In line with mounting evidence of a mechanistic link between primary AD pathology and CVD, these additive effects suggest interacting pathologic processes.

Correlates of Subjective and Mild Cognitive Impairment: Depressive Symptoms and CSF Biomarkers.

AIMS: To improve early diagnosis of dementia disease, this study investigates correlates of cognitive complaints and cognitive test performance in patients with subjective (SCI) and mild (MCI) cognitive impairment. METHODS: Seventy patients from a memory clinic, aged 45-79, with a score of 2 (n = 23) or 3 (n = 47) on the Global Deterioration Scale, were included. CSF biomarkers [Aß42, total tau (T-tau) and phosphorylated tau (P-tau)], depressive symptoms, cognitive performance, and complaints were examined. RESULTS: Correlation analysis showed that cognitive complaints increased with decreasing cognitive performance in SCI and decreased with decreasing performance in MCI. Linear regression models revealed that cognitive complaints were associated with depressive symptoms in both groups of patients, while cognitive performance was associated with CSF Aß42 and P-tau in SCI and with T-tau and P-tau in MCI. CONCLUSION: These results suggest that depressive symptoms are associated with cognitive complaints, while degenerative changes are associated with objective cognitive decline in high-risk predementia states.

Mild cognitive impairment: cerebrospinal fluid tau biomarker pathologic levels and longitudinal changes in white matter integrity.

PURPOSE: To evaluate the relationship between (a) pathologic levels of cerebrospinal fluid (CSF) total tau as an index of the intensity of ongoing neuronal degeneration and (b) longitudinal changes in white matter (WM) integrity in patients with mild cognitive impairment (MCI). MATERIALS AND METHODS: Participants gave written informed consent, and the Norwegian committee for medical research ethics approved the study. Thirty patients with MCI and nonpathologic CSF total tau levels, nine patients with MCI and pathologic CSF total tau levels, and 16 age-matched healthy control subjects underwent diffusion-tensor imaging at baseline and after a mean follow-up of 2.6 years ± 0.54 (standard deviation), with range of 1.58-3.98 years. The effect of diagnosis (MCI vs no MCI) at baseline and CSF tau levels at fractional anisotropy (FA), mean diffusivity, radial diffusivity (D(R)), and axial diffusivity were tested with tract-based spatial statistics. Differences in WM integrity at baseline and follow-up and change over time were compared among patients with pathologic CSF total tau levels (MCI high tau), patients with normal CSF total tau levels (MCI low tau), and healthy control subjects. Linear mixed-model between-group within-subject analyses were conducted to examine differences in rate of change over time in FA and D(R). RESULTS: Longitudinal analysis of regional WM change revealed significant decrease in FA (P = .038) and increase in D(R) (P = .018) in the MCI high-tau group relative to control subjects. For D(R), the changes were regionally specific to the right cingulum and the right superior and inferior longitudinal fasciculi. CONCLUSION: Reduction in WM integrity was greater in patients with MCI who had the most intense neuronal degeneration as indexed by using CSF total tau, suggesting that these patients might represent a subgroup of MCI with more intense WM degeneration who are possibly at greater risk of developing Alzheimer disease.

Diffusion tensor imaging surpasses cerebrospinal fluid as predictor of cognitive decline and medial temporal lobe atrophy in subjective cognitive impairment and mild cognitive impairment.

Neuropathological correlates of Alzheimer's disease (AD) emerge years before dementia. Biomarkers preceding cognitive decline and reflecting the causative processes can potentially aid early intervention and diagnosis. Diffusion tensor imaging (DTI) indirectly reflects tissue microstructure. To answer whether DTI is an early biomarker for AD and to explore the relationship between DTI and the established biomarkers of medial temporal lobe atrophy and cerebrospinal fluid (CSF) Aß(42), T-tau, and P-tau, we longitudinally studied normal controls and patients with subjective (SCI) or mild (MCI) cognitive impairment. 21 controls and 64 SCI or MCI cases recruited from a university-hospital based memory clinic were re-examined after two to three years. FreeSurfer was used for longitudinal processing of morphometric data, and DTI derived fractional anisotropy, radial diffusivity, and mean diffusivity were analyzed in Tract-Based Spatial Statistics. Using regression models, we explored and compared the predictive powers of DTI and CSF biomarkers in regard to cognitive change and atrophy of the medial temporal lobe. Both DTI and CSF biomarkers significantly predicted cognitive decline and atrophy in the medial temporal lobe. In this population, however, DTI was a better predictor of dementia and AD-specific medial temporal lobe atrophy than the CSF biomarkers. The case for DTI as an early biomarker for AD is strengthened, but further studies are needed to confirm these results.

White matter imaging changes in subjective and mild cognitive impairment.

BACKGROUND: To determine whether white matter (WM) memory network changes accompany early cognitive impairment and whether these changes represent early, pathologically independent axonal affection, we combined WM diffusion tensor imaging and cortical morphometric measurements of normal control subjects, patients with only subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). METHODS: We included 66 patients with SCI or MCI and 21 control subjects from a university-hospital-based memory clinic in a cross-sectional study. Morphometric analysis was performed in FreeSurfer, and Tract-Based Spatial Statistics was used for analysis of diffusion tensor imaging-derived WM fractional anisotropy, radial diffusivity (DR), and mean diffusivity (MD). Relationships between WM measures and stage were assessed with whole-brain voxelwise statistics and on a region-of-interest basis, with subsequent correction for cortical atrophy. RESULTS: In SCI patients, as compared with control subjects, there were widespread changes in DR and MD. No significant differences in thickness could be demonstrated. In MCI patients, as compared with control subjects, there were widespread changes in DR, MD, and fractional anisotropy; the precuneal and inferior parietal cortices were thinner; and the hippocampus was smaller. Multiple logistic regression analysis eliminated morphometry as an explanatory variable in favor of DR/MD for all regions of interest, except in the precuneus, where both thickness and DR/MD were significant explanatory variables. CONCLUSIONS: WM tract degeneration is prominent in SCI and MCI patients, and is at least in part independent of overlying gray matter atrophy.