Serum neurofilament light levels are correlated to long-term neurocognitive outcome measures after cardiac arrest

OBJECTIVE: To explore associations between four methods assessing long-term neurocognitive outcome after out-of-hospital cardiac arrest and early hypoxic-ischemic neuronal brain injury assessed by the biomarker serum neurofilament light (NFL), and to compare the agreement for the outcome methods. METHODS: An explorative post-hoc study was conducted on survivor data from the international Target Temperature Management after Out-of-hospital Cardiac Arrest trial, investigating serum NFL sampled 48/72-hours post-arrest and neurocognitive outcome 6 months post-arrest. RESULTS: Among the long-term surviving participants (N = 457), serum NFL (n = 384) was associated to all outcome instruments, also when controlling for demographic and cardiovascular risk factors. Associations between NFL and the patient-reported Two Simple Questions (TSQ) were however attenuated when adjusting for vitality and mental health. NFL predicted results on the outcome instruments to varying degrees, with an excellent area under the curve for the clinician-report Cerebral Performance Category (CPC 1-2: 0.90). Most participants were classified as CPC 1 (79%). Outcome instrument correlations ranged from small (Mini-Mental State Examination [MMSE]-TSQ) to strong (CPC-MMSE). CONCLUSIONS: The clinician-reported CPC was mostly related to hypoxic-ischemic brain injury, but with a ceiling effect. These results may be useful when selecting methods and instruments for clinical follow-up models

Neuropsychological outcome after cardiac arrest: a prospective case control sub-study of the Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest trial (TTM2)

Background: This study is designed to provide detailed knowledge on cognitive impairment after out-of-hospital cardiac arrest (OHCA) and its relation to associated factors, and to validate the neurocognitive screening of the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest trial (TTM2-trial), assessing effectiveness of targeted temperature management after OHCA. Methods: This longitudinal multi-center clinical study is a sub-study of the TTM2-trial, in which a comprehensive neuropsychological examination is performed in addition to the main TTM2-trial neurocognitive screening. Approximately 7 and 24 months after OHCA, survivors at selected study sites are invited to a standardized assessment, including performance-based tests of cognition and questionnaires of emotional problems, fatigue, executive function and insomnia. At 1:1 ratio, a matched control group from a cohort of acute myocardial infarction (MI) patients is recruited to perform the same assessment. We aim to include 100 patients per group. Potential differences between the OHCA patients and the MI controls at 7 and 24 months will be analyzed with a linear regression, using composite z-scores per cognitive domain (verbal, visual/constructive, working memory, episodic memory, processing speed, executive functions) as primary outcome measures. Results from OHCA survivors on the main TTM2-trial neurocognitive screening battery will be compared with neuropsychological test results at 7 months, using sensitivity and specificity analyses. Discussion: In this study we collect detailed information on cognitive impairment after OHCA and compare this to a control group of patients with acute MI. The validation of the TTM2 neurocognitive screening battery could justify its inclusion in routine follow-up. Our results may have a potential to impact on the design of future follow-up strategies and interventions after OHCA

Effects of Hypothermia vs Normothermia on Societal Participation and Cognitive Function at 6 Months in Survivors After Out-of-Hospital Cardiac Arrest

ImportanceThe Targeted Hypothermia vs Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) trial reported no difference in mortality or poor functional outcome at 6 months after out-of-hospital cardiac arrest (OHCA). This predefined exploratory analysis provides more detailed estimation of brain dysfunction for the comparison of the 2 intervention regimens.ObjectivesTo investigate the effects of targeted hypothermia vs targeted normothermia on functional outcome with focus on societal participation and cognitive function in survivors 6 months after OHCA.Design, Setting, and ParticipantsThis study is a predefined analysis of an international multicenter, randomized clinical trial that took place from November 2017 to January 2020 and included participants at 61 hospitals in 14 countries. A structured follow-up for survivors performed at 6 months was by masked outcome assessors. The last follow-up took place in October 2020. Participants included 1861 adult (older than 18 years) patients with OHCA who were comatose at hospital admission. At 6 months, 939 of 1861 were alive and invited to a follow-up, of which 103 of 939 declined or were missing.InterventionsRandomization 1:1 to temperature control with targeted hypothermia at 33 °C or targeted normothermia and early treatment of fever (37.8 °C or higher).Main outcomes and measuresFunctional outcome focusing on societal participation assessed by the Glasgow Outcome Scale Extended ([GOSE] 1 to 8) and cognitive function assessed by the Montreal Cognitive Assessment ([MoCA] 0 to 30) and the Symbol Digit Modalities Test ([SDMT] z scores). Higher scores represent better outcomes.ResultsAt 6 months, 836 of 939 survivors with a mean age of 60 (SD, 13) (range, 18 to 88) years (700 of 836 male [84%]) participated in the follow-up. There were no differences between the 2 intervention groups in functional outcome focusing on societal participation (GOSE score, odds ratio, 0.91; 95% CI, 0.71-1.17; P = .46) or in cognitive function by MoCA (mean difference, 0.36; 95% CI,−0.33 to 1.05; P = .37) and SDMT (mean difference, 0.06; 95% CI,−0.16 to 0.27; P = .62). Limitations in societal participation (GOSE score less than 7) were common regardless of intervention (hypothermia, 178 of 415 [43%]; normothermia, 168 of 419 [40%]). Cognitive impairment was identified in 353 of 599 survivors (59%).ConclusionsIn this predefined analysis of comatose patients after OHCA, hypothermia did not lead to better functional outcome assessed with a focus on societal participation and cognitive function than management with normothermia. At 6 months, many survivors had not regained their pre-arrest activities and roles, and mild cognitive dysfunction was common.Trial RegistrationClinicalTrials.gov Identifier: NCT0290830

Neurocognitive function following out-of-hospital cardiac arrest

Background: The brain is susceptible to hypoxic-ischemic brain injury in conjuction with out-of-hospital cardiac arrest (OHCA). Cognitive impairments are documented in about half of all OHCA survivors, however with a pronounced heterogeneity in measurements and findings. More detailed studies and instruments that are sensitive to OHCA-related cognitive impairment, including predictive models to identify individuals at risk, are needed. It is also unclear how different neurocognitive outcome methods are related to each other, to the brain injury, and to associated factors.Aims: The overall aim of this thesis was to explore the extent of neurocognitive impairment following OHCA in the late recovery phase. Specific aims per papers included in this thesis were: I) To examine the psychometric properties of an observer-reported questionnaire modified for usage after cardiac arrest, the Informant Questionnaire on Cognitive Decline in the Elderly-Cardiac Arrest (IQCODE-CA). II) To explore associations between four neurocognitive outcome methods administered in the late recovery phase and early hypoxic-ischemic brain injury assessed by the biomarker serum neurofilament light (NFL), and to compare the agreement for the four outcome methods. III) To describe the rationale and, IV) report initial results of detailed assessment of neurocognitive impairment in OHCA survivors, compare the cognitive performance to a cohort of participants following acute myocardial infarction (MI), and investigate the relationship between cognitive performance and the associated factors of emotional problems, fatigue, insomnia, and cardiovascular risk factors.Methods: I & II) Post-hoc analyses of surviving participants of the international multicenter Target temperature management 33 °C versus 36 °C after out-of-hospital cardiac arrest trial (TTM-trial), its biobank, and its cognitive sub-study, with a follow-up at 6 months post-arrest. III & IV) Prospective inclusion of surviving participants of the international multicenter Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest trial (TTM2-trial) at neuropsychological sub-study sites, recruitment of a matched non-arrest control group with acute MI, and an extensive neuropsychological assessment at approximately 7 months post-cardiac event.Results: I) The IQCODE-CA had acceptable psychometric properties and may be used alongside with performance-based measures when screening for post-arrest cognitive impairment. II) The clinician-report Cerebral Performance Category was mostly related to brain injury according to NFL, but with a ceiling effect. Although associations between patient-reports and performance-based measures were weak, all four outcome methods correlated significantly with each other. III & IV) Cognitive impairment on neuropsychological tests was generally mild among OHCA survivors (29% had at least borderline–mild impairment in ≥ 2 cognitive domains, and 14% had major impairment in ≥ 1 cognitive domain), but most pronounced in episodic memory, executive functions, and processing speed. OHCA survivors performed worse than MI controls. Diabetes and symptoms of anxiety, depression, and fatigue were associated with worse cognitive performance among the OHCA survivors.Conclusions: Cognitive impairment following OHCA is common. A post-OHCA follow-up service should screen for cognitive impairment using different neurocognitive outcome methods with acceptable psychometric properties. Since cognitive impairment is interrelated with emotional problems and fatigue, these areas should also be covered within routine screening. Patients with signs of impairment could be referred to neuropsychological assessment or team-based cognitive rehabilitation programs to optimize their recovery and long-term outcome

En utprovning av Hayling Test i svensk version - Psykometriska data och jämförelse med patienter med frontotemporal demens

Studiens syfte var att psykometriskt utprova en svenskspråkig version av Hayling Test, ett neuropsykologiskt test som framför allt avser att mäta verbal inhibitionsförmåga. Testet utprovades på en frisk kontrollgrupp (N = 76) i åldern 40-95 år. Studien fann ett signifikant negativt samband mellan ålder och prestationer på testet. Män presterade signifikant bättre än kvinnor på ett av delmåtten. Det förelåg en signifikant korrelation mellan hög utbildningsnivå och bättre testprestation på ett av delmåtten. Homogenitetsreliabiliteten var otillräcklig till bra, beroende på deltest. Interbedömarreliabiliteten var god till utmärkt. Begreppsvaliditeten var god då testet korrelerade signifikant positivt med ett annat test som avser att mäta inhibition, Color Word Interference Test (CWIT). Den diagnostiska validiteten undersöktes genom jämförelse mellan kontrollgruppen och en patientgrupp med frontotemporal demens (FTD; N = 30). Patientgruppen presterade signifikant sämre på testet, även om testet inte helt kunde skilja mellan grupperna. Det rekommenderas att några item och bedömningskriterier justeras för att förbättra användbarheten. Studiens slutsats är att den svenska versionen av Hayling Test kan användas vid neuropsykologisk utredning av inhibitorisk förmåga vid misstänkt FTD.The aim of this study was to examine the psychometric properties of an adapted Swedish version of the Hayling Test, a neuropsychological test which mainly intends to measure response inhibition. The test was administered to a healthy control group (N = 76) ranging in age from 40 to 95 years. The study found a significant negative correlation between age and test performance. Men performed significant better than women in one sub-scale. A high education level correlated significant with better test performance in one sub-scale. The internal consistency reliability varied between unacceptable to good, depending on the different sub-scales. Inter-rater reliability was good to excellent. Construct validity was good, as the test showed significant positive correlations with another test designed to measure inhibition, Color Word Interference Test (CWIT). The diagnostic validity was examined by comparing the control group with a group of patients with frontotemporal dementia (FTD; N = 30). The patient group performed significantly worse on the Hayling Test than the control group, although a slight overlap between groups was noted. Some modifications of items and scoring criteria are advised. This study concludes that the Swedish version of the Hayling Test can be of use within neuropsychological assessment of inhibition when FTD is suspected

Assessment of neurocognitive function after cardiac arrest

PURPOSE OF REVIEW: Impaired neurocognitive function is common in cardiac arrest survivors and the use of specific neurocognitive assessments are recommended in both clinical trials and daily practice. This review examines the most recent evidence to guide in the selection of neurocognitive outcome assessment tools after cardiac arrest. RECENT FINDINGS: Neurocognitive impairment after cardiac arrest was recently reported as one of the major predictors for societal participation, highlighting the need for neurocognitive assessments. A subjective report is a simple method to screen for cognitive problems, but divergent findings were reported when comparing with objective measures. A standardized observer report may be useful for cognitive screening postcardiac arrest. The Montreal Cognitive Assessment (MoCA) was recommended for cognitive screening after cardiac arrest. Detailed neurocognitive assessments were reported as valuable for in-depth evaluation of patients in interventional studies. The best time-point for neurocognitive assessments remains unknown. Recent findings report that most neurocognitive recovery is seen within the first months after cardiac arrest, with some improvement also noted between 3 and 12 months postcardiac arrest. SUMMARY: Neurocognitive assessments after cardiac arrest are important and the approach should differ depending on the clinical situation. Large, prospective, well designed studies, to guide the selection of neurocognitive assessments after cardiac arrest, are urgently needed