Longitudinal Neurocognitive and Pulmonological Profile of Long COVID-19: Protocol for the COVIMMUNE-Clin Study.

BACKGROUND: There is a dearth of information about "brain fog," characterized by concentration, word-finding, or memory problems, which has been listed in the new World Health Organization provisional classification "U09.9 Post-COVID-19 Condition." Moreover, the extent to which these symptoms may be associated with neurological, pulmonary, or psychiatric difficulties is unclear. OBJECTIVE: This ongoing cohort study aims to carefully assess neurocognitive function in the context of the neurological, psychiatric, and pulmonary sequelae of SARS-CoV-2 infection among patients with asymptomatic/mild and severe cases of COVID-19 after remission, including actively recruited healthy controls. METHODS: A total of 150 participants will be included in this pilot study. The cohort will comprise patients who tested positive for SARS-CoV-2 infection with either an asymptomatic course or a mild course defined as no symptoms except for olfactory and taste dysfunction (n=50), patients who tested positive for SARS-CoV-2 infection with a severe disease course (n=50), and a healthy control group (n=50) with similar age and sex distribution based on frequency matching. A comprehensive neuropsychological assessment will be performed comprising nuanced aspects of complex attention, including language, executive function, verbal and visual learning, and memory. Psychiatric, personality, social and lifestyle factors, sleep, and fatigue will be evaluated. Brain magnetic resonance imaging, neurological and physical assessment, and pulmonological and lung function examinations (including body plethysmography, diffusion capacity, clinical assessments, and questionnaires) will also be performed. Three visits are planned with comprehensive testing at the baseline and 12-month visits, along with brief neurological and neuropsychological examinations at the 6-month assessment. Blood-based biomarkers of neurodegeneration will be quantified at baseline and 12-month follow-up. RESULTS: At the time of submission, the study had begun recruitment through telephone and in-person screenings. The first patient was enrolled in the study at the beginning of April 2021. Interim data analysis of baseline information is expected to be complete by December 2021 and study completion is expected at the end of December 2022. Preliminary group comparisons indicate worse word list learning, short- and long-delayed verbal recall, and verbal recognition in both patient cohorts compared with those of the healthy control group, adjusted for age and sex. Initial volumetric comparisons show smaller grey matter, frontal, and temporal brain volumes in both patient groups compared with those of healthy controls. These results are quite robust but are neither final nor placed in the needed context intended at study completion. CONCLUSIONS: To the best of our knowledge, this is the first study to include objective and comprehensive longitudinal analyses of neurocognitive sequelae of COVID-19 in an extreme group comparison stratified by disease severity with healthy controls actively recruited during the pandemic. Results from this study will contribute to the nascent literature on the prolonged effects of COVID-19 on neurocognitive performance via our coassessment of neuroradiological, neurological, pulmonary, psychiatric, and lifestyle factors. TRIAL REGISTRATION: International Clinical Trials Registry Platform DRKS00023806; https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00023806. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/30259.

Time course of dementia following sepsis in German health claims data.

OBJECTIVE: We evaluated the short-, medium-, and long-term effects of sepsis on dementia incidence using German health claims data. METHODS: A total of 161,567 patients (65 years or older) were followed from 2004 to 2015 at quarterly intervals. Time since sepsis was categorized into 0 (the effective quarter of sepsis diagnosis), 1-8, and ≥9 quarters since the latest diagnosis of sepsis, taking into account admission to intensive care unit and controlling for delirium, surgery, age, sex, and comorbidities. Incident dementia was defined for all persons who did not have a validated dementia diagnosis in 2004 and 2005 and who received a first-time, valid diagnosis between 2006 and 2015. RESULTS: During the quarter of sepsis diagnosis, patients not admitted to intensive care had a 3.14-fold (95% CI 2.83-3.49) increased risk, and those with intensive care stay had a 2.22-fold (95% CI: 1.83-2.70) increased risk of receiving an incident dementia diagnosis compared with patients without sepsis. The impact of sepsis on incident dementia remained in the following 2 years, remitting only thereafter. CONCLUSIONS: For sepsis survivors, medium-term dementia risk remains elevated, whereas long-term risk may reach the level of those without sepsis, even after controlling for delirium. These findings encourage identifying modifiable components of hospital and rehabilitation care.

The Entorhinal Cortex Atrophy Score Is Diagnostic and Prognostic in Mild Cognitive Impairment.

BACKGROUND: Structural magnetic resonance imaging (MRI) is routinely performed in patients with mild cognitive impairment (MCI), but diagnostic accuracy to detect early cerebral atrophy is limited. OBJECTIVE: To validate the visual entorhinal cortex atrophy (ERICA) rating scale regarding diagnosis, biomarker status, neuropsychological profile, and dementia risk in MCI. METHODS: The ERICA score was retrospectively assessed regarding its discrimination of MCI (n = 80) from subjective cognitive decline and Alzheimer's disease (AD) dementia (n = 60, respectively), its prediction of conversion to dementia (median follow-up 28 months) and amyloid/tau biomarker status, and its association with neuropsychological tests. RESULTS: The ERICA score achieved 97% positive predictive value (PPV) for the presence of MCI. Discrimination between MCI and AD dementia (area under the curve: 0.71) was comparable to volumetry, and superior to the medial temporal lobe atrophy (MTA) score (p = 0.006). The PPV of the ERICA score for conversion to dementia was 83%, equivalent to tau status. It achieved 90% PPV for conversion when combined with tau, and 100% negative predictive value with verbal recall. While no measure predicted the predominantly positive amyloid status, the ERICA score was at least comparable to volumetry, and superior to the MTA score in predicting tau positivity (92% PPV for phospho-tau). The ERICA score was associated with verbal learning and memory, and, unlike the MTA score, also with AD-specific deficits in cued verbal recall. CONCLUSION: The ERICA score is a simple and valuable tool to exploit structural MRI for diagnosis and prognosis in MCI and is non-inferior to volumetry.

The ERICA Score: An MR Imaging-based Visual Scoring System for the Assessment of Entorhinal Cortex Atrophy in Alzheimer Disease.

Purpose To establish and evaluate a visual score focused on entorhinal cortex atrophy (ERICA), as the entorhinal cortex is one of the first brain structures affected in Alzheimer disease (AD). Materials and Methods In this retrospective study, ERICA was visually evaluated with magnetic resonance imaging (2009-2016). First, a four-point ERICA score was developed by using data in 48 consecutive subjects (20 patients with AD and 28 control subjects). Then, in the main analysis, ERICA and the standard medial temporal lobe atrophy (MTA) scores were determined in an independent cohort of 60 patients suspected of having AD (mean age, 69.4 years; range, 46-86 years) and in 60 age-matched patients with subjective cognitive decline (SCD) (mean age, 72.4 years; range 50-87 years). Score performances were evaluated with κ statistics, receiver operating characteristic analysis, t tests, and analysis of variance according to the Standards for Reporting of Diagnostic Accuracy Studies. Results Patients with AD had higher MTA scores (mean, 2.13) and ERICA scores (mean, 2.05) than patients with SCD (P < .001). An ERICA score of 2 or greater achieved a higher diagnostic accuracy (91%) than the MTA score (74%), with a sensitivity of 83% versus 57% and a specificity of 98% versus 92% in discriminating dementia caused by AD from SCD (P < .001). The ERICA score was correlated with amyloid ß 42/40 ratio (ρ = -0.54, P < .001) and with cerebrospinal fluid tau (ρ = 0.35, P = .001) and p-tau (ρ = 0.31, P = .004). In multivariable linear regression analysis, ERICA was associated with verbal learning and recall (ß = -.40 and -.41), nonverbal recall (ß = -.28), and cued recall (ß = -.41, P ≤ .002 for all). Conclusion An ERICA score of 2 or greater indicates probable AD with high diagnostic accuracy. © RSNA, 2018 Online supplemental material is available for this article.

Beyond the limits - ECPR in putative fatal circumstances.

The eligibility criteria for applying extracorporeal cardiopulmonary resuscitation (ECPR) in patients with cardiac arrest are currently unclear. For those patients with hypothermic cardiac arrest, the European Resuscitation Council (ERC) Guidelines recommend considering ECPR only for patients with potassium <8 mmol/L and a body temperature below 32°C, whereas the American Heart Association Guidelines (AHA) do not express this in a specific manner.We report the case of an urban unwitnessed out-of-hospital cardiac arrest patient found with her head immersed in water at a temperature of 23°C. The patient presented an unclear history and a dire combination of clinical and laboratory parameters (asystole, arterial blood gas: pH 6.8, potassium 8.3 mmol/L, lactate 16.0 mmol/L). Despite these poor prognostic indicators, ECPR was initiated after 95 minutes of CPR and the patient survived with a good neurological outcome.This case highlights the uncertainty in ECPR eligibility and prognostication, especially in those with hypothermia and water immersion for whom aggressive therapies may be warranted. Further data and improved strategies are required to delineate candidacy for this resource-intensive procedure better.

Characterization and clinical use of inflammatory cerebrospinal fluid protein markers in Alzheimer's disease.

BACKGROUND: Neuroinflammation has gained increasing attention as a potential contributing factor in Alzheimer's disease (AD) pathology. A clinical cerebrospinal fluid biomarker capable of monitoring this process during the course of the disease has yet to emerge, chiefly owing to contradictory research findings. In this study, we sought to clarify the utility of inflammatory biomarkers in diagnostic procedures of AD in three steps: (1) to screen for proteins that are robustly detectable in cerebrospinal fluid; (2) based on this analysis, to explore any associations between the analytically robust markers and salient pathological features of AD; and (3) to determine the discriminative power of these markers in the clinical diagnosis of AD. METHODS: From a total of 46 proteins, 15 that were robustly detectable in cerebrospinal fluid were identified. A subsequent analysis of these markers in a cohort of 399 patients (nondemented subjects, patients with mild cognitive impairment [MCI], and patients with AD, supplemented by smaller cohorts of other diseases) was conducted. Fluid biomarker data were related to AD pathology and neuropsychological markers and adjusted for confounders such as age, sex, apolipoprotein E genotype, and biobank storage time. RESULTS: Cerebrospinal fluid levels of C-reactive protein and soluble TREM2 differed between nondemented subjects, patients with MCI, or patients with AD and were associated with amyloid and tau pathology. Several markers were associated with tau pathology only or with other neurodegenerative diseases. Correlations between neuropsychological performance and inflammatory markers were weak, but they were most prominent in AD and for the most challenging cognitive tests. All investigated covariates had significant influence, with varying effects across the markers. Still, none of the markers achieved discriminative power of more than 70% to distinguish between patient groups defined by clinical or neuropathological categories. CONCLUSIONS: Basic analytical considerations proved indispensable for this type of study because only one-third of the tested markers were robustly detectable in cerebrospinal fluid. Detectable inflammatory protein markers were associated in multiple ways with AD pathology. Yet, even significantly associated markers were not powerful enough in terms of effect strength, sensitivity, and specificity, and hence they were not suited for direct use in clinical diagnostic practice. Targets other than those most commonly considered in this field of research might provide results with better clinical applicability.

Long-term cerebral consequences of sepsis.

Sepsis is a potentially fatal whole-body inflammatory state caused by severe infection, in which a maladaptive, system-wide inflammatory response follows initial attempts to eliminate pathogens, leading to a dangerous and often fatal increase in the permeability of the blood-brain barrier. These changes in the blood-brain barrier might lead to a major symptom of sepsis, sepsis-associated encephalopathy, which manifests as confusion with a rapid decline in cognitive functions, especially memory, or coma. Once presumed to be entirely reversible, research suggests that sepsis-associated encephalopathy could lead to permanent neurocognitive dysfunction and functional impairments, even after the patient has recovered. Sepsis might act as a major inflammatory hit and potentially increase the brain's susceptibility to neurodegenerative disease, further deterioration of cognitive ability, and risk of developing dementia in later life. Key opportunities for neuroprotective interventions and after-care for people who have survived sepsis might be lost because the long-term neurocognitive and functional consequences of sepsis are not fully characterised.

Clinical symptoms and risk factors in cerebral microangiopathy patients.

OBJECTIVE: Although the clinical manifestation and risk factors of cerebral microangiopathy (CM) remain unclear, the number of diagnoses is increasing. Hence, patterns of association among lesion topography and severity, clinical symptoms and demographic and disease risk factors were investigated retrospectively in a cohort of CM patients. METHODS: Patients treated at the Department of Neurology, University of Bonn for CM (n = 223; 98m, 125f; aged 77.32±9.09) from 2005 to 2010 were retrospectively enrolled. Clinical symptoms, blood chemistry, potential risk factors, demographic data and ratings of vascular pathology in the brain based on the Wahlund scale were analyzed using Pearson's chi square test and one-way ANOVA. RESULTS: Progressive cognitive decline (38.1%), gait apraxia (27.8%), stroke-related symptoms and seizures (24.2%), TIA-symptoms (22%) and vertigo (17%) were frequent symptoms within the study population. Frontal lobe WMLs/lacunar infarcts led to more frequent presentation of progressive cognitive decline, seizures, gait apraxia, stroke-related symptoms, TIA, vertigo and incontinence. Parietooccipital WMLs/lacunar infarcts were related to higher frequencies of TIA, seizures and incontinence. Basal ganglia WMLs/lacunar infarcts were seen in patients with more complaints of gait apraxia, vertigo and incontinence. Age (p = .012), arterial hypertension (p<.000), obesity (p<.000) and cerebral macroangiopathy (p = .018) were positively related to cerebral lesion load. For increased glucose level, homocysteine, CRP and D-Dimers there was no association. CONCLUSION: This underlines the association of CM with neurological symptoms upon admission in a topographical manner. Seizures and vertigo are symptoms of CM which may have been missed in previous studies. In addition to confirming known risk factors such as aging and arterial hypertension, obesity appears to increase the risk as well. Since the incidence of CM is increasing, future studies should focus on the importance of prevention of vascular risk factors on its pathogenesis.

Everyday memory deficits in very mild Alzheimer's disease.

Memory complaints of patients sometimes are not verified via standard cognitive testing. Acquisition of information in everyday life requires memorization in complex three-dimensional environments. The authors mimicked this with a photorealistic virtual environment (VE). Memory for verbal material and spatial scenery was tested in healthy controls (HC) and patients with mild Alzheimer's disease (AD); mini-mental state evaluation (MMSE) 25.7 ± 1.8 (mean ± standard deviation). The number of memorized items increased to 90% in both classical list learning and for items memorized in VE in HC. In contrast, only 40% of items were recalled in list learning and 20% in VE in AD patients. Unlike the gender difference favoring female HC on list learning, performance was alike for both genders in VE. We conclude that verbal learning abilities in healthy elderly subjects are alike in standard settings and under virtual reality conditions. In AD patients memory deficits that are relevant to everyday life yet not detectable with list learning are unmasked in virtual reality. In future, this may aid objective appraisal of interventions with regard to their everyday relevance.