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. 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. 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. 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.

Cohort studies that quantify volumetric brain data among individuals with different levels of COVID-19 severity are presently limited. It is still uncertain whether there exists a potential correlation between disease severity and the effects of COVID-19 on brain integrity. Our objective was to assess the potential impact of COVID-19 on measured brain volume in patients with asymptomatic/mild and severe disease after recovery from infection, compared with healthy controls, using artificial intelligence (AI)-based MRI volumetry. A total of 155 participants were prospectively enrolled in this IRB-approved analysis of three cohorts with a mild course of COVID-19 (n = 51, MILD), a severe hospitalised course (n = 48, SEV), and healthy controls (n = 56, CTL) all undergoing a standardised MRI protocol of the brain. Automated AI-based determination of various brain volumes in mL and calculation of normalised percentiles of brain volume was performed with mdbrain software, using a 3D T1-weighted magnetisation-prepared rapid gradient echo (MPRAGE) sequence. The automatically measured brain volumes and percentiles were analysed for differences between groups. The estimated influence of COVID-19 and demographic/clinical variables on brain volume was determined using multivariate analysis. There were statistically significant differences in measured brain volumes and percentiles of various brain regions among groups, even after the exclusion of patients undergoing intensive care, with significant volume reductions in COVID-19 patients, which increased with disease severity (SEV > MILD > CTL) and mainly affected the supratentorial grey matter, frontal and parietal lobes, and right thalamus. Severe COVID-19 infection, in addition to established demographic parameters such as age and sex, was a significant predictor of brain volume loss upon multivariate analysis. In conclusion, neocortical brain degeneration was detected in patients who had recovered from SARS-CoV-2 infection compared to healthy controls, worsening with greater initial COVID-19 severity and mainly affecting the fronto-parietal brain and right thalamus, regardless of ICU treatment. This suggests a direct link between COVID-19 infection and subsequent brain atrophy, which may have major implications for clinical management and future cognitive rehabilitation strategies.

Roughly one in five adults who meet criteria for long covid present with objective or subjective cognitive dysfunction or elevated symptoms of depression or anxiety lasting ≥12 weeks from an acute covid illness. These neuropsychiatric sequelae have considerable functional consequences at the level of the individual, society, and the broader economy. Neuropsychiatric long covid symptoms are thought to be causally diverse, and a range of risk factors as well as biological, psychological, and environmental mechanisms have been hypothesized to contribute to symptom development and persistence. When present, objective cognitive deficits tend to be modest for most individuals, with some evidence suggesting increased risk of dysfunction and decline specifically for older adults with a history of severe acute illness. Longitudinal data suggest a delayed emergence of psychiatric symptoms may occur in the weeks and months after an acute covid illness. Emerging research points to the early recovery period as a potential window of opportunity for intervention to alter patient trajectories, though evidence based treatment remains lacking.

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

Cognitive sequelae after recovery from an initial COVID-19 disease are present in a subset of affected individuals, coalescing around several important issues such as effects of age, COVID-19 disease severity, comorbidities, and other factors. Some neuropsychological symptoms appear more common among certain patient populations. Comorbidities may complicate neuropsychological assessment as well. Hence, we need a guideline-based evaluation to guide neuropsychological rehabilitation. Drawing from the recent revision of the German National Guideline for the Long- and Post-COVID Syndrome and current advances in international guidance on neuropsychological assessment, this article provides practical and scientifically informed recommendations for the neuropsychological assessment of individuals recovering from coronavirus-related diseases.

This review assesses neurocognitive studies on long-/post-COVID-19 adult patients, highlighting the research gaps. We categorize populations by infection severity, demographics, inclusion of controls, and psychological/biological factors. Methodologically, we analyzed 73 studies (95,600 subjects) from December 2019 to October 2022 using PRISMA-ScR guidelines and the PICO framework. Our findings revealed that most studies lacked control groups (88 %) and reported unclear overall cognitive outcomes (73 %). While the studies frequently assessed executive functions (86 %) and attention (85 %), there were few longitudinal studies. Varied reporting on sample sizes further complicated the analysis. The identified gaps encompass convenience sampling, limited longitudinal studies, and inadequate use of cognitive test batteries, leading to a discrepancy between expected and reported outcomes. The absence of standardized comparisons and inconsistent statistical methods exacerbated these gaps.