Assessing CT-based Volumetric Analysis via Transfer Learning with MRI and Manual Labels for Idiopathic Normal Pressure Hydrocephalus.

Background: Brain computed tomography (CT) is an accessible and commonly utilized technique for assessing brain structure. In cases of idiopathic normal pressure hydrocephalus (iNPH), the presence of ventriculomegaly is often neuroradiologically evaluated by visual rating and manually measuring each image. Previously, we have developed and tested a deep-learning-model that utilizes transfer learning from magnetic resonance imaging (MRI) for CT-based intracranial tissue segmentation. Accordingly, herein we aimed to enhance the segmentation of ventricular cerebrospinal fluid (VCSF) in brain CT scans and assess the performance of automated brain CT volumetrics in iNPH patient diagnostics. Methods: The development of the model used a two-stage approach. Initially, a 2D U-Net model was trained to predict VCSF segmentations from CT scans, using paired MR-VCSF labels from healthy controls. This model was subsequently refined by incorporating manually segmented lateral CT-VCSF labels from iNPH patients, building on the features learned from the initial U-Net model. The training dataset included 734 CT datasets from healthy controls paired with T1-weighted MRI scans from the Gothenburg H70 Birth Cohort Studies and 62 CT scans from iNPH patients at Uppsala University Hospital. To validate the model's performance across diverse patient populations, external clinical images including scans of 11 iNPH patients from the Universitatsmedizin Rostock, Germany, and 30 iNPH patients from the University of Alabama at Birmingham, United States were used. Further, we obtained three CT-based volumetric measures (CTVMs) related to iNPH. Results: Our analyses demonstrated strong volumetric correlations (ϱ=0.91, p<0.001) between automatically and manually derived CT-VCSF measurements in iNPH patients. The CTVMs exhibited high accuracy in differentiating iNPH patients from controls in external clinical datasets with an AUC of 0.97 and in the Uppsala University Hospital datasets with an AUC of 0.99. Discussion: CTVMs derived through deep learning, show potential for assessing and quantifying morphological features in hydrocephalus. Critically, these measures performed comparably to gold-standard neuroradiology assessments in distinguishing iNPH from healthy controls, even in the presence of intraventricular shunt catheters. Accordingly, such an approach may serve to improve the radiological evaluation of iNPH diagnosis/monitoring (i.e., treatment responses). Since CT is much more widely available than MRI, our results have considerable clinical impact.

Quantitative brain stem assessment in discriminating neurodegenerative disorders from normal pressure hydrocephalus.

BACKGROUND AND PURPOSE: Differentiating idiopathic normal pressure hydrocephalus (iNPH) from neurodegenerative disorders such as progressive supranuclear palsy (PSP), Multiple System Atrophy-parkinsonian type (MSA-P), and vascular dementia (VaD) is challenging due to overlapping clinical and neuroimaging findings. This study assesses if quantitative brain stem and cerebellum metrics can aid in this differentiation. METHODS: We retrospectively compared the sagittal midbrain area, midbrain to pons ratio, MR parkinsonism index (MRPI), and cerebellar atrophy in 30 PSP patients, 31 iNPH patients, 27 MSA-P patients, 32 VaD patients, and 25 healthy controls. Statistical analyses determined group differences, sensitivity, specificity, and the area under the receiver operating characteristic curves. RESULTS: There was an overlap in midbrain morphology between PSP and iNPH, as assessed with MRPI, midbrain to pons ratio, and midbrain area. A cutoff value of MRPI > 13 exhibited 84% specificity in distinguishing PSP from iNPH and 100% in discriminating PSP from all other conditions. A cutoff value of midbrain to pons ratio at <0.15 yielded 95% specificity for differentiating PSP from iNPH and 100% from all other conditions. A cutoff value of midbrain area at <87 mm2 exhibited 97% specificity for differentiating PSP from iNPH and 100% from all other conditions. All measures showed low sensitivity. Cerebellar atrophy did not differ significantly among groups. CONCLUSION: Our study questions MRPI's diagnostic performance in distinguishing PSP from iNPH. Simpler indices such as midbrain to pons ratio and midbrain area showed similar or better accuracy. However, all these indices displayed low sensitivity despite significant differences among PSP, MSA-P, and VaD.

Extracellular vesicles in plasma and cerebrospinal fluid in patients with COVID-19 and neurological symptoms.

INTRODUCTION: Increased levels of extracellular vesicles (EVs) are associated with haemostatic disturbances in various clinical settings. However, their role in COVID-19 patients is still not fully clear. In the present study we investigated EVs in plasma from patients with COVID-19 and neurological symptoms in relation to the activation of coagulation. METHODS: Nineteen COVID-19 patients with neurological symptoms and twenty-three aged-matched healthy individuals were included. Global coagulation assays were performed and levels of EVs were determined by flow-cytometry in plasma and cerebrospinal fluid (CSF). RESULTS: A procoagulant state characterized by significantly increased overall coagulation- (OCP) and overall haemostatic potential (OHP), diminished overall fibrinolytic potential (OFP) together with a denser fibrin structure was found in patients with COVID-19. Flow cytometry revealed elevated levels of plasma circulating EVs derived from neutrophils (MPO+) and platelets (CD61+), as well as EVs expressing phosphatidylserine (PS+) and complement component C5b-9 (TCC+) in patients with COVID-19 compared with controls. The concentrations of PS+, CD61+ and TCC+ EVs were positively correlated with OCP and OHP in COVID-19 patients. Moreover, we identified CD61+, MPO+ and endothelial cell-derived EVs, as well as EVs exposing PS and TCC in the CSF of patients suffering from neurological symptoms during COVID-19. CONCLUSION: The unique finding in this study was the presence of EVs in the CSF of COVID-19 patients with neurologic manifestations as well as higher expression of complement protein on circulating plasma EVs. EVs may indicate blood-brain barrier damage during SARS-COV-2 infection.

Levels of inflammatory cytokines MCP-1, CCL4, and PD-L1 in CSF differentiate idiopathic normal pressure hydrocephalus from neurodegenerative diseases.

BACKGROUND: Neuroinflammatory processes have been suggested to play a role in the pathophysiology of neurodegenerative diseases and post-hemorrhagic hydrocephalus, but have rarely been investigated in patients with idiopathic normal pressure hydrocephalus (iNPH). The aim of this study was to investigate whether levels of inflammatory proteins in CSF are different in iNPH compared to healthy controls and patients with selected neurodegenerative disorders, and whether any of these markers can aid in the differential diagnosis of iNPH. METHODS: Lumbar CSF was collected from 172 patients from a single center and represented iNPH (n = 74), Alzheimer's disease (AD) (n = 21), mild cognitive impairment (MCI) due to AD (n = 21), stable MCI (n = 22), frontotemporal dementia (n = 13), and healthy controls (HC) (n = 21). Levels of 92 inflammatory proteins were analyzed using a proximity extension assay. As a first step, differences between iNPH and HC were investigated, and proteins that differed between iNPH and HC were then compared with those from the other groups. The linear regressions were adjusted for age, sex, and plate number. RESULTS: Three proteins showed higher (MCP-1, p = 0.0013; CCL4, p = 0.0008; CCL11, p = 0.0022) and one lower (PD-L1, p = 0.0051) levels in patients with iNPH compared to HC. MCP-1 was then found to be higher in iNPH than in all other groups. CCL4 was higher in iNPH than in all other groups, except in MCI due to AD. PD-L1 was lower in iNPH compared to all other groups, except in stable MCI. Levels of CCL11 did not differ between iNPH and the differential diagnoses. In a model based on the four proteins mentioned above, the mean area under the receiver operating characteristic curve used to discriminate between iNPH and the other disorders was 0.91. CONCLUSIONS: The inflammatory cytokines MCP-1 and CCL4 are present at higher-and PD-L1 at lower-levels in iNPH than in the other investigated diagnoses. These three selected cytokines may have diagnostic potential in the work-up of patients with iNPH.

Myoclonus in patients with COVID-19: Findings of autoantibodies against brain structures in cerebrospinal fluid.

BACKGROUND AND PURPOSE: COVID-19 is associated with multiple neurological manifestations. The clinical presentation, trajectory, and treatment response for three cases of myoclonus during COVID-19 infection, with no previous neurological disease, are decsribed. METODS: Analysis of cerebrospinal fluid from the cases using indirect immunohistochemistry. RESULTS: Antibodies against rodent brain tissue, and similarities in staining patterns were observed, indicating the presence of antineuronal immunoglobulin G autoantibodies targeting astrocytes in the hippocampus. CONCLUSION: Our results demontrate cerebrospinal fluid antineuronal antibodies indicating an an autoimmune involvment in the pathogenesis in COVID-19 associated myoclonus.

Prognostic performance of blood neurofilament light chain protein in hospitalized COVID-19 patients without major central nervous system manifestations: an individual participant data meta-analysis.

BACKGROUND AND AIMS: To investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19). METHODS: We conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd 2022. We included studies with hospitalized adult COVID-19 patients without major COVID-19-associated central nervous system (CNS) manifestations and with a measurement of blood NfL in the acute phase as well as data regarding at least one clinical outcome including intensive care unit (ICU) admission, need of mechanical ventilation (MV) and death. We derived the age-adjusted measures NfL Z scores and conducted mixed-effects modelling to test associations between NfL Z scores and other variables, encompassing clinical outcomes. Summary receiver operating characteristic curves (SROCs) were used to calculate the area under the curve (AUC) for blood NfL. RESULTS: We identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2 ± 15.0 years, 68.1% males). Median NfL Z score at admission was elevated compared to the age-corrected reference population (2.37, IQR: 1.13-3.06, referring to 99th percentile in healthy controls). NfL Z scores were significantly associated with disease duration and severity. Higher NfL Z scores were associated with a higher likelihood of ICU admission, need of MV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need of MV and ICU admission, respectively. CONCLUSIONS: Blood NfL levels were elevated in the acute phase of COVID-19 patients without major CNS manifestations and associated with clinical severity and poor outcome. The marker might ameliorate the performance of prognostic multivariable algorithms in COVID-19.

Protein Expression Profile of ACE2 in the Normal and COVID-19-Affected Human Brain.

SARS-coronavirus 2 (SARS-CoV-2) that caused the coronavirus disease 2019 (COVID-19) pandemic has posed to be a global challenge. An increasing number of neurological symptoms have been linked to the COVID-19 disease, but the underlying mechanisms of such symptoms and which patients could be at risk are not yet established. The suggested key receptor for host cell entry is angiotensin I converting enzyme 2 (ACE2). Previous studies on limited tissue material have shown no or low protein expression of ACE2 in the normal brain. Here, we used stringently validated antibodies and immunohistochemistry to examine the protein expression of ACE2 in all major regions of the normal brain. The expression pattern was compared with the COVID-19-affected brain of patients with a varying degree of neurological symptoms. In the normal brain, the expression was restricted to the choroid plexus and ependymal cells with no expression in any other brain cell types. Interestingly, in the COVID-19-affected brain, an upregulation of ACE2 was observed in endothelial cells of certain patients, most prominently in the white matter and with the highest expression observed in the patient with the most severe neurological symptoms. The data shows differential expression of ACE2 in the diseased brain and highlights the need to further study the role of endothelial cells in COVID-19 disease in relation to neurological symptoms.

White matter changes should not exclude patients with idiopathic normal pressure hydrocephalus from shunt surgery.

INTRODUCTION: White matter changes (WMC) on brain imaging can be classified as deep white matter hyperintensities (DWMH) or periventricular hyperintensities (PVH) and are frequently seen in patients with idiopathic normal pressure hydrocephalus (iNPH). Contradictory results have been reported on whether preoperative WMC are associated with outcome after shunt surgery in iNPH patients. The aim of this study was to investigate any association between DWMH and PVH and shunt outcome in patients with iNPH, using magnetic resonance volumetry. METHODS: A total of 253 iNPH patients operated with shunt surgery and clinically assessed before and 12 months after surgery were included. All patients were investigated preoperatively with magnetic resonance imaging of the brain. The volumes of DWMH and PVH were quantified on fluid-attenuated inversion recovery images using an in-house semi-automatic volumetric segmentation software (SmartPaint). Shunt outcome was defined as the difference in symptom score between post- and preoperative investigations, measured on the iNPH scale, and shunt response was defined as improvement with ≥ 5 points. RESULTS: One year after shunt surgery, 51% of the patients were improved on the iNPH scale. When defining improvement as ≥ 5 points on the iNPH scale, there was no significant difference in preoperative volume of WMC between shunt responders and non-responders. If outcome was determined by a continuous variable, a larger volume of PVH was negatively associated with postoperative change in the total iNPH scale (p < 0.05) and negatively associated with improvement in gait (p < 0.01) after adjusting for age, sex, waiting time for surgery, preoperative level of symptoms, Evans' index, and disproportionately enlarged subarachnoid space hydrocephalus. The volume of DWMH was not associated with shunt outcome. CONCLUSIONS: An association between outcome after shunt surgery and volume of PVH was seen, but there was no difference between shunt responders and non-responders in the volumes of DWMH and PVH. We conclude that preoperative assessment of WMC should not be used to exclude patients with iNPH from shunt surgery.

Higher levels of neurofilament light chain and total tau in CSF are associated with negative outcome after shunt surgery in patients with normal pressure hydrocephalus.

BACKGROUND: Lumbar punctures are a common examination in the work-up of patients with idiopathic normal pressure hydrocephalus (iNPH) and cerebrospinal fluid (CSF) biomarkers should therefore be available for use in selection of shunt candidates. The aim of this study was to investigate if CSF biomarkers are associated with outcome after shunt surgery alone or in combination with comorbidity and imaging markers, and investigate associations between CSF biomarkers and symptoms. METHODS: Preoperative CSF biomarkers were analyzed in 455 patients operated with shunt surgery for iNPH at a single center during 2011-2018. Symptoms before and 12 months after shunt surgery were graded with the Swedish iNPH scale. Neurofilament light chain protein (NfL), total tau (T-tau), phosphorylated tau (P-tau) and amyloid beta1-42 (Aß1-42) CSF levels were measured. Evans' index and disproportionately enlarged subarachnoid space hydrocephalus were measured on preoperative CT-scans. Preoperative evaluation and follow-up 12 months after shunt surgery were available in 376 patients. RESULTS: Higher levels of NfL and T-tau were associated with less improvement after shunt surgery (ß = - 3.10, p = 0.016 and ß = - 2.45, p = 0.012, respectively). Patients whose symptoms deteriorated after shunt surgery had higher preoperative levels of NfL (1250 ng/L [IQR:1020-2220] vs. 1020 [770-1649], p < 0.001) and T-tau (221 ng/L [IQR: 159-346] vs. 190 [135-261], p = 0.0039) than patients with postoperative improvement on the iNPH scale. Among the patients who improved ≥ 5 levels on the iNPH scale (55%), NfL was abnormal in 22%, T-tau in 14%, P-tau in 6% and Aß1-42 in 45%, compared with normal reference limits. The inclusion of CSF biomarkers, imaging markers and comorbidity in multivariate predictive Orthogonal Projections to Latent Structures (OPLS) models to did not improve predictability in outcome after shunt surgery. CONCLUSIONS: Higher levels of T-tau and NfL were associated with a less favorable response to shunt surgery, suggesting a more active neurodegeneration in this group of patients. However, CSF levels of these biomarkers can be elevated also in patients who respond to shunt surgery. Thus, none of these CSF biomarkers, alone or used in combination, are suitable for excluding patients from surgery.

The timed up and go test in idiopathic normal pressure hydrocephalus: a Nationwide Study of 1300 patients.

BACKGROUND: The aim of this study was to describe the outcome measure timed up and go (TUG) in a large, nationwide cohort of patients with idiopathic normal pressure hydrocephalus (iNPH) pre- and post-operatively. Furthermore, to compare the TUG test to the 10-m walk test (10MWT), the iNPH scale, the modified Rankin scale (mRS) and the Mini Mental State Examination (MMSE), which are commonly applied in clinical assessment of iNPH. METHODS: Patients with iNPH (n = 1300), registered in the Swedish Hydrocephalus Quality Registry (SHQR), were included. All data were retrieved from the SHQR except the 10MWT, which was collected from patient medical records. Clinical scales were examined pre- and 3 months post-operatively. Data were dichotomised by sex, age, and preoperative TUG time. RESULTS: Preoperative TUG values were 19.0 [14.0-26.0] s (median [IQR]) and 23 [18-30] steps. Post-operatively, significant improvements to 14.0 [11.0-20.0] s and 19 [15-25] steps were seen. TUG time and steps were higher in women compared to men (p < 0.001) but there was no sex difference in improvement rate. Worse preoperative TUG and younger age favoured improvement. TUG was highly correlated to the 10MWT, but correlations of post-operative changes were only low to moderate between all scales (r = 0.22-0.61). CONCLUSIONS: This study establishes the distribution of TUG in iNPH patients and shows that the test captures important clinical features that improve after surgery independent of sex and in all age groups, confirming the clinical value of the TUG test. TUG performance is associated with performance on the 10MWT pre- and post-operatively. However, the weak correlations in post-operative change to the 10MWT and other established outcome measures indicate an additional value of TUG when assessing the effects of shunt surgery.

Antibody Responses to Severe Acute Respiratory Syndrome Coronavirus 2 in the Serum and Cerebrospinal Fluid of Patients With Coronavirus Disease 2019 and Neurological Symptoms.

Antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in serum and cerebrospinal fluid (CSF) samples from 16 patients with coronavirus disease 2019 and neurological symptoms were assessed using 2 independent methods. Immunoglobulin G (IgG) specific for the virus spike protein was found in 81% of patients in serum and in 56% in CSF. SARS-CoV-2 IgG in CSF was observed in 2 patients with negative serological findings. Levels of IgG in both serum and CSF were associated with disease severity (P < .05). All patients with elevated markers of central nervous system damage in CSF also had CSF antibodies (P = .002), and CSF antibodies had the highest predictive value for neuronal damage markers of all tested clinical variables.

Midbrain area and the hummingbird sign from brain MRI in progressive supranuclear palsy and idiopathic normal pressure hydrocephalus.

BACKGROUND AND PURPOSE: The main radiological finding in progressive supranuclear palsy (PSP) is reduced midbrain volume. Both qualitative (e.g., hummingbird sign) and quantitative (e.g., area measurements) markers have been noted. Recent studies have shown a similar reduction also in idiopathic normal pressure hydrocephalus (iNPH). The purpose was to investigate the reliability and accuracy of these markers in discriminating PSP from iNPH and controls. METHODS: Eight neuroradiologists viewed sagittal MR images of the midbrain from 104 subjects: 26 PSP patients, 40 iNPH patients, and 38 healthy controls. They visually assessed whether the hummingbird sign was present or not, grading their confidence from 1 to 5. Assessments were translated into a score between +5 and -5: from maximum confidence of presence to maximum confidence of absence. A positive median score was considered to indicate hummingbird sign. Sagittal midbrain area was manually measured in each subject. RESULTS: Seventy-seven percent of PSP patients, 65% of iNPH, and 3% of controls were visually assessed as having the hummingbird sign. Manually measured midbrain area also showed overlap between PSP and iNPH. Regarding discrimination of PSP patients, midbrain area measurements, using a cutoff of 90 mm2 , yielded a higher area under the curve (AUC = 0.86) than visual assessment scores (AUC = 0.83), and higher reliability. CONCLUSIONS: Measuring sagittal midbrain area is more accurate and reliable than visual assessment. Due to significant overlap in appearance, a midbrain with a hummingbird sign or reduced sagittal area should raise the suspicion of PSP only after other signs of iNPH have been considered.

The extent of neuroradiological findings in COVID-19 shows correlation with blood biomarkers, Glasgow coma scale score and days in intensive care.

BACKGROUND AND PURPOSE: A wide range of neuroradiological findings has been reported in patients with coronavirus disease 2019 (COVID-19), ranging from subcortical white matter changes to infarcts, haemorrhages and focal contrast media enhancement. These have been descriptively but inconsistently reported and correlations with clinical findings and biomarkers have been difficult to extract from the literature. The purpose of this study was to quantify the extents of neuroradiological findings in a cohort of patients with COVID-19 and neurological symptoms, and to investigate correlations with clinical findings, duration of intensive care and biomarkers in blood. MATERIAL AND METHODS: Patients with positive SARS-CoV-2 and at least one new-onset neurological symptom were included from April until July 2020. Nineteen patients were examined regarding clinical symptoms, biomarkers in blood and MRI of the brain. In order to quantify the MRI findings, a semi-quantitative neuroradiological severity scale was constructed a priori, and applied to the MR images by two specialists in neuroradiology. RESULTS AND CONCLUSIONS: The score from the severity scale correlated significantly with blood biomarkers of CNS injury (glial fibrillary acidic protein, total-tau, ubiquitin carboxyl-terminal hydrolase L1) and inflammation (C-reactive protein), Glasgow Coma Scale score, and the number of days spent in intensive care. The underlying radiological assessments had inter-rater agreements of 90.5%/86% (for assessments with 2/3 alternatives). Total intraclass correlation was 0.80. Previously reported neuroradiological findings in COVID-19 have been diverse and heterogenous. In this study, the extent of findings in MRI examination of the brain, quantified using a structured report, shows correlation with relevant biomarkers.

Imaging features associated with idiopathic normal pressure hydrocephalus have high specificity even when comparing with vascular dementia and atypical parkinsonism.

BACKGROUND: Vascular dementia (VaD) and atypical parkinsonism often present with symptoms that can resemble idiopathic normal pressure hydrocephalus (iNPH) and enlarged cerebral ventricles, and can be challenging differential diagnoses. The aim was to investigate frequencies of imaging features usually associated with iNPH and their radiological diagnostic accuracy in a sample containing the relevant differential diagnoses VaD, progressive supranuclear palsy (PSP), multiple system atrophy parkinsonian type (MSA-P), and healthy controls. METHODS: Nine morphological imaging features usually associated with iNPH were retrospectively investigated in MR images of 55 patients with shunt-responsive iNPH, 32 patients with VaD, 30 patients with PSP, 27 patients with MSA-P, and 39 age-matched healthy controls. Logistic regression and receiver operating characteristic curves were used to assess diagnostic accuracy, sensitivity, and specificity for each imaging finding. RESULTS: In a logistic regression model using iNPH diagnosis as a dependent variable, the following imaging features contributed significantly to the model: callosal angle (OR = 0.95 (0.92-0.99), p = 0.012), Evans' index * 100 (OR = 1.51 (1.23-1.86), p < 0.001), enlarged Sylvian fissures (OR = 6.01 (1.42-25.40), p = 0.015), and focally enlarged sulci (OR = 10.18 (1.89-55.02), p = 0.007). Imaging features with 95% specificity for iNPH were: callosal angle ≤ 71°, temporal horns ≥ 7 mm, Evans' index ≥ 0.37, iNPH Radscale ≥ 9, and presence of DESH, bilateral ventricular roof bulgings or focally enlarged sulci. A simplified version of the iNPH Radscale with only four features resulted in equally high diagnostic accuracy as the original iNPH Radscale. CONCLUSIONS: There is a notable overlap between some of the commonly used imaging markers regarding iNPH, VaD and atypical parkinsonism, such as PSP. However, this study shows that the specificity of imaging markers usually associated with iNPH was high even when comparing with these challenging differential diagnoses. The callosal angle was the single imaging feature with highest diagnostic accuracy to discriminate iNPH from its mimics. A simplified rating scale using only a few selected features could be used with retained specificity.

Different Inflammatory Signatures in Alzheimer's Disease and Frontotemporal Dementia Cerebrospinal Fluid.

BACKGROUND: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases. OBJECTIVE: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD. METHODS: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing. RESULTS: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14-1.53, q = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20-1.94, q = 0.045; and FTD: FC = 1.42, 95% CI 1.10-1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05). CONCLUSION: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.

Critical illness polyneuropathy, myopathy and neuronal biomarkers in COVID-19 patients: A prospective study.

OBJECTIVE: The aim was to characterize the electrophysiological features and plasma biomarkers of critical illness polyneuropathy (CIN) and myopathy (CIM) in coronavirus disease 2019 (COVID-19) patients with intensive care unit acquired weakness (ICUAW). METHODS: An observational ICU cohort study including adult patients admitted to the ICU at Uppsala University Hospital, Uppsala, Sweden, from March 13th to June 8th 2020. We compared the clinical, electrophysiological and plasma biomarker data between COVID-19 patients who developed CIN/CIM and those who did not. Electrophysiological characteristics were also compared between COVID-19 and non-COVID-19 ICU patients. RESULTS: 111 COVID-19 patients were included, 11 of whom developed CIN/CIM. Patients with CIN/CIM had more severe illness; longer ICU stay, more thromboembolic events and were more frequently treated with invasive ventilation for longer than 2 weeks. In particular CIN was more frequent among COVID-19 patients with ICUAW (50%) compared with a non-COVID-19 cohort (0%, p = 0.008). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAp) levels were higher in the CIN/CIM group compared with those that did not develop CIN/CIM (both p = 0.001) and correlated with nerve amplitudes. CONCLUSIONS: CIN/CIM was more prevalent among COVID-19 ICU patients with severe illness. SIGNIFICANCE: COVID-19 patients who later developed CIN/CIM had significantly higher NfL and GFAp in the early phase of ICU care, suggesting their potential as predictive biomarkers for CIN/CIM.

Biomarkers for central nervous system injury in cerebrospinal fluid are elevated in COVID-19 and associated with neurological symptoms and disease severity.

BACKGROUND AND PURPOSE: Neurological symptoms have been frequently reported in hospitalized patients with coronavirus disease 2019 (COVID-19), and biomarkers of central nervous system (CNS) injury are reported to be increased in plasma but not extensively studied in cerebrospinal fluid (CSF). This study examined CSF for biomarkers of CNS injury and other pathology in relation to neurological symptoms and disease severity in patients with neurological manifestations of COVID-19. METHODS: Nineteen patients with neurological symptoms and mild to critical COVID-19 were prospectively included. Extensive analysis of CSF, including measurement of biomarkers of CNS injury (neurofilament light chain [NfL] protein, glial fibrillary acidic protein [GFAp], and total tau), was performed and compared to neurological features and disease severity. RESULTS: Neurological symptoms included altered mental status (42%), headache (42%), and central (21%) and peripheral weakness (32%). Two patients demonstrated minor pleocytosis, and four patients had increased immunoglobulin G levels in CSF. Neuronal autoantibody testing using commercial tests was negative in all patients. Increased CSF levels of NfL protein, total tau, and GFAp were seen in 63%, 37%, and 16% of patients, respectively. Increased NfL protein correlated with disease severity, time in intensive care, and level of consciousness. NfL protein in CSF was higher in patients with central neurological symptoms. CONCLUSIONS: Although limited by the small sample size, our data suggest that levels of NfL protein, GFAp, and total tau in CSF are commonly elevated in patients with COVID-19 with neurological symptoms. This is in contrast to the standard CSF workup where pathological findings are scarce. NfL protein, in particular, is associated with central neurological symptoms and disease severity.

Acute necrotizing encephalopathy with SARS-CoV-2 RNA confirmed in cerebrospinal fluid.

Here, we report a case of COVID-19-related acute necrotizing encephalopathy where SARS-CoV-2 RNA was found in CSF 19 days after symptom onset after testing negative twice. Although monocytes and protein levels in CSF were only marginally increased, and our patient never experienced a hyperinflammatory state, her neurologic function deteriorated into coma. MRI of the brain showed pathologic signal symmetrically in central thalami, subinsular regions, medial temporal lobes, and brain stem. Extremely high concentrations of the neuronal injury markers neurofilament light and tau, as well as an astrocytic activation marker, glial fibrillary acidic protein, were measured in CSF. Neuronal rescue proteins and other pathways were elevated in the in-depth proteomics analysis. The patient received IV immunoglobulins and plasma exchange. Her neurologic status improved, and she was extubated 4 weeks after symptom onset. This case report highlights the neurotropism of SARS-CoV-2 in selected patients and emphasizes the importance of repeated lumbar punctures and CSF analyses in patients with suspected COVID-19 and neurologic symptoms.