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1.	Abdelhak, Ahmed, et al. (author) 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. 2023 In: Journal of neurology. - : Springer. - 1432-1459 .- 0340-5354. ; 270:7, s. 3315-3328 Journal article (peer-reviewed)abstract To investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19).We conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd2022. 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.We identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2±15.0years, 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 ahigher likelihood of ICU admission, need ofMV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need ofMV and ICU admission, respectively.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.
2.	Bodén, Robert, 1973-, et al. (author) Suppressing visual hallucinations in an adolescent by occipital transcranial magnetic stimulation: A single-case experimental research design. 2021 In: Neuropsychological rehabilitation. - : Informa UK Limited. - 1464-0694 .- 0960-2011. ; 33:2, s. 346-55 Journal article (peer-reviewed)abstract Visual hallucinations after central or peripheral impairment, commonly called Charles Bonnet syndrome, are often highly distressing and with few available treatment options. Here we report a case where an adolescent developed severely distressing visual hallucinations after hypoxic damage to the occipital cortex following a suicide attempt. The patient received active and sham occipital continuous theta-burst stimulation (cTBS) in a single-case experimental research design and a subsequent open phase, to evaluate cTBS as a Charles Bonnet treatment. The visual hallucinations seemed to decrease more during active than sham cTBS in the blind phase, and in the following week of repeated five daily treatments they almost disappeared. A normalization of increased activity in the lateral visual network after cTBS was observed on a functional magnetic resonance imaging resting-state analysis compared with 42 healthy controls. Visual evoked potentials stayed largely unchanged both in the sham-controlled blind phase and the subsequent open phase. During the two weeks after the open phase with repeated cTBS sessions, the visual hallucinations gradually reappeared and almost returned to the baseline level. Our findings suggest that active cTBS over the primary visual cortex can reduce visual hallucinations through modulation of downstream visual regions, though the effect is temporally limited.
3.	Braun, Madelen, et al. (author) 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 2022 In: Fluids and Barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 19:1 Journal article (peer-reviewed)abstract 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 (A beta 1-42) 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 (beta = - 3.10, p = 0.016 and beta = - 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 A beta 1-42 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.
4.	Cunningham, Janet L., et al. (author) Experiences in implementing immunopsychiatry in real life 2023 In: Journal of Affective Disorders Reports. - : Elsevier. - 2666-9153. ; 13 Journal article (peer-reviewed)abstract Immunological mechanisms, both alone and in combination, are associated with a broad range of psychiatric disorders encompassing autoimmune, autoinflammatory disorders but also genetic, metabolic, or other immunological disorders. Early treatment improves the outcome for autoimmune disorders, but early diagnosis is more difficult when isolated psychiatric symptoms are manifestations of autoimmunity. Treatment of these cases must encompass integrated models of disease, as both systemic autoimmunity and psychological processes influence mental health. Several challenges need to be overcome to efficiently merge psychiatric and somatic disease paradigms and medical care ranging from language and conceptual barriers to organizational barriers. Since 2015, the Immunopsychiatry team at Uppsala University has developed a collaborative multidisciplinary approach to improve and integrate care for patients with moderate to severe psychiatric disorders. Based on this experience, we have outlined the obstacles to be overcome in taking steps forward to achieve the long-term goal of understanding and early detection and identification of treatable immunological conditions within the psychiatric patient population; the described framework of evaluations and work-flow may serve as a model for other centers.
5.	Finnsson, Johannes, et al. (author) Glucose metabolism in the brain in LMNB1-related autosomal dominant leukodystrophy. 2019 In: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 139:2, s. 135-142 Journal article (peer-reviewed)abstract OBJECTIVE: LMNB1-related autosomal dominant leukodystrophy is caused by an overexpression of the protein lamin B1, usually due to a duplication of the LMNB1 gene. Symptoms start in 5th to 6th decade. This slowly progressive disease terminates with death. We studied brain glucose metabolism in this disease using 18 F-fluorodeoxyglucose positron emission tomography (PET).METHODS: We examined 8 patients, aged 48-64 years, in varying stages of clinical symptomatology. Two patients were investigated with quantitative PET on clinical indications after which six more patients were recruited. Absolute glucose metabolism was analyzed with the PVElab software in 6 patients and 18 healthy controls. A semiquantitative analysis using the CortexID software was performed in seven investigations, relating local metabolism levels to global glucose metabolism.RESULTS: The clinical quantitative PET revealed low global glucose metabolism, with the most marked reduction in the cerebellum. In the PVElab analysis, patients presented low mean glucose metabolism in the cerebellum, brainstem and global grey matter. In the semiquantitative analysis, 2 patients showed a decreased metabolism in the cerebellum and 4 patients a relatively higher metabolism in parts of the temporal lobes. Since none of the patients showed an increased metabolism in the quantitative analysis, we interpret these increases as "pseudo-increases" related to a globally reduced metabolism.CONCLUSIONS: Global reduction of grey matter glucose metabolism in this white matter disease most likely depends on a combination of cortical afferent dysfunction and, in later stages, neuronal loss. The lowest metabolism in the cerebellum is consistent with histopathological findings and prominent cerebellar symptoms.
6.	Finnsson, Johannes, et al. (author) Glucose metabolism in the brain in LMNB1-related autosomal dominant leukodystrophy; a PET study Other publication (other academic/artistic)
7.	Frithiof, Robert, et al. (author) Critical illness polyneuropathy, myopathy and neuronal biomarkers in COVID-19 patients: A prospective study 2021 In: Clinical Neurophysiology. - : Elsevier BV. - 1388-2457 .- 1872-8952. ; 132:7, s. 1733-1740 Journal article (peer-reviewed)abstract 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. (c) 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
8.	Fällmar, David, et al. (author) Arterial spin labeling-based Z-maps have high specificity and positive predictive value for neurodegenerative dementia compared to FDG-PET. 2017 In: European Radiology. - : Springer Science and Business Media LLC. - 0938-7994 .- 1432-1084. ; 27:10, s. 4237-4246 Journal article (peer-reviewed)abstract OBJECTIVE: Cerebral perfusion analysis based on arterial spin labeling (ASL) MRI has been proposed as an alternative to FDG-PET in patients with neurodegenerative disease. Z-maps show normal distribution values relating an image to a database of controls. They are routinely used for FDG-PET to demonstrate disease-specific patterns of hypometabolism at the individual level. This study aimed to compare the performance of Z-maps based on ASL to FDG-PET.METHODS: Data were combined from two separate sites, each cohort consisting of patients with Alzheimer's disease (n = 18 + 7), frontotemporal dementia (n = 12 + 8) and controls (n = 9 + 29). Subjects underwent pseudocontinuous ASL and FDG-PET. Z-maps were created for each subject and modality. Four experienced physicians visually assessed the 166 Z-maps in random order, blinded to modality and diagnosis.RESULTS: Discrimination of patients versus controls using ASL-based Z-maps yielded high specificity (84%) and positive predictive value (80%), but significantly lower sensitivity compared to FDG-PET-based Z-maps (53% vs. 96%, p < 0.001). Among true-positive cases, correct diagnoses were made in 76% (ASL) and 84% (FDG-PET) (p = 0.168).CONCLUSION: ASL-based Z-maps can be used for visual assessment of neurodegenerative dementia with high specificity and positive predictive value, but with inferior sensitivity compared to FDG-PET.KEY POINTS: • ASL-based Z-maps yielded high specificity and positive predictive value in neurodegenerative dementia. • ASL-based Z-maps had significantly lower sensitivity compared to FDG-PET-based Z-maps. • FDG-PET might be reserved for ASL-negative cases where clinical suspicion persists. • Findings were similar at two study sites.
9.	Fällmar, David, 1980-, et al. (author) Arterial Spin Labeling versus FDG-PET for Differential Diagnosis in Dementia – use of Z-maps for visual assessment Journal article (other academic/artistic)
10.	Fällmar, David, et al. (author) Att tänka på vid neuroradiologisk diagnostik av gravida och ammande: Om datortomografi, magnetkamera och kontrastmedel : [Conditions for performing CT and MRI scans in pregnant and lactating patients] 2023 In: Läkartidningen. - : Läkartidningen Förlag AB. - 0023-7205 .- 1652-7518. ; 120 Research review (peer-reviewed)abstract Many women are pregnant during several percent of their lives. Occasionally, there is a need for neuroradiological examinations during pregnancy or lactation. In our clinical work, we regularly see that female patients are being withheld relevant diagnostic scans during pregnancy, due to insufficient knowledge or an unbalanced comparison between benefits and risks. This article describes the current knowledge regarding conditions for performing CT and MRI scans in pregnant and lactating patients, including the use of contrast media. PET scans and reactions to contrast media are briefly mentioned, but interventional radiology is not discussed.
11.	Fällmar, David, et al. (author) [Conditions for performing CT and MRI scans in pregnant and lactating patients]. : Att tänka på vid neuroradiologisk diagnostik av gravida och ammande. 2023 In: Lakartidningen. - 1652-7518. ; 120 Journal article (peer-reviewed)abstract Many women are pregnant during several percent of their lives. Occasionally, there is a need for neuroradiological examinations during pregnancy or lactation. In our clinical work, we regularly see that female patients are being withheld relevant diagnostic scans during pregnancy, due to insufficient knowledge or an unbalanced comparison between benefits and risks. This article describes the current knowledge regarding conditions for performing CT and MRI scans in pregnant and lactating patients, including the use of contrast media. PET scans and reactions to contrast media are briefly mentioned, but interventional radiology is not discussed.
12.	Fällmar, David, et al. (author) Erfarenheter av att hålla en digital kurs i neuroradiologi för ST-läkare 2021 In: Neurologi i Sverige. ; :2, s. 14-17 Journal article (pop. science, debate, etc.)
13.	Fällmar, David, et al. (author) Imaging features associated with idiopathic normal pressure hydrocephalus have high specificity even when comparing with vascular dementia and atypical parkinsonism 2021 In: Fluids and Barriers of the CNS. - : BioMed Central (BMC). - 2045-8118. ; 18 Journal article (peer-reviewed)abstract 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 degrees, 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.
14.	Fällmar, David (author) Neuroradiologiska fynd vid Covid-19 2020 In: Neurologi i Sverige. ; 3:20, s. 62-65 Journal article (pop. science, debate, etc.)abstract Under sommaren har en tilltagande ström av artiklar om neuroradiologiska fynd vid covid-19 (härefter benämnt covid) publicerats och ännu fler ogranskade förhandsmanuskript cirkulerar i ett svåröverskådligt flöde. Mycket av innehållet är fallrapporter och opportuna ”short communications” men flera mellanstora studier har hunnit ut. Den här artikeln av David Fällmar syftar till att sammanfatta innehållet i några sådana rapporter som har neuroradiologiskt innehåll. Den är på inget sätt heltäckande, men artiklarnas likheter och skillnader är väl värda en stunds begrundan.
15.	Fällmar, David, 1980-, et al. (author) Reliable Z-score maps from low-dose 18F-FDG PET of the brain Other publication (other academic/artistic)
16.	Fällmar, David (author) Svensk forskning konsoliderar kunskap om normaltryckshydrocefalus 2020 In: Neurologi i Sverige. ; 3, s. 24-31 Journal article (pop. science, debate, etc.)abstract Normaltryckshydrocefalus (NPH) är ettvanligt tillstånd, som orsakar stort lidande, men är behandlingsbart. Det är också otill-räckligt utforskat. Därför är det glädjandeatt svensk NPH-forskning är framgångsrik. David Fällmar, neuroradiolog, berättarmer i denna artkikel.
17.	Fällmar, David, et al. (author) The extent of neuroradiological findings in COVID-19 shows correlation with blood biomarkers, Glasgow coma scale score and days in intensive care 2022 In: Journal of neuroradiology. - : Elsevier. - 0150-9861 .- 1773-0406. ; 49:6, s. 421-427 Journal article (peer-reviewed)abstract Background and purposeA 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 methodsPatients 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 conclusionsThe 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.
18.	Fällmar, David, 1980-, et al. (author) Validation of true low-dose 18F-FDG PET of the brain 2016 In: American Journal of Nuclear Medicine and Molecular Imaging. - Madison, USA : e-Century Publishing Corporation. - 2160-8407. ; 6:5, s. 269-276 Journal article (peer-reviewed)abstract The dosage of 18F-FDG must be sufficient to ensure adequate PET image quality. For younger patients and research controls, the lowest possible radiation dose should be used. The purpose of this study was to find a protocol for FDG-PET of the brain with reduced radiation dose and preserved quantitative characteristics. Eight patients with neurodegenerative disorders and nine controls (n=17) underwent FDG-PET/CT twice on separate occasions, first with normal-dose (3 MBq/kg), and second with low-dose (0.75 MBq/kg, 25% of the original). Five additional controls (total n=22) underwent FDG-PET twice, using normal-dose and ultra-low-dose (0.3 MBq/kg, 10% of original). All subjects underwent MRI. Ten-minute summation images were spatially normalized and intensity normalized. Regional standard uptake value ratios (SUV-r) were calculated using an automated atlas. SUV-r values from the normal- and low-dose images were compared pairwise. No clinically significant bias was found in any of the three groups. The mean absolute difference in regional SUV-r values was 0.015 (1.32%) in controls and 0.019 (1.67%) in patients. The ultra-low-dose protocol produced a slightly higher mean difference of 0.023 (2.10%). The main conclusion is that 0.75 MBq/kg (56 MBq for a 75-kg subject) is a sufficient FDG dose for evaluating regional SUV-ratios in brain PET scans in adults with or without neurodegenerative disease, resulting in a reduction of total PET/CT effective dose from 4.54 to 1.15 mSv. The ultra-low-dose (0.5 mSv) could be useful in research studies requiring serial PET in healthy controls or children.
19.	Fällmar, David, et al. (author) Visual Assessment of Brain Perfusion MRI Scans in Dementia : a Pilot Study 2016 In: Journal of Neuroimaging. - : Wiley. - 1051-2284 .- 1552-6569. ; 26:3, s. 324-330 Journal article (peer-reviewed)abstract PURPOSE: Functional imaging is becoming increasingly important for the detection of neurodegenerative disorders. Perfusion MRI with arterial spin labeling (ASL) has been reported to provide promising diagnostic possibilities but is not yet widely used in routine clinical work. The aim of this study was to compare, in a clinical setting, the visual assessment of subtracted ASL CBF maps with and without additional smoothing, to FDG-PET data.METHODS: Ten patients with a clinical diagnosis of dementia and 11 age-matched cognitively healthy controls were examined with pseudo-continuous ASL (pCASL) and 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET). Three diagnostic physicians visually assessed the pCASL maps after subtraction only, and after postprocessing using Gaussian smoothing and GLM-based beta estimate functions. The assessment scores were compared to FDG PET values. Furthermore, the ability to discriminate patients from healthy elderly controls was assessed.RESULTS: Smoothing improved the correlation between visually assessed regional ASL perfusion scores and the FDG PET SUV-r values from the corresponding regions. However, subtracted pCASL maps discriminated patients from healthy controls better than smoothed maps. Smoothing increased the number of false-positive patient identifications. Application of beta estimate functions had only a marginal effect.CONCLUSION: Spatial smoothing of ASL images increased false positive results in the discrimination of hypoperfusion conditions from healthy elderly. It also decreased interreader agreement. However, regional characterization and subjective perception of image quality was improved.
20.	Fällmar, David, 1980- (author) Visual assessment of perfusion and metabolism in neurodegenerative dementia 2016 Doctoral thesis (other academic/artistic)abstract A worldwide demographic shift is currently occurring, with rapidly increasing numbers of elderly individuals. Since the incidence of neurodegenerative disease generally increases with age, this entails an increase in dementia prevalence. There are several strong incentives for establishing robust and widely available imaging methods for the early diagnosis of these diseases. Atrophy patterns are evident only late in the disease process, and the distinction from healthy ageing can often be elusive. For early diagnosis, physiologic parameters such as perfusion or metabolism must be assessed. The available modalities all have restricted clinical usefulness. The main aim of this thesis was to advance the clinical usefulness of perfusion and metabolism imaging in patients with neurodegenerative dementia, with a focus on visual assessment.A cohort of patients with neurodegenerative dementia was included, along with an age-matched control group. All subjects underwent MRI, including a pseudocontinuous ASL sequence and FDG-PET. In papers II and III, a subgroup containing both patients and controls underwent a second FDG-PET with reduced dose. In paper IV, the material was combined with a similar cohort from Amsterdam.Paper I showed that spatial smoothing increased the correlation between visually assessed perfusion and metabolism levels as displayed with FDG-PET. However, the distinction between patients and healthy controls was less satisfactory due to false positives.Paper II showed that differences in regional standard uptake value ratios between normal- and low-dose FDG-PET were small and without clinically significant bias.Paper III showed that the diagnostic performance of Z-score maps showing regions of significant deficits in metabolism was highly similar in normal- and low-dose FDG-PET images. Paper IV showed that ASL perfusion-based Z-score maps can be used for diagnostic purposes with high specificity, but inferior sensitivity, compared to FDG-PET.In conclusion, the included studies address aspects of the visual assessment of perfusion and metabolism neuroimaging, with a focus on clinical usefulness in diagnosing neurodegenerative dementia.
21.	Fällmar, David, et al. (author) Z-score maps from low-dose 18F-FDG PET of the brain in neurodegenerative dementia. 2018 In: American Journal of Nuclear Medicine and Molecular Imaging. - 2160-8407. ; 8:4, s. 239-246 Journal article (peer-reviewed)abstract Neuroimaging is a central part of diagnostic work-up of patients with suspected neurodegenerative disease. FDG-PET can reveal pathological changes earlier and more reliably than morphological imaging. Diagnostic accuracy can be improved by constructing 3D SSP Z-score maps, showing patterns of significant deficits. During FDG-PET, the subject receives a moderate but not insignificant dose of ionizing radiation, and a dose reduction with retained image quality is desirable. With lower dose, repeated examinations can become a useful tool for monitoring disease progress and potential effects of disease-modifying interventions. The aim of this study was to evaluate Z-maps created from low-dose and normal-dose FDG-PET of the brain, with quantitative and qualitative methods. Nine patients with neurodegenerative disorders were prospectively enrolled and nine age-matched controls were recruited through advertising. All subjects (n=18) underwent two FDG-PET scans on separate occasions; a routine and a low-dose scan. The routine dosage of FDG was 3 MBq/kg, and low dosage was 0.75 MBq/kg. 3D-SSP images showing Z-scores of < -1.96 were created from 10-minute summations. The study was comprised of a quantitative part comparing the Z-scores, and a qualitative part where experienced nuclear medicine specialists visually assessed the images. Regarding the quantitative part, Bland-Altman analysis showed a slight constant bias (0.206). Regarding qualitative discrimination between patients and controls, the performance between normal- and low-dose were equal, both showing 72% sensitivity, 83% specificity and 78% accuracy. In this study, visual assessment of 3D-SSP Z-score maps from low-dose FDG-PET provided diagnostic information highly comparable to normal-dose, with minor quantitative discrepancies.
22.	Georgiopoulos, Charalampos, et al. (author) Quantitative brain stem assessment in discriminating neurodegenerative disorders from normal pressure hydrocephalus In: Journal of Neuroimaging. - 1051-2284. Journal article (peer-reviewed)abstract 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.
23.	Guath, Mona, et al. (author) Pupil dilation during negative prediction errors is related to brain choline concentration and depressive symptoms in adolescents 2023 In: Behavioural Brain Research. - : Elsevier BV. - 0166-4328 .- 1872-7549. ; 436 Journal article (peer-reviewed)abstract Depressive symptoms are associated with altered pupillary responses during learning and reward prediction as well as with changes in neurometabolite levels, including brain concentrations of choline, glutamate and gamma-aminobutyric acid (GABA). However, the full link between depressive symptoms, reward-learning-related pupillary responses and neurometabolites is yet to be established as these constructs have not been assessed in the same individuals. The present pilot study, investigated these relations in a sample of 24 adolescents aged 13 years. Participants completed the Revised Child Anxiety and Depression Scale (RCADS) and underwent a reward learning task while measuring pupil dilation and a single voxel dorsal anterior cingulate cortex (dACC) MEGA-PRESS magnetic resonance spectroscopy scan assessing choline, glutamate and GABA concentrations. Pupil dilation was related to prediction errors (PE) during learning, which was captured by a prediction error-weighted pupil dilation response index (PE-PDR) for each individual. Higher PE-PDR scores, indicating larger pupil dilations to negative prediction errors, were related to lower depressive symptoms and lower dACC choline concentrations. Dorsal ACC choline was positively associated with depressive symptoms, whereas glutamate and GABA were not related to PE-PDR or depressive symptoms. The findings support notions of cholinergic involvement in depressive symptoms and cholinergic influence on reward-related pupillary response, suggesting that pupillary responses to negative prediction errors may hold promise as a biomarker of depressive states.
24.	Haller, Sven, et al. (author) Susceptibility weighted imaging in dementia with Lewy bodies : will it resolve the blind spot of MRI? 2016 In: Neuroradiology. - : Springer Science and Business Media LLC. - 0028-3940 .- 1432-1920. ; 58:2, s. 217-218 Journal article (peer-reviewed)
25.	Latini, Francesco, Ph.D. 1982-, et al. (author) Can diffusion tensor imaging (DTI) outperform standard magnetic resonance imaging (MRI) investigations in post-COVID-19 autoimmune encephalitis? 2022 In: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 127:1 Journal article (peer-reviewed)abstract Background: Neurological and psychiatric manifestations related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are widely recognised. Standard magnetic resonance imaging (MRI) investigations are normal in 40-80% of symptomatic patients, eventually delaying appropriate treatment when MRI is unrevealing any structural changes. The aim of this study is to investigate white matter abnormalities during an early stage of post-COVID-19 (coronavirus disease 2019) encephalitis while conventional MRI was normal. Methods: A patient with post-COVID-19 autoimmune encephalitis was investigated by serial MRIs and diffusion tensor imaging (DTI). Ten healthy control individuals (HC) were utilised as a control group for the DTI analysis. Major projection, commissural and association white matter pathways were reconstructed, and multiple diffusion parameters were analysed and then compared to the HC average using a z-test for serial examinations. Results: Eleven days after the onset of neurological symptoms, DTI revealed early white matter changes, compared with HC, when standard MRI was normal. On day 68, DTI showed multiple white matter lesions compared with HC, visible at this time also by the MRI images, indicating inflammatory changes in different association and projection white matter pathways. Conclusion: We confirm a limitation in the sensitivity of conventional MRI at the acute setting of postCOVID-19 autoimmune encephalitis. A complementary DTI investigation could be a valuable diagnostic tool in early therapeutic decisions concerning COVID-19-related neurological symptoms.
26.	Lindskog, Cecilia, et al. (author) Protein Expression Profile of ACE2 in the Normal and COVID-19-Affected Human Brain. 2022 In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 21:9, s. 2137-2145 Journal article (peer-reviewed)abstract 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.
27.	Lubberink, Mark, et al. (author) Differential diagnosis of patients with parkinsonian syndrome using multilinear regression to disease-specific C-11-PE2I-PET templates and classification tree learning 2018 In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer. - 1619-7070 .- 1619-7089. ; 45, s. S409-S409 Journal article (other academic/artistic)
28.	Mulder, Jan, et al. (author) Autoimmune Encephalitis Presenting With Malignant Catatonia in a 40-Year-Old Male Patient With COVID-19 2021 In: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 178:6, s. 485-489 Journal article (other academic/artistic)abstract A 40-year-old man who had previously had symptoms of and a positive test for COVID-19, but had no other previous medical or psychiatric conditions or medication, presented to the emergency unit with acute debut of agitation, grimacing, and repetitive speech and movements (verbigeration and stereotypies); his behavior was bizarre, disorganized, hyperkinetic, and uncooperative and met DSM-5 criteria for catatonia. Twenty-two days before admission, the patient had developed COVID-19-related respiratory symptoms and fatigue, which did not require hospital care. He had tested positive for SARS-CoV-2 RNA in a naso-pharyngeal swab using the Abbott RealTime SARSCoV-2 assay on the Abbott m2000 platform (day 14; Figure 1A). Anosmia and ageusia were not present. During the several days before admission, he had suffered from a headache. On admission (day 22), he no longer had respiratory symptoms but he did have a fever (38.4 degrees C). He made no eye contact, his reflexes were normal, and Babinski's sign was absent. Treatment with antibiotics and acyclovir was initiated until the tests excluded bacterial infection and herpes encephalitis. Brain CT, MRI, and blood tests were unremarkable. The patient was lightly sedated with midazolam, followed with dexmedetomidine. Neuroleptics were not used. Lumbar puncture showed a high red blood cell count (19,000 cellsx10(6)/L) secondary to traumatic lumbar puncture. CSF cell count indicated pleocytosis, with 23x10(6)/L mononuclear and 8x10(6)/L polymorphonuclear cells. Signs of blood-brain barrier disruption were present, with elevated albumin levels in CSF, at 838 mg/L (reference, <400 mg/L), and the CSF/serum albumin quotient was 15.6 (reference, <6.8). Interleukin-6 (IL-6) in CSF was elevated at 102.1 pg/mL ( reference, <5 pg/mL), but CSF levels of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and tau protein were normal. PCR tests for SARS- CoV-2 were repeatedly negative in CSF and nasopharyngeal swabs. Antineuronal antibodies against N-methyl-D-aspartate receptor (NMDAR), glutamic acid decarboxylase, contactin-associated protein-like 2, leucine-rich, glioma inactivated 1, and ganglioside antibodies in serum and CSF were negative (Euroimmune, Lubeck, Germany). Hours later, the patient's state deteriorated, and his temperature rose to 39 degrees C. He became mutistic and showed signs of autonomic instability, with recurrent episodes of fluctuating heart rate and arterial blood pressure and periods of oxygen desaturation (Figure 1B). The hypertension was difficult to treat, despite high doses of clonidine and labetalol. Plasma lactate levels varied between 0.6 and 8 mmol/L (reference, 0.8-2.0 mmol/L), but myoglobulin and creatine kinase myocardial band (CKMB) remained normal. The patient's pupil size, reaction to light, and oculocephalic reflex were normal. Slow, horizontal roving eye movements were noted. The patient displayed decorticate posturing and increased tonus; he resisted movement of arms and jaw but had normal tonus in the legs. Hyperreflexia was present, with bilateral foot clonus and Babinski's sign but no neck stiffness. Anesthesia was induced with propofol and clonidine to facilitate endotracheal intubation. D-Dimer was slightly elevated (1.2 mg/L; reference <0.5 mg/L), without signs of thromboembolic events. Respiration and cardiovascular function remained stable. Continuous EEG monitoring showed nonspecific slowing with left hemisphere predominance without epileptiformactivity. An episode of asystole with spontaneous recovery, episodes of bradycardia of 27 bpm and repeated P waves without QRS complexes were interpreted as third-degree atrioventricular block. Signs of autoimmune encephalitis were present, but this case did not meet the proposed criteria (1, 2). Standard radiological findings were normal, and the discrete pleocytosis and elevated protein in CSF was nonspecific. Although the diagnosis remained uncertain, parainfectious autoimmune encephalitis was still suspected. Plasmapheresis was initiated and repeated three times over 4 days. After two courses, the patient was extubated and was autonomically stable. Eye movement was normalized and hyperreflexia was less prominent, but bilateral Babinski's sign persisted. Treatment was initiated with 1 g methylprednisolone per day. On day 28, the patient showed a dramatic improvement. He was awake, oriented, and communicative but had no memories from the past several days. He was distracted by complex visual hallucinations of black and white figures (animals and famous people) appearing on his right side. He described them as being in a mirror (suspected polyopia). These figures were often stationary but could make gestures. He also described an experience of feeling that the world was different-strange and unreal, with brighter colors (suspected hyperchromatopsia and derealization). He had frequent episodes of failing to recognize his right hand and leg as his own and experienced their movement as unexpected (alien hand syndrome). He denied the presence of other perceptual disturbances. His understanding of Swedish, his second language, seemed intact, but his responses were mostly monosyllabic. He could name his children and give his personal identification number but was slow and made mistakes in naming the months. Mild visual object agnosia was present. Simultanagnosia was prominent, he showed deficits in isolating figures in a tangled pictorial array, and he could depict details but excluded the global features of complex pictures. He could recall one of three objects after a short delay and draw a correct clock but required three repetitions of the instructions. He had difficulty mirroring and performing fine movements. Finally, he showed no signs of visual neglect and could read text. The patient's EEG was normal. A second lumbar puncture showed pleocytosis, 10 mononuclear cells and 1 polymorphonuclear cell x10(6)/L, elevated IgG levels and IgG index, and two oligoclonal bands in CSF not represented in serum, indicating intrathecal production of antibodies. The IL-6 level in CSF was normalized. GFAP and tau remained normal, but NfL was increased to 1,030 ng/L (reference, <890 ng/L). A second MRI and a standard neurological examination on day 31 were normal. The hallucinations were less frequent. The patient described increased emotional lability and mental fatigue, with disturbed short-term memory and decision making. He also found it challenging to recognize the voices and faces of acquaintances. Serology on day 33 was strongly positive (index 8.88 S/CO [signal/cutoff]) for IgG against SARS- CoV-2 analyzed with the CE-labeled SARS- CoV-2 IgG kit with nucleoprotein-based antigen with the Abbott Architect i2000SR Analyzer at the Laboratory of Clinical Microbiology, Uppsala University Hospital, as previously described (3). [F-18]fluorodeoxyglucose ([F-18]FDG) PET scan on day 35 (after treatment) showed high bilateral uptake in the striatum (caudate nucleus and putamen) compared with the cortex (Figure 1C). Using immunohistochemistry in the research lab, we detected IgG autoantibodies against mouse brain neuronal proteins in serum and CSF collected at admission (Figure 2). Neuronal labeling intensity was strongest in the CA3 in the hippocampal formation, layer V in the somatosensory cortex, and the paraventricular and reticular nucleus in the thalamus. A subset of ependymal cells located in the ventricle wall and choroid plexus revealed strong immunoreactivity of the (peri)nuclear compartment and cytoplasm. Immunoreactivity of neuropil was most intense in the caudate putamen, revealing neuronal processes and spine-like structures. Posttreatment IgG immunoreactivity in the (peri)nuclear compartment and neuropil was notably reduced, reaching the levels of reference CSF and serum.
29.	Persson, Jonas, 1983-, et al. (author) Intermittent theta burst stimulation over the dorsomedial prefrontal cortex modulates resting-state connectivity in depressive patients : A sham-controlled study 2020 In: Behavioural Brain Research. - : Elsevier BV. - 0166-4328 .- 1872-7549. ; 394 Journal article (peer-reviewed)abstract The mechanisms underlying repetitive transcranial magnetic stimulation (rTMS) treatment are largely unknown. Although there is a general lack of sham controlled studies, findings show altered functional connectivity to the stimulated region following treatment. When targeting the dorsolateral prefrontal cortex (dlPFC), connectivity with the subgenual anterior cingulate cortex (sgACC) is predictive of response, but less is known about the effects on functional connectivity of targeting the dorsomedial PFC (dmPFC). Here, 30 patients with an ongoing depressive episode were recruited and randomized to 20 sessions at target intensity of either active or sham intermittent theta burst stimulation (iTBS) over dmPFC. Those receiving sham were offered active treatment in a subsequent open phase. A seven minute resting-state scan and depressive symptom assessment was performed before and after treatment. After exclusions due to attrition and excessive head movements 23 patients remained for analysis. Seed-based resting-state connectivity was calculated using two seeds for the dmPFC target as well as the sgACC. A symptom related increase in dmPFC connectivity after active treatment, compared to sham treatment, was found. The effect was observed in a region overlapping the precuneus and the posterior cingulate cortex (PCC), suggesting an increase in the connectivity between the targeted salience network and the default mode network mediating improvement in depressive symptoms. Connectivity between the precuneus and both the sgACC and the treatment target was predictive of symptom improvement following active treatment. The findings have implications for understanding the mechanisms behind iTBS and may inform future efforts to individualize the treatment.
30.	Persson, Jonas, 1983-, et al. (author) Phosphodiesterase 10A levels are related to striatal function in schizophrenia : a combined positron emission tomography and functional magnetic resonance imaging study 2020 In: European Archives of Psychiatry and Clinical Neuroscience. - : Springer Science and Business Media LLC. - 0940-1334 .- 1433-8491. ; 270:4, s. 451-459 Journal article (peer-reviewed)abstract Pharmacological inhibition of phosphodiesterase 10A (PDE10A) is being investigated as a treatment option in schizophrenia. PDE10A acts postsynaptically on striatal dopamine signaling by regulating neuronal excitability through its inhibition of cyclic adenosine monophosphate (cAMP), and we recently found it to be reduced in schizophrenia compared to controls. Here, this finding of reduced PDE10A in schizophrenia was followed up in the same sample to investigate the effect of reduced striatal PDE10A on the neural and behavioral function of striatal and downstream basal ganglia regions. A positron emission tomography (PET) scan with the PDE10A ligand [11C]Lu AE92686 was performed, followed by a 6 min resting-state magnetic resonance imaging (MRI) scan in ten patients with schizophrenia. To assess the relationship between striatal function and neurophysiological and behavioral functioning, salience processing was assessed using a mismatch negativity paradigm, an auditory event-related electroencephalographic measure, episodic memory was assessed using the Rey auditory verbal learning test (RAVLT) and executive functioning using trail-making test B. Reduced striatal PDE10A was associated with increased amplitude of low-frequency fluctuations (ALFF) within the putamen and substantia nigra, respectively. Higher ALFF in the substantia nigra, in turn, was associated with lower episodic memory performance. The findings are in line with a role for PDE10A in striatal functioning, and suggest that reduced striatal PDE10A may contribute to cognitive symptoms in schizophrenia.
31.	Poom, Leo, et al. (author) Spotting the difference between pairs of nearly identical Perlin images : Influences of presentation formats 2022 In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 17:2 Journal article (peer-reviewed)abstract We investigated human performance in speed and precision of detecting a deviating visual target embedded in one of two otherwise identical non-figurative Perlin-noise images (i.e. a spot-the-difference task). The image-pairs were presented in four different presentation formats: spatially separated in horizontal or vertical direction while simultaneously presented, or sequentially separated on the same location with a brief delay or without any delay. In the two spatial conditions failure to detect the target within 30 sec (change blindness) occurred in about 6–7% of the trials, and with the brief delay 2.4% of the trials. Fast error-free detection (i.e. pop out) was obtained using the sequential format with no delay. Average detection time when target was detected was about 9 sec for the two spatial formats. Detection time was faster, about 6 sec, for the brief delay condition. In trials where detection was reported, the precision of locating the target was equal in the horizontal and brief delay conditions, and better than in the vertical condition. Misses obtained in the horizontal and brief delay conditions were also more strongly correlated than correlations between misses in the vertical and horizontal, and between the vertical and brief delay conditions. Some individuals’ performances when comparing images in the vertical direction were at chance level. This suggests influences of known poorer precision when making saccades in the vertical compared to horizontal direction. The results may have applications for radiologists since the stimuli and task is similar to radiologists’ task when detecting deviations between radiological images.
32.	Qu, Mingqi, et al. (author) DLG3/SAP102 protein expression in malformations of cortical development : A study of human epileptic cortex by tissue microarray 2009 In: Epilepsy Research. - : Elsevier BV. - 0920-1211 .- 1872-6844. ; 84:1, s. 33-41 Journal article (peer-reviewed)abstract The human DLG3 gene encodes the synapse-associated protein 102 (SAP102), which is concentrated in the postsynaptic densities of excitatory synapses and involved in receptor-mediated synaptic transmission via binding to the NR2B subunit of the NMDA receptor. In this study, we investigated the expression and cellular distribution of the DLG3/SAP102 protein in human epileptic cortex. Tissue microarrays of a large number of specimens from patients operated for medically intractable epilepsy were used for immunohistochemical screening with anti-DLG3 antibody. The cellular distribution of the protein was further investigated in samples of malformations of cortical development, and the amount of DLG3 protein in the total homogenate and in the postsynaptic membrane fraction of these samples was quantified by Western blot. We found a strictly neuronal expression of DLG3/SAP102 in epileptogenic cortex as well as in non-epileptic human cortex used for control. In focal cortical dysplasia and tuberous sclerosis complex, the protein was expressed in most neurons including dysplastic neurons, but not in giant cells. Increased expression of DLG3 protein was observed in the postsynaptic membrane fraction of patients with focal cortical dysplasia. Double-labeling experiments confirmed the exclusive neuronal character of the DLG3 expressing cells and the co-localization of the DLG3 protein with the NR2B subunit. Our results suggest a putative role for DLG3/SAP102 in cortical hyperexcitability and epileptogenicity of malformations of cortical development.
33.	Shams, Sara, et al. (author) MRI of the swallow tail sign : A useful marker in the diagnosis of lewy body dementia? 2017 In: American Journal of Neuroradiology. - 0195-6108 .- 1936-959X. ; 38:9, s. 1737-1741 Journal article (peer-reviewed)abstract BACKGROUND AND PURPOSE: There are, to date, no MR imaging diagnostic markers for Lewy body dementia. Nigrosome 1, containing dopaminergic cells, in the substantia nigra pars compacta is hyperintense on SWI and has been called the swallow tail sign, disappearing with Parkinson disease. We aimed to study the swallow tail sign and its clinical applicability in Lewy body dementia and hypothesized that the sign would be likewise applicable in Lewy body dementia. MATERIALS AND METHODS: This was a retrospective cross-sectional multicenter study including 97 patients (mean age, 65 ± 10 years; 46% women), consisting of the following: controls (n = 21) and those with Lewy body dementia (n = 19), Alzheimer disease (n = 20), frontotemporal lobe dementia (n = 20), and mild cognitive impairment (n = 17). All patients underwent brain MR imaging, with susceptibility- weighted imaging at 1.5T (n = 46) and 3T (n = 51). The swallow tail sign was assessed independently by 2 neuroradiologists. RESULTS: Interrater agreement was moderate (- = 0.4) between raters. An abnormal swallow tail sign was most common in Lewy body dementia (63%; 95% CI, 41%-85%; P = .001) and had a predictive value only in Lewy body dementia with an odds ratio of 9 (95% CI, 3-28; P < .001). The consensus rating for Lewy body dementia showed a sensitivity of 63%, a specificity of 79%, a negative predictive value of 89%, and an accuracy of 76%; values were higher on 3T compared with 1.5T. The usefulness of the swallow tail sign was rater-dependent with the highest sensitivity equaling 100%. CONCLUSIONS: The swallow tail sign has diagnostic potential in Lewy body dementia and may be a complement in the diagnostic work-up of this condition.
34.	Snöbohm, Carl, et al. (author) White matter changes should not exclude patients with idiopathic normal pressure hydrocephalus from shunt surgery 2022 In: Fluids and Barriers of the CNS. - : BioMed Central (BMC). - 2045-8118. ; 19:1 Journal article (peer-reviewed)abstract IntroductionWhite 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.MethodsA 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.ResultsOne 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.ConclusionsAn 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.
35.	Steinholtz, Linda, et al. (author) GABAA Receptor Availability in Relation to Cortical Excitability in Depressed and Healthy : A Positron Emission Tomography and Transcranial Magnetic Stimulation Study. 2024 In: Neuropsychobiology. - : S. Karger. - 0302-282X .- 1423-0224. ; 83:1, s. 17-27 Journal article (peer-reviewed)abstract INTRODUCTION: Gamma-aminobutyric acid (GABA) deficiency is suggested in depressive disorders, along with alterations in cortical excitability. However, whether these excitability changes are related to GABAA receptor availability is largely unknown. Our aim was to assess the correlation between these measures in depressed patients and healthy controls.METHODS: Twenty-eight patients with a major depressive episode, measured before and after participating in a clinical trial with repetitive transcranial magnetic stimulation (TMS), and 15 controls underwent [11C]flumazenil positron emission tomography to assess GABAA receptor availability and paired pulse TMS (ppTMS) to evaluate cortical excitability. Both whole-brain voxel-wise GABAA receptor availability and mean values from left hand motor cortex and left paracentral lobule were correlated to the ppTMS outcomes: short-interval intracortical inhibition reflecting GABAA receptor activity, long-interval intracortical inhibition representing GABAB receptor activity, intracortical facilitation reflecting glutamate N-methyl-D-aspartate-receptor activity, as well as the resting motor threshold (rMT), considered a global measure of corticospinal excitability.RESULTS: No significant differences in baseline GABAA receptor availability or cortical excitability were found between patients and controls. Additionally, no correlations were observed between baseline measurements of GABAA receptor availability and TMS outcomes. Changes in GABAA receptor availability in the hand motor cortex, between pre- and post-assessments, were inversely related to pre-post changes in hand rMT.CONCLUSION: We found that a change in GABAA receptor availability was inversely related to a change in rMT, suggesting a link between GABA deficiency and increased rMT previously observed in depressive episodes. The results highlight the complex mechanisms governing cortical excitability measures and offer new insight into their properties during the depressive state.
36.	Struckmann, Wiebke, et al. (author) Modulation of dorsolateral prefrontal cortex functional connectivity after intermittent theta-burst stimulation in depression : combining findings from fNIRS and fMRI 2022 In: NeuroImage. - : Elsevier. - 2213-1582. ; 34 Journal article (peer-reviewed)abstract Background: Resting-state functional magnetic resonance imaging (fMRI) can assess modulation of functional connectivity networks following repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. Functional near-infrared spectroscopy (fNIRS) is well suited for the concurrent application during rTMS treatment sessions to capture immediate blood oxygenation (oxy-Hb) effects, however limited in spatial resolution.Objective: To understand the network effects behind such a prefrontal fNIRS response during rTMS, and to test whether the fNIRS signal may be predictive of treatment response, we linked data from fNIRS and fMRI within a clinical intervention study.Methods: 42 patients with ongoing depression were recruited and randomized to receive active or sham intermittent theta-burst stimulation (iTBS) over the dorsomedial prefrontal cortex (dmPFC) twice daily for ten days at target intensity. Oxy-Hb was recorded with fNIRS during the first, fifth, and final day of iTBS, with the probe holders located laterally to the TMS coil over regions corresponding to the left and right dorsolateral prefrontal cortex (dlPFC). Resting-state fMRI scanning was performed before and after the whole iTBS treatment course. Functional connectivity analyses were then performed using dlPFC seeds from parcels of a brain atlas showing most overlap with the fNIRS probe locations during treatment.Results: After active iTBS, left dlPFC-connectivity to the right insula/operculum was reduced compared to sham. The left insula showed a connectivity reduction to the left dlPFC that correlated with an improvement in symptoms. In addition, the posterior parietal cortex showed a connectivity reduction to the left dlPFC that correlated with the fNIRS signal following active iTBS. Finally, the fNIRS oxy-Hb signal from the left dlPFC-seed during the first treatment day was predictive of dlPFC-connectivity change to precentral and temporal cortex regions.Conclusion: By linking findings from these two different methods, this study suggests that changes within both the salience network and the central executive network affect the fNIRS response to iTBS.
37.	Syk, Mikaela, 1990-, et al. (author) Biological markers for CNS damage in a patient cohort with suspected autoimmune psychiatric disease Other publication (other academic/artistic)abstract Background: This study describes the prevalence of CNS damage biomarkers and other CNS pathology in a psychiatric patient cohort enriched for clinical red flags of suspected autoimmune psychiatric disease. The study further explores how CNS damage biomarkers relate to clinical red flags and psychiatric features. Methods: 127 patients were included in the study. A routine cerebrospinal fluid (CSF) analysis was performed and anti-neuronal antibodies were measured. CNS damage biomarkers (neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAp) and total Tau (t-Tau)) in CSF were related to proposed clinical red flags for autoimmune psychiatric disease, other psychiatric features and MRI and EEG findings. Results: Twenty-seven per cent had elevated levels of CNS damage biomarkers and 21% had basic CSF analysis alterations. Six per cent had anti-neuronal antibodies in serum and 2% in CSF. Fifty percent of patients examined with MRI (n=88) had signs of atrophy and 41% had white matter changes. Twenty-five percent of patients with EEG recordings (n=70) had pathological EEG findings. Elevated NfL, GFAp and t-Tau levels were associated with the presence of clinical red flags. Elevated GFAp and t-Tau were also associated with higher psychiatric symptom ratings.Conclusions: Pre-selection based on clinical red flags for autoimmune psychiatric disease identifies a population where 27% have CSF signs of CNS tissue damage, 21% have CSF alterations suggesting neuroinflammation or blood-brain barrier dysfunction and 6% have anti-neuronal antibodies. Moreover, pathological levels of NfL, GFAp or t-Tau in CSF may be related to distinctive red flags and patterns of psychiatric manifestations.
38.	Virhammar, Johan, et al. (author) Acute necrotizing encephalopathy with SARS-CoV-2 RNA confirmed in cerebrospinal fluid 2020 In: Neurology. - 0028-3878 .- 1526-632X. ; 95:10, s. 445-449 Journal article (peer-reviewed)abstract 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.
39.	Virhammar, Johan, et al. (author) Biomarkers for central nervous system injury in cerebrospinal fluid are elevated in COVID-19 and associated with neurological symptoms and disease severity 2021 In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 28:10, s. 3324-3331 Journal article (peer-reviewed)abstract 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.
40.	Virhammar, Johan, et al. (author) Midbrain area and the hummingbird sign from brain MRI in progressive supranuclear palsy and idiopathic normal pressure hydrocephalus 2022 In: Journal of Neuroimaging. - : John Wiley & Sons. - 1051-2284 .- 1552-6569. ; 32:1, s. 90-96 Journal article (peer-reviewed)abstract 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.
41.	Widegren, Ebba, et al. (author) The influence of anterior cingulate GABA+ and glutamate on emotion regulation and reactivity in adolescents and adults 2024 In: Developmental Psychobiology. - : John Wiley & Sons. - 0012-1630 .- 1098-2302. ; 66:4 Journal article (peer-reviewed)abstract During adolescence, emotion regulation and reactivity are still developing and are in many ways qualitatively different from adulthood. However, the neurobiological processes underpinning these differences remain poorly understood, including the role of maturing neurotransmitter systems. We combined magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (dACC) and self-reported emotion regulation and reactivity in a sample of typically developed adolescents (n = 37; 13-16 years) and adults (n = 39; 30-40 years), and found that adolescents had higher levels of glutamate to total creatine (tCr) ratio in the dACC than adults. A glutamate i age group interaction indicated a differential relation between dACC glutamate levels and emotion regulation in adolescents and adults, and within-group follow-up analyses showed that higher levels of glutamate/tCr were related to worse emotion regulation skills in adolescents. We found no age-group differences in gamma-aminobutyric acid+macromolecules (GABA+) levels; however, emotion reactivity was positively related to GABA+/tCr in the adult group, but not in the adolescent group. The results demonstrate that there are developmental changes in the concentration of glutamate, but not GABA+, within the dACC from adolescence to adulthood, in accordance with previous findings indicating earlier maturation of the GABA-ergic than the glutamatergic system. Functionally, glutamate and GABA+ are positively related to emotion regulation and reactivity, respectively, in the mature brain. In the adolescent brain, however, glutamate is negatively related to emotion regulation, and GABA+ is not related to emotion reactivity. The findings are consistent with synaptic pruning of glutamatergic synapses from adolescence to adulthood and highlight the importance of brain maturational processes underlying age-related differences in emotion processing.
42.	Widegren, Ebba, et al. (author) The influence of anterior cingulate GABA+ and glutamate on emotion regulation and reactivity in adolescents and adults 2024 In: Developmental Psychobiology. - : John Wiley & Sons. - 0012-1630 .- 1098-2302. ; 66:4 Journal article (peer-reviewed)abstract During adolescence, emotion regulation and reactivity are still developing and are in many ways qualitatively different from adulthood. However, the neurobiological processes underpinning these differences remain poorly understood, including the role of maturing neurotransmitter systems. We combined magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (dACC) and self-reported emotion regulation and reactivity in a sample of typically developed adolescents (n = 37; 13–16 years) and adults (n = 39; 30–40 years), and found that adolescents had higher levels of glutamate to total creatine (tCr) ratio in the dACC than adults. A glutamate Í age group interaction indicated a differential relation between dACC glutamate levels and emotion regulation in adolescents and adults, and within-group follow-up analyses showed that higher levels of glutamate/tCr were related to worse emotion regulation skills in adolescents. We found no age-group differences in gamma-aminobutyric acid+macromolecules (GABA+) levels; however, emotion reactivity was positively related to GABA+/tCr in the adult group, but not in the adolescent group. The results demonstrate that there are developmental changes in the concentration of glutamate, but not GABA+, within the dACC from adolescence to adulthood, in accordance with previous findings indicating earlier maturation of the GABA-ergic than the glutamatergic system. Functionally, glutamate and GABA+ are positively related to emotion regulation and reactivity, respectively, in the mature brain. In the adolescent brain, however, glutamate is negatively related to emotion regulation, and GABA+ is not related to emotion reactivity. The findings are consistent with synaptic pruning of glutamatergic synapses from adolescence to adulthood and highlight the importance of brain maturational processes underlying age-related differences in emotion processing.

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