Molecular imaging of neuroinflammation in patients after mild traumatic brain injury: a longitudinal 123 I-CLINDE single photon emission computed tomography study.

BACKGROUND AND PURPOSE: Neuroinflammation has been proposed as part of the pathogenesis of post-concussion symptoms (PCS), but the inflammatory response of the human brain to mild traumatic brain injury (mTBI) remains unknown. We hypothesized that a neuroinflammatory response is present in mTBI at 1-2 weeks post-injury and persists in patients with PCS. METHODS: We scanned 14 patients with mTBI without signs of structural damage at 1-2 weeks and 3-4 months post-injury and 22 healthy controls once using the single photon emission computed tomography tracer 123 I-CLINDE, which visualizes translocator protein (TSPO), a protein upregulated in active immune cells. PCS was defined as three or more persisting symptoms from the Rivermead Post Concussion Symptoms Questionnaire at 3 months post-injury. RESULTS: Across brain regions, patients had significantly higher 123 I-CLINDE binding to TSPO than healthy controls, both at 1-2 weeks after the injury in all patients (P = 0.011) and at 3-4 months in the seven patients with PCS (P = 0.006) and in the six patients with good recovery (P = 0.018). When the nine brain regions were tested separately and results were corrected for multiple comparisons, no individual region differed significantly, but all estimated parameters indicated increased 123 I-CLINDE binding to TSPO, ranging from 2% to 19% in all patients at 1-2 weeks, 13% to 27% in patients with PCS at 3-4 months and -9% to 17% in patients with good recovery at 3-4 months. CONCLUSIONS: Neuroinflammation was present in mTBI at 1-2 weeks post-injury and persisted at 3-4 months post-injury with a tendency to be most pronounced in patients with PCS.

Ictal and interictal electric source imaging in pre-surgical evaluation: a prospective study.

BACKGROUND AND PURPOSE: Accurate localization of the epileptic focus is essential for surgical treatment of patients with drug-resistant epilepsy. Electric source imaging (ESI) is increasingly used in pre-surgical evaluation. However, most previous studies have analysed interictal (II) discharges. Prospective studies comparing the feasibility and accuracy of II and ictal (IC) ESI are lacking. METHODS: We prospectively analysed long-term video-electroencephalography recordings (LTM) of patients admitted for pre-surgical evaluation. We performed ESI of II and IC signals using two methods, i.e. equivalent current dipole (ECD) and a distributed source model (DSM). LTM recordings employed the standard 25-electrode array (including inferior temporal electrodes). An age-matched template head model was used for source analysis. Results were compared with intracranial recordings, conventional neuroimaging methods [magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT)] and outcome at 1 year after surgery. RESULTS: A total of 87 consecutive patients were analysed. ECD gave a significantly higher proportion of patients with localized focal abnormalities (94%) compared with MRI (70%), PET (66%) and SPECT (64%). Agreement between the ESI methods and intracranial recording was moderate to substantial (k = 0.56-0.79). A total of 54 patients were operated (47 patients more than 1 year ago) and 62% of them became seizure-free. The localization accuracy of II-ESI was 51% for DSM and 57% for ECD, and that for IC-ESI was 51% for DSM and 62% for ECD. The differences between the ESI methods were not significant. Differences in localization accuracy between ESI and MRI (55%), PET (33%) and SPECT (40%) were not significant. CONCLUSIONS: The II-ESI and IC-ESI of LTM data have high feasibility and their localization accuracy is similar to that of conventional neuroimaging methods.

Prolonged life of human acute hippocampal slices from temporal lobe epilepsy surgery.

Resected hippocampal tissue from patients with drug-resistant epilepsy presents a unique possibility to test novel treatment strategies directly in target tissue. The post-resection time for testing and analysis however is normally limited. Acute tissue slices allow for electrophysiological recordings typically up to 12 hours. To enable longer time to test novel treatment strategies such as, e.g., gene-therapy, we developed a method for keeping acute human brain slices viable over a longer period. Our protocol keeps neurons viable well up to 48 hours. Using a dual-flow chamber, which allows for microscopic visualisation of individual neurons with a submerged objective for whole-cell patch-clamp recordings, we report stable electrophysiological properties, such as action potential amplitude and threshold during this time. We also demonstrate that epileptiform activity, monitored by individual dentate granule whole-cell recordings, can be consistently induced in these slices, underlying the usefulness of this methodology for testing and/or validating novel treatment strategies for epilepsy.

Efficacy of the Danish epilepsy surgery programme.

OBJECTIVE: Despite optimal medical treatment, approximately one-third of patients with epilepsy continue to have seizures. Epilepsy surgery is widely accepted as a therapeutic option in the selected subset of patients with drug-resistant focal epilepsy. Here, we report the results of the Danish epilepsy surgery programme from 2009 to 2014. MATERIAL AND METHODS: A total of 169 consecutive patients, operated at Rigshospitalet, were included. Information was gathered from digital patient records. Before 1-year follow-up, two patients were lost to follow-up and three were referred to new surgery. RESULTS: The median years of drug resistance before operation were 11 years. At 1-year follow-up (n = 164), seizure outcomes were as follows: 65% Engel I (free from disabling seizures), 51% Engel IA (completely seizure free) and 9% Engel IV (no worthwhile improvement), and for patients operated in the medial temporal lobe (n = 114): 70% Engel I, 56% Engel IA, 5% Engel IV. The outcomes of the 53 patients needing intracranial EEG recording (ICR) were not significantly different from the patients only evaluated with surface EEG. None of the eight MRI-negative patients operated outside the medial temporal lobe after ICR were free of disabling seizures. 12% of MTLE patients developed de novo depression after epilepsy surgery despite good surgical outcome. Three patients required rehabilitation due to post-operative hemiplegia. CONCLUSION: The outcomes of the Danish epilepsy surgery programme align with international results found in recent meta-analyses. Serious complications to epilepsy surgery are seldom. In accordance with international recommendations, Danish drug-resistant patients should be referred to epilepsy surgery evaluation at an earlier stage of the disease.

Autoimmune encephalitis associated with voltage-gated potassium channels-complex and leucine-rich glioma-inactivated 1 antibodies - a national cohort study.

BACKGROUND AND PURPOSE: The aim of this study was to describe clinical and paraclinical characteristics of all Danish patients who tested positive for anti-voltage-gated potassium channels (VGKC)-complex, anti-leucine-rich glioma-inactivated 1 (LGI1) and anti-contactin-associated protein-2 antibodies in the serum/cerebrospinal fluid between 2009 and 2013 with follow-up interviews in 2015 and 2016. METHODS: We evaluated antibody status, symptoms leading to testing, course of disease, suspected diagnosis and time of admission as well as diagnosis and treatment. All magnetic resonance imaging, electroencephalography and 18 F-fluorodeoxyglucose positron emission tomography scans were re-evaluated by experts in the field. RESULTS: A total of 28/192 patients tested positive for VGKC-complex antibodies by radioimmunoassay and indirect immunofluorescence; 17 had antibodies to LGI1 and 6/7 of the available cerebrospinal fluids from these patients were seropositive. These 17 patients all had a clinical phenotype appropriate to LGI1 antibodies. The remaining 11 were LGI1 negative (n = 4) or not tested (n = 7). Of these, two had a phenotype consistent with limbic encephalitis. The remaining phenotypes were Guillain-Barré syndrome, Creutzfeldt-Jakob disease, neuromyotonia and anti-N-methyl-D-aspartate receptor encephalitis. Magnetic resonance imaging abnormalities were demonstrated in 69% of the LGI1-positive patients. Two patients with normal magnetic resonance imaging demonstrated temporal lobe hypermetabolism using 18 F-fluorodeoxyglucose positron emission tomography. Abnormal electroencephalography recordings were found in 86% of the patients. Upon follow-up (median 3.2 years), the median modified Rankin Scale score of anti-LGI1-positive patients was 2 and only two patients reported seizures in the past year. CONCLUSIONS: Patients diagnosed with anti-LGI1 autoimmune encephalitis increased significantly from 2009 to 2014, probably due to increased awareness. In contrast to seropositive anti-VGKC-complex patients, all anti-LGI1-positive patients presented with a classical limbic encephalitis. The majority of patients recovered well.

No correlation between body mass index and striatal dopamine transporter availability in healthy volunteers using SPECT and [123I]PE2I.

OBJECTIVE: Dopamine plays an important role in both the rewarding and conditioning effects of food. These effects involve mesolimbic, mesocortical, and nigrostriatal pathways. In humans, the most consistent finding has been reduced striatal dopamine D2/3 receptor availability. In striatum, dopamine is inactivated by reuptake via the dopamine transporter (DAT). The aim of the study was to test the hypothesis of lower DAT availability in obese healthy subjects using a selective DAT radiotracer in a sample of subjects with a wide range of BMI values. DESIGN AND METHODS: Thirty-three healthy subjects with a mean age of 48.4 ± 13.3 (range, 21-71) years and a mean BMI of 29.6 ± 7.8 kg/m2 (range, 21.0-49.5) were included in the study. We used [123I]PE2I and SPECT to measure DAT availability. RESULTS: Using multiple linear regression analyses with striatal DAT as the dependent variable and BMI, age and gender as predictors was performed. We found no correlation between BMI and striatal DAT availability in striatum (P = 0.99), caudate nucleus (P = 0.61), and putamen (P = 0.30). Furthermore, we found no group difference between obese/severely obese (BMI > 30 kg/m2) and normal weight controls (BMI ≤ 25 kg/m2). CONCLUSIONS: We did not find any correlation between BMI and DAT availability in healthy volunteers.

Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease.

Recently, a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 was reported as the cause of chromosome 9p21-linked frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS). We here report the prevalence of the expansion in a hospital-based cohort and associated clinical features indicating a wider clinical spectrum of C9ORF72 disease than previously described. We studied 280 patients previously screened for mutations in genes involved in early onset autosomal dominant inherited dementia disorders. A repeat-primed polymerase chain reaction amplification assay was used to identify pathogenic GGGGCC expansions. As a potential modifier, confirmed cases were further investigated for abnormal CAG expansions in ATXN2. A pathogenic GGGGCC expansion was identified in a total of 14 probands. Three of these presented with atypical clinical features and were previously diagnosed with clinical olivopontocerebellar degeneration (OPCD), atypical Parkinsonian syndrome (APS) and a corticobasal syndrome (CBS). Further, the pathogenic expansion was identified in six FTD patients, four patients with FTD-ALS and one ALS patient. All confirmed cases had normal ATXN2 repeat sizes. Our study widens the clinical spectrum of C9ORF72 related disease and confirms the hexanucleotide expansion as a prevalent cause of FTD-ALS disorders. There was no indication of a modifying effect of the ATXN2 gene.

Novel mutation in ATP13A2 widens the spectrum of Kufor-Rakeb syndrome (PARK9).

Kufor-Rakeb syndrome (KRS) is a rare autosomal recessive inherited juvenile parkinsonian syndrome caused by mutations in ATP13A2. We describe six patients from a consanguineous Greenlandic Inuit family, homozygous for a novel frame-shift mutation in exon 22 of ATP13A2 (c.2473C>AA, p.Leu825AsnfsX32). Disease onset varied from 10 to 29 years of age, the latest reported, and the clinical features were highly variable within a wide spectrum of an extrapyramidal-pyramidal syndrome with cognitive/psychiatric features. Ataxia was seen in two patients and axonal neuropathy in one, features not previously related to KRS. Dopamine transporter scans showed symmetrical, severely reduced uptake in striatum in two patients. Magnetic resonance imaging was without atrophy in one patient despite disease duration of 17 years, and cerebral and cerebellar atrophy was seen in another patient after 4 years of disease duration. The molecular pathogenic mechanisms of ATP13A2 mutations are discussed. The observation that the mutant transcript is not degraded by nonsense-mediated RNA decay and the fact that none of the eight heterozygous carriers from the family have KRS symptoms suggest that the mutant protein does not interfere and destroy the function of the wild-type ATP13A2 protein.

Reduced 5-HT2A receptor binding in patients with mild cognitive impairment.

Previous studies of patients with Alzheimer's disease (AD) have described reduced brain serotonin 2A (5-HT(2A)) receptor density. It is unclear whether this abnormality sets in early in the course of the disease and whether it is related to early cognitive and neuropsychiatric symptoms. We assessed cerebral 5-HT(2A) receptor binding in patients with mild cognitive impairment (MCI) and related 5-HT(2A) receptor binding to clinical symptoms. Sixteen patients with MCI of the amnestic type (mean age 73, mean MMSE 26.1) and 17 age and sex matched control subjects were studied with MRI and [(18)F]altanserin PET in a bolus-infusion approach. A significant global reduction of 20-30% in 5-HT(2A) binding (atrophy corrected) was found in most neocortical areas. Reduced 5-HT(2A) binding in the striatum correlated significantly with Neuropsychiatric Inventory depression and anxiety scores. We conclude that widespread reductions in 5-HT(2A) receptor binding were found in amnestic MCI, pointing at the presence of serotonergic dysfunction in prodromal AD. This may provide some of the pathophysiological background for the neuropsychiatric symptoms found in early AD.

Reduced midbrain-pons serotonin transporter binding in patients with obsessive-compulsive disorder.

OBJECTIVE: To evaluate current hypothesis regarding the pathophysiology of obsessive-compulsive disorder (OCD) by studying the serotonin receptor binding in patients with OCD using single photon emission computerized tomography (SPECT). METHOD: We studied nine patients (four men and five women, age range 21-56 years) fulfilling the DMS-III-R criteria for OCD using SPECT and the serotonin transporter (SERT) tracer (123)I-beta-CIT. SERT binding potential (BP2) was determined by Logan plot derived from seven scans obtained during 10-400 min. RESULTS: The binding of (123)I-beta-CIT in midbrain-pons was reduced in OCD patients when compared with controls (BP2 0.97 +/- 0.07 vs. 0.84 +/- 0.12, P = 0.011). There was no correlation between BP2 and any of the clinical variables (age at onset, disease duration, and Yale-Brown Obsessive-Compulsive Scale score). CONCLUSION: This study suggests a reduced serotonergic input into the fronto-subcortical circuits in OCD, thereby diminishing the inhibitory regulation of serotonin on these circuits.

Benzodiazepine receptor quantification in Huntington's disease with [(123)I]omazenil and SPECT.

OBJECTIVES: Increasing evidence suggests that metabolic changes predate neuronal death in Huntington's disease and emission tomography methods (PET and SPECT) have shown changes in glucose consumption and receptor function in early and possibly even presymptomatic disease. Because the GABA(A)-benzodiazepine receptor complex (BZR) is expressed on virtually all cerebral neurons BZR density images may be used to detect neuronal death. In this study the regional cerebral [(123)I]iomazenil binding to BZR was determined in patients with Huntington's disease and normal controls by a steady state method and SPECT. METHODS: Seven patients mildly to moderately affected by Huntington's disease and seven age matched controls were studied. Brain CT was performed on all subjects. In each subject two [(123)I]iomazenil-SPECT measurements were acquired-one with and one without infusion of flumazenil. The affinity constant of flumazenil (Kd) was calculated from the paired distribution volumes (DV) and the free plasma flumazenil concentration. The distribution volume of [(123)I]iomazenil in the unblocked condition (DV(0)) reflects the ratio between BZR density and Kd. RESULTS: Flumazenil Kd was similar in the Huntington's disease group and the control group (11.3 v 11.2 mM). For the Huntington's disease group a 31% reduction in striatal DV(0) (p=0.03) was found. In the cortical regions, DV(0) was similar in patients and in controls. In Huntington's disease, DV(0) correlated significantly with functional capacity (p=0.04) and chorea symptoms (p=0.02). The clinically least affected patients displayed DV(0)s within the range of those of the control group (19-35 ml/ml). CONCLUSIONS: The finding of an unchanged Kd of flumazenil in patients indicates that the BZR is functionally intact in Huntington's disease. That is, the reduction in DV(0) for BZR represents a selective decrease in the number of striatal BZRs. DV(0) significantly correlated with functional loss and [(123)I]iomazenil-SPECT could be an important tool for validation of the effect of future therapeutic strategies aimed at limiting oxidative stress and free radicals in Huntington's disease.

Dopamine D(2) receptor quantification in extrastriatal brain regions using [(123)I]epidepride with bolus/infusion.

The iodinated benzamide epidepride, which shows a picomolar affinity binding to dopamine D(2) receptors, has been designed for in vivo studies using SPECT. The aim of the present study was to apply a steady-state condition by the bolus/infusion approach with [(123)I]epidepride for the quantification of striatal and extrastriatal dopamine D(2) receptors in humans. In this way the distribution volume of the tracer can be determined from a single SPECT image and one blood sample. Based on bolus experiments, an algorithm using conventional convolution arguments for prediction of the outcome of a bolus/infusion (B/I) experiment was applied. It was predicted that a B/I protocol with infusion of one-third of the initial bolus per hour would be appropriate. Steady-state conditions were attained in extrastriatal regions within 3-4 h but the infusion continued up to 7 h in order to minimize the significance of individual differences in plasma clearance and binding parameters. A steady-state condition, however, could not be attained in striatal brain regions using a B/I protocol of 20 h, even after 11 h. Under near steady-state conditions a striatal:cerebellar ratio of 23 was demonstrated. Epidepride has a unique signal-to-noise ratio compared to [(123)I]IBZM but present difficulties for steady-state measurements of striatal regions. The bolus/infusion approach is particularly feasible for quantification of the binding potential in extrastriatal regions.

No effect of insulin on glucose blood-brain barrier transport and cerebral metabolism in humans.

The effect of hyperinsulinemia on glucose blood-brain barrier (BBB) transport and cerebral metabolism (CMRglc) was studied using the intravenous double-indicator method and positron emission tomography using [18F]fluorodeoxyglucose as tracer (PET-FDG). Sixteen normal healthy control subjects (25 +/- 4 years old) were studied twice during a euglycemic and a euglycemic-hyperinsulinemic condition. Our hypothesis was that high physiologic levels of insulin did not affect the BBB transport or net metabolism of glucose. During insulin infusion, arterial plasma insulin levels increased from 48.5 to 499.4 pmol/l. The permeability-surface area products for glucose and FDG BBB transport obtained with the double-indicator method remained constant during hyperinsulinemia. Similarly using PET-FDG, no changes were observed in the unidirectional clearance of FDG from blood to brain. k2* (FDG transport from brain to blood) increased significantly by 15 and 18% (gray and white matter, respectively), and k4* (dephosphorylation of FDG) increased by 18%. The increase in k2* may be caused by insulin inducing a decrease in the available FDG brain pool. The increase in k4* may be related to an increased loss of labeled products during insulin fusion. Irrespective of these changes, CMRglc remained unchanged in all brain regions. We conclude that hyperinsulinemia within the normal physiologic range does not affect BBB glucose transport or net cerebral glucose metabolism.