The neuronal component of gray matter damage in multiple sclerosis: A [(11) C]flumazenil positron emission tomography study.

OBJECTIVE: Using positron emission tomography (PET) with [(11) C]flumazenil ([(11) C]FMZ), an antagonist of the central benzodiazepine site located within the GABAA receptor, we quantified and mapped neuronal damage in the gray matter (GM) of patients with multiple sclerosis (MS) at distinct disease stages. We investigated the relationship between neuronal damage and white matter (WM) lesions and evaluated the clinical relevance of this neuronal PET metric. METHODS: A cohort of 18 MS patients (9 progressive and 9 relapsing-remitting) was compared to healthy controls and underwent neurological and cognitive evaluations, high-resolution dynamic [(11) C]FMZ PET imaging and brain magnetic resonance imaging. [(11) C]FMZ binding was estimated using the partial saturation protocol providing voxel-wise absolute quantification of GABAA receptor concentration. PET data were evaluated using a region of interest (ROI) approach as well as on a vertex-by-vertex basis. RESULTS: [(11) C]FMZ binding was significantly decreased in the cortical GM of MS patients, compared to controls (-10%). Cortical mapping of benzodiazepine receptor concentration ([(11) C]FMZ Bmax) revealed significant intergroup differences in the bilateral parietal cortices and right frontal areas. ROI analyses taking into account GM volume changes showed extensive decrease in [(11) C]FMZ binding in bilateral parietal, cingulate, and insular cortices as well as in the thalami, amygdalae, and hippocampi. These changes were significant in both progressive and relapsing-remitting forms of the disease and correlated with WM T2-weighted lesion load. [(11) C]FMZ cortical binding correlated with cognitive performance. INTERPRETATION: This pilot study showed that PET with [(11) C]FMZ could be a promising and sensitive quantitative marker to assess and map the neuronal substrate of GM pathology in MS.

Brain inflammation in a chronic epilepsy model: Evolving pattern of the translocator protein during epileptogenesis.

AIMS: A hallmark in the neuropathology of temporal lobe epilepsy is brain inflammation which has been suggested as both a biomarker and a new mechanistic target for treatments. The translocator protein (TSPO), due to its high upregulation under neuroinflammatory conditions and the availability of selective PET tracers, is a candidate target. An important step to exploit this target is a thorough characterisation of the spatiotemporal profile of TSPO during epileptogenesis. METHODS: TSPO expression, microglial activation, astrocyte reactivity and cell loss in several brain regions were evaluated at five time points during epileptogenesis, including the chronic epilepsy phase in the kainic acid-induced status epilepticus (KASE) model (n = 52) and control Wistar Han rats (n = 33). Seizure burden was also determined in the chronic phase. Furthermore, ¹8F-PBR111 PET/MRI scans were acquired longitudinally in an additional four KASE animals. RESULTS: TSPO expression measured with in vitro and in vivo techniques was significantly increased at each time point and peaked two weeks post-SE in the limbic system. A prominent association between TSPO expression and activated microglia (p < 0.001; r = 0.7), as well as cell loss (p < 0.001; r = -0.8) could be demonstrated. There was a significant positive correlation between spontaneous seizures and TSPO upregulation in several brain regions with increased TSPO expression. CONCLUSIONS: TSPO expression was dynamically upregulated during epileptogenesis, persisted in the chronic phase and correlated with microglia activation rather than reactive astrocytes. TSPO expression was correlating with spontaneous seizures and its high expression during the latent phase might possibly suggest being an important switching point in disease ontogenesis which could be further investigated by PET imaging.

Humanin Derivatives Inhibit Necrotic Cell Death in Neurons.

Humanin and its derivatives are peptides known for their protective antiapoptotic effects against Alzheimer's disease. Herein, we identify a novel function of the humanin-derivative AGA(C8R)-HNG17 (namely, protection against cellular necrosis). Necrosis is one of the main modes of cell death, which was until recently considered an unmoderated process. However, recent findings suggest the opposite. We have found that AGA(C8R)-HNG17 confers protection against necrosis in the neuronal cell lines PC-12 and NSC-34, where necrosis is induced in a glucose-free medium by either chemohypoxia or by a shift from apoptosis to necrosis. Our studies in traumatic brain injury models in mice, where necrosis is the main mode of neuronal cell death, have shown that AGA(C8R)-HNG17 has a protective effect. This result is demonstrated by a decrease in a neuronal severity score and by a reduction in brain edema, as measured by magnetic resonance imaging (MRI). An insight into the peptide's antinecrotic mechanism was attained through measurements of cellular ATP levels in PC-12 cells under necrotic conditions, showing that the peptide mitigates a necrosis-associated decrease in ATP levels. Further, we demonstrate the peptide's direct enhancement of the activity of ATP synthase activity, isolated from rat-liver mitochondria, suggesting that AGA(C8R)-HNG17 targets the mitochondria and regulates cellular ATP levels. Thus, AGA(C8R)-HNG17 has potential use for the development of drug therapies for necrosis-related diseases, for example, traumatic brain injury, stroke, myocardial infarction, and other conditions for which no efficient drug-based treatment is currently available. Finally, this study provides new insight into the mechanisms underlying the antinecrotic mode of action of AGA(C8R)-HNG17.

Interactions between glutamate, dopamine, and the neuronal signature of response inhibition in the human striatum.

Response inhibition is a basic mechanism in cognitive control and dysfunctional in major psychiatric disorders. The neuronal mechanisms are in part driven by dopamine in the striatum. Animal data suggest a regulatory role of glutamate on the level of the striatum. We used a trimodal imaging procedure of the human striatum including F18-DOPA positron emission tomography, proton magnetic resonance spectroscopy, and functional magnetic resonance imaging of a stop signal task. We investigated dopamine synthesis capacity and glutamate concentration in vivo and their relation to functional properties of response inhibition. A mediation analysis revealed a significant positive association between dopamine synthesis capacity and inhibition-related neural activity in the caudate nucleus. This relationship was significantly mediated by striatal glutamate concentration. Furthermore, stop signal reaction time was inversely related to striatal activity during inhibition. The data show, for the first time in humans, an interaction between dopamine, glutamate, and the neural signature of response inhibition in the striatum. This finding stresses the importance of the dopamine-glutamate interaction for behavior and may facilitate the understanding of psychiatric disorders characterized by impaired response inhibition.

Review of cardiovascular imaging in The Journal of Nuclear Cardiology in 2014: Part 1 of 2: Positron emission tomography, computed tomography, and neuronal imaging.

The year 2014 has been an exciting year for the cardiovascular imaging community with significant advances in the realm of nuclear and multimodality cardiac imaging. In this new feature of the Journal of Nuclear Cardiology, we will summarize some of the breakthroughs that were published in the Journal in 2014 in 2 sister articles. This first article will concentrate on publications dealing with cardiac positron emission tomography (PET), computed tomography (CT), and neuronal imaging.

Relationship between quantitative cardiac neuronal imaging with ¹²³I-meta-iodobenzylguanidine and hospitalization in patients with heart failure.

PURPOSE: Hospitalization in patients with systolic heart failure is associated with morbidity, mortality, and cost. Myocardial sympathetic innervation, imaged by (123)I-meta-iodobenzylguanidine ((123)I-mIBG), has been associated with cardiac events in a recent multicenter study. The present analysis explored the relationship between (123)I-mIBG imaging findings and hospitalization. METHODS: Source documents from the ADMIRE-HF trial were reviewed to identify hospitalization events in patients with systolic heart failure following cardiac neuronal imaging using (123)I-mIBG. Time to hospitalization was analyzed with the Kaplan-Meier method and compared to the mIBG heart-to-mediastinum (H/M) ratio using multiple-failure Cox regression. RESULTS: During 1.4 years of median follow-up, 362 end-point hospitalizations occurred in 207 of 961 subjects, 79 % of whom had H/M ratio <1.6. Among subjects hospitalized for any cause, 88 % had H/M ratio <1.6 and subjects with H/M ratio <1.6 experienced hospitalization earlier than subjects with higher H/M ratios (log-rank p = 0.003). After adjusting for elevated brain natriuretic peptide (BNP) and time since heart failure diagnosis, a low mIBG H/M ratio was associated with cardiac-related hospitalization (HR 1.48, 95 % CI 1.05 - 2.0; p = 0.02). CONCLUSION: The mIBG H/M ratio may risk-stratify patients with heart failure for cardiac-related hospitalization, especially when used in conjunction with BNP. Further studies are warranted to examine these relationships.

Gestational iron deficiency differentially alters the structure and function of white and gray matter brain regions of developing rats.

Gestational iron deficiency (ID) has been associated with a wide variety of central nervous system (CNS) impairments in developing offspring. However, a focus on singular regions has impeded an understanding of the CNS-wide effects of this micronutrient deficiency. Because the developing brain requires iron during specific phases of growth in a region-specific manner, we hypothesized that maternal iron deprivation would lead to region-specific impairments in the CNS of offspring. Female rats were fed an iron control (Fe+) or iron-deficient (Fe-) diet containing 240 or 6 µg/g iron during gestation and lactation. The corpus callosum (CC), hippocampus, and cortex of the offspring were analyzed at postnatal day 21 (P21) and/or P40 using structural and functional measures. In the CC at P40, ID was associated with reduced peak amplitudes of compound action potentials specific to myelinated axons, in which diameters were reduced by ∼20% compared with Fe+ controls. In the hippocampus, ID was associated with a 25% reduction in basal dendritic length of pyramidal neurons at P21, whereas branching complexity was unaffected. We also identified a shift toward increased proximal branching of apical dendrites in ID without an effect on overall length compared with Fe+ controls. ID also affected cortical neurons, but unlike the hippocampus, both apical and basal dendrites displayed a uniform decrease in branching complexity, with no significant effect on overall length. These deficits culminated in significantly poorer performance of P40 Fe- offspring in the novel object recognition task. Collectively, these results demonstrate that non-anemic gestational ID has a significant and region-specific impact on neuronal development and may provide a framework for understanding and recognizing the presentation of clinical symptoms of ID.

Subcellular mapping of dendritic activity in optic flow processing neurons.

Dendritic integration is a fundamental element of neuronal information processing. So far, few studies have provided a detailed spatial picture of this process, describing the properties of local dendritic activity and its subcellular organization. Here, we used 2-photon calcium imaging in optic flow processing neurons of the fly Calliphora vicina to determine the preferred location and direction of local motion cues for small branchlets throughout the entire dendrite. We found a pronounced retinotopic mapping on both the subcellular and the cell population level. In addition, dendritic branchlets residing in different layers of the neuropil were tuned to distinct directions of motion. Summing the local receptive fields of all dendritic branchlets reproduced the characteristic properties of these neurons' axonal output receptive fields. Our results corroborate the notion that the dendritic morphology of vertical system cells allows them to selectively collect local motion inputs with particular directional preferences from a spatially organized input repertoire, thus forming filters that match global patterns of optic flow. Furthermore, we suggest that the facet arrangement across the fly's eye shapes the subcellular direction tuning to local motion stimuli. These data illustrate a highly structured circuit organization as an efficient way to hard-wire a complex sensory task.

L-3,4-Dihydroxy-6-[F-18]fluorophenylalanine positron emission tomography demonstrating dopaminergic system abnormality in the brains of obsessive-compulsive disorder patients.

AIM: Obsessive-compulsive disorder (OCD) is a chronic disabling neuropsychiatric disorder. Current treatment modalities, such as pharmacological and behavioral methods, are sometimes unsatisfactory. The mesolimbic dopaminergic pathway is supposed to have a role in the pathogenesis of OCD. In this study, L-3,4-Dihydroxy-6-[F-18]fluorophenylalanine (F-18 FDOPA) positron emission tomography (PET) is exploited to investigate the possible abnormality of dopaminergic neuronal circuits in the brains of OCD patients in vivo. METHODS: The study subjects were recruited after psychological assessment and gave written informed consent to participate. The F-18 FDOPA PET scans were performed on five OCD patients and six healthy volunteers at 120 min after 185 MBq of F-18 FDOPA intravenous injection. The PET results were analyzed with the Statistical Parametric Mapping tool. RESULTS: Compared to the healthy subjects, the OCD brains showed increased dopaminergic metabolism in the left frontal premotor cortex (P < 0.001), along with trends toward an increase in the left posterior cingulate gyrus, the left cuneus, the left lingual gyrus, the right cuneus and precuneus, the right lingual gyrus, the right middle temporal gyrus, the left cerebellum, and the right cerebellum (P < 0.01). CONCLUSION: Our observations suggest that the increased dopaminergic neuronal function in these brain areas may be implicated in the pathogenesis of OCD.

The origin of nausea in migraine-a PET study.

BACKGROUND: Nausea is a common and disabling symptom of migraine. The origin of nausea is not well understood although functional connections between trigeminal neurons and the nucleus tractus solitarius may explain occurrence of nausea with pain. However, nausea occurs as a premonitory symptom in about a quarter of patients, suggesting that a primary brain alteration unrelated to the experience of pain may be the reason for nausea. METHODS: We performed positron emission tomography scans with H215O PET in premonitory phase of nitroglycerin-induced migraine and compared patients with and without nausea. RESULTS: The results showed activation in rostral dorsal medulla and periaqueductal grey (PAG) in the nausea group, which was absent in the no nausea group. The rostral dorsal medullary area included the nucleus tractus solitarius, dorsal motor nucleus of the vagus nerve and the nucleus ambiguus, all of which are thought to be involved in brain circuits mediating nausea. CONCLUSIONS: The results demonstrate that nausea can occur as a premonitory symptom in migraine, independent of pain and trigeminal activation. This is associated with activation of brain structures known to be involved in nausea. We conclude that nausea is a centrally driven symptom in migraine.

Characterizing infarction and selective neuronal loss following temporary focal cerebral ischemia in the rat: a multi-modality imaging study.

BACKGROUND AND PURPOSE: Current models dictate that, depending on occurrence of early reperfusion, the ischemic penumbra either undergoes or escapes infarction (i.e., "pan-necrosis"). However, tissue outcome following temporary middle-cerebral artery occlusion (tMCAo) in rodents can also include selective neuronal loss (SNL), which even if subtle may impede functional recovery. In order to explore the pathophysiology of ischemic stroke, determine potential therapeutic targets and monitor effects of therapy, in vivo imaging surrogates of these varied histopathological outcomes applicable in the clinical setting would be useful. Although hyperintense signal on T(2)-weighted MRI in the chronic post-stroke stage is considered a reliable surrogate of tissue infarction, SNL is not associated with T(2)W abnormal signal. In the clinical setting, the neuron-specific PET ligand (11)C-flumazenil (FMZ) has been used to identify both pan-necrosis and peri-infarct SNL, but this inference has not been histopathological confirmed so far. Here we investigated the late tissue sequelae of tMCAo in the rodent using in vivo T(2)W MRI and FMZ-PET against post mortem immunohistochemistry as gold standard. METHODS: Adult spontaneously hypertensive rats (SHRs) underwent 45 min distal-clip middle-cerebral artery occlusion and, 28 days later, FMZ-PET and T(2)W-MRI, immediately followed by immunohistochemistry for neuronal loss (NeuN), activated microglia and astrocytosis. Based on standard histopathological definitions, ischemic lesions were classified into pan-necrosis, partial infarction or SNL. NeuN changes and FMZ binding across the whole hemisphere were quantified in the same set of 44 regions-of-interest according to previously validated protocols; linear regressions between these two measures were carried out both within and across subjects. RESULTS: Both cortical pan-necrosis/partial infarction and SNL were present in all rats except one, where SNL was isolated and extensive. Infarction/partial infarction, but not SNL, was associated with T(2)W hyperintense signals and cortical atrophy. In contrast, FMZ binding was decreased in all types of lesions including SNL, in proportion with NeuN staining intensity both within (p<0.05 to <0.001) and across (p<0.001) subjects, including the subject that showed pure SNL (p=0.01). CONCLUSION: This novel study revealed three main facts: i) long-term histopathological cortical changes following 45 min tMCAo in SHRs included all three of SNL, partial infarction and frank infarction; ii) T2W MRI showed conspicuous high signal lesions for complete or partial infarction, but no changes for SNL; and iii) FMZ-PET was sensitive to all three types of tMCAo-induced histopathological changes, including isolated SNL, suggesting it is a valid surrogate for the histological sequelae of focal cerebral ischemia. In addition, the finding of almost universal completed cortical infarction at 28 days differed from our previous findings at 14-day survival using the same model and rat strain, where SNL was the almost exclusive outcome, possibly representing delayed infarct maturation. Prospective studies are needed to investigate this interesting possibility.

Assessment of cardiac autonomic neuronal function using PET imaging.

The autonomic nervous system is the primary extrinsic control of cardiac performance, and altered autonomic activity has been recognized as an important factor in the progression of various cardiac pathologies. Molecular imaging techniques have been developed for global and regional interrogation of pre- and postsynaptic targets of the cardiac autonomic nervous system. Building on established work with the guanethidine analogue ¹²³I-metaiodobenzylguanidine (MIBG) for single-photon emission tomography (SPECT), development of radiotracers and protocols for positron emission tomography (PET) investigation of autonomic signaling has expanded. PET is limited in availability and requires specialized centers for radiosynthesis and interpretation, but the higher resolution allows for improved regional analysis and kinetic modeling provides more true quantification than is possible with SPECT. A wider array of radiolabeled catecholamines, analogues of catecholamines, and receptor ligands have been characterized and evaluated. Sympathetic neuronal PET tracers have shown promise in the identification of several cardiac pathologies. In particular, recent studies have elucidated a mechanistic role for heterogeneous sympathetic innervation in the development of lethal ventricular arrhythmias. Evaluation of cardiomyocyte adrenergic receptor expression and the parasympathetic nervous system has been slower to develop, with clinical studies beginning to emerge. This review summarizes the clinical and the experimental PET tracers currently available for autonomic imaging and discusses their application in health and cardiovascular disease, with particular emphasis on the major findings of the last decade.

Tc-99m-HL91 imaging in the early detection of neuronal injury in a neonatal rat model of hypoxic ischemia.

OBJECTIVE: Hypoxic-ischemic insult in newborns results in progressive neuronal loss. For neuroprotective therapy to be effective, it is important to identify high-risk neonates soon after birth. 99mTc-labeled imaging agent, Tc-99m-HL91, developed as a putative hypoxic reagent, has been reported to demonstrate increased uptake in ischemic myocardium. We hypothesized that Tc-99m-HL91 is sensitive for the early identification of hypoxic-ischemic injury in neonatal rat brains. DESIGN: Laboratory investigation. SETTING: University research laboratory. SUBJECTS: Sprague-Dawley rat pups. INTERVENTIONS: Postnatal day-7 pups were divided into four groups: hypoxic-ischemia, hypoxia-only, ischemia-only, and controls. In the early (2 hrs), intermediate (20 hrs), and late (44 hrs) reoxygenation phases, Tc-99m-HL91 in vivo and ex vivo imaging and quantitative autoradiography were performed. Regions of interest were drawn to calculate the contrast ratio of Tc-99m-HL91 uptake between the ipsilateral and contralateral hemispheres. Pathology, cerebral blood flow, and blood-brain barrier damage were determined. MEASUREMENTS AND MAIN RESULTS: After hypoxic-ischemia, there were very few pyknotic neurons in the early phase, many pyknotic neurons in the intermediate phase, and extensive neuronal loss in the late phase postreoxygenation. Blood-brain barrier damage occurred in the early phase, progressed in the intermediate phase, and became extensive in the late phase. The hypoxia-only and ischemia-only pups showed no neuronal or blood-brain barrier damage and had higher cerebral blood flow postreoxygenation compared with the hypoxia-ischemia pups. Regions of interest analysis of in vivo and ex vivo images and autoradiography revealed significantly higher Tc-99m-HL91 contrast ratio at early and intermediate phases, not late phase of hypoxic-ischemic group. Hypoxic-ischemia group had significantly higher contrast ratio values in the early and intermediate phases than the hypoxia-only and ischemia-only groups. A contrast ratio value of 0.15 in the early phase on postnatal day 7 had a sensitivity of 0.95 and specificity of 0.89 in detecting significant hypoxic-ischemic lesions on postnatal day 21. CONCLUSION: Tc-99m-HL91 uptake is sensitive for the early detection of hypoxic-ischemic injury in neonatal brains.

Detection of ischemic neuronal damage with [¹8F]BMS-747158-02, a mitochondrial complex-1 positron emission tomography ligand: small animal PET study in rat brain.

The acute and subacute ischemic neuronal damage in rat brain caused by photochemically induced thrombosis (PIT) was imaged using [¹8F]BMS-747158-02 ([¹8F]BMS) for mitochondrial complex-1 (MC-1) and [¹¹C](R)-PK11195 ([¹¹C](R)-PK) for peripheral benzodiazepine receptor [PBR; translocator protein] at preischemic "Normal," 1 (day 1), and 7 days (day 7) after ischemic insult. When [¹8F]BMS was intravenously injected into "Normal" rat, it was rapidly taken up into the brain, in which it showed a homogeneous distribution, and the uptake was suppressed by rotenone, a specific MC-1 inhibitor. The specificity of [¹8F]BMS binding to MC-1 was also confirmed by living brain slice imaging. At day 1, [¹8F]BMS uptake was low in infarct and peri-infarct regions where neuronal damage was detected by 2,3,5-triphenyltetrazolium chloride (TTC) staining. At day 7, the damaged areas determined using [¹8F]BMS revealed some discrepancy from those detected by TTC staining, suggesting that TTC stained not only surviving cells but also activated microglial cells in the peri-infarct region. This was also confirmed by [¹¹C](R)-PK imaging and immunohistochemical assessment with Iba1 antibody. In contrast, the uptake pattern of [¹8F]BMS was consistent with immunohistochemical assessment with NeuN antibody at both days 1 and 7. These results demonstrated that [¹8F]BMS could be a promising positron emission tomography ligand to assess the neuronal damage induced by ischemic insult in both acute and subacute phases.

Correlation of levels of neuronal and glial markers with radiological measures of infarct volume in ischaemic stroke: a systematic review.

BACKGROUND: A blood test that quantified the extent of brain damage following ischaemic stroke might be a useful surrogate outcome measure in trials of acute stroke treatments. Measures of neuronal and glial damage, such as neuron-specific enolase (NSE), glial fibrillary acidic protein, tau-protein, myelin-basic protein and S100-ß are potential candidate biomarkers. AIM: We systematically reviewed the relevant literature to find studies that correlated blood levels of neuronal and glial damage markers with imaging measures of infarct volume. METHODS: We identified studies with a comprehensive search of databases and the reference lists of relevant studies. We included studies that: (1) measured the highest level, or area under the curve (AUC) over time of markers of cerebral damage, (2) calculated infarct volume, and (3) correlated the two measures. RESULTS: Seventeen studies met the criteria for the systematic review. There were sufficient data to provide summary estimates for S100-ß and NSE. The peak level and AUC over time of both markers correlated with subacute infarct volume. Measurements of S100-ß later than 24 h after stroke were better correlated with subacute infarct size than earlier measurements. However, scan times varied, and none was later than 8 days after stroke. CONCLUSION: Peak and AUC levels of NSE and S100-ß levels correlated with subacute infarct volume. Correlations of S100-ß with infarct volume were stronger when measured after 24 h than closer to admission. Exploratory studies within clinical trials are necessary before blood markers of cerebral tissue damage can be recommended as surrogate endpoints.

Where in-vivo imaging meets cytoarchitectonics: the relationship between cortical thickness and neuronal density measured with high-resolution [18F]flumazenil-PET.

MRI-based measurements of surface cortical thickness (SCT) have become a sensitive tool to quantify changes in cortical morphology. When comparing SCT to histological cortical thickness maps, a good correspondence can be found for many but not all human brain areas. Discrepancies especially arise in the sensory motor cortex, where histological cortical thickness is high, but SCT is very low. The aim of this study was to determine whether the relationship between cortical thickness and neuronal density is the same for different cytoarchitectonic areas throughout homo- and heterotypical isocortex. We assessed this relationship using high-resolution [(18)F]-labelled flumazenil (FMZ) PET and SCT-mapping. FMZ binds to the benzodiazepine GABA(A) receptor complex which is localized on axo-dendritic synapses, with a cortical distribution closely following the local density of neurons. SCT and voxelwise FMZ binding potential (BP(ND)) were assessed in ten healthy subjects. After partial volume correction, two subsets with a differential relationship between SCT and BP(ND) were identified: a fronto-parietal homotypical subset where neuronal density is relatively constant and mainly independent of SCT, and a subset comprising heterotypical and mainly temporal and occipital homotypical regions where neuronal density is negatively correlated with SCT. This is the first in-vivo study demonstrating a differential relationship between SCT, neuronal density and cytoarchitectonics in humans. These findings are of direct relevance for the correct interpretation of SCT-based morphometry studies, in that there is no simple relationship between apparent cortical thickness and neuronal density, here attributed to FMZ binding, holding for all cortical regions.

Variability in the subcellular distribution of ion channels increases neuronal diversity.

The exact location of an ion channel on the axo-somato-dendritic surface of a nerve cell crucially affects its functional impact. Recent high-resolution immunolocalization experiments examining the distribution of GABA and glutamate receptors, voltage-gated potassium and sodium channels and hyperpolarization-activated mixed cation (HCN) channels clearly demonstrate the lack of simple rules concerning their subcellular distribution. For example, the density of HCN1 subunits in pyramidal cells increases 60-fold from soma to distal dendrites but is uniform over the somato-dendritic surface of olfactory bulb external tufted cells and is highest in the axon of cortical and cerebellar basket cells. Such findings highlight the necessity of determining the precise subcellular location and density of each ion channel in every cell type. Here, I suggest that variations in the subcellular distribution of ion channels are previously unrecognized means of increasing neuronal diversity and, thus, the computational power of the brain.

Impaired cardiac sympathetic innervation in symptomatic patients with long QT syndrome.

PURPOSE: Increased sympathetic activation is a key modifier for arrhythmogenesis in patients with long QT syndrome (LQTS), a congenital channelopathy. Therefore, we investigated cardiac sympathetic function using 123I-metaiodobenzylguanidine (MIBG) single photon emission computed tomography (SPECT) in a cohort of symptomatic LQTS patients and correlated these findings with the underlying genotype. METHODS: [123I]MIBG SPECT was performed in 28 LQTS patients. Among these, 18 patients (64%) had a previous syncope and 10 patients (36%) survived sudden cardiac arrest. Patients were characterized in terms of genetic subtypes and QTc interval on surface ECGs. SPECT images were analysed for regional [123I]MIBG uptake in a 33-segment bullseye scheme and compared to those obtained from 10 age-matched healthy control subjects (43±12 years). RESULTS: An abnormal 123I-MIBG scan was found in 17 of 28 LQTS patients (61%) with a tracer reduction mainly located in the anteroseptal segments of the left ventricle. This finding was independent of the genetic LQTS subtype. In addition, no differences were found between LQTS patients with a QTc>500 ms vs <500 ms or those suffering from syncope vs VF (p>0.05). CONCLUSION: A distinct regional pattern of impaired cardiac sympathetic function was identified in the majority of symptomatic LQTS patients. This innervation defect was independent of the underlying genotype and clinical disease expression.

Residual striatal dopaminergic nerve terminals in very long-standing Parkinson's disease: a single photon emission computed tomography imaging study.

Molecular imaging studies of Parkinson's disease (PD) progression mostly focus on the first 5 years after disease onset, demonstrating rapid initial nigrostriatal neuronal loss. The fate of residual functional dopaminergic nerve terminals in patients with long-standing PD has not yet been specifically explored. Therefore, we performed [(123)I]-FP-CIT single photon emission computed tomography (SPECT) in 15 patients with very long-standing PD (mean disease duration 20.6 ± 6.3 years). Measurable uptake of [(123)I]-FP-CIT was still detected in the striata of all patients. As seen in early stages, reduction of tracer uptake in the putamen was more prominent than in the caudate nucleus. Asymmetry in tracer uptake between the two putamen and caudate nuclei was preserved. These findings indicate that degeneration of dopaminergic neurons in PD is not total even after many years of illness. Data should be considered in exploring underlying causes of progressive loss of nigrostriatal dopaminergic neurons and development of future novel dopaminergic therapeutic strategies in PD.

Multiparametric assessment of acute and subacute ischemic neuronal damage: a small animal positron emission tomography study with rat photochemically induced thrombosis model.

We evaluated sequential changes in rat brain function up to 14 days after focal ischemic insult with a small animal positron emission tomography (PET). Unilateral focal ischemic cerebral damage was induced by left middle cerebral artery occlusion with a photochemically induced thrombosis (PIT) method. PET scans were conducted with [(11)C](R)-PK11195 ([(11)C](R)-PK) for peripheral benzodiazepine receptor (PBR), [(11)C]flumazenil ([(11)C]FMZ) for central benzodiazepine receptor (CBR), and [(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG) for glucose metabolism at before (as "Normal") and after PIT. At 1 and 3 days after PIT, [(18)F]FDG indicated lower uptake in the infarct area. Interestingly, unexpectedly high-[(18)F]FDG uptake was observed in the peri-infarct area surrounding the infarct area at day 7. The high-[(18)F]FDG uptake region completely overlapped with the high-[(11)C](R)-PK uptake region at day 7, which resulted in the underestimation of neuronal damage. Immunohistochemical data also suggested that the high-[(18)F]FDG uptake peak at day 7 was caused by inflammation including microglial cell activation. In contrast, imaging with [(11)C]FMZ indicated cortical neuronal damage on days 7 and 14 without any disturbance by microglial formation. These results indicated that [(18)F]FDG might not be a suitable ligand for ischemic neuronal damage detection from acute to subacute phases.