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Central nervous system (CNS) drug discovery suffers from high attrition rates; translational neuroscience approaches aiming to reduce these high rates include the use of brain imaging technologies. However, there is a need to better understand what methods are being used and for what diseases and purposes. Our analysis of the literature found that magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) were the neuroimaging techniques used most often in clinical trials for the most prevalent CNS diseases: Alzheimer's disease (AD), Parkinson's disease (PD), depression, and schizophrenia. Moreover, the number of initiated clinical trials using MRI, PET, and SPECT increased over the period 1981–2021. Such insights indicate that the significant increase in the use of neuroimaging studies could decrease the attrition of novel drug candidates in late clinical development. [ABSTRACT FROM AUTHOR]

The aim of this review was to report the current literature concerning the use of nuclear imaging modalities for the investigation of the neurobiology of canine behavioral disorders. The conventionally used nuclear medicine modalities are positron emission tomography and single photon emission (computed) tomography. At this moment, information is scarce about their application in veterinary behavioral medicine and only present for single photon emission tomography studies in dogs, mainly using 99m Tc-ethyl cysteinate dimer to assess brain perfusion (and indirectly neuronal function) and 123 I-5-I-R91150 to evaluate the 5-hydroxytryptamine-2A receptor binding. Current results suggest that functional nuclear imaging provides useful noninvasive in vivo information about the neurobiology and therapeutic evaluation of canine behavioral disorders. Due to striking similarities with neurobiological alterations in human disorders, the dog also represents an interesting natural animal model for human neuropsychiatric diseases. [ABSTRACT FROM AUTHOR]

Emission imaging incorporates both the development of dedicated devices for data acquisition as well as algorithms for recovering images from that data. Emission tomography is an indirect approach to imaging. The effect of device modification on the final image can be understood through both the way in which data are gathered, using simulation, and the way in which the image is formed from that data, or image reconstruction. When developing novel devices, systems and imaging tasks, accurate simulation and image reconstruction allow performance to be estimated, and in some cases optimized, using computational methods before or during the process of physical construction. However, there are a vast range of approaches, algorithms and pre-existing computational tools that can be exploited and the choices made will affect the accuracy of the in silico results and quality of the reconstructed images. On the one hand, should important physical effects be neglected in either the simulation or reconstruction steps, specific enhancements provided by novel devices may not be represented in the results. On the other hand, over-modeling of device characteristics in either step leads to large computational overheads that can confound timely results. Here, a range of simulation methodologies and toolkits are discussed, as well as reconstruction algorithms that may be employed in emission imaging. The relative advantages and disadvantages of a range of options are highlighted using specific examples from current research scenarios. [ABSTRACT FROM AUTHOR]

Abstract: Background: Patients in chronic phase of myocardial infarction (MI) have decreased coronary flow reserve (CFR) in infarct related artery (IRA) that is proportional to the extent of microvascular/myocardial damage. We proposed a novel model for the assessment of microvascular damage and infarct size using Doppler echocardiography evaluation of CFRs of the IRA (LAD) and reference artery (RCA). Methods: Our study included 34 consecutive patients (28 men, mean age 50±11years) with first anterior STEMI and single vessel disease successfully treated with primary PCI. All patients underwent SPECT MPI for the assessment of infarct size (expressed as a percentage of myocardium with fixed perfusion abnormalities) and CFR evaluation of LAD and RCA. CFR derived percentage of microvascular damage (CFR PMD) was calculated as: CFR PMD=(CFR RCA−CFR LAD)/(CFR RCA−1)×100 (%). Results: CFR PMD correlated significantly with all parameters evaluating the severity of myocardial damage including: peak CK activity (r=0.632, p<0.001), WMSI (r=0.857, p<0.001), ejection fraction (r=−0.820, p<0.001), left ventricular end diastolic (r=0.757, p<0.001) and end systolic volume (r=0.794, p<0.001). Most importantly, CFR PMD (22±17%) correlated significantly with infarct size by SPECT MPI (21±17%) (r=0.874, p<0.001). Conclusions: CFR PMD derived from the proposed model was significantly related to echocardiographic and enzymatic parameters of infarct size, as well as to myocardial damage assessed by SPECT MPI in patients with successfully reperfused first anterior STEMI. [Copyright &y& Elsevier]

Background & Aims: Extrapyramidal and cerebellar symptoms belong to the most prominent features of episodic hepatic encephalopathy, and usually decrease upon ammonia-lowering therapy. Rapidly progressing parkinsonian symptoms, which are unresponsive to treatment of hepatic encephalopathy, indicate cirrhosis-related Parkinsonism. This study aims at analyzing the prevalence of cirrhosis-related Parkinsonism in patients with liver cirrhosis, and to study the functional status of the striatal dopaminergic system in these patients. Methods: 214 patients with liver cirrhosis who were consecutively seen at the out-patient clinic for liver transplant candidates and/or at the transplantation wards at Hannover Medical School, between August 1, 2008 and March 31, 2011, underwent a standardized neurological examination while on the waiting list or immediately after liver transplantation. Single photon emission computer tomography (SPECT) using 123I-beta-CIT, for the evaluation of the striatal dopamine transporter function, and 123I-IBZM for the evaluation of the striatal dopamine D2 receptor availability, was performed in 6 patients with cirrhosis-related Parkinsonism. Results: Cirrhosis-related Parkinsonism was diagnosed in 9 of 214 patients (4.2%). SPECT revealed significantly decreased dopamine receptor availability in 5 of 6 patients studied, and significantly decreased dopamine transporter availability in 3. Levodopa improved motor dysfunction in two of four patients treated, although only temporarily. Incomplete recovery was observed in two patients after liver transplantation. Conclusions: Cirrhosis-related Parkinsonism is more frequent than presumed. The presented data suggest pre- and postsynaptic alteration of striatal dopaminergic neurotransmission as a possible cause of cirrhosis-related Parkinsonism and reveal the limited effects of dopaminergic therapy. [Copyright &y& Elsevier]

Abstract: Although Parkinson disease (PD) is viewed traditionally as a motor syndrome secondary to nigrostriatal dopaminergic denervation, recent studies emphasize non-motor features. Non-motor comorbidities, such as cognitive impairment, are likely the result of an intricate interplay of multi-system degenerations and neurotransmitter deficiencies extending beyond the loss of dopaminergic nigral neurons. The pathological hallmark of parkinsonian dementia is the presence of extra-nigral Lewy bodies that can be accompanied by other pathologies, such as senile plaques. Lewy first identified the eponymous Lewy body in neurons of the nucleus basalis of Meynert (nbM), the source of cholinergic innervation of the cerebral cortex. Although cholinergic denervation is recognized as a pathological hallmark of Alzheimer disease (AD), in vivo neuroimaging studies reveal loss of cerebral cholinergic markers in parkinsonian dementia similar to or more severe than in prototypical AD. Imaging studies agree with post-mortem evidence suggesting that basal forebrain cholinergic system degeneration appears early in PD and worsens coincident with the appearance of dementia. Early cholinergic denervation in PD without dementia appears to be heterogeneous and may make specific contributions to the PD clinical phenotype. Apart from well-known cognitive and behavioral deficits, central, in particular limbic, cholinergic denervation may be associated with progressive deficits of odor identification in PD. Recent evidence indicates also that subcortical cholinergic denervation, probably due to degeneration of brainstem pedunculopontine nucleus neurons, may relate to the presence of dopamine non-responsive gait and balance impairments, including falls, in PD. [Copyright &y& Elsevier]

In psychiatry, neuroimaging facilitates the diagnosis of psychiatric disorders and the development of new medications. It is used to detect structural lesions causing psychosis and to differentiate depression from neurodegenerative disorders or brain tumors. Functional neuroimaging, mostly in the form of molecular neuroimaging with positron emission tomography or single photon emission tomography, facilitates the identification of therapeutic targets, the determination of the dose of a new drug needed to occupy its target in the brain, and the selection of patients for clinical trials. [ABSTRACT FROM AUTHOR]

Abstract: Treatments currently licensed for Alzheimer''s dementia target cholinergic brain systems. In vivo nicotinic receptor binding may provide an early marker of illness and treatment suitability. In this pilot, we examined nine patients with amnestic mild cognitive impairment (MCI) and 10 age and education matched healthy volunteers with high resolution SPECT and the nicotinic receptor ligand 5-123I-A-85380. Uptake data were analysed using voxel-based techniques for group comparisons and regression analyses with cognitive impairment as covariates. MCI patients had discrete reductions in uptake in medial temporal cortex. Correlations with cognitive impairment were found in left temporo-parietal areas (Addenbrooke''s Cognitive Examination) and bilateral temporo-limbic areas (Rey Auditory Verbal Learning Test), and right parahippocampal gyrus (Rey Complex Figure Test) within the patient group. In vivo nicotinic receptor binding appears to be sensitive to brain changes in MCI. Larger scale explorations of patients undergoing treatment will be necessary to evaluate its use in predicting or monitoring treatment response. [Copyright &y& Elsevier]

Gene- and cell-based therapeutic procedures have entered the cardiovascular field. Many of these novel interventions aim at cardiac regeneration and the initial experimental groundwork has been promising. But early clinical experience did not always confirm the experimental findings and it is felt that the full potential of cardiac gene and cell therapy has, by far, not been exploited. Conflicting clinical results emphasise the need for powerful non-invasive tools to monitor the success of therapy and identify most suitable candidates. As reviewed here, established clinical cardiac imaging tools, together with novel molecular-targeted approaches, are expected to advance the field of myocardial regeneration and to expedite progress and clinical translation. [Copyright &y& Elsevier]

The pig model is increasingly used in the field of neuroscience because of the similarities of its brain with human. This review presents the peculiarities of the anatomy and functions of the pig brain with specific reference to its human counterpart. We propose an approximate mapping of the pig's cortical areas since a comprehensive description of the equivalent of Brodmann's areas is lacking. On the contrary, deep brain structures are received more consideration but a true three-dimensional (3D) atlas is still eagerly required. In the second section, we present an overview of former works describing the use of functional imaging and neuronavigation in the pig model. Recently, the pig has been increasingly used for molecular imaging studies using positron emission tomography (PET). Indeed, the large size of its brain is compatible with the limited spatial resolution of the PET scanner built to accommodate a human being. Similarly, neuronavigation is an absolute requirement to target deep brain areas in human and in pig since the surgeon cannot rely on external skull structures for zeroing the 3D reference frame. Therefore, a large body of methodological refinements has been dedicated to image guided surgery in the pig model. These refinements allow now a millimetre precision: an absolute requirement for basal nuclei targeting. In the third section, several examples of ongoing studies in our laboratory were presented to illustrate the intricacies of using the pig model. For both examples, after a brief description of the scientific context of the experiment, we present, in detail, the methodological steps required to achieve the experimental goals, which are specific to the porcine model. Finally, in the fourth section, the anatomical variations depending on the breed and age are discussed in relation with neuronavigation and brain surgery. The need for a digitized multimodality brain atlas is also highlighted. [ABSTRACT FROM AUTHOR]

Abstract: Stereoselectivity is a basic property of many neuronal processes due to the spatial features of molecules involved in neurotransmission. Today, neuroimaging procedures are available for studying stereoselectivity in the living brain. Mirror-image radiotracers are the molecular tools that are used, together with single photon emission tomography (SPECT) and positron emission tomography (PET), for studying stereoselective neuronal mechanisms. This review presents the findings obtained in those studies of cholinergic, noradrenergic, dopaminergic, serotonergic, glutamatergic, opioid, cannabinoid, and second messenger neurotransmission. [Copyright &y& Elsevier]

Abstract: Glossolalia (or “speaking in tongues”) is an unusual mental state that has great personal and religious meaning. Glossolalia is experienced as a normal and expected behavior in religious prayer groups in which the individual appears to be speaking in an incomprehensible language. This is the first functional neuroimaging study to demonstrate changes in cerebral activity during glossolalia. The frontal lobes, parietal lobes, and left caudate were most affected. [Copyright &y& Elsevier]

Abstract: The pathophysiology of sleep-related motor diseases and sleep dysfunction in movement disorders is widely unknown as yet. Functional brain imaging, in particular radioisotope and magnetic resonance techniques, are powerful tools to investigate possible pathomechanisms of combined sleep and motor dysregulation. In patients with Restless legs syndrome (RLS), only a subtle striatal dopamine deficit was found in PET and SPECT despite a good treatment effect of dopaminergic drugs. Functional MRI suggested a central generator of periodic limb movements during sleep (PLMs) in RLS. In contrast, a marked striatal dopamine depletion was demonstrated in patients with REM sleep behaviour disorder (RBD) as the base for the clinical and nosological overlap of RBD with parkinsonian disorders. PET and SPECT also suggested that sleep abnormalities in Parkinson''s disease (PD), such as REM sleep diminution or increased PLMs, are indirect manifestations of the primary striatal dopamine deficiency. [Copyright &y& Elsevier]

Abstract: We evaluated the patterns of dopamine transporter loss in the striatum of ten controls, twenty patients with Parkinson''s disease (PD), and nine with progressive supranuclear palsy (PSP) using 123I-IPT single photon emission tomography (SPECT). Four ROIs in the striatum correspond to the head of caudate nucleus (ROI 1), a transitional region between head of caudate and putamen (ROI 2), anterior putamen (ROI 3), and posterior putamen (ROI 4). A striatal ratio of specific to nondisplaceable uptake (V3″) was calculated normalizing the activity of the ROIs to that of occipital cortex. V3″ values were significantly reduced in all ROIs of PD and PSP patients, compared with controls (p =0.001). V3″ value in ROI 2 was significantly lower in PSP group, compared with PD group (p =0.02). The percent reductions of striatal uptake in ROI 1, ROI 2, ROI 3 and ROI 4 were 56%, 53%, 64% and 78% in PD patients, whereas 75%, 72%, 75% and 77% in PSP patients, respectively. The reduction patterns of uptake were significantly different between PD and PSP groups (p =0.001). In PD patients, the percent reductions of 123I-IPT uptake were significantly greater in ROI 3 and 4 compared with ROI 1 or 2, whereas those were similar in all ROIs of PSP patients. In addition, PD patients showed a significantly higher posterior putamen/caudate ratio of reduced 123I-IPT uptake than the anterior putamen/caudate ratio (p =0.005). Our results implicate that 123I-IPT SPECT is a relatively simple and reliable technique that may be useful in differentiating PD from PSP. [Copyright &y& Elsevier]

Abstract: [123I]CNS-1261 [N-(1-naphthyl)-N′-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intrachannel PCP/ketamine/MK-801 site of the N-methyl-d-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intrachannel PCP/ketamine/MK-801 site) on [123I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [123I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [123I]CNS-1261 V T in most of the brain regions examined (P<.05). [123I]CNS-1261 appears to be a specific ligand in vivo for the intrachannel PCP/ketamine/MK-801 NMDA binding site. [Copyright &y& Elsevier]

Abstract: In obsessive–compulsive disorder (OCD), the success of pharmacological treatment with serotonin re-uptake inhibitors and atypical antipsychotic drugs suggests that both the central serotonergic and dopaminergic systems are involved in the pathophysiology of the disorder. We applied [123I]-2β-carbomethoxy-3β-(4-idiophenyl)tropane (β-CIT) and a brain-dedicated high-resolution single photon emission computed tomography (SPECT) system to quantify dopamine transporter (DAT) and serotonin transporter (SERT) availability. By comparing 15 drug-naïve patients with OCD and 10 controls, we found a significantly reduced availability (corrected for age) of striatal DAT and of thalamic/hypothalamic, midbrain and brainstem SERT in OCD patients. Severity of OCD symptoms showed a significant negative correlation with thalamic/hypothalamic SERT availability, corrected for age and duration of symptoms. Our data provide evidence for imbalanced monoaminergic neurotransmitter modulation in OCD. Further studies with more selective DAT and SERT radiotracers are needed. [Copyright &y& Elsevier]

Abstract: A 78-year-old housewife with major depression developed a right-sided infarction in the territory of the middle cerebral arteries, followed by acute post-stroke mania. Comparison between pre- and post-stroke SPECT scans demonstrated a unique pattern of left orbitofrontal hyperperfusion with extensive right frontal hypoperfusion. A functional imbalance between right and left orbitofrontal cortices may be important in mania. [Copyright &y& Elsevier]

We report a young, mentally retarded apprentice cook with a 2-month history of right upper extremity dystonia, for whom diazepam therapy was efficacious. We evaluated brain perfusion by single photon emission tomography (SPECT) before and after diazepam treatment. The abnormal hyperperfusion in the left thalamus and hypoperfusion in the left frontal cortex were normalized on the second SPECT under the successful diazepam treatment. These findings were indicative of functional changes in the left thalamus and left frontal cortex. [Copyright &y& Elsevier]

N-(1-napthyl)-N′-(3-[123I]-iodophenyl)-N-methylguanidine ([123I]CNS 1261) is a novel SPET ligand developed for imaging the NMDA receptor intra-channel MK 801/PCP/ketamine site. Data was acquired in 7 healthy volunteers after bolus injection of [123I]CNS 1261. Kinetic modeling showed reversible tracer binding. Arterial and venous time-activity curves overlapped after 90 min. The rank order of binding was: Thalamus > striatum > cortical regions > white matter. This distribution concurs with [11C]-ketamine and [18F]-memantine PET studies . These data provide a methodological basis for further direct in vivo challenge studies. [Copyright &y& Elsevier]

The aims of this study were to: (1) assess the effects of repetitive transcranial magnetic stimulation (rTMS) on brain activity in depressed patients as measured by single photon emission tomography (SPECT); (2) evaluate the predictive value of brain SPECT on the antidepressant efficacy of rTMS. Patients (n=17) received 1600 rTMS stimuli at a rate of 10 Hz, 5 days per week for 2 weeks to the left dorsolateral prefrontal cortex. Whole brain SPECT data were acquired using Tc99m–Bicisate. Regional cerebral blood flow (rCBF) was correlated with the % change in the 28-item Hamilton Depression Rating Scale Score (Δ-HDRS) and a semiquantitative region of interest (ROI) analysis was conducted. Prior to rTMS there was a significant left–right asymmetry favoring the right, whereas 2 weeks after the rTMS treatment this asymmetry was reversed. The rCBF in limbic structures was negatively correlated with the outcome and rCBF in several neocortical areas was positively correlated. Brain SPECT can provide information about mechanisms of action of rTMS and may have predictive value for the antidepressant efficacy of rTMS. [Copyright &y& Elsevier]

We tested the hypothesis that the degree of striatal dopamine D2 receptor blockade induced by typical antipsychotic treatment directly correlates with the presence and severity of depressive symptoms in schizophrenia. Clinical and [123I]-IBZM single-photon emission tomography (SPET) scan data obtained from 18 typical antipsychotic treated schizophrenic patients was analysed to evaluate the relationship between striatal D2 receptor occupancy and the depressive subscale of the Brief Psychiatric Rating Scale (BPRS-D). Striatal D2 receptor occupancy by typical antipsychotic drugs was significantly positively correlated with BPRS-D scores (r=0.52, p=0.025). This study suggests that high striatal dopamine D2 blockade by typical antipsychotic drugs may contribute to the emergence of depressive symptoms in typical antipsychotic treated schizophrenic patients. [Copyright &y& Elsevier]

: ObjectivesThe purpose of this study is to investigate the morphologic characteristics of the cardiac interstitium in the hibernating human myocardium and evaluate whether active remodeling is present and is an important determinant of functional recovery.: BackgroundMyocardial hibernation is associated with structural myocardial changes, which involve both the cardiomyocytes and the cardiac interstitium.: MethodsWe evaluated 15 patients with coronary disease with two-dimensional echocardiography and thallium-201 (201Tl) tomography before coronary bypass surgery. During surgery, transmural myocardial biopsies were performed guided by transesophageal echocardiography. Myocardial biopsies were stained immunohistochemically to investigate fibroblast phenotype and examine evidence of active remodeling in the heart.: ResultsAmong the 29 biopsied segments included in the study, 24 showed evidence of systolic dysfunction. The majority of dysfunctional segments (86.4%) were viable (201Tl uptake ≥60%). After revascularization, 12 dysfunctional segments recovered function as assessed with an echocardiogram three months after bypass surgery. Interstitial fibroblasts expressing the embryonal isoform of smooth muscle myosin heavy chain (SMemb) were noted in dysfunctional segments, predominantly located in border areas adjacent to viable myocardial tissue. Segments with recovery had higher SMemb expression (0.46 ± 0.16% [n = 12] vs. 0.10 ± 0.02% [n = 12]; p < 0.05) and a higher ratio of alpha-smooth muscle actin to collagen (0.14 ± 0.026 [n = 12] vs. 0.07 ± 0.01 [n = 12]; p < 0.05) compared with segments without recovery, indicating fibroblast activation and higher cellularity of the fibrotic areas. In addition, interstitial deposition of the matricellular protein tenascin, a marker of active remodeling, was higher in hibernating segments than in segments with persistent dysfunction (p < 0.05), suggesting an active continuous fibrotic process. Multiple logistic regression demonstrated a significant independent association between SMemb expression and functional recovery (p < 0.01).: ConclusionsFibroblast activation and expression of SMemb and tenascin provide evidence of continuous remodeling in the cardiac interstitium of the hibernating myocardium, an important predictor of recovery of function after revascularization. [Copyright &y& Elsevier]