Behavioral and immunohistological effects of cholinergic damage in immunolesioned rats: alteration of c-Fos and polysialylated neural cell adhesion molecule expression

The aim of this study was to determine the brain structures as well as the plasticity events associated with the behavioral effects of cholinergic damage. Rats were submitted to injection of 192 IgG-saporin in the medial septum/diagonal band of Broca complex and the nucleus basalis magnocellularis. The immunohistochemical expression of c-Fos protein and PSA-NCAM (polysialylated neural cell adhesion molecule) and the behavioral performances in the nonmatching-to-position task were assessed at various post-lesion times. Thus, 3 days after injection of the immunotoxin, increased c-Fos labeling was observed in the areas of infusion, indicating these cells were undergoing some plastic changes and/or apoptotic processes. A drastic increase was observed in the number of PSA-NCAM positive cells and in their dendritic arborization in the dentate gyrus. At 7 days post-lesion, no behavioral deficit was observed in immunolesioned rats despite the drastic loss of cholinergic neurons. These neurons showed decreased c-Fos protein expression in the piriform and entorhinal cortex and in the dentate gyrus. In the latter, PSA-NCAM induction was high, suggesting that remodeling occurred, which in turn might contribute to sustaining some mnemonic function in immunolesioned rats. At 1 month, cholinergic neurons totally disappeared and behavioral deficits were drastic. c-Fos expression showed no change. In contrast, the increased PSA-NCAM-labeling observed at short post-lesion times was maintained but the plastic changes due to this molecule could not compensate the behavioral deficit caused by the immunotoxin. Thus, as the post-lesion time increases, a gradual degeneration process should occur that may contribute to mnemonic impairments. This neuronal loss leads to molecular and cellular alterations, which in turn may aggravate cognitive deficits.     

Sex Differences in the Cholinergic Basal Forebrain in the Ts65Dn Mouse Model of Down Syndrome and Alzheimer's Disease

In the Down syndrome (DS) population, there is an early incidence of dementia and neuropathology similar to that seen in sporadic Alzheimer's disease (AD), including dysfunction of the basal forebrain cholinergic neuron (BFCN) system. Using Ts65Dn mice, a model of DS and AD, we examined differences in the BFCN system between male and female segmentally trisomic (Ts65Dn) and disomic (2N) mice at ages 5–8 months. Quantitative stereology was applied to BFCN subfields immunolabeled for choline acetyltransferase (ChAT) within the medial septum/vertical limb of the diagonal band (MS/VDB), horizontal limb of the diagonal band (HDB) and nucleus basalis of Meynert/substantia innominata (NBM/SI). We found no sex differences in neuron number or subregion area measurement in the MS/VDB or HDB. However, 2N and Ts65Dn females showed an average 34% decrease in BFCN number and an average 20% smaller NBM/SI region area compared with genotype‐matched males. Further, relative to genotype‐matched males, female mice had smaller BFCNs in all subregions. These findings demonstrate that differences between the sexes in BFCNs of young adult Ts65Dn and 2N mice are region and genotype specific. In addition, changes in post‐processing tissue thickness suggest altered parenchymal characteristics between male and female Ts65Dn mice.     

Long-Term Potentiation and Evoked Spike Responses in the Cingulate Cortex of Freely Mobile Rats

Long-term potentiation of synaptic efficiency is regarded as a major candidate for the role of the physiological mechanism of long-term memory. However, the limited development of concepts of the cellular and subcellular characteristics of the induction of long-term potentiation in animals in conditions of free behavior does not correspond to the importance of this question. The present study was undertaken to determine whether the characteristics of potentiation in the cingulate cortex in response to stimulation of fibers of the subiculo-cingulate tract are truly long-term, i.e., develop through all known phases and last at least 24 h, in freely moving animals. In addition, the study aims included identification of the effects of application of blockers of different types of glutamate receptors on the development of long-term potentiation and identification of the characteristics of spike responses of single cingulate cortex neurons to stimulation of the subiculo-cingulate tract. Long-term potentiation, lasting more than 24 h, was obtained in freely moving adult rats not treated with GABA blockers. Injection of glutamate NMDA synapse blockers led to significant decreases in evoked cingulate cortex potentials in response to test stimulation. Activatory short-latency spike responses were characterized by a low probability of spike generation, and this increased with increases in the stimulation current. These data demonstrated that it is methodologically possible to compare, in freely moving rats, the involvement of individual neurons in the mechanisms involved in learning one or another type of adaptive behavior and the dynamics of their evoked spike activity during the formation of long-term potentiation.     

Age‐Dependent Effect of β‐Amyloid Toxicity on Basal Forebrain Cholinergic Neurons and Inflammation in the Rat Brain

Beta‐amyloid (Aβ) accumulation, neuroinflammation, basal forebrain cholinergic loss and hippocampal degeneration are well‐described pathologies associated with Alzheimer's disease (AD). However, the role that age plays in the susceptibility of the brain to these AD pathologies and the relationships between them is still not well understood. This study investigated the age‐related response to intracerebroventricular injection of Aβ_25–35 in 3‐, 6‐ and 9‐month‐old rats. Aβ toxicity resulted in an age‐related increase in cholinergic loss and microglial activation in the basal forebrain along with neuronal loss in the hippocampal CA3 subfield. Performance in the Morris water maze revealed impairments in long‐term reference memory in 6‐month‐old Aβ administered animals, which was not seen in 3‐month‐old animals. These results support a role of Aβ administration in inducing age‐dependent cholinergic loss and neuroinflammation, and additionally provide evidence for a more age‐appropriate model of adult‐onset Aβ toxicity demonstrating pathological changes that reflect the early stages of AD pathogenesis including neuroinflammation, cholinergic loss and beginning stages of memory impairment.     

基底前脑巢蛋白免疫阳性神经元研究现状及展望

目的阐述基底前脑nestin免疫阳性神经元的研究现状,为后续研究提供依据。方法对近年发表的有关基底前脑nestin免疫阳性神经元的文献进行分析和综述。结果在人和大鼠的基底前脑存在着一群能表达nestin的成熟神经元,这群神经元是区别于胆碱能神经元和γ-氨基丁酸能神经元的独立的神经元。其形态和分布与胆碱能神经元相似,向海马、大脑皮质及丘脑投射,与学习记忆及神经元的可塑性有关。结论基底前脑nestin免疫阳性神经元的化学属性、纤维联系及电生理特征等有待于进一步研究。这些研究将有助于我们了解成熟神经元表达nestin的功能意义,并为相关疾病的诊治提供新的视角。     

Individual differences in emotion regulation and hemispheric metabolic asymmetry

Recent studies of emotion regulation have reported that frequent use of reappraisal is associated with greater experience of positive emotions and increased sense of well-being, which, in turn, have been observed in individuals with greater left-sided prefrontal cortical activity. We hypothesized that frequent use of reappraisal would be correlated with greater left-sided biases of metabolic activity in prefrontal regions as well as in subcortical structures to which the former are interconnected. Twenty male volunteers were scanned at rest with ¹⁸F-fluorodeoxyglucose positron emission tomography. Self-reported emotion regulation style and an emotional regulation task were administered outside the scanner. Results revealed that frequent reappraisers showed greater left-sided biases of metabolic activity in the dorsolateral prefrontal and caudate regions. Regulation successes in increasing emotions were associated with left-sided metabolic asymmetry in the anterior cingulate. Findings suggest that asymmetric metabolism in prefrontal and subcortical regions are associated with emotion regulation style and also with regulation success.     

Coupling of theta activity and glucose metabolism in the human rostral anterior cingulate cortex: an EEG/PET study of normal and depressed subjects

In rodents, theta rhythm has been linked to the hippocampal formation, as well as other regions, including the anterior cingulate cortex (ACC). To test the role of the ACC in theta rhythm, concurrent measurements of brain electrical activity (EEG) and glucose metabolism (PET) were performed in 29 subjects at baseline. EEG data were analyzed with a source localization technique that enabled voxelwise correlations of EEG and PET data. For theta, but not other bands, the rostral ACC (Brodmann areas 24/32) was the largest cluster with positive correlations between current density and glucose metabolism. Positive correlations were also found in right fronto-temporal regions. In control but not depressed subjects, theta within ACC and prefrontal/orbitofrontal regions was positively correlated. The results reveal a link between theta and cerebral metabolism in the ACC as well as disruption of functional connectivity within frontocingulate pathways in depression.     

18F-THK5351 PET Positivity and Longitudinal Changes in Cognitive Function in β-Amyloid-Negative Amnestic Mild Cognitive Impairment

PurposeNeuroinflammation is considered an important pathway associated with several diseases that result in cognitive decline. ¹⁸F-THK5351 positron emission tomography (PET) signals might indicate the presence of neuroinflammation, as well as Alzheimer’s disease-type tau aggregates. β-amyloid (Aβ)-negative (Aβ–) amnestic mild cognitive impairment (aMCI) may be associated with non-Alzheimer’s disease pathophysiology. Accordingly, we investigated associations between ¹⁸F-THK5351 PET positivity and cognitive decline among Aβ– aMCI patients.Materials and MethodsThe present study included 25 amyloid PET negative aMCI patients who underwent a minimum of two follow-up neuropsychological evaluations, including clinical dementia rating-sum of boxes (CDR-SOB). The patients were classified into two groups: ¹⁸F-THK5351-positive and -negative groups. The present study used a linear mixed effects model to estimate the effects of ¹⁸F-THK5351 PET positivity on cognitive prognosis among Aβ– aMCI patients.ResultsAmong the 25 Aβ– aMCI patients, 10 (40.0%) were ¹⁸F-THK5351 positive. The patients in the ¹⁸F-THK5351-positive group were older than those in the ¹⁸F-THK5351-negative group (77.4±2.2 years vs. 70.0±5.5 years; p<0.001). There was no difference between the two groups with regard to the proportion of apolipoprotein E ε4 carriers. Interestingly, however, the CDR-SOB scores of the ¹⁸F-THK5351-positive group deteriorated at a faster rate than those of the ¹⁸F-THK5351-negative group (B=0.003, p=0.033).ConclusionThe results of the present study suggest that increased ¹⁸F-THK5351 uptake might be a useful predictor of poor prognosis among Aβ– aMCI patients, which might be associated with increased neuroinflammation (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02656498","term_id":"NCT02656498"}}NCT02656498).     

18F-FDG PET/CT显像对可疑甲状腺原发病变的评估价值

目的 对18F-FDG PET/CT检查发现可疑甲状腺高代谢结节的发病率和良恶性进行回顾性分析.方法 回顾2010年11月至2013年5月间行18F-FDG PET/CT检查,发现甲状腺结节的2569例患者中,甲状腺呈高代谢灶的患者1219例,有病理证实及随访结果的67例.根据病变病理及随访结果,结合代谢情况、影像表现,对此67例甲状腺良恶性病变发病率进行分析.结果 甲状腺弥漫性病变恶性率与局灶性高代谢病变恶性率的差异有统计学意义（P＜0.01）.单发高代谢结节中,恶性结节及良性结节SUVmax值分别为6.63±4.49和3.07±1.42,两者之间差异有统计学意义（=2.436,P=0.035）.多发结节单发高代谢灶病变中,恶性及良性病变SUVmax值分别为5.72±2.47和3.37±0.74,两者之间差异无统计学意义.多发高代谢结节的良恶性SUVmax值差异无统计学意义（t=1.870,P=0.151）.结论 甲状腺高代谢结节有较高的恶性率,SUVmax值对单发高代谢结节的良恶性鉴别有意义.     

Inter-tissue Networks Between the Basal Forebrain,Hippocampus, and Prefrontal Cortex in a Model for Depression Caused by Disturbed Sleep

Disturbances in sleep are encountered in the majority of patients with depressive disorder. To elucidate the molecular mechanisms behind this relationship, we examined gene expression changes in a rodent model for disturbed sleep and depression. The animals were treated with daily injections of clomipramine to affect their sleep during early infancy. This early interference with sleep is known to induce depression-like behavior in adult animals. After 2 weeks of treatment, the change in gene expression was examined using the Affymetrix Rat 230.2 chip. We studied the gene expression in the basal forebrain, hippocampus, and frontal cortex and combined the results to reveal the otherwise indissectible networks between and around the tissues. The major disrupted pathways between the three brain areas were related to synaptic transmission, regulation of translation, and ubiquitinylation. The involved pathways were within the cellular components of the axons, growth cones, melanosomes, and pigment granules. A network analysis allowing for additional interactors, in the form of chemicals or gene products, revealed a disturbed communicational network between the different brain areas. This disturbed network is centered around serotonin, Mn(II), and Rhoa. The findings elucidate inter-tissue pathways and networks in the brain that are involved in sleep and mood regulation. The findings are of uttermost interest, some are quite predictable and obvious, but some are novel or have only been proposed by rare theoretical speculations (such as the melanosome and Mn(II) involvement). Equally important as the findings are the methods described in this article. In this study, we present two novel simple ways to perform system biological analysis based on gene expression array data. We used two already existing tools in a new way, and by careful planning of the input data, managed to extrapolate intricate hidden inter-tissue networks to build a molecular picture of disease.     

A comparison of in vivo and in vitro neuroimaging of 5-HT 1A receptor binding sites in the cat brain

To validate the cat as a suitable model for positron emission tomography imaging (PET) and to gain further knowledge on the anatomical distribution of the serotonin-1A receptor (5-HT 1A) in the feline brain, we used PET with [18F]MPPF and in vitro autoradiography with [3H]MPPF, [3H]8-OH-DPAT and [3H]paroxetine. PET radioactivity curves with [18F]MPPF were very reproducible in anaesthetized cats, with the highest radioactivity uptakes recorded in the hippocampus, cingulate cortex, septum, infralimbic cortex and raphe nucleus, whereas the lowest were found in the cerebellum. [3H]8-OH-DPAT binding displayed a comparable, albeit lower, regional distribution than with [3H]MPPF. Autoradiography also revealed the presence of 5-HT 1A receptor binding sites in the cortex and in the interpeduncular nucleus, due to its greater sensitivity and spatial resolution compared with PET imaging. The cat constitutes an interesting experimental model for PET imaging, as many physiological concepts have been well established with this animal. Our study also shows the advantages of combining complementary neuroimaging techniques such as in vivo PET imaging and in vitro autoradiography to visualize the distribution of the 5-HT 1A receptors.     

Evaluation of spatial resolution of a PET scanner through the simulation and experimental measurement of the recovery coefficient

Purpose: In order to measure spatial resolution of a PET tomograph in clinical conditions, this study describes and validates a method based on the recovery coefficient, a factor required to compensate underestimation in measured radioactivity concentration for small structures.Methods: In a PET image, the recovery factors of radioactive spheres were measured and their comparison with simulated recovery coefficients yielded the tomographic spatial resolution. Following this methodology, resolution was determined in different surrounding media and several conditions for reconstruction, including clinical conditions for brain PET studies. All spatial resolution values were compared with those obtained using classical methods with point and line sources.Results: In each considered condition, spatial resolution of the PET image estimated using the recovery coefficient showed good agreement with classical methods measurements, validating the procedure.Conclusion: Measurement of the recovery coefficient provides an assessment of tomographic spatial resolution, particularly in clinical studies conditions.     

Activation of Anterior Cingulate Cortex Extracellular Signal-Regulated Kinase-1 and -2 (ERK1/2) Regulates Acetic Acid-Induced, Pain-Related Anxiety in Adult Female Mice

In visceral pain, anxiety and pain occur simultaneously, but the etiogenesis of this effect is not yet well-described. The anterior cingulate cortex (ACC) is known to be associated with the affective response to noxious stimuli. The aim of the current study is to define the role of ACC extracellular signal-regulated (ERK)-1 and-2 (ERK1/2) activity in the development of pain-related anxiety/depression and the nocifensive response in acetic acid (AA)-elicited visceral pain. The model of visceral pain was created by intraperitoneal (ip) injection of AA to female Kunming mice. We found that AA injection resulted in a dynamic, bilateral ERK1/2 activation pattern in the ACC. Inhibition of ERK1/2 activation 2 hr after AA injection by subcutaneous (sc) injection of the mitogen-activating extracellular kinase (MEK) inhibitor, SL327, had no effect on the nocifensive responses, but did attenuate anxiety-like behavior, as determined by elevated plus-maze and open-field testing results. These data suggest that AA-induced visceral pain activates expression of ACC ERK1/2, which regulates visceral pain-related anxiety, but not the nocifensive response.     

In vivo benzodiazepine receptor occupancy by CL 218,872 visualized by positron emission tomography in the brain of the living baboon: modulation by GABAergic transmission and relation with anticonvulsant activity

Summary In vivo benzodiazepine receptor occupancy by increasing doses of CL 218,872 has been evaluated in the baboon Papio papio, using (¹¹C) RO 15-1788 as specific radioligand and positron emission tomography as external detection system. Although BZR heterogeneity has been previously demonstrated in the brain of the living baboon using PET, we did not observe in our studies that CL 218,872 interacts preferentially with one of the BZR subtypes. The monophasic pattern of the dose dependent CL 218,872 displacement curve and the corresponding in vivo Hill coefficient near unity suggest that CL 218,872 binds in cerebral baboon cortex with a similar affinity with BZ1 as well as BZ2 subtypes. The anticon-vulsant properties of CL 218,872 against bicuculline and allylglycine-induced seizures were correlated with benzodiazepine receptor occupancy by assessment of electroencephalographic activity during positron emission tomography studies. Our data confirmed in vivo the hypothesis of a partial agonist anticonvulsant activity of CL 218,872. At the same time, the use of a GABAantagonist (bicuculline) or an inhibitor of the GABA synthesis (allylglycine) suggested the existence of an allosteric interaction between benzodiazepine receptors and GABA receptors.     

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of macrophages in large vessel vasculitis: Current status and future prospects

Macrophages are key players in the pathogenesis of large-vessel vasculitis (LVV) and may serve as a target for diagnostic imaging of LVV. The radiotracer, ¹⁸F-FDG has proven to be useful in the diagnosis of giant cell arteritis (GCA), a form of LVV. Although uptake of ¹⁸F-FDG is high in activated macrophages, it is not a specific radiotracer as its uptake is high in any proliferating cell and other activated immune cells resulting in high non-specific background radioactivity especially in aging and atherosclerotic vessels which dramatically lowers the diagnostic accuracy. Evidence also exists that the sensitivity of ¹⁸F-FDG PET drops in patients upon glucocorticoid treatment. Therefore, there is a clinical need for more specific radiotracers in imaging GCA to improve diagnostic accuracy. Numerous clinically established and newly developed macrophage targeted radiotracers for oncological and inflammatory diseases can potentially be utilized for LVV imaging. These tracers are more target specific and therefore may provide lower background radioactivity, higher diagnostic accuracy and the ability to assess treatment effectiveness. However, current knowledge regarding macrophage subsets in LVV lesions is limited. Further understanding regarding macrophage subsets in vasculitis lesion is needed for better selection of tracers and new targets for tracer development. This review summarizes the development of macrophage targeted tracers in the last decade and the potential application of macrophage targeted tracers currently used in other inflammatory diseases in imaging LVV.     

The sensory guidance of movement: a comparison of the cerebellum and basal ganglia

We used positron emission tomography (PET) to compare the contribution of the cerebellum and basal ganglia to the sensory guidance of movement. In one condition the subjects used a computer mouse to draw a series of lines on a computer screen (DRAW). In the second condition the same lines were presented to the subjects, and they had to track the lines with a mouse pointer on the screen (COPY). In a third condition the subjects were again presented with the same lines, and they simply followed movements of the pointer with their eyes (EYES). In the fourth condition, the subjects fixated a central point, ignoring the sequence of presented lines (FIX). The pons and cerebellum were activated more during visually guided tracking than in freely generated drawing (COPY vs DRAW). The basal ganglia were activated equally in both DRAW and COPY. The prefrontal and inferior temporal cortex were activated more when subjects drew lines freely (DRAW) than when they copied them (COPY). We conclude that the cerebellum is specialized for using sensory information to correct movements, but that the basal ganglia are involved both in movements that are self-generated and in movements that are guided by external cues.     

Effect of destruction of gyrus cinguli in rat brain on the development of tolerance to the analgesic effect of morphine and physical dependence on morphine

We studied the effect of bilateral laser destruction of rat anterior cingulate gyrus on the analgesic effect of morphine and development of tolerance and physical dependence on morphine. Bilateral laser destruction of the anterior cingulate gyrus did not modulate pain sensitivity, analgesic effect of morphine, and development of morphine tolerance. Destruction of the cingulate gyrus alleviated symptoms of the abstinence syndrome in morphine-dependent animals. We showed that morphine-induced analgesia and morphine tolerance are not associated with activity of the anterior cingulate gyrus. However, this structure plays a key role in the development of physical dependence on morphine and abstinence syndrome.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 11, pp. 540–543, November, 2004     

Advances in the development of tau PET radiotracers and their clinical applications

Alzheimer’s disease and other neurodegenerative dementias belong to the family of tauopathies. These diseases are characterized by the deposition of insoluble tau aggregates possessing an enriched β-sheet structure. In vivo imaging of the tau deposits by positron emission tomography (PET) will facilitate the early and accurate diagnosis of these diseases, tracking of disease progression, assessment of disease severity, and prediction of disease prognosis. Furthermore, this technology is expected to play a vital role in the monitoring of treatment outcomes and in the selection of patients for the therapeutic trials of anti-dementia drugs. Recently, several tau PET tracers have been successfully developed and demonstrated as having high binding affinity and selectivity to tau protein deposits. Recent clinical studies using these tracers have demonstrated significant tracer retention in sites susceptible to tau deposition in Alzheimer’s disease, as well as correlations with the disease severity and cognitive impairment in cases with dementia. These tracers, thus, have the potential to effectively diagnose the tauopathies. Further longitudinal assessment will clarify the effect of the tau deposition on the neurodegenerative process and cognitive decline and the interaction of tau with amyloid-β in the human brain.     

Changes in cerebral blood flow under the prone condition with and without massage

To investigate changes in regional cerebral blood flow (rCBF) under the prone condition with and without light massage on the back, we measured rCBF quantitatively in healthy human subjects using positron emission tomography with H₂¹⁵O. Biochemical tests showed that the light massage (palm-pressure) reduced levels of stress-related serum cortisol and salivary stress protein chromogranin-A measured after the PET examination. Absolute rCBF significantly increased in the parietal cortex (precuneus) under the prone condition compared with the supine condition, and this rCBF increase was in parallel with comfortable sensation and slowing heart rate during the massage. Correlation analysis in statistical parametric mapping showed that the amygdalar and basal forebrain rCBF correlated with parasympathetic function (heart rate reduction), indicating involvement of the forebrain-amygdala system in mediating activities in the autonomic nervous system in the presence of comfortable sensation. To conclude, prone posture itself can stimulate the precuneus region to raise awareness, and the light massage on the back may help accommodate the brain to comfortable stimulation.     

Positron Emission Tomography in the Study of Aging and Senile Dementia

¹⁸F-2-deoxy-2-fluoro-D-glucose (¹⁸FDG) is a positron emitting tracer for rate of glucose utilization in brain. When used in conjunction with positron emission tomography (PET), the PET-FDG technique permits in vivo quantitation of regional brain metabolism in man. We have applied this technique to the study of regional brain function in normal aging and senile dementia. Preliminary results for 7 patients with senile dementia of the Alzheimer's type (SDAT) and 3 elderly normal subjects indicated a large, statistically significant (p < 0.01) diminution in rate of glucose utilization in SDAT. Furthermore, the degree of diminution in metabolic activity in SDAT was highly correlated with objective measures of degree of cognitive impairment. These results demonstrate the feasibility and potential utility of the PET-FDG technique for studying regional brain function in normal aging and dementia.