Emerging role of vascular burden in AT(N) classification in individuals with Alzheimer's and concomitant cerebrovascular burdens.

OBJECTIVES: Alzheimer's disease (AD) is characterised by amyloid-beta accumulation (A), tau aggregation (T) and neurodegeneration (N). Vascular (V) burden has been found concomitantly with AD pathology and has synergistic effects on cognitive decline with AD biomarkers. We determined whether cognitive trajectories of AT(N) categories differed according to vascular (V) burden. METHODS: We prospectively recruited 205 participants and classified them into groups based on the AT(N) system using neuroimaging markers. Abnormal V markers were identified based on the presence of severe white matter hyperintensities. RESULTS: In A+ category, compared with the frequency of Alzheimer's pathological change category (A+T-), the frequency of AD category (A+T+) was significantly lower in V+ group (31.8%) than in V- group (64.4%) (p=0.004). Each AT(N) biomarker was predictive of cognitive decline in the V+ group as well as in the V- group (p<0.001). Additionally, the V+ group showed more severe cognitive trajectories than the V- group in the non-Alzheimer's pathological changes (A-T+, A-N+; p=0.002) and Alzheimer's pathological changes (p<0.001) categories. CONCLUSION: The distribution and longitudinal outcomes of AT(N) system differed according to vascular burdens, suggesting the importance of incorporating a V biomarker into the AT(N) system.

Developmental complex trauma induces the dysfunction of the amygdala-mPFC circuit in the serotonergic and dopaminergic systems.

Developmental complex trauma is strongly associated with various psychiatric disorders in adulthood. Multiple lines of evidence have demonstrated that the amygdala-mPFC circuit regulates emotion and plays an important role in stress reactions. However, most studies on developmental trauma have mainly focused on neurological aspects in biological, behavioral, and structural changes with regard to a single stressor. In the present study, after applying complex stressors to the developmental phase, we would like to elucidate the functional changes in amygdala-mPFC circuit in the dopaminergic and serotonergic systems in the adult brain. Here, maternal separation and restraint stress were used to generate the trauma. The results showed that the body weights and corticosterone levels of animals exposed to developmental trauma decreased when compared to controls. In the neuroendocrine aspect, trauma leads to changes in proinflammatory cytokines, resulting in a decrease in IL-ß and an increase in TNF-α. In the neuroPET studies, the developmental trauma group displayed a reduction in serotonergic and dopaminergic PET uptake in the amygdala and mPFC. Collectively, our results indicate that developmental trauma weakens the serotonergic and dopaminergic systems in the amygdala-mPFC circuit.

Evaluation of the Effects of Developmental Trauma on Neurotransmitter Systems Using Functional Molecular Imaging.

Early life stress (ELS) is strongly associated with psychiatric disorders such as anxiety, depression, and schizophrenia in adulthood. To date, biological, behavioral, and structural aspects of ELS have been studied extensively, but their functional effects remain unclear. Here, we examined NeuroPET studies of dopaminergic, glutamatergic, and serotonergic systems in ELS animal models. Maternal separation and restraint stress were used to generate single or complex developmental trauma. Body weights of animals exposed to single trauma were similar to those of control animals; however, animals exposed to complex trauma exhibited loss of body weight when compared to controls. In behavioral tests, the complex developmental trauma group exhibited a decrease in time spent in the open arm of the elevated plus-maze and an increase in immobility time in the forced swim test when compared to control animals. In NeuroPET studies, the complex trauma group displayed a reduction in brain uptake values when compared to single trauma and control groups. Of neurotransmitter systems analyzed, the rate of decrease in brain uptake was the highest in the serotonergic group. Collectively, our results indicate that developmental trauma events induce behavioral deficits, including anxiety- and depressive-like phenotypes and dysfunction in neurotransmitter systems.

Inhibition of Colony-Stimulating Factor 1 Receptor by PLX3397 Prevents Amyloid Beta Pathology and Rescues Dopaminergic Signaling in Aging 5xFAD Mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. In this study, to investigate the effect of microglial elimination on AD progression, we administered PLX3397, a selective colony-stimulating factor 1 receptor inhibitor, to the mouse model of AD (5xFAD mice). Amyloid-beta (Aß) deposition and amyloid precursor protein (APP), carboxyl-terminal fragment ß, ionized calcium-binding adaptor molecule 1, synaptophysin, and postsynaptic density (PSD)-95 levels were evaluated in the cortex and hippocampus. In addition, the receptor density changes in dopamine D2 receptor (D2R) and metabotropic glutamate receptor 5 were evaluated using positron emission tomography (PET). D2R, tyrosine hydroxylase (TH), and dopamine transporter (DAT) levels were analyzed in the brains of Tg (5xFAD) mice using immunohistochemistry. PLX3397 administration significantly decreased Aß deposition following microglial depletion in the cortex and hippocampus of Tg mice. In the neuro-PET studies, the binding values for D2R in the Tg mice were lower than those in the wild type mice; however, after PLX3397 treatment, the binding dramatically increased. PLX3397 administration also reversed the changes in synaptophysin and PSD-95 expression in the brain. Furthermore, the D2R and TH expression in the brains of Tg mice was significantly lower than that in the wild type; however, after PLX3397 administration, the D2R and TH levels were significantly higher than those in untreated Tg mice. Thus, our findings show that administering PLX3397 to aged 5xFAD mice could prevent amyloid pathology, concomitant with the rescue of dopaminergic signaling, suggesting that targeting microglia may serve as a useful therapeutic option for neurodegenerative diseases, including AD.

Effects of P-gp and Bcrp as brain efflux transporters on the uptake of [18 F]FPEB in the murine brain.

The purpose of this study was to determine whether the brain uptake of [18 F]FPEB is influenced by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) as efflux transporters in rodents. To assess this possible modulation, positron emission tomography studies were performed in animal models of pharmacological or genetic ablation of these transporters. Compared with the control conditions, when P-gp was blocked with tariquidar, there was an 8%-12% increase in the brain uptake of [18 F]FPEB. In P-gp knockout mice, such as Mdr1a/b(-/-) and Mdr1a/b(-/-) Bcrp1(-/-) , genetic ablation models, there was an increment of 8%-53% in [18 F]FPEB uptake compared with that in the wild-type mice. In contrast, Bcrp knockout mice showed a decrement of 5%-12% uptake and P-gp/Bcrp knockout group displayed an increment of 5%-17% compared with wild type. These results indicate that [18 F]FPEB is possibly a weak substrate for P-gp.

Hypothalamic neuronal activation in non-human primates drives naturalistic goal-directed eating behavior.

Maladaptive feeding behavior is the primary cause of modern obesity. While the causal influence of the lateral hypothalamic area (LHA) on eating behavior has been established in rodents, there is currently no primate-based evidence available on naturalistic eating behaviors. We investigated the role of LHA GABAergic (LHAGABA) neurons in eating using chemogenetics in three macaques. LHAGABA neuron activation significantly increased naturalistic goal-directed behaviors and food motivation, predominantly for palatable food. Positron emission tomography and magnetic resonance spectroscopy validated chemogenetic activation. Resting-state functional magnetic resonance imaging revealed that the functional connectivity (FC) between the LHA and frontal areas was increased, while the FC between the frontal cortices was decreased after LHAGABA neuron activation. Thus, our study elucidates the role of LHAGABA neurons in eating and obesity therapeutics for primates and humans.

Effect of developmental stress on the in vivo neuronal circuits related to excitation-inhibition balance and mood in adulthood.

Introduction: Traumatic events in early life have a deleterious effect on the development of normal brain developments, which may be a cause of various psychiatric disorders in adulthood. Most prior studies focused on molecular biological aspects, and research on functional changes in neural circuits is still limited. We aimed to elucidate the effect of early life stress on in vivo excitation-inhibition and serotonergic neurotransmission in the adulthood using non-invasive functional molecular imaging (positron emission tomography, PET). Methods: To compare the effect of stress intensity, early life stress animal models were divided into single trauma (MS) and double trauma groups (MRS). MS was derived from maternal separation, whereas MRS was derived from maternal separation and restraint stress after birth. And to evaluate the stress vulnerability on the sex, we used male and female rats. Results: The MRS group showed greater weight loss and more severe depressive/anxiety-like behaviors than the MS and control groups. Corticosterone levels in MRS showed a greater extent of decline than in the MS group; however, there was no significant difference in the change of T3 and T4 between MS and MRS. In the PET, the stress exposure groups showed lower brain uptake for GABAergic, glutamatergic, and serotonergic systems compared with the control group. The excitatory/inhibitory balance, which was derived by dividing glutamate brain uptake into GABAergic uptake, increased as stress intensity increased. Neuronal degeneration in the stress exposure groups was confirmed by immunohistochemistry. In the sex comparison, female showed the greater changes of body weight, corticosterone level, depressive/anxiety-like behavior, and neurotransmission systems than those in male. Conclusion: Taken together, we demonstrated that developmental stress induces dysfunction of neurotransmission in vivo, and that females are more vulnerable to stress than males.

Effects of Escitalopram on the Functional Neural Circuits in an Animal Model of Adolescent Depression.

PURPOSE: Although escitalopram is known to be an effective drug for adult depression, its disease-modifying efficacy on adolescents remains controversial. The present study aimed to evaluate the therapeutic effect of escitalopram on behavioral aspects as well as functional neural circuits by means of positron emission tomography. PROCEDURES: To generate the animal models of depression, restraint stress was used during the peri-adolescent period (RS group). Thereafter, escitalopram was administered after the end of stress exposure (Tx group). We performed NeuroPET studies of glutamate, glutamate, GABA, and serotonin systems. RESULTS: The Tx group showed no body weight change compared to the RS group. In the behavioral tests, the Tx group also displayed the similar time spent in open arms and immobility time to those for RS. In the PET studies, brain uptake values for the Tx group revealed no significant differences in terms of glucose, GABAA, and 5-HT1A receptor densities, but lower mGluR5 PET uptake compared to the RS group. In the immunohistochemistry, the Tx group showed the significant loss of neuronal cells in the hippocampus compared to the RS group. CONCLUSION: The administration of escitalopram had no therapeutic effect on the adolescent depression.

Corrigendum: Amyloid pathology induces dysfunction of systemic neurotransmission in aged APPswe/PS2 mice.

[This corrects the article DOI: 10.3389/fnins.2022.930613.].

Amyloid pathology induces dysfunction of systemic neurotransmission in aged APPswe/PS2 mice.

This study aimed to investigate how amyloid pathology affects the functional aspects of neurotransmitter systems in Alzheimer's disease. APPswe/PS2 mice (21 months of age) and wild-type (WT) mice underwent positron emission tomography (PET) and magnetic resonance spectroscopy (MRS). First, we obtained 18F-FDG and 18F-florbetaben PET scans to evaluate neuronal integrity and amyloid pathology. Second, 18F-FPEB and 18F-FMZ PET data were acquired to assess the excitatory-inhibitory neurotransmission. Third, to monitor the dopamine system, 18F-fallypride PET was performed. Amyloid PET imaging revealed that radioactivity was higher in the AD group than that in the WT group, which was validated by immunohistochemistry. In the cortical and limbic areas, the AD group showed a 25-27% decrease and 14-35% increase in the glutamatergic and GABAergic systems, respectively. The dopaminergic system in the AD group exhibited a 29% decrease in brain uptake compared with that in the WT group. A reduction in glutamate, N-acetylaspartate, and taurine levels was observed in the AD group using MRS. Our results suggest that dysfunction of the neurotransmitter system is associated with AD pathology. Among the systems, the GABAergic system was prominent, implying that the inhibitory neurotransmission system may be the most vulnerable to AD pathology.

Validation of Image Qualities of a Novel Four-Mice Bed PET System as an Oncological and Neurological Analysis Tool.

Background: Micro-positron emission tomography (micro-PET), a small-animal dedicated PET system, is used in biomedical studies and has the quantitative imaging capabilities of radiotracers. A single-bed system, commonly used in micro-PET, is laborious to use in large-scale studies. Here, we evaluated the image qualities of a multi-bed system. Methods: Phantom imaging studies were performed to assess the recovery coefficients (RCs), uniformity, and spill-over ratios (SORs) in water- and air-filled chambers. 18F-FDG and 18F-FPEB PET images of xenograft and normal mice from the multi-bed and single-bed systems were compared. Results: For small diameters (< 3 mm), the RC values between the two systems differed significantly. However, for large diameters (> 4 mm), there were no differences in RC values between the two systems. Uniformity and SORs of both systems were within the tolerance limit of 15%. In the oncological study, the estimation of 18F-FDG uptake in the tumor was significantly lower in the multi-bed system than that in the single-bed system. However, 18F-FDG PET in xenograft mice with tumor size > 4 mm revealed the variation between subjects within the multi-bed system group to be less than 12%. In the neurological study, SUV for the multi-bed group was 25-26% lower than that for the single-bed group; however, inter-object variations within the multi-bed system were below 7%. Conclusions: Although the multi-bed system showed lower estimation of radiotracer uptake than that of the single-bed system, the inter-subject variations were within acceptable limits. Our results indicate that the multi-bed system can be used in oncological and neurological studies.

Evaluation of the neuroprotective effect of taurine in Alzheimer's disease using functional molecular imaging.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the leading cause of dementia, but therapeutic treatment options are limited. Taurine has been reported to have neuroprotective properties against dementia, including AD. The present study aimed to investigate the treatment effect of taurine in AD mice by functional molecular imaging. To elucidate glutamate alterations by taurine, taurine was administered to 5xFAD transgenic mice from 2 months of age, known to apear amyloid deposition. Then, we performed glutamate positron emission tomography (PET) imaging studies for three groups (wild-type, AD, and taurine-treated AD, n = 5 in each group). As a result, brain uptake in the taurine-treated AD group was 31-40% higher than that in the AD group (cortex: 40%, p < 0.05; striatum: 32%, p < 0.01; hippocampus: 36%, p < 0.01; thalamus: 31%, p > 0.05) and 3-14% lower than that in the WT group (cortex: 10%, p > 0.05; striatum: 15%, p > 0.05; hippocampus: 14%, p > 0.05; thalamus: 3%, p > 0.05). However, we did not observe differences in Aß pathology between the taurine-treated AD and AD groups in immunohistochemistry experiments. Our results reveal that although taurine treatment did not completely recover the glutamate system, it significantly increased metabolic glutamate receptor type 5 brain uptake. Therefore, taurine has therapeutic potential against AD.

Evaluation of the Neuroprotective Effect of Microglial Depletion by CSF-1R Inhibition in a Parkinson's Animal Model.

PURPOSE: Neuroinflammation in Parkinson's disease (PD) is known to play a pivotal role in progression to neuronal degeneration. It has been reported that colony-stimulation factor 1 receptor (CSF-1R) inhibition can effectively deplete microglia. However, its therapeutic efficacy in PD is unclear still now. PROCEDURES: To elucidate this issue, we examined the contribution of microglial depletion to PD by behavioral testing, positron emission tomography (PET) imaging, and immunoassays in sham, PD, and microglial depletion PD model (PLX3397 was administered to PD groups, with n = 6 in each group). RESULTS: The microglial depletion in PD model showed improved sensory motor function and depressive-like behavior. NeuroPET revealed that PLX3397 treatment resulted in partial recovery of striatal neuro-inflammatory functions (binding values of [18F]DPA-174 for PD, 1.47 ± 0.12, p < 0.01 vs. for PLX3397 in PD: 1.33 ± 0.26) and the dopaminergic (binding values of 18F-FP-CIT for PD, 1.32 ± 0.07 vs. for PLX3397 in PD: 1.54 ± 0.10, p < 0.01) and glutamatergic systems (binding values of [18F]FPEB for PD: 9.22 ± 0.54 vs. for PLX3397 Tx in PD: 9.83 ± 0.96, p > 0.05). Western blotting for microglia showed similar changes. CONCLUSION: Microglial depletion has inflammation-related therapeutic effects, which have beneficial effects on motor and nonmotor symptoms of PD.

Age dependency of mGluR5 availability in 5xFAD mice measured by PET.

The major pathologies of Alzheimer's disease (AD) are amyloid plaques and hyperphosphorylated tau. The deposition of amyloid plaques leads to synaptic dysfunction, neuronal cell death, and cognitive impairment. Among the neurotransmitters, glutamate is the most abundant in the mammalian brain and plays an important role in synaptic plasticity. With respect to synaptic transmission, metabotropic glutamate receptor 5 (mGluR5) is highly affected by amyloid pathology. However, the neuropathologic changes in the protein expression of mGluR5 in AD remain unclear. Therefore, to elucidate the alteration in mGluR5 expression with the progression of AD, we performed serial behavioral tests, longitudinal imaging studies, and histopathological immunoassay for both 5xFAD (n = 14) mice and age-matched wild-type mice (n = 14). The 5xFAD mice started showing severe hyperactivity and memory impairment from 7 months of age. In addition, mGluR5 positron emission tomography revealed that while the binding values in the wild-type mice were similar over time, those in 5xFAD mice fluctuated from 5 months of age. Furthermore, the 5xFAD mice presented a 35% decrease in the binding values of their cortical and subcortical areas at 9 months of age compared with those at 3 months of age. Magnetic resonance spectroscopy and histopathological studies showed similar changes. In conclusion, mGluR5 availability changes with age, and mGluR5 positron emission tomography could successfully detect this synaptic change in the 5xFAD mice.