Mirjam Brackhan

Introduction: Metformin is one of the most widely used drugs to control diabetes type 2. However, there is no indication of pausing metformin treatment before an ¹⁸ F-FDG PET scan. The aim of this study is to evaluate if metformin, in both patients and mice, can alter brain ¹⁸ F-FDG uptake. Methods: In vivo ¹⁸ F-FDG PET scans were carried out in male mice. Animals were treated with saline or metformin (300 mg/kg) 10 min before ¹⁸ F-FDG or chronically (3 weeks) in drinking water. Separately, patients with non-pathological ¹⁸ F-FDG brain scans were distributed into two groups: metformin-treated ( n = 12) and control patients ( n = 27). PET images were structurally normalized to brain templates, corrected to whole-brain activity, and compared using SPM12. Results: In mice, acute treatment induced a significant hypermetabolism in several brain regions including hippocampus (1.07 ± 0.07 vs 0.94 ± 0.08; p = 0.0002) and thalamus (1.17 ± 0.08 vs 1.00 ± 0.08; p = 0.0002). Chronic treatment increased tracer uptake only in cortical regions. Similarly, treated patients showed hypermetabolism in the temporal lobe (1.03 ± 0.04 vs 0.97 ± 0.04; p < 0.0001) and white matter and lower uptake in frontal cortical regions (1.24 ± 0.04 vs 1.28 ± 0.06; p = 0.0165). Linear regression to HbA1c showed a negative correlation to ¹⁸ F-FDG uptake in frontal and parietal cortical subregions, but no correlation to temporal lobe uptake. Discussion: Our results show that metformin treatment might modify ¹⁸ F-FDG uptake in temporal lobe structures. On the other hand, lower uptake in frontal cortex might be attributable to the diabetic condition. Thus, new studies modifying the treatment regimen in diabetic patients prior to performing an ¹⁸ F-FDG PET are warranted.

¹⁸ F-fluorodeoxyglucose positron emission tomography ( ¹⁸ F-FDG-PET) may be a useful tool as a biomarker of neurodegeneration. However, commercial brain templates may differ substantially from the PET images generated in new scanners in terms of resolution. We aimed to build an ¹⁸ F-FDG-PET image template using images acquired in a brain-dedicated PET to enable normalization optimization. A total of 167 patients underwent an ¹⁸ F-FDG-PET study on a brain-dedicated PET system. The images were automatically co-registered in Pmod 4.1, followed by iterative deformable registration in ANTs (Advanced Normalization Tools) to build the template. We obtained an ¹⁸ F-FDG-PET brain template with 1-mm ³ voxels and a 268 x 268 x 152 matrix to use as a reference for PET image normalization. In addition, we generated a map with 66 regions of interest (ROIs) manually adapted from the Automated Anatomical Labeling (AAL) ROI map for quantification of the normalized images and a mask to exclude extra-parenchymal regions. The development of a brain template with images acquired on the dedicated brain PET is of great utility for application in new scanners with improved resolution.

The lithium–pilocarpine rat model of status epilepticus (SE) is a well-established paradigm for studying epileptogenesis. Astrocyte reactivity has been implicated in modulating seizure susceptibility and neuroinflammation, yet its functional role in early epileptogenesis remains unclear. Herein, we evaluated the effects of Mdivi-1, a pharmacological inhibitor of mitochondrial fission protein Drp1, for its ability to modulate astrocytic mitochondrial dynamics and for its reported preventive neuroprotective properties. Mdivi-1 was administered shortly after SE onset, and we assessed brain glucose metabolism using [¹⁸F]FDG PET, alongside histological markers of neurodegeneration, astrocyte reactivity, and microglial activation, at 3 days post-SE. As expected, SE induced widespread brain hypometabolism measured by a VOI analysis, hippocampal neurodegeneration, and glial activation. Post-SE Mdivi-1 administration reduced hippocampal astrogliosis but neither conferred neuroprotection nor rescued glucose metabolism. On the contrary, Mdivi-1 exacerbated limbic–cortical hypometabolism when evaluated by SPM and normalized to whole brain tracer uptake and microglia-mediated neuroinflammation. These findings challenge the assumption that early astrocyte inhibition confers neuroprotection. Furthermore, early suppression of astrocyte reactivity after the damage has occurred may shift the neuroinflammatory response toward maladaptive microglial activation. Thus, while Mdivi-1 holds promise as a preventive neuroprotective agent, its use post-SE may have unintended adverse effects on the brain’s response to SE.

The lithium-pilocarpine rat model of status epilepticus (SE) is a well-established paradigm for studying epileptogenesis. Astrocyte reactivity has been implicated in modulating seizure susceptibility and neuroinflammation, yet its functional role in early epileptogenesis remains unclear. Herein, we evaluated the effects of Mdivi-1, a pharmacological inhibitor of mitochondrial fission protein Drp1, for its ability to modulate astrocytic mitochondrial dynamics and for its reported preventive neuroprotective properties. Mdivi-1 was administered shortly after SE onset and we assessed brain glucose metabolism using [¹⁸F]FDG PET, alongside histological markers of neurodegeneration, astrocyte reactivity, and microglial activation, 3 days post-SE. As expected, SE induced widespread brain hypometabolism measured by VOIs analysis, hippocampal neurodegeneration, and glial activation. Post-SE Mdivi-1 administration reduced hippocampal astrocyte reactivity but neither conferred neuroprotection nor rescued glucose metabolism. On the contrary, Mdivi-1 exacerbated cortical hypometabolism when evaluated by SPM normalized by whole brain tracer uptake and exacerbated microglial-mediated neuroinflammation. These findings challenge the assumption that early astrocyte inhibition confers neuroprotection. Furthermore, early suppression of astrocyte reactivity after the damage has occurred may shift the neuroinflammatory response toward a maladaptive microglial activation. Thus, while Mdivi-1 holds promise as a preventive neuroprotective agent, its use post-SE may have unintended adverse effects on early epileptogenic processes.

Epilepsy is a neurological disorder that affects a significant portion of the global population. However, its complexity and the lack of biomarkers hinder the study of its etiology, resulting in a lack of effective treatments to slow down or halt disease development, also called epileptogenesis. Animal models have proven to be a crucial tool for studying epileptogenesis, many exhibiting cellular, molecular, and functional alterations that resemble those found in human patients. This review examines preclinical studies that have utilized positron emission tomography, a non-invasive neuroimaging technique that has demonstrated correlation with the pathological features and behavioral comorbidities of the disease and a high predictive value for the severity of epileptogenesis. Positron emission tomography imaging has fostered the knowledge of the mechanisms driving epileptogenesis. This translational technique might be crucial for identifying biomarkers of epilepsy, identifying novel treatment targets and selecting and monitoring patients for potential future therapies.

4-aminopyridine (4-AP) is a non-selective blocker of voltage-dependent K⁺ channels used to improve walking in multiple sclerosis patients, and it may be useful in the treatment of cerebellar diseases. In animal models, 4-AP is used as a convulsant agent. When administered intrahippocampally, 4-AP induces acute local glucose hypermetabolism and significant brain damage, while i.p. administration causes less neuronal damage. This study aimed to investigate the effects of a single i.p. administration of 4-AP on acute brain glucose metabolism as well as on neuronal viability and signs of neuroinflammation 3 days after the insult. Brain glucose metabolism was evaluated by [¹⁸F]FDG PET neuroimaging. [¹⁸F]FDG uptake was analyzed based on volumes of interest (VOIs) as well as by voxel-based (SPM) analyses. The results showed that independently of the type of data analysis used (VOIs or SPM), 4-AP induced acute generalized brain glucose hypometabolism, except in the cerebellum. Furthermore, the SPM analysis normalized by the whole brain uptake revealed a significant cerebellar hypermetabolism. The neurohistochemical assays showed that 4-AP induced hippocampal astrocyte reactivity 3 days after the insult, without inducing changes in neuronal integrity or microglia-mediated neuroinflammation. Thus, acute brain glucose metabolic and neuroinflammatory profiles in response to i.p. 4-AP clearly differed from that reported for intrahippocampal administration. Finally, the results suggest that the cerebellum might be more resilient to the 4-AP-induced hypometabolism.

4-aminopyridine (4-AP) is a non-selective blocker of voltage-dependent K+ channels used to im-prove walking in multiple sclerosis patients, and it may be useful in the treatment of cerebellar diseases. In animal models, 4-AP is used as a convulsant agent. Intrahippocampal 4-AP induces acute local glucose hypermetabolism and significant brain damage, while i.p. administration causes less neuronal damage. This study aimed to investigate the effects of a single i.p. admin-istration of 4-AP on acute brain glucose metabolism and to assess the short-term effects on neu-ronal viability and signs of neuroinflammation. We evaluated 4-AP-induced acute changes in brain glucose metabolism by [18F]FDG PET neuroimaging evaluated by standard volumes of interest (VOIs) and voxel-based (SPM) analyses. We show that 4-AP induces acute generalized brain glucose hypometabolism, except in the cerebellum, area that was significantly more resilient to this effect. Accordingly, to the appropriate neurohistochemical assays, 4-AP induced hippocampal astrocyte reactivity 3 days after the insult, without changes in signs of neuronal integrity or micro-glia-mediated neuroinflammation. Thus, acute brain glucose metabolic and short-term neuroin-flammatory profiles in response to 4-AP i.p. clearly differ from that reported for intracerebral administration. Our results also suggest cerebellar metabolism as a potential marker of the effects of 4-AP.

Although the trigger for the neurodegenerative disease process is unknown, the relevance of aging stands out as a major risk for the development of neurodegeneration. In this review, we highlighted the relationship between the different cellular mechanisms that occur as a consequence of aging and transcription factor nuclear factor erythroid-2-related factor 2 (NRF2) and the connection with the TAU protein. We focused on the relevance of NRF2 in the main processes involved in neurodegeneration and associated with aging, such as genomic instability, protein degradation systems (proteasomes/autophagy), cellular senescence, and stem cell exhaustion, as well as inflammation. We also analyzed the effect of aging on TAU protein levels and its aggregation and spread process. Finally, we investigated the interconnection between NRF2 and TAU and the relevance of alterations in the NRF2 signaling pathway in both primary and secondary tauopathies. All these points highlight NRF2 as a possible therapeutic target for tauopathies.

Alzheimer’s disease (AD), the leading cause of dementia, is a growing health issue with very limited treatment options. To meet the need for novel therapeutics, existing drugs with additional preferred pharmacological profiles could be recruited. This strategy is known as ‘drug repurposing’. Here, we describe dimethyl fumarate (DMF), a drug approved to treat multiple sclerosis (MS), to be tested as a candidate for other brain diseases. We used an APP-transgenic model (APPtg) of senile β-amyloidosis mice to further investigate the potential of DMF as a novel AD therapeutic. We treated male and female APPtg mice through drinking water at late stages of β-amyloid (Aβ) deposition. We found that DMF treatment did not result in modulating effects on Aβ deposition at this stage. Interestingly, we found that glutathione-modified DMF interacts with the ATP-binding cassette transporter ABCC1, an important gatekeeper at the blood–brain and blood–plexus barriers and a key player for Aβ export from the brain. Our findings suggest that ABCC1 prevents the effects of DMF, which makes DMF unsuitable as a novel therapeutic drug against AD. The discovered effects of ABCC1 also have implications for DMF treatment of multiple sclerosis.

Alzheimer’s disease (AD) is the most common cause of dementia. Fingolimod has previously shown beneficial effects in different animal models of AD. However, it has shown contradictory effects when it has been applied at early disease stages. Our objective was to evaluate fingolimod in two different treatment paradigms. To address this aim, we treated male and female APP-transgenic mice for 50 days, starting either before plaque deposition at 50 days of age (early) or at 125 days of age (late). To evaluate the effects, we investigated the neuroinflammatory and glial markers, the Aβ load, and the concentration of the brain-derived neurotrophic factor (BDNF). We found a reduced Aβ load only in male animals in the late treatment paradigm. These animals also showed reduced microglia activation and reduced IL-1β. No other treatment group showed any difference in comparison to the controls. On the other hand, we detected a linear correlation between BDNF and the brain Aβ concentrations. The fingolimod treatment has shown beneficial effects in AD models, but the outcome depends on the neuroinflammatory state at the start of the treatment. Thus, according to our data, a fingolimod treatment would be effective after the onset of the first AD symptoms, mainly affecting the neuroinflammatory reaction to the ongoing Aβ deposition.