Inflammation, Anti-inflammatory Interventions, and Post-stroke Cognitive Impairment: a Systematic Review and Meta-analysis of Human and Animal Studies.

The pathophysiology and treatment of post-stroke cognitive impairment (PSCI) are not clear. Stroke triggers an inflammatory response, which might affect synapse function and cognitive status. We performed a systematic review and meta-analysis to assess whether patients with PSCI have increased levels of inflammatory markers and whether anti-inflammatory interventions in animals decrease PSCI. We systematically searched PubMed, EMBASE, and PsychInfo for studies on stroke. For human studies, we determined the standardized mean difference (SMD) on the association between PSCI and markers of inflammation. For animal studies, we determined the SMD of post-stroke cognitive outcome after an anti-inflammatory intervention. Interventions were grouped based on proposed mechanism of action. In patients, the SMD of inflammatory markers for those with versus those without PSCI was 0.46 (95% CI 0.18; 0.76; I2 = 92%), and the correlation coefficient between level of inflammation and cognitive scores was - 0.25 (95% CI - 0.34; - 0.16; I2 = 75%). In animals, the SMD of cognition for those treated with versus those without anti-inflammatory interventions was 1.43 (95% CI 1.12; 1.74; I2 = 83%). The largest effect sizes in treated animals were for complement inhibition (SMD = 1.94 (95% CI 1.50; 2.37), I2 = 51%) and fingolimod (SMD = 2.1 (95% CI 0.75; 3.47), I2 = 81%). Inflammation is increased in stroke survivors with cognitive impairment and is negatively correlated with cognitive functioning. Anti-inflammatory interventions seem to improve cognitive functioning in animals. Complement inhibition and fingolimod are promising therapies on reducing PSCI.

The Role of Astrocytes in Synapse Loss in Alzheimer's Disease: A Systematic Review.

Alzheimer's disease (AD) is the most common cause of dementia, affecting 35 million people worldwide. One pathological feature of progressing AD is the loss of synapses. This is the strongest correlate of cognitive decline. Astrocytes, as an essential part of the tripartite synapse, play a role in synapse formation, maintenance, and elimination. During AD, astrocytes get a reactive phenotype with an altered gene expression profile and changed function compared to healthy astrocytes. This process likely affects their interaction with synapses. This systematic review aims to provide an overview of the scientific literature including information on how astrocytes affect synapse formation and elimination in the brain of AD patients and in animal models of the disease. We review molecular and cellular changes in AD astrocytes and conclude that these predominantly result in lower synapse numbers, indicative of decreased synapse support or even synaptotoxicity, or increased elimination, resulting in synapse loss, and consequential cognitive decline, as associated with AD. Preventing AD induced changes in astrocytes might therefore be a potential therapeutic target for dementia. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=148278, identifier [CRD148278].

Both male and female APPswe/PSEN1dE9 mice are impaired in spatial memory and cognitive flexibility at 9 months of age.

Alzheimer's disease (AD) is the most common cause of dementia. Despite many years of research, very limited treatment options are available. Here we aim to establish a well-defined learning and memory performance test for an AD mouse model, which can be used in future studies to evaluate the effect of novel drugs, treatments, and interventions. We exposed 9-month-old APPswe/PSEN1dE9 mice to a battery of memory tests to determine which test is best suited to study memory deficits in this specific AD mouse model. Since in more recent years it has become clear that there are sex-dependent differences in AD pathology, we also assessed differences in performance between male and female mice. From our test battery, we conclude that the Barnes maze task, which spans multiple days, is better suited to study subtle learning and memory deficits in 9-month-old APPswe/PS1dE9 mice, than the 2 trial T-maze and Fear conditioning task. This test revealed deficits in both spatial memory and cognitive flexibility in the APPswe/PS1dE9 mice compared to wildtype littermates. Furthermore, we conclude that there are no sex dependent memory deficit differences in this AD mouse model at this age.