Social Health and Brain Reserve as Protective Factors for Dementia

Post by Megan McCullough

The takeaway

Good social health in older adults was associated with slower cognitive decline over time and higher cognition levels at baseline. High brain reserve, a measure of the brain’s resilience to damage, was also associated with slower cognitive decline suggesting that social health and brain reserve may be indicators of the propensity of an individual to develop dementia.

What's the science?

Although there are no current pharmacological treatments for dementia prevention, numerous social risk factors have been identified, indicating that dementia prevention may be possible. Previous research has shown that social support, social engagement, and other social health behaviors may be linked to a reduced risk of dementia development. Additionally, the brain reserve model of dementia suggests that individuals with more neurons or increased synaptic density are less at risk of cognitive deterioration. Although the social health model and brain reserve model both suggest protective factors against the effects of dementia, the interaction between these two models has not been investigated. This week in Annals of Neurology, Marseglia and colleagues aimed to investigate the interaction of social health and brain reserve on cognitive changes in a cohort of dementia-free older adults.

How did they do it?

Participants included 368 Swedish adults over the age of 60 who did not have dementia. These participants were followed for 12 years to assess the interactions between social health, brain reserve, and cognition over time. At the baseline assessments, a social health score was generated for each participant; this score was created from a questionnaire about social connections and social support. The authors also used magnetic resonance imaging (MRI) data to assess volumes of grey matter, white matter, and cerebrospinal fluid in each individual. These volumes were totaled and used as a measure of brain reserve. Cognitive function tests were administered throughout the study to assess different facets of cognition including episodic and semantic memory. Statistical analysis including one-way ANOVA, linear mixed-effect models, and stratified analyses were then run to explore the relationships between social health and brain reserve in the context of cognitive function.

What did they find?

The authors found that moderate to good social health and high brain reserve was associated with high cognitive performance and slower rates of cognitive decline over time. The statistical analyses that examined the interplay between these two factors showed that good social health was associated with higher cognition levels only in individuals who exhibited moderate to large brain reserves. This suggests that there are multiple protective factors that interact in slowing or preventing the development of dementia.

What's the impact?

This study found that a healthy social life and high levels of brain reserve are protective factors against age-related cognitive decline. Specifically, good social health can protect against cognitive decline in individuals with high levels of brain reserve. This research shows the relevance of promoting healthy social lives for individuals at risk of developing dementia. 

Access the original scientific publication here

How Aversive Memories Are Stored and Retrieved

Post by Leanna Kalinowski

The takeaway

Researchers have found that neuronal ensembles in one brain region recruit presynaptic neurons in other regions during the retrieval of aversive memories. 

What's the science?

Each of our memories is stored in neuronal ensembles – sparse groups of co-active neurons – across multiple different brain regions. Previous research has shown that the allocation of memories to these brain regions is not a random process; it is dependent on the level of CREB protein expressed within individual neurons. However, it is unclear how these cross-region connections are organized at the time of learning to ensure that the neuronal ensembles from different brain regions are coordinated when the memory is retrieved. This week in Neuron, Lavi and colleagues tested whether allocating aversive memories to neurons in one brain region impacts memory allocation in interconnected brain regions in mice.

How did they do it?

First, the researchers injected mice with a combination of three viruses into the basolateral amygdala (BLA; experiment 1) or insular cortex (IC; experiment 2), which are two interconnected brain regions that are crucial for conditioned taste aversion memories. The first virus carried the CREB gene, which biases the allocation of memories to a random subset of neurons within the injected brain region. The second virus was the rabies virus coupled with mCherry (a fluorescent marker), which allows researchers to visualize the location of presynaptic neurons that project to the injected region via retrograde tracing. The third virus encoded TVA, which is a protein that is essential for the rabies virus to travel to presynaptic neurons.

Four days after the viral injections, the mice underwent a conditioned taste aversion task, which teaches mice to associate a particular taste with an aversive stimulus (i.e., illness). During the habituation phase of this task, which lasted three days, mice received a daily water ration for 30 minutes per day from two tubes. Then, on the following day, the plain water was replaced with sugar water, and the mice were subsequently treated with an injection of lithium chloride. This injection induced feelings of illness, thereby leading mice to develop a learned aversion to sugar water. Aversion to sugar water was then tested three days later, after which their brains were collected and analyzed for neural activity using c-fos immunohistochemistry. 

To test whether these effects extend to other senses beyond taste (i.e., hearing), the researchers then injected the same three viruses into the BLA of a new cohort of mice and subsequently subjected them to an auditory fear conditioning task. In this task, mice were trained to associate an auditory stimulus (14kHz tones) with a foot shock. Aversion to the auditory stimulus was then tested three days later, after which their brains were collected and analyzed in the same manner as above.

What did they find?

Overall, the researchers found that the allocation of aversive memories in one brain region leads to the retrograde activation of presynaptic neurons (i.e., the target neuron sends a signal back to the presynaptic neuron) in other brain regions during memory allocation and retrieval. Specifically, using CREB to allocate taste aversion memories to the BLA leads to the recruitment of presynaptic neurons in the IC. This pattern was also observed in the opposite direction (i.e., allocating taste aversion memories to the IC leads to the recruitment of neurons in the BLA), suggesting that a bidirectional relationship between these two brain regions is necessary for coordinating taste aversion memory retrieval. Similar coordination was observed between the BLA and auditory cortex during auditory fear conditioning, demonstrating that these effects extend to other senses beyond taste aversion. 

What's the impact?

This study uncovered the mechanisms that underlie cross-regional memory allocation and retrieval, particularly for aversive memories. These results may pave the way in better understanding how cross-regional memory coordination is disrupted in neurological and psychiatric diseases. 

Access the original scientific publication here.

The Link Between Inflammation and Cognitive Impairment in Severe Mental Illness

 Post by Lani Cupo

The takeaway

A large, multivariate investigation of inflammation and cognition in severe mental illness reveals patterns of immune activation associated with poor verbal learning and processing speed in individuals across diagnoses.

What's the science?

The link between inflammation and mental illness has been investigated, however, the associations between immune activation and cognitive ability in severe mental illnesses, like schizophrenia and bipolar disorder, have often glossed over individual differences in both domains. To help clarify the relationship, variability amongst both healthy individuals and those with severe mental illness must be examined. This week in Molecular Psychiatry, Saether and colleagues attempt to capture individual variance between cognitive ability and inflammation in health and severe mental illness with a multivariate analysis technique, canonical correlation analysis (CCA).

How did they do it?

The authors had access to a large pool of participants (770 healthy controls [HC], 343 with schizophrenia, and 289 with bipolar disorder). Diagnoses were determined by clinical assessments conducted by trained psychologists and medical doctors. Clinical psychologists and trained researchers administered cognitive assessments, recording variables including fine-motor speed, psychomotor processing speed, mental processing speed, verbal learning, attention, verbal memory, semantic fluency, working memory, and cognitive control. To quantify inflammation, the authors included 22 markers of neuroinflamation from a blood sample. CCA is a technique that relates two independent set of variables (each called a variate) to one another, generating new linear combinations of variables (canonical variate pairs) reflecting patterns of covariation between variates. The significance of each resulting variate pair is assessed with permutation testing, allowing the authors to determine whether each pattern of covariance is likely to arise due to chance. The participant demographics can be mapped onto the correlations to examine subgroups within the patterns. The authors organized these “loading scores” (how individual participant scores mapped onto the canonical variates) into clusters using a clustering procedure (hierarchical clustering) to establish subgroups. They confirmed the stability of the identified clusters with a resampling technique.

What did they find?

From the CCA, the authors derived two significant canonical variate pairs representing relationships of covariance among the variables. Of these, the first canonical variate pair was determined to be more reproducible in a set of un-tested samples and, therefore, further examined. This canonical variate pair captured a correlation between poor verbal learning and psychomotor processing speed with an increased presence of 4 markers of innate immune activation. Mapping diagnoses onto the correlation revealed the potential for subgroups.

The clustering analysis revealed two subgroups; Cluster 1 included worse scores on cognitive domains and increased inflammatory markers, compared to Cluster 2. The majority of HCs were in Cluster 2, while the majority of participants with severe mental illness were in Cluster 1. Of the participants with severe mental illness, those in Cluster 1 exhibited worse functioning and symptomatology and higher pharmaceutical usage than those in Cluster 2. Overall, Cluster 1 represented a group that captured most of the participants with severe mental illness and exhibited decreased cognitive ability and increased inflammation. However, group assignments did transcend diagnosis.

What's the impact?

This study is one of the first to show how the relationship between cognitive dysfunction and inflammation transcends diagnosis. Regardless of diagnosis or impairment, there is a relationship between increased innate inflammation and cognitive dysfunction, emphasizing the importance of examining heterogeneity between individuals. In a subset of individuals with severe mental illness, this may provide an important link for future investigation and treatment approaches.

Access the original scientific publication here