Test profile for the identification of markers for cognitive function – University of Copenhagen

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Projects in Test profile for the identification of markers for cognitive function

Preclinical research

Oscillatory activity of different frequencies, from slow delta to fast gamma oscillations, can be recorded throughout the brain, and is suggested to be essential for cognitive functions by providing a temporal frame for cell assembly formation and information processing. 
Both the hippocampus and prefrontal cortex are central in memory formation and consolidation, and recent evidence suggests that the coordinated activity between the hippocampus and prefrontal cortex is of great importance.

We investigate how the communication and synchronization between the hippocampus and prefrontal cortex is altered during aging in rodents. 

This involves studying the direct, monosynaptic projection that exists between the hippocampus and prefrontal cortex and investigating potential age-related changes in the synchronicity between these brain areas. We do this by perturbing the hippocampal–prefrontal pathway specifically using optogenetics, while measuring neuronal activity using in vivo electrophysiology. We also use two-photon microscopy coupled with optogenetics to assess age-related changes in vessel diameter, red blood cell flux and calcium concentrations as a measure of neuronal activity.

Clinical research

Cognitive test scores in midlife reflect not only individual differences in age-related decline, but also individual differences in cognitive ability characterizing young adults. Using the Metropolit Cohort and CAMB data, we have demonstrated that there are substantial correlations between draft board intelligence scores and cognitive ability in late midlife, and 207 individuals with unusual large changes in cognitive ability from young adulthood to late midlife have been selected for detailed clinical evaluations such as comprehensive neuropsychological assessment, functional magnetic resonance imaging (fMRI), assessment of sleep patterns and oral health.

Several PhD-projects have included evaluations from these examinations:

  1. Late midlife sleep pattern and sleep structure and the association to age-related changes in cognition The Metropolit Birth 1953 Cohort
  2. Clinical, neurophysiological and molecular biological aspects of salivary gland function in relation to age-associated changes in cognitive function
  3. The dynamic brain - Activity patterns in cognitive ageing and during cerebral blood flow modulation
  4. Motor pattern in REM sleep behavior disorder and Parkinsonian disorders
  5. Inhibition in Parkinson’s disease: A focus on prepulse inhibition and Rapid eye movement sleep Behavior Disorder (RBD). 

The main conclusions of some of these PhD-projects are:

  • Subjective measurements of sleep in middle-aged males show an association between self rated sleep quality and cognition 
  • Results of examinations of hyposalivation, poorer dental health and increased expression of the molecular aging biomarker P16ink4a indicate that these may constitute potential peripheral correlates of cognitive decline in men in late midlife and
  • Using MRI, distinct alterations in functional brain organization related to cognitive decline have been found. Importantly, the fMRI studies suggest that cognitive decline is associated with a disrupted ability to produce network activity, and the default mode network that brain uses when preparing for a task is severely affected – similar to the pattern that is observed in patients with Alzheimer’s disease (AD). 

The interdisciplinary sub-project Altered level of deoxythymidine triphosphate is associated with cognitive impairment, aims to evaluate mitochondrial ROS production and whole-cell levels of deoxyribonucleotides triphosphates including dTTP as early biomarkers of dementia. 

The project shows no association between mitochondrial production of ROS and changes in cognitive ability in men in late midlife, whereas a significant correlation between whole-cell levels of dTTP and cognitive decline has been found. Moreover, a sub-project has established the infrastructure for performing 2-photon microscopy at CEHA.

We have identified unique variables relevant to healthy aging, including spontaneous glial calcium waves in vivo that increase the brain’s O2 use without increasing O2 supply at the same time, which may lead to increased frailty of the aged brain. Our work has also pointed to a special category of neurons that underlies basic elements of perception and cognition as being particularly vulnerable to aging.

Finally, our studies have indicated that animals with premature aging have defects in energy production in the hippocampus area, the brain region that is responsible for memory formation, providing unique insights into the consequences of early aging mechanisms.

Therefore, several novel potential biomarkers of cognitive decline have been found in first five year of Center for Healthy Aging based on the inclusion of approximately 200 participants. During the next three years approximately 300 additional participants will be included and examined. The examinations include cognitive test, sleep and depression questionnaire, MRI and EEG studies. The results from these studies will hopefully point to new avenues for prevention and intervention in order to change the course of unhealthy brain aging.