7 research outputs found
Cortisol, cognition and the ageing prefrontal cortex
The structural and functional decline of the ageing human brain varies by brain
region, cognitive function and individual. The underlying biological mechanisms are
poorly understood. One potentially important mechanism is exposure to
glucocorticoids (GCs; cortisol in humans); GC production is increasingly varied with
age in humans, and chronic exposure to high levels is hypothesised to result in
cognitive decline via cerebral remodelling. However, studies of GC exposure in
humans are scarce and methodological differences confound cross-study comparison.
Furthermore, there has been little focus on the effects of GCs on the frontal lobes and
key white matter tracts in the ageing brain. This thesis therefore examines
relationships among cortisol levels, structural brain measures and cognitive
performance in 90 healthy, elderly community-dwelling males from the Lothian
Birth Cohort 1936. Salivary cortisol samples characterised diurnal (morning and
evening) and reactive profiles (before and after a cognitive test battery). Structural
variables comprised Diffusion Tensor Imaging measures of major brain tracts and a
novel manual parcellation method for the frontal lobes. The latter was based on a
systematic review of current manual methods in the context of putative function and
cytoarchitecture. Manual frontal lobe brain parcellation conferred greater spatial and
volumetric accuracy when compared to both single- and multi-atlas parcellation at
the lobar level. Cognitive ability was assessed via tests of general cognitive ability,
and neuropsychological tests thought to show differential sensitivity to the integrity
of frontal lobe sub-regions. The majority of, but not all frontal lobe test scores shared
considerable overlap with general cognitive ability, and cognitive scores correlated
most consistently with the volumes of the anterior cingulate. This is discussed in
light of the diverse connective profile of the cingulate and a need to integrate
information over more diffuse cognitive networks according to proposed de-differentiation
or compensation in ageing. Individuals with higher morning, evening
or pre-test cortisol levels showed consistently negative relationships with specific
regional volumes and tract integrity. Participants whose cortisol levels increased
between the start and end of cognitive testing showed selectively larger regional
volumes and lower tract diffusivity (correlation magnitudes <.44). The significant
relationships between cortisol levels and cognition indicated that flatter diurnal
slopes or higher pre-test levels related to poorer test performance. In contrast, higher
levels in the morning generally correlated with better scores (correlation magnitudes
<.25). Interpretation of all findings was moderated by sensitivity to type I error,
given the large number of comparisons conducted. Though there were limited
candidates for mediation analysis, cortisol-function relationships were partially
mediated by tract integrity (but not sub-regional frontal volumes) for memory and
post-error slowing. This thesis offers a novel perspective on the complex interplay
among glucocorticoids, cognition and the structure of the ageing brain. The findings
suggest some role for cortisol exposure in determining age-related decline in
complex cognition, mediated via brain structure
Fetal gene therapy for neurodegenerative disease of infants
For inherited genetic diseases, fetal gene therapy offers the potential of prophylaxis against early, irreversible and lethal pathological change. To explore this, we studied neuronopathic Gaucher disease (nGD), caused by mutations in GBA. In adult patients, the milder form presents with hepatomegaly, splenomegaly and occasional lung and bone disease; this is managed, symptomatically, by enzyme replacement therapy. The acute childhood lethal form of nGD is untreatable since enzyme cannot cross the blood–brain barrier. Patients with nGD exhibit signs consistent with hindbrain neurodegeneration, including neck hyperextension, strabismus and, often, fatal apnea1. We selected a mouse model of nGD carrying a loxP-flanked neomycin disruption of Gba plus Cre recombinase regulated by the keratinocyte-specific K14 promoter. Exclusive skin expression of Gba prevents fatal neonatal dehydration. Instead, mice develop fatal neurodegeneration within 15 days2. Using this model, fetal intracranial injection of adeno-associated virus (AAV) vector reconstituted neuronal glucocerebrosidase expression. Mice lived for up to at least 18 weeks, were fertile and fully mobile. Neurodegeneration was abolished and neuroinflammation ameliorated. Neonatal intervention also rescued mice but less effectively. As the next step to clinical translation, we also demonstrated the feasibility of ultrasound-guided global AAV gene transfer to fetal macaque brains