In this symposium four speakers discussed different approaches to investigating the intersection between late-life depression and cognitive symptoms in Alzheimer disease. This was a fascinating insight into translational research in four diverse areas.
Dr Gwenn Smith, Johns Hopkins University School of Medicine, USA, looked at the possibility that serotonin might provide a link between mood changes and cognition, thinking about late-life depression as a risk factor or part of prodrome Alzheimer’s disease. In patients with late-life depression, scans showed a diffuse reduction in binding to the serotonin transporter, and a small increase in amyloid-β deposition (which was much smaller than that seen in mild cognitive impairment Alzheimer’s patients). There was a correlation between the reduction in serotonin transporter and poor performance on memory tests.
The serotonin system may provide a link between mood symptoms and cognitive decline
In patients with early Alzheimer’s disease, localized deposition of Tau protein in the raphe appears to be an early pathological sign. In addition, the patterns of Tau deposition and reduction in the serotonin transporter map well onto one another. The presence of changes in the serotonin transporter also added to changes in levels of Tau protein and the presence of amyloid-β in predicting memory deficits in patients with Alzheimer’s disease. This was true not only at cross-sectional sampling of patients but also longitudinally, when reductions in the serotonin transporter were associated with worsening of episodic verbal memory over time. Dr Smith speculated that the serotonergic system may confer a vulnerability to cognitive changes through over-production of serotonin in the absence of the transporter, leading to oxidative stress following serotonin metabolism.
Prof John O’Brien, University of Cambridge, UK, discussed the Positron emission tomography (PET) of neuroinflammation and the Tau protein in Alzheimer’s disease. Patients were drawn from the NIMROD study (Neuroimaging of Inflammation in Memory and other Related Disorders), and had Alzheimer’s disease. The tracer PK 11195 binding was shown to increase in patients with mild cognitive impairment due to Alzheimer's disease, indicating that neuroinflammation (microglial activation) may be an early pathological change in this disorder.
Data from this study were also used to provide evidence for how Tau protein spreads throughout the brain. Measures of functional connectivity using resting state fMRI, indicated an association between Tau and the degree of connectivity of brain areas – the greater the number of connections between areas the greater the amount of Tau protein present. This result is consistent with a prion-like, transneuronal spread of Tau throughout the brain from the original ‘seeded’ area.
There is evidence that Tau protein shows a prion-like, transneuronal spread in the brain
Dr Masafumi Ihara, National Cerebral and Cardiovascular Center, Japan, discussed models of vascular dementia and some possible approaches to its treatment. White-matter changes are a shared pathology across the various subtypes of vascular dementia, and white-matter hyperintensities contribute to the presentation of Alzheimer's disease. Prof Ihara is using hypoperfusion/ischaemic injury animal models of vascular dementia, which mirror well many of the changes seen in patients with vascular dementia. These several hypoperfusion models show good reproducibility of the white matter changes characterized by blood-brain barrier disruption, glial activation, oxidative stress, and oligodendrocyte loss following chronic cerebral hypoperfusion with or without ischemic stroke. Transgenic mice over-expressing the peptide hormone adrenomedullin showed facilitation of the recovery of cerebral blood flow following such ischaemic surgery. This recovery appeared to result from rich collateral growth from the arteries, and capillary outgrowth in the white matter. These changes restored and maintained white-matter integrity after the ischaemic injury, as well as preventing the development of behavioural deficits in working memory tasks. Professor Ihara stated that adrenomedullin is therefore a potential treatment for vascular dementia.
Emerging risks for the development of vascular dementia include infection and inflammation. In a cohort of patients following stroke, and in the general population, the presence of cnm+ S. mutans was strongly associated with cerebral microbleeds. In these populations, there were no overall effects of the presence of this bacterium on cognitive function, but there was a slight decline associated with its presence. As the collagen-binding protein cnm is specific to S. mutans, Prof Ihara proposed that this molecule could provide a target for immunotherapy in vascular dementia in the future.
Bacterial infection may prove a treatment target for vascular dementia in the future
Professor Hochang Benjamin Lee,Yale University School, USA, introduced the concept of using cardiovascular conditions as a way to study late-life stress and mood symptoms. Surgery is a common late-life stress, and coronary artery bypass graft (CABG) is the most common cardiac surgery. Delirium occurs in about 20–30% of patients following CABG. It was found that age, pre-operative depression and mild cognitive impairment were all independent predictors of the incidence and severity of post-CABG delirium. Therefore these factors may be useful in screening patients before surgery to estimate risk of delirium.
Chronic cerebral hypoperfusion is a risk factor for cognitive decline
Chronic cerebral hypoperfusion is a risk factor for cognitive decline. Patients with heart failure show a reduction in cerebral blood flow, alongside high rates of cognitive impairment and an increased risk of dementia. In patients who received a left-ventricular assist device, their cognitive scores improved substantially after surgery, which may have resulted from the increased cerebral blood flow. Thus, improving blood flow, as well as general well being may be ways to counteract cognitive impairment in the elderly.