The influence of depression and neuroinflammation on the progression of mild cognitive impairment to dementia: PET imaging of amyloid deposition and microglia activation

Mild cognitive impairment (MCI) can be defined as a transitional phase between
normal ageing and dementia disorders and is associated with a highly increased
risk for dementia due to Alzheimer*s disease. MCI is a stage in which early
neuropathology of dementia, especially Alzheimer*s disease occurs, but do not
meet the clinical criteria. Recent studies have also shown that presence of
late onset depression in patients significantly contributes to the progression
of dementia. The ability to detect subjects with MCI has attracted a lot of
interest due to the possibility that this might be the earliest stage at which
treatments for dementia, particularly Alzheimer*s disease can be attempted to
prevent irreparable damage that occurs with the progression of this disease.
The main pathological features in the Alzheimer*s brain are progressive
depositions of proteins called β-amyloid between nerve cells and
neurofibrillary tangles within the nerve cells that accumulate abnormally in a
predictable spatial pattern throughout the brain. β-amyloid begin to accumulate
in the brain in persons with MCI, where the plaques become more prevalent and
spread with the progression to Alzheimer*s disease. Microglia cells acts as
immune cells in the brain and are the first elements to respond after any kind
of disturbance in the brain. Under certain pathological conditions, such as
Alzheimer*s disease, resting microglia undergo microglia activation. This is
characterized by the proliferation and migration of microglia to the affected
area and increased production of pro-inflammatory mediators, including
deleterious free radicals and pro-inflammatory cytokines that are capable of
initiating or exacerbating the progression of Alzheimer*s disease pathology.
Cytokines are signalling proteins that play a pivotal part in the regulation of
the immune system. Human studies have provided considerable evidence in favour
of the view that abnormalities of cytokines contribute to the evolution of
psychiatric disturbances, including depression and dementia. Studies have also
shown that increased levels of cytokines in the brain plays a pivotal role in
neurodegenerative disorders. Depression, inflammation and inflammatory causing
factors may not only independently influence the progression of MCI to
Alzheimer*s disease, but may also work synergistically or additively with each
other in the progression of neurodegeneration. However, no research to our
knowledge has been done in order to determine the combined influences of
depression, neuroinflammation and β-amyloid, which are three of the major
factors in the pathogenesis to neurodegeneration.

To investigate the effect of late onset depression and inflammation on the
pathological progression from MCI to Alzheimer*s disease by determining the
correlation of microglia cell activation, β-amyloid deposition, brain volume,
peripheral inflammatory markers (IL-1β, TNF-α, INF- α and IL-6), peripheral
brain derived neurotrophic factor and cognition of healthy volunteers compared
to patients with late onset depression in the presence or absence of MCI.

This will be a follow up study to determine the correlation of MCI, depression
and inflammation in the progression of neurodegeneration of Alzheimer*s
disease. After informed consent of the volunteers had been obtained healthy
volunteers, patients with late onset depression, patients with MCI and patients
with MCI and late onset depression will undergo an examination and a battery of
tests to determine whether they have met the requirements for one of the
abovementioned groups. The examination will include psychiatric tests that
will be done to evaluate the presence and degree of depression.
Neuropsychological assessment will be done to aid in the diagnosis of MCI.
After a diagnosis of one of the abovementioned criteria, a structural brain
imaging using high resolution magnetic resonance imaging (MRI) will be done on
all of the abovementioned participants to determine the presence of vascular
lesions and structural brain volume. Volunteers will be excluded of the study
if the presences of cerebral vascular lesions or cerebral cancer have been
identified with MRI. The PET procedures will continue on healthy volunteers,
patients with late onset depression and patients with MCI but not on patients
who has MCI together with late onset depression after a volunteer has met the
requirements for one of the abovementioned groups. The same procedures will be
repeated 18 months later.

Not applicable