Advanced MR Neuroimaging in presenile dementia

The two most frequent causes of dementia before the age of 65 years (ie,
presenile dementia) are Alzheimer disease (AD, 35%) and frontotemporal dementia
(FTD, 15%). Typically, patients with AD suffer mainly from memory disturbances,
while in patients with FTD behavioural and language disturbances prevail.
Diagnosis of dementia and differentiation between AD and FTD in the early
stages of the disease may be difficult, as symptoms at this time may be mild
and unspecific, and memory disorders may also be present in FTD. As yet, there
is no diagnostic marker available to differentiate FTD from AD, and definitive
diagnosis is commonly made in the later stages of the disease on clinical and
neuropsychological grounds.
Differentiation between AD and FTD early in the disease is of clinical
importance for specific treatment and patient care strategies. Also, the
long-term disease course is different between AD and FTD, and early diagnosis
will provide patients and their family more certainty about the future in an
early stage of the disease. Further insight into the neuropathological changes
(atrophy, plasticity) occurring in FTD and AD may furthermore aid the future
development of therapeutic strategies, while the same neuroimaging techniques
can be used for treatment monitoring on a neurophysiological level.
Although AD and FTD affect different cognitive processes, in both diseases
brain plasticity may compensate in the early stages of the disease (Yetkin
2006). This compensation explains why differentiation in the early stages of
the disease based on clinical and neuropsychological findings is difficult:
diagnosis only becomes apparent when the disease progresses and compensatory
mechanisms fail.
On conventional magnetic resonance (MR) imaging, the hallmark of AD is atrophy
of the hippocampus, which is often not present in the early stages of the
disease, while it is also seen in advanced FTD. Imaging features of FTD are
profound frontotemporal atrophy, which again only becomes prominent as the
disease progresses and in the advanced stage may also be seen in AD.
Three advanced MR neuroimaging techniques hold promise for detecting changes in
the grey and white matter integrity, brain function and brain perfusion before
decrease in brain volume (atrophy) becomes visible.
With diffusion tensor imaging (DTI) the microstructure of the grey and white
matter can be assessed noninvasively. An increase of mean diffusivity (MD) and
reduction of fractional anisotropy (FA) indicate loss of parenchymal integrity,
occurring prior to actual brain volume loss.
With functional MR imaging (fMRI), activity of the brain can be measured
noninvasively. The compensatory processes that take place in the early stage of
disease may be visualised as increased and more dispersed brain activation when
compared with healthy controls. Such compensatory changes will be particularly
apparent in the early stages of the disease, affecting preferentially those
processes that are affected by AD and FTD. Conversely, once compensatory
mechanisms fail, reduced activation is to be expected (Rombouts 2003). As
memory disturbances are more prominent in AD and behaviour is more commonly
affected in FTD, we will use an encoding and retrieval memory task and a social
intelligence task respectively to engage these processes and study brain
function in the early stages of the disease.
Arterial spin labelling (ASL) is a non-invasive MR imaging technique with which
brain perfusion can be measured quantitatively. Hypoperfusion of specific brain
areas in FTD and AD is a well-established finding in the advanced disease
stages, and is traditionally assessed with positron emission tomography (PET)
and single photon emission computed tomography (SPECT). ASL has several
advantages over PET and SPECT imaging, in terms of its non-invasiveness, higher
spatial and temporal resolution and quantitative properties. In advanced AD
hypoperfusion is prominent in the parietal lobes, whereas the frontal lobes are
affected in advanced FTD. Feasibility studies of ASL for assessing patterns of
perfusion in these patient populations with advanced disease have shown
patterns of hypoperfusion that are similar to those found with PET and SPECT
imaging (Johnson 2005; Du 2006). We will determine if this hypoperfusion is
also discernable in early AD and FTD.

The purpose of this research line is to assess whether measures acquired with
advanced MR neuroimaging can be used as neuropathological markers for the early
diagnosis of dementia and differentiation between AD and FTD.
For each project, the specific research questions are listed below.
Project 1 - diffusion tensor imaging (DTI):
1. Do patients with presenile dementia have different mean diffusivity (MD;
increase) and fractional anisotropy (FA; decrease) of the hippocampus and the
(normal appearing) white matter compared to healthy controls?
2. Are DTI measures (FA, MD) of the hippocampus and the (normal appearing)
white matter early in the disease predictive of the definitive diagnosis of AD
or FTD?
3. Do early changes in MD and FA predict atrophy (decrease in volume) of the
areas predominantly affected in AD and FTD, namely the hippocampus, the
frontal, parietal and temporal lobe?
Project 2 - functional MR imaging ( fMRI):
4. Do patients with presenile dementia have different patterns of brain
activation for memory encoding and working memory compared to healthy controls?
5. Are fMRI measurements of memory encoding and working memory early in the
disease predictive of the definitive diagnosis of AD or FTD?
Project 3 - arterial spin labeling (ASL):
6. Do patients with presenile dementia have different brain perfusion
(hypoperfusion) compared to healthy controls?
7. Are brain hypoperfusion patterns early in the disease predictive of the
definitive diagnosis of AD or FTD?

Longitudinal case-control study.

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