Transcript Alzheimer’s disease (AD): imaging & cognition Wei Chen CCNI Journal Club

Alzheimer’s disease (AD):
imaging & cognition
Wei Chen
CCNI Journal Club
Alzheimer’s disease(AD)
 About 4 million people in the U.S. have AD.
 Nearly 10% of people 65 years of age and
older are affected by AD.
 It is estimated that by 2050, 14 million
Americans will have this disease and the
number could increase to 45 million in the
world.
 It’s best to start treatment early.
Definition of terms
 AD: patients with clinically probable AD according
to NINCDS-ADRDA (McKhann et al., 1984) or
DSMIV (American Psychiatric Association, 1994)
criteria.
 Mild AD: Patients with probable AD at a mild stage
of global cognitive impairment as assessed by
MMSE >20 and/or a CDR score 1.
 Accuracy: postmortem, biopsy or genetics.
Amygdala, Hippocampus and AD
 Medial temporal lobe (MTL) structures
have been reported to be involved
earliest and most extensively in the
pathology of AD.
Schematic diagram of the projections within the medial
temporal lobe ( A) & A more detailed diagram of (B).
Adapted from Lavenex and Amaral (2000).
Functional neuroimaging:
The identification of an abnormality in the
hippocampus or amygdala with non-invasive
imaging( mainly fMRI) is important as it could
facilitate the diagnosis of AD as well as monitoring
the treatment effect of certain drugs on AD and may
enable us to visualize these early brain changes in
the living subject.
Fox elicited fear response --positive (Red) and negative (blue) Bold
in rats Brain
Olfactory bulb
Amygdala
and
hippocampus
were involved
in the
emotional
processing
Prefrontal cortex
thalamus
hippocampus
hypothalamus
amygdala
Prolongation of T2 relaxation times of hippocampus and amygdala in AD:
Huali Wang, etc. Neuroscience Letters 363 (2004) 150–153.
showed the AD patients had longer T2 in hippocampus and amygdala than vascular dementia
(VaD) subjects and healthy elderly controls.
Linear regression analysis showed that, in AD, the right hippocampal T2 was correlated with Alzheimer’s Disease
Assessment Scale – Cognitive Subscale (ADAS-Cog )scores (r =0.495, P<0.001; Fig. 1),.
Mapping hippocampal and ventricular change in AD
Paul M. Thompson, etc. NeuroImage 22 (2004) ,1754– 1766.
The study has two goals:
 (1) to map 3D profiles of hippocampal and
ventricular change over time and compare
them in AD and healthy elderly subjects.
 (2) to map where these changes correlate
with cognitive decline.
Methods
 Used longitudinal MRI scanning (two scans:
baseline and follow-up) and cognitive testing
to study a group of AD subjects as their
disease progressed.
 A second, demographically matched group
of healthy elderly control subjects was also
imaged longitudinally (two scans) as they
aged normally.
MRI scanning in this paper
 3D T1-weighted images were acquired with
an inversion recovery segmented 3D
gradient echo sequence to resolve anatomy
at high resolution.
 Images were acquired in an oblique plane
perpendicular to the long axis of the
hippocampus with an acquisition matrix of
256 x 256 x 96 and zero filled to 2563.
Longitudinal ventricular maps (Mapping temporal horn dilatation).
The top row shows an average temporal horn model made for healthy controls at baseline (left) and at follow-up (right).
The color shows a measure of local enlargement.
The same maps in AD (second row) show greatly enlarged and progressively expanding temporal horns.
The bottom row shows a color-coded map of statistics that reveal the significance of the group difference (AD vs.
controls) at each time point. Most regions of the left temporal horn, and much of the right, show evidence for greater
expansion in AD. Permutation testing is used to assign an overall P value to the mapped effect , confirming its
significance.
P.M. Thompson et al. / NeuroImage 22 (2004) 1754–1766
Longitudinal hippocampal maps (Mapping 3D hippocampal atrophy).
The top row shows an average 3D hippocampal model made for healthy controls at baseline (left) and at follow-up
(right). The color shows a measure of local atrophy.
The same maps in AD (second row) show atrophied and progressively shrinking hippocampi.
The bottom row shows a color-coded map of statistics that reveals the significance of the group difference (AD vs.
controls) at each time point. Isolated regions of the left hippocampal head show evidence for greater atrophy in AD.
Permutation testing is used to assign an overall P value to the mapped effect.
P.M. Thompson et al. / NeuroImage 22 (2004) 1754–1766
Mapping cognitive linkages
These maps (top left) show regions on the temporal horns where expansion is associated with worse
performance on the MMSE. The hippocampal maps (top right) show regions where contraction is linked with
worse MMSE performance. These are cross-sectional comparisons based on baseline scans. Loss of tissue in
the left hippocampal head links with lower MMSE scores.
The final map is based on a composite measure of hippocampal atrophy divided by ventricular expansion. The
measure links more strongly with worse MMSE performance (bottom left) than either of the other maps
assessed individually. These strong links with declining cognition make these maps practically useful as
measures of disease progression.
P.M. Thompson et al. / NeuroImage 22 (2004) 1754–1766
Discussion
 Hippocampal volume reductions and ventricular
expansions progressed over time, with different patterns in
aging and dementia.
 Dynamic maps of the hippocampus and temporal horns
may be potential biomarkers of AD progression.
 The maps better localize disease effects and may help
identify factors that speed up or slow down brain
degeneration in clinical trials or genetic studies of
dementia.
P.M. Thompson et al. / NeuroImage 22 (2004) 1754–1766
AD Outlook
 Treatment of AD includes five major
components: neuroprotective strategies,
cholinesterase inhibitors, nonpharmacologic
interventions and psychopharmacologic
agents to reduce behavioral disturbances,
health maintenance activities, and an
alliance between clinicians and family
members and other caregivers responsible
for the patient.(n engl j med 351;1, www.nejm.org july
1, 2004)
 The loss of cholinergic neurons within the basal
forebrain is a major event in the development of
AD symptomology. This decrease in
acetylcholine (ACh) activity is linked to the
cognitive decline seen in AD patients and many
therapies rely on replacing the lost levels of ACh
in the brain (J Neurol Neurosurg Psychiatry
1999;66:137–147).
Using fMRI to study the
relationship between nicotinic acetylcholine
receptors (nAChR) and AD is of critical importance
in the future.
Thanks!!