Wei ChenWei Chen

CCNI Journal ClubCCNI Journal Club

Alzheimer’s disease (AD):Alzheimer’s disease (AD):

imaging & cognitionimaging & cognition

Alzheimer’s disease(AD)Alzheimer’s disease(AD) About 4 million people in the U.S. have AD. About 4 million people in the U.S. have AD. Nearly 10% of people 65 years of age and Nearly 10% of people 65 years of age and

older are affected by AD. older are affected by AD. It is estimated that by 2050, 14 million It is estimated that by 2050, 14 million

Americans will have this disease and the Americans will have this disease and the number could increase to 45 million in the number could increase to 45 million in the world.world.

It’s best to start treatment early.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 ADAmygdala, 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.

amygdala

hypothalamus

Olfactory bulb

Prefrontal cortex

thalamus

hippocampus

Fox elicited fear response --positive (Red) and negative (blue) Bold in rats Brain

Amygdala Amygdala and and hippocampus hippocampus were involved were involved in the in the emotional emotional processingprocessing

Prolongation of T2 relaxation times of hippocampus and amygdala in AD:Huali Wang, etc. Neuroscience Letters 363 (2004) 150–153.

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),.

showed the AD patients had longer T2 in hippocampus and amygdala than vascular dementia (VaD) subjects and healthy elderly controls.

Mapping hippocampal and ventricular change in ADPaul 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.

MethodsMethods

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.

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 ventricular maps (Mapping temporal horn dilatation).

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 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) 1754–1766P.M. Thompson et al. / NeuroImage 22 (2004) 1754–1766

AD OutlookAD Outlook

Treatment of AD includes five major Treatment of AD includes five major components: neuroprotective strategies, components: neuroprotective strategies, cholinesterase inhibitors, nonpharmacologic cholinesterase inhibitors, nonpharmacologic interventions and psychopharmacologic interventions and psychopharmacologic agents to reduce behavioral disturbances, agents to reduce behavioral disturbances, health maintenance activities, and an alliance health maintenance activities, and an alliance between clinicians and family members and between clinicians and family members and other caregivers responsible for the patient.(other caregivers responsible for the patient.(n n engl j med 351;1, www.nejm.org july 1, 2004) 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!!