The investigation of episodic memory in health and neurodegenerative disease

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

The study is designed to look at parts of the human brain involved in remembering information conveyed by spoken language. These areas of the brain are particularly affected by the disease process in Alzheimer‘s disease, the commonest form of dementia. Using an advanced imaging technique called magnetic resonance imaging (MRI), the areas of the brain that are active while a patient hears sentences containing factual information can be observed. We will also look at brain activity when the patient tries to remember sentences they have previously been told. We will observe the changes in the brains activity during these tasks as the disease progresses, by retesting the patients after a period of 9 months. In addition, the effects of a drug known to produce modest improvement of symptoms in AD will be assessed, to observe changes in activity in the brain‘s memory systems as the result of the treatment. The results from the brain imaging will be compared with the patient‘s performance on tests of memory function. If successful, this will offer a technique by which the treatment of AD, whether designed to improve symptoms or to result in cure of the condition, can be monitored and understood.

Technical Summary

Aims:
1) To observe the effects of Alzheimer‘s disease (AD) on the distributed neural systems supporting verbal memory encoding and retrieval using functional magnetic resonance imaging (fMRI).
2) To determine the potential for fMRI to study the efficacy of symptom- and disease-modifying agents in AD.
Objectives:
1) To determine the effects of AD on the activity and functional connectivity of the verbal memory encoding and retrieval systems in the medial temporal lobes, retrosplenial cortex and neocortex.
2) To investigate the modulatory effects of central cholinesterase inhibitor (ChI) therapy with serial fMRI studies.
Methodology:
The study populations will consist of 20 patients with mild AD, 20 with moderate AD and 20 matched normal subjects. A longitudinal study (9-12 months apart) will be performed on mild AD patients without ChI treatment, while the effects of introducing ChI in moderate AD patients will investigated in parallel.
Stimuli and Task Demands: The subjects will hear, and attempt to remember, simple factual, imageable sentences. Recall will follow a distractor task, based on simple number semantics, performed a variable number of times.
Functional imaging: Patients will be scanned using fMRI at 3.0T. Serial studies, to assess test-retest reliability, disease progression or response to ChI, will be performed. Functional images will be obtained with a T2-weighted gradient echo, echo planar-imaging (EPI) sequence. All data will be acquired using sparse sampling, which allows the stimuli to be presented in silence.
Image Analyses: Whole brain individual and group analyses will be performed. The neocortical, medial temporal lobe and retrosplenial regions will be defined on anatomical T1-weighted images of the normal subjects, with reference to published atlases of the regions. A mixed ANOVA will be used to analyse regional activity (local effect size) and inter-regional correlations from fMRI time series (functional connectivity) in the paent and control groups, with planned comparisons and post-hoc tests to identify differences between groups, and within groups as the result of disease progression or administration of symptom-modifying agents. Activity in sensory and motor areas will be analysed to determine whether the pathology of AD may alter the relationship between the haemodynamic response and neural activity.
Scientific and Medical Opportunities:
The study will provide new information about the effects of AD on the distributed neural systems supporting verbal memory encoding and retrieval, and the potential to exploit fMRI as a diagnostic tool in AD and as a surrogate marker of disease progression and treatment.

Publications


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Dhanjal NS (2008) Perceptual systems controlling speech production. in The Journal of neuroscience : the official journal of the Society for Neuroscience
Tiberi O (2015) Diagnosing and treating hepatic encephalopathy. in British journal of hospital medicine (London, England : 2005)
Woodhead ZV (2011) The visual word form system in context. in The Journal of neuroscience : the official journal of the Society for Neuroscience
 
Description Royal College of Physicians/Alzheimer's Society meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact I presented a poster at the meeting and members of the Alzheimer's Association patient body questioned me on my research and potential implications.

Increased awareness of the change in brain activity associated with progressive memory impairment in Alzheimer's disease by the officers of the Alzheimer's Society
Year(s) Of Engagement Activity 2010
 
Description University of the Third Age meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 100 members of the public attended. There were a number of questions and a lengthy discussion following the talk.

Many members of the audience expressed and interest in volunteering for the research studies.
Year(s) Of Engagement Activity 2008