Research
Grants and Training Awards
2002-2003
The
Alzheimer Society Research Program is a collaborative
funding effort between the Alzheimer Society of Canada
and its provincial affiliates. This document indicates
all grants and awards currently funded through the Research
Program, including those that were approved in 2001.
The
success of the Society's Research Program depends on
the financial support of its partners and private donors.
The Society gratefully acknowledges the support it receives
from all sources.
The
Alzheimer Society recognizes Mrs. Pauline Spatz for her
longstanding commitment to the Society's Research Program,
and for establishing the Dr. & Mrs. Albert Spatz
Doctoral Award. We are also pleased to acknowledge AstraZeneca
Canada, AstraZeneca USA, and the Canadian Institutes
of Health Research (CIHR) Rx&D, who continue as co-funding
partners in a special grants program to support biomedical
research related to Alzheimer's disease.
This
year, we are pleased to welcome the Institute of Aging
(CIHR) as a co-funding partner in our research grants
and training awards programs, and the Canadian Nurses
Foundation for its support of research in the area of
caregiving. We also acknowledge Mr. and Mrs. James Putnam
for establishing the James and Bernice Putnam Grant for
Biomedical Research, Mrs. Damarais Robinson for establishing
the Anne and Lauren Hansman Doctoral Award, and Joey's
Only Seafood Restaurants for establishing a doctoral
award in their name.
Finally,
a special word of thanks to provincial organizations
and local chapters of the Alzheimer Society for their
contributions to the awards listed here.
- Alzheimer
Society of British Columbia
- Alzheimer
Society of Alberta and Chapters
(Alberta/Wood Buffalo, Calgary, Edmonton, Grand Prairie,
Lethbridge and Area)
- Alzheimer
Society Of Saskatchewan
- Alzheimer
Society of Manitoba
- Alzheimer
Society of Ontario and Chapters
(Brant, Chatham-Kent, Cornwall & District, Durham
Region, Greater Simcoe County, Grey-Bruce, Hamilton & Halton,
Huron County, Kingston, Kitchener-Waterloo, Lanark County,
London & Middlesex, Muskoka, North East Simcoe County,
Ottawa-Carleton, Oxford, Peel, Perth , Peterborough & Area,
Prince Edward County, Sudbury-Manitoulin, Thunder Bay,
Timmins-Porcupine, Toronto, Windsor-Essex York Region)
- Federation
of Quebec Alzheimer Societies and Chapters
(Bas Saint-Laurent, Chaudière-Appalaches, Côte-Nord,
Drummond, Haut-Richelieu Lanaudière, Laurentides,
Laval, Maskoutains-Vallée des Patriotes, Mauricie,
Montréal, Outaouais québécois, Quebéc,
Rouyn-Noranda, Vallée de l'Or)
- Alzheimer
Society of New Brunswick
- Alzheimer
Society of Nova Scotia
- Alzheimer
Society of Prince Edward Island
- Alzheimer
Society of Newfoundland & Labrador
Research
Grants
Dr.
Isabelle Aubert
Sunnybrook and Women's College Health Sciences Centre,
Toronto, Ontario
New
2002 - $100,000
2003 - $100,000
Cholinergic
regeneration in the aging brain
This project is funded through the ASC/CIHR Rx&D/AstraZeneca
Biomedical Grants Program.
Degeneration
of brain cells (neurons) occurs at accelerated rates
in individuals diagnosed with Alzheimer disease (AD).
The degenerating neurons do not have the capacity to
spontaneously repair themselves and they eventually become
unable to sustain their functions adequately, which can
lead to decreased cell-to-cell communication (neurotransmission)
and behavioural deficits. Cholinergic neurons (i.e.,
neurons that release acetylcholine, a brain chemical
that is involved in neurotransmission) are especially
affected in AD. The degeneration of cholinergic neurons
in specific brain areas is likely to result in the deterioration
of memory functions (inability to learn new information
or to recall previously learned information), impairment
in speech and orientation to time and place, loss of
autonomy in daily living, and several neuropsychiatric
changes.
The
administration of agents that restore cholinergic communication
between neurons has the potential to improve cognitive
and related functions. However, at advanced stages of
AD, the severe degenerative state of cholinergic neurons
may limit the success of pharmacotherapy. One strategy
to overcome this limitation is to halt the degenerative
process and encourage cholinergic neurons to regenerate.
The proposed research aims at developing approaches to
allow for successful cholinergic regeneration in animal
models.
The
strategies to promote regeneration allow the recapitulation
of certain developmental events. More specifically, the
degenerating neurons must survive and re-grow structural
processes to re-establish contact with their original
target areas. To facilitate this repair, genetically-modified
cells producing cell-survival factors (e.g., nerve growth
factor, NGF) and growth-promoting substrates (e.g., cell
adhesion molecule L1) will be grafted where cholinergic
neurons are degenerating in the aging brain. The genetically-modified
cells producing NGF were designed so that NGF expression
can be suppressed, at the appropriate time, by simple
oral administration of an antibiotic. Such precise control
over NGF gene expression will allow optimal delivery
of this therapeutic factor, maximizing cholinergic regeneration
by creating NGF gradients from cell to body towards the
target area and providing a stable axonal growth-promoting
substrate (L1). Furthermore, this approach will limit
the undesirable side effects that could be caused by
prolonged delivery of NGF.
The
regulation of gene expression is an important issue in
the application of a gene therapy approach for neurodegenerative
disorders.
Dr.
Lynn Beattie
Co-Applicants: Dr. Gloria Gutman, Dr. Howard Feldman, Dr.
Clyde Hertzman
University of British Columbia, Vancouver, British Columbia
New
2002 - $58,520
2003 - $48,995
CSHA-BC
cohort linkage: Characterization, prediction and costs
of health services
This project is funded by the Alzheimer Society of British
Columbia.
From
the Canadian Study of Health and Aging (CSHA, 2000) it
is estimated that there will be 60,150 new cases of dementia
per year. Alzheimer's disease (AD) is the most common type
of dementia in Canada, making up almost two-thirds of
all dementias. CSHA has been a ten year Canadian initiative
to study the health of our elderly and the effect of
devastating diseases such as Alzheimer's disease. Participating
subjects are 65 years and older, and were interviewed
in 1991 and followed-up in 1996 (CSHA 2 and 2001 (CSHA3).
The British Columbia Linked Health Data (BCLHD) set is
a provincial administrative database that carries health
service utilization information such as hospitalizations,
physician visits, pharmacare, home care and long term
care. Our work to date has combined the information from
these two databases to evaluate the health care costs
of services and their relationship to factors such as
changes in memory and thinking, chronic diseases, support
of family, community, socioeconomic status, and institutionalization
and death.
The
objectives of this proposal are (a) to expand the data
set to include up-to-date information to the year 2000;
(2) to profile the health care service utilization and
costs over time with particular attention to cost consequences
of institutionalization and death; (3) to identify those
individuals from CSHA 1 who subsequently develop early
signs of memory loss or AD and compare their health service
costs to individuals who remain healthy in the community;
(4) to determine the effect on health service costs of
chronic diseases and health conditions using simple measures
of perceived health, ability to walk and ability to think;
(5) to evaluate the effects family and community supports
and socioeconomic status have on health service utilization
and costs. The merging of these databases creates a unique
opportunity to explore the impact of AD on health service
utilization costs. We believe that as memory and thinking
ability are lost, health service utilization and costs
increase though it is unclear as to the impact, if any,
the actual diagnosis of AD will have on costs. It is
expected that this research will assist in developing
appropriate policy and health service planning for the
elderly in Canada.
Dr.
Gabrielle L. Boulianne
The Hospital For Sick Children, Toronto, Ontario
Continuing
2001 - $96,620
2002 - $91,620
Genetic
modifiers and presenilins
This project is funded through the ASC/CIHR Rx&D/AstraZeneca
Biomedical Grants Program.
Insight
into the mechanisms underlying Alzheimer's disease (AD)
has come from the identification of mutations in three
genes, Amyloid Beta Protein Precursor, presenilin 1 and
presenilin 2, that have been linked with early-onset
familial AD (FAD). However, while mutations in these
genes are associated with almost 50% of FAD, they account
for less than 5% of all AD cases, which are mainly sporadic
and late-onset. This low frequency suggests that other
genes must play a role either as causative or susceptibility
factors in AD. Increasing evidence has implicated certain
versions (alleles) of Apolipoprotein E (i.e., ApoE4)
and a2-macroglobulin (A2M) as AD risk factors. However,
these two risk factors alone are unlikely to account
for all cases of AD and additional factors need to be
identified and their role in AD determined.
The
aim of this research is to identify and characterize
causative or susceptibility genetic risk factors in AD.
Powerful methods will be used to identify and characterize
genetic modifiers of presenilins in the fruit fly, Drosophila
melanogaster. The hypothesis is that genes that interact
with presenilin in a common pathway may contribute to
the pathogenesis of AD. Once identified the critical
parts of our Drosophila modifiers will be isolated and
examined in genetically engineered (transgenic) mice
where their roles in AD can be rigorously tested.
Dr.
Richard E. Brown
Dalhousie University, Halifax, Nova Scotia
Continuing
2001 - $50,000
2002 - $50,000
Behavioural
tests of mouse models of Alzheimer's disease
Genetically
engineered mouse models, being developed for Alzheimer's disease (AD) typically show neurological signs of AD,
but behavioural tests show equivocal results. In part,
this is because no systematic method of profiling the
AD-like behaviours of various mouse models of the disease
yet exists. The present experiments will conduct a thorough
battery of tests on the FVB/APP London mouse and FVB
control mice. The APP London mouse shows both early and
late AD-like neurological and behavioural symptoms and,
as such, may provide a better understanding of AD progression.
The tests employed will include (1) a battery of cognitive
tests including learning, memory, and executive function,
(2) a battery of non-cognitive tests for emotional, sensory,
and, motor disturbances, and (3) a developmental test
battery. Tests will be done on the development of mice
between birth and puberty, on young, medium age, and
old adult mice. Both males and females will be tested.
The results will determine the cognitive and behavioural
parameters that differentiate AD mice from controls,
and whether this mouse model shows the specific behavioural
deficits found in AD.
Dr.
Neena Chappell
Co-Applicants: Mr. Robert Colin Reid, Dr. Marilyn Bater,
Dr. John Gray
University of Victoria, Victoria, British Columbia
New
2002 - $59,920
2003 - $59,920
Quality
of life for people with Alzheimer type dementia and
their caregivers
This project is funded by the Alzheimer Society of British
Columbia, the ASC and the Canadian Nurses Foundation through
the Caregiving Research Program.
As
the population ages, it is important to provide quality
care for dementia sufferers in our long term care institutions.
However, research to date has failed to demonstrate that
dimensions of care (best practices) are related to desirable
outcomes for dementia sufferers. One of the reasons for
the inability to link best practices to outcomes for
dementia sufferers is the lack of comprehensive, valid
and reliable measures of dimensions of care. The intent
of this proposal is to develop these measures.
Since
accurate measurement of care interventions is needed
to establish the link between care quality and resident
outcomes, the research focuses on the methodological
task of measurement development of those dimensions of
care that are believed to reflect best practices; pre-admission
and admission procedures; staffing (including attitudes,
qualifications, ratios, mix and turnover); unit philosophy;
non-use of restraints (both physical and chemical); flexible
care and resident relevant activities; and the physical
environment. Of these six, four, pre-admission and admission
procedures, staff training and education, care philosophies
and expectations of administration, and flexible care
routines, require further development.
Working
with a minimum of 10 facilities, 20 units and an expert
panel that includes a clinical nurse specialist, geriatrician,
family member, cognitively altered long term care resident,
provincial ministry of health representative, and internationally
recognized research specialists in this area from the
United States, the researchers will use qualitative and
quantitative methods to develop a range of valid and
reliable measures.
Dr.
Bonnie Dobbs
Co-Applicants: Dr. A. Dobbs, Ms. L. Barrett, Dr. L. Harper,
Ms. A. Woods,
Dr. J. Triscott, Dr. A. Juby
University of Alberta, Edmonton, Alberta
New
2002 - $59,185
2003 - $59,717
Development
and assessment of psychoeducational group interactions
for: 1) individuals with Alzheimer's disease who have
lost their driving privileges and 2) for their primary
caregivers
The
loss of driving privileges can be very difficult for
a person with Alzheimer's disease (AD) to accept, yet all
drivers with AD will, at some point, have to stop driving.
The strong resistance and emotionality associated with
having to stop driving can be very disruptive and difficult
for the individual and caregivers as well. The difficulty
of the "stop driving" situation is not surprising
because of the central role that driving plays in meeting
transportation needs, and the symbolism it has for independence,
competence, and self-esteem. Clearly, both persons with
dementia who have to stop driving and their caregivers
could benefit from a support group designed and validated
to be effective in reducing the stress for the person
with AD and the caregiving burden for the caregiver.
The proposed research will assess the effectiveness of
a new group intervention designed to address commonly
experienced problems arising when the "stop driving" directive
comes. The program is based on principles found to be
effective for caregivers in other caregiving situations.
The group intervention emphasizes changing appraisals
of the stressor from global ill-defined problems (e.g., "X
is so disruptive I am at wit's end) that do not suggest
any coping strategy to specific problems that can be
addressed (e.g., "the constant questions about driving
are driving me crazy"). The caregiver will also
learn to distinguish between changeable (a person with
AD will continue to be unable and unsafe to drive) and
non-changeable (he or she repeatedly demanding the car
keys) stressors. When the strcssor is unchangeable, the
focus is on coping with the emotion and sense of loss.
When the stressor is changeable, appropriate problem
solving strategies should be selected. The group intervention
for the person with AD will not attempt to teach the
person to analyze and select strategies. Instead, the
group leader will take problems expressed by the participants
with AD, translate globally expressed problems into specific
problems, and work with the person regarding the changeable
or unchangeable status of the specific problem. Finally,
the group leader will work with the individual to reduce
the emotionality of unchangeable problems or to develop
solutions when the problems are changeable
Dr.
Francine Ducharme
Institut universitaire de gériatrie de Montréal,
Montréal, Québec
New
2002 - $57,850
2003 - $57,635
Health
status of older men who, as informal caregivers, care
for women with dementia in their homes
This program is funded by ASC and the Canadian Nurses Foundation
through the Caregiving Research Program.
This
research will investigate the relationship between caregiver
stress and health factors in a group of male primary
caregivers of community-dwelling women with Alzheimer's disease. A primary objective is to examine Pearlin's
theoretical model of caregiving for its ability to account
for health factors of male caregivers. Quantitative methods
will be used to provide measures related to each of the
factors or stressors identified in the caregiving model
(eg., conjugal relations, behavioural problems, family
conflict, social support, adaptive strategies). A second,
qualitative study, conducted with a subset of the larger
group, will focus on issues related to existing health
and social services, and whether or not they are accessible
and meet the needs of the male caregiver. This research
has implications for health and service delivery problems,
which may have to be modified to meet the unique needs
of men who act as caregivers for their spouses with dementia.
Dr.
Sherry Dupuis
Co-Applicant: Dr. James Gladstone
University of Waterloo, Waterloo, Ontario
New
2002 - $44,530
2003 - $44,530
Towards
an understanding of institution-based caregiving in
the dementia Context
Evidence
suggests that the caregiving role can change dramatically
over time, even within any one stage of caregiving (e.g.,
role caring in the community, role caring after the care
receiver is moved to a long-term care setting). Nonetheless,
a large majority of the research on caregiving examines
caregivers only at one point in time. Thus, knowledge
of the dynamics of the caregiving role and the changes
caregivers in the dementia context experience over time,
particularly as the disease progresses, is limited. The
purpose of this study is to examine changes within the
institution-based caregiving role over time for persons
caring for a relative with dementia. Continuing a study
currently being funded by the Alzheimer Society of Canada,
this next phase is meant to broaden our understanding
of institution-based caregiving roles by seeking to:
(a) document how the meanings and types of activities
associated with the caregiving role shift over the institution-based
caregiving career, particularly as the disease progresses;
(b) examine how the caregiving experience changes over
the institution based caregiving career and thus identify
the changing needs of dementia caregivers over time;
(c) examine how the relationships and interactions between
staff and caregivers shift over the institution-based
caregiving career; and (d) explore differences and similarities
in institution-based caregiving paths taken by different
subgroup of caregivers (e.g., female caregivers, male
caregivers, spouses, adult children, other caregivers.)
The
information from this study has important practice and
policy implications. If we can identify how the experience
in the caregiving role changes over time and the factors
associated with those changes, long-term care facilities
will be in a much better position to more effectively
meet the changing needs of caregivers who are providing
care to a relative or friend with dementia.
Dr.
Howard Feldman
Co-Applicants: Dr. B. Lynn Beattie, Dr. Dean J. Foti, Dr.
Sherri Hayden, Dr. David K.B. Li
UBC Hospital, Vancouver, British Columbia
New
2002 - $90,477
2003 - $90,477
A
serial magnetic resonance study of cognitively-impaired-not
demented patients and controls
This project is funded through the ASC/CIHR Rx&D/AstraZeneca
Biomedical Grants Program.
Individuals
with mild cognitive impairment (MCI) have a greater than
normal risk of developing Alzheimer's disease (AD). However,
our ability to distinguish those individuals who will
develop AD from those who will not is limited. Accordingly,
the overall purpose of this research is to develop a
method of identifying which individuals with MCI will
later develop AD. Specific objectives address the following
questions: (1) Can information regarding the size and
structure of certain brain regions be used to predict
who will get AD? (2) Do certain brain regions show faster
rates of deterioration in individuals with MCI compared
to individuals without MCI?
The
research will involve two groups of subjects: individuals
who are experiencing MCI and control subjects (those
not experiencing any cognitive impairment). Both groups
will receive comprehensive examinations several times
over a one-year period. All subjects will be examined
by a physician to determine their medical history and
to assign them to one of the two groups. All subjects
will also undergo cognitive testing (which will involve
tests of memory, problem-solving, and concentration)
and magnetic resonance imaging (MRI) examinations. The
MRI examinations will allow measurement of the size and
structure of certain brain regions over the one-year
period and enable comparison of how these brain regions
change in individuals who later develop AD versus those
who do not.
Dr.
Geoff Fernie
Co-Applicant: Dr. Sandra Black
Sunnybrook and Women's College Health Sciences Centre,
Toronto, Ontario
New
2002 - $53,758
2003 - $45,725
The
development of an intelligent cognitive orthosis to
facilitate independent toileting in Alzheimer's disease
Alzheimer's disease (AD) often results in a person not being able
to complete activities of daily living (ADL) such as
washing, dressing, or using the toilet. A common solution
is for a caregiver to continually watch the person and
provide verbal reminders when necessary. This loss of
independence and privacy can become very upsetting for
everyone involved, especially during toilet-related activities.
Perhaps privacy and dignity can be partially restored
by using an intelligent computerized device that can
provide these verbal reminders and monitor progress.
Thus, assistance would be provided, but a caregiver will
not be required to be present at all times.
The
objective of this research is to continue the development
of such a device. It will use artificial intelligence
to automatically learn about different users, adapt to
the users' behaviours, and can be easily set up by a
caregiver for most ADL tasks. Capabilities developed
and added to the existing devise include the recognition
of hand gestures, voice recognition and the addition
of visual as well as auditory feedback. The user will
hear verbal reminders (as in the present prototype) but
will also be able to see an image of the caregiver speaking
the reminder and demonstrating the required action.
A
prototype has been developed which has been shown to
increase the ability of people with severe levels of
dementia to wash their hands without the need for prompting
by a caregiver. The performance of the new prototype
will be compared with this current device during more
handwashing tests. These results will determine if enough
is known to design a marketable product, or if more research
is required.
Dr.
Gordon Glazner
St. Boniface Hospital Research Centre, Winnipeg, Manitoba
New
2002 - $99,700
2003 - $97,700
Mutant
PSI disrupts life and death balance between KFKB and
GADD153
This project is funded by the Alzheimer Society of Manitoba
through the ASC/CIHR Rx&D/AstraZeneca Biomedical Grants
Program.
Alzheimer's disease (AD) is the most common neurodegenerative disease
of aging, causing loss of mental faculties and motor
skills, personality alterations, and eventually death.
Although the cause of AD is unknown in the majority of
cases, there is a subset of AD that runs in families
(FAD) caused by specific mutations. Most of these cases
are caused by mutations in a protein called presenilin
(PS). We do not know the normal function of PS, nor do
we know why mutations cause FAD. However, we do know
that neurons that contain this mutation (mPS1) die more
quickly when put under stress. A striking change associated
with this augmented death is an increase in the amount
of calcium ion in the interior space (cytoplasm) of neurons.
This is a critical observation, since excess calcium
kills neurons in other conditions such as stroke. Closer
examination reveals that this excess calcium primarily
comes from the endoplasmic reticulum (ER), where PS resides.
Excessive ER calcium release activates an enzyme call
GADD153, which kills cells, though GADD153 has never
been examined in cells containing PS1. Somewhat paradoxically,
release of calcium from ER also stimulates activity of
an enzyme called NF-KB, which helps keep the cell alive.
NF-KB also feeds back to inhibit ER calcium release,
and so aids in reducing excessive calcium release. In
addition, NF-KB represses GADD153, to the point that
GADD153 is not detectable in healthy neurons. In our
early studies, we have found that NF-KB is not activated
normally in neurons containing mPS1. Since NF-KB inhibits
ER calcium release and GADD153, this means there is both
greater levels of cytoplasmic calcium and of a protein
that kills cells.
We
propose to examine the role that increases in GADD153
and repression of NF-KB may play in mPS1-mediated neuronal
death.
This
study may greatly increase our understanding of the way
in which mPS 1 increases vulnerability of neurons to
stress-induced death, and potentially give us a new target
of treatment for this disease. In addition, since GADD153
kills normal neurons during severe stress, it may also
lead to treatments for sporadic AD as well.
Dr.
Edith Hamel
McGill University, Montreal, Quebec
Continuing
2001 - $50,000
2002 - $50,000
The
role of inflammation in cerebrovascular and neuronal
dysfunctions associated with Alzheimer's disease
In
Alzheimer's disease (AD), blood supply problems are present
in several brain regions and appear in the early stages
of the disease, that is, before neurons begin to die.
In the more advanced stages of the disease, brain vessels
undergo significant changes and several vessels literally
degenerate. Recently, it was suggested that chronic inflammation
in the brain is a key factor in the onset of AD. A number
of molecules are produced when inflammation occurs, in
particular one called "transforming growth factor ß1
(TGF-ß1)". When a TGF-ß1 increase occurs
in mice, they develop cerebral vascular disorders as
they age, which are identical to those found in patients
with AD. We have shown that certain neurons degenerate
in the older mice, specifically the neurons that contain
acetylcholine, which are in fact the first to die in
AD, almost completely disappearing in the terminal stage.
In
this research program, we suggest that TGF-ß1 is
a key element in cerebral vascular and neurodegenerative
disorders associated with AD. In order to verify this
hypothesis, we will ?) study the effect of TGF-ß1
on the brain vessels' ability to dilate and contract
in response to several substances released by neurons
that are known to contract or dilate brain vessels, ii)
verify these responses in mice with an abundance of TGF-ß1
in order to verify the effect on long-term vasomotor
responses, iii) assess whether TGF- ß1 can lead
to changes in the receptors (proteins that enable the
substances released by the neurons to affect the vessels)
involved in the dilative and constrictor responses in
the brain vessels, and finally iv) assess effect, over
time, of TGF-ß1 on cholinergic neurons and verify
that this outcome is selective by comparing the effects
of TGF-ß1 on neurons containing serotonin. We will
also study vascular and neuronal targets for these neurons.
These
studies will allow us to evaluate the role of inflammation
and particularly of TGF-ß1 in cerebral vascular
responses, as well as the status of certain neurons.
The results may help identify therapeutic targets in
order to prevent certain circulation and neuronal problems
associated with AD.
Dr.
Krista Lanctôt
Co-Applicants: Dr. Nathan Hermann and Dr. Goran Eryavec
Sunnybrook and Women's College Health Sciences Centre,
Toronto, Ontario
Continuing
2001 - $49,732
2002 - $49,680
The
role of the GABAergic system in behavioural disorders
associated with Alzheimer's disease
Behavioural
disturbances are prominent in Alzheimer's disease (AD).
Aggressive behaviours are of particular concern because
they complicate management, increase caregiver burden
and often stimulate family members to institutionalize
the demented patient. Treatment of aggressive behaviour
is difficult but one approach is to develop drugs that
target biochemical abnormalities that are associated
with such behaviour.
One
type of natural brain chemical, gamma-aminobutyric acid
("GABA") may be linked to the presence of certain
behavioural disorders. Previous work has shown that GABA
is part of the control system for aggressive behaviour
in humans and animals. Autopsies have shown that GABA
is lower in some AD patients compared with healthy persons
of the same age. The investigators will measure changes
in the activity of GABA in AD patients, with and without
aggressive behaviours, to determine if the aggression
can be linked to concentrations of this brain chemical.
They also want to discover whether drugs that affect
GABA can reduce aggressive behaviour in AD patients.
Perhaps most importantly, they want to determine whether
GABA levels in the blood can be used to predict which
patient with AD will respond best to treatment with drugs
that affect GABA.
The
plan is to examine 32 AD patients, all with behavioural
disorders, 16 of whom suffer from aggressive episodes
on a regular basis, and 16 who do not. Brain GABA activity
will be estimated using blood GABA levels. In order to
measure blood GABA levels, one blood sample will be obtained
from each patient before treatment. Subsequently, each
patient will receive either valproate, a drug that works
through GABA or placebo (inactive drug) for a six-week
period. After six weeks, each patient will be switched
to the other therapy. Questionnaires will be administered
during patient and caregiver interviews to measure behaviour
after valproate compared to placebo. In this way, the
aim is to develop a simple blood test to determine whether
aggressive behaviours in AD patients will lessen following
treatment with valproate or related drugs.
Dr.
Krista Lanctôt
Co-Applicants: Ds. Paula Rochon, Dr. Sandra E. Black,Dr.
Morris Freedman, Dr. Jerry H. Gurwitz, Dr. Nathan Hermann,
Dr. David L. Streiner Sunnybrook and Women's College Health
Sciences Centre, Toronto, Ontario
New
2002 - $59,944
2003 - $59,529
Interactions
between herbal medicines and conventional drug therapy
Older
adults with dementia are frequent users of herbal medicines.
They are also likely to be taking multiple conventional
drug therapies and are therefore at risk for interactions
between herbal medicines and conventional drug therapies
that may lead to an adverse event. No studies have documented
the extent to which older adults experience adverse events
due to the interactions from taking a combination of
herbal medicines and conventional drugs. The objective
of this study is to explore potential interactions between
herbal medicines and conventional drug therapy (i.e.,
prescribed and over-the-counter) that may lead to adverse
events among older adults with Alzheimer's disease and
related dementias.
A
group of patients taking herbal medicine-conventional
drug therapy combinations that are reported in the literature
to be associated with an interaction that may lead to
an adverse drug event, will be identified. Six-month
follow-up interviews will be conducted with all patients
identified as possibly having an interaction, to determine
whether they develop an adverse drug event and compare
them to herbal users without identified interactions,
and nonherbal users. The aim is to have physicians recognize
that herbal medicines may interact with conventional
drug therapy and to consider them when making prescribing
decisions.
Dr.
Georges Levesque
Co-Applicant: Dr. Jean-Pierre Perreault
University of Sherbrooke, Sherbrooke, Quebec
Continuing
2001 - $47,610
2002 - $48,080
Ribozymes
against amyloid aggregation
The
neuropathological hallmarks of Alzheimer's disease (AD)
include amyloid-beta peptide (Ab) deposits (known as
senile or amyloid plaques). Multiple studies in transgenic
mice and cell lines provide strong evidence to support
the amyloid cascade as an early and critical event in
the development of AD. The hypothesis is that inhibition
or reduction of the amyloid protein precursor (APP) messenger
RNA expression will block the aggregation of Ab that
contributes to neuronal death in AD patients. The plan
is to use ribozyme to decrease the APP gene expression.
To test their hypothesis and the curative ability of
ribozyme, the researchers will: 1) engineer a delta ribozyme
that specifically cleaves APP; 2) characterize the effect
of the APP-delta ribozyme on amyloid-beta accumulation
in cells; 3) evaluate the possibility of using the engineered
APP-delta ribozyme as a gene therapy tool against amyloid
aggregations in vitro/in vivo. This approach has the
advantage of targeting the top of the amyloid cascade
as well as controlling the level of inhibition using
appropriate expression vectors.
Dr.
Sonia J. Lupien
Douglas Hospital, Verdun, Quebec
Continuing
2001 - $49,340
2002 - $49,340
The
Douglas Hospital longitudinal study of normal and pathological
aging
Scientific
studies have shown that elderly persons may be more vulnerable
to the negative impact of stress than young individuals.
The reason for this in scientific terms, is that stress
is defined by three major characteristics -- novelty,
unpredictability, and lack of control over a situation.
When these three characteristics are taken into account,
we see that elderly persons are faced, on a daily basis,
with highly stressful situations. For example, loss of
a spouse, unorganized retirement, loss of income, and
health problems all represent novel and unpredictable
situations over which elderly individuals might feel
they have little control.
Research
on animals has shown that stress induces the release
of stress hormones (particularly cortisol in humans)
which are secreted by the adrenal gland. These stress
hormones access the brain and have a negative impact
on the hippocampus, which plays a significant role in
learning and memory. In order to test whether this cascade
of events also occurs in humans, Dr. Lupien and her colleagues
have followed a population of 56 elderly persons (between
65 and 85 years old) for 4 to 10 years. Every year, the
participants visit the Douglas Hospital Clinical Research
Unit and blood samples (for analysis of cortisol levels)
are taken every hour for 24 hours. This is done since
cortisol follows a circadian rhythm, i.e., its levels
change with the time of the day. The data showed that
elderly individuals, with increased cortisol levels over
a 4-year period also had significant memory impairments.
Moreover, the impaired participants had 14% atrophy of
their hippocampus. These results suggest that because
of its impact on the hippocampus, chronic elevation of
cortisol might predispose the elderly to the emergence
of memory problems, and eventually dementia.
The
plan is to administer the same protocol to these individuals
over extended periods to measure the long-term impact
of cortisol changes on both memory performance and hippocampal
volume. Dr. Lupien will also measure exposure of these
individuals to environmental stressors and depression
to assess potential relationships between these factors
and stress hormone levels.
Dr.
Hazel MacRae
Mount Saint Vincent University, Halifax, Nova Scotia
New
2002 - $5,263
Living
with Dementia: The experience of the person who is
ill
This
study will use qualitative measures to determine what
Alzheimer's disease (AD), or other type of dementia, means
to the persons who have it and to ascertain the impact
it has on their everyday lives. Most of the research,
to date, has focused on the disease itself or the caregivers
of people with dementia; the perspective of the person
who has the disease has been largely ignored.
The
study will examine the social and psychosocial factors
that shape the individual's experience of the disease,
including his/her sense of self. It will also examine
the impact of the disease on aspects of life such as,
relationships, roles, and meaningful activities. How
persons with dementia manage the multiple situations
that comprise their everyday lives also will be investigated.
The
principal research instrument employed is the face-to-face
in-depth interview. An unstructured interview guide will
be used to focus the audio tape-recorded interviews.
The sample will be comprised of 15 individuals who have
been officially diagnosed with dementia and are in the
early stages of the disease. The data will be analyzed
using a grounded theory approach.
The
study will incorporate insights from the literature on
the social psychology of chronic illness in order to
help contribute to the development of a social psychology
of dementia. Knowledge of the psychosocial impact of
living with dementia and awareness of the patient's point
of view will help physicians, other health care professionals,
and caregivers to meet the psychosocial needs of persons
with dementia. Insights obtained will also be useful
to family members who struggle to understand what the
person with dementia is experiencing and what they can
do to help.
Dr.
Michael Mayne
Co-Applicant: Dr. Jonathon D. Geiger
St. Boniface Research Centre, Winnipeg, Manitoba
Continuing
2001 - $50,000
2002 - $50,000
Mutant
presenilin and ryanodine receptor interactions
This project is funded by the Alzheimer Society of Manitoba.
Early
onset forms of familial Alzheimer's disease (AD) have been
linked to two related genes; presenilin 1 (PS-1) and
presenilin 2 (PS-2). There is evidence that mutant forms
of presenilin genes increase deposits of ß-amyloid
protein (Aß) deposits which contribute to the build-up
of neuritic plaques in AD brains. Previous work indicates
that levels of intracellular calcium are important in
the production and release of Aß. This project
focuses on one pool of intracellular calcium that is
controlled by caffeine-sensitive sites that bind a plant
chemical known as ryanodine - so called ryanodine receptors.
Drs Mayne and Geiger found recently that ryanodine receptors
co-localize with mutant presenilin proteins within neurons
and that this co-localization correlates with dysregulation
of calcium homeostasis and sensitization of neurons to
neurotoxic insults. The investigators hypothesize that
presenilin proteins physically interact and directly
regulate the expression and function of ryanodine receptors.
Accordingly, using modern molecular biological techniques,
they will determine the extent to which mutant PS-1 physically
interacts with ryanodine receptors, as well as regulates
the expression and function of ryanodine receptors. The
results of these experiments may yield important new
mechanistic information about PS-1 and ryanodine receptors
and may identify ryanodine receptors as an important
target for therapeutic intervention in AD.
Dr.
Mark T. McDermott
Co-Applicant: Dr. Beatrice Leveugie
University of Alberta, Edmonton, Alberta
Continuing
2001 - $45,900
2002 - $47,750
Microscopic
investigation of the interactions between A-beta peptide
and Glycosaminolgycans
The
plethora of evidence supporting the role of Aß amyloid
peptide in the pathogenesis of Alzheimer's disease (AD)
has led to the development of anti-amyloid therapies.
Understanding the process of Aß aggregation and
Aß-mediated neurotoxicity and developing models
to examine and inhibit such effects are key goals in
the effort to design effective drugs for treating or
preventing AD.
The
main objective of this research is to develop a model
allowing the visualization and measurement of Aß aggregation
on immobilized glycosaminoglycans (GAGs). GAGs and more
particularly heparin sulfate (HS) are important co-factors
of the amyloidogenic process. The visualization at the
macromolecular level of the interaction of Aß with
various GAGs will reveal whether these linear polysaccharides
can act as a template allowing Aß seeding and initiation
of microfibril formation, or are involved at later stages
such as elongation and assembly of the preformed microfibrils
into large amyloid deposits. Using this model, the interaction
between Aß and structurally different heparins
will be studied to test the hypothesis that specific
structural features of the HS chain are involved in the
amyloidogenic process. The identification of such features
will be particularly useful for the design and selection
of anti-amyloid agents for the treatment of AD.
HS
is a natural component of the brain parenchyma and neuronal
cell surface. Because Aß binds tightly to HS it
is likely that anti-amyloid drugs will have to compete
in vivo with endogenous HS. None of the existing models
for the screening of inhibitors of fibril formation take
into consideration the role of HS. For this reason, it
is believed that the present model will be particularly
useful for the identification of anti-amyloid drug candidates
and will predict more accurately the in vivo therapeutic
utility of the tested drugs. The potential utility of
this model in the identification of new inhibitors of
amyloid formation will be tested using low molecular
weight heparin mimetics that have already shown promise
as anti-amyloid drug candidates.
Dr.
Edith McGeer
Co-Applicant: Dr. Patrick L. McGeer
University of British Columbia, Vancouver, British Columbia
Continuing
2001 - $99,384
2002 - $99,397
Neurotoxic
effects of inflammatory cytokines in vitro
This project is funded through the ASC/CIHR Rx&D/AstraZeneca
Biomedical Grants Program.
Recent
reports suggest that a new set of genes contribute significantly
to the risk of developing Alzheimer's disease (AD). These
are polymorphisms in cytokines long known to promote
peripheral inflammatory disorders such as rheumatoid
arthritis and other autoimmune diseases. The cytokines
in question are interleukin-1a, interleukin-1ß,
interleukin-6 and tumor necrosis factor-a. The gene modifications
occur in regions that influence the amount of protein
produced, but not the structure of the proteins themselves.
This
is different from previously reported genetic risk factors,
such as apolipoprotein E, the presenilins and amyloid
precursor protein, all of which involve production of
proteins different from normal. For this reason, the
effects of normal human cytokines, alone or in combination,
must be evaluated directly on various types of human
brain cells. To influence the onset of AD, it is hypothesized
that the cytokines must ultimately affect neuronal survival.
In this project, assay systems developed in the researchers'
lab will be used to test this hypothesis. The direct
neurotoxicity of human inflammatory cytokines, alone
and in combination, and at varying concentrations, will
be examined against human derived neuronal cell lines.
Their indirect effects on neurons will be evaluated in
their microglial neurotoxicity assay system which involves
stimulating human microglial cells in culture, separating
the supernatant, and exposing neuronal cell lines in
culture to the toxic secretions. The effects of the cytokines,
alone and in combination, will be tested to determine
their effects on influencing these neurotoxic secretions.
Since microglial cells and astrocytes are known to be
the main producers of the inflammatory cytokines in brain,
these effects will also be tested in the presence and
absence of human astrocytic cells. This research will
help resolve current controversies by indicating which
cytokines are most powerful in influencing neuronal survival
and at what concentrations. It will also provide information
as to whether the cytokines work independently, synergistically
or antagonistically at different concentrations. The
data should provide useful information regarding which
cytokines to target for the development of future therapeutic
agents for the prevention and treatment of AD.
Dr.
Patrick McGeer
University of British Columbia, Vancouver, British Columbia
Continuing
2001 - $97,675
2002 - $97,675
Relationship
of inflammatory cytokine polymorphism to Alzheimer's disease pathology
This project is funded through the ASC/CIHR Rx&D/AstraZeneca
Biomedical Grants Program.
The
inflammatory hypothesis of Alzheimer's disease (AD) suggests
that much of the neuronal destruction is caused by an
inflammatory reaction to the primary pathology. Evidence
includes the presence of many inflammatory markers in
AD brain and more than 20 epidemiological studies which
have found that persons, such as arthritics, taking anti-inflammatory
medication for other reasons are 50% less likely to develop
AD as age-matched controls. The hypothesis is also supported
by a pilot clinical trial in which the anti-inflammatory
drug indomethacin appeared to halt the progression of
the disease. Further support comes from recent reports
that genetic polymorphisms which increase the expression
of certain inflammatory mediators also increase the risk
of AD. These pro-inflammatory mediators are the cytokines,
IL-1a, IL-1ß, IL-6 and TNF-a. Dr. McGeer has developed
molecular biological and immunohistochemical techniques
which can now be applied to a study of these cytokines.
His laboratory has also built up a brain bank, which
now contains over 600 brains, more than 200 of which
are pathologically proven to be AD cases. For this project,
Dr. McGeer will genotype these brains for ApoE and all
the cytokine polymorphisms reported to influence AD onset
to test the hypothesis that the age of onset will vary
depending on the number of such polymorphisms present.
They will also test the hypothesis that the presence
of such polymorphisms will increase the expression of
the relevant cytokine(s), as measured by mRNA levels,
in affected regions of AD brain while having little effect
in regions that are relatively spared. The results should
be of help in genetic counselling and in the design of
clinical trials. It is hoped that they will also identify
those cytokines of particular importance in AD and thus
provide clues as to the directions in which the search
for new drugs should be concentrated.
Dr.
Hemant Paudel
Lady Davis Institute for Medical Research, Montreal, Quebec
New
2002 - $ 96,516
2003 - $100,000
14-3-3
protein and neurofibrillary pathology of Alzheimer's disease
This project is funded through the ASC/CIHR Rx&D/AstraZeneca
Biomedical Grants Program.
Senile
plaques and neurofibrillary tangles (NTs) are two neuropathological
hallmarks of Alzheimer's disease (AD). NTs develop inside
nerve cells and their topographical distribution reliably
correlates with the degree of dementia, the central symptom
of AD. NTs contain paired helical filaments (PHFs) as
the major fibrous component. Tau, a neuronal microtubule-associated
protein, is the major constituent of PHFs. Recent discoveries
of mutations in tau gene and their association with frontotemporal
dementia (an AD-related disorder) have confirmed that
tau abnormality leads to microtubule disruption, neurodegeneration
and dementia. However, no AD-specific mutation has been
found in tau gene to date. Instead PHF-tau (tau isolated
from PHFs) is abnormally phosphorylated (i.e., contains
more phosphate than normal tau). These observations indicate
that, in the AD brain, the tau phosphorylation/ dephosphorylation
balance is somehow perturbed. However it is still not
clear how tau phosphorylation is regulated in the normal
brain. Recently a multi protein complex containing tau,
tau-specific kinases, phosphatases, and an adapter protein
14-3-3 in brain extract was discovered. This result suggests
that 14-3-3 plays a central role in regulation of tau
protein phosphorylation in normal brain. 14-3-3 expression
has been reported to be upregulated in the AD brain.
This model predicts that upregulated 14-3-3 causes abnormal
tau phosphorylation, tau aggregation, microtubule disruption,
and neurodegeneration. The aim of the proposed study
is to describe the step by step biochemical and cellular
mechanism of PHF formation in the AD brain. Understanding
this mechanism is essential to designing therapeutic
strategies to retard NT formation in the brains of AD
patients.
Dr.
Maire E. Percy
Co-Applicants: David F. Andrews, Morris Freedman
Surrey Place Centre, Toronto, Ontario
Continuing
2001 - $47,540
2002 - $29,560
Risk
factors in dementia
Hemochromatosis
(HHC) is a genetic condition resulting in excessive uptake
of iron which is then deposited in multiple organs resulting
in damage to organs such as the liver, kidney, heart
and pancreas. Traditionally, the brain has been thought
to be to be protected from the effects of iron overload.
The question of metal ion involvement in the pathogenesis
of Alzheimer's disease (AD) is controversial but new evidence
suggests that mutations involved in HHC and iron overload
can contribute to neurodegenerative diseases. A recent
publication from Dr. Percy's lab reported an association
between two common HHC mutations and familial AD.
One
objective of the present research is to extend Dr. Percy's
studies to AD in the general population and to another
type of dementia, vascular dementia (VaD), to determine
if gene mutations responsible for HHC are involved in
the cause or development of these disorders.A second
objective is to investigate how HHC mutations might be
involved in the cause of AD and VaD. This work will focus
on the relation between HHC mutations, and B12 and homocysteine
(HCYS) levels in serum. The reason is that up to 30%
of the general population carries one or two HHC mutations.
Up to 20% of the elderly have low vitamin B12 and as
many as 30% have high levels of homocysteine (HCYS).
There is evidence of low B12 function and high levels
of HCYS in AD and VaD patients. The relationship between
B12, HCYS and body iron status will also be studied,
since the latter is abnormal in HHC.
The
investigators will use blood samples obtained from patients
with sporadic AD or VaD during a routine clinical examination.
Blood samples also will be obtained from healthy volunteers
in the general population matched to each case with respect
to gender, age (+/- 2 years) and time/location of blood
sampling. Genetic studies will be done on DNA extracted
from blood samples. Biochemical studies will be done
on plasma samples prepared from the blood.
The
investigators anticipate that the studies will show that
HHC mutations are significant new genetic risk factors
for AD and VaD. They also anticipate that there will
be a relationship between HHC mutations, vitamin B12
function, HCYS and markers of iron status in people with
AD and VaD. If HHC mutations are significant risk factors
for AD or VaD, and if they are associated with low B12,
high HCYS, and altered body iron status, such findings
will suggest that people with very early AD or VaD might
be treated by existing methods for reducing body iron
stores.
Dr.
Judes Poirier
Douglas Hospital Research Centre, Verdun, Quebec
Continuing
2001 - $100,000
2002 - $100,000
HMG
- CoA reductase: A novel candidate gene for sporadic
Alzheimer's disease
This project is funded through the ASC/CIHR R&xD/AstraZeneca
Biomedical Grants Program.
This
project seeks to identify some of the molecular mechanisms
involved in the loss of specific brain cells in Alzheimer's disease (AD). A protein called apolipoprotein E, which
serves as a shuttle for cholesterol transport between
different cells, was shown to be directly involved in
the process of regeneration in the brain. Dr. Poirier's
laboratory has documented a complex mechanism that regulates
the synthesis, the recycling and the transport of the
cholesterol during neuronal regeneration. Dr. Poirier
and his colleagues believe that certain anomalies (also
called mutations) in proteins involved in the transport
and production of cholesterol in the brain selectively
destroy specific groups of brain cells in AD. Half of
the clinical cases of AD that were examined in their
memory clinic exhibited abnormal cholesterol transport
due to a mutation in the apolipoprotein E gene (apoE4).
This means that at least one (most probably several)
other defective gene(s) remain to be identified to explain
the presence of AD in the non-apoE4 subjects. Based on
the hypothesis that there are other genes involved in
AD, Dr. Poirier and his colleagues began to examine the
fate of some key proteins that serve as accessory molecules
to apo/E in the brain of AD subjects. Their recent research
shows that one of these accessory proteins, called 3-Hydroxy-3-MethylGlutaryl-Coenzyme
A reductase (HMGCoA reductase) which is responsible for
the production of cholesterol in the brain, appears to
be defective in the AD brains. More importantly, a genetic
modification in the structure of the gene, called a polymorphism,
was shown to be strongly linked to the incidence of the
disease in humans. Dr Poirier will carefully examine
the structure of this gene and its expression level and,
attempt to determine if indeed the presence of a genetic
anomaly (DNA insertion) in the HMG-CoA reductase gene
plays a role in triggering common AD and/or in affecting
the rate of progression. Finally, Dr. Poirier will explore
the role of the HMG-CoA reductase in the pathophysiology
in AD.
Dr.
Elena Posse de Chaves
University of Alberta, Edmonton, Alberta
New
2002 - $60,000
2003 - $60,000
ApoE
and Alzheimer's disease: Understanding the differential
effect of apoE-3 and apoE-4 of amyloid beta-induced
neuronal death and degeneration
Recipient of the Mr. James and Mrs. Bernice Putnam Grant
for Biomedical Research
Alzheimer
disease (AD) is a degenerative brain disease that affects
one in 10 persons over 65 and nearly half of those over
85. Age and family history have been identified as potential
risk factors for AD.
The
apolipoprotein E (apoE) gene makes a protein that is
involved in carrying cholesterol in the bloodstream.
It occurs in three forms, or alleles, designated "2," "3," and,"4." We
now know, conclusively that the allele4 of apoE is a
strong risk factor for AD. There is also increasing evidence
that apoE, as well as the other major genetic factors
associated with AD influence the production, metabolism
and/or deposition of a very fundamental protein of AD:
amyloid-p peptide (AP). Nevertheless, the mechanisms
underlying the role of apoE in the development of AD
remain largely inconclusive.
In
attempting to elucidate those mechanisms, the present
research will focus on assessing whether Ab deposition
is a cause or effect of the disease. This will be achieved
by investigating whether neuronal death induced by Ab
precedes or is secondary to axonal degeneration. A related
project will use a novel in vitro system that allows
simulatenous culture of neurons and astrocytes to assess
the specific role of apoE in neuronal death. Finally,
the study will include an examination of the role of
apoE4 in clearing Ab -apoE complexes.
The
results obtained from this research will provide molecular
insights on the link between apoE4 and AD which could
be the foundation for the development of new therapeutic
strategies.
Dr.
Nabil Seidah
Clinical Research Institute of Montreal, Montreal, Quebec
Continuing
2001 - $50,000
2002 - $50,000
BACE
and BACE2: The B-secretases involved in Alzheimer's disease
Alzheimer's disease (AD) is caused by the degeneration of brain cells
in critical areas affecting memory and important cerebral
functions. Some of the molecules participating in the
causation and perpetuation of the metabolic anomalies
encountered in AD have been recently identified and novel
ones are also being evaluated. The enzymes, termed pro-protein
convertases (PCs), and ß- (BACE) and g- (Presenilins)
secretases are involved in the abnormal processing of
brain ß-Amyloid Precursor Protein (ßAPP)
and participate in direct production or in the regulation
of the level of the toxic amyloid Aß that results
in the destruction of critical brain areas. It is hypothesized
that the ß-secretases BACE and possibly BACE2 are
responsible for early events leading to the onset of
AD. Dr. Seidah's research program aims to define the
enzyme properties of the candidate ß-secretases
BACE and BACE2, primary enzymes likely involved in the
etiology of the AD pathology. He will first produce and
purify large quantities of these enzymes, then design
and synthesize specific molecules to test the activities
of these enzymes in the test tube. This will be followed
by the elaboration of strategies to measure and to inhibit
these secretases both in vitro and in cells. Finally,
the usefulness of these inhibitors will be tested in
a genetically engineered (transgenic) mice model of AD.
Dr.
Sylvain Williams
McGill University, Montreal, Quebec
New
2002 - $21,000
2003 - $21,000
Role
of IL-8 in the modulation of Ach neurons in the medial
septum: Novel insights into the function of chemokines
in the CNS and in Alzheimer's disease
Chemokines
are important regulatory factors of the immune system
that may have a critical role in the neuroinflammatory
process observed in Alzheimer's disease (AD). There is
evidence that the synthesis and expression of the chemokine,
IL-8 from glial cells, is strongly potentiated by amyloid-/3
and pro-inflammatory cytokines like IL-l/3 and rnFa.
Moreover, one of the IL-8 receptors (CXCR2) is known
to be up-regulated in the AD brain and is found in abundance
in dystrophic neuritic plaques that contain amyloid precursor
proteins. However, little is known about the function
of IL-8 in normal and pathological conditions. Are chemokines
like IL-8 beneficiary or detrimental in AD? Answers to
this question are important since they may open up new
avenues for therapeutical interventions at the level
of chemokines in AD. The issue of how chemokines work
in the brain was investigated by examining IL-8 actions
in septal cholinergic neurons which are known to degenerate
early in AD. To investigate the actions of IL-8 , a unique
approach combining electrophysiology and single-cell
RT-PCR was used. The combination of these tools will
enable examination of the effects of IL-8 on ACh signaling
and determine which IL-8 receptors are expressed in the
neurons investigated.
Research
with IL-8 revealed the novel finding that it can acutely
inhibit calcium currents due to a direct binding of specific
proteins to calcium ion channels. Direct evidence that
IL-8 can acutely reduce synaptically released acetylcholine
(Ach) from the septum and the hippocampus has been produced.
Taken together, these results are exciting since they
show that IL-8 release from glial cells may actually
be a signaling factor that modulates the excitability
of cholinergic neurons, which may have important consequences
in physiological conditions associated with AD. The plan
is to continue studying the actions of IL-8 on calcium
channels and examine how IL-8 reduces synaptic ACh release.
The
proposed research will yield new insights into how chemokines
work in normal conditions and in AD. It is suggested
that increased chemokine actions during the inflammatory
process produces important changes in cholinergic neuron
excitability and ACh release, and hence contribute to
cognitive deficits experienced by patients with AD. Knowing
the actions and the mechanism that underlie these chemokine
effects, could offer new insights into pharmacological
interventions to help counteract the inflammation and
the symptoms associated with AD.
Young
Investigator Grants
Dr.
Anne Decary
Co-Applicant: Dr. Jacque Montplaisir
Hôpital du Sacré Couer de Montréal,
Montreal, Quebec
New
2002 - $25,000
2003 - $25,000
Effects
of sleep disturbances and alertness level on cognitive
function in the elderly
This
research will examine sleep alterations with old age
and study their impact on cognitive functioning. Participants
will be 150 older women, who will sleep for three successive
nights at the Sleep Study Centre of the Sacre-Couer Hospital.
All participants will receive a battery of neuropsychological
tests after the third night. The predictions are that
individuals who show a sleep efficiency of 80% or higher
will perform better on the following tasks, than those
with lower efficiency: (1) objective vigilance (2) episodic
memory (3) cognitive and motor procedural memory (4)
executive function. As well, it is predicted that slow
wave sleep (delta) will correlate with episodic memory
performance, and Stage 2 sleep will correlate with motor
procedural memory. The results will provide baseline
data on the relationship between sleep patterns and cognitive
function in normal older people, and a basis for assessing
altered relationships in individuals with Alzheimer's disease
and related dementias.
Dr.
Allison Phinney
University of British Columbia, Vancouver, British Columbia
New
2002 - $24,784
2003 - $23,570
An
interpretive study of the lived body in Alzheimer's disease
This
research will explore the everyday experiences of people
with Alzheimer's disease (AD) in order to better understand
how the illness is experienced in and through the body.
Specifically, it will use videotaped observations and
interviews to examine the question of what the body conveys
about the meaning of living with AD. It will focus on
three areas: (1) movement and expression; (2) skills
and habits; (3) social interactions.
Qualitative
strategies will be used to analyse the videotaped data
from the observation sessions, with field notes and verbal
data from the interviews being used in a supplementary
fashion to enrich and clarify the results. Each individual
case will be analyzed, and comparisons will be made across
individuals in order to develop a comprehensive understanding
of how the meaning of AD is conveyed through the body.
The final results will be in the form of a richly detailed,
in-depth description that will include several different
themes with case examples being used to highlight the
important distinctions between them. Ultimate]y, the
intent of such a description is to provide a clearer
understanding of the everyday experience of the person
with AD.
The
use of visual data provides a distinctive and far richer
perspective on everyday experience than interview data
alone can provide. By providing a new and powerful vocabulary
for conveying the lived experience of AD, this work will
enable caregivers, clinicians and researchers to more
clearly articulate the needs of those with AD, and in
turn, identify more effective ways of meeting those needs.
Dr.
Anurag Tandon
University of Toronto, Toronto, Ontario
New
2002 - $25,000
2003 - $25,000
Conditional
knockout of nicastrin-presenilin protein complexes
All
the genes that are known to affect the development of
Alzheimer's disease (AD) converge upon a common biochemical
pathway that involves the amyloid beta (A13) molecule.
Overproduction of the A13 molecule is one of the central
characteristics of AD pathology. In fact, the brains
of individuals with AD contain high levels of soluble
A13 as well as aggregated deposits of A13 (plaques).
While the physiological role of A13, or its parent molecule,
13-amyloid precursor protein (13APP), is not clear, numerous
studies have shown that the A13 molecule is neurotoxic.
The cumulative conclusion from these studies is that
a substantial portion of the neurodegeneration in AD
brains is due to an excess of the A13 molecule. This
has lead to an intense effort in laboratories around
the world to develop therapies aimed at reducing the
production of the A13 molecule. Much of this effort has
focused on the biochemical processes that convert the
parent molecule 13APP to A13.
A
key step in the synthesis of A13 is an enzymatic activity
called gamma (y)-secretase. While the precise molecular
identity of y-secretase activity remains controversial,
it is recognized that y-secretase activity becomes functional
only when several proteins, including presenilin-l and
nicastrin, come together in a complex. Therefore, depletion
of presenilin-l and nicastrin complexes should prevent
the production of the neurotoxic A13 molecule.
This
work will test a novel strategy to deplete the functional
pool of presenilin-l and nicastrin complexes in cultured
cells. The plan is to express a mutant form of the nicastrin
molecule containing a specific targeting sequence that
causes the cellular machinery to degrade it quickly.
Because mutant nicastrin and presenilin-l will bind each
other in a complex before nicastrin is targeted for degradation,
the normal presenilin should also be carried along to
its destruction. Over time, this process will deplete
the cellular pool of presenilin-l, which is required
for y-secretase activity and for A13 synthesis. The prediction
is that this strategy will reduce the aberrant production
of the neurotoxic A13 molecule.
Dr.
Paul Verhoeff
Baycrest Centre for Geriatric Care, Toronto, Ontario
New
2002 - $25,000
2003 - $25,000
Imaging
amyloid plaques with PET in patients with Alzheimer's disease
There
is a critical need for protocols that take into account
not only neuropsychological, but also neuroimaging, biochemical
and genetic information to establish risk models for
Alzheimer's disease (AD) and predict rates of decline.
Evidence for increased amounts of amyloid deposits can
be found in people who are genetically predisposed to
get AD but who do not yet have the symptoms, and in Down's
syndrome patients before the onset of neurofibrillary
tangles, which are another early indicator of AD. The
use of neuroimaging to detect amyloid deposits may represent
a useful biologic marker of disease activity.
The
objective of the proposed research is to develop radiotracers
for positron emission tomography (PET) imaging and quantification
of amyloid plaques in the brains of patients with AD.
Preliminary data show that two promising PET amyloid
radiotracers, developed at our PET Centre, bind well
to the amyloid protein aggregates and with desirable
fat solubilities in live animals and humans. Time activity
curves of brain uptake of these two radio tracers will
be studied in live rats, and the more promising one will
be studied using PET in healthy human subjects and in
AD patients. The outcome is expected to lead to validated
laboratory tests for pre-symptomatic diagnosis, and monitoring
disease progression of AD.
Postdoctoral
Awards
Dr.
Angela Birt
Supervisor: Dr. Kenneth Rockwood
Dalhousie University, Halifax, Nova Soctia
New
2002 - $38,500
2003 - $38,500
An
investigation of intention and prospective memory ability
in Alzheimer's disease
Memory
loss, particularly for recent events, is one of the earliest
and most characteristic signs of Alzheimer's disease (AD).
Anecdotal evidence suggests that people in the early
stages of AD have greater difficulty remembering to do
things and to do them at the appropriate time (prospective
memory; ProM), than retrieving information from the past
(retrospective memory; RetM). Despite the potentially
serious consequences of prospective memory failures (e.g.,
forgetting to take medication or turn off the stove),
very little is known about such failures in AD and their
impact on everyday life.
An
important aspect of remembering to carry out future intentions
is the ability to formulate them in the first place.
A necessary component of forming intentions is the ability
to mentally project oneself into the future as a competent
agent. Although not formally tested, preliminary analyses
conducted on a study of expectations and effects of treatment
with the cholinesterase inhibitor, donepezil, in a group
of mild/moderate AD patients revealed that many experience
the loss of ability to form future intentions, but recovery
of this capacity can result from treatment. The primary
goals of this research are to investigate the clinical
utility of measures of ProM and intention in the assessment
of AD, as well as their potential for leading to clinically
significant treatment effects. To this end, a reliable
coding scheme for identifying instances of intention
in AD patients will be developed. This coding system
will then be applied to and tested further in a clinical
trial. In addition, objective tests of intention and
ProM abilities will be developed, administered, and compared
to the more qualitative measures, providing valuable
insight into the relationship between qualitative and
quantitative methodological constructs in AD research.
This work is intended to improve understanding of the
memory and cognitive deficits associated with AD and
to develop meaningful outcome measures for clinical trials
that translate into beneficial effects in patients' daily
lives.
Dr.
France Cloutier
Supervisor: Dr. Kenneth Rockwood
Université Laval, Laval, Quebec
New
2002 - $82,250
2003 - $82,250
Research
of patterns of treatment response pertaining to Alzheimer's disease
Recipient of the 2002 ASC/AstraZeneca/CIHR Rx&D Biomedical
Research Fellowship
The
proposed research will use the narrative experience of
patients with Alzheimer's disease (AD) to identify clinicians'
working models of effective disease treatment. A primary
aim is to use quantitative and qualitative methods to
assess a broad range of responses to help clinicians
determine treatment benefits. A second aim is to use
the behavioural results to help understand brain function
in AD. The research will improve understanding of existing
models and their ability to provide a comprehensive profile
of AD individuals' response to treatment.
Dr.
Anh Duong
Supervisor: Dr. Howard Chertkow
Lady Davis Institute for Medical Research, Montreal, Quebec
New
2002 - $38,500
2003 - $38,500
Transcranial
magnetic stimulation as a treatment for anomia in patients
with Alzheimer's Disease
The
overall objective of this project is to assess the therapeutic
efficacy of a new technique, transcranial magnetic stimulation
(TMS), in the treatment of anomia in patients with Alzheimer
disease (AD). Anomia, a difficulty in finding the right
word is most often evidenced through picture naming impairments.
At the discourse level, anomia may lead to the production
of a disorganized discourse that is vague and full of
irrelevant information. Anomia results from a disintegration
of conceptual knowledge in semantic memory such that
patients lose the ability to clearly understand the meaning
of an object. This ability to understand the meaning
of an object is believed to rely on the integrity of
the left posterior temporal (LPT) region. Because this
region is likely to be damaged in AD, it is hypothesized
that increasing neuronal function in this region will
result in increased naming and discourse performance.
Increasing neural function can be achieved using TMS,
a technology that can facilitate neural transmission
through the delivery of magnetic pulses.
Dr.
Walter S. Marcantoni
Supervisor: Dr. Sonia Lupien
Douglas Hospital Research Centre, Verdun, Quebec
Continuing
2001 - $38,500
2002 - $38,500
Impact
of street hormones on attention and memory encoding
process in elderly individuals
Memory
loss in the early stages of Alzheimer's disease (AD is
most often associated with hippocampal damage. In particular,
the hippocampal formation has been shown to play an essential
role in declarative memory. Brain imaging studies have
shown that a significant proportion of age-related impairments
in declarative memory is partly due to a failure to encode
stimuli adequately. Successful encoding of information
into long-term memory necessitates working memory (WM).
Research has shown that WM also declines in old age.
This age-related decline in WM processing may in part
be due to a reduction in the efficacy of attentional
mechanisms that minimize interference from irrelevant
information. Recent studies report that stress hormones
(glucocorticoids) have a significant impact on WM when
the levels of circulating glucocorticoids are acutely
elevated, while these hormones have a significant impact
on declarative memory function when the levels of circulating
glucocorticoids are chronically elevated. Based on this
evidence, a developmental view of cognitive impairments
in the elderly population is proposed, in which an acute
increase in circulating glucocorticoids in aged humans
could first impair WM function, thereby leading to encoding
deficits into long-term memory store. The mechanism by
which WM impairments lead to declarative memory deficits
would be related to a glucocorticoid-induced increase
in attentional interference at the time of encoding.
An increase in attentional interference, as induced by
stress hormones, may contribute to glucocorticoid-induced
memory deficits in the elderly population; however, this
suggestion has never been directly tested. Thus, the
present project will examine whether acute increases
in cortisol levels render subjects more susceptible to
attentional interference (tested directly with a Rapid
Stimulus Visual Presentation task), how these changes
are reflected by neural activity, as measured by functional
neuroimaging, and the impact these behavioural and neural
alterations have on mnesic operations. If early cognitive
markers of AD are related to cognitive functions which
are amenable to therapeutic interventions (i.e., increased
cortisol levels), the results would have implications
for preventative treatment
Dr.
Katherine S. McGilton
Supervisor: Dr. David Steiner
Baycrest Centre for Geriatric Care, Toronto, Ontario
Continuing
2001 - $38,500
2002 - $38,500
Relationships
between elderly residents of long-term care and their
careproviders: Measurement and program evaluation
Evaluations
of programs that aim to enhance quality of life of institutionalised
older adults have been described but they usually involve
residents who are cognitively intact. Most evaluations
have focussed on structure and process measures ranging
from the training of staff to how staff members speak
with residents, but these evaluations have failed to
include measures of relationships. This occurs despite
the fact that there is evidence that the most important
element of quality of life for the older person in long-term
care is having meaningful and genuine relationships with
the people who care for them, ie., their careproviders.
The purpose of this research is to develop new empirical
measures to (1) measure the quality and meaning of these
relationships, which are usually between nurses and/or
health care aides (the careproviders) and residents with
Alzheimer's disease (AD) living in long-term care facilities,
and (2) to evaluate programs when quality of life, including
staff-resident relationships, are a central part of the
program. With a better understanding and measurement
of staff-resident relationships, the development and
evaluation of new programs that promote quality of life
for persons with (AD) will be enhanced.
Dr.
Alex Mihailidis
Supervisor: Dr. Gloria Gutman and Dr. Geoff Fernie
Simon Fraser University, Burnaby, British Columbia
New
2002 - $38,500
2003 - $38,500
The
development of an intelligent cognitive orthosis to
facilitate independent toileting in Alzheimer's disease
Alzheimer
disease (AD) often results in a person not being able
to complete activities of daily living (ADL) such as
washing, dressing, or using the toilet. A common solution
is for a caregiver to continually watch the person and
provide verbal reminders when necessary. This loss of
independence and privacy can become very upsetting for
everyone involved, especially during toilet-related activities.
Perhaps privacy and dignity can be partially restored
by using an intelligent computerized device that can
provide these verbal reminders and monitor progress without
present.
The
objective of this research is to continue the development
of such a device. It will use artificial intelligence
(Al) to automatically learn about different users, adapt
to the users' behaviours, and be easily set up by a caregiver
for most ADL tasks. Capabilities developed and added
to the existing device include the recognition of hand
gestures, voice recognition and the addition of visual
as well as auditory feedback. The user will hear verbal
reminders but will also be able to see an image of the
caregiver speaking the reminder and demonstrating the
required action.
A
prototype has been developed and shown to increase the
ability of people with severe levels of dementia to wash
their hands without the need for prompting by a caregiver.
The performance of the new prototype will be compared
with this current device during more handwashing tests.
The new device will be refined and then tested during
toileting. The number of handwashing and toileting steps
the subjects can complete independently both with and
without the assistance of the device will be examined.
Dr.
Daniel Saumier
Supervisor: Dr. Howard Chertkow
Lady Davis Institute for Medical Research, Montreal, Quebec
New
2002 - $38,500
2003 - $38,500
Donepezil
treatment effects on visual and semantic processing
in Alzheimer's disease
Recent
evidence indicates that the cholinesterase inhibitor,
donepezil (Aricept), improves lexical-semantic memory
in patients with mild to moderate Alzheimer's Disease
(AD). However, this evidence also suggests that visual
memory might also be affected by this treatment. The
current project proposes to examine this issue by conducting
a series of experiments designed to decouple the effects
of semantic and visual processing as a function of donepezil
treatment outcome. These experiments will be performed
before and after treatment according to type of stimulus
material (familiar objects, computer generated shapes),
training (trained vs. untrained), and level of processing
(visual vs. semantic). These findings will indicate whether
donepezil improves both semantic and visual memory in
patients with mild to moderate AD, and thus reveal whether
there is a cholinergic chemistry to these memory systems.
Dr.
Zelan Wei
Supervisor: Dr. Xin Min Li
University of Saskatchewan, Saskatoon, Saskatchewan
Continuing
2001 - $81,000
2002 - $81,000
Neuroprotective
effects of Antipsychotics: Implications for Treatment
of Alzheimer's disease
Recipient of the 2001 ASC/AstraZeneca/CIHR x&D Biomedical
Research Fellowship
The
purpose of this research is to examine the effectiveness
of antipsychotic agents in reducing pathological and
behavioural symptoms of Alzheimer's disease (AD). Several
experiments are planned. One is to investigate the neuroprotective
effects of atypical antipsychotics in vitro models. The
hypothesis is that antipsychotics reduce cell death induced
by oxidative stress, which will be achieved by treating
cells with hydrogen peroxide and beta amyloid fragments.
Morphological markers of apoptosis and necrosis will
be defined and the effects of the antipsychotic drug,
Olanzapine, on cellular markers of apoptosis and antiapoptosis
will be investigated. Finally, the effects of Olanzapine
will be investigated in a transgenic mouse model by measuring
memory performance on the Morris water maze, and after
sacrifice, by histological analysis and investigation
of gene expression of apoptotic markers.
Given
the increasing use of atypical antipsychotics in the
behavioural management of AD, particularly in the more
advanced stages, this work may open up the possibility
that antipsychotic drugs have neuroprotective effects
in individuals at risk for AD. Olanzapine has some limitations
in clinical use for AD because of its anticholinergic
side effects, which may cause confusion in some individuals.
However, insight into the neurobiological action of such
drugs would be valuable in understanding their potential
use, not only in primary psychoses, but also in the neurodegenerative
disorders.
Doctoral
Awards
Ted
Allison
Supervisor: Dr. Craig W. Hawryshyn
University of Victoria, Victoria, British Columbia
New
2002 - $19,530
The
rainbow trout retina as a unique model of neuronal
apoptosis
This
research relates to the hypothesis that the inappropriate
reception of mitogenic (growth) factors leads to apoptotic
cell death in Alzheimer's disease (AD). This hypothesis
will be assessed in a new model of neural cell death
-the disappearance of the ultraviolet-sensitive (UV-)
cone from the retina of rainbow trout following treatment
with thyroid hormone. This model has several advantages,
including that of being able to study the events leading
up to neural cell death.
In
order to develop this model in situ hybridization labels
of photoreceptors have been developed to track their
fate, an antibody that robustly labels the UV-cone has
been developed, electrophysiology has been developed
to track developmental events within individuals, signaling
mechanisms of thyroid hormone are being elucidated and
tools have been introduced to examine cell proliferation
during hormone treatment. The purpose of the present
research is to use this model to gain further insight
into how cells die and apply this knowledge to the process
of cell death in AD.
Catherine
Burton
Supervisor: Dr. Esther Strauss
University of Victoria, Victoria, British Columbia
New
2002 - $19,530
2003 - $19,530
The
effects of inconsistency on functional status in Alzheimer's disease
This
research relates to the hypothesis that the inappropriate
reception of mitogenic (growth) factors leads to apoptotic
cell death in Alzheimer's disease (AD). This hypothesis
will be assessed in a new model of neural cell death
-the disappearance of the ultraviolet-sensitive (UV-)
cone from the retina of rainbow trout following treatment
with thyroid hormone. This model has several advantages,
including that of being able to study the events leading
up to neural cell death.
In
order to develop this model in situ hybridization labels
of photoreceptors have been developed to track their
fate, an antibody that robustly labels the UV-cone has
been developed, electrophysiology has been developed
to track developmental events within individuals, signaling
mechanisms of thyroid hormone are being elucidated and
tools have been introduced to examine cell proliferation
during hormone treatment. The purpose of the present
research is to use this model to gain further insight
into how cells die and apply this knowledge to the process
of cell death in AD.
Luisa
Cameli
Supervisor: Dr. Natalie Phillips
Concordia University, Quebec
New
2002 - $19,530
2003 - $19,530
Grammar
and the lexicon in a native and second language: Evidence
of a double dissociation between Alzheimer and Parkinson's
Disease
Many
individuals with Alzheimer's disease (AD) speak more than
one language. Knowing how AD affects a native (Ll) and
a second language (L2) is likely to impact the quality
of services and care provided to these individuals. Research
suggests that AD may affect an L2 more than an Ll, but
no empirical study to date has directly examined the
link between memory and language ability in bilingual
AD patients. It has been argued that: 1) the lexicon
for Ll and L2, and L2 grammar, are dependent upon declarative
memory (conscious memory for specific events)and thereby
supported by medial temporal lobe (MTL) structures, 2)
Ll grammar is dependent upon the procedural memory system
(memory for skills and habits) and thereby supported
by basal ganglia circuits. The goal of this study is
to test the dissociation between the lexicon and grammar
in bilingual AD and Parkinson (PD) patients.
AD
patients will be selected for anomia and mild dementia
(reflecting MTL damage) and PD patients for hypokinesia
(reflecting damage to the caudate nuclei). Each patient
group will have its own appropriate control group. All
participants will be English-French bilinguals who meet
stringent criteria for L2 acquisition, and half of each
group will have English as an Ll. Declarative and procedural
memory will be evaluated in the visuoperceptual and verbal
domains. Language will be evaluated with free speech,
the Past Tense Generation task, and two subtests of the
Bilingual Aphasia Test (BAT). The Past Tense Generation
task is based on the premise that the past tense of regular
verbs is produced by implementing the "+ ed" procedure
(e.g., "walked"), whereas that of irregular
verbs must be retrieved from declarative memory (e.g., "woke").
In
Ll, AD patients are expected to be selectively impaired
in generating the past tense of irregular verbs and PD
patients to be selectively impaired in generating the
past tense of regular verbs. In L2, AD patients are expected
to be impaired in generating the past tense of irregular
and regular verbs, since in L2 both the lexicon and grammar
are dependent upon declarative memory. PD patients are
not expected to be impaired in L2 given their intact
declarative memory. The Syntactic Comprehension (SC)
and Synonyms-Antonyms (SA) subtests of the BAT complement
the Past Tense Generation task by testing receptive grammar
and lexical comprehension, respectively. AD patients
are expected to perform well on SC in Ll but not L2 (since
L1 grammar is supported by procedural memory and L2 grammar
by declarative memory), and to be impaired on SA in L1
and L2. PD patients, given their deficit in procedural
memory, are expected to be selectively impaired on SC,
in Ll only. To validate the link between memory and language,
it is expected that measures of declarative memory will
correlate with language performance for the AD group
only, and that measures of procedural memory will correlate
with language performance for the PD group only. These
results could explain the tendency of AD patients to
revert to L 1 in an L2 context.
Dara
Dickstein
Supervisor: Dr.Wilfred Jefferies
University of British Columbia, Vancouver, British Columbia
New
2002 - $19,530
The
involvement of microglia and P97 in Alzheimer's disease
pathology
Alzheimer
disease (AD) is a disorder of the central nervous system
which results in progressive memory loss and cognitive
decline. Characteristic plaques in the brain consist
primarily of amyloid beta, although there are other protein
deposits in the brain such as neurofibrillary tangles.
Moreover, there is considerable inflammation in the regions
of the amyloid plaques. This inflammation is mediated
by microglia, the proposed immune cells of the brain.
Once activated, microglia become concentrated in the
regions of amyloid beta deposits where they are able
to infiltrate the plaques. It is not known whether activated
microglia are responsible for, or a result of amyloid
beta plaque pathology. Our lab has shown that activated
microglia, uniquely associated with the plaques, express
melanotransferrin, also known as p97, a member of a family
of iron binding proteins. In addition to its localization
in micrgolia, we have demonstrated that levels of p97
are elevated in the serum and cerebrospinal fluid of
AD individuals. Since metals have been implicated in
amyloid plaque formation and since p97 is known to bind
to iron and other metals such as copper and aluminum,
p97 may be a useful diagnostic marker for the disease.
To
examine the role of microglia in plaque formation, transgenic
(Tg2576) mice will be generated that are homozygous deficient
for the CSF-1 gene, thus lack microglia, and that are
heterozygous for the human amyloid precursor protein
gene. The brains of these mice and control littermates
will be assessed for the presence of plaques and microglia
at various ages. To assess p97 as a biomarker for AD,
serum will be collected from the Tg2576 mouse and littermates,
each month for 12 months. The next step will be to determine
if activated microglia express p97. A demonstrated relationship
between activated microglia and increased expression
of p97 would represent a significant advance in understanding
the mechanism of plaque formation, and would have implications
for treatment development.
Patricia
Ebert
Supervisor: Dr.Holly Tuokko
University of Victoria, Victoria, British Columbia
New
2002 - $19,530
2003 - $19,530
Psychosocial
predictors of success following memory intervention
in elderly participants
Recipient of the Joey's Only Seafood Restaurant Award
Educational
and memory intervention programs have been developed
to help older adults better understand and deal with
age-associated memory changes. In addition, similar programs
have been developed to help older adults with dementia
(e.g., Alzheimer's Disease) and their caregivers better
cope with the progressive memory problems associated
with dementia.
Although
these programs have been shown to be beneficial for the
majority of older adults, not everyone responds equally
and some individuals do not seem to benefit from these
types of programs at all. Recently, the role of dementia,
cognitive impairments, and current memory performance
has been investigated to better understand why some older
adults benefit and others do not. However, little research
has been done to determine the impact of psychosocial
factors such as personality characteristics, current
coping abilities, and emotional functioning on memory
interventions for the older adults. This study will examine
the role these factors have on older adults who do and
do not benefit from memory intervention programs. Greater
understanding of these factors will increase our knowledge
of memory functioning in older adults and of memory impairments
associated with dementia, and lead to the development
of better designed memory intervention programs.
Sonia
Franciosi
Supervisor: Dr. James McLarnon
University of British Columbia, Vancouver, British Columbia
Continuing
2001 - $19,530
2002 - $19,530
Beta-amyloid
induced intracellular signaling and functional responses
in cultured human microglia
This award is funded by the Alzheimer Society of British
Columbia.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized
by dementia, and associated with the presence of amyloid
beta (Ab)-containing extracellular plaques, intraneuronal
neurofibrillary tangles, inflammation of the brain, and
neural death. Microglia, the immune cells of the CNS,
have been found in large numbers to be reactive in brain
tissue of AD patients, specifically in neuritic plaques.
Activation of microglia is associated with phagocytosis,
the release of various signalling molecules, and subsequent
propagation of the immune response which contribute significantly
to the immunopathology of AD. Evidence suggests that
microglia promote the destruction of Ab plaques through
phagocytosis but are overwhelmed by the size of Ab plaques
leading to neurotoxicity due to their release of cytotoxic
substances such as proteolytic enzymes. The aim of the
proposed research is to characterize the cellular mechanisms
involved in microglial immune responses in AD. This characterization
will include measurement of how stimuli with particular
relevance to AD activate microglia, the functional processes
of microglia subsequent to stimulus actions and the signaling
pathways coupling activation to their cellular functions.
Modulation of the intracellular signaling pathways associated
with microglial activation in AD would be therapeutic
in the progression of AD. The hypothesis is that changes
in intracellular levels of Ca2+ [Ca2+]i and changes in
expressions of membrane channels induced by Ab are involved
in the activation and processing of signals by microglia.
Ab would be rapidly perfused onto human microglia and
measurements of changes in [Ca2+]i and membrane currents
will be recorded over 24 hours. Long term studies include
investigating the responses to stimuli by microglia incubated
with Ab for extended periods of time. This work has major
significance to the pathogenesis of AD. Modifications
to the intracellular signaling pathways upon stimulation
with microglia activators such as Ab, would inhibit production
of neurotoxins and thus contribute to potential therapies
for AD.
Sophie
Gaudrealt
Supervisor: Dr. Judes Poirier
Institute de Recherche en Santé du Canada, Québec
New
2002 - $19,530
2003 - $19,530
Characterization
of expression levels and effects of caveolin in synaptogensis
and impact of the modulation of its expression in LTP
The
proposed research involves the protein, caveoline, which
has been implicated in memory loss associated with Alzheimer's disease (AD). Caveoline inhibits the enzyme phospholipase
A2 (PLA2) which, in turn, helps to mediate long-term
potentiation in the hippocampus, a process that is considered
essential to long-term memory. This research will take
a multidisciplinary approach to studying links between
caveolin expression, PAL2 levels, neuronal degeneration,
and learning and memory. The results will contribute
to understanding basic mechanisms underlying AD onset
and the progression of the disease, particularly in the
early stages.
Sandeep
Gill
Supervisor: Dr. Jane Rylett
The John P. Robarts Institute, London, Ontario
New
2002 - $19,530
2003 - $19,530
Characterization
of the function and nuclear mechanism of 83kDA choline
Acetyltransferase
The
correlation between decreased levels of choline acetyltransferase
(ChAT) activity and the onset/progression of Alzheimer's disease (AD) is well known. ChAT is found in cholinergic
neurons where its function is to catalyze the reaction
between acetyl-CoA and choline to form the neurotransmitter
acetylcholine. In addition to the cytosollc 69 kDa ChAT
(N-ChAT) found in eukaryotic neurons, there is a novel
nuclear 82 kDa isoform of ChAT (M-ChA T) found only in
human cholinergic neurons. Furthermore, this novel human
enzyme isoform contains a nuclear localization signal
(NlS), which causes 82 kDa ChAT to be translocated into
the nucleus. This project will attempt to characterize
the nuclear function of 82 kDa ChAT by focussing on four
major hypotheses; 1) 82 kDa ChAT is a nuclear shuttling
protein, 2) 82 kDa ChAT is a DNA-binding protein, 3)
82 kDa ChAT can alter phenotypic expression of neurons/cells
and, 4) 82 kDa ChAT acetylates alternative nuclear substates
Identifying
the importance of nuclear 82 kDa ChATs function will
elucidate the biochemical mechanism and function of ChAT
and lead to increased understanding of ChAT's role in
AD.
Meredith
Kierstead
Supervisor: Dr. J. McLaurin University of Toronto, Toronto,
Ontario
New
2002 - $19,530
2003 - $19,530
Alzheimer's disease: Inositol and Amyloid-Beta Interactions
Recipient of the Anne & Lauren Hansman Doctoral Award
The
proposed research focuses on the exploration of therapeutic
strategies will hinder the interaction of the amyloid
beta peptide (Af3) with auxiliary molecules and slow
the progression of Alzheimer's disease (AD).
Recent
discoveries have demonstrated that the C-terminal of
Ab is involved in the formation and stabilization of
Ab fibers. Key players in this process include acidic
phospholipids and fatty acids. The hypothesis is that
myo-inositol, as it lacks phosphate groups, may obstruct
the interaction of A with such fiber promoting molecules.
Likewise, a role has been established for two other inositol
isomers, epi- inositol and scyllo-inositol, in the attenuation
of Ab-induced neurotoxicity. In vitro, both epi- and
scyllo- inositol attenuate Ab-induced cell death, and
at lower concentrations than myo-inositol. As such, treatment
with either of the two isomers may result in a more profound
inhibition/decrease in Ab toxicity or amyloid deposition
in vivo. In this project, epi- and scyllo- inositol will
be administered to mice in their drinking water and by
gavage. Behavioural studies will determine their effect
on memory impairment and brain tissue will be analyzed
for alterations in biochemical and histological properties.
Furthermore, the amount of Ab present in the brain and
in the peripheral system for all inositol stereoisomers
tested, will be measured. This will determine the extent
of Ab clearance from the brain to the peripheral system,
and thus, shed light onto the mechanism of Ab clearance.
It will also determine any potential side effects of
the inositol treatments. Such studies will help to elucidate
the biochemical pathway of Ab aggregation and clearance
as well as facilitate the advancement of therapeutics
not only for AD, but also potentially for other amyloidogenic
diseases.
Jennifer
D. Klages
Supervisor: Dr. John Fisk
Dalhousie University, Halifax, Nova Scotia
Continuing
2001 - $19,530
2002 - $19,530
The
role of proton magnetic resonance spectroscopy in differentiating
dementia subtypes
Biological
markers are an important part of early identification
of Alzheimer's disease (AD) as they help to differentiate
between AD, other dementias, and mild cognitive impairment
(MCI) that may develop into dementia. The aim of this
project is to differentiate between elderly persons with
early AD and those with a vascular basis of cognitive
impairment using both biological and behavioural markers.
The biological marker will be metabolic abnormalities
that precede structural changes in specific brain regions,
using Proton Magnetic Resonance Spectroscopy (IH-MRS).
The behavioural markers will be neuropsychological tests
of memory, language, spatial and executive abilities.
The relationship between IH-MRS abnormalities and neuropsychological
measures will also be investigated. Patients who meet
the diagnostic criteria for vascular dementia, MCI, or
mild AD (DSM-IV), will be identified through standardized
cognitive and functional screening assessment and a CT
scan. IH-MRS studies have found significant decreases
in N-Acetyl-Aspertate (NAA) in persons with mild to moderate
AD versus controls, in both the grey (temporal region)
and the white (frontal region) matter. Importantly, the
reduction of NAA was observed even in patients with no
significant brain atrophy or reduction in regional cerebral
blood flow on PET scans, which implies that NAA may be
a sensitive marker of cellular pathology. Reduced levels
of NAA have also been significantly correlated with cognitive
dysfunction in persons with AD. These finding are of
particular importance when one considers that NAA does
not seem to change with normal aging. With the recent
advances in available treatments and prevention strategies
for AD and vascular dementia (i.e., cholinesterase inhibitors
vs. vascular risk reduction), more sensitive and specific
case definition is essential for future studies and for
the clinical care of these populations.
Pia
Kontos
Supervisor: Dr. Ann Robertson
University of Toronto, Toronto, Ontario
New
2002 - $19,530
2003 - $19,530
Exploring
the embodied experiences of Alzheimer's disease
Current
understanding of Alzheimer's disease (AD) is shaped predominantly
by research in neurobiology and neuropsychology. Knowledge
of the subjective experience of AD is far less developed.
The neglect of research on subjective experiences of
people with AD has been attributed to the assumption
that cognitive deficiencies lead to a loss of 'selfhood'
and the belief that there is no subjective state on which
to report. Much of the AD literature promotes the view
that individuals with dementia experience a steady erosion
of 'selfhood', to the point at which no person remains.
The proposed research challenges this view by examining
the lived experiences of individuals with AD through
a framework of 'bodily memory' in which the physical
body is said to play a significant role in conceptions
of 'self'.
Using
an ethnographic research approach, the experimenter becomes
'immersed' in the everyday activities of persons with
moderate to late stage AD in order to generate an in-depth
description of their everyday experiences. In addition,
a phenomenological approach will be taken to directly
observe and describe how persons with DAT use their bodies
in interaction with others (eye contact, facial expression,
gestures, locomotion). As well, records will be kept
of their likes/dislikes (food, music, activities, colour),
their expression of style (mannerisms, hair, clothes,
accessories), social mores, social graces, and etiquette.
Insights
generated from this research could transform health and
social policies guiding the delivery of care for individuals
with AD , which, in turn could ideally lead to improved
quality of life for sufferers .
Alain
Legault
Supervisor: Dr. Francine Ducharme
Université de Montréal, Montréal,
Québec
New
2002 - $19,530
Exploratory
study of the empowerment process of participants in
a mental health promotion program for natural caregivers
of the elderly with dementia living in a facility
The
proposed research is part of a large multi-centre randomized
study evaluating a health promotion program for those
who care for persons with dementia. The work will build
on evidence that the quality of life of institutionalised
individuals with Alzheimer's disease (AD) or related dementias
depends on the types of relationships formed with their
caregivers. Residents are adversely affected by relationships
that undermine feelings of empowerment but there is a
limited literature that links such feelings to general
health in this population. This study will follow a 'grounded
theory' approach that allows for exploration of empowerment
phenomena in all its diversity with simultaneous data
recording. A number of caregivers (n=15 to 20) will be
interviewed to glean key concepts and themes related
to empowerment factors for caregivers. The results will
have implications for quality of care and for developing
interventions that will increase residents' feelings
of empowerment.
Penny
Maccourt
Supervisor: Dr. Holly Tuokko
University of Victoria, Victoria, British Columbia
Continuing
2001 - $19,530
2002 - $19,530
A
comparative study of elderly persons and health care
professionals in regard to making long-term care decisions
for marginally incompetent elderly persons living alone
Health
care professionals are often in the position of making
long-term care decisions about elderly persons who are
marginally incompetent, particularly when they live alone
and are considered "at risk". However, there
are no standardized objective criteria for assessing
either risk or capability to live alone. In this study,
a scenario will be presented to participants. In the
scenario an elderly woman , Mrs.Smith, lives alone,"at
risk" , and wishes to remain there. The task of
the respondents is to choose between community support
services' and institutional services for Mrs. Smith,
based on what they think is most appropriate for her,
given the description of her situation and information
sheets provided about both forms of service in their
region. Questions will be asked about these decisions
to reveal the values that underlie them, and to explore
under what circumstances (eg: perceived risks, burden
on children) respondents might alter their original decision.
Respondents will also be asked what steps should be taken
if Mrs. Smith refuses their recommendations. The values
that underlie long-term care decision-making in regard
to marginally incompetent elderly persons to be explored
are: paternalism, beneficence, autonomy, family interdependence,
and "at risk". The sample will consist of 80
health care professionals and 80 community dwelling elderly
persons. Packages will be distributed to each respondent
that includes a questionnaire. The questionnaire will
consist of three sections: (1) demographic information,
2) an assessment of the respondents' personal experiences
with and feelings about the care of frail elderly individuals
with cognitive impairment, and long term care choices,
3) the Mrs. Smith scenario with questions asking respondents
to choose between institutional care and community support
services. The ultimate aim of the research is to improve
long-term care for moderately cognitively impaired elderly
by ensuring that they reside in appropriate environments.
Sharon
Moalem
Supervisor: Dr. Maire Percy
University of Toronto, Toronto, Ontario
Continuing
2001 - $19,530
2002 - $19,530
Hemochromatosis
and Alzheimer's disease
Hemochromatosis
is a condition of iron dysmetabolism resulting in excessive
uptake of dietary iron, which is then deposited in multiple
organs, causing free radicals and oxidative damage. The
question of metal ion involvement in the pathogenesis
of Alzheimer's disease (AD) is still controversial, since
the brain is thought to be protected from the effects
of excess iron. New evidence is now suggesting that metal
ions such as iron may indeed be involved in AD. This
research builds on the findings of a larger study to
determine the frequencies of the two common hemochromatosis
mutations (C282Y and H63D) in a large group of well characterised
patients with probable sporadic AD (N=100), a group of
patients with vascular dementia (N=100) and age and gender
matched healthy normal individuals (N=100). While it
remains to be established exactly how iron contributes
to these processes, this work is important in that it
is the first genetic association with AD for which potential
therapeutic approaches are already readily available.
Some of these therapeutic approaches would involve the
monitoring of iron levels in individuals considered at
risk who are identified through genetic and hemotological
screening and then treated accordingly. Actual treatments
could range from physician directed phlebotomy to the
use of available chelating therapeutics such as desferrioxamine.
The genes responsible for hemochromatosis are thought
to be the most common genetic mutation in North America
and damage from excessive iron is preventable through
early identification of those at risk. Therefore, the
study's attempt to elucidate the involvement of Hfe mutations
associated with hereditary hemochromatosis in AD and
vascular dementia is of extreme clinical importance.
Tia
Moffat
Supervisor: Dr. Steffany Bennett
University of Ottawa, Ottawa, Ontario
New
2002 - $19,530
2003 - $19,530
Molecular
mechanisms of PAF signaling contributing to Alzheimer's disease-like neuropathology
Alzheimer's disease (AD) is a progressive, neurodegenerative condition
that is characterized by neuronal apoptosis (cell death).
Cerebral inflammation leads to elevated levels of molecules
such as PAF that can directly initiate this apoptosis.
The PAF receptor (PAFR-GPCR) is found in many neurons,
and may initiate the apoptosis signal induced by PAF.
However, recent data suggest that PAF-mediated signaling
is more complicated than initially anticipated, since
rat neurons exposed to PAF underwent apoptosis in a receptor-mediated
fashion, yet did not express PAFR-GPCR. Furthermore,
transfection experiments showed that PAFR-GPCR expression
prevented PAF-induced neuronal apoptosis. This suggests
the existence of a novel PAF binding protein that may
trigger apoptosis, while PAFR-GPCR may promote cell survival.
The enzyme, GSK-3f3, can facilitate apoptosis when tyrosine-phosphorylated,
and can promote survival when serine-phosphorylated.
The present research will test the hypothesis that PAF
induces neuronal apoptosis through a pathway that promotes
GSK-3f3 tyrosine phosphorylation and determine if PAF
neurotoxicity is linked to AD pathology.
Kevin
Peters
Supervisors: Dr.Peter Graf and Dr. Sherri Hayden
University of British Columbia, Vancouver, British Columbia
New
2002 - $19,530
2003 - $19,530
Neuropsychological
subgrouping of cognitively-impaired-not-demented individuals
The
overall objective of this research is to identify early
predictors of dementia. A specific objective is to determine
whether subgroups with distinct profiles of neuropsychological
test performance exist in a large group of Cognitively-Impaired-Not-Demented
(CIND) patients. A secondary objective is to determine
whether these profiles have predictive power, whether
they predict differential outcomes (dementia/no dementia)
and/or developmental courses (gradual or accelerated
disease progression).
The
research will examine the neuropsychological test data
for a large group of 340 CIND patients who are involved
in a longitudinal study currently being conducted at
eight different sites across Canada. Neuropsychological
tests have already been administered to CIND patients
at the Vancouver site. Cluster analyses will be performed
to determine whether subgroups of CIND individuals exist
such that each subgroup can be characterized by its own
neuropsychological profile The second stage of the analysis
will involve the test data obtained during two subsequent
annual visits, and will address the secondary objective.
Regression analyses will be performed to determine whether
the profiles of neuropsychological test performance predict
the course and outcome of CIND patients.
Jacinthe
Savard
Supervisors: Dr. Nicole Leduc and Dr. Paule Lebel
University de Montréal, Montréal, Québec
Continuing
2001 - $19,530
2002 - $19,530
Use
of services at day centres by persons with dementia
and their caregivers
This
project will explore what makes adult day programs effective
for clients with Alzheimer's disease (AD) and their caregivers.
All day programs in Quebec will be surveyed in order
to understand the types and frequency of activities offered
in day programs, the support services provided, and the
training of the staff. From the programs surveyed, four
will be examined in more detail. Two 'well attended'
programs will be compared to two 'poorly attended' programs
in order to better understand, from the clients' perspectives,
what attributes make programs helpful or not. The results
of this project will provide valuable information for
the development of new day programs as well as the modification
of existing ones.
Deborah
Siegal
Supervisors: Dr. David Westaway and Dr. Howard Mount
University of Toronto, Toronto, Ontario
New
2002 - $19,530
2003 - $19,530
NGF
and cholinomimetic therapy in a mouse model of Alzheimer's disease
Loss
of basal forebrain cholinergic (CBF) neurons is a prominent
feature of Alzheimer disease (AD). As CBF neurons are
sensitive to nerve growth factor (NGF), NGF may have
neuroprotective effects on CBF neurons in AD patients.
However, current knowledge regarding the beneficial effects
of NGF is derived from experimental paradigms that, do
not replicate the biochemical changes and slow progression
of AD neuropathology. Furthermore, in vitro data strongly
suggest that elevation of NGF in the AD brain could,
in fact, cause neuronal damage through interaction with
its p75 receptor.
The
present research will investigate the utility of NGF
supplementation in light of the toxic effects elicited
by interaction of NGF with its p75 receptor. The study
will examine behaviour, neuronal survival, beta-amyloid
deposition, and neuropathology in a transgenic mouse
model of AD pathology (TgCRND8 mice) expressing a mutated
form of human amyloid precursor protein (APP). These
mice, which express behavioural and neuropathological
characteristics of AD, will be bred with mice engineered
to express NGF in the presence or absence of its P75
receptor. In addition to these in vivo studies, neuronal
survival studies will also be done using cultured neurons.
This study may provide a novel approach for simultaneous
symptomatic improvement, through enhanced cholinergic
activity , and neuroprotection, through NGF trophic effects.
Lianne
Stanford
Supervisor: Dr. Richard E. Brown
Dalhousie University, Halifax, Nova Scotia
New
2002 - $19,530
2003 - $19,530
Development
of standardized texts for cognition in knock-out and
mutant mice
Recipient of the 2002 Dr. & Mrs. Albert Spatz Doctoral
Award
The
aim of this project is the development of a standardized
cognition battery for knockout and mutant mice. A second
aim is to test putative cognitive enhancers to determine
which aspects of learning and memory are improved. With
the development of standardized tests for behavioural
analysis testing for learning and memory, it is possible
to correlate behavioural observations with neural substrates.
By linking aspects of learning and memory to neural substrates,
the efficacy of drugs designed to improve learning and
memory can be tested. After behavioural testing, the
mice will be perfused, and the brains analyzed for differences
in acetylcholine as well as for morphological differences.
By utilizing both behavioural and traditional neuroscience
techniques, transgenic models of Alzheimer' Disease can
be evaluated and the benefits of putative cognitive enhancers
can be tested.
Kevin
Woo
Supervisor: Dr. Joel Katz
University of Toronto, Toronto, Ontario
Continuing
2001 - $19,530
2002 - $19,530
Pain
in patients with dementia during dressing change
Recipient of the 2001 Dr. & Mrs. Albert Spatz Doctoral
Award
Pain
is one of the most common concerns among people with
Alzheimer's disease (AD) and related dementias. Such individuals
suffer chronic pain from a variety of sources, including
venous ulcers, arterial ulcers, and pressure ulcers,
as well as pressure pain during dressing change. Persistent
pain has been associated with negative mood, decreased
activities of daily living, sleep disturbance, and social
withdrawal in the elderly population. Further research
is required to improve the quality of care in people
with dementia by alleviating their pain and suffering.
The present study will be the first randomized control
trial to examine pain in people with dementia. Self-report
and pain-related behaviours will be used to assess the
effectiveness of acetaminophen and 30mg codeine in alleviating
wound pain during dressing change in a large group of
elderly individuals admitted to in-patient units in an
acute care hospital. Patients with an open wound for
more than one week will be recruited. Drug-treated and
placebo groups will be matched for cognitive function
and severity of pain. The main prediction is that cognitively-impaired
individuals will react differently to analgesic effects
of the drugs. Dose modifications and follow-up work will
be directed by treatment response and side effects to
medication. The long-term aim is to profile the pain
response of individuals with dementia in a way that will
result in reduced suffering and improved care.
Yan
Zhang
Supervisor: Dr. Andrea Leblanc
Lady Davis Institute for Medical Research, Montreal, Quebec
Continuing
2001 - $19,530
2002 - $19,530
Inhibition
in human neuronal apoptosis in Alzheimer's disease
Neuronal
dysfunction and loss are pathological and clinical hallmarks
of Alzheimer's disease (AD). Apoptosis is thought to be
related to the mechanism of progressive neuronal loss
in AD. Recently, caspases, a family of cysteine proteases
have received considerable attention for their roles
in neuronal loss in AD. Direct microinjection of recombinant
active caspase-6 into human neurons induces a protracted
and selective apoptosis in a time- and dose-dependent
manner, which is consistent with the progressive feature
of AD, and may be involved in neuronal loss and amyloidogenesis
of AD. As well, sublethal doses of caspase-6 increases
the vulnerability of neurons to oxidative stress, which
may be a major cause of neuronal damage of the aging
brain. The objectives of the proposed research are to
determine if both caspase-6 and oxidative stress are
involved in human neuronal apoptosis and, if so, identify
the regulatory mechanisms. This will be achieved by (1)
screening for caspase-6 inhibitors from a human astrocytic
cDNA library and, (2) screening for anti-oxidants from
human neuronal cDNA library using yeast based functional
assay. The cDNAs from human neurons will be cloned downstream
of a galactose promoter into yeast cells. In this way,
the expression of cDNAs is controlled by the treatment
of galactose or glucose. Finally, the inhibitory roles
in human neurons will be confirmed by examining apoptosis
in neurons microinjected with the identified anti-death
cDNAs. The results of these experiments may identify
inhibitors of human neuronal cell death against active
caspase-6 and oxidative stress, and have both theoretical
and practical significance in the improvement of AD therapy
by inhibiting neuronal loss.
Research
Grants and Training Awards 2010-2011 (current)
Research
Grants and Training Awards 2009-2010
Research
Grants and Training Awards 2008-2009
Research
Grants and Training Awards 2007-2008
Research
Grants and Training Awards 2006-2007
Research
Grants and Training Awards 2005-2006
Research
Grants and Training Awards 2004-2005
Research
Grants and Training Awards 2003-2004
Research Grants and
Training Awards 2001-2002
|
