IPA Bulletin
Recent Advances - Volume 19, Number 4
New Developments in Parkinson's, Alzheimer's and Dementia Research
John O'Brien and Robert Barber
PARKINSON’S DISEASE
Is olanzapine effective in treating druginduced
psychosis in patients with Parkinson’s
disease?
Possibly not, at least according to the
results from two placebo-controlled,
double-blind studies focusing on patients
with dopamimetic-induced psychosis (Breier
et al. Biol Psychiatry 2002;52(5):438).
Patients were titrated to a maximum dose of
15mg/day of olanzapine (or placebo) over 4
weeks without any adjustment to
dopamimetic therapy. There was no difference
in symptom reduction between groups
but patients on olanzapine developed more
side effects, particularly motor symptoms of
Parkinson’s disease.
ALZHEIMER’S DISEASE
Risk factors for Alzheimer’s disease
Results from a larger prospective study
(the Canadian Study of Health and
Ageing, n=6,434) were recently published
and provide further insights into the risk
factors for Alzheimer’s disease (Lindsay et al.
Am J Epidemiol 2002;156(5):445-53).
Perhaps as expected, factors linked to an
increased risk of AD were apoE epsilon4,
increasing age and fewer years of education.
Conversely, regular physical activity and the
use of wine, coffee and nonsteroidal antiinflammatory
drugs were associated with a
lower risk. The authors suggest further studies
should examine these potential protective
associations, especially the possible benefits
of regular activity and exercise.
Caffeine and reduced risk of Alzheimer’s
disease
In a small study of 54 patients and 54 controls,
Maia and de Mendoca (European
Journal of Neurology 2002; 9; 1-6) found
that patients with Alzheimer’s disease consumed
significantly less coffee than controls
in the preceding years and caffeine intake
was associated with a 60% reduction in the
likelihood of getting Alzheimer’s disease.
Caffeine is an alkylxanthine, the same chemical
class which includes drugs such a
propentofylline which are purported to
work by modulating glial cell activity.
Although a small preliminary study, the
thought that caffeine or a constituent of coffee
might do the same is an intriguing
prospect deserving further examination.
Antioxidants and Alzheimer’s disease
The debate as to the potential value or
otherwise of antioxidant use as a protective
measure for Alzheimer’s disease
continues. In two widely publicized, large
prospective studies in JAMA, antioxidant use
was associated with reduced risk. In the first
study, Engelhart et al report data from the
Rotterdam Study, a population-based,
prospective cohort study of 5,395 participants
conducted in the Netherlands (JAMA.
2002;287:3223-3229). After a mean followup
of six years, 197 participants developed
dementia, of whom 146 had Alzheimer disease.
After adjusting for confounders, use of
antioxidative supplements, high intake of
vitamin C and vitamin E was associated
with lower risk of Alzheimer disease. This
relationship was most pronounced among
smokers and was not affected by ApoE4
genotype.
In a second study, Morris et al examined
another community cohort of 815 residents
65 years and older who were free of
AD at baseline and followed up for a mean
of 3.9 years (JAMA. 2002;287:3230-3237).
Increasing vitamin E intake from foods was
associated with decreased risk of developing
AD after adjustment for confounders, with
relative risk reduction of 0.3 for those with
the highest intake. However, in this study
the protective association of vitamin E was
observed only among persons who were
APOE 4 negative. These two studies both
provide important new data confirming
possible preventative strategies but clearly
further work is needed before a uniform
picture emerges of exactly who benefits
from what.
Does treatment with simvastatin reduce
Abeta levels in Alzheimer’s disease?
There is growing interest that statins may
have benefits in Alzheimer’s disease
(AD) independent of their cholesterol-lowering
actions, though the mechanism by
which they may exert their effect remains
uncertain. Researchers from Germany completed
a 26 week randomized, placebo-controlled,
double blind trial using simvastatin
to determine whether it has any biological
effect in reducing Abeta levels in AD
(Simons et al. Ann Neurol 2002;52(3):346-
50). The study involved 44 patients with a
clinical diagnosis of AD of varying severity
but all had normal cholesterol levels. CSF
levels of both Abeta40 and Abeta42 were
measured. Analysis of all subjects failed to
demonstrate any drug effect on their level,
though subjects with mild dementia had
some reduction in Abeta40. The relevance of
these mixed findings remains unclear.
Additional insights into this topic can be
found in the review by Crisby et al. entitled
“Statins in the prevention and treatment of
Alzheimer disease” (Alzheimer Dis Assoc
Disord 2002;16(3):131-6).
Vaccines, neuroinflammatory processes, new
treatments and Alzheimer’s disease
New studies continue to hint at the
potential benefits of Abeta antibodies
in modifying Abeta(1-42) levels, as recently
shown by Dodel et al. (Ann Neurol
2002;52(2):253-6). They found intravenous
immunoglobulin treatment significantly
reduced Abeta(1-42) in the CSF compared
to baseline readings. However, translating
these findings into a safe and effective treatment
has so far proved elusive, partly
because a small proportion of patients in
clinical trials developed symptoms of brain
inflammation. For a more comprehensive
review of the situation, interested readers
may wish to read the review by Munch and
Robinson entitled the “Potential neurotoxic
inflammatory responses to Abeta vaccination
in humans” (J Neural Transm 002;109:
1081-7). Readers of the IPA Bulletin may
also find a report from the 8th International
Conference on Alzheimer’s Disease and
Related Disorders of interest. “New
Alzheimer’s treatments that may ease the
mind” (Science 2002;297:1260-62). summarizes
current thinking and findings in relation
to the key therapeutic strategies for
Alzheimer’s disease aimed at beta-amyloid,
metal chelation, vaccines, statins, neurotransmitter
targets and other potentially preventative
intervention.
DEMENTIA
Positive link between depressive symptoms
and dementia
As outlined by Wilson and colleagues
from the United States (Neurology
2002;59(3):364-70), various cross-sectional
and retrospective studies have demonstrated
a putative link between depression and
Alzheimer’s disease, but the evidence base
from longitudinal studies is thinly spread yet
necessary in order to evaluate the full extent
of this association. To examine this issue further,
they completed a seven-year prospective
study of Catholic clergy members free
of dementia at the time of recruitment.
Baseline frequency of depressive symptoms
was relatively low but was subsequently associated
with both the risk of developing AD
and the rate of cognitive decline. Indeed the
risk of AD increased by an average of 19%
for each depressive symptom, adding support
to the notion of a link between depressive
symptoms and AD at least in older
people.
Is mild cognitive impairment prodromal for
vascular dementia?
This was the title and aim of a study by
Meyer et al. published in Stroke
(2002;33:1981-85). Just fewer than 300
subjects were assessed for more than three
years with regular neuropsychological testing
and annual neuroimaging. Results: 25% of
the cohort developed mild cognitive impairment
(MCI, n=73/291) with 48% of these
subjects developing Alzheimer’s disease (AD)
and 20% developing vascular dementia
(VaD). The remainder were either stable or
improved. Overall, approximately 55%
(n=15/27) of subjects who developed VaD
(n=27/291) had prodromal MCI. Subjects
without evidence of MCI before the onset of
VaD were more likely to have a history of
infarcts(s) in contrast to those with MCI,
where small vessel disease was more common.
There were no differences in the neuropsychological
profiles of MCI subjects
who converted to AD or VaD, but after a
diagnosis of dementia performance on cognitive
tests for VaD and AD evolved differently,
with subjects with AD showing ongoing
deterioration.
Dementia after stroke
Adding to the body of evidence underscoring
a link between stroke disease
and the onset of dementia, Desmond et al.
reported the findings of their longitudinal
study on the incidence of dementia following
stroke (Stroke 2002;33(9):2254-62).
Their sample consisted on 334 patients with
ischemic stroke disease and 241 controls free
of both dementia and stroke disease. After
adjusting for various confounders, the relative
risk of incident dementia associated
with stroke was 3.8. The overall risk was also
increased in the presence of intercurrent
medical problems which could potentially
cause cerebral hypoxia or ischemia, leading
the authors to speculate that cerebral hypoperfusion
may underpin some cases of
dementia after stroke.
Dementia and its effects on stroke survival and
cost of treating other diseases
Accepting dementia as a recognized outcome
of stroke disease as noted above,
Desmond et al. set themselves the further
task of determining whether dementia was
also a risk factor for inauspicious outcomes,
or more specifically in context of their study,
a predictor of long-term survival (Neurology
2002;59(4):537-43). They followed up 453
patients with stroke disease for 10 years and
found dementia was indeed an independent
risk for increased mortality. The risk was not
specific to any type of dementia but
increased with dementia severity. They speculated
that this could reflect a composite of
factors including the undertreatment of
stroke survivors with dementia, reduced
patient compliance with treatment regimens
and increased burden of cerebrovascular
pathology. These findings overlap with the
results of a separate study by Sloan et al.
(Alzheimer Dis Assoc Discord
2002;16(3):137-43) examining the effects
of Alzheimer’s disease on the cost of treating
other diseases, including stroke disease.
Perhaps not surprisingly, patients with AD
were more expensive to treat but this was
largely due to their greater propensity to
experience more adverse outcomes (such
as higher death and hospitalization rates)
when ill.
John T. O'Brien and Robert Barber are the Research
Editors of the IPA Bulletin. They welcome readers' comments via
e-mail (J.T.O'Brien@ncl.ac.uk).
