IPA Bulletin
Recent Advances - Volume 20, Number 1
John O'Brien and Robert Barber
New Developments in Parkinson's, Alzheimer's and Dementia Research
Further Potential Hazards of Amyloid immunotherapy
In addition to the previously recognized complication of immunotherapy-induced
encephalitis in some humans, a further potential hazard of immunotherapy is
described by Pfeifer et al (Science, 2002; 298:5597). They used passive immunization
(mice were given antibodies to beta amyloid)
in the APP23 transgenic mice model of Alzheimer's disease. They noted, as in previous
immunization studies, a significant
reduction in amyloid burden in the immunized
mice. However, there was also found
to be an increase in cerebral hemorrhage in
the immunized mice and the authors suggest
caution in case beta amyloid immunization
may increase the risk of stroke in humans
with Alzheimer's disease.
Is Shunting of Therapeutic Benefit in
Alzheimer's Disease?
Whether CSF changes (either increased
pressure or alteration in protein or
metabolite concentrations) have any effect
on the progression of Alzheimer's disease
remains unclear, though some authors have
suggested that ventriculo-periteneal shunting
may be therapeutically useful. This practice
is given some support from a pilot study
described by Silverbird et al (Neurology
2002;59:1139-1145) who undertook a randomized
controlled trial of 29 AD subjects
(normal pressure hydrochephalus was
excluded) who were randomized to shunt on
no treatment groups and followed every
three months for one year. For patients randomized
to surgery there were no deaths
and mean dementia rating scores showed a
trend towards stability over 12 months,
compared to a decline in the control group
(p=0.06). Interestingly, there was a concomitant
decrease in ventricular CSF concentrations
of AD biomarkers (A-beta1-42 and
map-tau). The authors feel their results
point to the need for a large randomized
double-blind controlled clinical trial which
they inform us is now underway.
Further Questions Regarding the Outcome of
Mild Cognitive Impairment
There continues to be quite a marked discrepancy
between the outcome of mild
cognitive impairment when epidemiological
studies are compared to well characterized
clinic populations. The latter tend to show
relative stability of diagnosis and reasonably
consistent results in terms of an increased
risk for subsequent dementia, the former
often being at variance with this. Larrieu et
al (Neurology 2002;59:1594-1599) describe a
five year follow-up study of over 1,200 subjects
from a population based cohort of nondemented
elderly people from two areas in
South West France. At baseline, they found a
prevalence of MCI of 2.8% and an incidence
of 1% per year. Whilst they found MCI to
be a good predictor of AD (annual conversion
rate of 8.3%) it also proved a very
unstable diagnosis with almost half the subjects
reverting to normal. The authors speculate
that the weaknesses in the predictive
value in many cases may be based on variability
and error in psychometric tests used.
Can Cognitive Training Really Improve
Cognitive Ability? A Randomized Control Trial
Whether "use it or lose it" really applies
to human brain function still
intrigues all researchers, clinicians and, most
of all, patients and carers. The evidence base
for cognitive training interventions to
improve mental abilities is limited, so the
recent study of Ball et al (Journal of the
American Medical Association 2002;
228:2271-2285) is important in this regard.
They report a randomized controlled (but
single-blind) trial of almost 3,000 (nondemented)
people who were assigned to
memory training, reasoning, speed of processing
or control training groups (training
consisting of 10 sessions lasting around one
hour). All training programs improved performance
on cognitive and perceptual abilities
which was maintained at two year follow-up. However, generalizability of interventions
in terms of improving everyday
functioning could not be demonstrated. The
authors suggest that training effects were a
magnitude equivalent to the amount of
decline that might be expected in elderly
people without dementia over a 7 to 14 year
interval. They suggest that a much longer
follow-up may be needed to show that effects
have benefit in terms of function.
Wine Over Beer for Dementia Prevention?
This intriguing question is raised by data
from the Copenhagen City Heart study
reported by Truelsen et al (Neurology
2002;59:1313-1319), a case control study of
83 subjects with dementia compared to over
1,600 non-demented subjects. Alcohol
intake and type of alcohol had been assessed
15 years previously. The authors found (perhaps
surprisingly) that total alcohol intake
had no significant effect on the subsequent
risk of dementia. However, intake of wine
was significantly associated with a low risk
of dementia while beer was significantly
associated with an increased risk of dementia.
The authors are keen to point out that
their results did not indicate that people
should increase wine consumption to avoid
dementia, but suggest that there may be certain
substances in wine (such as flavinoids
and other antioxidants) which may reduce
the risk of dementia (differential intake of
red and white wine was not reported). A
sub-analysis focusing only on Alzheimer's
disease cases showed a similar trend but fell
short of significance.
Is Homocysteine a Risk Factor for
Depression as well as Dementia?
Anumber of previous studies have suggested
a relationship between raised
homocysteine and depression, though negative
findings have also been reported. A
study by Tiemeier (American Journal of
Psychiatry 2002;159:2099-2101) report data
from the Rotterdam Study of almost 4,000
elderly people who underwent folate, vitamin
B12 and homocysteine blood levels,
March 2003 o IPA BULLETIN 17
RESEARCH & PRACTICE
with depression diagnosed by the CES-D
scale and the Present State Examination for
those scoring above a certain cut-off.
Homocysteine levels were compared in 278
people with depressive symptoms (including
112 with major-type depression) and 416
controls. Raised homocysteine, low B12 and
folate deficiency all related to depression.
This relationship was reduced after adjustment
for functional disability and cardiovascular
disease, though remained significant
for vitamin B12 leading the authors to
conclude that low B12 may be related to
depression.
Homocysteine and Cognitive Function
Further data from the Rotterdam study
reported by Prins et al (Neurology
2002;59:1375-1380) examines the association
between plasma homocystene concentrations
and cognitive performance in the
non-demented elderly. In studying over
1,000 people, they reported increasing
homocysteine levels were associated with
lower scores on psychomotor speed, memory
function and global cognitive function
which were not mediated by structural brain
changes (as assessed by ratings of atrophy
and white matter change). The relationship
was most marked for psychomotor speed.
The authors hypothesize the relationship
may be mediated by cerebrovascular disease
(despite the negative findings regarding
white matter change), direct neurotoxicity,
impaired methylation of transmitters and
brain membrane constituents or the promotion
of beta amyloid mediated neurotoxicity.
This further adds to the growing body of
research emphasizing the need for controlled
studies of reducing homocystine levels in
terms of cognitive, affective and functional
outcome.
New Way of Assessing Response to
Cholinesterase Inhibitors
Rockwood and colleagues (Journal of
Neurology, Neurosurgery and Psychiatry
2002;73:500-507) plus an editorial by
Burns (page 471) explore new ways of
assessing treatment outcomes to drug interventions
in Alzheimer's disease, or in fact
any dementia. They used a measure called
the goal attainment scaling (GAS). In
essence, it measures individual problems
identified by patients and carers elicited by
open ended introductory questions. As
Burns indicates, attention is then focused on
specific problems identified by the patient
and carers which become the goals of treatment.
Using this approach Rockwood et al.
found that patients, carers and physicians
differ in their expectations and impressions
of treatment with a cholinesterase inhibitor.
Interestingly, clinically important changes
correlated only modestly with psychometric
tests, though treatment with donepezil largely
met the goals of the patients, carers and
physicians for the first six months. As the
authors discuss, GAS seems to be tapping
into something different than the usual
domains of enquiry, and they suggest that
the GAS can supplement the CIBIC-plus in
future treatment trials.
Early and Widespread Cholinergic Loss in
Dementia with Lewy bodies
An autopsy study by Tiraboschi et al.
(Archives of General Psychiatry, 2002;
59:946-951) assessed cholinergic function in
patients with a confirmed diagnosis of
Alzheimer's disease (AD) and dementia with
Lewy bodies (DLB). Although, as reported
in other studies, cholinergic deficits were
observed in both groups, cholinergic deficits
was more pronounced in subjects with DLB
and were more prominent in the earlier
stages of illness. This led the authors to conclude
that cholinergic enhancers may be
more effective in DLB than AD, especially
in the early stage of disease progression.
Clinical Trials with Memantine in
Vascular Dementia
Memantine, a glutaminergic antagonist
at the N-methyl-D-aspartate
(NMDA) receptor, has been used in
Germany for the treatment of dementia for
some years. Interest has increased after it was
recently licensed for use in moderate to
severe Alzheimer's disease (AD) in other
European countries. To further explore its
use, Wilcock et al. (Int Clin Psychopharmacol
2002;17:297-305) reported their findings of
a 28 week double-blind, placebo-controlled,
randomized multi-center study of memantine
(20 mgs daily) in vascular dementia.
Subjects had an MMSE between 10 and 22
and overall 548 patients were entered into
the intention to treat analysis. Memantine
improved cognitive function relative to
placebo by a median of 2 points on the
ADAS-cog. However there were no significant
differences between groups in the clinical
global impression of change. Pooled
analysis of two placebo controlled trials (this
study and the one of Orgonozo et al, Stroke
2002; 33:1834-9) is reported in Cerebrovascular
Disease (Mobius and Stoffler
2002;13 suppl 2:61-66). The pooled group
consisted of 900 patients with 710 entered
in to the final analysis. Interestingly, the cognitive
benefits of memantine were more pronounced
for patients with small vessel disease
(n=553, mean difference in ADAS-cog
after 6 months = 2.0, p=0.002) in contrast
to those with large vessel disease (n=214,
mean difference = 0.9, p= not significant).
This differential effect may be due to heterogeneity
of vascular dementia and the different
mechanisms that underpin the cognitive
decline in patients with vascular dementia.
Whether memantine will be licensed for vascular
dementia remains to be determined.
Could Donepezil Improve Cognitive
Impairment in Patients with Schizophrenia?
Buchanan et al. (Schizophrenia Research,
2003;59:29-33) have completed a pilot
study to examine the effects of donepezil on
cognitive function in patients with schizophrenia.
This was a small study of 15 subjects
who were stable on olanzapine. The
study was of short duration-six weeks-
and open labeled. Intriguingly, treatment
resulted in improvements in manual dexterity,
memory performance and speed of processing.
As the authors acknowledge, such a
small study requires replication and further
testing before firm conclusions can be
drawn.
Neuropsychiatric Symptoms in
Cognitive Impairment
The prevalence of neuropsychiatric symptoms
in cognitive impairment (MCI)
was investigated by researchers from the
Cardiovascular Health Study (Lyketsos et al.
JAMA 2002;288:1475-1483). They completed
the neuropsychiatric inventory (NPI)
in 320 people with MCI, as well as 362
with a diagnosis of dementia. Overall, the
authors found that neuropsychiatric symptoms
in MCI had a prevalence between that
of healthy participants and those with
dementia. The most frequent symptom was
depression (20%) followed by apathy (15%)
and irritability (15%). The most frequent
clinically significant symptom (with a high
disturbance score) was sleep disturbance followed
by irritability, depression, apathy and
eating disturbance. The authors speculate
that the intermediate prevalence of these
symptoms supports the hypothesis that MCI
is a precursor syndrome to dementia.
Hormone Replacement Therapy and the
Incidence of Alzheimer's Disease in
Older Women
Debate continues regarding the significance
of hormone replacement therapy
(HRT) in Alzheimer's disease. It is postulated
that estrogens may have neuroprotective
effects on the aging brain, including protection
against vascular risk factors, beta amyloid
formation, cholinergic transmission and
oxidative stress. A further prospective study
published in JAMA determined the incidence
of dementia among 1,357 men and
1,889 women resident in Utah, United
States-the so called Cache County Study
(Zandi et al, 2002; 288:2123-2129). They
found women who used HRT had a reduced
risk of Alzheimer's disease but no benefit was
conferred with HRT use unless such use
exceeded 10 years. The debate continues!
Further Findings from the Cache County Study
Researchers from the Cache County study
(Zandi et al. Neurology 2002 59(6) 880-6)
also examined the link between the use of
non steroidal anti inflammatory drugs
(NSAIDs), aspirin compounds and histamine
H2 receptor antagonists and
Alzheimer's disease (AD). Results indicated
that long term use of NSAIDs modestly
reduced the incidence of AD provided such
use was well before the onset of dementia.
No protection was conferred from recent
exposure to the medication leading the
authors to conclude that the use of NSAIDs
for the primary prevention of AD is unlikely
to show effects with treatment until the participants
have been followed for several years.
Is Personality Related to Depression
in Stroke Patients?
To examine the potential link between personality
and post-stroke depression, Aben et al. (Stroke 2002;33:2391-2395) consecutively
evaluated these variables in 190
patients with stroke disease. Depressive
symptoms, assessed at five time points from
one month to twelve months, had a cumulative
incidence of approximately 40%. They
found patients with a high neuroticism score
had nearly a five times greater risk of developing
depression independent of lesion location.
While indicating the need for further
research, the researchers emphasized the
importance of evaluating the role of personality
in post-stroke depression.
A double-blind, randomized study of
rapid-acting intra-muscular olanzapine and
lorazepam in the treatment of acutely agitated
patients with dementia was conducted.
Meehan et al (Neuropsychapharmacology
2002;26:494-504) investigated the efficacy
and safety of intramuscular injections of
olanzapine and lorazepam in the treatment
of agitation associated with dementia. They
randomized 272 patients with Alzheimer's
disease or vascular dementia to one of four
interventions: intramuscular olanzapine
(2.5 mgs), intramuscular olanzapine (5
mgs), intramuscular lorazepam (1 mg) or
placebo. Preliminary evaluations were made
at 2 hours and continued for 24 hours
using various measures of agitation. There
were no significant differences between the
active treatments and all treatments were
superior to placebo on most measures of
agitation. The 5 mg dose of olanzapine had
the fastest onset and overall the effects of
olanzapine were longer lasting than that of
lorazepam. The authors concluded that
rapidly acting intramuscular formulation of
olanzapine may contribute significantly to
the treatment of patients with acute
dementia-related agitation.
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).
