IPA Bulletin
Recent Advances - Volume 19, Number 1
John O'Brien and Bob Barber
The Cholinergic System and Psychosis in Alzheimer’s Disease
Further support for the notion that cholinergic dysfunction is related to
psychotic features in dementia is provided in a report by Lai et al.
(Neurology 2001; 57: 805-811). From a prospective study the authors
examined behavioral features in 26 patients with Alzheimer’s disease
(AD) compared to 14 controls and investigated muscarinic M1 and M2
receptors in frontal and temporal cortex. While overall M2 receptor
density was reduced in the frontal cortex in those with AD, increased
density in frontal and temporal cortex was found in a subgroup of AD
patients who had psychotic features compared to those without. The
authors suggest this increased density may reflect upregulation of M2
receptors on surviving cholinergic terminals in the face of cholinergic
deficit or preservation of M2 receptors on non-cholinergic neurons. The
study provides further scientific rationale for the use of cholinomimetic
drugs in AD.
Clinical Accuracy of Diagnosis of
Parkinson’s Disease
Hughes et al. provide an analysis of 100 consecutively diagnosed cases
of Parkinson’s disease (PD), followed to autopsy, within the UK PD
Brain Bank (Neurology 2001; 57:1497-1499). Clinical diagnosis was
made according to three different sets of criteria, which all performed
well in terms of positive predictive value. The UK PD Society Brain
Research Centre criteria had the highest positive predictive value (92%)
when judged against postmortem. Diagnostic accuracy is higher than in
some other similar studies, though taken overall evidence suggests that
accuracy for the clinical diagnosis of PD is around 80 to 90 percent–
similar to that for probable AD.
Frequency of Post-Stroke Dementia
A study investigating the three-year incidence of post-stroke dementia
is reported by Henon et al. (Neurology 2001; 57:1216-1222). The
authors used a retrospective validated assessment of cognitive function
(IQCODE) in 202 stroke patients who were then followed for three years.
Around 15 percent were excluded because of pre-stroke dementia, but
despite this, almost 30 percent developed dementia after three years,
with most of this occurring in the first six months. Predictors of post-stroke
dementia were advanced age, pre-existing cognitive decline, silent
infarcts, diabetes and severity of stroke. Two-thirds of cases were thought
to have vascular dementia and one-third AD.
The authors concluded that their study confirmed high rates of post-stroke
dementia and suggested that underlying degenerative pathology
may play an important role in many cases.
Do Non-Steroidal Anti-inflammatory Drugs Reduce the
Risk of Alzheimer’s Disease?
Controversy continues in this area and further data are provided by a
seven-year follow-up of the Rotterdam Study (Veld et al., New England
Journal of Medicine 2001; 345:1515-1521). Following up almost 7,000
people aged over 55, dementia developed in 394 subjects of whom the
vast majority had AD. Risk of AD was reduced in those with long-term
(more than 24 months) use of anti-inflammatories, but not in those
with shorter term use. Use of NSAIDs was associated with reduction in
risk of AD but not vascular dementia. Results from this study further fuel
interest in the large studies of anti-inflammatories that are currently
ongoing.
A possible mechanism by which anti-inflammatories may reduce preva-lence
of AD is provided by Ku et al., who found that, in tissue culture,
non-steroidals reduced the concentration of the amyloidogenic form of
the A beta peptide (A beta 1-42) (Nature 2001; 414:212-216). In addition,
short-term treatment of ibuprofen in transgenic mice expressing
mutant APP reduced levels of A beta 1-42 in the brain. The authors
say they feel that the non-steroidals may be achieving this by altering
activity of gamma secretase, the enzyme involved in “non-amyloido-genic”
APP splicing.
Is Late-Life Depression a “Vascular” Depression?
Further evidence suggesting this may be the case is provided by Hickie et
al. (Psychological Medicine 2001; 31:1403-1412). The authors report
on an examination of vascular risk factors and genotype in a group of
78 “older” subjects (though not elderly, as the mean age is 54 years)
and 22 controls. Vascular risk factors were more common in patients
than controls, particularly in those with late onset disorder. ApoE geno-type
did not differ between groups, nor was it associated with late onset
depression, though patients with late onset depression did have a higher
prevalence of mutations of the methylenetetrahydrofolate reductase
enzyme (MTHFR). This enzyme is involved in regulating homocysteine
levels and mutations may result in increased levels. While homocysteine
was not measured in this study, results suggest that this would be an
interesting line of feature research. Overall this study provides further
support for a link between vascular disease and late life depression.
Possible Link between Beta-Amyloid and
Alpha Synuclein
A link between alpha synuclein, the protein that builds up in patients
with Parkinson’s disease and dementia with Lewy bodies, and beta-amy-loid,
the peptide which accumulates in Alzheimer’s disease, has been
suggested by Masliah et al. (Proceedings of the National Academy of
Sciences 2001; 10:1073). They found that A beta protein increased the
accumulation of alpha synuclein. In a separate report Shumura and
colleagues (Science 2001; 293:263-269) have shown an association
between Parkin and alpha synuclein. Mutations in Parkin have been
identified in rare juvenile onset recessive forms of PD which are not
associated with Lewy bodies. Parkin is a ubiquitin-protein ligase (ubiq-uitination
being an important step in the degradation of proteins) and
mutant Parkin loses this activity. The authors showed that alpha synuclein
is an important substrate of this ligase activity and suggested that
one particular form of synuclein, alpha synuclein 22, accumulates as a
result. This raises important questions as to whether this accumulation
is responsible for neurotoxicity in PD.
Stroke Prevention
The significance of stroke as a major cause of morbidity and mortality
is without question, but how effective are prevention strategies targeted
at the control of blood pressure (BP)? In a large randomised study
involving more than 6,000 subjects from 10 countries and 172 collaborating
centres, researchers (Progress Collaborative Group Lancet
2001;358:1033-41, plus commentary by Staessen and Wang, p1026-
1027) found a combined antihypertensive regime of perindopril, an ACE
inhibitor, plus indapamide, a diuretic, reduced the risk of stroke by 43
percent in subjects with a history of stroke or transient ischemic attack
(TIA). Overall, the active treatment groups (perindopril with or without
indapamide) had an annual stroke incidence of 2.7 percent compared
to 3.8 percent in the placebo group, though single therapy with perindopril
had a similar outcome to placebo. The benefit was independent of
whether the subjects were hypertensive, leading the authors to conclude
the regime should be considered routinely for patients with a history of
stroke or TIA irrespective of their BP.
Vascular Dementia in Japan
In an effort to resolve the debate as to whether there are real differences
in the ratio of AD and Vascular dementia (VaD) between Western countries
and Japan, Ikeda et al. carried out a detailed population survey in
Japan of over 1000 community-dwelling elderly subjects aged over 65
years (Neurology 2001;57:839-44). Using standardized clinical criteria
aided by CT scanning they found an overall prevalence of dementia of
just under 5%, comparable to other published studies. However, VaD
was the commonest diagnosis accounting for just under 50 percent of
dementia cases, compared to 35 percent with AD, indicating there are
differences in the prevalence of dementia sub-types between Western
countries and Japan.
Significance of Silent Infarcts?
To investigate the long-term clinical significance of radiologically
confirmed
silent infarcts, Bernick et al. followed up over 3,300 participants
of the Cardiovascular Health Study (Neurology 2001;57:1222-9).
Subjects underwent an MRI scan and just under 30 percent had evidence
of clinically silent infarcts. These subjects subsequently had a
higher risk of a symptomatic stroke suggesting their significance
should not be overlooked.
Cognitive Differences between Alzheimer’s Disease and
Subcortical Ischemic Vascular Dementia
Which neuropsychological tests best differentiate AD from subcortical
ischemic VaD? Researchers from Canada examined 10 neuropsychologi-cal
tests and found tests of recognition memory and verbal fluency
offered the best overall sensitivity and specificity in discriminating the
two diseases (Tierney et al. Arch Neurol 2001; 58:1654-9). Consistent
with previous reports, recognition memory was better preserved in
ischemic dementia and verbal fluency in AD.
Does Estrogen Therapy Reduce the Risk
of Stroke Recurrance?
Viscoli and colleagues undertook a randomised controlled study to evaluate
the efficacy of estrogen-replacement therapy in the secondary prevention
of stroke (New England Journal of Medicine 2001;345:1243-
9). More than 600 postmenopausal women (mean age 71 years) with a
recent history of cerebrovascular disease were enrolled and followed-up
for nearly three years. They found estrogen therapy had no positive benefit
on stroke recurrence or death, indeed subjects receiving estrogen
had a higher risk of fatal stroke.
The authors concluded this therapy should not be prescribed for the secondary
prevention of cerebrovascular disease!
Safety of Antiplatelet and Anticoagulant Therapy
Concerns about the safe use of antiplatelet and anticoagulant therapy in
nursing home patients with stroke disease may lead to their under utilization.
Quilliam et al. investigated the risk of bleeding complications
associated with these medications in elderly nursing home stroke survivors
(Stroke 2001;32:2299-2304). They found the numbers needed to
harm one resident with aspirin was 467, and with warfarin 126.
They concluded that the risk associated with these treatments was
relatively small.
Drs.John T. O’Brien and Robert
Barber are the Research Editors
of the IPA Bulletin. They welcome
readers’ comments via email (J.T.O’Brien@ncl.ac.uk) or fax
(+44.191.219.5040).
John T. O’Brien also is Deputy
Editor of the IPA Bulletin.
