IPA Bulletin
Recent Advances - Volume 18, Number 3
John O'Brien and Bob Barber
Independent researchers have shown a remarkable convergence of
findings, which together point to a new susceptibility locus for late onset Alzheimer’s disease (AD) on chromosome 10. Results were published
in Science (290) in December 2000. In summary, Ertekin-Taner
et al. (pp2303-4) found linkage of plasma Abeta42 to a locus on chromosome
10 in late-onset AD. A second study by Myers et al. (pp2304-5)
found a locus on chromosome 10 that modified the risk for AD independent
of the APOE genotype. Bertram et al. (pp2302-3) also found
linkage to chromosome 10 near to the insulin-degrading enzyme,
which is thought to degrade Abeta in neurons and microglia.
Cerebrolysin is a nootropic drug that can pass the blood-brain barrier
and appears to exert a regulatory effect on neuronal metabolism. Bae
and colleagues from Korea conducted a multicentre randomised, placebo
controlled trial to assess its efficacy in AD (JAGS 2000 48:1566-
1571). The study design was relatively short (4 weeks) and used a
small sample size (active treatment = 34, placebo = 19), though there
were no dropouts. Subjects had mild to moderate AD (MMSE range 10-
24) and all were hospital inpatients, probably because the treatment
was administered via intravenous infusion. Standardized outcome
measures were employed, and despite the short duration of the trial
active treatment resulted in significant improvements in ADAS-Cog,
Clinical Global Impression of Severity and MMSE. However, no differences
were observed in measures of activities of daily living. In conclusion,
the authors suggested the treatment was both safe and effective,
whilst indicating longer trials were necessary.
The association between depression and suicide in the elderly is well
recognized, but are personality factors important too? Harewood et al.
(International Journal of Geriatric Psychiatry 2001 16:155-165) completed
psychological autopsies of 100 suicides occurring between 1995-
98. In addition to replicating the strong link between depression and
suicide (present in over 60% of individuals), they also found an association
with personality variables (in 44%), particularly anankastic and
anxious traits. The authors concluded that both personality factors
and depression are important risk factors for suicide in the elderly.
In recent years the importance of mixed pathology, mostly AD and vascular,
in causing cognitive decline in late life has been emphasized.
Such studies have usually relied on carefully selected cases. A large
study from the UK Cognitive Function and Ageing Study (Lancet 2001;
257:169-75) has recently reported neuropathological findings on 209
community dwelling individuals assessed prospectively, of whom 48%
were demented. Both cerebrovascular (78%) and AD (70%) pathologies
were common. Two thirds of those with dementia had neuropathological
features of probable or definite AD, though an equivalent amount of
plaque pathology was seen in a third of those without dementia.
Similar findings were reported with regard to cerebrovascular pathology.
Vascular lesions were equally common in demented and nondemented
people, though multiple vascular lesions were more common
in those with dementia. The authors concluded that, although AD and
vascular pathologies were the major determinates of cognitive decline
in this sample, most patients had mixed disease and there were no
clear thresholds of these features which predict a dementia status.
Additional factors are likely to determine whether the presence of
pathological change is associated clinically with cognitive failure.
The nature of “pre-dementia” syndromes remains a matter of hot
debate, with terms such as age-associated memory impairment (AAMI),
ageing-related cognitive decline (ARCD), cognitive impairment no
dementia (CIND) and mild cognitive impairment (MCI) each with
their champions. Recent interest has tended to focus on MCI, usually
defined as memory impairment 1.5 standard deviations below that for
age-matched norms, in the absence of global cognitive decline and
associated with subjective cognitive complaint. MCI is now the focus of
several multi-centre therapeutic trials. However, a population based
validation study (Ritchie et al, Neurology 2001; 56:37-42) challenges
the validity of MCI. In a sample of 833 subjects, MCI was found to be a
poor predictor of dementia within a three-year follow-up period, with
only an 11% “conversion” rate. MCI was also inherently an unstable
diagnosis, with subjects frequently changing category between different
assessment points. In contrary, subjects classified as having ARCD had
a much higher conversion rate (29%) to dementia over three years and
represented diagnostically a more stable group. Clearly the last word
has not been had on the most appropriate way to classify those at the
very early stages of cognitive decline.
A study published in JAMA (Hendrie et al. 2001 285:739-747) used the
same method and investigators to measure the incidence of dementia
and Alzheimer’s disease (AD) in two distinct communities, one industrialized
(African Americans residing in Indianapolis) and one nonindustrialized
(Yoruba residents of Ibadan, Nigeria). The incidence of
dementia and AD was lower among the Yoruba compared to the African
Americans, which led the researchers to suggest that further exploration
of population differences may identify potentially modifiable environmental
or genetic factors in dementia.
As reported in a previous Bulletin, “vaccination” with beta-amyloid
peptide can reduce amyloid burden in a transgenic model of AD. But
does this cause measurable gains in memory function and behavior? In
two separate studies reported in Nature, Morgan et al. (2000, 408:982-
985) found beta-vaccinated mice performed better in various learning
and memory tasks than control mice, and indeed did as well as nontransgenic
mice. Janus and colleagues (2000, 408:979-982) also found
beta-vaccination improved cognitive function, though without altering
the total levels of beta-amyloid.
Whether specific neuropathological changes in AD are linked to
specific behavioral and psychological symptoms has proved difficult to
confirm. Tekin et al., reporting in the Ann Neurol (2001 49:355-361),
found an association between agitation and abnormal motor behavior
and increased neurofibrillary tangles (NFTs) in the orbitofrontal area,
whereas apathy was associated with increased NFTs in the anterior cingulate.
In a separate study, Farber et al. (Arch Gen Psych 2000
57:1165-1173) found psychotic symptoms were independently associated
with the severity of dementia and also the burden of neocortical NFTs.
Finally, Sweet et al. (Arch Neurol 2001 58:466-472) found subjects with
a history of psychosis had a selective increase in a subtype of striatal
dopamine receptor –D(3). Neuroleptic treatment appeared to reduce
the affinity of the D(3) receptor, indicating it may be an important target
for antipsychotics in AD.
This controversial topic was the subject of a further, large
population-based
study with over 100,000 individuals in each limb (Seshadri et al.
Arch Neurol 2001 58:435-440). Consistent with previous negative findings,
the use of postmenopausal ERT was not associated with a reduced
risk of Alzheimer’s disease.
The aim of developing disease-modifying drugs for AD led researchers
from Switzerland (Nitsch et al. Ann Neurol 2000, 48:913-918) to examine
the effects of a selective muscarinic M1 agonist, AF102B, on beta-amyloid
levels in CSF. The sample size was relatively small and results
preliminary, but they found activation of M1 receptors was associated
with reduced beta-amyloid levels. We await the findings of more substantive
studies with interest.
An autopsy study by Yasojima and collaborators from Canada
(Neuroscience Letters 2001 297:97-100) examined the regional distribution
of an enzyme called neprilysin, which is thought to be involved in
the degradation of beta-amyloid protein. The concentration of
neprilysin mRNA was lowest in those areas of the brain vulnerable to
plaque formation, particularly the hippocampus and temporal gyrus,
leading the authors to conclude that low levels of neprilysin could lead
to deficient degradation of beta-amyloid. This in turn could contribute
to the pathogenesis of AD.
To evaluate the diagnostic value of CSF-tau and CSF-Abeta42 in AD,
Andreasen et al. (Arch Neurol 2001 58:373-379) undertook weekly CSF
analysis for one year in a community sample of subjects referred for
investigation of cognitive impairment. Increased CSF-tau and decreased
CSF-Abeta42 levels were found in subjects with AD. Overall, the test performed
well at discriminating subjects with AD from those with psychiatric
disorders and nondemented individuals, but was less good at discriminating
between different types of dementia.
Drs. John O'Brien and Bob Barber are the Research
Editors of the IPA Bulletin. They welcome readers' comments via
e-mail (J.T.O'Brien@ncl.ac.uk) or
fax (+44 191 219 5040). John O’Brien
also is Deputy Editor of the IPA Bulletin.
