IPA Bulletin
Recent Advances - Volume 18, Number 4
John O'Brien and Bob Barber
With mounting interest in possible “vaccines” for Alzheimer’s disease
(AD), Hyman and colleagues (Annals of Neurology 2001; 49:808-810) tested over 350 individuals to see whether the presence of autoantibodies
to beta-amyloid conferred protection from developing dementia.
Autoantibodies to beta-amyloid were common, occurring in just
over 50% of individuals, often in very low concentrations. But there was
no link between their concentration and the risk of developing dementia
nor with plasma levels of beta-amyloid itself. The authors concluded
that low levels of autoantibodies to beta-amyloid are common and
offer no obvious protection against developing dementia.
Researchers from Japan and the United States have produced further
evidence that a candidate enzyme—called neprilysin—could prove to
have a vital role in the pathogenesis of AD (Iwata et al., Science 2001;
292: 1550-1552, www.sciencemag.org). Rather than focusing on factors
that may lead to too much beta-amyloid deposition, they have taken a
different approach and searched for enzymes—in this case neprilysin
—that are involved in its degradation. The central premise is that it is
important to identify and understand both the degradation and synthesis
pathways involved in amyloid accumulation. Using animal modeling,
their initial findings indicate that deficiencies in neprilysin lead to
deficits in the degradation of amyloid. Whether AD is a “neprilysin deficient
disorder” remains to be proven, but the authors concluded that
even a partial down-regulation of neprilysin activity, which could be
caused by aging, could contribute to AD development by promoting
amyloid accumulation.
A recent issue of Neurology contains three papers submitted under the
auspices of the American Academy of Neurology (AAN) concerning evidence-
based practice guidelines for dementia. These include early
detection of dementia in the form of mild cognitive impairment
(Petersen et al., Neurology 2001; 56:1133-1142), diagnosis of dementia
(Knopman et al., Neurology 2001; 56:1143-1153) and the management
of dementia (Doody et al., Neurology 2001; 56:1154-1166).
They are accompanied by a thought provoking commentary by Hogan
and McKeith (Neurology 2001; 56:1131-1132). Some of their main,
and perhaps most controversial, findings can be summarized as follows.
Apart from the 14-3-3 protein for suspected Creutzfeldt Jakob
Disease genetic and cerebrospinal fluid markers are unproven for sporadic
AD; routine structural neuroimaging should be applied to all suspected
cases of dementia; those with subjective complaints and objective
evidence of impairment (but not-demented, i.e., “Mild Cognitive
Impairment (MCI)” cases) should be identified and monitored over
time. Management guidelines include considering cholinesterase inhibitors in those with mild to moderate AD and both vitamin E and
selegiline for slowing disease progression. Estrogen should not be prescribed
to treat AD and the guideline regarding ischemic vascular
dementia, that “there are no adequately controlled trials demonstrating
pharmacological efficacy for any agent in ischemic vascular dementia”
should change in the foreseeable future as the results of rigorous, well
conducted trials become available.
A community-based, prospective, study of non-demented patients with
Parkinson’s disease (PD) (Aarsland et al., Neurology 2001; 56:730-
736) found that, over a 4.2 year period, patients with PD had a six-fold
increased risk of becoming demented compared to subjects without the
disorder. Risk factors for developing dementia were advancing age,
increasing severity of Parkinsonism (Hoen and Yahr score >2) and
Mini-Mental State Examination (MMSE) score of under 29. Further
studies of dementia in PD, and its association to dementia with Lewy
Bodies, are clearly required.
The neuropathological basis of cognitive impairment in AD, that of
plaque and tangle pathology and cholinergic loss, has been reliably
demonstrated by several studies. However, little is known about neuropathological
correlates of non-cognitive symptoms. In a recent study
Tekin et al. (Annals of Neurology 2001; 49:355-361) report a clinicopathological
study of 31 patients assessed with the neuropsychiatric
inventory. They found an association between agitation and aberrant
motor behavior and tangle pathology in the orbital frontal cortex, an
association between apathy and tangle burden in the anterior cingulate.
Such data fit with the known function of these areas and provide
further evidence for the neurobiological basis of non-cognitive disturbance
in dementia.
Although often assumed, there is little direct evidence that cognitive
decline is “predated” by the neuropathological changes of plaques and
tangles. A small but rigorous prospective study of 14 people with serial
neuropsychological testing before death (Goldman et al., Neurology
2001; 56:361-367) found that those with neuropathological evidence of
mild AD, showed progressive neuropsychological decline during life.
Those with “pre-clinical AD”, who had tangle pathology in medial
temporal lobe structures, showed no decline in performance during life
similar to those with “healthy brains”. Although a small sample, this
suggests that serial neuropsychological testing may not be a good way
of detecting early AD change and that other markers may need to be
developed.
Neuropathology of Mild Cognitive Impairment (MCI)
Despite the considerable recent interest in MCI, the neuropathological
basis of this disorder remains unclear. Kordower et al. (Annals of
Neurology 2001; 49:202-213) report a neuropathological study of
patients with AD, MCI, or no impairment who had been clinically
assessed within 12 months of death. Cases of MCI (as well as AD) displayed
significant cell loss in layer two of the entorhinal cortex compared
to controls, a finding which correlated with performance on tasks
of declarative memory and performance on the MMSE. These results
suggest that pathology in the entorhinal cortex, long associated with AD,
may be also affected in those with MCI.
Epidemiological differences, such as the high prevalence of vascular
dementia in countries such as Japan and China and the low rates of
AD in Nigeria, continue to fuel debate as to whether such differences
are real (and therefore potentially informative regarding aetiology) or
affected by methodological and/or cultural differences. A thoughtful
review by Suh and Shah (Acta Psychiatrica Scandinavica 2001;
104:4-12) examines all epidemiological studies between 1966 and
1999. The authors find that, while in the 1980s vascular dementia was
more prevalent than AD in Korea, Japan and China, AD is twice as
prevalent in studies during the 1990s. The authors eloquently discuss
the complex interplay between changes in longevity and variations in
incidence and mortality which can impact on epidemiological findings,
concluding that changes in prevalence over time can be
explained by transition from a low incidence, high mortality society to
a high incidence high mortality society. As many risk factors for
vascular dementia are known (unlike AD) improved medical care and
survival would, just in itself, lead to a reduction in vascular
dementia and an increase in AD. (See Suh’s article in IPA Bulletin,
September, 2001. – ED.)
The under-reporting of AD on death certificates is known to be a pitfall in
conducting studies which rely on this mode of case ascertainment. The
same seems to be true of PD (Bayer et al., Acta Neurological
Scandinavica 2001; 103:7-11). This community-based study of PD found
that only 56% of death certificates mentioned the disorder either as an
underlying or contributing cause of death. Studies relying on this method
of diagnosis would under-report cases by approximately half.
Another study suggesting a relationship between B12/folate/homocystine
and AD is reported (Wang et al., Neurology 2001; 56:1188-1194). The
authors investigated 370 people aged over 75 with B12 levels assessed at
baseline on subjects followed for three years. Subjects with low levels of
B12 or folate had twice the risk of developing AD as those with normal
levels. Associations were even stronger in those who had above average
baseline cognition. This study adds to growing evidence suggesting the
need for studies investigating the effects of supplementation on development
of dementia.
Detecting alcohol abuse in late life can be difficult with estimates varying
from 2% to22%. Using data from the Canadian Study of Health and
Aging, a large national cohort of over 10,000 older persons, Thomas
et al. (Journal of American Geriatrics Society 2001; 49:415-420)
found nearly 9% of subjects had definite alcohol abuse and just under
4% questionable abuse. Excessive alcohol use was associated with cognitive
impairment and a greater risk of short-term mortality. The authors
advocate screening to detect individuals at risk of harm.
The complications of delirium are well established. But can the risk of
delirium as a complication of surgery for hip fractures be reduced?
Involving a geriatrician to proactively identify and help to manage risk
factors for delirium around the time of surgery reduced delirium by over
one-third (50% compared to 32% in the intervention group). It also
reduced severe delirium by over one-half (Marcantonio et al., Journal of
the American Geriatrics Society 2001; 49:516-522), and the length of
hospital stay was unaffected. The authors suggest further research is
necessary to assess the effectiveness of the interventions in more varied
clinical settings, and further work needs to be done if the protocol is to
be incorporated into routine practice.
Testosterone replacement therapy in normal men may have physical
benefits, such as improving bone mass, muscle strength and body composition.
Cherrier and colleagues (Neurology 2001; 57:80-88) set out to
test whether it could also have benefits on cognition. Using a randomized,
double blind, placebo-controlled study design, they injected 25 subjects
either with active drug or placebo for 6 weeks. They found testosterone
significantly improved spatial memory, spatial ability and verbal
memory. If larger and longer studies replicate this finding then it may
open up new therapeutic interventions, though the precise mechanism
for this finding remains to be determined.
Schulz et al. (JAMA 2001; 285:3123-3129) explored the effects of
bereavement of a family member on their caregiver. They found that the
experiences of the caregiver prior to death influenced how they adjusted
after death. Carers already stressed before the death continued to report a
high level of distress, but showed an overall improvement in health risk
behaviors. Conversely for individuals classified as “noncaregiver”, the
death of their spouse led to increased depression and weight loss.
Readers interested in Pick’s disease and frontotemporal dementia should
find a supplement of Neurology (2001; 56) of value. The supplement summarizes the clinical, biochemical, and molecular features of the
disorder with all contributions coming from an international meeting concerned with FTD and Pick’s disease held in Philadelphia in 1999.
Stirred by the hypothesis that exogenous estrogens may reduce the risk
of dementia in postmenopausal women, Geerlings et al. (JAMA 2001;
285:1475-1481) set out to see whether there was any link between the
length of the reproductive period, as a measure of the time exposed to
endogenous estrogens, and the risk of dementia. Studying a large cohort
(n=3601) they found women with more reproductive years and a natural
menopause had an increased risk of dementia, a finding which ran
counter to their original hypothesis.
A prospective population study from Finland examined the association
between AD in later life and midlife blood pressure readings and serum
cholesterol levels (Kivipelto et al. BMJ 2001; 322:1447-1451). With a
mean follow up period of 21 years, the study found raised systolic, but
not diastolic, blood pressure and high cholesterol levels increased the
risk of AD. The risk of AD was highest in the presence of both risk factors,
with an odds ratio of 3.5.
Following the demonstrable efficacy of cholinesterase inhibitors in AD,
trials of these agents in several other disorders are under way. However, a
recent report on treatment in progressive supranuclear palsy (PSP)
(Fabbrini et al., Acta Neurological Scandinavica 2001; 103:123-125)
suggests little evidence of efficacy in this disorder. The authors examined
six patients at baseline and at three months after treatment with 10 mg
of donepezil, finding that there was no effect on cognitive dysfunction or
on activities of daily living. Although there is some evidence of cholinergic
dysfunction in PSP, this limited study does not suggest cholinergic
replacement is beneficial.
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.
