IPA Bulletin
Recent Advances - Volume 16, Number 3
John O'Brien and Bob Barber
Should future generations of patients suffering from Parkinson’s disease
be worried about inheriting the same condition? Possibly not according to
findings of a twin study reported in the Journal of American Medical
Association (Tanner et al. 1999; 281:341-346). They observed similar rates of
Parkinson’s disease concordance in monozygotic and dizygotic twins and
concluded that genetic factors are unlikely to play a significant role in the
development of the disease in patients over the age of 50 years. These
findings point to the importance of environmental factors in the etiology of
the disorder.
“Challenging the cholinergic hypothesis in Alzheimer Disease (AD),” Davies
and colleagues report that cholinergic deficits may not appear until the last
stages of illness (Journal of American Medical Association 1999; 281:1433 and
1401-1406). Their autopsy findings on 81 patients (64 female, mean age 87
years) failed to find any significant deficits in key cholinergic markers
(choline acetyltransferase and acetylcholinesterase) in patients with early
and moderate AD. Correlations between loss of cholinergic enzyme markers and
clinical and neuropathological measures of dementia severity were found if,
and only if, the patients with severe dementia were included in the analysis.
These findings led the authors to speculate that acetylcholinesterase
inhibitors may be effective only in patients with moderate- to late-stage
dementia.
Sloane and collaborators (Journal of American Geriatrics Society 1999;
47:439-445) conducted a descriptive longitudinal survey of 203 nursing home
residents who were classified as “severe disruptive vocalizers.” Subjects
tended to be demented, have multiple medical problems and were often highly
dependent. Nearly all were audible at least 50 feet away, half were physically
restrained and three-quarters were taking psychotropic medication. They
subcategorized subjects into “screamers” (nonverbal noises) and “talkers”
(used words) and found those who “screamed” had greater cognitive and hearing
impairment and higher dependency needs. Perhaps consistent with clinical
experience, there was a high probability of mortality within 6 months (nearly
25%), especially in older subjects who were physically abusive.
The controversy regarding possible potential protective effects of
education and estrogen replacement therapy (ERT) on cognitive function in
later life was examined in a longitudinal study of non-demented women (n=9651,
aged 65 years and older) (Matthews et al., Journal of American Geriatrics
Society 1999; 47:518-523). Using a modified mini-mental status exam (mMMSE;
maximum score of 26) they found the percentage of women scoring 23 or less at
baseline were 14.3% for current ERT users, 14.5% for past users and 20.5% for
"never users." Past but not current ERT users exhibited smaller declines upon
retesting compared to never users. However, by comparison, educational
attainments predicted both initial and change test scores and with age were
the most powerful predictor of cognitive function. The authors concluded that
formal education, rather than current oral ERT use, protects against
age-related cognitive decline.
The benefits of donepezil treatment for AD were consolidated by the
findings of a multinational clinical trial (Burns et al., Dementia 1999;
10:237-244) and an economic evaluation study (O’Brien et al., Journal of
American Geriatrics Society 1999; 47:570-578). The clinical trial demonstrated
a dose-response effect, with patients receiving 10mg/day of donepezil
experiencing greater benefits in all outcome measures than those treated with
5mg/day dose. To evaluate the cost benefits of donepezil, O’Brien and
associates used an economic modeling approach, and based on the limited
available data, predicted that the use of donepezil for mild-to-moderate AD
would result in lower overall costs. However, despite these economic benefits,
they predicted patients receiving donepezil for a 5-year period would only be
in a “non-severe” stage for two months less than those without treatment.
One of the most difficult clinical questions in patients with memory
disorders can be whether they are fit to drive. A clinical evaluation of
driving ability, the gold standard for such decisions, is not available in
many countries. Heikkla et al. (Acta Neurologica Scandinavica 1999;
99:349-355) compared the driving ability of post-stroke patients assessed by a
traffic psychologist to a clinical assessment undertaken by a neurologist.
Patients and carers also rated their own driving ability. Reassuringly, the
traffic psychologist and neurologist agreed on driving ability in 75% of cases
though patients and carers both tended to overestimate driving ability. This
indicated the need to rely on objective evaluations, rather than subjective
reports, of cognitive abilities when assessing driving ability.
Several studies have demonstrated the efficacy of anti-platelet agents for
the secondary prevention of ischemic stroke. The second European Stroke
Prevention Study (ESPS2) showed that acetylsalicylic acid and dipyridamole
were both effective, with the combination of both agents being additive in
terms of prevention. Sivenius et al. (Acta Neruologica Scandinavica 1999;
99:54-60) analyzed whether age influenced the protective effects of
anti-platelet agents in the study. No influence of age was found, leaving the
authors to conclude that combination therapy with dipyridamole and
acetylsalicylic acid was superior to either agent being used alone a secondary
prevention of ischemic stroke, irrespective of patient age.
Clinical ward rounds are a basic and routine part of clinical work, though
their usefulness and acceptability to patients and carers are perhaps not
questioned as often as they should be. Bains and Vassilas (Ageing and Mental
Health 1999; 3:184-187) studied the experiences of 67 carers of dementia
sufferers who had attended an inpatient ward round in the UK. Sixty-five
percent of carers did not find the experience stressful and a similar
proportion found the experience positive. Only nine percent found the
experience a negative one. When asked whether they would have preferred to
have spoken to the consultant alone, rather than meeting the multidisciplinary
team together, only a third of carers said this would have been their
preference. The main comments made were that the carers would have preferred
to know more about the purpose and composition of the ward round in advance.
Most clinicians recognize the high risk of relapse in elderly patients
with recurrent depressive disorders, and the beneficial effects of
prophylactic antidepressant medication in such patients has been shown.
However, the issue of relapse of elderly patients with first episode
depression after stopping antidepressants has not previously been examined.
Flint & Rifat (American Journal of Psychiatry 1999; 156:943-945) studied
21 patients over the age of 60 who had recovered from a first life-time
episode of major depression and had taken maintenance antidepressant
medication for two years without risk or recurrence. Antidepressants were
withdrawn and patients followed for another two years. Over this period,
relapse rate was 61% (12 out of 21), though fortunately, 10 of the 11 who
restarted antidepressants responded. Further work is needed, but such findings
support the view of some clinicians that long-term prophylactic medication is
required in the elderly even after one episode of major depression.
It is known that mutations in Presenilin 1 (PS1) are the main cause of
early onset familial AD and more than 40 missense mutations have been
reported. However, the patho mechanisms of AD due to PS1 mutations remain
unknown. Chui et al. (Nature Medicine 1999; 5:560-564) studied PS1 transgenic
mice with mutant PS1. They found accelerated neurodegeneration in transgenic
mice in older animals which was not associated with amyloid plaque formation.
Such work fits with studies showing that PS1 mutations facilitate apoptotic
neuronal death in vitro. The authors conclude that the pathological effect of
PS1 mutations seems to occur upstream of the amyloid cascade. Gouo et al.
(Nature Medicine 1999; 5:101-106) examined culture hippocampal cells, also
from mice with PS1. They found that cultured neurones had increased the
vulnerability to death induced by glutamate, which was due to preserved
calcium homeostasis (as agents that suppress calcium influx or release
protected neurones against this effect). The authors felt their findings
established a direct link between a genetic defect which causes AD and
exitotoxic neuronal degeneration, opening new avenues for therapeutic
intervention in AD.
The extent to which memory complaints predict cognitive decline remains
uncertain, with most studies showing a stronger link with depression than with
future impairment. Geerlings et al. (American Journal of Psychiatry 1999;
156:531-537) report on a prospective study of 3,778 non-demented people aged
65 to 84 followed up for an average of 3.2 years. The authors found that
memory complaints were a relatively strong predictor (odds ratio 2.9) of
progression to AD, while depression was not. Subtle cognitive impairment (MMSE
<26) was also associated with an increased rate of progression. There was
an interaction between memory complaints and cognition, so that memory
complaints predicted decline in those who were cognitively normal, but not in
those with impaired baseline cognition. Such results emphasize the need to
take such complaints seriously.
The association between depressive disorders and cognitive decline also
remains controversial, though in another large prospective study, Yaffe et al.
(Archives of General Psychiatry 1999; 56:425-430) found that depressive
symptoms did predict decline over four years in 5,781 elderly
community-dwelling women. Possible mechanisms outlined by the authors include
the early expression of depressive symptoms in dementia, shared genetic or
other risk factors, or neurobiological changes underpinning both, the toxic
effects of prolonged raised cortisol levels or the effects of treatment.
Clearly, further work in this area is required.
It is fairly well accepted that elderly patients are less likely to
complain of sadness or depression than younger subjects. Some have suggested
that this is part of the reason that epidemiological studies sometimes find
depression to be less prevalent among elderly subjects. Whether this decreased
likelihood to report sadness is a cohort effect is not clear, but the subject
of a report by Gallo et al. (Psychological Medicine 1999; 29:341-350). As part
of the Baltimore Epidemiological Catchment Area study, the authors
re-evaluated 1,651 adults (approximately 25% of whom were over 65) 13 years
after an initial interview in 1981. They found that older adults at follow-up,
just as older adults at baseline, were less likely to endorse sadness than
younger people. The authors suggest, though acknowledge their results do not
prove, that the observed age differences in reporting depression do not
reflect a cohort effect.
Drs. John O'Brien and Bob Barber are the IPA Bulletin's
research editors. They welcome comments via (fax) +44 191 219 5040 or (e-mail)J.T.O'Brien@ncl.ac.uk
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.
