IPA Bulletin
Recent Advances - Volume 14, Number 2
John O'Brien and Bob Barber
It is with great enthusiasm, but also some trepidation, that we launch this
new feature for the IPA Bulletin. As anyone trying to keep abreast of current
literature knows, there are many excellent studies published. Selecting
only 15 or 20 to comment on in each issue is an extremely difficult and, of
necessity, somewhat arbitrary exercise.
However, we will attempt to regularly review recently published research
reports of note and highlight a few that may be of particular interest to IPA
members. Our aim is for a balanced column that spans the whole spectrum
of interests within IPA, from day-to-day clinical issues to molecular
biology. For pure journalistic value, some items of purely anecdotal
interest also will be included.
The column will undoubtedly reflect a very personal view, open to criticism
for exclusion of some very worthy reports that may, in time, prove of great
import. This seems both unavoidable and inevitable, yet we feel it
should not preclude a column such as this. One thing we would emphasise
is that no judgement will generally be passed on the scientific validity of
any work mentioned. Not only does lack of space preclude this, but all
will have been subject already to a peer review process. With regard to
methodological strengths, weaknesses, and other issues, the reader should
consult the individual paper. Indeed, stimulating wider readership of
the literature is one of the aims of this column. Reports are not listed
in any order of merit or even chronology.
Differentiation between depressive disorder and grief reactions is
often clinically problematic, partly because no clear definition for
"abnormal grief" currently exists. Diagnostic criteria for complicated
grief disorder have now been proposed (Horowitz et al., American Journal of
Psychiatry 154: 904-910). These include a number of symptoms and a
time from bereavement of at least 14 months (12 months being specifically
avoided because of possible anniversary reactions). The authors hope
that the new diagnosis may help clinicians formulate and treat pathology not
currently adequately covered by ICD-10 or DSM-IV.
Supplements of interest to IPA members include the May 1997 supplement
to the American Journal of Psychiatry, which contains APA guidelines for the
management of Alzheimer’s disease, and the July 1997 supplement to
Neurology, comprised of a series of articles entitled "The changing standard
of care in Parkinson’s disease: current concepts and controversies."
The issue of how best to screen for depression in different populations
continues to provoke debate. Chochinov et al., (American Journal of
Psychiatry 154: 674-676) investigated screening measures in the terminally
ill. They concluded that a single- item screening measure performed
better than longer questionnaires. The single item was, in effect,
"Are you depressed?"
While heritable factors undoubtedly predispose to the development of
Parkinson’s disease, the underlying genetic basis remains elusive. A
mutation in the alpha-synuclein gene, which codes for a presynaptic protein
thought to be involved in neuronal plasticity, has been described
(Polymeropoulos et al., Science 276: 2045-2047). Such a finding may
facilitate understanding of the pathophysiology of this and other related
disorders.
The importance of genetics in determining cognitive function in old age
is further supported by a Swedish twin study that looked at same sex twin
pairs aged 80 or over, excluding those with a clear dementia (McClearn et
al., Science 276: 1560-1563). The estimate of heritability for general
cognitive ability was found to be 62%, a figure similar to that found in
adolescent twins. However, possible genes underlying this effect were
not examined.
Aggression is again highlighted as a major problem in the management of
patients with Alzheimer’s disease (Eastley and Wilcock, International
Journal of Geriatric Psychiatry 12: 484-487). The authors found one in
five sufferers from Alzheimer’s disease was assaultive, and that this
behaviour was associated with male sex and the presence of dyspraxia.
Creutzfeldt-Jakob disease (CJD) continues to cause concern, particularly
in the UK where a possible link with the epidemic of Bovine Spongiform
Encephalopathy (BSE) in cattle has been postulated. Cousens et al.,
(British Medical Journal 315: 389-396) analysed all CJD cases between 1970
and 1996. They found the number of CJD cases rose from about 10 per
year in the early 1970s to 40 per year in the 1990s, the most increase
occurring in those aged over 70. While the overall increase might be
consistent with a link with BSE, the increase in the elderly contrasts with
the so-called new variant cases of CJD that occur in younger sufferers and
that have been most closely linked with BSE. Increased case
ascertainment may be part of the explanation as similar increases in CJD
were also observed in countries where BSE is rare or absent. An excess
of CJD was confirmed among workers on dairy farms but, once again, the
incidence was similar to other countries where BSE is absent or rare.
This argues against a specific link with BSE and, despite being at some
increased risk, the risk of dairy farmers remains extremely low, with
incidence less than 10 cases per million.
Mutations in Presenilin 1 are now known to be important in some cases
(about 25%) of familial early onset Alzheimer’s disease. Wong et al.,
(Nature 387: 288-294) characterise mice with targeted disruption of the PS1
gene. PS1 was found to be essential for mouse embryonic development
and to be involved in Notch 1 signal transduction. Notch 1 is
essential for somite segmentation and, although the mechanism remains
unknown, it is of interest that mutations in a gene involved with embryonic
development can lead to dementia in late life.
Schmidt et al., (American Journal of Pathology 151: 69-80) describe a
hitherto unrecognised protein and unique plaque-like lesions throughout the
grey matter of patients with Alzheimer’s disease. Using a new
monoclonal antibody (AMY117), several plaques were identified that
were not visualised by amyloid plaques and that did not co-localise with
beta-amyloid deposits. Such lesions were also found in elderly Down’s
syndrome subjects, but not in control subjects unless beta-amyloid plaques
also were present. The significance of these lesions is unclear, but
they potentially represent a third major lesion in AD, in addition to
beta-amyloid plaques and tau tangles.
The significance and cause of "normal" age-related cognitive decline
remains the subject of much debate and two articles come to opposing
views. Starr et al., (Age and Ageing 26: 295-300) prospectively
studied 603 subjects and found that decline in Mini-Mental State Examination
(MMSE) score was virtually insignificant unless concurrent health problems
or medication supervene. They felt that any age-related cognitive
decline, if it occurred, accounted for less than 0.1 MMSE point per
year. However, Korten et al., (Psychological Medicine 27: 919-930)
reported a longitudinal sample of 1135 people and found that initial
impairments on the MMSE score predicted a poor prognosis in the very
elderly, and that decline in at least one cognitive area was almost
universal among those over 85.
The association between the ApoE4 allele and late-onset Alzheimer’s
disease is undisputed, though the relevance with regard to other disorders
remains unclear. Two reports (Gustafsen et al. Dementia and
Geriatric Cognitive Disorders 8: 240-243; Stevens et al., Neurology
48: 1526-1529) find that ApoE4 also is associated with an increased risk of
developing Frontal Lobe Dementia (FLD). These results may be of
significance with regard to the pathophysiology of FLD but may also impact
on recent discussions about the utility of ApoE testing in clinical
differential diagnosis.
Other genetic markers of frontotemporal dementia also are receiving
attention. Several groups have now identified a link to chromosome
17. A consensus statement (Foster et al., Annals of Neurology 41:
706-715) concluded that there was sufficient evidence to link
"frontotemporal dementia and Parkinsonism" to chromosome 17. The need
for further work and the collection of additional cases was highlighted.
Sexual relationships in dementia sufferers receive little attention,
though one study (Ballard et al., International Journal of Geriatric
Psychiatry 12: 447-451) found that a quarter of married dementia sufferers
were currently involved in a continuing sexual relationship and 40% of those
carers who were not sexually active were dissatisfied with this. The
authors highlight this area as important for further study.
More data on the possible protective effect of estrogens in Alzheimer’s
disease (AD) comes from the Baltimore Longitudinal Study of Aging (Kawas et
al., Neurology 48: 1517-1521), which showed that the relative risk for
developing AD in those using estrogen replacement therapy was 0.46, a
significantly reduced risk compared to those who did not. However, no
beneficial effect was found for longer duration of estrogen replacement
therapy.
Another result from the Baltimore Longitudinal Study of Aging (Stewart
et al., Neurology 48: 626-632) examined the association between use of
non-steroidal anti-inflammatories (NSAID’s) and future development of
AD. The relative risk of developing dementia for those with two or
more years of NSAID use was 0.4, a significantly reduced risk.
However, when considering aspirin alone the overall relative risk was not
significantly reduced. The authors felt this may be due to most
elderly individuals taking a prophylactic dose (less than 100 mg) against
heart disease, a dose not adequate for anti-inflammatory effects.
Sano et al. (New England Journal of Medicine 336: 1216-1222) conducted a
double-blind, placebo-controlled, randomised multi-centre trial of 341
patients with AD who received the selective monoamine oxidase inhibitor
Selegiline (10 mg per day), alphatocopherol (Vitamin E, 2000 IU per day),
both together, or placebo for two years. No significant differences in
outcome between the four groups were found, although, despite random
assignment, the placebo group had a significantly higher MMSE score.
If this was included as a covariate, significant delays in time to primary
outcome (death, institutionalisation, or severe dementia) were then found
for patients treated with Selegiline, Vitamin E, or combination
therapy. The authors concluded that in those with moderately severe
impairment (mean MMSE scores approximately 12), treatment with Selegiline or
Vitamin E may slow disease progression.
The significance of different pathologies in the aetiology of cognitive
decline and the heterogeneity of dementia remain key areas of
research. A study of nuns in the United States (Snowdon et al.,
Journal of the American Medical Association 277: 813-817) reports on 102
nuns who were prospectively assessed during life and received autopsy
examination. Among subjects who met neuropathological criteria for AD,
those with brain infarcts (particularly lacunar infarcts in the basal
ganglia, thalamus, or deep white matter) had a higher prevalence of dementia
than those without infarcts. In addition, fewer neuropathological
lesions of AD resulted in dementia in those with lacunar infarcts than in
those without, suggesting an additive role of pathology. In contrast,
among those who did not meet neuropathological criteria for AD, infarcts
were only weakly associated with poor cognitive function and dementia.
It appears there is a strong relationship between cerebrovascular disease
and cognitive decline, particularly in those with concomitant Alzheimer-type
pathology.
The issue of driving in late life remains an important area of clinical
concern. Among 5579 drivers aged over 67 involved in serious crashes
in Quebec, there was a significantly increased risk with exposure to long,
but not short, half-life benzodiazepines (Hemmelgarn et al., Journal of the
American Medical Association 278: 27-31). This may prove to be yet
another reason why long half-life benzodiazepines should not be prescribed
to elderly patients.
The vogue for antioxidants is given a further boost by a prospective
study of 442 subjects from Basel, Switzerland (Perrig et al., Journal of the
American Geriatric Society 45: 718-724). Significant stability of
levels of plasma antioxidants over time (22 years) was found, and
antioxidants were significant predictors of semantic memory performance,
with higher levels of ascorbic acid and beta-carotene being associated with
better memory performance. This remained so after controlling for
possible confounding variables such as age, education, and sex.
Further information on the link between Apolipoprotein E4 and
Alzheimer’s disease is provided by Blacker et al., (Neurology 48: 139-147)
who found that in subjects with AD, ApoE4 exerted its maximum effect before
the age of 70. The authors underscore the need to identify additional
genetic factors involved in Alzheimer’s disease beyond the age of 70.
The possible role of ApoE4 in dementia associated with boxing is highlighted
by a study of 30 boxers. Those scoring highly on the chronic brain
injury (CBI) scale all possessed at least one ApoE4 allele, a significant
difference from those without CBI impairment (Jordan et al., Journal of the
American Medical Association 278: 136-140). This small study suggests
that possession of an ApoE4 allele may be associated with increased severity
of chronic neurological deficits after boxing.
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.
