IPA Bulletin
Recent Advances - Volume 17, Number 3
John O'Brien and Bob Barber
Diabetes is a risk factor for dementia Although Type II
diabetes is a known risk factor for stroke, and so may be expected to
be linked to vascular dementia, it has not clearly been demonstrated
as a risk factor for dementia. Results from the Rotterdam study (Ott
et al., Neurology 1999; 53: 1937-1942), which followed over 6,000 elderly
subjects, found that baseline diabetes was an independent risk factor
for subsequent development of both dementia (relative risk 1.9) and,
more specifically, Alzheimer's disease (AD) (relative risk 1.9). Patients
at highest risk were those whose diabetes needed insulin treatment
(relative risk 4.3). The authors calculated the diabetes-attributable
risk for dementia to be almost 9%, concluding that diabetes may have
contributed to the clinical syndrome in a substantial proportion of
dementia patients.
Sex and dementia While prevalence studies clearly demonstrate
a higher frequency of dementia in women compared to men, this dif-ference
may reflect increased longevity in women, and incidence
studies on gender differences in dementia are conflicting. A recent
report from the EURODEM studies (Anderson et al., Neurology 1999; 53:
1992-1997), which pooled four population-based studies involving
almost 13,000 subjects, found that after age 85, there were significant
sex differences in AD incidence. Women were more at risk than men
and, after age 90, their rate was three times higher. Perhaps against
expectation, there were no sex differences in incidence rates for
vascular dementia.
Does vitamin B12 deficiency cause depression? The effects
of vitamin B12 and folate in maintaining central nervous system
function are well known. Low B12 levels have been described in
some studies of hospital psychiatric patients. Penninx et al. (American
Journal of Psychiatry 2000; 157: 715-721) report the results of an epi-demiological
sample of 700 women aged over 65 who had vitamin
B12, folate, and homocysteine levels performed in addition to the
Geriatric Depression Scale. While homocysteine, folate, and
anemia were not associated with depression status, vitamin B12
deficiency was associated with severe depression. Those with low
levels were twice as likely to be severely depressed as non-deficient
subjects. As with any cross-sectional study, causality cannot be
demonstrated but this finding should prompt further research into
the link between B12 deficiency and psychiatric disorder.
Late onset schizophrenia: What's in a name? The nosology
of non-affective, non-organic psychosis in late life has a checkered
history. The exclusion of paraphrenia from ICD-10 and DSM-IV has
been mourned by many clinicians. To move this controversial area
forward, an International Consensus Meeting was held, the results of
which have been reported (Howard et al., American Journal of Psychiatry
2000; 157: 172-178). The group, consisting of leading researchers in
this area from around the world, achieved consensus on diagnosis,
nomenclature, treatment guidelines, and future research directions.
It was suggested that when the disorder occurred between the ages of
40 and 60, it be termed "late onset schizophrenia," while cases occur-ring
after age 60 should be termed "very late onset schizophrenia-like
psychosis." The group felt these terms had face validity and clinical
utility and that general adoption of these categories would foster
systematic investigation and research of such patients, which would
ultimately clarify the relationship of such diagnoses to early onset
schizophrenia and other disorders.
Dementia and centenarians The old chestnut of whether every-one
will develop dementia if they live long enough continues to be
debated. Blansjaar et al. (International Journal of Geriatric Psychiatry; 15:
219-225) identified all people over the age of 100 living in a Dutch
catchment area of 250,000 inhabitants. Fifteen of 17 were examined
with clinical interviews and cognitive tests. All 15 were demented;
the dementia was moderate to severe in 12 cases. The authors
conclude that their most conservative estimate of the prevalence of
dementia in those aged 100 or more would be 88%. This interesting
study should prompt further investigation of the "very old old," which
may provide important insights into the link between AD and
"normal" aging.
Cholinesterase inhibitors in Dementia with Lewy Bodies
(DLB) Two recent reports provide further evidence for the efficacy of
cholinesterase inhibitors in Dementia with Lewy Bodies. Lanctot and
Herrman (International Journal of Geriatric Psychiatry 2000; 15: 338-345)
report seven patients treated with donepezil 5-10 mg daily.
Five of the seven patients were rated as improving on at least one
behavioral symptom, while three showed a marked improvement in
behavior. In a larger study, McKeith et al. (International Journal of Geriatric
Psychiatry 2000; 15: 387-392) report on the use of rivastigmine 3-12 mg
in 11 patients with DLB treated for 12 weeks. Almost half the patients
were judged to have experienced very significant clinical improve-ments
in terms of behavior, and overall mean scores on the
Neuropsychiatric Inventory fell for delusions, apathy, agitation and
hallucinations. There was no evidence that Parkinsonian symptoms
deteriorated; indeed, these tended to improve. These reports high-light
the need for large, multi-center, randomized, double-blind stud-ies
in this disorder.
Antidepressant use in the elderly Clinicians remain divided
as to what class of antidepressant should be the first choice when
treating elderly patients with depression. However, whatever the
merits of any particular class, a study by Mamdani et al. (American
Journal of Psychiatry 2000; 157: 360-367) shows that antidepressant use
in the population of Ontario has changed from 1993 to 1997. The
proportion of overall antidepressant use in the elderly increased from
9.3% to 11.5%. The pattern of prescription also changed dramatically,
with SSRIs accounting for less than 10% of antidepressant prescrip-tions
in 1993 but 45% of those in 1997. Along with this, annual costs
for antidepressants increased by 150%, of which approximately half
the increase was due to the shift to prescribing SSRIs in favor of
tricyclic. The authors highlight the substantial financial impact of a
switch to SSRIs, suggesting further research should address balancing
the costs of newer agents vs. their advantages.
Efficacy of ECT Two studies, though not focusing specifically on
the elderly, provide further information about efficacy of ECT.
Sackeim et al. (Archives of General Psychiatry 2000; 57: 425-434)
conducted a double-blind study of depressed subjects randomized to
bilateral ECT or unilateral ECT at three different doses (50%, 150% or
500% above seizure threshold). High dose unilateral and bilateral
ECT were equivalent and were twice as effective as low or moderate
dose unilateral ECT. As has previously been documented, bilateral
ECT resulted in significantly greater impairments in memory than
any dose of unilateral ECT. The authors suggest that high dose
(500% above seizure threshold) unilateral ECT is as effective as
bilateral ECT.
Bailine et al. (American Journal of Psychiatry 2000; 157: 121-123)
compared bi-frontal and bi-temporal ECT in 48 depressed subjects.
They found that bi-frontal electrode placement was as clinically
effective as bi-temporal but resulted in less cognitive impairment.
Further studies will need to determine whether high dose unilateral
temporal or bi-frontal ECT should be the treatment of choice.
Therapeutics in Alzheimer's disease Testing whether a
biological hypothesis has clinical relevance is undoubtedly a chal-lenge.
On the back of other studies that have found an association
between reduced estrogen levels and AD (such as Manly et al. in
Neurology 2000; 54: 833-837), Mulnard and colleagues from the USA
(JAMA 2000;283: 1007-15, plus editorial comments by Shaywitz and
Shaywitz 1055-56) used a double-blind, placebo-controlled trial
design to examine the efficacy of estrogen replacement in the treat-ment
of mild to moderate AD. The one-year clinical trial involved
120 women and used standardized outcome measures. No benefit of
estrogen was observed on cognitive, functional, or global outcomes.
As the authors speculate, the hypothesis that estrogen has a
preventative role in AD is yet to be fully tested.
The potential therapeutic benefits of the "inflammatory hypothesis"
of AD were examined in another randomized, placebo-controlled clini-cal
trial (Aisen et al., Neurology 2000;54: 588-593). In this instance
prednisone was prescribed for one year (10mg/day) after a four-week
introductory phase (20mg/day). Subjects were mildly impaired with
mean MMSE scores above 21. Again, standardized outcome mea-sures
were used and no beneficial clinical effect was observed.
Indeed, treatment with prednisone was associated with greater
behavioral decline. The authors acknowledged that although higher
doses may, at least theoretically, be required to suppress brain
inflammation, the associated health risks of prolonged treatment
with high-dose prednisone is likely to pose substantial risks.
Driving and dementia Should people who are diagnosed as suf-fering
from dementia automatically lose their right to drive? A study
by Carr et al. (JAGS 2000;48:18-22) retrospectively analyzed the fre-quency
of car crashes in a group of elderly subjects enrolled in a lon-gitudinal
study of aging and AD. They found subjects with mild AD
(clinical dementia rating of less than 1) who were still driving had
low crash rates, which were comparable to normal age-matched con-trols,
even after adjusting for the level of road exposure. The authors
recommended that further prospective studies should attempt to
identify better predictors for crashes than diagnosis alone.
Insights into molecular pathology Animal models are increas-ingly
being used to examine the molecular substrates of dementias
(as reviewed by Emilien et al. Arch Neurol 2000;57:176-181). A further
demonstration of this technique was reported in Science by Masliah
and colleagues in a joint USA/Japan collaboration (2000; 287:
1265-1268). They used transgenic mice to explore the pathological
significance of abnormal accumulation of a-synuclein, a protein that
may be actively involved in synaptic function and plasticity.
Pathologically, abnormal expressions of this protein, referred to as
a-synucleinopathies, have been described in a range of disorders,
most notably Parkinson's disease (see also Solano et al. Ann Neurol
2000;47:201-210) and DLB. The transgenic model provided further
evidence supporting a link between increased accumulation and
expression of a-synuclein, cell damage, and dopaminergic loss.
Seeing is believing Researchers reporting in Nature Biotechnology
(Louie et al. 2000;18:321-325) have developed a technique that takes
conventional magnetic resonance imaging (MRI) beyond the imagin-able
and used it to detect and probe cellular processes (see also
commentary in Science 2000;287:1575). The technique uses a contrast
enhancing metal, gadolinium, which is delivered to the cell in a
protective coating. This cloak, and therefore the gadolinium, is
released when it reacts with a specific enzyme, in this instance beta-galactosides,
thereby increasing the MRI signal and allowing the
enzyme to be detected. So far the researchers have only applied the
technique to a specific enzyme in living tadpoles, but with future
modifications it raises exciting diagnostic and therapeutic opportunities.
Depression in stroke and later life Understanding the factors
that contribute to post-stroke depression is likely to improve the
detection and management of this important condition. Singh and
colleagues (Stroke 2000; 31:637-644) examined the relationship
between functional and neuroanatomic factors in this disorder.
Following subjects from the Sunnybrook Stroke Study (n=81/449) for
one year after the index stroke, they found that although inferior
frontal lesions were associated with an increased risk of depression,
the extent of functional impairment imparted the greatest overall risk
and best predicted outcome over time. The authors highlighted the
need for careful screening of all patients with stroke disease, irre-spective
of the lesion location.
Post-operative delirium The high prevalence and clinical impor-tance
of post-operative delirium in the elderly is well recognized, but
few prospective studies have longitudinally assessed its prevalence
and associations, particularly after minor surgery. Milstein et al.
(Ageing and Mental Health 2000; 4: 178-181) followed 197 patients dur-ing
cataract removal. Just over 5% suffered from post-operative delir-ium
and the occurrence of delirium was associated with older age
and more frequent use of benzodiazepine pre-medication. The study
included both general and local anesthesia and, perhaps surprisingly,
the type of anesthesia was not associated with subsequent risk of
delirium.
Does fasting cause stroke? Ramadan is a special month for
Muslims, as fasting during Ramadan is a religious duty. Akhan et al.
(Acta Neurologica Scandinavica 2000; 101: 259-261) used this as an
opportunity to compare stroke incidence during Ramadan compared
to other months over a four-year period in southwest Turkey. They
found no differences between stroke incidence or age and sex distrib-ution
of this during Ramadan compared to the rest of the year. Not
only Muslims, but anyone who fasts for whatever reason, will be
reassured that no association with stroke was found!
Attitudes toward cardiopulmonary resuscitation (CPR)
in the elderly Richardson et al. (Ageing and Mental Health 1999; 3:
336-339) report a survey of 418 UK geriatricians and 294 UK old age
psychiatrists who were asked their views on CPR in various clinical
scenarios. Old age psychiatrists were more likely to suggest CPR in
almost all cases, whether the patients had dementia or not. For
patients with severe dementia 11% of psychiatrists compared with
only 3% of geriatricans suggested they would initiate CPR. When
asked if they themselves would wish CPR when suffering from
severe dementia, only 4% of psychiatrists and 1% of geriatricians
expressed a wish for this.
Diagnosing vascular dementia (VaD) Despite the develop-ment
of operational clinical criteria, inconsistencies in the diagno-sis
of vascular dementia are well recognized. Chiu and collaborators
(Arch Neurol 2000;57: 191-196) compared the relative classification
rates and interrater reliability of the four criteria in common use
and found considerable discrepancies. Their findings indicated
that estimates of the incidence and prevalence of VaD would vary
significantly depending on the criteria selected. The implications
of this study, and wider topic of VaD itself, were discussed in an
editorial (Bowler and Hachinski: 170-171) in the same issue.
Significance of periventricular white matter lesions The
controversy surrounding the clinical significance of periventricular
white matter changes were highlighted by two different studies.
Smith et al. (Neurology 2000; 54:838-842) examined the relationship
between postmortem MRI, clinical and pathological findings in
subjects recruited from the the Nun Study (n=52/678). They found
no obvious link to support a connection between periventricular
lesions and reduced cognitive or functional performance. In
contrast, an in vivo examination of subjects (n=1,077) from the
Rotterdam Scan Study (de Groot et al. Ann. Neurol. 2000; 47:145-151)
found an association between the severity of periventricular lesions
on MRI and cognitive impairment. The clinico-pathological status
of these changes still needs further clarification.
Quality of life is improving Some good news: a questionnaire
survey from the USA (Liao et al. JAMA 2000; 283:512-518) indicates
that the quality of life in the last year of life in people aged 85 years
and over was better in 1993 than in 1986. Readers of the IPA Bulletin
may be interested to read a review by Jorm entitled "Does old age
reduce the risk of anxiety and depression? A review of epidemiolog-ical
studies across the life span" (Psychological Medicine 2000; 30:11-
22). The article discusses some of the mechanisms that may attenuate
aging-related risk for anxiety and depression.
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.
