IPA Bulletin
Recent Advances - Volume 19, Number 2
John O'Brien and Bob Barber
Supplements of Interest
The November 2001 Ageing and Mental Health includes a section on
legal aspects of dementia. The February 2002 issue of British Journal of
Psychiatry is a special issue devoted to old age psychiatry. Issues covered
include: genetics, cost of care, frontotemporal dementia, dementia with
Lewy bodies, vascular dementia and late onset depressive disorder.
Community Prevalence of Dementia Sub-types
Community prevalence rates for dementia in the over 65’s show wide variation,
particularly in subtypes that might be difficult to recognize such as
dementia with Lewy bodies. Stevens et al (British Journal of Psychiatry
2002; 180:270-276) describe a study of 1085 people selected by a “door
knocking” approach. Of these, 107 met screening criteria for dementia.
Prevalence rates were: 31.3% Alzheimer’s disease, 21.9% vascular dementia,
10.9% dementia with Lewy bodies, 7.8% frontal lobe dementia. It is
not surprising that Alzheimer’s disease and vascular dementia were the
two most common dementia sub-types. However, this community study
provides important corroboratory evidence from prevalence rates derived
from hospital cohorts that dementia with Lewy bodies and frontotemporal
dementia are the third and fourth most common causes of neurodegenerative
dementia in the elderly after Alzheimer’s disease.
Sub clinical” Effects of Vascular Disease on Cognition
It is well recognized that stroke can impair cognitive function, however,
associations between more subtle manifestations of vascular disease and
cognitive function have not been well studied in representative population
samples. Elwood et al (Age and Ageing 2002; 31:43-48) describe a
population sample of 1,500 men in South Wales who were assessed
regarding vascular risk factors and underwent neuropsychological
examination. They found that those with evidence of cardiac or peripheral
vascular disease had impaired cognition compared to those without,
with the vascular risk factors causing a reduction equivalent to
about four to five years of additional age. The authors argue that studies
are needed to determine the possible effects of aspirin in ameliorating
cognitive decline in such cohorts.
Variant CJD Described in Elderly Patients
More than 100 cases of variant CJD have now been described. This new
clinicopathological variant of CJD was defined in 1996, and is thought
to be caused by transmission of bovine spongiform encephalopathy
from cattle to man. To date, characteristics have been a younger age
group (mean age 29) combined with other features such as absence of
characteristic EEG changes and presence of high signal intensity in the
pulvinar of the thalamus on MRI. Lorains et al (Lancet 2001;
257:1239-40) describe what seems to be the first case of variant CJD
occurring in an elderly patient. A 74-year-old retired electrician presented
with visual hallucinations and paranoid delusions preceded by pains
in his hands. He was cognitively impaired and admitted to a psychiatric
unit for treatment of psychotic illness where investigations were normal.
He developed unsteadiness and falls, CT was unremarkable and a working
clinical diagnosis of multi-infarct dementia was suspected. A diagnosis
of variant CJD was made at autopsy. The authors suggest occurrence
of variant CJD in an elderly patient is unlikely to be a unique
event and their case report reinforces the need of careful investigation of
patients of all ages with progressive neuropsychiatric disorders.
Outcome of Mild Cognitive Difficulties
Palmer et al (American Journal of Psychiatry 2002; 159:436-442)
provide further evidence on the outcome and stability of diagnostic categories
associated with early cognitive difficulties. They describe a
prospective study of the over 75’s in Stockholm, assessed at baseline and
three and six years. The authors describe the outcome of non-demented
subjects at baseline who fulfil criteria for “cognitive impairment, no
dementia.” (CIND). At follow-up, 34% had died, 35% progressed to
dementia, 11% remained stable and 25% actually improved.
Interestingly, the absence of a subjective memory complaint predicted
improvement (odds ratio 5.4). The authors conclude that CIND is a heterogeneous
condition with similar proportions of subjects progressing to
dementia, death and cognitive improvement over three years.
Hyponatremia is Frequent in Elderly
Psychiatric Patients
Hyponatremia is a well-recognized adverse effect associated with a variety
of antidepressant drugs, including selective serotonin reuptake
inhibitors and venlafaxine, though it can be seen with virtually any
antidepressant. Kirby et al (International Journal of Geriatric
Psychiatry 2002; 17:231-237) described a study of 199 inpatients in an
elderly psychiatric ward in Melbourne, of whom 74 were prescribed
either an SSRI or venlafaxine. Of those subjects on SSRI or venlafaxine,
39% developed hyponatremia compared with less than 10% of those not
prescribed these agents. In addition, 10 out of the 14 on venlafaxine
were hyponatremic. Controlling for other variables, the odds ratio for
developing hyponatremia on such treatment was 3.5. The authors conclude
that their results show high rates of hyponatremia after antidepressant
prescription in the elderly. They recommend checking sodium
levels before and after commencement of treatment.
Vascular Risk Factors and Late Onset Mania
There has been much discussion about the association between vascular
factors and late onset depressive illness, leading to the concept of “vascular
depression” as a potentially important cause of late onset depression.
Cassidy and Carroll (Psychological Medicine 2002; 32:359-362)
described the records of 366 bipolar patients and examined vascular risk
factors. Cases of late onset disorder were matched to early onset cases and had significantly greater likelihood of having vascular risk factors
and high cholesterol levels. The authors suggest that late onset mania
may be a distinct subtype with a possibly different, vascular etiology.
Additionally, control of vascular risk factors may impact on the incidence
of late onset mania as well as late onset depression.
Does the Clinical Phenotype of Familial and Sporadic
Late Onset Alzheimer’s Disease Differ?
This is the issue addressed by Holmes and Lovestone (International
Journal of Geriatric Psychiatry 2002; 17:146-149), who examined 374
patients with late onset Alzheimer’s disease from a community register
and compared phenotypes in those with or without a first-degree family
history of dementia (which was found in 27% of cases). There were no
differences in clinical phenotype, including rate of cognitive decline,
duration of dementia or frequency of non-cognitive symptoms, though
familial cases had an earlier age of onset (mean 77.2 years) compared
to late onset cases (mean 78.3 years).
Does the Incidence of Alzheimer’s Decline?
The literally “age old” question of whether everyone will develop
Alzheimer’s disease if they live long enough, or whether incidence stabilizes
in late life is addressed by data from the Cache County study
reported by Miech et al (Neurology 2002; 58:209-218). This longitudinal
study of 3,308 subjects examined 185 cases with incident dementia
over three years. Incidence of both dementia and Alzheimer’s disease
increased almost exponentially from age 85 to 90 but then appeared to
decline after age 93 for men and 97 for women. There was a clear interaction
between age and the presence of the Apolipoprotein E4 allele,
which supports other published work that the main effect of ApoE is in
terms of accelerating the onset of Alzheimer’s disease, while not appreciably
altering lifetime risk which may actually decline in very late life.
Smoking Decreases the Risk of Parkinson’s Disease
The effects of smoking on Alzheimer’s disease remain controversial, with
initial studies suggesting a decreased risk and later studies suggesting
an increased risk in smokers. The evidence in Parkinson’s disease is that
smoking is protective. This is reported in a twin study by Tanner et al
(Neurology 2002; 58:581-588), who examined 113 twin pairs from a
veteran twins cohort in which at least one twin had Parkinson’s disease.
The investigators found that within twin pairs, risk of Parkinson’s disease
was inversely correlated with dose (in pack years) of cigarette
smoking, with the effect most pronounced in monozygotic twins. Since
monozygotic twins are genetically identical, and more similar behaviorally
than dizygotic twins, the authors argue that their results provide
strong evidence of a true biological protective effect of cigarette smoking
in preventing Parkinson’s disease.
Are Psychotic Symptoms Really Rare in the Very Old?
This view is somewhat challenged by a study of psychotic symptoms and
paranoid ideation in a non-demented sample of community dwellers
over 85 years of age in Gothenberg, Sweden, reported by Ostling and
Skoog (Archives of General Psychiatry 2002; 59:53-59). The authors
followed subjects for three years investigating psychotic symptoms, mortality
and incident dementia. The prevalence of any psychotic symptom
was surprisingly high at 10.1% (hallucinations 6.7%, delusions 5.5%),
and hallucinations were associated with both depression and visual
deficits. Hallucinations, delusions and paranoid ideation were each
related to an increased incidence of subsequent dementia, suggesting
that these symptoms might be important early manifestations of degenerative
brain disease in the over 85’s.
Following recent in vitro reports that modifying cholinergic activity
could favorably influence amyloid pathology, researchers from Finland
(Liu et al. Exp Neurol 2002; 173(2):196-204) set about testing the effects
of a cholinesterase inhibitor (in this instance, metrifonate) on the production
and deposition of amyloid beta-peptide in transgenic mice. In
summary, they found metrifonate had no effect on amyloid pathology in
vivo and concluded that cholinesterase inhibitors are unlikely to slow the
progression of amyloid deposition in Alzheimer’s disease.
Is Selegiline Useful in Treating Alzheimer’s Disease?
Not according to a meta-analysis of 14 published studies up to 1998
reported by Willcock et al (International Journal of Geriatric
Psychiatry 2002; 17:175-183). The authors found that overall results
pointed to statistically significant improvement between selegiline and
placebo around 4 to 17 weeks, which then disappeared at later assessment
periods. This effect was present on both cognitive performance and
activities of daily living. The authors conclude that while there is some
evidence selegiline improves cognition and activities of daily living in
the short term, the magnitude of the effect did not reach clinical importance
and there is no evidence of long-term benefits.
Does Donepezil Improve Cognition in Patients with Downs
Syndrome and Alzheimer’s Disease?
A pilot study is described by Prasher et al (International Journal of
Geriatric Psychiatry 2002; 17:270-278), who performed a 24-week
double blind, placebo controlled parallel group trial of 30 subjects with
Downs syndrome who had mild to moderate Alzheimer’s disease.
Donepezil treatment was associated with reductions in deterioration in
the severe impairment battery and a dementia scale compared to placebo
though differences did not reach statistical significance. Somewhat
surprisingly perhaps, non-cognitive symptoms (as measured by the
Neuropsychiatric Inventory) showed less improvement than in the treated
group compared to placebo patients. Side effect profile was similar to
that described in those with Alzheimer’s disease in the absence of Downs
syndrome. The authors conclude their pilot study shows donepezil to be
safe and well tolerated in those with Downs syndrome and suggests that
larger studies are needed to demonstrate whether cholinesterase
inhibitors have clear therapeutic benefit.
Homocystine and Alzheimer’s Disease
Another report suggesting that raised homocystine levels may be associated
with an increased risk of having Alzheimer’s disease is reported by
Seshadri et al (New England Journal of Medicine 2002; 346:476-
483). Using data from the Framingham Heart Study (when homocystine
levels were measured in the late 1980s in 1,100 subjects with a
mean age of 75) they found, eight years later, 10% had developed
dementia and that the 30% with the highest homocystine levels at baseline
had twice the risk of developing Alzheimer’s disease as those with
average levels. The authors calculated the relative risk of Alzheimer’s
disease was 1.8 for each increase of one standard deviation in homocystine
values above baseline. These results clearly point to the need for
long-term studies in reducing homocystine levels using folic acid and
vitamin B6/B12.
Cholinergic Activity in Patients with Mild Cognitive Impairment
Sometimes research can start to unravel, or at least question, established
wisdom. One such study comes from the U.S.’s DeKosky and colleagues
(Ann Neurol 2002;51(2):145-55). They examined the activity of the
cholinergic system (using choline acetyltransferase (ChAT) as the marker)
in normal subjects as well as those with mild cognitive impairment
(MCI) and Alzheimer’s disease (AD) of varying severity. In subjects with
AD, only those with end-stage disease had ChAT levels below the normal
range. But the absence of any change in subjects with mild AD lead the
authors to conclude that the cognitive deficits in early AD involve
changes other than simply cholinergic loss. Further, in subjects with
MCI, ChAT activity in the hippocampus and frontal lobe was actually
higher than normal subjects—suggesting a possible compensatory
mechanism involving the upregulation of cholinergic transmission
during the early stages of dementia. If this finding is replicated, the
authors speculate that this upregulation could be an important factor
in preventing conversion from MCI to AD.
Could Lipid-lowering Agents Protect Against Dementia?
Rockwood et al. (Arch Neurol 2002;59(2):223-227) examined this
potential link using data from the Canadian Study of Health and Aging.
Adjusting for potential confounders, they found LLA use was indeed
associated with a lower risk of dementia, especially those with
Alzheimer’s disease, though only in people under 80 years. Interestingly,
in a separate study (Locatelli et al. Ann Neurol 2002;59(2):213-216),
statins were found to reduce brain cholesterol turnover, providing one
potential explanation how they could reduce the risk of AD.
Screening Embryos for Alzheimer’s Disease: The First Report
Writing in JAMA, Verlinsky and colleagues (2002;287(8):1018-21)
described the first clinical pregnancy and birth of child born free of an
inherited form of early onset Alzheimer’s disease (AD). They used the
technique of preimplantation genetic diagnosis (PGD) to detect and
then preselect embryos free of the predisposing disorder—in this
instance AD caused by V717L mutation. The 30-year-old patient had a
family history of early-onset AD caused by the mutation but was asymptomatic
at the time of the procedure. After undergoing PGD, she gave
birth to a healthy child, free of the mutation.
Efficacy and Safety of Donepezil in Nursing Home Patients with Alzheimer’s Disease
To further evaluate the use of cholinesterase inhibitors in Alzheimer’s
disease (AD), Tariot et al. (J Am Geriatr Soc 2001;49(12):1590-1599)
completed a 24-week RCT using donepezil involving just over 200
patients living in nursing homes. Subjects had a diagnosis of probable
or possible AD, or AD with cerebrovascular disease, a mean mini-mental
state examination (MMSE) score of around 14 and average age of nearly
86 years. Overall, despite such factors as a high level of co-morbidity,
advanced age and the high use of other medications, donepezil was
viewed to be safe with acceptable tolerability. In terms of clinical
impact, compared to placebo, active treatment performed better on the
chosen measure of cognitive function (MMSE scores at weeks 8, 16 and
20) and also with respect to the overall dementia severity at 24-weeks
(as measured by the clinical dementia rating—CDR). However, there
were no differences between active treatment and placebo on the primary
outcome measure—the Neuropsychiatric Inventory-Nursing
Home Version (NPI-NH). Both groups improved relative to baseline.
In addition, there were no group differences on a scale measuring
self-maintenance. The authors consider the results support the use of
donepezil in nursing home residents with AD, while acknowledging
uncertainties regarding its role in the management of behavioral
symptoms.
Do Memory Training Groups Work?
The growing number of individuals presenting at the early stages of
memory failure has prompted interest in the appropriate management
of this group. Rapp et al (Ageing and Mental Health 2002; 6:5-11)
describe a randomized clinical trial investigating the efficacy of cognitive
and behavioral treatment which included education, relaxation,
memory skills training and restructuring compared to placebo. At six
month follow-up, there was a non-significant trend for the intervention
group to have better word list recall than controls and intervention subjects
reported better memory appraisals. While more research is needed,
the authors suggest their study provides some evidence that those with
MCI can benefit from non-pharmacological treatment such as memory
enhancement training.
Drs.John T. O’Brien and Robert
Barber are the Research Editors
of the IPA Bulletin. They welcome
readers’ comments via email (J.T.O’Brien@ncl.ac.uk) or fax
(+44.191.219.5040).
