IPA Bulletin
Recent Advances - Volume 17, Number 4
John O'Brien and Bob Barber
Coffee reduces risk of Parkinson’s disease
Looking for evidence to support one’s indulgences may be a bad
habit, but a study published in the Journal of the American Medical
Association by Ross and colleagues (2000; 283:2674-2679) provides
some comfort to coffee connoisseurs. They prospectively followed
up 8,000 subjects (from the Honolulu Heart Program) after 30 years
and found the risk of developing Parkinson’s disease (PD) was
five-fold higher in those drinking no coffee compared to those with
high coffee intake (without any associated increase in overall
mortality). The authors felt the relationship was unrelated to other
nutrients in coffee, to milk or sugar, and suggested the main
element is caffeine intake. The mechanism underpinning any possible
causative link is, however, not known and, unfortunately, clinical
trials using caffeine in PD have so far proved ineffective.
Snowdrops, daffodils and Alzheimer’s disease: a new treatment?
Galantamine, originally derived from snowdrop and daffodil bulbs,
is a reversible cholinesterase inhibitor and an allosteric modulator
of nicotinic cholinergic receptors. Results from two Phase III clinical
trials using galantamine in the treatment of Alzheimer’s disease
(AD) have recently been published in Neurology (Raskind et al. 2000;
54:2261-68 and Tariot et al. 2000; 54:2269-76). Standard primary
efficacy measures were used (ADAS-cog and CIBIC-plus). After
treatment (for between 5 to 6 months), significant differences were
observed between active treatment (total dose of 16mg, 24mg or
32mg/day, given as single tablets taken twice daily) compared to
placebo in both primary measures. Improvements in ADAS-Cog
scores from baseline were between 1.5 to 1.8 points for the three
treatment groups. Compared to the placebo group, a dosage
regimen of 24mg/d (for 6 months) gave the greatest difference on
ADAS-cog scores (3.9 points); there were no additional benefits in
increasing the dose from 24 to 32mg/day. About 70% of treated
patients were assessed to be either stable or improved after 6
months compared to 55% on placebo. One study (Tariot et al.)
used the Neuropsychiatric Inventory (NPI) to assess the effects of
treatment on behavioral symptoms. Compared to baseline, the
placebo group scores deteriorated, whereas those on treatment
(16 and 24mg/d) remained the same after 5 months. The double-blind
phases of both studies gave mixed results on the effects of
treatment on the activity of daily functioning (ADL), with no benefit
in one study and a significant difference compared to placebo in the
other (Tariot et al.). After a further 6-month, open-label extension
(Raskind et al.), ADAS-Cog and ADL scores had not significantly
changed from baseline for patients receiving 24mg/day. Overall,
gastrointestinal symptoms were the commonest adverse effect, and
discontinuation rates were lower when the dose was slowly escalated
(over 8 weeks). The drug is now marketed in the UK for the treatment
of AD, and is likely to be more widely available wordwide in 2001.
Association between IL1 alpha polymorphism and
Alzheimer’s disease
The inflammatory hypothesis of Alzheimer’s disease is given a
boost by a reported association between an interleukin one
alpha polymorphism and Alzheimer’s disease (Du et al. Neurology
2000; 35: 480-483). A case control study revealed an increased
frequency of allele 2 (46%) in those with AD, compared to controls
(34%). There was no evidence of an interaction between the IL-1a
allele and apoe4 polymorphisms or age or gender. The authors
conclude their data strongly supports association between the
IL1a allele 2, particularly in homozygotes, and late onset AD.
An accompanying editorial (page 480) discusses the possible
significance of this for the inflammatory hypothesis of AD.
Neural stem cell transplantation in Alzheimer’s disease
Adult brain cells have been regarded as highly specialized, with
little, if any, potential to differentiate into other types of cells. This
understanding has been called into question following the findings
of a study published in Science (Clarke et al. 2000; 288:1660-1663).
Researchers injected cultured neural stem cells into mouse
embryos and discovered that they were able to differentiate into
nearly every type of tissue. The potential implications of this finding
needs further clarification, but indicates that adult neural stem
cells, under the right environmental conditions, retain a greater
developmental capacity than previously appreciated. Limited
clinical trials using neural stem cell transplantation in Alzheimer’s
disease are scheduled to begin in late 2001.
Alzheimer-type pathology in cognitively normal subjects
An interesting study (Schmitt et al. Neurology 2000; 55:370-376)
classified non-demented subjects using three well recognized
neuropathological criteria for Alzheimer’s disease (AD). Of the 59
subjects studied, about 49% met the Khachaturian criteria for AD
and 25% met CERAD criteria. There were no differences in cognitive
function (measured annually prior to death) between subjects who
met these criteria compared to those who did not, leading the
authors to conclude that the ageing brain may be able to withstand
a certain amount of structural change without meaningful impact on
cognitive performance. However, a smaller number of subjects
(11%) also met the National Institute on Aging-Reagan Institute
criteria for AD (NIA-RI), and in these subjects there was an association
between pathologic change and memory impairment. The more
recently introduced NIA-RI criteria place greater emphasis on
neurofibrillary tangles (NFT) than the other two criteria, raising the
possibility that NFT may be more closely linked to the pre-symptomatic
stage of AD.
Risk factors and imaging correlates of psychotic symptoms in
Alzheimer’s disease
Two recent studies have confirmed the high prevalence of
delusions (51-55%) and hallucinations (41%) in Alzheimer’s
disease (AD) (Wilson et al. JNNP 2000; 69:172-177 and Paulsen et al.
Neurology 2000; 54:1965-1971). Both studies found psychotic symptoms
were associated with the rate of cognitive decline. In addition,
Paulsen and colleagues also found an association with the severity
of cognitive impairment, the type of cognitive impairment (particularly
tasks sensitive to frontal lobe dysfunction) and the emergence of
extra-pyramidal signs. The authors suggested these findings lend
support to hypofrontality model of psychosis in AD. This accords
with a functional imaging study (Mega et al. JNNP 2000; 69:167-171)
reporting that perfusion deficits in patients with AD with psychotic
symptoms may have a disproportionate impairment of frontal
lobes and related subcortical and parietal structures.
Lewy bodies: are they important?
There has been a lack of consensus regarding the significance
between Lewy bodies (LB) and cognitive impairment in dementia.
Two recent postmortem studies have examined this issue. Hurtig
et al. (Neurology 2000; 54:1916-1921) found alpha-synuclein
positive LBs were highly sensitive (91%) and specific (90%)
neuropathologic markers of dementia in subjects with idiopathic
parkinsonism. In this series, cortical LBs were better indicators of
dementia than classical Alzheimer-type change. In a separate
study, Haroutunian et al. (Arch Neurol 2000; 57:1145-1150) examined
273 autopsies from nursing home residents. Eighty-three percent
of subjects did not have LB pathology, but in the remainder the
density of LBs positively correlated with the degree of cognitive
impairment, independent to any other neuropathological lesion,
including Alzheimer-type pathology. This correlation was observed
whether or not subjects met diagnostic criteria for Alzheimer’s
disease. The authors concluded that LB signify a process that has
a direct and distinct impact on cognition.
Memory impairment in subcortical vascular dementia:
why does it happen?
Why do patients with extensive subcortical vascular disease (SVD)
have memory impairment in the absence of medial temporal lobe
or diencephalic strokes? This was the question posed by Reed
and colleagues from the USA (Ann Neurol 2000; 48:275-284). Using
positron emission tomography they found memory in
subjects with SVD correlated with prefrontal lobe metabolism,
whereas in subjects with Alzheimer’s disease (AD) memory
correlated with hippocampal and temporal lobe metabolism.
Concluding that different mechanisms may underpin memory
failure in SVD and AD, the authors suggested that memory
impairment in SVD could be understood in terms of deficits in
frontal lobe function, leading to ineffective organizing and
retrieval of information, rather than storage as in AD.
Does lesion location influence depression after stroke?
This remains a controversial issue, as the much-quoted association
between left-sided strokes and risk of subsequent depression has
been questioned by many studies. A recent systematic review
(Carson et al. Lancet 2000; 356: 122-126) examined 143 reports
and concluded that there was no difference in relative risk of
depression after left- compared to right-hemisphere strokes.
Interestingly, community studies suggested an opposite association,
between right-sided lesions and depression, but the authors
consider exclusion of aphasic patients may have been an
important confounder. The debate will continue.
Associations of suicide in the elderly
Given the high rates of suicide in the elderly, surprisingly few
large studies looking at clinical correlates have been performed.
Harwood et al. (International Journal of Geriatric Psychiatry 2000;
Fifty percent had seen their GP in the month before death, though
half of these consultations were for physical complaints. Only
15% were under psychiatric care at the time of death. Strategies
for detecting those at risk of suicide would seem to need to focus
on primary care, though GPs would have difficulty identifying
those at risk because of the high proportion of physical com-plaints.
The authors suggest that, given the high proportions of
drug overdoses in this sample, effective strategies to prevent sui-cide
might include improving the prescribing of analgesics and
antidepressants.
New variant CJD: incidence and new diagnostic criteria
New variant Creutzfeldt-Jakob disease (nvCJD), a disorder primarily
found in the UK (and linked to BSE in cattle), has increased in the
UK by 23% per year between 1994-2000, according to figures
published in The Lancet (Andrews et al. 2000; 356:481-482), though
the absolute number remains low: a total of 75 individuals affected
since 1994. However, a demonstration by Collinge et al. (Proceedings
of The National Academy of Sciences 2000; 97: 10248-53), that mice
can harbor hamster prions at high levels while remaining
asymptomatic, has rekindled the debate as to whether healthy
human carriers for nvCJD may exist. Most worrying of all, the
incubation period of variant CJD is still unknown and estimates
of numbers of humans that might be affected still range from
hundreds to almost 200,000.
Diagnostic criteria for nvCJD were published in Annals of Neurology
(Will et al. 2000; 47:575-582). Examining subjects referred to the
UK National CJD Surveillance Unit, nearly all subjects with nvCJD
presented with early psychiatric symptoms. After 6 months,
neurological symptoms became more evident, particularly ataxia,
persistent painful sensory symptoms, involuntary movements
such as myoclonus, and advancing cognitive impairment. The EEG
in nvCJD usually showed nonspecific slow wave activity and not
the “typical” appearances of sporadic CJD. CSF immunoassay for
protein 14-3-3 had a lower sensitivity for detecting nvCJD (present
in approximately 50% of cases) than sporadic CJD (Zerr et al. Annals
of Neurology 2000; 48:323-329). MRI scanning was seen as the most
useful non-invasive investigation to date, with over 70% of cases
having bilateral pulvinar high signal. The potential role of tonsillar
biopsy was not explored in this study. Overall, the new criteria for
probable nvCJD had a sensitivity of 77% and specificity of 100%.
Driving and dementia
Dubinski et al. (Neurology 2000; 54: 2205-2210) describe a report of
the Quality Standard Sub-Committee of the American Academy of
Neurology, which is an evidence-based review on risk of driving
and Alzheimer’s disease. The authors conclude that driving was
found to be mildly impaired even in drivers with a Clinical
Dementia Rating (CDR) of 0.5, if they had a diagnosis of Alzheimer’s
disease. However, this impairment was no greater that that which
is already tolerated in other segments of the driving population
(such as young drivers or those with legal levels of alcohol).
However, drivers with Alzheimer’s disease at a severity of CDR1
were found to pose a significant safety problem, both from crashes
and assessments of driving performance.
Do death wishes reflect psychiatric disorder?
This remains somewhat controversial. A large study by Forsell
et al. (Acta Psychiatrica Scandinavica 2000; 102: 135-138) found that
almost 12% of an elderly population expressed a wish to die.
Subjects were followed up three years later and all those who had
death wishes at both time points had psychiatric disorder. Of
those having death wishes at just one of the examinations, 70%
had psychiatric disorder. The authors conclude that there is a need
for psychiatric examination whenever elderly people express a wish
to die.
Risk factors for developing dementia after stroke
Cerebrovascular disease is one of the most common causes of
cognitive impairment. Barba et al. (Stroke 2000; 31:1494-1501)
examined risk factors for developing dementia after stroke. Not
surprisingly, they found a combination of factors independently
contributed, including age, atrial fibrillation, pre-existing cognitive
impairment, stroke severity, and renal impairment. Dementia was
equally frequent after ischaemic and haemorrhagic stroke
(approximately 30%). Whether modifying these risk factors reduces
the prevalence of post-stroke dementia remains to be determined.
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.
