IPA Bulletin
Recent Advances - Volume 20, Number 2
John O'Brien and Robert Barber
New Developments in Parkinson's, Alzheimer's and Dementia Research
Be warned, this month’s column contains more than the usual share of studies reporting
links between diet and brain diseases. In summary, unsaturated fats and seafood remain
goodies, caffeine clearly has its problems but may protect against Parkinson’s, while the
evidence for antioxidants and vitamins continues to remain less clear than we would like.
However, in all studies possible confounders (for example factors related to socioeconomic
class) remain a problem.
ALZHEIMER’S DISEASE
First autopsy result from Alzheimer vaccine trial As previously reported in this column, the pioneering Alzheimer vaccine study in
humans had to be stopped last year when, very unfortunately, at least 15 of the 360 participants
developed brain inflammation (probable T-cell meningo-encephalitis). The results of the first autopsy of such a case has
now been reported by workers in Southampton (Nicoll et al, Nature Medicine 9:448-
452). The patient described died 42 weeks into the trial after receiving five beta amyloid
injections. When compared with pathology expected in a case of Alzheimer’s disease, there
appeared to be a significant and widespread reduction of beta-amyloid plaques. Moreover,
areas devoid of plaques still showed tau pathology, T-cell activity and inflammation,
indirectly suggesting that plaques had actually been cleared from these areas, as has been previously
described in animal models. An accompanying editorial described the results as suggesting an “astonishingly powerful effect of
the vaccine clearance of beta-amyloid from much of the cerebral cortex.” Clearly we will
be hearing much more about the vaccine story and other amyloid-based therapies in
the future.
Is intracellular or extracellular beta-amyloid the villain? This issue is yet to be resolved, but a recent study (Meyer-Luehann et al, Nature
Neuroscience 6:370-377) of transgenic APP mice suggest that extracellular diffusion of
beta-amyloid is central to cerebral amyloid agenesis. They performed neural transplants
and showed that amyloid deposits formed within grafts implanted into transgenic animals
after a few months, irrespective of whether the graft came from a transgenic or normal (wild type) animal. Similarly, grafts
from transgenic mice into normal (wild type) mice did not develop plaques. This strongly
suggests diffusion of extracellular amyloid as the culprit and further indicates that strategies
for eliminating amyloid may well be helpful in AD.
A possible link between Insulin, ApoE and Alzheimer disease? Abnormal amyloid processing in Alzheimer’s disease could result from over production of Abeta (possibly the case in
familial, early-onset AD) and/or defects in its clearance (possibly the case in late-onset AD).
Insulin-degrading enzyme (IDE) has emerged as a key candidate enzyme involved in the
breakdown and removal of amyloid, and may therefore be implicated in late-onset AD. To
test this hypothesis, Cook and colleagues (Am J Pathol 2003; 162:313-9) measured IDE in
subjects with late-onset AD and normal controls and found IDE was indeed reduced (by
around 50%) in AD subjects, but only those who were APOE epsilon4+. These findings
will help to understand reported links between diabetes and AD, but further studies are necessary.
The authors conclude that reduced IDE is a significant risk factor for AD, and may interact with APOE status to affect
Abeta metabolism.
Do antioxidant vitamins or dietary fats reduce the risk of Alzheimer's disease?
The answer for antioxidants and vitamins is probably no (Luchsinger et al. Arch Neurol 2003;60:203-8). In this study 980
subjects free of dementia were followed up for 4 years and their dietary consumption evaluated
using semiquantitative food questionnaires. In conclusion, neither dietary, supplemental,
nor total intake of carotenes and vitamins were associated with a deceased risk of
AD. However, a separate study from the same edition of the Archives of Neurology found a
high intake of saturated fats was associated with an increased risk, whereas intakes of
mega-6 polyunsaturated and monounsaturated fat appeared to be protective of AD (Morris
et al. 194-200).
Seafood is good for the brain Sticking with diet, a study (Barberger-Gateau et al, British Medical Journal
325:932-933 from the Paquid study of over 1,600 people in southwestern France examined
the association between diet and subsequent dementia. Over a seven year follow-up
period 170 new cases of dementia (mostly Alzheimer’s) occurred and there was a
significant trend between increasing consumption of fish or seafood and decreasing
incidence of dementia. However, there was also an association between eating seafood
and high socioeconomic class, meaning that confounders could not be excluded, though
the protective effects of fish and seafood have also been suggested by results from the Rotterdam
Study.
Smart probes to diagnoses Alzheimer’s disease? Advances in so-called “molecular imaging” continue, and following experimental
studies using radiolabelled probes to identify amyloid in brain tissue, collaborators from
the Mayo Clinic, Minnesota (Poduslo et al. Neurol Biol 2002;11:315-29) tested a new
probe with the potential to map the presence and distribution of beta-amyloid plaques
using MRI. The probe, which incorporates gadolinium, a well-established MRI contrast
agent, was tested using mice tissue. It successfully passed through the blood brain barrier,
binding to amyloid and could be detected using a very powerful MRI scanner. Subject
to further technical refinement, this technique could enable early detection of Alzheimer’s disease as well as providing paradigm
to monitor the use of anti-amyloid drug. Perhaps one day we will be asking our
friendly radiologist to determine the burden
of amyloid and tau in our patients?
Using serial MRI to monitor disease progression in Alzheimer’s disease Cross-sectional neuroimaging studies are now well-established and have shown
distinct differences between subjects with AD and normal adults. As technologies develop
researchers are increasingly exploring the value of longitudinal MRI studies in dementia.
Du et al. (Neurology 2003;60:481-6) found annual atrophy rates in the entorhinal
cortex were greater in subjects with AD than normal control (4.3% vs 1.4%), and that
serial MRI was a better diagnostic indicator of AD than single, one-off MRI measurements.
A small but interesting study from Institute of Neurology (Schott et al. Ann Neurol
2003;53:181-8) examined the role of serial MRI in the presymptomatic diagnosis of AD.
They found greater atrophy rates for subjects with presymptomatic familial Alzheimer’s
disease compared to normal subjects, and again particularly in medial temporal lobe
structures, such as the hippocampus and entorhinal cortex. Interestingly, by extrapolating
their data backwards they estimated that pathological atrophy had been evolving at
least 3 to 4 years (95% CI, 0.7-7.5) before the emergence of symptoms.
Serial MRI, like “molecular imaging,” has the potential to evaluate the effects of therapeutic
trials in dementia on key biological outcomes, in this instance the rate of atrophy.
This is what Jack et al. (Neurology 2003; 60:253-60) set out to do, though unfortunately
the trial itself of milameline, a muscarinic agonist, was aborted due to lack of
efficacy. However the MRI component continued and 192 of the 362 patients with AD
enrolled in the study completed two scans a year apart. Annual atrophy rates for the hippocampus
were consistent with previous reports (4.9%) and consistent across the multiple sites involved in the study. Interestingly,
they found decline over time was more consistently observed in the imaging measures
compared with the clinical measures. For example, they estimated the number of subjects
per arm required to detect a 50% reduction in the rate of decline over a one year would
be 241 for the MMSE compared to 21 for hippocampal volume.
STROKE
Alcohol consumption and risk of stroke Reynolds et al. used a meta-analysis design to examine the relationship
between alcohol consumption and risk of stroke. Their findings published in JAMA
(2003;289: 579-88) found a nonlinear relationship between consumption and total and
ischemic stroke. Overall, compared with abstainers, high levels of consumption (more
than 60g / day) was associated with an increased relative risk of total stroke (1.64; 95%
CI, 1.39-1.93) and ischemic stroke (1.69; 95% CI, 1.34-2.15). Conversely, a consumption
of less than 12g/ day or 12-24g/day was associated with a reduced relative risk of ischemic
stroke (RR = 0.80 and 0.72 respectively), leading the authors to conclude that heavy consumption is a risk factor for stroke
whilst light or moderate drinking may be protective.
Could fish consumption reduce stroke disease? Probably yes, according to the results of a large cohort study (He et al. JAMA
2002; 288:3130-6). The researchers profiled the dietary intake of over 43,000 subjects in
the USA using a semi-quantitative questionnaire, and then tracked their progress and occurrence
of stroke disease over a 12 year period. They found eating fish at least once a month or more, compared to less than once
per month, reduced the risk of stroke in men. (relative risk = 0.57; 95% confidence interval
0.35-0.95). Interestingly, the association was only found with ischemic stroke, and there
was no link with hemorrhagic stroke.
Cognitive Behavioural Therapy (CBT) for depression after stroke Depressive symptoms after stroke are common (Berg et al. Stroke 2003;34: 138-43), but do psychological therapies offer
an effective alternative to medication? Researchers from Nottingham (Lincoln et al.
Stroke 2003;34: 111-5) used a randomized controlled design to evaluate the potential
benefits of CBT in depression occurring after stroke. 39 subjects received CBT, 41 standard
care and 43 attention placebo intervention. No significant differences were observed between
groups across a range of outcome measures, including mood, level of functioning,
and satisfaction with care. The authors concluded that CBT was found to be
ineffective, but nevertheless suggested further studies before drawing any final conclusions.
PARKINSON’S DISEASE
Coffee and Parkinson’s disease
We have also previously reported on the finding that caffeine consumption appears
to protect against Parkinson’s disease in men but not women. Analysis of data from
the Nurses Health Study (A longitudinal study of over 77,000 women) was reported
by Ascherio and colleagues (Neurology 2003; 60:790-795). They looked at the interaction
between caffeine and hormone replacement. The results suggested that caffeine seemed
to reduce the risk of Parkinson’s disease in women who did not use post menopausal
hormones but actually increased the risk amongst those using hormones. The postulated
beneficial effect of caffeine in Parkinson’s disease might be due to antagonism of the
A2A adenosine receptors. Other possible mechanisms postulated by the authors include
premorbid personality traits or early environmental or genetic factors which cause aversion
toward “addictive” behaviors and PD.
Diet and Parkinson’s
We may well be what we eat according to a study published in the Annals of Neurology (2002; 52:793-801) which suggests
that eating large amounts of dairy products predisposes to Parkinson’s disease. The study
found that men who ate approximately three or more servings of dairy products a day had a
six year risk almost three times higher than those who ate less than one serving a day.
OTHER RESEARCH
Deaths from Variant CJD
As UK residents we must express self interest in this topic which (fortunately)
is a UK rather than an international issue, though many other countries are watching
this remarkable story of a transmissible dementia with great interest. The latest figures
(Andrews et al, Lancet 2003; 361:751-752) report figures from 1994 (the year of first case
description) to 2002. Although too early to be certain, it appears that onset of new
cases peaked in 1999 and deaths peaked in 2000 (when there were 28 deaths from variant CJD). Whilst data from
further years are needed to be certain, it does seem clear that a feared exponential increase in cases is not occurring.
However, the authors rightly urge caution against concluding that the epidemic is in permanent decline as
some genotypes may have longer incubation periods than others. For example, it has already been shown
that those who are methionine homozygous at codon 129 of the PRNP gene are particularly susceptible.
Randomised control trial of interventions for nursing home residents
Researchers from Sydney (Brodaty et al. J Clin Psychiatry 2003; 64:63-72) conducted a trial to
compare interventions for nursing home patients suffering from dementia complicated by depression and/or
psychosis. The study, which ran for 12 weeks and included nearly 90 patients from 11 homes, randomised
patients to one of 3 interventions: standard care; psychogeriatric case management; general practitioners
with specialist psychogeriatric consultation. Overall, there were no differences on a range of outcomes measures,
though all 3 groups showed improvements in depression and psychosis from their baseline pre-treatment
scores. The authors, reflecting on their findings, comment on the difficulties and feasibility of conducting
service-oriented research in nursing homes.
Bits & Bobs: review articles and journal issues of interest
Readers of the Bulletin may find the following review articles of interest: Mild Cognitive Impairment
(MCI) in older people (Burns and Zaudig, Lancet 2002;360: 1963-5); The Dementias (Ritchie and
Lovestone, Lancet 2002;360: 1759-66); Amyloid Beta Therapeutic strategies in Alzheimer’s disease
(Morelli et al. Neurochem Res 2002;27:1387-99); A Meta-analysis on the Efficacy of Cholinesterase Inhibitors in the
Treatment of Neuropsychiatric Symptoms (Trinh et al. JAMA 2003;289:210-6); Use of Quetiapine in Elderly
Patients (Tariot and Ismail, J Clin Psychiatry 2002;63 suppl 13:21-6) and Vascular Cognitive Impairment
(O’Brien et al, Lancet Neurology 2003; 2: 89-98) which is the product from an IPA Special Expert Meeting.
Anyone interested in the contribution of vascular pathology to cognitive impairment and cognitive and
non-cognitive features of dementia should take note of an excellent recent volume of the Annals of the New
York Academy of Sciences (Volume 977) entitled “Alzheimer’s disease. Vascular Aetiology and Pathology”
edited by Jack Delatore, Raj Kalaria, NG Kanji Nakajima and Ken Nagata, published November 2002. The
volume effectively represents the proceedings of the Third World Congress on vascular factors in
Alzheimer’s disease held in April 2002 in Kyoto, Japan and contains brief papers from research groups covering
the areas of epidemiology, basic vascular mechanisms, clinical vascular mechanisms, genetics, pathology and
pathogenesis, lipid metabolism, neuroimaging and treatment. It will serve as a very useful resource for
researchers in this area of growing importance.
John T. O'Brien and Robert Barber are the Research
Editors of the IPA Bulletin. They welcome readers' comments via
e-mail (J.T.O'Brien@ncl.ac.uk).
