IPA Bulletin
Recent Advances - Volume 18, Number 1
John O'Brien and Bob Barber
A challenge to the view that dementia is an acquired disease is
provided by Whalley et al. (Neurology 2000; 55:1455-1459) in a study of linking lower mental ability in childhood and late (but not
early) onset dementia. Using data from the 1921 Scottish birth cohort who had cognitive ability assessed in 1932, they
demonstrated mental ability scores were significantly lower in children who eventually developed late onset dementia. Whether
poor mental ability in childhood really reflects the earliest manifestations of a degenerative brain disease, or is simply
identifying a vulnerable brain which is later susceptible to age-related degenerative disease is unclear, though findings clearly have relevance for the cognitive reserve hypothesis.
Olanzapine has benefits in the treatment of specific behavioral and psychological symptoms according to the results of a USA multicenter randomized, placebo-controlled trial (Street et al. Arch
Gen Psych 2000;57:968-76). The 6-week trial involved just over 200 elderly patients with established Alzheimer’s disease (mean MMSE = 6.7, all nursing home residents). Overall, low-dose
olanzapine (5 and 10mg) gave the most favorable outcomes in terms of reduced psychosis and/or aggression, with high-dose
olanzapine (15mg) being no different than placebo. As with risperidone, lower doses of olanzapine appear to give the best
balance of efficacy and tolerability, especially when treating patients with moderate to severe dementia.
Using a case control design, Jick et al. (Lancet 2000; 356:1627-1631)
compared 284 subjects with dementia with over 1,000 controls. The adjusted relative risk for those prescribed statins was 0.3 and
was independent of the presence or absence of hyperlipidemia. The authors conclude that in this population (aged 50 years and
over) those prescribed statins had a lower risk of developing dementia. Although a cross-sectional study, the possibility of a 70% lower prevalence of Alzheimer’s disease in the group
receiving statins should prompt further research including prospective clinical trials.
Optimistic results from the first randomized, placebo-controlled
treatment study in dementia with Lewy bodies (DLB) were published in the Lancet (McKeith et al. 2000;
356:2031-2036). The rationale for this study was based on the known deficits in
cholinergic neurotransmission in DLB and the resulting hypothesis that drugs that enhance brain cholinergic function could be of benefit.
One hundred and twenty patients with DLB were treated with rivastigmine, a cholinesterase inhibitor (ChE), at daily doses up
to 12mg or placebo for 20 weeks. Patients on active treatment not only performed better and faster on a range of
neuropsychological tests, particularly attentional tasks, but also showed significant improvements in core psychiatric symptoms, most
notably apathy, anxiety, delusions and hallucinations. Importantly for this patient group, rivastigmine was well tolerated
with no change in parkinsonian symptoms, leading the authors to conclude that ChE may be a more rational choice of treatment in
patients with DLB than neuroleptics.
The need for effective treatments of agitation in Alzheimer’s disease (AD) was the focus of a recent randomized, placebo-controlled trial. Teri and co-workers (Neurology 2000;55:1271-1278)
set about comparing two psychotropic medications, haloperidol (mean dose 1.8mg/d) and trazodone (mean dose 200mg/d), a psychological intervention (“behavioral management techniques”),
as well as placebo. Nearly 150 patients with AD were recruited, though the final number for each treatment group was between
20 to 25, with mean MMSE scores of between 12-14. Perhaps unexpectedly, symptoms did not respond differentially to the
different treatments as hypothesized, and there were no significant differences on outcome between treatments. Perhaps expectedly, in their conclusion the authors raised the need for
more efficacious treatments.
Exciting new animal modeling of Alzheimer’s disease (AD) suggests that regular nasal mucosal administration of amyloid-beta peptide may reduce plaque burden, as well as cerebral
inflammatory markers, raising hopes of a novel immunological approach to the prevention and treatment of AD (Weiner et al. Ann Neurol 2000;48:567-79). Using transgenic mice that develop AD-like
pathological change, researchers from Harvard Medical School administered a synthetic amyolid-beta peptide to the mice every
week for 6-7 months. Compared to control animals, those exposed to the peptide had a lower burden of amyloid-beta and a
decrease in a range of inflammatory markers, consistent with an immune response to the synthetic peptide. Importantly, these
results provide the first confirmation of the experiments by Schenk et al. published in Nature in 1999
(400:173-177). Using the same transgenic mice model, parentally administered amyloid-beta not only prevented the development of amyloid plaques in mice “immunized” early in life, but also reduced the burden of
plaques in animals administered the “vaccine” after they had formed. As outlined in the editorial by Levey (Ann Neurol 2000; 48:553-555), these studies could lead to powerful new treatment strategies in Alzheimer’s disease (AD), but ultimately the success
of this approach will depend not only on its safety and efficacy in reducing amyloid burden in humans but also whether amyloid
burden per se plays a central causative role in sporadic AD.
In order to map the progression of synaptic loss and cholinergic deficits in Alzheimer’s disease (AD), Tiraboschi and colleagues (Neurology 2000;55:1278-1283) completed autopsy analysis on 89
patients with AD, stratified by severity as determined by the last recorded MMSE result (MMSE score =20, “mild”; score =10-19, “moderate”; and score =1 to 9, “severe”). Interestingly, neither
synaptic loss nor cholinergic dysfunction was evident in patients with mild AD. Indeed, synaptic decline was greatest in patients at
moderate stage, with cholinergic loss maximal in late stages, leading the authors to suggest an asynchronous pattern decline
of synapses and cholinergic activity.
Researchers from Germany (Bigl et al. Neurosci Lett, 2000; 107-10)
used transgenic mice to examine the cellular expression of beta-site amyloid precursor protein-cleaving enzyme, BACE; a key
enzyme putatively involved in amyloid deposition (see Science 1999; 286:735, as reported in this column). The authors found the pattern of regional expression of BACE mRNA did not correlate
with the pattern of beta-amyloid deposits, and neurons surrounding amyloid plaques showed similar levels of BACE mRNA expression
as neurons in areas free of amyloid deposits, thereby failing to confirm any direct link.
Using an RCT design, Williams et al. (JAMA 2000; 284:1519-1526)
compared the effectiveness of drug treatment (paroxetine up to 40mg/d) and psychotherapy (“problem-solving treatment,” PST) in
treating older primary care patients (n=415) with dysthymia or minor depression. There were no differences between the two
active treatments, but only patients treated with paroxetine showed improvement over and above placebo. Indeed, the
response to PST was highly variable across sites, possibly reflecting varying experience and skills among the therapists. The positive effects of paroxetine were generally more consistent and
stronger in dysthymia than minor depression. The authors suggest that given their own findings and the current state of knowledge
more generally, drug treatment should be considered as first-line treatment in dysthymia, but PST could not be recommended for
older persons with minor depression or dysthymia in primary care. In addition, because the treatment for minor depression was less robust, medication should be reserved for patients with more
severe impairments, but they stressed the importance of actively monitoring patients with minor depression.
The therapeutic role of nonsteroidal anti-inflammatory drugs
(NSAID) and aspirin in dementia remains controversial. New evidence from the Sydney Older Persons Study (Broe et al. Arch Neurol
2000; 57:1586-1591) found a relatively specific association between such drugs and Alzheimer’s disease (AD), with no evidence of a
dosage effect. Overall, results showed an inverse association between NSAID, aspirin and, unexpectedly,
angiotensin-converting enzyme inhibitors and AD but not vascular dementia. Responses were equivalent for low and high doses, leading the authors to conclude that results did not support a high-dose
anti-inflammatory action of nonsteroidal anti-inflammatory drugs or aspirin in AD.
Two recent studies have investigated the association between
cystatin C gene (CST3) polymorphism and late-onset Alzheimer’s disease (AD). Crawford et al. (Neurology 2000, 55:763-768) found in
subjects over 80 years old the GG genotype contributed to a two-fold increase in risk of developing the disease, in contrast to apolipoprotein E (APOE) where the risk tended to decrease with
age. Finckh et al. (Arch Neurol 2000; 57:1579-1583) found homozygosity for BB CST3 was associated with late-onset AD
(odds ratio 3.8), especially for those aged 75 years and older (OR = 8.8). The effect was also independent of APOE status.
The implications of this association needs further clarification, but the effects appear to be separate to APOE and may relate
to variations in the structure of an amyloidogenic cysteine precursor inhibitor.
Researchers from China (Zhang et al. Neurosci Lett 2000; 292:41-44)
used an in vitro design to examine the potential protective benefits of acetylcholinesterase inhibitors (ACHI). Pretreating rat cell lines
with an ACHI, including huperzine B, a novel ACHI, tacrine, donepezil and galantamine, reduced the amount of hydrogen peroxide-induced toxicity. The authors suggest the neuroprotective
effects of ACHI may contribute to their clinical efficacy in Alzheimer’s disease, possibly be reducing free radical related
neurodegeneration.
To try to find out more about caregivers’ views regarding risks and
benefits for potential disease-modifying therapies in Alzheimer’s disease, Karlawish et al. (Neurology 2000; 55:1008-1014) interviewed
40 carers of patients with Alzheimer’s disease. Carers rated the effects of treatments on survival as “very important” and delay to
nursing home placement as “extremely important.” Perhaps not surprisingly, the importance of any benefit on survival was related
to higher assessments of the patients’ health and quality of life and lower ratings of the carers’ burden. Two-thirds of caregivers were prepared to accept some risk of death from gastrointestinal
bleeding in order to slow disease progression by one year. Results may be useful in trying to determine risks and benefits for
treatments for Alzheimer’s disease and such work emphasizes the need to determine views of patients themselves.
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.
