IPA Bulletin
Recent Advances - Volume 19, Number 3
John O'Brien and Bob Barber
Clinical and Experimental Trials in Alzheimer’s Disease
Further negative treatment trials have been published. These include no
benefit with nimesulide (cyclooxygenase-2 inhibitor) (Aisen et al.
Neurology 2002:58;1050-4) and ondansetron (Dysken et al. AJGPysch
2002:10(2):212-5). Animal experiments using transgenic mice to investigate
the potential impact of nicotine in AD have however shown some
interesting findings. Nordberg et al. (J Neurochem 2002:81;655-8)
found nicotine treated mice had a significant reduction in amyloid beta
peptide plaques, leading the authors to suggest nicotine drug treatment
may be a novel protective therapy in Alzheimer’s disease.
Galantamine and Vascular Dementia
Might cholinesterase inhibitors be clinically useful in dementias apart
from Alzheimer’s disease? This is the issue addressed by a study of
galantamine in a combined group of subjects with probable vascular
dementia or Alzheimer’s disease with concurrent cerebrovascular disease
(Erkinjuntti et al, Lancet 2002 359: 1298-1290). Galantamine
(24mg/day) was significantly superior to placebo in terms of benefit on
cognition (ADAS-cog), global outcome, activities of daily living and
behavioral symptoms. The effect on ADAS-cog appeared greater (-2.7,
p=0.0005) in the Alzheimer group than the probable vascular group
(-1.9, p=0.06), though this may be due to the smaller number of vascular
dementia patients included. While further studies are awaited, it is
clear that the presence of concurrent vascular pathology should be no
bar to treatment of Alzheimer’s disease with cholinesterase inhibitors.
Homocysteine: Guilty or Innocent?
Evidence is mounting to implicate homocysteine in the development of
dementia. Reports of increased serum homocysteine in patients with
Alzheimer’s disease, vascular dementia and atherothrombolic vascular
events (McCaddon et al. Neurology 2002:58;1395-9) are emerging. It is
thought that homocysteine potentiates oxidative neuronal injury.
Further studies include the recent report from Vermeer et al. (Ann
Neurol 2002:51;285-9). They studied over 1000 subjects aged 60 – 90
years and found the risk of both silent infarcts and white matter lesions
on MRI were strongly associated with homocysteine levels, a finding
independent of other cardiovascular risk factors. Hogervorst et al. (Arch
Neurol 2002:59;787-93) also studied the relationship between plasma
homocysteine and white matter changes on CT in subjects with
Alzheimer’s disease. They found more extensive white matter change
was linked to higher levels in AD.
Taking a different tack, Pratico et al. (Arch Neurol 2002:59;972-6)
investigated a specific marker of oxidative stress (isoprostane 8,12-isoiPF(
2alpha)-VI) in subjects with mild cognitive impairment. They
found elevated levels of this marker, leading the authors to conclude
that subjects with MCI have increased oxidative stress before the onset of
symptomatic dementia, which in turn could be a risk factor for AD.
Dementia Subtypes in the Community
To examine the relative frequency of the different types of dementia in
the community, Stevens and Associates from London (Br J Psych
2002:180;270-6) screened a representative sample of older people living
in the community. They found Alzheimer’s disease occurred in 31% of
subjects with dementia, followed by vascular dementia (22%), dementia
with Lewy bodies (11%) and frontal lobe dementia (8%). The authors
comment that DLB and FLD occur often enough for there to be a need to
incorporate them in future diagnostic classifications and criteria.
Hypertension and Its Link With Dementia
Following on from studies reporting hypertension in mid life may predispose
to Alzheimer’s disease later in life, researchers from New York
(Posner et al. Neurology 2002:58;1175-81) conducted a longitudinal
study to see whether hypertension in late life itself also contributes to AD.
They found no link between hypertension and AD after 65 years.
However, elevated blood pressure was associated with vascular dementia,
especially when occurring in combination with other vascular risk factors,
such as heart disease and diabetes.
Could the link between hypertension and dementia be white matter
lesions? In a prospective study from Rotterdam, de Leeuw et al. (Brain
2002:125;765-72) found hypertension was associated with increased
white matter changes on MRI. Interestingly, subjects with poorly controlled
hypertension had the highest risk, raising the possibility that adequate
treatment could reduce whiter matter pathology and any associated
cognitive decline.
As an aside, in a very large neuroimaging study (n=3236) Steffens and
colleagues (Stroke 2002:33;1636-44) found white matter lesions were
also implicated in depressive symptoms.
Incidence of Alzheimer’s Disease in Very Late Life
Investigators in the USA (Miech et al. Neurology 2002:58;209-18) found,
not surprisingly, that the incidence of Alzheimer’s disease increased with
advancing age but peaked by 90 years of age and then declined in men
(after 93 years) and women (after 97 years).
Searching for Biological Markers of Alzheimer’s Disease
In the search for a diagnostic biological marker for Alzheimer’s disease,
Hu et al. from China (Am J Pathol 2002:160;1269-78) developed a highly
sensitive assay to measure tau in the CSF. They found a ratio of hyperphosphorylated
tau to total tau to be both sensitive for AD (over 90%)
and specific, between 86 to 100% against various conditions, including
vascular dementia. They authors believed these findings offer a very
promising peripheral marker.
Using Information from Informants to Predict Conversion from MCI to AD
Obtaining a reliable collateral history has long been a central part in
the diagnostic evaluation of someone with suspected dementia. But how
good is this information in predicting who will convert from MCI to AD?
Tabert et al. (Neurology 2002:58;758-64) compared the predictive utility
of self reported and informant-reported functional deficits in patients
with MCI. They found informant reported functional deficits were
indeed predictive of AD at 2 years follow up, but particularly when with
subjects tended to under report their decline.
Do Clinicians Follow Dementia Practice Guidelines?
Getting guidelines into clinical practice is known to be a problem. A
recent study surveyed 200 clinicians regarding their use of practice recommended
guidelines (Rosen et al, Alzheimer’s Disease and
Associated Disorders 2002;16:15-23). The vast majority of respondents
undertook neurological assessment and informant history. However,
only 2/3rds regularly performed a standardized test such as the Mini-
Mental State Examination or screened for depression. In keeping with
other surveys, only 1/3rd regularly discussed the diagnosis and cause of
the illness directly with the patients and a similar proportion routinely
referred caregivers or patients to support groups or advised on respite
care. Less than 30% provided advice to caregivers on how to manage
behavioral problems. Results suggest there continues to be marked variability
in the assessment and management of patients with dementia.
Do Psychosocial Interventions Improve Challenging
Behaviors in Dementia?
Most clinicians would advocate the use of psychosocial interventions for
behavioral problems before moving to pharmacotherapy. The somewhat
limited evidence base to justify this practice is boosted by a study by Opie
et al (International Journal of Geriatric Psychiatry 2002;17:6-13)
who individually tailored psychosocial, nursing and medical interventions
to 99 nursing home residents with severe dementia and behavioral
disturbance. Residents were randomly allocated to either an early or late
intervention group. The intervention consisted of care plans formulated
by a multidisciplinary team with medical, nursing and psychosocial
interventions. Multidisciplinary interventions were shown to reduce the
frequency and severity of challenging behaviours.
Cardiopulmonary Resuscitation and Depression
Wherever possible, it is clearly important to involve patients in deciding
whether or not to accept cardiopulmonary resuscitation. It might be
expected that some such views are influenced by mental state, and a
study by Eggar et al (International Journal of Geriatric Psychiatry
2002; 17:170-174) strongly supports this view. They investigated 50 consecutively
admitted day and inpatients with depression and compared
views on the acceptability of cardiopulmonary resuscitation before and
after treatment for depression. Initially, 70 inpatients declined resuscitation
and all but one changed their minds once they had recovered from
depression. Results clearly indicate that in elderly people who decline
resuscitation, the presence of depression should be specifically considered
as it might well influence their decision.
Cholesterol and Cognitive Decline
Evidence continues to accumulate regarding the association between
cholesterol levels and cognition and the possible protective effect of
statins. Yaffe et al (Archives of Neurology 2002;59:378-384) report an
observational study of 1,037 post-menopausal women with coronary
heart disease followed for four years. Those with scores <1.5 standard
deviations below the mean were classified as having cognitive impairment.
Those with the highest LDL cholesterol had lower MMSE scores
and significantly increased likelihood of cognitive impairment (odds
ratio 1.76). Statin users had significantly higher MMSE scores compared
to non-users, findings that appeared to be independent of lipid levels.
This was a cross-sectional study (in that the MMSE was only performed
at the end of the study), but the authors conclude that high LDL cholesterol
were associated with cognitive impairment and that results indicate
the need for further studies of statins and cognitive outcome.
New Amyloid Lowering Drug
Following the disappointment of translating amyloid vaccination studies
from mice to man, other strategies are being investigated that might
lower amyloid in the blood. Pepys et al (Nature 2002;417:254-259)
describe a new drug (CPHPC), which is a competitive inhibitor of binding
of serum amyloid protein to amyloid fibrils. The drug was administered
by intravenous infusion to patients with systemic amyloidosis, and
serum amyloid concentrations were significantly reduced. In a further
study, 19 subjects were given intravenous or subcutaneous CPHPC for
periods of up to nine months and serum amyloid values were reduced to
approximately 5 percent of pre-treatment levels. No adverse clinical
effects were noted. Since binding of serum amyloid P to amyloid fibrils
protects them from proteolytic degradation, the authors postulate that
removal of SAP in vivo will reduce stability of amyloid deposits and promote
their regression. They suggest that the compound has potential
uses in Alzheimer’s disease.
Neurogenesis in Adult Hippocampus
A large body of evidence supports substantial neurogenesis in brain area
such as the hippocampus in several mammalian species. However, are
such cells functionally active? Van Praag et al (Nature 2002;415:1030-
1034) investigated this issue by examining neuronal structure of dentate
granule cells in hippocampal slices taken from mice. They found that
one-month-old neurons had structural properties similar to mature
dentate granule cells and that, after four months, they had a 60 percent
increase in morphological characteristics such as dendritic length and
spine density. Importantly, they had electrophysiological properties similar
to those of functional granule cells. The authors’ hypothesis that
these newly formed neurons may be necessary either to replace dying
cells or to enhance plasticity in the mature brain. However, the extent
and significance of neurogenesis in human brain remains unknown.
Impaired Fear Conditioning in Alzheimer’s Disease
Conditioning of the fear response is basic and conscious memory that
mediates both normal and pathological responses to aversive stimuli. It
is critically dependent on the amygdala. Hamann et al (Neuropsychologia
40;1187-1195) examined classical fear conditioning in
patients with Alzheimer’s disease and controls. An aversive stimulus
(loud noise) was paired with a green rectangle whilst a red rectangle
was not. AD subjects showed a marked impairment in conditioning
which might be due to amygdala involvement. A possible clinical consequence
may be that they are at greater risk of injury.
Does Auditory Dysfunction Precede Alzheimer’s Disease?
This is the question addressed by Gates et al (Journal of the American
Geriatric Society 2002;50:482-488) using data from the well known
prospective Framingham Heart Study. They examined 740 subjects initially
free from dementia of whom 40 subsequently received a diagnosis
of Alzheimer’s disease. Central auditory speech processing deficits are
clinically manifest by the difficulty in hearing speech with competing
auditory input (e.g., background noise) with no difficulty in speech
comprehension. This can be tested using a speech recognition task
which presents two verbal inputs simultaneously (content poor sentences
on an interesting narrative). The presence of central auditory
processing deficit was strongly associated (odds ratio 10.8) with subsequent
development of probable Alzheimer’s disease, with positive predictive
value of 47 percent. The authors conclude that central auditory
speech processing deficits may be an early manifestation (by several
years) of probable Alzheimer’s disease.
Predictors of Nursing Home Placement in Dementia
Several previous studies have shown that several factors apart from cognitive
impairment determine the likelihood of a patient with dementia
entering institutional care. This is confirmed by a large study reported by
Yaffe et al (Journal of the American Medical Association 287:2090-
2097), who developed and validated a prognostic model to determine the
predictors of nursing home placement among 5,788 community living
people with advanced dementia followed for three years. Predictors of
placement were ethnicity, ADL impairment, MMSE score less than 20 and
one or more difficult behaviors. Caregiver characteristics included age
over 65 and higher Zarit burden scale scores. Results confirm that several
factors influence nursing home placement in addition to cognitive
impairment, and that both patient factors (such as behavioral disturbance)
and carer factors (such as stress) are very important determinants.
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).
