546
0.4, 95% CI 0.2–0.7, X2 ¼ 8.2, p ¼ 0.004). When all the
variables were controlled for, only functional impair-
ment consistently remained independently associated
with emotional distress with a trend for physical illness
(OR 3.5, 95%CI 1.1–10.3, p ¼ 0.03, OR 2.2, 95%CI 0.8–
6.1, p ¼ 0.06).
Comment
Between 1 in 3 and 1 in 5 community older adults had
physical and emotional distress. Physical symptoms
commonly occurred together and with psychological
distress contributed to impairment in functioning.
Functional impairment was independently associated
with emotional distress. In a previous paper we reported
that dependence was associated with memory difficulty,
stroke, physical impairment and depression (Uwakwe
et al., 2009). The relationship between subjective memory
complaints, objective cognitive test and incident demen-
tia remain inconsistent across studies. One possible
mechanism is the contribution of various sociodemo-
graphic and health factors that generate co-occurring
physical illnesses which activate memory complaints.
In spite of physical and mental distress, the majority
of the older adults still rated their health as good or fair,
which may perhaps be partly accounted for by the fact
that generally, most Nigerians express satisfaction with
life irrespective of any hardships.
Our small non-representative sample (with the
possibility of having excluded those with more
disablement), the use of subjective health conditions,
Towards development of drugs targeting both amyloid and
tau pathologies of Alzheimer’s disease
Hypothesis-driven experimental investigation is a well-
established scientific process. However, a hypothesis
can only contribute to efficiently finding a true
solution if controversies between the hypothesis and
experimental data are actively used to modify the
original hypothesis, or to formulate a new hypothesis
that better explains experimental data.
Amyloid plaques and neurofibrillary tangles are the
pathological hallmarks of Alzheimer’s disease (AD).
The amyloid cascade hypothesis, the most widely
proposed pathogenic mechanism for AD, suggests that
elevated beta amyloid protein is the cause of AD, while
tau pathology is a downstream manifestation of the
Copyright # 2011 John Wiley & Sons, Ltd.
Letters to the Editor
the non graded nature of the KADL and the
impossibility of implying any causal direction in a
cross sectional investigation are some of the obvious
weaknesses of this report.
Conflict of interest
None declared.
References
Goldberg DP, Gater R, Sartorius N, Ustun TB, Piccinelli M, Gureje O, Rutter C. 1997.
The validity of two versions of the GHQ in the WHO study of mental illness in
general health care. Psychol Med 27: 191–197.
Katz S, Ford AB, Moskwitz RW. 1963. Studies of illness in the aged. The index of
Activities of Daily Living:A standardized measure of biological and psychosocial
function. JAMA 184: 914–919.
Uwakwe R, Ibeh CC, Modebe AI, Emeka BO, Ezeama N, Njelita I, Ferris C, Prince M.
2009. The epidemiology of dependence in older people in Nigeria: prevelance,
determinants, informal care and health service utilization. A 1066 Dementia
Research Group Cross Sectional Survey. J Am Geriatr Soc 57: 1620–1627.
RICHARD UWAKWE1, IFEOMA MODEBE1, IFEOMA ANNE NJELITA2,
2
AND NKIRU NWAMAKA EZEAMA
1
The Unit of Psychiatric Research, Faculty of Medicine,
College of Health Sciences, Nnamdi Azikiwe University
Nnewi Campus, Nigeria
2
Nnamdi Azikiwe University Teaching Hospital,
Nnewi, Nigeria
Published online in Wiley Online Library
(wileyonlinelibrary.com).
DOI: 10.002/gps.2528
amyloid pathology (Williams, 2009). How can we test
the validity of this hypothesis? The best way to test the
amyloid cascade hypothesis may be to show that drugs
developed from this hypothesis provide the expected
clinical benefits. However, efforts in targeting the
removal of amyloid plaques from the brain of patients
with AD have been disappointing. Neither plaque-
removing vaccines, nor the gamma-secretase modu-
lator tarenflurbil have demonstrated clinical benefits,
which leads us to question the validity of the amyloid
cascade hypothesis that has driven AD research for the
past decade (Williams, 2009). The lack of progress in
developing therapeutic drugs based on the amyloid
Int J Geriatr Psychiatry 2011; 26: 545–549.
Letters to the Editor
hypothesis might indicate that some of the basic
assumptions of AD causality, and the search for
effective therapeutic agents, are in need of major
reassessment and redirection (Williams, 2009).
Recently, a ‘‘dual pathway’’ hypothesis of causality of
late-onset AD was proposed to resolve controversies
between the amyloid cascade hypothesis and recent
experimental data (Small and Duff, 2008). While the
amyloid cascade hypothesis assumes a serial model of
causality (whereby abnormal elevations in beta amyloid
levels drive tau hyperphosphorylation and other down-
stream manifestations), the dual pathway hypothesis
suggests that elevation of beta amyloid levels and tau
hyperphosphorylation are linked to separate mechan-
isms but driven by a common upstream molecular
defect. While the recent antiamyloid drug trial failures
have led to the general acknowledgment that effective
therapeutic agents should target both amyloid and tau
pathologies, the prevailing view is that a mixture of
drugs will be needed; some that reduce beta amyloid and
amyloid plaques, and others that reduce tau phos-
phorylation and tangles (Small and Duff, 2008).
However, the dual pathway model, by which singular
molecular defects may drive both abnormalities,
provides a pharmacological rationale for searching
out and developing single agents that can ameliorate
both core defects of AD (Small and Duff, 2008).
As a possible single agent targeting both amyloid and
tau pathologies, there are interesting indications that
activating the M1 muscarinic cholinergic receptor can
reduce both amyloid and tau pathologies in AD
(Caccamo et al., 2006). As expected, stimulation of
muscarinic acetylcholine receptors, in particular the
M1 subtype, has been shown to have a beneficial effect
in restoring cognition, and in attenuating both
amyloid and tau pathologies in 3
Tg-AD mice with
plaques and tangles (Caccamo et al., 2006). The M1
muscarinic receptor is coupled to phospholipase C-b1
via the a subunit of Gq proteins, and this signaling
cascade is involved in memory performance and AD
(Shin et al., 2005). More importantly, because
phospholipase C-b1 is coupled to multiple G-protein
coupled receptors (Shin et al., 2005), it may prove
beneficial to discover additional single agents that can
reduce both amyloid and tau pathologies.
How can we monitor whether a candidate agent
targeting both amyloid and tau pathologies reduces
amyloid pathology, tau pathology, or both, in living
humans? Multitracer positron emission tomography
(PET) imaging using 2-(1-{6-[(2-[18F]fluoroethyl)
(methyl)amino]-2-naphthyl}ethylidene)malononitrile
(FDDNP) and [11C] Pittsburgh Compound-B (PIB)
may provide a means to distinguish amyloid and tau
Copyright # 2011 John Wiley & Sons, Ltd.
547
Figure 1 Pittsburgh Compound-B (PIB) positron emission tomography
(PET) fusion image (right) over an anatomical magnetic resonance (MR)
image (middle), and FDDNP positron emission tomography (PET)
fusion image (left) over an anatomical magnetic resonance (MR) image
(middle). The images were acquired from an 83-year-old woman with
Alzheimer’s disease (Mini Mental State Examination (MMSE) ¼ 18/30
and Clinical Dementia Rating (CDR) ¼ 1). FDDNP binds to amyloid
plaques and tangles, and PIB selectively binds to amyloid plaques. Note
that the FDDNP–PET image shows strong FDDNP binding in the
medial temporal cortex but that the PIB–PET image shows little PIB
binding in the same region. This suggests that the FDDNP binding in
the medial temporal cortex of this patient predominantly represents
tangle accumulation. On the contrary, the lateral temporal cortex, where
amyloid pathology is known to be predominantly accumulated, shows
high FDDNP binding as well as high PIB binding. Therefore, this
combined PET imaging using both PIB and FDDNP in the same subject
can contribute to monitor the effect of agents targeting amyloid path-
ology and/or tau pathology (Modified from Shin et al., 2008).
pathologies in living human subjects (Shin et al., 2008).
FDDNP is a PET radiotracer that binds to both amyloid
plaques and neurofibrillary tangles, while PIB binds to
amyloid plaques selectively. Combined PET imaging
using both PIB and FDDNP in the same subject may,
therefore, help distinguish amyloid pathology from
tau pathology in living humans (see Figure 1). In
conclusion, multitracer PET imaging using PIB and
FDDNP may help to test the effect of drugs targeting
amyloid pathology and tau pathology in living humans.
Conflict of interest
None declared.
Key Points
 Recently, repeated clinical trial failures in devel-
oping disease-modifying drugs that target amyloid
pathology in Alzheimer’s disease (AD) suggest that
some of the basic assumptions of AD causality
warrant major reassessment and redirection.
 Several lines of evidence indicate that effective
therapeutic agents should target not only amyloid
pathology but also tau pathology.
 Multitracer positron emission tomography ima-
ging using [11C]PIB and [18F]FDDNP may help
test the effects of drugs that target both amyloid
and tau pathologies.
Int J Geriatr Psychiatry 2011; 26: 545–549.
548 Letters to the Editor

References JONGHAN SHIN1,2

1
Neuroscience Research Institute, Gachon University of
Caccamo A, Oddo S, Billings LM, et al. 2006. M1 receptors play a central role in Medicine and Science, Incheon, Republic of Korea
modulating AD-like pathology in transgenic mice. Neuron 49: 671–682. 2
Shin J, Kim D, Bianchi R, Wong RK, Shin HS. 2005. Genetic dissection of theta rhythm
Department of Psychiatry, New York University School of
heterogeneity in mice. Proc Natl Acad Sci USA 102: 18165–18170. Medicine, New York, NY, USA
Shin J, Lee SY, Kim SH, Kim YB, Cho SJ. 2008. Multitracer PET imaging of amyloid
plaques and neurofibrillary tangles in Alzheimer’s disease. Neuroimage 43: 236–244.
Small SA, Duff K. 2008. Linking a beta and tau in late-onset Alzheimer’s disease: a dual Published online in Wiley Online Library
pathway hypothesis. Neuron 60: 534–542.
Williams M. 2009. Progress in Alzheimer’s disease drug discovery: an update. Curr
(wileyonlinelibrary.com).
Opin Investig Drugs 10: 23–34. DOI: 10.002/gps.2543

A meta-analysis of studies comparing the effectiveness of

three cognitive screening tests in the detection of dementia
populations

Dear Editor
Detection of early dementia has been identified as a
health service priority and the use of cognitive
screening tools is recommended to facilitate this.
Cognitive screening tests consist of systematic,
structured questions or tasks that are easily scored,
and can usually be equated to a ‘caseness’ or ‘non-
caseness’ category highlighting where further clinical
assessment is indicated. This meta-analysis considered
studies that directly compare the effectiveness of the
MMSE with revisions/developments of it in identifying
dementia populations.
The Mini Mental State Examination (MMSE) is the
most widely used cognitive screening test. It was
developed as a bedside tool to evaluate the cognitive
status of elderly people in clinical settings. Attempts
have been made to develop the MMSE by extending its
content (Modified MMSE, 3MS/MMMSE; Adden-
brooke’s Cognitive Examination, ACE). Thirteen
papers were included that reported direct comparisons
of the MMSE with either the Modified Mental State
Examination (3MS; six studies) or the ACE (seven
studies). This included comparison of the MMSE with
revised versions of the ACE (ACE-R; one study) and
the 3MS (3MS-R; one study).
The meta-analysis was based on the method of
Hasselblad and Hedges (1995) for integrating data on
diagnostic and screening tests. The effect size was
calculated for each test in each study using the
standardized difference between the means for control
and dementia sample groups. Where means and
standard deviations were not reported, values of
sensitivity and specificity were used to calculate
effectiveness values. A value of combined effectiveness
across each group of studies was derived using the
standard error to weight the effectiveness values.
The effectiveness values calculated for each of the 13
studies showed that the extensions (ACE or 3MS) had
the same or a higher effectiveness value than the MMSE
in every comparison. Effectiveness values were found
to be homogeneous, therefore a random effects model

Table 1 Weighted mean effectiveness values for ACE/MMSE and 3MS/MMSE studies

Tests compared No. Total no. Total no. Test Weighted mean 95% Confidence
studies cases controls effectiveness interval

ACE/MMSE 7 943 1871 ACE 2.170 1.8412.499

MMSE 1.727 1.4621.992
3MS/MMSE 6 656 507 3MS 2.210 1.8132.607
MMSE 2.039 1.6052.473

Copyright # 2011 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2011; 26: 545–549.