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Abnormalities in the Pattern of Platelet Amyloid Precursor Protein Forms in Patients With Mild Cognitive Impairment and Alzheimer Disease
Alessandro Padovani, MD, PhD;
Barbara Borroni, MD;
Francesca Colciaghi, PhD;
Carla Pettenati, MD;
Elisabetta Cottini, MD;
Chiara Agosti, MD;
Gian Luigi Lenzi, MD;
Carlo Caltagirone, MD;
Marco Trabucchi, MD;
Flaminio Cattabeni, PhD;
Monica Di Luca, PhD
Arch Neurol. 2002;59:71-75.
ABSTRACT
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Context Patients affected by sporadic Alzheimer disease (AD) show a significant
alteration of amyloid precursor protein (APP) forms in platelets when compared
with patients with dementia but without AD and age-matched controls.
Objective To evaluate the ratio of platelet APP forms (APPr) in early-stage AD
and mild cognitive impairment (MCI) and its potential as a biomarker for the
early identification of AD.
Setting Community population-based sample of patients admitted to 4 AD centers
for investigation of cognitive disturbances.
Design and Methods Thirty-five patients with mild AD (mAD), 21 patients with very mild
AD (vmAD), 30 subjects with MCI, and 25 age-matched controls were included.
The APPr was evaluated by Western blot analysis in platelet homogenate.
Results Compared with controls (mean ± SD, 0.93 ± 0.3), the mean
APPr was decreased in patients with mAD (0.44 ± 0.24; P<.001) and patients with vmAD (0.49 ± 0.3; P<.001). Regarding the MCI group, a significant decrease in APPr
was found compared with controls (0.62 ± 0.33; P<.001). Fixing a cutoff score of 0.6, sensitivity was 88.6% (31/35)
for patients with mAD and 85.7% (18/21) for patients with vmAD, whereas specificity
was 88% (22/25) for controls. Among patients with MCI, 18 (60%) of 30 individuals
displayed APPr values below the cutoff.
Conclusions Alteration of platelet APP forms is an early event in AD, and the measurement
of APPr may be useful for the identification of preclinical AD in patients
with MCI.
INTRODUCTION
ALZHEIMER DISEASE (AD) is a chronic neurodegenerative disorder characterized
by a progressive cognitive and memory decline. It is defined by senile plaques,
neurofibrillary tangles, and amyloid angiopathy, neuropathologic hallmarks
that allow for a definitive diagnosis of the disease.1-2
In fact, pathologically confirmed preclinical AD occurs before the development
of cognitive impairment,3 suggesting that AD
lesions must be present for a sufficient length of time to produce neuronal
or synaptic loss.4 On the other hand, there
is evidence that in most cases the disease progresses to the stage of dementia
after only several years from the appearance of the first behavioral symptoms.5-7
In this regard, great attention has been devoted to the transitional
stage of cognitive impairment between normal aging and early AD, so-called
mild cognitive impairment (MCI).8-9
Mild cognitive impairment refers to the clinical state of individuals who
are memory impaired but are otherwise functioning well and do not meet clinical
criteria for dementia.10-12
There is evidence that individuals with MCI are at an increased risk for developing
AD, and several investigators13-15
strongly believe that virtually all patients with MCI have neuropathologic
AD. Nevertheless, proposed criteria for MCI may well apply to a heterogeneous
population affected by drug-induced states, affective disorders, or systemic
diseases. Early detection is, therefore, vitally important, but at present
the diagnostic process requires an extensive follow-up study based on clinical
and laboratory examinations.16-17
It would be desirable to have a biomarker that helps identify patients
affected by AD at the so-called predementia stage when pharmacologic effects
on cognitive functioning and symptom progression could be most beneficial.
In the past few years, different biochemical parameters in cerebral spinal
fluid (CSF) or plasma have been investigated, and several studies18-21 have
shown that tau levels or a combination of tau and ß-amyloid levels in
CSF might increase the discrimination of AD and may predict the development
of AD in patients with MCI.
Recently, different authors22-24
have tried to identify peripheral markers of AD, focusing mostly on the amyloid
precursor protein (APP), a protein expressed ubiquitously in several splice
variants, which is believed to play a key role in the pathogenesis of AD through
the formation of the Aß peptide.
In this regard, it has been observed that patients affected by sporadic
AD show a significant alteration of the immunoreactivity of the APP forms
in platelets when compared with patients with dementia but without AD and
age-matched controls,25-27
suggesting that the measurement of the ratio of APP forms (APPr) may represent
a reliable and sensitive marker for AD.28-30
These observations define the frame of the present study, which aims
to investigate whether APP changes in platelets occur at the earliest clinically
detectable stage of AD. More specifically, we addressed the following questions:
(1) Is the platelet APPr decreased in patients who fulfill criteria for MCI,
very mild AD (vmAD), and mild AD (mAD) compared with age-matched controls?
(2) How accurate is the APPr in discriminating among mAD, vmAD, and age-matched
controls? (3) What proportion of patients with MCI show alterations of APP
forms in platelets?
PATIENTS AND METHODS
PATIENTS
Participants were recruited from different neurologic and geriatric
centers in Italy (Clinica Neurologica, Università degli Studi di Brescia;
Centro Alzheimer, Ospedale di Rho; Dipartimento Scienze Neurologiche, Università
"La Sapienza"; Istituto di Ricerca a Carattere e Cura Scientifica, Santa Lucia)
using a standardized diagnostic protocol. The study was conducted in accordance
with local clinical research regulations, and informed consent was required
from all subjects and caregivers when indicated.
All subjects performed a somatic and neurologic examination. The following
laboratory studies were performed on the sample population: routine examination,
complete blood cell count, sedimentation rate, vitamin B12 and
folic acid measurement, thyroid hormone dosage measurement, syphilis serologic
testing, and homocysteine measurement. All patients underwent a brain imaging
study (computed tomography or magnetic resonance imaging). The behavioral
and global cognitive evaluation was conducted according to a standardized
battery, which included the following tools: Clinical Dementia Rating scale
(CDR),31 Mini-Mental Status Examination (MMSE),32 Alzheimer Disease Assessment Scale,33
Neuropsychiatric Inventory,34 Geriatric Depression
Scale,35 Hamilton Anxiety Rating Scale,36 instrumental activities of daily living,37 and activities of daily living.38
The neuropsychologic testing was accomplished by the following tests: Raven
Coloured Progressive Matrices,39 Controlled
Oral Word Association Test,40 Category Fluency
(animal names),41 Clock Drawing Test,42 Rey Complex Figure Copy and Recall,43
Story Recall Test,44 and Trail-Making Test.45
The diagnosis of MCI was based on Mayo Clinic criteria: (1) subjective
memory complaint, (2) normal activities of daily living, (3) normal general
cognitive functioning, (4) abnormal verbal and/or nonverbal memory for age,
and (5) absence of dementia.8-9
The diagnosis of dementia and probable AD was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV)46 and on
National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's
Disease and Related Disorders Association criteria,47
respectively. Patients with AD entered this study only if their MMSE score
was 19 of 30 or higher. These patients were grouped as having vmAD (CDR score,
0.5) or mAD (CDR score, 1).
The following exclusion criteria were designed for probable AD as the
cause of their dementia: (1) major depressive disorder, bipolar disorder,
schizophrenia, substance use disorder, or mental retardation according to
criteria of DSM-IV; (2) cerebrovascular disorders,
hydrocephalus, and intracranial mass, documented by computed tomography or
magnetic resonance imaging within the past 12 months; (3) abnormalities in
serum folate and vitamin B12 levels, syphilis serologic test results,
or thyroid hormone levels; (4) a history of traumatic brain injury or other
neurologic disease (eg, Parkinson disease, Huntington disease, seizure disorders);
and (5) considerable medical problems (eg, poorly controlled diabetes or hypertension;
cancer within the past 5 years; clinically significant hepatic, renal, cardiac,
or pulmonary disorders). All these criteria were also adopted for patients
with MCI and the control group. The control group comprised 2 subgroups: healthy
individuals (including healthy volunteers, spouses, or caregivers) and patients
without dementia (including patients with stroke, myelopathies, and head trauma).
To avoid potential pharmacologic confounding effects on platelet physiologic
findings, patients taking psychotropic agents, nootropic drugs, cholinergic
or anticholinergic agents, antiplatelet agents, anticoagulants, corticosteroids,
or serotoninergic drugs entered the study only after being drug free for at
least 14 days before blood collection and platelet preparation.
PLATELET COLLECTION AND PREPARATION
Blood samples were obtained from fasting participants between 9 AM and
10 AM. A blood sample (27 mL) was drawn, carefully releasing the tourniquet
immediately after its application, from a vein in the antecubital fossa using
a 19-gauge needle, and collected into 3 mL of 3.8% sodium citrate (in the
presence of 2450 mg/dL [136 mmol/L] of glucose). Each sample was mixed gently
and centrifuged at 200g for 10 minutes to separate
platelet-rich plasma within 30 minutes after blood drawing. Platelet-rich
plasma was separated from the blood pellet by means of a plastic pipette,
avoiding aspiration of the buffy coat. Platelets were then collected by further
centrifugation at 3000g for 20 minutes. The platelet
pellet was stored at -80°C. Immunoblot experiments were performed
with monoclonal antibody 22C11 as described elsewhere.23, 26
Patient information and case diagnosis were unknown to the laboratory investigators
who received and analyzed the blood samples.
STATISTICAL ANALYSIS
Comparisons among groups was performed using factor analysis of variance
with post hoc analyses (Tukey honestly significant difference test for unequal
sample sizes). Sensitivity (ie, the proportion of patients with AD and low
APPr) and specificity (ie, the proportion of controls with high APPr) were
calculated using a cutoff score (normal APPr, >0.6) from a study performed
on a large sample of patients with AD and control individuals (data not shown).
RESULTS
The analysis was performed on 111 blood samples from individuals 55
to 90 years old. The groups consisted of 35 patients diagnosed as having mAD,
21 patients with vmAD, 30 subjects with MCI, and 25 age-matched controls.
Demographic and clinical characteristics of the study population are given
in Table 1.
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Table 1. Demographic and Clinical Characteristics of the Study Population*
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Whole platelet homogenates from each patient and control were processed
for Western blot analysis by means of monoclonal antibody 22C11 raised against
the N-terminal domain of APP, thereby recognizing all APP forms. Thereafter,
the optical density of the bands at 106, 110, and 130 kd was measured by image
analysis; the APPr between the highest (130) and the lower (106-110) bands
was determined.
Comparison between platelet APPr levels among the 4 subgroups are presented
in Table 2. There was a significant
decrease in the level of APPr in the mAD group compared with the control group
(P<.001). An APPr decrease was also found in the
vmAD group (P<.001) compared with controls. No
significant differences were found between the vmAD group and the mAD group.
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Table 2. APR in the Different Groups*
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With regard to the MCI group, a significant decrease in APPr values
was found compared with the control group (P<.001).
There was no significant difference between the MCI and both the vmAD and
the mAD groups, although in the MCI group, there was higher variability and
greater overlapping of APPr values with the control group (Figure 1).
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Figure 1. Amyloid precursor protein ratio
(APPr) in controls and patients. MCI indicates mild cognitive impairment;
vmAD, very mild Alzheimer disease; and mAD, mild Alzheimer disease.
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Sensitivity and specificity data for APPr using the cutoff score are
presented in Figure 2. Sensitivity
was 88.6% (32/35) for mAD and 85.7% (18/21) for vmAD, whereas specificity
was 88% (22/25) for the control group. By using this cutoff score, 18 (60%)
of 30 patients with MCI displayed APPr values below the cutoff.
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Figure 2. Percentage of patients below the
cutoff among the different groups. MCI indicates mild cognitive impairment;
vmAD, very mild Alzheimer disease; and mAD, mild Alzheimer disease. Gray bars
indicate the percentage of patients below the cutoff score ( 0.6); white
bars, percentage of patients over the cutoff score (>0.6).
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COMMENT
Our results demonstrate that alteration in APP metabolism is an early
event in sporadic AD and that most patients with MCI have prodromal AD according
to the platelet APPr. These findings extend previous reports26, 28, 48-49
and confirm that APP metabolic changes are widespread, involving central and
peripheral tissues early in the disease.50
The mechanisms that lead to platelet APP alterations and their relation
to the pathologic changes typically found in the AD brain are still poorly
understood. Although unlikely to contribute to cerebral amyloid deposition,
platelet-associated APP forms provide an appropriate tissue to study APP biochemistry
and metabolism in both healthy and diseased patients.51
Further, the findings of the present study agree with other AD-related platelet
features, such as abnormal activation,23, 52
increased membrane fluidity,53 alterations
of phospholipases (A and C),54 and protein
kinase C levels.55
According to these observations, platelets have been proposed as a source
of human biological material that mirrors, in the peripheral compartment,
the occurrence and evolution of AD-related biochemical processes that develop
in the central nervous system.27 Moreover,
on the basis of the results derived from different clinical settings which
showed that the sensitivity and specificity of the measurement of platelet
APPr for AD was high, it has been claimed that this assay holds the potential
to be a clinical marker, though not a single definitive test, that might be
of helpful and adjunctive value to strengthen the diagnosis of AD.29, 48
In the present study, this assumption is further substantiated since
this biomarker also seems to have clinical value in the very early phase of
AD. Most patients with mAD and vmAD showed a significant APPr decrease, with
a sensitivity higher than 80% in either mAD or vmAD. In our opinion, these
values seem promising for clinical diagnostic purposes and parallel results
on CSF biomarkers. As recently reported, such CSF biomarkers as protein tau
and Aß1-42 levels, or the combination of the 2, have high diagnostic
accuracy levels for AD18-21,56
and, more interestingly, high sensitivity for the prediction of AD in patients
with MCI.57 Similarly, the present study showed
a decrease of APPr in a large proportion (almost two thirds) of individuals
who fulfill widely accepted criteria for MCI. These data agree with recent
neuropathological studies3-4 and
suggest that changes in platelet APP metabolism may predate the onset of clinical
dementia and already be detectable when cognitive impairment is barely detectable
and there is no impact on daily activities, as in the so-called MCI condition.
The term MCI has been used by investigators
in an attempt to characterize a condition that may serve as an independent
predictor of AD. On these grounds, recent clinicopathologic and longitudinal
studies have claimed that MCI actually represents early-stage AD. Nevertheless,
not every elderly individual with memory deficits progresses to AD dementia,
and there is evidence from postmortem studies that supports other non-AD causes
of memory decline. Further, MCI has also been related to several etiologic
factors, such as affective disorders, drug-induced states, infarcts, system
diseases, and other concomitant diseases, including blood pressure disturbances.3, 14, 58 Our data partially
support the concept that MCI refers to a heterogeneous population, although
the relatively large number of patients with MCI and APPr abnormalities is
consistent with the view that these patients are at high risk for AD, if not
prodromal AD, and that AD can be identified at earlier stages.
Our study has some limitations. First, follow-up of the patients or
neuropathological data to confirm the diagnosis are not presently available.
We carefully devoted much attention on the diagnostic issue by using widely
established standardized criteria to minimize the risk of diagnostic errors.
Nevertheless, we agree that studies with patients with neuropathologically
confirmed disease are needed to determine the real predictive value of platelet
APPr for AD. Second, as with any hospital-based sample, there may be selection
biases in our groups, particularly among the patients with MCI. According
to inclusion and exclusion criteria, this study was restricted to individuals
with minimal confounding comorbidity and pharmacologic treatment, limiting
the number of ambiguous cases as much as possible. This might have determined
an overestimation of the accuracy measures. On the other hand, some exclusion
criteria are still required to avoid interfering or confounding factors on
the physiology of platelets and, therefore, on the reliability of the assay.
Finally, the study was based on a relatively small sample size, and follow-up
is lacking. In this regard, other authors29
have reported very similar findings on APPr in patients with AD, suggesting
that the measurement of APPr might be useful to monitor the disease. Furthermore,
to determine the real clinical usefulness in the prediction of AD, a longitudinal
study on MCI and vmAD has been already planned.
In conclusion, the results of the present study suggest that low platelet
APPr is already found in early-phase AD and MCI. These findings may have a
role in the diagnostic workup of patients with MCI, identifying patients who
will likely develop AD. This will be especially important because in this
phase drugs may have the greatest potential of improving symptoms or slowing
the disease process.
AUTHOR INFORMATION
Accepted for publication September 7, 2001.
Author Contributions: Study concept and
design (Drs Padovani, Borroni, Trabucchi, Cattabeni, and Di Luca); acquisition of data (Drs Padovani, Pettenati, Cottini, and Agosti); analysis and interpretation of data (Drs Padovani, Colciaghi, Lenzi,
Caltagirone, and Di Luca); drafting of the manuscript (Drs Padovani,
Borroni, Colciaghi, Cottini, and Di Luca); critical revision of the
manuscript for important intellectual content (Drs Pettenati, Agosti,
Lenzi, Caltagirone, Trabucchi, and Cattabeni); obtained funding
(Drs Padovani, Lenzi, and Cattabeni); administrative, technical, and
material support (Dr Borroni); study supervision (Drs
Caltagirone and Di Luca).
This study was supported by grants 9906158271-004 (Dr Di Luca) and 9906158271-003
(Dr Padovani) from MURST 40% and from "Progetto Finalizzato Alzheimer" Ministero
della Salute.
We thank Luca Rozzini, MD, Paola Corsini, MD, and Barbara Vicini, MD,
for participation in patient enrollment and Roberto Monastero, MD, for helpful
discussion and editorial review. We also thank the subjects who donated their
time to take part in the study and the staff of the Unità di Neurologia
degli Spedali Civili of Brescia for accommodating the study.
Corresponding author and reprints: Alessandro Padovani, MD, PhD,
Dipartimento Scienze Mediche e Chirurgiche, Clinica Neurologica, Università
degli Studi di Brescia, Piazza Ospedale 1, 25125, Brescia, Italia (e-mail: padovani{at}bshosp.osp.unibs.it).
From the Department of Neurology, University of Brescia, Brescia (Drs
Padovani, Borroni, Cottini, and Agosti), Centre of Excellence for Neurodegenerative
Disease and Department of Pharmacological Sciences, University of Milan, Milan
(Drs Colciaghi, Cattabeni, and Di Luca); Alzheimer Centre, Passirana-Rho,
Milan (Dr Pettenati), Department of Neurology, "La Sapienza" University of
Rome, Rome (Dr Lenzi), Istituto di Ricerca a Carattere e Cura Scientifica,
Santa Lucia "Tor Vergata" University of Rome, Rome (Dr Caltagirone), and Gruppo
di Ricerca Geriatria, Brescia (Dr Trabucchi), Italy.
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