The platelet amyloid precursor protein ratio as a diagnostic marker for Alzheimer’s disease in Thai patients (original) (raw)
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Alzheimer's & Dementia, 2012
Studies have shown that platelet APP ratio (representing the percentage of 120-130 kDa to 110 kDa isoforms of the amyloid precursor protein) is reduced in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). In the present study, we sought to determine if baseline APP ratio predicts the conversion from MCI to AD dementia after 4 years of longitudinal assessment. Fifty-five older adults with varying degrees of cognitive impairment (34 with MCI and 21 with AD) were assessed at baseline and after 4 years. MCI patients were re-classified according to the conversion status upon follow-up: 25 individuals retained the diagnostic status of MCI and were considered as stable cases (MCI-MCI); conversely, in nine cases the diagnosis of dementia due to AD was ascertained. The APP ratio (APPr) was determined by the Western blot method in samples of platelets collected at baseline. We found a significant reduction of APPr in MCI patients who converted to dementia upon follow-up. These individuals had baseline APPr values similar to those of demented AD patients. The overall accuracy of APPr to identify subjects with MCI who will progress to AD was 0.74 ± 0.10, p = 0.05. The cut-off of 1.12 yielded a sensitivity of 75 % and a specificity of 75 %. Platelet APPr may be a surrogate marker of the disease process in AD, with potential implications for the assessment of abnormalities in the APP metabolism in patients with and at risk for dementia. However, diagnostic accuracy was relatively low. Therefore, studies in larger samples are needed to determine whether APPr may warrant its use as a biomarker to support the early diagnosis of AD.
Archives of Neurology, 2003
Background: Alteration of the amyloid precursor protein (APP) forms ratio has been described in the platelets of patients with dementia of Alzheimer type (DAT) and in a subset of subjects with mild cognitive impairment (MCI). Objective: To evaluate the potential role of the platelet APP forms ratio in predicting progression from MCI to DAT. Design: Thirty subjects with MCI underwent a clinical and neuropsychological examination and a determination of the platelet APP forms ratio. Subjects were followed up periodically for 2 years, and the progression to dementia was evaluated. Setting: Community population-based sample of patients admitted for memory complaints. Results: Patients who progressed to DAT at the 2-year follow-up (n=12) showed a significant decrease of baseline platelet APP forms ratio values (mean ± SD, 0.36 ± 0.28) compared with stable MCI subjects (mean±SD, 0.73±0.32) (PϽ.01) and patients who developed other types of dementia (mean±SD, 0.83±0.27) (P =.03). By fixing a cutoff score of 0.6, 10 (83%) of the 12 DAT patients showed baseline values below the cutoff, whereas 10 (71%) of 14 subjects who either developed non-Alzheimer-type dementia or maintained cognitive functions had values in the normal range. Conclusion: Mild cognitive impairment is a major risk factor for DAT, and Alzheimer disease-related pathological changes can be identified in patients converting to DAT within a 2-year follow-up.
Platelet amyloid precursor protein processing: A bio-marker for Alzheimer's disease
Journal of the Neurological Sciences, 2006
The amyloid precursor protein (APP) in brain is processed either by an amyloidogenic pathway by β-secretase and γ-secretase to yield Aβ (β-amyloid 4 kDa) peptide or by α-secretase within the βamyloid domain to yield non-amyloidogenic products. We have studied blood platelet levels of a 22-kDa fragment containing the Aβ (β-amyloid 4 kDa) peptide, β-secretase (BACE1), α-secretase (ADAM10), and APP isoform ratios of the 120-130 kDa to 110 kDa peptides from 31 Alzheimer's disease (AD) patients and 10 age-matched healthy control subjects. We found increased levels of Aβ4, increased activation of β-secretase (BACE1), decreased activation of α-secretase (ADAM10) and decreased APP ratios in AD patients compared to normal control subjects. These observations indicate that the blood platelet APP is processed by the same amyloidogenic and non-amyloidogenic pathways as utilized in brain and that APP processing in AD patients is altered compared to control subjects and may be a useful bio-marker for the diagnosis of AD, the progression of disease and for monitoring drug responses in clinical trials.
Blood cell markers in Alzheimer Disease: Amyloid Precursor Protein form ratio in platelets
Experimental gerontology
A correct clinical diagnosis in the early stage of Alzheimer Disease (AD) is mandatory given the current available treatment with acetylcholine esterase inhibitors. Moreover, a early to preclinical diagnosis would allow to identify patients eligible for future disease-modifying therapies. In the last ten years, we have focused our attention on peripheral markers, evaluating the role of platelet Amyloid Precursor Protein (APP) forms as a reliable tool for AD diagnosis since preclinical stages. APP is the key player in AD pathogenesis, and platelets contain all the enzymatic machinery to its processing, thus being the ideal candidate where to study AD pathogenetic mechanisms. In this review, we summarise the published data regarding the usefulness of platelet APP form ratio in the diagnosis of early AD. Approaches combining APP form ratio along with neuroimaging markers show the promise to accurately identify AD, even in the pre-symptomatic stage.
Amyloid Precursor Protein in Platelets of Patients With Alzheimer Disease
Archives of Neurology, 2001
Background: Amyloid precursor protein (APP) forms with apparent molecular weights of 130, 110, and 106 kd are present in human platelets. It has been demonstrated that Alzheimer disease (AD) is specifically associated with a decreased APP forms ratio in platelets. Objective: To investigate whether acetylcholinesterase (AChE) inhibitor treatment modifies the ratio of platelet APP forms in patients with AD. Patients and Methods: From a large sample of patients with probable AD, 30 with mild to moderate AD were selected. Each patient underwent a clinical evaluation including the Mini-Mental State Examination (MMSE) and platelet APP forms analysis at baseline and after 30 days. During this interval, 20 of 30 patients with AD were treated with donepezil hydrochloride (5 mg/d), a piperidine phosphate-based cholinesterase inhibitor. Platelets were subjected to Western blot analysis using monoclonal antibody (22C11). The ratio between the immunoreactivity of the higher-molecular-weight APP form (130 kd) and the lower forms (106 and 110 kd) was measured. Results: All patients taking donepezil completed the 30 days of treatment without adverse effects. The platelet APP forms ratio at baseline did not differ between the 2 AD groups (mean ± SD optical density ratio: untreated AD, 0.47 ± 0.12; treated AD, 0.38 ± 0.18), whereas a significant difference was found at follow-up (mean ± SD optical density ratio: untreated AD, 0.45±0.17; treated AD, 0.77±0.29; PϽ.001). A significant improvement in MMSE scores in treated AD patients was observed from baseline (16.9 ± 3.8) to 30 days (18.9±4.42) (PϽ.009, 30 days vs baseline), but no significant correlation was found in treated AD patients between MMSE score improvement and APP forms/ ratio increase (P=.09). Conclusions: Administration of AChE inhibitors increases the ratio of APP forms in platelets of patients with AD, suggesting a potential effect of AChE inhibitors on APP trafficking or processing in a peripheral cell.
Mechanisms of Ageing and Development, 2001
Alzheimer Disease (AD) is characterized by the progressive deposition of b-amyloid in the parenchyma and cerebral microvasculature. The b-amyloid peptide derives from the metabolism of a larger precursor, Amyloid Precursor Protein (APP). This protein is present in central nervous system, but it is also expressed in peripheral tissues such as circulating cells. An alteration of the APP forms pattern in platelets has been recently reported in AD patients when compared to platelets both of control subjects or non AD patients (NADD). The accuracy of the assay to identify AD is high and decreased levels are found throughout the course of AD with a significant association with severity of symptoms. Moreover, a recent study has demonstrated that AD patients on donepezil (5 mg daily) for 4 weeks displayed two-fold increase in their APPr baseline levels up to normal range. Thus, platelet APP ratio (APPr) holds the potential to be a clinical marker, which might be of helpful and : S 0 0 4 7 -6 3 7 4 ( 0 1 ) 0 0 3 1 5 -3
Amyloid precursor protein in platelets: A peripheral marker for the diagnosis of sporadic AD
Neurology, 2001
Article abstract-Background: An altered pattern of amyloid precursor protein (APP) forms consisting in a reduced ratio between the upper (130 kDa) and the lower (106 to 110 kDa) immunoreactivity bands has been described in platelets of patients with AD. Objective: To evaluate the sensitivity and the specificity of platelet APP forms' ratio (APPr) as a marker for AD. Methods: Eighty-five patients with probable AD and 95 control subjects (CON), including healthy individuals and neurologic patients, entered the study. Platelet APPr was evaluated by means of Western Blot analysis and immunostaining in the whole platelet homogenate, and calculated by the ratio between the optical density (OD) of the upper (130 kDa) and the lower (106 to 110 kDa) APP immunoreactive bands. Results: Mean APPr levels were decreased in AD patients (mean OD Ϯ SD ϭ 0.35 Ϯ 0.18) compared with the CON group (mean OD Ϯ SD ϭ 0.92 Ϯ 0.38) (DF 1, 178, p Ͻ 0.0001). Accuracy levels measured by Receiver Operating Curve analysis showed that a cutoff level of 0.57 resulted in a sensitivity of 88.2% and a specificity of 89.4%, with an area under the curve of 0.945. APPr levels were significantly associated with disease severity (mild AD versus moderate AD: p Ͻ 0.0001; moderate AD versus severe AD: p Ͻ 0.05). Conclusion: Platelet APPr allowed to differentiate AD from normal aging and other dementing disorders with high sensitivity and specificity. These findings suggest that platelet APPr may be of help as an adjunctive diagnostic tool in clinical practice.
European Journal of Pharmacology, 2000
Alzheimer disease is a progressive neurodegenerative disease, characterised by a progressive cognitive and memory decline. From a neuropathological point of view, Alzheimer disease is defined by the presence of characteristic lesions, i.e. mature senile plaques, neurofibrillary tangles (NFTs) and amyloid angiopathy. In particular, accumulation of the amyloid beta-peptide in the brain parenchyma and vasculature is an invariant event in the pathogenesis of both sporadic and familial Alzheimer cases. Amyloid beta-peptide originates from a larger precursor, the amyloid precursor protein (APP) ubiquitously expressed. Among the different peripheral cells expressing APP forms, platelets are particularly interesting since they show concentrations of its isoforms equivalent to those found in brain. Moreover, a number of laboratories independently described alterations in APP metabolism/concentration in platelets of Alzheimer patients when compared to control subjects matched for demographic characteristics. These observations defined the frame of our work aimed to investigate if a correlation between levels of platelet APP forms and Alzheimer disease could be detected. We have reported that patients affected by Alzheimer disease show a differential level of platelet APP forms. This observation has several implications: APP processing abnormalities, believed to be a very early change in Alzheimer disease in neuronal compartment, do occur in extraneuronal tissues, such as platelets, thus, suggesting that Alzheimer disease is a systemic disorder; further, our data strongly indicate that a differential level of platelet APP isoforms can be considered a potential peripheral marker of Alzheimer disease allowing for discrimination between Alzheimer and other types of dementia.