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Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-143135 IOS Press
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Markers for the Risk of Progression from Mild Cognitive Impairment to Alzheimer’s Disease
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Laura Burattia , Simona Balestrinia , Claudia Altamurab , Giovanna Viticchia , Lorenzo Falsettic , Simona Luzzia , Leandro Provincialia , Fabrizio Vernierib and Mauro Silvestrinia,∗
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a Neurological
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b Neurology
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Clinic, Marche Polytechnic University, Ancona, Italy Unit, Campus Bio-Medico University, Rome, Italy c Internal and Subintensive Medicine, Ospedali Riuniti Ancona, Italy
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Handling Associate Editor: Jack de la Torre
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Abstract. Background: Defining reliable markers of conversion to dementia could be the first step in order to identify appropriate treatment strategies for mild cognitive impairment (MCI) patients. Objective: To develop a tool able to predict the risk of progression from MCI to Alzheimer’s disease (AD). Methods: 406 MCI patients were included and followed for a one-year period. Demographic characteristics, vascular risk factors, extent of cerebrovascular lesions, markers of carotid atherosclerosis investigated with an ultrasonographic assessment (plaque index and intima-media thickness) and cerebrovascular reactivity to apnea (breath-holding index) were considered as potential predictors of conversion. Results: 106 (26%) MCI patients showed a conversion to AD. Plaque index, intima-media thickness, and breath-holding index were relevant predictors of conversion (p = 0.042; p = 0.003; p < 0.001, multivariate logistic regression analysis). A simplified scoring system was devised based on the magnitude of the estimated multinomial logistic regression  coefficient results. A total score was calculated as the sum of each predictive factor which resulted in a 0–5 range. The optimal cut-off score was ≥3 (sensitivity, 23.6%, 95% CI 15.9%–32.8%; specificity, 97.7%, 95% CI 95.3%–99.1%; positive likelihood ratio, 10.1, 95% CI 4.5%–22.7%; negative likelihood ratio, 0.78, 95% CI 0.70%–0.87%). The AUC was 0.71 (95% CI, 0.65–0.77). Conclusions: Our findings show the possibility to obtain a predictive indicator of the risk of conversion from MCI to dementia by considering the presence of both atherosclerotic changes in the carotid district and impairment of cerebral hemodynamics. Such an approach may allow us to formulate a correct prognosis in more than 70% of patients with amnesic MCI.
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dA
Accepted 6 January 2015
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Keywords: Alzheimer’s disease, atherosclerosis, carotid arteries, cerebral hemodynamics, mild cognitive impairment, ultrasonography
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INTRODUCTION
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Mild cognitive impairment (MCI) is regarded as the intermediate stage of cognitive impairment between ∗ Correspondence
to: Mauro Silvestrini, MD, Clinica Neurologica, Universit`a Politecnica delle Marche, Azienda OspedalieroUniversitaria Ospedali Riuniti, Via Conca 1, 60020 Ancona, Italy. Tel.: +39 071 596 4530; Fax: +39 071 887 262; E-mail: [email protected].
the changes seen in normal cognitive aging and those associated with dementia [1, 2]. The presumed clinical value of MCI is its ability to identify individuals that are at higher risk of dementia. Mild cognitive deficits usually emerge some years prior to a diagnosis of dementia, and higher rates of progression to dementia have been associated with a diagnosis of MCI [3]. Defining a role for factors involved in the modulation of the risk of progression from MCI to Alzheimer’s
ISSN 1387-2877/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved
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0) or with small subcortical focal lesions, defined as areas of high signal intensity on T2-weighted images but isointense with normal brain parenchyma on T1-weighted images (grade 1), were classified as “normal”, while those with a score >1 were considered as “pathologic”. Each patient underwent clinical history assessment, general and neurological physical examination, a complete blood sample collection for laboratory tests, and a cardiological evaluation with electrocardiogram. Moreover, we performed a standardized screening for vascular risk factor assessment including blood sample collection for laboratory tests. Neuropsychological evaluation A complete neuropsychological and neuropsychiatric battery (including the MMSE, the Mental Deterioration Battery, Trail Making A and B, Test of Judgment, and Neuropsychiatric Inventory) was performed.
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MATERIALS AND METHODS Study population
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disease (AD) would have important practical implications, especially as it would offer some targets of action to influence the progression of cognitive decline [4]. Although different studies have suggested that cerebrovascular impairment may have a role in increasing the risk of AD [5–7], there is scarce evidence that conventional treatment of common vascular risk factors can be a fully satisfactory approach to adequately counteract the risk of developing dementia [8]. Possible explanations to justify the apparent contradiction between the demonstration of a role of vascular factors in promoting cognitive decline and the lack of evidence that their treatment can support a beneficial effect can be searched in the different individual predisposition of developing vascular and degenerative cerebral damage or in the different individual response to ad hoc treatments [8, 9]. In this respect, the use of diagnostic approaches to assess vascular status, and then to supply information about the individual susceptibility to develop damage secondary to the exposition to vascular risk factors, has been suggested to identify subjects with increased risk of cognitive impairment progression [10]. In this study, we aimed to investigate the possibility to develop a tool based on the performance of noninvasive vascular tests, which is able to predict the risk of progression from MCI to dementia.
Patients were selected from consecutive subjects referred to our dementia outpatient services by general practitioners during a 2-year period. The only inclusion criterion was a diagnosis of amnesic MCI (aMCI) according to the National Institute on Aging and the Alzheimer’s Association diagnostic criteria [11] and to Petersen’s criteria [12]. We excluded all subjects with severe general or neurological conditions, major psychiatric pathologies, focal neurological signs at physical examination, clinical history of cerebrovascular disease or hearth diseases, basal score 1.5 mm measured from the media-adventitia interface to the intima-lumen interface [16]. The plaque degree was calculated in all arterial vessels. Carotid plaques were defined as a thickening over 1.2 mm not including the whole vessel surface. In each arterial segment, the plaque degree was quantified as follows: 0: no plaque, 1: one small plaque 50% of vessel diameter or multiple plaques with at least one medium plaque. The plaque index was calculated by adding the scores of the right and left carotid arteries [17]. Since there was a large dispersion of subjects in the different categories, the subjects were divided into two groups based on the plaque index (PI) value
Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-143135 IOS Press
3
roo f
2
Markers for the Risk of Progression from Mild Cognitive Impairment to Alzheimer’s Disease
or P
1
5
Laura Burattia , Simona Balestrinia , Claudia Altamurab , Giovanna Viticchia , Lorenzo Falsettic , Simona Luzzia , Leandro Provincialia , Fabrizio Vernierib and Mauro Silvestrinia,∗
6
a Neurological
7
b Neurology
8
Clinic, Marche Polytechnic University, Ancona, Italy Unit, Campus Bio-Medico University, Rome, Italy c Internal and Subintensive Medicine, Ospedali Riuniti Ancona, Italy
uth
4
9
Handling Associate Editor: Jack de la Torre
14 15 16 17 18 19 20 21 22 23 24 25 26
cte
13
rre
12
Abstract. Background: Defining reliable markers of conversion to dementia could be the first step in order to identify appropriate treatment strategies for mild cognitive impairment (MCI) patients. Objective: To develop a tool able to predict the risk of progression from MCI to Alzheimer’s disease (AD). Methods: 406 MCI patients were included and followed for a one-year period. Demographic characteristics, vascular risk factors, extent of cerebrovascular lesions, markers of carotid atherosclerosis investigated with an ultrasonographic assessment (plaque index and intima-media thickness) and cerebrovascular reactivity to apnea (breath-holding index) were considered as potential predictors of conversion. Results: 106 (26%) MCI patients showed a conversion to AD. Plaque index, intima-media thickness, and breath-holding index were relevant predictors of conversion (p = 0.042; p = 0.003; p < 0.001, multivariate logistic regression analysis). A simplified scoring system was devised based on the magnitude of the estimated multinomial logistic regression  coefficient results. A total score was calculated as the sum of each predictive factor which resulted in a 0–5 range. The optimal cut-off score was ≥3 (sensitivity, 23.6%, 95% CI 15.9%–32.8%; specificity, 97.7%, 95% CI 95.3%–99.1%; positive likelihood ratio, 10.1, 95% CI 4.5%–22.7%; negative likelihood ratio, 0.78, 95% CI 0.70%–0.87%). The AUC was 0.71 (95% CI, 0.65–0.77). Conclusions: Our findings show the possibility to obtain a predictive indicator of the risk of conversion from MCI to dementia by considering the presence of both atherosclerotic changes in the carotid district and impairment of cerebral hemodynamics. Such an approach may allow us to formulate a correct prognosis in more than 70% of patients with amnesic MCI.
co
11
Un
10
dA
Accepted 6 January 2015
28
Keywords: Alzheimer’s disease, atherosclerosis, carotid arteries, cerebral hemodynamics, mild cognitive impairment, ultrasonography
29
INTRODUCTION
27
30
Mild cognitive impairment (MCI) is regarded as the intermediate stage of cognitive impairment between ∗ Correspondence
to: Mauro Silvestrini, MD, Clinica Neurologica, Universit`a Politecnica delle Marche, Azienda OspedalieroUniversitaria Ospedali Riuniti, Via Conca 1, 60020 Ancona, Italy. Tel.: +39 071 596 4530; Fax: +39 071 887 262; E-mail: [email protected].
the changes seen in normal cognitive aging and those associated with dementia [1, 2]. The presumed clinical value of MCI is its ability to identify individuals that are at higher risk of dementia. Mild cognitive deficits usually emerge some years prior to a diagnosis of dementia, and higher rates of progression to dementia have been associated with a diagnosis of MCI [3]. Defining a role for factors involved in the modulation of the risk of progression from MCI to Alzheimer’s
ISSN 1387-2877/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved
31 32 33 34 35 36 37 38 39
47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66
67
68
69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88
roo f
46
or P
45
0) or with small subcortical focal lesions, defined as areas of high signal intensity on T2-weighted images but isointense with normal brain parenchyma on T1-weighted images (grade 1), were classified as “normal”, while those with a score >1 were considered as “pathologic”. Each patient underwent clinical history assessment, general and neurological physical examination, a complete blood sample collection for laboratory tests, and a cardiological evaluation with electrocardiogram. Moreover, we performed a standardized screening for vascular risk factor assessment including blood sample collection for laboratory tests. Neuropsychological evaluation A complete neuropsychological and neuropsychiatric battery (including the MMSE, the Mental Deterioration Battery, Trail Making A and B, Test of Judgment, and Neuropsychiatric Inventory) was performed.
dA
44
MATERIALS AND METHODS Study population
cte
43
rre
42
disease (AD) would have important practical implications, especially as it would offer some targets of action to influence the progression of cognitive decline [4]. Although different studies have suggested that cerebrovascular impairment may have a role in increasing the risk of AD [5–7], there is scarce evidence that conventional treatment of common vascular risk factors can be a fully satisfactory approach to adequately counteract the risk of developing dementia [8]. Possible explanations to justify the apparent contradiction between the demonstration of a role of vascular factors in promoting cognitive decline and the lack of evidence that their treatment can support a beneficial effect can be searched in the different individual predisposition of developing vascular and degenerative cerebral damage or in the different individual response to ad hoc treatments [8, 9]. In this respect, the use of diagnostic approaches to assess vascular status, and then to supply information about the individual susceptibility to develop damage secondary to the exposition to vascular risk factors, has been suggested to identify subjects with increased risk of cognitive impairment progression [10]. In this study, we aimed to investigate the possibility to develop a tool based on the performance of noninvasive vascular tests, which is able to predict the risk of progression from MCI to dementia.
Patients were selected from consecutive subjects referred to our dementia outpatient services by general practitioners during a 2-year period. The only inclusion criterion was a diagnosis of amnesic MCI (aMCI) according to the National Institute on Aging and the Alzheimer’s Association diagnostic criteria [11] and to Petersen’s criteria [12]. We excluded all subjects with severe general or neurological conditions, major psychiatric pathologies, focal neurological signs at physical examination, clinical history of cerebrovascular disease or hearth diseases, basal score 1.5 mm measured from the media-adventitia interface to the intima-lumen interface [16]. The plaque degree was calculated in all arterial vessels. Carotid plaques were defined as a thickening over 1.2 mm not including the whole vessel surface. In each arterial segment, the plaque degree was quantified as follows: 0: no plaque, 1: one small plaque 50% of vessel diameter or multiple plaques with at least one medium plaque. The plaque index was calculated by adding the scores of the right and left carotid arteries [17]. Since there was a large dispersion of subjects in the different categories, the subjects were divided into two groups based on the plaque index (PI) value
