Neurobiol Lipids 5, 2 (26 December 2006) find out how to cite this article

Alexander Christov¹, Sally Jett², Kimberley Peck², Germaine Odenheimer², Elliott D. Ross², Paula Grammas³

¹ Dept. of Pathology, University of Oklahoma Health Science Center;
² The Center for Alzheimer's and Neurodegenerative Disorders, VA Medical Center, Oklahoma City, Oklahoma 73104;
³Garrison Institute on Aging,Texas Tech Health Sciences Center, Lubbock, Texas

Address and Correspondence: Paula Grammas, PhD, Texas Tech University Health Sciences Center, Garrison Institute on Aging
3601 4th Street  Stop 9424, Lubbock, Texas 79430

Email: paula.grammas@ttuhsc.edu, tel: (806) 743-3610, fax: (806) 743-3636

Submitted: 4 April 2006; Accepted: 28 September 2006; Published online: 26 December, 2006
Copyright © 2006 A Christov and colleagues, Licensee Neurobiology of Lipids

Article view and respond options:

GOOGLE SCHOLAR CITATION

DOAJ CITATION

FULL TEXT

ACROBAT .PDF

SUBMIT E-LETTER

CITED IN...

AUTHORPUBMED

ABSTRACT LAY ABSTRACT INTRODUCTION METHODS

RESULTS DISCUSSION ACKNOWLEDGEMENT WEB ENHANCED REFERENCES

Background: Mechanisms involved in the pathogenesis of cardiovascular disease appear to also be relevant for Alzheimer’s disease (AD). Reactive oxygen species (ROS) generation, which is altered in the AD brain, is also perturbed in platelets in AD. The objective of this study was to determine if impaired cognition is associated with hyperlipidemia, cardiovascular disease, or altered platelet function.

Methods: A retrospective clinical study that evaluated cognitive function, hyperlipidemia and cardiovascular disease in the elderly was performed. In addition, platelet characteristics  were compared among patients with normal and impaired cognitive function.

Results: Patients with hyperlipidemia or cardiovascular disease scored more poorly on  the Mini-Mental State Examination (MMSE) and on the Global Deterioration Scale than controls. MMSE scores correlated with platelet ROS levels and there was an association between platelet ROS levels and membrane fluidity.

Conclusions: These data suggest that impaired cognitive function is associated with  hyperlipidemia and altered platelet function.

Understanding the risk factors that contribute to the development of cognitive problems in the elderly is critical to developing preventative strategies as well as treatments for dementia. Recent reports suggest that risk factors associated with the development of heart disease, such as high blood lipids,  are also important for the development of Alzheimer’s disease (AD). Although the brain is the major organ affected by AD, research indicates that other cell types in the body show changes in this disease, and studying these more readily accessible cells could provide important information about  disease progression. In this study we examined medical records to evaluate cognitive function, blood lipids and cardiovascular disease in the elderly. In addition, we examined isolated blood cells (platelets) and analyzed their biochemical features. Our results show that patients with high blood lipids or cardiovascular disease scored more poorly on  two tests of brain cognitive function. Also, cognitive test scores correlated with changes in platelet characteristics. These data suggest that defining high blood lipids as a risk factor for dementia could lead to novel therapeutic approaches using dietary modifications.

Links between the development of cardiovascular disorders and cognitive impairment have been identified in an increasing number of clinical studies [1,2,3,4,5].  The clinical presentation of Alzheimer's disease (AD), which is the most common form of age-associated dementia, and vascular dementia can barely be differentiated at late life stages [6,7] and it has been suggested that these disorders co-exist resulting in “vascular cognitive impairment” [8].  Although AD is classified as a neurodegenerative dementia, there is epidemiological and pathological evidence of an association with vascular risk factors and vascular pathology [9,10,11,12,13]. The importance of cardiovascular disease as modifier of dementia expression is supported by results from the Nun study which concluded that cerebrovascular disease plays an important role in determining the presence and severity of clinical AD symptoms [14]. A recent study correlates vascular risk factors with the incidence of mild cognitive impairment (MCI) and its progression to dementia [15].

The idea that dietary lipids, long-linked to an increased risk of cardiovascular disease, could also play a role in the pathogenesis of AD has received support. In a cholesterol-fed rabbit model of human coronary heart disease there is production and accumulation of amyloid b (Ab) in the brain [9]. Removing cholesterol from the rabbits diet can reverse the accumulation of Ab and reductions of cholesterol produced by statins decrease production of Ab. Similarly, a high fat/ high cholesterol diet increases Ab deposition in a transgenic mouse model of AD amyloidosis [16]. In humans, a decreased prevalence of AD has been observed in patients on cholesterol-lowering statins [17]. Recent reports suggest that elevated total cholesterol in mid-life is a risk factor for the late-life development of AD [18,19].

Important pathogenic mechanisms are likely common to both Alzheimer’s and cardiovascular disease [20].  For example, oxidative stress appears to be a trigger in the complex chain of events leading to both atherosclerosis and AD. Numerous studies demonstrate markers of oxidative stress, such as protein carbonyls and 3-nitrotyrosine, in both the brains and CSF of AD patients [21,22,23]. We have shown that the brain microvasculature in AD patients has elevated levels of oxidized proteins [24]. Enhanced reactive oxygen species (ROS) production in aging or AD is not restricted to the brain, but can also been seen in several peripheral tissues. In this regard, enhanced ROS generation in lymphocytes from AD patients has been documented [25]. Indeed, AD-related changes are not confined to the CNS but also occur in peripheral cells, especially platelets [26].  There is a significant alteration of amyloid precursor protein (APP) forms in platelets isolated from AD patients compared to age-matched controls [27].  Platelet APP isoform ratios have been shown to correlate with declining cognitive function in AD. In addition, platelet activation and membrane fluidity are altered in platelets isolated from AD patients compared to control patients [28,29].

The objective of this study was to determine if impaired cognition is associated with hyperlipidemia, cardiovascular disease, or altered platelet function.

Retrospective assessment of medical records. A retrospective assessment of medical records of individuals at least 65 years of age was performed. Cognitive impairment had been evaluated in those individuals by both a neurologist and a nurse practitioner at the Center for Alzheimer's and Neurodegenerative Disorders, VA Medical Center, Oklahoma City between December, 2000 and June, 2003. The two tools utilized were the Folstein Mini-Mental State Examination (MMSE) test, to assess cognitive impairment and the Global Deterioration Scale (GDS) to determine the severity of dementia [30,31,32,33].  Patient records were also examined to determine plasma lipid profiles, blood pressure readings and history of cardiovascular disease.  Patients were defined as "hyperlipidemic" if the medical records indicated elevated total cholesterol (200 mg/dl), LDL cholesterol (129 mg/dl), or triglycerides (150 mg/dl), at the time or up to three years prior to their cognitive evaluation or if they were taking cholesterol lowering agents at the time of their cognitive evaluation. Controls in this study consisted of patients that were not on cholesterol-lowering agents and had normal blood lipid content.

The medical records of 167 patients were examined. Based on exclusion criteria (described below) 98 patients were excluded from analysis. Of the remaining 69 participants 98% were male. Fifty nine patients were identified as Caucasians, one as African American, one as Hispanic, one as Indian/Spanish. The race of seven remaining patients was not identified. For 67% of the patients the data used in the study were collected at their initial examination at the Center. Study participants presented with a spectrum of cognitive deficits. Among this group 16% were diagnosed with AD.  The remaining patients were examined at the Center after recommendation by a primary care provider or a relative (7%) because of complaints of memory loss (43%) or because of early symptoms of behavioral or cognitive problems not typical for AD, i.e. language decline, non-memory cognitive complaints, changes in comportment or personality, etc (34%).

The criteria for exclusion from participation in the study were: clinically diagnosed alcoholism, or consuming more than 14 drinks per week; cancer - internal malignancy or melanoma diagnosed within the past 5 years; any neurological disorder potentially associated with impaired cognitive performance including stroke (diagnosed clinically), multiple sclerosis, Parkinson's disease, serious head injury, brain surgery, brain cancer, Huntington's disease, normal pressure hydrocephalus, Down's syndrome, diffuse mental retardation, chronic psychosis, or epilepsy.

Collection of peripheral blood and cognitive assessment.  Peripheral blood samples were obtained from 19 patients (65-75 years of age, n = 5; >75 years of age, n = 14) at the time of their cognitive evaluation at the Center for Alzheimer's and Neurodegenerative Disorders, VA Medical Center, Oklahoma City. Cognitive assessments were performed as described above. Patients presented with a spectrum of cognitive deficits ranging from mild cognitive impairment to dementia.  Written informed consent was obtained. This study was reviewed and approved by the Institutional Review Board, University of Oklahoma Health Sciences Center.

Isolation of platelets. Two 4.5 ml blood samples were taken from each patient in Vacutainer evacuated blood collection tubes containing 0.5 ml 3.8% buffered citrate solution and platelets isolated as we have previously described [34]. Briefly, platelet-rich plasma (PRP) was obtained by centrifugation of blood samples at 180 x g for 20 min. The supernatant was collected using a Pasteur pipette without disturbing the leukocyte interface layer that separates plasma from red blood cell sediment and centrifuged again (180 x g for 20 min) to remove residual erythrocytes and leukocytes. Platelets were isolated from PRP by centrifugation at 3000 x g for 3 min, washed twice in HEPES buffer (pH 6.3) and resuspended in HEPES buffer (pH 7.4).

Detection of reactive oxygen species (ROS). ROS in the platelets were labeled with the fluorescent indicator 5-(and-6)-carboxy-2’,7’dichlorodihydrofluorescein (carboxy-H2DCFDA), as we have previously described [35]. Platelets were resuspended in HEPES buffer (pH 7.4) containing 300 mM carboxy-H2DCFDA followed by incubation for 1 h at 37⁰C in the dark. Fluorescence intensity of carboxy-H2DCFDA excited at 488 nm was measured using a FACS Calibur Automated Benchtop Flow Cytometer.

Measurement of membrane fluidity. 1,3-bis-(1-pyrenyl)propane (BPP) (Molecular Probes Inc., Eugene, OR, USA), an intramolecular excimer probe consisting of two pyrene moieties linked by a three-carbon alkyl spacer that dissolves readily in a membrane environment, was used as a fluorescent indicator of changes in membrane fluidity. Membrane fluidity was measured by determining the ratio between the maximum fluorescence emission intensity of the pyrene excimer and monomer forms. Fluorescence was excited at 325 nm, and the emission intensity at a 90⁰ angle to excitation light was measured using a  Perkin Elmer Luminescence Spectrometer LS50B, as we have previously described [34]. Excimer/monomer ratios (I_exc /I_mon ) were  calculated by dividing fluorescence emission intensity at 486 nm by that recorded at 376 nm after background noise subtraction. BPP, dissolved in ethanol (4x10^-5 M), was added to the platelet suspended in HEPES buffer (pH 7.4) at a final concentration of  8x10^-7 M, followed by incubation at 37⁰C for 18 h with gentle shaking. Excess dye was washed out at 3000 x g for 3 min and the labeled platelets resuspended in incubation buffer.

Statistical analysis.  To evaluate the effect of hyperlipidemia or cardiovascular disease on cognitive function, MMSE and GDS scores of patients from different groups were analyzed using chi-square test, analysis of variance (ANOVA) and Student’s t-test. To assess the hypothesis that cognitive function may be related to specific changes in platelet characteristics, correlation analysis was used to compare scores on the MMSE and GDS to values for platelet  ROS and membrane fluidity.

Hyperlipidemia affects MMSE and GDS scores. Among study participants with cognitive dysfunction, patients 65 to 75 years old with hyperlipidemia exhibited greater cognitive impairment compared to control patients with normal lipid levels.  Patients with hyperlipidemia showed significantly (p = 0.01, r²= 0.41) lower MMSE scores than patients with no hyperlipidemia (Figure 1A). We found no significant difference in MMSE scores between patients with high lipids levels (n=18) and controls (n=16) that were older than 75 years of age (Figure 1A).
 

FIGURE 1A Hyperlipidemia affects MMSE scores Note: you may need to resize your browser window for better figure view Hyperlipidemia affects MMSE scores. Cognitive function of study participants 65 to 75 years of age and patients older than 75 with normal blood lipids (controls) or hyperlipidemia (hyperlipidemic) was evaluated by MMSE (this panel) and GDS (Fig 1B). **p = 0.01.

The severity of dementia, as assessed by GDS scores, was worse in patients 65 to 75 years of age with hyperlipidemia, however, the statistical significance of the effect was borderline (p = 0.05). In addition, there was no effect of hyperlipidemia on GDS scores in patients over 75 years of age (Figure 1B). There was no correlation between elevated levels of individual blood lipid types (e.g. LDL, triglycerides) and cognitive impairment (data not shown).
 

FIGURE 1B Hyperlipidemia affects GDS scores Note: you may need to resize your browser window for better figure view Hyperlipidemia affects MMSE and GDS scores. Cognitive function of study participants 65 to 75 years of age and patients older than 75 with normal blood lipids (controls) or hyperlipidemia (hyperlipidemic) was evaluated by MMSE (Fig. 1A) and GDS (this panel). *p = 0.05.

Cognitive function is lower in the presence of cardiovascular disease. Analyzing our results based on the standard that an MMSE score of 23 points is the threshold for detection of cognitive impairment, we found that the degree of dementia, as assessed by the GDS score was significantly (p = 0.02, r²= 0.24) worse in patients 75 years of age or older in those with cardiovascular disorders compared to patients with no history of cardiovascular disease (Figure 2).
 

FIGURE 2 Cognitive function is lower in the presence of cardiovascular disease Note: you may need to resize your browser window for better figure view Cognitive function is lower in the presence of cardiovascular disease. Patients with impaired performance on MMSE (< 23) were divided into those with (CVD) and those without cardiovascular disease (no CVD) and the severity of dementia assessed by GDS. *p = 0.02.

Higher platelet ROS levels are associated with poor mental function. Platelets isolated at the time of the patient’s cognitive assessment were analyzed by flow cytometry to determine ROS levels. Our results indicated that higher ROS levels in platelets correlated significantly (p = 0.02, r = -0.54, r² = 0.29, n=14) with lower scores on the MMSE (Figure 3A). Also, we found a significant (p = 0.03, r = 0.53, r² = 0.28, n=13) correlation between the severity of dementia, assessed by GDS scores, and platelet ROS levels (Figure 3B).
 

FIGURE 3 Higher platelet ROS levels are associated with poor mental function Note: you may need to resize your browser window for better figure view Platelets isolated at the time of the patient’s cognitive assessment were analyzed by flow cytometry to determine ROS levels and correlated with MMSE scores (Panel A, above) (n = 14), *p = 0.02; and GDS scores (Panel B, below) (n = 13), *p = 0.03. Note: you may need to resize your browser window for better figure view

Platelet ROS levels and membrane fluidity correlate. Surface membrane fluidity, an indicator of platelet activation, was examined by the pyrene excimer-to-monomer fluorescence ratio method. The results showed a statistically significant negative correlation (p = 0.03, r = -0.43, r² = 0.18, n=19) between increased ROS levels and platelet membrane fluidity (Figure 4).
 

FIGURE 4 Platelet ROS levels and membrane fluidity correlate Note: you may need to resize your browser window for better figure view Platelet ROS levels and membrane fluidity correlate. Correlation analysis between platelet surface membrane fluidity (Iexc/Imon) and intracellular ROS levels (mean H2DCF-fluorescence intensity per cell) was performed. *p = 0.03, r = -0.43, r2 = 0.18, n=19.

Data from animal studies support the idea that hyperlipidemia affects AD-like pathology. Using diet-induced hypercholesterolemia in rabbits, several groups have shown an increase in Ab and apolipoprotein E levels as well as microglial activation in the temporal cortex and frontal cortex of hyperlipidemic rabbits but not in controls [9,36,37,38]. In humans, emerging data suggest that elevated total cholesterol, especially in mid-life, is a risk factor for the late-life development of AD [18,19]. The idea that age may modulate the effects of hyperlipidemia may explain disparate reports where correlations between hypercholesterolemia and AD have been found by some groups but not by others [39,40]. In the current study, we detected an age-dependent effect of hyperlipidemia. While patients 65 to 75 years of age with hyperlipidemia showed significantly lower MMSE scores and higher severity of dementia compared to patients with normal lipid levels, there were no differences between hyperlipidemic patients and those with normal lipid values in these cognitive parameters among patients older than 75 years of age.  Although, no correlation between the elevated level of a specific type of circulating lipids and the level of cognitive impairment was detected, the data presented in this paper suggest that hyperlipidemia contributes to the development of cognitive impairment and underscore hyperlipidemia as a modifiable risk factor for the development of dementia.

In addition to hyperlipidemia, cardiovascular disease has been implicated as an independent risk factor for AD. There is epidemiological and pathological evidence of an association with vascular risk factors and vascular pathology [1,10,11,12]. Several studies have documented high blood pressure and hyperhomocysteineimia as risk factors for dementia [41,42,43,44]. In animal studies, activation of microglia in the brains of humans with heart disease has been documented [38]. Snowdon et al. [14] indicate that cerebrovascular disease plays an important role in determining the presence and severity of clinical AD symptoms. Our results showing a relationship between poor GDS scores and a history of cardiovascular disease support the idea that cardiovascular disease contributes to cognitive decline.

Recent studies have suggested that AD-related changes occur in circulating platelets [26,27,28,29]. In the current study, we demonstrate a significant correlation between MMSE scores and platelet ROS levels. Platelet ROS levels are also associated with  dementia and platelet membrane fluidity. A link between hyperlipidemia and platelet APP metabolism has been reported [27]. In a group of AD patients that are matched for disease severity those with high cholesterol levels show lower APP ratios compared to AD patients with normal cholesterol levels. These findings confirm the association between cholesterol and AD, and suggest that in vivo cholesterol directly affects APP processing. Altered patterns of APP forms have been suggested as predictive of cognitive decline in AD patients [45]. Abnormalities in oxidative processes and excessive oxidative stress, hallmark features of the AD brain, have also been shown to occur in peripheral cells including lymphocytes and platelets [25,26]. These abnormalities in oxidative processes occur in early stages of AD, which suggests that the deficits are not just secondary to the neurodegeneration. Mitochondrial cytochrome c oxidase activity is significantly reduced in both the brain and in platelets from AD patients compared to controls [46]. Our results showing a correlation between elevated platelet levels of ROS and impaired cognitive function support the idea that oxidative changes in platelets are associated with AD pathology.

Sources of support: This work was supported in part by grants from the National Institutes of Health (AG15964), National Institutes of Health (AG 020569), the Alzheimer's Association and the Presbyterian Health Foundation.  Dr. Grammas is the recipient of the Shirley and Mildred Garrison Chair in Aging. The authors gratefully acknowledge the secretarial assistance of Melanie Beery and Terri Stahl.

1. de la Torre JC.  Alzheimer disease as a vascular disorder: nosological evidence. Stroke. 33, 1152-1162 (2002) [ PubMed ][ Related article ][ Back2Text ].

2. Kang JH, Logroscino G, De Vivo I, Hunter D, Grodstein F. Apolipoprotein E, cardiovascular disease and cognitive function in aging women. Neurobiol Aging. 26, 475-484 (2005) [ PubMed ][ Back2Text ].

3. Chen M, Fernandez HL. Alzheimer movement re-examined 25 years later: is it a "disease" or a senile condition in medical nature? Front Biosci.6, E30-E40 (2001) [ PubMed ][ Back2Text ].

4. Gauthier S, Ferris S. Outcome measures for probable vascular dementia and Alzheimer's disease with cerebrovascular disease. Int J Clin Pract. 120, 29-39 (2001) [ PubMed ][ Back2Text ].

5. Erkinjuntti T. Clinical deficits of Alzheimer's disease with cerebrovascular disease and probable VaD. Int J Clin Pract.  120, 14-23 (2001) [ PubMed ][ Back2Text ].

6. Blauw GJ, Bollen EL, van Buchem MA, Westendorp RG. Dementia at old age: a clinical end-point of atherosclerotic disease. Eur Heart J. 3, N16-N19 (2001) [ PubMed ][ Back2Text ].

7. Stewart R. Vascular dementia: a diagnosis running out of time. Br J Psychiatry. 180, 152-156 (2002) [ PubMed ][ Back2Text ].

8. Haring HP. Cognitive impairment after stroke. Curr Opin Neurol. 15, 79-84 (2002) [ PubMed ][ Back2Text ].

9. Sparks DL, Martin TA, Gross DR, Hunsaker JC 3rd.  Link between heart disease, cholesterol, and Alzheimer’s disease: a review. Microsc Res Tech.50, 287-290 (2000) [ PubMed ][ Back2Text ].

10. Stewart R, Prince M, Mann A. Vascular risk factors and Alzheimer’s disease. Aust N Z J Psychiatry. 33, 809-813 (1999) [ PubMed ][ Back2Text ].

11. Schmidt R, Schmidt H, Fazekas F. Vascular risk factors in dementia. J Neurol. 247, 81-87 (2000) [ PubMed ][ Back2Text ].

12. Shi J, Perry G, Smith MA, Friedland RP. Vascular abnormalities: the insidious pathogenesis of Alzheimer’s disease. Neurobiol Aging. 21, 357-361 (2000) [ PubMed ][ Back2Text ].

13. Pansari K, Gupta A, Thomas P. Alzheimer’s disease and vascular factors: facts and theories. Int J Clin Pract. 56, 197-203 (2002) [ PubMed ][ Back2Text ].

14. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA.277, 813-817 (1997) [ PubMed ][ Back2Text ].

15. Panza F, Solfrizzi V, Colacicco AM, D’Introno A, Capurso C, Palasciano R, et al. Cerebrovascular disease in the elderly: lipoprotein metabolism and cognitive decline. Aging Clin Exp Res. 18, 144-148 (2006) [ PubMed ][ Back2Text ].

16. Refolo LM, Pappolla MA, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, et al. Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis. 7, 321-331 (2000) [ PubMed ][ Related NoL records ][ Related articles at PubMed ][ Back2Text ].

17. Wolozin B, Kellman W, Ruosseau P, Celesia GC, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arch Neurol. 57, 1439-1443 (2000) [ PubMed ][ Back2Text ].

18. Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, et al. Apoliprotein E epsilon 4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med. 137, 149-155 (2002) [ PubMed ][ Back2Text ].

19. Laitinen MH, Ngandu T, Rovio S, Helkala EL, Uusitalo U, Viitanen M, et al. Fat intake at midlife and risk of dementia and Alzheimer’s disease: a population-based study. Dement Geriatr Cogn Disord. 22, 99-107 (2006) [ PubMed ][ Back2Text ].

20. Sparks DL, Kuo YM, Roher A, Martin T, Lukas RJ. Alterations of Alzheimer’s disease in the cholesterol-fed rabbit including vascular inflammation. Preliminary observations. Ann NY Acad Sci. 903, 335-344 (2000) [ PubMed ][ Back2Text ].

21. Aksenov MY, Aksenova MV, Butterfield DA, Geddes JW, Markesbery WR. Protein oxidation in the brain in Alzheimer’s disease. Neuroscience. 103, 373-383 (2001) [ PubMed ][ Back2Text ].

22. Lovell MA, Markesbery WR. Ratio of 8-hydroxyguanine in intact DNA to free 8-hydroxyguanine is increased in Alzheimer disease ventricular cerebrospinal fluid. Arch Neurol. 58, 392-396 (2001) [ PubMed ][ Back2Text ].

23. Butterfield DA, Perluigi M, Sultana R. Oxidative stress in Alzheimer’s disease brain: New insights from redox proteomics. Eur J Pharmacol. 545, 39-50 (2002) [ PubMed ][ Back2Text ].

24. Hensley K, Williamson K, Maidt ML, Gabbita P, Grammas P, Floyd RA. Determination of biological oxidative stress using high performance liquid chromatography with electrochemical detection (HPLC-ECD). J High Resol Chromatogr.22, 429-437 (1999) [ Back2Text ].

25. Leutner S, Schindowski K, Frolich L, Maurer K, Kratzch T, Eckert A, et al. Enhanced ROS-generation in lymphocytes from Alzheimer’s patients. Pharmacopsychiatry. 38, 312-315 (1999) [ PubMed ][ Back2Text ].

26. Gibson GE, Huang HM. Oxidative processes in brain and non-neuronal tissues as biomarkers of Alzheimer's disease. Front Biosci. 7, d1007-1015 (2005); Gibson GE, Huang HM. Oxidative stress in Alzheimer's disease. Neurobiol Aging. 26, 575-578 (2005) [ PubMed ][ Back2Text ].

27. Borroni B, Colciaghi F, Pastorino L, Pettenati C, Cottini E, Rozzini L, et al. Amyloid precursor protein in platelets of patients with Alzheimer disease: effect of acetylcholinesterase inhibitor treatment. Arch Neurol. 58, 442-446 (2001) [ PubMed ][ Back2Text ].

28. Sevush S, Jy W, Horstman LL, Mao WW, Kolodny L, Ahn YS et al. Platelet activation in Alzheimer disease. Arch Neurol. 55, 530-536 (1998) [ PubMed ][ Back2Text ].

29. Kozubski W, Swiderek M, Kloszewska I, Gwozdzinski K, Watala C. Blood platelet membrane fluidity and the exposition of membrane protein receptors in Alzheimer disease (AD) patients - preliminary Study. Alzheimer Dis Assoc Disord. 16, 52-54 (2002) [ PubMed ][ Back2Text ].

30. Farina E, Fioravanti R, Chiavari L, Imbornone E, Alberoni M, Pomati S, et al. Comparing two programs of cognitive training in Alzheimer's disease: a pilot study. Acta Neurol Scand. 105, 365-371 (2004) [ PubMed ][ Back2Text ].

31. Tabert MH, Albert SM, Borukhova-Milov L, Camacho Y, Pelton G, Liu X, et al. Functional deficits in patients with mild cognitive impairment: prediction of AD. Neurology. 58, 758-764 (2004) [ PubMed ][ Back2Text ].

32. Tekin S, Fairbanks LA, O'Connor S, Rosenberg S, Cummings JL. Activities of daily living in Alzheimer's disease: neuropsychiatric, cognitive, and medical illness influences. Am J Geriatr Psychiatry. 9, 81-86 (2001) [ PubMed ][ Back2Text ].

33. Harwood DG, Barker WW, Ownby RL, Mullan M, Duara R.  Apolipoprotein E genotype and cognitive impairment in community-dwelling black older adults. Int J Psychiatry Med. 32, 55-67 (2002) [ PubMed ][ Back2Text ].

34. Christov A, Kostuk WJ, Jablonsky G, Lucas A.  Fluorescence spectroscopic analysis of circulating platelet activation during coronary angioplasty. Lasers Surg Med. 28, 414-426 (2001) [ PubMed ][ Back2Text ].

35. Hamdheydari L, Christov A, Ottman T, Hensley K, Grammas P.  Oxidized LDLs affect nitric oxide and radical generation in brain endothelial cells. Biochem Biophys Res Commun. 31, 486-490 (2003) [ PubMed ][ Back2Text ].

36. Wu CW, Liao PC, Lin C, Kuo CJ, Chen ST, Chen HI, et al.  Brain region-dependent increases in beta-amyloid and apolipoprotien E levels in hypercholesterolemic rabbits. J Neural Transm. 110, 641-649 (2003) [ PubMed ][ Back2Text ].

37. Shie FS, Jin LW, Cook DG, Leverenz JB, LeBoeuf RC.  Diet-induced hypercholesterolemia enhances brain A beta accumulation in transgenic mice. Neuroreport. 13, 455-459 (2002) [ PubMed ][ Back2Text ].

38. Streit WJ, Sparks DL.  Activation of microglia in the brains of humans with heart disease and hypercholesterolemic rabbits. J Mol Med. 75, 130-138 (1997) [ PubMed ][ Back2Text ].

39. Evans RM, Hui S, Perkins A, Lahiri DK, Poirier J, Farlow MR et al.  Cholesterol and APOE genotype interact to influence Alzheimer’s disease progression. Neurology. 62, 1869-1871 (2004) [ PubMed ][ Back2Text ].

40. Tan ZS, Seshadri S, Beiser A, Wilson PW, Kiel DP, Tocco M, et al.  Plasma total cholesterol level as a risk factor for Alzheimer disease: the Framingham Study. Arch Intern Med. 163, 1053-1057 (2003) [ PubMed ][ Back2Text ].

41. Launer LJ, Masaki K, Petrovitch H, Foley D, Havlik RJ. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. JAMA. 274, 1846-1851 (1995) [ PubMed ][ Back2Text ].

42. Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L, et al. 15-year longitudinal study of blood pressure and dementia. Lancet. 347, 1141-1145 (1996) [ PubMed ][ Back2Text ].

43. Diaz-Arrastia R. Hyperhomocysteinemia: a new risk factor for Alzheimer’s disease? Arch Neurol. 55, 1407-1408 (1998) [ PubMed ][ Back2Text ].

44. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 346, 476-483 (2002) [ PubMed ][ Back2Text ].

45. Borroni B, Colciaghi F, Archetti S, Marcello E, Caimi L, Di Luca M, et al. Predicting cognitive decline in Alzheimer disease. Role of platelet amyloid precursor protein. Alzheimer Dis Assoc Disord. 18, 32-34 (1999) [ PubMed ][ Back2Text ].

46. Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi EA, et al. Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer’s disease. Neurobiol Aging. 23, 371-376 (2002) [ PubMed ][ Back2Text ].
 

CLICK HERE OR PRESS <CTRL><D> TO BOOKMARK THIS ARTICLE

SEARCH PUBMED FOR RELATED ARTICLES

This article should be cited in the following way: Christov A, Jett S, Peck K, Odenheimer G, Ross ED, Grammas P. Is there a link between cognitive impairment and cardiovascular disorders in elderly? Neurobiol. Lipids  Vol. 5, 2 (26 December 2006) Freely available at: http://neurobiologyoflipids.org/content/5/2/ ( Provide web address when citing this paper ) Please note: Because Neurobiology of Lipids is published online only, the articles should be cited with an article number rather than with traditional (printed) page numbers. Acrobat (.PDF) reprints of NoL article, however,  serve the algorithmic needs of tenure committees to count published print pages.

This article has been cited by other articles: To have your contribution listed here, cite this Neurobiology of Lipids article in your next manuscript submission. Find out how to cite this article .