Top

Published in:

Open Access 01-12-2015 | Research article

Exploring the effects of coexisting amyloid in subcortical vascular cognitive impairment

Authors: Elizabeth Dao, Ging-Yuek Robin Hsiung, Vesna Sossi, Claudia Jacova, Roger Tam, Katie Dinelle, John R. Best, Teresa Liu-Ambrose

Published in: BMC Neurology | Issue 1/2015

Abstract

Background

Mixed pathology, particularly Alzheimer’s disease with cerebrovascular lesions, is reported as the second most common cause of dementia. Research on mixed dementia typically includes people with a primary AD diagnosis and hence, little is known about the effects of co-existing amyloid pathology in people with vascular cognitive impairment (VCI). The purpose of this study was to understand whether individual differences in amyloid pathology might explain variations in cognitive impairment among individuals with clinical subcortical VCI (SVCI).

Methods

Twenty-two participants with SVCI completed an ¹¹C Pittsburgh compound B (PIB) position emission tomography (PET) scan to quantify global amyloid deposition. Cognitive function was measured using: 1) MOCA; 2) ADAS-Cog; 3) EXIT-25; and 4) specific executive processes including a) Digits Forward and Backwards Test, b) Stroop-Colour Word Test, and c) Trail Making Test. To assess the effect of amyloid deposition on cognitive function we conducted Pearson bivariate correlations to determine which cognitive measures to include in our regression models. Cognitive variables that were significantly correlated with PIB retention values were entered in a hierarchical multiple linear regression analysis to determine the unique effect of amyloid on cognitive function. We controlled for age, education, and ApoE ε4 status.

Results

Bivariate correlation results showed that PIB binding was significantly correlated with ADAS-Cog (p < 0.01) and MOCA (p < 0.01); increased PIB binding was associated with worse cognitive function on both cognitive measures. PIB binding was not significantly correlated with the EXIT-25 or with specific executive processes (p > 0.05).

Regression analyses controlling for age, education, and ApoE ε4 status indicated an independent association between PIB retention and the ADAS-Cog (adjusted R-square change of 15.0 %, Sig F Change = 0.03). PIB retention was also independently associated with MOCA scores (adjusted R-Square Change of 27.0 %, Sig F Change = 0.02).

Conclusion

We found that increased global amyloid deposition was significantly associated with greater memory and executive dysfunctions as measured by the ADAS-Cog and MOCA. Our findings point to the important role of co-existing amyloid deposition for cognitive function in those with a primary SVCI diagnosis. As such, therapeutic approaches targeting SVCI must consider the potential role of amyloid for the optimal care of those with mixed dementia.

Trial registration

NCT01027858

Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005;366(9503):2112–7. doi:10.1016/S0140-6736(05)67889-0.PubMedPubMedCentral

Dementia: a public health priority. World Health Organization. 2012.

Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature. 2004;430(7000):631–9. doi:10.1038/nature02621.PubMedPubMedCentral

Tulving E. Episodic memory: from mind to brain. Annu Rev Psychol. 2002;53:1–25. doi:10.1146/annurev.psych.53.100901.135114.PubMed

Moorhouse P, Rockwood K. Vascular cognitive impairment: current concepts and clinical developments. Lancet Neurol. 2008;7(3):246–55. doi:10.1016/S1474-4422(08)70040-1.PubMed

Erkinjuntti T. Subcortical ischemic vascular disease and dementia. Int Psychogeriatr. 2003;15 Suppl 1:23–6. doi:10.1017/S1041610203008925.PubMed

Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke. 2011;42(9):2672–713. doi:10.1161/STR.0b013e3182299496.PubMedPubMedCentral

Breteler MM, van Swieten JC, Bots ML, Grobbee DE, Claus JJ, van den Hout JH, et al. Cerebral white matter lesions, vascular risk factors, and cognitive function in a population-based study: the Rotterdam Study. Neurology. 1994;44(7):1246–52.PubMed

Jellinger KA, Attems J. Neuropathological evaluation of mixed dementia. J Neurol Sci. 2007;257(1–2):80–7. doi:10.1016/j.jns.2007.01.045.PubMed

10.

Kalaria RN. The role of cerebral ischemia in Alzheimer’s disease. Neurobiol Aging. 2000;21(2):321–30.PubMed

11.

Rockwood K, Macknight C, Wentzel C, Black S, Bouchard R, Gauthier S, et al. The diagnosis of “mixed” dementia in the Consortium for the Investigation of Vascular Impairment of Cognition (CIVIC). Ann N Y Acad Sci. 2000;903:522–8.PubMed

12.

Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69(24):2197–204. doi:10.1212/01.wnl.0000271090.28148.24.PubMed

13.

Zekry D, Hauw JJ, Gold G. Mixed dementia: epidemiology, diagnosis, and treatment. J Am Geriatr Soc. 2002;50(8):1431–8.PubMed

14.

Wang BW, Lu E, Mackenzie IR, Assaly M, Jacova C, Lee PE, et al. Multiple pathologies are common in Alzheimer patients in clinical trials. Can J Neurol Sci. 2012;39(5):592–9.PubMed

15.

Jellinger KA, Attems J. Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathol. 2010;119(4):421–33. doi:10.1007/s00401-010-0654-5.PubMed

16.

Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 2010;9(11):1118–27. doi:10.1016/S1474-4422(10)70223-4.PubMed

17.

Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD. Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer’s disease. Lancet. 1999;354(9182):919–20. doi:10.1016/S0140-6736(99)02355-7.PubMed

18.

Nagy Z, Esiri MM, Jobst KA, Morris JH, King EM, McDonald B, et al. The effects of additional pathology on the cognitive deficit in Alzheimer disease. J Neuropathol Exp Neurol. 1997;56(2):165–70.PubMed

19.

Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry. 1984;141(11):1356–64.PubMed

20.

Royall DR, Mahurin RK, Gray KF. Bedside assessment of executive cognitive impairment: the executive interview. J Am Geriatr Soc. 1992;40(12):1221–6.PubMed

21.

Koski L. Validity and applications of the Montreal cognitive assessment for the assessment of vascular cognitive impairment. Cerebrovasc Dis. 2013;36(1):6–18. doi:10.1159/000352051.PubMed

22.

O’Brien J, Lilienfeld S. Relevant clinical outcomes in probable vascular dementia and Alzheimer’s disease with cerebrovascular disease. J Neurol Sci. 2002;203–204:41–8.PubMed

23.

Mohs RC, Kawas C, Carrillo MC. Optimal design of clinical trials for drugs designed to slow the course of Alzheimer’s disease. Alzheimers Dement. 2006;2(3):131–9. doi:10.1016/j.jalz.2006.04.003.PubMed

24.

Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL, Black SE, et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke. 2006;37(9):2220–41. doi:10.1161/01.STR.0000237236.88823.47.PubMed

25.

Liu-Ambrose T, Eng JJ, Boyd LA, Jacova C, Davis JC, Bryan S, et al. Promotion of the mind through exercise (PROMoTE): a proof-of-concept randomized controlled trial of aerobic exercise training in older adults with vascular cognitive impairment. BMC Neurol. 2010;10:14. doi:10.1186/1471-2377-10-14.PubMedPubMedCentral

26.

Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695–9. doi:10.1111/j.1532-5415.2005.53221.x.PubMed

27.

Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–98.PubMed

28.

Sled JG, Zijdenbos AP, Evans AC. A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Trans Med Imaging. 1998;17(1):87–97. doi:10.1109/42.668698.PubMed

29.

Smith SMB JM. SUSAN-a new approach to low level image processing. Int J Comput Vis. 1997;23:1.

30.

Smith SM. Fast robust automated brain extraction. Hum Brain Mapp. 2002;17(3):143–55. doi:10.1002/hbm.10062.PubMed

31.

McAusland J, Tam R, Wong E, Riddehough A, Li D. Optimizing the Use of Radiologist Seed Points for Improved Multiple Sclerosis Lesion Segmentation. IEEE Trans Biomed Eng. 2010. doi:10.1109/TBME.2010.2055865.PubMed

32.

Parzen E. On estimation of a probability density function and mode. Ann Math Stat. 1962;33:1065–76.

33.

Lam B, Middleton LE, Masellis M, Stuss DT, Harry RD, Kiss A, et al. Criterion and convergent validity of the Montreal cognitive assessment with screening and standardized neuropsychological testing. J Am Geriatr Soc. 2013;61(12):2181–5. doi:10.1111/jgs.12541.PubMed

34.

Dong Y, Sharma VK, Chan BP, Venketasubramanian N, Teoh HL, Seet RC, et al. The Montreal Cognitive Assessment (MoCA) is superior to the Mini-Mental State Examination (MMSE) for the detection of vascular cognitive impairment after acute stroke. J Neurol Sci. 2010;299(1–2):15–8. doi:10.1016/j.jns.2010.08.051.PubMed

35.

Kirk A. Target symptoms and outcome measures: cognition. Can J Neurol Sci. 2007;34 Suppl 1:S42–6.PubMed

36.

Stokholm J, Vogel A, Gade A, Waldemar G. The executive interview as a screening test for executive dysfunction in patients with mild dementia. J Am Geriatr Soc. 2005;53(9):1577–81. doi:10.1111/j.1532-5415.2005.53470.x.PubMed

37.

Royall DR, Rauch R, Roman GC, Cordes JA, Polk MJ. Frontal MRI findings associated with impairment on the Executive Interview (EXIT25). Exp Aging Res. 2001;27(4):293–308. doi:10.1080/03610730109342350.PubMed

38.

Roman GC, Royall DR. Executive control function: a rational basis for the diagnosis of vascular dementia. Alzheimer Dis Assoc Disord. 1999;13 Suppl 3:S69–80.PubMed

39.

Royall DR, Chiodo LK, Polk MJ. Executive dyscontrol in normal aging: normative data, factor structure, and clinical correlates. Curr Neurol Neurosci Rep. 2003;3(6):487–93.PubMed

40.

Wechsler D. Wechsler adult intelligence scale. 4edth ed. New York: NCS Pearson; 2008.

41.

Trenerry M. Stroop neuropsychological screening test manual. Odessa, FL: Psychological Assessment Resources; 1989.

42.

Allen DN, Haderlie MM. Trail-making test. The Corsini Encyclopedia of Psychology: Wiley; 2010.

43.

Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007;27(9):1533–9. doi:10.1038/sj.jcbfm.9600493.PubMed

44.

Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab. 1996;16(5):834–40. doi:10.1097/00004647-199609000-00008.PubMed

45.

Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, et al. Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(−)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab. 1990;10(5):740–7. doi:10.1038/jcbfm.1990.127.PubMed

46.

Lopresti BJ, Klunk WE, Mathis CA, Hoge JA, Ziolko SK, Lu X, et al. Simplified quantification of Pittsburgh Compound B amyloid imaging PET studies: a comparative analysis. J Nucl Med. 2005;46(12):1959–72.PubMed

47.

Price JC, Klunk WE, Lopresti BJ, Lu X, Hoge JA, Ziolko SK, et al. Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B. J Cereb Blood Flow Metab. 2005;25(11):1528–47. doi:10.1038/sj.jcbfm.9600146.PubMed

48.

Collins DL, Neelin P, Peters TM, Evans AC. Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space. J Comput Assist Tomogr. 1994;18(2):192–205.PubMed

49.

Park JH, Seo SW, Kim C, Kim SH, Kim GH, Kim ST, et al. Effects of cerebrovascular disease and amyloid beta burden on cognition in subjects with subcortical vascular cognitive impairment. Neurobiol Aging. 2014;35(1):254–60. doi:10.1016/j.neurobiolaging.2013.06.026.PubMed

50.

Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008;65(11):1509–17. doi:10.1001/archneur.65.11.1509.PubMedPubMedCentral

51.

Jagust WJ, Bandy D, Chen K, Foster NL, Landau SM, Mathis CA, et al. The Alzheimer’s Disease Neuroimaging Initiative positron emission tomography core. Alzheimers Dement. 2010;6(3):221–9. doi:10.1016/j.jalz.2010.03.003.PubMedPubMedCentral

52.

Yaqub M, Tolboom N, Boellaard R, van Berckel BN, van Tilburg EW, Luurtsema G, et al. Simplified parametric methods for [11C] PIB studies. NeuroImage. 2008;42(1):76–86. doi:10.1016/j.neuroimage.2008.04.251.PubMed

53.

Hsiung GY, Sadovnick AD, Feldman H. Apolipoprotein E epsilon4 genotype as a risk factor for cognitive decline and dementia: data from the Canadian Study of Health and Aging. CMAJ. 2004;171(8):863–7. doi:10.1503/cmaj.1031789.PubMedPubMedCentral

54.

Doraiswamy PM, Sperling RA, Johnson K, Reiman EM, Wong TZ, Sabbagh MN, et al. Florbetapir F 18 amyloid PET and 36-month cognitive decline: a prospective multicenter study. Mol Psychiatry. 2014;19(9):1044–51. doi:10.1038/mp.2014.9.PubMedPubMedCentral

55.

Resnick SM, Sojkova J, Zhou Y, An Y, Ye W, Holt DP, et al. Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C] PiB. Neurology. 2010;74(10):807–15. doi:10.1212/WNL.0b013e3181d3e3e9.PubMedPubMedCentral

56.

Villemagne VL, Pike KE, Darby D, Maruff P, Savage G, Ng S, et al. Abeta deposits in older non-demented individuals with cognitive decline are indicative of preclinical Alzheimer’s disease. Neuropsychologia. 2008;46(6):1688–97. doi:10.1016/j.neuropsychologia.2008.02.008.PubMed

57.

Forsberg A, Engler H, Almkvist O, Blomquist G, Hagman G, Wall A, et al. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging. 2008;29(10):1456–65. doi:10.1016/j.neurobiolaging.2007.03.029.PubMed

58.

Pike KE, Savage G, Villemagne VL, Ng S, Moss SA, Maruff P, et al. Beta-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer’s disease. Brain. 2007;130(Pt 11):2837–44. doi:10.1093/brain/awm238.PubMed

59.

Okello A, Koivunen J, Edison P, Archer HA, Turkheimer FE, Nagren K, et al. Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study. Neurology. 2009;73(10):754–60. doi:10.1212/WNL.0b013e3181b23564.PubMedPubMedCentral

60.

Wolk DA, Price JC, Saxton JA, Snitz BE, James JA, Lopez OL, et al. Amyloid imaging in mild cognitive impairment subtypes. Ann Neurol. 2009;65(5):557–68. doi:10.1002/ana.21598.PubMedPubMedCentral

61.

Collette F, Van der Linden M, Salmon E. Executive dysfunction in Alzheimer’s disease. Cortex. 1999;35(1):57–72.PubMed

62.

Sgaramella TM, Borgo F, Mondini S, Pasini M, Toso V, Semenza C. Executive deficits appearing in the initial stage of Alzheimer’s disease. Brain Cogn. 2001;46(1–2):264–8.PubMed

63.

Gibbons LE, Carle AC, Mackin RS, Harvey D, Mukherjee S, Insel P, et al. A composite score for executive functioning, validated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants with baseline mild cognitive impairment. Brain Imaging Behav. 2012;6(4):517–27. doi:10.1007/s11682-012-9176-1.PubMedPubMedCentral

64.

Lee MJ, Seo SW, Na DL, Kim C, Park JH, Kim GH, et al. Synergistic effects of ischemia and beta-amyloid burden on cognitive decline in patients with subcortical vascular mild cognitive impairment. JAME Psychiatry. 2014;71(4):412–22. doi:10.1001/jamapsychiatry.2013.4506.

65.

Nordlund A, Rolstad S, Klang O, Edman A, Hansen S, Wallin A. Two-year outcome of MCI subtypes and aetiologies in the Goteborg MCI study. J Neurol Neurosurg Psychiatry. 2010;81(5):541–6. doi:10.1136/jnnp.2008.171066.PubMed

66.

Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch Neurol. 2004;61(3):378–84. doi:10.1001/archneur.61.3.378.PubMed

67.

Carmichael O, Schwarz C, Drucker D, Fletcher E, Harvey D, Beckett L, et al. Longitudinal changes in white matter disease and cognition in the first year of the Alzheimer disease neuroimaging initiative. Arch Neurol. 2010;67(11):1370–8. doi:10.1001/archneurol.2010.284.PubMedPubMedCentral

68.

Pasi M, Salvadori E, Poggesi A, Ciolli L, Del Bene A, Marini S, et al. White matter microstructural damage in small vessel disease is associated with Montreal Cognitive Assessment but not with mini mental state examination performances: Vascular Mild Cognitive Impairment Tuscany study. Stroke. 2015;46(1):262–4. doi:10.1161/STROKEAHA.114.007553.PubMed

69.

Van Petten C, Plante E, Davidson PS, Kuo TY, Bajuscak L, Glisky EL. Memory and executive function in older adults: relationships with temporal and prefrontal gray matter volumes and white matter hyperintensities. Neuropsychologia. 2004;42(10):1313–35. doi:10.1016/j.neuropsychologia.2004.02.009.PubMed

70.

Rolstad S, Berg AI, Eckerstrom C, Johansson B, Wallin A. Differential Impact of Neurofilament Light Subunit on Cognition and Functional Outcome in Memory Clinic Patients with and without Vascular Burden. J Alzheimers Dis. 2015;45(3):873–81. doi:10.3233/JAD-142694.PubMed

71.

Lee JH, Kim SH, Kim GH, Seo SW, Park HK, Oh SJ, et al. Identification of pure subcortical vascular dementia using 11C-Pittsburgh compound B. Neurology. 2011;77(1):18–25. doi:10.1212/WNL.0b013e318221acee.PubMed

Title: Exploring the effects of coexisting amyloid in subcortical vascular cognitive impairment
Authors: Elizabeth Dao
Ging-Yuek Robin Hsiung
Vesna Sossi
Claudia Jacova
Roger Tam
Katie Dinelle
John R. Best
Teresa Liu-Ambrose
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: BMC Neurology / Issue 1/2015
Electronic ISSN: 1471-2377
DOI: https://doi.org/10.1186/s12883-015-0459-1

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Exploring the effects of coexisting amyloid in subcortical vascular cognitive impairment

Abstract

Background

Methods

Results

Conclusion

Trial registration

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2015

A comparison of the brief international cognitive assessment for multiple sclerosis and the brief repeatable battery in multiple sclerosis patients

Asystole in the epilepsy unit

Singapore Tele-technology Aided Rehabilitation in Stroke (STARS) trial: protocol of a randomized clinical trial on tele-rehabilitation for stroke patients

When battery exhaustion lets the lame walk: a case report on the importance of long-term stimulator monitoring in deep brain stimulation

Migraine-specific quality of life questionnaire and relapse of medication overuse headache

Antibodies against phosphorylcholine are not altered in plasma of patients with Alzheimer’s disease