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Anxiety is related to Alzheimer cerebrospinal fluid markers in subjects with mild cognitive impairment

Published online by Cambridge University Press:  07 September 2012

I. H. G. B. Ramakers ,
F. R. J. Verhey ,
P. Scheltens ,
H. Hampel ,
H. Soininen ,
P. Aalten ,
M. Olde Rikkert ,
M. M. Verbeek ,
L. Spiru  and
K. Blennow
...Show all authors
I. H. G. B. Ramakers*
Affiliation:
Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, The Netherlands
F. R. J. Verhey
Affiliation:
Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, The Netherlands
P. Scheltens
Affiliation:
Department of Neurology, Alzheimer Center, VU Medical Center, Amsterdam, The Netherlands
H. Hampel
Affiliation:
Department of Psychiatry, Psychosomatic Medicine, and Psychotherapy, University of Frankfurt, Frankfurt am Main, Germany
H. Soininen
Affiliation:
Department of Neurology, University and University Hospital of Kuopio, Kuopio, Finland
P. Aalten
Affiliation:
Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, The Netherlands
M. Olde Rikkert
Affiliation:
Department of Geriatrics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
M. M. Verbeek
Affiliation:
Department of Neurology and Laboratory Medicine, Alzheimer Center Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
L. Spiru
Affiliation:
‘Carol Davila’ University of Medicine and Pharmacy, Bucharest, Romania
K. Blennow
Affiliation:
Clinical Neurochemistry Laboratory, Göteborg University, Sahlgren's University Hospital, Mölndal, Sweden
J. Q. Trojanowski
Affiliation:
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
L. M. Shaw
Affiliation:
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
P. J. Visser
Affiliation:
Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, The Netherlands Department of Neurology, Alzheimer Center, VU Medical Center, Amsterdam, The Netherlands
*
*Address for correspondence: I. H. G. B. Ramakers, Ph.D., Maastricht University, Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience, PO Box 616, 6200 MD Maastricht, The Netherlands. (Email: i.ramakers@maastrichtuniversity.nl)
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Abstract

Background

Anxiety, apathy and depression are common in subjects with mild cognitive impairment (MCI) and may herald Alzheimer's disease (AD). We investigated whether these symptoms correlated with cerebrospinal fluid (CSF) markers for AD in subjects with MCI.

Method

Subjects with MCI (n=268) were selected from the ‘Development of screening guidelines and criteria for pre-dementia Alzheimer's disease’ (DESCRIPA) and Alzheimer's Disease Neuroimaging Initiative (ADNI) studies. We measured amyloid β(1-42) protein (Aβ42) and total tau (t-tau) in CSF. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory.

Results

Depressive symptoms were reported by 55 subjects (21%), anxiety by 35 subjects (13%) and apathy by 49 subjects (18%). The presence of anxiety was associated with abnormal CSF Aβ42 [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.6–3.3] and t-tau (OR 2.6, 95% CI 1.9–3.6) concentrations and with the combination of abnormal concentrations of both Aβ42 and t-tau (OR 3.1, 95% CI 2.0–4.7). The presence of agitation and irritability was associated with abnormal concentrations of Aβ42 (agitation: OR 1.6, 95% CI 1.1–2.3; irritability: OR 2.2, 95% CI 1.5–3.3). Symptoms of depression and apathy were not related to any of the CSF markers.

Conclusions

In subjects with MCI, symptoms of anxiety, agitation and irritability may reflect underlying AD pathology, whereas symptoms of depression and apathy do not.

Keywords

Alzheimer's diseaseanxietyapathybiomarkerscerebrospinal fluiddepressionmild cognitive impairmentneuropsychiatric symptoms
Type
Original Articles
Information
Psychological Medicine , Volume 43 , Issue 5 , May 2013 , pp. 911 - 920
Copyright
Copyright © Cambridge University Press 2012

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References

Aisen, PS, Petersen, RC, Donohue, MC, Gamst, A, Raman, R, Thomas, RG, Walter, S, Trojanowski, JQ, Shaw, LM, Beckett, LA, Jack, CR Jr., Jagust, W, Toga, AW, Saykin, AJ, Morris, JC, Green, RC, Weiner, MW (2010). Clinical Core of the Alzheimer's Disease Neuroimaging Initiative: progress and plans. Alzheimer's and Dementia 6, 239–246.CrossRefGoogle Scholar
Andreasen, N, Hesse, C, Davidsson, P, Minthon, L, Wallin, A, Winblad, B, Vanderstichele, H, Vanmechelen, E, Blennow, K (1999). Cerebrospinal fluid β-amyloid(1–42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease. Archives of Neurology 56, 673–680.CrossRefGoogle ScholarPubMed
APA (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn, revised. American Psychiatric Association: Washington, DC.Google Scholar
Apostolova, LG, Cummings, JL (2007). Neuropsychiatric manifestations in mild cognitive impairment: a systematic review of the literature. Dementia and Other Geriatric Cognitive Disorders 25, 115–126.CrossRefGoogle ScholarPubMed
Barnes, LL, Schneider, JA, Boyle, PA, Bienias, JL, Bennett, DA (2006). Memory complaints are related to Alzheimer disease pathology in older persons. Neurology 67, 1581–1585.CrossRefGoogle ScholarPubMed
Berlow, YA, Wells, WM, Ellison, JM, Sung, YH, Renshaw, PF, Harper, DG (2010). Neuropsychiatric correlates of white matter hyperintensities in Alzheimer's disease. International Journal of Geriatric Psychiatry 25, 780–788.CrossRefGoogle ScholarPubMed
Buerger, K, Ewers, M, Pirttila, T, Zinkowski, R, Alafuzoff, I, Teipel, SJ, DeBernardis, J, Kerkman, D, McCulloch, C, Soininen, H, Hampel, H (2006). CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease. Brain 129, 3035–3041.CrossRefGoogle ScholarPubMed
Cummings, JL, Mega, M, Gray, K, Rosenberg-Thompson, S, Carusi, DA, Gornbein, J (1994). The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 44, 2308–2314.CrossRefGoogle ScholarPubMed
DeKosky, ST (2008). Taking the next steps in the diagnosis of Alzheimer's disease: the use of biomarkers. CNS Spectrums 13, 7–10.CrossRefGoogle ScholarPubMed
Devier, DJ, Pelton, GH, Tabert, MH, Liu, X, Cuasay, K, Eisenstadt, R, Marder, K, Stern, Y, Devanand, DP (2009). The impact of anxiety on conversion from mild cognitive impairment to Alzheimer's disease. International Journal of Geriatric Psychiatry 24, 1335–1342.CrossRefGoogle ScholarPubMed
Engelborghs, S, Maertens, K, Vloeberghs, E, Aerts, T, Somers, N, Marien, P, De Deyn, PP (2006). Neuropsychological and behavioural correlates of CSF biomarkers in dementia. Neurochemistry International 48, 286–295.CrossRefGoogle ScholarPubMed
Fagan, AM, Shaw, LM, Xiong, C, Vanderstichele, H, Mintun, MA, Trojanowski, JQ, Coart, E, Morris, JC, Holtzman, DM (2011). Comparison of analytical platforms for cerebrospinal fluid measures of Aβ1–42, total tau, and p-tau181 for identifying Alzheimer's disease amyloid plaque pathology. Archives of Neurology 68, 1137–1144.CrossRefGoogle ScholarPubMed
Feldman, HH, Ferris, S, Winblad, B, Sfikas, N, Mancione, L, He, Y, Tekin, S, Burns, A, Cummings, J, del Ser, T, Inzitari, D, Orgogozo, JM, Sauer, H, Scheltens, P, Scarpini, E, Herrmann, N, Farlow, M, Potkin, S, Charles, HC, Fox, NC, Lane, R (2007). Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study. Lancet Neurology 6, 501–512.CrossRefGoogle ScholarPubMed
Folstein, MF, Folstein, SE, McHugh, PR (1975). ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 12, 189–198.CrossRefGoogle Scholar
Gabryelewicz, T, Styczynska, M, Luczywek, E, Barczak, A, Pfeffer, A, Androsiuk, W, Chodakowska-Zebrowska, M, Wasiak, B, Peplonska, B, Barcikowska, M (2007). The rate of conversion of mild cognitive impairment to dementia: predictive role of depression. International Journal of Geriatric Psychiatry 22, 563–567.CrossRefGoogle ScholarPubMed
Geda, YE, Roberts, RO, Knopman, DS, Petersen, RC, Christianson, TJ, Pankratz, VS, Smith, GE, Boeve, BF, Ivnik, RJ, Tangalos, EG, Rocca, WA (2008). Prevalence of neuropsychiatric symptoms in mild cognitive impairment and normal cognitive aging: population-based study. Archives of General Psychiatry 65, 1193–1198.CrossRefGoogle ScholarPubMed
Gudmundsson, P, Skoog, I, Waern, M, Blennow, K, Palsson, S, Rosengren, L, Gustafson, D (2007). The relationship between cerebrospinal fluid biomarkers and depression in elderly women. American Journal of Geriatric Psychiatry 15, 832–838.CrossRefGoogle ScholarPubMed
Hansson, O, Zetterberg, H, Buchhave, P, Londos, E, Blennow, K, Minthon, L (2006). Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurology 5, 228–234.CrossRefGoogle ScholarPubMed
Lanari, A, Amenta, F, Silvestrelli, G, Tomassoni, D, Parnetti, L (2006). Neurotransmitter deficits in behavioural and psychological symptoms of Alzheimer's disease. Mechanisms of Ageing Development 127, 158–165.CrossRefGoogle ScholarPubMed
Landes, AM, Sperry, SD, Strauss, ME, Geldmacher, DS (2001). Apathy in Alzheimer's disease. Journal of the American Geriatric Society 49, 1700–1707.CrossRefGoogle ScholarPubMed
Lyketsos, CG, Lopez, O, Jones, B, Fitzpatrick, AL, Breitner, J, DeKosky, S (2002). Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the Cardiovascular Health Study. JAMA 288, 1475–1483.CrossRefGoogle ScholarPubMed
Mattsson, N, Zetterberg, H, Hansson, O, Andreasen, N, Parnetti, L, Jonsson, M, Herukka, SK, van der Flier, WM, Blankenstein, MA, Ewers, M, Rich, K, Kaiser, E, Verbeek, M, Tsolaki, M, Mulugeta, E, Rosen, E, Aarsland, D, Visser, PJ, Schroder, J, Marcusson, J, de Leon, M, Hampel, H, Scheltens, P, Pirttila, T, Wallin, A, Jonhagen, ME, Minthon, L, Winblad, B, Blennow, K (2009). CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 302, 385–393.CrossRefGoogle ScholarPubMed
Modrego, PJ, Ferrandez, J (2004). Depression in patients with mild cognitive impairment increases the risk of developing dementia of Alzheimer type: a prospective cohort study. Archives of Neurology 61, 1290–1293.CrossRefGoogle ScholarPubMed
Mueller, SG, Weiner, MW, Thal, LJ, Petersen, RC, Jack, C, Jagust, W, Trojanowski, JQ, Toga, AW, Beckett, L (2005). The Alzheimer's disease neuroimaging initiative. Neuroimaging Clinics of North America 15, xi–xii.CrossRefGoogle ScholarPubMed
Olsson, A, Vanderstichele, H, Andreasen, N, De Meyer, G, Wallin, A, Holmberg, B, Rosengren, L, Vanmechelen, E, Blennow, K (2005). Simultaneous measurement of β-amyloid(1–42), total tau, and phosphorylated tau (Thr181) in cerebrospinal fluid by the xMAP technology. Clinical Chemistry 51, 336–345.CrossRefGoogle ScholarPubMed
Palmer, K, Berger, AK, Monastero, R, Winblad, B, Backman, L, Fratiglioni, L (2007). Predictors of progression from mild cognitive impairment to Alzheimer disease. Neurology 68, 1596–1602.CrossRefGoogle ScholarPubMed
Palmer, K, Di Iulio, F, Varsi, AE, Gianni, W, Sancesario, G, Caltagirone, C, Spalletta, G (2010). Neuropsychiatric predictors of progression from amnestic-mild cognitive impairment to Alzheimer's disease: the role of depression and apathy. Journal of Alzheimer's Disease 20, 175–183.CrossRefGoogle ScholarPubMed
Ramakers, IH, Visser, PJ, Aalten, P, Kester, A, Jolles, J, Verhey, FR (2010). Affective symptoms as predictors of Alzheimer's disease in subjects with mild cognitive impairment: a 10-year follow-up study. Psychological Medicine 40, 1193–1201.CrossRefGoogle ScholarPubMed
Reijn, TS, Rikkert, MO, van Geel, WJ, de Jong, D, Verbeek, MM (2007). Diagnostic accuracy of ELISA and xMAP technology for analysis of amyloid β42 and tau proteins. Clinical Chemistry 53, 859–865.CrossRefGoogle ScholarPubMed
Robert, PH, Berr, C, Volteau, M, Bertogliati, C, Benoit, M, Sarazin, M, Legrain, S, Dubois, B (2006). Apathy in patients with mild cognitive impairment and the risk of developing dementia of Alzheimer's disease: a one-year follow-up study. Clinical Neurology and Neurosurgery 108, 733–736.CrossRefGoogle ScholarPubMed
Rozzini, L, Chilovi, BV, Trabucchi, M, Padovani, A (2005). Depression is unrelated to conversion to dementia in patients with mild cognitive impairment. Archives of Neurology 62, 505.CrossRefGoogle ScholarPubMed
Schmand, B, Jonker, C, Hooijer, C, Lindeboom, J (1996). Subjective memory complaints may announce dementia. Neurology 46, 121–125.CrossRefGoogle ScholarPubMed
Shaw, LM, Vanderstichele, H, Knapik-Czajka, M, Clark, CM, Aisen, PS, Petersen, RC, Blennow, K, Soares, H, Simon, A, Lewczuk, P, Dean, R, Siemers, E, Potter, W, Lee, VM, Trojanowski, JQ (2009). Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Annals of Neurology 65, 403–413.CrossRefGoogle ScholarPubMed
Sierksma, AS, van den Hove, DL, Steinbusch, HW, Prickaerts, J (2010). Major depression, cognitive dysfunction and Alzheimer's disease: is there a link? European Journal of Pharmacology 626, 72–82.CrossRefGoogle ScholarPubMed
Sinoff, G, Werner, P (2003). Anxiety disorder and accompanying subjective memory loss in the elderly as a predictor of future cognitive decline. International Journal of Geriatric Psychiatry 18, 951–959.CrossRefGoogle ScholarPubMed
Sjogren, M, Vanderstichele, H, Agren, H, Zachrisson, O, Edsbagge, M, Wikkelso, C, Skoog, I, Wallin, A, Wahlund, LO, Marcusson, J, Nagga, K, Andreasen, N, Davidsson, P, Vanmechelen, E, Blennow, K (2001). Tau and Aβ42 in cerebrospinal fluid from healthy adults 21–93 years of age: establishment of reference values. Clinical Chemistry 47, 1776–1781.CrossRefGoogle ScholarPubMed
Skogseth, R, Mulugeta, E, Jones, E, Ballard, C, Rongve, A, Nore, S, Alves, G, Aarsland, D (2008). Neuropsychiatric correlates of cerebrospinal fluid biomarkers in Alzheimer's disease. Dementia and Other Geriatric Cognitive Disorders 25, 559–563.CrossRefGoogle ScholarPubMed
Starkstein, SE, Mizrahi, R, Capizzano, AA, Acion, L, Brockman, S, Power, BD (2009). Neuroimaging correlates of apathy and depression in Alzheimer's disease. Journal of Neuropsychiatry and Clinincal Neurosciences 21, 259–265.CrossRefGoogle ScholarPubMed
Sunderland, T, Linker, G, Mirza, N, Putnam, KT, Friedman, DL, Kimmel, LH, Bergeson, J, Manetti, GJ, Zimmermann, M, Tang, B, Bartko, JJ, Cohen, RM (2003). Decreased β-amyloid1–42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA 289, 2094–2103.CrossRefGoogle ScholarPubMed
Tapiola, T, Alafuzoff, I, Herukka, SK, Parkkinen, L, Hartikainen, P, Soininen, H, Pirttila, T (2009). Cerebrospinal fluid β-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Archives of Neurology 66, 382–389.CrossRefGoogle ScholarPubMed
Teng, E, Lu, PH, Cummings, JL (2007). Neuropsychiatric symptoms are associated with progression from mild cognitive impairment to Alzheimer's disease. Dementia and Geriatric Cognitive Disorders 24, 253–259.CrossRefGoogle ScholarPubMed
Trojanowski, JQ, Vandeerstichele, H, Korecka, M, Clark, CM, Aisen, PS, Petersen, RC, Blennow, K, Soares, H, Simon, A, Lewczuk, P, Dean, R, Siemers, E, Potter, WZ, Weiner, MW, Jackv, CR Jr., Jagust, W, Toga, AW, Lee, VM, Shaw, LM (2010). Update on the Biomarker Core of the Alzheimer's Disease Neuroimaging Initiative subjects. Alzheimer's and Dementia 6, 230–238.CrossRefGoogle ScholarPubMed
Visser, PJ, Verhey, F, Knol, DL, Scheltens, P, Wahlund, LO, Freund-Levi, Y, Tsolaki, M, Minthon, L, Wallin, AK, Hampel, H, Burger, K, Pirttila, T, Soininen, H, Rikkert, MO, Verbeek, MM, Spiru, L, Blennow, K (2009). Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet Neurology 8, 619–627.CrossRefGoogle ScholarPubMed
Visser, PJ, Verhey, FR, Boada, M, Bullock, R, De Deyn, PP, Frisoni, GB, Frolich, L, Hampel, H, Jolles, J, Jones, R, Minthon, L, Nobili, F, Olde Rikkert, M, Ousset, PJ, Rigaud, AS, Scheltens, P, Soininen, H, Spiru, L, Touchon, J, Tsolaki, M, Vellas, B, Wahlund, LO, Wilcock, G, Winblad, B (2008). Development of screening guidelines and clinical criteria for predementia Alzheimer's disease. The DESCRIPA Study. Neuroepidemiology 30, 254–265.CrossRefGoogle ScholarPubMed
Visser, PJ, Verhey, FR, Ponds, RW, Kester, A, Jolles, J (2000). Distinction between preclinical Alzheimer's disease and depression. Journal of the American Geriatrics Society 48, 479–484.CrossRefGoogle ScholarPubMed
Vos, S, van Rossum, I, Burns, L, Knol, D, Scheltens, P, Soininen, H, Wahlund, LO, Hampel, H, Tsolaki, M, Minthon, L, Handels, R, L'Italien, G, van der Flier, W, Aalten, P, Teunissen, C, Barkhof, F, Blennow, K, Wolz, R, Rueckert, D, Verhey, F, Visser, PJ (2012). Test sequence of CSF and MRI biomarkers for prediction of AD in subjects with MCI. Neurobiology of Aging. Published online 19 January 2012. doi:10.1016/j.neurobiolaging.2011.12.017.CrossRefGoogle ScholarPubMed
Weiner, MW, Aisen, PS, Jack, CR Jr., Jagust, WJ, Trojanowski, JQ, Shaw, L, Saykin, AJ, Morris, JC, Cairns, N, Beckett, LA, Toga, A, Green, R, Walter, S, Soares, H, Snyder, P, Siemers, E, Potter, W, Cole, PE, Schmidt, M (2010). The Alzheimer's Disease Neuroimaging Initiative: progress report and future plans. Alzheimer's and Dementia 6, 202–211.e7.CrossRefGoogle Scholar
Wilson, RS, Schneider, JA, Bienias, JL, Arnold, SE, Evans, DA, Bennett, DA (2003). Depressive symptoms, clinical AD, and cortical plaques and tangles in older persons. Neurology 61, 1102–1107.CrossRefGoogle ScholarPubMed
Wolz, R, Aljabar, P, Hajnal, JV, Hammers, A, Rueckert, D (2010). LEAP: learning embeddings for atlas propagation. Neuroimage 49, 1316–1325.CrossRefGoogle ScholarPubMed
Wuwongse, S, Chang, RC, Law, AC (2010). The putative neurodegenerative links between depression and Alzheimer's disease. Progress in Neurobiology 91, 362–375.CrossRefGoogle ScholarPubMed