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Cognitive deficits in first-degree relatives of bipolar patients: the use of homogeneous subgroups in the search of cognitive endophenotypes

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
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Abstract

Previous studies have demonstrated impairments in attention, memory and executive functions in euthymic bipolar patients (BP) as well as their unaffected first-degree relatives, albeit in an attenuated form. Subsequently, cognitive deficits are discussed as a possible endophenotype of bipolar disorder. However, recent studies showed that only a subgroup of BP shows cognitive impairments. The aim of the present study was to investigate cognitive functioning in relatives compared to BP, to find out if the differentiation in a cognitive deficit vs. non-deficit subgroup is valid for relatives of BP, too. Therefore, the performance of 27 unaffected relatives of BP, 27 euthymic BP and 27 HC were compared using a neuropsychological test battery. The results showed that BP exhibited a reduced psychomotor speed and deficits in working memory compared to relatives and HC. Relatives performed significantly slower (psychomotor speed) as compared to HC (p = 0.024); performance in the other test measures lie between BP and HC. Furthermore, a detailed evaluation of the data indicated that only subgroups of BP and relatives exhibited cognitive impairments in the implemented tests. However, the deficit and non-deficit groups did not differ in sociodemographic and clinical variables from each other, possibly due to the small sample size. In conclusion, our results suggest that reduced psychomotor speed could serve as a potential endophenotype for bipolar disorder which should be investigated along the developmental trajectory of this disorder, also to examine whether abnormalities therein precede onset of the first mood episode. Furthermore, the division of relatives into subgroups aids in the identification of stable trait markers and high-risk bipolar groups and could enable early prevention strategies. As to that more research using distinct and homogeneous subgroups is necessary.

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References

  • Aminoff SR, Jensen J, Lagerberg TV, Hellvin T, Sundet K, Andreassen OA, Melle I (2012) An association between affective lability and executive functioning in bipolar disorder. Psychiatry Res. doi:10.1016/j.psychres.2011.12.044

    Google Scholar 

  • Aminoff SR, Hellvin T, Lagerberg TV, Berg AO, Andreassen OA, Melle I (2013) Neurocognitive features in subgroups of bipolar disorder. Bipolar Disord 15(3):272–283. doi:10.1111/bdi.12061

    Article  PubMed  PubMed Central  Google Scholar 

  • Ando J, Ono Y, Wright MJ (2001) Genetic structure of spatial and verbal working memory. Behav Genet 31(6):615–624

    Article  CAS  PubMed  Google Scholar 

  • Antila M, Tuulio-Henriksson A, Kieseppa T, Eerola M, Partonen T, Lonnqvist J (2007) Cognitive functioning in patients with familial bipolar I disorder and their unaffected relatives. Psychol Med 37(5):679–687. doi:10.1017/S0033291706009627

    Article  PubMed  Google Scholar 

  • Antila M, Kieseppa T, Partonen T, Lonnqvist J, Tuulio-Henriksson A (2011) The effect of processing speed on cognitive functioning in patients with familial bipolar I disorder and their unaffected relatives. Psychopathology 44(1):40–45. doi:10.1159/000317577

    Article  PubMed  Google Scholar 

  • Arts B, Jabben N, Krabbendam L, van Os J (2008) Meta-analyses of cognitive functioning in euthymic bipolar patients and their first-degree relatives. Psychol Med 38(6):771–785. doi:10.1017/S0033291707001675

    Article  CAS  PubMed  Google Scholar 

  • Aschenbrenner S, Tucha O, Lange KW (2000) Regensburger Wortflüssigkeitstest. Hogrefe Verlag, Göttingen, Handanweisung

    Google Scholar 

  • Balanza-Martinez V, Rubio C, Selva-Vera G, Martinez-Aran A, Sanchez-Moreno J, Salazar-Fraile J, Vieta E, Tabares-Seisdedos R (2008) Neurocognitive endophenotypes (endophenocognitypes) from studies of relatives of bipolar disorder subjects: a systematic review. Neurosci Biobehav Rev 32(8):1426–1438. doi:10.1016/j.neubiorev.2008.05.019

    Article  PubMed  Google Scholar 

  • Bearden CE, Hoffman KM, Cannon TD (2001) The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review. Bipolar Disord 3 (3):106–150 (discussion 151–103)

  • Beck AT, Steer RA, Ball R, Ranieri W (1996) Comparison of beck depression inventories -IA and -II in psychiatric outpatients. J Pers Assess 67(3):588–597. doi:10.1207/s15327752jpa6703_13

    Article  CAS  PubMed  Google Scholar 

  • Bonnin CM, Martinez-Aran A, Torrent C, Pacchiarotti I, Rosa AR, Franco C, Murru A, Sanchez-Moreno J, Vieta E (2010) Clinical and neurocognitive predictors of functional outcome in bipolar euthymic patients: a long-term, follow-up study. J Affect Disord 121(1–2):156–160. doi:10.1016/j.jad.2009.05.014

    Article  CAS  PubMed  Google Scholar 

  • Bonnin CM, Sanchez-Moreno J, Martinez-Aran A, Sole B, Reinares M, Rosa AR, Goikolea JM, Benabarre A, Ayuso-Mateos JL, Ferrer M, Vieta E, Torrent C (2012) Subthreshold symptoms in bipolar disorder: impact on neurocognition, quality of life and disability. J Affect Disord 136(3):650–659. doi:10.1016/j.jad.2011.10.012

    Article  CAS  PubMed  Google Scholar 

  • Bora E, Vahip S, Akdeniz F, Ilerisoy H, Aldemir E, Alkan M (2008) Executive and verbal working memory dysfunction in first-degree relatives of patients with bipolar disorder. Psychiatry Res 161(3):318–324. doi:10.1016/j.psychres.2007.09.002

    Article  PubMed  Google Scholar 

  • Bora E, Yucel M, Pantelis C (2009) Cognitive endophenotypes of bipolar disorder: a meta-analysis of neuropsychological deficits in euthymic patients and their first-degree relatives. J Affect Disord 113(1–2):1–20. doi:10.1016/j.jad.2008.06.009

    Article  PubMed  Google Scholar 

  • Bourne C, Aydemir O, Balanza-Martinez V, Bora E, Brissos S, Cavanagh JT, Clark L, Cubukcuoglu Z, Dias VV, Dittmann S, Ferrier IN, Fleck DE, Frangou S, Gallagher P, Jones L, Kieseppa T, Martinez-Aran A, Melle I, Moore PB, Mur M, Pfennig A, Raust A, Senturk V, Simonsen C, Smith DJ, Bio DS, Soeiro-de-Souza MG, Stoddart SD, Sundet K, Szoke A, Thompson JM, Torrent C, Zalla T, Craddock N, Andreassen OA, Leboyer M, Vieta E, Bauer M, Worhunsky PD, Tzagarakis C, Rogers RD, Geddes JR, Goodwin GM (2013) Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis. Acta Psychiatr Scand 128(3):149–162. doi:10.1111/acps.12133

    Article  CAS  PubMed  Google Scholar 

  • Clark L, Sarna A, Goodwin GM (2005) Impairment of executive function but not memory in first-degree relatives of patients with bipolar I disorder and in euthymic patients with unipolar depression. Am J Psychiatry 162(10):1980–1982. doi:10.1176/appi.ajp.162.10.1980

    Article  PubMed  Google Scholar 

  • Daban C, Mathieu F, Raust A, Cochet B, Scott J, Etain B, Leboyer M, Bellivier F (2012) Is processing speed a valid cognitive endophenotype for bipolar disorder? J Affect Disord 139(1):98–101. doi:10.1016/j.jad.2012.02.028

    Article  PubMed  Google Scholar 

  • Domschke K, Reif A (2012) Behavioral genetics of affective and anxiety disorders. Curr Topics Behav Neurosci 12:463–502. doi:10.1007/7854_2011_185

    Article  Google Scholar 

  • Drysdale E, Knight HM, McIntosh AM, Blackwood DH (2013) Cognitive endophenotypes in a family with bipolar disorder with a risk locus on chromosome 4. Bipolar Disord 15(2):215–222. doi:10.1111/bdi.12040

    Article  PubMed  Google Scholar 

  • Fan J, Wu Y, Fossella JA, Posner MI (2001) Assessing the heritability of attentional networks. BMC Neurosci 2:14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Faraone SV, Seidman LJ, Kremen WS, Toomey R, Pepple JR, Tsuang MT (2000) Neuropsychologic functioning among the nonpsychotic relatives of schizophrenic patients: the effect of genetic loading. Biol Psychiatry 48(2):120–126

    Article  CAS  PubMed  Google Scholar 

  • Ferrier IN, Chowdhury R, Thompson JM, Watson S, Young AH (2004) Neurocognitive function in unaffected first-degree relatives of patients with bipolar disorder: a preliminary report. Bipolar Disord 6(4):319–322. doi:10.1111/j.1399-5618.2004.00122.x

    Article  PubMed  Google Scholar 

  • Finkel D, Pedersen NL, McGue M, McClearn GE (1995) Heritability of cognitive abilities in adult twins: comparison of Minnesota and Swedish data. Behav Genet 25(5):421–431

    Article  CAS  PubMed  Google Scholar 

  • Frangou S, Haldane M, Roddy D, Kumari V (2005) Evidence for deficit in tasks of ventral, but not dorsal, prefrontal executive function as an endophenotypic marker for bipolar disorder. Biol Psychiatry 58(10):838–839. doi:10.1016/j.biopsych.2005.05.020

    Article  PubMed  Google Scholar 

  • Glahn DC, Bearden CE, Niendam TA, Escamilla MA (2004) The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder. Bipolar Disord 6(3):171–182. doi:10.1111/j.1399-5618.2004.00113.x

    Article  PubMed  Google Scholar 

  • Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160(4):636–645. doi:10.1176/appi.ajp.160.4.636

    Article  PubMed  Google Scholar 

  • Gourovitch ML, Torrey EF, Gold JM, Randolph C, Weinberger DR, Goldberg TE (1999) Neuropsychological performance of monozygotic twins discordant for bipolar disorder. Biol Psychiatry 45(5):639–646

    Article  CAS  PubMed  Google Scholar 

  • Gunning-Dixon FM, Raz N (2000) The cognitive correlates of white matter abnormalities in normal aging: a quantitative review. Neuropsychology 14(2):224–232

    Article  CAS  PubMed  Google Scholar 

  • Harvey PD, Wingo AP, Burdick KE, Baldessarini RJ (2010) Cognition and disability in bipolar disorder: lessons from schizophrenia research. Bipolar Disord 12(4):364–375. doi:10.1111/j.1399-5618.2010.00831.x

    Article  PubMed  Google Scholar 

  • Hellvin T, Sundet K, Simonsen C, Aminoff SR, Lagerberg TV, Andreassen OA, Melle I (2012) Neurocognitive functioning in patients recently diagnosed with bipolar disorder. Bipolar Disord 14(3):227–238. doi:10.1111/j.1399-5618.2012.01004.x

    Article  PubMed  Google Scholar 

  • Kaller CP, Unterrainer JM, Kaiser S, Weisbrod M, Aschenbrenner S (2011) Tower of London—Freiburger version. Version 21. Schuhfried GmbH, Mödling

  • Keri S, Kelemen O, Benedek G, Janka Z (2001) Different trait markers for schizophrenia and bipolar disorder: a neurocognitive approach. Psychol Med 31(5):915–922

    Article  CAS  PubMed  Google Scholar 

  • Kieseppa T, van Erp TG, Haukka J, Partonen T, Cannon TD, Poutanen VP, Kaprio J, Lonnqvist J (2003) Reduced left hemispheric white matter volume in twins with bipolar I disorder. Biol Psychiatry 54(9):896–905

    Article  PubMed  Google Scholar 

  • Kim D, Kim JW, Koo TH, Yun HR, Won SH (2015) Shared and distinct neurocognitive endophenotypes of schizophrenia and psychotic bipolar disorder. Clin Psychopharmacol Neurosci Off Sci J Korean Coll Neuropsychopharmacol 13(1):94–102. doi:10.9758/cpn.2015.13.1.94

    Article  Google Scholar 

  • Klimes-Dougan B, Ronsaville D, Wiggs EA, Martinez PE (2006) Neuropsychological functioning in adolescent children of mothers with a history of bipolar or major depressive disorders. Biol Psychiatry 60(9):957–965. doi:10.1016/j.biopsych.2006.03.031

    Article  PubMed  Google Scholar 

  • Kremen WS, Goldstein JM, Seidman LJ, Toomey R, Lyons MJ, Tsuang MT, Faraone SV (1997) Sex differences in neuropsychological function in non-psychotic relatives of schizophrenic probands. Psychiatry Res 66(2–3):131–144

    Article  CAS  PubMed  Google Scholar 

  • Kulkarni S, Jain S, Janardhan Reddy YC, Kumar KJ, Kandavel T (2010) Impairment of verbal learning and memory and executive function in unaffected siblings of probands with bipolar disorder. Bipolar Disord 12(6):647–656. doi:10.1111/j.1399-5618.2010.00857.x

    Article  PubMed  Google Scholar 

  • Kurtz MM, Gerraty RT (2009) A meta-analytic investigation of neurocognitive deficits in bipolar illness: profile and effects of clinical state. Neuropsychology 23(5):551–562. doi:10.1037/a0016277

    Article  PubMed  PubMed Central  Google Scholar 

  • Lehrl S, Triebig G, Fischer B (1995) Multiple choice vocabulary test MWT as a valid and short test to estimate premorbid intelligence. Acta Neurol Scand 91(5):335–345

    Article  CAS  PubMed  Google Scholar 

  • Luciano M, Wright M, Smith GA, Geffen GM, Geffen LB, Martin NG (2001) Genetic covariance among measures of information processing speed, working memory, and IQ. Behav Genet 31(6):581–592

    Article  CAS  PubMed  Google Scholar 

  • Mann-Wrobel MC, Carreno JT, Dickinson D (2011) Meta-analysis of neuropsychological functioning in euthymic bipolar disorder: an update and investigation of moderator variables. Bipolar Disord 13(4):334–342. doi:10.1111/j.1399-5618.2011.00935.x

    Article  PubMed  Google Scholar 

  • Maziade M, Rouleau N, Gingras N, Boutin P, Paradis ME, Jomphe V, Boutin J, Letourneau K, Gilbert E, Lefebvre AA, Dore MC, Marino C, Battaglia M, Merette C, Roy MA (2009) Shared neurocognitive dysfunctions in young offspring at extreme risk for schizophrenia or bipolar disorder in eastern quebec multigenerational families. Schizophr Bull 35(5):919–930. doi:10.1093/schbul/sbn058

    Article  PubMed  Google Scholar 

  • McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A (2003) The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry 60(5):497–502. doi:10.1001/archpsyc.60.5.497

    Article  PubMed  Google Scholar 

  • Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry J Mental Sci 134:382–389

    Article  CAS  Google Scholar 

  • Niemann H, Sturm W, Thöne-Otto AIT, Wilmes K (2011) California verbal learning test, version 21. Schuhfried GmbH, Mödling

    Google Scholar 

  • Pierson A, Jouvent R, Quintin P, Perez-Diaz F, Leboyer M (2000) Information processing deficits in relatives of manic depressive patients. Psychol Med 30(3):545–555

    Article  CAS  PubMed  Google Scholar 

  • Pompei F, Jogia J, Tatarelli R, Girardi P, Rubia K, Kumari V, Frangou S (2011) Familial and disease specific abnormalities in the neural correlates of the Stroop task in bipolar disorder. NeuroImage 56(3):1677–1684. doi:10.1016/j.neuroimage.2011.02.052

    Article  PubMed  Google Scholar 

  • Posthuma D, Baare WF, Hulshoff Pol HE, Kahn RS, Boomsma DI, De Geus EJ (2003) Genetic correlations between brain volumes and the WAIS-III dimensions of verbal comprehension, working memory, perceptual organization, and processing speed. Twin Res Off J Int Soc Twin Stud 6(2):131–139. doi:10.1375/136905203321536254

    Article  Google Scholar 

  • Puhr U, Wagner M (2011) Interferenztest nach Stroop. Version 24-Rev. 1. Schuhfried GmbH, Mödling

  • Raust A, Daban C, Cochet B, Henry C, Bellivier F, Scott J (2014) Neurocognitive performance as an endophenotype for bipolar disorder. Front Biosci (Elite Ed) 6:89–103

    Google Scholar 

  • Reitan RM, Wolfson D (1997) The influence of age and education on neuropsychological performances of persons with mild head injuries. Appl Neuropsychol 4(1):16–33. doi:10.1207/s15324826an0401_3

    Article  CAS  PubMed  Google Scholar 

  • Ryan KA, Vederman AC, McFadden EM, Weldon AL, Kamali M, Langenecker SA, McInnis MG (2012) Differential executive functioning performance by phase of bipolar disorder. Bipolar Disord 14(5):527–536. doi:10.1111/j.1399-5618.2012.01032.x

    Article  PubMed  PubMed Central  Google Scholar 

  • Schulze KK, Walshe M, Stahl D, Hall MH, Kravariti E, Morris R, Marshall N, McDonald C, Murray RM, Bramon E (2011) Executive functioning in familial bipolar I disorder patients and their unaffected relatives. Bipolar Disord 13(2):208–216. doi:10.1111/j.1399-5618.2011.00901.x

    Article  PubMed  Google Scholar 

  • Sepede G, De Berardis D, Campanella D, Perrucci MG, Ferretti A, Serroni N, Moschetta FS, Del Gratta C, Salerno RM, Ferro FM, Di Giannantonio M, Onofrj M, Romani GL, Gambi F (2012) Impaired sustained attention in euthymic bipolar disorder patients and non-affected relatives: an fMRI study. Bipolar Disord 14(7):764–779. doi:10.1111/bdi.12007

    Article  PubMed  Google Scholar 

  • Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. The Journal of clinical psychiatry 59(Suppl 20):22–33 (quiz 34–57)

  • Strakowski SM, Adler CM, Almeida J, Altshuler LL, Blumberg HP, Chang KD, DelBello MP, Frangou S, McIntosh A, Phillips ML, Sussman JE, Townsend JD (2012) The functional neuroanatomy of bipolar disorder: a consensus model. Bipolar Disord 14(4):313–325. doi:10.1111/j.1399-5618.2012.01022.x

    Article  PubMed  Google Scholar 

  • Swan GE, Carmelli D (2002) Evidence for genetic mediation of executive control: a study of aging male twins. J Gerontol Ser B Psychol Sci Soc Sci 57(2):P133–P143

    Article  Google Scholar 

  • Torrent C, Martinez-Aran A, del Mar Bonnin C, Reinares M, Daban C, Sole B, Rosa AR, Tabares-Seisdedos R, Popovic D, Salamero M, Vieta E (2012) Long-term outcome of cognitive impairment in bipolar disorder. J Clin Psychiatry 73(7):e899–e905. doi:10.4088/JCP.11m07471

    Article  PubMed  Google Scholar 

  • Torres IJ, Boudreau VG, Yatham LN (2007) Neuropsychological functioning in euthymic bipolar disorder: a meta-analysis. Acta Psychiatr Scand Suppl 434:17–26. doi:10.1111/j.1600-0447.2007.01055.x

    Article  PubMed  Google Scholar 

  • Vieta E, Reinares M, Rosa AR (2011) Staging Bipolar Disorder. Neurotox Res 19(2):279–285

    Article  PubMed  Google Scholar 

  • Volkert J, Kopf J, Kazmaier J, Glaser F, Zierhut KC, Schiele MA, Kittel-Schneider S, Reif A (2014) Evidence for cognitive subgroups in bipolar disorder and the influence of subclinical depression and sleep disturbances. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol. doi:10.1016/j.euroneuro.2014.07.017

    Google Scholar 

  • Watson D, Clark LA, Tellegen A (1988) Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 54(6):1063–1070

    Article  CAS  PubMed  Google Scholar 

  • Young RC, Biggs JT, Ziegler VE, Meyer DA (1978) A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry J Mental Sci 133:429–435

    Article  CAS  Google Scholar 

  • Zalla T, Joyce C, Szoke A, Schurhoff F, Pillon B, Komano O, Perez-Diaz F, Bellivier F, Alter C, Dubois B, Rouillon F, Houde O, Leboyer M (2004) Executive dysfunctions as potential markers of familial vulnerability to bipolar disorder and schizophrenia. Psychiatry Res 121(3):207–217

    Article  PubMed  Google Scholar 

  • Zimmermann PF, B (2011) Test battery of attentional performance, version 2.2. Herzogenrath: Psytest

Download references

Acknowledgments

We acknowledge all participants who took part in the present study. JV was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences, University of Wuerzburg and by the RTG 1256/2 “gk emotions”.

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Volkert, J., Haubner, J., Kazmaier, J. et al. Cognitive deficits in first-degree relatives of bipolar patients: the use of homogeneous subgroups in the search of cognitive endophenotypes. J Neural Transm 123, 1001–1011 (2016). https://doi.org/10.1007/s00702-016-1581-y

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