Dermatoglyphic anomalies and neurocognitive deficits in sibling
Psychiatry Research 137 (2005) 215 – 221 www.elsevier.com/locate/psychres Dermatoglyphic anomalies and neurocognitive deficits in sibling pairs discordant for schizophrenia spectrum disorders Araceli Rosa a,*, Manuel J. Cuesta b, Vıctor Peralta b, Amalia Zarzuela b, ´ Fermın Serrano , Alfredo Martınez-Larrea b, Lourdes Fananas a ´ b ´ ˜ ´ a Unitat d’Antropologia, Facultat de Biologia, Universitat de Barcelona, Avinguda Diagonal 645, 08028 Barcelona, Spain b Psychiatric Unit, Virgen del Camino Hospital, Irunlarrea s/n, 31008 Pamplona, Spain Received 23 January 2003; received in revised form 19 September 2004; accepted 20 July 2005Abstract The neurodevelopmental hypothesis of schizophrenia suggests that adverse genetic loading in conjunction withenvironmental factors early in fetal life causes a disruption of neural development, decades before the symptomaticmanifestation of the disease. Neurocognitive deficits have been observed early on the course of schizophrenia, and theirassociation with an early developmental brain lesion has been postulated. Dermatoglyphics have been analyzed inschizophrenia as markers of prenatal brain injury because of their early fetal ontogenesis and susceptibility to the sameenvironmental factors that can also affect cerebral development. The aim of our study was to conduct a comparativeexamination of neurocognitive functions and dermatoglyphic variables in 89 sibling pairs discordant for schizophreniaspectrum disorders. Therefore, we investigated the association between these two markers to explore the prenatal origin ofcognitive deficits in schizophrenia. The affected siblings were significantly impaired on all the cognitive variables assessed(Wisconsin Card Sorting Test, Trail Making Test and Continuous Performance Test) and had a greater number ofdermatoglyphic anomalies. These results suggest the influence of intrauterine environmental factors in the siblings affectedwith schizophrenia. However, we did not detect a significant association between these two vulnerability markers in theschizophrenic patients, suggesting the role of genetic or late environmental factors in the origin of the neurocognitivedeficits found in these patients.D 2005 Elsevier Ireland Ltd. All rights reserved.Keywords: Dermatoglyphics; Neurocognition; Discordant sibling pairs; Psychosis; Prenatal markers; Neurodevelopment 1. Introduction Kraepelin’s concept of schizophrenia as an early * Corresponding author. Tel.: +34 93 402 14 61. dementia (dementia praecox) captured two core fea- E-mail address: email@example.com (A. Rosa). tures of the illness, namely cognitive dysfunction and0165-1781/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.psychres.2005.07.006
216 A. Rosa et al. / Psychiatry Research 137 (2005) 215–221a characteristic early age of onset. The neurodevelop- they remain unchanged and can act as bfossilsQ of themental hypothesis of schizophrenia was first formu- prenatal environment. For that reason, they have beenlated by Clouston (1891), who noted a high-arched used as markers of fetal malneurodevelopment withpalate in many of the patients he regarded as having reasonable success in the study of schizophrenia spec-dadolescent insanityT. However, it was not until the trum disorders. In these studies, three types of mea-end of the 1980s that the hypothesis reemerged with sure are typically used: quantitative counts of thethe detection of neuropathological and neuroimaging ridges on digits and hands, measures of asymmetryfindings that suggested that schizophrenia was char- between the left and right hands, and qualitativeacterised by abnormal brain development (Murray and dermatoglyphic abnormalities. Studies in schizophre-Lewis, 1987; Weinberger, 1987). nia spectrum disorders have shown lower ridge Several studies have demonstrated that a signifi- counts (total finger ridge count and a–b ridge count)cant proportion of schizophrenic patients show neu- (Turek, 1990; Fananas et al., 1990, 1996; Bracha et ˜ ´ropsychological impairments from early in the course al., 1991; Davis and Bracha, 1996; Fearon et al.,of their illness (Goldberg et al., 1995; Cuesta et al., 2001), higher levels of fluctuating asymmetry (Mar-1998). Although the range of neurocognitive deficits kow and Wandler, 1986; van Oel et al., 2001) anddescribed is extremely broad, the cognitive functions dermatoglyphic abnormalities including ridge disso-most frequently compromised are attention, executive ciations (RD) and abnormal palmar flexion creasesfunction, set shifting, and general and working mem- (APFC) in patients compared with healthy controlsory (Goldberg et al., 1987; Weickert et al., 2000). and unaffected monozygotic twins (van Os et al.,Despite the large number of studies exploring these 1997; Rosa et al., 2000, 2002).deficits, their nature and their association with an Although the risk for schizophrenia appears to beearly developmental brain lesion, genetic or environ- increased by problems in neurodevelopment, little ismental in origin, are still controversial. known about the origin of its more subtle cognitive Family studies suggest that cognitive deficits in sequelae. A possible approach to explore this relation-schizophrenia may serve as a marker of the genetic ship is to study the association between markers ofvulnerability to the disorder since relatives of patients prenatal insult [e.g. minor physical anomalies (MPAs)with schizophrenia exhibit subtle cognitive impair- and dermatoglyphics] and neurocognitive functioningments in attention, executive functioning, and sen- in patients with schizophrenia. Previous studies ofsory-motor functions (Cannon et al., 1994; Saoud et MPAs and information processing have led to contra-al., 2000; Staal et al., 2000). Nevertheless, prenatal dictory results (O’Callaghan et al., 1991; Green et al.,environmental factors such as viral or toxin exposure 1989). However, only one previous study has looked ator perinatal hypoxia are associated with both general the relationship between dermatoglyphic anomaliesintellectual impairment and more specific cognitive and neurocognitive deficits (Green et al., 1994). Thatdeficits, demonstrating the importance of the prenatal study failed to show an association between the neuro-and perinatal environment to the cognitive potential developmental markers studied (dermatoglyphic asym-of the human brain (Kremen et al., 1994; Rosa et al., metry and total finger ridge count) and three measures2001). One marker of environmental influences acting of information processing (Continuous Performanceduring prenatal brain development is dermato- Test, neuromotor speed and executive functioning).glyphics. Epidermal ridges share ectodermal origins To address these points, the aim of this study waswith the central nervous system. Their initial forma- to explore the presence of neurocognitive and derma-tion takes place about the 11th week; however, their toglyphic abnormalities in sibling pairs discordant forcritical stage of differentiation occurs in fetal months schizophrenia. We planned to explore the association3–4, coinciding with a critical phase of brain devel- between neurodevelopmental markers, previouslyopment (Rakic, 1988). Their morphology is geneti- reported altered in schizophrenia spectrum disorderscally determined but is susceptible to the same (dermatoglyphics) and selected neurocognitive func-environmental factors that can also disrupt brain tions in order to establish if there is evidence todevelopment (Babler, 1991). Intriguingly, once der- support early prenatal origin of the cognitive deficitsmatoglyphic development is complete, by week 24, found in these patients.
A. Rosa et al. / Psychiatry Research 137 (2005) 215–221 2172. Methods they assess cognitive domains that have consistently been implicated in schizophrenia spectrum disorders:2.1. Subjects (1) The Wisconsin Card Sorting Test (WCST), a test of executive function and set shifting. The number of The sample consisted of 89 patients with schizo- perseverative errors (WCST-PE) was used as an indexphrenia spectrum disorders from the Psychiatric Unit, of test performance (Heaton, 1993). (2) Form B of theVirgen del Camino Hospital, Pamplona. For each Trail Making Test (TMTb) (Reitan, 1958), a test ofpatient, the healthy sibling nearest in age to the set-shifting ability that assesses frontal lobe functionpatient was selected. We attempted whenever possi- and attention. The score used was the time taken toble to identify the same-gender sibling pairs. The complete the task. (3) The computerised version of thegender composition of the pairs was: male patient– Continuous Performance Test (CPT) (Cornblatt,male sibling: 31 (34.8%); female patient–male sib- 1996), a measure of sustained attention. The dV wasling: 10 (11.2%); male patient–female sibling: 36 used as a measure of sensitivity for this test. All the(40.5%); and female patient–female sibling: 12 participants were assessed by an experienced psycho-(13.5%). Siblings were interviewed with the Interna- logist (AZ) and patients were at the discharge stage.tional Personality Disorders Examination scale(IPDE) (Loranger et al., 1994) to exclude major 2.3. Dermatoglyphic variablespsychiatric illness in siblings. The DSM-IV diagnostic breakdown of patients Palm and fingerprints were taken by FS using awas as follows: schizophrenia (n = 48, 54%); schizo- non-inky method (Prints-kit, Printscan Verificationphreniform disorder (n = 8, 9%); schizoaffective dis- SystemsLtd., Printscan Distributorship, UK). Derma-order (n = 11, 12.4%); psychotic mood disorder toglyphic analysis was conducted by AR blind to(n = 14, 15.7%); delusional disorder (n = 2, 2.2%); the diagnosis, sex and neurocognitive profile of thebrief psychotic disorder (n = 5, 5.6%); and atypical individuals.psychosis (n = 1, 1.1%). The dermatoglyphic variables analyzed were: (1) Demographic data, including age, educational the total a–b ridge count (TABRC) and (2) the pre-level, gender and other variables of interest for the sence of abnormal palmar flexion creases (APFC) anddiscordant sib pairs, are summarised in Table 1. Writ- ridge dissociation in fingers and palms (RD) (see Rosaten informed consent was obtained from all partici- et al., 2001, for more details).pants after they had received a complete description ofthe study’s aims and procedures. 2.4. Statistical analysis2.2. Cognitive assessment All statistical analyses were performed using STATA software (StataCorp, 1999). As the data The neuropsychological battery that was adminis- were obtained, sibling-pairs differences between sib-tered to all individuals (patients and siblings) con- lings on the quantitative measures (i.e., cognitivesisted of the following three tests, selected because variables and total a–b ridge count) were analyzed using two-tailed t-tests for paired samples. For dif-Table 1 ferences between siblings on the qualitative vari-Demographic characteristics and duration of the illness, in years, in ables (i.e., abnormal palmar flexion creases andthe sample of 89 sib pairs discordant for schizophrenia and schizo- presence of ridge dissociations), the McNemar testphrenia spectrum disorders was used. Affected sibs Healthy sibs Associations between the cognitive and dermato- Mean F S.D. Mean F S.D. glyphic variables were calculated by using multipleAge 26.8 F 5.8 27.7 F 6.8 regression or logistic regression depending on theEducation 11.9 F 3.7 12.7 F 4.1 nature of the dermatoglyphic variable used. Associa-Age at onset 21.5 F 5.4 – tions were expressed as regression coefficients (b) orDuration of illness 5.2 F 5.9 – odds ratios (OR). The association analyses were
218 A. Rosa et al. / Psychiatry Research 137 (2005) 215–221adjusted for sex, age, years of education and illness Table 3duration as possible confounding factors. Associations between the dermatoglyphic variables analyzed (TABRC and presence APFC/RD) and the neurocognitive variables (WCST-PE, TMTb and the dV), in the sample of patients affected by schizophrenia spectrum disorders3. Results Patients with schizophrenia spectrum disorders TABRC APFC/RD As hypothesised, patients performed significantly b P OR Pworse than their healthy siblings on all the neuropsy-chological tasks assessed: executive function (WCST- WCST-PE 0.02 0.8 0.9 0.5 TMTb 0.01 0.5 1 0.4PE: t = 2.9, df = 77, P = 0.005), set shifting (TMTb: dV À1.1 0.4 0.7 0.2t = 7.7, df = 78, P = 0.000), and attention (CPT: t = 3.3, b: multiple regression coefficient between the quantitative derma-df = 75, P = 0.001) (Table 2). To explore a more homo- toglyphic variable TABRC and the neurocognitive variables ana-genous patient group, we narrowed the definition of lyzed (WCST-PE, TMTb and dV).patients to DSM-IV schizophrenia and schizophreni- OR: odds ratio from the logistic regression analysis betweenform disorder). This subgroup, which consisted of 49 qualitative dermatoglyphic abnormalities and neurocognitive testspairs, demonstrated the same results (executive func- considered.tion: t = 2.1, df = 47, P = 0.05; set shifting: t = 6.4,df = 48, P = 0.000; attention: t = À 3.1, df = 47, In this regard, a statistically significant excess ofP = 0.004) (Table 2). Deficits were characterised by a either APFC or RD was found in the affected sibshigher number of perseverative errors on the WCST, compared with the unaffected sibs (McNemar test:more time taken to complete the TMT-B, and P b 0.001) (Table 2).decreased accuracy on the CPT dV index. The findings remained unchanged when we exam- Data on total a–b ridge count (TABRC) were avail- ined the narrow criteria subgroup (TABRC: t = 0.7,able on 76 pairs. In the affected siblings, mean TABRC df = 47, P = 0.4; APFC/ RD, McNemar test: P = 0.01).was 80.1 (S.D. = 11.6) and in the healthy siblings 80.2 Multiple regression analysis did not show a significant(S.D. = 12.1). For this variable, no large or significant association between lower TABRC and impaireddifferences were found between the discordant sibs executive function, cognitive flexibility on TMTb or(t = À 0.1, df = 75, P = 0.9) (Table 2). sustained attention (dV) in patients (Table 3). Similarly, Abnormal palmar flexion creases were more fre- logistic regression did not show that the presence ofquent in the patients (48.1%) compared with their APFC/RD was associated with the aforementionedhealthy sibs (36.7%). Ridge dissociation was present neurocognitive variables in the group of patientsin 29% of the patients and in 17% of the healthy sibs. (Table 3).Table 2Neurocognitive and dermatoglyphic scores in: (a) patients affected by schizophrenia spectrum disorders (SZSD) (n = 79 pairs) and their siblingsand (b) patients with schizophrenia and schizophreniform disorder (SZ) (n = 49 pairs) Patients with SZSD Siblings of SZSD patients Patients with SZ Siblings of SZ patients Mean F S.D. Mean F S.D. Mean F S.D. Mean F S.D.WCST-PE 19.1 F10.5 14.5 F 10.5 18.3 F 10.4 14.6 F 10.8TMTb 120.3 F 48.8 76.4 F 25.5 119.3 F 49.1 73.5 F 25.1dV 0.6 F 0.9 1.0 F 0.9 0.6 F 0.9 1.1 F 0.9TABRC 80.1 F11.6 80.2 F 12.1 80.6 F 12.3 79.62 F 10.0APFC/RD 72.8% 42% 69.4% 42%WCST-PE: number of perseverative errors of the Wisconsin Card Sorting Test.TMTb: form b of the Trail Making Test.dV: Continuous Performance Test measure of sensitivity dV.TABRC: total a–b ridge count.APFC/RD: presence of either abnormal palmar flexion creases and/or dermatoglyphic ridge dissociation.
A. Rosa et al. / Psychiatry Research 137 (2005) 215–221 2194. Discussion relationship does not exist. The cognitive disturbances could be manifestations of prenatal disruptions in In this study selected cognitive functions (executive brain formation that could lead to further neural dys-function, set shifting and sustained attention) and der- maturation that can manifest in adolescence and adult-matoglyphic variables (a–b ridge count and presence of hood as schizophrenia. Nevertheless, we have noabnormal palmar flexion creases/dermatoglyphic ridge grounds to expect that the neurodevelopmental insultdissociations) were analyzed in a young group of sib hypothesised to intervene in the causation of neuro-pairs discordant for psychosis. The adult siblings cognitive impairment necessarily occurs during theapproach used offers advantages insofar as that for short time window in which epidermal ridge develop-some variables stratification bias is reduced. ment takes place (i.e., between 11th and 24th weeks of The first finding from this study was that affected fetal life). Indeed, the link between early brain devel-sibs were significantly impaired in the cognitive func- opmental disturbance and neurocognitive alterationtions studied compared with their unaffected sibs. could still be plausible if we assume the interactionThis finding adds to the growing body of literature of predisposing genes and hazardous intrauterinesuggesting that neurocognitive deficits may be gener- environmental factors may actually happen after theally characteristic of schizophrenia (e.g., Goldberg et period of dermatoglyphic formation. Furthermore, ital., 1987). As we only assessed the well relatives of should be contemplated that the neurocognitivepatients and did not include a healthy control group, impairment found in schizophrenia is probably notwe are not able to establish whether the neurocogni- entirely caused by pure neurobiological abnormalities.tive deficits found characterize both schizophrenic Educational factors, drug treatments, behaviouralpatients and their well siblings, nor can we discuss peculiarities, and the effects of the illness itself, asquestions concerning a genetic origin of these deficits. well as other environmental variables, probably have a Regarding the markers of prenatal suffering ana- role in determining performance in these cognitivelyzed, the total a–b ridge count (TABRC) did not tests.differ between the sib pairs. Our dermatoglyphic find- Another possible explanation for the lack of asso-ings for this variable contrasted with several previous ciation in this and the previous studies may be that thestudies that found lower TABRCs in schizophrenic cognitive deficits might be linked to the genetic liabi-patients compared with unrelated healthy controls lity for schizophrenia, whereas these neurodevelop-(e.g., Fananas et al., 1990). Regarding the other der- ˜ ´ mental markers may reflect extragenic processes.matoglyphic variables analyzed, patients showed Nonetheless, studies of cognitive deficits in monozy-higher frequencies of abnormal palmar flexion creases gotic twin pairs discordant for schizophrenia contra-and ridge dissociations. These dermatoglyphic dict a sole genetic effect. In addition, magneticabnormalities have also been associated with psycho- resonance imaging studies, neuroanatomic, and neu-sis in previous studies carried out in twins (van Os et rophysiological studies in discordant twins for schizo-al., 1997; Rosa et al., 2000, 2002). Our results support phrenia have demonstrated that the abnormalitiesthe suggestion that intrauterine environmental factors found in the affected twin compared with the healthyearly in pregnancy are associated with the suscepti- co-twin were compatible with this hypothesis (Suddathbility to schizophrenia. et al., 1990; Weinberger et al., 1992). With this in Finally, we do not find any association between the mind, genetically sensitive designs such as the twinneurocognitive and the neurodevelopmental markers method are appropriate to disentangle genetic factorsassessed (TABRC and APFC/RD). Our results are and shared environmental factors; unfortunately, theseconsistent with the two previous studies in which effects cannot be determined from the current analyses.the markers of neurodevelopment (minor physicalanomalies and/or dermatoglyphics) and the informa-tion-processing measures were not found to be asso- Acknowledgmentsciated (Green et al., 1989, 1994). However, the failureto find an association between the dermatoglyphic and This research was supported by a grant from thecognitive variables assessed does not mean that such a Theodore and Vada Stanley Foundation. Araceli Rosa
220 A. Rosa et al. / Psychiatry Research 137 (2005) 215–221was awarded a PhD grant from the University of Bar- zygotic twins discordant and concordant for the disorder.celona, and Amalia Zarzuela was awarded by the Schizophrenia Research 17, 77 – 84. Green, M.F., Satz, P., Gaier, D.J., Ganzell, S., Kharabi, F., 1989.Fondo de Investigacion Sanitaria (Spain, FIS 00/0132). ´ Minor physical anomalies in schizophrenia. Schizophrenia Bul- We thank the patients, families and staff from the letin 15, 91 – 99.hospital whose generosity made this project possible. Green, M.F., Bracha, H.S., Satz, P., Christenson, C.D., 1994. Pre-Finally, we thank Dr. Marco Picchioni, Dr. Brendan liminary evidence for an association between minor physical anomalies and second trimester neurodevelopment in schizo-Kelly and Dr. Neus Barrantes-Vidal for constructive phrenia. Psychiatry Research 53, 119 – 127.criticism and suggestions in the last version of the Heaton, R., 1993. Wisconsin Card Sorting Test Manual. 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