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Memory deficits in late-onset schizophrenia
Schizophrenia Research 151 (2013) 85–90
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Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Memory deficits in late-onset schizophrenia Clara Brichant-Petitjean a, Cindy Legauffre b, Nicolas Ramoz c, Jean Ades c,d, Philip Gorwood c, Caroline Dubertret b,c,d,⁎ a
AP-HP, Department of Psychiatry, Fernand Widal Hospital, Paris, France AP-HP, Department of Psychiatry, Louis Mourier Hospital, Colombes, France INSERM U675-U894, Center of Psychiatry and Neurosciences, Paris, France d University Paris 7 Denis Diderot, Faculty of Medicine, Paris, France b c
a r t i c l e
i n f o
Article history: Received 28 December 2012 Received in revised form 29 July 2013 Accepted 14 August 2013 Available online 13 October 2013 Keywords: Late-onset schizophrenia Cognitive deficits Neuropsychological tests Memory impairment
a b s t r a c t Late-onset schizophrenia (LOS) is a controversial diagnosis, mainly characterized by more positive symptoms and less deterioration. LOS could be considered as either an extreme of typical schizophrenia (but for old age patients, and short duration of the disorder), or an independent group of patients with a specific diagnosis, with no clear evidence in favor or against any of these hypotheses. The aim of the present study is to characterize the memory cognitive profile of LOS patients without related organic factors (N = 25), compared to early-onset schizophrenic patients (EOS, N = 44), matched for the duration of the disorder, and healthy controls (HC, N = 23), matched for the age of patients. Lifetime clinical symptoms and functioning were collected using the DIGS and the PANSS, and components of memory capacity were assessed with the Forward and Backward Digit Span Tasks, Rey Complex Figure and Verbal Fluency Tests. LOS patients were performing significantly better than EOS patients on the digit span task, Rey's complex figure at T1 score and phonemic verbal fluency. However, LOS had significantly lower performances than healthy controls on the digit span task and on both verbal fluency tests. This study provides evidence that LOS had intermediate outcome compared to EOS and controls. LOS can therefore be in line with a dimensional clinical approach of schizophrenia, whereby it presents few memory deficits and few disorganization and negative symptoms with mostly positive symptoms and possibly etiopathogenic specificities. Further studies including more specific memory assessment tests and larger samples are needed to confirm the present finding. © 2013 Elsevier B.V. All rights reserved.
1. Introduction The onset of schizophrenia in late life has always been a controversial area of study, as schizophrenia is mainly occurring between 15 and 25 years old (Gorwood et al., 1995). The development of psychotic symptoms is nevertheless a common occurrence in late life, and cognitive impairment associated with psychosis is often prominent in dementia, schizophrenia, and mood disorders. This mixing of symptoms has inevitably led to diagnostic confusion with regard to elderly patients with new-onset psychosis (La Salvia and Chemali, 2011). In 1943, M. Bleuler, described the characteristics of “late-onset schizophrenia”, occurring over 40 years of age and characterized by less blunted affect and less formal thought disorder (Bleuler, 1943). The French concept of chronic hallucinatory psychosis [“Psychose Hallucinatoire Chronique”], individualized by Ballet (1911), has always been part of a classificatory debate between European and American psychiatrists. ⁎ Corresponding author at: Hôpital Louis Mourier, 178 rue des Renouillers, 92700 Colombes, France. Tel.: +33 147606409; fax: +33 147606740. E-mail address: [email protected] (C. Dubertret). 0920-9964/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2013.08.021
This disorder is characterized by late-onset, occurring mostly in women, with rich and frequent hallucinations and almost no formal thought disorder (Dubertret et al., 2004a, 2004b). In the DSM-III (American Psychiatric Association, 1980), the diagnosis of schizophrenia was excluded if symptoms do not begin before the age of 45. Shortly after, in the DSM-III-R (American Psychiatric Association, 1987), a distinction was proposed between “early-onset” (EOS) and “late-onset” schizophrenia (LOS) (when the disease begins after 45 years of age) (La Salvia and Chemali, 2011). The notion of age of onset was simply abandoned in the DSM IV (American Psychiatric Association, 1994). However, the DSM-IV does mention in the appendix that schizophrenia “may also begin after the age of 45 and that in that case, has a number of characteristics: (1) a higher proportion of wedded women, (2) more persecutory delusions and hallucinations, (3) fewer negative symptoms or disorganized speech, (4) less affect flattening and a (5) better social functioning, even though these patients are more socially isolated”. In 2000, Howard et al. published the findings of an international working group on LOS (Howard et al., 2000). The literature review and guidelines emphasized the fact that LOS is probably not a homogeneous entity but a syndrome with clinically and biologically relevant subtypes,
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starting after the age of 44 years old. The dimensional clinical approach proposed by the DSM-V could help to better characterize clinical characteristics of patients with schizophrenia. Cognitive deficits are considered to be core features of schizophrenia and their role is crucial, particularly in terms of prognosis and functional disability (Heinrichs and Zakzanis, 1998; Johnson-Selfridge and Zalewski, 2001). Cognitive deficits might also represent an endophenotype of schizophrenia, as we showed that they are being shared by nonaffected relatives (Breton et al., 2011). Memory is one of the most impaired cognitive functions, with deficits in semantic and episodic memories (Chen et al., 2000; Thoma et al., 2009) as well as visuo-spatial and phonological working memories (Fuller et al., 2009; Kim et al., 2010). Studies on cognition and late-onset psychosis show conflicting results that probably reflect the clinical heterogeneity of this entity (Rajji and Mulsant, 2008). Performances in patients with a late-life onset are significantly lower than that of healthy subjects (Convert et al., 2006; Vahia et al., 2010). Studies comparing LOS patients to EOS have also shown conflicting results in cognitive performances, but all these studies have included heterogeneous groups of patients. “Late-life psychosis” includes various diagnostics, such as late-onset first psychotic episodes associated with prodromal dementia, manic or depressive episodes or even organic brain disorders (Girard et al., 2011). Therefore all these different entities, whereby only the age at onset is a significant criterion, are not comparable. We believe that the cognitive deficits of patients with LOS must be characterized regardless of the effect of aging and related organic factors. We thus sought to characterize the memory profile of a specific group of patients, meeting the DSM-IV criteria for schizophrenia after the age of 45, thus excluding all psychotic episodes associated either with prodromal dementia, with affective disorders or with organic brain disorders. The main objective of this study is to compare the memory cognitive profile of LOS patients to that of EOS patients and healthy controls, all subjects being under 65 years. The main hypothesis is that the memory profile in LOS is significantly less damaged than that of EOS, even when controlling for the duration of the disorder. We also compared the performance of the LOS patients without related organic factors to that of healthy subjects matched for age. 2. Materials and methods 2.1. Subjects We recruited 25 outpatients with LOS (onset after 45), 44 outpatients with EOS (onset before 45), and 23 healthy controls from a psychiatric department of a French teaching hospital in the Parisian suburb. A total of 92 subjects were evaluated by a trained psychiatrist using the Diagnostic Interview for Genetic Studies (DIGS) (Nurnberger et al., 1994), a semi-structured interview screening socio-demographic characteristics as well as a lifetime diagnoses (according to DSM-IV criteria) for schizophrenia and other psychiatric disorders. Clinical symptoms were assessed using the Positive And Negative Syndrome Scale (PANSS) (Kay et al., 1989). Age at onset was defined as the age at which the first positive symptoms were documented, including hallucinations, delusions, thought disorder, and/or catatonic behavior. We then calculated the duration of the illness by subtracting the age of onset from the age at interview. Inclusion criteria required (1) meeting the DSM-IV criteria for schizophrenia, (2) having a stable state with no change in medication or symptoms for at least 4 weeks before the cognitive evaluation and (3) having no mental retardation or severe cognitive aging deterioration. The EOS and LOS patients were comparable for (1) duration of schizophrenia, (2) educational level and (3) psychotropic medication. The control sample was recruited through partners of patients admitted in the psychiatric department. None of the healthy controls had a personal history or first-degree family history of bipolar or psychotic disorder according to the Family History-Research Diagnostic Criteria
(FH-RDC) (Andreasen et al., 1977) and none of them were taking any psychotropic medication. This control group was matched to the LOS group for (1) age and (2) gender, to control the factors influencing cognitive performance. The subjects (patients and controls) had no history of current substance abuse, brain injury, neurological disease, medical condition or medication known to be associated with neuropsychological impairment. All participants had normal or corrected-to-normal vision. We did not include patients over 65 years of age, to limit the potential bias of age-related cognitive deficits. We also used the Mini Mental State Examination (MMSE) as a screening tool for overall cognitive impairment. This test helped to exclude subjects with marked cognitive impairment, when the final score was under 28. None of the recruited subjects had mental retardation as evaluated by the National Adult Reading Test (NART) (Bright et al., 2002). During their hospitalization, the subjects had had a comprehensive clinical examination, biological investigations and a brain imaging (CT or MRI), in order to look for any possible organic cause of late-onset psychosis. Patients and healthy volunteers all gave their written informed consent. The study protocol was approved by the French Ethics and Data Protection and Freedom of Information Commissions. 2.2. Neurocognitive measures Patients and controls completed three neurocognitive tests evaluating different components of memory: The Rey–Osterrieth Complex Figure Test (ROCF) is a widely used task (Tupler et al., 1995) which consists in copying a geometric figure and then reproducing it from memory, either immediately (T0) and after a delay (T1). The test permits the evaluation of visuospatial working memory and episodic memory, as well as abilities, attention, and planning. The Digit span Forward Task (WAIS III-R subtest) (Grégoire and Van der Linden, 1997), a common measure of short-term memory, consists of a list of random numbers which is read out loud at the rate of one per second. The test begins with two to three numbers, increasing until the person commits errors. At the end of a sequence, the patient is asked to recall the items in order. In the Backward digit span task (WAIS III-R subtest) (Grégoire and Van der Linden, 1997), the procedure is roughly the same, except that subjects are asked to recall the digits in backward order, which measures the auditory working memory. The results on the forward and backward digit span tasks are age-corrected. In the Verbal Fluency Tests subjects have to say as many words as possible from a category within 60 s. This category is semantic, such as animals or fruits, then phonemic, such as words that begin with letter p. The performance measure is the total number of words. These tests evaluate semantic memory as well as executive functions, such as mental flexibility (Cardebat et al., 1990). 2.3. Statistical analysis LOS and EOS patients and healthy controls were compared using chi-square (χ2) analyses for sociodemographic distributions. Continuous variables were compared between the three groups using a univariate analysis of variance (one way ANOVA). For all cognitive tasks showing significant between-groups global differences, post-hoc oneby-one differences were looked for. We first compared memory performances in LOS and EOS patients to find out whether the impairments constitute a specific feature of early-onset or not. We then compared the performance of LOS to that of healthy controls to find out whether memory performance differed in the two groups. As groups differed significantly on demographic variables, an adjustment was done on
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gender, age and level of education for the inter-group comparisons using analyses of covariance (ANCOVA). Adjusted p values are presented in the tables and text. Pearson correlations were performed to analyze the relationship between age at onset or duration of the illness and cognitive performance. Differences were considered to be significant if p b 0.05. Statistical analyses were carried out using the SPSS for Windows (version 17.0). 3. Results 3.1. Demographic characteristics We recruited 69 patients with DSM-IV criteria for schizophrenia who had neuropsychological exam results out of 210 patients who did not meet inclusion criteria. Twenty three healthy controls, with identical inclusion criteria were free of any psychiatric disease (DSM-IV axis I), and any condition known to affect cognitive function. The demographic and clinical characteristics of the three samples are shown in Table 1. LOS patients were significantly older (p b 0.001) than EOS patients, but with no significant differences for age at interview. Furthermore, they had no significant difference regarding duration of disorder and educational level. There was a significantly higher proportion of women in the LOS than in the EOS patients' group (p b 0.0001). LOS patients were not significantly more married than EOS (p = 0.487) but they lived more often alone (p = 0.003) and worked more than EOS (p b 0.0001). EOS and LOS patients also differed significantly in terms of age of onset (p b 0.001), and in terms of first degree familial history of schizophrenia, which was significantly lower in the LOS group (p = 0.007). Moreover, EOS have significantly higher scores than LOS patients on the PANSS total score (p b 0.0001), as well as on the positive, negative and general PANSS sub-scores (p = 0.05, p b 0.0001 and p b 0.001, respectively). However, patients did not differ significantly in terms of type of antipsychotic treatment (atypical versus conventional; 73% for EOS vs 72% for LOS, p = 0.80), nor in terms of benzodiazepines (46% for EOS vs 30% for LOS) or anticholinergics (30% for EOS vs 26% for LOS). Controls had a higher level of education than the LOS patient groups (p = 0.002) but they had no significant difference of age (p = 0.148). 3.2. Results on the neuropsychological tests Fig. 1 shows that LOS patients have an intermediate profile between the EOS patients and the healthy subjects on most cognitive tests. The mean score values on all neuropsychological tests are shown in Table 2.
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Patients with LOS had significantly better performances compared to EOS on the digit span task, forward and global score (p = 0.031, 0.018, respectively), Rey's complex figure at T1 score (p = 0.046) and phonemic verbal fluency (p = 0.016). On the other hand, LOS was slower than EOS for the time required to draw the Rey's complex figure (p = 0.032) (Table 2). We found a positive correlation between the poorer performance in the phonemic verbal fluency tests and the lower age at onset of the disease (r = 0.37, p = 0.002). No correlation between cognitive impairments and duration of the illness was observed (data not shown). We also found a negative correlation between the poorer performance in the phonemic verbal fluency tests and higher positive, negative general and total PANSS scores (r = -0.29 p = 0.015, r = -0.35 p = 0.003, r = -0.29 p = 0.016 and r = -0.36 p = 0.003). No other correlation between cognitive impairments and PANSS scores was observed (data not shown). LOS had significantly lower performances than healthy controls on the digit span task, backward (p = 0.033) and global score (p = 0.037) and on the phonemic (p = 0.003) and semantic (p = 0.009) verbal fluency tests. Regarding the Rey figure tests, LOS drew significantly slower than controls (p = 0.009 at T0 and p = 0.027 at T1) but had similar performances scores. 4. Discussion Patients with late-onset schizophrenia were performing different memory tasks at a significantly lower level than controls but mainly better than patients with early-onset schizophrenia, placing memory performances of LOS patients in an intermediate position between EOS patients and healthy controls for most of the tests. According to some literature data, performances in patients with a late-life onset are significantly lower than that of healthy subjects (Convert et al., 2006; Vahia et al., 2010). However, studies on cognition and late-onset psychosis show conflicting results when comparing the neuropsychological characteristics of LOS patients to those of EOS. Some studies show that patients with “late life psychosis” suffer from lower cognitive performances than EOS (Miller et al., 1991; Almeida et al., 1995) but they conclude that the lack of a clear pattern of impairment among the patients with a late-onset psychosis may be the result of their clinical and cognitive diversity. Other studies find that EOS and LOS have similar cognitive profiles (Jeste et al., 1995; Vahia et al., 2010; Girard et al., 2011). Jeste et al. (1995) found similar performances between EOS and LOS. Girard's
Table 1 Demographic and clinical characteristics of two groups of patients with schizophrenia (with late versus early onset) and a healthy control group. ANOVA between-groups
ANCOVA between two-group differences
Characteristics (mean, SD)
Patients with LOS N = 25
Patients with EOS N = 44
Controls N = 23
F (df = 2)
p
LOS versus EOS p
LOS versus controls p
Age, years Years of education Age at onset Duration of the illness PANSS positive PANSS negative PANSS general PANSS total score
50.88 10.80 42.58 9.12 13.36 14.76 26.20 54.32
(9.16) (2.84) (7.23) (7.11) (4.46) (7.97) (7.29) (17.64)
35.36 10.91 23.07 12.25 15.84 26.81 34.03 76.40
(8.25) (2.32) (6.45) (7.10) (5.07) (6.20) (6.26) (12.71)
46.87 13.3
28.17 8.09
b0.001 b0.001
b0.001 0.160 b0.001 0.086 0.046 b0.001 b0.001 b0.001
0.148 0.002 NA NA NA NA NA NA
Characteristics (N, %) Gender (male) Marital status (married) Living arrangements (alone) Professional situation (working) First degree familial history of schizophrenia
28% 20% 52% 48% 4%
36 6 8 3 14
82% 13.63% 18.18% 6.82% 32%
8 16 3 21 0
p b0.001 b0.001 0.002 b0.001 b0.001
p b0.001 0.487 0.003 b0.001 0.007
p
7 5 13 12 1
(9.68) (2.49) NA NA NA NA NA NA
PANSS pos: PANSS positive symptom subscale; PANSS neg: PANSS negative symptom subscale; PANSS gen: PANSS general symptom subscale; PANSS tot: PANSS total score;
NA NA NA NA NA NA
35% 70% 13% 91% 0%
χ2 (df = 2) 23.99 24.23 12.16 46.40 15.01
0.612 b0.001 0.004 0.001 0.332
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Digit Span Forward Task Score
*
15
15
10
Digit Span Task Global and Age Corrected Scaled Score
Backward Digit Span Task Score
*
20
*
*
10 10
**
EO
LO
S
S
pa tie nt s
pa tie nt s
ol s
Phonemic Verbal Fluency Test (Score) SemanticVerbalFluency Test (Score)
*
*
** 40
*
** *
30
300
300
on tr
Rey Figure Test T1 (Score) Rey Figure Test T1 (Time: s) 900 700 500 400
400
C
S LO
Rey Figure Test T0 (Score) Rey Figure Test T1 (Time: s) 1000 750 500 500
pa tie nt s
ol s on tr C
EO
LO
S
S
pa tie nt s
ol s on tr C
0
S
0
EO
0
pa tie nt s
5
pa tie nt s
5
20
200
200
10
100 0
s
s
nt pa
pa
tie
tie
ol tr on C
S EO
LO
S EO
LO
nt
s
s tie pa
tie pa S
C
S EO
nt
s nt
s tr on
tie pa
tie pa S LO
ol
nt
s nt
s ol tr on C
0
s
0
S
100
*: p<0.05,**: p<0.01 Fig. 1. Digit span task global, phonemic verbal fluency test and Rey figure test T1 performances in LOS patients, EOS patients and controls.
Canadian study sought to characterize and compare the cognitive profile and natural evolution of patients presenting late-onset psychotic symptoms (LOPS) to those of elderly patients (aged over 50) with EOS and to those of two control groups (Girard et al., 2011): most EOS and LOPS patients presented significant cognitive deficits with or without dementia when compared to controls. However, Girard's study did not adjust for the duration of the illness. Finally, in Vahia's study, LOS patients had better verbal memory, but LOS patients had better verbal memory with most differences remaining significant after adjusting for age, gender, severity of negative or deficit symptoms, and duration of illness (Vahia et al., 2010). Comparative studies of EOS and LOS patients in most cases have reported no differing profiles of cognitive performance, but studies did not always take into account demographic
and clinical variable such as duration of the illness and age at interview (Schmid et al., 2011). In accordance with our results, other studies have shown that LOS patients have better neuropsychologic performances compared to EOS. Rajji et al. (2009) showed that individuals with EOS have severe cognitive deficits, whereas those with LOS have some relatively preserved cognitive functions. Another study comparing early-onset and middle-aged onset schizophrenic patients shows that the latter have better neuropsychologic performances, particularly in learning and abstraction/cognitive flexibility and possibly larger thalamic volumes (Palmer et al., 2001). These findings and our results support the view that severity of the disease process is associated with different ages at onset rather than with the duration of the disorder. Other studies also
Table 2 Mean score values (SD) on the neurocognitive tests for LOS and EOS patients and controls. ANOVA betweengroups
ANCOVA between two-group differences
Mean (SD)
Patients with LOS versus EOS (N = 25)
Patients with EOS (N = 44)
Controls (N = 23)
F (df = 2)
p
LOS versus EOS pa
LOS versus controls pb
Digit span forward task score Backward digit span task score Digit span task global and age-corrected scaled score Rey figure test T0 (score) Rey figure test T0 (time) Rey figure test T1 (score) Rey figure test T1 (time) Phonemic verbal fluency test Semantic verbal fluency test
8.68 4.76 7.96 29 262.57 14.16 171.04 11.48 15.68
7.73 4.75 6.49 31.28 219.28 11.31 117.05 9.27 17.47
10.33 6.9 10.62 33.2 125.68 18.54 107.18 16.57 22.91
11.54 7.85 16.54 0.2 6.52 9027 3.08 25.39 9.46
b0.001 0.001 b0.001 0.822 0.002 b0.001 0.05 b0.001 b0.001
0.031 0.492 0.018
0.08 0.033 0.037
0.134 0.046 0.032 0.016 0.891
0.009 0.161 0.027 0.003 0.009
a b
Adjusted for sociodemographic variables (sex). Adjusted for sociodemographic variables (educational level).
(1.80) (1.67) (2.46) (5.68) (190.97) (6.02) (161.65) (3.73) (5.34)
(2.12) (2.30) (2.88) (33.37) (118.77) (6.95) (60.98) (4.22) (5.95)
(2.18) (2.43) (2.50) (2.31) (49.26) (6.13) (37.21) (3.76) (6.75)
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support the hypothesis of an influence of age of onset on illness course in patients with schizophrenia spectrum disorders (Kao and Liu, 2010). A recent study sought to assess the contribution of age at onset to variation in cognitive functioning in a large sample of patients with schizophrenia spectrum disorder and found that earlier onset was associated with worse performance on immediate recall and sustained attention (Van der Werf et al., 2012). These data are in accordance with our results: a significant positive correlation between the poorer performance in the phonemic verbal fluency tests and the lower age at onset of the disease. In addition, our results suggested that the cognitive deficits of people with LOS are specific rather than solely as a result of aging and related factors. In this study, LOS patients have a MMES score upper 28 and no organic cause of late-onset psychosis. Previous studies' contradictory results probably reflect the clinical heterogeneity of this entity. For instance, organic related psychosis in LOS group may explain a part of heterogeneous results when compared to the EOS group (Almeida et al., 1995; Girard et al., 2011). Having limited the potential bias of organic or age-related cognitive deficits, we mainly found better memory performances in LOS compared to EOS. Our findings therefore support the view that severity of the disease process is associated more with different ages at onset than with the duration of the disorder. However, some studies support the idea that schizophrenia has a progressively deteriorating course, showing that the longer the illness duration, the poorer the cognitive performances, for example on visuomotor process and delayed visual memory tasks (Cuesta et al., 1998). Cuesta et al. (1998) found that these neuropsychological disturbances associated with illness duration, were different from those related to aging, educational background, gender and treatment status. One neuroimaging study has also shown that right medial temporal, medial cerebellar and bilateral anterior cingulate gray matter volume, and white matter volume in the right posterior limb of the internal capsule, were all negatively correlated with illness duration in patients with chronic schizophrenia. These morphologic correlations were not a function of chronological age or age at illness onset (Velakoulis et al., 2002). On the other hand, other studies investigating the progression of neuropsychological impairment in schizophrenia challenge these views. A previous study, comparing schizophrenic patients with different durations of illness, showed that performances in the Wisconsin Card Sorting Test (WCST) and semantic fluency were both impaired at an early stage in the illness and did not significantly deteriorate as the illness duration increased. The data support a lack of progression in prefrontal dysfunction and in most other cognitive domains (Chen et al., 1996). Another study also suggests that cognitive functions do not markedly decline during the adulthood of patients with schizophrenia and that the course of schizophrenia is more consistent with a static encephalopathy than a dementing disorder (Hyde et al., 1994). One study supports the hypothesis that cognitive deficits associated with schizophrenia cannot be considered a unitary trait, but emerge along different hypothetical trajectories (Stratta et al., 2004). We do not yet know for sure what exact relationship exists between each cognitive deficit and each clinical symptom. Several studies show that schizophrenic patients present deficits in each subsystem component of working memory and that these deficits are correlated with negative symptoms and disorganization. Dibben et al. (2009) published a meta-analysis showing that the negative signs are associated with performances on the verbal fluency test (Dibben et al., 2009). These data are interesting because it is the verbal fluency test for which we found a significant trend between EOS and LOS and poor performance in the phonemic verbal fluency tests was correlated with high negative PANSS scores. We also found a significant positive correlation between age at onset and phonetic verbal fluency performance and no correlation between the illness duration and cognitive performance in all patients. Moreover, studies show that performances in episodic memory and working memory tasks are significantly negatively correlated with
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hallucinations, whereas delusions are not significantly associated with memory performances (Berenbaum et al., 2008). These data are coherent with that LOS subjects, who have lower positive PANSS scores, have better memory capacities and learning abilities and therefore a higher level of social and professional functioning. Our results can be interpreted in the light of these literature data, which show a significant difference between LOS and EOS on most memory performances. However, apart from the phonemic verbal fluency test, we did not find any other correlation between PANSS scores and other memory tests. Despite the consensual criteria proposed by International Classifications, schizophrenia appears to be a heterogeneous clinical entity composed of a group of related disorders. The considerable inter-patient clinical and cognitive heterogeneity has led to move away from the categorical approach and to treat schizophrenic disorders in a more dimensional clinical approach: the various schizophrenic symptoms can be divided into several independent clinical dimensions, underpinned by different substrata and determinism and coexisting in varying degrees from one patient to the next. The identification of a fivedimensional clinical structure had already been shown by other teams (Maziade et al., 1995; Serretti and Olgiati, 2004). Among the proposed revisions in the development of the DSM-V, a recommendation has been made to utilize the assessment of dimensions instead of subtypes. This approach, which provides an interesting approach of the continuum between normality and psychosis, would reflect the distinct psychopathological domains in psychotic illnesses which have distinctive patterns of treatment-response, implications, and course. The cognitive profile could therefore be integrated as being a distinct dimension to characterize each clinical picture. This dimensional approach may further help to distinguish possible etiopathogenic factors involved in LOS. Many functional neuroimaging studies have been performed mainly in young patients with schizophrenia, but LOS still remains largely unexamined by these techniques. Recent studies have reported abnormalities in white matter integrity in LOS patients, which may contribute to the pathophysiology of LOS (Casanova and Lindzen, 2003; Chen et al., 2013). In terms of genetic data, studies have sought to find candidate genes involved in the etiopathogeny of schizophrenia or appeared to modify the schizophrenia phenotype such as age at onset. Polymorphisms located in BDNF, dopa decarboxylase (DDC), and Dopamine receptor (D2) genes have been be significantly associated with late age of onset: they appear to have a modifying rather than causative effect and could act as modulators of age of onset and hence be used as predictors of later age at onset in early onset schizophrenia (Krebs et al., 2000; Børglum et al., 2001; Dubertret et al., 2004b; Rasmussen et al., 2006; Ayalew et al., 2012; Voisey et al., 2012). Particularly, the 32-bp deletion allele in Chemokine receptor (CCR5) and rs 1800497 located in DRD2 genes have been involved in late-onset-schizophrenia patients and may act as a modifier by delaying the onset of schizophrenia without affecting the disease susceptibility (Rasmussen et al., 2006; Dubertret et al., 2010). This study has strengths and limitations. The principal strengths include the homogenous group of LOS limiting the effect of aging and organic factors on cognitive performances. However, some limitations should be considered in interpreting these findings. Firstly, the main limitation is the number of subjects included which did not have sufficient statistical power to allow us to make a strict matching between subjects and to show a significant difference between the groups for all tests. However, the main factors influencing cognition (age, sex, educational level, duration of the illness and treatments with cognitive impact such as antipsychotics, benzodiazepines and anticholinergics) were controlled in our work. Moreover, the evaluation of the subjects was very thorough in terms of neuropsychological assessment, using many of the memory tests commonly used in studies on schizophrenia. The second limitation is that the memory tests in this work are used to assess different cognitive abilities, such as executive functions and attention. Despite these limitations, this study provides evidence that LOS belongs to the broad continuous spectrum of schizophrenic disorders
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and it can be considered as an extreme of typical schizophrenia. Schizophrenia in this definition seems to be fundamentally heterogeneous. However, LOS can be in line with a dimensional clinical approach, whereby it presents few memory deficits, as well as few disorganization and negative symptoms with mostly positive symptoms. This is a preliminary study. Its needs further researches to confirm these results with more specific memory assessment tests and a larger cohort of subjects. Role of the funding sources No funding source was obtained for this study.
Contributors C. Dubertret designed the study and wrote the protocol. C. Brichant-Petitjean managed the literature searches, provided data and wrote the first draft of the manuscript. C. Legauffre and J. Ades provided data. C. Dubertret and N. Ramoz undertook the statistical analysis. C. Dubertret and P. Gorwood revised the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest All other authors declare no conflicts of interest that influence their work.
Acknowledgment The authors wish to acknowledge the kind assistance of patients and nurses who participated in the study.
References Almeida, O.P., Howard, R.J., Levy, R., David, A.S., Morris, R.G., Sahakian, B.J., 1995. Cognitive features of psychotic states arising in late life (late paraphrenia). Psychol. Med. 25 (4), 699–714. American Psychiatric Association, 1980. DSM-III: Diagnostic and Statistical Manual of Mental Disorder, third ed. The Association, Washington, DC. American Psychiatric Association, 1987. DSM-III-R: Diagnostic and Statistical Manual of Mental Disorder, third ed., revised. The Association, Washington, DC. American Psychiatric Association, 1994. Mini DSM-IV TR: Diagnostic and Statistical Manual of Mental Disorders, fourth ed. APA, Washington, DC. Andreasen, N.C., Endicott, J., Spitzer, R.L., Winokur, G., 1977. The family history method using diagnostic criteria. Reliability and validity. Arch. Gen. Psychiatry 34 (10), 1229–1235. Ayalew, M., Le-Niculescu, H., Levey, D.F., Jain, N., Changala, B., Patel, S.D., Winiger, E., Breier, A., Shekhar, A., Amdur, R., Koller, D., Nurnberger, J.I., Corvin, A., Geyer, M., Tsuang, M.T., Salomon, D., Schork, N.J., Fanous, A.H., O'Donovan, M.C., Niculescu, A.B., 2012. Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. Mol. Psychiatry 17 (9), 887–905. Ballet, G., 1911. La Psychose hallucinatoire Chronique. Encephale 11, 401–411. Berenbaum, H., Kerns, J.G., Vernon, L.L., Gomez, J.J., 2008. Cognitive correlates of schizophrenia signs and symptoms: hallucinations and delusions. Psychiatr. Res. 159 (1–2), 163–166. Bleuler, M., 1943. Late schizophrenic clinical pictures. In German Fortschr. Neurol. Psychiatr. 15, 259–290. Børglum, A.D., Hampson, M., Kjeldsen, T.E., Muir, W., Murray, V., Ewald, H., Mors, O., Blackwood, D., Kruse, T.A., 2001. Dopa decarboxylase genotypes may influence age at onset of schizophrenia. Mol. Psychiatry 6 (6), 712–717. Breton, F., Planté, A., Legauffre, C., Morel, N., Adès, J., Gorwood, P., et al., 2011. The executive control of attention differentiates patients with schizophrenia, their first-degree relatives and healthy controls. Neuropsychologia 49 (2), 203–208. Bright, P., Jaldow, E., Kopelman, M.D., 2002. The National Adult Reading Test as a measure of premorbid intelligence: a comparison with estimates derived from demographic variables. J. Int. Neuropsychol. Soc. 8 (6), 847–854. Cardebat, D., Doyon, B., Puel, M., Goulet, P., Joanette, Y., 1990. Formal and semantic lexical evocation in normal subjects. Performance and dynamics of production as a function of sex, age and educational level. Acta Neurol. Belg. 90 (4), 207–217. Casanova, M.F., Lindzen, E.C., 2003. Changes in gray-/white-matter ratios in the parahippocampal gyri of late-onset schizophrenia patients. Am. J. Geriatr. Psychiatry 11 (6), 605–609. Chen, E.Y., Lam, L.C., Chen, R.Y., Nguyen, D.G., Chan, C.K., 1996. Prefrontal neuropsychological impairment and illness duration in schizophrenia: a study of 204 patients in Hong Kong. Acta Psychiatr. Scand. 93 (2), 144–150. Chen, R.Y., Chen, E.Y., Chan, C.K., Lam, L.C., Lieh-Mak, F., 2000. Verbal fluency in schizophrenia: a reduction in semantic store. Aust. N. Z. J. Psychiatry 34 (1), 43–48. Chen, L., Chen, X., Liu, W., Wang, Q., Jiang, T., Wang, J., Wang, X., Zhou, B., Tang, J., 2013. White matter microstructural abnormalities in patients with late-onset schizophrenia identified by a voxel-based diffusion tensor imaging. Psychiatry Res. 212 (3), 201–207. Convert, H., Védie, C., Paulin, P., 2006. Late-onset schizophrenia or chronic delusion. Encephale 32 (6), 957–961. Cuesta, M.J., Peralta, V., Zarzuela, A., 1998. Illness duration and neuropsychological impairments in schizophrenia. Schizophr. Res. 33 (3), 141–150. Dibben, C.R., Rice, C., Laws, K., McKenna, P.J., 2009. Is executive impairment associated with schizophrenic syndromes? A meta-analysis. Psychol. Med. 39, 381–392.
Dubertret, C., Adès, J., Gorwood, P., 2004a. Clinical and etiopathogenic specificities of the French concept of Psychose Hallucinatoire Chronique compared to schizophrenia. Schizophr. Bull. 30 (1), 173–184. Dubertret, C., Gouya, L., Hanoun, N., Deybach, J., Ades, J., Hamon, M., Gorwood, P., 2004b. The 3′ region of the DRD2 gene is involved in genetic susceptibility to schizophrenia. Schizophr. Res. 67, 75–85. Dubertret, C., Bardel, C., Ramoz, N., Martin, P.M., Deybach, J., Ades, J., Gorwood, P., Gouya, L., 2010. A genetic schizophrenia-susceptibility region located between the ANKK1 and DRD2 genes. Prog. Neuropsychopharmacol. Biol. Psychiatry 34 (3), 492–499. Fuller, R.L., Luck, S.J., Braun, E.L., Robinson, B.M., McMahon, R.P., Gold, J.M., 2009. Impaired working visual memory consolidation in schizophrenia. Neuropsychology 23 (1), 71–80. Girard, C., Simard, M., Noiseux, R., Laplante, L., Dugas, M., Rousseau, F., et al., 2011. Lateonset-psychosis: cognition. Int. Psychogeriatr. 23 (8), 1301–1316. Gorwood, P., Leboyer, M., Jay, M., Payan, C., Feingold, J., 1995. Gender and age at onset in schizophrenia: impact of family history. Am. J. Psychiatry 152 (2), 208–212. Grégoire, J., Van der Linden, M., 1997. The effect of age on forward and backward digit spans. Neuropsychol. Dev. Cogn. B Aging Neuropsychol. Cogn. 4, 140–149. Heinrichs, R.W., Zakzanis, K.K., 1998. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 12 (3), 426–445. Howard, R., Rabins, P.V., Seeman, M.V., Jeste, D.V., 2000. Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. Am. J. Psychiatry 157, 172–178. Hyde, T.M., Nawroz, S., Goldberg, T.E., Bigelow, L.B., Strong, D., Ostrem, J.L., Weinberger, D.R., Kleinman, J.E., 1994. Is there cognitive decline in schizophrenia? A cross-sectional study. Br. J. Psychiatry 164 (4), 494–500. Jeste, D.V., Harris, M.J., Krull, A., Kuck, J., McAdams, L.A., Heaton, R., 1995. Clinical and neuropsychological characteristics of patients with early-onset schizophrenia. Am. J. Psychiatry 152 (5), 722–730. Johnson-Selfridge, M., Zalewski, C., 2001. Moderator variables of executive functioning in schizophrenia: meta-analytic findings. Schizophr. Bull. 27 (2), 305–316. Kao, Y.C., Liu, Y.P., 2010. Effects of age of onset on clinical characteristics in schizophrenia spectrum disorders. BMC Psychiatry 10, 63. Kay, S.R., Opler, L.A., Lindenmayer, J.P., 1989. The Positive and Negative Syndrome Scale (PANSS): rationale and standardisation. Br. J. Psychiatry (Suppl. (7)), 59–67. Kim, J., Matthews, N.L., Park, S., 2010. An event-related FMRI study of phonological verbal working memory in schizophrenia. PLoS One 5 (8), e12068. Krebs, M.O., Guillin, O., Bourdell, M.C., Schwartz, J.C., Olie, J.P., Poirier, M.F., Sokoloff, P., 2000. Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. Mol. Psychiatry 5 (5), 558–562. La Salvia, E., Chemali, Z., 2011. A perspective on psychosis in late life and deficits in social cognition. Harv. Rev. Psychiatry 19 (4), 190–197. Maziade, M., Roy, M.A., Martinez, M., Cliche, D., Fournier, J.P., Garneau, Y., et al., 1995. Negative, psychoticism, and disorganized dimensions in patients with familial schizophrenia or bipolar disorder: continuity and discontinuity between the major psychoses. Am. J. Psychiatry 152 (10), 1458–1463. Miller, B.L., Lesser, I.M., Boone, K.B., Hill, E., Mehringer, C.M., Wong, K., 1991. Brain lesions and cognitive function in late-life psychosis. Br. J. Psychiatry 158, 76–82. Nurnberger Jr., J.I., Blehar, M.C., Kaufmann, C.A., York-Cooler, C., Simpson, S.G., HarkavyFriedman, J., et al., 1994. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch. Gen. Psychiatry 51 (11), 849–859. Palmer, B.W., McClure, F.S., Jeste, D.V., 2001. Schizophrenia in late life: findings challenge traditional concepts. Harv. Rev. Psychiatry 9 (2), 51–58. Rajji, T.K., Mulsant, B.H., 2008. Nature and course of cognitive function in late-life schizophrenia: a systematic review. Schizophr. Res. 102 (1–3), 122–140. Rajji, T.K., Ismail, Z., Mulsant, B.H., 2009. Age at onset and cognition in schizophrenia: meta-analysis. Br. J. Psychiatry 195 (4), 286–293. Rasmussen, H.B., Timm, S., Wang, A.G., Søeby, K., Lublin, H., Fenger, M., Hemmingsen, R., Werge, T., 2006. Association between the CCR5 32-bp deletion allele and late onset of schizophrenia. Am. J. Psychiatry 163 (3), 507–511. Schmid, L.A., Lässer, M.M., Schröder, J., 2011. [Symptoms and cognition in geriatric schizophrenia]. [Article in German]. Fortschr. Neurol. Psychiatr. 79 (5), 267–276. Serretti, A., Olgiati, P., 2004. Dimensions of major psychoses: a confirmatory factor analysis of six competing models. Psychiatry Res. 127 (1–2), 101–109. Stratta, P., Arduini, L., Daneluzzo, E., Rinaldi, O., di Genova, A., Rossi, A., 2004. Relationship of good and poor Wisconsin Card Sorting Test performance to illness duration in schizophrenia: a cross-sectional analysis. Psychiatry Res. 121 (3), 219–227. Thoma, R.J., Monnig, M., Hanlon, F.M., Miller, G.A., Petropoulos, H., Mayer, A.R., et al., 2009. Hippocampus volume and episodic memory in schizophrenia. J. Int. Neuropsychol. Soc. 15 (2), 182–195. Tupler, L.A., Welsh, K.A., Asare-Aboagye, Y., Dawson, D.V., 1995. Reliability of the ReyOsterrieth complex figure in use with memory-impaired patients. J. Clin. Exp. Neuropsychol. 17 (4), 566–579. Vahia, I.V., Palmer, B.W., Depp, C., Fellows, I., Golshan, S., Kraemer, H.C., et al., 2010. Is lateonset schizophrenia a subtype of schizophrenia? Acta Psychiatr. Scand. 122 (5), 414–426. Van der Werf, M., Köhler, S., Verkaaik, M., Verhey, F., Van Os, J., 2012. Cognitive functioning and age at onset in non-affective psychotic disorder. Acta Psychiatr. Scand. 126 (4), 274–281. Velakoulis, D., Wood, S.J., Smith, D.J., Soulsby, B., Brewer, W., Leeton, L., Desmond, P., Suckling, J., Bullmore, E.T., McGuire, P.K., Pantelis, C., 2002. Increased duration of illness is associated with reduced volume in right medial temporal/anterior cingulate grey matter in patients with chronic schizophrenia. Schizophr. Res. 57 (1), 43–49. Voisey, J., Swagell, C.D., Hughes, I.P., Lawford, B.R., Young, R.M., Morris, C.P., 2012. A novel DRD2 single-nucleotide polymorphism associated with schizophrenia predicts age of onset: HapMap tag-single-nucleotide polymorphism analysis. Genet. Test. Mol. Biomark. 16 (2), 77–81.
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Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Memory deficits in late-onset schizophrenia Clara Brichant-Petitjean a, Cindy Legauffre b, Nicolas Ramoz c, Jean Ades c,d, Philip Gorwood c, Caroline Dubertret b,c,d,⁎ a
AP-HP, Department of Psychiatry, Fernand Widal Hospital, Paris, France AP-HP, Department of Psychiatry, Louis Mourier Hospital, Colombes, France INSERM U675-U894, Center of Psychiatry and Neurosciences, Paris, France d University Paris 7 Denis Diderot, Faculty of Medicine, Paris, France b c
a r t i c l e
i n f o
Article history: Received 28 December 2012 Received in revised form 29 July 2013 Accepted 14 August 2013 Available online 13 October 2013 Keywords: Late-onset schizophrenia Cognitive deficits Neuropsychological tests Memory impairment
a b s t r a c t Late-onset schizophrenia (LOS) is a controversial diagnosis, mainly characterized by more positive symptoms and less deterioration. LOS could be considered as either an extreme of typical schizophrenia (but for old age patients, and short duration of the disorder), or an independent group of patients with a specific diagnosis, with no clear evidence in favor or against any of these hypotheses. The aim of the present study is to characterize the memory cognitive profile of LOS patients without related organic factors (N = 25), compared to early-onset schizophrenic patients (EOS, N = 44), matched for the duration of the disorder, and healthy controls (HC, N = 23), matched for the age of patients. Lifetime clinical symptoms and functioning were collected using the DIGS and the PANSS, and components of memory capacity were assessed with the Forward and Backward Digit Span Tasks, Rey Complex Figure and Verbal Fluency Tests. LOS patients were performing significantly better than EOS patients on the digit span task, Rey's complex figure at T1 score and phonemic verbal fluency. However, LOS had significantly lower performances than healthy controls on the digit span task and on both verbal fluency tests. This study provides evidence that LOS had intermediate outcome compared to EOS and controls. LOS can therefore be in line with a dimensional clinical approach of schizophrenia, whereby it presents few memory deficits and few disorganization and negative symptoms with mostly positive symptoms and possibly etiopathogenic specificities. Further studies including more specific memory assessment tests and larger samples are needed to confirm the present finding. © 2013 Elsevier B.V. All rights reserved.
1. Introduction The onset of schizophrenia in late life has always been a controversial area of study, as schizophrenia is mainly occurring between 15 and 25 years old (Gorwood et al., 1995). The development of psychotic symptoms is nevertheless a common occurrence in late life, and cognitive impairment associated with psychosis is often prominent in dementia, schizophrenia, and mood disorders. This mixing of symptoms has inevitably led to diagnostic confusion with regard to elderly patients with new-onset psychosis (La Salvia and Chemali, 2011). In 1943, M. Bleuler, described the characteristics of “late-onset schizophrenia”, occurring over 40 years of age and characterized by less blunted affect and less formal thought disorder (Bleuler, 1943). The French concept of chronic hallucinatory psychosis [“Psychose Hallucinatoire Chronique”], individualized by Ballet (1911), has always been part of a classificatory debate between European and American psychiatrists. ⁎ Corresponding author at: Hôpital Louis Mourier, 178 rue des Renouillers, 92700 Colombes, France. Tel.: +33 147606409; fax: +33 147606740. E-mail address: [email protected] (C. Dubertret). 0920-9964/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2013.08.021
This disorder is characterized by late-onset, occurring mostly in women, with rich and frequent hallucinations and almost no formal thought disorder (Dubertret et al., 2004a, 2004b). In the DSM-III (American Psychiatric Association, 1980), the diagnosis of schizophrenia was excluded if symptoms do not begin before the age of 45. Shortly after, in the DSM-III-R (American Psychiatric Association, 1987), a distinction was proposed between “early-onset” (EOS) and “late-onset” schizophrenia (LOS) (when the disease begins after 45 years of age) (La Salvia and Chemali, 2011). The notion of age of onset was simply abandoned in the DSM IV (American Psychiatric Association, 1994). However, the DSM-IV does mention in the appendix that schizophrenia “may also begin after the age of 45 and that in that case, has a number of characteristics: (1) a higher proportion of wedded women, (2) more persecutory delusions and hallucinations, (3) fewer negative symptoms or disorganized speech, (4) less affect flattening and a (5) better social functioning, even though these patients are more socially isolated”. In 2000, Howard et al. published the findings of an international working group on LOS (Howard et al., 2000). The literature review and guidelines emphasized the fact that LOS is probably not a homogeneous entity but a syndrome with clinically and biologically relevant subtypes,
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starting after the age of 44 years old. The dimensional clinical approach proposed by the DSM-V could help to better characterize clinical characteristics of patients with schizophrenia. Cognitive deficits are considered to be core features of schizophrenia and their role is crucial, particularly in terms of prognosis and functional disability (Heinrichs and Zakzanis, 1998; Johnson-Selfridge and Zalewski, 2001). Cognitive deficits might also represent an endophenotype of schizophrenia, as we showed that they are being shared by nonaffected relatives (Breton et al., 2011). Memory is one of the most impaired cognitive functions, with deficits in semantic and episodic memories (Chen et al., 2000; Thoma et al., 2009) as well as visuo-spatial and phonological working memories (Fuller et al., 2009; Kim et al., 2010). Studies on cognition and late-onset psychosis show conflicting results that probably reflect the clinical heterogeneity of this entity (Rajji and Mulsant, 2008). Performances in patients with a late-life onset are significantly lower than that of healthy subjects (Convert et al., 2006; Vahia et al., 2010). Studies comparing LOS patients to EOS have also shown conflicting results in cognitive performances, but all these studies have included heterogeneous groups of patients. “Late-life psychosis” includes various diagnostics, such as late-onset first psychotic episodes associated with prodromal dementia, manic or depressive episodes or even organic brain disorders (Girard et al., 2011). Therefore all these different entities, whereby only the age at onset is a significant criterion, are not comparable. We believe that the cognitive deficits of patients with LOS must be characterized regardless of the effect of aging and related organic factors. We thus sought to characterize the memory profile of a specific group of patients, meeting the DSM-IV criteria for schizophrenia after the age of 45, thus excluding all psychotic episodes associated either with prodromal dementia, with affective disorders or with organic brain disorders. The main objective of this study is to compare the memory cognitive profile of LOS patients to that of EOS patients and healthy controls, all subjects being under 65 years. The main hypothesis is that the memory profile in LOS is significantly less damaged than that of EOS, even when controlling for the duration of the disorder. We also compared the performance of the LOS patients without related organic factors to that of healthy subjects matched for age. 2. Materials and methods 2.1. Subjects We recruited 25 outpatients with LOS (onset after 45), 44 outpatients with EOS (onset before 45), and 23 healthy controls from a psychiatric department of a French teaching hospital in the Parisian suburb. A total of 92 subjects were evaluated by a trained psychiatrist using the Diagnostic Interview for Genetic Studies (DIGS) (Nurnberger et al., 1994), a semi-structured interview screening socio-demographic characteristics as well as a lifetime diagnoses (according to DSM-IV criteria) for schizophrenia and other psychiatric disorders. Clinical symptoms were assessed using the Positive And Negative Syndrome Scale (PANSS) (Kay et al., 1989). Age at onset was defined as the age at which the first positive symptoms were documented, including hallucinations, delusions, thought disorder, and/or catatonic behavior. We then calculated the duration of the illness by subtracting the age of onset from the age at interview. Inclusion criteria required (1) meeting the DSM-IV criteria for schizophrenia, (2) having a stable state with no change in medication or symptoms for at least 4 weeks before the cognitive evaluation and (3) having no mental retardation or severe cognitive aging deterioration. The EOS and LOS patients were comparable for (1) duration of schizophrenia, (2) educational level and (3) psychotropic medication. The control sample was recruited through partners of patients admitted in the psychiatric department. None of the healthy controls had a personal history or first-degree family history of bipolar or psychotic disorder according to the Family History-Research Diagnostic Criteria
(FH-RDC) (Andreasen et al., 1977) and none of them were taking any psychotropic medication. This control group was matched to the LOS group for (1) age and (2) gender, to control the factors influencing cognitive performance. The subjects (patients and controls) had no history of current substance abuse, brain injury, neurological disease, medical condition or medication known to be associated with neuropsychological impairment. All participants had normal or corrected-to-normal vision. We did not include patients over 65 years of age, to limit the potential bias of age-related cognitive deficits. We also used the Mini Mental State Examination (MMSE) as a screening tool for overall cognitive impairment. This test helped to exclude subjects with marked cognitive impairment, when the final score was under 28. None of the recruited subjects had mental retardation as evaluated by the National Adult Reading Test (NART) (Bright et al., 2002). During their hospitalization, the subjects had had a comprehensive clinical examination, biological investigations and a brain imaging (CT or MRI), in order to look for any possible organic cause of late-onset psychosis. Patients and healthy volunteers all gave their written informed consent. The study protocol was approved by the French Ethics and Data Protection and Freedom of Information Commissions. 2.2. Neurocognitive measures Patients and controls completed three neurocognitive tests evaluating different components of memory: The Rey–Osterrieth Complex Figure Test (ROCF) is a widely used task (Tupler et al., 1995) which consists in copying a geometric figure and then reproducing it from memory, either immediately (T0) and after a delay (T1). The test permits the evaluation of visuospatial working memory and episodic memory, as well as abilities, attention, and planning. The Digit span Forward Task (WAIS III-R subtest) (Grégoire and Van der Linden, 1997), a common measure of short-term memory, consists of a list of random numbers which is read out loud at the rate of one per second. The test begins with two to three numbers, increasing until the person commits errors. At the end of a sequence, the patient is asked to recall the items in order. In the Backward digit span task (WAIS III-R subtest) (Grégoire and Van der Linden, 1997), the procedure is roughly the same, except that subjects are asked to recall the digits in backward order, which measures the auditory working memory. The results on the forward and backward digit span tasks are age-corrected. In the Verbal Fluency Tests subjects have to say as many words as possible from a category within 60 s. This category is semantic, such as animals or fruits, then phonemic, such as words that begin with letter p. The performance measure is the total number of words. These tests evaluate semantic memory as well as executive functions, such as mental flexibility (Cardebat et al., 1990). 2.3. Statistical analysis LOS and EOS patients and healthy controls were compared using chi-square (χ2) analyses for sociodemographic distributions. Continuous variables were compared between the three groups using a univariate analysis of variance (one way ANOVA). For all cognitive tasks showing significant between-groups global differences, post-hoc oneby-one differences were looked for. We first compared memory performances in LOS and EOS patients to find out whether the impairments constitute a specific feature of early-onset or not. We then compared the performance of LOS to that of healthy controls to find out whether memory performance differed in the two groups. As groups differed significantly on demographic variables, an adjustment was done on
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gender, age and level of education for the inter-group comparisons using analyses of covariance (ANCOVA). Adjusted p values are presented in the tables and text. Pearson correlations were performed to analyze the relationship between age at onset or duration of the illness and cognitive performance. Differences were considered to be significant if p b 0.05. Statistical analyses were carried out using the SPSS for Windows (version 17.0). 3. Results 3.1. Demographic characteristics We recruited 69 patients with DSM-IV criteria for schizophrenia who had neuropsychological exam results out of 210 patients who did not meet inclusion criteria. Twenty three healthy controls, with identical inclusion criteria were free of any psychiatric disease (DSM-IV axis I), and any condition known to affect cognitive function. The demographic and clinical characteristics of the three samples are shown in Table 1. LOS patients were significantly older (p b 0.001) than EOS patients, but with no significant differences for age at interview. Furthermore, they had no significant difference regarding duration of disorder and educational level. There was a significantly higher proportion of women in the LOS than in the EOS patients' group (p b 0.0001). LOS patients were not significantly more married than EOS (p = 0.487) but they lived more often alone (p = 0.003) and worked more than EOS (p b 0.0001). EOS and LOS patients also differed significantly in terms of age of onset (p b 0.001), and in terms of first degree familial history of schizophrenia, which was significantly lower in the LOS group (p = 0.007). Moreover, EOS have significantly higher scores than LOS patients on the PANSS total score (p b 0.0001), as well as on the positive, negative and general PANSS sub-scores (p = 0.05, p b 0.0001 and p b 0.001, respectively). However, patients did not differ significantly in terms of type of antipsychotic treatment (atypical versus conventional; 73% for EOS vs 72% for LOS, p = 0.80), nor in terms of benzodiazepines (46% for EOS vs 30% for LOS) or anticholinergics (30% for EOS vs 26% for LOS). Controls had a higher level of education than the LOS patient groups (p = 0.002) but they had no significant difference of age (p = 0.148). 3.2. Results on the neuropsychological tests Fig. 1 shows that LOS patients have an intermediate profile between the EOS patients and the healthy subjects on most cognitive tests. The mean score values on all neuropsychological tests are shown in Table 2.
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Patients with LOS had significantly better performances compared to EOS on the digit span task, forward and global score (p = 0.031, 0.018, respectively), Rey's complex figure at T1 score (p = 0.046) and phonemic verbal fluency (p = 0.016). On the other hand, LOS was slower than EOS for the time required to draw the Rey's complex figure (p = 0.032) (Table 2). We found a positive correlation between the poorer performance in the phonemic verbal fluency tests and the lower age at onset of the disease (r = 0.37, p = 0.002). No correlation between cognitive impairments and duration of the illness was observed (data not shown). We also found a negative correlation between the poorer performance in the phonemic verbal fluency tests and higher positive, negative general and total PANSS scores (r = -0.29 p = 0.015, r = -0.35 p = 0.003, r = -0.29 p = 0.016 and r = -0.36 p = 0.003). No other correlation between cognitive impairments and PANSS scores was observed (data not shown). LOS had significantly lower performances than healthy controls on the digit span task, backward (p = 0.033) and global score (p = 0.037) and on the phonemic (p = 0.003) and semantic (p = 0.009) verbal fluency tests. Regarding the Rey figure tests, LOS drew significantly slower than controls (p = 0.009 at T0 and p = 0.027 at T1) but had similar performances scores. 4. Discussion Patients with late-onset schizophrenia were performing different memory tasks at a significantly lower level than controls but mainly better than patients with early-onset schizophrenia, placing memory performances of LOS patients in an intermediate position between EOS patients and healthy controls for most of the tests. According to some literature data, performances in patients with a late-life onset are significantly lower than that of healthy subjects (Convert et al., 2006; Vahia et al., 2010). However, studies on cognition and late-onset psychosis show conflicting results when comparing the neuropsychological characteristics of LOS patients to those of EOS. Some studies show that patients with “late life psychosis” suffer from lower cognitive performances than EOS (Miller et al., 1991; Almeida et al., 1995) but they conclude that the lack of a clear pattern of impairment among the patients with a late-onset psychosis may be the result of their clinical and cognitive diversity. Other studies find that EOS and LOS have similar cognitive profiles (Jeste et al., 1995; Vahia et al., 2010; Girard et al., 2011). Jeste et al. (1995) found similar performances between EOS and LOS. Girard's
Table 1 Demographic and clinical characteristics of two groups of patients with schizophrenia (with late versus early onset) and a healthy control group. ANOVA between-groups
ANCOVA between two-group differences
Characteristics (mean, SD)
Patients with LOS N = 25
Patients with EOS N = 44
Controls N = 23
F (df = 2)
p
LOS versus EOS p
LOS versus controls p
Age, years Years of education Age at onset Duration of the illness PANSS positive PANSS negative PANSS general PANSS total score
50.88 10.80 42.58 9.12 13.36 14.76 26.20 54.32
(9.16) (2.84) (7.23) (7.11) (4.46) (7.97) (7.29) (17.64)
35.36 10.91 23.07 12.25 15.84 26.81 34.03 76.40
(8.25) (2.32) (6.45) (7.10) (5.07) (6.20) (6.26) (12.71)
46.87 13.3
28.17 8.09
b0.001 b0.001
b0.001 0.160 b0.001 0.086 0.046 b0.001 b0.001 b0.001
0.148 0.002 NA NA NA NA NA NA
Characteristics (N, %) Gender (male) Marital status (married) Living arrangements (alone) Professional situation (working) First degree familial history of schizophrenia
28% 20% 52% 48% 4%
36 6 8 3 14
82% 13.63% 18.18% 6.82% 32%
8 16 3 21 0
p b0.001 b0.001 0.002 b0.001 b0.001
p b0.001 0.487 0.003 b0.001 0.007
p
7 5 13 12 1
(9.68) (2.49) NA NA NA NA NA NA
PANSS pos: PANSS positive symptom subscale; PANSS neg: PANSS negative symptom subscale; PANSS gen: PANSS general symptom subscale; PANSS tot: PANSS total score;
NA NA NA NA NA NA
35% 70% 13% 91% 0%
χ2 (df = 2) 23.99 24.23 12.16 46.40 15.01
0.612 b0.001 0.004 0.001 0.332
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Digit Span Forward Task Score
*
15
15
10
Digit Span Task Global and Age Corrected Scaled Score
Backward Digit Span Task Score
*
20
*
*
10 10
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LO
S
S
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pa tie nt s
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on tr
Rey Figure Test T1 (Score) Rey Figure Test T1 (Time: s) 900 700 500 400
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Rey Figure Test T0 (Score) Rey Figure Test T1 (Time: s) 1000 750 500 500
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*: p<0.05,**: p<0.01 Fig. 1. Digit span task global, phonemic verbal fluency test and Rey figure test T1 performances in LOS patients, EOS patients and controls.
Canadian study sought to characterize and compare the cognitive profile and natural evolution of patients presenting late-onset psychotic symptoms (LOPS) to those of elderly patients (aged over 50) with EOS and to those of two control groups (Girard et al., 2011): most EOS and LOPS patients presented significant cognitive deficits with or without dementia when compared to controls. However, Girard's study did not adjust for the duration of the illness. Finally, in Vahia's study, LOS patients had better verbal memory, but LOS patients had better verbal memory with most differences remaining significant after adjusting for age, gender, severity of negative or deficit symptoms, and duration of illness (Vahia et al., 2010). Comparative studies of EOS and LOS patients in most cases have reported no differing profiles of cognitive performance, but studies did not always take into account demographic
and clinical variable such as duration of the illness and age at interview (Schmid et al., 2011). In accordance with our results, other studies have shown that LOS patients have better neuropsychologic performances compared to EOS. Rajji et al. (2009) showed that individuals with EOS have severe cognitive deficits, whereas those with LOS have some relatively preserved cognitive functions. Another study comparing early-onset and middle-aged onset schizophrenic patients shows that the latter have better neuropsychologic performances, particularly in learning and abstraction/cognitive flexibility and possibly larger thalamic volumes (Palmer et al., 2001). These findings and our results support the view that severity of the disease process is associated with different ages at onset rather than with the duration of the disorder. Other studies also
Table 2 Mean score values (SD) on the neurocognitive tests for LOS and EOS patients and controls. ANOVA betweengroups
ANCOVA between two-group differences
Mean (SD)
Patients with LOS versus EOS (N = 25)
Patients with EOS (N = 44)
Controls (N = 23)
F (df = 2)
p
LOS versus EOS pa
LOS versus controls pb
Digit span forward task score Backward digit span task score Digit span task global and age-corrected scaled score Rey figure test T0 (score) Rey figure test T0 (time) Rey figure test T1 (score) Rey figure test T1 (time) Phonemic verbal fluency test Semantic verbal fluency test
8.68 4.76 7.96 29 262.57 14.16 171.04 11.48 15.68
7.73 4.75 6.49 31.28 219.28 11.31 117.05 9.27 17.47
10.33 6.9 10.62 33.2 125.68 18.54 107.18 16.57 22.91
11.54 7.85 16.54 0.2 6.52 9027 3.08 25.39 9.46
b0.001 0.001 b0.001 0.822 0.002 b0.001 0.05 b0.001 b0.001
0.031 0.492 0.018
0.08 0.033 0.037
0.134 0.046 0.032 0.016 0.891
0.009 0.161 0.027 0.003 0.009
a b
Adjusted for sociodemographic variables (sex). Adjusted for sociodemographic variables (educational level).
(1.80) (1.67) (2.46) (5.68) (190.97) (6.02) (161.65) (3.73) (5.34)
(2.12) (2.30) (2.88) (33.37) (118.77) (6.95) (60.98) (4.22) (5.95)
(2.18) (2.43) (2.50) (2.31) (49.26) (6.13) (37.21) (3.76) (6.75)
C. Brichant-Petitjean et al. / Schizophrenia Research 151 (2013) 85–90
support the hypothesis of an influence of age of onset on illness course in patients with schizophrenia spectrum disorders (Kao and Liu, 2010). A recent study sought to assess the contribution of age at onset to variation in cognitive functioning in a large sample of patients with schizophrenia spectrum disorder and found that earlier onset was associated with worse performance on immediate recall and sustained attention (Van der Werf et al., 2012). These data are in accordance with our results: a significant positive correlation between the poorer performance in the phonemic verbal fluency tests and the lower age at onset of the disease. In addition, our results suggested that the cognitive deficits of people with LOS are specific rather than solely as a result of aging and related factors. In this study, LOS patients have a MMES score upper 28 and no organic cause of late-onset psychosis. Previous studies' contradictory results probably reflect the clinical heterogeneity of this entity. For instance, organic related psychosis in LOS group may explain a part of heterogeneous results when compared to the EOS group (Almeida et al., 1995; Girard et al., 2011). Having limited the potential bias of organic or age-related cognitive deficits, we mainly found better memory performances in LOS compared to EOS. Our findings therefore support the view that severity of the disease process is associated more with different ages at onset than with the duration of the disorder. However, some studies support the idea that schizophrenia has a progressively deteriorating course, showing that the longer the illness duration, the poorer the cognitive performances, for example on visuomotor process and delayed visual memory tasks (Cuesta et al., 1998). Cuesta et al. (1998) found that these neuropsychological disturbances associated with illness duration, were different from those related to aging, educational background, gender and treatment status. One neuroimaging study has also shown that right medial temporal, medial cerebellar and bilateral anterior cingulate gray matter volume, and white matter volume in the right posterior limb of the internal capsule, were all negatively correlated with illness duration in patients with chronic schizophrenia. These morphologic correlations were not a function of chronological age or age at illness onset (Velakoulis et al., 2002). On the other hand, other studies investigating the progression of neuropsychological impairment in schizophrenia challenge these views. A previous study, comparing schizophrenic patients with different durations of illness, showed that performances in the Wisconsin Card Sorting Test (WCST) and semantic fluency were both impaired at an early stage in the illness and did not significantly deteriorate as the illness duration increased. The data support a lack of progression in prefrontal dysfunction and in most other cognitive domains (Chen et al., 1996). Another study also suggests that cognitive functions do not markedly decline during the adulthood of patients with schizophrenia and that the course of schizophrenia is more consistent with a static encephalopathy than a dementing disorder (Hyde et al., 1994). One study supports the hypothesis that cognitive deficits associated with schizophrenia cannot be considered a unitary trait, but emerge along different hypothetical trajectories (Stratta et al., 2004). We do not yet know for sure what exact relationship exists between each cognitive deficit and each clinical symptom. Several studies show that schizophrenic patients present deficits in each subsystem component of working memory and that these deficits are correlated with negative symptoms and disorganization. Dibben et al. (2009) published a meta-analysis showing that the negative signs are associated with performances on the verbal fluency test (Dibben et al., 2009). These data are interesting because it is the verbal fluency test for which we found a significant trend between EOS and LOS and poor performance in the phonemic verbal fluency tests was correlated with high negative PANSS scores. We also found a significant positive correlation between age at onset and phonetic verbal fluency performance and no correlation between the illness duration and cognitive performance in all patients. Moreover, studies show that performances in episodic memory and working memory tasks are significantly negatively correlated with
89
hallucinations, whereas delusions are not significantly associated with memory performances (Berenbaum et al., 2008). These data are coherent with that LOS subjects, who have lower positive PANSS scores, have better memory capacities and learning abilities and therefore a higher level of social and professional functioning. Our results can be interpreted in the light of these literature data, which show a significant difference between LOS and EOS on most memory performances. However, apart from the phonemic verbal fluency test, we did not find any other correlation between PANSS scores and other memory tests. Despite the consensual criteria proposed by International Classifications, schizophrenia appears to be a heterogeneous clinical entity composed of a group of related disorders. The considerable inter-patient clinical and cognitive heterogeneity has led to move away from the categorical approach and to treat schizophrenic disorders in a more dimensional clinical approach: the various schizophrenic symptoms can be divided into several independent clinical dimensions, underpinned by different substrata and determinism and coexisting in varying degrees from one patient to the next. The identification of a fivedimensional clinical structure had already been shown by other teams (Maziade et al., 1995; Serretti and Olgiati, 2004). Among the proposed revisions in the development of the DSM-V, a recommendation has been made to utilize the assessment of dimensions instead of subtypes. This approach, which provides an interesting approach of the continuum between normality and psychosis, would reflect the distinct psychopathological domains in psychotic illnesses which have distinctive patterns of treatment-response, implications, and course. The cognitive profile could therefore be integrated as being a distinct dimension to characterize each clinical picture. This dimensional approach may further help to distinguish possible etiopathogenic factors involved in LOS. Many functional neuroimaging studies have been performed mainly in young patients with schizophrenia, but LOS still remains largely unexamined by these techniques. Recent studies have reported abnormalities in white matter integrity in LOS patients, which may contribute to the pathophysiology of LOS (Casanova and Lindzen, 2003; Chen et al., 2013). In terms of genetic data, studies have sought to find candidate genes involved in the etiopathogeny of schizophrenia or appeared to modify the schizophrenia phenotype such as age at onset. Polymorphisms located in BDNF, dopa decarboxylase (DDC), and Dopamine receptor (D2) genes have been be significantly associated with late age of onset: they appear to have a modifying rather than causative effect and could act as modulators of age of onset and hence be used as predictors of later age at onset in early onset schizophrenia (Krebs et al., 2000; Børglum et al., 2001; Dubertret et al., 2004b; Rasmussen et al., 2006; Ayalew et al., 2012; Voisey et al., 2012). Particularly, the 32-bp deletion allele in Chemokine receptor (CCR5) and rs 1800497 located in DRD2 genes have been involved in late-onset-schizophrenia patients and may act as a modifier by delaying the onset of schizophrenia without affecting the disease susceptibility (Rasmussen et al., 2006; Dubertret et al., 2010). This study has strengths and limitations. The principal strengths include the homogenous group of LOS limiting the effect of aging and organic factors on cognitive performances. However, some limitations should be considered in interpreting these findings. Firstly, the main limitation is the number of subjects included which did not have sufficient statistical power to allow us to make a strict matching between subjects and to show a significant difference between the groups for all tests. However, the main factors influencing cognition (age, sex, educational level, duration of the illness and treatments with cognitive impact such as antipsychotics, benzodiazepines and anticholinergics) were controlled in our work. Moreover, the evaluation of the subjects was very thorough in terms of neuropsychological assessment, using many of the memory tests commonly used in studies on schizophrenia. The second limitation is that the memory tests in this work are used to assess different cognitive abilities, such as executive functions and attention. Despite these limitations, this study provides evidence that LOS belongs to the broad continuous spectrum of schizophrenic disorders
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and it can be considered as an extreme of typical schizophrenia. Schizophrenia in this definition seems to be fundamentally heterogeneous. However, LOS can be in line with a dimensional clinical approach, whereby it presents few memory deficits, as well as few disorganization and negative symptoms with mostly positive symptoms. This is a preliminary study. Its needs further researches to confirm these results with more specific memory assessment tests and a larger cohort of subjects. Role of the funding sources No funding source was obtained for this study.
Contributors C. Dubertret designed the study and wrote the protocol. C. Brichant-Petitjean managed the literature searches, provided data and wrote the first draft of the manuscript. C. Legauffre and J. Ades provided data. C. Dubertret and N. Ramoz undertook the statistical analysis. C. Dubertret and P. Gorwood revised the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest All other authors declare no conflicts of interest that influence their work.
Acknowledgment The authors wish to acknowledge the kind assistance of patients and nurses who participated in the study.
References Almeida, O.P., Howard, R.J., Levy, R., David, A.S., Morris, R.G., Sahakian, B.J., 1995. Cognitive features of psychotic states arising in late life (late paraphrenia). Psychol. Med. 25 (4), 699–714. American Psychiatric Association, 1980. DSM-III: Diagnostic and Statistical Manual of Mental Disorder, third ed. The Association, Washington, DC. American Psychiatric Association, 1987. DSM-III-R: Diagnostic and Statistical Manual of Mental Disorder, third ed., revised. The Association, Washington, DC. American Psychiatric Association, 1994. Mini DSM-IV TR: Diagnostic and Statistical Manual of Mental Disorders, fourth ed. APA, Washington, DC. Andreasen, N.C., Endicott, J., Spitzer, R.L., Winokur, G., 1977. The family history method using diagnostic criteria. Reliability and validity. Arch. Gen. Psychiatry 34 (10), 1229–1235. Ayalew, M., Le-Niculescu, H., Levey, D.F., Jain, N., Changala, B., Patel, S.D., Winiger, E., Breier, A., Shekhar, A., Amdur, R., Koller, D., Nurnberger, J.I., Corvin, A., Geyer, M., Tsuang, M.T., Salomon, D., Schork, N.J., Fanous, A.H., O'Donovan, M.C., Niculescu, A.B., 2012. Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. Mol. Psychiatry 17 (9), 887–905. Ballet, G., 1911. La Psychose hallucinatoire Chronique. Encephale 11, 401–411. Berenbaum, H., Kerns, J.G., Vernon, L.L., Gomez, J.J., 2008. Cognitive correlates of schizophrenia signs and symptoms: hallucinations and delusions. Psychiatr. Res. 159 (1–2), 163–166. Bleuler, M., 1943. Late schizophrenic clinical pictures. In German Fortschr. Neurol. Psychiatr. 15, 259–290. Børglum, A.D., Hampson, M., Kjeldsen, T.E., Muir, W., Murray, V., Ewald, H., Mors, O., Blackwood, D., Kruse, T.A., 2001. Dopa decarboxylase genotypes may influence age at onset of schizophrenia. Mol. Psychiatry 6 (6), 712–717. Breton, F., Planté, A., Legauffre, C., Morel, N., Adès, J., Gorwood, P., et al., 2011. The executive control of attention differentiates patients with schizophrenia, their first-degree relatives and healthy controls. Neuropsychologia 49 (2), 203–208. Bright, P., Jaldow, E., Kopelman, M.D., 2002. The National Adult Reading Test as a measure of premorbid intelligence: a comparison with estimates derived from demographic variables. J. Int. Neuropsychol. Soc. 8 (6), 847–854. Cardebat, D., Doyon, B., Puel, M., Goulet, P., Joanette, Y., 1990. Formal and semantic lexical evocation in normal subjects. Performance and dynamics of production as a function of sex, age and educational level. Acta Neurol. Belg. 90 (4), 207–217. Casanova, M.F., Lindzen, E.C., 2003. Changes in gray-/white-matter ratios in the parahippocampal gyri of late-onset schizophrenia patients. Am. J. Geriatr. Psychiatry 11 (6), 605–609. Chen, E.Y., Lam, L.C., Chen, R.Y., Nguyen, D.G., Chan, C.K., 1996. Prefrontal neuropsychological impairment and illness duration in schizophrenia: a study of 204 patients in Hong Kong. Acta Psychiatr. Scand. 93 (2), 144–150. Chen, R.Y., Chen, E.Y., Chan, C.K., Lam, L.C., Lieh-Mak, F., 2000. Verbal fluency in schizophrenia: a reduction in semantic store. Aust. N. Z. J. Psychiatry 34 (1), 43–48. Chen, L., Chen, X., Liu, W., Wang, Q., Jiang, T., Wang, J., Wang, X., Zhou, B., Tang, J., 2013. White matter microstructural abnormalities in patients with late-onset schizophrenia identified by a voxel-based diffusion tensor imaging. Psychiatry Res. 212 (3), 201–207. Convert, H., Védie, C., Paulin, P., 2006. Late-onset schizophrenia or chronic delusion. Encephale 32 (6), 957–961. Cuesta, M.J., Peralta, V., Zarzuela, A., 1998. Illness duration and neuropsychological impairments in schizophrenia. Schizophr. Res. 33 (3), 141–150. Dibben, C.R., Rice, C., Laws, K., McKenna, P.J., 2009. Is executive impairment associated with schizophrenic syndromes? A meta-analysis. Psychol. Med. 39, 381–392.
Dubertret, C., Adès, J., Gorwood, P., 2004a. Clinical and etiopathogenic specificities of the French concept of Psychose Hallucinatoire Chronique compared to schizophrenia. Schizophr. Bull. 30 (1), 173–184. Dubertret, C., Gouya, L., Hanoun, N., Deybach, J., Ades, J., Hamon, M., Gorwood, P., 2004b. The 3′ region of the DRD2 gene is involved in genetic susceptibility to schizophrenia. Schizophr. Res. 67, 75–85. Dubertret, C., Bardel, C., Ramoz, N., Martin, P.M., Deybach, J., Ades, J., Gorwood, P., Gouya, L., 2010. A genetic schizophrenia-susceptibility region located between the ANKK1 and DRD2 genes. Prog. Neuropsychopharmacol. Biol. Psychiatry 34 (3), 492–499. Fuller, R.L., Luck, S.J., Braun, E.L., Robinson, B.M., McMahon, R.P., Gold, J.M., 2009. Impaired working visual memory consolidation in schizophrenia. Neuropsychology 23 (1), 71–80. Girard, C., Simard, M., Noiseux, R., Laplante, L., Dugas, M., Rousseau, F., et al., 2011. Lateonset-psychosis: cognition. Int. Psychogeriatr. 23 (8), 1301–1316. Gorwood, P., Leboyer, M., Jay, M., Payan, C., Feingold, J., 1995. Gender and age at onset in schizophrenia: impact of family history. Am. J. Psychiatry 152 (2), 208–212. Grégoire, J., Van der Linden, M., 1997. The effect of age on forward and backward digit spans. Neuropsychol. Dev. Cogn. B Aging Neuropsychol. Cogn. 4, 140–149. Heinrichs, R.W., Zakzanis, K.K., 1998. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 12 (3), 426–445. Howard, R., Rabins, P.V., Seeman, M.V., Jeste, D.V., 2000. Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. Am. J. Psychiatry 157, 172–178. Hyde, T.M., Nawroz, S., Goldberg, T.E., Bigelow, L.B., Strong, D., Ostrem, J.L., Weinberger, D.R., Kleinman, J.E., 1994. Is there cognitive decline in schizophrenia? A cross-sectional study. Br. J. Psychiatry 164 (4), 494–500. Jeste, D.V., Harris, M.J., Krull, A., Kuck, J., McAdams, L.A., Heaton, R., 1995. Clinical and neuropsychological characteristics of patients with early-onset schizophrenia. Am. J. Psychiatry 152 (5), 722–730. Johnson-Selfridge, M., Zalewski, C., 2001. Moderator variables of executive functioning in schizophrenia: meta-analytic findings. Schizophr. Bull. 27 (2), 305–316. Kao, Y.C., Liu, Y.P., 2010. Effects of age of onset on clinical characteristics in schizophrenia spectrum disorders. BMC Psychiatry 10, 63. Kay, S.R., Opler, L.A., Lindenmayer, J.P., 1989. The Positive and Negative Syndrome Scale (PANSS): rationale and standardisation. Br. J. Psychiatry (Suppl. (7)), 59–67. Kim, J., Matthews, N.L., Park, S., 2010. An event-related FMRI study of phonological verbal working memory in schizophrenia. PLoS One 5 (8), e12068. Krebs, M.O., Guillin, O., Bourdell, M.C., Schwartz, J.C., Olie, J.P., Poirier, M.F., Sokoloff, P., 2000. Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. Mol. Psychiatry 5 (5), 558–562. La Salvia, E., Chemali, Z., 2011. A perspective on psychosis in late life and deficits in social cognition. Harv. Rev. Psychiatry 19 (4), 190–197. Maziade, M., Roy, M.A., Martinez, M., Cliche, D., Fournier, J.P., Garneau, Y., et al., 1995. Negative, psychoticism, and disorganized dimensions in patients with familial schizophrenia or bipolar disorder: continuity and discontinuity between the major psychoses. Am. J. Psychiatry 152 (10), 1458–1463. Miller, B.L., Lesser, I.M., Boone, K.B., Hill, E., Mehringer, C.M., Wong, K., 1991. Brain lesions and cognitive function in late-life psychosis. Br. J. Psychiatry 158, 76–82. Nurnberger Jr., J.I., Blehar, M.C., Kaufmann, C.A., York-Cooler, C., Simpson, S.G., HarkavyFriedman, J., et al., 1994. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch. Gen. Psychiatry 51 (11), 849–859. Palmer, B.W., McClure, F.S., Jeste, D.V., 2001. Schizophrenia in late life: findings challenge traditional concepts. Harv. Rev. Psychiatry 9 (2), 51–58. Rajji, T.K., Mulsant, B.H., 2008. Nature and course of cognitive function in late-life schizophrenia: a systematic review. Schizophr. Res. 102 (1–3), 122–140. Rajji, T.K., Ismail, Z., Mulsant, B.H., 2009. Age at onset and cognition in schizophrenia: meta-analysis. Br. J. Psychiatry 195 (4), 286–293. Rasmussen, H.B., Timm, S., Wang, A.G., Søeby, K., Lublin, H., Fenger, M., Hemmingsen, R., Werge, T., 2006. Association between the CCR5 32-bp deletion allele and late onset of schizophrenia. Am. J. Psychiatry 163 (3), 507–511. Schmid, L.A., Lässer, M.M., Schröder, J., 2011. [Symptoms and cognition in geriatric schizophrenia]. [Article in German]. Fortschr. Neurol. Psychiatr. 79 (5), 267–276. Serretti, A., Olgiati, P., 2004. Dimensions of major psychoses: a confirmatory factor analysis of six competing models. Psychiatry Res. 127 (1–2), 101–109. Stratta, P., Arduini, L., Daneluzzo, E., Rinaldi, O., di Genova, A., Rossi, A., 2004. Relationship of good and poor Wisconsin Card Sorting Test performance to illness duration in schizophrenia: a cross-sectional analysis. Psychiatry Res. 121 (3), 219–227. Thoma, R.J., Monnig, M., Hanlon, F.M., Miller, G.A., Petropoulos, H., Mayer, A.R., et al., 2009. Hippocampus volume and episodic memory in schizophrenia. J. Int. Neuropsychol. Soc. 15 (2), 182–195. Tupler, L.A., Welsh, K.A., Asare-Aboagye, Y., Dawson, D.V., 1995. Reliability of the ReyOsterrieth complex figure in use with memory-impaired patients. J. Clin. Exp. Neuropsychol. 17 (4), 566–579. Vahia, I.V., Palmer, B.W., Depp, C., Fellows, I., Golshan, S., Kraemer, H.C., et al., 2010. Is lateonset schizophrenia a subtype of schizophrenia? Acta Psychiatr. Scand. 122 (5), 414–426. Van der Werf, M., Köhler, S., Verkaaik, M., Verhey, F., Van Os, J., 2012. Cognitive functioning and age at onset in non-affective psychotic disorder. Acta Psychiatr. Scand. 126 (4), 274–281. Velakoulis, D., Wood, S.J., Smith, D.J., Soulsby, B., Brewer, W., Leeton, L., Desmond, P., Suckling, J., Bullmore, E.T., McGuire, P.K., Pantelis, C., 2002. Increased duration of illness is associated with reduced volume in right medial temporal/anterior cingulate grey matter in patients with chronic schizophrenia. Schizophr. Res. 57 (1), 43–49. Voisey, J., Swagell, C.D., Hughes, I.P., Lawford, B.R., Young, R.M., Morris, C.P., 2012. A novel DRD2 single-nucleotide polymorphism associated with schizophrenia predicts age of onset: HapMap tag-single-nucleotide polymorphism analysis. Genet. Test. Mol. Biomark. 16 (2), 77–81.