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Neuroanatomical and Neuropsychological Features of Euthymic Patients with Bipolar Disorder
Neuroanatomical and Neuropsychological Features of Euthymic Patients with Bipolar Disorder Christophe Delaloye, Ph.D., Fabienne de Bilbao, Ph.D., Guenae¨l Moy, Ph.D., Sandra Baudois, M.S., Kerstin Weber, M.S., Leticia Campos, M.S., Alessandra Canuto, M.D., Umberto Giardini, M.D., Armin von Gunten, M.D., Raluca Ioana Stancu, M.D., Philip Scheltens, M.D., Franc¸ois Lazeyras, Ph.D., Philippe Millet, Ph.D., Panteleimon Giannakopoulos, M.D., Gabriel Gold, M.D.
Objective: Previous studies reported that the severity of cognitive deficits in euthymic patients with bipolar disorder (BD) increases with the duration of illness and postulated that progressive neuronal loss or shrinkage and white matter changes may be at the origin of this phenomenon. To explore this issue, the authors performed a case– control study including detailed neuropsychological and magnetic resonance imaging analyses in 17 euthymic elderly patients with BD and 17 healthy individuals. Methods: Neuropsychological evaluation concerned working memory, episodic memory, processing speed, and executive functions. Volumetric estimates of the amygdala, hippocampus, entorhinal cortex, and anterior cingulate cortex were obtained using both voxel-based and region of interest morphometric methods. Periventricular and deep white matter were assessed semiquantitatively. Differences in cognitive performances and structural data between BD and comparison groups were analyzed using paired t-test or analysis of variance. Wilcoxon test was used in the absence of normal distribution. Results: Compared with healthy individuals, patients with BD obtained significantly lower performances in processing speed, working memory, and episodic memory but not in executive functions. Morphometric analyses did not show significant volumetric or white matter differences between the two groups. Conclusions: Our results revealed impairment in verbal memory, working memory, and processing speed in euthymic older adults with BD. These cognitive deficits are comparable both in terms of affected functions and size effects to those
Received June 17, 2008; revised March 9, 2009; accepted June 24, 2009. From the Division of Geriatric Psychiatry, University Hospitals of Geneva and Faculty of Medicine, Switzerland (CD, FdB, GM, SB, KW, LC, AC, UG, PG); Faculty of Psychology and Science of Education, University of Geneva, Switzerland (CD); Division of Old Age Psychiatry, University Hospitals of Lausanne, Hospices-CHUV, Switzerland (AvG, RIS, PG); Alzheimer Center and Department of Neurology, VU Medical Center, Amsterdam, the Netherlands (PS); Department of Radiology, University Hospitals of Geneva, Switzerland (FL); Clinical Neurophysiology and Neuroimaging Unit, University Hospitals of Geneva, Switzerland (PM); and Department of Rehabilitation and Geriatrics, University Hospitals of Geneva, Switzerland (GG). Send correspondence and reprint requests to Dr. Christophe Delaloye, Service de Psychiatrie Ge´riatrique—Ho ˆ pitaux Universitaires de Gene`ve, 2 Chemin du Petit-Bel-Air, 1225 Cheˆne-Bourg, Switzerland. e-mail: [email protected] © 2009 American Association for Geriatric Psychiatry
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Delaloye et al. previously reported in younger cohorts with BD. Both this observation and the absence of structural brain abnormalities in our cohort do not support a progressively evolving neurotoxic effect in BD. (Am J Geriatr Psychiatry 2009; 17:1012–1021) Key Words: Bipolar disorder, neuropsychology, neuroimaging, older adults
T
he impact of bipolar disorder (BD) on cognitive functions is still a controversial issue. There is growing evidence that, besides the well known changes that occur during the manic and depressive phases,1 BD is also associated with neuropsychological impairments that persist during the euthymic state.2 In fact, recent reviews reported executive function, memory and attention/processing impairments in young and middle-aged euthymic patients with BD.3,4 A growing body of evidence indicates that the severity of cognitive deficits in euthymic patients with BD is mostly related to the duration of illness.3 Thus, one would expect more pronounced neuropsychological impairment in elderly patients with longstanding BD.5 Studies focusing on the neuropsychological performance of older euthymic patients with BD are, however, sparse.5–7 Most of them were based on global neuropsychological scales, such as the Mattis Dementia Rating Scale, which do not allow the investigation of subtle cognitive deficits.7 Several biological alterations may lead to an increased cognitive vulnerability in older patients with BD. It has been postulated that repeated stress in BD increases glucocorticoid levels8 and might result in cumulative cortical neuronal loss or shrinkage in brain areas highly saturated in glucocorticoid receptors, such as the amygdala, hippocampus, and anterior cingulate cortex.9 In addition, stress-induced glucocorticoid secretion may reduce cellular resilience, making certain neurons more vulnerable to concomitant insults, such as ischemia or hypoglycemia. Alternatively, Kauer-Sant’anna et al.10 found a failure of inflammatory defense in patients with severe BD leading to a reduction in brain-derived neurotrophic factor that could be associated with loss of hippocampal neurons. Finally, increased deep white matter and periventricular hyperintensities were also described in older adults with BD compared with controls and could contribute to the acceleration of cognitive decline.11,12 Both neuropsychological data and
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structural magnetic resonance imaging (MRI) studies in elderly patients with BD are still scarce.13,14 To determine whether the pattern of cognitive deficits and structural abnormalities in older euthymic patients with BD are similar to those reported among younger patients with BD, we performed a prospective case– control study including a detailed neuropsychological analysis that covered a wide variety of cognitive domains (e.g., working memory, episodic memory, processing speed, and executive functions) and detailed MRI investigation including volumetric estimates of the amygdala, hippocampus, entorhinal, and anterior cingulate cortex performed with a region of interest (ROI) morphometric method, a voxel-based analysis, and a semiquantitative assessment of white matter hyperintensities (WMH).
METHODS Participants Seventeen euthymic elderly patients with BD with BD I (nine patients) and BD II (eight patients) and 17 age-, gender-, and education-matched healthy individuals were included in the study. Patients with BD were recruited either from the psychogeriatric outpatient service of the University Hospitals of Geneva, Switzerland, or through advertisements in specialized journals. Controls were also recruited through advertisements in local newspapers. The diagnosis of BD (patients) or the absence of a psychiatric condition (healthy individuals) was established using the Mini International Neuropsychiatric Interview15 administered by a geropsychiatrist. Euthymia was defined according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria (absence of depressive symptoms for at least 2 months). In addition, all participants had to obtain a score below 5 on the Geriatric Depression Scale 15-items16 and on
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Patients with BD in Old Age the Young Mania Rating Scale17 at inclusion. Clinical assessment of euthymia and administration of the two scales were performed by the same geropsychiatrist. Exclusion criteria for both groups were history of major neurologic disorders or head trauma, presence of a current or a past psychiatric diagnosis (other than BD for the group of patients), based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, current systemic medical disease requiring inpatient treatment, less than 4 years of formal education, and hearing, vision, or motor impairment precluding neuropsychological testing. After the formal acceptance of the research protocol by the local ethics committee, written informed consent was obtained before inclusion. Cognitive Measures Processing Speed. A simple reaction time task was used to assess processing speed.18 Participants had to press a key as quickly as possible when the visual signal stimulus appeared. The score of interest was the mean latency of the 120 test trials. Working Memory. Working memory was indexed by the Letter-Number Sequencing subtest of the Wechsler Memory Scale III, which involved auditory tracking of letters and numbers, then recalling all the numbers in ascending order, followed by all the letters in alphabetical order.19 The score of interest was the number of correct sequences produced. Episodic Memory. Episodic memory was assessed with two tests: the cued recall (CR) 48 items test20 and the consortium to establish and registry for Alzheimer’s Disease (CERAD) Word List Memory.21 The CR48 task comprised 48 different words, belonging to 12 different semantic categories. The 48 words were presented as written words on 12 consecutive cards. Participants were invited to encode these words with the help of semantic cues (e.g., fruit, raspberry). On completion of each card, an immediate CR was realized (e.g., fruit?). Once the 48 words were encoded, a CR task was performed (e.g., which were the fruits?). The score of interest was the number of words correctly recalled. The CERAD Word List Memory test involves memorization of a list of 10 words that was presented over three trials. After 5 minutes, a delayed recall was measured (number of words correctly retrieved). Executive Functions. Mental shifting capacity was indexed by the Color Trail Making Test, which com-
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prises two parts.22 In Part A, the participant had to connect a series of 25 encircled numbers in numerical order as quickly as possible. Part B tested cognitive flexibility skills by requiring participants to shift sets by matching number with colors in a progressive and alternating pattern (e.g., 1, pink; 2, yellow; and 3-pink). Completion time for each part was the dependent measure. The score of interest was the flexibility cost computed by a relative ratio ([completion time Part B ⫺ completion time Part A]/completion time Part A). Inhibition capacity was assessed by the French version of the standard Stroop color-word interference task, which included three subtests.23 The first subtask displayed solid color patches in one of four colors (red, blue, yellow, and green). The second subtask used neutral words printed in one of these four basic colors. The third subtask contained color words printed in an incongruous ink color (e.g., word yellow printed in red ink). In each subtask, participants were instructed to name the ink color of the stimuli as quickly and as accurately as possible. Completion time for each subtask was the dependent measure. The score of interest was the interference effect, which was computed by a relative ratio ([completion time subtask 3 ⫺ completion time subtask 2]/completion time subtask 2). Updating capacity was measured by the Consonant Updating Test.24 Participants had to recall, in the same order as their presentation, the last four elements of a list including four, six, or eight consonants. Once all the consonants of a given list were presented, participants heard a beep, which set off the recall. Participants never knew in advance how many consonants were included in each list. The task included 12 lists of consonants with four lists by condition (no update, two updates, and four updates). The main dependent variable was the number of consonants recalled correctly in each condition. The score of interest was based on the updating costs, which were determined by a relative ratio (2-updating cost: [2 updates ⫺ 0 update]/0 update and 4-updating cost: [4 updates ⫺ 0 update]/0 update). MRI Procedures The MRI imaging was performed at 3 Tesla (Siemens). Coronal slices were obtained from three-dimensional Magnetization Prepared Rapid Gradient Echo (MPRAGE) sequence with the following parameters: repetition time (TR) 2,500 ms, echo time
Am J Geriatr Psychiatry 17:12, December 2009
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Delaloye et al. (TE) 2.94 ms, inversion time (TI) 1,100 ms, flip angle 9°, isotropic resolution of 0.9 mm3, acquisition time 8 minutes 40 seconds. In addition, three-dimensional T2 weighted imaging was obtained with the following parameters: TE ⫽ 383 ms, TR ⫽ 3,200 ms, field of view (FOV) ⫽ 230 mm, acceleration factor (parallel imaging) 2, matrix size 256 ⫻ 256 ⫻ 240. ROI Analysis. Anterior cingular and entorhinal cortices and hippocampal and amygdala perimeters were traced manually on each contiguous coronal slice using a ROI procedure of ANALYZE software (Version 8, Mayo Foundation). Neuroanatomic boundaries of the hippocampus and amygdala were based on those of Watson et al.25 Anatomic guidelines for outlining the entorhinal and anterior cingular cortices were those described by Bernasconi et al.26 and Sassi et al.27 respectively. References to sagittal and horizontal planes were performed whenever necessary to improve identification of structure boundaries. Each brain structure was delimited by a manual contour from which the corresponding volume was calculated using the ANALYZE software. The total volume of each structure was then calculated by summing all values obtained from ROIs applied on consecutive slices (slice thickness: 0.9 mm). Intracranial volumes, defined as all gray and white matter in the cerebrum (including cerebellum and stem), and the CSF were measured automatically from the segmented images. Normalized volumes for brain regions of interest were determined by using the following formula: (absolute volume [mm3]/ intracranial volume [mm3]) ⫻ 1.000. All measurements were performed by a trained rater blind to participant’s group. Voxel-Based Morphometry. The data were analyzed with SPM5 software. Standard statistical parametric mapping processing was used to analyze MRI for voxel-based morphometry (VBM).28 Images were segmented using the standard T1 template and a priori gray matter, white matter, and CSF atlases provided by SPM. Spatially normalized (1 ⫻ 1 ⫻ 1 mm3) data were modulated to account for local volume changes due to nonlinear coregistration. Gray matter images were smoothed with a 8 mm Gaussian kernel. Assessment of WMH. Assessment of white matter lesions was performed in T2-weighted sequences with the Scheltens semiquantitative scale.29 Periventricular hyperintensities were rated as 0 ⫽ absent, 1 ⫽ ⱕ5 mm, or 2 ⫽ ⬎5 mm and ⬍10 mm. WMH were rated as 0 ⫽ no abnormalities, 1 ⫽ ⬍3 mm and
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n ⱕ5, 2 ⫽ ⬍3 mm and n ⬎6, 3 ⫽ 4 –10 mm and n ⱕ5, 4 ⫽ 4 –10 mm and n ⬎6, 5 ⫽ ⱖ11 mm and n ⬎1, and 6 ⫽ confluent, in frontal, parietal, occipital, and temporal white matter. Basal ganglia (caudate nucleus, putamen, globus pallidus, thalamus, and internal capsule) and infratentorial foci hyperintensities were similarly rated from 1 to 6. Statistical Analysis Differences in mean or median performance between patients with BD and comparison group were analyzed using paired t-test or analysis of variance. To respect assumptions of normality (Shapiro-Wilk) and homogeneity of variance (Levene’s test), the relative ratio scores of the Stoop color test and the mean latencies of the simple reaction time test were modified before analysis by means of logarithmic transformation. Wilcoxon Matched-Pairs Signed Rank test was used in the absence of normal distribution. Data were analyzed with SPSS version 15.0 and StatXact Version 4. For VBM analysis, statistical threshold of p ⬍0.001 (uncorrected) was used.
RESULTS Demographic and Clinical Characteristics The demographic and clinical characteristics of the series are summarized in Table 1. There were no significant differences in age (t[16] ⫽ 0.62, p ⫽ 0.54), education (t[16] ⫽ ⫺0.11, p ⫽ 0.91), and Charlson Cormorbidity Index30 score (S ⫽ 29.5, p ⫽ 0.77; the S value is the minimum value between the positive ranks’ sum and the negative ranks’ sum associated with the difference between each paired measures). The scores on the Geriatric Depression Scale and the Young Mania Rating Scale confirmed patient’s euthymic mood state. Patients were already under treatment at inclusion. We did not interfere with their medication as the treatment was prescribed naturalistically. Fourteen patients received mood stabilizers (lithium: 29%, valproic acid: 35%, and other anticonvulsants: 12%). This treatment was associated with atypical antipsychotics in 18% of the cases, serotonin or noradrenalin reuptake inhibitors in 12% of the cases, and benzodiazepines in 12% of the cases.
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Patients with BD in Old Age
TABLE 1.
Demographic and Clinical Characteristics of the Present Series Groups BD (N ⴝ 17)
Characteristics Age (years) Educationa Score GDS (max 15) Score YMRS (max 44) Score CCI (max 19) Age of onset (years) Duration of illness Percentage of current smokers/past smokers/never smokers
Comparison (N ⴝ 17)
M
SD
M
SD
69.00 13.12 1.47 1.06 1.29 39.35 29.65
(5.85) (3.72) (1.58) (1.47) (2.82) (15.6) (15.7)
69.24 13.12 1.35 0.00 0.76 — —
(6.02) (3.25) (1.32) (0.00) (0.97) — —
18/53/29
20/47/33
Notes: GDS: Geriatric Depression Scale; YMRS: Young Mania Rating Scale; CCI: Charlson Comorbidity Index. a Number of years of education completed.
In 12% of the cases, there was a concomitant prescription of antipsychotics, antidepressants, and benzodiazepines. Healthy individuals did not receive psychotropic medication.
Processing Speed. Older patients with BD were statistically slower than the comparison group (t[16] ⫽ 2.31, p ⬍0.05) in the simple reaction time test. Working Memory. The group of patients with BD presented a significantly lower (t[16] ⫽ 3.12, p ⬍0.01) score in the Letter-Number-Sequencing test. Episodic Memory. Older patients with BD obtained a significantly lower CR score on the CR 48 items test
Neuropsychological Data Performances on cognitive tests are provided in Table 2.
TABLE 2.
Patient and Comparison Groups’ Raw Score Performance in Neuropsychological Tests Groups BD (N ⴝ 17)
Processing speed Simple reaction time: latencies (ms) Working memory Letter-Number Sequence: Score Episodic memory Cued Recall 48 items: Score Cerad 10 words: Delayed recall score Executive function Flexibility Color Trail Making Test: Relative ratio score Inhibition Stroop Colour: Relative ratio score Updating Consonant Updating: 2 updating cost Updating Consonant Updating: 4 updating cost a
Comparison (N ⴝ 17)
M
SD
M
SD
t/Za
p
Effect Size, r
348.27
73.48
289.82
76.93
t关16兴 ⫽ 2.31
0.034
0.42
8.18
2.40
10.47
2.24
t关16兴 ⫽ 3.12
0.007
0.45
21.88 5.82
5.04 1.70
29.12 7.41
6.22 1.42
t关16兴 ⫽ 4.55 t关16兴 ⫽ 2.50
0.0003 0.01
0.55 0.46
1.05
0.55
0.95
0.48
Z ⫽ 0.36
0.72
—
0.71
0.50
0.63
0.26
t关16兴 ⫽ 0.60
0.56
—
⫺0.24
0.21
⫺0.07
0.10
t关16兴 ⫽ 2.75
0.01
0.46
⫺0.14
0.30
⫺0.10
0.19
t关16兴 ⫽ 0.55
0.59
—
t: paired t test and Z: Wilcoxon test.
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Delaloye et al. (t[16] ⫽ 4.55, p ⬍0.01) and a significantly lower delayed recall score on the CERAD Word List Memory Test (S ⫽ 5, p ⫽ 0.01) than the comparison group. Executive Functions. The flexibility cost in the Color Trail Making Test did not differ between BD and comparison groups (S ⫽ 60, p ⫽ 0.69). This was also the case for the interference score of the Stroop color Test (t[16] ⫽ 0.60, p ⫽ 0.56). Regarding the updating consonant test, the two groups differed on the two-updating cost (t[16] ⫽ 2.75, p ⫽ 0.01) but not on the four-updating cost (t[16] ⫽ 0.55, p ⫽ 0.59). MRI Data Table 3 summarizes the mean normalized volumes of each brain ROI by group of participants. There were no significant differences in hippocampal (t[16] ⫽ 1.58, p ⫽ 0.13), entorhinal cortex (t[16] ⫽ 0.28, p ⫽ 0.78), anterior cingulate (t[16] ⫽ 1.09, p ⫽ 0.29), and amygdala (t[16] ⫽ 0.11, p ⫽ 0.92) volume between BD and comparison groups. A volume asymmetry was observed only for the hippocampus (F[1,16] ⫽ 26.23, p ⬍0.01), the right hippocampal volume being larger than the left one. The degree of this asymmetry did not differ between patients and healthy individuals (F[1,16] ⫽ 0.15, p ⫽ 0.71). VBM analysis did not reveal any significant difference in gray matter volumes between patients with
TABLE 3.
BD and healthy individuals at the cluster level as reported in Table 3. Table 4 summarizes the mean rating score of WMH according to the Scheltens semiquantitative scale. Periventricular hyperintensities scores were comparable between BD and comparison groups (S ⫽ 46.5, p ⫽ 0.70). This was also the case for hyperintensities in neocortical white matter (S ⫽ 6, p ⫽ 0.62). Besides, BD and healthy controls had virtually no hyperintensities in basal ganglia and infratentorieal areas. Importantly, duration of illness had no impact on cognitive performances, cerebral volumes, and WMH scores.
CONCLUSION From a neuropsychological standpoint, and as already reported in younger cohorts with BD,4 euthymic older patients with BD had lower performances in tests measuring processing speed, working memory, and episodic memory compared with healthy individuals. However, the observed effect size falls within the moderate-to-large range and is similar overall to that reported in studies focusing on younger patients with BD.4 Consistent with the find-
Differences in Regional Gray Matter Volumes Between BD (N ⴝ 17) and Comparison Groups (N ⴝ 17) in Voxel-Based Analysis Coordinatesa
Higher in BD Superior frontal gyrus Postcentral gyrus Thalamus Superior frontal gyrus Postcentral gyrus Superior frontal gyrus Superior frontal gyrus Paracentral lobule Lower in BD Cingulate gyrus Caudate Thalamus (ventral anterior)
Hemisphere
x
y
Left Left Left Left Left Right Left Left
1 ⫺16 0 1 ⫺54 12 ⫺27 ⫺6
19 ⫺47 ⫺1 34 ⫺13 ⫺9 1 ⫺28
Right Right Right
22 15 13
8 20 0
Peakb t test
Peakc Z Score
No.d of Voxels
pe (Uncorrected)
63 80 2 55 48 73 66 80
4.22 3.96 3.9 3.81 3.78 3.78 3.6 3.53
3.74 3.54 3.5 3.44 3.41 3.41 3.28 3.22
170 549 60 61 70 123 58 55
0.24 0.05 0.49 0.49 0.46 0.32 0.50 0.51
28 ⫺11 ⫺1
4.16 4.13 3.99
3.69 3.67 3.57
77 145 83
0.43 0.28 0.42
z
a
Coordinates of the voxel of maximal statistical significance within each region. Value of the t test with 32 degrees of freedom for the voxel of maximal statistical significance. c Z scores corresponding to the t test for the voxel of maximal statistical significance in each region; all voxels reported in the table were significant at the one-tailed p ⬍0.001 level, uncorrected. d Total number of contiguous voxels in each region that surpassed the initial threshold of Z ⬎3.08 (p ⬍0.001). e Level of statistical significance for each voxel cluster before correction for multiple comparisons. b
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Patients with BD in Old Age
TABLE 4.
Mean Normalized Regional Brain Volumes and White Matter Hyperintensity Scores in Older and Comparison Groups With BD Groups BD (N ⴝ 17)
Mean normalized volumes of the brain region of interesta Hippocampal total Hippocampal left Hippocampal right Entorhinal cortex total Anterior cingulate cortex total Amygdalar total Sheltens’ Scale Scores Periventricular hyperintensities WMH in deep white matter Basal ganglia Infratentorial Sum of all subscores
Comparison (N ⴝ 17)
M
SD
M
SD
3.42 1.66 1.76 1.13
0.55 0.28 0.28 0.24
3.69 1.79 1.90 1.15
0.49 0.24 0.26 0.17
2.31
0.45
2.52
0.68
1.76
0.32
1.77
0.26
0.94
1.14
1.41
1.23
3.12
4.30
3.06
3.57
0.35 0 4.47
0.86 0 5.46
0.29 0.06 4.76
0.59 0.24 4.89
Mean normalized volumes: ( 关absolute volume of ROI in mm3/ intracranial volume in mm3兴 ⫻ 1.000). a
ings of Martino et al.,6 this observation suggests that the BD-related pattern of cognitive impairment remains stable both in terms of affected functions and severity in old age. The lower score of the patients with BD on the CR 48 test revealed a genuine episodic memory deficit as this test controls for cognitive processing during encoding minimizing the effect of impaired attention or inefficient strategies.20 Unlike what is usually reported in previous contributions,2 we did not observe executive dysfunctions in our patients with BD. This discrepancy could be partly explained by sample differences. The patients with BD included in this study were free from lifetime psychiatric comorbidities such as substance abuse, known to influence executive function performance.31 Alternatively, two methodological reasons may explain the relative preservation of executive functions in our cohort with BD. First, we used relative ratio score to obtain a purer measure of executive functions. Because patients with BD are known to be slower than controls,4 a higher executive cost is already expected on the
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mere basis of this slowing. It is crucial to control for this issue to avoid reporting as an executive dysfunction what is in fact an artifact of general slowing.32 This fact is not taken into account in many prior studies.2 Second, executive functions in BD have often been measured using tasks that combine multiple executive functions (e.g., Wisconsin Card Sorting Test) without an a priori hypothesis. In this study, we selected three executive tests, each one focusing on a single executive component of the tripartite model developed by Miyake et al.33 With respect to brain volumetry, we found no significant differences between euthymic older adults with BD and controls. Previous studies in younger cohorts of patients with BD reported volumetric abnormalities that mainly affected the prefrontal lobe (including the orbitofrontal, dorsolateral, subgenual, and anterior cingulate cortex) and postulated that these alterations may partly explain the executive dysfunctions observed in these patients.34 In our study, neither the preservation of executive functions nor the absence of frontal lobe volume abnormality in the voxel-based analysis support this scenario. Our ROI analysis was limited to the hippocampal formation, entorhinal, amygdala, and anterior cingulate cortex, four brain areas reliably delineated in morphometric studies and known to be vulnerable to the possible progressive neurotoxic effect of glucocorticoids. Previous structural MRI analyses of these regions provide conflicting data. Most of the prior studies revealed no significant volume alteration in the hippocampus of younger cases with BD.35,36 In contrast, larger amygdala35,37 and smaller anterior cingulate volumes27,38 were found in younger cases with BD. However, in their meta-analysis, Konarski et al.34 concluded that volume alterations in these two brain structures are too inconsistent to draw any firm conclusions. Recently, an age-related reduction of amygdala volume in BD was reported by Doty et al.39 This difference with our results may be explained by the old age of the present cohort (i.e., 40 years older compared with that investigated by Doty et al.39). Interestingly, these authors suggested that their cohort of patients with BD could not benefit from the neuroprotective effects of medication (e.g., lithium) given the limited period of treatment. Consequently, they postulated that the group difference on amygdala volume could decrease in old age
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Delaloye et al. due to the neuroprotective effect of the long-term treatment. It is thus possible that the lack of brain volume differences in our study reflects the neuroprotective effect of mood stabilizers. However, in the absence of prospective data related to drug prescription in the present series, this hypothesis cannot be tested. Moreover, it should be kept in mind that despite its conceptual attractiveness, the possibility of structural preservation related to the prescription of mood stabilizers in old age is still a controversial issue.40,41 Finally, to our knowledge, the volume of entorhinal cortex in BD has not been investigated in case– control studies. As for volumetric data,34 the relationship between BD and WMH remains controversial42,43 mostly because of sample differences. For instance, higher degree of WMH was found only in patients with BD with a history of severe mania12 or with manic episode disease onset.44 Using a strict selection of elderly cases with BD and careful case– control matching for clinical and demographic variables, we demonstrate that elderly patients with BD show neither volumetric differences in hippocampus, amygdala, entorhinal, and anterior cingulate cortex nor a higher degree of WMH, when compared with healthy individuals. In particular, the absence of increased WMH in our group of elderly patients with BD may reflect the similar burden of somatic comorbidities in the BD and comparison groups. Indeed, a previous study postulated that the association between WMH and affective disorders, such as depression, is mediated by nonpsychiatric comorbidities such as current smoking or physical disability.45 These observations in older cases with BD complete the recent observations of Scherk et al.46 who found no structural abnormalities in gray and white matter volumes in middle-aged patients with BD and indicate these volumes changes do not occur in the longitudinal course of the illness. This is further supported by the fact that length of illness was not related to neuroimaging and neuropsychological parameters in our study. Strengths of this study include the careful exclusion of lifetime psychiatric comorbidities (which could affect both cognitive performances and structural imaging data in BD), comparable somatic comorbidities and pairwise matching for demographic variables between the two diagnostic groups, detailed assessment of cognitive performances, volumetric analyses using both ROI and VBM, and concomitant assessment of WMH.
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Our strict inclusion criteria may have induced a selection of patients with less severe BD disease (e.g., lower number of manic episodes). Although the design adopted in this study can provide a more precise evaluation of the effect of BD on cognition and structural brain volume, it may also lead to an underestimation of this effect.3 Several limitations should also be taken into account. First, because this study focused on the exploration of the effect of BD on brain structures and cognition in elderly, we cannot comment on the possible relationships between structural alterations and cognitive performances in our series. For instance, the amygdala is known to be preferentially activated by emotional stimuli not included in this study. Second and as in previous studies,5,6 the sample size is relatively small. Given this limitation, no distinction was made between BD I and BD II. Third, the effect of additional clinical parameters such as the number of previous episodes and history of psychotic symptoms was not addressed. Finally, the type of medications was not considered in our analysis because the psychotropic treatment was prescribed naturalistically. Thus, we cannot exclude an effect of medication on cognitive performances in euthymic cases with BD. In conclusion, this cross-sectional study reveals that the cognitive deficits observed in elderly euthymic patients with BD are comparable both in terms of affected functions and size effects to those described in younger cohorts with BD. Moreover, the present cohort with BD did not display significant vascular or volumetric brain abnormalities. Altogether these data do not support a progressively evolving neurotoxic effect in BD. Future longitudinal studies in large series of carefully documented patients with BD I and II are needed to explore further the cognitive and neuroanatomical repercussions of this disorder in late life. The authors thank Franc¸oise Hofer, Claire Ragno Paquier, Corinne Dubois Remund, Se´bastien Urben, Jose´phine Tillmann, Abba Moussa, Corina Meiler-Mititelu, Karsten Ebbing, Montserrat Mendez Rubio, Franc¸oise Lanet, and Reto Meuli for their contribution to this work. This work was realized in collaboration with the Center for Biomedical Imaging (CIBM) of the Geneva-Lausanne Universities, and the EPFL. This work was supported by the Swiss National Science Foundation (FNRS 3200BO-112018). CD and FdB contributed equally to this work.
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Patients with BD in Old Age References 1. Gunning-Dixon FM, Murphy CF, Alexopoulos GS, et al: Executive dysfunction in elderly bipolar manic patients. Am J Geriatr Psychiatry 2008; 16:506 –512 2. Mur M, Portella MJ, Martinez-Aran A, et al: Persistent neuropsychological deficit in euthymic bipolar patients: executive function as a core deficit. J Clin Psychiatry 2007; 68:1078 –1086 3. Bearden CE, Hoffman KM, Cannon TD: The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review. Bipolar Disord 2001; 3:106 –150; discussion 151–103 4. Torres IJ, Boudreau VG, Yatham LN: Neuropsychological functioning in euthymic bipolar disorder: a meta-analysis. Acta Psychiatr Scand Suppl 2007; 17–26 5. Schouws SN, Zoeteman JB, Comijs HC, et al: Cognitive functioning in elderly patients with early onset bipolar disorder. Int J Geriatr Psychiatry 2007; 22:856 – 861 6. Martino DJ, Igoa A, Marengo E, et al: Cognitive and motor features in elderly people with bipolar disorder. J Affect Disord 2008; 105:291–295 7. Gildengers AG, Butters MA, Seligman K, et al: Cognitive functioning in late-life bipolar disorder. Am J Psychiatry 2004; 161:736 –738 8. Nemeroff CB, Widerlov E, Bissette G, et al: Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984; 226:1342–1344 9. Brambilla P, Harenski K, Nicoletti M, et al: Differential effects of age on brain gray matter in bipolar patients and healthy individuals. Neuropsychobiology 2001; 43:242–247 10. Kauer-Sant’anna M, Kapczinski F, Andreazza AC, et al: Brainderived neurotrophic factor and inflammatory markers in patients with early- vs late-stage bipolar disorder. Int J Neuropsychopharmacol 2008; 4:1–12 11. Beyer JL, Taylor WD, MacFall JR, et al: Cortical white matter microstructural abnormalities in bipolar disorder. Neuropsychopharmacology 2005; 30:2225–2229 12. Altshuler LL, Curran JG, Hauser P, et al: T2 hyperintensities in bipolar disorder: magnetic resonance imaging comparison and literature meta-analysis. Am J Psychiatry 1995; 152:1139 –1144 13. Beyer JL, Kuchibhatla M, Payne ME, et al: Hippocampal volume measurement in older adults with bipolar disorder. Am J Geriatr Psychiatry 2004; 12:613– 620 14. Beyer JL, Kuchibhatla M, Payne M, et al: Caudate volume measurement in older adults with bipolar disorder. Int J Geriatr Psychiatry 2004; 19:109 –114 15. Sheehan DV, Lecrubier Y, Sheehan KH, et al: The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59(suppl 20):22–33; quiz 34 –57 16. Yesavage JA, Brink TL, Rose TL, et al: Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res 1982; 17:37– 49 17. Young RC, Biggs JT, Ziegler VE, et al: A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978; 133:429 – 435 18. Hultsch DF, MacDonald SWS, Hunter MA, et al: Intraindividual variability in cognitive performance in older adults: comparison of adults with mild dementia, adults with arthritis, and healthy adults. Neuropsychol 2000; 14:588 –598 19. Wechsler DA. WAIS-III Administration and Scoring Manual. San Antonio, Psychological Corporation, 1997 20. Ivanoiu A, Adam S, Van der Linden M, et al: Memory evaluation with a new cued recall test in patients with mild cognitive
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impairment and Alzheimer’s disease. J Neurol 2005; 252: 47–55 21. Welsh KA, Butters N, Mohs RC, et al: The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part V. A normative study of the neuropsychological battery. Neurology 1994; 44: 609 – 614 22. Maj M, D’Elia L, Satz P, et al: Evaluation of two new neuropsychological tests designed to minimize cultural bias in the assessment of HIV-1 seropositive persons: a World Health Organization study. Arch Clin Neuropsychol 1993; 8:123–135 23. Stroop JR: Studies of interference in serial verbal reactions. J Exp Psychol Gen 1935; 18:643– 661 24. Morris N, Jones DM: Memory updating in working memory: the role of the central executive. Br J Psychiatry 1990; 81:111–121 25. Watson C, Andermann F, Gloor P, et al: Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging. Neurology 1992; 42:1743–1750 26. Bernasconi N, Bernasconi A, Andermann F, et al: Entorhinal cortex in temporal lobe epilepsy: a quantitative MRI study. Neurology 1999; 52:1870 –1876 27. Sassi RB, Brambilla P, Hatch JP, et al: Reduced left anterior cingulate volumes in untreated bipolar patients. Biol Psychiatry 2004; 56:467– 475 28. Mechelli A, Price CJ, Friston KJ, et al: Voxel-based morphometry of the human brain: methods and applications. Curr Med Imaging Rev 2005; 1:105–113 29. Scheltens P, Barkhof F, Leys D, et al: A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci 1993; 114:7–12 30. Charlson ME, Pompei P, Ales KL, et al: A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40:373–383 31. Liappas I, Theotoka I, Kapaki E, et al: Neuropsychological assessment of cognitive function in chronic alcohol-dependent patients and patients with Alzheimer’s disease. In Vivo 2007; 21:1115–1118 32. Verhaeghen P, De Meersman L: Aging and the Stroop effect: a meta-analysis. Psychol Aging 1998; 13:120 –126 33. Miyake A, Friedman NP, Emerson MJ, et al: The unity and diversity of executive functions and their contributions to complex “Frontal Lobe” tasks: a latent variable analysis. Cogn Psychol 2000; 41:49 –100 34. Konarski JZ, McIntyre RS, Kennedy SH, et al: Volumetric neuroimaging investigations in mood disorders: bipolar disorder versus major depressive disorder. Bipolar Disord 2008; 10:1–37 35. Blumberg HP, Kaufman J, Martin A, et al: Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder. Arch Gen Psychiatry 2003; 60:1201–1208 36. Strasser HC, Lilyestrom J, Ashby ER, et al: Hippocampal and ventricular volumes in psychotic and nonpsychotic bipolar patients compared with schizophrenia patients and community control subjects: a pilot study. Biol Psychiatry 2005; 57:633– 639 37. Altshuler LL, Bartzokis G, Grieder T, et al: An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia. Biol Psychiatry 2000; 48:147–162 38. Lochhead RA, Parsey RV, Oquendo MA, et al: Regional brain gray matter volume differences in patients with bipolar disorder as assessed by optimized voxel-based morphometry. Biol Psychiatry 2004; 55:1154 –1162 39. Doty TJ, Payne ME, Steffens DC, et al: Age-dependent reduction of amygdala volume in bipolar disorder. Psychiatry Res 2008; 163:84 –94
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Delaloye et al. 40. Forester BP, Streeter CC, Berlow YA, et al: Brain lithium levels and effects on cognition and mood in geriatric bipolar disorder: a lithium-7 magnetic resonance spectroscopy study. Am J Geriatr Psychiatry 2009; 17:13–23 41. Fountoulakis KN, Vieta E: Treatment of bipolar disorder: a systematic review of available data and clinical perspectives. Int J Neuropsychopharmacol 2008; 11:999 – 1029 42. Silverstone T, McPherson H, Li Q, et al: Deep white matter hyperintensities in patients with bipolar depression, unipolar depression and age-matched control subjects. Bipolar Disord 2003; 5:53–57
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43. Krabbendam L, Honig A, Wiersma J, et al: Cognitive dysfunctions and white matter lesions in patients with bipolar disorder in remission. Acta Psychiatr Scand 2000; 101:274 –280 44. Gulseren S, Gurcan M, Gulseren L, et al: T2 hyperintensities in bipolar patients and their healthy siblings. Arch Med Res 2006; 37:79 – 85 45. Jorm AF, Anstey KJ, Christensen H, et al: MRI hyperintensities and depressive symptoms in a community sample of individuals 60 – 64 years old. Am J Psychiatry 2005; 162:699 –705 46. Scherk H, Kemmer C, Usher J, et al: No change to grey and white matter volumes in bipolar I disorder patients. Eur Arch Psychiatry Clin Neurosci 2008; 258:345–349
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Objective: Previous studies reported that the severity of cognitive deficits in euthymic patients with bipolar disorder (BD) increases with the duration of illness and postulated that progressive neuronal loss or shrinkage and white matter changes may be at the origin of this phenomenon. To explore this issue, the authors performed a case– control study including detailed neuropsychological and magnetic resonance imaging analyses in 17 euthymic elderly patients with BD and 17 healthy individuals. Methods: Neuropsychological evaluation concerned working memory, episodic memory, processing speed, and executive functions. Volumetric estimates of the amygdala, hippocampus, entorhinal cortex, and anterior cingulate cortex were obtained using both voxel-based and region of interest morphometric methods. Periventricular and deep white matter were assessed semiquantitatively. Differences in cognitive performances and structural data between BD and comparison groups were analyzed using paired t-test or analysis of variance. Wilcoxon test was used in the absence of normal distribution. Results: Compared with healthy individuals, patients with BD obtained significantly lower performances in processing speed, working memory, and episodic memory but not in executive functions. Morphometric analyses did not show significant volumetric or white matter differences between the two groups. Conclusions: Our results revealed impairment in verbal memory, working memory, and processing speed in euthymic older adults with BD. These cognitive deficits are comparable both in terms of affected functions and size effects to those
Received June 17, 2008; revised March 9, 2009; accepted June 24, 2009. From the Division of Geriatric Psychiatry, University Hospitals of Geneva and Faculty of Medicine, Switzerland (CD, FdB, GM, SB, KW, LC, AC, UG, PG); Faculty of Psychology and Science of Education, University of Geneva, Switzerland (CD); Division of Old Age Psychiatry, University Hospitals of Lausanne, Hospices-CHUV, Switzerland (AvG, RIS, PG); Alzheimer Center and Department of Neurology, VU Medical Center, Amsterdam, the Netherlands (PS); Department of Radiology, University Hospitals of Geneva, Switzerland (FL); Clinical Neurophysiology and Neuroimaging Unit, University Hospitals of Geneva, Switzerland (PM); and Department of Rehabilitation and Geriatrics, University Hospitals of Geneva, Switzerland (GG). Send correspondence and reprint requests to Dr. Christophe Delaloye, Service de Psychiatrie Ge´riatrique—Ho ˆ pitaux Universitaires de Gene`ve, 2 Chemin du Petit-Bel-Air, 1225 Cheˆne-Bourg, Switzerland. e-mail: [email protected] © 2009 American Association for Geriatric Psychiatry
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Delaloye et al. previously reported in younger cohorts with BD. Both this observation and the absence of structural brain abnormalities in our cohort do not support a progressively evolving neurotoxic effect in BD. (Am J Geriatr Psychiatry 2009; 17:1012–1021) Key Words: Bipolar disorder, neuropsychology, neuroimaging, older adults
T
he impact of bipolar disorder (BD) on cognitive functions is still a controversial issue. There is growing evidence that, besides the well known changes that occur during the manic and depressive phases,1 BD is also associated with neuropsychological impairments that persist during the euthymic state.2 In fact, recent reviews reported executive function, memory and attention/processing impairments in young and middle-aged euthymic patients with BD.3,4 A growing body of evidence indicates that the severity of cognitive deficits in euthymic patients with BD is mostly related to the duration of illness.3 Thus, one would expect more pronounced neuropsychological impairment in elderly patients with longstanding BD.5 Studies focusing on the neuropsychological performance of older euthymic patients with BD are, however, sparse.5–7 Most of them were based on global neuropsychological scales, such as the Mattis Dementia Rating Scale, which do not allow the investigation of subtle cognitive deficits.7 Several biological alterations may lead to an increased cognitive vulnerability in older patients with BD. It has been postulated that repeated stress in BD increases glucocorticoid levels8 and might result in cumulative cortical neuronal loss or shrinkage in brain areas highly saturated in glucocorticoid receptors, such as the amygdala, hippocampus, and anterior cingulate cortex.9 In addition, stress-induced glucocorticoid secretion may reduce cellular resilience, making certain neurons more vulnerable to concomitant insults, such as ischemia or hypoglycemia. Alternatively, Kauer-Sant’anna et al.10 found a failure of inflammatory defense in patients with severe BD leading to a reduction in brain-derived neurotrophic factor that could be associated with loss of hippocampal neurons. Finally, increased deep white matter and periventricular hyperintensities were also described in older adults with BD compared with controls and could contribute to the acceleration of cognitive decline.11,12 Both neuropsychological data and
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structural magnetic resonance imaging (MRI) studies in elderly patients with BD are still scarce.13,14 To determine whether the pattern of cognitive deficits and structural abnormalities in older euthymic patients with BD are similar to those reported among younger patients with BD, we performed a prospective case– control study including a detailed neuropsychological analysis that covered a wide variety of cognitive domains (e.g., working memory, episodic memory, processing speed, and executive functions) and detailed MRI investigation including volumetric estimates of the amygdala, hippocampus, entorhinal, and anterior cingulate cortex performed with a region of interest (ROI) morphometric method, a voxel-based analysis, and a semiquantitative assessment of white matter hyperintensities (WMH).
METHODS Participants Seventeen euthymic elderly patients with BD with BD I (nine patients) and BD II (eight patients) and 17 age-, gender-, and education-matched healthy individuals were included in the study. Patients with BD were recruited either from the psychogeriatric outpatient service of the University Hospitals of Geneva, Switzerland, or through advertisements in specialized journals. Controls were also recruited through advertisements in local newspapers. The diagnosis of BD (patients) or the absence of a psychiatric condition (healthy individuals) was established using the Mini International Neuropsychiatric Interview15 administered by a geropsychiatrist. Euthymia was defined according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria (absence of depressive symptoms for at least 2 months). In addition, all participants had to obtain a score below 5 on the Geriatric Depression Scale 15-items16 and on
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Patients with BD in Old Age the Young Mania Rating Scale17 at inclusion. Clinical assessment of euthymia and administration of the two scales were performed by the same geropsychiatrist. Exclusion criteria for both groups were history of major neurologic disorders or head trauma, presence of a current or a past psychiatric diagnosis (other than BD for the group of patients), based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, current systemic medical disease requiring inpatient treatment, less than 4 years of formal education, and hearing, vision, or motor impairment precluding neuropsychological testing. After the formal acceptance of the research protocol by the local ethics committee, written informed consent was obtained before inclusion. Cognitive Measures Processing Speed. A simple reaction time task was used to assess processing speed.18 Participants had to press a key as quickly as possible when the visual signal stimulus appeared. The score of interest was the mean latency of the 120 test trials. Working Memory. Working memory was indexed by the Letter-Number Sequencing subtest of the Wechsler Memory Scale III, which involved auditory tracking of letters and numbers, then recalling all the numbers in ascending order, followed by all the letters in alphabetical order.19 The score of interest was the number of correct sequences produced. Episodic Memory. Episodic memory was assessed with two tests: the cued recall (CR) 48 items test20 and the consortium to establish and registry for Alzheimer’s Disease (CERAD) Word List Memory.21 The CR48 task comprised 48 different words, belonging to 12 different semantic categories. The 48 words were presented as written words on 12 consecutive cards. Participants were invited to encode these words with the help of semantic cues (e.g., fruit, raspberry). On completion of each card, an immediate CR was realized (e.g., fruit?). Once the 48 words were encoded, a CR task was performed (e.g., which were the fruits?). The score of interest was the number of words correctly recalled. The CERAD Word List Memory test involves memorization of a list of 10 words that was presented over three trials. After 5 minutes, a delayed recall was measured (number of words correctly retrieved). Executive Functions. Mental shifting capacity was indexed by the Color Trail Making Test, which com-
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prises two parts.22 In Part A, the participant had to connect a series of 25 encircled numbers in numerical order as quickly as possible. Part B tested cognitive flexibility skills by requiring participants to shift sets by matching number with colors in a progressive and alternating pattern (e.g., 1, pink; 2, yellow; and 3-pink). Completion time for each part was the dependent measure. The score of interest was the flexibility cost computed by a relative ratio ([completion time Part B ⫺ completion time Part A]/completion time Part A). Inhibition capacity was assessed by the French version of the standard Stroop color-word interference task, which included three subtests.23 The first subtask displayed solid color patches in one of four colors (red, blue, yellow, and green). The second subtask used neutral words printed in one of these four basic colors. The third subtask contained color words printed in an incongruous ink color (e.g., word yellow printed in red ink). In each subtask, participants were instructed to name the ink color of the stimuli as quickly and as accurately as possible. Completion time for each subtask was the dependent measure. The score of interest was the interference effect, which was computed by a relative ratio ([completion time subtask 3 ⫺ completion time subtask 2]/completion time subtask 2). Updating capacity was measured by the Consonant Updating Test.24 Participants had to recall, in the same order as their presentation, the last four elements of a list including four, six, or eight consonants. Once all the consonants of a given list were presented, participants heard a beep, which set off the recall. Participants never knew in advance how many consonants were included in each list. The task included 12 lists of consonants with four lists by condition (no update, two updates, and four updates). The main dependent variable was the number of consonants recalled correctly in each condition. The score of interest was based on the updating costs, which were determined by a relative ratio (2-updating cost: [2 updates ⫺ 0 update]/0 update and 4-updating cost: [4 updates ⫺ 0 update]/0 update). MRI Procedures The MRI imaging was performed at 3 Tesla (Siemens). Coronal slices were obtained from three-dimensional Magnetization Prepared Rapid Gradient Echo (MPRAGE) sequence with the following parameters: repetition time (TR) 2,500 ms, echo time
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Delaloye et al. (TE) 2.94 ms, inversion time (TI) 1,100 ms, flip angle 9°, isotropic resolution of 0.9 mm3, acquisition time 8 minutes 40 seconds. In addition, three-dimensional T2 weighted imaging was obtained with the following parameters: TE ⫽ 383 ms, TR ⫽ 3,200 ms, field of view (FOV) ⫽ 230 mm, acceleration factor (parallel imaging) 2, matrix size 256 ⫻ 256 ⫻ 240. ROI Analysis. Anterior cingular and entorhinal cortices and hippocampal and amygdala perimeters were traced manually on each contiguous coronal slice using a ROI procedure of ANALYZE software (Version 8, Mayo Foundation). Neuroanatomic boundaries of the hippocampus and amygdala were based on those of Watson et al.25 Anatomic guidelines for outlining the entorhinal and anterior cingular cortices were those described by Bernasconi et al.26 and Sassi et al.27 respectively. References to sagittal and horizontal planes were performed whenever necessary to improve identification of structure boundaries. Each brain structure was delimited by a manual contour from which the corresponding volume was calculated using the ANALYZE software. The total volume of each structure was then calculated by summing all values obtained from ROIs applied on consecutive slices (slice thickness: 0.9 mm). Intracranial volumes, defined as all gray and white matter in the cerebrum (including cerebellum and stem), and the CSF were measured automatically from the segmented images. Normalized volumes for brain regions of interest were determined by using the following formula: (absolute volume [mm3]/ intracranial volume [mm3]) ⫻ 1.000. All measurements were performed by a trained rater blind to participant’s group. Voxel-Based Morphometry. The data were analyzed with SPM5 software. Standard statistical parametric mapping processing was used to analyze MRI for voxel-based morphometry (VBM).28 Images were segmented using the standard T1 template and a priori gray matter, white matter, and CSF atlases provided by SPM. Spatially normalized (1 ⫻ 1 ⫻ 1 mm3) data were modulated to account for local volume changes due to nonlinear coregistration. Gray matter images were smoothed with a 8 mm Gaussian kernel. Assessment of WMH. Assessment of white matter lesions was performed in T2-weighted sequences with the Scheltens semiquantitative scale.29 Periventricular hyperintensities were rated as 0 ⫽ absent, 1 ⫽ ⱕ5 mm, or 2 ⫽ ⬎5 mm and ⬍10 mm. WMH were rated as 0 ⫽ no abnormalities, 1 ⫽ ⬍3 mm and
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n ⱕ5, 2 ⫽ ⬍3 mm and n ⬎6, 3 ⫽ 4 –10 mm and n ⱕ5, 4 ⫽ 4 –10 mm and n ⬎6, 5 ⫽ ⱖ11 mm and n ⬎1, and 6 ⫽ confluent, in frontal, parietal, occipital, and temporal white matter. Basal ganglia (caudate nucleus, putamen, globus pallidus, thalamus, and internal capsule) and infratentorial foci hyperintensities were similarly rated from 1 to 6. Statistical Analysis Differences in mean or median performance between patients with BD and comparison group were analyzed using paired t-test or analysis of variance. To respect assumptions of normality (Shapiro-Wilk) and homogeneity of variance (Levene’s test), the relative ratio scores of the Stoop color test and the mean latencies of the simple reaction time test were modified before analysis by means of logarithmic transformation. Wilcoxon Matched-Pairs Signed Rank test was used in the absence of normal distribution. Data were analyzed with SPSS version 15.0 and StatXact Version 4. For VBM analysis, statistical threshold of p ⬍0.001 (uncorrected) was used.
RESULTS Demographic and Clinical Characteristics The demographic and clinical characteristics of the series are summarized in Table 1. There were no significant differences in age (t[16] ⫽ 0.62, p ⫽ 0.54), education (t[16] ⫽ ⫺0.11, p ⫽ 0.91), and Charlson Cormorbidity Index30 score (S ⫽ 29.5, p ⫽ 0.77; the S value is the minimum value between the positive ranks’ sum and the negative ranks’ sum associated with the difference between each paired measures). The scores on the Geriatric Depression Scale and the Young Mania Rating Scale confirmed patient’s euthymic mood state. Patients were already under treatment at inclusion. We did not interfere with their medication as the treatment was prescribed naturalistically. Fourteen patients received mood stabilizers (lithium: 29%, valproic acid: 35%, and other anticonvulsants: 12%). This treatment was associated with atypical antipsychotics in 18% of the cases, serotonin or noradrenalin reuptake inhibitors in 12% of the cases, and benzodiazepines in 12% of the cases.
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Patients with BD in Old Age
TABLE 1.
Demographic and Clinical Characteristics of the Present Series Groups BD (N ⴝ 17)
Characteristics Age (years) Educationa Score GDS (max 15) Score YMRS (max 44) Score CCI (max 19) Age of onset (years) Duration of illness Percentage of current smokers/past smokers/never smokers
Comparison (N ⴝ 17)
M
SD
M
SD
69.00 13.12 1.47 1.06 1.29 39.35 29.65
(5.85) (3.72) (1.58) (1.47) (2.82) (15.6) (15.7)
69.24 13.12 1.35 0.00 0.76 — —
(6.02) (3.25) (1.32) (0.00) (0.97) — —
18/53/29
20/47/33
Notes: GDS: Geriatric Depression Scale; YMRS: Young Mania Rating Scale; CCI: Charlson Comorbidity Index. a Number of years of education completed.
In 12% of the cases, there was a concomitant prescription of antipsychotics, antidepressants, and benzodiazepines. Healthy individuals did not receive psychotropic medication.
Processing Speed. Older patients with BD were statistically slower than the comparison group (t[16] ⫽ 2.31, p ⬍0.05) in the simple reaction time test. Working Memory. The group of patients with BD presented a significantly lower (t[16] ⫽ 3.12, p ⬍0.01) score in the Letter-Number-Sequencing test. Episodic Memory. Older patients with BD obtained a significantly lower CR score on the CR 48 items test
Neuropsychological Data Performances on cognitive tests are provided in Table 2.
TABLE 2.
Patient and Comparison Groups’ Raw Score Performance in Neuropsychological Tests Groups BD (N ⴝ 17)
Processing speed Simple reaction time: latencies (ms) Working memory Letter-Number Sequence: Score Episodic memory Cued Recall 48 items: Score Cerad 10 words: Delayed recall score Executive function Flexibility Color Trail Making Test: Relative ratio score Inhibition Stroop Colour: Relative ratio score Updating Consonant Updating: 2 updating cost Updating Consonant Updating: 4 updating cost a
Comparison (N ⴝ 17)
M
SD
M
SD
t/Za
p
Effect Size, r
348.27
73.48
289.82
76.93
t关16兴 ⫽ 2.31
0.034
0.42
8.18
2.40
10.47
2.24
t关16兴 ⫽ 3.12
0.007
0.45
21.88 5.82
5.04 1.70
29.12 7.41
6.22 1.42
t关16兴 ⫽ 4.55 t关16兴 ⫽ 2.50
0.0003 0.01
0.55 0.46
1.05
0.55
0.95
0.48
Z ⫽ 0.36
0.72
—
0.71
0.50
0.63
0.26
t关16兴 ⫽ 0.60
0.56
—
⫺0.24
0.21
⫺0.07
0.10
t关16兴 ⫽ 2.75
0.01
0.46
⫺0.14
0.30
⫺0.10
0.19
t关16兴 ⫽ 0.55
0.59
—
t: paired t test and Z: Wilcoxon test.
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Delaloye et al. (t[16] ⫽ 4.55, p ⬍0.01) and a significantly lower delayed recall score on the CERAD Word List Memory Test (S ⫽ 5, p ⫽ 0.01) than the comparison group. Executive Functions. The flexibility cost in the Color Trail Making Test did not differ between BD and comparison groups (S ⫽ 60, p ⫽ 0.69). This was also the case for the interference score of the Stroop color Test (t[16] ⫽ 0.60, p ⫽ 0.56). Regarding the updating consonant test, the two groups differed on the two-updating cost (t[16] ⫽ 2.75, p ⫽ 0.01) but not on the four-updating cost (t[16] ⫽ 0.55, p ⫽ 0.59). MRI Data Table 3 summarizes the mean normalized volumes of each brain ROI by group of participants. There were no significant differences in hippocampal (t[16] ⫽ 1.58, p ⫽ 0.13), entorhinal cortex (t[16] ⫽ 0.28, p ⫽ 0.78), anterior cingulate (t[16] ⫽ 1.09, p ⫽ 0.29), and amygdala (t[16] ⫽ 0.11, p ⫽ 0.92) volume between BD and comparison groups. A volume asymmetry was observed only for the hippocampus (F[1,16] ⫽ 26.23, p ⬍0.01), the right hippocampal volume being larger than the left one. The degree of this asymmetry did not differ between patients and healthy individuals (F[1,16] ⫽ 0.15, p ⫽ 0.71). VBM analysis did not reveal any significant difference in gray matter volumes between patients with
TABLE 3.
BD and healthy individuals at the cluster level as reported in Table 3. Table 4 summarizes the mean rating score of WMH according to the Scheltens semiquantitative scale. Periventricular hyperintensities scores were comparable between BD and comparison groups (S ⫽ 46.5, p ⫽ 0.70). This was also the case for hyperintensities in neocortical white matter (S ⫽ 6, p ⫽ 0.62). Besides, BD and healthy controls had virtually no hyperintensities in basal ganglia and infratentorieal areas. Importantly, duration of illness had no impact on cognitive performances, cerebral volumes, and WMH scores.
CONCLUSION From a neuropsychological standpoint, and as already reported in younger cohorts with BD,4 euthymic older patients with BD had lower performances in tests measuring processing speed, working memory, and episodic memory compared with healthy individuals. However, the observed effect size falls within the moderate-to-large range and is similar overall to that reported in studies focusing on younger patients with BD.4 Consistent with the find-
Differences in Regional Gray Matter Volumes Between BD (N ⴝ 17) and Comparison Groups (N ⴝ 17) in Voxel-Based Analysis Coordinatesa
Higher in BD Superior frontal gyrus Postcentral gyrus Thalamus Superior frontal gyrus Postcentral gyrus Superior frontal gyrus Superior frontal gyrus Paracentral lobule Lower in BD Cingulate gyrus Caudate Thalamus (ventral anterior)
Hemisphere
x
y
Left Left Left Left Left Right Left Left
1 ⫺16 0 1 ⫺54 12 ⫺27 ⫺6
19 ⫺47 ⫺1 34 ⫺13 ⫺9 1 ⫺28
Right Right Right
22 15 13
8 20 0
Peakb t test
Peakc Z Score
No.d of Voxels
pe (Uncorrected)
63 80 2 55 48 73 66 80
4.22 3.96 3.9 3.81 3.78 3.78 3.6 3.53
3.74 3.54 3.5 3.44 3.41 3.41 3.28 3.22
170 549 60 61 70 123 58 55
0.24 0.05 0.49 0.49 0.46 0.32 0.50 0.51
28 ⫺11 ⫺1
4.16 4.13 3.99
3.69 3.67 3.57
77 145 83
0.43 0.28 0.42
z
a
Coordinates of the voxel of maximal statistical significance within each region. Value of the t test with 32 degrees of freedom for the voxel of maximal statistical significance. c Z scores corresponding to the t test for the voxel of maximal statistical significance in each region; all voxels reported in the table were significant at the one-tailed p ⬍0.001 level, uncorrected. d Total number of contiguous voxels in each region that surpassed the initial threshold of Z ⬎3.08 (p ⬍0.001). e Level of statistical significance for each voxel cluster before correction for multiple comparisons. b
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Patients with BD in Old Age
TABLE 4.
Mean Normalized Regional Brain Volumes and White Matter Hyperintensity Scores in Older and Comparison Groups With BD Groups BD (N ⴝ 17)
Mean normalized volumes of the brain region of interesta Hippocampal total Hippocampal left Hippocampal right Entorhinal cortex total Anterior cingulate cortex total Amygdalar total Sheltens’ Scale Scores Periventricular hyperintensities WMH in deep white matter Basal ganglia Infratentorial Sum of all subscores
Comparison (N ⴝ 17)
M
SD
M
SD
3.42 1.66 1.76 1.13
0.55 0.28 0.28 0.24
3.69 1.79 1.90 1.15
0.49 0.24 0.26 0.17
2.31
0.45
2.52
0.68
1.76
0.32
1.77
0.26
0.94
1.14
1.41
1.23
3.12
4.30
3.06
3.57
0.35 0 4.47
0.86 0 5.46
0.29 0.06 4.76
0.59 0.24 4.89
Mean normalized volumes: ( 关absolute volume of ROI in mm3/ intracranial volume in mm3兴 ⫻ 1.000). a
ings of Martino et al.,6 this observation suggests that the BD-related pattern of cognitive impairment remains stable both in terms of affected functions and severity in old age. The lower score of the patients with BD on the CR 48 test revealed a genuine episodic memory deficit as this test controls for cognitive processing during encoding minimizing the effect of impaired attention or inefficient strategies.20 Unlike what is usually reported in previous contributions,2 we did not observe executive dysfunctions in our patients with BD. This discrepancy could be partly explained by sample differences. The patients with BD included in this study were free from lifetime psychiatric comorbidities such as substance abuse, known to influence executive function performance.31 Alternatively, two methodological reasons may explain the relative preservation of executive functions in our cohort with BD. First, we used relative ratio score to obtain a purer measure of executive functions. Because patients with BD are known to be slower than controls,4 a higher executive cost is already expected on the
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mere basis of this slowing. It is crucial to control for this issue to avoid reporting as an executive dysfunction what is in fact an artifact of general slowing.32 This fact is not taken into account in many prior studies.2 Second, executive functions in BD have often been measured using tasks that combine multiple executive functions (e.g., Wisconsin Card Sorting Test) without an a priori hypothesis. In this study, we selected three executive tests, each one focusing on a single executive component of the tripartite model developed by Miyake et al.33 With respect to brain volumetry, we found no significant differences between euthymic older adults with BD and controls. Previous studies in younger cohorts of patients with BD reported volumetric abnormalities that mainly affected the prefrontal lobe (including the orbitofrontal, dorsolateral, subgenual, and anterior cingulate cortex) and postulated that these alterations may partly explain the executive dysfunctions observed in these patients.34 In our study, neither the preservation of executive functions nor the absence of frontal lobe volume abnormality in the voxel-based analysis support this scenario. Our ROI analysis was limited to the hippocampal formation, entorhinal, amygdala, and anterior cingulate cortex, four brain areas reliably delineated in morphometric studies and known to be vulnerable to the possible progressive neurotoxic effect of glucocorticoids. Previous structural MRI analyses of these regions provide conflicting data. Most of the prior studies revealed no significant volume alteration in the hippocampus of younger cases with BD.35,36 In contrast, larger amygdala35,37 and smaller anterior cingulate volumes27,38 were found in younger cases with BD. However, in their meta-analysis, Konarski et al.34 concluded that volume alterations in these two brain structures are too inconsistent to draw any firm conclusions. Recently, an age-related reduction of amygdala volume in BD was reported by Doty et al.39 This difference with our results may be explained by the old age of the present cohort (i.e., 40 years older compared with that investigated by Doty et al.39). Interestingly, these authors suggested that their cohort of patients with BD could not benefit from the neuroprotective effects of medication (e.g., lithium) given the limited period of treatment. Consequently, they postulated that the group difference on amygdala volume could decrease in old age
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Delaloye et al. due to the neuroprotective effect of the long-term treatment. It is thus possible that the lack of brain volume differences in our study reflects the neuroprotective effect of mood stabilizers. However, in the absence of prospective data related to drug prescription in the present series, this hypothesis cannot be tested. Moreover, it should be kept in mind that despite its conceptual attractiveness, the possibility of structural preservation related to the prescription of mood stabilizers in old age is still a controversial issue.40,41 Finally, to our knowledge, the volume of entorhinal cortex in BD has not been investigated in case– control studies. As for volumetric data,34 the relationship between BD and WMH remains controversial42,43 mostly because of sample differences. For instance, higher degree of WMH was found only in patients with BD with a history of severe mania12 or with manic episode disease onset.44 Using a strict selection of elderly cases with BD and careful case– control matching for clinical and demographic variables, we demonstrate that elderly patients with BD show neither volumetric differences in hippocampus, amygdala, entorhinal, and anterior cingulate cortex nor a higher degree of WMH, when compared with healthy individuals. In particular, the absence of increased WMH in our group of elderly patients with BD may reflect the similar burden of somatic comorbidities in the BD and comparison groups. Indeed, a previous study postulated that the association between WMH and affective disorders, such as depression, is mediated by nonpsychiatric comorbidities such as current smoking or physical disability.45 These observations in older cases with BD complete the recent observations of Scherk et al.46 who found no structural abnormalities in gray and white matter volumes in middle-aged patients with BD and indicate these volumes changes do not occur in the longitudinal course of the illness. This is further supported by the fact that length of illness was not related to neuroimaging and neuropsychological parameters in our study. Strengths of this study include the careful exclusion of lifetime psychiatric comorbidities (which could affect both cognitive performances and structural imaging data in BD), comparable somatic comorbidities and pairwise matching for demographic variables between the two diagnostic groups, detailed assessment of cognitive performances, volumetric analyses using both ROI and VBM, and concomitant assessment of WMH.
Am J Geriatr Psychiatry 17:12, December 2009
Our strict inclusion criteria may have induced a selection of patients with less severe BD disease (e.g., lower number of manic episodes). Although the design adopted in this study can provide a more precise evaluation of the effect of BD on cognition and structural brain volume, it may also lead to an underestimation of this effect.3 Several limitations should also be taken into account. First, because this study focused on the exploration of the effect of BD on brain structures and cognition in elderly, we cannot comment on the possible relationships between structural alterations and cognitive performances in our series. For instance, the amygdala is known to be preferentially activated by emotional stimuli not included in this study. Second and as in previous studies,5,6 the sample size is relatively small. Given this limitation, no distinction was made between BD I and BD II. Third, the effect of additional clinical parameters such as the number of previous episodes and history of psychotic symptoms was not addressed. Finally, the type of medications was not considered in our analysis because the psychotropic treatment was prescribed naturalistically. Thus, we cannot exclude an effect of medication on cognitive performances in euthymic cases with BD. In conclusion, this cross-sectional study reveals that the cognitive deficits observed in elderly euthymic patients with BD are comparable both in terms of affected functions and size effects to those described in younger cohorts with BD. Moreover, the present cohort with BD did not display significant vascular or volumetric brain abnormalities. Altogether these data do not support a progressively evolving neurotoxic effect in BD. Future longitudinal studies in large series of carefully documented patients with BD I and II are needed to explore further the cognitive and neuroanatomical repercussions of this disorder in late life. The authors thank Franc¸oise Hofer, Claire Ragno Paquier, Corinne Dubois Remund, Se´bastien Urben, Jose´phine Tillmann, Abba Moussa, Corina Meiler-Mititelu, Karsten Ebbing, Montserrat Mendez Rubio, Franc¸oise Lanet, and Reto Meuli for their contribution to this work. This work was realized in collaboration with the Center for Biomedical Imaging (CIBM) of the Geneva-Lausanne Universities, and the EPFL. This work was supported by the Swiss National Science Foundation (FNRS 3200BO-112018). CD and FdB contributed equally to this work.
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