Gray matter deficits in young onset schizophrenia are independent of age of onset

~{!§i{~i{~ii~iiiii i iiiiiiiiii~~iii!iiiii~i

A RTICLES Gray Matter Deficits in Young Onset Schizophrenia Are Independent of Age of Onset RIGINAL

Kelvin O. Lim, Debra Harris, Michael Beal, Anne L. Hoff, Kyungtak Minn, John G. Csernansky, William O. Faustman, Laura Marsh, Edith V. Sullivan, and Adolf Pfefferbaum

This study examined whether the degree of brain dysmorphology observable in adulthood was related to onset age of schizophrenic symptoms. Brain magnetic resonance imaging (MRI) scans were acquired in 57 men with schizophrenia, whose age at MRI was 19-53 years, and whose symptom onset ranged from age 7 to 29 years; all were inpatients in a state hospital Volumes of intracranial space, cortical gray matter (GM) and white matter (WM), and cerebrospinal fluid (CSF) in lateral and third ventricles and cortical sulci were derived from MRI scans and corrected by regression analysis for variations attributable to age and head size, quantified in a control sample of healthy communi~ volunteers. The schizophrenic patients had larger volumes of cortical and ventricular CSF and smaller volumes of cortical GM but not WM than age-matched controls, whether or not volumes were adjusted for head size and age norms. Age of onset did not correlate with any of the five age-adjusted brain measures. Neither current age, length of illness, nor symptom severi~ correlated with age-normalized volumes of cortical GM, sulcal CSF, or ventricular CSF. These observations are consistent with the theory that brain structure deficits' 1) first develop prior to symptom onset (perhaps during the prenatal and~or early childhood process of GM development); 2) probably establish a vulnerability to subsequent dysfunctionality; but 3) are nonprogressive.

Key Words: Schizophrenia, age of onset, brain, gray matter BIOL PSYCHIATRY 1996;40:4--13

Introduction The gross morphological brain abnormalities of schizophrenia include enlargements of cerebrospinal fluid (CSF) From the Psychiatry Service, Veterans Affairs Palo Alto Health Care System and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California (KOL, WOF, LM, EVS, AP), Biological Psychiatry Treatment and Research Unit, Napa State Hospital, Napa, California (DH, MB, ALF, KM), Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri (JGC).

© 1996 Society of Biological Psychiatry

spaces and widespread cortical gray matter (GM) volume deficits, and have been well documented in cross-sectional studies [reviewed by Pearlson and Marsh (1993)]. Schizophrenia is typically a disease with onset in late adolescence or early adulthood, a period during which cortical

Address reprint requests to Dr. K. Lim. Psychiatry Service (116A), VA Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA 94304. Received October 24, 1994; revised March 6, 1995.

0006-3223/96/$15.00 SSDI 0006-3223(95)00356-L

Age of Schizophrenia Onset and GM Deficits

GM in normal development undergoes significant reduction, but cortical white matter (WM), as observed in vivo with magnetic resonance imaging (MRI) (Pfefferbaum et al 1994) and postmortem (Yakovlev and Lecours 1967), continues to increase in volume. The course of schizophrenia through the adult life span coincides with another course of dynamic change in brain volume that includes a period of stable WM volume, gradual reduction in cortical GM volume, and increase in ventricular and sulcal CSFfilled spaces (Jernigan et al 1990; Jernigan and Tallal 1990; Murphy et al 1993; Pfefferbaum et al 1994). Thus, normal developmental and aging effects need to be taken into account when interpreting observed brain dysmorphology in schizophrenia. Studies adopting this approach have shown that the brains of schizophrenic patients age at a normal rate (Marsh et al 1994; Zipursky et al 1992); however, at any given age, they have less cortical GM volume than would be expected for their age. Enlarged ventricles have been observed in young adult patients early in the course of the illness in some (Degreef et al 1992; DeLisi et al 1991; Schulz et al 1983; Weinberger et al 1982) but not all (DeLisi et al 1992) studies. Cross-sectional computed tomography (CT) studies have generally not found ventricular enlargement to be related to length of illness, once normal aging changes are taken into account [reviewed by Raz and Raz (1990)]. Some MRI cross-sectional studies have reported a lack of association with length of illness for measures of cortical tissue (Marsh et al 1994; Zipursky et al 1992), whereas others have found an association, particularly of temporal lobe (DeLisi et al 1991) or cortical sulci (O'Callaghan et al 1992). Taken together, these observations largely support the proposition that certain brain morphological changes occur prior to the clinical manifestations of the illness and do not progress further over the course of the illness, at least through middle age. Such in vivo findings along with neuropathological data have led to theories embracing the concept of an early neurodevelopmental abnormality that results in a fixed alteration of brain structure. Subsequent maturational event or events trigger the preexisting vulnerability and set in motion little understood events resulting in illness onset (Bloom 1993; Feinberg 1983; Murray et al 1992; Weinberger 1987). Schizophrenia onset can be defined in terms of unusual behavior, definable schizophrenic symptoms, or actual psychiatric hospitalization (Beiser et al 1993). Epidemiological studies show onset age differs according to the definitions of illness onset used (H~ifner et al 1993). Linking illness onset to the emergence of definable symptoms avoids both the ambiguity of defining the onset of the prodromal period, as well as possible socioeconomic and cultural biases inherent in first hospitalization for a psychotic young person (Costello and Janiszewski 1990). The

BIOLPSYCHIATRY 1996;40:4 13

5

age of onset of schizophrenic symptoms peaks at around age 25 in men (H~ifner et al 1989). Few neuroimaging studies have explicitly reported on the relationship between age of onset and brain abnormalities. One found no significant differences in ventricular measures between "early" and "late" onset cases, using a cutoff age of 25 for men (Johnstone et al 1989). Another reported a significant negative association between age at first psychiatric contact and volume of the lenticular nuclei, but no significant relationship with inferomedial cortical GM volume deficit (Jernigan et al 1991c). In the present study, we examined clinically well-described adult male schizophrenic patients with illness onsets occurring before, during, or after adolescence (ages 7-29), a time when significant volume brain changes normally occur (Jernigan et al 1991b; Pfefferbaum et al 1994). Any association with onset age over this limited age range could lead to inferences regarding the impact of a pathogenic event at different points in the trajectory of brain maturation or could provide indirect evidence concerning the timing of the process that leads to the cortical GM volume deficit. We used MRI to quantify volumes of cortical GM, WM, sulcal CSF, and ventricles in severely ill schizophrenic patients and in an age- and sex-matched normal comparison group. Given our previous finding in adult-onset schizophrenia (Zipursky et al 1992), we expected to observe cortical GM but not WM volume deficits, and sulcal and ventricular enlargement in the patients as compared with the control subjects. Further, we questioned whether the extent of brain dysmorphology, relative to age and head size norms would be greater in patients with an earlier onset. In addition, we investigated the relationships between length of illness and age at MRI and brain volumes derived from MRI.

Methods and Materials Patients with Schizophrenia Patients were recruited from all of the adult inpatient units that care for male patients at the Napa State Hospital (NSH). NSH serves as a referral facility for patients from county mental health programs, predominantly from northern California. All patients were screened with a common procedure, including physical and laboratory examinations, a structured psychiatric interview, careful review of records, and, when available, information from family members regarding age of onset. Institutional Review Board and administrative approval was obtained at the participating institutions (NSH and the California Health and Welfare Agency, Stanford University, and the Department of Veterans Affairs). Written informed con-

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1996;40:4 13

Table 1. Initial Population Sampled and Reasons for Exclusion Patients in male wards at Napa State Hospital Chart diagnosis other than schizophrenia No documentable age of onset Acute medical illness Neurological condition Alcohol dependence or substance abuse Discharged before could enter study Unmanageable Refused participation Dropped out after entering Total exclusions Patients completing study

734 222 80 13 69 III 120 28 27 7 677 57

sent was obtained from patients or from their guardians with the patients' agreement. Recruitment proceeded in two waves. Initial recruitment focused on two groups of patients, those with a chart diagnosis of schizophrenia, for whom there was documented evidence that Section A symptom criteria of the DSM-III-R diagnosis of schizophrenia were met before their 15th birthday, and those with a young adult onset age for schizophrenia, i.e., 18 or older. Then, patients with age of onset occurring at 15-17 years of age were sought to provide a continuum of age of onset. The charts of all patients admitted to or currently hospitalized at NSH during the period of this study (n = 734) were reviewed to identify those with a chart diagnosis of schizophrenia (Table 1). All of these charts were then reviewed for exclusionary factors, such as presence of physical or neurological illness or substance abuse. In particular, patients were excluded if they had: acute medical illness; history of antineoplastic chemotherapy; known HIV-positive status; neurological condition (current seizure disorder, psychosurgery, or head injury with loss of consciousness of more than 30 rain or with definite neurologic sequelae); chromosomal abnormality [e.g., Kleinfelter syndrome (XXY)]; or history of alcohol dependence, intravenous amphetamine use, inhalant use (glue, gasoline, etc.), or recent (within last 30 days) substance abuse. Some subjects were not in the study because of impending discharge from hospital, family objections, treatment team objections, lack of cooperation, or recent history of unmanageable violence. Consenting subjects underwent psychiatric evaluation by two independent interviewers (psychiatrists and psychiatric residents), one using the Structured Clinical Interview for DSM-III-R for patients (SCID-P) (Spitzer et al 1992; Williams et al 1992), and the other a DSM-III-R criteria checklist. In

addition, a complete blood count, chemistry panel, urinalysis, thyroid function tests (T3, T4, and TSH), B-12, and folate were obtained as part of the screening process for this MRI protocol. This study is based on 57 subjects who met all study criteria, gave consent, and completed the procedures. Their ages of onset ranged from 7 to 29 years (mean 17 -+ 4 years). At the time of MRI, they were age 19-53 years (mean 36 -+ 8 years), had been ill from 4 to 40 years (mean 19 + 8 years), and had been hospitalized in NSH from 2 months to 39 years. Age of onset was defined as the earliest documentable age at which Section A criteria for a DSM-III-R diagnosis of schizophrenia were met [ 1) at least two of the following symptoms: delusions, hallucinations, incoherence, catatonic behavior, flat or grossly inappropriate affect; 2) bizarre delusions; or 3) prominent hallucinations]. This age, originally estimated from the chart, was reviewed by two psychiatrists who reached a consensus after interviewing the patient, any available family members, conservators, or other reliable informants, and reviewing available original treatment records. A third reviewer later examined these records from a subset of 25 patients to make an independent determination of age of onset. Pearson correlation between both sets of ratings was .97. The current clinical condition of the patient was evaluated using the 18-item brief psychiatric rating scale (BPRS) (Overall and Gorham 1988), Global Assessment of Functioning Scale (GAF) (American Psychiatric Association 1987), and Clinical Global Impression Scale of severity of illness (CGI). BPRS ratings performed closest to time of MRI were used for this analysis: scores were derived by taking the average of two calibrated raters (41 subjects) or using the rating by a single experienced clinician (16 subjects). In a largely overlapping NSH sample, clinician agreement on total BPRS scores was .82 (Spearman correlation coefficient). GAF and CGI ratings were all done by a single psychiatrist. Evaluators were not blind to age of onset. A negative symptom score was derived by summing scores for the following BPRS items: blunted affect, emotional withdrawal, and motor retardation. Prior work (Thiemann et al 1987) has shown that the BPRS items yield a score that correlates very strongly with overall scores from the Scale for the Assessment of Negative Symptoms (Andreasen and Olsen 1982). A positive symptom score was derived by summing scores for the following BPRS items: hallucinatory behavior, unusual thought content, conceptual disorganization (Faustman 1994). Patients were administered an adaptation of the SatzMogel version of the Wechsler Adult Intelligence ScaleRevised (WAIS-R) Verbal scale, referred to as the prorated Verbal IQ. To compute this score, every third item of the Information and Vocabulary and every other item of

Age of Schizophrenia Onset and GM Deficits

the Similarities subtest was given (Satz and Mogel 1962). In order to estimate premorbid intellectual function, the Reading subtest of the Wide Range Achievement TestRevised (WRAT-R) was given (Jastak and Wilkinson 1984). The demographic and clinical characteristics of the schizophrenic group and the age-matched subsample are described in Tables 2 and 3.

Normal Control Group A normal control group of 52 men was matched in age to the patient group but had significantly more years of education than the patients [t(107) = 11.86, p < .0001]. The comparison subjects were 21-53 years old (mean age = 37 -+ 9) and were drawn from a larger control group consisting of 73 men, 21-70 years old (mean age = 44.1 + 13.8 years). This full group was recruited prospectively from the community to participate in a study of normal aging, as well as to serve as a healthy comparison group for other patient populations studied in this laboratory. MRI data from these 73 subjects or subsamples of them have been described elsewhere (Mathalon et al 1993a; Pfefferbaum et al 1992; Pfefferbaum et al 1994; Zipursky et al 1992), and provide the age and head size norms for MRI data used in this analysis. Normal comparison subjects were recruited through advertisement and screened in our laboratory by a psychiatrist using the Schedule for Affective Disorders and Schizophrenia--Lifetime (SADS) (Endicott and Spitzer 1978). Subjects were considered for entry into this study if they had no history of medical or neurological illness or trauma that would affect the central nervous system (CNS), and no current or past psychiatric and nonalcoholic drug use problems. Screening included a medical and psychiatric history, physical examination, and a panel of blood tests (complete blood count, SMA-20). Subjects were excluded if they met Research Diagnostic Criteria (Spitzer et al 1975) for substance abuse in the past year or had drunk more than 4 standard drinks a day for a period exceeding 1 month. All subjects provided written informed consent.

MRI Scanning MRI ACQUISITION. The patients were transported from the NSH to Stanford University Medical Center for MRI scanning. All subjects were scanned using a 1.5T General Electric Signa MRI scanner. Image acquisition parameters and procedures have been previously described (Lira and Pfefferbaum 1989; Pfefferbaum et al 1994; Zipursky et al 1992). Axial MR images were acquired using a spin-echo sequence with a field of view of 24 cm and a 256 × 256 matrix. Acquisition was gated to every other cardiac cycle

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Table 2. Clinical Characteristics and Demographics of Schizophrenics and Normal Comparison Group

Age (years) Mean SD

Range Height (cm) Mean

SO Range Head size (cc) Mean

SD

Range Race

White Nonwhite Education (years)

Mean SD Range ProratedVerbal IQ Mean

SD Range Wide Range Achievement Test IQ Mean Range SD

ClinicalGlobal Impressions score Mean SD Range Brief psychiatric rating scale (BPRS)--total Mean

SD Range BPRS negative symptom score Mean

SD Range BPRS positive symptom score Mean SD Range

Schizophrenics (n = 57)

Normal comparison group (n = 52)

35.95 8.17 19-53

36.98 8.91 21-53

175.88 7.84 157.48-198.12

178.66 6.99 165-193

1306.09 137.2 1037.4-1693.8

1344.41 116.33 1128.7-1653.5

65% 35%

88% 12%

10.7" 2.1 4-16

16.42 2.54 115-23

85.92 23.8 46-145

88.15 52-134 19.43

5.53 0.93 3-7

59.36 13.21 26-84

9.77 2.87 3-16

14.44 4.52 3-21

"p < .0001.

for an effective repetition time (TR) of >2400 msec with one excitation for each of 256 phase encodes. Early and late echoes were obtained at 20 msec and 80 msec. All axial images were oriented in an oblique plane, perpen-

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Table 3. Associations between Clinical Characteristics of Schizophrenic Patients and Age at Scan, Age of Onset, and Length of Illness

Table 4. Estimated Volumes (in cc) for Brain Measures of Schizophrenic and Normal Comparison Group Normal

A g e at

Age of

Length of

scan

onset

illness

Age of onset

r = .32"

comparison

(n = 57)

g r o u p (n = 52)

Cortical CSF

L e n g t h o f i l l n e s s (years)

r = .87 ~'

r

E d u c a t i o n (years)

r = .40'

r - .53 h

r-

-.22

Prorated V e r b a l I Q

r = .28 ~

r - . 15

r

.21

Wide Range Achievement

-.20

r = .01

r =

r -

.04

.06

Test Clinical Global

Schizophrenics

Mean

45.75"

39.27

SD

11.79

10.58

C o r t i c a l gray m a t t e r Mean

114.23 h

SD

13.05

Mean

74.42

74.00

SD

13.5

11.95 19.12

r = -.01

r -

-.28 ~

r = . 16

B P R S total

r =

r-

-.10

r = -.13

Negative symptoms

r = -.13

r =

.40'

r-

-.07

Lateral ventricles

Positive symptoms

r = -.13

r =

.09

r -

-.18

M e a n -+ S D

28.48 b

SD

14.07

Impression .0.8

df = 1/55. a p < .05; b p < .0001; " p < .01.

Cortical white matter

MRI IMAGE ANALYSIS. All images were stored on magnetic tape, transferred to optical disks for analysis, and coded to allow processing to be performed blind to subject identity, age, diagnosis, and neuroradiologist's report. For each data set, the most inferior section above the level of the orbits, where the anterior horns of the lateral ventricles could be seen bilaterally, was identified as an index section. Seven consecutive sections, beginning at the index section and proceeding superiorly, were analyzed for each subject. The index section or the section below it was used for quantification of the third ventricle. Each of the MRI sections was segmented into CSF, GM, and WM compartments, using a semiautomated image analysis technique (Lira and Pfefferbaum 1989), and divided into an inner 55% region (to facilitate quantification of central CSF, which arose primarily but not exclusively from the ventricular system) and an outer 45% (to facilitate quantification of the cortical tissue volumes and sulcal CSF). CSF, GM, and WM pixels were summed bilaterally within this cortical region.

8.14

Third ventricles M e a n _+ S D

0.52'

0.34

SD

0.29

0.16

~p < .01;

dicular to the sagittal plane, and passing through the anterior and posterior commissures, which were identified from a midsagittal image. Beginning inferiorly at the base of the pons, 17-20 sections were collected, each 5 mm thick, with a 2.5-ram intersection skip to reduce crosstalk. The subjects also underwent a coronal acquisition series for another study; one section from this sequence was used for head height measurement, which was integral to the estimation of the head size. Head size was estimated by modeling the intracranial volume as a sphere, using head height as the diameter of the sphere and the area of the index slice as a plane passing through the center of the sphere (Mathalon et al 1993a).

129.61

14.48

bp <

.0001; Cp < .001.

Statistical Analysis Pixel counts for GM, WM, and CSF were transformed into cubic centimeters (cc) to provide estimates of the absolute volume encompassed by cortical GM, WM, and CSF (sulci), as well as the lateral and third ventricles. These "raw" scores, which are presented in Table 4, do not take into account normal variation associated with differences in head size or aging and thus were corrected using a two-step regression analysis to adjust for normal variation in head size and age, estimated from the total sample of 73 normal comparison subjects. This two-step process, described previously (Mathalon et al 1993a; Pfefferbaum et al 1992) yields a Z score. For normal comparison subjects, the expected mean Z score is 0 with a SD of 1. For patients, Z scores provide volume estimates relative to that which would be expected from normal comparison subjects of a particular head size and age (Mathalon et al 1993b). Group comparisons were based on the 57 schizophrenic patients and 52 age-matched control subjects. Statistical analysis for comparing groups was a two-tailed t test. Relationships between variables were tested using Pearson correlations, multiple regression, and where appropriate, Mann-Whitney U tests. We treated age of onset as both a continuous variable and a dichotomous measure. The use of continuous variables maximizes statistical power; however, in separately examining the patients with onset age <15 years, we could evaluate a unique and unusual group of patients whose onset of psychosis predates the completion of normal neurodevelopmental processes occurring during adolescence.

Age of Schizophrenia Onset and GM Deficits

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Tissue

Results

Clinical and Demographic Characteristics The schizophrenic patients were severely ill as indicated by their mean BPRS score of approximately 60 (Table 2). Total BPRS score was not associated with age of onset (Table 3); however, the negative symptom score (the total for blunted affect, emotional withdrawal, and motor retardation BPRS items) and the CGI were both associated with age of onset, with the earlier onset subjects being more severely affected. Age at scan significantly correlated with age of onset and length of illness. As might be expected, patients with later onset had more years of education. Although the -< 14-year-old onset patients did not show a distinct pattern of brain morphology, they did have higher negative symptom scores than the -> 18-yearold onset group [F(1,40) = 4.63, p < .05] and a trend for higher CGI scores [F(1,40) = 3.17, p : .08]. A detailed examination of the neuropsychological characteristics of these very early onset patients compared to the larger group will be the subject of a separate report. The normal comparison group were age-matched to the schizophrenic patients and closely matched in height. The patients had smaller head size (intracranial volume) than the normal comparison subjects, although the difference was not significant (Table 2). Among the schizophrenics, age of onset was not associated with height or head size.

Volumes

3"1

[] SZ(n~57)

2 1 1~~

ImNC$(n=$Z)

Gray

Matter

9

WhiteMatter

CSF V o l u m e s

3" z...................................................... ~-.............................. ~.........................

-1........................................................................................................... -2 .................................................................................................................

-3

*p<.O01,*'p<.OOOl SulcalCSF Lateral Ventricles

3rd Ventricle

Figure 1. Group Z scores for cortical GM and WM (upper), and sulcal, lateral, and third ventricular CSF (lower) for schizophrenic (SZ) and normal control subjects (NCS). For tissue measures, a negative Z score denotes deficit relative to age and head size norms. For CSF measures, a positive Z score denotes abnormality in the form of enlarged CSF-filled spaces.

Group Differences in MRI Volumes For measures of tissue, lower Z scores signify less and higher Z scores more volume than would be expected for a given head size and age. Thus, low Z scores for tissue measures and high Z scores for CSF measures signify volume abnormalities. Compared with the control group, the patient group had significantly lower Z scores for volumes of cortical GM [t(107) = 7.375, p = .0001] but not cortical WM, which showed a trend for a group difference in the opposite direction It(107) = 1.884, p < 07]. For CSF, the patient group had greater volumes than did the comparison group in the cortical sulci [t(107) = 3.611, p = .0005], lateral ventricles It(107) = 5.546, p = .0001], and third ventricle [t(107) = 4.688, p = .0001]. Thus, the schizophrenic patients had smaller cortical GM and larger sulcal and ventricular CSF volumes than were expected for their head size and age (Figure 1). These analyses were repeated using raw MRI volumes (cc) and revealed the same pattern of group differences in cortical GM and cortical and ventricular CSF, with no difference in WM.

Relationship of MRI Volumes to Age of Onset and Length of Illness in the Schizophrenic Patients By using age-corrected Z scores, we were able to assess the contributions of age of onset and length of illness to brain volume abnormalities, independent of differences attributable to normal aging as reflected by current age. Pearson correlations of age of onset and length of illness against MRI measures revealed no association (r values for age of onset ranged from .003 to .19; r values for length of illness ranged from .01 t o . 14). The upper limits of the 95% confidence interval for the correlations involving age of onset ranged f r o m . 14 (lateral ventricles) to .20 (third ventricle) and for length of illness, from .03 (cortical sulci) to .07 (third ventricle). Thus, even at the 95% confidence level, none of these correlations would be statistically significant. Since age at MRI was significantly associated with both age of onset and length of illness (Table 3), we next used multiple regression analyses to examine the contributions of age of onset and length of illness in predicting the age-corrected volumes of the MRI

10

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K.O. Lim et al

1996;40:4-13

Cortical Gray Matter

................... •

NI

•

. _1~

10

i..,,_.~. ........

= ..................

eoo°teO|, •, g o~ ~,j~ O e o 8 e8 .• |o 15 20 Age at Onset

;...

•

25

Cortical While Matter

4 3 2 1 C 03 -1 .,~

3~ 2~

oo

o|°e

•

•

• ..

~

°!

03

o •

10

3O

o

15 20 Age at Onset

25

10

30

• "

15

20

25

30

Age at Onset

Third Ventricle

° •

Do ,

°

o-

-11

11 o 03

:: ;-..... ;

-2 -3 -4

Lateral Ventricles

tq

Cortical CSF

4'

:;,.....

•

"

|"

O0o

,,

8

2"

....

-,,fr~ t , ~ J - ~ - - - ' - - O,

•

•

-4; 5

10

15 20 Age at Onset

25

30

5

10

15 20 Age of Onset

25

30

Figure 2. Z scores of individual schizophrenic patients for cortical GM, WM, and sulcal, lateral, and third ventricular CSF plotted as a function of age of onset of illness. Brain volumes in none of the regions of interest were significantly correlated with onset age over the range studied.

measures. Neither age of onset nor length of illness was a significant predictor of these brain measures (p values for age of onset and length of illness each ranged from .26 to .96). The profound lack of association between age of onset as a continuous measure and brain measures can be seen in Figure 2. A substantial subgroup (n = 21) of our sample developed documented schizophrenic symptomatology at an early age, 7-14 years of age. Therefore, we performed an analysis of variance, comparing these younger onset patients to those with a more typical age of onset, i.e., -->18 years of age (n = 21). No significant group effect for any brain measure emerged (p values ranged from .23 for the third ventricle to .98 for cortical WM). From Figure 2 it is apparent that age of onset, as defined and over the range studied, does not define any brain morphological subgroup.

Relationship of MRI Measures to Clinical Variables Among the schizophrenic patients, exploratory correlations using both parametric and nonparametric statistics were performed to test the relationships between MRI Z scores (cortical GM volumes and lateral ventricular CSF volume) and symptom severity (the CGI, BPRS total score, negative symptom score, and positive symptom

score). Neither cortical GM nor lateral ventricular volumes correlated significantly with any symptom measures.

Discussion These adult schizophrenic patients, many with preadolescent or early adolescent onset, showed a marked (1.5 SD) deficit in cortical GM volume and enlargement of cortical sulcal and ventricular CSF volumes compared with agematched normal control subjects. The age at which psychotic symptoms first appeared, however, was not related to the degree of brain dysmorphology observed in adulthood. Brain MRI volumes were expressed as deviations from age and head size norms, derived from a community sample, and thus took head size and age at MRI into account. By using multiple regression analysis, we also took into account the association between current age and a g e of onset in this sample and still observed that onset age, over a range encompassing only what is commonly referred to as "early" onset, was not a significant predictor of degree of brain dysmorphology. Any association between onset age and brain morphology in late-onset schizophrenia is not addressed in this report. Neurodevelopmental theories of the etiology of schizo-

Age of Schizophrenia Onset and GM Deficits

phrenia posit disturbances affecting both developmental and regressive events: the pre-, peri-, and postnatal processes of nerve cell development and migration (Cannon and Mednick 1992; Murray et al 1992; Weinberger 1987) and the process of synaptic pruning (Feinberg 1983; Feinberg et al 1990; Huttenlocher 1979). Disruption of these early and late developmental and regressive events in different parts of the brain may be linked or may occur independently of each other. For cortical GM, an in vivo cross-sectional MRI study places completion of cortical GM growth and beginning of regressive pruning around age 5 years (Pfefferbaum et al 1994), well before the youngest onset age in the current study. Thus the lack of any relationship between cortical GM deficit and age of onset found in this study suggests that the cortical GM deficit most likely reflects impoverished early development of cell bodies. A recent study in our laboratory in which adult patients with congenital rubella, an illness with known prenatal etiology, had significantly smaller intracranial and cortical GM volumes than would be expected for their age (Lira et al 1995) provides a possible model for this early neurodevelopmental process in schizophrenia. In contrast, disruption of later neurodevelopmental regressive events, such as synaptic pruning (Feinberg 1983; Feinberg et al 1990; Huttenlocher 1979), could well account for Jernigan and colleague's (Jernigan et al 1991 c) observation of enlarged subcortical structures, the lenticular nuclei, in schizophrenia. The observed negative association, where larger lenticular nuclei volume was related to earlier age of onset, makes this particularly plausible. Like us, however, they also found no association between cortical GM deficits and age of onset (Jernigan et al 1991c). Whether early neurodevelopmental lesions and later neurodevelopmental regressive processes act independently or in concert to produce the cortical and subcortical GM effects reported in this study and in Jernigan's study remains to be determined. In the current study, the normal comparison group had significantly more years of education than the patients, a phenomenon attributable to some extent to the disruptive effect of their illness on the education of these patients. Although educational differences between successive comparison groups have been implicated in failure to replicate apparent deficits in brain morphology in schizophrenic groups (Andreasen et al 1990a), there is little reason to believe that educational differences per se contribute significantly to the large group differences in cortical GM volume observed. Years of education was not associated with cortical GM or ventricular volumes within either the schizophrenic or the control groups. Furthermore, an analysis of covariance indicated that group differences persisted after controlling for education across both groups.

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The second major observation of this study is the lack of association of either cortical GM volume deficits or cortical and ventricular enlargement with length of illness. Similar observations have been made in other crosssectional studies (Andreasen et al 1990b; Marsh et al 1994; Zipursky et al 1992). Our use of the age regression model enabled this complex relationship to be observed independently of the normal aging process, and provides strong evidence that neither cortical GM volume deficit nor ventricular and sulcal CSF enlargement progress over the early course of the illness in schizophrenics. This observation can be contrasted with the brain dysmorphology associated with age in chronic alcoholics, among whom the GM volume deficit is greater in older than younger subjects (Pfefferbaum et al 1992). These studies are of course limited by their cross-sectional nature, and the observed results require confirmation with longitudinal study. ! There was a clear lack of association between illness severity or symptom type and brain dysmorphology. This suggests that the widespread cortical GM volume deficit that occurs very early in the developing brain of preschizophrenics has little direct association with subsequent global clinical manifestations of the disorder, at least within the range of variance available in this sample. One possibility is that the GM deficit that occurs, perhaps prenatally (Lyon et al 1989), deprives those affected of the redundancy inherent in the normally developing brain and makes them vulnerable to subsequent dysregulation, for example, of corticolimbic circuits (Csernansky et al 1991). Our findings are consistent with some neuroimaging studies of first break schizophrenics showing significant ventricular enlargement even at the earliest stage of clinically observable symptoms (Degreef et al 1992; DeLisi et al 1991; Schulz et al 1983; Weinberger et al 1982); however, not all patients scanned at their first break demonstrate ventricular enlargement (DeLisi et al 1992). Some limitations of the present study derive from the fact that patients were drawn from a state hospital that serves as a referral center for schizophrenics who cannot be maintained in a community or outpatient setting; who in the main have been ill for a long time; and for whom reliable establishment of "first signs of illness" was not possible, often because relevant records were no longer available. We chose, for reasons of greater reliability, to define illness onset in terms of emergence of psychotic symptoms, rather than "first signs of illness." The interval between beginning of the prodrome and emergence of psychotic symptoms can range from days to years (Beiser et al 1993); thus, our study does not address the possibility of a relationship between cortical GM deficit and prodromal onset. Another limitation of this study of age of onset in

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schizophrenia is the selection bias resulting from recruitment of only men, thus precluding questions relating to gender differences. Prospective, longitudinal, in vivo, brain imaging studies of schizophrenic patients (men and women), first scanned close to the time of their first psychotic break, need to be done to determine whether a cortical G M volume deficit is present at this time in all patients, regardless of illness severity or gender, or only in those who continue to do poorly. The schizophrenic patients examined in this study represent a unique population clinically, because they were at the severe end of the spectrum of behavioral management, and biologically, because they exhibited highly significant brain volume abnormalities. For cortical GM, the volume deficit was on average a 1.5 SD. This volume deficit is larger than that typically reported in community samples of schizophrenic patients. Thus, despite the limitations noted above, the brain abnormalities were amply severe and variable to address the issue of

K.O. Lira et al

whether age of onset could predict the magnitude of brain dysmorphology observed in adulthood. The results of this study reveal a lack of relationship between age of onset and brain dysmorphology, and thus are consistent with a premorbid, nonprogressive hypothesis of brain dysmorphology, at least in male schizophrenic patients.

This research was supported by the National Institutes of Health (MH 30854); the Norris Foundation; the Department of Veterans Affairs; the California Department of Mental Health; and Napa State Hospital. We are indebted to staff of the VA Palo Alto Health Care System, especially Stacie DeMent; staff of Napa State Hospital, especially Nick Fotius, MD, Mark Gustafson, Scott Espinoza, and Robert Mone for their critical roles in patient care, transportation, and scanning; Jody M. Rawles and Brian Matsumoto for image and data processing; Daniel H. Mathalon, PhD for helpful discussions; and Margaret Rosenbloom for significant contributions to the manuscript. A preliminary report of these data was presented at the Annual Meeting of the Society for Biological Psychiatry, May 1994, Philadelphia, PA.

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