Reduced Purkinje Cell Size in the Cerebellar Vermis of Elderly ...

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Richard L. Doty, Ph.D., and Steven E. Arnold, M.D.. Objective: The authors' goal was to compare the size and linear density of Purkinje cells in the cerebellar ...
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Reduced Purkinje Cell Size in the Cerebellar Vermis of Elderly Patients With Schizophrenia Khoa D. Tran, B.A., Gregory S. Smutzer, Ph.D., Richard L. Doty, Ph.D., and Steven E. Arnold, M.D.

Objective: The authors’ goal was to compare the size and linear density of Purkinje cells in the cerebellar vermis of subjects with and without schizophrenia. Method: Blocks of alcohol-fixed cerebellar vermis were dissected at autopsy from the brains of 14 elderly patients with schizophrenia and 13 elderly subjects with no history of neuropsychiatric illness. The blocks of vermis were sectioned and stained with 1% cresyl violet. The linear density and cross-sectional area of Purkinje cells were measured by using computer-assisted image analysis. The subjects with schizophrenia had been assessed with clinical rating scales within 1 year prior to death. Results: The average cross-sectional areas of Purkinje cells of the patients with schizophrenia were significantly smaller (by 8.3%) than those of the subjects without neuropsychiatric illness. No difference in Purkinje cell linear density was observed between the two groups. Significant correlations were seen between Purkinje cell size and scores on the Mini-Mental State, the Brief Psychiatric Rating Scale, and the antipsychotic drug dose. Conclusions: These data indicate cerebellar involvement in schizophrenia; they are also consistent with reports of reduced neuronal size in other brain regions of patients with schizophrenia. These findings support a model of widespread central nervous system abnormality in schizophrenia. (Am J Psychiatry 1998; 155:1288–1290)

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he cerebellum has been viewed traditionally as a central nervous system (CNS) structure dedicated to motor control. However, recent evidence from neurobehavioral and functional neuroimaging studies indicates additional roles for the cerebellum in such diverse cognitive processes as attention, sensory discrimination, verbal learning and memory, working memory, and complex problem solving (1). Furthermore, abnormalities in cerebellar structure and function have also Received Dec. 4, 1997; revision received April 22, 1998; accepted May 5, 1998. From the Center for Neurobiology and Behavior, Department of Psychiatry; the Smell and Taste Center, Department of Otorhinolaryngology: Head and Neck Surgery; and the Department of Neurology, University of Pennsylvania School of Medicine. Address reprint requests to Dr. Arnold, Department of Psychiatry, University of Pennsylvania School of Medicine, 142 Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA 191044283; [email protected] (e-mail). Supported by a grant from the Scottish Rite Benevolent Foundation’s Schizophrenia Research Program, grants MH-43880 and MH-55199 from NIMH, and grant DC-00161 from the National Institute on Deafness and Other Communication Disorders. The authors thank the residents and staff of the Penn Schizophrenia Mental Health Clinical Research Center and the Department of Pathology and Laboratory Medicine; Li-Ying Han and Catherine Choi for their assistance; and all the patients and their families whose generosity made this research possible.

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been described (2). The purpose of the current neuropathological investigation was to determine linear density and cell size of the Purkinje cell layer in the cerebellum of elderly individuals with schizophrenia compared with nonneuropsychiatric subjects and to study possible relationships between these morphometric and clinical features. METHOD Subjects included 14 patients with chronic schizophrenia. Their mean age at death was 80.3 years (SD=8.0). Three were men and 11 were women. The mean postmortem interval was 11.0 hours (SD=3. 6). The comparison group comprised 13 age-comparable, sex-comparable, and postmortem-interval-comparable normal subjects with no known history of neuropsychiatric disorder. Their mean age at death was 79.3 years (SD=11.8). Four were men and nine were women. The mean postmortem interval was 12.2 hours (SD=6.2). All subjects with schizophrenia had been participants in a prospective clinicopathological study at the University of Pennsylvania Mental Health Clinical Research Center (3). Diagnoses were established by consensus among clinicians using DSM-III-R criteria. All patients had been assessed with clinical rating scales within 1 year prior to death. All autopsies were conducted at our institution in a uniform manner. Minor neuropathological abnormalities (e.g., lacunar infarcts), none of which affected the cerebellum, were found in four patients with schizophrenia and three comparison subjects.

Am J Psychiatry 155:9, September 1998

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FIGURE 1. Representative Purkinje Cells of a Normal Subject (A) and a Subject With Schizophrenia (B) (Magnified by 400)

Parasagittal blocks of the superior cerebellar vermis (including the central lobule and culmen) were dissected at autopsy, immersed in alcohol fixative (70% ethanol, 150 mM NaCl) for 24 hours, and then paraffin-embedded. Ten-micron-thick sections were Nisslstained with 1% cresyl violet, as previously described (4). All histologic data were obtained by a single operator (K.D.T.), who was blind to case information. Representative microscopic fields were randomly and systematically sampled in each section. Starting from a random point within the section, we identified successive clockwise fields at low magnification. At each point, magnification was raised and the field was video-captured for computer-assisted image analysis by using a Leitz DMRB research microscope, Sony CCD video camera, and Macintosh computer with NIH Image 1.59 software (National Institutes of Health, Rockville, Md.). The linear densities of Purkinje cells were determined by counting the number of Purkinje cells per millimeter line length in 15 fields magnified by 100 per case. Next, we obtained Purkinje cell cross-sectional areas in 50 Purkinje cells with clearly visible nucleoli per case from 9–29 fields magnified by 200. After digitization of the captured image, customized NIH Image software was used to automatically delineate Purkinje cell somata, as previously described (4). After further manual editing to exclude portions of proximal dendrites or other artifacts that were not automatically excluded, Purkinje cell cross-sectional areas were determined. Preliminary scatterplots with correlation analyses were performed to assess possible effects of age, sex, and postmortem interval in each of the two groups. Between-group morphometric differences were analyzed by using Student’s t test (two-tailed) and the Mann-Whitney U test. We then studied possible correlations between Purkinje cell density and size and clinical variables, including age at onset, duration of illness, antipsychotic medication dose (converted to chlorpromazine equivalents), Mini-Mental State score, Brief Psychiatric Rating Scale (BPRS) score, Scale for the Assessment of Negative Symptoms (SANS) score, Scale for the Assessment of Positive Symptoms (SAPS) score, and Abnormal Involuntary Movement Scale (AIMS) score, as previously described (3).

comparison group (r=–0.58, df=11, p