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Central inhibitory deficits in OCD and tourette syndrome
664
BIOL PSYCHIATRY 1994;35:615-747
177. ECS EFFECTS ON NEURONAL DNA STRAND BREAKS A. Khan, H. Lai, Y. Nishimura, M.H. Mirolo, & N.P. Singh Departments of Psychiatry and Behavioral Sciences, and Pharmacology, University of Washington, Seattle, WA Although electroconvulsive therapy (ECT) is the most effective treatment for depression and related disorders, it has withstood considerable review and criticism over the past 50 years. Its exact mechanism of action for ameliorating psychopathological symptoms or its exact mechanism of action for its untoward effects on memory and related cognitive functions are unknown, Because of the profound changes seen in function and behavior, it is likely that ECT results in molecular changes within brain cells. To explore the basic mechanisms involved, we studied ECS's effects on DNA damage in neurons. We measured DNA single strand breaks as an index of DNA damage using our alkaline microgel electrophoresis technique. We compared the effects of repeated ECS with sham ECS in both hippocampal cells as well a~ cells from the rest of the brain in the rat. We also studied the combined effects of ECS and low.level X-rays irradiation. With a sample of 31 young male Sprague Dawley rats; 7 received ECS (once daily for 3 days), 8 received sham ECS, 8 received ECS followed by X-ray exposure (200 fads), and 8 received sham ECS followed by X-ray exposure. Our results indicate that ECS alone had no significant effect on DNA single strand breaks in brain cells, but potentiated the effects of X-rays on DNA breaks.
178. CENTRAL INHIBITORY DEFICITS IN OCD AND TOURETI'E SYNDROME N.R. Swerdlow, S. Zinner, H. Hartston, D. Filion, & M. Magula¢ Department of Psychiatry, UCSD School of Medicine, La Jolla, CA 92093.0804 We measured sensorimotor gating of acoustic startle and theoretically related measures of central inhibition in patients with Obsessive Compulsive Disorder (OCD) or Tourette Syndrome (TS), and in well-screened controls, Prepulse inhibition (PPI) of acoustic startle is a measure of sensorimotor gating that occurs when a response to a startling stimulus is inhibited by a weak prepulse. Other tests assessedcognitive interference (Stroop) and visuospatial interference (Negative Priming), Controls were carefully screened for medical or psyci:iatric illness, OCD and "IS subjects underwent structured and semistructured interviews to confirm diagnoses and symptom characteristics. Eiectromyelographic measures of acoustic startle and PPi were recorded in all subjects, as was performance on Stroop and Negative Priming tasks. OCD subjects exhibited significantly less PP] than controls when 2-16 dB(A) above background prestimuli were presented 100 msec prior to a ! 18 dB(A) startle stimulus, In the same paradigm, adult "IS subjects exhibited normal amounts of PPI. Further studies in adult TS subjects revealed normal amounts of PP] using prestimuli presented 200 and 500 msec prior to the startling stimulus. Startle amplitude, habituation, latency and latency facilitation in OCD and'IS subjects were also compared to controls. Inhibitory deficits were noted in OCD and adult TS subjects in both Stroop and Negative Priming paradigms. Measures of central inhibition in children with TS were compared to measures in age-matched normal controls. Deficient gating of obsessions in OCD and tics in TS is accompanied by objective, quantifiable evidence of impaired sensorimotor, cognitive or visuospatial gating.
FRIDAY,, MAY 20
179. PUTAMEN VOLUME REDUCTION VIEWED BY MRI IN MILD HUNTINGTON'S DISEASE G.J. Harris l, S.E. Folstein 1, E.H. Aylward 2, P.E. Barta2, G.D. Pearlson 2, & C.E. Peyser3 tTufts University/New England Medical Center, Boston, MA 02111; 2The Johns Hopkins Medical Institutions, Baltimore, MD 21287-7362; 3Veterans Administration Medical Center, Menlo Park, CA 94025 Neostriatal atrophy and neuronal loss are the characteristic pathological features of Huntington's disease (HD). Frequently no caudate atrophy is found early in the illness, although neuroradiologic studies often show caudate atrophy in patients with moderate HD. Using a computerized image analysis system with magnetic resonance brain images, we measured volumes of putamen and caodate nucleus and bicaudate ratios (BCR), blind to diagnosis, in 15 patients with mild Huntington's disease and 19 age and sex-matched controls. Putamen exhibited the greatest atrophy; it was reduced 50.1% in mean volume in HD patients compared to controls (p<0.00000 I). Discriminant function analysis was 94% effective in identifying diagnostic group based on putamen volume alone, while caudate measures had considerable overlap. Correction of putamen volume for head size led to 100% separation by group. By contrast, caudate volume was reduced 27.7% (p,-0.004). BCR was increased 28.5% in HD patients (p-0.0002). Putamen measures and BCR correlated with neurological exam scores, but caudate volume did not. Volumetric measurement of putamen is a more sensitive indicator of brain abnormalities in mild HD than measures of caudate atrophy.
180. APOLIPOPROTEIN e4 ALLELE AND FAMILIAL RISK IN ALZHEIMER'S DISEASE G. Li, J.M. Siiverman, L. Altstiel, H. Haroutunian, S. Birstein, R. Mohs, & K.L. Davis Bronx VA Medical Center, New York, NY 10468 & Mount Sinai School of Medicine, New York, NY 10029 Apolipoprotein ¢4 (APe. c4) has been reported to be associated with late onset familial and sporadic forms of Alzheimer's disease (AD). This study examines a relationship between the presence of the APe-c4 allele in AD probands and familial risk of primary progressive dementia (PPD) in first degree relatives. Forty six neuropathologically diagnosed definite or probable AD probands with an Ape c genotype were recruited from our Alzheimer's Disease Research Center or the Jewish Home and Hospital for the Aged. Demographic and diagnostic data were collected on the 339 first degree relatives of the 46 AD probands through family informants. The Cox proportional hazards regression model was employed for statistical analyses. Of the 46 AD probands, 21 (45.7%) had at least one APe-c4 allele. In the Cox proportional hazards regression model analysis, ~h~ APe-c4 allele in AD probands was significantly correlated with hazaz~s rates of PPD in the relatives (coefficient [~] - - !.23, exp (~) - .29, 95% Confidence interval [CI]: .10 - .87), i.e., relative risk (.29) of PPD in the relatives for AD probands with the APe-c4 allele was significantly lower than for those with no APe-c4 allele. After adjusting for the age-at-onset of AD probands, which was significantly associated with hazard rate of PPD in the relatives (1~--.09, exp (J3)-.90, 95% CI: .87-.94), the association was even stronger (exp (~) -.14, 95 % CI: .04-.44). These results suggest that familial risk for PPD differs between the AD Probands with and without APe-c4 allele.
BIOL PSYCHIATRY 1994;35:615-747
177. ECS EFFECTS ON NEURONAL DNA STRAND BREAKS A. Khan, H. Lai, Y. Nishimura, M.H. Mirolo, & N.P. Singh Departments of Psychiatry and Behavioral Sciences, and Pharmacology, University of Washington, Seattle, WA Although electroconvulsive therapy (ECT) is the most effective treatment for depression and related disorders, it has withstood considerable review and criticism over the past 50 years. Its exact mechanism of action for ameliorating psychopathological symptoms or its exact mechanism of action for its untoward effects on memory and related cognitive functions are unknown, Because of the profound changes seen in function and behavior, it is likely that ECT results in molecular changes within brain cells. To explore the basic mechanisms involved, we studied ECS's effects on DNA damage in neurons. We measured DNA single strand breaks as an index of DNA damage using our alkaline microgel electrophoresis technique. We compared the effects of repeated ECS with sham ECS in both hippocampal cells as well a~ cells from the rest of the brain in the rat. We also studied the combined effects of ECS and low.level X-rays irradiation. With a sample of 31 young male Sprague Dawley rats; 7 received ECS (once daily for 3 days), 8 received sham ECS, 8 received ECS followed by X-ray exposure (200 fads), and 8 received sham ECS followed by X-ray exposure. Our results indicate that ECS alone had no significant effect on DNA single strand breaks in brain cells, but potentiated the effects of X-rays on DNA breaks.
178. CENTRAL INHIBITORY DEFICITS IN OCD AND TOURETI'E SYNDROME N.R. Swerdlow, S. Zinner, H. Hartston, D. Filion, & M. Magula¢ Department of Psychiatry, UCSD School of Medicine, La Jolla, CA 92093.0804 We measured sensorimotor gating of acoustic startle and theoretically related measures of central inhibition in patients with Obsessive Compulsive Disorder (OCD) or Tourette Syndrome (TS), and in well-screened controls, Prepulse inhibition (PPI) of acoustic startle is a measure of sensorimotor gating that occurs when a response to a startling stimulus is inhibited by a weak prepulse. Other tests assessedcognitive interference (Stroop) and visuospatial interference (Negative Priming), Controls were carefully screened for medical or psyci:iatric illness, OCD and "IS subjects underwent structured and semistructured interviews to confirm diagnoses and symptom characteristics. Eiectromyelographic measures of acoustic startle and PPi were recorded in all subjects, as was performance on Stroop and Negative Priming tasks. OCD subjects exhibited significantly less PP] than controls when 2-16 dB(A) above background prestimuli were presented 100 msec prior to a ! 18 dB(A) startle stimulus, In the same paradigm, adult "IS subjects exhibited normal amounts of PPI. Further studies in adult TS subjects revealed normal amounts of PP] using prestimuli presented 200 and 500 msec prior to the startling stimulus. Startle amplitude, habituation, latency and latency facilitation in OCD and'IS subjects were also compared to controls. Inhibitory deficits were noted in OCD and adult TS subjects in both Stroop and Negative Priming paradigms. Measures of central inhibition in children with TS were compared to measures in age-matched normal controls. Deficient gating of obsessions in OCD and tics in TS is accompanied by objective, quantifiable evidence of impaired sensorimotor, cognitive or visuospatial gating.
FRIDAY,, MAY 20
179. PUTAMEN VOLUME REDUCTION VIEWED BY MRI IN MILD HUNTINGTON'S DISEASE G.J. Harris l, S.E. Folstein 1, E.H. Aylward 2, P.E. Barta2, G.D. Pearlson 2, & C.E. Peyser3 tTufts University/New England Medical Center, Boston, MA 02111; 2The Johns Hopkins Medical Institutions, Baltimore, MD 21287-7362; 3Veterans Administration Medical Center, Menlo Park, CA 94025 Neostriatal atrophy and neuronal loss are the characteristic pathological features of Huntington's disease (HD). Frequently no caudate atrophy is found early in the illness, although neuroradiologic studies often show caudate atrophy in patients with moderate HD. Using a computerized image analysis system with magnetic resonance brain images, we measured volumes of putamen and caodate nucleus and bicaudate ratios (BCR), blind to diagnosis, in 15 patients with mild Huntington's disease and 19 age and sex-matched controls. Putamen exhibited the greatest atrophy; it was reduced 50.1% in mean volume in HD patients compared to controls (p<0.00000 I). Discriminant function analysis was 94% effective in identifying diagnostic group based on putamen volume alone, while caudate measures had considerable overlap. Correction of putamen volume for head size led to 100% separation by group. By contrast, caudate volume was reduced 27.7% (p,-0.004). BCR was increased 28.5% in HD patients (p-0.0002). Putamen measures and BCR correlated with neurological exam scores, but caudate volume did not. Volumetric measurement of putamen is a more sensitive indicator of brain abnormalities in mild HD than measures of caudate atrophy.
180. APOLIPOPROTEIN e4 ALLELE AND FAMILIAL RISK IN ALZHEIMER'S DISEASE G. Li, J.M. Siiverman, L. Altstiel, H. Haroutunian, S. Birstein, R. Mohs, & K.L. Davis Bronx VA Medical Center, New York, NY 10468 & Mount Sinai School of Medicine, New York, NY 10029 Apolipoprotein ¢4 (APe. c4) has been reported to be associated with late onset familial and sporadic forms of Alzheimer's disease (AD). This study examines a relationship between the presence of the APe-c4 allele in AD probands and familial risk of primary progressive dementia (PPD) in first degree relatives. Forty six neuropathologically diagnosed definite or probable AD probands with an Ape c genotype were recruited from our Alzheimer's Disease Research Center or the Jewish Home and Hospital for the Aged. Demographic and diagnostic data were collected on the 339 first degree relatives of the 46 AD probands through family informants. The Cox proportional hazards regression model was employed for statistical analyses. Of the 46 AD probands, 21 (45.7%) had at least one APe-c4 allele. In the Cox proportional hazards regression model analysis, ~h~ APe-c4 allele in AD probands was significantly correlated with hazaz~s rates of PPD in the relatives (coefficient [~] - - !.23, exp (~) - .29, 95% Confidence interval [CI]: .10 - .87), i.e., relative risk (.29) of PPD in the relatives for AD probands with the APe-c4 allele was significantly lower than for those with no APe-c4 allele. After adjusting for the age-at-onset of AD probands, which was significantly associated with hazard rate of PPD in the relatives (1~--.09, exp (J3)-.90, 95% CI: .87-.94), the association was even stronger (exp (~) -.14, 95 % CI: .04-.44). These results suggest that familial risk for PPD differs between the AD Probands with and without APe-c4 allele.