- Email: [email protected]
P2-386
Poster P2:: Monday Posters group had increased rates of brain atrophy, 2.10 (1.13) %/yr vs 0.57 (0.28) %/yr, and ventricular expansion (as a percentage of brain) 0.68% (0.27%) vs 0.14% (0.10%). For 90% power to detect a 20% reduction in atrophy rate (controlling for control atrophy rate), fewer patients per arm are required using ventricular volumes (133) compared to RTL (235), LTL (265) or brain atrophy (287 using BSI). Conclusion: The semantic dementia patients had significantly more left temporal lobe atrophy (⬃55% of control mean) than right (⬃85% of control mean). However, rates of temporal atrophy were greater on the right than left (p⬍0.05) suggesting acceleration of RTL atrophy after an initial phase of faster LTL atrophy. For trials of potentially disease-modifying therapies either temporal lobe has marginally greater power than whole brain in terms of tracking progression. Ventricular measures may offer reduced sample sizes but this must be balanced against the possibility of ventricular change being affected by factors other than neurodegeneration. P2-385
NON-INVASIVE OPTICAL IMAGING OF AMYLOID IN APP-TRANSGENIC MICE
Brian J. Bacskai1, Scott Raymond1,2, Anand T.N. Kumar1,3, David A. Boas3, 1Mass General Hospital, Charlestown, MA, USA; 2 Harvard Biophysics, HST Program, Cambridge, MA, USA; 3Martinos Center, Dept. of Radiology, MGH, Charlestown, MA, USA. Contact e-mail: [email protected] Background: An imaging technique sensitive to amyloid-beta accumulation in the brain would allow early diagnosis and effective drug screening with longitudinal monitoring. Objective(s): Our goals are to develop novel small molecule contrast agents that are near infrared fluorescent, cross blood-brain barrier, and target Abeta specifically. In combination, we are developing novel tomographic approaches to detect these agents with high sensitivity and high spatial resolution. Methods: We used a combination of mathematical modeling, imaging of model phantoms, and screening of potential fluorescent contrast agents with microscopy to determine that optical detection of appropriate fluorophores will allow non-invasive imaging of plaque burden. Results: Monte Carlo simulations of turbid media with varying densities of fluorophores to mimic plaque specific and nonspecific binding in the brain suggest that the sensitivity of detection of amyloid burden is high using realistic tissue optical parameters and photophysical properties from a known fluorophore. Phantoms that simulate the complex geometry of a mouse were used to evaluate our home-made time-domain fluorescence imaging instrument and demonstrate that fluorescent signals with different lifetimes can be resolved in 3-dimensions. Screening of novel and existing near-infrared fluorophores resulted in several compounds with desirable properties as in vivo contrast agents. Using the new time-domain imaging algorithm, we will image transgenic mouse models of Alzheimer’s disease non-invasively to estimate plaque burden. Post-mortem confirmation of pathology will be used to correlate the in vivo results. Conclusions: These results, from simulations, to phantom measurements and in vivo imaging show that development of contrast agents and imaging approaches will allow sensitive imaging of amyloidbeta deposition in living APP mice with 3-dimensional information. This approach will accelerate pre-clinical drug development in animal models, and would ultimately translate to clinical imaging. Supported by NIH: EB00768, RR14075. P2-386
HASHIMOTO’S ENCEPHALOPATHY PRESENTING WITH SUBACUTE CEREBELLAR DEGENERATION AND COGNITIVE DECLINE; STRUCTURAL AND FUNCTIONAL IMAGING DATA
Seol-Heui Han1, Seung-Yun Chung2, 1Konkuk University Hospital, Seoul, Republic of Korea; 2Our Lady of Mercy Hospital, Catholic University of Korea, Incheon, Republic of Korea. Contact e-mail: [email protected]
S359
Hashimoto’s encephalopathy (HE) is a rare life threatening but treatable condition which usually manifests in patients suffering from chronic lymphocytic thyroiditis. We would like to describe clinical, EEG, MRI and PET changes in a HE patient presenting with subacute cerebellar syndrome and cognitive decline. A 56-year-old lady complained of slowly progressive dysarthria and gait disturbance commencing 8 months before. She first noted difficulty in writing due to increasing tremors and experienced difficulty in speaking. She subsequently developed progressive unsteadiness of gait and intermittent urinary incontinence. She had no episode of seizure. Neurological examination showed head titubation, intention tremors, scanning speech, and ataxic gait. On neuropsychological exam, her MMSE was 24/30, Boston Naming Test, 32/60 (4.09%ile), Rey Copy, 29/36 (32.64%ile). Her frontal lobe executive function was mildly impaired. Initial EEG showed sharp wave on left frontotemoral (F7) with intermittent slow background. Brain MRI revealed marked cerebellar and brainstem atrophies, which is reminiscent of multisystem trophy, Various tumor markers (AFP, CEA, CA-19-9, CA-125, NSE) were negative, Genetic tests for SCA 1, 3, 6, 7 were normal. Markers for the paraneoplastic conditions (Anit-hu, ant-Ri, anti-Yo) were normal. Whole body F18-FDGPET scan revealed hypometabolism of bilateral cerebellar hemispheres and hypermetabolism of thyroid. Her thyroid function test revealed euthyroid state, however, antimicrosomal antibody, 4069.2 U/mL (reference 0-60 U/mL); antithymoglobulin antibody 166.5 (reference 0-60 U/mL), TSH-R antibody 0.05, which prompted us to make a diagnosis of HE and start intravenous methylprednisolone 1.0 g/day for 5 days and oral prednisolone thereafter. Her clinical condition was markedly improved after corticosteroid treatment. Repeat EEG four weeks after steroid therapy demonstrated no epileptiform discharges. Levels of antithyroid autoantibodies were reduced (anithyloglobulin Ab 12.4 U/mL; anti-microsomal Ab 18.1 U/mL). Her cognitive function was also improved. HE should be considered in the clinical setting of unexplained, non-familial cerebellar syndrome and cognitive decline. Sufficient clinical suspicion in the absence of vascular, infectious, inflammatory, paraneoplastic, metabolic, and toxic causes justifies a trial of high-dose steroid treatment. “This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea.(A050079).” P2-388
A TRANSITION FROM COMPRESSED RISPERIDONE TABLETS TO ORALLY DISINTEGRATING RISPERIDONE TABLETS, DOES SYMPTOM DECOMPENSATION OCCUR?
Pierre Chue1, Rosanna Prinzo2, Carin Binder3, 1CLiP, Edmonton, Canada; 2Janssen-Ortho Inc., Toronto, ON, Canada; 3Janssen-Ortho Inc., Toronto, Canada. Contact e-mail: [email protected] Background: Orally disintegrating risperidone tablets (Risperdal* M-TABs*) present an alternative method of drug delivery that may benefit patients/physicians struggling with compliance and swallowing issues. An orally disintegrating formulation may help improve compliance and medication intake since it dissolves within 5 seconds (Chue et al, 2004). Objective(s): To evaluate safety and maintenance of effect in subjects transitioned from compressed risperidone tablets to orally disintegrating risperidone tablets. Methods: Patientsⱖ18 years with a DSM-IV diagnosis of Major Depressive Disorder (MDD) or Dementia (D) with baseline CGI-Severityⱕ3 (mildly ill) and minimum of 2 weeks prior oral risperidone therapy at a stable dose of 0.5, 1.0 or 2.0 mg/day were recruited, then switched to an equivalent dose of orally disintegrating risperidone tablets and assessed 4 weeks later. Other psychotropic meds were permitted providing the dose was stable for a minimum of 4 weeks pre-entry and were expected to remain stable. Maintenance of effect was measured using the CGI-Severity scale. Secondarily, a Likert scale was used to measure the severity of anxiety, depression or psychotic symptoms present, ranging from 1⫽“none”, 2⫽“mild”, 3⫽“moderate”, 4⫽“marked”, 5⫽“severe”. All MDD patients were on pre-existing anti-depressants pre-study entry and most Dementia patients (13/20) were on a pre-existing cholinesterase inhibitor. Results: N⫽25 (MDD), N⫽20 (D). Mean age⫽49.2⫹/-13.8
NON-INVASIVE OPTICAL IMAGING OF AMYLOID IN APP-TRANSGENIC MICE
Brian J. Bacskai1, Scott Raymond1,2, Anand T.N. Kumar1,3, David A. Boas3, 1Mass General Hospital, Charlestown, MA, USA; 2 Harvard Biophysics, HST Program, Cambridge, MA, USA; 3Martinos Center, Dept. of Radiology, MGH, Charlestown, MA, USA. Contact e-mail: [email protected] Background: An imaging technique sensitive to amyloid-beta accumulation in the brain would allow early diagnosis and effective drug screening with longitudinal monitoring. Objective(s): Our goals are to develop novel small molecule contrast agents that are near infrared fluorescent, cross blood-brain barrier, and target Abeta specifically. In combination, we are developing novel tomographic approaches to detect these agents with high sensitivity and high spatial resolution. Methods: We used a combination of mathematical modeling, imaging of model phantoms, and screening of potential fluorescent contrast agents with microscopy to determine that optical detection of appropriate fluorophores will allow non-invasive imaging of plaque burden. Results: Monte Carlo simulations of turbid media with varying densities of fluorophores to mimic plaque specific and nonspecific binding in the brain suggest that the sensitivity of detection of amyloid burden is high using realistic tissue optical parameters and photophysical properties from a known fluorophore. Phantoms that simulate the complex geometry of a mouse were used to evaluate our home-made time-domain fluorescence imaging instrument and demonstrate that fluorescent signals with different lifetimes can be resolved in 3-dimensions. Screening of novel and existing near-infrared fluorophores resulted in several compounds with desirable properties as in vivo contrast agents. Using the new time-domain imaging algorithm, we will image transgenic mouse models of Alzheimer’s disease non-invasively to estimate plaque burden. Post-mortem confirmation of pathology will be used to correlate the in vivo results. Conclusions: These results, from simulations, to phantom measurements and in vivo imaging show that development of contrast agents and imaging approaches will allow sensitive imaging of amyloidbeta deposition in living APP mice with 3-dimensional information. This approach will accelerate pre-clinical drug development in animal models, and would ultimately translate to clinical imaging. Supported by NIH: EB00768, RR14075. P2-386
HASHIMOTO’S ENCEPHALOPATHY PRESENTING WITH SUBACUTE CEREBELLAR DEGENERATION AND COGNITIVE DECLINE; STRUCTURAL AND FUNCTIONAL IMAGING DATA
Seol-Heui Han1, Seung-Yun Chung2, 1Konkuk University Hospital, Seoul, Republic of Korea; 2Our Lady of Mercy Hospital, Catholic University of Korea, Incheon, Republic of Korea. Contact e-mail: [email protected]
S359
Hashimoto’s encephalopathy (HE) is a rare life threatening but treatable condition which usually manifests in patients suffering from chronic lymphocytic thyroiditis. We would like to describe clinical, EEG, MRI and PET changes in a HE patient presenting with subacute cerebellar syndrome and cognitive decline. A 56-year-old lady complained of slowly progressive dysarthria and gait disturbance commencing 8 months before. She first noted difficulty in writing due to increasing tremors and experienced difficulty in speaking. She subsequently developed progressive unsteadiness of gait and intermittent urinary incontinence. She had no episode of seizure. Neurological examination showed head titubation, intention tremors, scanning speech, and ataxic gait. On neuropsychological exam, her MMSE was 24/30, Boston Naming Test, 32/60 (4.09%ile), Rey Copy, 29/36 (32.64%ile). Her frontal lobe executive function was mildly impaired. Initial EEG showed sharp wave on left frontotemoral (F7) with intermittent slow background. Brain MRI revealed marked cerebellar and brainstem atrophies, which is reminiscent of multisystem trophy, Various tumor markers (AFP, CEA, CA-19-9, CA-125, NSE) were negative, Genetic tests for SCA 1, 3, 6, 7 were normal. Markers for the paraneoplastic conditions (Anit-hu, ant-Ri, anti-Yo) were normal. Whole body F18-FDGPET scan revealed hypometabolism of bilateral cerebellar hemispheres and hypermetabolism of thyroid. Her thyroid function test revealed euthyroid state, however, antimicrosomal antibody, 4069.2 U/mL (reference 0-60 U/mL); antithymoglobulin antibody 166.5 (reference 0-60 U/mL), TSH-R antibody 0.05, which prompted us to make a diagnosis of HE and start intravenous methylprednisolone 1.0 g/day for 5 days and oral prednisolone thereafter. Her clinical condition was markedly improved after corticosteroid treatment. Repeat EEG four weeks after steroid therapy demonstrated no epileptiform discharges. Levels of antithyroid autoantibodies were reduced (anithyloglobulin Ab 12.4 U/mL; anti-microsomal Ab 18.1 U/mL). Her cognitive function was also improved. HE should be considered in the clinical setting of unexplained, non-familial cerebellar syndrome and cognitive decline. Sufficient clinical suspicion in the absence of vascular, infectious, inflammatory, paraneoplastic, metabolic, and toxic causes justifies a trial of high-dose steroid treatment. “This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea.(A050079).” P2-388
A TRANSITION FROM COMPRESSED RISPERIDONE TABLETS TO ORALLY DISINTEGRATING RISPERIDONE TABLETS, DOES SYMPTOM DECOMPENSATION OCCUR?
Pierre Chue1, Rosanna Prinzo2, Carin Binder3, 1CLiP, Edmonton, Canada; 2Janssen-Ortho Inc., Toronto, ON, Canada; 3Janssen-Ortho Inc., Toronto, Canada. Contact e-mail: [email protected] Background: Orally disintegrating risperidone tablets (Risperdal* M-TABs*) present an alternative method of drug delivery that may benefit patients/physicians struggling with compliance and swallowing issues. An orally disintegrating formulation may help improve compliance and medication intake since it dissolves within 5 seconds (Chue et al, 2004). Objective(s): To evaluate safety and maintenance of effect in subjects transitioned from compressed risperidone tablets to orally disintegrating risperidone tablets. Methods: Patientsⱖ18 years with a DSM-IV diagnosis of Major Depressive Disorder (MDD) or Dementia (D) with baseline CGI-Severityⱕ3 (mildly ill) and minimum of 2 weeks prior oral risperidone therapy at a stable dose of 0.5, 1.0 or 2.0 mg/day were recruited, then switched to an equivalent dose of orally disintegrating risperidone tablets and assessed 4 weeks later. Other psychotropic meds were permitted providing the dose was stable for a minimum of 4 weeks pre-entry and were expected to remain stable. Maintenance of effect was measured using the CGI-Severity scale. Secondarily, a Likert scale was used to measure the severity of anxiety, depression or psychotic symptoms present, ranging from 1⫽“none”, 2⫽“mild”, 3⫽“moderate”, 4⫽“marked”, 5⫽“severe”. All MDD patients were on pre-existing anti-depressants pre-study entry and most Dementia patients (13/20) were on a pre-existing cholinesterase inhibitor. Results: N⫽25 (MDD), N⫽20 (D). Mean age⫽49.2⫹/-13.8