ANPA Abstracts

P1. Functional improvement after stroke: a role for complementary medicine

Theresa D. Hernández, Kristina McFadden, Alicia Segal, Bonnie Ivankovich, Christina Gavito, Shelah Huerta

Background: Stroke is associated with chronic disability in the United States. Deficits related to motor function (e.g., physical activity levels, range of motion) are especially recalcitrant, despite traditional rehabilitation. Complementary and alternative medicine (CAM) is a frequently utilized option for stroke-associated deficits. A pilot study of the CAM modality Jin Shin (e.g., acupressure) found arm surface temperature asymmetry to be reduced relative to placebo treatment in chronic stroke patients. The functional relevance of this finding, however, is unknown. Objective: The present study tested the hypothesis that Jin Shin treatment would improve motor function in comparison to placebo, and explored the relationship between functional improvement and arm surface temperature. Method: Seven individuals with chronic deficits at least 19 months post-stroke, were randomly assigned to receive 8 weeks of Jin Shin or placebo treatments prior to crossover into the opposite treatment using a single-blind design. Results: Moderate physical activity levels were significantly increased following the Jin Shin treatment phase (p=0.04, Cohen’s d=0.52) in comparison to the placebo phase. There was a trend towards increased range of elbow motion following active treatment. The findings could not be accounted for by expectancy, treatment order or credibility. The relationship between functional improvement and treatment-associated changes in arm surface temperature was not uniform. Conclusions: Jin Shin treatment had a positive effect on motor function in individuals at least 19 months post-stroke. Based on these results, the CAM modality Jin Shin warrants further study as an option for chronic stroke-associated deficits and disability.

P2. Etiology of frontal network syndromes in isolated subtentorial stroke

Michael Hoffman

Background: The neurobiology of the frontal network syndromes (FNS) that may occur with isolated subtentorial stroke is unknown. Suggested mechanisms include channel (neural network) or due to state dependent (neurotransmitter perturbation) Objective: Evaluate for frontal network syndromes in young people post subtentorial stroke who have recovered neurologically. Method: Young people (18 to 49 years old) with isolated cerebellar or brainstem subtentorial stroke (ST) that had recovered to independency (Rankin score ≤2) with minimal or no residual neurological deficit by NIH stroke score, (NIHSS) ≤4, enabling resumption of former employment. Comparison was made to [age-, education-matched] young people with parieto-occipital lobe infarcts with frontal tests surveying the principal FNS (apathy, disinhibition, executive dysfunction, emotional intelligence). Results: Young stroke patients (N=511) were analyzed for cerebellar infarcts (N=43, 8.4%) or brainstem infarcts (N=36, 7.0%). After exclusions, 16 patients (cerebellum, N=10, pons, N=6) were compared to 16 parieto-occipital infarct patients. Overall 11/16 (69%) patients in the subtentorial stroke group and 5/16 (31%) in the parieto-occipital group (p=0.05) manifested one or more of the principal FNS syndromes. Mean apathy T scores (ST= 67.1, p=0.05), disinhibition T scores (ST=67.2, p=0.0004), executive function T scores (ST=71.3, p=0.006) and emotional intelligence SS (ST=93, p=0.03), were all significantly different but not for WCST error percentage T score (ST= 45.0, p=0.8). Conclusions: The mismatch of scant neurological deficit and FNS in the majority of subtentorial stroke compared to parieto-occipital stroke, gives support to isolated subtentorial stroke being a neurotransmitter perturbation that may be amenable to neuropharmacological management.

P3. Functional neuroanatomical atlas of TBI, part 2: applications for neuropsychiatric practice

Robin A. Hurley, Katherine H. Taber

Background: Combat-related traumatic brain injuries (TBI) are occurring with increasing frequency. Many of our returning soldiers are utilizing non-governmental clinicians for healthcare. Some soldiers need/seek treatment for symptoms of mild-moderate combat-related TBI. It is imperative for the practicing clinician to be skilled at recognition of this condition, understand the vulnerable neuroanatomical areas, and be able to correlate that anatomy with possible functional deficits. Method: Part 1 of this exhibit (ANPA 2006 meeting presentation) synthesized blast injury physics with associated anatomy maps and clinical examples. As a follow-up, the relevant recent scientific findings on combat-related injury, the latest pertinent memory/emotion circuit data, and correlated symptom literature were reviewed and synthesized. Principles derived from medical informatics were used to create new integrated information-dense color-coded user-friendly guides to these vulnerable circuits. Results: The most common areas for combat-related brain injury contain many of the emotion and memory circuits (e.g. frontal and parietal lobes, cerebellum, temporal tip, and basal ganglia). Lesions to any location along these circuits can result in similar cognitive, emotional, or behavioral deficits. Commonly encountered post-deployment clinical presentations are dissected using these illustrated maps/diagrams. Conclusions: Neuropsychiatric symptoms from TBI may not become evident for weeks, months, or years. It is imperative that the clinician understand the divisions of the emotion and memory circuits and be able to readily associate/match functional deficits to anatomical areas. These innovative materials serve as visual “external memory” aids for rapid association and recall. They can be easily used in teaching, clinical case correlation, and radiographic consultation.

P4. Frontal lobe dysfunction from frontal-subcortical circuit disruption: linking clinical deficits and white matter changes on MRI

Eliot Licht

Background: Executive and behavioral functions depend on a network of frontal-subcortical circuits. Components of this system include the caudate, putamen, globus pallidus and thalamus. Disruption of these "relay stations" can produce a rich array of cognitive and behavioral syndromes reflecting disturbances in specific dorsolateral, orbitofrontal or anterior cingulate circuits. Improved integration of clinical and radiographic findings may identify biomarkers with predictive value. In this pilot study we report frontal lobe functions in patients with predominantly subcortical cerebrovascular disease that included the thalamus. Method: Six study subjects 73.5 years old were identified from a database of Neurobehavior Service patients with vascular cognitive impairment as a 1 ⁰ or 2 ⁰ diagnosis. Inclusion criteria included subcortical cerebrovascular disease involving >1 thalamus. A modified Rotterdam Scan Study Scale (RSSS) was used to assess white matter changes. Results: Five of the six subjects (83%) had MMSE scores ≤26 (range=16 to 28) and borderline or impaired Digit Span (≤5 Forward; ≤3 Backward). On Frontal lobe tasks, five of the six (83%) had decreased Verbal Fluency but six of the six (100%) had deficits on Luria hand sequences, go/no-go or alternating programs. Modified RSSS: Periventricular white matter lesions range: 3 TO subcortical white matter changes: small or medium. Besides thalamic lacunae, six of the six (100%) had ≥1 other lacunae (e.g., basal ganglia or caudate). Conclusions: Executive planning deficits are frequent in patients with frontal-subcortical circuit lacunae that include the thalamus. Directed testing demonstrated frontal lobe dysfunction even with mild periventricular or subcortical white matter lesions.

P5. Head injury severity correlates with cognitive impairment in recent but not remote traumatic brain injury

Aaron M. McMurtray, Eliot Licht, Tuty Yeo, Ronald E. Saul, Mario F. Mendez

Background: The severity of traumatic brain injury (TBI) usually predicts the severity of cognitive deficits. With the passage of time, however, cognition often improves, suggesting that the severity of deficits may not be predictable from the severity of TBI. Objective: This study compared the relationship between TBI severity and cognitive performance in patients with recent and remote TBI. Method: This study included 46 patients who presented consecutively during a 1-year period for evaluation of cognitive difficulties related to TBI. Twenty-three patients had a recent TBI (>5 years) and 23 others had a remote TBI (<10 years). Patients were individually matched for age at time of TBI, years of education, and TBI severity. TBI severity was based on the period of posttraumatic amnesia (PTA) and included mild (PTA >30 minutes), moderate (30 minutes to 24 hours), and severe (>24 hours). Results: In the patients with recent but not remote, TBI, severity negatively correlated with performance on the Mini-Mental State Examination (MMSE, p<0.05), and measures of attention (p<0.05), verbal fluency (p<0.05), verbal memory (p<0.05). Patients with remote TBI performed better than patients with recent TBI on the MMSE (p=0.05), and measures of attention (p<0.05), verbal memory (p=0.04), and frontal/executive functions (p=0.04). Conclusions: These results suggest cognitive performance may improve years after TBI, and TBI severity may be most useful for predicting short but not long-term cognitive outcomes.

P6. Quetiapine for early posttraumatic mania

Timothy J. Oster, Hal S. Wortzel, C. Alan Anderson, Christopher M. Filley, David B. Arciniegas

Background: Mania is an infrequent but problematic consequence of traumatic brain injury (TBI), particularly in the early postinjury period. Posttraumatic mania may respond to lithium or anticonvulsants, but these agents can adversely affect cognitive, motor, and functional recovery. Atypical antipsychotics are useful for the treatment of acute idiopathic mania, but there are no reports describing their use for the treatment of posttraumatic mania. Case report: A 42-year old right-handed man with no prior psychiatric history sustained a severe motor vehicle-related TBI, resulting in hemorrhagic contusions of the right basoventral, peri-insular, and anterior temporal areas, and the bilateral anterior inferior frontal lobes; bifrontal axonal injury; and right perisylvian subarachnoid hemorrhage. Upon admission to neurorehabilitation, he demonstrated persistently irritable and euphoric mood, decreased need for sleep, excessive energy, pressured speech, disinhibition, agitation, and absence of insight regarding the pathological nature of these symptoms. His initial Young Mania Rating Scale (YMARS) score was 32. Quetiapine was titrated to 900 mg/day over the following 10 days. YMARS scores on Treatment Days 13, 20, and 24 were improved to 16, 11, and 7, respectively. Use of quetiapine did not appear to adversely affect the patient’s cognitive, motor, or functional recovery. Conclusions: Quetiapine may be a useful alternative to lithium and anticonvulsants for the treatment of early posttraumatic mania. In this case, rapid titration of quetiapine to anti-manic doses was well tolerated and effective. Further studies are needed to evaluate the usefulness of quetiapine for the treatment of posttraumatic mania.

P7. Personality changes after traumatic brain injury within 3 months of injury

Vani Rao, Jennifer Spiro, Kathy Knoll, Michael Makley, Edward Cornwell

Background: Personality changes after traumatic brain injury (TBI) are commonly reported clinically but have not been the subject of much research. Little is known about the prevalence and correlates of personality changes in adults after TBI. What is well-known is that people with personality changes after TBI have interpersonal problems, difficulties with communication, and sometimes even alienation from friends/family. Objective: To investigate the correlates of personality changes after TBI. Method: Forty-seven participants within 3 months of traumatic brain injury had a neuropsychiatric evaluation. Personality change after TBI was determined by administering a semi-structured psychiatric interview. History was also obtained from collateral informants. Participants also underwent a neuropsychological battery. Results: Participants with and without personality change were compared using t tests or chi-square tests. Participants did not differ in age, education, income, personal or family psychiatric history, injury location (frontal vs. non-frontal lobe injury), or on neuropsychological performance. Participants with moderate-severe injury (80%) were more likely to have personality change than subjects with mild injury (20%), FET=0.03. Conclusions: Personality change soon after TBI is associated with TBI severity, but not demographic, psychiatric, or neuropsychological factors.

P8. Depression after traumatic brain injury: prevalence and risk factors

Vani Rao, Jennifer Spiro, Kathy Knoll, Michael Makley, Edward Cornwell, David Schretlen

Background: Depression after traumatic brain injury (TBI) is the most common psychiatric sequelae of traumatic brain injury. Understanding risk factors is important as this can lead to early diagnosis and treatment. There is some literature on the psychosocial factors but only minimal literature on the neuroanatomical correlates. Objective: To determine the prevalence and risk factors associated with development of depression for the first time after TBI (DAT). Method: Patients recruited within 3 months of closed TBI were followed longitudinally for 1 year. Semi-structured psychiatric interviews were used to diagnose depression and other variables. In addition all participants were also given a comprehensive battery of neuropsychological tests. Participants with (N=15) and without (N=28) depression after TBI were compared on several variables using t tests or chi-square tests. Results: The prevalence of depression after TBI was: 34% at <3 months, 25% at 6 months, and 15% at 12 months. The two groups did not differ in age, education, income, family psychiatric history of mood disorder, activities of daily living, and/or social functioning exam. On neuropsychological performance, the depressed group performed more poorly than the nondepressed group on tests of frontal functioning, but the results were not statistically significant. On tests of verbal and visual memory, the depressed group performed moor poorly and the results achieved statistical significance. Conclusions: Bilateral temporal lobe dysfunction is probably associated with the development of depression after TBI. Future research will focus on increased sample size and neuroimaging measures.

P9. Prevalence and risk factors of apathy after traumatic brain injury

Vani Rao, Jennifer Spiro, Kathy Knoll, Michael Makley, Edward Cornwell

Background: Apathy after TBI is not uncommon. Kant et al. ( Brain 1998) has reported a prevalence rate of 10% for primary apathy syndrome and 60% for apathy with major depression. There is only minimal literature on the factors associated with development of apathy. A better understanding of this syndrome will enhance both the patient’s and caregivers’ quality of life. Objective: To determine the prevalence and risk factors associated with development of apathy for the first time after TBI. Method: Patients recruited within 3 months of closed TBI were followed longitudinally for 1 year. Apathy was diagnoses by two ways: 1) Semi-structured psychiatric interviews. A diagnosis of Primary Apathy Syndrome was given when there was a clear history from the participant and collateral informants of primary loss of motivation, and 2) The Apathy Evaluation Scale (AES). A score of >30 was considered to be diagnostic of apathy. To determine correlates of apathy, linear regression analyses were done with the AES as the dependent variable and Glasgow Coma Scale, annual income, education level, and major depression as independent variables. Results: The point prevalence of primary apathy syndrome was: 10% <3 months, 13% at 6 months and 23% at 12 months. Increased TBI severity, higher annual income and lower education level were statistically significant predictors of apathy and accounted for 84% of the variance. Interestingly, depression was not a significant predictor. Conclusions: People with severe TBI are at risk for the development of apathy. Future research will focus on neuropsychological and neuroimaging correlates of apathy.

P10. Apoptotic changes in the cortex and hippocampus following minimal brain trauma in mice

Shaul Schreiber, Vadim Tashlykov, Yeshayahu Katz, Ofer Zohar, Pick G. Chaim

Background: Interpretation of cellular and molecular pathogenesis of minimal traumatic brain injury is a clinical and scientific problem, especially due to the high prevalence of motor vehicle and other accidents. Pathogenetic brain mechanisms following traumatic impact are usually investigated by using models of severe or moderate trauma. Objective: Apoptotic neuronal degeneration after notable brain trauma is a well known phenomenon, but the source of its activation is not clear, especially after mild brain trauma. Method: We used a closed head weight-drop experimental model to induce minimal brain injury in mice. Pellets of 5, 10, 15, 20, 25 and 30 g were dropped on the right side of a mouse’s head under light ether anesthesia. No abnormal behavioral or neurophysiological changes were seen following the head trauma. Morphological assessment was done 72 hours after the traumatic impact using TUNEL assay and silver staining. Results: We found gradual increase of TUNEL-positive and silver-impregnated cells number in different cortical and hippocampal regions of both injured and contralateral hemispheres. The threshold of traumatic impact that caused a significant activation was 10g to 15 g pellets (evident by silver staining), and 15g to 20g for apoptosis. The most sensitive zones for trauma were anterior cingulate cortex and CA3 area of hippocampus. No bilateral hemispheric differences were found. Conclusions: Even closed head minimal traumatic brain injury can cause diffuse neuronal damage and apoptosis. This results correlate with cognitive and behavioral deficits described for both mice following mTBI and persons who present with a variety of mental disturbances described after post concussion syndrome .

P11. Prevalence of alcohol and illicit drug problems pre- and posttraumatic brain injury

Jennifer Spiro, Kathy Knoll, Michael Makley, Edward Cornwell, Vani Rao

Background: Drug and alcohol problems are common in people with TBI. Not only alcohol/illicit drugs intoxication is a risk factor for sustaining TBI but are also associated with poor TBI outcomes. Some studies have shown that soon after the brain injury, people with pre-TBI history of alcohol/drug problems are very likely to engage in behaviors associated with reduction or abstinence of drugs and alcohol. Objective: To determine the prevalence of alcohol and drug problems before and after TBI. Method: Patients recruited within 3 months of closed TBI were followed longitudinally for 1 year. Semi-structured psychiatric interviews were used to diagnose Axis I psychiatric disorders. Those with either a diagnosis of alcohol/drugs “abuse” or “dependence” were grouped together as having “problems.” Results: The prevalence of pre-TBI alcohol problem was 67% and drug problem 55%. Interestingly, the prevalence dropped during follow-ups, which were at <3 months of TBI, 6 and 12 months. The rates at these three time periods for alcohol and drugs were, respectively: 21% and 11%; 28% and 16%; and 33% and 20%. Conclusions: The drop in prevalence may be because trauma patients at Johns Hopkins from where the majority are recruited receive substance abuse counseling and referrals to substance abuse programs. Thus, the occurrence of trauma can lead to “teachable moments” soon after the event which can in turn lead to a positive change in behavior. More studies are needed to determine what factors are associated with maintenance of the reduced prevalence soon after TBI.

P12. Daytime sleepiness after traumatic brain injury

Jennifer Spiro, Kathy Noll, Michael Makley, Edward Cornwell, Vani Rao

Background: Sleep problems are common after TBI. There is some literature on insomnia after TBI but minimal literature on daytime sleepiness. Sleepiness during the day can result in poor daytime performance and can result in poor quality of life. Objective: To determine the prevalence of daytime sleepiness and assess factors associated with it. Method: Sleep habits 1 month before and within 3 months after injury of 49 TBI subjects were evaluated. Daytime sleepiness was evaluated using the Medical Outcomes Scale–Sleep scale. Subjects also had semi-structured psychiatric evaluation. Scores at baseline and within 3 months of injury were compared using a repeated measures analysis of variance. Regression models were created to examine predictors of daytime sleepiness within 3 months after injury. Results: Mean daytime sleepiness scores significantly differed between baseline (17.16 [SD=17.69]) and within 3 months after injury (28.86 [SD=27.49]), F=6.71, p=0.013. Higher scores indicate greater daytime sleepiness. Increased age and higher apathy scores (from the Apathy Evaluation Scale) significantly predicted increased daytime sleepiness, R ² =0.27, F=4.47. p=0.002. Conclusions: Daytime sleepiness after TBI is a common and disabling problem. Future studies should focus on causes of post-TBI daytime sleepiness and treatment interventions.

P13. Evaluation of the suitability of SPECT imaging for use in mild TBI litigation

Hal S. Wortzel, Timothy Oster, Christopher M. Filley, C. Alan Anderson, David B. Arciniegas

Background: Cerebral SPECT imaging may identify functional brain abnormalities following mild TBI, and some parties may seek to introduce SPECT findings as evidence in legal proceedings related to TBI. However, independent reviews of the rules of evidence relevant to the introduction of SPECT in such cases have not been published. Objective: To review the literature regarding SPECT and mild TBI, apply current legal rules of evidence, and make recommendations regarding the use of SPECT for forensic purposes. Method: A Medline and PsycInfo database search for the years 1965 to 2006 anchored to TBI (and related MeSH terms) and SPECT was performed, and peer-reviewed practice parameters regarding SPECT imaging were reviewed. Rules of evidence based on Frye v. United States, Daubert vs. Merrell Dow Pharmaceuticals, the Federal Rules of Evidence, and General Electric v. Joiner were used to evaluate the suitability of SPECT imaging in mild TBI litigation. Results: The theory behind SPECT abnormalities after TBI is a subject of active investigation, and findings from such investigations have been subjected to peer-review and publication. However, there remain substantial uncertainties regarding the rates of error and also disagreements regarding the methods for performing clinical cerebral SPECT imaging in this context. Additionally, the usefulness of cerebral SPECT imaging in the evaluation of TBI is not generally accepted in the scientific community. Conclusions: Cerebral SPECT imaging in the setting of mild TBI does not meet the evidentiary standards required for forensic purposes. The use of SPECT imaging in this context is not recommended.

P14. Cortisol levels co-vary with anterior cingulate cortex rCMR during high dose estrogen: a PET study

William E. Ottowitz, Darin Dougherty, Martin Lindquist, Alan Fischman, Janet E. Hall

Background: Several studies have shown that cortisol affects neuropsychological functions mediated by the prefrontal cortex (PFC). Estrogen (E2) also affects these functions and is further known to impact cortisol regulatory processes. Objective: To determine whether interactions of cortisol with the PFC are modified by E2, we evaluate whether E2 infusion alters correlation of cortisol with the regional cerebral metabolic rate (rCMR) of the PFC. Method: FDG-PET scans and cortisol blood samples were collected in ten postmenopausal women at 0, 24, and 72 hours. A graded E2 infusion was initiated after the 0 hour scan. Cortisol values were entered into a voxel-wise covariate analyses for each scanning session (SPM99). Results: E2 levels at time 0, 24, and 72 hours were [mean, pg/mL (standard error)] 30.5 (11.6), 347.1 (162.4), and 472.2 (223.6), respectively. Cortisol levels were 8.1 (3.5), 9.7 (4.6), and 8.8 (3.0), (0, 24, and 72 hours respectively). E2 levels were increased at 24 hours (p<0.001), and further increased at 72 hours (p<0.001). Cortisol values showed no differences (p=NS). Cortisol positively co-varied with the rCMR of different portions of the anterior cingulate cortex (ACC) at 72 hours, but not during baseline or 24 hours (MNI coordinates [12, 38, 22], [–8, 20, 30], and [10, 44, 12], all p<0.001). Conclusions: These findings suggest that correlations between cortisol and activity of the ACC are modified by E2. Specifically, cortisol may be most linked to function of the ACC during high E2 states. Thus, future studies designed to evaluate ACC function may benefit from concurrent evaluation of cortisol and E2.

P15. Rapid change of lateral brain perfusion is highly significantly associated with measures of executive functioning

Daniel Schuepbach, Daniel Hell

Background: Executive functioning can be neuropsychologically assessed by the Stockings of Cambridge (SOC) and the Wisconsin Card Sorting Test (WCST). We have recently shown rapid and significant modulations of peak mean cerebral blood flow velocity (MFV) of the middle cerebral arteries (MCA) during SOC—that is, brain perfusion was up-regulated during mental planning, and kept about equally during movement execution. Objective: This study investigated the linkage between differences of rapid MFV modulation (planning/movement execution) and performance during SOC and also WCST. Method: Twenty healthy subjects underwent this functional transcranial Doppler sonography study (fTCD) with bilateral assessments of the MCA and the anterior cerebral arteries (ACA) during difficult problems of SOC and WCST. Measures of rapid MFV were calculated during the initial threes of mental planning/movement execution and held against task accuracy (SOC) and perseverative errors (WCST). Results: The difference between rapid MFV modulation during planning and movement execution of the left MCA was inversely associated with task accuracy of SOC (r=–0.64, p=0.002), perseverative errors (r=–0.69, p =0.0008) and a composite measure of SOC and WCST (r=–0.74, p=0.0002). High performers of executive functioning had a 20 times larger difference of MFV modulation (left MCA) than low performers (p=0.009). Conclusions: These findings demonstrate a close association between rapid modulation of cerebral hemodynamics in the left lateral hemisphere and pivotal measures of executive functioning. Rapid regulation of brain perfusion along distinct cognitive conditions is a pivotal mechanism of brain behavior relationship.

P16. Impaired rapid modulation of cerebral hemodynamics during planning in schizophrenia

Daniel Schuepbach, Silvan Weber, Daniel Hell

Background: There is evidence that patients with schizophrenia show deficits in planning abilities, and the Stockings of Cambridge (SOC) is a neuropsychological measure of planning performance. We recently demonstrated abnormalities of peak mean cerebral blood flow velocity (MFV), assessed by functional transcranial Doppler sonography (fTCD), in the middle cerebral arteries (MCA) during SOC in patients with chronic schizophrenia. Objective: By introducing a means of kinetic change of brain perfusion, we undertook this study to examine rapid modulation of cerebral hemodynamics during SOC in schizophrenia. Method: We included 21 patients with chronic schizophrenia in the study. They underwent bilateral fTCD measurements of the MCA and also of the anterior cerebral arteries (ACA) during performance of SOC. This task was divided into conditions of mental planning and movement execution. Twenty healthy subjects with known cerebral hemodynamic characteristics were taken as comparison group. Results: In the MCA (i.e., lateral hemispheres), healthy subjects rapidly modulated the early cerebral hemodynamic response along distinct conditions (increased kinetics during planning, approximately zero values during movement execution) of SOC (p=0.006), whereas patients showed no significant changes (p>0.1). Instead a uniform and decreased development of the early cerebral hemodynamic response irrespective of condition was detected in the territory of the MCA. Conclusions: The findings of this study suggest that rapid modulation of early cerebral hemodynamcis is normally heterogeneous across conditions of a planning task, and they support the notion that there is a prominent deficit within the lateral hemispheres in patients with schizophrenia.

P17. Mindfulness meditation: evidence of decreased rumination as a mechanism of symptom reduction

Jennifer J. Bortz, Jay D. Summers, Teri B. Pipe

Background: Cognitive neuroscience has recently begun to examine the protective effects of meditation on neuronal cell loss, immunosuppression, and stress reduction. Mechanisms by which such changes occur, however, are largely unknown. Objective: As part of a larger study assessing biological markers of stress in professional caregivers, we examined the effect of mindfulness meditation on a self-report measure of rumination and cognitive inefficiency. Method: Thirty-three nursing professionals were randomly assigned to either a brief mindfulness meditation course (MMC) or an advanced leadership training course (ALTC). Concurrent curriculums centered upon stress reduction in structured healthcare environments. Subjects participated in a series of 2-hour classes over 4 consecutive weeks. The SCL-90-R was administered at baseline and within one week of course completion. Results: Among MMC participants, change scores on the OCD subscale of the SCL-90-R revealed a significant decline in subjects’ report of negative rumination, behavior, and cognitive inefficiency (p=0.019). Conclusions: Mindfulness meditation is a skill acquired through practice in sustaining attention on a specific object (e.g., breath, sound) that exists in the present moment. This skill is improved as one simultaneously develops the ability to decrease both the frequency and the amount of time that attention veers off-track, or is otherwise diverted by intrusive thoughts unrelated to the object of attention. Our findings suggest that meditation practice serves to diminish unwanted rumination which, in turn, may underlie improvement in biological and related stress-reduction outcomes. Implications regarding neuroanatomical correlates and neuroplasticity of meditation training will be discussed.

P18. Cognitive and behavioral consequences of early childhood deprivation: an example of acquired autistic spectrum disorder

Richard B. Ferrell, Peter K. Isquith, Mathew A. Garlinghouse, Laura A. Flashman, Thomas W. McAllister

Background: Though there is general understanding that severe neglect in infancy and childhood is harmful, remarkably little is known about specific psychological, cognitive, and social consequences of profound deprivation. Recent reports describe clinical features resembling autism in a disproportionate number of children adopted from Romanian orphanages into families in the United Kingdom and the Netherlands after the fall of the Ceauçescu regime. These children had experienced severe deprivation. Reported biopsychosocial consequences include medical disorders, cognitive impairment, and emotional and behavioral disorders such as indiscriminate friendliness, absence of attachment, and emotional disorders. “Quasi-autistic patterns” and “post-institutional autistic syndrome” are terms used to describe this phenomenon. Case report: We present an illustrative example of a 17-year-old boy with a history of impulsivity, angry outbursts, self-absorption, lack of empathy, and emotional lability. He was adopted from an orphanage in Eastern Europe at age 5. In adolescence, interactions with women were often socially and sexually inappropriate, such as asking strangers for a hug or asking about details of their personal sexual lives. An assault charge resulted from an event that included inappropriate sexual touching. On interview he avoided eye contact. Speech showed diminished or flat prosody and perseveration. He did not demonstrate effective social pragmatics such as appropriate turn-taking in conversation. Neuropsychological data suggested executive functioning deficits with borderline to low average range intellectual skills (full scale IQ scores of 74, 75, and 81). The overall clinical picture was consistent with Asperger’s disorder, with poor social reciprocity, limited scope of interests, and only mild language delays. Conclusions: Severe deprivation in early childhood has been associated with developmental disorders in the autistic spectrum. Awareness of this phenomenon would help clinicians understand disordered behavior and cognition occurring in children adopted from orphanages.

P19. Youth with impulsive aggression: anticonvulsant medication compliance and outcome

William I. Fisher, Glenda Kroll, Dan T. Matthews, Larry Fisher

Background: There is limited research on intermittent explosive disorder in adults, and even less in juveniles. Anticonvulsant medications have been reported to benefit the more difficult cases, especially those with comorbid affective symptoms. Objective: It is predicted that, for intermittent explosive disorder in juveniles, compliance with anticonvulsant medication will be a significant factor in long term outcome. Method: Subjects included 115 juveniles (ages 11 to 18; 86 male, 29 female) who met criteria for intermittent explosive disorder and all were stabilized on, and discharged on, anticonvulsant medication following 90 to 120 days in residential treatment. Caregivers, in a mail survey at 12 months post-discharge, rated the subject’s improvement in physical aggression (frequency and severity) and indicated if the subject had been compliant with their medication. Results: Twenty-nine caregivers responded to the survey after 12 months. For the compliant group, 14 of 14 (100%) rated the subject as improved in frequency and 13 of 14 (93%) rated the subject improved in severity of aggression. For the non-compliant group, 10 of 15 (66%) rated the subject as improved in frequency and nine of 15 (60%) rated the subject as improved in severity of aggression. Chi-square analysis was significant for both frequency and severity. Conclusions: Study limitations include low response rate, and the fact that unknown factors may have contributed to noncompliance. However, the study does suggest that, for juveniles with intermittent explosive disorder, compliance with mood stabilizing anticonvulsant medication may be a significant factor in long-term management of aggression.

P20. The effect of depression on executive functioning in attention deficit hyperactivity disorder

Glen E. Getz, Michael D. Franzen

Background: A high co-morbidity exists between attention deficit hyperactivity disorder (ADHD) and depression. Studies have reported that 24% to 30% of children diagnosed with ADHD also suffer from depression. Interestingly, both ADHD and depression are associated with cognitive impairment. However, it remains unclear as to whether cognitive differences occur between children with ADHD and those diagnosed with co-morbid ADHD and depression. The goal of this study, then, was to examine cognitive data in children diagnosed with ADHD as compared to co-morbid ADHD and depression. Method: Twenty children who met criteria for ADHD, Predominately Combined subtype and 20 co-morbid ADHD, Predominately Combined Subtype, and depression were matched for sex, age, race and education. Measures of cognitive functioning included portions of the Behavior Rating Inventory of Executive Functioning (BRIEF), Wisconsin Card Sorting Task (WCST) and Continuous Performance Test (CPT). Results: Analysis of variance tests revealed that compared to the ADHD-only group, the co-morbid group were rated as having more impairment on the BRIEF (F [1, 39]=7.42, p=0.009) and demonstrated more perseverative responses on the WSCT (F[1, 39]=4.4., p=0.04). However, there were no differences between the groups in the number of commission errors on the CPT. Discussion: Our results suggest that children diagnosed with co-morbid ADHD and depression may have worse executive functioning skills, but comparable attentional abilities as compared to ADHD-only children. This information can be utilized for therapeutic purposes. Other areas of executive functioning should be examined in this population.

P21. The neuroanatomy of pseudobulbar affect

Omar Ghaffar, Laurie Chamelian, Anthony Feinstein

Background: Pseudobulbar affect (PBA) is defined as episodes of involuntary crying, laughing, or both in the absence of a matching subjective mood state. Although this neuropsychiatric syndrome is found in diverse neurological diseases, its neuroanatomic correlates have not been well-characterized. Objective: To elucidate the neuroanatomical correlates of PBA, we conducted a case-controlled 1.5T MRI volumetric study of multiple sclerosis (MS) patients with (N=14) and without (N=14) PBA. Method: Patients in both groups were matched on demographic and relevant disease related variables. Patients with co-morbid psychiatric disorders were excluded. Brain lesions (hyper- and hypointense) for each subject were localized to one of 26 brain regions using a semi-automated approach generated from Talairach co-ordinates. Between-group statistical comparisons were undertaken with α set at 0.01 for the primary analysis. Results: Discrete regional differences in lesion volume were noted in six regions: Brainstem hypointense lesions, bilateral inferior parietal and medial inferior frontal hyperintense lesions, and right medial superior frontal hyperintense lesions were all significantly higher in the PBA group. Using a logistic regression model, none of these single areas emerged as a statistically significant independent predictor of PBA, but five areas together accounted for 76% of the variance when it came to explaining the presence of PBA. Conclusions: MS patients with PBA have a distinct pattern of brain lesions when compared to a matched MS sample without PBA. The lesion data support a widely dispersed neural network involving frontal, parietal, and brainstem regions in the pathophysiology of PBA.

P22. Characterization of late- and very-late-onset first psychotic episode

Caroline Girard, Martine Simard

Background: The prevalence and initial symptoms of late-onset psychoses are a controversial matter. Recently, a group of experts suggested that these disorders could be differentiated according to the age of onset of psychosis: late-onset (LOS: onset >40 years) versus very-late-onset schizophrenia-like psychosis (VLOS: onset >60 years). Objective: The goal of this study was to investigate the prevalence and initial symptoms of the LOS and VLOS nosological groups proposed in a psychiatric setting. Method: The files of patients who presented with psychotic symptoms were analyzed. Symptoms were scored using the SAPS and SANS. Groups’ symptoms were compared using chi-squares and t tests. A stepwise logistic regression analysis was executed to determine which clinical characteristics were the most predictive of the groups’ classification. Results: Among the 1,731 files reviewed, 1.3% of patients developed their first symptoms after the age of 40, and 0.7% after the age of 60. LOS patients were more apathetic, presented more abnormal psychomotor activity and reference delusions than the VLOS. Persecutory delusions, auditory hallucinations, inappropriate social behaviour and anhedonia were very frequent in the two groups while negative symptoms were uncommon. A stepwise logistic regression analysis entering apathy and abnormal psychomotor activity demonstrated an overall classification accuracy of 95.7%, with 92.3% of the LOS and 100% of the VLOS being correctly classified. Conclusions: LOS and VLOS are rare. Apathy and abnormal psychomotor activity can properly differentiate VLOS and LOS. Thus the classification proposed by the group of experts seems to be partially supported.

P23. An fMRI study of frontal-striatal dysfunction during attention shifting in obsessive-compulsive disorder

Bon-Mi Gu, Ji-Young Park, Seung Jae Lee, Do-Hyung Kang, So Young Yoo, Jong-Min Lee, Jun Soo Kwon

Background: Dysfunction of frontal-striatal circuitry has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD) and the frontal-striatal circuitry in known as important to successfully shift attention and behavior. Also several neuropsychological studies reported set-shifting deficit in OCD patients. Set-shifting tasks, in which subjects undertake two tasks that run alternately in a rapid fashion, may help to clarify the nature of deficits in cognitive flexibility in OCD. Objective: The objective of this study was to localize the different pattern of set-shifting between healthy and OCD subjects. Method: Event-related fMRI data were collected for 18 OCD patients (seven drug naïve and 11 medicated OCD) and 16 healthy subjects during the performance of a set-shifting task. The set-shifting task has two conditions, which were set-shifting and set-stay conditions. The behavioral data were analyzed with SPSS and the fMRI data were analyzed using SPM2. Results: Compared to the healthy subjects, OCD patients showed significant interactions between sets and response in behavioral data. For the set-shifting versus set-stay contrast in fMRI data, healthy subjects showed more activation in the left thalamus, caudate body and right superior frontal lobe compared to OCD subjects. Conclusions: These results showed the different brain activation in the frontal-striatal circuits with impaired set-shifting ability in the OCD group.

P24. Peculiar behavior and cognitive dysfunction in a patient with schizophrenia: Wernicke-Korsakoff Syndrome in disguise

Colin J. Harrington, Wendy Froehlich

Background: Psychiatric patients are frequently admitted to the hospital with co-morbid medical illness. Evaluation of the mental status and cognitive function of these patients is an important component of the neuropsychiatric consultation. Non-psychiatric clinicians may misattribute many forms of abnormal behavior to primary psychiatric disease and truncate the differential diagnostic process. Neuropsychiatric consultation must consider whether observed abnormal behavior is due to an exacerbation of a primary psychiatric disorder or results from a medically induced neurobehavioral syndrome. Objective: The authors describe the case of a middle-aged man with a history of schizophrenia, alcohol abuse, and noncompliance who presented with complaints of generalized weakness and anorexia. Examination throughout the course of hospitalization noted varying degrees of cognitive dysfunction generally described as “confusion.” Assessment early on was most consistent with a diagnosis of acute encephalopathy with associated visual hallucinosis. Follow-up examination noted significant improvement in attentional function and resolution of hallucinosis, but was marked by residual disorientation, poor short-term memory, and bizarre responses to clinical queries. Despite documentation of anterograde memory dysfunction, confabulation, reports from family that the patient was not at his baseline, and clarification that the psychosis of schizophrenia occurs atop a clear sensorium, the primary medical team invoked the diagnosis of schizophrenia to explain his residual cognitive dysfunction and peculiar behavior. MRI of the brain was eventually ordered, demonstrating findings consistent with a diagnosis of Wernicke-Korsakoff Syndrome. Conclusions: This case highlights the importance of careful cognitive assessment and broad differential diagnostic consideration in the evaluation of frequently occurring but non-specifically described confusion.

P25. Echophenomena in Tourette’s disorder predict emotional empathy and are associated with increased grey matter volume in frontal mirror and parietal default mode neural systems

Neil A. Harrison, Andrea E. Cavanna, Bogdan Draganski, Mary M. Robertson, Richard S. Frackowiak, Hugo D. Critchley

Background: Echophenomena, including echopraxia (mimicry of motor behaviors), are common in Tourette’s disorder. Emotional empathy score in healthy subjects is predicted by magnitude and rapidity of mimicry of facial expressions, measured using EMG. Recent fMRI studies highlight activation of “mirror neuron” regions, concerned with processing socially meaningful information, during facial expression mimicry. We therefore used empathy questionnaires and structural neuroimaging to explore the empathetic style and neural correlates of echopraxia in TS. We predicted that echopraxia positive (EP+) Tourette’s disorder individuals will show higher trait empathy and exhibit greater grey matter volume in mirror neuron regions. Method: Seventy consecutive individuals with Tourette’s disorder were recruited from a specialist Tourette’s disorder clinic. Echopraxia was assessed using a specifically targeted clinical interview including 24 specially developed echopraxia-induction procedures. Subjects mirroring one or more actions were labeled EP+. Forty-seven of the 70 also underwent high contrast T1-weighted structural MRI neuroimaging. All subjects were assessed for emotional and cognitive empathy (Davis Interpersonal Reactivity Index), tic severity (YGTSS), depression (BDI), obsessive-compulsive symptoms (LOI), and anxiety (STAI). Results: 30 subjects (43%) were EP+. EP+ subjects scored significantly higher than EP subjects on Davis subscales of empathic concern (p=0.01), personal distress (p=0.03) and fantasy scores (p=0.02). Neuroimaging revealed EP+ subjects to have greater grey matter volumes in left pre-frontal “mirror neuron” and rostral inferior parietal cortical regions. Conclusions: Echopraxia in Tourette’s disorder is associated with enhanced empathetic concern and corresponding increased brain volume within “mirror” and “default mode” systems supporting cognitive processes related to both internal and external aspects of self and other.

P26. Abnormalities in white matter structure in autism spectrum disorders detected by diffusion tensor imaging

Roger J. Jou, Sarah J. Paterson, Andrea P. Jackowski, Marcel Jackowski, Xenophon Papademetris, Nallakandi Rajeevan, Lawrence H. Staib, Robert T. Schultz

Background: The neurobiology of autism spectrum disorders is currently unknown. One hypothesis states that autism spectrum disorders are attributable to impaired connectivity between those cortical areas responsible for social and language function. Objective: To test the hypothesis that abnormal white matter connectivity exists between those cortical regions implicated in social and language function. Method: Diffusion tensor magnetic resonance imaging was performed 20 males, ages 9 to 22 years: 10 with autism spectrum disorders and 10 typically developing controls (TDC). Subjects were group-matched according to age, handedness, and full-scale IQ. Fractional anisotropy (FA), a useful measure of the structural integrity of axonal tracts, was compared between groups using an integrated image analysis software suite. Volumes of interest (VOIs) were identified using predetermined probability and cluster thresholds. Diffusion tensor tractography was performed to confirm anatomic location of all VOIs. Results: Significantly reduced FA values were observed along portions of the following white matter structures: corpus callosum, cingulum, superior and inferior longitudinal fasciculi, and inferior fronto-occipital fasciculus. Significantly reduced FA values were also observed bilaterally in the white matter adjacent to the fusiform gyri. All findings survived after co-varying for age, FSIQ, and TBV. Tractography yielded fiber bundles bearing strong resemblance to those major fiber tracts known to course through the identified VOIs. Conclusions: These data provide evidence for impaired corticocortical connectivity in autism spectrum disorders. Aberrant axonal connections between those cortical areas implicated in social cognition and language function may contribute to the impairments characteristic of autism spectrum disorders.

P27. The differential diagnosis of congenital disorders that include psychosis

Margo Lauterbach, Aimee Stanislawski-Zygaj, Sheldon Benjamin

Background: Neuropsychiatrists are often called upon to evaluate psychotic individuals for possible neurological or neurodevelopmental etiologies after acquired neurological and other medical disorders have been ruled out. A large number of relatively rare congenital neuropsychiatric conditions that include psychosis have been described. Clear guidance on the neuropsychiatric evaluation and differential diagnosis of these conditions is difficult to find in standard textbooks. Objective: To address this dearth of information we set out to concisely describe the neurodevelopmental disorders in the differential diagnosis of psychosis, their neurodiagnostic and laboratory evaluations, and relative prevalence . Method: A literature search was conducted for disorders that may present with psychosis, utilizing PubMed, with search terms including psychosis, metabolic, genetic, congenital and neurodevelopmental disorders. All disorders described in case reports or case series and literature reviews, including their references, were included. Epidemiological, diagnostic and treatment information was gathered via textbooks, PubMed, and other online resources (including OMIM). Results: We identified over 30 congenital disorders that may present from childhood through adulthood and include psychosis. To guide neuropsychiatric assessment, conditions are grouped according to estimated prevalence and associated neuropsychiatric features. Diagnostic and laboratory investigations are recommended. Conclusions: As consultants frequently called upon to evaluate atypical presentations of psychosis, neuropsychiatrists should be aware of congenital disorders that can present with psychosis, however rarely. We recommend a differential diagnostic approach based on estimated prevalence of the disorders and their most prominent associated neuropsychiatric features.

P28. A randomized controlled fixed-dose trial of olanzapine for psychosis in Parkinson’s disease

Michelle J. Nichols, Johanna M. Hartlein, Meredith Albin, Brad A. Racette, Kevin J. Black

Background: Psychosis is a common and debilitating side effect of long-term dopaminergic treatment of Parkinson’s disease. Though clozapine is an effective treatment, need for blood monitoring has limited its first-line use. Objective: Since olanzapine shows similar receptor affinity to clozapine, it was hypothesized that this drug may be an effective alternative to clozapine for treatment of drug-induced psychosis. Method: We conducted a four-week, double-blind, placebo-controlled, fixed dose trial of olanzapine (0, 2.5 mg, or 5 mg) in 23 Parkinson’s patients with drug-induced psychosis while allowing for clinically realistic dose adjustments of dopamimetic mid-study. Brief Psychiatric Rating Scale (BPRS), videotaped and rated by blinded observer, and CGI (Clinical Global Impression) were primary tests of efficacy; Unified Parkinson’s Disease Rating Scale motor subscale III (UPDRS III) was the primary measure of tolerability. Results: Fourteen patients completed the study (seven on placebo, two on 2.5 mg olanzapine, five on 5mg olanzapine). Intention-to-treat analysis found no significant differences among treatment groups in study completion or serious adverse events. However, a disproportionate number of olanzapine vs. placebo group subjects reported mild side effects (p=0.0356), many citing motor worsening. In study completers, analysis by repeated measures ANOVA revealed no significant difference in BPRS psychosis reduction (p=0.536), parkinsonism (p=0.608), or any other measured parameters (CGI, MMSE, Beck Depression Inventory, Hamilton Depression score, Parkinson’s Disease Questionnaire, Schwab-England ADL assessment, and sleep scores) between olanzapine and placebo groups. Conclusions: This study adds to the growing body of evidence that olanzapine is an ineffective treatment for medication-induced psychosis in Parkinson’s disease.

P29. The visual scanning pattern of human faces: a precise diagnostic instrument in autism

Fernanda Tebexreni Orsati, Elizeu Coutinho Macedo, Salomão José Schwartzman, Tomanik Marcos Mercadante

Autism is a complex neurodevelopmental disorder characterized by impairment in social, communication and behavior domains. It is part of a broad spectrum of disorders: pervasive developmental disorders. The recent researches on this field are focused on precise diagnostic and endophenotypes characterization. The study of visual scanning pattern in pervasive developmental disorders population can determine neurobiological aspects; moreover, it can explain how they explore the environment. Objective: The authors describe the gaze pattern of autistic population in human faces. Method: Nine pervasive developmental disorders subjects (mean age=11.37) were assessed. The gaze parameters were recorded by the equipment Tobii ^® 1750. The stimulus were: 24 black and white human faces, presented for 4 seconds. Three variables were randomized: gender (men or woman); position (normal or rotated in 180°); and eyes (present or omitted). Results: The mean number of fixations in the face is 7.3 and in the eye region is 3.7. It shows that 51.73% of the total number of fixations is in the eye region. No significant difference in number of fixation was observed between the variables. Discussion: The gaze pattern of pervasive developmental disorders subjects shows that half of the total number of fixations is in the eye region. It has been recently shown that the pattern of typical subjects is that 75% of total fixations are in the eye region. Summarizing, the pervasive developmental disorders subjects show different visual scanning strategies then typical subjects what would influence the perception of faces, expressions and could explain the social impairment of this population. This pattern could be characterized as a new precise diagnostic instrument.

P30. Dissociation of awareness of different components of illness in schizophrenia

Laura A. Flashman, Robert M. Roth, Thomas W. McAllister, Jo Cara Pendergrass, Matthew A. Garlinghouse, Andrew J. Saykin

Background: Poor awareness of illness is common in patients with schizophrenia. There is debate, however, as to whether the abnormality is restricted to unawareness of psychiatric symptoms, or whether unawareness of illness is accompanied by difficulty recognizing problems in other areas of functioning such as cognition and everyday behaviors. Objective: We examined these contrasting hypotheses by evaluating the relationship between clinician-rated awareness of illness and the self-perception of executive functions in patients with schizophrenia. Method: Twenty-three patients with schizophrenia and 25 healthy comparison subjects completed the Behavior Rating Inventory of Executive Function–Adult version (BRIEF-A) Self Report form. Patients were evaluated using the Scale for the Assessment of Unawareness of Mental Disease (SUMD), Scale for the Assessment of Positive Symptoms, and Scale for the Assessment of Negative Symptoms. Results: Patients reported significantly more daily problems than comparison subjects for eight of the nine aspects of executive functioning assessed. Overall awareness of having a mental illness was associated with report of greater problems on only two of the nine BRIEF-A scales. Subjective executive functioning was unrelated to awareness of positive or negative symptoms, and did not differ between patients having good (N=15) as opposed to poor (N=8) awareness of illness. Conclusions: The present findings indicate that in patients with schizophrenia, being aware of one’s psychiatric illness and symptoms is relatively independent of recognition of everyday problems with executive function. These results raise the possibility that different neural mechanisms underlie awareness of symptoms and awareness of cognitive functioning.

P31. Evaluation of SLITRK1 as a candidate gene for Tourette’s disorder

Jeremiah M. Scharf, Priya Moorjani, Jes Fagerness, Jill Platko, Cornelia Illmann, Brian Galloway, Eric Jenike, David Pauls, Tourette’s Syndrome International Genetics Consortium

Background: Tourette’s disorder is one of the most heritable neuropsychiatric conditions, yet no definitive Tourette’s disorder susceptibility gene has been identified to date. Recently, a genetic variant in the SLITRK1 gene (var321) was reported to be associated with Tourette’s disorder in a small number of families. Objective: To screen a large collection of TS families for SLITRK1 var321 polymorphisms and test all common variants and major haplotypes across the SLITRK1 gene for genetic association with Tourette’s disorder or chronic tics. Method: Subjects included 1,047 patients with either Tourette’s disorder or chronic tics as well as their parents (2,296 total individuals from 646 families). Diagnoses were confirmed by a consensus of Tourette’s disorder clinical investigators. Genotyping of single nucleotide polymorphisms (SNPs) across the SLITRK1 gene, including var321, was performed on DNA from each individual. Common SNPs (>5% allele frequency) were selected from the HapMap database using the program Tagger. Family-based association analyses were performed using the program FBAT. Results: We found the previously reported var321 polymorphism in only one Tourette’s disorder patient (0.1% of patients). In addition, two unaffected parents carried the putative Tourette’s disorder risk variant. None of these individuals transmitted SLITRK1 var321 to a total of four offspring with Tourette’s disorder. Preliminary family-based association studies across the entire SLITRK1 gene revealed no common SNPs or haplotypes that were associated with either Tourette’s disorder or chronic tics. Conclusions: Despite the encouraging initial report, SLITRK1 does not appear to be a major contributing gene to Tourette’s disorder in the general population and should not be tested for in routine clinical practice.

P32. Neuropsychological correlates of N400 anomalies in patients with schizophrenia

Kyung Soon Shin, Do-Hyung Kang, Young Youn Kim, Myung-Sun Kim, Jun Soo Kwon

Background: N400 component could be a useful neurophysiological index to probe the disturbed functional and structural integrity of the fronto-temporal network, which is consistently implicated in the neuropsychological disturbance of schizophrenia. Objective: The goal of the present study is to investigate the N400 anomalies and its relationship with neuropsychological disturbance of schizophrenia. Method: Twelve patients with schizophrenia and 12 healthy comparison subjects, matched for age, sex, education and handedness, underwent both the neuropsychological test and the electrophysiological recordings employing semantic violation paradigm. Results: The patients with schizophrenia showed the reduced N400 amplitude and worse performance in terms of the frontal lobe function test compared to healthy participants. Furthermore, there were significant positive correlations between the N400 amplitude and the neuropsychological performances of Stroop task and Wisconsin Card Sorting Test in patients with schizophrenia. Conclusions: Our results suggest the possibility that N400 anomalies reflect the disturbed integrity of the fronto-temporal network of the schizophrenia evidenced by neuropsychological deficits. In addition, we concluded that the N400 amplitude is candidate for endophenotype marker of schizophrenia by revealing the relation of neuropsychological deficits.

P33. CYP2D6 metabolizer status and atomoxetine dosing in children and adolescents with ADHD

Paula T. Trzepacz, David W. Williams, Peter D. Feldman, Jennifer W. Witcher, Jan K. Buitelaar

Background: Genotype status can affect metabolism of medications by hepatic cytochrome P ₄₅₀ 2D6 (CYP2D6), with higher serum concentrations occurring in poor metabolizers than extensive metabolizers. Previous reports show the nonstimulant atomoxetine is well tolerated in ADHD patients whether they are poor metabolizers and extensive metabolizers. Objective: To determine how genotype status for CYP2D6 relates to efficacy, tolerability, and safety, we pooled data from two near-identical open-label clinical trials of atomoxetine in children and adolescents with DSM-IV-diagnosed attention-deficit/hyperactivity disorder (ADHD) where dose titrations were made according to clinical response and blinded to genotype. Method: Subjects were assessed weekly for up to 10 weeks and dosed up to a maximum of 1.8 mg/kg/d. Efficacy was measured at baseline and each visit using the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator (ADHD-RS). Adverse events, EKGs, growth data and blood chemistries were collected. Results: PM subjects (N=87) received a mean dose that was 0.1 mg/kg/d lower than extensive metabolizers (N=1239), had somewhat better efficacy on the ADHD-RS, and had comparable adverse events, except for a 4.0-bpm greater increase in mean pulse rate and a 1.0-kg greater weight loss. Fridericia QTc changes did not differ between groups and did not relate to dose in poor metabolizers. Conclusions: Genotyping is not necessary in the clinical management of children and adolescents with ADHD because physicians dose atomoxetine to essentially comparable levels of efficacy and safety without knowledge of genotype metabolizer status. Atomoxetine is a nonstimulant, highly specific norepinephrine reuptake inhibitor that is an alternative to stimulants in the treatment of ADHD.

P34. The effects of subthalamic deep brain stimulation on pathological gambling in Parkinson disease: a multicenter case series

Valerie Voon, Claire Ardouin, Julia Worbe, Virginie Czernecki, Nehmann Abouazzar, Hussein Hosseini, Antoine Pelissolo, Elena Moro, Eugenie Lhommee, Yves Agid, Alim Benabid, Pierre Pollak, Luc Mallet, Paul Krack

Background: Dopaminergic medication-related (DRT) pathological gambling in Parkinson’s disease can have marked consequences but can improve with medication change. However, some patients are unable to tolerate medication change. Subthalamic stimulation (STN DBS) is effective for Parkinson’s disease and allows for a marked dose decrease. Objective: The authors describe eight Parkinson’s disease patients with pathological gambling following STN DBS. Method: Parkinson’s disease patients with DRT-related pathological gambling were identified from 600 STN DBS patients (three centers) using chart review. The patients were followed with systematic open behavioral assessment and standardized psychiatric disorders, motor, mood and apathy assessment. Results: Seven patients (six men; Parkinson’s disease onset at mean age=41.7 [SD=8.5]; age at surgery=53.8 [SD=8.9]; preoperative LEDD=1390mg/d [SD=354]) had preoperative active pathological gambling (mean=7 years) intolerant to medication changes. Pathological gambling resolved postoperatively (mean=18 months [range=0 to 48]) although two patients had early transient exacerbation. Improvement paralleled LEDD decrease (mean=75% decrease) and levodopa-induced dyskinesia improvement. Pathological gambling resolved only with ropinorole discontinuation in one patient. An eighth patient had de novo postoperative pathological gambling temporally linked to new onset pramipexole monotherapy with symptom cessation with pramipexole discontinuation. The patient had no behavioral effects with preoperative pramipexole and had postoperative mental set maintenance impairment. Conclusions: DRT-related pathological gambling in Parkinson’s disease can potentially improve with STN DBS over the long term. However, as short term exacerbation can occur we emphasize careful selection and follow-up. Potential mechanisms include: 1) dose decrease or dopamine agonist cessation; 2) relative motor selectivity of stimulation;.3) discontinuation of sensitizing effect of pulsatile medication administration; or 4) STN stimulation enhancement of natural reward motivation.

P35. Progression of the posterior fossa syndrome

Susan Beckwitt Turkel, Mark Krieger, Lan Chen, Rima Jubran, Jane Tavare

Background: In our earlier retrospective study, children with midline posterior fossa lesions were found to have severe dysphoria, irritability, mutism, inconsolability, and ataxia postoperatively. But not all children with acute cerebellar lesions develop these symptoms. Objective: This study was undertaken to answer the question, how often and under what circumstances do symptoms of cerebellar dysphoria and mutism (the posterior fossa syndrome or acute cerebellar cognitive affective disorder), occur. Method: We prospectively evaluated all children with posterior fossa tumors who were admitted to Childrens Hospital Los Angeles from March 2004,through March 2006. Most were seen preoperatively, and all were seen within one week after surgery. Results: Twenty-two patients were enrolled in the study, 12 boys and 10 girls, ranging in age from 14 months to 15 years, mean age 7.5 years, similar to the retrospective study. When seen postoperatively, four children did not exhibit any symptoms of the posterior fossa syndrome, and one was delirious. Of the others, seven were akinetic, seven were mute, seven were irritable, and three were dysphoric. Four who were akinetic evolved into dysphoria over days to weeks. Conclusions: No anatomic or surgical differences could be found to explain the clinical variations between these patients or between the retrospective and prospective studies. Perhaps the previous retrospective study was biased for patients with obvious, distressing symptoms, which were not as common in the prospective study. Of importance is the observation that symptoms changed during the course of the postoperative period.

P36. An fMRI study of the neural mechanisms of palinopsia

Martin A. Goldstein, Michael E. Silverman, Annabel K. Wang, Oliver Tuescher

Background: Palinopsia is a visual phenomenon marked by persistent “after-images.” It is distinct from physiologic after-images which transiently occur after stimulus extinction. Although visual processing circuitry is implicated, the precise neural substrates of palinopsia remain elusive. Objective: To characterize the functional neuroanatomy mediating perseveratory after-images in a 42-year-old woman previously treated with immunomodulator therapy for chronic hepatitis C infection. Method: One hundred twenty stimuli were serially presented at varying onsets in a counter-balanced pseudo-randomized order (SOA=4 sec). Average Visual Angle=2.6°×3.0°. The subject was instructed to attend to each image and, once removed, respond using a button press to after-images presence (AI +) or absence (AI −). Image acquisition was performed on a Siemens 3T MRI scanner using a gradient EPI BOLD sequence (TR=2000 ms; TE=30 ms; flip angle=90°; FoV=210mm × 210 mm; 3.0 mm thickness; 1 mm gap; matrix=64×64). Image analysis was conducted using SPM2. Results: A significant difference in after-images occurrence was revealed as a function of stimulus onset (X ² [3]=12.26, p≤0.01). Contrasting mean BOLD responses associated with AI+ versus AI- trials demonstrated AI+ associated activation of a discrete neural network including dorsal anterior cingulate, thalamus, caudate, and right parietal regions. Conclusions: After-images can be associated with activation of a distinct neural network. These findings potentially offer insight into neural mechanisms mediating a broad range of paroxysmal sensory phenomena (e.g., “flashback”), particularly those involving disturbances of visual perception of “where” and “when.” Further, these findings may have implications for elucidating neural mechanisms by which inflammatory mediators (e.g., cytokines) can affect neuropsychiatric function.

P37. Dyskinesia following MDMA abuse

James A. Wilcox

We present three men who developed dyskinesia after long term abuse of MDMA. The literature reports cases of stiffness and rigidity after MDMA abuse, but this is the first report of involuntary movements. Each patient used MDMA heavily for three years and eventually developed chorea with dyskinetic movements. Genetic testing ruled out inherent risk factors for movement disorders. None of the patients had ever used neuroleptics. MRI revealed atrophy to the caudate. We suggest that the neurotoxicity of MDMA may occur in ways not previously detected or discussed in the literature.

P38. Acute embolic stroke masquerading as major depression with psychotic features

Amy S. Aloysi, James Murrough

Background: There is extensive literature on the neuropsychiatric sequelae of stroke. Left anterior lesions have been associated with depression, while right sided lesions have been linked with mania or psychosis. These behavioral syndromes are usually identified subsequent to the vascular event. We present an unusual case of acute psychotic depression with precise temporal correlation with embolic events in the right anterior cingulate and left thalamus. Case history: A 55-year-old man without past psychiatric history was referred to the Psychiatric ER by his medical doctor for a “one week history of acute psychosis.” He admitted to depressed mood, suicidal ideation, and auditory hallucinations telling him to kill himself. He had been poorly compliant with outpatient treatment for diabetes, hyperlipidemia, and peripheral neuropathy. He was admitted to a psychiatric unit and prescribed citalopram and risperidone. On admission, his MMSE was 21/30, with deficits in orientation, concentration, and visuospatial domains. He showed perseveration, slowed Luria maneuvers, and slight left sided facial droop. An MRI ordered to evaluate the degree of cerebrovascular disease revealed multiple acute embolic strokes, including right anterior cingulate and left thalamic lesions, having occurred within two weeks. Conclusions: This case presents the simultaneous development of an affective disorder with psychotic features time-locked to acute embolic lesions in certain brain regions. It illustrates how acute neurological events can mimic idiopathic psychiatric disorders, and thus the need for complete neurological assessment in patients presenting to psychiatrists. Rapid identification of underlying neurological illness may prevent further damage to the central nervous system, and reduce future neuropsychiatric disability.

P1. The relationship between depressive symptoms and prefrontal hypoperfusion in patients with dementia of the Alzheimer’s type demonstrated by eZIS

Hisanori Akiyama

Background: Depressive symptoms are common in Alzheimer’s disease and contribute to clinical morbidity. Previous studies have suggested that hypoperfusion in the prefrontal cortex and anterior cingulate gyrus are involved in the pathophysiology of depression. Using eZIS, we investigated the relationship between depressive symptoms and prefrontal hypoperfusion in Alzheimer’s disease. Method: ^99m Tc-ECD-SPECT and Neuropsychiatric Inventory (NPI) were performed in twenty-seven patients diagnosed as having dementia of Alzheimer’s type (DAT) with DSM-IV. These patients were divided into depression groups (N=15) and nondepression groups (N=12) using the NPI depression items. All data from SPECT images were analyzed using eZIS software. Scores in four regions were determined by Z-values; these regions consisted of each side of the prefrontal cortex and anterior cingulate gyrus. We compared mean scores between the depression groups and nondepression groups. Results: The mean scores of the bilateral prefrontal cortex for the depression groups were significantly higher (p<0.05) than those of the nondepression groups. There were no significant differences in the scores of bilateral anterior cingulate gyrus between these two groups. (Mann-Whitney U-test). Conclusions: These findings suggest that hypoperfusion in the prefrontal area contributes to the expression of depressive symptoms in patients with DAT.

P2. Bupropion suicidality analysis in adult major depressive disorder clinical trials

Donna S. Wightman, April E. Harriett, Nathalie E. Richard, Joseph P. Horrigan, Jack G. Modell

Background: This analysis of safety data for bupropion was initiated in light of concerns about emergent suicidality during antidepressant treatment. Objective: The objective of this review was to assess the risk of suicidal behavior or suicidal ideation in adult patients with major depressive disorder treated with bupropion compared to placebo. Method: The statistical plan was based on methods used by FDA for their analysis of pediatric antidepressant suicidality data. 6,754 adults were included in this analysis from randomized, placebo-controlled major depressive disorder trials. A text string search of the adverse event database and CRF comment logs was used to identify potential suicidal events. For positive matches, narratives were prepared and were assessed by three independent suicide experts at Columbia University, and classified using the Columbia University Suicidality Classification of adverse event ratings. A subject was determined to have a suicidal behavior or ideation event if his/her event was assigned a rating of 1-4 and a suicidal behavior event if assigned a rating of 1 to 3. Results: The data show that the incidence of suicidal behavior or ideation was bupropion: 11/3179 (0.35%) versus placebo: 9/2310 (0.39%); the odds ratio for suicidal behavior was estimated to be 1.09 (95% CI: 0.44 to 2.74), or in suicidal behavior bupropion: 7/3179 (0.22%) versus placebo: 2/2310 (0.09%); the odds ratio for suicidal behavior was estimated to be 3.27 (95% CI: 0.72 to 23.07). No completed suicides were reported while on treatment in this population. Conclusions: Both suicidal ideation and behavior in bupropion-treated patients were rare, and there was no statistically greater risk for suicidal behavior or ideation in bupropion-treated patients compared to placebo-treated patients.

P3. Depression following traumatic brain injury: an open-label study of citalopram

Mark J. Rapoport, Florance Chan, Krista L. Lanctot, Nathan Herrmann, Scott McCullagh, Anthony Feinstein

Background: Significant depression occurs in approximately 20% of patients following traumatic brain injury (TBI), and commonly interferes with physical rehabilitation goals. There have been several studies published to date claiming high levels of response associated with the newer antidepressants for the treatment of depression in patients with TBI. However, most of these studies had very small sample sizes and many did not have clear definitions of response. Objective: Here, we sought to examine the antidepressant treatment outcome in a larger sample of adults with depression following TBI seen at a tertiary care center. Method: Sixty-five TBI patients who met criteria for depression (DSM-IV criteria for mood disorder due to TBI) as evaluated by a psychiatrist were treated with open-label citalopram at doses between 10 and 50 mg/day, for up to 10 weeks. The Hamilton Depression Rating Scale (HAM-D) was used to assess the severity of depression. Results: In our sample, the mean age was 40.0 (SD=19) years and 58% were men. The TBI severity was mild in 51% of the patients, moderate in 48%, and severe in 1%. The mean HAM-D at baseline was 23.7 (SD=7). At 6 weeks, 54 subjects were assessed and 27.8% responded (“≥50% reduction in HAM-D score”) with 24.1% in remission (“HAM-D score of ≤7”). At 10 weeks, 26 subjects were assessed and 46.2% responded with 26.9% in remission. Conclusions: The response rate in the present sample was substantially lower than previously reported in the literature. Other multidisciplinary treatment modalities will be needed to achieve adequate control of symptoms.

P4. Antipsychotics and motor vehicle collisions in patients with dementia

Mark Rapoport, Frank Molnar, Donald Redelmeier, David Juurlink, Paula Rochon, Nathan Herrmann, Brandon Zagorski, John Morris, Anna Byszewski

Background: Alzheimer’s disease poses significant risks to road safety. Antipsychotics may be a marker of increased risk. Objective: To determine the risk of serious motor vehicle collisions associated with antipsychotic prescriptions in patients with mild-to-moderate Alzheimer’s disease. Specifically, we planned to determine whether patients who were treated with a cholinesterase inhibitor (CI) and subsequently involved in a collision as the driver were more likely to have been dispensed an antipsychotic in the four months preceding the collision than those who did not have a collision. Method: We conducted a population-based, nested case-control study by linking various Ontario healthcare and transportation databases from January 1, 1999, to March 31, 2004. The cohort consisted of older adults who had received a prescription for a CI. Cases involved in collisions were matched by age and gender to controls not involved in collisions, and compared for exposure to antipsychotics in the 120 days prior to collision (or matched index date for controls), while controlling for previous violations, previous drug exposure, and prior psychiatric admissions. Results: 2,538 cases were matched to 7,469 comparison subjects. The overall antipsychotic 120-day exposure rate was 1.3% (n=296). The cases had a lower exposure rate at 0.9 % (N=22) compared to the comparison subjects 1.5% (N=108) yielding an adjusted odds ratio of 0.43 (0.23, 0.82). Conclusions: The most parsimonious explanation of this counter-intuitive finding is that these subjects are restricting their driving exposure. This self-restriction however is incomplete, and many patients with both Alzheimer’s disease and recent antipsychotic treatment are involved in collisions.

P5. Sensitivity and specificity of the clinical diagnostic criteria for vascular dementia: a critical review

Sandra Wiederkehr, Martine Simard, Claudette Fortin, Robert Van Reekum

Background: Several sets of clinical criteria such as the Hachinski Ischemic Scales, the DSM-III, DSM-III-R, and DSM-IV criteria, ICD-10, ADDTC, and NINDS-AIREN have been proposed to diagnose vascular dementia. Objective: The goal was to compare these various criteria and critically review their sensitivity and specificity rates in order to clarify their capacity to properly diagnose vascular dementia. Method: Sixteen studies were selected following a PubMed/Medline search covering the years from 1975 to 2006. These studies were hierarchically organized according to their purposes and quality of experimental designs. Results: The eight clinical criteria sets yielded different sensitivity and specificity results, and presented marked variability in reported incidence and prevalence estimates as well as in frequency rates. None of the clinical diagnostic criteria satisfactorily differentiated mixed dementia from vascular dementia but were better at excluding pure Alzheimer’s disease. Nevertheless, the ADDTC criteria were the most sensitive criteria and perhaps the most useful in clinical settings. The NINDS-AIREN were consistently found to be the most specific criteria, and thus the most useful in research. Conclusions: The current sets of criteria for vascular dementia were not interchangeable. A major limitation of the reviewed studies was the absence of clinicopathological validation of vascular dementia diagnosis using prospective longitudinal experimental designs. Moreover, most of the criteria provided a description of the cognitive deficits based on the Alzheimer’s-type clinical criteria. A definition of the cognitive syndrome and the methods of assessment, as well as a definition of the associated vascular causes/lesions should be clearly specified in future guidelines.

P6. Modified Mini Mental State Exam (3MS) as a predictor of follow-up DRS-II total scores in carotid artery stenting

Robert B. Burr, Rodney Raabe, Lynn Dahlstrom, Robert Short

Background: Diagnostic tools that are easily administered and clinically sensitive are important in clinical and research neuroscience. Screening tools are often selected to replace lengthy assessment procedures. However, this often sacrifices clinical relevance and sensitivity. The Mini-Mental State Examination (MMSE) is routinely used as a screening tool in clinical and research settings. However, in certain populations, the sensitive of the MMSE at detecting dysfunction has been debated. The Mini Mental Modified (3MS) with improved domain specific questions and additional memory assessment was developed as an alternative to the MMSE. This study investigated the relationship between MMSE and 3MS to Dementia Rating Scale-II Total scores in a group of subjects enrolled in an FDA-IDE study to monitor long-term cognitive outcome in carotid stenting using a neuroprotective device. Method: Neuropsychological data was analyzed from 35 subjects (25 men, 10 women; mean age=73 [SD=9] ; 12 [SD=2.8] years of education). Subjects underwent cognitive evaluation at baseline, and 3 month and 6 months post stenting. Results: DRS-II Total scores at 6 months correlated with baseline, 3- and 6-month MMS and 3MS scores. However, 6-month DRS scores correlated most highly with baseline 3MS scores (r=0.78). These findings suggest that when a cognitive screening measure is required, the 3MS is better at predicting long term cognitive status than the MMSE.

P7. Association between features of the insulin resistance syndrome and Alzheimer’s disease

Khalid A. Elnagar, Essam Moussa

Background: The etiology of Alzheimer's disease is still unknown. Insulin is a hormone that helps regulate blood sugar. Obesity, high blood pressure and diabetes are associated with a condition called insulin resistance, in which the body needs more and more insulin to balance sugar levels. Because insulin resistance plays a central role in the pathogenesis of several important human diseases, we need to examine the relation between insulin resistance syndrome and Alzheimer’s disease. Objective: To examine the relationship between Alzheimer’s disease and insulin resistance. Method: We examined the relationship between Alzheimer’s disease and insulin resistance syndrome in 12 men and 12 women ages 64 to 78 years in comparison with healthy subjects. Alzheimer’s disease patients were randomly selected from the psychiatric clinic at New Jeddah Hospital, while healthy subjects were chosen from patients’ spouses and the local community. Results: Women with Alzheimer’s disease, compared with healthy subjects, have higher HOMA-IR (p=0.003), and higher FBG (p=0.002). Similar differences were present in men but were not statistically significant except for FBG (p=0.04). Conclusions: Patients with Alzheimer’s disease have higher prevalence of insulin resistance syndrome, and this may be secondary to being overweight but a causal relationship cannot be excluded.

P8. Very early onset Alzheimer's disease: is genetic testing mandatory?

Christopher M. Filley, Yvonne D. Rollins, C. Alan Anderson, David B. Arciniegas, Katherine L. Howard, Bette K. Kleinschmidt-DeMasters

Background: Autosomal dominant Alzheimer’s disease is often due to a mutation in presenilin-1 (PS1), presenilin-2 (PS2), or amyloid precursor protein (APP) genes. Cases may begin in adults younger than 35 (very early onset), and diagnosis may be challenging because dementia is so uncommon in this age group. Controversy also exists regarding genetic testing. We present a case of Alzheimer’s disease without Down’s syndrome beginning at age 32, and review the literature on the genetics of Alzheimer’s disease before age 35. Case history: A 32-year old man developed memory impairment and apathy leading to progressive dementia and death at age 36. Family history included undiagnosed dementia in his mother and brother, who died at age 42 and 40, respectively. Laboratory tests, MRI, EEG, and CSF 14-3-3 protein testing identified no etiology; PET showed frontoparietal hypometabolism. Genetic testing for Alzheimer’s disease-associated mutations was not performed. Autopsy verified Alzheimer’s disease. The literature search confirmed the rarity of very early onset non-Down’s syndrome Alzheimer’s disease, with less than 100 reported cases beginning before age 35. The youngest age of onset was 24 years. In all cases in which genetic analysis was available, either a PS1 mutation or linkage to chromosome 14 was reported. Conclusions: Non-Down’s syndrome Alzheimer’s disease is extremely rare in adults younger than 35, but is tightly linked with PS1 mutations. PS2 and APP mutations appear not to be associated with Alzheimer’s disease onset before 35 years. Genetic testing for PS1 mutations can be offered to individuals with unexplained dementia occurring before age 35, but patients such as ours underscore the fact that very early onset Alzheimer’s disease is virtually always due to a PS1 mutation.

P9. Evaluation of the therapeutic response to donepezil in patients with dementia of the Alzheimer’s type by 3DSRT

Shigeaki Higashiyama, Joji Kawabe, Hiroshi Hashimoto, Hisanori Akiyama, Ethshi Kawamura, Kenji Torii, Koki Inoue, Nobuo Kiriike, Susumu Shiomi, Yuichi Inoue

Background: In a quantitative evaluation of the therapeutic response in Alzheimer’s type dementia, comparing pre- and post-treatment regional cerebral blood flows, uptake in certain types of cerebral regions of interests (ROIs) were previously measured. However, ROI analysis is associated with problems, such as poor reproducibility and a lack of objectivity. The aim was to investigate the evaluation of a therapeutic response by a three-dimensional stereotaxic ROI template (3DSRT), using fully automated ROI analysis software, capable of objectively estimating rCBF. So we compared the effect of the therapeutic response of three-dimensional stereotactic surface projections (3D-SSP). Method: Brain perfusion single photon emission tomography (SPECT) studies and Alzheimer's Disease Assessment Scale–Japan Cognitive Subscale function test ADAS-Jcog tests were performed for 22 patients (16 women and six men; mean age=73.6 years) who were diagnosed as dementia of the Alzheimer’s type both before and after treatment. On 3DSRT, we compared the ratios of the rCBF values of the parietal lobes, temporo-occipital lobes, hippocampus, corpus callosum and the frontal lobes/cerebellar hemispheres before and after treatment. On 3DSSP, we examined the cinguli gyrus bilaterally, and scored the change in Z value there. Results: During the ADAS-Jcog inspection, while improvement was noted in 10 patients, the remaining 12 showed no improvement in the ADAS-Jcog score. In 10 patients who had recognitive improvement following ADAS-Jcog inspection, eight patients showed improvement in 3DSSSP and seven patients in 3DSRT respectively. In the other 12 patients, no improvement was revealed by ADAS-Jcog inspection, while 11 patients showed no improvement in 3DSSP and 3DSRT, respectively.

P10. A functional neuroimaging study of appetite loss in Alzheimer’s disease

Zahinoor Ismail, Nathan Herrmann, Lana Rothenburg, Adolpho Cotter, Farrell Leibovitch, Shahryar Rafi-Tari, Krista Lanctot, Sandra Black

Background: Alzheimer’s disease is frequently associated with changes in appetite. The neural correlates of these changes are unknown. Objective: This study investigated the relationship between regional cerebral perfusion and appetite change in Alzheimer’s disease. Method: Sixty-nine patients with probable or mixed Alzheimer’s disease were characterized as being with (N=23) or without (N=46) appetite loss based on the Neuropsychiatric Inventory (NPI) Appetite Subscale. 99mTc-ECD SPECT scans were co-registered to a standardized template in Talairach space generating mean ratios of uptake referenced to the cerebellum. Regions of interest (ROIs) included anterior cingulate cortex (ACC), middle mesial temporal cortex (MTC-m), inferior mesial temporal cortex (MTC-i), insula (INS), orbitofrontal cortex (OFC) and thalamus-hypothalamus (THAL). Results: Backward stepwise logistic regression analysis of these ROIs showed hypoperfusion in the L-OFC (p=0.004) and R-THAL (p=0.073), and relative sparing of perfusion in the R-OFC (p=0.002) and L-MTC-m (p=0.014) predicted loss of appetite (chi-square=13.59, p=0.009, R ² =0.248). Conclusions: Hypoperfusion in the left orbitofrontal and right thalamus/hypothalamus, and relative sparing of perfusion in the right orbitofrontal and left middle mesial temporal cortices emerged as predictors of appetite loss in this sample of Alzheimer’s disease patients. These findings are consistent with impairments in the extrinsic motivational pathways of eating and impaired reward value of food.

P11. Differential diagnosis of early-onset dementia

Mario F. Mendez, Eliot A. Licnt, Rochelle Woods, Aaron M. McMurtray, Ron E. Saul

Background: Despite potentially devastating consequences, clinicians frequently misdiagnose the early onset dementias. A major diagnostic challenge is distinguishing early-onset Alzheimer’s disease (EAD), subcortical ischemic vascular disease (SIVD), and frontotemporal dementia (FTD), the three most common progressive, early-onset dementias. Objective: To assess the diagnostic contribution of clinically-useful mental status tests in distinguishing patients with EAD, SIVD and FTD. We propose that EAD results in early posterior parietal area involvement whereas SIVD and FTD result in early frontal systems involvement. These differences are reflected in mental status measures that assess visuoperceptual and frontal-executive functions. Method: We applied the Perceptual Assessment Battery (PAB) and the Frontal Assessment Battery (FAB) to 15 EAD patients (58.6 [SD=4.9] years old; MMSE=22.1 [SD=4.2]), 15 SIVD patients (59.1 [SD=4.1] years old; MMSE=22.5 [SD=4.5]), 15 FTD patients (58.1 [SD=5.2] years old; MMSE=23.9 [SD=4.4]), and 15 healthy subjects (58.6 [SD=5.1] years old). The PAB is a 54-item test of figure-ground analysis, visual synthesis, and spatial localization. The FAB is an 18-item test of frontal-executive abilities. Results: When compared with healthy subjects on the PAB, the EAD and SIVD groups, but not FTD, were significantly different (t=15.35, p<0.001 and t=2.26, p<0.05, respectively). When compared to controls on the FAB, the SIVD and FTD groups, but not EAD, were significantly different (t=5.26, p<0.001 and t=6.41, p<0.001, respectively). The FAB/PAB ratio scores were highly discriminatory for all three dementias (F=27.68, p<0.001 with all post-hoc combinations significant). Conclusions: The combination of PAB and FAB can differentiate the early onset dementias. Patients with EAD, SIVD, and FTD will have distinguishing patterns reflecting differences in early regional neuropathology.

P12. Brain SPECT: a useful, practical and cost-effective adjuvant modality for the differential of dementia, with and without comorbidity

Dan G. Pavel, Michael J. Schrift, Ovidio DeLeon, Steven R. Best, Jessica Chang, Irina Craita

Objective: The authors evaluate the contribution of Brain SPECT as adjuvant in the differential of dementias of various etiologies with and without comorbidity. Method: The authors employed high resolution brain SPECT: triple head camera, Tc-HMPAO. Orthogonal and temporal slices displayed in a discrete color code; four levels of thresholded volumes and eight color-coded Talairach surface views. Population: 79 people were referred for memory problems or dementia differential. Age: 53 to 89 (53% were men). Results: Semiquantitative evaluation of 1) hemispheric cortex, including orbito-frontal, precuneus and lateral temporal areas; 2) limbic and paralimbic structures; 3) striatum structures; 4) cerebellum and pons. In 81% of the cases, abnormalities suggested single or mixed etiology and in some, pointed to comorbidity patterns (e.g., depression, anxiety, psychosis). In 15% of the cases, there were no definite cortical nor posterior cingulate abnormalities but only subcortical abnormal features. In 4%, no definite abnormal features were found. Patterns of abnormality suggested : predominant Alzheimer’s disease (including early Alzheimer’s disease due to Down’s syndrome progression); FTD; Lewy Body disease; Vascular dementias. In 14 cases with longitudinal follow-up, progression of disease was definite or subtle. Conclusions: The quality and clarity of the images obtained provided 1) “finger print” of the functional status at a point in time; 2) contributed to validation of presumed diagnosis; 3) useful in longitudinal follow-up; 4) helped in tailoring the prescription to patient and comorbidity; and 5) prognostic information. If properly done and displayed, brain SPECT is a clear, practical, useful, cost-effective adjuvant in dementia differential diagnosis.

P13. 2-year longitudinal sensitivity of cognitive measures in pre-diagnosis Huntington's disease in the predict-Huntington’s disease cohort

Julie C. Stout, Sarah Queller, Douglas R. Langbehn, Shannon A. Johnson, Noelle E. Carlozzi, Kevin Duff, Leigh Beglinger, Jane S. Paulsen

Background: Huntington’s disease is an autosomal dominant neurodegenerative disease causing motor, cognitive, and psychiatric abnormalities, and premature death. A key to developing Huntington’s disease treatments is the identification of clinical and biological markers of the subtle changes that characterize the earliest disease process and its progression toward diagnosis. Objective: To identify neurocognitive measures sensitive to change over a two-year period in the predict-Huntington’s disease cohort. Method: Using neurocognitive tests, we studied 32 CAG-healthy subjects and 193 CAG-expanded pre-diagnosis participants. Of the CAG-expanded participants, 97 were greater than 15 years from estimated diagnosis and 96 were less than 10 years from estimated diagnosis (based on CAG expansion and age). For each test, we compared the groups on standardized change over two years, controlling for age, education, gender, and pre-morbid IQ. Results: On most tests, the near-onset group performed worse than controls. In some cases, the near-onset group remained stable, whereas the comparison group showed practice effects; thus, the effects were detectable only in comparison to healthy subjects. Those far from onset typically performed similarly to controls. Effect sizes for the two-year change in those near onset ranged from negligible to moderate (Cohen’s d=0 to 0.5.). Conclusions: Over 2 years, the tests most sensitive to change were olfactory identification, speeded tapping, Trail-Making Test, Part B, and the Stroop Word subtest. These measures may be candidates for detecting drug effects in clinical trials during the pre-diagnosis period.

P14. Dementia, agitation, sleep and visual hallucinations: two case reports and review of the literature

Kaloyan S. Tanev, Donal O’Hanlon, Jonathan Jacobson

Background: Visual hallucinations are observed in normal individuals during sleep or sensory deprivation, in ophthalmologic disorders, with localized or generalized CNS disorders, or with psychiatric disorders. We review the phenomenology and etiology of visual hallucinations, and propose four mechanisms for the generation of visual hallucinations. Known neuropsychiatric syndromes associated with visual hallucinations and disinhibition are described (e.g., Charles Bonnet Syndrome, frontal lobe syndromes, Lewy Body dementia). The authors also review the relationship between visual hallucinations and sleep disorders. Case history: We describe two elderly patients hospitalized in a medical psychiatry unit for agitation. Both patients had impaired vision preceding the visual hallucinations. One lost his vision due to ischemic neuritis, developing visual hallucinations shortly afterwards. The other patient had had macular degeneration for 6 years and visual hallucinations for 4 years. Both patients experienced complex visual hallucinations and were unable to distinguish the visual hallucinations from reality. They had acted on the content of the visual hallucinations (e.g., one believed a baby was trapped inside a chair and cut the chair open to release the baby). Functional brain scans showed decreased blood flow/metabolism in the frontal and temporal lobes in both patients. Treatment consisted of mood stabilizers and antipsychotics for agitation, and melatonin, stimulants, and bright light therapy for the patients’ severely disrupted sleep wake cycles. Sleep cycles and agitation improved. Visual hallucinations persisted, but their content became less distressing to the patients. Conclusions: The two cases illustrate the relationship between complex visual hallucinations, agitation, dementia, and disrupted sleep cycles. The importance of monitoring and correcting patients’ sleep/wake cycles is emphasized.

P15. Evidence-based selection of outcome measures for clinical trials: the Huntington's disease toolkit project

Julie C. Stout, Allison Tomusk, Sarah Queller, Barbara Walker, Jason Dawson, Scott Hastings

Background: Putative neuroprotective compounds are being developed for the treatment of Huntington’s disease. Clinical trials in pre-diagnostic and early Huntington’s disease will determine whether any of these compounds can delay Huntington’s disease onset or slow progression. Objective: The Huntington’s disease toolkit Web site will provide an evidence based resource to help clinical trialists select optimal outcome measures with detectable sensitivity to the early disease process. While the process for selecting preferred and non-preferred cognitive tests is illustrated here, a similar method will be used to identify optimum motor, functional, psychiatric, neuroimaging, electrophysiological, and wet biomarkers. Method: We conducted a systematic review of the literature published since 1993 (advent of PCR genetic analysis) to identify studies that: 1) compared pre-diagnosis or early Huntington’s disease (<5 years since diagnosis) over time or to a gene-negative control group, and 2) contained sufficient data on a cognitive test to compute effect sizes (ESs) using metaanalysis. Results: Tests are categorized as Preferred, Non-Preferred or Insufficient Evidence based on ESs, with longitudinal studies constituting the strongest evidence. The large majority of tests are categorized as Insufficient Evidence . Preferred tests include The University of Pennsylvania Smell Test (UPSIT) and the Word subtest of the Stroop which show significant ESs across all study types and are correlated with proximity to onset and striatal volume. Non-Preferred tests include the Token test, Letter and Category Fluency and Mini Mental State Examination. Conclusions: The Huntington’s disease toolkit illustrates an evidence based strategy to select outcome measures for clinical trials of neuroprotective compounds.

P16. What frontotemporal dementia reveals about the neurobiological basis of morality

Rochelle J. Woods, Mario F. Mendez

Background: There is evidence that moral behavior is a product of evolution and an innate aspect of the human brain. Studies of patients with frontotemporal dementia (FTD) can provide a further opportunity to clarify the neurobiology of morality. FTD is characterized by difficulty modulating social behavior. Patients lack social propriety and may perform sociopathic acts. In addition, FTD patients often lack empathy for others. These findings suggest alterations in the nature of morality in patients with FTD. Objective: To investigate the basis of disturbed moral judgment in patients with frontotemporal dementia (FTD) and to review the implications for the neurobiological basis of morality. Method: We administered a series of 10 morality vignettes to 21 patients with FTD compared to 21 comparably-impaired patients with Alzheimer’s disease and 21 healthy subjects. All FTD patients met consensus criteria for FTD and had supporting functional neuroimaging changes in frontotemporal regions. The Alzheimer’s disease patients met NINCDRS-ADRDA criteria for clinically probable Alzheimer’s disease. Results: All groups showed the retention of knowledge for moral behavior and the ability to make “impersonal” moral judgments. However, on the moral vignettes, the FTD patients were impaired in their ability to make immediate, emotionally-based moral judgments, compared with the Alzheimer’s disease patients and the healthy subjects. Conclusions: These findings are consistent with an attenuation of the automatic emotional identification with others that is part of the innate moral sense. Such a disturbance may result from ventromedial frontal dysfunction in FTD and supports the presence of an intrinsic “morality network” in the brain.

P17. Psychotic symptoms in frontotemportal dementia

Rochelle J. Woods, Jill S. Shapira, Eliot A. Licht, Ronald Saul, Mario F. Mendez

Background: Frontotemporal dementia (FTD) is a neuropsychiatric disorder from degeneration of the frontal and anterior temporal lobes. Most patients with FTD present with psychiatric symptoms, yet psychotic symptoms are rarely reported among them. Objective: To characterize the prevalence of presenting psychotic symptoms among FTD patients. Method: We evaluated the frequency of delusions, hallucinations, and paranoid ideation among 74 patients with FTD. All patients met consensus criteria for FTD and had supporting functional neuroimaging changes in frontotemporal regions. Their records and symptoms were reviewed and the FTD Inventory administered. The FTD Inventory includes a psychiatric checklist (5-point Likert scale). For each patient, the degree of hypoperfusion/hypometabolism on single photon emission tomography (SPECT) or positron emission tomography (PET) was independently coded into left or right frontal or temporal quadrants. Results: The occurrence of delusions or hallucinations is rare, present in only two patients (2.7%) with Likert psychosis scores of 3 or more (moderately or extremely characteristic). The mean psychotic symptoms were 1.18 (SD=0.45). Both patients had delusions that varied in their specific content, for example, being married to different movie stars and another of having relationships with others. The psychotic symptom score correlated with right frontal hypoperfusion/hypometabolism. Conclusions: Psychotic symptoms are rare in early FTD. Involvement of the right frontal region may predispose to self-referential delusional ideation in a minority of patients. These findings can help in the initial diagnosis of FTD.

P18. Profile of idiopathic Parkinson's disease with and without vascular risk factors: results of a clinical database study

Marie-Claude Bédard, Evelyne Matteau, Nicolas Dupré, Martine Simard

Background: The impact of vascular risk factors (VRF) in idiopathic Parkinson’s disease (IPD) is controversial. Objective: This study aimed at exploring some clinical and demographic characteristics of IPD with (IPD-VRF) and without vascular risk factors (IPD-noVRF). Method: This study compared 67 IPD-VRF and 57 IPD noVRF on demographical, clinical and cognitive (MMSE) variables. Patients in the IPD-VRF group presented at least one of the following VRF: hypertension, diabetes, smoking in the past 10 years, hypercholesterolemia, anterior infarct and/or CVA. Results: History of smoking (66%), hypercholesterolemia (51%) and hypertension (45%), were the most frequently VRF in IPD. No difference was found between the groups on age and gender. The educational level was lower in IPD-VRF group than in IPD-noVRF (t[122]=–2.85, p=0.005). The IPD-noVRF were younger than the IPD-VRF at the onset of first symptoms (t[121]=2.72, p=0.007), and when they first received the diagnosis (t[122]=3.01, p=0.003). Their disease duration was also longer (t[122]=–2.94, p=0.004). The IPD-VRF received more statins than the IPD-noVRF (chi-square=1, N=120)=33.46, p=0.000). An ANCOVA, controlling for education, statins intake and disease duration, revealed that the MMSE score was significantly higher in IPD-noVRF (M=26.4, SD=4.8) than in IPD-VRF (M=25.8, SD=3.3) (F[4, 112]=3.53, p=0.009). Conclusions: These findings suggest that IPD-VRF differ from IPD-noVRF. The presence of VRF may affect cognition in IPD.

P19. Testosterone depletion and cognitive impairment in elderly men: a relationship with Alzheimer’s disease?

Martine Simard, Séverine Hervouet, Hélène Forget

Background: Animal research demonstrated a link between reductions in testosterone (T) levels, the development of the amyloid beta (Aβ) and tau proteins, and the presence of the APOEϵ4 allele. The Aβ and tau proteins are neuropathological characteristics whereas the APOEϵ4 allele is a risk factor of Alzheimer’s disease. On the other hand, several studies showed that a decline in T correlates with aging. Given that the risk to develop Alzheimer’s disease increases with age, a relationship between the development of Alzheimer’s disease, hypogonadal men, and reductions of T should exist. Objective: The goal of this study was to critically appraise the studies examining, in elderly hypogonadal and Alzheimer’s disease men, the T levels and cognitive functioning, and the effects of T substitution treatment on cognition. Method: A search of MEDLINE/PsycInfo databases was conducted. The key terms included “testosterone,” “male hormone,” “androgens,” “gonadotropin,” “cognition,” “cognitive function,” “Alzheimer’s disease,” “dementia,” “aging,” and “men.” Peer-reviewed articles were included. Single cases were excluded. Results: The reviewed data showed that T levels were generally lower in the Alzheimer’s disease than in healthy groups, and that elderly men with high T levels had better cognition than those with low T levels. Other studies did not report any relationship between T levels and cognition. T substitution treatments generally yielded improvement in cognition in hypogonadal and Alzheimer’s disease men. Conclusions: Methodological limitations of the existing data include the lack of longitudinal studies, and small sample sizes. However, there seems to be a relationship between pathological aging, cognitive impairment and reductions of T.

P20. Mild cognitive impairment associated with high levels of affective symptoms

John C. Adair, Janice E. Knoefel

Objective: To determine clinical characteristics of mild cognitive impairment as a function of affective symptoms at initial evaluation. Background: Current concepts of mild cognitive impairment recognize heterogeneity in clinical manifestations that may be relevant to etiology. Method: Patients were diagnosed as mild cognitive impairment based on normal global cognition (age- and education-adjusted Mini Mental State Examination, MMSE>25th percentile), verbal learning scores at least 1.5 SD below norms, performance within 1 SD of norms on other cognitive tests, no dementia or impaired activities of daily living, and modified Hachinski Ischemic Scale (HIS) <5. Patients were classified into high or low affective symptom groups based on Geriatric Depression Scale (GDS) scores (high≥15, N=37; low<11, N=97). Patients were not included in low GDS group if they had prior diagnosis of or treatment for affective disorder. Groups were compared regarding demographic features, cognitive test scores, and activities of daily living scale scores. Results: Patients in the low GDS group were significantly older (75.9 [SD=6.3] vs. 72.9 [SD=3.8], p=0.03) and tended to have more years of education. After adjusting for age and education, mean MMSE scores were higher for low GDS patients (27.0 [SD=1.8] vs. 25.9 [SD=2.3], p=0.003). The low GDS group also performed better on recognition memory (p=0.013) and letter fluency (p=0.03). No between-group differences were observed for HIS score, confrontation naming, category fluency, any other memory measures, or ADL scale scores. Conclusions: Patients with mild cognitive impairment with excessive affective symptoms may comprise a distinctive type with relatively greater extra-mnemonic cognitive impairment.

P21. Cognitive and functional relevance of white matter integrity in mild cognitive impairment and Alzheimer’s disease

Alexander P. Auchus, Juebin Huang

Background: The cognitive and functional relevance of cerebral white matter abnormalities in patients with Alzheimer’s disease and mild cognitive impairment remains controversial. Objective: Using diffusion tensor imaging (DTI), an MRI technique with increased sensitivity for detecting microstructural brain changes, we sought to determine associations between regional white matter integrity and severity of cognitive and functional impairment in subjects with Alzheimer’s disease and MCI. Method: Thirteen subjects (six with mild Alzheimer’s disease and seven with amnestic mild cognitive impairment) participated in this pilot study. The Mini Mental State Examination (MMSE) and the Clinical Dementia Rating Scale (CDR) were administered to each subject. DTI images were obtained using a single shot, pulsed gradient, echo planar protocol with twelve non-collinear gradient directions. Fractional anisotropy (FA) was calculated in the normal appearing white matter of the frontal, temporal, parietal and occipital lobes. Correlations of FA values with MMSE scores and CDR-SB (sum of boxes scores) were calculated using Spearman’s rank correlation coefficient. Results: FA in the temporal white matter was significantly correlated with CDR-SB score (r _s =–0.57, p=0.04). Trends toward significant correlations were observed between temporal white matter FA and MMSE scores (r _s =0.52, p=0.07) and between frontal white matter FA and CDR-SB scores (r _s =–0.51, p=0.08). Conclusions: In this exploratory study of Alzheimer’s disease and mild cognitive impairment, lower FA values in temporal and frontal white matter were associated with greater degrees of cognitive and functional impairment. We infer that a clinically relevant loss of microstructural white matter integrity may underlie these observations.

P22. Apathy and mild cognitive impairment: a population-based study

Yonas E. Geda, Walter A. Rocca, Rosebud Roberts, David S. Knopman, S. Pankratz, Ronald C. Petersen

Objective: The authors measure the prevalence of apathy in MCI and normal aging in a defined population from the Mayo Clinic Study of Aging. Method: The prevalence of apathy was measured by neuropsychiatric inventory (NPI), a semi-structured interview with established validity and reliability. Results: Consistent with the matched design, conditional logistic Regression analysis was conducted on data acquired from 154 participants with MCI and 462 individually matched cognitively healthy persons. By design, there was no difference in sex or age distribution between the two groups. There was a significant difference in median education between the two groups (13 years for healthy subjects vs. 12 years for mild cognitive impairment (p=0.006). The difference remained significant when education was dichotomized at 12 years of education (p=0.002). Therefore, education was controlled by analysis. The prevalence of apathy was 22.1% (N=34/154) in mild cognitive impairment, where as it was 5.4% (N=25/462) in cognitively healthy elderly. This difference was highly significant (OR=5.1, 95% CI=2.8 to 9.2; p<0.0001). Conclusions: The prevalence of apathy in our study is comparable to the Cardiovascular Health Study that used a similar design (population-based) and measurement instrument (NPI); however, we report a higher frequency of apathy. Apathy may be a possible distinguishing neuropsychiatric feature between mild cognitive impairment and normal cognitive aging.

P23. Is the Mattis Dementia Rating Scale (MDRS) sensitive to mild cognitive impairment?

Evelyne Matteau, Leonie Jean, Martine Simard, Yves Turgeon

Objective: Little is known about the clinical utility of the Mattis Dementia Rating Scale (MDRS) to identify patients presenting at a pre-clinical phase of dementia. This study aims to determine the usefulness of the MDRS in detecting patients with mild cognitive impairment–amnesic type (MCI-A) and Alzheimer's disease. Method: This retrospective study included data from 21 MCI-A, 23 Alzheimer’s disease, and 28 healthy comparison subjects who were assessed using the MDRS and other neuropsychological tests. Age-corrected scaled scores for the MDRS-total and MDRS-subscales were calculated and compared between the three groups. Results: A modified analysis of covariance (ANCOVA, correcting for years of schooling) revealed that the performances of the three groups were significantly different on all MDRS subscales. Alzheimer’s disease patients performed significantly worse on all subtests compared with the other groups (all p<0.0001). MCI-A patients scored significantly lower than healthy comparison subjects on the MDRS-Total (MCI-A=9.7 [SD=2.4]; HCS=12.1 [SD= 1.8]; p=0.000), Initiation/Perseveration (MCI-A=8.6 [SD= 2.8]; HCS=10.2 [SD= 1.6]; p=0.038) and Memory subscales-scores (MCI-A=10.0 [SD= 2.8]; HCS=12.2 [SD= 1.7]; p=0.001). A stepwise DFA was conducted for the outcome classification healthy comparison subjects versus MCI-A. The discriminant model based upon Memory and Initiation/Perseveration subtests age-corrected scaled scores showed 67% sensitivity and 86% specificity (LR ⁺ =4.8, LR ⁻ =0.38). Finally, a ROC analysis established that the optimal cutoff to screen for MCI-A is 138 on 144. Conclusions: These findings suggest that mild cognitive impairment and Alzheimer’s disease patients may be correctly identified using the MDRS.

P24. Cognitive and behavioral symptoms in multiple sclerosis patients with cortical demyelination

Brendan J. Kelley, Shanu Roemer, Stephen Weigand, Kristine Thomsen, Jayawant Mandrekar, Claudia F. Lucchinetti

Background: Cognitive, behavioral and other cortical presentations are reported to be uncommon among multiple sclerosis (MS) patients. The pathological substrate of these symptoms is unknown. Objective: To investigate the prevalence of cognitive and behavioral symptoms in MS cases with pathologic evidence of cortical demyelination (CDM). Method: We reviewed pathologic data on 91 patients enrolled in the International Cooperative MS Lesion Project, who had undergone diagnostic brain biopsies to exclude alternative diagnoses. Thirty-nine patients had cortical and white matter available for pathological analysis. Results: Fourteen of the 39 patients had histopathologic evidence of cortical demyelination. Nine were female and median age at biopsy was 36 years (range=26 to 69 years). Median time from symptom onset to biopsy was 2.5 months (range=0.3 to 259 months). Presenting symptoms included: memory complaints (N=4), encephalopathy/confusion (N=3), aphasia (N=2), seizure (N=2), visual field abnormality (N=2), and stupor/coma (N=1). This represented the fist attack in 50% of the patients. Nine patients had clinically definite MS, two had laboratory supported MS, and three had clinically isolated syndromes at last follow-up. Cortical symptoms became more prevalent over the disease course, which was relapsing-remitting in ten patients, monophasic in three patients, and uncertain in one. Conclusions: Prominent cortical dysfunction, including cognitive/behavioral abnormalities and seizures are common presentations among MS patients who have biopsy evidence of CDM. These presentations often cause diagnostic confusion due to the perception that they do not occur in MS. Pathological evidence for CDM may contribute to these cognitive presentations.

P25. Multiple sclerosis and depression: a diffusion MRI study

Linda Moradzadeh, Anthony Feinstein, Nancy Lobaugh, Joel Ramirez

Background: Patients with multiple sclerosis (MS) have lifetime rates of major depression approaching 50%. MRI studies suggest that lesions distributed in prefrontal and anterior temporal regions are implicated in the pathogenesis of mood change. To date, there are no studies looking at the association between depression and MRI indices of normal appearing brain tissue (NABT). Objective: To assess the relationship between depression and indices of NABT in MS patients. Method: Subjects included 35 MS patients with major (N=20) and minor (N=15) depression. Subjects completed the Beck Depression Inventory-revised (BDI-II), were interviewed with the Structured Clinical Interview for DSM-IV and underwent MRI that included diffusion tensor imaging (DTI) sequences. Bilateral regions of interest (ROI) that focused on NABT were defined for the medial inferior prefrontal and anterior temporal brain parenchyma. Functional anisotropy (FA) measurements were obtained from the four ROIs. Results: There were no significant correlations between total BDI scores and FA values for the four ROIs. However, two significant albeit modest inverse correlations were found between the Cognitive-Affective dimension of the BDI-II and FA values in the right (r=–0.4, p=0.02) and left ( r=–0.3; p=0.059) medial inferior prefrontal cortices. Conclusions: Our data extend the findings from previous MS research by looking beyond lesion volume and location and demonstrating an association between core depressive symptoms and structural abnormalities present in NABT. A breakdown in neuronal organization in pivotal prefrontal regions, as demonstrated by a decline in FA may help explain the high prevalence of depression in MS patients.

P26. Parent ratings of executive functioning in children with cystinosis

Angela O. Ballantyne, Amy M. Spilkin, Lynne R. Babchuck, Doris A. Trauner

Background: Executive functions underlie some of the most important aspects of daily life, including problem solving, planning, organizing, and the monitoring of behavior. These functions, however, are often not assessed in more structured situations such as cognitive or school testing. Executive dysfunction has been observed in a number of genetic, neurological, and/or metabolic disorders. Cystinosis is a genetic metabolic disease that affects multiple organs, including the brain. A specific cognitive profile of visuospatial deficits and intact language and general cognition has been found, yet there are no data on executive functions in these individuals. Objective: This study was designed to complement cognitive data collected in the laboratory setting, and provides meaningful questionnaire data from parents on the daily executive functioning of their children with cystinosis. Method: The Behavior Rating Inventory of Executive Function (BRIEF), a comprehensive parent rating scale of executive functioning, was collected on 17 children with cystinosis and 13 matched comparison subjects (ages 6 to 17 years). Results: Results indicate that in daily life, children with cystinosis demonstrate a significantly greater degree of executive dysfunction compared to comparison subjects (although not in the “Clinical” range) on the Global Executive Composite, as well as on the following indices: Initiate, Working Memory, Plan/Organize, Organization of Materials, Monitor, and Metacognition. Conclusions: Individuals with cystinosis demonstrate subtle but significant difficulties in various aspects of executive functioning, as reported by their parents. This suggests that difficulties with executive functioning may impact the daily lives of these children, and these data have implications for designing appropriate interventions.

P27. Executive functioning in individuals with cystinosis

Amy M. Spilkin, Angela O. Ballantyne, Lynne R. Babchuck, Doris A. Trauner

Background: Cystinosis is a genetic metabolic disease that affects multiple organs, including the brain. Neurological and post-mortem studies have found structural brain abnormalities including cerebral atrophy, white matter necrosis, ventricular dilatation, and cystine crystal deposition. Neuropsychological studies have found relatively normal intelligence, and a clustering of deficits (e.g., in arithmetic, visuospatial functioning, and social-behavioral skills) that often go hand-in-hand with executive function deficits, yet the latter area has not been studied to date. Objective: This is the first study to systematically examine executive functioning in cystinosis. It will serve to further our understanding of the neuropsychological effects of the disease. Method: The Delis-Kaplan Executive Function System (D-KEFS), a comprehensive test of executive functioning, was administered to 19 individuals with cystinosis (ages 8 to 32 years). Results: Preliminary results indicate that individuals with cystinosis performed in the low average to below average range on a number of executive functioning indices, indicating possible difficulties in the areas of cognitive flexibility, concept formation, inhibition, and problem solving. Conclusions: Individuals with cystinosis demonstrate deficits in executive functioning, as well as in visuospatial skills, arithmetic skills, and socio-behavioral skills. These findings further define the behavioral phenotype of this disorder and help elucidate the potential mechanism by which cystinosis affects the brain. The behavioral profile seen in cystinosis has also been documented in a number of genetic, neurological, and/or metabolic disorders that affect white matter. Moreover, this study has implications for everyday functioning and quality of life for individuals with cystinosis and their families.

P28. Long-term neuropsychological outcome following neuroinvasive West Nile Virus infection

David B. Arciniegas, Kimberly L. Frey, Elizabeth Kozora, Donald C. Rojas, Deborah A. Hall, C. Alan Anderson

Background: Neuroinvasive West Nile virus infection (WNV-CNS) produces severe acute cognitive impairments. However, the frequency and types of long-term neuropsychological deficits produced by WNV-CNS have not been described. Objective: The authors characterize the long-term neuropsychological sequelae of WNV-CNS. Method: Fourteen subjects (five women), 61.8 (SD=6) years old with 14 (SD=1.8) years of education, were evaluated 22.3 (SD=4.3) months following WNV-CNS. The Mini Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and a battery of neuropsychological tests (NPB) were administered. The NPB included: RBANS, WCST, TMT Parts A & B, COWAT, Animal Naming, Stroop CWT, and WAIS-III Similarities. Performance ≥ 1 SD below normative data-derived performance expectations on the MMSE, FAB, and on at least 20% of tests on the NPB was considered impaired. Relationships between cognitive performance and age, education, gender, and psychiatric symptoms (SCL-90-R) scores were also investigated. Results: Cognitive impairment was observed in three subjects (21.4%) on the MMSE, seven subjects (50%) on the FAB, and five subjects (35.7%) on the NPB. Cognitive impairment was more common and severe among older subjects. There were no relationships between cognitive performance and either gender or education, and no relationships between cognitive impairment and either depressive or anxious symptoms. Conclusions: WNV-CNS produces persistent cognitive impairment of at least mild severity and in a predominantly dysexecutive pattern in a substantial minority of affected persons. Such impairments occur more commonly in older patients and are not solely attributable to psychiatric symptoms. Further study of the neuropsychological sequelae of WNV-CNS is needed.

P29. Evaluation of cognitive screening to detect early HIV neurocognitive impairment: a pilot project

Kristin M. Brousseau, Samantha MaWhinney, Christopher M. Filley, Elizabeth Connick

Background: HIV neurocognitive impairment (HNCI) remains common but may not be appreciated in early stages. Screening tools for cognitive impairment have limitations; the Mini-Mental State Examination (MMSE) and the HIV Dementia Scale (HDS) both lack sufficient sensitivity to detect the subtle cognitive impairment that may occur early in HNCI. The Frontal Assessment Battery (FAB) may be more useful for detecting HNCI. Objective: To compare the relative sensitivities of the MMSE, HDS, and FAB in detecting cognitive impairment in HIV-1 infected individuals. Method: 25 HIV-1 infected adults, with no other possible causes of cognitive impairment, were prospectively enrolled from a university-based infectious disease clinic. Each subject received the MMSE, HDS, FAB, a review of cognitive, emotional, behavioral and neurological symptoms, and an elemental neurological examination. Cognitive impairment was defined as ≥ 2 SD below normative-data based performance expectations on one test or ≥ 1 SD below normative-data based performance expectation on at least two tests. Results: Cognitive impairment was detected significantly more frequently using the FAB (64%) compared to the MMSE (24%; p=0.0094) and the HDS (24%; p=0.0044). Impairment on the FAB correlated with abnormal findings on neurological examination (p=0.033), and memory (p=0.03) and executive function (p=0.0168) complaints. There was no significant difference between the MMSE and the HDS in detecting cognitive impairment. Conclusions: The FAB is more sensitive to cognitive impairment than the MMSE and HDS in HIV-1 infected individuals. The FAB may be able to detect early impairment of frontal-subcortical systems, and improve the early recognition of HNCI.

P30. Detection of HIV neurocognitive impairment: screening vs. practice as usual

Kristin M. Brousseau, Samantha MaWhinney, Christopher M. Filley, Elizabeth Connick

Background: Cognitive impairment in HIV-1 infected individuals can be difficult to detect and may go unrecognized or under recognized in a busy clinical practice. Though screening examinations for other HIV-related complications are routine, screening for CI is rarely performed. Objective: To compare the frequency of cognitive impairment identified by cognitive screening to that documented in the medical records in a university-based infectious disease clinic. Method: 25 HIV-1 infected adult outpatients from a university-based infectious disease clinic, with no known other possible causes of cognitive impairment, were prospectively administered the Mini Mental State Examination, HIV Dementia Scale, and Frontal Assessment Battery. CI was defined as ≥ 2 SD below normative-data based performance expectations on one test or ≥ 1 SD below normative-data based performance expectations on at least two tests. A comprehensive chart review was also undertaken to identify documentation of cognitive impairment in these 25 subjects’ medical records using key search terms. Results: Cognitive screening identified 56% of subjects as having cognitive impairment. In contrast, cognitive impairment was noted in the chart of only 12 % (p=0.0026) on the same day as the clinic visit, and in 24% (p=0.0269) on review of all medical records (p=0.0269). Conclusions: Cognitive screening improves the likelihood of detecting cognitive impairment, a commonly occurring complication of HIV-1 infection for which treatment, especially early treatment, is often effective. Routine screening for cognitive impairment, as a part of comprehensive clinical care in HIV+ persons, may help improve the recognition, diagnosis, and treatment of this comorbidity, and improve health outcomes in HIV-1 infection.

P31. Cognitive performance correlates with score on the scale for the assessment and rating of ataxia in spinocerebellar ataxia types 1,2,3, and 6

Aaron M. McMurtray, Eliot Licht, Susan Perlman, Mario F. Mendez

Background: Cognitive impairment can be troubling to patients with spinocerebellar ataxia (SCA) and their families, adversely affect quality of life, and even progress to dementia, yet can be difficult for clinicians to detect. Previous studies suggest cognitive impairment may correlate with ataxia severity in SCA, possibly aiding clinicians in identifying those who would benefit from cognitive evaluation. Objective: This study compares ataxia severity with cognitive performance in patients with SCA1, 2, 3, and 6, the most common SCA types resulting from polyglutamine expansions. Method: A total of 25 patients (SCA1=6, SCA2=4, SCA3=11, SCA6=4) presenting consecutively to a university based ataxia clinic during a one year period with genetically confirmed diagnoses of SCA1, 2, 3, or 6 were included. On presentation all patients completed a neuropsychological testing battery comprised of measures selected to avoid interference from motor disability. Ataxia severity was assessed using the Scale for the Assessment and Rating of Ataxia (SARA). Results: SARA score correlated with performance on tests of attention (r=–0.58, p < 0.01), mental control (r=–0.46, p=0.04), visuospatial abilities (r=–0.46, p=0.03), and frontal/executive function (r=–0.52, p=0.02), but not with performance on tests of verbal fluency, verbal memory, generative naming, or with Beck Depression Scale score. Conclusions: The results of this study suggest that the SARA score predicts cognitive impairment in the SCAs, and that cognitive deficits correlate with the severity of ataxia in the SCAs.

P32. A novel scoring method for the intersecting pentagon copying task and its use in autopsy-confirmed Alzheimer's disease

Victoria S. Pelak, Al Anderson, David Arciniegas, Chris Filley

Background: Visuospatial dysfunction in Alzheimer’s disease is often assessed using the intersecting pentagon copying (IPC) task from the Mini Mental State Examination (MMSE). Ranked and valid IPC scoring does not exist. Objective: To develop and examine the reliability of a novel, quantitative scoring method for the IPC task, and compare IPC task to MMSE scores in definite Alzheimer’s disease patients with and without prominent visuospatial complaints (PVSC). Method: We designed a 30-point Intersecting Pentagon Assessment Scale (IPAS) to quantify IPC task performance on the MMSE. We measured inter-rater and intra-rater reliability by intraclass correlation coefficients (ICC). IPAS performance was defined as: ≥21=normal or mildly impaired, 10 to 20=moderately impaired, ≤9=severely impaired. We then applied the IPAS to MMSE data of 8 autopsy-confirmed Alzheimer’s disease patients. Results: IPAS inter-rater ICC values were 0.953 (Trial 1) and 0.946 (Trial 2). IPAS intra-rater ICC was 0.927 to 0.999. The eight patients had 29 IPC tasks, and three patients had PVSC. IPAS performance was worse than MMSE performance for only one of three patients with PVSC. IPAS performance was worse than MMSE performance for only one IPC task drawn by one of five patients without PVSC. Conclusions: IPAS is a novel scoring method for the IPC task with a high degree of inter- and intra-rater reliability. In autopsy-proven Alzheimer’s disease, level of impairment measured by IPAS was comparable to MMSE impairment, even in patients with PVSC. More sensitive and specific measures of visuospatial function are necessary to capture complex visuospatial dysfunction in Alzheimer’s disease.

P33. A case report on the efficacy of errorless vs. errorful learning in a 68-year-old woman with amnestic mild cognitive impairment

Leonie Jean, Marie-Eve Bergeron, Martine Simard

Background: Individuals with amnestic mild cognitive impairment (A-MCI) are at high risk of developing dementia, especially Alzheimer’s disease. In an attempt to help a woman with A-MCI to memorise names, two techniques already contrasted in Alzheimer’s disease were compared: the errorless (EL) and errorful (EF) learning. The EL technique aims at keeping to a minimum the errors during learning, whereas EF does not. C ase report: “ Mrs. M,” a 68-year-old single woman with 12 years of education, was evaluated two times in 23 months. On both occasions, her cognitive profile was characterised by a predominant deficit (1.5 SD below the comparison mean) on the California Verbal Learning Test. She complained of memory failures (regarding name retrieval) but her activities of daily living were not impaired; she thus met the criteria for A-MCI. Two training and one follow-up sessions took place using EL and EF learning to support the retention of 10 people’s names (five in each condition). Three test trials were completed at the end of each session and at 4-week follow-up. Results: Results showed that 97% of the names learned with EL were correctly recalled after training compared to 80% of those learned with EF learning. At follow-up, 53% and 27% of the EL and EF trained items, respectively, were correctly recalled. Conclusions: EL learning has been superior over the EF to recall names, at the end of the training sessions and 4 weeks later as previously observed in Alzheimer’s disease. In this regard, the evaluation of this technique with a larger sample of A-MCI individuals might be of interest.

P34. Subjective integrity of working memory is related to brain activation during an n-back task in schizophrenia

Robert M. Roth, Laura A. Flashman, Jo Cara Pendergrass, Nancy S. Koven, Matthew A. Garlinghouse, Thomas W. McAllister, Andrew J. Saykin

Background: Neuroimaging studies of individuals with schizophrenia have observed underactivation of dorsolateral prefrontal cortex (DLPFC) during performance on working memory tasks. In contrast, little is known regarding whether these patients perceive themselves as having working memory problems. Objective: We examined the self-perception of executive functions in patients with schizophrenia, and evaluated whether the subjective integrity of working memory was related to brain activation during performance on a working memory task. Method: Twenty-one patients with schizophrenia and 17 healthy comparison subjects completed the Behavior Rating Inventory of Executive Function–Adult version (BRIEF-A) Self Report form, and a subset (10 patients, eight healthy comparison subjects) completed an auditory-verbal 3-back working memory task while undergoing functional magnetic resonance imaging (fMRI). fMRI was carried out on a 1.5T GE magnet and data were processed and analyzed using SPM2. Analyses focused on the 3-back (high working memory load) greater than 0-back (vigilance condition) contrast. Results: Patients reported significantly more daily problems than comparison subjects for most aspects of executive functions, the working memory scale yielding the largest effect size (partial eta-squared=0.35), and were less accurate during the 3-back. Patients also showed the expected bilateral DLPFC hypoactivation during the task. Regression analyses revealed that subjectively better working memory functioning in daily life was associated with greater bilateral DLPFC activation in the patient group during the scan. Conclusions: The present findings indicate that patients with schizophrenia can identify problems with their working memory in daily life, and that this perception relates to abnormality of neural circuitry subserving working memory.

P35. Evaluating the affective component of the cerebellar cognitive-affective syndrome

Uri Wolf, Mark Rapoport, Tom A. Schweizer

Background: A Cerebellar Cognitive-Affective Syndrome has been described in patients with cerebellar injury displaying affective and personality changes. While widely cited, these claims have not been systematically reviewed. Objective: In this paper we critically review the affective component of the Cognitive–Affective Syndrome. Method: A MEDLINE and EMBASE search for the period from 1966 to September 2006 for articles relating to the cerebellum and affective symptoms (including personality changes) was performed. We selected papers with subjects with isolated cerebellar lesions or cerebellar disease. We excluded studies of primary psychiatric disorders as well as disorders that do not primarily affect the cerebellum. Results: Fifty-six papers were selected. Personality and affective changes identified included apathy, disinhibition, impulsivity, and depression. Forty-two were case-series or case reports. Eight were reviews. Only two of the six cohort studies with a control group were of isolated cerebellar lesions (with a total of 29 patients), the remaining four studies were of diseases primarily affecting the cerebellum. Only one cohort study with a comparison group utilized a standardized evaluation of affect or personality. Conclusions: Though affective and personality changes have been widely attributed to cerebellar injury, there is limited controlled evidence to support this. Most of the few controlled studies include subjects with lesions not isolated to the cerebellum. Of the two controlled studies looking at isolated cerebellar lesions, no rigorous standardized testing was performed. Validating the Cognitive Affective Syndrome requires a controlled prospective cohort design, using rigorous standardized scales and an appropriate sample size.

P36. A neuropsychiatric model for religiosity and ritualistic behavior

Vinoth Jagaroo, David L. Maxwell

Background: Religious belief and ritualistic behavior have received peripheral attention in neuropsychiatry. While they are steadily becoming topics of interest, a cohesive neuropsychiatric framework for the study of religiosity is lacking. The little discussion on the topic hinges largely on behavioral phenomena in temporal lobe epilepsy. Objective: To frame a theoretical model for neuropsychiatric interpretation of religiosity by incorporating recent neurobiological data on cortico-limbic systems. Method: Data on cortico-limbic neural architecture were surveyed in relation to the existing discussion on temporo-limbic behavior. Data on neural pathways were clustered as distinct networks within a broader system. Results: The data describe a large network resulting in a cooperative-competitive dynamic between emotion, motivation, executive, and motor subsystems. They emphasize the extended amygdala's role in coordinating multiple limbic regions; orbital PFC networks for sensory integration, medial PFC visceromotor systems, and their limbic afferents constituting a sensori-visceromotor link and orbito-medial emotional guidance system; ventral striatopallidal regions where limbic and dorsolateral PFC projections overlap; and cortico-limbic projection/laminar patterns that make for particular limbic vulnerability in neurobehavioral conditions. Conclusions: Interictal, temporo-limbic behavior provides a central component in a neuropsychiatric model for religiosity, but clarified cortico-limbic neural circuitry can better explain sensory-limbic hyperconnection and traits such as hypermoralism, obsessionalism and emotional valence. Religio-ritualistic traits can be viewed as results of evolutionary maladaptation of neural systems. In addition to providing a framework for interpreting religiosity, such theoretical integration is needed to understand personalities beset with a particular sense of moral destiny and aggressive pursuit of religio-moral causes.