Henry Riordan

The timing of brain morphological changes in schizophrenia and their relationship to clinical outcome

The present study is an examination of ventricular and temporal lobe size in 50 DSM-III-R first-episode schizophreniform or schizoaffective patients who were ill for less than 6 months. Two-year clinical follow-up and magnetic resonance imaging (MRI) scan analyses are also reported from data collected on an initial group of 30 first-episode schizophrenic patients and controls. Left ventricular enlargement, which was present in our previously published report of first-episode cases of schizophrenia, is not present to the same extent in this larger group of schizophreniform patients closer to the onset of their illness, and no temporal lobe volume reduction was detected. However, lateral ventricular size at the time of the first-episode was generally correlated with outcome--the larger the ventricles, the poorer the outcome. No mean change in ventricular or temporal lobe size was found at rescanning 2 years later, but the degree of ventricular change was inversely correlated with the number of hospitalizations and the amount of time spent in hospital; it did not correlate with temporal lobe size. When rescanned, some patients showed change greater than 20% in ventricular size and 10% in temporal lobe size. Thus, these findings need further evaluation by serial scans over a longer time period before it can be determined that no progression of brain structural abnormalities is occurring as part of the pathology of schizophrenia, even in a subgroup of patients.

Neuroanatomic substrates of semantic memory impairment in Alzheimer's disease: patterns of functional MRI activation.

Impairment in semantic processing occurs early in Alzheimers disease (AD) and differential impact on subtypes of semantic relations have been reported, yet there is little data on the neuroanatomic basis of these deficits. Patients with mild AD and healthy controls underwent 3 functional MRI auditory stimulation tasks requiring semantic or phonological decisions (match-mismatch) about word pairs (category-exemplar, category-function, pseudoword). Patients showed a significant performance deficit only on the exemplar task. On voxel-based fMRI activation analyses, controls showed a clear activation focus in the left superior temporal gyrus for the phonological task; patients showed additional foci in the left dorsolateral prefrontal and bilateral cingulate areas. On the semantic tasks, predominant activation foci were seen in the inferior and middle frontal gyrus (left greater than right) in both groups but patients showed additional activation suggesting compensatory recruitment of locally expanded foci and remote regions, for example, right frontal activation during the exemplar task. Covariance analyses indicated that exemplar task performance was strongly related to signal increase in bilateral medial prefrontal cortex. The authors conclude that fMRI can reveal similarities and differences in functional neuroanatomical processing of semantic and phonological information in mild AD compared to healthy elderly, and can help to bridge cognitive and neural investigations of the integrity of semantic networks in AD.

Effects of crack cocaine on neurocognitive function

Because crack cocaine appears to have a preferential effect on the metabolic and electrophysiological activity of the frontal and temporal regions of the brain (Pascual-Leone et al., 1991a, 1991b; Volkow, 1992), we hypothesized that cognitive measures of those regions would be impaired in crack cocaine users relative to measures in normal volunteers. We used logistic regression to determine the relationship of cocaine usage to neuropsychological test performance. We compared 38 patients with an average of 3.6 (SD = 2.5) years of crack cocaine use and 24.5 (SD = 28.1) days of abstinence to 54 normal volunteers on a battery of neuropsychological tests. Statistical adjustments were made for the effects of age, education, socioeconomic class, and level of depression. Our findings were mixed with regard to purported measures of executive/frontal functioning, with worse performance associated with cocaine usage on the Booklet Categories Test, but better performance associated on others (number of categories on the Wisconsin Card Sorting Test, Controlled Oral Word Association). Cocaine usage was associated with impairment on measures of spatial, but not verbal memory, confrontation naming, and Trail-making Test, Part B, a measure of perceptual-motor speed and cognitive flexibility. In summary, it appears that continuous crack cocaine use produces a dissociative pattern in neuropsychological test performance with improvement on some measures, but deterioration on others. The permanence of these effects remains to be determined with longitudinal studies.

Familial thyroid disease and delayed language development in first admission patients with schizophrenia

One hundred consecutive first admission patients with a DSM-III-R diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder were compared with 100 randomly selected community controls. Childhood histories of physical, medical, and perinatal trauma, as well as physical and cognitive development, were examined by structured interviews with all available mothers of patients and controls. The prevalence of specific psychiatric disorders and several medical illnesses among first degree and more distant relatives was determined by family history questionnaires. The patient group did not have an excess of childhood head injuries, serious infections, or perinatal/birth complications compared with controls. With social class level taken into account, it was found that the acquisition of reading skills occurred significantly later in patients than controls. Family histories of schizophrenia and thyroid disorders were significantly more frequent among patients than controls. These data fail to indicate any childhood physical or medical environmental trauma that could lead to an increased risk for schizophrenia, although patients were substance abusers to a greater extent than controls. This study also confirms the already known contribution of familial factors and suggests an association of the inheritance of thyroid disorders with schizophrenia. Delayed development of reading skills suggests that precursers of illness may appear early in life before psychosis is evident.

Neuropsychological Correlates of Methylphenidate Treatment in Adult ADHD With and Without Depression

The purpose of this study was to characterize the neuropsychological profiles of adult patients with attention deficit hyperactivity disorder (ADHD) alone and ADHD with active comorbid depression, and to evaluate changes in the neuropsychological profile in these two groups following a trial of methylphenidate. Forty patients with ADHD were classified into two groups based on their affective status resulting in a group of 21 patients with ADHD alone and 19 patients with ADHD and active comorbid symptoms of depression (ADHD-D). All subjects received a comprehensive neuropsychological evaluation including measures of cognitive, motor and affective functioning before and after treatment. Fifteen normal controls were also assessed at a yoked time interval. At baseline, both patient groups showed impairment in verbal memory, motor and processing speed, visual scanning, and auditory and visual distractibility. Following treatment, both patient groups showed improvement across all neuropsychological measures while controls remained relatively stable over time. Improvement in neuropsychological test performance was not related to gender, affective status or referral source. Patients with active comorbid symptoms of depression show a similar neuropsychological profile and appear equally likely to benefit from methylphenidate intervention as patients with ADHD alone.

Contribution of organizational strategy to verbal learning and memory in adults with attention-deficit/hyperactivity disorder

Statistical mediation modeling was used to test the hypothesis that poor use of a semantic organizational strategy contributes to verbal learning and memory deficits in adults with attention-deficit/hyperactivity disorder (ADHD). Comparison of 28 adults with ADHD and 34 healthy controls revealed lower performance by the ADHD group on tests of verbal learning and memory, sustained attention, and use of semantic organization during encoding. Mediation modeling indicated that state anxiety, but not semantic organization, significantly contributed to the prediction of both learning and delayed recall in the ADHD group. The pattern of findings suggests that decreased verbal learning and memory in adult ADHD is due in part to situational anxiety and not to poor use of organizational strategies during encoding.

Critical Pathways to Success in CNS Drug Development

Animal-based models of major CNS disorders are described in detail, and the ability of the latest in vitro and computer-based models to simulate CNS disease states and predict drug efficacy and side-effects are examined. Particular attention is given to the growing use of biomarkers and how they can be used effectively in early human trials as signals of potential drug efficacy, as well as the increasingly important role of imaging studies to guide dose selection. Cognitive assessments that can be useful indicators of effect in patient populations are also discussed.

Effect of Six Months of Treatment with V0191 in Patients with Suspected Prodromal Alzheimer's Disease

New criteria related to prodromal Alzheimers disease (AD) have been proposed to overcome the issue of heterogeneity of patients with mild cognitive impairment (MCI) and to better define patients in early stage AD. Only few therapeutic trials, if any, have been reported using this newly defined population. The objective of this study was to assess the clinical efficacy and safety of a novel pro-cholinergic drug (V0191) in patients with prodromal AD. Two hundred forty two (242) patients with a diagnosis of prodromal AD were randomized in an approximately 1 : 1 ratio to receive either 1500 mg V0191 or matching placebo once daily for 24 weeks. Changes in global cognitive functioning were assessed using the Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-cog; responder rate as primary efficacy measure). Standardized measures of memory, executive function, attention, functional capacity, and apathy were also obtained. Despite some interesting trends at week 12 and conversion rates favoring V0191, no statistically significant differences in cognitive function between V0191 and placebo were noted. In addition to the absence of drug efficacy on this population, several design features may have hindered this study, including insufficient powering to assess changes in cognition over time, a relatively short duration of treatment, and the lack of validated clinical trial measures designed to assess the prodromal AD population. Lessons learned in AD study design optimization, including those presented in this paper, could be valuable for further investigation with pro-cholinergic drugs such as V0191.

430 – Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging: A meta-analytic study

BACKGROUND Although many quantitative magnetic resonance imaging studies have found significant volume reductions in the hippocampi of patients with schizophrenia compared with those of normal control subjects, others have not. Therefore, the issue of hippocampal volume differences associated with schizophrenia remains in question. METHODS Two meta-analyses were conducted to reduce the potential effects of sampling error and methodological differences in data acquisition and analysis. Eighteen studies with a total patient number of 522 and a total control number of 426 met the initial selection criteria. RESULTS Meta-analysis 1 yielded mean effect sizes of 0.37 (P<.001) for the left hippocampus and 0.39 (P<.001) for the right, corresponding to a bilateral reduction of 4%. Meta-analysis 2 indicated that the inclusion of the amygdala in the region of interest significantly increased effect sizes across studies (effect size for the left hippocampus and amygdala, 0.67; for the right, 0.72), whereas variables such as illness duration, total slice width, magnet strength, the use of the intracranial volume as a covariate, measurement reliability, and study quality did not. No laterality differences were observed in these data. CONCLUSIONS Schizophrenia is associated with a bilateral volumetric reduction of the hippocampus and probably of the amygdala as well. These findings reinforce the importance of the medial temporal region in schizophrenia and are consistent with frequently reported memory deficits in these patients. Future quantitative magnetic resonance imaging studies evaluating the hippocampal volume should measure the hippocampus and amygdala separately and compare the volumetric reduction in these structures to that observed in other gray matter areas.

Evaluation of beta amyloid loss to CSF sample collection and storage containers

Background Methods (cont) Henry J. Riordan, PhD1, Yoka Thomas2, Neal R. Cutler, MD3, Mark Leibowitz, MD2, Kathryn Rogers2, Kathryn Dawson, Ph.D.1, Michele Malone2, Steve Unger, PhD2, William Nowatzke PhD2 1Worldwide Clinical Trials (WCT), King of Prussia, PA, 2WCT Drug Development Solutions, San Antonio and Austin, TX , 3 WCT, Beverly Hills, CA Evaluation of Beta Amyloid Loss to CSF Sample Collection and Storage Containers No conflicts of interest exist in the research and development of this poster Background:. The accurate quantification of CSF biomarkers is paramount in the development of AD drugs but measurement has varied due to handling and storage material characteristics. The purpose of this study was to systematically evaluate an assortment of CSF collection/storage materials in hopes of identifying those associated with the least amount of CSF beta amyloid (Aβ) loss. Methods: Nine separate types of collection/storage tubes were compared to an aliquotted control pipetted directly from the source polypropylene conical vial for three isoforms of Aβ (38, 40, 42). Coefficient of variations determined sample accuracy based on two collections corresponding to regular Rainin pipet tips and Rainin Low-Retention pipet tips. Additionally, two common long tubing types (Tygon and Silastic) were compared across various cumulative CSF quantities of 2, 4, 6, 8, 10 and 12 mLs. Results: Grand mean differences in storage/collection tubes were evident (28.4, -29.4 and 34.8% for Aβ40, 38, and 42, respectively). ANOVA results for differences among types of tubes was highly significant p = 0.005. Tukey post-hoc comparisons suggested that the Sarstedt 10mL SC Tube (15x92 RB PP GWB Str cat# 62.610.201) had the lowest mean loss across Aβ species (-9.7) and differed significantly from all other tube types but one, even after adjustment for multiplicity. For tubing types a regression analysis with percent difference as the response, volume of CSF an explanatory variable, and tubing type as the factor of interest was performed with a quadratic term added to the model. Aβ40, 38 and 42 were analyzed separately and for each analysis the quadratic term was significant (p < 0.05). For both Aβ40 and 38 there was a significant difference due to tube type (p = 0.037) with Silastic having a lower response consistently across all CSF volumes. For Aβ42 there was an interaction between volume and tubing type (p = 0.049) suggesting that for lower CSF volumes (under 6mL) Silastic is superior but for larger volumes Tygon is better. Conclusions: This study supports the use of specific collection/storage and tubing types when conducting CSF biomarker studies in order to reduce the loss of Aβ due to nonspecific binding. • For the larger collection tubes (1st three listed in table below) 1 mL pooled CSF was added, for the smaller tubes 200μL of the pooled CSF was added to each tube. A control was aliquotted directly from the pooled CSF unto the assay plate and ran with the samples. • Coefficient of variations determined sample accuracy based on two collections corresponding to regular Rainin pipet tips and Rainin Low-Retention pipet tips • Means were compared across tube types via ANOVA and post-host tests. • Six feet of each tubing type (Tygon and Silastic) were used to assess differences in tubing type. A 60mL syringe with pooled CSF was filled, attached to the appropriate tubing and ~2mL increments of CSF were allowed to flow through. • Collections were made for each time point and 2 replicates were analyzed from each (6 time points total). Results were compared to the mean of 4 results pipetted directly from syringe with no tubing attached. • For tubing types a regression analysis was performed with the percent differences as the response, the size of the tube as the continuous explanatory variable and tube type as the factor of interest. • As confirmed by the plots of the observed data there was curvature in the data. Therefore, a log transformation was not able to linearize this relationship so a quadratic term was added to the regression model as shown below. Y = intercept + a*type +b*size + c*size2 + d*size*type • Each AB class (40, 38 and 42) was analyzed separately. • For each analysis the quadratic term was significant (p < 0.05). • In order to determine if various amyloid-targeting drugs/vaccines have been successfully able to impact their intended targets in their predicted manner more data is needed regarding the variability of CSF measurement due to collection techniques and materials. • This study was designed to assess the nonspecific loss of CSF due to storage and handling materials commonly used in CSF procedures at various clinical sites. • The goal of this research was to suggest materials associated with the lowest and most stable levels of loss and attempt to standardize CSF collection and storage procedures. Results • This study highlights the large variability in non-specific binding of CSF amongst various collection/storage and tubing types with differences often exceeding changes associated with drugs targeting Aβ. • Careful selection and control of CSF handling and storage apparatus is necessary in order to more accurately assess changes in CSF associated with drug and vaccine treatment. Collection/Storage Tubes The percent differences were calculated as 100 (value – control average)/control average Conclusions Results (cont.) Tube Description AB40 AB38 AB42 Nalgene Cryogenic 5mL vial -21.8 -21.8 -25.4 Sarstedt 10mL SC Tube 16x79 RBS PP cat# 60.551 -32.1 -26.8 -28.9 Sarstedt 10mL SC Tube 15x92 RB PP GWB Str cat# 62.610.201 -7.0 -11.7 -10.4 Bio Plas 0.5mL siliconized screw cap micro tube cat# 4200SLS -28.4 -27.9 -37.8 Sarstedt micro tube 0.5mL PP cat# 72.730 -33.9 -33.2 -39.5 Fisherbrand microcentrifuge tubes 0.5mL natural cat# 02681370 -39.7 -38.8 -45.9 Fisherbrand microcentrifuge tubes 1.5mL Low Retention Natural cat# 02681320 -30.8 -34.6 -39.7 Sarstedt micro tube 1.5mL Low Binding cat#72706600 -28.9 -34.2 -40.8 Sorenson microcentrifuge tubes 1.7mL natural low binding cat# 39640T -32.8 -35.8 -45.2 For Aβ40 the size by type interaction was not significant (p = 0.8824) and was dropped from the model. There was a significant difference due to tube type (p = 0.0372) with Silastic having a lower response consistently across volume. For Aβ42 there was an interaction between size and type (p = 0.0486). This implies that the effect of type depends on the volume of CSF. A plot of the predicted values shows that for low volumes Silastic is better but for larger volumes the mean response for Tygon is better. •ANOVA results for differences among types of tubes was highly significant p = 0.005. * Tukey post-hoc comparisons suggested that the Sarstedt 10mL SC Tube (15x92 RB PP GWB Str cat# 62.610.201) had the lowest mean loss across Aβ species (-9.7) and differed significantly from all other tube types but one, even after adjustment for multiplicity Aβ 40