The Use of Episodic Memory Tests for Screening in Clinical Trials for Early Alzheimer's Disease: A Comparison of the Free and Cued Selective Reminding Test (FCSRT) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

BACKGROUND: Screening procedures for early Alzheimer's disease (AD) trials seek to efficiently identify participants who fulfill clinical and biomarker criteria for AD and enrich for those most likely to experience significant clinical progression during the study. Episodic memory performance is often assessed in screening, but the utility of different memory tests for optimizing screening efficiency and/or rates of clinical progression remains uncertain. OBJECTIVES: Cross-study comparisons of the effects of inclusion criteria based on performance on the Free and Cued Selective Reminding Test (FCSRT) or the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) on screen-failure rates for episodic memory and ß-amyloid (Aß) positivity (by CSF or PET) and on subsequent rates of clinical disease progression in randomized participants across three clinical trials in early (prodromal-to-mild) AD. DESIGN: Secondary analyses of cross-sectional and longitudinal clinical trial data. SETTING: Multi-center international clinical trials. PARTICIPANTS: Individuals with prodromal-to-mild AD screened and/or randomized in clinical trials for crenezumab (CREAD, CREAD2) or semorinemab (Tauriel). Cross-sectional analyses of screening data for episodic memory impairment included participants from CREAD2 (n=2897) and Tauriel (n=887) and for Aß positivity included participants from CREAD (n=1138), CREAD2 (n=1119), and Tauriel (n=483). Longitudinal analyses of rates of clinical progression included participants from CREAD (n=779), CREAD2 (n=773), and Tauriel (n=331). MEASUREMENTS: Cross-sectional analyses examined eligibility rates per cutoffs defined for the FCSRT (CREAD, CREAD2) or RBANS (Tauriel) and per Aß positivity using CSF and/or PET biomarkers. Longitudinal analyses examined rates of clinical progression on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the 13-item version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), and Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL). RESULTS: Lower rates of study eligibility per episodic memory criteria were seen with the FCSRT (CREAD2) relative to the RBANS (Tauriel), but similar rates of eligibility per Aß positivity criteria were seen amongst participants with episodic memory impairment per the cutoffs used on either assessment. Similar rates of clinical decline over 18 months on the CDR-SB, ADAS-Cog13, and ADCS-ADL were observed in study populations enriched using the FCSRT (CREAD, CREAD2) or the RBANS (Tauriel). CONCLUSIONS: Cutoffs for episodic memory impairment on the FCSRT used in the CREAD and CREAD2 studies are more stringent than those on the RBANS used in the Tauriel study, resulting in lower rates of eligibility. However, given that study enrichment with either test yields similar rates of Aß positivity and clinical progression, considerations beyond these factors may drive the decision of which assessment to use for screening in early AD clinical trials.

PEGylation enhances the therapeutic potential for insulin-like growth factor I in central nervous system disorders.

OBJECTIVE: Due to its potent neurotrophic activity, insulin-like growth factor I (IGF-I) has been proposed many times for therapeutic application in disorders of the central nervous system (CNS). However, insufficient brain delivery to yield beneficial central without peripheral side effects have prevented clinical development in most instances. DESIGN: We recently reported the generation of a polyethylene-glycol modified IGF-I variant (PEG-IGF-I) with prolonged half-life and less acute side effects, but with fully maintained slow anabolic activity. Here we investigated if these beneficial properties result in improved brain availability of the drug, thereby reaching therapeutically relevant steady-state concentrations to elicit beneficial effects on neuronal function. RESULTS: After a single subcutaneous injection, PEG-IGF-I reached much higher steady-state levels in brain tissue and cerebrospinal fluid compared with IGF-I. Two weeks treatment with PEG-IGF-I was sufficient to modulate brain plasticity processes, as judged by changes in synaptic proteins and related animal behavior. Furthermore, chronic treatment of a mouse model of brain amyloidosis with PEG-IGF-I reverted deficits in insulin/IGF-I signaling, synaptic proteins and cognitive performance. CONCLUSIONS: Our data generate the therapeutic potential for PEG-IGF-I to treat CNS disorders by systemic drug application, and in addition scientifically support its application in disorders of synaptic function and neuronal development.

Enrichment through biomarkers in clinical trials of Alzheimer's drugs in patients with mild cognitive impairment.

Clinical trials of disease modifying drugs for Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) might benefit from enrichment with true AD cases. Four hundred five MCI patients (143 converters and 262 nonconverters to AD within 2 years) of the Alzheimer's disease Neuroimaging Initiative (ADNI) were used. Markers for enrichment were hippocampal atrophy on magnetic resonance (MRI), temporoparietal hypometabolism on FDG PET, cerebrospinal fluid (CSF) biomarkers (Abeta42, tau, and phospho-tau), and cortical amyloid deposition (11C-PIB positron emission tomography (PET)). Two separate enrichment strategies were tested to A) maximize the proportion of MCI converters screened in, and B) minimize the proportion of MCI converters screened out. Based on strategy A, when compared with no enrichment and ADAS-Cog as an outcome measure (sample size of 834), enrichment with 18F-FDG PET and hippocampal volume lowered samples size to 260 and 277 cases per arm, but at the cost of screening out 1,597 and 434 cases per arm. When compared with no enrichment and clinical dementia rating (CDR-SOB) as an outcome measure (sample size of 674), enrichment with hippocampal volume and Abeta42 lowered sample sizes to 191 and 291 cases per arm, with 639 and 157 screened out cases. Strategy B reduced the number of screened out cases (740 for [11C]-PIB PET, 101 hippocampal volume, 82 ADAS-COG and 330 for [18F]-FDG PET) but at the expense of decreased power and a relative increase size (740 for [11C]-PIB PET, 676 for hippocampal volume, 744 for ADAS-Cog, and 517 for [18F]-FDG PET). Enrichment comes at the price of an often relevant proportion of screened out cases, and in clinical trial settings, the balance between enrichment of screened in and loss of screened out patients should be critically discussed.

Dynamic contrast-enhanced magnetic resonance imaging as a surrogate marker of tumor response to anti-angiogenic therapy in a xenograft model of glioblastoma multiforme.

PURPOSE: To evaluate the effects of a neutralizing anti-vascular endothelial growth factor (anti-VEGF) antibody on tumor microvascular permeability, a proposed indicator of angiogenesis, and tumor growth in a rodent malignant glioma model. MATERIALS AND METHODS: A dynamic contrast-enhanced magnetic resonance imaging (MRI) technique, permitting noninvasive in vivo and in situ assessment of potential therapeutic effects, was used to measure tumor microvascular characteristics and volumes. U-87, a cell line derived from a human glioblastoma multiforme, was implanted orthotopically into brains of athymic homozygous nude rats. RESULTS: Treatment with the monoclonal antibody A4.6.1, specific for VEGF, significantly inhibited tumor microvascular permeability (6.1 +/- 3.6 mL min(-1)100 cc(-1)), compared to the control, saline-treated tumors (28.6 +/- 8.6 mL min(-1)100 cc(-1)), and significantly suppressed tumor growth (P <.05). CONCLUSION: Findings demonstrate that tumor vascular permeability and tumor growth can be inhibited by neutralization of endogenous VEGF and suggest that angiogenesis with the maintenance of endothelial hyperpermeability requires the presence of VEGF within the tissue microenvironment. Changes in tumor vessel permeability and tumor volumes as measured by contrast-enhanced MRI provide an assay that could prove useful for clinical monitoring of anti-angiogenic therapies in brain tumors.

Comparison of gadopentetate dimeglumine and albumin-(Gd-DTPA)30 for microvessel characterization in an intracranial glioma model.

To compare the performance of macromolecular albumin gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)30 and low molecular weight gadopentetate dimeglumine for microvessel characterization, we examined an intracranial 9L glioma model in which increased angiogenesis, hypervascularity, and hyperpermeability mimic characteristics of clinical malignant brain tumors. Dynamic MRI data were analyzed using a bidirectional, two-compartment kinetic model to extract quantitative estimates for fractional blood volume (fBV) and permeability surface area product (PS). Three criteria were used for comparison of contrast agent performance: (a) tumor conspicuity, defined as the contrast-to-noise ratio (CNR); (b) dynamic range of differential permeability estimates between tumor and normal brain; (c) reasonableness of blood volume estimates. Gadopentetate was superior to macromolecular albumin-(Gd-DTPA)30 for detection of 9L brain gliomas and for measurements of hyperpermeability.

Assessing tumor angiogenesis using macromolecular MR imaging contrast media.

MRI enhanced with a macromolecular contrast medium (MMCM) has previously been shown to estimate tumor microvascular characteristics that correlate closely with histologic microvascular density, an established surrogate of tumor angiogenesis. A similar MMCM-enhanced MRI technique has now been used to investigate the acute tumor microvascular effects of antibody-mediated inhibition of vascular endothelial growth factor (VEGF), a well-studied and potent angiogenesis stimulator. Athymic rats xenografted with a human breast carcinoma (MDA-MB-435) were imaged after administration of albumin-gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA30) using a heavily T1-weighted three dimensional-spoiled gradient-refocused acquisition in a steady-state pulse sequence before and 24 hours after treatment with anti-VEGF antibody (single dose of 1 mg). Changes in longitudinal relaxivity (delta R1) were analyzed using a bidirectional two-compartment kinetic model to estimate tumor fractional blood volume (fBV) and permeability surface area product (PS). Data showed a significant decrease (P < 0.05) of tumor PS with respect to macromolecular contrast medium at 24 hours after treatment with anti-VEGF antibody. No significant change was observed in fBV. Suppression of tumor microvascular permeability induced by anti-VEGF antibody can be detected and quantified by MMCM-enhanced MRI. MRI grading of tumor angiogenesis and monitoring of anti-angiogenesis interventions could find wide clinical application.

Two cases of neurological manifestations in eosinophilia: variations of one disease?

The hypereosinophilic syndrome is characterized by a long-lasting increase in circulating eosinophils in the absence of a definable etiology and by manifestations of multisystem involvement. It must be differentiated from the eosinophilia-myalgia syndrome related to the ingestion of L-tryptophan, although the clinical features may be similar. Two patients with hypereosinophilia not related to L-tryptophan intake are described who both became clinically symptomatic with neurological manifestations of acute and subacute onset: one with eosinophilic fasciitis and the other with painful polyneuropathy. Both responded well to corticosteroids.

Concurrence of cortex and platelet serotonin2 receptor binding characteristics in the individual and the putative regulation by serotonin.

Changes in the central and peripheral serotonergic receptor activity have been reported to be involved in depression and suicidality. To elucidate the interdependence between central and peripheral receptor sites and their regulation by serotonin, we estimated intra-individual serotonin2 receptor binding characteristics in porcine cortex synaptosomes and in platelet membranes using 3H-LSD as ligand and ketanserin as competitor and quantified the relevant serotonin concentrations. A positive correlation between the apparent half maximal saturation concentration, KD, of the receptor in cortex synaptosomes and platelet membranes (r = 0.65, p = 0.0046, n = 18), and between the apparent maximal binding capacity, Bmax, of the receptor in cortex synaptosomes and platelets (r = 0.52, p = 0.027, n = 18) was observed. The blood serotonin concentrations correlated negatively with the maximal binding capacity, Bmax, in platelets (r = -0.77, p = 0.0002, n = 18). These results suggest that the binding characteristics of the central and peripheral serotonin2 receptor are similar, and that the platelet receptor activity may be regulated by blood levels of serotonin.

Human brain cortex and platelet serotonin2 receptor binding properties and their regulation by endogenous serotonin.

In patients with affective disorder and suicidality up-regulation of the serotonin2 receptor has been observed in brain and on platelets. Although the pharmacological profiles of the receptor in brain synaptosomes and platelet membranes are similar, it is a matter of debate whether the platelet serotonin2 receptor reflects the characteristics of the receptor in the brain and whether serotonin regulates the receptor activity. To answer these questions we measured in healthy human subjects the platelet serotonin2 receptor activity and blood serotonin concentrations. In an attempt to find whether the serotonin2 receptor activity in brain cortex synaptosomes and on platelets is similarly expressed we investigated the receptor's binding characteristics in neurosurgical patients. The results suggest that in men and women increased platelet serotonin concentrations correlate with a decrease in platelet membrane serotonin2 receptor affinity. The affinities of the brain cortex synaptosomal and platelet membrane serotonin2 receptor correlate intra-individually. These data suggest that the platelet serotonin2 receptor affinity appears to be regulated at the cellular level by blood serotonin and that the binding characteristics of the serotonin2 receptor in brain cortex synaptosomes corresponds to that on platelets. The latter finding supports the hypothesis of the platelet as a model for neuronal function.