Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease

Introduction: CAD106 is designed to stimulate amyloid-β (Aβ)-specific antibody responses while avoiding T-cell autoimmune responses. The CAD106 first-in-human study demonstrated a favorable safety profile and promising antibody response. We investigated long-term safety, tolerability and antibody response after repeated CAD106 injections. Methods: Two phase IIa, 52-week, multicenter, randomized, double-blind, placebo-controlled core studies (2201; 2202) and two 66-week open-label extension studies (2201E; 2202E) were conducted in patients with mild Alzheimer’s disease (AD) aged 40 to 85 years. Patients were randomized to receive 150μg CAD106 or placebo given as three subcutaneous (2201) or subcutaneous/intramuscular (2202) injections, followed by four injections (150 μg CAD106; subcutaneous, 2201E1; intramuscular, 2202E1). Our primary objective was to evaluate the safety and tolerability of repeated injections, including monitoring cerebral magnetic resonance imaging scans, adverse events (AEs) and serious AEs (SAEs). Further objectives were to assess Aβ-specific antibody response in serum and Aβ-specific T-cell response (core only). Comparable Aβ-immunoglobulin G (IgG) exposure across studies supported pooled immune response assessments. Results: Fifty-eight patients were randomized (CAD106, n = 47; placebo, n = 11). Baseline demographics and characteristics were balanced. Forty-five patients entered extension studies. AEs occurred in 74.5% of CAD106-treated patients versus 63.6% of placebo-treated patients (core), and 82.2% experienced AEs during extension studies. Most AEs were mild to moderate in severity, were not study medication-related and did not require discontinuation. SAEs occurred in 19.1% of CAD106-treated patients and 36.4% of placebo-treated patients (core). One patient (CAD106-treated; 2201) reported a possibly study drug-related SAE of intracerebral hemorrhage. Four patients met criteria for amyloid-related imaging abnormalities (ARIA) corresponding to microhemorrhages: one was CAD106-treated (2201), one placebo-treated (2202) and two open-label CAD106-treated. No ARIA corresponded to vasogenic edema. Two patients discontinued extension studies because of SAEs (rectal neoplasm and rapid AD progression, respectively). Thirty CAD106-treated patients (63.8%) were serological responders. Sustained Aβ-IgG titers and prolonged time to decline were observed in extensions versus core studies. Neither Aβ1–6 nor Aβ1–42 induced specific T-cell responses; however, positive control responses were consistently detected with the CAD106 carrier. Conclusions: No unexpected safety findings or Aβ-specific T-cell responses support the CAD106 favorable tolerability profile. Long-term treatment-induced Aβ-specific antibody titers and prolonged time to decline indicate antibody exposure may increase with additional injections. CAD106 may be a valuable therapeutic option in AD

Assessment of cognitive outcome measures in teenagers with 15q13.3 microdeletion syndrome

Purpose: 15q13.3 microdeletion syndrome causes a spectrum of neuropsychological disorders, including intellectual disability and autism. We aimed to determine if any or all of three neurocognitive tests (the KiTAP, CogState, and Stanford-Binet) were suitable for assessment of cognitive function in affected individuals. Methods: The KiTAP, CogState, and Stanford-Binet tests were administered to ten individuals with 15q13.3 microdeletion syndrome (12-21 years of age), and the results were analyzed to determine feasibility, potential for improvement, and internal consistency. Results: 15q13.3 microdeletion patients were able to complete the components assessed for each of the three tests. Minimal basal and ceiling effects were observed. Patients scored below the 50th percentile on the large majority of test components. Internal consistency was acceptable (≥0.7) for the components assessed. Conclusions: The KiTAP, CogState, and Stanford-Binet are valid tests of cognitive function in 15q13.3 microdeletion patients. These tests may be considered for use as objective outcome measures in future clinical trials, assessing change in neurological function over a period of pharmacological treatment

Decrease of mGluR5 receptor density goes parallel with changes in enkephalin and substance P immunoreactivity in Huntington's disease: a preliminary investigation in the postmortem human brain

Group 1 metabotropic glutamate subtype 5 receptors (mGluR5) contribute to the control of motor behavior by regulating the balance between excitation and inhibition of outputs in the basal ganglia. The density of these receptors is increased in patients with Parkinson's disease and motor complications. We hypothesized that similar changes may occur in Huntington's disease (HD) and aimed at testing this hypothesis in a preliminary experimental series in postmortem human brain material obtained from HD patients. Using autoradiography, we analyzed mGluR5 density in the putamen, caudate nucleus and cerebellum (control region) in postmortem tissue samples from three patients with HD and three controls with two mGluR5-specific radioligands ([3H]ABP688 and [11C]ABP688). The density of enkephalin (Enk)- or substance P (SP)-containing neurons was assessed using immunohistochemical and cell-counting methods. [3H]ABP688 binding in HD was reduced in the caudate (-70.4 %, P /=90 % decrease in the density of Enk- and SP-containing neurons in the caudate and putamen of HD patients vs controls (P < 0.001). In contrast to earlier observations in PD, in HD, compared to controls, the mGluR5 density was significantly lower in the caudate nucleus. The decrease in neuronal density suggests that neuronal loss was largely responsible for the observed decrease in mGluR5

Association of Long-Term Nicotine Abstinence With Normal Metabotropic Glutamate Receptor-5 Binding

BACKGROUND Nicotine addiction is a major public health problem and is associated with primary glutamatergic dysfunction. We recently showed marked global reductions in metabotropic glutamate receptor type 5 (mGluR5) binding in smokers and recent ex-smokers (average abstinence duration of 25 weeks). The goal of this study was to examine the role of mGluR5 downregulation in nicotine addiction by investigating a group of long-term ex-smokers (abstinence >1.5 years), and to explore associations between mGluR5 binding and relapse in recent ex-smokers. METHODS Images of mGluR5 receptor binding were acquired in 14 long-term ex-smokers, using positron emission tomography with radiolabeled [11C]ABP688, which binds to an allosteric site with high specificity. RESULTS Long-term ex-smokers and individuals who had never smoked showed no differences in mGluR5 binding in any of the brain regions examined. Long-term ex-smokers showed significantly higher mGluR5 binding than recent ex-smokers, most prominently in the frontal cortex (42%) and thalamus (57%). CONCLUSIONS Our findings suggest that downregulation of mGluR5 is a pathogenetic mechanism underlying nicotine dependence and the high relapse rate in individuals previously exposed to nicotine. Therefore, mGluR5 receptor binding appears to be an effective biomarker in smoking and a promising target for the discovery of novel medication for nicotine dependence and other substance-related disorders

Changes in mGluR5 density, and enkephalin and substance P immunoreactivity in Huntington’s disease

Background Group 1 metabotropic glutamate subtype 5 receptors (mGluR5) help control motor behavior by regulating the balance between excitation and inhibition of outputs in the basal ganglia. The density of these receptors is increased in patients with Parkinson’s disease and motor complications. We hypothesized that similar changes occur in Huntington’s disease (HD). Methods We analyze mGluR5 density in the putamen, caudate nucleus and cerebellum (control region) from postmortem tissue samples from three patients with HD and three controls with mGluR5-specific radioligands ([3H]ABP688 and [11C]ABP688). The density of enkephalin (Enk)- or substance P (SP)-containing neurons was assessed using immunohistochemical and stereological methods. Results [3H]ABP688 binding in HD was reduced in the caudate (-70.4%, P < 0.001), in the putamen (-33.3%, P = 0.053), and in the cerebellum (-8.79%, P = 0.930) versus controls. Results with [11C]ABP688 were similar; there was good correlation between [11C]ABP688 and [3H]ABP688 binding ratios. Total cell density was similar in all three brain regions in HD patients and controls. Neuronal density was 69% lower in the caudate (P = 0.002) and 64% lower in the putamen (P < 0.001) of HD patients versus controls. Both direct and indirect pathways were affected, with ≥ 90% decrease in the density of Enk- and SP-containing neurons in the caudate and putamen of HD patients versus controls (P < 0.001). Conclusion The mGluR5 density was significantly lower in HD caudate than in controls. The decrease in neuronal density suggests that neuronal loss was largely responsible for the observed decrease in mGluR5

Marked global reduction in mGluR5 receptor binding in smokers and ex-smokers determined by [11C]ABP688 positron emission tomography

Nicotine addiction is a major public health problem, resulting in primary glutamatergic dysfunction. We measured the glutamate receptor binding in the human brain and provided direct evidence for the abnormal glutamate system in smokers. Because antagonism of the metabotropic glutamate receptor 5 (mGluR5) reduced nicotine self-administration in rats and mice, mGluR5 is suggested to be involved in nicotine addiction. mGluR5 receptor binding specifically to an allosteric site was observed by using positron emission tomography with [(11)C]ABP688. We found a marked global reduction (20.6%; P < 0.0001) in the mGluR5 distribution volume ratio (DVR) in the gray matter of 14 smokers. The most prominent reductions were found in the bilateral medial orbitofrontal cortex. Compared with 14 nonsmokers, 14 ex-smokers had global reductions in the average gray matter mGluR5 DVR (11.5%; P < 0.005), and there was a significant difference in average gray matter mGluR5 DVR between smokers and ex-smokers (9.2%; P < 0.01). Clinical variables reflecting current nicotine consumption, dependence and abstinence were not correlated with mGluR5 DVR. This decrease in mGluR5 receptor binding may be an adaptation to chronic increases in glutamate induced by chronic nicotine administration, and the decreased down-regulation seen in the ex-smokers could be due to incomplete recovery of the receptors, especially because the ex-smokers were abstinent for only 25 wk on average. These results encourage the development and testing of drugs against addiction that directly target the glutamatergic system

Metabotropic glutamate receptor 5 binding in patients with obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a disabling, mostly chronic, psychiatric condition with significant social and economic impairments and is a major public health issue. However, numerous patients are resistant to currently available pharmacological and psychological interventions. Given that recent animal studies and magnetic resonance spectroscopy research points to glutamate dysfunction in OCD, we investigated the metabotropic glutamate receptor 5 (mGluR5) in patients with OCD and healthy controls. We determined mGluR5 distribution volume ratio (DVR) in the brain of ten patients with OCD and ten healthy controls by using [11C]ABP688 positron-emission tomography. As a clinical measure of OCD severity, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was employed. We found no significant global difference in mGluR5 DVR between patients with OCD and healthy controls. We did, however, observe significant positive correlations between the Y-BOCS obsession sub-score and mGluR5 DVR in the cortico-striatal-thalamo-cortical brain circuit, including regions of the amygdala, anterior cingulate cortex, and medial orbitofrontal cortex (Spearman's ρ's⩾ = 0.68, p < 0.05). These results suggest that obsessions in particular might have an underlying glutamatergic pathology related to mGluR5. The research indicates that the development of metabotropic glutamate agents would be useful as a new treatment for OCD

Reduced metabotropic glutamate receptor 5 density in major depression determined by [(11)C]ABP688 PET and postmortem study

Clinical and preclinical evidence suggests a hyperactive glutamatergic system in clinical depression. Recently, the metabotropic glutamate receptor 5 (mGluR5) has been proposed as an attractive target for novel therapeutic approaches to depression. The goal of this study was to compare mGluR5 binding (in a positron emission tomography [PET] study) and mGluR5 protein expression (in a postmortem study) between individuals with major depressive disorder and psychiatrically healthy comparison subjects

Reduced Metabotropic Glutamate Receptor 5 Density in Major Depression Determined by [11C]ABP688 Positron Emission Tomography and Postmortem Study

Objective: Clinical and preclinical evidence suggest a hyperactive glutamatergic system in clinical depression. Recently, the metabotropic glutamate receptor 5 (mGluR5) has been proposed as an attractive target for discovery of novel therapeutic approaches against depression. The goal of this study was to compare mGluR5 binding (PET study) and mGluR5 protein expression (postmortem study) between subjects with major depressive disorder and healthy controls. Method: Images of mGluR5 receptor binding were acquired using PET and [11C]ABP688 that binds to an allosteric site with high specificity in 11 unmedicated subjects with major depression and 11 matched healthy controls; the amount of mGluR5 protein was investigated using Western blot method in brain samples of 15 depressed subjects and 15 matched controls (postmortem study). Results: The PET study revealed decreased regional mGluR5 binding in the prefrontal cortex, the cingulate cortex, the insula, the thalamus and the hippocampus of the depressed individuals (uncorrected p<0.001). Severity of depression correlated negatively with mGluR5 binding in the hippocampus (cluster-level corrected p=0.029). The postmortem study showed reduced mGluR5 protein expression in the prefrontal cortex (Brodmann's area 10) in depression (p<0.014), while prefrontal mGluR1 protein expression was unchanged. Conclusions: The reductions in mGluR5 binding found in the depressed sample are compatible with reduced protein expression in postmortem tissue. Thus, both studies suggest that basal or compensatory changes in excitatory neurotransmission play roles in the pathophysiology of major depression