The modulation of adult neuroplasticity is involved in the mood-improving actions of atypical antipsychotics in an animal model of depression

Depression is a prevalent psychiatric disorder with an increasing impact in global public health. However, a large proportion of patients treated with currently available antidepressant drugs fail to achieve remission. Recently, antipsychotic drugs have received approval for the treatment of antidepressant-resistant forms of major depression. The modulation of adult neuroplasticity, namely hippocampal neurogenesis and neuronal remodeling, has been considered to have a key role in the therapeutic effects of antidepressants. However, the impact of antipsychotic drugs on these neuroplastic mechanisms remains largely unexplored. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 3 weeks of stress exposure, animals were treated with two different antipsychotics: haloperidol (a classical antipsychotic) and clozapine (an atypical antipsychotic). We demonstrated that clozapine improved both measures of depressive-like behavior (behavior despair and anhedonia), whereas haloperidol aggravated learned helplessness in the forced-swimming test and behavior flexibility in a cognitive task. Importantly, an upregulation of adult neurogenesis and neuronal survival was observed in animals treated with clozapine, whereas haloperidol promoted a downregulation of these processes. Furthermore, clozapine was able to re-establish the stress-induced impairments in neuronal structure and gene expression in the hippocampus and prefrontal cortex. These results demonstrate the modulation of adult neuroplasticity by antipsychotics in an animal model of depression, revealing that the atypical antipsychotic drug clozapine reverts the behavioral effects of chronic stress by improving adult neurogenesis, cell survival and neuronal reorganization.This work was co-funded by the Life and Health Sciences Research Institute (ICVS), and Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (Projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023). This work has been also funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE) and by National funds, through the FCT, under the scope of the project POCI-01-0145-FEDER-007038. We thank Luís Martins and Ana Lima for the technical assistanceinfo:eu-repo/semantics/publishedVersio

Comparison of thallium-201 SPECT redistribution patterns and rubidium-82 PET rest-stress myocardial blood flow imaging

To compare regional thallium-201 SPECT redistribution patterns with rubidium-82 PET, we studied 81 patients with both imaging modalities. Sixty patients had significant coronary artery disease. All patients underwent PET imaging after dipyridamole infusion, while SPECT imaging was performed after exercise stress (38 patients) and dipyridamole (43 patients). Sixty-eight percent of patients with prior infarct had fixed defects on SPECT, compared to 39% with PET. Sixty-one percent of patients with prior infarct had PET perfusion defects which exhibited ‘reflow’ or normal rubidium-82 tracer uptake (p < 0.05 vs. SPECT). Similar results were seen in patients without prior infarct (26% fixed defects on SPECT vs. 12% for PET, p < 0.05). Regional analysis showed that 57% of fixed SPECT defects corresponded to PET defects with reflow or normal rubidium-82 uptake, while 78% of ‘fixed’ PET defects corresponded to fixed SPECT defects. PET reflow and normal rubidium-82 uptake in sites of fixed thallium-201 SPECT perfusion defects suggest that imaging modalities employing separate tracer injections at rest and after stress, such as rubidium-82 PET, may be more specific in the assessment of myocardial viability, especially in patients with prior myocardial infarction.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42537/1/10554_2005_Article_BF01151577.pd

Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease

Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the 'preclinical' stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome.CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85-0.94 95% confidence interval [CI]) and 0.88 (0.81-0.94 CI), respectively.Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions