Phosphodiesterase as a Target for Cognition Enhancement in Schizophrenia

2020 ◽  
Vol 20 (26) ◽  
pp. 2404-2421
Author(s):  
Mayasah Y. Al-Nema ◽  
Anand Gaurav
Keyword(s):  
Cognitive Impairment ◽  
Negative Symptoms ◽  
D2 Receptor ◽  
Brain Regions ◽  
Dopamine System ◽  
Medical Need ◽  
Pde Inhibitors ◽  
Cognition Enhancement ◽  
Preclinical And Clinical Studies ◽  
The Brain

Schizophrenia is a severe mental disorder that affects more than 1% of the population worldwide. Dopamine system dysfunction and alterations in glutamatergic neurotransmission are strongly implicated in the aetiology of schizophrenia. To date, antipsychotic drugs are the only available treatment for the symptoms of schizophrenia. These medications, which act as D2-receptor antagonist, adequately address the positive symptoms of the disease, but they fail to improve the negative symptoms and cognitive impairment. In schizophrenia, cognitive impairment is a core feature of the disorder. Therefore, the treatment of cognitive impairment and the other symptoms related to schizophrenia remains a significant unmet medical need. Currently, phosphodiesterases (PDEs) are considered the best drug target for the treatment of schizophrenia since many PDE subfamilies are abundant in the brain regions that are relevant to cognition. Thus, this review aims to illustrate the mechanism of PDEs in treating the symptoms of schizophrenia and summarises the encouraging results of PDE inhibitors as anti-schizophrenic drugs in preclinical and clinical studies.

Neural Mechanisms of Negative Symptoms

1989 ◽  
Vol 155 (S7) ◽  
pp. 93-98 ◽  
Author(s):  
Nancy C. Andreasen
Keyword(s):  
Frontal Cortex ◽  
Negative Symptoms ◽  
Neural Mechanism ◽  
Brain Regions ◽  
Brain Dysfunction ◽  
Neural Mechanisms ◽  
Dementia Praecox ◽  
Intellectual Abilities ◽  
The Brain ◽  
Psychic Mechanisms

When Kraepelin originally defined and described dementia praecox, he assumed that it was due to some type of neural mechanism. He hypothesised that abnormalities could occur in a variety of brain regions, including the prefrontal, auditory, and language regions of the cortex. Many members of his department, including Alzheimer and Nissl, were actively involved in the search for the neuropathological lesions that would characterise schizophrenia. Although Kraepelin did not use the term ‘negative symptoms', he describes them comprehensively and states explicitly that he believes the symptoms of schizophrenia can be explained in terms of brain dysfunction:“If it should be confirmed that the disease attacks by preference the frontal areas of the brain, the central convolutions and central lobes, this distribution would in a certain measure agree with our present views about the site of the psychic mechanisms which are principally injured by the disease. On various grounds, it is easy to believe that the frontal cortex, which is specially well developed in man, stands in closer relation to his higher intellectual abilities, and these are the faculties which in our patients invariably suffer profound loss in contrast to memory and acquired ability.” Kraepelin (1919, p. 219)

scholarly journals Rewiring of the Serotonin System in Major Depression

2021 ◽  
Vol 12 ◽  
Author(s):  
Faranak Vahid-Ansari ◽  
Paul R. Albert
Keyword(s):  
Mental Illness ◽  
Cognitive Impairment ◽  
Major Depression ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Chronic Treatment ◽  
Brain Regions ◽  
Synaptic Organization ◽  
Serotonin System ◽  
The Brain

Serotonin is a key neurotransmitter that is implicated in a wide variety of behavioral and cognitive phenotypes. Originating in the raphe nuclei, 5-HT neurons project widely to innervate many brain regions implicated in the functions. During the development of the brain, as serotonin axons project and innervate brain regions, there is evidence that 5-HT plays key roles in wiring the developing brain, both by modulating 5-HT innervation and by influencing synaptic organization within corticolimbic structures. These actions are mediated by 14 different 5-HT receptors, with region- and cell-specific patterns of expression. More recently, the role of the 5-HT system in synaptic re-organization during adulthood has been suggested. The 5-HT neurons have the unusual capacity to regrow and reinnervate brain regions following insults such as brain injury, chronic stress, or altered development that result in disconnection of the 5-HT system and often cause depression, anxiety, and cognitive impairment. Chronic treatment with antidepressants that amplify 5-HT action, such as selective serotonin reuptake inhibitors (SSRIs), appears to accelerate the rewiring of the 5-HT system by mechanisms that may be critical to the behavioral and cognitive improvements induced in these models. In this review, we survey the possible 5-HT receptor mechanisms that could mediate 5-HT rewiring and assess the evidence that 5-HT-mediated brain rewiring is impacting recovery from mental illness. By amplifying 5-HT-induced rewiring processes using SSRIs and selective 5-HT agonists, more rapid and effective treatments for injury-induced mental illness or cognitive impairment may be achieved.

scholarly journals Cognitive Impairment and Diminished Neural Responses Constitute a Biomarker Signature of Negative Symptoms in Psychosis

2020 ◽  
Vol 46 (5) ◽  
pp. 1269-1281 ◽  
Author(s):  
Matthew E Hudgens-Haney ◽  
Brett A Clementz ◽  
Elena I Ivleva ◽  
Matcheri S Keshavan ◽  
Godfrey D Pearlson ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Resting State ◽  
Negative Symptoms ◽  
Resting State Fmri ◽  
Neural Responses ◽  
Full Spectrum ◽  
Medical Need ◽  
Anti Saccades ◽  
Biomarker Signature ◽  
Oculomotor Abnormalities

Abstract The treatment of negative symptoms (NS) in psychosis represents an urgent unmet medical need given the significant functional impairment it contributes to psychosis syndromes. The lack of progress in treating NS is impacted by the lack of known pathophysiology or associated quantitative biomarkers, which could provide tools for research. This current analysis investigated potential associations between NS and an extensive battery of behavioral and brain-based biomarkers in 932 psychosis probands from the B-SNIP database. The current analyses examined associations between PANSS-defined NS and (1) cognition, (2) pro-/anti-saccades, (3) evoked and resting-state electroencephalography (EEG), (4) resting-state fMRI, and (5) tractography. Canonical correlation analyses yielded symptom-biomarker constructs separately for each biomarker modality. Biomarker modalities were integrated using canonical discriminant analysis to summarize the symptom-biomarker relationships into a “biomarker signature” for NS. Finally, distinct biomarker profiles for 2 NS domains (“diminished expression” vs “avolition/apathy”) were computed using step-wise linear regression. NS were associated with cognitive impairment, diminished EEG response amplitudes, deviant resting-state activity, and oculomotor abnormalities. While a connection between NS and poor cognition has been established, association to neurophysiology is novel, suggesting directions for future mechanistic studies. Each biomarker modality was related to NS in distinct and complex ways, giving NS a rich, interconnected fingerprint and suggesting that any one biomarker modality may not adequately capture the full spectrum of symptomology.

scholarly journals Apolipoprotein E4 effects on topological brain network organization in mild cognitive impairment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gretel Sanabria-Diaz ◽  
Lester Melie-Garcia ◽  
Bogdan Draganski ◽  
Jean-Francois Demonet ◽  
Ferath Kherif
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Late Onset ◽  
Brain Regions ◽  
Brain Network ◽  
Theory Approach ◽  
Characteristic Path Length ◽  
Cross Sectional ◽  
Adaptive Mechanisms ◽  
The Brain

AbstractThe Apolipoprotein E isoform E4 (ApoE4) is consistently associated with an elevated risk of developing late-onset Alzheimer’s Disease (AD); however, less is known about the potential genetic modulation of the brain networks organization during prodromal stages like Mild Cognitive Impairment (MCI). To investigate this issue during this critical stage, we used a dataset with a cross-sectional sample of 253 MCI patients divided into ApoE4-positive (‛Carriers’) and ApoE4-negative (‘non-Carriers’). We estimated the cortical thickness (CT) from high-resolution T1-weighted structural magnetic images to calculate the correlation among anatomical regions across subjects and build the CT covariance networks (CT-Nets). The topological properties of CT-Nets were described through the graph theory approach. Specifically, our results showed a significant decrease in characteristic path length, clustering-index, local efficiency, global connectivity, modularity, and increased global efficiency for Carriers compared to non-Carriers. Overall, we found that ApoE4 in MCI shaped the topological organization of CT-Nets. Our results suggest that in the MCI stage, the ApoE4 disrupting the CT correlation between regions may be due to adaptive mechanisms to sustain the information transmission across distant brain regions to maintain the cognitive and behavioral abilities before the occurrence of the most severe symptoms.

scholarly journals Assessment of 9-OH- and 7,8-diol-benzo[a]pyrene in Blood as Potent Markers of Cognitive Impairment Related to benzo[a]pyrene Exposure: An Animal Model Study

Toxics ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 50
Author(s):  
Lynda Saber Cherif ◽  
Lei Cao-Lei ◽  
Sophie Farinelle ◽  
Claude P. Muller ◽  
Jonathan D. Turner ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Elevated Plus Maze ◽  
Brain Regions ◽  
Model Study ◽  
Plus Maze ◽  
Subunit Expression ◽  
Animal Model Study ◽  
Hole Board ◽  
Dose Dependent ◽  
The Brain

The potent neurotoxicity of benzo[a]pyrene (B[a]P) has been suggested to be a susceptibility factor accelerating the onset of brain tumours and the emergence of neurobehavioural disturbances. B[a]P has been shown to be neurotoxic, acting directly on both the central and peripheral nervous systems, as well as indirectly via peripheral organs like liver and gut. By using a realistic B[a]P exposure scenario (0.02–200 mg/kg/day, 10 days) in mice, we elucidated brain-specific B[a]P metabolism and at identified hydroxylated B[a]P metabolites in serum which could be used as markers of cognitive impairment. Repeated oral administration of B[a]P led to, at the doses of 20 and 200 mg/kg/day, significant overexpression of Cyp1a1/Cyp1b1 in 2 out of the 3 brain regions considered, thereby suggesting the ability of the brain to metabolize B[a]P itself. At the same doses, mice exhibited a reduction in anxiety in both the elevated plus maze and the hole board apparatus. Concomitantly, B[a]P triggered dose-dependent changes in Nmda subunit expression (Nr1 and Nr2a/Nr2b) in areas involved in cognition. We detected 9-OH-B[a]P and 7,8-diol-B[a]P in serum at the level for which cognitive impairment was observed. We suggest that these metabolites may, in the future be exploited as potent biomarkers of B[a]P-induced cognitive impairments.

Brain atrophy and lesion load as explaining parameters for cognitive impairment in multiple sclerosis

2005 ◽  
Vol 11 (5) ◽  
pp. 524-531 ◽  
Author(s):  
R HC Lazeron ◽  
J B Boringa ◽  
M Schouten ◽  
B MJ Uitdehaag ◽  
E Bergers ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cognitive Impairment ◽  
Social Impact ◽  
Demyelinating Disease ◽  
Word List ◽  
Brain Regions ◽  
Cognitive Test ◽  
Lesion Load ◽  
Whole Brain ◽  
The Brain

Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system, with lesions widespread through the brain and spinal cord. An important manifestation is cognitive impairment, which, though difficult to measure, may have a major social impact. To better understand the relationship between structural tissue damage and cognitive impairment, we examined the extent and spatial distribution of brain lesions, as measured by magnetic resonance imaging (MRI), in relation to abnormal cognitive performance as measured by the Brief Repeatable Battery (BRB) in 82 MS patients. Possible confounders, like fatigue, pain and depression were also assessed. Brain MR image analysis included hyperintense T2 and hypointense T1 lesion load in the whole brain and the four lobes separately, as well as whole brain volume measurements. Cognitive impairment (defined as more than two abnormal tests) was found in 67% of the patients. Moderately strong correlations were found between the subtests of the BRB and the lesion loads in the brain regions hypothesized to be associated with that cognitive test, although these correlations were in general not much stronger than those between the subtests and the overall lesion load (due to strong interrelationships). The Spatial Recall Test correlated best with parietal lesion load; the Symbol Digit Modalities Test, the Paced Auditory Serial Addition Task (PASAT) and the Word List Generation best with frontal, parietal and temporal lesion load; while the Verbal List Generation Test Index correlated only with atrophy. Atrophy and lesion load were the main factors determining the test scores, explaining 10-25% of the variance in the test results, and were more important than fatigue, pain and depression; only depression had a minor, but significant, additional effect on the PASAT. In conclusion, cognitive impairment in MS is moderately dependent on amount (and distribution) of structural brain damage, especially in the more physically impaired patients group.

scholarly journals The Effects of Acupuncture at Real or Sham Acupoints on the Intrinsic Brain Activity in Mild Cognitive Impairment Patients

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Baohui Jia ◽  
Zhishun Liu ◽  
Baoquan Min ◽  
Zhenchang Wang ◽  
Aihong Zhou ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Brain Activity ◽  
Low Frequency ◽  
Resting State Fmri ◽  
Brain Regions ◽  
Brain Network ◽  
Healthy Controls ◽  
The Difference ◽  
The Brain

Accumulating neuroimaging studies in humans have shown that acupuncture can modulate a widely distributed brain network in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) patients. Acupuncture at different acupoints could exert different modulatory effects on the brain network. However, whether acupuncture at real or sham acupoints can produce different effects on the brain network in MCI or AD patients remains unclear. Using resting-state fMRI, we reported that acupuncture at Taixi (KI3) induced amplitude of low-frequency fluctuation (ALFF) change of different brain regions in MCI patients from those shown in the healthy controls. In MCI patients, acupuncture at KI3 increased or decreased ALFF in the different regions from those activated by acupuncture in the healthy controls. Acupuncture at the sham acupoint in MCI patients activated the different brain regions from those in healthy controls. Therefore, we concluded that acupuncture displays more significant effect on neuronal activities of the above brain regions in MCI patients than that in healthy controls. Acupuncture at KI3 exhibits different effects on the neuronal activities of the brain regions from acupuncture at sham acupoint, although the difference is only shown at several regions due to the close distance between the above points.

scholarly journals An ALE Meta-Analysis of Specific Functional MRI Studies on Subcortical Vascular Cognitive Impairment

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenwen Xu ◽  
Yu Song ◽  
Shanshan Chen ◽  
Chen Xue ◽  
Guanjie Hu ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Functional Connectivity ◽  
Meta Analysis ◽  
Vascular Cognitive Impairment ◽  
Brain Regions ◽  
Angular Gyrus ◽  
Imaging Biomarkers ◽  
Precentral Gyrus ◽  
The Brain ◽  
Subcortical Vascular Cognitive Impairment

Background: Subcortical vascular cognitive impairment (sVCI), caused by cerebral small vessel disease, accounts for the majority of vascular cognitive impairment, and is characterized by an insidious onset and impaired memory and executive function. If not recognized early, it inevitably develops into vascular dementia. Several quantitative studies have reported the consistent results of brain regions in sVCI patients that can be used to predict dementia conversion. The purpose of the study was to explore the exact abnormalities within the brain in sVCI patients by combining the coordinates reported in previous studies.Methods: The PubMed, Embase, and Web of Science databases were thoroughly searched to obtain neuroimaging articles on the amplitude of low-frequency fluctuation, regional homogeneity, and functional connectivity in sVCI patients. According to the activation likelihood estimation (ALE) algorithm, a meta-analysis based on coordinate and functional connectivity modeling was conducted.Results: The quantitative meta-analysis included 20 functional imaging studies on sVCI patients. Alterations in specific brain regions were mainly concentrated in the frontal lobes including the middle frontal gyrus, superior frontal gyrus, medial frontal gyrus, and precentral gyrus; parietal lobes including the precuneus, angular gyrus, postcentral gyrus, and inferior parietal lobule; occipital lobes including the lingual gyrus and cuneus; temporal lobes including the fusiform gyrus and middle temporal gyrus; and the limbic system including the cingulate gyrus. These specific brain regions belonged to important networks known as the default mode network, the executive control network, and the visual network.Conclusion: The present study determined specific abnormal brain regions in sVCI patients, and these brain regions with specific changes were found to belong to important brain functional networks. The findings objectively present the exact abnormalities within the brain, which help further understand the pathogenesis of sVCI and identify them as potential imaging biomarkers. The results may also provide a basis for new approaches to treatment.

Starving the brain: Structural abnormalities and cognitive impairment in adolescents with anorexia nervosa

2001 ◽  
Vol 6 (2) ◽  
pp. 146-152 ◽  
Author(s):  
Debra K. Katzman ◽  
Bruce Christensen ◽  
Arlene R. Young ◽  
Robert B. Zipursky
Keyword(s):  
Anorexia Nervosa ◽  
Cognitive Impairment ◽  
Structural Abnormalities ◽  
The Brain

Brain FDG PET for the Etiological Diagnosis of Clinically Uncertain Cognitive Impairment During Delirium in Remission

2020 ◽  
Vol 77 (4) ◽  
pp. 1609-1622
Author(s):  
Franziska Mathies ◽  
Catharina Lange ◽  
Anja Mäurer ◽  
Ivayla Apostolova ◽  
Susanne Klutmann ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Fdg Pet ◽  
False Negative ◽  
Ground Truth ◽  
Etiological Diagnosis ◽  
Geriatric Unit ◽  
Positron Emission ◽  
The Brain ◽  
Hospitalized Geriatric Patients

Background: Positron emission tomography (PET) of the brain with 2-[F-18]-fluoro-2-deoxy-D-glucose (FDG) is widely used for the etiological diagnosis of clinically uncertain cognitive impairment (CUCI). Acute full-blown delirium can cause reversible alterations of FDG uptake that mimic neurodegenerative disease. Objective: This study tested whether delirium in remission affects the performance of FDG PET for differentiation between neurodegenerative and non-neurodegenerative etiology of CUCI. Methods: The study included 88 patients (82.0±5.7 y) with newly detected CUCI during hospitalization in a geriatric unit. Twenty-seven (31%) of the patients were diagnosed with delirium during their current hospital stay, which, however, at time of enrollment was in remission so that delirium was not considered the primary cause of the CUCI. Cases were categorized as neurodegenerative or non-neurodegenerative etiology based on visual inspection of FDG PET. The diagnosis at clinical follow-up after ≥12 months served as ground truth to evaluate the diagnostic performance of FDG PET. Results: FDG PET was categorized as neurodegenerative in 51 (58%) of the patients. Follow-up after 16±3 months was obtained in 68 (77%) of the patients. The clinical follow-up diagnosis confirmed the FDG PET-based categorization in 60 patients (88%, 4 false negative and 4 false positive cases with respect to detection of neurodegeneration). The fraction of correct PET-based categorization did not differ between patients with delirium in remission and patients without delirium (86% versus 89%, p = 0.666). Conclusion: Brain FDG PET is useful for the etiological diagnosis of CUCI in hospitalized geriatric patients, as well as in patients with delirium in remission.

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