Value Proposition of FDA-Approved Artificial Intelligence Algorithms for Neuroimaging.

PURPOSE: The number of FDA-cleared artificial intelligence (AI) algorithms for neuroimaging has grown in the past decade. The adoption of these algorithms into clinical practice depends largely on whether this technology provides value in the clinical setting. The objective of this study was to analyze trends in FDA-cleared AI algorithms for neuroimaging and understand their value proposition as advertised by the AI developers and vendors. METHODS: A list of AI algorithms cleared by the FDA for neuroimaging between May 2008 and August 2022 was extracted from the ACR Data Science Institute AI Central database. Product information for each device was collected from the database. For each device, information on the advertised value as presented on the developer's website was collected. RESULTS: A total of 59 AI neuroimaging algorithms were cleared by the FDA between May 2008 and August 2022. Most of these algorithms (24 of 59) were compatible with noncontrast CT, 21 with MRI, 9 with CT perfusion, 8 with CT angiography, 3 with MR perfusion, and 2 with PET. Six algorithms were compatible with multiple imaging techniques. Of the 59 algorithms, websites were located that discussed the product value for 55 algorithms. The most widely advertised value proposition was improved quality of care (38 of 55 [69.1%]). A total of 24 algorithms (43.6%) proposed saving user time, 9 (15.7%) advertised decreased costs, and 6 (10.9%) described increased revenue. Product websites for 26 algorithms (43.6%) showed user testimonials advertising the value of the technology. CONCLUSIONS: The results of this study indicate a wide range of value propositions advertised by developers and vendors of AI algorithms for neuroimaging. Most vendors advertised that their products would improve patient care. Further research is necessary to determine whether the value claimed by developers is actually demonstrated in clinical practice.

In Semliki Forest virus encephalitis, suppressor of cytokine signaling 4 (SOCS4) is an essential modulator of immune responses that mediates the balance between immunopathology and virus clearance.

Central nervous system virus infections are a major cause of morbidity and mortality worldwide and a significant global public health concern. As in many tissues, inflammation and immune responses in the brain, despite their protective roles, can also be harmful. Control of brain inflammation is important in many neurological diseases from encephalitis to multiple sclerosis and neurogenerative disease. The suppressors of cytokine signaling (SOCS) proteins are a key mechanism controlling inflammatory and immune responses across all tissues including the brain. Using a mouse model system, we demonstrate that lack of SOCS4 results in changes in the pathogenesis and clinical outcome of a neurotropic virus infection. Relative to wild-type mice, SOCS4-deficient mice showed accelerated clearance of virus from the brain, lower levels of persisting viral RNA in the brain, increased neuroinflammation and more severe neuropathology. We conclude that, in the mouse brain, SOCS4 is a vital regulator of antiviral immunity that mediates the critical balance between immunopathology and virus persistence.

Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus Infections.

Virus infections of the central nervous system (CNS) cause important diseases of humans and animals. As in other tissues, innate antiviral responses mediated by type I interferons (IFNs) are crucially important in controlling CNS virus infections. The maturity of neuronal populations is an established critical factor determining the outcome of CNS virus infection. Using primary cultures of mouse cortical neurons, we investigated the relationships between neuronal maturation, type I IFN responses, and the outcome of Semliki Forest virus infection. The virus replicated better, infected more cells, and produced higher titres of infectious viruses in immature neurons. Complete transcriptome analysis demonstrated that resting immature neurons have low transcriptional competence to mount antiviral responses. They had no detectable transcription of the genes Ddx58 and Ifih1, which encode key RNA virus cytoplasmic sensors RIG-I and MDA5, and very low expression of genes encoding key regulators of associated signalling pathways. Upon infection, immature neurons failed to mount an antiviral response as evidenced by their failure to produce chemokines, IFNs, and other cytokines. Treatment of immature neurons with exogenous IFNß prior to infection resulted in antiviral responses and lower levels of virus replication and infectious virus production. In contrast, resting mature neurons generated a robust antiviral response. This was augmented by pretreatment with IFNß. Infection of mature neurons derived from IFNAR-/- mice did not make an antiviral response and replicated virus to high levels.

A biosensor of protein foldedness identifies increased "holdase" activity of chaperones in the nucleus following increased cytosolic protein aggregation.

Chaperones and other quality control machinery guard proteins from inappropriate aggregation, which is a hallmark of neurodegenerative diseases. However, how the systems that regulate the "foldedness" of the proteome remain buffered under stress conditions and in different cellular compartments remains incompletely understood. In this study, we applied a FRET-based strategy to explore how well quality control machinery protects against the misfolding and aggregation of "bait" biosensor proteins, made from the prokaryotic ribonuclease barnase, in the nucleus and cytosol of human embryonic kidney 293T cells. We found that those barnase biosensors were prone to misfolding, were less engaged by quality control machinery, and more prone to inappropriate aggregation in the nucleus as compared with the cytosol, and that these effects could be regulated by chaperone Hsp70-related machinery. Furthermore, aggregation of mutant huntingtin exon 1 protein (Httex1) in the cytosol appeared to outcompete and thus prevented the engagement of quality control machinery with the biosensor in the cytosol. This effect correlated with reduced levels of DNAJB1 and HSPA1A chaperones in the cell outside those sequestered to the aggregates, particularly in the nucleus. Unexpectedly, we found Httex1 aggregation also increased the apparent engagement of the barnase biosensor with quality control machinery in the nucleus suggesting an independent implementation of "holdase" activity of chaperones other than DNAJB1 and HSPA1A. Collectively, these results suggest that proteostasis stress can trigger a rebalancing of chaperone abundance in different subcellular compartments through a dynamic network involving different chaperone-client interactions.

Marginal zone B cells acquire dendritic cell functions by trogocytosis.

Marginal zone (MZ) B cells produce broad-spectrum antibodies that protect against infection early in life. In some instances, antibody production requires MZ B cells to display pathogen antigens bound to major histocompatibility complex class II (MHC II) molecules to T cells. We describe the trogocytic acquisition of these molecules from conventional dendritic cells (cDCs). Complement component 3 (C3) binds to murine and human MHC II on cDCs. MZ B cells recognize C3 with complement receptor 2 (CR2) and trogocytose the MHC II-C3 complexes, which become exposed on their cell surface. The ubiquitin ligase MARCH1 limits the number of MHC II-C3 complexes displayed on cDCs to prevent their elimination through excessive trogocytosis. Capture of C3 by MHC II thus enables the transfer of cDC-like properties to MZ B cells.

A linkage and exome study implicates rare variants of KANK4 and CAP2 in bipolar disorder in a multiplex family.

OBJECTIVES: Bipolar disorder (BD) is a neuropsychiatric disorder with a complex pattern of inheritance. Although many genetic studies have been conducted on BD, its genetic correlates remain uncertain. This study was aimed at  identifying the genetic underpinnings of the disorder in an Indian family, which has been under comprehensive clinical evaluation and follow-up for over 12 years. METHODS: We analysed a four-generation family with several of its members diagnosed for BD employing a combination of genetic linkage and exome analysis. RESULTS: We obtained suggestive LOD score for a chromosome 1 and a chromosome 6 marker (D1S410; LOD = 3.01, Ó¨ = 0; and D6S289; LOD = 1.58, Ó¨ = 0). Manual haplotyping of the regions encompassing these two markers helped delimit a critical genomic interval of 32.44 Mb (D1S2700-D1S435; chromosome 1p31.1-13.2) and another of 10.34 Mb (D6S470-D6S422; chromosome 6p22.3-22.2). We examined the exomic sequences corresponding to these two intervals and found rare variants, NM_181712.4: c.2461G>T (p.Asp821Tyr) in KANK4 at 1p31.1-13.2; and NM_006366:c.-93G>A, in the 5' UTR of CAP2 at 6p22.3-22.2. CONCLUSIONS: Our studysuggests involvement of KANK4 or CAP2 or both in BD in this family. Further analysis of these two genes in BD patients and functional evaluation of the allelic variants identified are suggested.

Genetic testing for clinically suspected spinocerebellar ataxias: report from a tertiary referral centre in India.

Spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative syndromes, characterized by a wide range of muscular weakness and motor deficits, caused due to cerebellar degeneration. The prevalence of the syndromes of SCA varies across the world and is known to be linked to the instability of trinucleotide repeats within the high-end normal alleles, along with susceptible haplotype. We estimated sizes of the CAG or GAA repeat expansions at the SCA1, SCA2, SCA3, SCA12 and frataxin loci among 864 referrals of subjects to genetic counselling and testing (GCAT) clinic, National Institute of Mental Health and Neurosciences, Bengaluru, India, with suspected SCA. The most frequent mutations detected were SCA1 (n = 100 (11.6%)) and SCA2 (n = 98 (11.3%)) followed by SCA3 (n = 40 (4.6%)), FRDA (n = 20 (2.3%)) and SCA12 (n = 8 (0.9%)).

A thiol probe for measuring unfolded protein load and proteostasis in cells.

When proteostasis becomes unbalanced, unfolded proteins can accumulate and aggregate. Here we report that the dye, tetraphenylethene maleimide (TPE-MI) can be used to measure cellular unfolded protein load. TPE-MI fluorescence is activated upon labelling free cysteine thiols, normally buried in the core of globular proteins that are exposed upon unfolding. Crucially TPE-MI does not become fluorescent when conjugated to soluble glutathione. We find that TPE-MI fluorescence is enhanced upon reaction with cellular proteomes under conditions promoting accumulation of unfolded proteins. TPE-MI reactivity can be used to track which proteins expose more cysteine residues under stress through proteomic analysis. We show that TPE-MI can report imbalances in proteostasis in induced pluripotent stem cell models of Huntington disease, as well as cells transfected with mutant Huntington exon 1 before the formation of visible aggregates. TPE-MI also detects protein damage following dihydroartemisinin treatment of the malaria parasites Plasmodium falciparum. TPE-MI therefore holds promise as a tool to probe proteostasis mechanisms in disease.Proteostasis is maintained through a number of molecular mechanisms, some of which function to protect the folded state of proteins. Here the authors demonstrate the use of TPE-MI in a fluorigenic dye assay for the quantitation of unfolded proteins that can be used to assess proteostasis on a cellular or proteome scale.

Transcriptional profiles for distinct aggregation states of mutant Huntingtin exon 1 protein unmask new Huntington's disease pathways.

Huntington's disease is caused by polyglutamine (polyQ)-expansion mutations in the CAG tandem repeat of the Huntingtin gene. The central feature of Huntington's disease pathology is the aggregation of mutant Huntingtin (Htt) protein into micrometer-sized inclusion bodies. Soluble mutant Htt states are most proteotoxic and trigger an enhanced risk of death whereas inclusions confer different changes to cellular health, and may even provide adaptive responses to stress. Yet the molecular mechanisms underpinning these changes remain unclear. Using the flow cytometry method of pulse-shape analysis (PulSA) to sort neuroblastoma (Neuro2a) cells enriched with mutant or wild-type Htt into different aggregation states, we clarified which transcriptional signatures were specifically attributable to cells before versus after inclusion assembly. Dampened CREB signalling was the most striking change overall and invoked specifically by soluble mutant Httex1 states. Toxicity could be rescued by stimulation of CREB signalling. Other biological processes mapped to different changes before and after aggregation included NF-kB signalling, autophagy, SUMOylation, transcription regulation by histone deacetylases and BRD4, NAD+ biosynthesis, ribosome biogenesis and altered HIF-1 signalling. These findings open the path for therapeutic strategies targeting key molecular changes invoked prior to, and subsequently to, Httex1 aggregation.

Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis.

Competing models exist in the literature for the relationship between mutant Huntingtin exon 1 (Httex1) inclusion formation and toxicity. In one, inclusions are adaptive by sequestering the proteotoxicity of soluble Httex1. In the other, inclusions compromise cellular activity as a result of proteome co-aggregation. Using a biosensor of Httex1 conformation in mammalian cell models, we discovered a mechanism that reconciles these competing models. Newly formed inclusions were composed of disordered Httex1 and ribonucleoproteins. As inclusions matured, Httex1 reconfigured into amyloid, and other glutamine-rich and prion domain-containing proteins were recruited. Soluble Httex1 caused a hyperpolarized mitochondrial membrane potential, increased reactive oxygen species, and promoted apoptosis. Inclusion formation triggered a collapsed mitochondrial potential, cellular quiescence, and deactivated apoptosis. We propose a revised model where sequestration of soluble Httex1 inclusions can remove the trigger for apoptosis but also co-aggregate other proteins, which curtails cellular metabolism and leads to a slow death by necrosis.

Determinants of Onset of Huntington's Disease with Behavioral Symptoms: Insight from 92 Patients.

BACKGROUND: Huntington's disease (HD) is a genetically mediated neurodegenerative disorder characterized by presence of involuntary movements, behavioral problems and cognitive dysfunctions. Though few patients with HD may have behavioral symptoms at onset of the disease, studies comparing patients with behavioral symptoms at the onset of HD with those having motor symptoms are sparse. OBJECTIVE: Objective of this study is to determine the differences in the demographic and genetic characteristics of patients with behavioral symptom at the onset of HD from those with motor symptoms. METHODS: A chart review of 92 patients with HD who had attended the neurology outpatient clinics of National Institute of Mental Health and Neurosciences, India was done. Demographic and genetic characteristics of HD patients with onset of the disease with initial behavioral symptoms (HD-iB) were compared with patients with onset of the disease with initial motor symptoms (HD-iM). RESULTS: The principal findings in our study were (i) higher proportion of patients with HD-iB had a positive family history of HD, (ii) maternal inheritance of HD was more frequent among those with HD-iB, and (iii) There is no significant difference between the CAG repeat length between HD-iB and HD-iM groups. CONCLUSION: Presence of family history of HD especially inheritance of HD from mother may be associated with behavioral symptoms at the onset of HD. CAG repeat length in patients with HD-iB does not differ from those with HD-iM.

A systematic examination of brain volumetric abnormalities in recent-onset schizophrenia using voxel-based, surface-based and region-of-interest-based morphometric analyses.

BACKGROUND: Brain morphometric abnormalities in schizophrenia have been extensively reported in the literature. Whole-brain volumetric reductions are almost universally reported by most studies irrespective of the characteristics of the samples studied (e.g., chronic/recent-onset; medicated/neuroleptic-naïve etc.). However, the same cannot be said of the reported regional morphometric abnormalities in schizophrenia. While certain regional morphometric abnormalities are more frequently reported than others, there are no such abnormalities that are universally reported across studies. Variability of socio-demographic and clinical characteristics across study samples as well as technical and methodological issues related to acquisition and analyses of brain structural images may contribute to inconsistency of brain morphometric findings in schizophrenia. The objective of the present study therefore was to systematically examine brain morphometry in patients with recent-onset schizophrenia to find out if there are significant whole-brain or regional volumetric differences detectable at the appropriate significance threshold, after attempting to control for various confounding factors that could impact brain volumes. METHODS: Structural magnetic resonance images of 90 subjects (schizophrenia = 45; healthy subjects = 45) were acquired using a 3 Tesla magnet. Morphometric analyses were carried out following standard analyses pipelines of three most commonly used strategies, viz., whole-brain voxel-based morphometry, whole-brain surface-based morphometry, and between-group comparisons of regional volumes generated by automated segmentation and parcellation. RESULTS: In our sample of patients having recent-onset schizophrenia with limited neuroleptic exposure, there were no significant whole brain or regional brain morphometric abnormalities noted at the appropriate statistical significance thresholds with or without including age, gender and intracranial volume or total brain volume in the statistical analyses. CONCLUSIONS: In the background of the conflicting findings in the literature, our findings indicate that brain morphometric abnormalities may not be directly related to the schizophrenia phenotype. Analysis of the reasons for the inconsistent results across studies as well as consideration of alternate sources of variability of brain morphology in schizophrenia such as epistatic and epigenetic mechanisms could perhaps advance our understanding of structural brain alterations in schizophrenia.

Shortened telomere in unremitted schizophrenia.

AIM: Telomere attrition has been noted in many neuropsychiatric and neurodegenerative syndromes, and may indicate a shared molecular pathology across conditions. We evaluated telomere length in subjects with remitted and unremitted schizophrenia and in control subjects. METHODS: We measured telomere length as relative telomere/single-copy gene ratios in subjects with schizophrenia (n = 71) using quantitative real-time polymerase chain reaction. This was compared with relative telomere/single-copy gene ratios in age-matched controls without neuropsychiatric illness (n = 73). RESULTS: The relative telomere/single-copy gene ratios were significantly lower in subjects with unremitted schizophrenia when compared with control subjects (r = -0.281, P = 0.003), as well as the individuals with remitted schizophrenia. CONCLUSION: The lower relative telomere length in unremitted schizophrenia subjects may thus indicate shared biological pathways with other neurodegenerative disorders that are also characterized by increased cellular senescence.

Reduced telomere length in neurodegenerative disorders may suggest shared biology.

Early cell death is a feature of neurodegenerative disorders. Telomere shortening is related to premature cellular senescence and could be a marker for cellular pathology in neurological diseases. Relative telomere length in dementia (N=70), Huntington's disease (N=35), ataxia telangiectasia (N=9), and age-group matched control samples (N=105) was measured as relative telomere copy/single copy gene ratios. Individuals with Huntington's disease had the lowest relative telomere copy/single copy gene ratio (0.21), followed by ataxia telangiectasia (0.31) and dementia (0.48). The younger control group had the highest relative telomere copy/single copy gene ratio (1.07). The reduced telomere length could be indicative of shared biological pathways across these disorders contributing to cellular senescence.

Does latitude as a zeitgeber affect the course of bipolar affective disorder?

BACKGROUND: Bipolar disorder (BD) is characterized by recurrent episodes of mood dysregulations and depression is considered as the most frequent form of relapse. However, there is some evidence that in tropical countries, the course might be different with fewer depressive episodes. This study aims to examine the frequency of depressive and manic episodes in a sample of subjects with BD from India. METHODS: Index subjects and a reliable informant (a family member) were interviewed with Diagnostic Interview for Genetic studies and a life chart was drawn to ascertain the episodes of illness in addition to reviewing their clinical case records. The mean total episode frequency and the mean manic and depressive episode frequency were estimated for this study. RESULTS: Data on the total episode number and number of manic and depressive episodes separately was available in 439 subjects. The subjects had been ill for 7.45 years, had experienced an average of 3.29 episodes of mania and 1.08 episodes of depression. Thus episodes of mania were seen to be more frequent. CONCLUSION: It has been increasingly recognized that circadian rhythm abnormalities could play an important role in the relapse and symptom expression of bipolar disorder. The mania predominance in the course of BD in this population contrasts from the depressive predominance in other studies. We suggest that this phenomenon could be a function of latitudinal gradient in the expression of BD using the zeitgeber hypothesis.

Summaries of oral sessions at the XXI World Congress of Psychiatric Genetics, Boston, Massachusetts, 17-21 October 2013: state of the field.

The XXI World Congress of Psychiatric Genetics (WCPG), sponsored by the International Society of Psychiatric Genetics (ISPG), took place in Boston, Massachusetts, on 17-21 October 2013. Approximately 900 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported.

Trinucleotide repeats and haplotypes at the huntingtin locus in an Indian sample overlaps with European haplogroup a.

Huntington's disease (HD), an autosomal dominant neurodegenerative syndrome, has a world-wide distribution. An estimated 2.5-10/100,000 people of European ancestry are affected with HD, while the Asian populations have lower prevalence (0.6-3.8/100,000). The epidemiology of HD is not well described in India, and the distribution of the pathogenic CAG expansion, and the associated haplotype, in this population needs to be better understood. This study demonstrates a distribution of CAG repeats, at the HTT locus, comparable to the European population in both normal and HD affected chromosomes. Further, we provide an evidence for similarity of the HD halpotype in Indian sample to the European HD haplogroup.

Identifying a predictive model for response to atypical antipsychotic monotherapy treatment in south Indian schizophrenia patients.

Atypical antipsychotic (AAP) drugs are the preferred choice of treatment for schizophrenia patients. Patients who do not show favorable response to AAP monotherapy are subjected to random prolonged therapeutic treatment with AAP multitherapy, typical antipsychotics or a combination of both. Therefore, prior identification of patients' response to drugs can be an important step in providing efficacious and safe therapeutic treatment. We thus attempted to elucidate a genetic signature which could predict patients' response to AAP monotherapy. Our logistic regression analyses indicated the probability that 76% patients carrying combination of four SNPs will not show favorable response to AAP therapy. The robustness of this prediction model was assessed using repeated 10-fold cross validation method, and the results across n-fold cross-validations (mean accuracy=71.91%; 95%CI=71.47-72.35) suggest high accuracy and reliability of the prediction model. Further validations of these results in large sample sets are likely to establish their clinical applicability.