Neuropsychiatric consequences of childhood group A streptococcal infection: A systematic review of preclinical models

In recent years, clinical studies have shown strong epidemiological evidence of an increased risk of developing neuropsychiatric disorders after childhood exposure to streptococcal infection, including the Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS). New preclinical studies on group A streptococcus (GAS) exposure investigate how to disentangle the influences of immune activation to induce long-term neurobehavioral effects associated with neuropsychiatric disorders such as obsessive–compulsive disorder, schizophrenia or autism. The present systematic review collects neurobehavioral evidence regarding the use of GAS exposure in animal models to study the vulnerability to different neuropsychiatric disorders, improving our understanding of its possible causes and consequences, and compares its contribution with other preclinical models of immune activation in a variety of paradigms. Specifically, we reviewed the effects of postnatal GAS exposure, in comparison with post- and prenatal exposure to Lipopolysaccharide (LPS) and Polyinosinic:polycytidylic acid (Poly I:C), on the long-term effects concerning psychomotor, cognition and socioemotional outcomes in rodents. GAS exposure in animal models has revealed different behavioral alterations such as reduced locomotion and motor coordination, a deficit in sensorimotor gating, learning, working memory, altered social behavior, and increased anxiety and stereotyped behavior. Most of the results found are in accordance with other immune activation models –LPS and Poly I:C–, with some discrepancies. The systematic review of the literature supports the preclinical model of GAS exposure as a valid model for studying the neurobehavioral consequences of streptococcal infections. Future studies on streptococcal infection could contribute increasing our knowledge on preventive actions or treatments for neuropsychiatric disorders.     

Current therapies and therapeutic decision making for childhood‐onset movement disorders

Movement disorders differ in children to adults. First, neurodevelopmental movement disorders such as tics and stereotypies are more prevalent than parkinsonism, and second, there is a genomic revolution which is now explaining many early‐onset dystonic syndromes. We outline an approach to children with movement disorders starting with defining the movement phenomenology, determining the level of functional impairment due to abnormal movements, and screening for comorbid psychiatric conditions and cognitive impairments which often contribute more to disability than the movements themselves. The rapid improvement in our understanding of the etiology of movement disorders has resulted in an increasing focus on precision medicine, targeting treatable conditions and defining modifiable disease processes. We profile some of the key disease‐modifying therapies in metabolic, neurotransmitter, inflammatory, and autoimmune conditions and the increasing focus on gene or cellular therapies. When no disease‐modifying therapies are possible, symptomatic therapies are often all that is available. These classically target dopaminergic, cholinergic, alpha‐adrenergic, or GABAergic neurochemistry. Increasing interest in neuromodulation has highlighted that some clinical syndromes respond better to DBS, and further highlights the importance of “disease‐specific” therapies with a future focus on individualized therapies according to the genomic findings or disease pathways that are disrupted. We summarize some pragmatic applications of symptomatic therapies, neuromodulation techniques, and some rehabilitative interventions and provide a contemporary overview of treatment in childhood‐onset movement disorders. © 2019 International Parkinson and Movement Disorder Society     

Whole genome association studies of neuropsychiatric disease: An emerging era of collaborative genetic discovery

Family history, which includes both common environmental and genetic effects, is associated with an increased risk for many neuropsychiatric diseases. Investigators have identified several disease-causing mutations for specific neuropsychiatric disorders that display Mendelian segregation. Such discoveries can lead to more rational drug design and improved intervention from a better understanding of the underlying biological mechanisms. However, a key challenge of genetic discovery in human complex diseases, including neuropsychiatric disorders, is that most diseases with genetic components display non-Mendelian patterns of inheritance. Recent advances in human population genetics include high-density genome-wide analyses of single nucleotide polymorphisms (SNPs) that make it possible to study complex genetic contributions to human disease. This approach is currently the most powerful strategy for analyzing the genetics of complex diseases. Genome-wide SNP analyses often require a large collaborative effort to collect, manage, and disseminate the numerous samples and corresponding clinical data. In this review we discuss the use of publicly available biorepositories for the collection and distribution of human genetic material, associated phenotypic information, and their use in genome-wide investigations of human neuropsychiatric diseases.     

A clinical overview of cholinesterase inhibitors in Alzheimer's disease

This review provides an overview of the three most widely used cholinesterase (ChE) inhibitors: donepezil, rivastigmine, and galantamine. Differences in pharmacologic profiles will be discussed, and consideration will be given to how such differences may relate to and influence the clinical efficacy and tolerability of the various agents. In addition to providing cognitive benefits in patients with Alzheimer's disease (AD), growing clinical evidence also suggests that ChE inhibitors can produce favorable and clinically relevant effects on neuropsychiatric/behavioral disturbances and activities of daily living. Furthermore, recent data indicate that these agents may be effective at all levels of disease severity and for all rates of disease progression. The clinical utility of ChE inhibitors in a wider spectrum of dementias which share a common cholinergic deficit, such as Lewy body dementia, Parkinson's disease dementia, and vascular dementia, is currently under investigation. Beyond symptomatic relief, data suggest that ChE inhibitors may also slow the underlying disease process. As clinical and research experience with these agents continues to accumulate, the differences in their effects will become more apparent and will help physicians tailor ChE inhibition treatment to the needs of the individual patient.     

Neuroconnectivity and valproic acid: The myelin hypothesis

Neuropsychiatric medications that directly alter the epigenome, such as valproic acid, can under certain conditions reactivate critical developmental periods and thus impact adult neuroconnectivity. In animal models valproic acid was shown to inhibit the process of postnatal myelination and to replicate age-dependent decline in remyelination efficiency. The human central nervous system's myelination process, unlike that of non-human primates commonly used in the experimental models, is an intricate heterochronous process that continues well into adult life and which probably underlies later life neurocognitive changes and plasticity. Chronic exposure to valproic acid, especially in patients with epilepsy and neuropsychiatric disorders, may profoundly affect this process and its developmental trajectory. Further studies using novel MRI methods that allow in vivo mapping of myelination trajectories across the lifespan are urgently required to address the potential effects of valproic acid on brain development.     

Neuropsychiatric movement disorders following streptococcal infection

The aim of this study was to describe post-streptococcal movement disorders that form part of the acute rheumatic fever complex. The clinical records of patients diagnosed with Sydenham's chorea were analyzed retrospectively to investigate epidemiology, the significance of socioeconomic deprivation, clinical manifestations, treatments, outcomes, long-term morbidity, and disease evolution. Forty-two patients (21 males, 21 females) were diagnosed with Sydenham's chorea. The median presentation age was 9 years 8 months (range 3y 5mo to 13y 2mo). Nineteen patients were of indigenous African ancestry; 23 were of mixed ancestry. All patients lived in poverty and had poor access to medical care. Twelve of the total group had disabling symptoms for longer than 2 years; six of these patients developed paediatric autoimmune neuropsychiatric disorder associated with Streptococcus (Paediatric autoimmune neuropsychiatric disorder associated with Streptococcus [PANDAS]), five Tourette syndrome (TS), and one learning difficulties. Poor outcome was significantly more prevalent in patients of mixed ancestry, in those with a positive family history, previous behavioural problems, or a failure to complete 10 days of penicillin and 'bed-rest'/hospitalization. Sydenham's chorea is one manifestation of post-streptococcal neuropsychiatric movement disorders. This study demonstrates that patients can present with one diagnosis and evolve other neuropsychiatric conditions such as TS and PANDAS. In the South African context, it is important to delineate neuropsychiatric movement disorders associated with streptococcal infections. The potential genetic susceptibility should be explored.     

Mapping causal pathways from genetics to neuropsychiatric disorders using genome‐wide imaging genetics: Current status and future directions

Imaging genetics aims to identify genetic variants associated with the structure and function of the human brain. Recently, collaborative consortia have been successful in this goal, identifying and replicating common genetic variants influencing gross human brain structure as measured through magnetic resonance imaging. In this review, we contextualize imaging genetic associations as one important link in understanding the causal chain from genetic variant to increased risk for neuropsychiatric disorders. We provide examples in other fields of how identifying genetic variant associations to disease and multiple phenotypes along the causal chain has revealed a mechanistic understanding of disease risk, with implications for how imaging genetics can be similarly applied. We discuss current findings in the imaging genetics research domain, including that common genetic variants can have a slightly larger effect on brain structure than on risk for disorders like schizophrenia, indicating a somewhat simpler genetic architecture. Also, gross brain structure measurements share a genetic basis with some, but not all, neuropsychiatric disorders, invalidating the previously held belief that they are broad endophenotypes, yet pinpointing brain regions likely involved in the pathology of specific disorders. Finally, we suggest that in order to build a more detailed mechanistic understanding of the effects of genetic variants on the brain, future directions in imaging genetics research will require observations of cellular and synaptic structure in specific brain regions beyond the resolution of magnetic resonance imaging. We expect that integrating genetic associations at biological levels from synapse to sulcus will reveal specific causal pathways impacting risk for neuropsychiatric disorders.     

The corticotopic organization of the human basal forebrain as revealed by regionally selective functional connectivity profiles

The cholinergic basal forebrain (CBF), comprising different groups of cortically projecting cholinergic neurons, plays a crucial role in higher cognitive processes and has been implicated in diverse neuropsychiatric disorders. A distinct corticotopic organization of CBF projections has been revealed in animal studies, but little is known about their organization in the human brain. We explored regional differences in functional connectivity (FC) profiles within the human CBF by applying a clustering approach to resting‐state functional magnetic resonance imaging (rs‐fMRI) data of healthy adult individuals (N = 85; 19–85 years). We further examined effects of age on FC of the identified CBF clusters and assessed the reproducibility of cluster‐specific FC profiles in independent data from healthy older individuals (N = 25; 65–89 years). Results showed that the human CBF is functionally organized into distinct anterior‐medial and posterior‐lateral subdivisions that largely follow anatomically defined boundaries of the medial septum/diagonal band and nucleus basalis Meynert. The anterior‐medial CBF subdivision was characterized by connectivity with the hippocampus and interconnected nodes of an extended medial cortical memory network, whereas the posterior‐lateral subdivision was specifically connected to anterior insula and dorsal anterior cingulate components of a salience/attention network. FC of both CBF subdivisions declined with increasing age, but the overall topography of subregion‐specific FC profiles was reproduced in independent rs‐fMRI data of healthy older individuals acquired in a typical clinical setting. Rs‐fMRI‐based assessments of subregion‐specific CBF function may complement established volumetric approaches for the in vivo study of CBF involvement in neuropsychiatric disorders.     

Erythrocyte choline concentrations in psychiatric disorders

Erythrocyte choline has been used as a potential indirect measure of cholinergic function in the central nervous system (CNS). We review the literature and present some new data on erythrocyte choline concentrations in patients with neuropsychiatric disorders. Our data and most of the reviewed studies report modest elevations in mean erythrocyte choline values in patients with affective illnesses, psychoses, dementia, and other neuropsychiatric disorders when compared to controls. Within each disorder, the increased mean erythrocyte choline concentrations are due to subgroups of patients with especially high values. These subgroups of patients with elevated erythrocyte choline levels appear to have clinical characteristics that distinguish them from patients with normal choline values. Finally, the dramatic rise in erythrocyte choline concentration produced by lithium therapy is reviewed, and the implication of this effect, in particular, the possibility that pretreatment or posttreatment erythrocyte choline concentrations may predict response to lithium, is discussed.     

Convergent functional genomic studies of omega-3 fatty acids in stress reactivity,bipolar disorder and alcoholism

Omega-3 fatty acids have been proposed as an adjuvant treatment option in psychiatric disorders. Given their other health benefits and their relative lack of toxicity, teratogenicity and side effects, they may be particularly useful in children and in females of child-bearing age, especially during pregnancy and postpartum. A comprehensive mechanistic understanding of their effects is needed. Here we report translational studies demonstrating the phenotypic normalization and gene expression effects of dietary omega-3 fatty acids, specifically docosahexaenoic acid (DHA), in a stress-reactive knockout mouse model of bipolar disorder and co-morbid alcoholism, using a bioinformatic convergent functional genomics approach integrating animal model and human data to prioritize disease-relevant genes. Additionally, to validate at a behavioral level the novel observed effects on decreasing alcohol consumption, we also tested the effects of DHA in an independent animal model, alcohol-preferring (P) rats, a well-established animal model of alcoholism. Our studies uncover sex differences, brain region-specific effects and blood biomarkers that may underpin the effects of DHA. Of note, DHA modulates some of the same genes targeted by current psychotropic medications, as well as increases myelin-related gene expression. Myelin-related gene expression decrease is a common, if nonspecific, denominator of neuropsychiatric disorders. In conclusion, our work supports the potential utility of omega-3 fatty acids, specifically DHA, for a spectrum of psychiatric disorders such as stress disorders, bipolar disorder, alcoholism and beyond.     

Targeted treatments for cognitive and neurodevelopmental disorders in tuberous sclerosis complex

Until recently, the neuropsychiatric phenotype of tuberous sclerosis complex (TSC) was presumed to be caused by the structural brain abnormalities and/or seizures seen in the disorder. However, advances in the molecular biology of the disorder have shown that TSC is a mammalian target of rapamycin (mTOR) overactivation syndrome, and that direct molecular pathways exist between gene mutation and cognitive/neurodevelopmental phenotype. Molecularly-targeted treatments using mTOR inhibitors (such as rapamycin) are showing great promise for the physical and neurological phenotype of TSC. Pre-clinical and early-phase clinical studies of the cognitive and neurodevelopmental features of TSC suggest that some of the neuropsychiatric phenotypes might also be reversible, even in adults with the disorder. TSC, fragile X, neurofibromatosis type 1, and disorders associated with phosphatase and tensin homo (PTEN) mutations, all signal through the mTOR signaling pathway, with the TSC1-TSC2 protein complex as a molecular switchboard at its center. Together, these disorders represent as much as 14% of autism spectrum disorders (ASD). Therefore, we suggest that this signaling pathway is a key to the underlying pathophysiology of a significant subset of individuals with ASD. The study of molecularly targeted treatments in TSC and related disorders, therefore, may be of scientific and clinical value not only to those with TSC, but to a larger population that may have a neuropsychiatric phenotype attributable to mTOR overactivation or dysregulation.     

The burden of complex genetics in brain disorders

BACKGROUND: Few data estimate the impact of complex genetics in neuropsychiatric illness, making it likely that this impact could be underappreciated. OBJECTIVE: To provide estimates of the impact of complex genetics in neuropsychiatric disorders in the United States, based on estimates of disease costs to US society, disease heritability, and mendelian contributions to disease.Data Sources, Study Selection, and DATA EXTRACTION: Costs were estimated from literature sources and Lewin-National Foundation for Brain Research estimates updated for population growth and consumer price index inflation. Heritability estimates came from available twin data. Estimates of mendelian contributions came from the Online Mendelian Inheritance in Man database and our perspectives. CONCLUSIONS: Brain and nervous system disorders may cost the United States as much as US dollars 1.2 trillion annually, and affect many millions of Americans each year. Twin data suggest that more than 40% of the societal burden of brain disorders is likely to be genetically mediated. Most of this disease burden arises from complex multigene genetics as well as from environmental influences. The large sizes of these complex genetic burdens should encourage careful molecular and clinical work to link disease-vulnerability allelic variants with the pathogenesis, nosologic characteristics, prevention, diagnostics, and therapeutics of brain disorders.     

Post-streptococcal autoimmune disorders of the central nervous system

Group A Streptococcus can induce autoimmune disease in humans with particular involvement of the heart, joints, and brain. The spectrum of post-streptococcal disease of the central nervous system (CNS) has been widened recently and includes movement disorders (chorea, tics, dystonia, and Parkinsonism), psychiatric disorders (particularly emotional disorders), and associated sleep disorders. Neuroimaging and pathological studies indicate that the most vulnerable brain region is the basal ganglia. The immunopathogenesis of the disease is incompletely defined, and although there is some support for autoantibody-mediated disease, several conflicting studies cast doubt on the autoantibody hypothesis. It has been speculated that post-streptococcal autoimmunity has a role in common neuropsychiatric disease but the evidence is conflicting and routine screening of patients with Tourette syndrome and obsessive-compulsive disorder for post-streptococcal autoimmune abnormalities is not be recommended at present. However, post-streptococcal disorders of the CNS remain a useful model of neuropsychiatric disease, which may improve our understanding of abnormal movements and behaviours in children.     

Potential trade‐offs in treatment of premanifest Huntington's disease

The potential long‐term consequences of treatments delaying manifestations of neurodegenerative diseases have not been explored. Using Huntington disease (HD) data and Markov chain Monte Carlo methods, we simulated the effects of therapies with equivalent effects on time to onset of HD and survival with HD. Our results suggest substantial potential trade‐offs in effects of these therapies; significant delays in time to onset of HD were accompanied by significant prolongations of survival after onset of HD. Under a variety of assumptions, treatments delaying onset of HD result in some patients likely to have a greater increase in survival with manifest HD compared to delays in time to onset of HD. Our results suggest that future work in HD should be sensitive to the potential existence of such trade‐offs and that understanding the preferences of HD patients and the broader HD community will be increasingly important. Future research, trial design, and treatment strategies in HD and other mid‐life‐onset neurodegenerative disorders should consider the possibility of trade‐offs in long‐term consequences of disease‐modifying treatments. © 2015 International Parkinson and Movement Disorder Society     

Acetylcholinergic neurotransmission and the beta-amyloid cascade: implications for Alzheimer's disease

Alzheimer's disease is characterized by both decreases in acetylcholinergic neurotransmission and increases in beta-amyloid accumulation. Currently, available clinical psychopharmacologic treatment is focused on increasing acetylcholinergic neurotransmission, whereas no clinical treatments to directly reduce beta-amyloid accumulation are available. Cholinesterase inhibitors improve cognition, certain neuropsychiatric symptoms and functional impairment in patients with mild-to-moderate Alzheimer's disease, and it is believed that this is mainly symptomatic treatment. However, this review discusses various levels of interaction between acetylcholinergic neurotransmission and the beta-amyloid cascade, which suggest that some specific acetylcholinergic treatments may reduce beta-amyloid accumulation, and therefore may slow disease progression over the long term. Various suggestions are made on how such potential disease-modifying effects could be studied in the future.     

Evaluating Rare Variants in Complex Disorders Using Next-Generation Sequencing

Determining the genetic architecture of liability for complex neuropsychiatric disorders like autism spectrum disorders and schizophrenia poses a tremendous challenge for contemporary biomedical research. Here we discuss how genetic studies first tested, and rejected, the hypothesis that common variants with large effects account for the prevalence of these disorders. We then explore how the discovery of structural variation has contributed to our understanding of the etiology of these disorders. The rise of fast and inexpensive oligonucleotide sequencing and methods of targeted enrichment and their influence on the search for rare genetic variation contributing to complex neuropsychiatric disorders is the next focus of our article. Finally, we consider the technical challenges and future prospects for the use of next-generation sequencing to reveal the complex genetic architecture of complex neuropsychiatric disorders in both research and the clinical settings.     

Diabetes,insulin and new therapeutic strategies for Parkinson’s disease: Focus on glucagon-like peptide-1 receptor agonists

Parkinson's disease and diabetes mellitus are two chronic disorders associated with aging that are becoming increasingly prevalent worldwide. Parkinson is a multifactorial progressive condition with no available disease modifying treatments at the moment. Over the last few years there is growing interest in the relationship between diabetes (and impaired insulin signaling) and neurodegenerative diseases, as well as the possible benefit of antidiabetic treatments as neuroprotectors, even in non-diabetic patients. Insulin regulates essential functions in the brain such as neuronal survival, autophagy of toxic proteins, synaptic plasticity, neurogenesis, oxidative stress and neuroinflammation. We review the existing epidemiological, experimental and clinical evidence that supports the interplay between insulin and neurodegeneration in Parkinson's disease, as well as the role of antidiabetic treatments in this disease.     

Emerging treatments: replacement therapy with choline or lecithin in neurological diseases.

This review evaluates the theoretical background and experimental data behind a new development: the replacement therapy of deficient central cholinergic systems with the dietary precursors choline or lecithin. Cholinergic deficiency states are possibly present in five neurological entities: Huntington's chorea, Tardive Dyskinesia, Gilles de la Tourette's disease, Friedreich's ataxia and pre-senile dementia. Preliminary data from various laboratories, including our own, in each of these disorders indicate that some clinical improvement can occasionally be seen, and that this approach deserves further investigation.     

Personality change in old age

PURPOSE OF REVIEW: The present short review summarizes some of the most important personality changes in older adults. RECENT FINDINGS: Personality changes in old age are usually minimal. Cluster B personality disorders appear to become less prevalent. Significant changes in personality are typically associated with frontotemporal lobar degeneration (e.g., slowly progressive sociopathy), Alzheimer's disease, mild cognitive impairment due to incipient dementia or underlying medical illness. SUMMARY: Therefore, we suggest that a significant change in personality in old age always warrants careful neuropsychiatric examination.