Focus: The Aging Brain: The Significance of the Default Mode Network (DMN) in Neurological and Neuropsychiatric Disorders: A Review

The relationship of cortical structure and specific neuronal circuitry to global brain function, particularly its perturbations related to the development and progression of neuropathology, is an area of great interest in neurobehavioral science. Disruption of these neural networks can be associated with a wide range of neurological and neuropsychiatric disorders. Herein we review activity of the Default Mode Network (DMN) in neurological and neuropsychiatric disorders, including Alzheimer’s disease, Parkinson’s disease, Epilepsy (Temporal Lobe Epilepsy - TLE), attention deficit hyperactivity disorder (ADHD), and mood disorders. We discuss the implications of DMN disruptions and their relationship to the neurocognitive model of each disease entity, the utility of DMN assessment in clinical evaluation, and the changes of the DMN following treatment.     

Single-Cell Gene Expression Analysis: Implications for Neurodegenerative and Neuropsychiatric Disorders

Technical and experimental advances in microaspiration techniques, RNA amplification, quantitative real-time polymerase chain reaction (qPCR), and cDNA microarray analysis have led to an increase in the number of studies of single-cell gene expression. In particular, the central nervous system (CNS) is an ideal structure to apply single-cell gene expression paradigms. Unlike an organ that is composed of one principal cell type, the brain contains a constellation of neuronal and noneuronal populations of cells. A goal is to sample gene expression from similar cell types within a defined region without potential contamination by expression profiles of adjacent neuronal subpopulations and noneuronal cells. The unprecedented resolution afforded by single-cell RNA analysis in combination with cDNA microarrays and qPCR-based analyses allows for relative gene expression level comparisons across cell types under different experimental conditions and disease states. The ability to analyze single cells is an important distinction from global and regional assessments of mRNA expression and can be applied to optimally prepared tissues from animal models as well as postmortem human brain tissues. This focused review illustrates the potential power of single-cell gene expression studies within the CNS in relation to neurodegenerative and neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia, respectively.     

NCAM Mimetic Peptides: Potential Therapeutic Target for Neurological Disorders

The neural cell adhesion molecule (NCAM) plays a pivotal role in the development and maintenance of the nervous system via homophilic (NCAM–NCAM) and heterophilic (NCAM-other molecules) interactions. Many synthetic peptides have been engineered to mimic these interactions and induce NCAM-downstream signaling pathways. Such NCAM mimetics have displayed neuritogenic and neuroprotective properties, as well as synaptic modulation in vitro and in vivo. Furthermore, they have been used successfully in preclinical studies to treat neurological disorders including stroke, traumatic brain injury and Alzheimer’s disease. This review focuses on recent progress in the development of NCAM mimetic peptides, in particular, on establishing C3, plannexin, and FGL as therapeutic candidates for neurological disorders.     

Cryptic and Complex Chromosomal Aberrations in Early-Onset Neuropsychiatric Disorders

Structural variation (SV) is a significant component of the genetic etiology of both neurodevelopmental and psychiatric disorders; however, routine guidelines for clinical genetic screening have been established only in the former category. Genome-wide chromosomal microarray (CMA) can detect genomic imbalances such as copy-number variants (CNVs), but balanced chromosomal abnormalities (BCAs) still require karyotyping for clinical detection. Moreover, submicroscopic BCAs and subarray threshold CNVs are intractable, or cryptic, to both CMA and karyotyping. Here, we performed whole-genome sequencing using large-insert jumping libraries to delineate both cytogenetically visible and cryptic SVs in a single test among 30 clinically referred youth representing a range of severe neuropsychiatric conditions. We detected 96 SVs per person on average that passed filtering criteria above our highest-confidence resolution (6,305 bp) and an additional 111 SVs per genome below this resolution. These SVs rearranged 3.8 Mb of genomic sequence and resulted in 42 putative loss-of-function (LoF) or gain-of-function mutations per person. We estimate that 80% of the LoF variants were cryptic to clinical CMA. We found myriad complex and cryptic rearrangements, including a “paired” duplication (360 kb, 169 kb) that flanks a 5.25 Mb inversion that appears in 7 additional cases from clinical CNV data among 47,562 individuals. Following convergent genomic profiling of these independent clinical CNV data, we interpreted three SVs to be of potential clinical significance. These data indicate that sequence-based delineation of the full SV mutational spectrum warrants exploration in youth referred for neuropsychiatric evaluation and clinical diagnostic SV screening more broadly.     

Clinical and Laboratory Aspects of Insulin Autoantibody-Mediated Glycaemic Dysregulation and Hyperinsulinaemic Hypoglycaemia: Insulin Autoimmune Syndrome and Exogenous Insulin Antibody Syndrome

Autoimmune glycaemic dysregulation and hyperinsulinaemic hypoglycaemia mediated by insulin autoantibodies is an increasingly recognised but controversial phenomenon described in both exogenous insulin naïve (insulin autoimmune syndrome) and exposed (exogenous insulin antibody syndrome) individuals. There has been a significant proliferation of case reports, clinical studies and reviews in the medical literature in recent years which have collectively highlighted the discrepancy between experts in the field with regard to the nomenclature, definition, proposed pathophysiology, as well as the clinical and biochemical diagnostic criteria associated with the condition. The essential characteristics of the condition are glycaemic dysregulation manifesting as episodes of hyperglycaemia and unpredictable hyperinsulinaemic hypoglycaemia associated with high titres of endogenous antibodies to insulin. Although the hypoglycaemia is often life-threatening and initiation of targeted therapies critical, the diagnosis is often delayed and attributable to various factors including: the fact that existence of the condition is not universally accepted; the need to exclude surreptitious causes of hypoglycaemia; the diverse and often complex nature of the glycaemic dysregulation; and the challenge of diagnostic confirmation. Once confirmed, the available therapeutic options are expansive and the reported responses to these therapies have been variable. This review will focus on our evolving understanding, and the associated diagnostic challenges – both clinical and laboratory – of this complex condition.     

Proline Metabolism in Neurological and Psychiatric Disorders

Proline plays a multifaceted role in protein synthesis, redox balance, cell fate regulation, brain development, and other cellular and physiological processes. Here, we focus our review on proline metabolism in neurons, highlighting the role of dysregulated proline metabolism in neuronal dysfunction and consequently neurological and psychiatric disorders. We will discuss the association between genetic and protein function of enzymes in the proline pathway and the development of neurological and psychiatric disorders. We will conclude with a potential mechanism of proline metabolism in neuronal function and mental health.     

Optimal Brain MRI Protocol for New Neurological Complaint

Background/Purpose

Patients with neurologic complaints are imaged with MRI protocols that may include many pulse sequences. It has not been documented which sequences are essential. We assessed the diagnostic accuracy of a limited number of sequences in patients with new neurologic complaints.

Methods

996 consecutive brain MRI studies from patients with new neurological complaints were divided into 2 groups. In group 1, reviewers used a 3-sequence set that included sagittal T1-weighted, axial T2-weighted fluid-attenuated inversion recovery, and axial diffusion-weighted images. Subsequently, another group of studies were reviewed using axial susceptibility-weighted images in addition to the 3 sequences. The reference standard was the study''s official report. Discrepancies between the limited sequence review and the reference standard including Level I findings (that may require immediate change in patient management) were identified.

Results

There were 84 major findings in 497 studies in group 1 with 21 not identified in the limited sequence evaluations: 12 enhancing lesions and 3 vascular abnormalities identified on MR angiography. The 3-sequence set did not reveal microhemorrhagic foci in 15 of 19 studies. There were 117 major findings in 499 studies in group 2 with 19 not identified on the 4-sequence set: 17 enhancing lesions and 2 vascular lesions identified on angiography. All 87 Level I findings were identified using limited sequence (56 acute infarcts, 16 hemorrhages, and 15 mass lesions).

Conclusion

A 4-pulse sequence brain MRI study is sufficient to evaluate patients with a new neurological complaint except when contrast or angiography is indicated.     

Metabolomic Assays of Postmortem Brain Extracts: Pitfalls in Extrapolation of Concentrations of Glucose and Amino Acids to Metabolic Dysregulation In Vivo in Neurological Diseases

Neurochemical Research - Glucose utilization is reduced in vulnerable brain regions affected by neurological disorders, especially Alzheimer’s disease (AD), but the basis for abnormal glucose...     

Autophagy and Neuronal Cell Death in Neurological Disorders

Autophagy is implicated in the pathogenesis of major neurodegenerative disorders although concepts about how it influences these diseases are still evolving. Once proposed to be mainly an alternative cell death pathway, autophagy is now widely viewed as both a vital homeostatic mechanism in healthy cells and as an important cytoprotective response mobilized in the face of aging- and disease-related metabolic challenges. In Alzheimer’s, Parkinson’s, Huntington’s, amyotrophic lateral sclerosis, and other diseases, impairment at different stages of autophagy leads to the buildup of pathogenic proteins and damaged organelles, while defeating autophagy’s crucial prosurvival and antiapoptotic effects on neurons. The differences in the location of defects within the autophagy pathway and their molecular basis influence the pattern and pace of neuronal cell death in the various neurological disorders. Future therapeutic strategies for these disorders will be guided in part by understanding the manifold impact of autophagy disruption on neurodegenerative diseases.Soon after the discovery of lysosomes by de Duve in the 1950s, electron microscopists recognized the presence of cytoplasmic organelles within membrane-limited vacuoles (Clark 1957) and observed what appeared to be the progressive breakdown of these contents (Ashford and Porter 1962). Proposing that “prelysosomes” containing sequestered cytoplasm matured to autolysosomes by fusion with primary lysosomes, de Duve and colleagues (de Duve 1963; de Duve and Wattiaux 1966) named this process “autophagy” (self-eating). Neurons, as cells particularly rich in acid phosphatase-positive lysosomes, were a preferred model in the initial investigations of autophagy. Early studies of pathologic states such as neuronal chromatolysis (Holtzman and Novikoff 1965; Holtzman et al. 1967) linked neurodegenerative phenomena to robust proliferation of autophagic vacuoles (AVs) and lysosomes. Although de Duve appreciated the importance of lysosomes for maintaining cell homeostasis, he was especially intrigued with their potential as “suicide bags” capable of triggering cell death by releasing proteases into the cytoplasm. Despite some support for this notion (Brunk and Brun 1972), the concept was not significantly embraced until many decades later. Instead, for many years, lysosomes and autophagy were mainly considered to perform cellular housekeeping and to scavenge and clean up debris during neurodegeneration in preparation for regenerative processes. The connection between autophagy and neuronal cell death reemerged in the 1970s from observations of Clarke and colleagues, who presented evidence that the developing brain deployed autophagy as a form of programmed neuronal cell death during which autophagy was massively up-regulated to eliminate cytoplasmic components, at once killing the neuron and reducing its cell mass for easy removal. Self-degradation was suggested as a more efficient elimination mechanism than apoptosis, which requires a large population of phagocytic cells and access of these cells to the dying region (Baehrecke 2005). Indeed, the best evidence for this process is in the context of massive cell death, as in metamorphosis and involutional states (Das et al. 2012).Clarke proposed that autophagic cell death (ACD)—type 2 programmed cell death (PCD)—could be a relatively common alternative route to death distinct from apoptosis—type 1 PCD (Clarke 1990)—or caspase-independent cell death—type 3 PCD (Fig. 1). The distinguishing features of ACD are marked proliferation of AVs and progressive disappearance of organelles but relative preservation of cytoskeletal and nuclear integrity until late in the process (Schweichel and Merker 1973; Hornung et al. 1989). In this original concept of ACD or type 2 PCD, death is achieved by autophagic digestion of organelles and essential regulatory molecules and elimination of death inhibitory factors (Baehrecke 2005). With the advent of the molecular era of autophagy research in the 1990s, it became possible to verify the most important implication of ACD, namely, that the death could be prevented by inhibiting autophagy genetically or pharmacologically. Meanwhile, reports of prominent lysosomal/autophagic pathology in Alzheimer’s disease (AD) (Cataldo et al. 1997; Nixon et al. 2000, 2005) and other neuropathic states (Anglade et al. 1997; Rubinsztein et al. 2005) raised important questions about whether autophagy pathology signifies a prodeath program or an attempt to maintain survival—a critical question for any potential therapy based on autophagy modulation. In this article, we will examine evidence for the various neuroprotective roles of autophagy and review our current understanding of how specific stages of autophagy may become disrupted and influence the neurodegenerative pattern seen in major adult-onset neurological diseases. We will particularly focus on how neurons regulate the balance between prosurvival autophagy and well-established cell death mechanisms in making life or death decisions.Open in a separate windowFigure 1.Neuronal cell death: three general morphological types of dying cells in the developing nervous system, as initially classified by Schweichel and Merker (1973) and later Clarke (1990). (A,B) Type 1 (“apoptotic”) cell death: (A) A neuron, from the brain of a postnatal day 6 mouse pup, in the middle of apoptotic degeneration showing cell shrinkage, cytoplasmic condensation, ruffled plasma membrane, and a highly electron-dense nucleus. Endoplasmic reticulum (ER) is still recognizable and some are dilated. A small number of autophagic vacuoles (AVs) can be seen (arrows). (B) A late-stage apoptotic neuron displaying electron-dense chromatin balls (CB), each surrounded by a small amount of highly condensed cytoplasm. (Panel from Yang et al. 2008; reprinted, with permission, from the American Association of Pathologists and Bacteriologists.) (C) Type 2 (“autophagic”) cell death: a deafferented isthmo-optic neuron in developing chick brain after uptake of horseradish peroxidase to highlight (electron dense) endocytic and autophagic compartments. The cell death pattern features pyknosis, abundant AVs, and sometimes dilated ER and mitochondria. (Panel from Hornung et al. 1989; reproduced, with permission, from John Wiley & Sons) (D) Type 3 (“cytoplasmic, nonlysosomal”) cell death: a motoneuron displaying markedly dilated rough ER, Golgi, and nuclear envelope, late vacuolization, and increased chromatin granularity. (Panel from Chu-Wang and Oppenheim 1978; reproduced, with permission, from John Wiley & Sons) Scale bars, 1 µm (A,B); 2 µm (C,D).     

Protective Role of Capsaicin in Neurological Disorders: An Overview

Neurochemical Research - Different pathological conditions that begin with slow and progressive deformations, cause irreversible affliction by producing loss of neurons and synapses. Commonly it is...     

Coenzyme Q10 Depletion in Medical and Neuropsychiatric Disorders: Potential Repercussions and Therapeutic Implications

Coenzyme Q10 (CoQ10) is an antioxidant, a membrane stabilizer, and a vital cofactor in the mitochondrial electron transport chain, enabling the generation of adenosine triphosphate. It additionally regulates gene expression and apoptosis; is an essential cofactor of uncoupling proteins; and has anti-inflammatory, redox modulatory, and neuroprotective effects. This paper reviews the known physiological role of CoQ10 in cellular metabolism, cell death, differentiation and gene regulation, and examines the potential repercussions of CoQ10 depletion including its role in illnesses such as Parkinson’s disease, depression, myalgic encephalomyelitis/chronic fatigue syndrome, and fibromyalgia. CoQ10 depletion may play a role in the pathophysiology of these disorders by modulating cellular processes including hydrogen peroxide formation, gene regulation, cytoprotection, bioenegetic performance, and regulation of cellular metabolism. CoQ10 treatment improves quality of life in patients with Parkinson’s disease and may play a role in delaying the progression of that disorder. Administration of CoQ10 has antidepressive effects. CoQ10 treatment significantly reduces fatigue and improves ergonomic performance during exercise and thus may have potential in alleviating the exercise intolerance and exhaustion displayed by people with myalgic encepholamyletis/chronic fatigue syndrome. Administration of CoQ10 improves hyperalgesia and quality of life in patients with fibromyalgia. The evidence base for the effectiveness of treatment with CoQ10 may be explained via its ability to ameliorate oxidative stress and protect mitochondria.     

Human Mitochondrial Transmembrane Metabolite Carriers: Tissue Distribution and Its Implication for Mitochondrial Disorders

Mitochondrial transmembrane carrier deficiencies are a recently discovered group of disorders, belonging to the so-called mitochondriocytopathies. We examined the human tissue distribution of carriers which are involved in the process of oxidative phosphorylation (adenine nucleotide translocator, phosphate carrier, and voltage-dependent anion channel) and some mitochondrial substrate carriers (2-oxoglutarate carrier, carnitine-acylcarnitine carrier, and citrate carrier). The tissue distribution on mRNA level of mitochondrial transport proteins appears to be roughly in correlation with the dependence of these tissues on mitochondrial energy production capacity. In general the main mRNA expression of carriers involved in mitochondrial energy metabolism occurs in skeletal muscle and heart. Expression in liver and pancreas differs between carriers. Expression in brain, placenta, lung, and kidney is lower than in the other tissues. Western and Northern blotting experiments show a comparable HVDAC1 protein and mRNA distribution for the tested tissues. Patient's studies showed that cultured skin fibroblasts may not be a reliable alternative for skeletal muscle in screening for human mitochondrial carrier defects.