Crisis Standard of Care: Management of Infantile Spasms during COVID‐19

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156180/2/ana25792_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156180/1/ana25792.pd

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

MORPHOMETRIC EVIDENCE THAT THE TOTAL NUMBER OF SYNAPSES ON PURKINJE NEURONS OF OLD F344 RATS IS REDUCED AFTER LONG-TERM ETHANOL TREATMENT AND RESTORED TO CONTROL LEVELS AFTER RECOVERY

Abstract — Clinical symptoms of alcohol abuse may be confused with symptoms of age-related neuropathologies in human patients. It is important, therefore, to determine the relationships between alcohol abuse and changes in brain structures in well-controlled studies of ageing subjects. Currently there is little well-documented information of this type available. The purpose of this study was to determine whether long-term ethanol treatment during ageing would lead to reductions in synaptic input to cerebellar Purkinjc neurons (PN) of old F344 rats that; (1) were more severe than those attributable to ageing alone; (2) might be responsible for an ethanol-related deletion of dendritic segments of PN in old F344 rats shown previously in this laboratory. The total number of synapses per PN dendritic arbor was determined after ethanol treatment of old F344 rats for 40 weeks between 12 and 22 months of age and in similarly treated rats given a subsequent 20-week period of recovery between 22 and 27 months of age. Groups of age-matched rats fed a chow diet and water and rats pair-fed an isocaloric liquid diet lacking ethanol served as controls. The volume of the molecular layer per PN arbor and the numerical density of synapses in the molecular layer was determined from light microscopic preparations of a fixed volume of the cerebellar cortex. Photographic montages of the ultrastructure of the molecular layer of the cerebellum were also prepared from each rat for measurements of synaptic numerical densities. From th

Cerebral Developmental Abnormalities in a Mouse with Systemic Pyruvate Dehydrogenase Deficiency.

UNLABELLEDPyruvate dehydrogenase (PDH) complex (PDC) deficiency is an inborn error of pyruvate metabolism causing a variety of neurologic manifestations. Systematic analyses of development of affected brain structures and the cellular processes responsible for their impairment have not been performed due to the lack of an animal model for PDC deficiency.METHODSIn the present study we investigated a murine model of systemic PDC deficiency by interrupting the X-linked Pdha1 gene encoding the α subunit of PDH to study its role on brain development and behavioral studies.RESULTSMale embryos died prenatally but heterozygous females were born. PDC activity was reduced in the brain and other tissues in female progeny compared to age-matched control females. Immunohistochemical analysis of several brain regions showed that approximately 40% of cells were PDH(-). The oxidation of glucose to CO2 and incorporation of glucose-carbon into fatty acids were reduced in brain slices from 15 day-old PDC-deficient females. Histological analyses showed alterations in several structures in white and gray matters in 35 day-old PDC-deficient females. Reduction in total cell number and reduced dendritic arbors in Purkinje neurons were observed in PDC-deficient females. Furthermore, cell proliferation, migration and differentiation into neurons by newly generated cells were reduced in the affected females during pre- and postnatal periods. PDC-deficient mice had normal locomotor activity in a novel environment but displayed decreased startle responses to loud noises and there was evidence of abnormal pre-pulse inhibition of the startle reflex.CONCLUSIONSThe results show that a reduction in glucose metabolism resulting in deficit in energy production and fatty acid biosynthesis impairs cellular differentiation and brain development in PDC-deficient mice

Glucose and acetate oxidation to CO₂ and glucose-carbon and acetate-carbon incorporation into fatty acids by brain slices from of P15 and P35 control and PDC-deficient females.

a<p>Data are means (nmol of labeled substrate converted/g tissue/h) ± S.D. (n = 5–6).</p>b<p>P<0.05.</p

Plot a shows the acoustic startle response.

<p>Plot b shows pre-pulse inhibition of the acoustic startle response as a function the intensity of the pre-pulse stimulus. Pre-pulse intensity was measured in decibels (dB). PDC-deficient mice had markedly decreased startle responses and evidence of impaired pre-pulse inhibition of the acoustic startle response at the highest pre-pulse stimulus intensity. Error bars indicate standard error of the mean. Data are reported as mean ± SEM (n = 4).</p

Quantitation of number of the Purkinje cell nuclei in P35 control and PDC-deficient females.

<p>(A) Gaussian histogram of the Purkinje cell nuclei counts. (B) Average counts of the Purkinje cell nuclei. Twenty sections from 2 brains from each group were analyzed. Sections were spaced at 350 mm. Area of the Purkinje cell layer was randomly chosen, its length was 200 µm. Data are means ± S.D., *represents P<0.05.</p

Genetic analysis of the <i>Pdha1</i> locus in control and PDC-deficient female progeny.

<p>(A) Depiction of wild-type (<i>Pdha1^wt)</i>, floxed (<i>Pdha1^flox8</i>), and null (<i>Pdha1</i>^Δ<i>ex8</i>) <i>Pdha1</i> alleles and the primers (arrows above the allele representations) used for genotypic analysis. (B) Genotypic analysis of the <i>Pdha1</i> locus in brain (B), liver (L), heart (H) and skeletal muscle (SM) tissues from a female offspring (genotye: <i>Pdha1</i>^Δ<i>ex8</i><i>/Pdha1^wt; Cre^all+</i>) produced from mating a floxed homozygous female with a <i>Cre</i> transgenic male. Upper gel [genotypes: wild-type allele (700 bp), floxed allele (800 bp), and null allele (400 bp)]. Lower gel: [genotype: <i>Cre</i> transgene (240 bp)]. − (minus) Lane: DNA from a wild-type female (700 bp), and+(plus) Lane: floxed allele (800 bp; upper gel) from a floxed female and null allele (240 bp; lower gel) from a PDC-deficient female included as negative and positive controls. M: DNA marker.</p

Immunostaining for BrdU and NeuN of the cerebella from P5 control and PDC-deficient females.

<p>BrdU was injected intraperitoneally (50 mg/kg body weight; 3 times 2 h apart), into 14-day pregnant dams. They were allowed to deliver pups naturally and nurse them. On P5 female progeny brain slices were immunolabeled with BrdU (red, upper panel) using rat anti-BrdU antibody (Oxford Biotechnology) and NeuN (green, middle panel) using mouse monoclonal antibody (Chemicon). Granule cell layer is marked by arrows. Bar is 50 µm.</p