Reduced Cholinergic Basal Forebrain Integrity Links Neonatal Complications and Adult Cognitive Deficits After Premature Birth

BACKGROUND Prematurely born individuals have an increased risk for long-term neurocognitive impairments. In animal models, development of the cholinergic basal forebrain (cBF) is selectively vulnerable to adverse effects of perinatal stressors, and impaired cBF integrity results in lasting cognitive deficits. We hypothesized that cBF integrity is impaired in prematurely born individuals and mediates adult cognitive impairments associated with prematurity. METHODS We used magnetic resonance imaging-based volumetric assessments of a cytoarchitectonically defined cBF region of interest to determine differences in cBF integrity between 99 adults who were born very preterm and/or with very low birth weight and 106 term-born control subjects from the same birth cohort. Magnetic resonance imaging-derived cBF volumes were studied in relation to neonatal clinical complications after delivery and intelligence measures (IQ) in adulthood. RESULTS In adults who were born very preterm and/or with very low birth weight, cBF volumes were significantly reduced compared with term-born adults (-4.5% [F1,202 = 11.82, p = .001]). Lower cBF volume in adults who were born very preterm and/or with very low birth weight was specifically associated with both neonatal complications (rpart,92 = -.35, p < .001) and adult IQ (rpart,88 = .33, p = .001) even after controlling for global gray matter and white matter volume. In a path analytic model, cBF volume significantly mediated the association between neonatal complications and adult cognitive deficits. CONCLUSIONS We provide first-time evidence in humans that cBF integrity is impaired after premature birth and links neonatal complications with long-term cognitive outcome. Data suggest that cholinergic system abnormalities may play a relevant role for long-term neurocognitive impairments associated with premature delivery.

[1]  H. Helenius,et al.  A randomized controlled trial of rivastigmine for chronic sequels of traumatic brain injury—What it showed and taught? , 2009, Brain injury.

[2]  F. Vaccarino,et al.  Neurobiology of premature brain injury , 2014, Nature Neuroscience.

[3]  Rebecca D. Folkerth,et al.  Gray matter injury associated with periventricular leukomalacia in the premature infant , 2007, Acta Neuropathologica.

[4]  S. Heishman,et al.  Meta-analysis of the acute effects of nicotine and smoking on human performance , 2010, Psychopharmacology.

[5]  Christian Sorg,et al.  Correspondence Between Aberrant Intrinsic Network Connectivity and Gray-Matter Volume in the Ventral Brain of Preterm Born Adults. , 2015, Cerebral cortex.

[6]  D. Arciniegas.  The cholinergic hypothesis of cognitive impairment caused by traumatic brain injury , 2003, Current psychiatry reports.

[7]  Martin Sarter,et al.  Developmental origins of the age-related decline in cortical cholinergic function and associated cognitive abilities , 2004, Neurobiology of Aging.

[8]  Saroj Saigal,et al.  An overview of mortality and sequelae of preterm birth from infancy to adulthood , 2008, The Lancet.

[9]  T. Baldeweg,et al.  Total brain white matter is a major determinant of IQ in adolescents born preterm , 2011, Annals of neurology.

[10]  R. Freedman,et al.  Perinatal choline effects on neonatal pathophysiology related to later schizophrenia risk. , 2013, The American journal of psychiatry.

[11]  E. Mufson,et al.  Maternal choline supplementation improves spatial mapping and increases basal forebrain cholinergic neuron number and size in aged Ts65Dn mice , 2014, Neurobiology of Disease.

[12]  J. Volpe.  Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances , 2009, The Lancet Neurology.

[13]  J. Bremner,et al.  MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders , 2005, Molecular Psychiatry.

[14]  Rebecca D Folkerth,et al.  Neuron deficit in the white matter and subplate in periventricular leukomalacia , 2012, Annals of neurology.

[15]  J. Allsop,et al.  Quantification of Deep Gray Matter in Preterm Infants at Term-Equivalent Age Using Manual Volumetry of 3-Tesla Magnetic Resonance Images , 2007, Pediatrics.

[16]  S. Stahl.  Cholinesterase inhibitors for Alzheimer's disease. , 1998, Hospital practice.

[17]  Chiara Nosarti,et al.  Grey and white matter distribution in very preterm adolescents mediates neurodevelopmental outcome. , 2008, Brain : a journal of neurology.

[18]  B. Pappas,et al.  Neonatal lesion of forebrain cholinergic neurons: Further characterization of behavioral effects and permanency , 2005, Neuroscience.

[19]  H. Heinsen,et al.  Longitudinal measures of cholinergic forebrain atrophy in the transition from healthy aging to Alzheimer's disease , 2013, Neurobiology of Aging.

[20]  P. Snyder,et al.  Microdosing of scopolamine as a “cognitive stress test”: Rationale and test of a very low dose in an at-risk cohort of older adults , 2014, Alzheimer's & Dementia.

[21]  Sheng Zhang,et al.  Resting state functional connectivity of the basal nucleus of Meynert in humans: In comparison to the ventral striatum and the effects of age , 2014, NeuroImage.

[22]  Christopher J. Cannistraci,et al.  Regional brain volume abnormalities and long-term cognitive outcome in preterm infants. , 2000, JAMA.

[23]  Peter Bartmann,et al.  Preterm Cognitive Function Into Adulthood , 2015, Pediatrics.

[24]  Y. Sohn,et al.  Volumetric analysis of the substantia innominata in patients with Parkinson's disease according to cognitive status , 2012, Neurobiology of Aging.

[25]  L. Calzà,et al.  Prenatal glucocorticoid exposure affects learning and vulnerability of cholinergic neurons , 2007, Neurobiology of Aging.

[26]  Ann-Beth Moller,et al.  National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications , 2012, The Lancet.

[27]  Derek K. Jones,et al.  Cholinergic Basal Forebrain Structure Influences the Reconfiguration of White Matter Connections to Support Residual Memory in Mild Cognitive Impairment , 2015, The Journal of Neuroscience.

[28]  M. Hasselmo,et al.  Modes and Models of Forebrain Cholinergic Neuromodulation of Cognition , 2011, Neuropsychopharmacology.

[29]  Oliver Wilhelm,et al.  TBS-TK Rezensionen Wechsler Intelligenztest für Erwachsene WIE. Deutschsprachige Bearbeitung und Adaptation des WAIS-III von David Wechsler , 2010 .

[30]  Christian Sorg,et al.  Extensive and interrelated subcortical white and gray matter alterations in preterm-born adults , 2015, Brain Structure and Function.

[31]  Kristopher J Preacher,et al.  SPSS and SAS procedures for estimating indirect effects in simple mediation models , 2004, Behavior research methods, instruments, & computers : a journal of the Psychonomic Society, Inc.

[32]  E K Perry,et al.  Cholinergic activity in autism: abnormalities in the cerebral cortex and basal forebrain. , 2001, The American journal of psychiatry.

[33]  C. Van Petten,et al.  Relationship between hippocampal volume and memory ability in healthy individuals across the lifespan: review and meta-analysis. , 2004, Neuropsychologia.

[34]  I. Maidment,et al.  Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Parkinson's disease. , 2012, The Cochrane database of systematic reviews.

[35]  H. Möller,et al.  Measurement of basal forebrain atrophy in Alzheimer's disease using MRI. , 2005, Brain : a journal of neurology.

[36]  Christelle Anaclet,et al.  Basal forebrain control of wakefulness and cortical rhythms , 2015, Nature Communications.

[37]  K. Amunts,et al.  Reduction of basal forebrain cholinergic system parallels cognitive impairment in patients at high risk of developing Alzheimer's disease. , 2010, Cerebral cortex.

[38]  W. Deng,et al.  Neurobiology of injury to the developing brain , 2010, Nature Reviews Neurology.

[39]  J. Pantel,et al.  Mild Cognitive Impairment in the Elderly is Associated with Volume Loss of the Cholinergic Basal Forebrain Region , 2010, Biological Psychiatry.

[40]  D. Gadian,et al.  The Effect of Early Human Diet on Caudate Volumes and IQ , 2008, Pediatric Research.

[41]  T. Arendt,et al.  The cholinergic system in aging and neuronal degeneration , 2011, Behavioural Brain Research.

[42]  M. Johnston.  Neurotransmitter alterations in a model of perinatal hypoxic‐ischemic brain injury , 1983, Annals of neurology.

[43]  F. Gil-Bea,et al.  Neonatal stress affects vulnerability of cholinergic neurons and cognition in the rat: Involvement of the HPA axis , 2009, Psychoneuroendocrinology.

[44]  Lea T Grinberg,et al.  Cognitive Correlates of Basal Forebrain Atrophy and Associated Cortical Hypometabolism in Mild Cognitive Impairment. , 2016, Cerebral cortex.

[45]  Jon Skranes,et al.  Brain volumes and cognitive function in very-low-birth-weight (VLBW) young adults. , 2014, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[46]  S. Mirra,et al.  The nucleus basalis of Meynert in neurological disease: A quantitative morphological study , 1985, Annals of neurology.

[47]  F. Leslie,et al.  The effects of perinatal choline supplementation on hippocampal cholinergic development in rats exposed to alcohol during the brain growth spurt , 2012, Hippocampus.

[48]  Chiara Nosarti,et al.  Preterm birth and structural brain alterations in early adulthood , 2014, NeuroImage: Clinical.

[49]  Niklas Långström,et al.  Preterm birth and mortality and morbidity: a population-based quasi-experimental study. , 2013, JAMA psychiatry.

[50]  Jasvinder Singh,et al.  Acetylcholinesterase inhibitors for schizophrenia. , 2012, The Cochrane database of systematic reviews.

[51]  H. Heinsen,et al.  Atrophy of the Cholinergic Basal Forebrain Over the Adult Age Range and in Early Stages of Alzheimer's Disease , 2012, Biological Psychiatry.

[52]  David C. Van Essen,et al.  Cortical structural abnormalities in very preterm children at 7years of age , 2015, NeuroImage.

[53]  L. Papile.  Preterm Birth and Psychiatric Disorders in Young Adult Life , 2012 .

[54]  Philip G. F. Browning,et al.  Acetylcholine Facilitates Recovery of Episodic Memory after Brain Damage , 2012, The Journal of Neuroscience.

[55]  Jenifer Juranek,et al.  Brain Volumes in Adolescents With Very Low Birth Weight: Effects on Brain Structure and Associations With Neuropsychological Outcomes , 2011, Developmental neuropsychology.

[56]  J. Nierenberg,et al.  Hippocampus and basal forebrain volumes modulate effects of anticholinergic treatment on delayed recall in healthy older adults , 2015, Alzheimer's & dementia.

[57]  Stefan Klöppel,et al.  Subregional basal forebrain atrophy in Alzheimer's disease: a multicenter study. , 2014, Journal of Alzheimer's disease : JAD.