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Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients.

ABSTRACT: Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. Neurological and behavioral abnormalities observed in ADA-SCID patients surviving after stem cell transplantation or gene therapy represent an unresolved enigma in the field. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after short- and long-term enzyme replacement therapy with PEG-ADA. These included motor dysfunction, EEG alterations, sensorineural hypoacusia, white matter and ventricular alterations in MRI as well as a low mental development index or IQ. Ada-deficient mice were significantly less active and showed anxiety-like behavior. Molecular and metabolic analyses showed that this phenotype coincides with metabolic alterations and aberrant adenosine receptor signaling. PEG-ADA treatment corrected metabolic adenosine-based alterations, but not cellular and signaling defects, indicating an intrinsic nature of the neurological and behavioral phenotype in ADA deficiency.

SUBMITTER: Sauer AV

PROVIDER: S-EPMC5225479 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients.

Sauer Aisha V AV Hernandez Raisa Jofra RJ Fumagalli Francesca F Bianchi Veronica V Poliani Pietro L PL Dallatomasina Chiara C Riboni Elisa E Politi Letterio S LS Tabucchi Antonella A Carlucci Filippo F Casiraghi Miriam M Carriglio Nicola N Cominelli Manuela M Forcellini Carlo Alberto CA Barzaghi Federica F Ferrua Francesca F Minicucci Fabio F Medaglini Stefania S Leocani Letizia L la Marca Giancarlo G Notarangelo Lucia D LD Azzari Chiara C Comi Giancarlo G Baldoli Cristina C Canale Sabrina S Sessa Maria M D'Adamo Patrizia P Aiuti Alessandro A

Scientific reports 20170111

Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. Neurological and behavioral abnormalities observed in ADA-SCID patients surviving after stem cell transplantation or gene therapy represent an unresolved enigma in the field. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after short- and long-term enzym ...[more]

PMID: 28074903

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Project description:IntroductionTraumatic brain injury (TBI) may alter dementia progression, although co-occurring neuropsychiatric symptoms (NPS) have received less attention. Originally designed to evaluate behavioral disruption prior to dementia diagnosis, the mild behavioral impairment (MBI) construct relates NPS to underlying neural circuit disruptions, with probable relevance across the progression of neurodegenerative disease. Therefore, the MBI construct may represent a valuable tool to identify and evaluate related NPS both preceding diagnosis of all-cause dementia throughout the progression of disease, representing an important area of inquiry regarding TBI and dementia. This investigation sought to evaluate the effect of TBI on NPS related by the MBI construct in participants progressing from normal cognitive status to all-cause dementia.MethodsUsing National Alzheimer's Coordinating Center data, individuals progressing from normal cognition to all-cause dementia (clinician diagnosed) over 7.6 ± 3.0 years were studied to estimate prevalence of MBI domains in 124 participants with prior TBI history (57 with loss of consciousness [LOC] <5 minutes, 22 with LOC >5 min, 45 unknown severity) compared to 822 without. MBI domain prevalence was evaluated (1) prior to dementia onset (including only time points preceding time at dementia diagnosis, as per MBI's original definition) and (2) throughout dementia progression (evaluating all available time points, including both before and after dementia diagnosis).ResultsMore severe TBI (LOC >5 minutes) was associated with the social inappropriateness MBI domain (adjusted odds ratio = 4.034; P = 0.024) prior to dementia onset, and the abnormal perception/thought content domain looking across dementia progression (adjusted hazard ratio [HRadj] = 3.703; P = 0.005). TBI (all severities) was associated with the decreased motivation domain looking throughout dementia progression (HRadj. = 1.546; P = 0.014).DiscussionTBI history is associated with particular MBI profiles prior to onset and throughout progression of dementia. Understanding TBI's impact on inter-related NPS may help elucidate underlying neuropathology with implications for surveillance, detection, and treatment of behavioral concerns in aging TBI survivors.HighlightsThe mild behavioral impairment (MBI) construct links related neuropsychiatric symptoms (NPS) by probable underlying neural network dysfunction.Traumatic brain injury (TBI) with loss of consciousness (LOC) > 5 minutes was associated with pre-dementia social inappropriateness.TBI was associated with decreased motivation looking across dementia progression.TBI with LOC > 5 minutes was associated with abnormal perception/thought content.The MBI construct may be useful for examining related NPS across dementia progression.

Dataset Information

Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients.

Publications

Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients.

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