title: Theoretical exploration of the neural bases of behavioural disinhibition, apathy and executive dysfunction in preclinical Alzheimer's disease in people with Down's syndrome: potential involvement of multiple frontal-subcortical neuronal circuits.
abstract: BACKGROUND
  Recent research has suggested a specific impairment in frontal-lobe functioning in the preclinical stages of Alzheimer's disease (AD) in people with Down's syndrome (DS), characterised by prominent changes in personality or behaviour. The aim of the current paper is to explore whether particular kinds of change (namely executive dysfunction (EDF), disinhibition and apathy), associated in the literature with disruption of different underlying frontal-subcortical circuits, are a) more or less frequently reported than others and b) related to poor performance on tasks involving different cognitive processes.
  
  
  METHODS
  Seventy-eight participants (mean age 47 years, range 36-72) with DS and mild to moderate intellectual disability (based on ICD-10 criteria), without a diagnosis of dementia of Alzheimer's type (DAT) or other psychiatric disorders, were selected from a larger sample of older adults with DS (n = 122). Dementia diagnosis was based on the CAMDEX informant interview, conducted with each participant's main carer. Informant-reported changes in personality/behaviour and memory were recorded. Participants were scored based on symptoms falling into three behavioural domains and completed five executive function (EF) tasks, six memory tasks (two of which also had a strong executive component) and the BPVS (as a measure of general intellectual ability). Multiple regression analyses were conducted to determine the degree to which the behavioural variables of 'EDF', 'disinhibition' and 'apathy', along with informant-reported memory decline and antidepressant medication use, predicted performance on the cognitive tasks (whilst controlling for the effects of age and general intellectual ability).
  
  
  RESULTS
  Strikingly, disinhibited behaviour was reported for 95.7% of participants with one or more behavioural change (n = 47) compared to 57.4% with reported apathy and 36.2% with reported EDF. 'Disinhibition' score significantly predicted performance on three EF tasks (designed to measure planning, response inhibition and working memory) and an object memory task, (also thought to place high demands on working memory), while 'apathy' score significantly predicted performance on two different tasks, those measuring spatial reversal and prospective memory (p < 0.05). Informant reported memory decline was associated only with performance on a delayed recall task while antidepressant medication use was associated with better performance on a working memory task (p < 0.05).
  
  
  CONCLUSIONS
  Observed dissociation between performance on cognitive tasks associated with reported apathy and disinhibition is in keeping with proposed differences underlying neural circuitry and supports the involvement of multiple frontal-subcortical circuits in the early stages of DAT in DS. However, the prominence of disinhibition in the behavioural profile (which more closely resembles that of disinhibited subtype of DFT than that of AD in the general population) leads us to postulate that the serotonergically mediated orbitofrontal circuit may be disproportionately affected. A speculative theory is developed regarding the biological basis for observed changes and discussion is focused on how this understanding may aid us in the development of treatments directly targeting underlying abnormalities.
authors.affiliation: University of Cambridge, Department of Psychiatry, Cambridge Intellectual & Developmental Disabilities Research Group, Cambridge, UK. slb49@medschl.cam.ac.uk
authors.forename: S L
authors.initials: SL
authors.lastname: Ball
authors.forename: A J
authors.initials: AJ
authors.lastname: Holland
authors.forename: P C
authors.initials: PC
authors.lastname: Watson
authors.forename: F A
authors.initials: FA
authors.lastname: Huppert
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000453:epidemiology*; D001921:Brain / Q000503:physiopathology*; D002648:Child; D002653:Child Behavior Disorders / Q000175:diagnosis / Q000503:physiopathology*; D003072:Cognition Disorders / Q000175:diagnosis / Q000453:epidemiology*; D015897:Comorbidity; D004314:Down Syndrome / Q000175:diagnosis / Q000453:epidemiology*; D005260:Female; D005625:Frontal Lobe / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000503:physiopathology*; D009483:Neuropsychological Tests; D011582:Psychological Theory; D012720:Severity of Illness Index