AETIOLOGY: PART 2

Mike Akroyd, 4th July 2014

Aims

Illustrate how aetiology fits into MRCPsych: Paper 1 and beyond

Explore aetiological factors of older adult and child psychiatric illness (General adult covered in part 1 – handouts

available from Mandy if anyone needs one)

Objectives

“By the end of this session I will be able to...” Identify aetiological factors involved in

older adult and child psychiatric disorder Answer some exam questions on the above

Older adults

Dementia Delirium

Alzheimer’s disease

c.50-60% of dementia Also commonest presenile dementia Identified genetic and environmental

factors?

Alzheimer’s disease – Genetic

Illness Gene Comments

Early onset familial Alzheimer’s disease

Presenilin 1 Chromosome 14

Presenilin 2 Chromosome 1

Amyloid precursor protein

On chromosome 21 – hence increased risk in Down’s syndrome

Late onset Alzheimer’s disease

Apolipoprotein E4(ApoE4)

Increases risk of developing disease

Heterozygotes (1 copy)

= 3 x risk Homozygotes (2

copies)= 10 x risk

Other alleles (E1,E2,E3) do not increase risk

Ubiquilin 1 Candidate gene

Alzheimer’s disease – Environmental No direct causality Possibility of interactions with genetic

factors

Alzheimer’s disease – Environmental Low educational attainment History of head injury Cerebrovascular disease History of depression High homocysteine levels Diabetes mellitus

(Aluminium exposure? – weak evidence)

?Damage making brain more vulnerable to neurodegeneration

Alzheimer’s disease – Environmental Some protective factors:

Use of NSAIDS Reduce risk by <50% Effect on APP metabolism

HRT Statins? Cognitive/physical activity in mid-life

‘Use it or lose it’

Other neurodegenerative disorders Dementia with Lewy bodies

15-20% dementias A ‘synucleinopathy’

(Like Parkinson’s diesease) Main feature is abnormal aggregation of α-

synuclein Association with ApoE4 Environmental factors not established

Other neurodegenerative disorders Parkinson’s disease

c.1% of over 55s Mostly idiopathic Rare autosomal dominant form

Mutations in α-synuclein, UCHL1, NR4A2, LRRK2 Rare autosomal recessive form

Mutations in parkin, DJ1, Pink1 Environmental risk factors

Toxin exposure, solvents, CO, well water Smoking and ?caffeine protective

Other neurodegenerative disorders Frontotemporal dementias

2nd most common cause of presenile dementia 7% of later life dementia Largely unknown aetiology

(aetiologies – several diseases within this umbrella: e.g. Pick’s; lobar atrophy; semantic dementia; MND + dementia)

1/3 have a 1st degree relative with FTD Familial FTD subgroups - autosomal dominant

inheritance Chromosome 17 – FTDP-17 Tau protein processing

Other neurodegenerative disorders Huntington’s disease

Single gene, autosomal dominant Complete penetrance New mutations are rare Chromosome 4p – encodes Huntingtin

Trinucleotide repeat CAG (encodes Glutamine) Normal = <30 repeats Huntington’s = >36 repeats ‘Anticipation’

Expansion increases in offspring Earlier age of onset

Vascular dementia

20-25% of dementias Prevalence increases with age

Roughly doubles with every 5 years of age Risk factors same as for other vascular

disease Smoking, diabetes, hyperlipidaemia

Other aetiological factors

Trauma Head injury Repeated trauma – dementia pugilistica

Organic Infections (HIV, vCJD, neurosyphillis) Metabolic (dialysis, hypo/hyperthyroidism,

Cushing’s) Deficiencies (B12, Folate) Toxins (alcohol, heavy metals, solvents) Normal pressure hydrocephalus

Delirium

15-30% of patients on medical/surgical wards

Increased risk in Older adults Existing dementia

Delirium

Medication Opiates, anticholinergics, sedatives, digoxin, diuretics, lithium, steroids

Physical illness Infections, hypo/hyperglycaemia, organ failure, thiamine deficiency, electrolyte imbalance

Neurological Tumour, head injury, infection, epilepsy

Toxins Alcohol, opiates, carbon monoxide

Don’t forget... Constipation, pain

Child and Adolescent

ADHD ASD Eating disorders

ADHD

Using DSM-IV ADHD criteria, UK prevalence = 3%

Using ICD-10 hyperkinetic disorder criteria = 1.7%

M:F = 3:1

Increasing prevalence Increased recognition?

ADHD – Genetics

Heritability = 60-90% Parents and siblings = 8 x increased risk Genes for dopamine receptors

implicated DAT1 (Dopamine transporter) DRD4 (Dopamine receptor)

ADHD – Birth & pregnancy

Prenatal

Maternal smoking – dose-dependent relationship with ADHD

Maternal cocaine use may increase risk

Maternal stress – increased serum cortisol – may increase risk

Perinatal

Very low birth weight = 2 x risk

Birth complication = increased risk (difficult to quantify)

ADHD – Environmental

No evidence for food additives increasing overactivity

Some evidence for lead intoxication and zinc deficiency

ADHD – Social

Chronic exposure to difficult early environment Eg. severe social deprivation increases risk

No evidence that parenting in normal range causes ADHD Parenting can alter course/prognosis

Maternal psychopathology and low socioeconomic status associated with ADHD

No association between large family size or paternal antisocial behaviour and ADHD

Autistic Spectrum Disorders

Lifetime prevalence of ASD = 1% Lifetime prevalence of autism =

0.1-.0.3% Autism: M:F = 4:1

ASD – Genetics

Heritability > 90%, MZ concordance up to 90%

Chromosomes 2, 7, 15 Siblings of probands with autism show

increased risk of range of cognitive abnormalities Supports idea of wider phenotype Siblings of probands:

Risk of autism 5%

Risk of ASD c.10%

Risk of autistic traits 20-30%

ASD – Birth & Pregnancy

Children with autism more likely to have suffered birth trauma

ASD – Organic

Organic brain disorder Larger brain volumes than controls Hypoactivation of amygdala,

frontotemporal areas 1/3 have high peripheral 5HT levels Associated with Fragile X, Rett

syndrome, tuberous sclerosis

No evidence for relationship between autism and schizophrenia

Eating disorders

Anorexia – 0.7% of female pupils/students M:F = 1:10-20

Bulimia – c.1% of women 16-40 M:F = 1:10

ED – Genetics

Anorexia MZ concordance = 55%; DZ concordance =

5% Bulimia

MZ concordance = 35%; DZ concordance = 30%

(Higher heritability in anorexia) 1st degree relatives of people with

anorexia Increased risk of any ED

ED – Genetics

Family history of other illnesses/traits increase risk of ED

Family history of:

Associated with anorexia

Associated with bulimia

Depression

Substance misuse

(especially alcohol)

Perfectionism

Obesity

ED – Family influences

NICE recommend FT in anorexia Parenting

Low contact, high expectation, parental discord, physical or sexual abuse

“Enmeshment, over-protectiveness and lack of conflict resolution” – Minuchin, 1978

Anorexia dissipates family tensions Family attitudes to:

Body shape, exercise, food (“family dieting”)

ED – Other

Social Western societies Occupational/recreational need for certain

body shape Competitive riding, ballet

Pre-morbid personality Low self-esteem Anxiety disorders Anorexia – perfectionism Bulimia – obesity, early menarche

Which of the following theories suggests that schizophrenia occurs when individuals who are vulnerable to the disease undergo a life stress which precipitates the initial episode ?

a. Kindling effect

b. Abberant connectivity

c. Neurodevelopmental hypothesis

d. Stress-diathesis model

e. Social model

A mother wants to know what is the risk of schizophrenia in her son who smokes cannabis?

a. Four-fold increase in risk

b. Two-fold increase in risk

c. Four-fold decrease in risk

d. Two-fold decrease in risk

e. No association between cannabis and schizophrenia

Which of the following does not increase the risk of developing bipolar disorder?

a. Family history of depression

b. Family history of schizoaffective disorder

c. Family history of schizophrenia

d. Cyclothymic personality

e. Family history of bipolar disorder

Which of the following is not a vulnerability factor for depression as described by Brown and Harris?

a. Lack of confiding relationship

b. Loss of parent before age of 11

c. Not working outside the home

d. Having 3 or more children under the age of 14

e. None of the above

A person who feels like he has lost his place is society due to being made redundant goes on to commit suicide. According to Emile Durkheim what type of suicide would that be?

a. Anomic

b. Altruistic

c. Egoistic

d. Fatalistic

e. Holistic

Which of the following risk factor is likely to be causative in a young man diagnosed with schizophrenia?

a. Alcoholism

b. HLADR2 gene

c. Being a migrant

d. Having lost his mother before the age of 14

e. Living alone

Which of the following genes has no association with Alzheimer’s disease?

a. DRD4b. Ubiquilin 1c. Presenilin 2d. APPe. ApoE

Protective factors for development of Alzheimer’s disease do not include:

a. Use of aspirinb. Cognitive activityc. High serum homocysteined. Use of HRTe. None of the above factors are

protective

In families with Huntington’s disease, the illness tends to present earlier in successive generations. This phenomenon is known as:

a. Heritabilityb. Penetrancec. Expectationd. Anticipatione. Incidence

ADHD is associated with increased maternal serum:

a. Dopamineb. Cortisolc. Serotonind. Testosteronee. GABA

Heritability in autism is thought to be

a. 15%b. 30%c. 50%d. 75%e. 90%

Autism is not associated with:

a. Fragile X syndromeb. Tuberous sclerosisc. Angelman syndromed. Rett syndromee. Birth complications

Which of the following aetiological factors favours a diagnosis of bulimia over anorexia?

a. History of perfectionist traitsb. Family history of depressionc. History of obesityd. Enmeshed parenting stylee. History of sexual abuse