Lecture 24

Question 1

Dementia

Answer 1

Progressive impairments to memory, thinking and behaviour that affect the ability to perform everyday activities as a result of a neurological disorder.

Common causes are neurodegenerative disease, MS, multiple stroked and repeated brain trauma (chronic traumatic, encephalopathy)

Question 2

Alzheimer’s

Answer 2

Neurodegenerative disorders: progressive memory loss, motor deficits and eventual death

10% of population over 65 and 50% of people over 85

Misfolded beta-amyloid

beta-amyloid precursor protein (APP) genes are located on chromosome 21 - (the one with 3 in downs). This is a protein in the cell membrane, it is cut by secretases into smaller fragments.

Usually this is ok as its 40aas long. When this goes wrong, 42aa segments are chopped off. These aggregate

Question 3

Pernsenilin

Answer 3

Protein that forms part of secretases which cut APP

Mutations in presenilin can cause it to preferentially generate the abnormal long form beta-amyloid, which causes early onset Alzheimer’s disease.

Question 4

Apolopoprotein E (ApoE)

Answer 4

Glycoprotein that transports cholesterol in the blood and plays a role in cellular repair

Presence of the E4 allele of the apoE gene increases risk of late onset Alz

Question 5

Beta amyloid

Answer 5

Protein found in excessive amounts in brains of patients with Alz disease

Question 6

Amyloid plaque

Answer 6

Extracellular aggregation of beta-amyloid protein surrounded by glial cells and degenerating neurons

Question 7

Tau protein

Answer 7

Microtubual that becomes hyper phosphorylated in alz disease disrupting intracellular transport

Question 8

Neurofibrillary tangle

Answer 8

Intracellular accumulation of twisted Tau protein in dying neurons

Question 9

Alzheimer’s disease risk factors

Answer 9

Age is the biggest

Next is traumatic brain injury

Impact of lifestyle:

Alz disease is less prevalent in well educated people that

Question 10

Alz treatment

Answer 10

No cure. Little treatment

Tring to develop them, immunotherapy is promising.

We can kill A beta protein of tau or both. So far has not helped.

One family gets loads of tau but no alz. Somehow does not get phosphorylated.

Question 11

ALS

Answer 11

Degenerative, attacks spine and morto neurons

3 in 100000. Starts after 50

Spasticity, exaggerated stretch reflexes, atrophy and death

90% sporadic mutations. Takes two or more genes to cause ALS

10% inherited

10-20% of the inherited ones adre due to a mutation that makes superoxidase dismutase (SOD1) on chromosome 21

Toxic gain of fx which causes folding and aggregation, impaired axonal transport and mitochondrial misfunction.

ALS and frontotemporal dementia (STD) are a part of the same disease spectrum

No cure

Drug which reduces glutamate-induced cytotoxicity which increases life by 3 months

Usually 2-4 year life after diagnosis

Stephan Hawking lived for 50 years/

Question 12

Why do neurodegenerative disorders persist?

Answer 12

Have a gene component

But these come on late, so little evolutionary pressure to remove them as we only lived beyond 60s recently

It is likely that some of these genese might have been neutral or even advantageous in the past as our environment was different.

Question 13

Gene-environment interactions for heritable brain disorders

Answer 13

Persisted because these were not selected against in old environments

Late onset disorders , due to long lives
Obesity and diabetes, unnaturally appealing food surpluses
Asthma, due to unnatural levels of antigens and pollutants
Addiction to highly purified drugs (like heroin)
Depression and anxiety rates have changed a lot and vary culturally

Large variations across cultures and recent history and straightforward environmental reasons for the variability of these diseases indicates gene-environment interaction.

Question 14

Natural selection and psychiatric disorders

Answer 14

Most of our genes are at 100% fixation (100% of the population has them) cos they promote survival in our ancestral environment better than others did

These genes make up the species-typical human genome. Its normal neurodevelopment product is human nature.

Gene mutations which decrease reproductive success are quickly eliminated. Even slightly disadvantageous genes (1% reduction in fitness removed within 100 generations). So why have these survived?

20-80% of variance is explained by DNA

4% prevalence so very common

Harmful to reproductive success (half the average fertility rate)

Maybe some of the genes associated with mental health were advantageous before. They could have been selected for or gone to fixation

Question 15

Genes and schizophrenia

Psychiatric diagnoses and their issues

Answer 15

1% of population

No one bad gene, rather hundreds f common gene variants each increase risjk slightly

One idea was that certain combos fo these genes cause schiz but others are advantageous. However the siblings of schiz ppl do not have this.

Massive overlap in gene causes for multiple mental health issues. So no schiz risk genes, just many genes that can cause mental illness.

Unsurprising as diseases even with the same diagnosis are heterogeneous. While diagnoses are useful for describing common clusters associated with diseases, symptoms can arise from multiple circuits in the brain (no one mechanism)

Diagnostic criteria based on historical convention and convenience mainly.

Question 16

Mutation-selection balance

Answer 16

Mental ddisorder susceotiblility genes are always being selected against
New ones keep coming up
Most of us have many low-fitness genes that arose in the family in the last 100 generations. Slowly being weeded out but new ones come in.

Question 17

Neurodevelopmental robustness

Answer 17

The genome has arisen to buffer insults

Allows variation to accumulate if this is not too severe cos these might provide a buffer to anew thing

Slightly bad genes which do not cause a disease can accumulate this way and collectively compromise the evolved interaction of everything in the brain, reducing the overall robustness of brain development.

Symmetry could be an indicator of robustness. Because the two sides develop independently, from the same set of instructions, if the instructions are clear there will be symmetry. If a bit confusing, more warped.

Symmetry is part hereditary and correlates with intelligence, attractiveness and health. Less symmetric might mean less robust?

Question 18

Knowing dna and avoiding illness

Answer 18

Not useful

No preventative measures for psych disorders apart from low alcohol, drugs, exercise, low stress no smoking diet etc

If we knew all the genes maybe we could edit them but we do not.

Question 19

Schizophrenia

Answer 19

1%

Social withdrawal, disorganized thinking, abnormal speech and an inability to understand reality

Comes on gradually, 20% recover the rest do not

30-50% do not think they are ill and so do not comply with treatment

Comes on in puberty and in women at menopause so likely requires change in hormones. Likley due to incorrect brain maturation.

Negative symptoms: The absence of something; social withdrawal, reduced emotional expression, poverty of speech and reduced motivation

Cognitive symptoms: disorganized and irrational thinking, learning and memory issues, poor problem solving

Positive symptoms: presence of delusions (often of persecution), grandeur or control that contradict reality and hallucinations

Usually negative first then cognitive and then positive.

Many patients with schizophrenia also exhibit neurological symptoms, such as poor control of eye movements and unusual facial expressions, and the illness is associated with subtle differences in brain structure.

Question 20

Causes of Schizophrenia

Answer 20

The causes of schizophrenia include environmental and genetic factors.

Estimates of the heritability of schizophrenia is around 80%. Heritability measures the fraction of phenotype variability that can be attributed to genetic variation.

Risk of developing schizophrenia if…
both of you parents have it (or an identical twin has it) is ~50%
one of your parents has it is ~13%
your sibling has it is ~8%

Around 5% of cases are attributed to rare gene copy number variations (duplicated or missing genes), which are frequently comorbid with autism and intellectual disabilities.

Environmental factors:

mother’s nutrition during pregnancy
mother’s stress during pregnancy
certain infections (particularly during pregnancy)
birth month
being raised in a city
childhood trauma
social isolation
perinatal hypoxia / brain damage

Evidence indicates that incidence of schizophrenia is related to several environmental factors that could affect development in utero: season of birth, viral epidemics, population density, and parental smoking.

Question 21

The seasonality effect

Answer 21

The seasonality effect: A disproportionately large number of schizophrenic patients are born in February, March, April, and May

Question 22

MZ twins and schiz

Answer 22

Prenatal environments of monochorionic twins (i.e., they share one placenta) are more similar than those of dichorionic twins.

Some evidence suggests that the concordance rate for schizophrenia is much higher for monochorionic twins and than in dichorionic twins, which suggests the prenatal environment is an important factor.

Question 23

Childhood and schiz

Answer 23

Symptoms of schizophrenia are not normally seen in childhood, but behavioral and anatomical evidence indicates that abnormal prenatal development is associated with schizophrenia

Behavioural: Children who go on to develop schizophrenia display less sociability and deficient psychomotor functioning as kids.

Anatomical: Minor physical abnormalities are often seen in children who go on to develop schizophrenia, such as partial webbing of the two middle toes and a high-steepled palate.

Question 24

Treatment of Schiz

Answer 24

There is no cure for schizophrenia. The main treatment is medication, often in combination with psychological and social supports.

Many drugs have been developed that relieve the positive symptoms of schizophrenia. They typically block dopamine D2 receptors and are called antipsychotics or neuroleptics.

In contrast, dopamine receptor agonists, like crystal meth and cocaine, tend to temporarily elicit certain aspects of the positive symptoms of schizophrenia in people who do not have the disorder. Thus…

Question 25

The dopamine hypothesis

Answer 25

The Dopamine Hypothesis: excessive dopamine D2 receptor activity, particularly in the nucleus accumbens (striatum), underlies the positive symptoms of schizophrenia.

Dopamine D2 receptor antagonists typically reduce the positive symptoms of schizophrenia but not the negative symptoms.

Some evidence suggests that the negative symptoms of schizophrenia result from abnormal activity in the prefrontal cortex.

For example, the negative symptoms of schizophrenia are similar to those produced by damage to the prefrontal cortex, and schizophrenic patients do poorly on neuropsychological tests that are sensitive to prefrontal damage

In general, the negative symptoms of schizophrenia may be caused by hypofrontality, which is decreased activity of the frontal lobes, particularly the dorsolateral prefrontal cortex, which may relate to hypoactivity of local dopamine D1 receptors.

While excess dopamine signaling in the striatum has been associated with the positive symptoms of schizophrenia, reduced dopamine signaling in the prefrontal cortex has been associated with the negative symptoms.

It is possible that schizophrenics have too little dopamine in the prefrontal cortex and too much elsewhere.

The atypical antipsychotic clozapine has been found (in monkeys) to simultaneously decrease dopamine levels in the striatum and increase dopamine levels in the prefrontal cortex

Question 26

Atypical antipsychotic medications

Answer 26

Recently developed medications which aim to reduce both the positive symptoms and negative symptoms of schizophrenia. They typically influence the activity of several neurotransmitter receptors (beyond blocking the dopamine D2 receptor).

Question 27

Clozapine

Answer 27

First of the atypical antipsychotic medications. It blocks both dopamine D2 and serotonin 2A receptors.

Question 28

Aripiprazole

Answer 28

An atypical antipsychotic. It acts as partial agonist at the dopamine D2 and D3 receptors. It is thought to reduce dopamine receptor activity in the striatum (nucleus accumbens) but boost it in the prefrontal cortex.

Question 29

Aripiprazole

Answer 29

The atypical antipsychotic Aripiprazole is a partial dopamine D2 receptor agonist.

A partial agonist is a drug with very high affinity for a receptor but it activates it less than the normal ligand does.

A partial agonist can act as an agonist in regions of low concentration of normal ligand and as antagonist in regions of high concentrations