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Brain & behaviour > Lecture 9 - Ageing and the brain, Normal and Pathological function > Flashcards

Lecture 9 - Ageing and the brain, Normal and Pathological function Flashcards

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1
Q

What are the 2 biological theories of brain ageing

******

A

2 biological theories as to why there are individual differences in ageing

  1. Physiological/ molecular reasons as to why people differ in ageing
  2. Genomic reasons as to why people differ in ageing
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2
Q

Outline Physiological/ molecular reasons as to why people differ in ageing - as a biological theory of brain ageing

A

• Free Radicals can damage vital molecules in the cell (like collagen or proteins

  • Most importantly: can damage DNA - this impacts production of enzymes and hormones
  • quite good at dealing with these when we’re young, get much worse as you get older

•Accumulation of Toxic Waste Cell products
- similarly, are better at removing these when you are younger - get worse when you get older

•Oxidative stress
- e.g. can affect collagen - which keeps your skin smooth. Smoking -> oxidative stress -> wrinkles

Individual differences in how you deal with free radicals, toxic waste and oxidative stress

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3
Q

Outline genomic reasons as to why people differ in ageing - as a biological theory of brain ageing

A

•somatic mutations; genetic errors; programmed cell death (apoptosis)
- many argue that a cell can only reproduce so many times, a limit on how many times it can multiply - determine by your genetics - how long ancestors lived for

•Programmed cell death (apoptsis) - when a cell is not entirely corect; it is usually programmed to die - but in cancers, the mechanism telling the cell to die doesnt work, so the cell grows and damages surrounding areas - killing the organism eventually

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4
Q

What things can vary in how they age?

A 
Between People:
•Skin
•Cognitions
•strength
- can all vary with age

Within people:
-different organs/ systems age at different rates
•Nerves conducting - doesnt really age much
•neither does heart rate
•Kidney blood flow (used to get rid of waste products) - reduces after a while
•Maximum breathing and 02 steeply declines
•Female fertility - drops the most/ steepest
- menopause affects:
- accelerates ageing of your skin
- insulin
- thyroid
- endocrinology is effect (vulnerable to PD/ dementia?)

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5
Q

What did Evans & Williams (1992) say about disease free organs age

A

Evans & Williams (1992)
- said that: in disease free organ systems, there is not much age-related loss
- In healthy systems (if we never got a disease)
•Cardiac - not much change, slight decrease in exercise capacity
•Pulmonary (e.g. total lung capacity) - not much change, VO2 max decreases a bit though
•Renal - e.g. kidney blood flow - decreases, glomerular filtration rate decreases (clearance of drugs)

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6
Q

What is glomerular filtratrion rate and whys it important?

A

Refers to the clearance of drugs in the kidney
- It’s a problem because drugs are usually tested on young men who have a different glomerular filtration rate - so when the drugs are given to older people, its a problem

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7
Q

What problems can old people have?

** - deficits in sensory

A
  • Not all old people stay healthy, e.g:
    •Vascular, Kidney, liver, lung.. disease
    •CV problems common
    •Deficits in sensory system (cataract, deafness)
    •Immune system is less capable and slower - cancers
    •Endocrine changes in ageing
  • all can affect the functioning of the brain
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8
Q

What did Schaie (1988) find about Verbal Meaning Test over time

A

Schaie (1988) firstly did a cross-sectional test

  • to see how peoples scores on the Verbal Meaning Test - a synonyms test
  • Shows that in the cross-sectional study, people got worse with age

Then did a longitudinal study

  • so from the cross-sectional data you might expect people to get worse with age
  • but in the longitudinal age, there is not much change
  • the differences therefore must lie between cohorts
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9
Q

Outline cohort effects in ageing

A

There are differences in cohorts

  • the old people we have now were exposed to illness but survived, so genetically they have good immune systems that they pass on to us
  • Generation before them did not as much
  • Differences in lifestyle and vulnerability to diseases
    • e.g. our grandparents all smoked, were very active with chores, survived hunger during WW2, etc etc
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10
Q

What do general findings about intellectual performance and ageing show?

A
  • Early cross-sectional studies were ‘contaminated’ by cohort effects
  • Longitudinal studies, show long periods of stability - followed by decline
    BUT
    decline is greater on some tasks than on others
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11
Q

Outline Hold and Dont Hold WAIS (Wechsler) Subtests

******

A
  1. Verbal Scale (Hold)
    - not sensitive to age, might even be improved
    - stuff like:
    •Information, •Comprehension, •Arithmetic, •Similarities, • Digit-span, •Vocabulary
  2. Performance Scale (Don’t Hold)
    - decline often, but dont keep with age, often because they depend on speed
    - Stuff like:
    •Digit symbol, •Picture completion, •Block Design, •Picture Arrangement, •Object assembly
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12
Q

Outline the digit span test

A

It’s a hold test

  • read a string of digits out and ask them to repeat after you, add one each time
  • this ability doesnt change much with normal ageing
  • 5-6 = low
  • 7= average
  • 8-9 = High
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13
Q

Outline the Symbol Digit Modalities Test

******* children and exercise?

A

It’s a dont hold test

  • measures complex speed
  • test of concentration, speed of information processing, writing speed, working memory capacity
  • Give them a key with numbers and there corresponding symbols
  • tell them to fill in which symbol is which number, up until a certain point - then afterwards, tell them to to do it as fast an as accurately as you can
  • dont tell them, but you give them 90 seconds - see how long it takes them to fill it in
  • Improves in children if they had been doing exercise compared to sitting still
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14
Q

Outline the Stroop Test

A

It’s a dont hold test
- also measures complex speed
- Tests people ability to inhibit their automated response - you have to do it as quickly as possible
X - can only be used on literate people

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15
Q

What is the role of Dopamine in ageing?

*******

A

Inverted U Shape with Dopamine Agonists

  • too much or too little = cant do the task very well
  • COMT is the enzyme that breaks down Dopamine - and the effect of COMT is determined by your genotype, there 2 types of this genotype:
    1. Val Genotype: Causes HIGH COMT Activity - and thus LESS DOPAMINE
    2. Met Genotype: Causes LOW COMT Activity - and thus HIGH DOPAMINE
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16
Q

What are the 2 types of COMT genotypes

A
  1. Val Genotype: Causes HIGH COMT Activity - and thus LESS DOPAMINE
  2. Met Genotype: Causes LOW COMT Activity - and thus HIGH DOPAMINE

Val carriers are more affected by frontal ageing than met carriers

Might be implicated in psychosis - too much dopamine
or Schizophrenia - not as much DA in frontal regions = negative symptoms

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17
Q

Why dont we give people Amphetamines (DA Agonists) to reverse ageing?

A

Amphetamines have been proven to:
- Improve working memory
- Information processing speed
Because they increase Dopamine

We dont do this because if we increase DA synthesis, we create lots of Free Radicals

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18
Q

What did Backman (2006) say about Dopamine and ageing

*******

A

D1 and D2 receptor bindings go down with advancing age

  • this is associated with deficits in cognitive and motor functioning
  • to do with the link between the Basal Ganglia (e.g. putamen/ caudate) to the frontal lobes
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19
Q

What are the 2 problems in ageing?

A
  1. Dopamine

2. Glutamate toxicity

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20
Q

Outline the process of Glutamate Toxicity
- 6 stages
?????????????????
*******

A
  1. When you age, there is a decline in supply of oxygen to the brain - causing Hypoxia
    - due to main arteries hardening, small arteries becoming damaged
  2. Cells start firing a lot, perhaps in a sort of panic
  3. This causes lots of calcium to enter the cell, but also for calcium stores to be expelled from the cell
  4. This causes lots of damage - a massive amount of free radicals - damage the cell membrane, the cell protein synthesis
  5. Massive calcium coming in/ going out also causes lots of water to rush in; in order to maintain homeostasis
  6. This causes the cell to swell and blow up massively - causing lots of damage to cell, making it hard to function

This process has many different names: Glutmate Cascades, NMDA Cascades, Messenger Cascades, Hypoxic Cascades

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21
Q

How is glutamate involved in ageing?

*******

A
  • Its one of the major excitatory NT’s
  • Again has a curvillinear association - there are optimal levels for optimal memory
  • Can cause Glutamate Toxicity as you age
  • Which can also occur in TBI
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22
Q

How does Glutmate Toxicity occur in Alzheimers

*******

A

Amyloid Plaques make this process more likely

- can treat with NMDA Antagonists - but this causes memory issues normally

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23
Q

Outline the Case of Auguste D
?????????????????
*******

A

August D - From Dr. Alois Alzheimer
- Provided one of the first cases of this dementia
- she was a 51-year old women with early onset dementia. Symptoms included:
•Progressive Cognitive Impairment
•Focal Symptoms
- suggesting there is a vascular component
•Hallucinations
&
•Delusions
- can occur in Az
•Psychosocial Incompetence

24
Q

If you have a relative who got Az before the age of…

?????????????????

A

If you have a relative who got Az before the age of 65
- you are likely to get it

These days, Az usually occurs after 65

  • there is a rare type of it called Sporadic Az that Auguste D had
  • she was likely to have a relative who get Az before the age of 65
25
Q

What is the name of Alois Alzheimers book?

******

A

On a peculiar disease of the cerebral cortex (1907)

- talked about neurofibiliary tangles

26
Q

Outline neurofibrillary tangles
????????????????
*******

A

Alzheimer stained cells and looked at them under a x400 microscope

  • observed how they were no longer structurally functional, due to misfolded proteins in it
  • this is called Tauopathy: A neurofibrillary tangle
  • It is unclear why Az’s start tangling, perhaps due to infection
  • but this is a hallmark of Az - if we can stop this from occuring it would be good
27
Q

Outline Amyloid Plaques
?????????????????
*******

A

Plaques are made from fatty substances, and form perhaps in response to the cell no longer functioning/ dying

  • but they become toxic in their own right
  • drugs that treated these plaques caused infections in the brain
28
Q

What factors are associated with the formation of these abnormal brain stuffs
?????????????????
*******

A

Alzheimers probably starts in your 30s

  • when there is perhaps hits on the head, infections, lifestyle choices
  • lots of factors associated with the misfolding of protein, and the plaques forming due to cells not being functional
  • perhaps its caused by genetics, pollution etc lots of things
29
Q

Outline the Cholinergic Hypothesis in Alzheimers Disease
?????????????????
******

A

The Nucleus Basalis of Meynert produces Acetylcholine (ACh)

  • In Az, there is a reduction in presynaptic reuptakers for ACh, as well as an overall production reduction
  • there is less being made, and there is less being reuptaken
  • Therefore, Az is associated with a reduction in Ach
  • ACh and ChAT (enzyme that produces ACh) are correlated with cognitive impairment in Az - as ACh and ChAT reduce, impairment also gets worse
  • Sometimes happen with serotonin but that is more associated with dementia
30
Q

Whats the enzyme that helps produce ACh

A

ChAT: Choline Acetyltransferase

31
Q

How can you treat the Cholingergic Hypothesis

?????????????????

A

As a treatment you can use Cholinesterase Inhibitor Treatment
- prevents the breakdown of ACh, keeping it active in the cell

X - not very effective long term
X - side effects - gastrointestinal, feeling sick or bloated etc

32
Q

So although Glutamate toxicity is involved in normal ageing, how is Glutamate Toxicity implicated in Alzheimers?
?????????????????
******

A

In the brain, astrocytes are used to convert Glutamate (excitatory) to GABA (Inhibitory) and vice versa
- and this is influenced by the enzyme GAD

But in LATE Az, there is often a reduction in GABA in parts of the brain, e.g. cortex, hippocampus, but NOT Basal Ganglia

  • also a reduction in GAD - the enzyme that converts GABA to glutamate
  • so having less of this inhibitor, means that Glutamate is much more toxic in the brain
  • If the conversion from Glutamate to GABA doesnt occur, for whatever reason, and as Glutamate interacts with those plaques - there is much more Glutamate Toxicity
  • One of the new treatments looks at reduction of GABA in late AD
33
Q

How does the DSM define Dementia?

*******

A

Acquired, irreversible, global impairment of intellect, memory and personality, but without impairment of consciousness

34
Q

Are there any good treatments currently for dementia/ Alzheimers?
- whats BDNF

A

No - not many good treatments for dementia and Alzheimers
- you cant undamage the brain

  • You can try to increase the BDNF - Brain-derived Neurotrophic factor. E.g. through exercising
  • this would help dendrites sproud and to some extent make up for the damage
35
Q

What are the post-mortem signs for Alzheimers Disease?
?????????????????
*************

A
  • Extracellular Amyloid Deposition
  • Intraneuronal neurofibrillary Tangles (NFTs)
  • Neuronal Cell Death
  • Synaptic Loss
  • Should check for physiological symptoms - as they occur first, could even be in your 30s
36
Q

Outline the clinical Manifestation of Alzheimers Disease

******* onset

A
  1. Early loss of short term memory (recall and learning)
    - Day-to-day forgetfulness
  2. Progressive, gradual loss of longer-term memory
  3. Other cognitive impairments; visuo-spatial; spatial and temporal orientation; language; planing; personality change
    - can impact on social/ occupational function
    - Not caused by other morbidity
  • 6-12 years from onset to death
37
Q

Outline types of dementiat

?????????????????

A
  1. Alzheimers Disease: 50-70%
    - gradual memory, cognition, personality
    - 80% of dementia cases have Az pathology post-mortem
  2. Vascular Dementia: 20%
    - planning/ organising, personality
  3. Lewy Bodies Dementia: 20%
    - Parkinsons symptoms
    - visual hallucinations, movement, fluctuating consciousness, REM Dreams
  4. Frontotemporal Dementia: 5-15%
    - Personality changes (disinhibited/ moody), aphasia, movement problems, word finding problems)
    - Usually get it under 60 years old
5. Others
•Korsakoff's Dementia (Thalamus implicated)
•Huntingdons Chorea (Genetic)
•Tumours can cause a dementia
•Creutzfeldt-Jakob Disease (CJD)
- also features folding proteins
•HIV can cause dementia
•TBI if severe enough can cause a dementia
38
Q

Outline Lewy Body Disease

******

A

Definition:
•Lewy bodies build up in brain
•makes it hard for cells to function

Symptoms:
•Changes in alertness/ attention, confusion
•Daytime Sleepiness, REM Sleep disorder (acting out)
•Vivid Visual hallucinations
•Parkinsonian symptoms: movement and posture, muscle stifness
•Language/ planing problems
•Later loss of memory

Treatment
•Over sensitivity for Antipsychotics, tend to not give them to these patients

39
Q

What is CERAD

A

CERAD Stands for:

- Consortium to Establish A Registry for Alzheimer’s Disease

40
Q

What did CERAD find when comparing Diagnoses to post-mortem

A
  • Found that 95% of cases of Az were correctly identfied

- 17% were negative cases, that actually did have Az when they thought they didnt

41
Q

outline the 4 CERAD Misclassification classes

*****

A

FN = false negative FP = False Positive
•FN 1: Mild: When they had mild cognitive impairment, mostly correct diagnoses
•FN 2: Mixed: When AD was not recognised, thought to be something else but it was AD
•FN 3: Psychiatry: Thought it was something different but revealed to be AD
•FP 4: ODS: Thought it was AD but it was another dementia

42
Q

Outline Vascular Dementia also known Multiple-infarcts dementia (MID)

A

Multiple Infarcts in cortical/ sub-cortical grey matter
OR
White matter demyelination; lacunae; incomplete infarction
-

Associated with atherosclerosis (hardening or narrowing of the arteries), hypertension and usual risk factors (e.g. smoking)

Sudden/ stepwise loss in ability - not gradual like az

  • focal symptoms (a focal area in the brain causing a symptom)
  • e.g. lose a limbs movement, face starts drooping etc
  • Focal symptoms are typical of Vascular - not so common in Alzheimers, but was in Auguste D
43
Q

Whats an Infarct in Vascular Dementia?

A

Infarction is tissue death due to inadequate blood supply to the affected area

44
Q

What is atherosclerosis

A

hardening/ narrowing of the arteries

45
Q

Whats a focal symptom

A

a focal area in the brain is causing a symptom

46
Q

What happens to white matter in Vascular Dementia
?????????????????
*******

A

White matter degenerates

  • the ventricles spread out
  • deep and extended into the grey areas
  • called white matter disease
47
Q

Whats the differences between Alzheimers Disease and Vascular Dementia
**
?????????????????

A

AD:
- onset is 30+, but more common above 65
- MORE WOMEN THAN MEN- more so as you age
•Perhaps due to survival, as women live 2-12 years longer
- PROGRESSIVE, GRADUAL LOSS OF MEMORY, PERSONALITY CHANGE ETC

VaD/ MID

  • Onset 40+, or above 70+
  • MORE MEN THAN WOMEN
  • highly variable - one stroke might cause another
  • STEPWISE LOSS OF ABILITIES
  • possible focal damage
48
Q

What are the clinical differences between VaD and AD
?????????????????
*********

A

Verbal memory often spared for a long time in VaD
- but executive function is better in AD. SO:

  • Criteria that require verbal memory to be impaired will have low specificity - wont determine which one it is
Overlap between the two dementia categories, need other information:
•History - is it suddent or gradual?
- CV problems?
- Relatives?
- Brain scans
- lifestyle

•Physical examination and lab measures
- to exclude other causes

49
Q

What are the 3 categories of cognitive tests for early dementia

A
  1. Memory Tests
    - e.g. HVLT, CVLT, Rey
  2. Tests for Global Cognitive function
    - MMSE, ADAS-Cog, BMIC, CERAD
  3. Other cognitive tests
    - BNT, CLOX, Fluency, PAL etc
50
Q

Outline the Hopkins Verbal Learning Test

A

Get given a bunch of words, with several categories that each word would belong to
- some categories have more vivid imagery associated with it

For instance, animals, will likely be best remembered - as they are early acquired in our lifetimes - people usually recall these late on into the disease

Then there are other categories that dont have as vivid imagery associated with them - e.g. gemstones

  • and aren’t as used as frequently in language
  • So late Az might struggle with those ones

Primacy and recency effects still occur

51
Q

Outline results for the HVLT

A

VCL and VaD - Vascular dementias scored worse than controls - but better than probable, possible and mixed AD

Half of the psychiatry group seemed to score similar to Alzheimers
- because you can have bizarre behaviours that may look like psychiatry, but its actually Az

52
Q

Outline the comparison between Brandt (1990) and OPTIMA (2000)

A

Looked at HVLT in controls and in AD
- Both found higher difference between controls and AD

Brandt (1990)’s controls scored lower, but this was because they were younger, more educated, and were likely to be women

OPTIMA (2000) Controlled for this stuff, so their controls scored lower, but still higher than AD

53
Q

Outline MMSE

A

Tests several categories:

(10 q’s): Orientation
- where are you, whats the date

(3 q’s): Registration
- Show them 3 items, what are they?

(5) : Attention and calculation
- spell ‘world’ backwards
- count in 3’s backward from 70

(3) Recall
- shown items, then remove them and ask them to recall them

(9) Language
- Showing people sentences ask them to read it, or act out what is said

SCORING:
above 28 = you’re probably okay
24-30 = uncertain cognitive impairment
- doesn’t mean you don’t have dementia, could still have it
18-23 = mild to moderate impairment - probably have dementia
<17 = severe

54
Q

What’s a bad thing about MMSE

A

X - sensitive to education, high education would do well on this test

55
Q

Outline the Floor and ceiling effects in the HVLT and MMSE**

A

X - in MMSE there is a ceiling effect - all the controls get really high and get bunched up towards the end
- very easy for people to fail the test and get above the cut off, diagnosed with the problem, even though they didnt get it

√ - HVLT - much more spread out, so every score means something

  • it’s more conclusive as to who has it and who doesnt have it
  • it’s not as all or nothing

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