Dementia Syndromes- Vickers Flashcards
What is the definition of dementia?
• Change in functioning from previous levels
• Deterioration in cognition, personality and
behaviour
• Are diseases, not just due to brain ageing
What are some diseases which cause dementia?
– Alzheimer’s disease
– Frontotemporal dementia
– Lewy body dementia
– Vascular (multi-infarct) dementia
• Small vessel diseaseWhat is vulnerable to degeneration in Dementia?
Early research indicated that nerve cells that make a neurotransmitter called Acetylcholine vulnerable
to degeneration.”
Current therapeutic strategies make use of Acetylcholinesterase inhibitors - what are some of the names of the drugs used?
Acetylcholinesterase Inhibitors”
Tacrine (Cognex)
Donepezil (Aricept) -
Rivastigmine (Exelon) -
Other therapeutic strategies used in dementia
Estrogen" Vitamin E" Anti-oxidants" Anti-inflammatory agents" Statins"
Alzhimers disease
• Major cause of age-related dementia”
• Insidious onset”
• Progressive and degenerative condition”
Explain the histopathalogical changes that occur in Alzheimers disease -
there are 2 major proteins affected- what are these? which is inside and which is outside the nueronal cell
Only affect a certain type of neurons
So in Alzheimer’s disease they only lose 20-30% of neurons – but these are key in relation to function
Beta -amyloid plaques (outside)
Tau protein causing neurofibrillary tangles (inside)
Describe the formation of beta amyloid plaques
Beta-amyloid plaques
- Spherical deposits in the brain, outside the cells
- Extracellular spherical mass of fibrils composed of the beta-amyloid peptide
Beta-amyloid is derived from the AMYLOID PRECURSOR PROTEINn (APP) & is a normal component of the body.
Function of APP thought to be to do with something like stopping synapses. When something happens and APP gains 2 amino-acids, this increases its ability to stick to each other. These ‘oligomers’ are toxic. But then they keep aggregating into polymers (big clumps) which are insoluble
Dystrophic neurites – dendrites & axons that look abnormal
Beta-amyloid undergoes a conformational change to become insoluble, forming the fibrils of the plaque (distorts the architecture of the brain). Plaques can form within a few days.
These sit between the neurons, they are insoluble, they deposit & grow.
Describe the pathogenesis of the neurofibrillary tangles
2) Neurofibrillary tangles
- Inside the cells are neurofibrillary tangles
- Come from a protein called Tau
- TAU is a microtubule association protein – it stabilizes/connects together the microtubules. Recall microtubules are used for transport inside the cell.
Mutation causes the Tau to aggregate inside the cell body – becomes hyperphosphorylated & winds itself up into paired helical filaments which gums up the inside of the cell
Dementia is described as a disease of disconnection- why?
• Alzheimer’s disease attacks higher association areas of the neocortex
o So we can no longer communicate between these areas
• It is the long neurons that are affected
• We start off with changes around the hippocampus (area involved in memory)
o Start of here & then spread
There are two genetic traits which are ingrained with alzheimers, what are these?
• Familial Alzheimer’s Disease (FAD)
Genetic risk factors (for sporadic Alzheimers)
• Apolipoprotein E
What is FAD? What mutations are associated?
<10% of AD cases
Develop AD a lot earlier
Linked to mutations in
- Amyloid Precursor Protein Gene – Chr 21 (Down’s syndrome)
- Presenilin 1 gene – Chr 14
- Presenilin 2 gene – Chr 1
- Increase amount of gamma-secretase which increases Abeta amino acids so more bad amyloid
For sporadic Alzheimers, there are some genetic factors, what are these?
Apolipoprotein E
o Moves cholesterol around body, controls lipids& fats. ALLELIC VARIATIONS AFFECT RISK
- Apo-E2 – decreased risk of developing dementia
- Apo-E4 – increases risk (this is dependent on how many copies of the allele you have got – if you have more, you are more likely to develop a Dementia). Apo-E4 causes inflammation & leaky blood vessels & breaks down the BBB (leaky, harder to regulate what moves in & out)
Questions in AD still remain unanswered
What is the underlying neuronal deficit that leads to dementia?
- Neurofibrillary tangle formation?
- Frank neuronal loss?
- Change in synapses/synaptic physiology (change in structure, shape – cant communicate)
- Atrophy: loss of brain substance
• Shrinks, sulci expand, ventricles expand – could even be related to the myelin
What is the relationship between beta-amyloid & neuronal pathology
We know that Beta amyloid is important
Small subset of cases linked with mutation in amyloid precursor protein gene
Amyloid fibril deposition is an early feature of brain changes leading to dementia
Plaques cause damage to axons
What actually causes the damage?
- Beta-amyloid precursor protein
- OR Form oligomers & aggregated plaques. Oligomers can be directly neurotoxic.
Cortical Synapse loss actually exceeds neuronal loss in AD
• probably due to some toxic mechanism
What is the amyloid cascade hypothesis
• Amyloid Cascade Hypothesis
o Abnormal processing of beta-amyloid precursor protein → Deposition of insoluble beta-amyloid into plaques → Neurofibrillary degeneration & nerve cell loss
Describe the histopathological progression in AD
• Start off with a diffuse plaque → • Neuritic plaques, tangles, neuron & synapse loss → • Cognitive impairment → • Functional loss Diagnosis to death is about 5 years.
what are some of the NEGATIVE risk factors for DEMENTIA
- Ageing
- Vascular health
- Family hx
- Head injury? (neurons primed
what are some of the POSITIVE risk factors for DEMENTIA
- Family hx
- Education at a younger age
- Work complexity?
- Mental activity?
- Social engagement?
Use it or loose it hypothesis
- Does maintaining an active mental life contribute to building ‘cognitive reserve’ (more connections) and thus reducing the risk of dementia or mild cognitive impairment
- You wont show overt symptoms as early if you have a bigger cognitive reserve
Frontotemporal Disease:
Also known as Pick’s disease, Lobar atrophy
40-60 years of age (most cases have a genetic link)
What % of dementias are assoc. with frontotemporal dementia?
- Approx. 10-20% of dementias
* Can overlap with symptoms of Amyotrophic Lateral Sclerosis ie MND (ALS-FTD)
What are the CLINICAL SIGNS of Frontotemporal Dementia
Behavioural & personality changes (disinhibited & restless)
Repetitive & ritualistic behaviour
Changes in diet & personal hygiene
Disturbance in common language (particularly expression, becomes mute)
Pervasive apathy (not enjoy things they previously did enjoy)
Initial memory problems aren’t severe (unlike Alzheimer’s disease!)
What are the clinical SIGNS of AD
Repeat statements and questions over and over, not realizing that they’ve asked the question before
Forget conversations, appointments or events, and not remember them later
Routinely misplace possessions, often putting them in illogical locations
Eventually forget the names of family members and everyday objects
Depression
Social withdrawal
Mood swings
Distrust in others
Irritability and aggressiveness
Changes in sleeping habits
Wandering
Loss of inhibitions
Delusions, such as believing something has been stole
What % Of Frontotemporal dementia have a hereditary link?
40%
15% of those with hereditary link are associated with a mutation- what is this? in FTD
• Approx 15% of hereditary FTD linked to chromosome 17 (tau gene)
Tau gene mutation you can develop FTD
What are other mutations seen in FTD
FTD-ALS variants
• Progranulin gene mutations
• Hexanucleotide repeat expansion in non-coding region of the C9ORF72 gene
Histopathalogically what would you see?
• Pick bodies
- Filamentous intracellular inclusions
- Variable presence in FTD
Lewy Body Dementia
May be related to Parkinson’s disease
Same pathology but starts in a different place
Often confused with Alzheimer’s disease but it has a more rapid progression
• ~ 15% of dementia cases
What % of dementia is Lewy Body Dementia?
15% of dementia cases
What is LBD characterised by?
- Characterised by Lewy Bodies in the neocortex - Comprised of ubiquitin, neurofilament & alpha-synuclein protein
- Extremely sensitive to antipsychotic medications
What are the clinical features of LBD?
- Rapidly progressing
- Visual hallucinations (more common in LBD than any other)
- Parkinsonism - movement – associated with Lewy Bodies in Substantia Nigra
Can have sleep disturbances, mood swings & aggressive behaviour
VASCULAR DEMENTIA
- Aka ‘multi-infarct’ dementia, Binswager disease, mixed dementia, single infarct dementia etc
- Overlap with other dementias. Shares risk factors with other vascular disorders
Vascular Dementia Features
- Typically small vessel disease
- Lacunar infarcts
- Some have congophilic amyloid angiopathy
Clinical Features of Vascular Dementia
• Mood & behaviour changes • Frontal executive functions → memory deficits • Gait problems • Step-wise pattern for degeneration o i.e. one mini-stroke then another
