list the brain regions mostly affected in down syndrome and briefly decribe the major pathological changes observed at anatomical and cellular level?
Please discuss neurotransmiiter abberant changes and insight on other changes?
Frontal lobe, hippocampus, cerreellum, brainstem prefrontal cortex.
Anatomical- From the onset of birth we can already see the brains weight in proportion body weight is 20% lower. after 6months we can see shortening of the frontal lobe and a cerrebellum is 75% the size of normals, Brainstem is aslo diminished in size.. somethings possibly lnked to cognitive ands speech deficits
- In the prenatal stages we begin t observe issues on the cellular level in the PFC and hippocampus. This is noticeable in the HPC as there is 65% the normal neuronal count in the DG.
- as disease that is normally associate with issue in neruonal circuitry, we can see this when looking at the branching of dendrites and there spines, key location of synapses. Branching is significanlty reduced and size and density of spines is reduced.
Trisonomy 21 the cause of DS is the biggest genetic risk factor of AD, and this dementia is a variable trait of DS.
- amyloid plaque deposits can be seen in the ealry 20s being seen in 100% of DS patients by the 30s, simmilar progressive depsoition of toxic AD linked tau pathology can also be observed.
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- Abberant level sof neurotrasmitters and signalling molceules have been seen in developement.
- reduced GABA (excitatory in developement), histamine and serotonin.
- deficits in cholinergic systems.
Deficits in developemental siganlling would likely have long lasting negative impacts of the wriing and developement of cortical connections and synaptic function, Deficts that appear to be present later on with the issues seen with denrites.
- A growing argument looking at hippocampus, cerebellum and PFC deficits was these are late forming rgions during development, and thus this could be linked to delayed developement of neurons.
- it is pstulated this could be a slowed cell cycle or neuronal proliferation.
- Ideas for delayed neuronal development can be seen by late myeelination of DG neurons in DS.
- Idea supported in IPSC cells. Astrocytes have been shown to support neruogenesis in normal cells. using asttrocted induced from IPSCs stemming from a DS patients show a loss of this support. possibly explaing te deficits in a range of cortical regions.
Discuss the link between AD and Downsyndrome
AD is charcaterised by the formation of amyloid beta plaques. This is produced via this incorrect processing of the precursor APP via the beta gamma pathway instead of the alpha gamma pathway.
The APP gene is found on chromosome 21, the location of trisonomy in DS. triplication of APP alone has been shown to cause alzheimers alone in some pedigrees, thus this make DS the biggest genetic risk factor of AD.
Although other dose related changes occuring in (Human chromosome 21) HSA21s 230 coding genes likley contribute to aspects of the disease, the dementia and AD ia likely a direct risk of this.
in the early 20s amyloid beta depostion can be observed, and this is seen in 100% by the 30s. a simmiliar progression is seen n the toxic AD related tau pathology.
It usually takes a delay of 20 years following pathology to see symptoms and the same dlay can be seen in DS patients who develop AD.
Briefly outline the advanatges and disadvantages of using animal models to study Down syndrome
Firstly we much look at the issues with other methods:
Human samples:
- Not readily available very difficult to get them quickly for RNA or protein studies.
-We can observe them throughout the life span of a patient.
IPSCs
- These are great as we can produce neurons with the genetic make up of patients
- But we can create all forms of neurons.
- Althoyugh we can create small circuits in organoids these are not the same as the real thing.
- We canot see the effects of aging.
MICE:
- ve in condtions shoing life long changes it is hard to correlate between humans and mice. although their life span is accelertaed relative to our own is does not do so on a linear scale. difficult then to see why learning rate declines or what AD linked changes are occuring.
- ve- not all neuronal regions are maintained in mice and their ciruitry is much more basic. +ve HOWEver, The core areas like the thalamus and cerrebellum which are damaged in DS are maintained
- ve We cannot constantly test the brain from snapshots of anatomical changes, +ve HOWEVER, we can test are collective periods like 3months, 12months and birth, somethings not possible in other examples.
- ve- mice show mosaicism, which is a big issue in the TGC moduse model as it means not all of their cells will express the trisonomy. so these are not perfect recapitualtions of the disease.
+ve They are genetically versatile. We can quite easily to manipulate them best demonstrated by the existence of the TRIchromosomic mice model of DS (Tgc). This shows HAS TRISONOMY OF 75% of the HSA21 genes and shows clear motor defits, and implication of the HPC.
+ve, a NEGATIVE would be the fact the i mice the homologous regions of the human long arm of CH21 is split between CH16 (whole),17 *part) and 10. (part). but te developement of partial trisonomy has overcome this issue. And the bulk of genes are still maintained. (shared ancestor e.t.c)
- The are relatively easy to egt confrotable in a lab environemnt and easy to test behvaiourally, allowing the easy asessement of how trisonomy may imapct key behvaiours, like memory, motor skills.
-They breed relatively well something important weh trying to narrow down specific trisonomy impacts in partial trisonomy tests.
-We have assess to all tissues at all stages of life.
What are the primary clinical presentations of Down syndrome and what is the genetic cause? What is the biggest risk factor?
Cogntive impairment (issues with working memory, attention an intelectual ability with a small proportion hahving an IQ over 60. hypotonia, lack of muscle tone, AD phenotype (forgetful)
variale symptoms: dementia linked to AD, heart defects, autoimmune diseases (some have developed MS and some even autoimmune forms of type 1 diabetes)
The genetic cause is a dose related increase in the 230 coded genes by the hsa21. TRISONOMY 21.
the biggest risk factor is the maternal age. having a child at 30- 1/935 increased to 1/85 at 40.
what impact has prenatal testing for DS had on the incidence rate?
Prenatal testing is available for trisonomy 21, but this has not increased abortion rates and thus had no effect on incidence.
outline in greater detail the deficits seen in cognition, language and memory in DS patients? include some rarer characteristics sen also
Cognitive deficits
- This is te most common form of intelectual disability with 40% having an IQ between 50 and 60 and only 1% between 70-80.
- Althougth their emotional control is largely sparred.
- We observe deficts in learning rate (which progressively gets worse over time) and executive tasks, likely linked to the deficits in the PFC.
Language-
- Althought the recognition of language is relatively normal there are a large range of deficits.
- phonetic language- issue understanding speech patterns and sounds.
- syntactic- issue putting words into proper senstences.
- Articulation- this is an issue to pronounce and produce speech. although this is largely related to the DS having an abnormally large tongue. its also could be related to issues with fine moevemnt related to the reduced cerrebellar size.
- verbal memory- struggle rememebering words.
memory-
- Implicit memory, This being procedural memory like riding a bike is largely sparred.
- Primary issues with declaritive memory. These deficits are most clear when acrrying out complex task, as these reuqire both endoing of memory and recall it main be damage with these mechanisms at fault. (seen in word list memory trials, unlike many trials this was reported to be wrost then mental age matched controls.)
- This also could be related to HPC issues and its link to declaritive memory.
- better visuo-spatial learning vs visuo-object learning also observed, This is related to the relaitvely maintained develpement of the dorsal visuals system vs he ventral visual system.
It is important t recognise in these trials that 67% of DS something hearing loss. This could contribute to speech issue developement, in particular articulation, but it also could cause issues with testing. This is caused by otitis media in 78% of cases which is the swelling of the middle ear and so is an obstructive hearing loss.
-rare cases can also be sleep disruption seen in many patients. This is often attributed to sleep apnoea which coauses an occlusion of the air way and the fragementation of sleep.
What are the Findings from mouse models of DS
Unlike in humans we can look at the electrophysiology is mice using recording electrodse>
-The have discovered increased LTD in the HPC. LTP is related to the consolidaion of declaritve memory in the HPC and thus this could likely expalin some of the memory and learning deficits in DS.
- Behavioural trials- show MTL deficits in mice with reduced perfomance in MWM. a spatial cognition trial which tests the HPC role in spatial memory.
- The have also identified excessive inhibition of the DG, possibly due to the enhanced GABA action in adulthood, to the same effect. (GABA inverse agonists were innefective as treatments. This could pottentialy contribute to LTD.
A big break through method has been partial trisonomy.
- This involves duplicating specific regions on 1 of the chromosomes in mice to produce a trisonomy in that specific region wit homologs to human CH21. So all or a bit of CH16, or some of 17 or 10. They can then screen fro phenotypes through behvaioural and functional studies and relate this to a a gene within this region.
- An attempt to narrow this down can then be done by crossing an trisonomy for a specific gene in the region e.g APP with a mice with a 1 allele KO for the gene. hence offfspring have 2 or 3, if we see recovery of the phenotype in 2s then we know the phenotype is related to this.
-Theta and Gamma waves were altered in DS models and this was mapped to trisonomy on chromosome 16.
- more recently these methods have led to the identification of DYRK1a.
-a serine theronine kinase with role in neurogenesis and the regaltion of the dendritic tree. these are 2 features effected in DS.
=It has an imapct on APP and TAU, which are key to the AD links in DS.
ideas for therapeutics for DS?
Most methods hav failed. GABA INVERSE agonists to reduce GABA activity was inefective.
Although this was effective at removing MTL deficits in MWM in mice models, showing quicker aquisition of the platform location.
Give the link of anitdepressant like fluoxetine to boosting AHN this is now being investigated.
