Module 2: Neurological and Psychiatric Disorders of the Central Nervous System Flashcards

Question

**_Lecture 3, Prion Disease: Clinical and Pathological features_** What happens to the Prp protein in Prion diseases?

Answer 1

normal = PrPc, scrapie isoform = PrPsc, abnormal human isoform = PrPp (is actually the same as PrPsc) * prion protein is a cell surface glycoprotein, its funtion is not well know but thought to be involved in signal transduction and vesicle trafficing * it’s resistant to degradation by proteinase K * the pathological isoform PrPp is present in prion disease and the infectious agent. * There is a conversion from alpha helix into beta pleated sheet that is more tightly bound and is the stucture for all amyloids. * This deposits insoluble protiens in the brain

Answer 2

**Rapid progression of a clinical hisotry consistent with dementia or movement disorder** **Sporadic CJD** - rare but accounts for 80% of prion diseases - affects both genders equally - the mean age of onset is 57-66 years but it can also occur at 17 years or 80 years - progression is rapid: - declines in cognitive and motor function over a few weeks (progressive dementia),EEG changes like in dementia * motor signs (ataxia, bradykinesia and spasticity) due to corticospinal tract dysfunction * memory deficits * cognitive deficits * visual disturbances **Iatrogenic CJD** - you can also get CJD iatrogenically, through transplantations, for example: - dural transplant - growth hormone (ground up brains used to harvest GH) **Gerstmann-Straussler-Scheinker (GSS) Syndrome** - slow progression (duraEon = 4-5 years) - mild demenEa occurs late in the disease - mean age of death is 50 **Fatal Familial Insomnia (FFI)** - characterised by insomnia - demenEa occurs late in the disease

Answer 3

There are 3 bands depending on how many polysaccharide chains are attached - the nature of attached glycan is also important - four patterns: - types 1 and 2 = sporadic CJD - type 3 = iatrogenic CJD - type 4 = variant CJD

Answer 4

Lesions in fatal non-missile head injury * *• Primary** - skull fracture (75%) - surface contusions (95%) - diffuse axonal injury (30%) - intracranial haematoma (60%) * *• Secondary** - brain swelling (53%) - ischaemic brain damage (55%) - infection (4%) - due to raised ICP (75%)

Answer 5

**Brain swelling** - causes raised ICP • vasodilatation and increased cerebral bloood volume (congestive) • blood vessel damage (vasogenic oedema) • increased water content of cells (cytotoxic cerebral oedema) Can lead to uncle herniation if there is supratentorial pressure

Answer 6

**_Fractures:_** -can lead to otorrhea or rhinorrhea - there’s a risk of infection - signs of a skull-based fracture: • Baile’s sign (bruise beneath ear) • Raccoon eyes **_Contusions:_** When the brain is in **collision with the skull**, surface bruising occurs since the anterior fossa is not smooth, any movement can cause localised bleeding. **Coup or countercoup** injury can occur (the brain rebounding within the skull) **_Diffuse axonal injury (DAI):_** Happens at the moment of injury, has shear and tensile forces affecting axons. Commonest cause of coma (when no bleed) Midline stuctures are particularly vulnerable DAI grading: • **grade 1**: parasagital frontal, internal capsule, cerebellum • **grade 2:** grade 1 + corpus callosum • **grade 3**: grade 2 + dorsal brainstem Pathogenesis- Primary axonomy = axolemma damage, allowing Ca2+ influx and eventually development of swelling. Causeing cytoskeleton dyruption and functional impairment. Secondary axonomy = increased neuron sensitivity to excitotic and hypoxic damage. **Traumatic axonal injury-** at least some is present in neary all head injuries **Intracranial haematoma -** 66% of fatal non-missile head injury. 10%extradural and 56% subdural,subarachnoid, intracerebral

Answer 7

Dementia pugilistica (aka. Chronic Traumatic Encephalopathy, CTE) **definition of CTE pathology = presence of:** • **foci of perivascular neurofibrillary tangles (NFT)** and astrocytic tangles • **irregular cortical distribution** of NFTs and astrocytic tangles particularly in the depths of the sulci. • clusters of subpial and periventricular astrocytic tangles in the cerebral cortex, diencephalon, basal ganglia and brainstem • **neurofibrillary tangles** in the cerebral cortex located **preferentially in the superficial layers** • tau pathology in AD vs CTE - the most important thing is that **_astrocytic tangles are not present in Alzheimer’s disease but prominent in CTE_** **_Evidence_** * now it's generally accepted that head injury can promote the generation of Aß deposits diffusely in the brain; epidemiological studies showed that troops with head injuries in WWII showed significantly increased risk of dementia after 50 years (including vascular dementias) * since the 1920s it had been known that the repetative brain trauma associated with boxing may produce a progressive neurological deterioration * microscopically, there are extensive tau immunoreactive neurofibrillary tangles, astrocytic tangles and spindelshaped/ threadlike neurites throughout the brain * proposed as a tauopathy * in a study of 85 subjects with a history of repetitive mild TBI, who were athletes and military personnel, 68 of them showed some degree of CTE pathology. **_Environmental and genetic risks:_** Apolipoprotein E4 allele is associated with more Ab protein plaques follwoing head injury

Answer 8

Behvioural/mood varients (generally younger onset) cognitive impairments (generally older onset)

Answer 9

AD prevalence is very high at older ages: - age 65-69 = 1.3% - age **85-89** = **20.3%** 700 000 people have dementia in the UK - projected to increase to **940 000 by 2021** - estimated cost per annum in UK is **\> £17 billion** In the UK, the economic impact of dementia dwarfs the costs of other diseases but the annual government and charity spend on dementia research is **12 times lower than on cancer research**

Answer 10

**The key neuropathology of AD is:** * Extracellular Plaques * Neurofibrillary Tangles * Cerebral Amyloid Angiopathy * Neuronal Loss (cerebral atrophy) amyloid is any protein that has formed a beta pleated sheet structure and has aggregated

Answer 11

* - ACh turnover decreases with age * - AD is characterised chemically by cerebral cholinergic transmiier deficits * - cholinergic deficits underlie memory loss and related cognitive problems * - decrease in cholinergic markers strongly correlate with dementia severity * - so if you restore cholinergic function, you could reduce cognitive loss * - you can either: 1. load up with a precursor (e.g. lecithin), but this was ineffective 2. could give a receptor agonist to maintain the action on the post synaptic receptor 3. inhibit acetylchloinesterase **_(this has been the main approach to therapy)_**

Answer 12

* Anti-cholinesterases * Tacrine (Cognex), Donepezil (Aricept), Rivastigmine (Exelon) * All reported to produce mild benefits in early AD but **do not prevent disease progression** * Nicotinic ACh receptors * Galantamine (Reminyl) * Glutamate anatagonist * Memantine * May also be of use for vascular dementia

Answer 13

**_•Cortical atrophy_** - in a healthy brain, there’s tight folding of the gyri, and ventricles are normal sized - but in AD, the ventricles are much bigger, there’s shrinkage of the hippocampus, and general cortical atrophy - the primary motor and sensory cortices are unaffected - this happens in many neurodegenerative diseases so it’s not diagnostic * *_• Astrocytes_** - the red blob is a plaque and the purple stuff around it is reactive astrocytes responding to them * *_• Neurofibrillary tangles_** - you can see paired helical filaments in AD - these are made of tau, which is a microtubule associated protein (MAP), and is involved in the stabilisation of microtubules, dependent on their phosphorylation state - in AD, **_tau is hyperphosphorylated_** and you can see it in the cytoskeleton of the neuron * *_• Senile plaques_** - the brain’s way of coping with excess proteins is by just dumping them outside the cells - this happens in AD, where the ß-amyloid aggregates are dumped outside the neurons, but it doesn’t seem to correlate with symptoms; there’s probably a threshold for this -their evolution is from **diffuse to target shaped** **_• Cerebral amyloid angiopathy_** - this is when there are amyloid deposits in cerebral blood vessels; they rarely can detach and cause ischaemic stroke * *_• Glial reaction_** - glia try to phagocytose the Aß in the plaque

Answer 14

diagnosis of Alzheimer’s disease requires a slow progressive course, senile plaques and neurofibrillary tangles, and **Braak stave IV or greater**+ cortical neuritic plaques - if the disease progression is much faster, it could be prion disease instead **_Staging of tau pathology in Alzheimer’s disease_** - the first three stages are presymptomatic - people only affected in these stages show “mild cognitive impairment”, aka MCI - the pathology starts in the anterior hippocampus, then progresses to the posterior hippocampus, transentorrhinal cortex of the hippocampus (where the 6 layer structure of the hippocampus turns into a 3 layer structure) then progresses through the temporal lobe - then you see pathology in the occipital cortex and the primary motor corte

Answer 15

**_Amyloid-ß peptide -_** is the protien that forms Amyloid plaques, it is **_PART OF Amyloid PRECURSOR PROTIEN_** **_Amyloid Precursor Protien (APP) -_** APP is a membrane bound glycoprotein, its processing can be **_NON-AMYLOIDOGENIC_** or **_AMYLODOGENIC_**. The latter is the pathological pathway that leads to **_Amyloid-ß peptide_** production outside the cell membrane - APP processing can be broken down in 2 ways either with - on a neuronal cell membrane, there are 3 proteins involved in the processing of APP - in **normal conditions**, **_alpha secretase_** **_breaks down APP_** and releases solid APP-alpha; then **one of the fragments (83-aa)** is broken down by **gamma secretase and removed** - in Alzheimer’s, **_beta secretase cuts beta amyloid_** at a different site to form a **_99-aa fragment_**, which is broken down by gamma secretase again - this makes a beta amyloid monomer, which aggregates in toxic forms (in proto-fibrils to fibrils to clumped plaques) - these get deposited on the neuronal cells - this causes neuronal damage, by **_activating the inflammatory cascade_** - maybe these plaques are just an end-stage process and it’s just a way of dumping the protein outside, and it’s actually the oligomers or monomers that are the most harmful

Answer 16

The Amyloid-B Peptide forms dimers which then form oligomers and eventually fibrils. Effects include: 1. **Hyper-phorsphorylating TAU** the million $$$$ question in **HOW DOES THIS HAPPEN** 2. Affecting the proteosome to prevent normal cell breakdown 3. Calcium regulation disruption 4. affecting the mitochondria to produce **_Reactive Oxygen Species_** 5. Moving the Amyloid plaques outside the cell which is thought to be toxic

Answer 17

**• age.** biggest risk factor **• family history** • **Down’s syndrome**, by 35/40. Reason is that the APP gene is on Chromosome 21 • **previous head trauma** head injury can lead to “punch drunk syndrome” (CTE) - 30% of head injury paEents that have Aß deposits also have a high incidence of the ApoE4 allele * **Parkinson’s disease** * **depression**

Answer 18

All of these ultimately cause excess Amyloid Beta Production: Early Onset * **Chromosome 21** – Early onset Familial AD, mutation in **APP gene** * **Chromosome 14** – Early onset FAD, **presenilin-1**, integral membrane protein, role in intracellular signalling * **Chromosome 1** – **Presenilin-2** Late Onset * **Chromosome 19** – Late onset/sporadic AD, **Apolipoprotein E4**, roles in lipid metabolism and heart disease. which has roles in lipid metabolism, heart disease and membrane repair There are 3 alleles of apolipoprotein E, * **E2,E3,E4** * of which **_ApoE4_** gives the highest risk of developing AD (this allele is much more common in AD patients than normal controls). Heterozygous E4 gives twice as much risk and a **Homozygous E4 allele gives an 10 times higher risk** of Alzheimer's Disease **Epigenetics:** Aberrant methylation profile Disruption of histone proteins Altered chromatin remodelling; all can play a role in pathogenesis of AD. Epigenetic therapies may prove beneficial.

Answer 19

There are two main approaches • **symptomatic or palliative** relief without attenuation of pathology • curative therapy by means of a causal approach: _stop aggregation of Aß_ • _clear Aß deposits_ with a _vaccine or neprilysin_ • _reduce the expression of APP_ (but it’s also important physiologically, so maybe you affect normal processes) • _alter metabolism of APP_ (favour the non amyloidogenic pathway) • control expression of regulators of APP • _anti-inflammatories_ (but then these, esp. NSAIDs, can cause gut problems; plus by the time you put someone who’s symptomatic on anti-inflammatories, the disease process has already gone too far) • _growth factors_ (not sure what they’re trying to make grow and where) • Tissue transplants (but this might be difficult because it’s not a focal pathology, it’s a v diffuse process)

Answer 20

- candidate secretases to target: * *_- alpha secretase_** – is a normal cleavage enzyme; we could try to make this more efficient or increase its expression - TNF-alpha converEng enzyme (TACE) - ADAM17 (a disintegrin metalloproteinase) * *_- beta secretase_** (which is amyloidogenic with gamma secretase) we could inhibit its expression - BACE1 * *_- gamma secretase_** - presenilin

Answer 21

one immunisation trial of Aß-42 was stopped because of meningoencephalitis in some patients (as an inflammatory reaction to the vaccine) - but afterwards, they did an autopsy of the patients who died from the meningoencephalitis and saw that they had ***_cleared the neuropathology anyway_*** **_How does the vaccine work?_** - Could it be that the antibodies to Aß are recruiting microglia, which clear the damage? - or the antibodies themselves neutralise the Aß plaques? - or maybe the antibodies pull Aß out of the brain through the BBB, where it can be cleared? - although the number of patients was small, the approach made no difference in terms of survival (disease course was unaffected) so it’s tempting to write off this approach, but then maybe it was just a matter of timing – they immunised the patients too late in the disease stage - the trial had no plan to follow up; v bad. ***_- also, when they checked the autopsies, they found that 25% of the “AD patients” didn’t even have AD… one of them was autauopathy, some had vascular dementia; so they weren’t even treating the right people!_***

Answer 22

cortical areas and circuits are involved in cognitive functions and AD - there’s gradual atrophy in this patient over tiime - after 2 years the hippocampus gets much smaller and there’s lots of atrophy - one way to check if the treatment has worked is through imaging over time - **_Since tau pathology correlates beier with symptoms_**, maybe we should look at tau to see progression of the disease. The

Answer 23

in ppl with iatrogenic prion disease, there’s a subset who seem to have a lot of Aß pathology - but the media exaggerated it and made ppl think that it was actually infectious (while in reality, it was only formed if you surgically introduced the Aß into patients - which doesn’t happen otherwise)

Answer 24

- Frontotemporal dementia is an umbrella clinical term that encompasses a group of neurodegenerative diseases characterised by progressive deficits in behaviour, executive function or language - frontotemporal dementia is a common type of dementia, particularly in patients younger than 65 - the disease can mimic many psychiatric disorder because of the prominent behavioural features - various underlying neuropathological entities lead to the frontotemporal dementia clinical phenotype, all of which are characterised by the selective degeneration of the frontal and temporal cortices

Answer 25

* in the years prior to presentatoin, they had word-finding difficulties, language impairments and later progressive personality change (since it affects the frontal lobe) * there were also neuropsychiatric changes in facial recognition, verbal fluency, etc.

Answer 26

The TAU protien can have **6 isoforms** It can either have **3 or 4 microtubule binding domains (R)**, and **0,1 or 2 unknown function inserts (N)** Alzheimer's is a 3R and 4R Tauopathy CBP and PSP (parkinson plus disorders) are 4R Tauopathies Picks is a 3R Tauopathy

Answer 27

* Pick bodies are very obvious, and there are some probably agerelated tau tangles as well * one brain section was stained with TDP43 (not progranulin antibodies) and they found that the pathology was quite unique and included: - cat’s eyes (intranuclear inclusions) - other neuritic inclusions * **_C9ORF72_** mutation in chromosome 9p: - you can see cats eyes and neuritic pathology - inclusions are usually found in the cerebrum, but it’s uncommon for them to be in the granular cell layer of the cerebellum; that are positive for ubiquitin but negative for TDP43 and tau - is it like alpha synuclein, where there are cytoplasmic granular aggregations? - will the things aggregate into a body like in FTLD? - current insights into the C9ORF72 repeat expansion diseases of the FTLD/ALS spectrum suggest there’s clinical phenotypic heterogeneity and it’s very confusing to figure out what the diagnosis is * Involvement of **_TDP-43 in both FTLD-TDP and MND/ALS_** also provided a firm molecular link between **_FTLD and MND/ALS_** underpinning the notion that these two large groups of neurodegenerative disorders represent two, often overlapping ends of a disease spectrum * This is also supported by clinical data indicating that about **_30% of patients with FTD develop clinical signs of MND/ALS_** and that **_50% of MND/ALS patients show some evidence of cognitive deficits_**

Answer 28

A Chronic inflammatory **_multifocal, demyelinating_** disease of the central nervous system of unknown cause, **_resulting in loss of myelin_** and **_oligodendrocyte and astrocyte pathology_** Mortality the mean disease duration is between 40-50 years life expectancy is reduced by 7-14 years

Answer 29

Between 80 and 240 cases per 100,000 in Northern European and American Countries. In the UK the prevalence is **126 per 100,000** (285 women, 113 men). Incidence is 9.64 per 100,000 per year. There is distrinct latitutde variation, the risk is higher in areas of higher latitude. The role of Vitamin D in the development of MS is added to by a low Vit D intake increasing risk. The time of exposure is important, **migrants older than 15** from high risk countries to low ones **retained their high risk**. But ones aged **younger than 15** from high risk to low risk, **aquired the lower risk** of the migration destination. Birth times also are important. Highest rates are among those who are born in May and lowest for those in Nov. Is VIt D during pregnancy playing a role?

Answer 30

**_Virus_** Risk of MS is twice as high in those who have has EBV. Disease severity and risk of MS corrlate with antiEBV antibodies titres. **_Genetic_** first degree relatives have a 10-25x greater risk of MS. **25% to 30% concordance rate in monozygotic twins**. Only 30% of the disease is attributed to genes. HLA-class II genes exert the strongest effect, accounting for 20-60% of the genetic risk, **_Hormones_** Women are twice as likely to get MS than men, relapsing rates are much higher around preganancy.

Answer 31

**_Relapses and Progression_** **_Relapses:_** Episodic, acute neurological symptoms lasting for more than 24 hours. Spontaneous recovery often occurs, especially in early attack with young pateints. Common symptoms of relapses * Monocular vision loss (rarely bilateral) * Weakness of Limbs, spasticity, hyperreflexia * Impaired coordination * Sensory loss * urinanry urgency * sexual dysfunction * diplopia * ataxic gait * seizures and psychiatric disturbances * severe fatigue Symptoms are highly variable since the location of lesions is so variable. **_Progression_** = the slow accumulation of ireversible loss of function for at least a year.

Answer 32

**_RR MS_** Mean age of onset is 30 (F:M = 2/3:1), optic neuritis and sensory distrubances are common onest symptoms. 70% of patients have at least a 5 year relapse free period. Annulaized relapse rate decreases over time (17% less every 5 years). 85% of relapsing remmiting MS patients convert to secondary progressive MS after 25 years from onest. **_SP MS and PP MS_** Primary progressive MS and Secondary progressive MS start at the same age.

Answer 33

**Clinical history and Exam:** **Dissemination in time (DIT)** and **Dissemination in Space (DIS) of CNS lesions.** **MRI:** Very god at picking up white matter lesions less good at grey matter ones. Typical plaque locations are periventricular, , corpus callosum, brainstem and cerebellum. **_CSP analysis:_** Increased production of CSF immunoglobulin. oligoclonal bands (OCB) in CSF only (not in serum). **_Electrophysiology:_** Visual evoked protentials. If abnormal, they indicate visual pathway dysfunction (even in patients with no visual symptoms)

Answer 34

Acute disseminated encephalomyelitis (ADEM) (monophasic, demyelinating process of CNS) = have low frequency oligoclonalbands (OCB) Neuromyelitis potica = always test for aquaporin 4 antibodies to cancel this out when diagnosis MS. Also has low frequency OCB. And this never enters the progressive stage.

Answer 35

Mean time to EDSS 6 (need assistance to walk) is 20 years No features can predict the outcome in the single patient. A**ge at onset** and progressive course from onset are the most adverse prognostic factors. **_Good prognostic indicators:_** - young onset - female - optic neuritis or only sensory symptoms at onset - low frequency of early attacks - complete symptom remission - long first inter attack interval **_Bad prognostic indicators_** - older than 40 years at onset - male - insidious pyramidal tract involvement - prominent cerebellar involvement - frequent early attacks - rapid development of fixed disability

Module 2: Neurological and Psychiatric Disorders of the Central Nervous System Flashcards

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