Pathology and Disease of the CNS Flashcards

Question

How do vetebral fractures/dislocations cause spinal cord pathology?

Answer 1

Vertebral fractures/dislocations can cause severe **acute spinal cord compression** when hard bone imparts pressure upon the delicate spinal cord. Results in a **thinned spinal cord and haemorrhaging** at the site. Complications of acute spinal cord compression: * Get further injury along the spinal cord away from compression site of injury due to hamorrhaging blood **compressing nerves** within the confines of the spinal cord.

Answer 2

**Infections** * When barriers to the brain are disrupted/opened during trauma **Hydrocephalus ** * Neurologic disorder that is caused by a disruption in the balance between the formation, flow, or absorption of CSF in the brain, resulting in an increase in the volume that the CSF occupies in the CNS * Results most commonly following TBI's due to scar tissue blocking reabsorption of CSF into subarachnoid spaces. * Dilated ventricles observed. **Epilepsy** **Chronic Traumatic Encephalopathy** * Is a dementing illness that develops after TBI due to neuronal loss and brain atrohpy. * Is associated to the abnormal deposition of Tau protein + A-beta plaques in brain cortex.

Answer 3

Normal ICP = 1-15 mmHg Emergency mmHg = \>25 mmHg

Answer 4

1. Trauma/Contusions 2. Tumour 3. Infarction 4. Haemorrhage 5. Infection 6. Cerebral oedema 7. Overproduction, obstruction to flow or absorption of CSF (e.g contusion scarring of CSF pathways or CSF producing tumours)

Answer 5

Cranial contents consist of brain, CSF and blood * These contents are contained within a fixed container - expansion of any of them, or introduction new contents, elevates the pressure within the cranium. * ~ 150mL each of blood and CSF - rest brain. The initial response to an expanding brain lesion is the **_expulsion of as much CSF and venous blood as possible_** to compensate for the lesion. The ICP rises when this can't be done any further. As a result of raised ICP, herniation of brain tissue can occur through dural openings. Danger: as ICP approaches cerebral arterial pressure, brain perfusion ceases. * **CPP = MAP - ICP**

Answer 6

1. **Vasogenic Cerebral Oedema** * Increased extracellular fluid due to blood brain barrier disruption with increased vascular permeability (following inflammation, necrosis or neoplasms) * Predominantly involves white matter * Is steroid susceptible - can be treated with steroids 2. **Cytotoxic Cerebral Oedema** * Increased intracellular fluid secondary to neuronal, glial of endothelial cell membrane injury. * Generally a result of hypoxic/ischemic insults like stroke * Involved white and grey matter * Not responsive to steroid treatment

Answer 7

**_Symptoms: _** - Headache - Vomiting - Blurred vision **_Signs:_** - Depressed conscious state - Cushings triad (hypertension, bradycardia and irregular respiration): - (Decreased cerebral perfusion triggers a reflex increase in BP; Baroreceptors respond to this increase in BP causing a reflex bradycardia; Compression of respiratory centers in the medula causes irregular respiration) - Papilloedema (if ICP recent onset) - Pupil changes – dilation unilaterally or bilaterally (features of herniation) **Late signs:** - Abnormal posturing (decerebrate and decorticate) – late sign - Brain ischaemia symptoms such as dellirium and LOC

Answer 8

_***Subfalcine (cingulate) herniation** *_occurs when unilateral or asymmetric expansion of a cerebral hemisphere **displaces the cingulate gyrus under the falx cerebrei**. This may lead to compression of the anterior cerebral artery and its branches or the corpus callosum (risk of infarct to corpus callosum) ## Footnote ***_Transtentorial (uncal) herniation_*** occurs when the **uncus (parahypocampal gyrus) herniates under tentorium cerebelli**, which compresses the contralateral cerebral peduncle (ipsi hemiparesis), stretches the ipsilateral III CN (ipsi, mydriasis) and compresses the PCA resulting in occipital lobe infarct. The midbrain is compressed therefore affecting the ascending reticular activating system resulting in LOC. ***_Tonsilar herniation_*** occurs when t**onsils of the cerebellum are displaced into the foramen magnum**. This compresses the medulla and compromises life threatening cardiovascular and respiratory centres.

Answer 9

**_Normal neuron_** * Central nucleus and dense Nissl substance (granules of rER with rosettes of free ribosomes for protein production) **_Up to 2 week post injury_** * Peripheral nucleus and loss of Nissl substance * **_Wallerian Degeneration_** * Degeneration of axon and myelin sheath distal to the site of injury * Debris is phagocytosed by macrophages * Muscle fibre atrophy of this neuron -\> use it or lose it principle **_Up to 3 weeks post-injury_** * Scwann cells proliferate to form a compact cord * Growing axons penetrate the Schwann cell cord * Some sprouting may occur which will largely be unuseful - only need one branch to reinnervate the target lost by injury * Muscle fibre atrophy **_3 months post-injury_** * Successful regeneration * Electrical activity restored * Muscle fibre regeneration

Answer 10

If the PNS unsuccessfully regenerates, **_neuroma formation_** may occur. Neuroma formation refers to aberant axon growth that can't find the right target of re-innervation. It results in a bundle of nerve fibres with no innervation which can cause severe pain when spontaneously stimulated.

Answer 11

Schwann cells and extracellular matrix in distal axon segments provide a guide in both iinstances but is more continuous in a crush injury. **The more precise the allignement; the better the regeneration and recovery of function is.** Cutting an axon misaligns the proximal and distal axons more than simply crushing them. Microsurgery is the main therapeutic approach to PNS injury.

Answer 12

**_Primary Injury_** ## Footnote Immediate physical damage and cell loss. Remove the primary cause of the damage and prevent further damage **_Secondary Injury_** *Minutes to Hours: Degenerative insults:* * Ischemia * Ca²⁺influx * Lipid peroxidation and free radical production * Glutamate excitotoxicity * BBB breakdown *Hours to days/weeks: Immune response:* * Immune cell infiltration * Microglial activation * Cytokines, chemokines and metalloproteases *Days to weeks: Degeneration:* * Axonal degeneration * Demyelination * Apoptosis - neuronal and oligodendrical * Phagocytosis of debris * **_Astrocytic gliosis and glial scarring_** * Cavity formation and meningeal fibroblast migration

Answer 13

In response to CNS injury, there is an upregulation of astrocyte cytoskeletal protein GFAP (glial fibrillary acidic protein); which is induces **astrocytic gliosis** As a result of this, astrocytes: * Hypertrophy * Proliferate * Interdigitate their processes to form more of a barrier * Secrete cytokine and growth factors * Secrete ECM that is highly inhibitive of axonal regrowth * Upregulate expression of developmental guidance molecules. All of these factors contribute to the formation of the **glial scar**. The glial scar forms a barrier betwwen the injury site and undamaged tissue (protective) but also prevents the regeneration of axons through this area of injury. Need to manipulate a balance between protection and regeneration of injured CNS tissue

Answer 14

1. **_Lack of Trophic Support_** * Encourage axons to grow by providing growth promoting factors * ***Neurotrophins*** ******2. **_Axon regrowth inhibited by the injury environment _** * Inhibit growth blocking factors * ***Astrocytic gliosis & glial scar*** * ***Myelin inhibitors*** * ***Developmental guidance molecules*** *

Answer 15

**Myelin inhibitors** located on the **myelin debris** of oligodendricytes are inhibitory molecules in the injury environment that bind to regrowing axons/dendrites and repress their growth cones. Myelin proteins are inhibitive of regrowth under normal physiology in order to prevent abberant sprouting of neurons. Myelin proteins include: _Nogo_, _MAG_ (myelin associated glycoprotein) and _OMgp_ (oligodendrocyte/myelin glycoprotein). **_These proteins all bind to Nogo receptors and activate the Rho signalling pathway which neuronal growth cone formation. Thus stunts regrowth_**

Answer 16

Axon guidance molecules promote, repel or guide axon growth - typically during developmental stages of human life. Many of these axon guidance molecules are upregulated or re-expressed following CNS injury (particularly via astrocyte production); the majority of which are repellant and inhibitive of axonal regrowth. **Ephrins/Eph** are a particular type of axon guidance molecule that is up-regulated by reactive astrocytes in the injury environment. **EphA4** and ephrinA5 are significant axonal repellants. These axon guidance molecules converge on the Rho kinase pathway to affect growth cone regulation

Answer 17

Rho kinase pathway is an important mechanism of neuronal growth cone regulation. It lies downstream to a number of growth inhibitor receptors (NOGO, Ephrin, Semaphorin etc.). It is for this reason that it is a promising target of CNS injury therapeutics. Activation of the Rho pathway by these receptors results in stunted activity of the neuronal growth cone and suppression of regeneration. Rho inhibitors are under clinical trial currently

Answer 18

There are two plausible ways of utilising stem cells to replace neuronal cells lost to CNS injury: 1. **_Activation of endogenous CNS stem cells_** There are two main neurogenic regions of the brain that contain neural stem cells: * Subventricular zone of the lateral ventricle * Subgranular zone of the dentate gyrus in hippocampus (involved in memory/learning) These areas don't normally repair CNS because they have difficulty in **_proliferating, migrating, differentiating and surviving_** to be effective. Therapies are in development to try to facilitate the use of these cells in repairing the CNS. 2. **_Transplantation of stem/progenitor cells_** Culturing embryonic stem cells, induced pluripotent stem cells and endogenous adult stem cells for transplantation into affect sites to replace lost neuronal cells.

Answer 19

It is likely that a combination of therapies will be required. Unsure whether axons that regenerate and make connections will be a) topographically accurate (correct target) or b) functionally acurate. Physical therapy and muscle/neuronal activity be important to functional improvement.

Answer 20

**Stroke** is a clinical term refering to the **development of a focal or global neurological deficit relating to a vascular event.** The vascular event can be variable in type, position and severity. Note: transient clinical events may occur as a result of vascular events or "silent" vascular events may occur where there are no observable/noticable impacts of the event of function.

Answer 21

**_Infarction (75%)_** * Death of tissue due to inadequate blood flow **_Intra Haemorrhage (20%)_** * Tissue injury due to the rupture of blood vessels and subsequent loss of blood **_Non-traumatic Subarachnoid Haemorrhage (5%)_** * Escape of blood primarily into the subarachnoid space

Answer 22

Stroke is the third leading cause of death (10% of all deaths) Significant incidence of morbidity in survivours -\> lead disabled lives of varying severity. Risk factors include: * Aging * Hypertension * Cardiac Disease (e.g. Atrial Fibrillation) * Hyperlipidaemia * Diabetes Mellitus * Hypercoagulable States * Smoking * Obesity

Answer 23

Cerebral infarction is the necrosis of cerebral tissue in a particular vascular distribution due to: 1. Vessel occlusion by **embolus** (most common) 2. Inadequate blood supply due to **narrowed vessel lumen** * Atherosclerosis * Thrombosis * Hypertensive vessel thickening * Amyloid angiopathy 3. Severe **hypoperfusion due to cardiac failure**

Answer 24

All vessels = cardiac failure Large artery occlusion = Thrombotic \< Embolic Small vessel occlusion = Thrombotic and embolic Venous occlusion = Thrombotic

Answer 25

**Thrombotic endocraditis **is the deposition of a coagulative mass of thrombotic material onto the valves of the heart. It occurs as a result of **hypercoagulative states**, **deformed valves** or certain types of **infection**. The mass can culture microbes (infective endocarditis) which can cause underlying damage to of the valve. There is significant potential for parts of these masses to **_embolise and occlude vessels_** downstream; including that of the cerebrum.

Answer 26

**P****robe-patent interatrial septum **is congenital deficiency in the inter-atrial septa septa of the heart that occurs in 1/3 of all people. This communication allows for a potential thrombus to pass from the right atrium to the left atrium. The **venous system is the most common site of emboli formation **and this deficiency provides a route to arterial system rather than the pulmonary system where a pulmonary embolus was more likely to form. In these cases, the propensity to have cerebral emboli is elevated.

Answer 27

The three most common sites of athersclerosis include: 1. **Basillar Artery** 2. **Proximal Middle Cerebral Artery** 3. **Terminating ends of Internal Carotid Artery** The Circle of Willis have reasonably sized vessels communicating between the basillar/vertebral and internal carotid arterial systems which allows for the compensation of blockages of the main branches.

Answer 28

1. Luminal narrowing 2. Ulceration of plaques

Answer 29

**Carotid endarterectomy** is an operation conducted to prevent ulcerated or stenotic atherosclerosis of the common/internal carotid artery from causing a cerebral infarction -\> prophylactic Athersclerosis at the biforcation of the common carotid is a common pathology. It causes narrowing, restricting flow or give rise to emboli that result in strokes.

Answer 30

**_First 6 Hours_** There is little change in appearance during the first 6 hours of irreversible injury. **_6-48 hours_** * Ischemic neuronal change with both cytotoxic and vasogenic oedema predominating = **Swelling** * Loss of the **demarcation between white- and gray matter** structures. * Endothelial and glial cells, mainly astrocytes, swell, and myelinated fibers begin to disintegrate - **cell membrane breakdown** * Evidence of **herniation** if severe enough * Neuronal changes * initially swell but ultimately shrink * become highly eosinophilic * nucleus condenses/pyknosis * nucleus eventually lost. **_Days to Weeks_** * Swelling resides * Tissue undergoes liquefactive necrosis * high volume of necrotic material and macrophages removing debris histologically * porrige like consistancy macroscopically **_Months to a year_** * Scarring * Formation of cystic spaces filled with CSF

Answer 31

Cerebral infarctions can directly cause death by: 1. Damaging vital centres of the brainstem 2. Cerebral swelling / raised intracranial pressure (herniation risk) But most commonly, **patients tend to die from causes secondary to the stroke event** - these patients tend to have co-morbidities with similar risk factors to stroke. This includes: 1. Pneumonia 2. Cardivascular Disease 3. Pulmonary thromboembolism

Answer 32

Common pathologies include: ## Footnote 1. **_Hypertensive small vessel disease_** 2. **_Amyloid Angiopathy_** (congophilic angiopathy) 3. Blood disorders 4. Tumour 5. Vasculitis 6. Vascular malformation 7. Drugs (by causing hypertension or causing vasculitis)

Answer 33

Hypertensive haemorrhages are characterised by the presence of **small vessel disease = hyaline artiolosclerosis. ** It tends to occur in deep grey matter (and some deep white matter) but no cortex areas: * **Basal ganglia/thalamus** * **Lobar white matter** * **Cerebellum** * **Pons** **Hyaline arteriolosclerosis** results from chronic hypertension. It leads to the deposition of hyaline-like plaques in the walls of small arteries. This causes wall thinckening and narrowing of the lumen. **Depositions within the wall makes it weaker and it dilates or "balloons"**. This predisposes the vessel to rupturing -\> resulting in a cerebral haemorrhage. Note: hyaline arteriolosclerosis can also lead to thrombosis at the earlier stages where the lumen narrows.

Answer 34

**Cerebral amyloid angiopathy (CAA) **involves the deposition of amyloidogenic peptides, particularly A-beta Amyloid (same as Alzheimer's disease), in the walls of small and medium meningeal and cortical blood vessels = **superficial blood vessels of the cortex** Deposition of A-beta plaques in the walls of these vessels can weaken them and cause haemorrhage. This condition is associated to superficial cerbral haemorrhages - tend to keep reoccuring over time and are affect people of varying ages. These CAA cerebral haemorrhages are highly associated to **Alzheimer's Disease **(same plaques)

Answer 35

It is highly unlikely that multiple haemorrhages would develop concurrently as a result of hypertensive or CAA haemorrhages. It is more likely to be a systemic problem. Presentations like this are typical of **coagulopathies of the blood** leading to the thrombosis of small vessels in any region of the brain.

Answer 36

**Congenital arteriovenous malformation** involves the improper positioning of blood vessels within a blood supply circuit. In cerebral haemorrhages, arterioles with high pressure blood directly pass this blood to venous vessels **without a any capillary formations**. The venules are unable to handle this pressure and rupture to cause haemorrhage.

Answer 37

**Subarachnoid haemorrhages (non-traumatic)** tend to result from **vessels before they have penetrated the cerebral tissue**. They tend to be larger vessels - such as branches of the **Circle of Willis.** Common causes include: 1. _Rupture of Saccular/Berry aneurysm _ 2. _Rupture of other types of aneurysm_ * mycotic (infective) * atherosclerotic 3. _Extension of intracerebral haemorrhage that leaks into the subarachnoid space._

Answer 38

* Sex and Age (Male and Elderly) * Polycystic kidney disease * Coarction of Aorta * Type III collagen deficiency (and similarly) * Hypertension * Smoking/alcohol

Answer 39

**Saccular aneurysms **are large "berry-like" aneurysm at sites of **congenital weakness** in involved vessels -\> absence of smooth muscle and internal elastic lamina. They tend to occur at **sites of arterial bifurcation **and in the **anterior cerebral circulation** more commonly than the posterior cerebral circulation. The most common sites include: 1. **Middle Cerebral Artery (MCA) bi/trifurcation** 2. **Junction of ICA and Posterior Communicating Artery** 3. **Anterior Communicating Artery (ACA)**

Answer 40

1. Subarachnoid Haemorrhage 2. Cerebral oedema and raised ICP 3. Vasospasm and Infarction * blood products in the subarachnoid space are spasmogenic * cause vasoconstriction of cerebral vessels -\> ischemia and infarction to distal supply. * need to clip aneurysm ASAP to prevent blood loss 4. Ventricular obstruction / hydrocephalus * Healing fibrosis that occludes the openings of the ventricular system into the subarachnoid space -\> back up of CSF to expand ventricles -\> raised ICP

Answer 41

1. Loss of inhibitory neurons & gain of excitatory neurons (aberrant sprouting connections 2. Alterations in intrinsic cellular excitability 3. Alteration in synaptic transmission 4. Alterations in the neuronal environment (glial cells)

Answer 42

The hippocampus - part of the medial temporal lobe - is a particularly sensitive structure to induce epileptic activity in humans and animal models. It has four subregions: dentate gyrus, CA1, CA2 and CA3 that all show unidirectional circuitry In humans and animal models of mesial temporal lobe epilepsy (a common form of epilepsy) epileptogenic remodelling demonstrates a consistent pattern known as **mesial temporal sclerosis:** * Cell loss in CA1, CA3 and dentate gyrus region * Mossy fibre sprouting * Gliosis

Answer 43

Seizure themselves are thought to accelerate the pathology of aberrant epileptic networks - making further seizures common. It is uncertain whether the neurobiological changes seen in epileptic circuits cause epilepsy or the result of epilepsy itself.

Answer 44

The distribution of epilepsy incidence is **_bimodal_** It is more common in the **_young_** (children and adolescents) and the **_elderly_** The aetiology of epilepsy differs between the age groups: **_Infancy/early childhood:_** due to congenital/perinatal CNS insults **_Late childhood/early adulthood:_** idiopathic/genetic causes **_Adult/elderly:_** most symptomatic epilepsy; caused by a variety of insults including degenerative disease, tumours, trauma and vascular events.

Answer 45

Most common to least common: 1. Mesial temporal sclerosis 2. Malformations of cortical development 3. Low grade tumours 4. Vascular malformations 5. Encephalomalacia

Answer 46

**_Mesial temporal sclerosis_** is the most common pathology found in MRI's of adult patients of partial epilepsy. It is refractory (unaffected) to medical therapy but... good prognosis with **_epilepsy surgery _**

Answer 47

**_Focal cortical dysplasia_** Focal regions of disturbed cortical development and architecture. * Aetiology is unknown - not genetic * MRI shows thickening of cortex, loss of demarcation between white and grey matter, gyrus abnormalities and increased T2 signals **_Periventricular Nodular Heterotopia_** Generalised malformation due to abnormal neuronal migration * Nodular masses form of grey matter lining the ventricles (bilateral or unilateral) * Cortex and neurological functional normal * Inherited (X-linked or autosomal recessive)

Answer 48

**Low grade tumors** are implicated in 15% of patients with partial epilepsy. Most common cause of new onset partial seizures in adults 35-55 y.o Gliomas (most common 88%), meningiomas and neuroepithelial tumors are the main types Tend to occur in cortex \> subcortex

Answer 49

Vascular lesions are responsible for 10% of medical resistant partial epilepsy - is difficult to control Two types of vascular lesions are particularly linked: **_Arteriovenous malformations_** Congenital vascular abnormalities consisting of communicating arteries and veins without intervening capillary beds. **_Cavernomas_** Tangled mass of tightly arranged abnormal vessels made of common hypocellular walls * seizures common (40-70%) but haemorrhage rare

Answer 50

**_Focal encephalomalacia_** are focal lesions (soft or loss of tissue) that result from previous destructive insults such as trauma, stroke, infection etc.

Answer 51

**_Anti-epileptic drugs_** * Treat the symptoms; not the underlying epileptic condition * Decreases the frequency and severity of seizures * Treatments required for years - often a lifetime **_Surgery_** * Can only be attempted in patients with focal epilepsy where the origin of seizures can be localised to a brain section. This section can then be resected if safe to do so. * 80% success in appropriate cases **_Neurostimulators _** **_Dietary_**

Answer 52

Any future advances in anti-epileptic treatment will be a multi-faceted approach that addresses: ## Footnote 1. Medically refractory seizures are the most common types of seizures - need to treat them 2. Currently medication have poor tolerability - cognitive slowing etc. 3. No anti-epileptogenic or disease modifying treatments - all drug therapies treat the symptoms 4. Better treatment of co-morbidities (psychiatric and cognitive deficits)

Answer 53

**Unstable repeat expansions **are a class of genetic conditions characterised by an expansion of a segment of DNA within a specific gene. The expansion consists of repeating units of three or more nucleotides in series. They are a form of **dynamic mutation **as the size of expansion varies person to person; genertation to generation. * Expansion size increases in subsequent generations of progeny -\> this is known as anticipation. * **Anticipation** is associated with earlier disease onset and/or greater disease severity

Answer 54

Although not certain, it is though that slipped mispairing during DNA replication contributes to expanded repeat regions. 1. Replicating strand detaches inappropriately from the template strand during DNA replication 2. This leads to the replicating strand slipping from its proper allignment to the template strand by a single repeat length - it loops out. 3. An additional replicating repeat is sysnthesised to replace it. 4. The newly synthesised strand contains an extra repeat.

Answer 55

There are generally three outcomes of unstable expanded repeats: 1. **Non-coding repeats causing a loss of protein function** * as a result of impaired transcription of the affected gene protein * example: Fragile X and Friedreich ataxia 2. **Non-coding repeats that confer novel properties to the RNA** * leads to RNA with toxic gain of function * example: Myotonic dystropy (1 and 2) 3. **Repeats in a codon that confer novel properties in the affected protein** * Novel gain of function due to the production of a modified protein which overrides the normal protein function * example: Huntington's disease, spinocerebellar ataxia

Answer 56

Huntington's disease is an **autosomal dominant neurodegenerative disease** It affects 1/10,000-20-000 people It is late onset generally; small proportion of early onset in severe cases. Main features include: * Movement/motor disorders * Cognitive disorder * Psychiatric disorder

Answer 57

***_Early features/prodrome _*** Clumsiness, agitation, irritability, apathy, anxiety, disinhibition, delusions/hallucinations, abnormal eye movements and depression ***_Middle features_*** Involuntary movements, chorea, trouble with balance and walking, trouble with activities that require manual dexterity, slow voluntary movements, general weakness, weight loss, speech difficulties (dysarthria) and stubbornness ***_Late features_*** **Rigidity**, **bradykinesia** (difficulty initiating and continuing movements), serious weight loss, inability to walk, inability to speak, **danger of choking on food**, inability to care for oneself

Answer 58

Huntington's disease results from expansion in the HTT (HD) gene found in chromosome 4. * Repeat region located within exon 1 (of 6) * Involves repeat of CAG -\> coding polyglutamine The normal protein product is **Huntingtin (HTT)** * has a role in transcription, intracellular transport, intracellular signalling and reducing apoptosis Expanded CAG HTT product (**polyQ-huntingtin**) has a toxic effect in basal ganglia * particularly spiny neurons Early affects appear only in the brain despite the gene being expressed throughout the body * there is sometyhing specific to the brain environment that exaggerates onset and severity in the brain

Answer 59

Huntingtons Disease results in the progressive degeneration and loss of medium spiny neurons in the striatum of the basal ganglia PolyQ-Huntingtin is cleaved by caspases and other enzymes to generate **toxic N-terminal fragments** with altered conformations. These fragments form aggregates and nuclear inclusions. Note that the nuclear inclusions may actually be a protective cellular response to the disease. Loss of function of normal HTT and possible RNA toxicity might also contribute to pathogenicity,

Answer 60

Normal = \<26 repeats 'Normal' but increased risk of offspring HD anticipation = 27-35 Zone of reduced penetrance = 36-39 Affected = \>40 Classically, HD was tested using PCR-electrophoresis-autoradiography in order to determine repeat numbers. Modernly, PCR--**fragment analysis**-electrophoresis-fluorescence detection used.

Answer 61

**Freidreich Ataxia **is an autosomal recessive dynamic mutation to intron non-coding regions. It affects 2-4/100,000 Carrier frequency of 1/60 (1/100 in Indo-Europeans) Age of onset is around puberty (mean age 10) ; usually less than 25 years old. Main features include: 1. Progressive limb and gait ataxia 2. Cardiomyopathy 3. Diabetes mellitus

Answer 62

**Freidreich Ataxia **involves the **GAA repeat** expansion of the **FXN gene found on Chr 9** Unstable repeat expansion occurs within **intron 1 ** * causes abnormal DNA structure and/or induces reduced protein production Expansion accounts for 94-98% of cases * Compouns heterozygotes with GAA repeats and other single point mutations comprise remaining 2-6% Normal protein is produced; but there is insufficient amounts of it due to altered gene expression of the intronic DNA. Leads to mitochondrial mediated oxidative damage (via Iron)

Answer 63

Normal = 5-33 repeats Pre-mutation range = 34-65 reppeats Affected = 66-1700 repeats Note: alleles longer than 27 GAA triplet repeats are often interupted by a **(GAGGAA)n sequence that is protective -\> stabilises the allele**

Answer 64

**Spinocerebellar Ataxia (SA) **is an autosomal dominant unstable expanding repeat. There are various types of SA (~35 described; 10 due to unstable repeat expansions) and their frequency varies across populations Generally a late onset neurodegenerative disease Main features: * Progressive degeneration of the cerebellum, brainstem and spinocerebellar tracts * leading to gait, hand, coordination, speech and eye movement deficits * Phenotypic variation

Answer 65

Classical PCR-Gel electophoresis or Modern PCR- fragment analysis

Answer 66

* Different implications in laboratory diagnosis of genetic disease * Implications for not only patient, but also other family members * Formal consent, genetic counselling and confidentiality issues, especially with predictive testing (restricted access to results) * Insurance (life, disability) implications (NB family history) * Predictive testing in children not usually encouraged (NB ‘mature minors’) * Prenatal testing, including pre-implantation genetic diagnosis (PGD) possible – need to know mutation/haplotype in parent

Answer 67

**Age** * exponential doubling of incidence with each decade after age 50 **Familial/Genetic** * Trisomy 21 * Apolipoprotein E * APP mutations * Gene dosage of A-beta/APP gene **Education** **Head Trauma** **Smoking** **Vascular Disease** **Diabetes**

Answer 68

Amyloid Cascade Hypothesis describes protein aggregation in Alzheimer disease. Amyloid precursor protein (APP) cleavage by α-secretase and γ-secretase produces a harmless soluble peptide, whereas amyloid precursor protein cleavage by β-secretase and γ-secretase releases Aβ peptides, which form pathogenic aggregates and contribute to the characteristic plaques and tangles of Alzheimer disease

Answer 69

Synaptic toxicity is thought to be mediated by A-beta synaptic toxicity. This arises from A-beta monomer dispersing in the brain onto the membrane surfaces of the neuron at intra- and extra-synaptic sites.

Answer 70

Metal -protein attenuating compound (MPAC) has been shown effective in sequestering and reducing the A-beta load in mouse models of Alzheimers Disease

Answer 71

**¹¹C-PIB is a radioactive ligand that binds to A-beta amyloid** in the brain allowing the viewing and quantification of A-beta. Neocortical imaging intensity of¹¹C-PIB greater than 1.5 is indicative of Alzheimers Disease Studies investigating this imaging method as a diagnostic tool for AD concluded that there is **approximately 30 years between complete normality and clinical AD** Alternatively, measurements of A-beta in the CSF can be reflective of cerebrum levels.

Answer 72

Kuru is an aggressive cerebellar degenerative condition as a result of a prion disease transmitted by canabolism in Kuru region of Papua New Guinea. Was characterised by trembling and shaking (the definition of Kuru) It mainly affected females and children Implementation of public health and awareness surrounding food processes has all but eradicated the disease over the last 50 years.

Answer 73

Starting in 1995, a series of cases of a CJD-like illness came to medical attention in the United Kingdom. This illness was different from typical CJD in several important respects: the disease **affected young adults**, **behavioral disorders figured prominently in the early stages** of the disease, and the neurologic syndrome **progressed more slowly** than in individuals with other forms of CJD. The neuropathologic findings and molecular features of these new cases were similar to those of CJD, suggesting a close relationship between the two illnesses, with multiple lines of evidence indicating that the new variant form of CJD was linked to exposure to **bovine spongiform encephalopathy**

Answer 74

Pathogenesis of prion disease vCJD/BSE involves the **conversion of PrP^cto PrP^res**. **α-helical PrP ^c may shift to the β-sheet PrP ^sc conformation** - either spontaneously as a result of genetic mutations to PRNP gene that encodes PrP^c or transmissible prion diseases. PrP^res may also be acquired from exogenous sources, such as contaminated food, medical instrumentation, or medicines. Once present, **PrP^sc converts additional molecules of PrP^c into PrP^sc through physical interaction**, eventually leading to the formation of pathogenic PrP^scaggregates

Answer 75

It is now reasonable to assume that vCJD patients blood is infectious; and that sCJD (secondary) blood may be infectious. Estimated incubation period is 6-15 years; initial outbreak of BSE was ~1988-1993 in UK. This suggest a peak blood infectivity at the current time. Have had the primary bovine to human phase; entering a secondary human to human transmission period now that will peak in 2020

Answer 76

The first gene to be identified as a cause of autosomal dominant PD encodes **α -synuclein**, an abundant lipid-binding protein normally associated with synapses. * normally a soluble protein that sits in the vesicular membrane * mutated a-synuclein interactions with metal dopamine cause it to abnormal fold into non-soluble aggregates This protein is a major component of the **Lewy body**, which is the diagnostic hallmark of PD. * **Lewy bodies** are large inclusions of a-synuclein in the cytoplasm of cells of the **Substantia Nigra** The occurrence of disease caused by changes in gene copy number implies a **gene dosage effect**, and suggests that polymorphisms in the α-synuclein promoter that alter its expression may influence the risk of PD. Like Aβ in Alzheimer disease, α-synuclein has been **demonstrated to form aggregates; of these, small oligomers appear to be the most toxic to neurons**.

Answer 77

You can monitor the progression of AD by **measuring the levels of VMAT 2** **VMAT 2 **is a protein that normal a-synuclein contributes to the formation of. Abnormal a-synuclein doesn't form the VMAT 2 protein and levels of it drop.

Answer 78

**Catatonia** is motor immobility as evidenced by cataplexy or stupor Patients are incapable of initiating movements -\> maintain postures and positions. Still don't understand how this occurs