Mbchb3 Pathology


• More common w advancing age
• 2% of people over 65 yrs have parkinsons
• 8% of those with parkinsons develop it before the age of 40
• average duration from dx to death – 13 yrs

Cardinal Clinical Features
• Rest Tremor
• Bradykinesia or slowness of mvment – impassive face, impaired rapid alternating mvements, abnormal gait (reduced or absent arm swinging, shortened stride length, freezing)
o Asymmetrical
o Loss of internal metronome but can follow external cues eg walking up stairs no problem
• Rigidity
• Postural abnormalities – difficulty arising from chair or rolling over in bed, stooped posture, tendency to take several steps to turn, falling
Note – these sx often absent first thing in morning – its thought dopamine is stored up while asleep (basal ganglia turns off at night)

• Two or more cardinal feats
• Progressive course
• Response to levodopa
• No alternative cause for pt sx

• Degeneration of dopaminergic neurons in substantia nigra
• Inclusion bodies (lewy bodies)
Lewy Bodies
• intracytoplasmic inclusion body's especially noted in pigmented brainstem neurons and seen in Parkinson's disease
Inclusion Bodies
• distinctive structures frequently formed in the nucleus or cytoplasm in cells infected with certain filterable viruses
• in some instances, inclusion body’s are known to be infective and probably represent aggregates of virus particles in combination with cellular material

• unknown – probably multifactorial
• Genetic susceptibility – gene mutation on chrom 4 causes early onset of hereditary form of parkinsons
• Toxins – MPTP-parkinsonism
• Infections – von economo’s encephalitis

Tx – Drugs
• L-Dopa + Dopa decarboxylase Inhibitor
o Dopamine cant cross bbb but L-dopa can
o Dopa de-carboxylase converts dopa into dopamine
o Dopa decarboxylase inhibitor cant cross bbb so doesn’t stop conversion in brain but does stop conversion elsewhere reducing side effects
o Side effects include vomiting and nausea (dopamine acts on the vomiting center in the medulla)
o Carb/Ldopa comibined (brain names – sinemet, madopar)
o Blood levels of L dopa fluctuate but clinical response consistent as l-dopa is stored in vesicles and released consistently
o However – over time, more and more vesicles lose their storage capacity and you end up with an immediate and pronounced effect after taking the drug but this quickly wears off, hence you end up taking the drug more often
o The high levels of L-dopa in action also create a roller coaster where you shoot over the top and have extra writhing mvments – L-dopa induced dyskinesia
o As parkinson’s progresses – therapeutic window thus ↓
o After 10 yrs, one side may be hyperactive while the other has parkinson’s effects – so do you keep giving tx?
• Dopamine agonists
• Anticholinergics
• Monoamine oxidase (MAO) B Inhibitor
• Catechol-o-methyltransferase (COMT) inhibitors

Tx – Surgery (for advanced dis)
• Stereotactic thalamotomy (for tremor)
• Stereotactic pallidotomy (improve all feats of parkinsons dis incl dyskinesias)
• Transplantation of dopamine producing tis (ie fetal tis)
• Deep brain stimulation – inhibits overactive neurons w/o the need for a destructive procedure

Late complications of Parkinsons
• Cogv abnormalities – confusion, hallucinations, dementia
• Emoal disturbances – anxiety, depression
• Postural hypotension
• Fluctuations – 50% of pts after 5 yrs of tx: dyskinesia, on-off fluctuations
While the brunt is on the dopamine sys – other NTs are affected thus making it a diffuse dis – tx reqd for depression, pain, low bp etc (multi-dis med juggling)


Ataxia – incoordination
Alcohol – a cerebellar toxin meaning that the sx and signs of cerebellar dis are v similar to signs you would see in a drunk

Key Sx and Signs
• Truncal and gait ataxia
o Unsteady while sitting w/o support
o Stands and walks w broad base
o Steps irregular in timing, distance and side-to-side
o Highlighted by walking heel-toe (tandem gait) or on heels
o Reflects dis of mid-line cerebellar structures
o May be the only sign of cerebellar dis
• Limb ataxia
o Sx inlc clumsiness, difficulty writing
o Abnormal drift of outstretched arms
o Rebound after sudden displacement of outstretched limb
o Dysmetria (intention tremor) – on finger-nose-finger, heel-knee-shin tests
 Dysmetria – ability to control distance, power and speed of an act is impaired
o Impaired rapid alternating mvments
o Reflects dis of cerebellar hemisphere
o Ataxia on same side as affected cerebellar hemisphere
• Dysarthria
o Loss of articulation → slurred, staccato speech
 Phrase – british constitution
• Abnormal eye movements
o Nystagmus – rhythmic, oscillatory mvments of one or both eyes
o Often assoc w oscillopsia – oscillations of evt
o Oscillation – to and fro
• +/- vertigo
o sensation that evt is swaying side to side or to and fro (rotation, sensation of spinning or whirring)
• +/- nausea/vomiting

Other Points about Cerebellar Dis
• Tone – normal or reduced
• Power – tendon reflexes, plantar response, sensation → normal
o Joint sensation not impaired – can close eyes and will sway but not fall over
• Assoc sx and signs – many diseases of cerebellum affect other parts of the nervous sys as well

Causes of Cerebellar Dis
• Congenital abnormalities
• Inherited, degenerative diseases of cerebellum
o 50% genetic
• Inflammation, demyelination
o MS
o Autoimmune dis
• Tumors
o Primary
o Secondary (mets)
• Vascular dis
o Ischaemic stroke (infarct)
o Often assoc w infarction of brain stem
o hemorrhage
• Infections
o Bacteria – cerebellar abscess
o Virus
o Prion dis (creutzfeldt-jakob dis)
• Metabolic disorders
o Hypoxia, ischaemia, hyperthermia
o Toxins – alcohol, drugs, heavy metals
o Vit deficiencies – thiamine
o Hereditary metabolic disorders
o hypothyroidism

• 2/100,000
• no spec tx or cure


Def – epilepsy is a condition in which pts have recurrent, unprovoked epileptic seizures – an epileptic seizure comprises an abnormal and excessive electrical discharge from neurons in the cerebral cortex
• Epilepsy is a syndrome for which there are many possible causes rather than a specific dx
• Epilepsy does not always produce a loss of consciousness
• Loss of consciousness may result from other path processes

Separate seizures for classification of both epileptic seizures and epilepsies
• Partial seizure – involves neurons in one part of brain only
• Generalized seizure – involves all neurons of brain
• A seizure may start as a partial seizure and secondarily generalize

• Seizures may occur when there is an imbalance betw excitatory and inhibitory neurons
• Both excitatory and inhibitory NT depend on a variety of ion channels
• Some ion channels voltage gated, some ligand gated
• Ion channels are found along axons and around synapses
• There are regional differences in relative amounts of diff receptors
• There is substantial plasticity of ion channels

Excitatory neurotransmission
• Major NT glutamate (Glu)
• 3 types of glu receptors – NMDA, non-NMDA, metabotropic
2. NMDA Receptors
• activated by NMDA
• when receptor occupied, opens channel for monovalent (Na and K) and divalent cations (esp Ca2+)
• absol requirement for glycine as co-agonist
• activation is much slower than non-NMDA receptors
• when hyperpolarized, Mg2+ blocks channel – Mg2+ expelled when membrane partially depolarized – results in pos feedback
2. Non-NMDA Receptors
• activated by AMPA and kainic acid – not activated by NMDA
• ion channels permeable to both Na and K ions (monovalent cations)
• relatively impermeable to Ca2+
• rapidly activated and inactivated
3. Metabotropic Receptors
• coupled to G proteins, second msngrs, not ion channels
• role in devt/prevention of seizures unclear but probably v impt
Excitatory Transmission
• both NMDA and non-NMDA receptors are co-localised at most excitatory synapses
• depol of presynaptic terminal results in entry of Ca2+
• fusion of vesicles w specialized regions of pre-synaptic membr
• exocytosis of contents into synaptic cleft
• non-NMDA channels open quickly – produce partial depol
• Partial depol results in expulsion of Mg2+ from NMDA channels – produces further Ca2+ entry
• Further depol

Inhibitory Transmission
• GABA (gamma amino butyric acid)
• GABAa receptors – linked to ion channel – binds 2 molecs of GABA
• Opens Cl- channel – hyperpolarizes neuron
• Allostric binding sites which modulate Cl- channel

Many drugs may induce seizures by interfering w neurotransmission
• Systemic agents may –
o Block GABAa receptors
 Bicuculline (competitive antagonist)
 Picrotoxin (non-competitive antagonist)
 Penicillin – enters open GABA channel and occludes them
o Activate Glu receptors
o Unblock NMDA receptors – low Mg
o Block glycine receptors – strychnine
o Block K currents w 4-aminopyridine

Drugs to Treat Seizures also act on ion channels/receptors
1. Na Channel Blockers
• Eg – phenytoin, carbamazepine
• Act on voltage sensitive Na channels of excitatory neurons
• Stablise Na currents in inactive form – delay recovery
• Prevent sustained repetitive firing from extended depol
2. Enhance Gaba-ergic transmission
• Vigabatrin, tiagabine
• Benzodiazepines
• phenobarbitone
3. Reduce glutamatergic transmission
• topirimate, felbamate

Possible mechanisms for producing epileptogenesis
1. Anatomic rearrangements of local circuits
• many excitatory axons have collateral branches that activate neurons within the local region of CNS
• may contribute to either feedback inhibition or excitation
• under normal circumstances, feedback inhibition is more powerful
• if there is neuronal death, sprouting of unlesioned axons occurs to fill in dendritic regions – form new circuits
2. freq dependent changes in synaptic efficacy
• repeated expos of animal to subclinical electr stim eventually progresses to spontaneous recurrent sz (kindling)
o assoc w changes in ion channels
o excitatory synapses potentiated when fire repetitively
o inhibitory synapses tend to ↓ in efficacy when fire repetitively
3. changes in local receptors
• NMDA receptors may change after neuronal injury
• Some of these changes may be perpetuated by seizures themselves ie vicious cycle
• Seizures may – alter gene expression and mRNA levels, produce glial changes, neuronal sprouting and neuronal death, produce alterations in synaptic circuitry/receptor expression

• Hallmark of Localisation related epilepsy (partial seizures) is interictal spike
• Occurs when group of neurons in a restricted area are activated simultaneously in an abnormally hypersynchronised way
• Neurons undergo a large depolarizing shift (DS) in membrane potential – lasts approx 200ms
• Burst of APs are superimposed on the depolarizing shift
• These events are produced experimentally when GAGA inhibition is reduced
• Excessive synchronization is due to activation of recurrent excitatory circuits
• Devt and spread of epileptic activity into normal brain due to combination of recurrent circuitry and normal freq dependent plasticity of excitatory and inhibitory synapses, maybe also altered NMDA, AMPA components – altered glu uptake, altered K buffering by glia

Clinical Feats

Generalized Seizures
• Loss of responsiveness is present at onset of seizure and motor manifestations are bilateral and symmetrical
1. Generalized seizures w major motor manifestations (convulsions)
• Tonic seizures – sustained bilateral contraction of axial and limb muscles
• Clonic seizures – regular repeated bilateral contractions of axial and limb muscles
• Tonic Clonic seizures – tonic (sustained) contraction followed by clonic motor mvments
• Myoclonic seizures – sudden brief jerks of axial and limb muscles
• Epileptic spasms – brief tonic contractions of bilateral axial and limb muscles w an initial myoclonic component – typically last 2-10 secs and occur in a cluster
2. Generalized seizures w no or minor motor manifestations
• Absence seizures – abrupt onset and end – relatively brief – EEG shows generalized spike and slow wave discharge at 3-4 Hz
• Atypical absences – of longer duration, more gradual onset and finish, may be followed by confusion
o EEG – shows slower genralised spike and slow wave discharge at 2.5Hz approx
• Atonic seizures – sudden loss of muscle tone causing a collapse of head and trunk
• Astatic seizures – epileptic falls when the seizure type (tonic, myoclonic, atonic) unknown

Partial Seizures
1. Simple Partial Seizures
• Consciousness preserved – termed an aura if evolves into a diff type of seizure
• Sx are determined by part of brain involved in discharge
• Visual – typically bright or dark spots
• Somatosensory – typically parasthesiae
• Auditory – buzzing or ringing sounds
• Psychic – sensation that int or ext evt is experienced in a distorted manner – an object or situation may be perceived as familiar or foreign (dejavu) or remote and small
• Abdominal – vague unpleasant sensations often assoc w nausea
• Olfactory or gustatory – smell or taste usu unpleasant
Focal Motor Seizures
• Versive seizures – lateral deviation of eyes, followed by deviation of head and trunk (may occur w or w/o loss of consciousness)
2. Complex Partial Seizures
• Partial seizures in which there is a loss of consciousness
• Typically pt is unresponsive and they may have amnesia for the episode

Classification of Epilepsies
• Epilepsies are classified according to the type of seizures, age of onset, assoc neurological abnormalities, EEG feats and underlying cause
• Not all pts have epilepsy that can be easily classified
• Idiopathic epilepsy – implies brain is normal apart from tendency to seizures – may be either partial or generalized
• Symptomatic epilepsy – occurs when epilepsy is 2ndry to known neurological d/o – eg tuberous sclerosis
• Cryptogenic epilepsy – occurs when there are other feats (eg MR, ataxia, spasticity) but the underlying pathology has not been identified


• A seizure is a convulsion or transient abnormal event resulting from a paroxysmal discharge of cerebral neurons
• Epilepsy is the continuing tendency to have such seizures (even if long interval separates the attacks)
• Generalised convulsion (grand mal fit) – most common recognized event
• Over 2% of popn have two or more seizures during lifetime
• 0.5% - epilepsy is an active prob
• often no clear cause is found
• stimes epilepsy is caused by a brain tumor or follows a stroke
• during a seizure – large grps of neurons are activated repeatedly and hypersynchronously
• there is failure of inhibitory synaptic contact betw neurons
• this causes EEG high voltage spike and wave activity – electrophysiological hallmark of epilepsy
• partial seizure – activity confined to one area of cortex w recognizable clinical pattern – this activity either remains local or spreads to become a generalized seizure (this spread is called 2ndry generalization of a partial seizure)
• an area of brain becomes epileptogenic either bec neurons have a predisposition to be hyperexcitable – either following abnormal migration patterns in utero or acquired (eg tumors or brain trauma)
Seizure Threshold
• each individual has a threshold for seizure activity
• experimentally some chemicals induce seizures in all subjects
• generalized – implies abnormal activity that is bilateral in brain w bilateral motor manifestations – consciousness is impaired
• partial seizure – describes localized seizure
o simple – w/o loss of consciousness
o complex – w loss of consciousness
• unclassifiable seizure
Generalised Seizure Types
• Tonic-Clonic seizures (grand mal / generalized major convulsions)
o Following a vague warning – tonic phase commences (body becomes rigid for up to a min)
o Pt utters a cry and falls, tongue is usu bitten, there may be incontinence of urine or faeces
o Clonic phase begins – a generalized convulsion, with frothing at mouth and rhythmic jerking of muscles – can last from a few secs to a few mins
o Seizures normally self limiting followed by drowsiness, confusion and coma for several hours
• Typical absences (petit mal)
o Almost invariably begins in childhood
o Each attack is accompanied by 3Hz spike and wave EEG activity
o Activity ceases – pt stares and pales slightly for a few secs
o The eyelids twitch, a few mus jerks may occur
o After an attack – normal activity resumed
o Typical absence attcks are never due to acqd lesions such as tumors they are a devtal abnormality of neuronal contrl
o Children w absence attacks tend to develop generalized tonic-clonic seizures in adult life (primary generalized epilepsy)
o Petit mal only describes these 3Hz absences – clinically similar attacks are also caused by partial seizures of temporal lobe origin
Partial Seizure Types
• Partial Seizures (focal seizures)
o Simple or complex
o Aura – describes effects of initial focal electr events – eg unusual smell, limb tingling, or a strange inner feeling
• Focal motor seizures
o Simple partial seizure
o Originate in motor cortex
o Clinical evidence is the spread of activity called the march of the seizure (begins at mouth or thumb and spreads to limb on opp side of epileptic focus)
• Temporal lobe seizures
o Describe feelings of unreality or undue familiarity w surroundings
o Absence attacks, vertigo, visual hallucinations may also occur
• Found in under one-third of cases
• Cerebrovascular dis – 15%, cerebral tumors – 6%, post traumatic epilepsy – 2%


• Disorder of abnormal thought, perception, beh, mood and attention ie an altered sense of reality
• Onset 15-35 yrs – 1% Popn
• Positive – delusions, auditory hallucinations
• Negative – withdrawal, flattened mood

Biochemical Theories

1. Dopamine Hypothesis
• Schizophrenic sx due to overactivity of dopamine systems in mesolimbic/cortical sys
Two Dopamine Pathways
• Substantia nigra compacta – caudate-putamen (movement control of Parkinson’s)
• Ventral tegmental area – frontal cortex, nucleus accumbens, olfactory areas, ventral striatum (schizophrenia)
• Amphetamines → ↑ dopamine release → paranoid psychosis, exacerbates schizophrenic sx, blocked by DA (dopamine) antagonists
• all known Anti-psychotic drugs block dopamine receptors – this correlates highly with clinical efficacy

2. Glutamate Hypothesis
• ↓ glutamate systems → schizophrenia sx
• phencyclidine (PCP, angeldust) → best model of psychosis (better than amphetamine model)
o models both pos and neg sx – PCP is a non-competitive NMDA receptor antagonist
• Neuroleptics → ↑ glutamate release
• ↑ DA + ↓ Glutamate → Schizophrenia sx
• Agonists of glycine site on NMDA receptor significantly improved neg sx of schizophrenia when added to pts on convential neuroleptic med

NMDA Receptors
• N-methyl-D-aspartate
• Glutamate, Glycine and PCP binding sites
• Depol –
• Glutamate + glycine → opens channel → calcium influx → neuronal depol
• Mg occupies and blocks channel
• Depol → efflux of Mg (voltage dependent)
• PCP binds inside channel → blocks ion flow (non-competitive antagonist)

Neuroleptic Drugs – Anti-psychotics

• req 2-3 wks chr use to obtain full therapeutic effect
• Chlorpromazine
o Phenothiazine
o Tricyclic – related to TC anti-depressants
o Revolutionized psychiatry – prior to this was incarceration
o Dopamine antagonist
o Side effects – anti-muscarinic – inhibiting the actions of muscarine or the effects of parasym stimulation eg atropine – muscarinic is cardiac inhibition, vasodilation, salivation, bronchoconstriction, GI stim
• Haloperidol
o V widely used
o Dopamine antagonist
note – chlorpromazine and haloperidol best for pos sx
• Clozapine
o Resurgence of use
o Side effects – incl agranulocytosis (WBC d/o characterized by ↓ circ neutrophils)
o Effective against neg sx (in addition to pos sx)
• Risperidone
o Dopamine and serotonin antagonist

Mechanism of Action and Site of Action
• All Dopamine receptor antagonists (D1-D5)
D1 Receptors
• ↑ cAMP
• high in striatum
• relevant to Parkinsons
• D5 sim to D1
D2 Receptors
• ↓ cAMP
• high in striatum
D3 Receptors
• sim to D2 but concentrated in limbic sys
D4 Receptors
• sim to D2 but concentrated in cortex and limbic sys
• Haloperidol and chlorpromazine have equal affinity for D2 and D4 receptors
• Clozapine has a 10 fold greater affinity for D4 than for D2
• Haloperidol and Chlorpromazine show extra-pyramidal side effects such as tardive dyskinesia (fly catching) – Parkinson like sx – 30% effected
o ESPs possibly caused by block of D2 receptors in straitum (extrapyramidal motor sys) nigrostrital DA pway
o Clozapine does not cause ESPs perhaps due to low D2 affinity
• Theory - Therapeutic effects caused by block of D4/D3 receptors in limbic sys/cortex – mesolimbic/cortical pway
OR alternative theory
• D2 receptors in cerebral cortex mediate anti-psychotic effects and D2 receptors in striatum the extra-pyramidal side effects of neuroleptics incl clozapine
• Based upon studies of chr neuroleptic admin showing D2 receptor upregulation only in cortex w clozapine but in cortex and striatum w haloperidol

Stedmans Def Schizophrenia
• Disorder of perception, content of thought and thought processes (hallucinations and delusions)
• Extensive withdrawal of the individual’s interest from other people and outside world and investment in their own world
• Considered a spectrum of schizophrenic disorders rather than as a single entity w distinction stimes made betw process schizophrenia and reactive schizophrenia


• Define dementia
• Define alzheimer’s disease
• Know prevalence of dementia and alzheimers
• To appreciate the clinical conseqs of the dis
• Describe essential neuropathological and neurochemical feats
• Outline the main theories of causation of alzheimers
• Know basis of the cholinergic hypothesis and how it is applied to some current tx strategies for alzheimers

• Dementia
o Syndrome is a decline (often gradual) from the individual’s previous level of function in terms of memory and one or more other higher cognitive functions -
 Abstract thinking
 Judgement
 Language
 Praxis (performance of an action)
 OR a change in personality
o This change must be of sufficient magnitude to interfere with the pts usual activities of daily living such as work, social life or rships
• Senile Dementia of the Alzheimer’s Type (SDAT)
o Most common type of dementia w a gradual progressive dementia not explained by other known factors
o Strictly, SDAT is a pathological dx w the clinical dx being an educated guess, partly by excluding other causes

Pathology of SDAT
• This distinguishes it from other dementias
• Key characteristics of SDAT brain
o Extensive and progressive loss of neurons
o Histological findings of tangles and plaques
• Gross Changes
o Compared w non-SDAT controls, the brains of SDAT pts examined post-mortem show several changes related to widespread atrophy of the cortex
 Shrinkage of the gyri w widened sulci
 Enlarged ventricles
 Shrinkage of amygdala and hippocampus
o Image analysis techniques – reveal the loss of neurons at around 30% in pts aged 70-90 yrs
o This cortical degeneration and loss of neurons is consistent w dementia but what causes the neuronal loss?

1. Neurofibrillary Tangles
• These tangles are found in great concentrations within the neurons of SDAT brains (esp cortex and hippocampus) and are v rare in normal elderly
• Were detected by Alzheimer in the first case he reported of alzheimer’s disease
• Tangles correlates well w cogv impairment
• Neurofibrillary tangles are made up of paired helical filaments (PHFs) - entwined polymers mostly composed of tau protein (z protein)
• In healthy neurons, tau protein binds to tubulin and in so doing stabilizes microtubules which help maintain the shape and structure of cells
• In SDAT brains, tau protein becomes excessively phosphorylated and this impairs its ability to bind tubulin – the hyperphosphorylated polymer aggregates into PHFs and large tangles
• Tau protein phosphorylation is an active area of research for several pharmaceutical companies – however although we know that tangles are highly characteristic of SDAT, we do not know for sure what role (if any) they play in the dis process
• Are tangles neurotoxic? In some parts of SDAT brain (partic limbic sys) one finds tangles outside cells, apparently left over from neurons that have been destroyed suggesting they may be neurotoxic – but in other parts of the brain, extensive cell death can occur w/o the presence of tangles, which suggests that other factors are involved, which have yet to be identified
2. Plaques
• Extracellular plaques, along w intracellular tangles are a defining feat of SDAT
• Like tangles, plaques are a histological finding, visible in stained tis samples examined under microscope
• These plaques are small (up to 200um) spherical deposits, found in EC spaces in brains of SDAT pts, partic cortex and hippocampus
• They are composed of pleated sheats of an insoluble protein known as P-amyloid – the term senile plaques is often used, but they are found in SDAT cases irrespective of age
• Plaques are a universal finding in SDAT, but some plaques are found in normally aged people and it is possible to have a high conc of P-amyloid plaques w/o dementia
• Diffuse plaques are EC deposits of P-amyloid, found in normal elderly people as well as in SDAT cases – they may represent an early stage of a pathological process or may be entirely benign
• Neurotic plaques consist of a core of EC amyloid within a cluster of nerve endings in which normal structures have been disrupted – neuritic plaques are also found in both SDAT and normal brains, but the presence of paired helical filaments is characteristic of SDAT
• At present – the role of P-amyloid plaques in the dis process is unclear, they may be a cause of neuronal degen or a product of it
• P-amyloid protein is derived from a larger protein, amyloid precursor protein (APP), which is found in many tissues of healthy individuals and in many species – it traverses cell membranes and may be involved in cell communication (though its precise role is unknown)
• In normal metab – the long EC domain is cleaved from APP resulting in a soluble protein which may have some regulatory function
• P-amyloid is the result of abnormal metab with cleavage taking place at two other sites
• The circulatory apolipoprotein – Apo E4 – interacts w P-amyloid to form plaques – in one type of early onset familial SDAT, the dis is caused by a mutation in the gene on chrom 21 which generates APPZ – this was an impt discovery as it provides one of the few pieces of reliable knowledge about the causes of SDAT (but it only relates to an extremely rare form of familial early onset SDAT which affects less than 12 families worldwide)

Cholinergic Theory
• For the present, the cholinergic hypothesis is the only explanation of SDAT which has produced approved txs specific to SDAT
• The theory is founded on two observations made in the 70s –
o In SDAT brains, cholinergic nerves in the cortex are significantly and selectively depleted
o Blockage of cholinergic receptors in normal humans causes memory loss
• Following on from these observations – it was suggested that SDAT is a dis of central cholinergic nerves and that SDAT plaques might result from the degen of cholinergic n fibers
• The therapeutic implication here is that improving cholinergic neurotransmission might alleiviate sx and/or slow down dis progression
• Tacrine (an acetyl choline esterase inhibitor) – the first drug approved for SDAT – is designed to improve cholinergic neurotransmission
• Memric (cholinergic agonists) also approved and so is its likely main rival donepezil (E2020/aricept) and exelon (both acetyl choline esterase inhibitors)
• Because cholinergic neurotransmission occurs throughout the nervous sys, one of the main issues for drugs in this area is ho to improve or preserve cholinergic neurotransmission in the brain w/o causing unacceptable systemic side effects

Other NT systems
• As well as Ach, other NTs operate in the brain – what happens to these in SDAT
• Nor-adr neurons typically show a 10-30% loss in cortical activity and there is a modest level of denervation – these deficits don’t correlates significantly w the degree of dementia
• Dopaminergic neurons – little effected in SDAT
• Serotonin – more complex – on ave, there is a loss of 30-50% of serotonergic cortical innervation and levels of 5HT post mortem, and a sim loss of subcortical neurons
o However in living subjects, levels of 5-H1AA (the main metabolite of 5HT are ↑ in CSF suggested ↑ 5HT t/o – this ↑ correlates sig w the degree of dementia in SDAT
• In cortical neurons themselves, sev other NTs are impt
• GABA and somatostatin are inhibitory NTs (not thought to be critically depleted in SDAT)
• However, there is emerging evidence that cortical neurons producing glutamate may be impt in SDAT
• Important thing t grasp here is the complexity of the NT syss – hence, expectations of cholinergic replacement/manipulation therapy should be realistic, given that cholinergic depletion is only one of many path changes in SDAT and cholinergic NT is only part of a v complex sys

Genetic Factors
• At present 4 genes have been identified which are related to SDAT
• APP gene (discussed earlier)
o Chrom 19 – it encodes for abnormal form of APP, but is only present in a small percent of cases of early onset SDAT
• Apo E4 (discussed earlier)
o Chrom 21 – linked w a more common form of late onset familial SDAT
o Product of this gene is apolipoprotein E4 – occurs as three phenotypes – E2, E3, E4 – and each individual inherits a gene encoding one phenotype from each parent
o So your apo e4 genotype may be E3/E3, E3/E4 etc – the percentage of one apo E4 gene more than doubles the risk of SDAT while the E4/E4 genotype carries an 8* fold risk of SDAT (meaning that most individuals are affected by age 80)
o However – most people w SDAT don’t have an apo34 gene (most common genotype is E3/E3)
o One immed application however is in clinical drug trials – subjects can now be subdivided by apo E genotype and therefore by level of risk for rate of dis progression – ie if a drug is effective in some pts and not others

Cholinergic Theory Continued
• Two types of cholinergic receptors – nicotinic and muscarinic
• There are 5 subtypes of muscarinic receptors
• Both types of receptors are found in the CNS
• In peripheral nerves, specific sites and functions have been identified for each receptor type eg stimulation of muscarinic receptors slows the heart rate and ↑ mus tone in the gut while nicotinic receptors are found on skeletal mus
Cholinergic Neurotransmission – where?
• Cerebral cortex contains no cell bodies of cholinergic neurons, but is rich in projections from cholinergic neurons whose cell bodies are to be found beneath the cortex, in the basal forebrain and upper brain stem
• Ie – the cortex is innervated by cholinergic neurons situated in the subcortex
• The cortical neurons with which these cholinergic nerve fibers interconnect have nicotinic and/or muscarinic receptors
• Cholinergic innervation of cortex generally widespread but the areas where cholinergic n fibers are partic dense are the amygdale, hippocampus, areas of cortex near the limbic areas and the temporal lobe
• Remem – In SDAT, amygdala and hippocampus are shrunk
• In keeping w this distbn within the cortex – the cholinergic nervous sys has been implicated in functions such as sleep and arousal, mood and emotions and esp attention and mem
• Cholinergic neurotransmission also takes place throughout the peripheral nervous sys – in theory, enhancing cholinergic neurotransmission could lead to major systemic adverse effects
Cholinergic Depletion – where and how much?
• Does not necessarily mean the cholinergic neuron is absent or dead – rather it usu means a deficit in pre-synaptic neurotransmission (this is the target of cholinergic drugs)
• Cholinergic depletion means a ↓ in activity of AChE (present pre- and 17os synaptically) or the enzyme involved in its synthesis, ChAT (only present pre-synaptically)
• Many post mortem histochem studies have found large reductions (up to 90%) in ChAT activity (pre-synap) in SDAT cases and several studies have found similarly large reductions in AChE activity – this loss of cholinergic neurotransmission in the cortex is one of the most consistent findings in SDAT
• Histochem studies of SDAT pt brains enable one to study the density of cholinergic fibers – in keeping w the ↓ in AChE and ChAT, there are also reductions of up to 85% in cholinergic fibers projecting into the cortex
• The loss of cholinergic innervation is bilaterally symmetrical, but variable from one region of brain to another eg areas most severely affected (>75% loss) are in the temporal lobe (cf primary motor area - <30%)
• Cortical neurons which interconnect w cholinergic n fibers projecting into the cortex have cholinergic receptors – (cholinoceptive neurons) – another consistent finding in SDAT is that cortical nicotinic receptors are significantly reduced (cf muscarinic receptors are preserved or show only small depletions)
• Beneath the cortex, in basal forebrain and brainstem where the cholinergic neurons have their cell bodies – there is a reduction in ChAT activity (30-90%) and a loss (30-95%) of cholinergic neurons in SDAT
• However other subcortical cholinergic neurons which project into areas of the brain other than the cortex show little or no depletion in SDAT – this suggests that the dis is not the result of some gen failure of cholinergic neurotransmission, but of something specific to the cortex, or more precisely, to the cholinergic innervation of the cortex
• Do these reductions in cholinergic innervation and neurotransmission cause the cogv deficits seen in SDAT – provisional answer is yes, but…
o Yes - The areas of the cortex most severely affected are known to be concerned w functions that are disturbed in SDAT such as emo and mem
o Yes - Some studies have shown that there is correlation betw a. the degree of dementia and reductions in ChAT activity and b. the extent of the sub-cortical neuronal loss
o But in the cortex of SDAT pts, neuronal loss and the appearance of plaques and tangles are v widespread in and not confined to areas rich in cholinergic fibers
• In practice, so far, cholinergic replacement therapy has been the only drug devt strategy that has produced results, but so far, these results have been less than dramatic
• All this suggests that although the cholinergic theory has stimulated research which has shed new light on SDAT, and describes one of its most prominent feats, it does not provide a complete explanation
• It follows that expectations of cholinergic replacement therapy should be correspondingly modest
Cholinergic Depletion and Normal Ageing
• Neuronal cell loss is normal in the ageing brain
• Cholinergic depletion - ↓ in cortical ChAT and AChE activity and loss of cortical cholinergic fibers and subcortical neurons – all occur in aged individuals who are not demented
• The degree of cholinergic depletion assoc w normal ageing is however much less and appears at a more advanced age
• When you compare the brains of SDAT pts w those of normal subjects of the same age, the relative depletion of cortical cholinergic innervation is more marked in younger pts (<78yrs) – this may be bec cholinergic depletion is more impt in early onset SDAT or may be from changes due to normal ageing narrow the gap betw normal and SDAT affected brains
Cholinergic Depletion, Plaques and Tangles
• Cholinergic depletion may play some causative role in plaque formation –
o Modest correlation betw degree of cholinergic loss and the density of plaques
o In rat, experimentally induced sub-cortical lesions give rise to cortical plaques
o Muscarinic stim of neurons may promote the non-amyloidogenic (normal) processing of APP, so cholinergic depletion may promote synth of P-amyloid
o Some evidence that cholinergic loss occurs earlier than deficits in other NT syss
• However, cholinergic depletion does not explain everything – plaques contain fibers from other NT syss and none of the above observations explain the existence of tangles
• As for tangles – there is no simple rship betw cortical depletion and tangle density – some but not studies have found a weak correlation betw ↓ cortical CHaT activity and tangle density – on the other hand, there is a strong correlation betw tangle density and loss of cortical cholinergic fibers
• Could the causation operate in the reverse direction – could it be that cortical cholinergic projections are partic susceptible to some other prime mover of the dis process – there is some evidence which points in this direction eg - Lesions of SDAT are not uniform in all cholinergic neurons but primarily affect those which innervate the cortex

Sx of Alzheimers
• Memory – ST>LT, trouble finding words (if you don’t find a lang prob early in the dis – probably not alzheimers) – procedural mem unaffected usu
• Personality – behal probs – frontal lobe that regulates socially unacceptable beh goes – pts don’t have a lot of insight into their dis

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