What is Cognition?

Cognition - the process of thinking, knowing, understanding and making sense of the world
around you
 Attention
 Memory
 Exec function
 Language
 Calculation
 Praxis
 Visuospatial skills
 
These are the key aspects of cognition.
 
Attention
Attention can be classified by:
 Arousal
 Sustained attention
 Divided attention
 Selective attention
 
Altered attention and alertness and concepts is related concepts to delirium
 
Testing for Attention
 Orientation n time and space (also depends on episodic memory)
 Digit span - forward/backwards
 Reciting months of the year or days of the week
 Serial 7s
 Spell WORLD backwards
 The STROOP Test - neuropsychological test where patient says the colour of the world
and resist temptation to read out what the word says
 
Episodic Memory
Anterograde Amnesia - memory loss for newly experienced information. Events after disease
process has set in (eg memory loss following the head injury is anterograde)
Retrograde Amnesia - memory loss of past events
 
Ribot's Gradient - description that shows pattern of memory loss in patients where they forget
recent material first and then longer term material.
 
 Memory
 Long-term memory
o Explicit – episodic +semantic
o Implicit - (basal ganglia, cerebellum, cortex)
 Short-term (working) memory
o Frontal lobe (DLPFC)
 
Episodic memory - medial temporal lobe (contains hippocampus)
Semantic memory - memory for words, meanings, GK - stored in anterior temporal lobe
 
Working memory - 10-15 seconds and is organised by frontal lobe in dorsolateral prefrontal
cortex.
  
Implicit memory - NOT available to consciousness. This is like motor skills (e.g riding a bike).
Conditioned reflex responses, habits are here. This is organised in some structures like the
basal ganglia and cerebellum.
 
Importance of Frontal Lobes: Executive Behaviours
 Judgement control of inhibition
 Goal setting and motivation
 Social behaviour personality
 Abstract Reasoning
 Planning
 Flexibility and Problem Solving
 
Frontal-temporal dementia - if you ask this patient about social behaviour and personality they
will often lack insight about this. They've maybe turned to criminal, violent behaviour that is
out of character. They might start doing embarrassing things in public.
 
Language
 Aphasia - no speech
 Dysphasia - defective speech output; language disorder. Nominal dysphagia - person
struggles retrieve words or vocabulary, naming people may be hard
 Wernicke's Aphasia - fluent dysphasia. Patients talk ok but they have major problems
understanding spoken speech. Fluent speech but struggling to comprehend speech. Speech is
riddled with errors and potentially lack insight.
 Broca's - patients stutter a lot and struggle a lot. They have insight and frustrated as they try
and express themselves but are unable to do it.
 
Agraphia/Dysgraphia - complete inability to write. Dysgraphia is defective function to writing.
 
Alexia - inability to read and dyslexia is a reading problem
 
Left hemisphere in most important in these calculation and language disorders
 
Calculaton - dominant parietal lobe, angular gyrus.
 
Acalcula - inability to comprehend or write numbers properly
Anarithmetria - difficulty with sums and calculations,
 
Lesion in parietal lobes than may extend to angular gyrus and there may be problems with the
above
 
Praxis/Dyspraxia - inability to move body part despite having motor and sensory function
 
Dyspraxia: Theres different kinds of dyspraxia and can be related to patients knowledge of
conceptual information.
 
Visuospatial ability
All about patients ability to process and identify whats around them and link the visual
information to spatial positioning of objects to their orientation in space.
 
 Visual Cortex in occipital lobe then feeds into parietal - understanding between spatial
relationships and orientation of objects around them
 
Visual cortex feeding into temporal - need to know what it is youre seeing and retrieve
memories that may help identify what youre seeing.
 
Deficits: (most patients in right)
 Topographical disorientation - patient has problems finding way about environment they
already know
 Difficulties with dressing
 Mis-reaching for objects
 Visual Neglect
 Visual object agnosia - unable to visualise objects around them despite having clear vision
 Prosopagnosia - not able to recognise face
 
Dementia - general clinical features
 Syndrome with chronic, progressive (usually irreversible) cognitive impairment due to brain
disease
 Deterioration from higher level function
 Multiple cognitive deficits
 Chronic Duration > 6 months
 Impact on social/occupational function
 Personality change/disintegration
 Decline in emotional control/motivation
 No clouding of consciousness (exclude delirium) - no impairment of alertness, arousal etc.
 
Spectrum of cognitive impairment
1. Age related decline
2. Mild cognitive impairment - patients aware they have cognition problem but it doesn't
impact daily function. However in tests theyd perform below expectation. You are at
higher risk of going to dementia syndrome
3. Dementia
 
Alzheimer's is the most common type of dementia.
 
 
Cognitive Testing
 Addenbrookes Cognitive Exam
 More sensitive than MMSE in early disease
 Covers executive function
 Much more details, broader in terms of cognitive domains
 Time consuming - cut of scores of 88 and 82
 
 MMSE
 Shorter, 30
 Easy to administer
 High inter-rater reliability (high rate of correlation of scores between psychiatrists)
 Not very sensitive to mild disease or early
 Poorly covers executive function
 
Reversible Dementias
 B12
 Folate deficiency
 Hypothyroidism
 Hydrocephalus
 Wilson's Disease - disorder of copper metabolism. Accumulation of copper which is toxic to
brain
 Cerebral Vasculitis
 Depression
 Whipple's Dementia - bacterial infection in GI tract
 Metabolic Problems
 
Delirium
Acute onset of confusion that could get better if medically treated.
Acute neuropsychiatric syndrome
 Prevention is KEY
 
Hallmark Features
 Impaired consciousness
 Hyperactive or hypoactive
 Acute onset
 Change in cognition
 Cognitive deficits
 Visual hallucinations (and other psychotic symptoms)
 Sleep-wake cycle disruption
 Affect changes
 In most cases, evidence of an underlying direct cause
 
 
Differentiating Delirium from Dementia

 
Non-Pharmacological Approaches
 Noise control
 Orientating influences
 Fluid balance/ diet/ bowel/ habit/ pain control
 Communication
 Limit variation in staff
 Recognise the patients frailty
 
Patients who are distressed and not responding to non-pharm approaches and they may be a
risk in behaviour.
 
Actively hallucinating, delusional..
Define Neurodegenerative Disease
 Neuronal death that is systemic and symmetrical
 Cortex = Alzheimers and frontotemporal dementia
 Basal Ganglia - movement disorder (Parkinsons, Huntingsons)
 Cerebellum and spinal cord - ataxia
 
Pathophysiology of neurodegenerative disease
Most are due to protein miss-folding - leads to accumulation and aggregation
 
Protein Accumulation:
 Beta-amyloid
 Tau
 Alpha-synuclein
 TDP-43
 
Reaction - inflammatory response in areas affected due to misfolded protein accumulation
 
Unremitting progression - it gets progressively worse resulting in a slow decline
 

Differences between aging and dementia

Aging
 Increase in forgetfulness after 50
 Slowing of response times
 Physical changes - vision, hearing, sensory, motor impairment
 
Dementia
 Impaired STM and LTM
 Impairment of intellectual ability
 Multiple cognitive domains
 Personality changes
 Interferes with activities of daily live
 Consciousness is preserved
 
"Dementia and delirium have significant overlap and can both occur at the same time"
 

 
 
Differential Diagnosis of Dementia
"AVDEMENTIA"
1. Alzheimer's Disease
2. Vascular disease
3. Drugs, depression, delirium
4. Ethanol
5. Metabolic
6. Endocrine - thyroid, diabetes
7. Neurological
8. Tumour, toxin, trauma
9. Infection
10. Autoimmune
 
Outline the reversible causes of dementia
1. Hypothyroidism
2. Normal pressure hydrocephalus
3. Drugs - opiates, sedatives, anticholinergics
4. Tumours
5. Neurosyphilis
6. Chronic subdural haematoma
7. Whipple's disease
8. Nutritional - vitamin Deficiency
9. Psychiatric disorder
 
Describe the clinical features of Alzheimer's Disease
 Progressive disease
 Preclinical -mild cognitive impairment --> major cognitive impairment (dementia)
 There is a significant decline in cognition
 
Risk factors include:
 Environmental - head injury
 Genetics - APP, presenillin-1,2, Apolipoprotein epsilon 4
 Down syndrome
 Female
 
Diagnosis
1. Onset - insidious onset (not acute)
2. Clear history of worsening condition
3. Initial ad most prominent deficits are: Amnestic (episodic memory alteration), non-amnestic,
progressive aphasia, visuospatial deficit, executive dysfunction
 
Variance of Alzheimer's Disease
 Age at onset
 Disease progression
 Disease duration
 Symptoms at onset:
 Predominantly frontal - prominent behavioural alteration
 Predominantly occipital- prominent visuospatial alteration
 
Epidemiology:
Age: 10%> 65
40% > 85
 
Survival: 6-12 years
 
 
Histopathology of Alzheimer's Disease
 Reduced Brain Weight
 Atrophy in different places
 Weight of forebrain: hindbrain is reduced
 
Macro findings for Alzheimer's
 Ventricles are large compared to normal. Ventriculomegaly.
 Marked atrophy of temporal lobe. Atrophy of medical temporal lobe leads to losses of
episodic memory.
 Neocortical grey matter is thin
 
Two types of lesions in Alzheimer's
 Neurofibrally tangles - Abnormal phosphorylated version of Tau Protein. Tau is deposited
inside of neurones. This is present in neurone.
 
 Beta-amyloid plaques - increased inflammation due to misfolded proteins; form aggregates
within brain parenchyma; cerebral amyloid angiopathy. Same abnormal protein present in
parenchyma and in grey matter there is neuritic plaques and also in meninges.
 
It makes vessels prone to rupture, hard, inflexible. Intracerebral haemorrhage spontaneous in over
65 may have predisposed Beta-amyloid angiopathy.
 
 
 Signs of AD is first noticed in entorhinal cortex then the hippocampus.
 At this stage, person might show no clinical symptoms
 Affected regions begin to atrophy with associated neuronal loss
 Changes can begin years before symptoms appear.

 
AD spreads through the brain. The cerebral cortex begins to atrophy with more neuronal loss.
 
Mild AD -
 Memory loss
 Confusion
 Trouble handling money
 Poor judgement
  Mood changes and anxiety
 
Moderate AD -
 Increased memory loss - confusion and difficulty recognising people
 Difficulty with language and thoughts
 Restlessness
 Agitation
 Wandering and repetitive statements
 
Severe AD
 Pathology throughout neocortex
 Severe cortical atrophy
 Complete dependence
 Ventriculomegaly
 Shrunken hippocampus and cortex
 Weight loss, seizures, increased sleeping, loss of bladder and bowel control, penumonia
death
 
Vascular Dementia
1. Infarction - multiple large infarcts
 Caused by atheroscelerosis
 Areas affected: basal ganglia, thalamus, pons, IC
 
2. Leukoaraiosis
 Disease of white matter
 Loss of axons, myelin and oligodendrocytes
 Perivascular tissue loss
 Dilation of perivascular spaces
 
3. Haemorrhage
 Large basal ganglia haemorrhages - often secondary to hypertension
 Small haemorrhages in cortex and white matter - amyloid beta protein angiopathy
 
4. Mixed Dementia
 AD and vascular disease are not mutually exclusive
 
"the red dead neurone" - earliest changes in brain in ischaemia. If theres been ischaemic insult
within the first hour you should start seeing these changes in the brain.
 
Clinical Features
 Underlying vascular pathology
 Subcortical - small vessel disease
 Cortical multi-infarcts - large vessel disease
 Symptoms are specific to areas which are affected
 
Risk factors:
Age: >60y
Obesity
Hypertension
Cigarette smoking
 
Lewy Body Dementia
This is an umbrella term for Parkinson's disease dementia and dementia with Lewy Bodies
Characterised: Visual Hallucinations and fluctuating consciousness
 
Synucleinopathy - misfolded alpha synuclein aggregates
 
Fibrillar aggregation - aggregation of insoluble fibrils of alpha-synuclein in neuronal or glial cells
Lewy bodies - builds up from fibrillar aggregation
In LBD - Lewy Bodies form in cerebral cortex - leads to Dementia
Parkinsons diease - lewy bodies pathology in nigrostriatial system leading to etrapyramidal
movement disorder
 
 
Clinical Features of LBD
 Visual hallucinations
 Fluctuating consciousness
 Sleep disorders
 Parkinsonism TRAP!
 Lewy Bodies in cerebral cortex and nigrostriatial pathways
 

 
Frontotemporal Dementia
Group of neurodegenerative disorders characterised by frontal lobe and temporal lobe atrophy on
MRI
It is sometimes called Pick's Disease
 
Clinical Features:
 Age onset: younger 45-65
 Frontal lobe dysfunction: behavioural/personality change, disinhibition, depression,
agitation
 Temporal Dysfunction - impairment of language function, progressive word finding ability
 
Tau protein accumulation - Pick's Disease. Tau is deposited in neurones
Knife-edge gyri.
 
  Refers to diseases that result in protein aggregation due to miss folding. Thereby gaining
toxic activity or losing the normal function.
 
Which amino acid does transcription always start with?
 Methionine
 
Which of the following post translational modifications targets the proteins for destruction?
 Ubiquitination
 
Protein degradation can occur by two methods:
 Lysosomal
 Proteosomal
 

Loss of proteostasis contributes to the pathogenesis of many human pathologies, including

Alzheimer's disease.

Fate of a newly synthesised protein

 New protein goes into lumen of ER and it straight away begins folding and modification
 Correct folding leads to assembly and sent into vesicle to go to destination
 Misfolding causes retention and removal of protein from cell
 
Protein Folding
 Proteins will self-assemble into a 3D conformation
 Conformation determined by primary structure
  Hydrophobicity (you don’t want this on outside of protein molecule as it lives in hydrophilic
environment) is an important determinant of final conformation. You want hydrophilic AA on
outside and hydrophobic on inside
 
 Some proteins need time to fold
 They vary in time taken to reach final conformation
 Cellular environment is highly crowded which display molecular effects on other proteins
and this increases the tendency for aggregation
 
Molecular Chaperones
 Help proteins conform properly
 Broad family with multi functions
 It is any protein that helps other proteins stabilise and allow them to acquire its fixed
conformation without being present in final structure
 It does this by selectively binding to hydrophobic amino acids. Finds hydrophobic AA on
outside and bind to them, shielding them from interactions with other proteins
 Different classes of structurally unrelated chaperones exist, forming cooperative pathways
and networks
 
Lots of different functions:
 De novo folding
 Refolding
 Oligometric assembly
 Protein trafficking
 Proteolytic degradation
 

 
1: ribosome synthesises the protein and immediately a chaperone binds
2: chaperone coats the polypeptide as it grows
 
 Once made it now has a safer environment to assume normal conformation and then can go
to be nativ polypeptide
 It can also use a chaperonin and it works in a similar way forming a cylinder to which
polypeptide is placed, providing a protective environment
 
What happens if Protein becomes mis-folded?
There is lots of quality control in the ER.
 
30% of newly synthesised proteins are misfolded.
 

 
 Newly synthesised glycoprotein and immediately it gets glucosylated (glucoses are attached)
 A group of enzymes cleave of sugar groups leaving one
 This helps provide a binding site for chaperones
 Glucosidase leaves of sugar proud meaning chaperones wont bind and you hope theres a
correctly formed protein
 If its correctly folded it is allowed to exit ER
 If it is incorrectly folded..GLUCOSYLTRANSFERASE is important
 GT detects hydrophobic amino acids on the outside of the protein and if detected it sends
polypeptide back to start of the sequence in an attempt to refold
 Eventually it will stop trying and will be targeted for the proteasome.
 
Proteasome
 Proteins that are missfolded are removed by proteosome
 These are large multisubunit structures
 They degrade proteins
 Theyre found in cytosol and nucleus
 Consist of a CAP and lots of alpha and beta subunits
 
  
Ubiquitin-Proteasome System

 
 Misfolded proteins get ubiquitin tag
 It gets polyubiquitinated which is done by addition of Ubiquitin through enzymes ubiquitin
ligases
 You need a minimum of 4 PU and forms a recognition site for CAP of proteosome
 It recognises the CAP and missfolded protein gets threaded through proteosome
 Proteolysis then occurs
 
If missfolding allowed to accumulate the proteins will aggregate and this is the molecular basis of
neurodegenerative diseases.
 

 
Alzheimers Disease
 Most common form of dementia
  Progressive and fatal, affecting language, memory and vision as well as emotion and
personality.
Early onset familial AD: amyloid precursor protein (APP), Presenilin -1,-2
 
Sporadic AD: apolipoproteinE epsilon4 allele
 
Histologically there are two abnormal structures in the brains of people with AD:
 Amyloid plaques in extracellular space
 Neurofibrillary tangles in cytoplasm
 
Both are composed of misfolded proteins.
 

 
Amyloid plaques appear as large diffuse masses in the cortex which contain an accumulation of
specific protens.
Neurofibrillary tangles appear as flame-shapes skeins formed by the abnormal accumulation of
cytoskeletal components, in particular TAU.
 
 
Amyloid precursor Protein (APP)

 
  Ubiquitous transmembrane protein found in neurones
 It is subject to posttranslational processing; it gets cleaved to form different proteins with
different properties
 In normal(non-amyloidogenic): APP goes out of membrane and is cleaved and makes
sAPPalpha.
 In abnormal (amyloidogenic): in accumulation of amyloid plaques, different enzymes work
on APP. B-secretase cleaves above transmembrane domain and gamma-secretase cleaves in
transmembrane domain and liberates amyloid-beta peptide.
 
 AD is associated with APP and presenillin and presenillin is component of gamma-secretases
Altered APP processing gives rise to amyloid -peptide (A
 
The Amyloid Hypothesis

 THE CURRENT THINKING OF PATHOGENESIS IS THE AH

 Basically, we start with formation of amyloid beta plaques (the abnormal cleavage of APP)
which form oligomers and trigger inflammatory response causing Tau aggregation and tangles
 This causes synaptic and neuronal loss
 
Its important to note that cleavage of ABP and it changes the secondary structure from largely alpha
helical rich structure to a beta pleated sheet. There is a change in the secondary structure of the
protein.
 
Neurofibrillary Tangles ('Tauopathies')
 Main component of tangles are paired helical filaments (PHFs) - these are long fibrous
proteins and are composes of Tau which is a microtubule associated protein
 Staining for Tau in AD there is a characteristic 'flame' staining pattern
 Tauopathy is found in a number of other dementias
 
 
 Tau is in all our cells and it’s a microtubule associated protein
 Microtubules are organised through polymerisation of alpha and beta tubulin
 Microtubules are involved in a number of processes
 They are stabilised by MAPs like Tau - Tau coats microtubule stabilising it and align with
other parallel microtubules.
 If Tau is phosphorylated - the result is that it disassociates from microtubules and causes
depolarisation - regulating its function
 
Tau Phosphorylation

 
 However in pathological situation there is shift to more phospho-Tau
(HYPERPHOSPHORYLATED Tau - it is phosphorylated more than normal)
 As a result youll have microtubule dysfunction as youll have it always breaking down and not
forming them
 Hyperphosphorylation causes a change in protein conformation and results in paired helical
filaments and neuronal fibrillary tangles - resulting in eventual cell death
 
Possible Causes of Tau aggregation
 Linked directly to hyper-phosphorylation through number of reasons:
 Potential imbalance of kinases and phosphatases
 CDK5 and GSK3Beta both phosphorylate Tau - may be overactive
  Tau mutations which make it look like its phosphorylated (putting glutamic acid tends to
mimic a phosphate group)
 Other covalent modifications of Tau
 

 Tau goes from alpha helical to beta sheet containing structure

 

 
Dementia with Lewy Bodies (DLB)
 Shares symptoms with AD and Parkinson's
 Presence of cortical Lewy Bodies in the neurones
 Alpha-synuclein aggregation
 

 Misfolding of AS results in beta sheets that further aggregate into higher order insoluble
structures (fibrils): These are the building blocks for Lewy Bodies
 
Theyre in a number of different conditions:
 Parkinsons
 Dementia with Lewy Bodies
 Multiple System Atrophy
 Other rare disorders eg. Neuroaxonal dystrophies
 
Transmissible Spongiform Encephalopathies (TSEs)/ Prion Diseases
 Mad cow disease is part of TSE
 Family of rare, progressive & fatal neurodegenerative disease
 Aetiological Agent: Prion
 Loss of motor coordination and behavioural changes
 Importantly: inherited, sporadic and acquired
 Long incubation periods
 Characterised by spongiform appearance of the brain due to neuronal loss and a failure to
induce an inflammatory response
 

 
 
 Variant CJD was culprit during mad cow disease where ingested contaminated food was
transfering nfectious agent to individuals
 
 Kuru: tribe in PNG
 
 
Prion Proteins
 Prion proteins is called PRPC and is ubiquitous
 Infectious agent called PRPSC and there is appearance of beta pleated sheet
 This goes on to form prion rods forming plaques and neuronal death
 
CJD v AD

 PRP can be infectious in abnormal form and put into normal brain the person will develop
Prion disease
 
 The way this happens is that it is believed to induce the normal cellular component to adopt
a new protein conformation
 When PRPSC encounters PRPC it comes together and induces normal form to adopt the
abnormal secondary structure
 
Cognitive Enhancers
 2 classes of cognitive enhancer in dementia:
 Cholinesterase Inhibitors - licensed for mild to moderate AD and PDD. Demethizil,
Revastigmine, Galanthamine.
 One partial glutamate antagonist; licensed for moderate to severe AD (Amantine)
 
Normal Cholinergic Synapses
1. Arriving action potential depolarises the synaptic knob
2. Calcium ions enter the cytoplasm and Ach released through exocytosis of synaptic vesicles
3. Ach binds to Na+ channel receptors on post-synaptic cleft
4. Depolarisation occurs and ends as the Ach is broken down by Cholinesterase into Acetate
and Choline
5. Synaptic knob reabsorbs choline from the synaptic cleft - this is the RATE LIMITING STEP in
Ach synthesis
 
Cholinergic Hypothesis
Hypothesis is around cholinergic system.
Arnold Pick described people with a slow decline in STM associated with decline in cognition.
Cholinergic loss in and around frontal cortex and hippocampal area.
 
Benefits and side effects of Cholinesterase Inhibitors (e.g. Donepezil)
Benefits
 Little efficacy as Ach has little impact on proteinopathies
 MMSE increased by 1 point only; highly variable
 
Side Effects
 Cholinergic - nausea, vomiting, GI Distress, muscle cramps, diarrhoea, dizziness, muscle
cramps, fatigue, anorexia
 Serious effects: peptic ulcers, cardiac problems
 
Use of cholinesterase inhibitors in other types of dementia
Frontotemporal Dementia
Clinicians do not sue cholinesterase inhibitors. Suggested more harm risk than benefit.
 No cholinergic deficits (more marked 5-HT deficits so SSRIs can be useful)
 Cholinesterase inhibitors likely to worsen agitation
 
Vascular Dementia
 No convincing evidence from trials of benefit
 
Mild Cognitive Impairment
 No evidence of benefit in initial cognitive function or in reducing the progression to
dementia.
 
DLB and Parkinsons disease dementia
Association with marked cortical deficits of acetylcholine
 Cholinesterase inhibitors are licensed in PDD and result in a 1 point MMSE improvement
 DLB can present with very distressing visual hallucinations and secondary delusions
 Antipsychotics cause a significant increase in both mortality and morbidity - DO NOT
PRESCRIBE!
 Visual hallucinations are correlated with the depth of the cortical cholinergic deficit
 
Quetiapine is also used first line as treatment for psychosis in PD (which is a common
problem even in patients without dementia), although trial evidence suggests lack of
efficacy. Clozapine, which is associated with significant risks, is probably the only
antipsychotic that is definitely effective in psychosis in PD. For the same reason it is also,
very rarely, used in DLB but it should be remembered that it also has significant
anticholinergic side effects.
 
Glutamate
 Major excitatory neurotransmitter
 AMPA and NMDA receptors - both are ionotropic receptors but the NMDA receptor
only is permeable to calcium (both respond to sodium and potassium)
 AMPA is involved in fast synaptic transmission
 
NMDA receptor antagonists are used:
 Memantine - used in moderate/severe AD
 When cholinesterase inhibitors are not tolerated
 
 Glutamate acts on AMPA and NMDA receptors on post synaptic membrane
 Presynaptic action potential releases glutamate into synaptic cleft
 It acts on both types of receptors
 AMPA - mediate electrical signal during weak electrical stimulation
 NMDA - has Magnesium++ bound to it therefore blocked
 Long term potentiation - stronger presynaptic action potential - AMPA receptors depolarise
so much than Magnesium++ is expelled from NMDA
 Thus NMDA can respond to glutamate
 
Memantine
 Blocks spot where glutamate woulde binded to
 Reduces action potential
 Effectively stops hyperexcitation of cell
 
 
 
 Glutamte normally allows for stronger depolarisation - allows calcium to enter postsynaptic
cleft
 Increased calcium causes activated protein kinases
 This increases the insertion of AMPA receptors
 Increased effectiveness of long term receptors
 
Glutamate in AD
There is reduced glutamate clearance - causes chronic overactivity
Increased glutamate - increased presynaptic sign
Memory disruption via NMDA receptor due to chronic excitotoxicity
Reduced NMDA receptors in hippocampus of neocortex
 
 
Memantine blocks NMDA receptors preventing glutamate overactivity
 
Mechanism of AD
 Blocks NMDA receptors - low affinity voltage dependant antagonist of Mg2+
 In AD - too much glutamate due to reduced clearance
 This causes Magnesium to leave the NMDA and continuous calcium influx
 Thus there is no on-off release to build sensitivty
 
Memantine replaces the magnesium ion. In pathology - it does not leave since membrane potential
is too low. Normal glutamate release will allow the memantine to leave and allows controlled and
regulated calcium influx.
 
 
Efficacy of memantine
1. Mmse BENEFIT OF ONLY 0.7-1.2
2. Used in moderate dementia if cholinesterase inhibitors are not tolerated
3. Used in severe dementia
4. Has no effect in mild, vascular and frontotemporal dementia
 
BPSD
Behavioural and Psychological symptoms of dementia
1. Depression - due to increased monoamingeric function
2. Agitation and aggression - associated with greater cholinergic deficit and increased D2/D3
receptor availability in striatum
3. Sleep wake cycle changes - potentially due to decreased melatonin
 
Treatments:
Antidepressants - setraline, citalopram (SSRIs)
Used in depression and frontotemporal dementia
 
Cholinesterase Inhibitors - show to be effective to reduce neuropsychiatric symptoms of dementia.
Have the greatest effect on apathy
 
Memantine - less likely to develop agitation in patients who take this drug
 
Antipsychotics - risperidone and aripiprazole (atypicals)
 Used for severe agitation/aggression
 Side effects: increased risk of cerebrovascular adverse events, increased mortality. Do not
use them for Insomnia, andering and abnormal vocalisations