People and Illness Week 4 Flashcards
Describe mild cognitive impairment
- Subjective awareness of cognition problem (e.g. memory), doesn’t impact on day-to-day function, would perform below expected on neuropsychological testing
- Higher risk of progressing to frank dementia
- Lifestyle and medical intervention to prevent progression
Describe the pathology of Pick’s disease
- Phosphorylated Tau accummulation causing Pick body formation
- Walnut brain, knife edge atrophy - very severe atrophy, advanced in frontal region
Compare CJD to Alzheimer’s disease
- Similarities
- Both fatal neurodegenerative diseases
- Inherited and sporadic forms
- Amyloid deposits
- Increased beta-sheet secondary structures
- Differences
- Unrelated protein aggregates - APP vs PrPc
- PrPsc is infectious
Describe the protein aggregation which causes dementia with Lewy bodies
- Alpha synuclein aggregates
- Misfolding into beta-pleated sheet structure of alpha-synuclein (dimers, trimers and oligomers) that further aggregate into higher-order insoluble structures (fibrils) - building blocks for Lewy bodies
Define delirium
Acute neuropsychiatric syndrome characterised by confusion
Compare Tau in a physiological state to Tau in a pathological state
- Physiological Tau - balance between phosphorylated and non-phosphorylated Tau, allows neurite growth, axonal transport, microtubule dynamics
- Pathological Tau - too much phosphorylated Tau = Tau filament formation (neurofibrillary tangles), microtubule dysfunction, cell death
List the risk factors for Alzheimer’s disease
- Increasing age - 2x risk every 5 years from 60
- Genetics -
- Early onset familial - amyloid precursor protein (APP), presenilin-1/2
- Sporadic - apolipoprotein 4 allele (APOE4)
- Down syndrome
- Female gender (2/3 are female)
- Head injury
Describe the tertiary structure of proteins
- Overall conformation of protein/3D arrangement
- Stabilised by interactions between R groups
- Hydrophobic interactions between non-polar R groups
- Hydrogen bonds between polar R groups
- Disulfide bonds
Give examples of disorders of praxis
- Dyspraxia/apraxia - errors of action conception (knowledge of actions/item function), action production (production/control of movement)
- E.g. ideational apraxia, imitation of gestures, orobuccal movement, use of imagined objects, lower limb apraxia
List the hallmark features of delirium
- Impaired consciousness
- Hyperactivity (active, tachycardic) or hypoactive subtype (reduced alertness, may look depressed) - can alternate between
- Fluctuation in mental state - more disturbed overnight
- Acute onset - hours to days
- Change in cognition from baseline, cognitive deficits
- Visual hallucinations (and other pyschiatric symptoms e.g. delusions)
- Sleep-wake cycle disruption
- Affect changes
How is glutamate involved in Alzheimer’s disease?
- Major excitatory neurotransmitter, acts on NMDA and AMPA receptors
- NMDA - permeable to calcium ions, blocked by magnesium (voltage-dependent blockade), long-term potentiation (slow gated kinetic)
- Memtantine replaces glutamate to stimulate NMDA receptor
- Long-term potentiation - long-lasting enhancement of the effectiveness of synaptic transmission
- Calcium activated kinases - increase effectiveness of existing receptors, increase number of receptors
- In Alzheimer’s
- Reduced glutamate clearance - chronic over-activity (excitotoxicity) could be part of pathology - disrupts memory formation via NMDA
- Glutamate loss - reduction of pyramidal neurons - entorhinal cortex, CA1 and subiculum areas of hippocampus (glutamate containing)
- Reduction in NMDA receptors in the hippocampus and neocortex
How common is Alzheimer’s disease
60% of neurodegenerative dementias
List the types of dementia
- Alzheimer’s - most common
- Vascular
- Dementia with Lewy bodies
- Frontotemporal
- Mixed - common but not often diagnosed (two distinct/discreet patholgies within brain)
- Other
Describe frontotemporal dementias
- Sporadic/inherited
- Heterogenous group of dementias
- Younger patients - 45-65
- Frontal lobe dysfunction - behavioural/personality changes, disinhibition, depression, agitation
- Cognitive and memory impairment
- E.g. Pick’s disease
Describe the differential psychiatric diagnosis for dementia
- Normal aging
- Delirium
- Mild cognitive impairment
- Amnestic syndrome - Korsakoff’s
- Chronic brain damage e.g. head injury or anoxia (static level of impairment)
- Depression - pseudo-dementia
- Late onset schizophrenia or other psychosis
- Learning disability - same level of impaired function throughout life
- Malingering presentation - feigns illness for secondary gain
- Dissociation - after psychological trauma
List the further investigations done in dementia diagnosis
- HIV + syphillus serology
- Chest X-ray
- CT/MRI - atrophy of brain, vascular disease
- EEG - electrical activity in brain (delirium = diffuse slowing)
- Lumbar puncture
- ECG
- SPECT - blood flow in brain, also dopamine (for Lewy body dementia/Parkinson’s disease dementia)
How do proteinopathies cause disease?
Accumulation of misfolded proteins results in aggregates, thereby gaining toxic activity or losing the normal function
Describe the pharmacological treatment of dementia with Lewy bodies
- Antipsychotics cause significant mortality/morbidity
- Rivastigmine (cholinesterase inhibitor) improves
Which area of the brain is responsible for praxis?
Usually L hemisphere - parietal and frontal lobe
What causes the behavioural and psychiatric symptoms of dementia?
- Complex cortical-subcortical circuits that affect behaviour and areas of brain atrophy/dysfunction
- Depression associated with reduced monoaminergic function
- Agitation and aggression associated with cholinergic deficit and increased D2/3 receptor availability in striatum
List types of proteinopathies, aggregated proteins involved and the neurodegenerative diseases which result
- Amyloidosis
- A-beta accumulates
- Causes Alzheimer’s disease
- Prionopathy
- PrP accumulates
- Causes Crutzfeldt-Jakob disease
- Tauopathy
- Hyperphosphorylated Tau accumulates
- Causes frontotemporal lobar degeneration, Alzheimer’s disease, progressive supranuclear palsy and Pick’s disease
- Synucleopathy
- Alpha-synuclein accumulates
- Causes Parkinson’s disease, Lewy body disease
Describe the mechanism of action of cholinesterase inhibitors
Low Ach causes cognitive symptoms (especially nucleus basalis of Meynert), cholinesterase breaks down acetyl choline from synapse - anticholinesterase inhibitors stop breakdown of acetyl choline, increase cholinergic action
List the routes of transmission in Prion diseases
- Sporadic Creutzfeldt-Jakob disease – unknown
- Iatrogenic CJD – exposure to contaminated hormones, tissues, blood products
- Variant CJD – ingestion of contaminated food
- Kuru – ritualistic cannibalism
- Familial CJD – genetic (germline PRNP mutations)
- Gerstmann-Straussler-Scheinkler syndrome – genetic (germline PRNP mutations)
- Fatal familial insomnia – genetic (germline PRNP mutations)
Which area of the brain is responsible for calculation?
L hemisphere - angular gyrus in parietal lobe crucial
List the pharmacological treatments of dementia
- Cognition enhancers, 2 classes
- Cholinesterase inhibitors e.g. rivastigmine, donepezil, galantamine - liscensed for mild to moderate Alzheimer’s disease and Parkinson’s disease dementia
- Partial glutamine agonist - memantine, licensed for moderate to severe Alzheimer’s disease
Describe the control of protein folding by the ER
- Newly synthesised glycoprotein, gets glycosylated (add sugar groups)
- Glucosidase I and II cleave off sugar groups
- Gives binding sites for chaperones e.g. calnexin and calreticulin, allow time for protein to fold and find correct conformation
- Glucosyltransferase determines if it is correctly folded or not
- Correctly folded à exits ER
- Incorrectly folded à glucosyltransferase adds sugar groups, try to refold
- Eventually will stop trying to refold – must have mutation, removed by ER-associated protein degradation (proteasome)
Describe the aetiology of delirium
Predisposing factors (age, dementia, vascular disease, drugs) + precipitating factors
Precipitating factors
- Infection
- Stroke
- Drugs e.g. opioids, steroids, digoxin
- MI
- Fractures
- Cancer
- Electrolyte/fluid balance problems
- Heart failure
- Diabetes
- PVD
- Alcohol withdrawal
Describe the normal brain changes which occur with aging
- Loss of brain volume, atrophy with age
- Increase in forgetfulness after age 50, slowing of response times, physical changes (vision, hearing, sensory/motor impairment)
What are molecular chaperones?
- Any protein that interacts with, stabilises or helps another protein acquire its functionally active conformation, without being present in its final structure
- Selectively binds to short stretches of hydrophobic amino acids, provides safe environment for folding
- Different classes of structurally unrelated chaperones exist, forming cooperative pathways/networks
- Proteome-maintenance functions - de novo folding, refolding, oligomeric assembly, protein trafficking, proteolytic degradation
- Can also use chaperonin - form cylinder into which new polypeptide is placed, safe environment for folding
Describe transmissible spongiform encephalopathies/Prion diseases
- Family of rare, progressive and fatal neurodegenerative diseases
- Loss of motor coordination and behavioural changes
- Can be inherited, sporadic, acquired
- Long incubation periods
- Characteristic spongiform changes associated with neuronal loss, and a failure to induce an inflammatory response
- Aetiological agent = prion
- PrPc (normal) à PrPsc (infectious)
Describe the secondary structure of proteins
- Alpha helices
- Results from H bonds forming between carbonyl oxygen atom of each peptide bone with the amide H atom from an amino acid 4 positions towards the C-terminus
- Results in periodic spiral, 3.6 amino acids per turn
- Confers directionality on the helix
- R groups face outwards, covering the helix
- Beta pleated sheets
- Each strand is 5-8 amino acid residues
- Hydrogen bonding between strands of polypeptides forms the planar sheet
- Directionality - parallel or anti-parallel
- R groups project from both faces of the sheet
Describe the prevalence of dementia
65+ prevalence is 7.1%
1 in 79 of entire UK population
Describe the structure of neurofibrillary tangles
- Main components of tangles are paired helical filaments - long fibrous proteins ‘braided’ together, typical flame shape
- Consists of the microtubule-associated protein Tau
Describe the non-pharmacological treatment/prevention of delirium
- Control noise and lighting
- Orientating influences - calendars, clocks, familiar objects, family
- Fluid balance, diet, bowel habit, pain control
- Regular communication/reassurance from staff, address sensory impairment
- Limit variation in staff
- Encourage normal sleep cycle and side room if possible
- Early mobilisation
- Avoid ward transfers
- Consider necessity of some procedures
- Recognise frailty
Describe the use of antipsychotics in dementia
- Use in
- Severe agitation
- Risk of harm to themselves or others - usually physical aggression
- Psychosis - watchful waiting first
- Not for - insomnia, wandering, abnormal vocalisations
- If stable for 3 months then cautiously withdraw, lowest possible effective dose for shortest possible time
When are cholinesterase inhibitors used/not used?
1st line treatment for Alzheimer’s, small improvement in Parkinson’s disease dementia, not useful in frontotemporal dementia, vascular dementia or mild cognitive impairment
Describe the amyloid hypothesis
- A beta monomers
- A beta oligomers
- A beta fibrils and plaques
- Inflammatory response - Tau aggregates and tangles
- Synaptic and neuronal loss
- Inflammatory responses - cognitive decline and disability
Secondary structure changes - alpha helix to beta sheets
Describe the structure of proteins
- Primary - sequence of amino acids in polypeptide chain
- Secondary - local folding, hydrogen bonds, alpha helices and beta pleated sheets
- Tertiary - long range folding
- Quaternary - multimeric organisation, subunits (e.g. haemaglobin)
- Supramolecular - large scale assemblies (e.g. collagen)
- Structure determines function - regulation, movement, signalling, transport, catalysis
List causes of dementia/apparent dementia
- Parenchymal/degeneration
- Alzheimer’s disease, vascular dementia, fronto-temporal dementia, Parkinson’s disease, Huntington’s disease, Wilson’s disease, MS, progressive supranuclear palsy
- Intracranial
- Tumour, head injury, subdural haematoma, cerebrovascular accident, normal pressure hydrocephalus
- Infection
- Crutzfeldt-Jakob disease, neurosyphillus, HIV associated dementia, TB
- Endocrine
- Hypothyroidism, hyperparathyroidism, Cushing’s and Addison’s
- Metabolic
- Uraemia, hepatic encephalopathy, hypogylycaemia, hypo/hypercalcaemia, hyper/hypomagnaesmia
- Vitamin deficiency
- B12, folate, thiamine, niacin
- Toxins
- Alcohol, lead
List the standard blood tests done in diagnosis of dementia
- Full blood count
- Inflammatory markers - ESR, CRP
- Glucose
- U + E (renal)
- LFTs
- Thyroid function
- Bone profile - calcium
- Urinalysis
- B12, folate
Describe visuospatial skills
- Process and identify what is around you and link this to position in space
- Visual cortex, projects to parietal lobe (sensory - spatial positioning and orientation) and temporal lobe (recognising things)
Describe the cause of vascular dementia
- Not neurodegenerative, underlying vascular pathology
- Small vessel disease - subcortical infarcts
- Large vessel disease - cortical multi-infarcts
- Hypertension
- Vascular risk factors - smoking, diabetes
When are proteins degraded by proteosomes?
Short half-life
Key metabolic enzymes
Defective proteins
Give examples of disorders of language
Aphasia - speaking
Agraphia - writing
Alexia - reading
Dysphasia (e.g. Wernicke’s and Broca’s) - speech
Describe the pathology of vascular dementia
- Brain weight normal, no significant atrophy
- Areas of cystic disruption - previous infarcts
- Mild ventriculomegaly
- Loss of white matter
- Red eosinophilic neurons - normally more basophillic (= red dead neurons - one of the earliest changes seen in brain in ischaemia, within 30 minutes)
Describe the clinical features of dementia with Lewy bodies
- Progressive cognitive decline
- Fluctuating consciousness
- Visual hallucinations
- Parkinsonism - motor disorders
Define anterograde and retrograde amnesia
Anterograde amnesia - not able to recall newly experienced information/memories from after disease process has set in
Retrograde amnesia - past information/before disease process has set in
How are the behavioural and psychiatric symptoms of dementia treated?
- Antidepressants - SSRIs sertraline and citalopram reduce agitation
- Cholinesterase inhibitors - reduce severity of neuropsychiatric symptoms, greatest effect on apathy
- Memtantine - slightly less likely to develop agitation, larger effect in moderate to severe AD
- Antipsychotics - atypical especially risperidone (licensed) and aripiprazole mainly for severe agitation/aggression, harmful - increase CV risk and mortality
Describe the ubiquitin-proteasome system
- Proteasomal degradation of proteins
- Polyubiquitination - minimum of 4 polyubiquitin tags
- PolyUb protein recognised by CAP of proteasome
- PolyUb removed, protein unfolded
- Protein threaded through proteasome
- Proteolysis
Describe the effects of mild, moderate and severe cortical atrophy in Alzheimer’s
- Mild - memory loss, confusion, trouble handling money, poor judgement, mood changes, anxiety
- Moderate - increased memory loss and confusion, problems recognising people, difficulty with language and thoughts, restlessness, agitation, wandering and repetitive statements
- Severe - completely dependent requiring nursing home care, weight loss, seizures, increased sleeping, loss of bladder and bowel control, death usually occurs from pneumonia
When are proteins degraded by lysosomes?
Long half-life, membrane proteins, extracellular proteins
Describe the pathology of Alzheimer’s disease
- Reduced brain weight (normal = 1250-1500g, 96g less in Alzheimer’s)
- Forebrain:hindbrain, normal is 8-10:1
- Macroscopic
- Enlarged ventricles - bilateral ventriculomegaly (due to atrophy)
- Temporal lobe atrophy (sulcal widening)
- Neocortical grey matter thinned
- Entorhinal cortex then hippocampus affected first
- Microscopic
- Two types of lesion - neurofibrillary tangles, amyloid plaques
- Neurofibrillary tangles - phosphorylated Tau, in cytoplasm
- Amyloid plaques - neuritic plaques (cerebral amyloid angiopathy, vessels hard and prone to rupture) in extracellular space
Compare the pathology of Parkinson’s disease to dementia with Lewy bodies
- Parkinson’s - pathology in nigrostriatal system, clinical effect = extrapyramidal movement disorder
- Alpha-synucleinopathy in cortex, SN/LC, dorsal vagal nucleus, myenteric plexus, autonomic ganglia
- Dementia with Lewy bodies - pathology in cerebral cortex, clinical effect = dementia
- Alpha-synucleinopathy in cortex, SN/LC, dorsal vagal nucleus and myenteric plexus
What determines protein folding?
- Proteins self-assemble into 3D conformation
- Protein conformation determined by primary structure
- Hydrophobicity important - some R groups are very hydrophobic, in a hydrophilic environment so need hydrophilic groups on outside
- Tendency for proteins to aggregate - folding takes time, environment is highly crowded (concentrations 300-400g/l)
Define proteostasis
Protein homeostasis - synthesis, folding, processing, assembly, degradation, localisation, trafficking
Loss of proteostasis contributes to pathogenesis of many human pathologies (including Alzheimer’s disease)
Describe the cognitive testing done in dementia diagnosis
- Addenbrooke’s cognitive examination - 100-point test, more senitive than MMSE in early disease, covers executive function, time consuming (cut-off scores - 88/82)
- MMSE - easier, faster, shouldn’t have variation in scoring, insensitive to early impairments, poorly covers executive function, influenced by age/education/socioeconomic status, useful screening tool and good for monitoring change
List the side effects of cholinesterase inhibitors
Nausea, vomiting, diarrhoea, muscle cramps, dizziness, fatigue, anorexia, cardiac adverse events, peptic ulcers/GI bleeding
Monitor BP, HR and GI side effects
Describe the pharmacological management of delirium
- Used if non-pharmacological methods ineffective, risk to self or others, actively hallucinating/psychosis
- Treat medical problem
- Treat delirium
- Antipsychotics - haloperidol, olanzapine, risperidone, aripipoazole, quetiapine
- Benzodiazepines - lorazepam, diazepam (in alcohol/substance abuse withdrawal or seizure disorders)
- Other - melatonin (sleep), trazodone (anti-depressant - low doses manage agitation and correct sleep cycle/affect)
Define executive reasoning
Group of cognitive skills e.g. planning, decision making, motivation, setting goals
Controlled by the frontal lobes
Describe the normal and abnormal function of APP
- Normal function unclear, widespread in CNS
- Normal cleavage (non-amyloidogenic) - cleaved just above transmembrane domain by alpha secretases to give sAPP alpha
- Abnormal cleavage (amyloidogenic)
- Cleaved by beta secretases above transmembrane domain to give sAPP beta, then in the transmembrane domain by gamma secretases (contain presenilin) to give A beta
What are the methods of protein degredation?
Lysosomal or proteosomal
List causes of Tau aggregation
- Imbalances of kinases and phosphatases (Cdk5 and GSK3 beta)
- Tau gene mutations
- Covalent modifications of Tau - change in conformation, dissociation from microtubules
- = detachment of Tau from microtubules, increased unbound Tau, misfolded Tau, pretangles, beta-sheet containing structures, neurofibrillary tangles
Describe the general clinical features of dementia
- Syndrome with chronic, progressive (usually irreversible) cognitive impairment due to brain disease
- Deterioration from higher level of function
- Multiple cognitive deficits
- Chronic duration >6 months
- Impact on social/occuptational function
- Personality change/disintegration (more in some types than others, especially frontotemporal)
- Decline in emotional control/motivation
Describe the pathology of prion diseases
- Neuronal loss, ‘vacuolation’ – spongiform cerebral cortex
- Amyloid plaques
Describe the structure and function of proteasomes
- Protein degrading machines
- Cytosol and nucleus
- Hollow, cylindrical structures + CAP, 60 subunits
- Alpha subunits - non-enzymatic
- Beta subunits - proteolytic activity
- Degrade proteins via the ubiquitin-proteasome system
Describe the aetiology of common neurodegenerative diseases
- Often genetic - cerebellar ataxia, frontotemporal dementia
- Often sporadic - Alzheimer’s disease, Parkinson’s disease, ALS
- Always genetic - Huntington’s disease
- Always sporadic - PSP, MSA
Describe the pathology of dementia with Lewy bodies
- Pallor of brainstem pigmented nuclei - substantia nigra
- Classical Lewy bodies - bright eosinophilic structures, alpha synuclein aggregates
Compare delirium and dementia
- Delirium
- Rapid onset
- Acute medical cause
- Consciousness impaired
- Major sleep-wake cycle disturbance
- Considerable fluctuation in 24 hour period
- Agitation, restlessness
- More prominent visual hallucinations
- Prominent labile affect, distress
- Dementia
- Slow progression, insidious
- Chronic progressive cause
- Clear consciousness (usually)
- Relatively less disturbance
- Worse in evening - ‘sun-downing’
- Relatively more settled
- Lability less common
Describe the diagnosis of dementia
- Clinical assessment
- Corroborative history - family members
- General physical examinations
- Standard (+/- specialised) bloods
- Structured cognitive testing
Describe the clinical features of vascular dementia
- Stepwise progression
- Memory impairments
- Lack of insight
What kind of memory loss occurs in dementia?
Ribot’s gradient - pattern of memory loss, will forget more recent material first then more long term as time goes on
Hippocampal atrophy in Alzheimer’s disease - loss of anterograde episodic memory
Describe the mechanism of action of memtantine
- NMDA receptor agonist, improves memory by restoration of homeostais in the glutaminergic system - used in combination with cholinesterase inhibitors or if they are ineffective/not tolerated
- No significant effect in mild dementia, vascular dementia or frontotemporal dementia
- Possible small effect in DLB but case reports of pyschosis
- Side effects - dizziness, headache, constipation, drowsiness and hypertension
Define cognition and list the aspects of cognition
Thinking, knowing, understanding
Includes - attention/orientation, memory, executive functioning, language, calculation, praxis and visuospatial ability
Describe the structure of amino acids
Describe the normal function of Tau protein
- Normal function - microtubule associated protein (transport of vesicles etc.), coats microtubules and stabilises
- Phosphorylation - Tau dissociates from microtubules, depolymerised - breaks microtubule function
Describe the prevalence of delirium
Occurs in 15-30% of hospital inpatients aged over 65
Describe the features of a neurodegenerative disease
- Neuronal death, systematic (symmetrical) loss
- Cortex - Alzheimer’s, frontotemporal dementia
- Basal ganglia - movment disorder (Parkinson’s/Huntington’s)
- Cerebellum and spinal cord - ataxia
- Protein accumulation and inclusions are primary pathology
- Beta-amyloid, Tau, alpha-synuclein, TDP-43
- Secondary changes - reaction (inflammation)
- Unremitting progression
- Unkown or genetic cause
Give examples of disorders of calculation
Acalculia - can’t comprehend/write numbers
Anarithmetria - can’t manipulate numbers to do arithmetic
Describe the spectrum of cognitive impairment
Age related cognitive impairment < mild cognitive impairment < dementia
Give examples of visuospatial skill disorders
- Topographical disorientation - difficulty moving around previously familiar environment
- Difficulties dressing - dressing apraxia
- Mis-reaching for objects
- Visual neglect - only eat one half of plate, draw clock face on one side
- Visual object agnosia - can’t recognise objects
- Prosopagnosia - don’t recognise familiar faces
- Constructional dyspraxia - can’t draw cube (R parietal lobe)
Define dementia
An overall term that describes a group of symptoms associated with a decline in memory or other cognitive skills severe enough to reduce a person’s ability to perform everyday activities
Describe the features of Alzheimer’s disease
- Significant decline in cognition, cognitive defects interfere with independence in everyday activities
- Clear history of worsening
- Initial and most prominent deficits are:
- Amnestic - episodic memory alteration
- Non-amnestic - progressive aphasia, visuospatial deficit, executive dysfunction
- Not always homogenous, may vary in:
- Age at onset
- Disease progression
- Disease duration
- Symptoms at onset - predominantly frontal (behavioural), predominantly occipital (visuospatial)
