Week 3 - Dementia - Neurodegenerative Disorders Flashcards
Outline Brodman’s cortical map.
- Cerebral cortex - memory, language and cognition (dementia).
- Basal ganglia - movement disorders.
- Cerebellum - coordination, ataxia.
- Motor neurons - weakness/paralysis.
E.g. when there is a memory, language or cognition problem in history → suspect cerebral cortex disorder.
Describe the function of the limbic system, hippocampus and thalamus?
- Limbic system - controls emotions and instinctive behaviour (includes the hippocampus and parts of the cortex).
- Hippocampus - where short-term memories are converted to long-term memories.
- Thalamus - receives sensory and limbic information and sends to cerebral cortex (cognition).
- Limbic system important in Broca’s area - process info and learn from experience.
- Hippocampus - central damage in Alzheimer’s disease and other major dementias. Where short term memories are converted to long term memories.
- Thalamus - assimilates information, synthesises a result and sends it to motor and sensory cortex and memory. Sends to cerebral cortex after processing → gives understanding.
What is dementia?
• Loss of higher cognitive function, normal level of consciousness.
- Loss of higher cognitive function (ability to process info, emotions, language), preserved consciousness.
Outline the classification of CNS degenerations.
- Neuronal degenerations
Primary degenerations:
• Global - Alzheimer’s (commonest), Lewy body, Fronto-temporal dementia.
- Global degeneration - affecting whole brain.
- Global characterised by dementia.
• Selective/System - Parkinsons, Huntingtons, MND (motor neuron).
Secondary degenerations:
• Toxic, metabolic (genetic), infections (CJD), vascular (CVA).
• Alcohol, drugs, vitamin B12 deficiency.
- Myelin degenerations
• Demyelinating disorders - Multiple sclerosis, vitamin B12 deficiency.
• Dysmylinating disorders - Leukodystrophies.
Who is Alzheimer?
• German psychiatrist, 1901.
- 51 year male patient.
- Behavioural abnormality.
- Short term memory loss.
- Seen a 51 year male patient with a behavioural abnormality and short term memory loss.
• Contacted colleague Franz Nissl (pathologist).
- Silver stain, observed amyloid plaques and neurofibrillary tangles (NF).
- Identified and developed a new stain → observed amyloid plaques, neurofibrillary tangles and neuronal degeneration.
• Case presented at Berlin 1906.
• Established International Brain Research Organisation.
Outline Alzheimer’s disease.
- Commonest cause of dementia.
- Dementia - loss of cognition with preserved consciousness.
- Increasing incidence - due to ageing, toxins, diet, pollution… (have all been implicated).
- > 45% of adults over 85y are demented (>30y, rapid >70y).
- Age related.
- Brain starts regenerating after 30y.
• Recent memory loss (hippocampus) + aphasia, agnosia, apraxia.
- Recent memory loss most important feature of Alzheimer’s disease.
- Processing of information specifically language.
• Sporadic 90%, >60y, genetic/familial ~10% early.
- Sporadic most common. 90% of cases do not know etiology. Occurs after the age of 60y.
- Genetic/familial cases are rare (~10%), start early.
• Trisomy 21 (Down sy) → excess APP → early Alzheimer disease.
- Most common example of genetic dementia/Alzheimer’s is Down Syndrome → excess amyloid protein precursors → develop early Alzheimer’s before 50y.
Describe the pathology of Alzheimer’s disease.
• Cortical atrophy, limbic, temporal, hippocampus.
- Neurofibrillary (NF) tangles (tau) - intracellular.
- Neuritic plaques (Aβ amyloid) - extracellular.
- Amyloid angiopathy around blood vessels.
• tau and amyloid are neurotoxic → atrophy of neurons and reactive gliosis.
- Do not know exact aetiology but the pathogenesis is cortical atrophy - atrophy of the neurons. Starts in limbic system, temporal lobe and hippocampus → explains dementia.
- Microscopically characterised by 3 features - neurofibrillary tangles within the cell due to abnormal tau protein, neuritic plaques (extracellular - amyloid plaques), deposition of amyloid around the blood vessels leading to narrowing and ischaemia. All damaging to nerves → leads to atrophy of the neurons and reactive gliosis.
Explain the pathogenesis of Neurofibrillary Tangles within neurons.
- Formation of intracellular neurofibrillary tangles.
- Axons and dendrites - long processes supported by internal skeleton of microtubules.
- Microtubules are stabilised by sticky glue like proteins known as tubulin associated units (tau protein - necessary for function of neurons).
- In Alzheimer’s - microtubule tau protein breaks down forming large clusters of glue. Glue no longer supporting the tubule → breaks down.
- When the tubule breaks down, the nerve fibres break down, very irregular → leads to neuronal degeneration.
- Characteristic feature microscopically is NF tangle (abnormal tau proteins within cell).
- Within the cell, NF tangle is positive by Nissl stain (dark spots within neurons).
• Breakage of normal binding tau protein leads to collapse of microtubules and tau proteins clump → NF tangles.
Explain the pathogenesis of Amyloid plaques.
- Deposition of amyloid plaques outside the cell (extracellular) AKA neuritic plaques.
- Amyloid precursor protein normal part of cell membrane. Normally it breaks down by alpha and gamma enzymes into multiple small fragments which are recycled.
- In Alzheimer’s - amyloidogenic - abnormal breaking of only 2 fragments due to beta enzymes → results in Aβ peptide.
- Aβ peptides are insoluble/non-digestible. No other enzymes to break down → accumulates over the years into irregular clusters of abnormal filaments (amyloid fibrils) → leads to plaques.
- Plaques plus tangles are the two important features*
Describe the morphology of Alzheimer’s disease.
• NF tangles inside cell and neurotic/amyloid plaques outside the cell together leads to atrophy → loss of neuronal tissue more importantly in the limbic system and the temporal lobe. Also in the cortex in advanced cases. Leads to compensatory dilation of ventricles and narrowing of the gyri/widening of the sulci.
Gross:
• Limbic, temporal, cortical atrophy (atrophy of limbic system, temporal lobe and cortex).
• Narrow gyri.
• Widened sulci.
• White matter loss leading to dilated ventricles (compensatory hydrocephalus).
Microscopy:
• Intraneural Neurofibrillary tangles
• Interstitial amyloid Neuritic plaques
• Amyloid Angiopathy (amyloid deposited in the blood vessels leading to narrowing).
Describe the progression of Alzheimer’s disease.
- Always starts in limbic system/hippocampus/thalamus → then it starts spreading anteriorly then posteriorly from the temporal lobe.
- Gradually spreads to whole cortex.
- Memory loss is the first sign of AD.
- Confusion, poor judgement.
- Language and thoughts, restlessness, agitation.
- Inability, dependence on others for care.
- Weight loss, seizures, loss of bladder and bowel control.
- Infections, groaning, moaning or grunting.
- Death usually occurs from aspiration pneumonia, respiratory failure or septicaemia.
- Memory loss*
- Confusion, poor judgement.
- Difficulty with language, forming words, thoughts, restlessness, agitation.
- Gradually becomes so severe that they cannot do their normal routine/daily work - depend on others for care.
- Normally progesses over many years.
Identify the clinical features of Alzheimer’s disease.
Impairment of higher intellectual function, with alterations in mood and behaviour.
• Impairment of ability to remember information acquired in the past.
- Short-term & long-term memory both affected (short-term more so).
• Progression of disease = language deficits, loss mathematical skills, loss motor skills.
• Patients initially aware of problems but eventually deny anything is wrong (anosognosia).
• Depression is common.
• Occasionally patients become aggressive.
Slow but sure progression - eventually, patient becomes severely disabled, mute & immobile.
What are the stages of Alzheimer’s disease?
- Early/Pre-clinical
• Degeneration starts cortex and progresses to hippocampus.
• Neuronal loss leads to shrinkage.
• Changes begin 10-20yrs before symptoms - first sign is memory loss.
2. Mild/Moderate • Involves cerebral cortex. • Mild signs: - Memory loss and confusion. - Difficulty handling money. - Poor judgement. - Mood changes and anxiety. • Moderate signs: - ↑ memory loss and confusion. - Problems recognising people. - Difficulty language and thought. - Restlessness and agitation. - Wandering. - Repetitive statements.
3. Severe • Extreme shrinkage of brain. • Patients are completely dependent on others for care. • Symptoms: - Weight loss. - Seizures. - Skin infections. - Groaning, moaning or grunting. - Loss of bladder and bowel control. • Death usually occurs from aspiration pneumonia or infections.
Describe the diagnosis of Alzheimer’s disease.
• Significant damage will have occurred prior to the diagnosis - deposition of amyloid (can be detected in CSF).
- Atrophy in β amyloid positive norma persons is detectable even after 1 year.
• Active use of brain protects against Alzheimer’s.
- Mentally stimulating activity in early life protects against AD - use it or lose it.
- Coffee protects against Alzheimer’s. Tea protects against Parkinson’s.
Outline the management of Alzheimer’s disease.
- Investigations to exclude other treatable causes of dementia (true diagnosis [histology] only after death)
- No known treatment but anticholinesterases have been thought to be of some benefit
- Management is primarily supportive
- If depression is present - treatment of depression by antidepressants etc. may be helpful
- NB: Higher skills in grammar, density of ideas, mentally stimulating activity, coffee = protective.
Summary Alzheimer’s disease.
• Commonest cause of dementia.
• 90% sporadic idiopathic late age.
• 10% early genetic/familial e.g. Trisomy 21.
• Degeneration starts in limbic system.
- Starts in limbic system, spreads through temporal lobe and then whole cortex.
• Loss of memory, cognition, language.
- Memory loss is the earliest sign. Loss of cognition, language difficulties (major features).
• Progressive, chronic, ~25y death.
- Progressive disease leading to death due to infections and respiratory failure.
• Gross - cortical atrophy with compensatory dilation of ventricles.
• Micro - neuronal loss with gliosis.
1. Neuritic plaque (amyloid).
2. Neurofibrillary tangles (tau).
3. Amyloid angiopathy.
Outline Parkinson’s disease.
• ‘Shaking Palsy’ tremor, rigidity and bradykinesia.
- Characteristic triad - tremor, rigidity (rigid muscles), bradykinesia (slow movements).
• Due to damage to nigrostriatal dopaminergic system (movement).
- Related to dopamine. Dopamine is involved in all human emotions. Target for many recreational drugs.
• Parkinson’s disease - primary atrophy of substantia nigra (Parkinsonism - secondary - drugs, toxins, other dis).
- Neurodegenerative disorder affecting the substantia nigra - the origin of dopaminergic system.
- Parkinsonism is due to secondary suppression of dopaminergic neurons due to drugs, toxins and other disorders.
• Dopaminergic nerves with α-synuclein - Lewy body inclusions.
- Dopaminergic neurons have α-synuclein inclusions known as Lewy bodies.
• Clinical features:
- Adults (45-60y), diminished facial expressions (early sign), stooped posture.
- Festinating gait and fine rolling resting tremors. Dementia in some cases (late - neurodegenerative).
- When dementia arises <1 year of onset, Lewy body dementia (LBD) - (PD+AD).
• When dementia arises within one year of motor symptoms - known as LBD - features of Parkinson’s + Alzheimer’s.
Identify the components of the dopaminergic system.
Dopaminergic system - affects movement, behaviour, prolactin (central control).
- Nigro-striatal - movement.
- Mesolimbic & Mesocortical - behaviour.
- Tuberoinfundibular - prolactin.
Describe the pathology of Parkinson’s disease.
- Gross - loss of neuromelanin pigment in substantia nigra.
- Neuronal degeneration.
- Reactive gliosis.
- Lewy bodies (α-synuclein) in neurons.
- Cut-section of brainstem - normal person (substantia nigra) and atrophy in case of Parkinson’s disease (loss of neuromelanin).
- Microscopy - pigmented neurons markedly decreased. Neurons show Lewy bodies - rounded inclusion of α-synuclein.
Describe the aetiology/pathogenesis and morphology of Parkinson’s disease.
Aetiology
• Majority are idiopathic (no known cause).
- May be due to MPTP toxin in heronin drug users.
• Some cases are familial – many genes have been identified.
Pathogenesis - unclear.
- Atrophy of substantia nigra → depletion of dopinergic neurons.
- Reduced dopaminergic output from substantia nigra to globus pallidus.
- Reduced inhibition on subthalmic nucleus → neurons more active → inhibit cortex.
- Bradykinesia.
Morphology Gross: • Atrophy of substantia nigra - Depletion dopinergic neurons • Loss of pigment in substantia nigra
Microscopy:
• Neuronal loss, degeneration.
• Loss of neurons replaced by gliosis.
• Lewy bodies (α-synuclein) in neurons.
Identify the clinical features of Parkinson’s disease.
- Diminished facial expressions & stooped posture.
- Slow voluntary movements, festinating gait, rigidity & loss postural reflexes, fine rolling tremors.
- Tremor, bradykinesia (slowness of movement) & rigidity.
- Inhibition of movement and dementia in some cases.
Outline the management of Parkinson’s disease.
- Diagnosis is made clinically.
- Drug therapy → Levodopa + peripheral-acting dopa-decarboxylase inhibitor.
- Stereotactic thalamotomy (surgery) can be used to treat tremor.
- Supportive therapy (eg. physiotherapy & speech pathology).
What is Diffuse Lewy body Demetia (DLD)?
• Dementia with Lewy bodies (DLB).
• 10-15% of Parkinsons.
• Dementia within 1y of motor symptoms.
- Parkinson’s associated with severe dementia that starts early within 1y of motor symptoms.
• Parkinsons + Alzheimers (combined atrophy of substantia nigra and cortex).
• Lewy body (α-synuclein) in many parts of cortex and substantia nigra (along with atrophy).
• Visual hallucinations - characteristic finding that helps differentiating from just Parkinsons and Alzheimers.
• Atrophy of substantia nigra and cortex.
• Rapidly progressive - early death.
Outline Parkinsonism & Atypical Parkinsonism.
Parkinsonism: clinical syndrome. “Anti-dopaminergic effects”
• Drugs: dopamine antagonists, MPTP toxin in heroin, pesticides.
Produces symptoms similar to Parkinson’s disease - substantia nigra is normal.
Atypical Parkinsonism:
• Other neurodegenerative disorders with Parkinson features.
1. Progressive Supranuclear Palsy (PSP): Tau, Nuchal dystonia, falls.
- Associated with tau protein similar to Alzheimer’s, spinal nuchal dystonia and frequent falls.
- Corticobasal Degeneration (CBD): Jerking movement of limbs.
- Associated with jerky movement of limbs. - Multiple System Atrophy (MSA): PD + Autonomic (orthostatic hypotension) + cerebellar atrophy (ataxia).
- PD with autonomic abnormalities (typically orthostatic hypotension) and cerebellar atrophy leading to ataxia (multisystem atrophy).
