Neurodegeneration Flashcards
What structures are required for consolidation of declarative memory?
• Hippocampus and entorhinal cortex (medial temporal lobe structures) required for reinforcement (consolidation) of declarative memory
What projects to and from the entorhinal area?
o Projections to and from all over cortex are funnelled through hippocampus, entorhinal area.
o Entorhinal area has massive projection to cortex and receives massive projections from cortex
What are the earliest lesions which can be seen in Alzheimer’s disease?
Earliest lesions we see in Alzheimer’s is entorhinal cortex
What is the basis of declarative memory anatomically?
• Strengthened connections between cortical areas is the basis of declarative memory
What is important in recall of information anatomically?
• Activation of strengthened networks is the basis of recall
What is the function of the dorsolateral prefrontal cortex?
• Areas such as dorsolateral prefrontal cortex is important in network activation (recall) and storage
How is memory distributed in the brain?
• Memory distributed across modality-specific areas and association areas
o It’s really in the connections
Describe what ageing does to the brain
• Do not lose neurons as you age- may be minor loss of neurons
• Mild cortical atrophy
o Mainly white matter shrinkage
o Minor grey matter atrophy
• Get peroxidised lipids in neurons (lipofuscin)- but it is benign
• Most changes that do occur with age in the brain (permanent or temporary) relate to the cerebrovasculature
• Stroke (loss of blood flow) is the most common neurological disorder and a major cause of death
• Most subtle vascular changes may also occur- mild ischaemia, especially with atherosclerosis can cause temporary disability
Do most people get cognitive disorders or experience mild cognitive decline?
• Majority of people do not see cognitive disorders in their lifetime
o Most people will have some Alzheimer-type pathology but not sufficient to affect function
• Mild cognitive decline is common in late age
What are the problems with defining late age and what is the impact of this?
- Late age refers to more advanced years
- Definition of late age has changed in the last 50 years
- Need to be cautious when considering cross-sectional vs longitudinal design of population ageing studies
What is dementia?
• Dementia- a significant decline in at least 2 areas of higher cognition such as memory, language, planning, judgement, abstraction, calculation and personality- category term. A collection of clinical symptoms, not a disease.
What defines a syndrome within dementia?
• A constellation of symptoms define the syndrome
What are examples of specific dementia symptoms
• Specific dementia symptoms include- o Prefrontal areas affect judgement, impulsivity, emotional expression o Memory areas in MTL o Language areas o Modality specific areas o Higher association areas e.g. parietal o Behaviour: amygdala, hypothalamus, prefrontal areas o Striatum: habits, personality
Describe how dementia was referred to starting from 2013
• 2013- DSMV abandoned the term dementia in lieu of:
o Mild cognitive impairment (MCI)
Some cases of mild cognitive impairment may be prodromal dementia that is, person will go on to develop dementia
Major area of research clinically
o Severe cognitive impairment (dementia)
What are the trends of incidence vs prevalence of dementia and why?
• As a consequence of greater numbers of people living to later ages, the prevalence of dementia is increasing: however, the incidence is actually decreasing in many parts of the world
How many cases of dementia would occur in the next 30-35 years?
Estimated 1000000 cases in Australia in the next 30-35 years
What are different types of dementia?
• Types of dementia include: o Alzheimer’s disease o Vascular dementia o Frontotemporal dementias o Lewy body disease o HIV/AIDS related dementia o Korsakoff’s dementia
What percentage of all dementia cases does Alzheimer’s disease account for?
Alzheimer’s disease accounts for 50-70% of all dementia cases
What types of dementias are treatable?
• Some dementias may be treatable o Intracranial masses o Encephalitis o Meningitis o Vitamin deficiency o Depression-related dementia
Describe when Alzheimer’s disease is diagnosed
- Probable diagnosis during life based on cognitive features and progression
- Definitive diagnosis is post mortem, however the clinical assessment is now highly accurate
Describe the onset and progression of Alzheimer’s disease
- Insidious onset
* Slow (rather than abrupt or stepwise) progression
Describe the duration of Alzheimer’s disease
• Duration is 5-12 years, but likely long prodromal (disease has been there before the symptoms) period
o Mostly diagnosed retrospectively
Describe Alzheimer’s disease symptoms
• Memory signs appear early
o Repetition
o Getting lost
o Inability to do calculations and following conservations
o Trouble orienting to space and time
o Losing things
o Hiding things
• Early on, daily activities of living are intact but may need instruction, breaking down tasks
• Other cognitive signs appear later
o Behavioural changes (agitation, paranoia)
o Aphasias
o Apraxias
o Activities of daily living (dressing, eating, bathing)
o Agitation
What is exclusion criteria for Alzheimer’s disease diagnosis
• Exclusion criteria for alzheimer’s disease diagnosis
o Movement disorders
o Abrupt onset
o Delirium, seizures, focal signs
What are the risk factors for Alzheimer’s disease?
• Risk factors for Alzheimer’s disease o Age- highest risk factors o Genetics- less than 1% of cases have a defined genetic link Autosomal dominant mutations- Amyloid Precursor Protein (APP), Presenilin 1, Presenilin 2 o Cardiovascular risk factors Diabetes type II Midlife hypertension Smoking Atrial fibrillation Previous stroke High cholesterol o Head injury o Low educational attainment (may be study bias or socioeconomic factors)
What 2 markers does post mortem diagnosis of Alzheimer disease require?
Extracellular amyloid deposits
Intracellular neurofibrillary tangles
Describe the production and deposition process and location of extracellular amyloid deposits, as well as their correlation with Alzheimer’s symptoms in Alzheimer’s disease
Extracellular amyloid deposits
• Amyloid is produced by abnormal cleavage of the amyloid precursor protein
• Some familial forms of the disease associated with APP mutations
• Amyloid beta is deposited extra-neuronally in plaques in the brain but in particular in cortical layers
o Not inside of cells, but outside of cells
• Amyloid beta is deposited within and around blood vessels
• Not well-correlated with dementia symptoms compared to tangles
Describe the production and deposition location of intracellular neurofibrillary tangles in Alzheimer’s disease
Intracellular neurofibrillary tangles
• Occurs through
o Microtubule associated protein tau becomes hyper-phosphorylated
o Hyperphosphorylated tau (Hp-tau) fills the neuron
o Hp-tau forms fibrils that collect into tangles within neurons
o Neurons eventually die, tangle left behind (ghost tangle)
• Inside neurons
• There is high density of tangles in hippocampus and entorhinal cortex
Describe the stages of AD symptomatically and neurofibrillarily
• Stages of AD-
o Stages I-III
No symptoms
Neurofibrillary tangles start to appear in hippocampus and entorhinal cortex
o Stages III-IV
Subtle symptoms appear- memory affected early
Will have lots of neurofibrillary tangles in medial temporal lobe
o Stages V-VI
Other cognitive symptoms- clinical diagnosis
Tangles have spread to rest of cortex- temporal neocortex, then limbic and association cortex
• Tangles are also found in hypothalamus, amygdala and brainstem
What does progression of Alzheimer’s disease cognitive dysfunction correlate with? Explain.
• Progression of alzheimer’s disease cognitive dysfunction correlates with the location of neuronal pathology
o Alzheimer’s disease- early
Anterograde amnesia- no new memories
Atrophy and neuronal pathology (tangles) in hippocampus/entorhinal cortex
o Alzheimer’s disease- later
Retrograde- old memories lost
Previously consolidated memories erode
Atrophy and neuronal pathology (tangles) in the neocortex
• Disconnection of the memory trace as nodes- neurons- in the network succumb to tangle formation
What is frontotemporal dementia and what area of the brain does it affect?
• FTD is a group of disorders/syndromes with different aetiologies, frequencies, progression, symptoms and genetics
• They have in common atrophy in frontal and temporal lobes: striking specificity
o But different proportions of frontal and temporal atrophy- frontal atrophy is usually the most profound
o Symptoms more likely to be frontal related symptoms
What percentages of dementias does frontotemporal dementia account for?
• FTD accounts for just about 10-15% of dementias overall, all ages considered
o Frontotemporal dementia is relatively rare compared to AD
For people under 50 years, what percentage of dementia cases does FTD account for? What is the onset of FTD?
• For persons under 50 years, FTD accounts for more than 50% of dementias
o Large proportion of patients have young onset (40s and 50s but may be as young as 20 years)
Compared to Alzheimer’s disease, what proportion of patients have a genetic link to frontotemporal dementia
• Larger proportion of patients have genetical link compared to AD
What are the symptoms of frontotemporal dementia?
• Clinical features of FTD related to brain regions
o Behavioural abnormalities related to prefrontal areas
Decreased initiative
Social disinhibition, impulsivity, loss of restraint
Poor planning
Emotional blunting, difficulty regulating emotion
Stereotypical behaviours
• Repetitive behaviours, mimicking behaviours, compulsive behaviours
o Aphasias
Some forms of FTD have primarily a language dysfunction
Related to atrophy in Wernicke’s and Broca’s language areas
o Memory dysfunction- temporal lobe areas and DLPF cortex
Usually appears later, can be a minor feature and often not as severe as in AD
o Movement disorders
Some subtypes of FTD show parkinsonism
• More likely to have an early age of onset (midlife- 40-50 years)
What is the duration of symptoms for frontotemporal dementia
o 2 to 15 year duration of symptoms
What is the problem with understanding frontotemporal dementia? What is currently known about the process of frontotemporal dementia?
• Problems with understanding FTD
o Microscopic pathology in FTD not well understood compared to AD
o Frontotemporal dementia was once called Pick’s disease (protein also made of tau)
o However, most cases of FTD do not have Pick bodies (only 5% had Pick bodies), so most cases no longer classified as Pick’s disease
o Inflammation is common: astrocyte and microglia reaction
What are the causes of Parkinson’s disease?
• Causes-
o Genetics (15%)
Associated with dysfunction of pre-synaptic proteins or mitochondrial dysfunction
More likely with early onset forms of disease (40-45)
o Prions (infectious agents: alpha synuclein, gut)
Parkinson’s disease could spread from the gut from the vagus nerve and up to brain- transmits alpha synuclein to the brain
o Head trauma (vibrations)
o Toxins (MPTP)
Straight to dopaminergic cells in substantia nigra pars compacta and kills them
How can you protect from Parkinson’s neurodegeneration and how does each method work?
• Protectors from neurodegeneration
o Anti-oxidants-> have been shown to help a neuron in distress and help them survive
o Exercise-> releases growth hormones in brain to help cells in distress survive better
o Coffee-> stimulates locomotion
o Smoking -> stops breakdown of dopamine at synapse
What are the motor signs of parkinson’s disease
o Motor signs- diagnosis with 2 of these signs- one has to be tremor or bradykinesia Resting tremor (4-7 Hz) • Starts unilateral but becomes bilateral Lead-pipe rigidity (hypertonia) • Muscles become stiff Akinesia • No movement- almost frozen Bradykinesia • Slow movement Loss of posture reflex Hypomimia • Expressionless face Dysphagia • Trouble swallowing Dysarthria • Problems with speech Micrographia • Very small writing Cog-wheel rigidity • No smooth hand movement Festinant gait • Short, sharp steps Freezing
What are the non-motor symptoms of Parkinson’s disease
o Non-motor symptoms (often occur prodromally) Anosmia (smell) Sleep Fatigue/Apathy Psychiatric/depression issues Somatosensory/ pins and needles Gastrointestinal Autonomic Cognition (towards the end of the disease course)
What are the two forms of Parkinson’s disease
• Two forms of the disease
o Tremor dominant form of disease- tremor but not necessarily akinesia, bradykinesia or rigidity
Better form of the disease
o Akinetic form of disease- but don’t necessarily have tremor
Worst form of the disease
What neurons are lost in parkinson’s disease? How much of these neurons need to be lost before the disease becomes apparent?
• Drop of substantia nigra pars compacta dopaminergic cells and loss of their terminations in the striatum (dopaminergic terminals)
o 50-70% loss needed before signs of the disease become evident
• Some serotoninergic and noradrenergic loss
How does Parkinson’s disease progress?
• Progressive
o Continued toxin/gene/prion (self-propagation)
o Glial attack neurons and cause them to become dysfunctional and die
What are pathological features of Parkinson’s disease
• Lewy body (alpha synuclein)
• Mitochondria dysfunction caused by alpha synuclein
o Lowered ATP production
o Increase in reactive oxygen species which will disrupt neurons and cause it to die
What is the mechanism of Parkinson’s disease
• Mechanisms
o Due to destruction of dopaminergic direct pathway (nigrostriatal pathway), Indirect pathway become overactive which inhibits GABAergic cells in globus pallidus external, which project to subthalamic nucleus
o Subthalamic nucleus becomes overactive- its glutamatergic cells (excitatory) project to globus pallidus internal which stimulates it
o Globus pallidus internal has inhibitory projections to the thalamus
Too much inhibition to thalamus which means it can no longer project to the cortex-> suppression in cortex-> movement is suppressed -> causes motor symptoms (tremor, akinesia, bradykinesia, rigidity)
