Alzheimer's Flashcards
1
Q
Define Alzheimer’s and break down the epidemiology
A
- Alzheimer disease (AD) is a neurodegenerative disorder marked by cognitive and behavioural impairment that significantly interferes with social and occupational functioning.
- Alzheimer’s disease is the most common form of dementia.
- The principal risk factor for Alzheimer’s disease is age. The incidence of the disease doubles every 5 years after 65 years of age
- Sporadic Alzheimer’s disease can affect adults at any age, but usually occurs after age 65 and is the most common form of Alzheimer’s disease.
- Familial Alzheimer’s disease is a very rare genetic condition, caused by a mutation in one of several genes.
- Dementia affects almost 50 million people worldwide, which is predicted to increase
- Dementia is the second leading cause of death of Australians
- The disease is twice as common among women as among men, partly because women have a longer life expectancy.
- In 2018, there is an estimated 436, 366 Australians living with dementia. Without a medical breakthrough, the number of people with dementia is expected to increase
2
Q
Describe the characteristics of the brain with Alzheimer’s
A
- Microscopic level
- Macroscopic changes: Preclinical vs Mild AD
- Preclinical: The hippocampus and medial temporal lobe are the initial sites of tangle deposition and atrophy
- Mild disease: The disease begins to affect the cerebral cortex, memory loss continues, and changes in other cognitive abilities emerge. The clinical diagnosis of AD is usually made during this stage
- Severe disease: In the last stage of AD, plaques and tangles are widespread throughout the brain, and areas of the brain have atrophied further.
3
Q
List neuropathologic changes in AD
A
- amyloid plaques: Extracellular amyloid beta deposition in the cerebral cortex and subcortical grey matter
- neurofibrillary tangles: Comprised of the intracellular accumulation of hyperphosphorylated tau protein
Other features include:
- Cerebral amyloid angiopathy is often found in cases with parenchymal amyloid beta deposits
- Lewy bodies-inclusions of abnormal alpha-synuclein accumulation (amygdala)
- Vascular brain injury- are caused by oligemia, hypoxemia or ischemia involving small blood vessels in the brain
4
Q
Descrube overall the role of protein abnormalities in Alzheimer’s
A
- Plaques and tangles are important pathological features of Alzheimer’s disease.
- Alzheimer’s-related brain changes may result from a complex interplay among abnormal tau and beta-amyloid proteins and several other factors.
- It appears that abnormal tau accumulates in specific brain regions involved in memory
- Beta-amyloid clumps into plaques between neurons. As the level of beta- amyloid reaches a tipping point, there is a rapid spread of tau throughout the brain.
5
Q
Describe the amyloid hypothesis
A
- Aβ peptides are natural products of metabolism consisting of 36 to 43 amino acids
- Monomers of Aβ 40 are much more prevalent than the aggregation-prone and damaging Aβ42 species.
- β-amyloid peptides originate from proteolysis of the amyloid precursor protein by sequential enzymatic actions.
- An imbalance between production and clearance, and aggregation of peptides, causes Aβ to accumulate, and this excess may be the initiating factor in Alzheimer’s disease.
- In the Alzheimer’s brain, abnormal levels of this naturally occurring protein clumps together to form plaques that collect between neurons and disrupt cell function
- This idea, called the “amyloid hypothesis,” is based on studies of genetic forms of Alzheimer’s disease, including Down’s syndrome, and evidence that Aβ42 is toxic to cells
6
Q
Describe amyloid plaques
A
- While the pathogenesis of AD remain unclear, all forms of AD appear to share overproduction and/or decreased clearance of amyloid beta peptides
- Amyloid Precursor Protein(APP) is associated with the cell membrane. After it is made, APP sticks through the neuron’s membrane, partly inside and partly outside the cell
- Amyloid beta peptides are produced by the endoproteolytic cleavage of mature protein translated from the amyloid precursor protein (APP) gene and are cleaved by beta-secretase and gamma-secretase.
- Enzymes act on the APP and cut it into fragments of protein, one of which is called beta-amyloid
- Presenilin forms part of the gamma- secretase complex, and mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2) appear to favour production of amyloid beta overall, or more neurotoxic forms of amyloid beta
- The beta-amyloid fragments begin coming together into clumps outside the cell, then join other molecules and non-nerve cells to form insoluble plaques
- The ultimate neurotoxin in AD is debated, but experimental evidence highlights small aggregates of amyloid beta peptides called oligomers, as opposed to larger aggregates called fibrils
7
Q
Describe neurofibrillary tangles
A
- The pathogenesis of AD also involves a second protein, tau. Tau is a microtubule- associated protein that aids in microtubule assembly and stabilization
- in AD, tau becomes hyperphosphorylated and aggregates to form paired helical filament (PHF) tau, a major component of neurofibrillary tangles within the neuronal cytoplasm
- The accumulation of this altered protein is toxic to neurons in experimental models
- In addition, transmission of pathologic forms of tau between neurons has been proposed to account for the spread of AD in the brain, which follows a distinct progression across brain regions as AD advances
8
Q
Describe neurofibrillary tangles - in detail
A
- The major component of the tangles is an abnormally hyperphosphorylated aggregated form of tau.
- Healthy neurons have an internal support structure partly made up of structures called microtubules.
- Tau is an abundant soluble protein in axons, it promotes assembly and stability of microtubules.
- In AD, tau is changed chemically. It begins to pair with other threads of tau, which become tangled together. When this happens, the microtubules disintegrate, collapsing the neuron’s transport system.
- Hyperphosphorylated tau is insoluble, lacks affinity for microtubules, and self-associates into paired helical filament structures to form tangles inside neurons. Enzymes that add and those that remove phosphate residues regulate the extent of tau phosphorylation.
- These tangles block the neuron’s transport system, which harms the synaptic communication between neurons and later the death of the neurons.
9
Q
Describe the progrssion of Alzheimer’s via the synapse
A
- Alzheimer’s disease may be primarily a disorder of synaptic failure.
- Hippocampal synapses begin to decline in patients with mild cognitive impairment (a limited cognitive deficit often preceding dementia) in whom remaining synaptic profiles show compensatory increases in size.
- In mild Alzheimer’s disease, there is a reduction of about 25% in the presynaptic vesicle protein synaptophysin.
- With advancing disease, synapses are disproportionately lost relative to neurons, and this loss is the best correlate with dementia.
- Aging itself causes synaptic loss, which particularly affects the dentate region of the hippocampus.
10
Q
List some risk factors for AD
A
- Advancing age
- Family history of dementia
- Apolipoprotein E (APOE) epsilon 4 (e4) allele.
- Obesity
- Insulin resistance
- Vascular factors
- Dyslipidaemia
- Hypertension
- Down syndrome
- Traumatic brain injury
11
Q
Describe early-onset AD
A
- AD is highly heritable, even in so-called sporadic cases. The genetic basis for AD is understood most clearly in the early-onset form, which accounts for less than 1 percent of cases.
- Early-onset AD follows an autosomal dominant inheritance pattern related to mutations in genes that alter amyloid beta protein production, aggregation, or clearance, including amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2).
- Such mutations are highly penetrant, meaning that carriers have a nearly 100 percent chance of developing the disease in their lifetime.
- Other early-onset cases without mutations can present clinically prior to 65 years of age. While a percentage of them have higher proportions of APOE e4.
- Individuals with Down syndrome, who have an additional gene dose of APP due to trisomy of chromosome 21, inevitably develop AD pathology, and symptoms emerge at an earlier age, 10 to 20 years younger than the general population with AD.
12
Q
Describe late onset AD
A
- The genetic basis of late-onset AD is more complex, with susceptibility likely conferred by a variety of more common but less penetrant genetic factors interacting with environmental and epigenetic influences.
- The most firmly established genetic risk factor for late-onset AD is APOE; carriers of one e4 allele are at two- to threefold increased odds of developing AD compared with noncarriers, and those with two e4 alleles are at approximately 8- to 12-fold increased odds.
- The strength of the association may be modified by several factors, including gender, race, and vascular risk factors.
- Many more candidate susceptibility genes have been identified through genome-wide association studies and other techniques. The average allelic summary odds ratios for these candidates are modest, ranging from approximately 1.1 to 1.5 in most cases.
13
Q
Describe AD clinical features
A
- Memory impairment is the most common initial symptom of AD dementia.
- In patients with the typical form of the illness, deficits in other cognitive domains may appear with or after the development of memory impairment.
- Executive dysfunction and visuospatial impairment are often present relatively early, while deficits in language and behavioural symptoms often manifest later in the disease course.
- These deficits develop and progress insidiously. Less commonly, language deficits, visuospatial abnormalities, or even executive functions may be impaired as the most prominent initial symptom.
14
Q
List how diagnosis is made and some diagnostic tools
A
- Currently, an autopsy or brain biopsy is the only way to make a definitive diagnosis of AD.
- In clinical practice, the diagnosis is usually made on the basis of the history and findings on Mental Status Examination.
- Computerised tomography (CT) scans, magnetic resonance imaging (MRI), single photon emission computerised tomography (SPECT) and positron emission tomography (PET) to visualise the living brain.
- CT/MRI Brain are particularly important for ruling out potentially treatable causes of progressive cognitive decline, such as chronic subdural hematoma or normal-pressure hydrocephalus.
- Hippocampal atrophy can easily be seen on an MRI scan and is currently used to aid diagnosis of AD.
- Lumbar puncture: CSF levels of tau and phosphorylated tau are often elevated in AD, whereas amyloid levels are usually low. At present, however, routine measurement of CSF tau and amyloid is not recommended except in research settings.
PET/SPECT Scan
- PET-FDG (Positron emission tomography- 18F Fluorodeoxyglucose) scans are now available through the MBS for more accurate earlier diagnosis.
- PET scans works by measuring the concentration of glucose in the brain to reveal how different parts of the brain are using energy.
- Single photon emission computed tomography (SPECT) image brain perfusion
PET scanning
- Glucose metabolism in the brain is altered in dementia and these changes can be visualised using FDG-PET scan.
- Recent research also suggests that FDG-PET can detect early brain changes before the emergence of dementia symptoms and predict progression to dementia.
15
Q
Briefly describe treatment
A
- The majority of patients with newly diagnosed Alzheimer’s disease should be offered a trial of cholinesterase inhibitor for symptomatic treatment of cognition and global functioning by improving communication between neurons.
- A number of drugs are currently available in Australia for use by people with AD. These drugs fall into two categories, cholinesterase inhibitors and a partial N - methyl-D-aspartate (NMDA) antagonist (Memantine).
- Psychotropic medications are often used to treat secondary symptoms of AD, such as depression, anxiety, agitation, and sleep disorders.
- They are considered symptomatic therapies and are not believed to be neuroprotective or to alter underlying disease course.
