alzheimers and dementia Flashcards
types of dementia (umbrella term)
alzheimers (62%)
vascular (17%)
mixed (105)
lewy body (4%)
fronto-temporal (2%)
parkinsons (2%)
overview of dementia (all types)
- major cognitive dysfunctioning
- global impairement of higher cortical functions
- no gross clouding of consciousness
- usually progressive and irreversible
general symptoms of dementia
impairment in:
- memory
- capacity to solve problems of day-to-day living
- performance of learned perceptuo-motor skills
- correct use of social skills
- control of emotional reactions
expression of dementia is highly dependent on…
age
approx 42% of proportion= 95 years old
alzheimers disease overview
- most common type
- named after alois alzheimer (reported in PM pathology in 1906)
- most cases develop after the age of 65 but there are also early-onset forms (mix of idiopathic and genetic)
- progressive degenerative
- diagnosis to death (average 8 years, 3-18)
progression of AD- early stage
usually starts in the temporal lobe and the hippocampal formation
1. memory loss of recently aquired facts (hippocampus)
2. subtle problems with executive functions (pre-frontal cortex)
3. apathy- loss of motivational drive (parahippocampal regions, entorhinal cortex)
progression of AD- mid stage
progresses through frontal lobe and extends through temporal lobe- inferior frontal (progressive deterioration)
1. LTM becomes impaired (hippocampus, cortical regions)
2. loss of independence (loss of place/GRID cells)
3. speech difficulties (disruption of broca and wernicke)
progression of AD- late stage
extensive atrophy throughout the cortex
1. complete loss of independence (cortex)
2. massively reduced language skills (broca and wernicke)
3. impaired swallowing which can lead to aspiration pneumonia- brainstem (most common cause of death in AD patients)
gross neuropathology of AD
- shrinkage of cerebral cortex
- enlarged ventricles
- hippocampal atrophy
- lose a quater of brain material
- sunken gyri
atypical AD
- posterior cortical atrophy- degeneration starts in the occipital and posterior regions of the parietal lobes
- frontal variant- degeneration starts in frontal lobes
- logopenic aphasia- degeneration in the left temporal cortex and inferior parietal lobule
what are the 4 potential mechanisms for AD?
- amyloid hypothesis
- tau hypothesis
- inflammatory hypothesis
- cholinergic hypothesis
what is the amyloid hypothesis?
- accumulation of amyloid-β in the brain is the primary cause of AD
- this acts as a trigger for intraneural (tau based) tangle formation and leads to
neuronal death and dementia - primary cause of degenartion
what is the tau hypothesis?
- hyperphosphorylation of tau protein results in tangle development and loss of cellular function in the brain
- tau protein aggregation can cause neurodegeneration
wholly independent of amyloid –β deposition - tau is microtubule associated protein
what is the inflammatory hypothesis?
- both pro-inflammatory and immunosuppressant responses may play a role in the development of neurodegeneration
what is the cholinergic hypothesis?
- deficiency of the neurotransmitter acetylcholine in the brain of alzheimer’s
patients - where theory started
neuropathological hallmarks of AD- plaques
- plaques are protein fibres
- amyloid beta peptides, when produced becomes soluble and forms plaques in intracellular space
- degenerative nerve endings of plaques surroudnded by active glial/microglial cells
APP processings
amyloid precursor protein (APP) is a highly conserved protein and has functions in synaptic formation/repair and anterograde axonal transport
- APP is produced by an alpha and gamma secretase enzyme to produced amyloid protein (soluble)
in AD, processing is changed and this gives rise to amyloid-beta (insoluble)
amyloid hypothesis and APP
- amyloid beta produced by cleavage of amyloid Precursor Protein (APP) by β- and γ- secretase.
- APP cleavage produces an number of isoforms - Aβ40 is the most common while Aβ42 is the most toxic form
- deposition of plaques causes activation of an inflammatory response (e.g. microglial
activation, release of cytokines etc) leading to neurodegeneration
evidence for amyloid hypothesis- early onset familial AD
- occurs in people aged 30-60
- linked to mutations on chromosomes 1, 14 and 21 expressing proteins presenilin 2, presenilin 1 and amyloid precursor protein (APP),
respectively. - presenilins are components of gamma-sectretase linked to the (mis)processing
of APP to produce amyloid plaques
evidence for amyloid hypothesis- late onset sporadic AD
APOE4, (major serum lipoprotein involved in cholesterol metabolism) which is the major AD genetic risk factor for sporadic AD, leads to excess amyloid buildup in
the brain before AD symptoms arise
evidence for amyloid hypothesis- transgenic mouse models
mouse mutants for APP and presenilins in various combinations show AD-like symptoms – though not necessarily with amyloid buildup!
neuropathological hallmarks of AD- tangles
neurofibrillary tangles (flame shaped) containing the tau protein
role of tau: microtubule-associated protein
tau stabilises microtubules which are structural components of the cytoskeleton
- transport protein
- expressed in axons
tau: in disease
- tau is hyperphosphorylated
- dissociates from microtubules (disassemble)
- this leads to misfolding and
aggregation into neurofibrillary
tangles
what is the result of misfoldign and aggregation of microtubules?
straight filaments, paired helical filaments and twisted ribbons
- this means axon is lost therefore neurons are lost (no synaptic transmission)
what do neurofibrillary tangles form?
beta-sheets (very difficult to break down)
leads to progressive loss
evidence for inflammation: PGE2
link between amyloid and inflammatory response (microglia)
- PGE2 is pro-inflammatory, acting via EP2 receptor (activate microglia)
- in young cells, low levels of EP2
- EP2 is upregulated in aged cells which leads to reduced cell movement (chemotaxis)
- this leads to increased production of COX-2 which generates more PGE2 and further activation of EP2
what is COX-2?
toxic cytokines
what is PGE2?
PGE2 is a key mediator of inflammation in the brain
it is produced by microglial cells (the brain’s immune cells) in response to amyloid-beta plaques
what is EP2?
EP2 contributes to the inflammatory response by promoting the production of pro-inflammatory cytokines (PGE2)
interaction of amyloid and inflammatory response
amyloid built up as you get more AB42, trying ot prevent inflammatory system from dealing with it
TF build up in plaques
evidence for inflammation: IL-33
- IL-33 is a cytokine which enhances innate immune response
- reduced amyloid plaque formation
- promotes phagocytic activity of microglia
- reverses deficits in LTP and memory performance
difference between PGE2 and IL-33
IL-33 prevents production of plaques whereas PGE2 enhances production
cholinergic hypothesis suggestion
suggests that loss of cholinergic projections from the basal forebrain complex to the neocortex and hippocampus is the primary driver for the
progression of alzheimer’s disease
(loss of excitatory drives)
transgenic animals and the cholinergic hypothesis
transgenic animals carrying mutations seen in early onset alzheimer’s disease do
not show loss of cholinergic neurons
BUT no loss of neurons does not necessarily equate to normal function
evidence for cholinergic hypothesis
anatomical analysis of post-mortem brains with advanced alzheimer’s disease shows substantial
loss of cholinergic projection neurons from the basal forebrain
HE studies of brains from ealier phases
of the disease do not show significant loss of
cholinergic neurons and selective lesions of cholinergic pathways do not correlate well with loss of cognitive function
treaments for AD
acetylcholine esterase (ACE) inhibitors are one of the few treatments that have been shown to slow disease progression (supports cholinergic hypothesis)
