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
