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Summary Chapter 6
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Summary Chapter 6 + lecturenotes
AD is one of the most common causes for dementa in older people and is cause of death number 4.
AD prevalence increases with age: between 65-74 years old, 3% has it, but among those of 85 and
older, almost 50% has it. Risk factors include age, presence of Apolipoprotein E4, severe head
trauma, multple small head traumas, CV diseases, family history with AD and Down’s syndrome,
presence of extrapyramidal signs, hypothyroidism, and sex (more women than men). A higher
educaton may serve as a protectve factor.
All 4 cortcal lobes are characterized by atrophy in AD. Atrophy does not mean primarily cell death,
but a shrinkage of neurons. In AD the hippocampus is severely afected by the atrophy, more than in
normal aging. Also the basal forebrain (septum and NBM) is severely afected, together with
important structures for neurotransmiter producton: LC, DRN and PPTN. The afected areas are not
only the cause of diminished functoning, they also afect several other brain regions to where they
project (for example septum to hippocampus and basal forebrain to hypothalamus).
Reduced metabolism in AD is refected in a deterioraton of mitochondrial enzyme actvity.
Mitochondria play a role in the producton of ATP (adenosine triphosphate), which is required for
energy-demanding actons. Reduced metabolism in frontal cortex, middle frontal gyrus and
temporoparietal cortex. Reduced metabolism may precede neuropathology.
AD is characterized by extracellular neuritc amyloid plaques and intraneuronal neurofbrillary
tangles. They ofen occur in the cerebral cortex, partcularly parietal and temporal lobes. In inital
stages of AD they are found in the entorhinal cortex, and later they spread to the hippocampus and
all other cortcal areas except for primary sensorimotor areas. However, not all AD patentshave
these plaques and tangles. In fnal stages, plaques are also found in subcortcal areas: striatum,
thalamus, hypothalamus. Hypothesis: Amyloid plaques become neuritc plaques by means of an
infammatory process. These neuritc plaques consttute neurofbrillary tangles which are neurotoxic
and lead to cell death. However, it is controversial; sometmes there are tangles without plaques.
Brain areas that are known for neuronal loss in AD are: frontal cortex, middle temporal gyrus,
entorhinal cortex, parahippocampal cortex, hippocampus and LC.
Many neurotransmiters are afected in AD, but the most severely afected neurotransmiter system
is the cholinergic one. During normal aging, there is some cholinergic loss in the temporal lobe. In
early stages of AD, this might not be very diferent and hard to distnguish. However, when the
disease progresses, the number of cholinergic neurons will decrease. There is a loss of these neurons
in the cerebral cortex, entorhinal cortex, hippocampus, and amygdala. A cholinergic defcit could
initate the producton of amyloid and formaton of tangles, but not very hard evidence for this. A
decline in memory capacites may be linked to a loss of cholinergic neurons, but it can never be
completely impaired by this neuron loss. The impairment is accompanied by plaques and tangles in
the brain areas mentoned above. Loss of cholinergic systems is observed in the septohippocampal
pathway and the pathway from the NBM to the cerebral cortex.
There is a close cooperaton between diferent neurotransmiter systems, such as the cholinergic and
serotonergic systems. An imbalance between the two systems in the cerebral cortex can result in
cognitve decline and behavioral disturbances (psychosis, hyperactvity, aggressive behavior and
depression). Defcits in the cholinergic system may increase the risk of problems with other
neurotransmiter systems as well. In AD we see a depleton of both systems in frontal and temporal
lobe. Low cholinergic actvity is associated with aggressive behavior and cognitve impairment.
Serotonergic defcit in frontal cortex is associated with over-actvity, and the same defcit in the
temporal cortex is associated with psychosis.
Also a close cooperaton between noradrenergic and serotonergic system. In normal situatons,
serotonergic axons have inhibitory efect on the regeneratve process of noradrenergic neurons. The
, regeneraton of serotonergic axons was hampered in the absence of noradrenergic neurons.
Furthermore there is a reciprocal connecton between the DRN/serotonergic system and the LC/
noradrenergic system.
In AD also the dopaminergic system is afected; connectons between the substanta nigra and the
PFC and the hippocampus are interrupted. Also the dopaminergic receptors in the hippocampus
appear to be afected. Disrupton in these dopaminergic projectons can lead to a variety of
behavioral and personality abnormalites, due to an imbalance between the dopaminergic and
cholinergic neurotransmiter systems. In case of a cholinergic defcit, the dopaminergic system
transmission will be increased hyperactvity. In case of a dopamine defcit, apathy may result.
Both neurotransmiter systems are involved in the frontostriatal circuit, so neuropathology there
may result in these clinical manifestatons. Symptoms such as slowness in thinking + motor actvity
can be seen as a result of damage in all functonal circuits in early AD. The symptoms are also seen in
depression (subcortcal disorder; shifing levels of neurotransmiters). However in depression more
recogniton > actve recall (forgefulness) and in AD amnesia.
The majority of AD patents have sufered vascular pathology in the brain. Vascular problems in AD
may be expressed as cerebral amyloid (AD) angiopathy (vascular pathology) (CAA). CAA deposits
protein in blood vessel walls of brain, causing ischemia and hemorrhage. Cerebral ischemia initates
the degeneraton and death of neurons. Cognitve decline in AD patents with CAA is worse than in
AD patents without CAA. The presence of cerebrovascular diseases aggravates the course of AD. Also
the reverse might be true; AD increases the risk for a cerebrovascular disease. Vascular pathology
may further contribute to white mater lesions.
Areas that play an essental role in the ARAS are all afected in AD! Plaques and tangles are
prominent in subcortcal areas and especially in the forebrain; severely impinging on the NBM’s
cholinergic projectons severe disrupton of global brain arousal.
Accumulaton of tangles and plaques, together with atrophy can cause damage to various circuits:
frontostriatal, frontohippocampal, frontocerebellar, hippoparietal and nigrostriatal. The PFC, ACC
and hippocampus show the most severe neuropathology, even in early stages of the disease. The last
mentoned circuit interrupts the connectons and dopaminergic projectons between the SN and PFC
and hippocampus. Also the frontostriatal is dependent on dopaminergic inputs, and thus is also
afected. The medial temporal lobe (hippocampus and EC and parahippocampal cortex) show marked
degeneraton as well, interruptng the frontohippocampal circuit. Damage to hippocampus hinders
communicaton between hippocampus and PFC mediated by the EC. Also the hippoparietal circuit is
disrupted because of damage to the hippocampus. A decrease in communicaton between these
regions emerges also from degeneraton of dendrites, and decrease in number of synapses. For
example; in face memorizing task, AD patents did not show a functonal relatonship between right
PFC and right hippocampus; normally aging older people did.
Symptomatology
Cortcal dementa types are characterized by:
- Behavioral disturbances: apathy, aberrant motor behavior, sleep disturbance
- Behavioral/personality disturbances: depression, anxiety, irritability/lability and
agitaton/aggression.
Some symptoms can be seen as signs of hyperactvity, which may arise due to frontal cortex
dysfunctoning. However, depression and apathy may be of subcortcal origin; deterioraton in
several neurotransmiter systems is seen in AD, but those are also afected in depression.
The performance of most cognitve tasks relies on intact cortcal and subcortcal circuitry. Many
cognitve functons are therefore afected in AD. Partcularly category fuency appears to be afected
in AD. The task appeals to both EF (cognitve fexibility and productvity) and intact semantc and
long-term memory all are impaired in AD. Furthermore, difficultes with planning observed in AD
may express itself in impairment in (I)ADL. Monitoring one’s own behavior plays a major role in
efficient performance; requires a high level of disease insight and self-efficacy, things that lack in
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