Lecture 15; November 5, 2013

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Aging & dementia

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Aging
A gradual decline in cognitive abilities is
typical of the aging process, and not
necessarily a concern in and of itself.
However, a decline in mental functioning that
is more rapid than expected, or begins early
in life is cause for concern.
An age-related cognitive decline that reaches
a pathological level is called dementia.
There are many varieties of dementia, each of
which have different biological causes,
symptoms, and treatment options.

In this class we will discuss two disorders in

this category: Alzheimers disease and
Parkinsons disease.
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Author Terry Pratchett was diagnosed

with early-onset Alzheimers, and is
among a minority of public figures who
speaks publicly about their condition.

Alzheimers disease
Alzheimers disease was first characterized at the
beginning of the 20th century by neuropathologist Alois
Alzheimer and his friend Emil Kraepelin (who you
may recall from the schizophrenia lecture).
Alzheimer examined the brain of Auguste Deter, a
woman who showed symptoms of early-onset
dementia, and noted that the space between neurons
was littered with scraps of protein.
Moreover, he noted that the brain showed marked
signs of deterioration including widespread reductions
in gray matter.
Alzheimer published a case study on this patient, and
thanks to the endorsement of his findings by Kraeplin,
the disease he characterized came to be known as
Alzheimers disease (AD).
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Alois Alzheimer (1864-1915)

Symptoms of AD
The primary symptoms of AD, particularly
during the early stages of its development,
are problems with memory.
These include the loss of previous memories
(retrograde amnesia) as well as deficits in
storing new memories (anterograde
amnesia).

People with AD also have deficits in

executive function the ability to execute
complicated tasks with multiple steps.
This is partly due to problems with shortterm memory and frontal lobe function.

Other symptoms include:

Agnosia: failure to recognize objects.

Apraxia: impaired motor function.
Aphasia: impaired language function.

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Cooking is an everyday task that requires a

surprising amount of thought, planning, and
ability to sequence and time events.
Problems in the kitchen can be an early sign
of the deficits in executive function
characteristic of AD.

Course and prevalence of AD

Cognitive deterioration in AD is slow during the early and later stages
of the disease, but quite rapid during the middle stage.
The average survival time from the time of diagnosis is 8 years.

Symptoms usually appear as mild absentmindedness at first. Written

and spoken language may become simpler and more concrete.
As the disease progresses, symptoms become more severe.
Language skills decline, leading to problems communicating.
Noticeable deficits in long-term memory begin to appear.
Affect and emotion begin to be affected. Individuals may become
irritable, aggressive, or prone to emotional outbursts.
Individuals may become confused and wander away.

Anosogonsia (a not, nosos disease, gnosis knowing (G.)) is a

lack of awareness that one has a disease, and this is often seen in
people with mid-stage AD.
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Course and prevalence of AD

During the final stage of AD, the individual has
become completely dependent on caregivers,
and is quite often institutionalized in a nursing
home.
Extreme apathy and exhaustion are common
at this stage, and muscle mass may
deteriorate substantially.
Language skills are nearly non-existent, but
some emotional signals and words are still
understood.

AD usually appears during the 60s and 70s,

though early-onset AD can appear as early as
the 40s.
Early-onset AD is also called pre-senile
dementia.

AD accounts for approximately 50% of the

cases of dementia, and aects more than 5
million Americans.
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Book recommendation

In Search of Memory Eric R. Kandel

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Now, a few words on memory

Memory has not been a focus of this
course, but since AD is a
neurodegenerative disease that primarily
aects memory, it is worth a look.
Long-term memory can be divided into
three stages:
Encoding: the process of converting
sensory information stored in working
memory into a more permanent form with
associational links to the individuals other
memories.
Storage: the long-term storage of
memories.
Retrieval: the process re-accessing
stored memories and temporarily
returning them to working memory. This
is somewhat analogous to opening files
on your computer.
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Memory at the synapse

Most synapses in higher level brain regions are
dynamic they are capable of re-arranging
themselves, and increasing or decreasing the
eciency with which they transmit information.
This is called synaptic plasticity.
Synapses that are repeatedly stimulated tend to
become stronger. The formal name for this
process is long-term potentiation (LTP). It
involves:

Stimulation of NMDA type glutamate receptors.

Changes in gene expression and protein synthesis
at the synapse.
Insertion of more AMPA type glutamate receptors
into the post-synaptic membrane. This makes the
synapse more sensitive to glutamate in the future.

The opposite of this process is called long-term

depression (LTD), which occurs after persistent
weak stimulation of the synapse.
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Memory and neural networks

Through LTP and LTD, synapses maintain a
record of their history of activation.
Synapses that are frequently stimulated become
stronger and easier to stimulate in the future.
This principle can be summarized by the aphorism
Neurons that fire together wire together.

In theory, one could trace the unique

combination of neurons and synapses activated
by each unique experience, thought, or emotion.
Since there are billions of neurons and trillions of
synapses, doing this is not actually possible yet.

Following this trace would reveal a unique

network of neurons, and this may be how
memories are physically stored in the brain.
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A helpful(?) analogy

Imagine the campus quad covered in fresh snow.

The first people to walk from one place to another must
work to blaze a trail through the snow.

As more and more people cross the quad, they tend to gravitate toward following the path laid by
others. In the end, the path becomes worn in, and easier to travel.
This ultimately leaves a unique trace through the snow, reflecting (hopefully) the path of least
resistance.

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A helpful(?) analogy

Now imagine if there was some kind of obstacle the

suddenly blocked o the path.

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People would have to find their way around the obstacle,

invariably taking less ecient routes to their destination.
They may arrive later than expected, or get lost, or simply
give up and go home

Applying the analogy to the brain

After years of learning, the adult brain has developed very

ecient neural networks that are well suited to its purposes.

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Applying the analogy to the brain

If a crucial neuron dies, that doesnt mean the entire circuit is

lost, but it does mean that it will work less eciently.

In practice, this could mean that more kinds of stimuli are needed to activate the
same memory.
For example, this could be the dierence between recognizing someone from their
face and only recognizing them after seeing their face and hearing them talk.

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Alzheimers disease in the brain

Gross anatomical examination of post-mortem AD brains shows shrunken

cortical gyri, reduced gray matter, and massively enlarged ventricles.
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Alzheimers disease in the brain

Not surprisingly, the cause of brain shrinkage
is neural death.
For this reason, AD is referred to as a
neurodegenerative disease.

A common finding in post-mortem analysis of

AD brains is the presence of amyloid-
plaques.
These are clusters of misfolded, defective
proteins that accumulate in and around
neurons.
Amyloid- plaques are neurotoxic. As they
accumulate, they choke off adjacent neurons,
leading to cell death.

Amyloid- plaques in AD brain tissue

Another common finding is neurofibrillary

tangles.

Neurofibrillary tangles are clumps of defective

neurofibrils proteins that normally make up the
cytoskeletal structure of neurons.
This defect in neurofibril formation is due to an
excess of hyperphosphorylated Tau proteins.

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High-magnification image of neurofibrillary tangle in

AD brain.

Alzheimers disease in the brain

Until recently, it was impossible to definitively diagnose AD until post-mortem examination of the
brain.
Positron-emission tomography (PET) imaging can now be used to quantify amyloid- in the
living brains, through the use of a special radioactive dye to which it binds specifically.

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Alzheimers disease in the brain

Neural degeneration in AD follows a predictable pattern, beginning first in the frontal

and temporal lobes, then spreading to other regions.
This progression explains why the earliest symptoms of AD are cognitive
impairments, memory loss, and reduced impulse control.
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Illustration from J.P.J. Pinel, Biopsychology. Allyn & Bacon, 2011

Genetics
Many of the genes that are most strongly
associated with AD are directly involved in
producing or processing the amyloid protein.
The majority of AD cases are not inherited.
Mutations in the gene coding for the amyloid
precursor protein (APP) increase the risk for
AD.
APP is post-translationally processed into
amyloid-. The function of this protein is
unknown.

Presenilin 1 and 2 code for genes that are

involved in processing APP.
Improper processing of APP leads to amyloid-
plaques.
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Treatment of AD
There is presently no drug that can deal with the
underlying pathology of AD (plaques and
tangles). Every treatment currently in use can,
at best, temporarily mitigate some deficits.
Acetylcholinesterase inhibitors:
Increases levels of acetylcholine by inhibiting the
enzyme that normally breaks it down. E.g.
Aricept.

NMDA antagonists:

Dying neurons haphazardly dump excess

amounts of glutamate into the brain. These levels
of glutamate are toxic to neurons, and can lead to
a chain reaction of cell death.
By blocking the NMDA glutamate receptor, it is
possible to protect neurons from this
phenomenon. E.g. Namenda.

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Treatment of AD

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Illustration from Barlow & Durand, Abnormal Psychology: An Integrated Approach. Cengage, 2011

Parkinsons Disease (PD)

PD is a neurodegenerative disease that
aects roughly 1 in every 1000 people
worldwide.
PD is characterized by problems with the
motor system including:
Tremor at rest: involuntary rhythmic
movements of the limbs, but only while they
are not otherwise being used.
Rigidity: increased muscle tone, jerky
movements (cogwheel rigidity).
Bradykinesia: slowed movements (brady
slow, kinesia movement (G.)). Can also
progress to a complete lack of movement
called akinesia.
Postural instability: impaired balance,
increased risk of falling over.
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Parkinsonism
Individuals with PD have a characteristic way
of walking called the Parkinsonian gait.
People with PD tend to walk with flat feet (as
opposed to the heal-toe pattern used by
healthy people). As the disease advances
they begin to take smaller shuing steps.
As they walk, individuals with PD tend to
stoop forward. This is called festination (to
hurry (L.)).
All of the symptoms of PD are collectively
known as Parkinsonism. PD is the most
common cause of Parkinsonism, but it is not
the only one.
Antipsychotic drugs that reduce dopamine
signaling can also cause Parkinsonism as part
of the extrapyramidal symptoms.
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Neurobiology of PD
PD is associated with the death of neurons in
a region of the midbrain called the
substantia nigra (black substance (L.))
Neurons in the substantia nigra produce
dopamine. Axons from this area project to
the caudate nucleus, and other parts of the
striatum/basal ganglia.
This system ties into the brains
extrapyramidal motor system, and helps
regulate movement.

The nigrostriatal dopamine pathway

Most of the time, it is not known why these

neurons decide to die.

There are genetic causes, but the associated

mutations are rare.
The main environmental risk factor for PD is
heavy exposure to pesticides, but this only
explains a subset of cases.

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Illustration from Kolb & Wishaw, An Introduction to Brain and Behavior. Sinauer, 2014

Treatment of PD

There is no cure for PD that can reverse neuron death in the

substantia nigra. Every treatment that is currently available is
aimed at compensating for this death.

Since Parkinsonism is caused by reduced dopamine in the

basal ganglia/striatum, one solution is to add more dopamine
to the body.

This can be accomplished with dopamine agonists such as

bromocriptine, or with the chemical precursor to dopamine:
L-DOPA.

L-DOPA is not a drug, per se, rather it is a compound that the

brain converts into dopamine. When given in large quantities,
the brain produces correspondingly large quantities of
dopamine.

Dopamine itself cannot be given as a drug, because it cannot cross

the blood-brain barrier.

Dopaminergic therapies are eective in the short-term, but have

a number of side eects including dyskinesias, hallucinations,
and occasionally increases in impulsive behavior.

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