15. aging & dementia

12 01neurLecture 15; November 5, 2013Aging & 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.

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).

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 short-

term memory and frontal lobe function.

Other symptoms include: Agnosia: failure to recognize objects. Apraxia: impaired motor function. Aphasia: impaired language function.

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.


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.


Book recommendation

In Search of Memory Eric R. Kandel


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.


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.


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.


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.


A helpful(?) analogy Now imagine if there was some kind of obstacle the

suddenly blocked o the path.

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.


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.


Alzheimers disease in the brain

Gross anatomical examination of post-mortem AD brains shows shrunken cortical gyri, reduced gray matter, and massively enlarged ventricles.


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.

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.

Amyloid- plaques in AD brain tissue

High-magnification image of neurofibrillary tangle in AD 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.



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.

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.


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.


Treatment of AD

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.


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.


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.

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.

The nigrostriatal dopamine pathway

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.

15. aging & dementia

Documents

symptoms of early

parkinsons disease

nosos disease

disease progresses

primary symptoms of

earlyonset alzheimers

early stages

early sign