1. Dementia Supischa Theerasasawat Eric Pfeiffer, M.D J. Wesson Ashford
And
Staff of National Institute on Aging

2. DEMENTIA: DEFINITION
A clinical syndrome, due to loss of brain cells, characterized by memory loss and other cognitive impairments, to the extent that the individual is showing impaired social or occupational functioning

4. Causes of Dementia Alzheimer’s disease – 65% Vascular Dementia – 10 %
Mixed AD and VaD – 10 %
Lewy Body Dementia – 5-10 %
Post-traumatic brain injury and post-encephalitic dementia – 5-10 %

7. Alzheimer’s Disease: What it is
A disease in which brain cells die prematurely and progressively, leaving the individual with impaired memory capacity, decision-making capacity, and eventually self-care capacity.

8. What it does: continued
It lasts anywhere from two to twenty-two years
It affects ten percent of all older people
At age 65 only one percent have the disease
At age75 this has gone up to ten percent
At age 85 this has gone up to 35 percent
At age 90 it is nearly fifty percent

9. Prevalence and Impact of AD
AD is the most common cause of dementia in people 65 years and older
Affects 10% of people over the age of 65 and 50% of people over the age of 85
Approximately 4 million dementia patients in the United States
Annual treatment costs = $100 billion
AD is the fourth leading cause of death in the United States
The overwhelming majority of patients live at home and are cared for by family and friends
Evans DA. Milbank Q. 1990;68: Alzheimer’s Association. Available at: Accessed 5/9/2001.

10. The Brain’s Vital Statistics
Adult weight: about 3 pounds
Adult size: a medium cauliflower
Number of neurons: 100,000,000, (100 billion)
Number of synapses (the gap between neurons): 100,000,000,000, (100 trillion)

11. Inside the Human Brain Other Crucial Parts
Hippocampus: where short-term memories are converted to long-term memories
Thalamus: receives sensory and limbic information and sends to cerebral cortex
Hypothalamus: monitors certain activities and controls body’s internal clock
Limbic system: controls emotions and instinctive behavior (includes the hippocampus and parts of the cortex)
Slide 12

12. Neurotransmitter in AD
Acetylcholine
Glutamate

13. Acetylcholine Pathways
Two major cholinergic projections within CNS
Ascending reticular activating system
Sleep-wake cycles
Cortical structures: neocortex, hippocampus and amygdala
Learning and memory function

14. Cholinergic deficit in AD
Progressive loss of cholinergic neurones
Progressive decrease in avaliable Ach
Impairment in ADL, behavior and cogniton

15. Glutamate pathways
Glutamate is the fast excitatory neurotransmitter in regions associated with cognition and memory.
Cortical and subcortical structures that contained glutaminergic receptors are structurally damage in AD.
Glutamate acts as an excitotoxin causing neuronal death when excessive levels are chronically released.

16. The Glutamate Hypothesis of Alzheimer’s Disease
Glutamatergic Neurotransmission
Normal glutamate stimulates 70% of excitatory synapses (physiological)
Abnormal glutamate stimulation can cause neuronal toxicity and may impair learning (pathological)
Rationale for NMDA Antagonists
Normalization of glutamatergic neurotransmission may maintain or improve cognition and prevent neurotoxicity
NMDA = N-methyl-D-aspartate
Source: Greenamyre JT. Prog Neuropsychopharmacol Biol Psychiatry. 1988;12:

18. N-Methyl-D-Aspartate Receptors
Normal resting membrane potentials, extracellular Mg2+ ions will block the pore of NMDA

19. Blockade of NMDA receptors can produce amnesia and hallucination.
Excessive activation of NMDA receptors can lead to massive Ca2+ influx and trigger irreversible process leading to cell death.

20. Pathways for excitotoxicity in AD
Energy deficiency
Decrease in membrane potential
Decrease glutamate uptake
Increase glutamate release
Glutamate levels
NMDA receptor activation
Increased Ca2+ influx
Excitotoxicity

22. Clinical AD Impaired of short-term memory, unable to use cues
Relative preservation of remote memory
Mild difficulty with word-finding
Visuospatial involvement
Reduced ability to plan, judge, and organize
Relatively preserved social behavior (apathy)

23. Atypical Early Features of AD

26. Plaques and Tangles: The Hallmarks of AD
AD and the Brain
Plaques and Tangles: The Hallmarks of AD
The brains of people with AD have an abundance of two abnormal structures:
beta-amyloid plaques, which are dense deposits of protein and cellular material that accumulate outside and around nerve cells
neurofibrillary tangles, which are twisted fibers that build up inside the nerve cell
An actual AD plaque
An actual AD tangle
Slide 16

27. AD and the Brain Beta-amyloid Plaques
Amyloid precursor protein (APP) is the precursor to amyloid plaque.
1. APP sticks through the neuron membrane.
2. Enzymes cut the APP into fragments of protein, including beta-amyloid.
3. Beta-amyloid fragments come together in clumps to form plaques. 1. 2.
In AD, many of these clumps form, disrupting the work of neurons. This affects the hippocampus and other areas of the cerebral cortex. 3.
Slide 17

28. Neurofibrillary Tangles
AD and the Brain
Neurofibrillary Tangles
Neurons have an internal support structure partly made up of microtubules. A protein called tau helps stabilize microtubules. In AD, tau changes, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles.
Slide 18

29. AD Research: the Search for Causes
Studies at the Cellular and Molecular Level
Oxidative damage from free radical molecules can injure neurons.
Homocysteine, an amino acid, is a risk factor for heart disease. A study shows that an elevated level of homocysteine is associated with increased risk of AD.
Scientists are also looking at inflammation in certain regions of the brain and strokes as risk factors for AD.
Slide 27