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

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

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 %

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.

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

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;68:267-289. Alzheimer’s Association. Available at: www.alz.org/hc/overview/stats.htm. Accessed 5/9/2001.

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

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

Neurotransmitter in AD Acetylcholine Glutamate

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

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

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.

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;12:421-430.

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

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.

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

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)

Atypical Early Features of AD

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

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

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

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