Dementia is a loss of brain function that occurs with certain diseases.

It affects memory, thinking, language, judgment, and behavior. (taken from Latin, originally meaning "madness", from de"without" + ment, the root of mens "mind")

Memory loss itself doesn t mean that the person has dementia.

Irreversible types, like:

Alzheimer s disease (AD). Vascular dementia. Lewy body dementia (LBD Dementia pugilistica.

Reversible types, like: Can be result from:

Metabolic problems and endocrine abnormalities. Nutritional deficiencies Infections. Poisoning.

Emil Kraepelin

Dr. Alois Alzheimer

Is a slowly progressive disease of the brain that affect cognitive, function and behavior.

Age. Genetics. Smoking and alcohol use. Cholesterol. Atherosclerosis. Plasma homocysteine. Diabetes. Mild cognitive impairment. Head injury

Most of early onset is related to alterations on chromosomes 1, 14, 21. Genes located on chromosome14 produce presenilin 1 and on chromosome 1 produce presenilin2. Both presenilin 1 and 2 encode for membrane proteins that may be involved in amyloid precursor protein (APP) processing. Mutations in presenilin genes, that result in reduced activity of secretase, important in -amyloid peptide formation ( AP).

Late-onset of AD is thought to be linked to the apolipoprotein E (Apo E) genotype. Genes responsible for produce Apo E located on chromosome 19. There are three subtypes of Apo E (E2, E3, E4) Inheritance of E4 is believed to account for much of genetic risk.

Neutritic plaques. Neurofibrilary tangles (NFTs). Degeneration of neurons and synapses. Cortical atrophy.

 Amyloid peptide aggregation and deposition leading the formation of plaques. Hyperphosphorylation of tau protein leading to NFT development. Inflammatory processes. Dysfuction of the neurovasculature. Oxidative stress. Mitochondrial dysfuction

to

Amyloid cascade hypothesis.

Amyloid cascade hypothesis.

Amyloid cascade hypothesis.

Neurofibrillary tangles

Amyloid cascade hypothesis.

Amyloid cascade hypothesis.

The cholinergic hypothesis.

Multiple neuronal pathways are destroyed in AD. Widespread cell destruction results in a variety of neurotransmitter deficits. Cholinergic abnormalities are most prominent. In late AD number of cholinergic neurons are reduced, and there loss in N receptors in hippocampus and cortex.

Other neurotransmitter abnormalities Serotonergic neurons of the raphi nuclei and noradrenergic cells of locus cerulus are lost. Abnormalities appear in glutamate pathways of the cortex and limbic structures, where loss of neurons focus on excitatoxicity models

The areas of the brain affected in Alzheimer s disease

Cognitive :
Memory loss (poor recall and losing items). Aphasia. Apraxia. Agnosia. Disorientation. Impaired executive function.

Noncognitive:
Depression, psychotic symptoms. Behavioral disturbances.

Functional:
Inability to care for self.

Earliest stage of AD

plaques and tangles begin to form in brain areas involved in: Learning and memory Thinking and planning

Mild to Moderate AD

Plaques and tangles also spread to areas involved in: Speaking and understanding speech Your sense of where your body is in relation to objects around you

Severe AD

The brain shrinks dramatically due to widespread cell death. Individuals lose their ability to communicate, to recognize family and loved ones and to care for themselves.

8 years average. Range 2-20 years

Medical history. analysis of cerebrospinal fluid for beta or tau proteins Neuropsychological testing. Brain-imaging scan amyloid

Neuropsychological testing.
Mini-mental state examination (MMSE). Orientation to time Orientation to place Registration Attention & Calculation Recall Language

5 points 5 points 3 points 5 points 3 points 9 points

Mild : MMSE score (26-18). Moderate: MMSE score (17-10). Severe : MMSE score (9-0)

Brain-imaging scan

Goals of treatment:
Symptomatically treat cognitive difficulties and preserve patient function as long as possible Treating the psychiatric and behavioral sequelae that occur as a result of disease.

Treatment can be divided into: Non-pharmacologic Pharmacologic.

Non-pharmacologic
Symptoms such as sleep disturbances, wandering, urinary incontinence, agitation, and aggression. treated using behavioral interventions rather than medications whenever s possible. Educated the patient and care giver on the course of illness, prognosis, available treatments, and quality of life.

Non-pharmacologic
Caregiver must be prepared to face the changes in life that will occur. some modifications to the home environment may be necessary but it should remain familiar

Cholinesterase inhibitors

Cholinesterase inhibitors
- Tacrine was the first drug. - Newer drugs: - Donepezil. - Rivastigmine. - Galantamine. - Show similar adverse effects. -Mild to moderate GI symptoms.(nausea,vomiting). -Urinary incontinence, dizziness, headache, syncope, bradycardia, sweating.(dose-related side effects)

Antiglutamatergic
-Memantine. -Only NMDA-antagonist currently available. -Has 100% bioavailability. -Protein binding is low. -Not metabolized by the liver. -Excreted unchanged in the urine. -Side effects: - Constipation. - Confusion. - Dizziness. - Headache. - Coughing. - Hypertension.

Drug name

Brand name

Approved For

FDA Approved

1. donepezil 2. galantamine 3. memantine 4. rivastigmine 5. tacrine

Aricept Razadyne Namenda Exelon Cognex

All stages Mild to moderate Moderate to severe Mild to moderate Mild to moderate

1996 2001 2003 2000 1993

Targets for future drugs:

Beta-amyloid Tau protein Inflammation Insulin resistance

Future drugs and clinical trails

Docosahexanenoic acid (DHA)

Clinical trail completed. In the study of normal age-related memory trouble, participants who took DHA had greater score improvement on a test of visual memory and learning. In the Alzheimer study, those who took DHA had no greater benefit overall than those who received the placebo. Participants without the APOe4 Alzheimer risk gene may have benefited more than those who have the risk gene.

Future drugs and clinical trails

solanezumab (LY2062430): Mechanism: Monoclonal (laboratory-produced) antibody to betaamyloid. May bind to beta-amyloid and remove it from the brain before it accumulates into plaques. ACC-001 Mechanism: A "vaccine" that stimulates the body to produce its own antibodies against beta-amyloid

Future drugs and clinical trails

PBT-2 (clioquinol) Mechanism: Acts in several ways to prevent aggregation of beta-amyloid into plaques.

Participants who received PBT2 performed better on several tests of thinking and judgment and had lower levels of beta-amyloid in their spinal fluid.

Physical exercise and diet Social connections and intellectual activity Others.

I now begin the journey that will lead me into the sunset of my life.

RONALD REAGAN

References: Pharmacotherapy, Dipiro. www.alz.org www.medicinenet.com www.wikipedia.com