1 Dr.Wael Mansy, Ph.D. Department of Clinical Pharmacy College of Pharmacy / King Saud University

Cognition Cognition refers to all the processes by which the sensory input is transformed, reduced, elaborated, stored, recovered, and used. It involves the perception of sensory input and the ability to learn and manipulate new information, recognize familiar objects and recollect past experiences, solve problems, think abstractly, and make judgments. Dementia Dementia is a syndrome of deterioration in cognitive function severe enough to interfere with occupational or social performance. It is a common and disabling disorder in the elderly and is becoming a growing public health problem because of rapidly increasing numbers of elderly people in the developed countries of the world. 2

DEMENTIA Dementia or non-normative cognitive decline can be caused by any disorder that permanently damages large association areas of the cerebral hemispheres or subcortical areas subserving memory and learning. The essential feature of dementia is impairment of short- and long-term memory, which is associated with deficits in abstract thinking, impaired judgment and other higher cortical functions, or personality change. The disturbance should be sufficiently severe as to interfere significantly with work or social activities. 3

4 Common causes of dementia: 1.Alzheimer disease 2.vascular dementia 3.frontotemporal dementia 4.Creutzfeldt-Jakob disease 5. Wernicke-Korsakoff syndrome 6.Huntington chorea.

5 Alzheimers 1.Dementia of the Alzheimer type occurs in middle or late life and accounts for 60% to 80% of all cases of dementia. 2. The disorder affects more than 4.5 million Americans and may be the fourth leading cause of death in the USA. 3.In 2006, there were 26.6 million sufferers worldwide.

6 Alzheimers 4.The risk for development of Alzheimer disease increases with age, and it is estimated that almost 50% of individuals 85 years of age and older live with this illness, which affects almost twice as many women as men. 5. It is projected that, unless a cure or prevention is developed, there will be 14 million Americans with Alzheimer disease by the year 2050, (1 in 85 people globally ).

 Alzheimer's disease (AD), also known as Senile Dementia of the Alzheimer Type (SDAT) or simply Alzheimer’s is the most common form of dementia.  This incurable, degenerative, terminal disease was first described by a German psychiatrist and neuropathologist Alois Alzheimer in  Alzheimer's disease (AD) is a slowly progressive disease of the brain that is characterized by impairment of memory and eventually by disturbances in reasoning, planning, language, and perception.  Many scientists believe that Alzheimer's disease results from an increase in the production or accumulation of a specific protein (beta-amyloid protein) in the brain that leads to nerve cell death. 7

8

 The major microscopic features are the presence of neuritic (senile) plaques, neurofibrillary tangles, and amyloid angiopathy.  The neuritic plaques are patches or flat areas composed of clusters of degenerating nerve terminals arranged around a central amyloid core.  The dominant component of the amyloid core is amyloid beta (Aβ), a peptide derived from the proteolysis of a larger membranes panning amyloid precursor protein (APP). 9 Stages of Alzheimer's disease

 There is increasing evidence that Aβ is the critical molecule in the pathogenesis of Alzheimer disease.  Full-length APP has an intracellular region, a membrane-spanning sequence, and an extracellular region.  The normal degradation of APP involves cleavage in the middle of the Aβ domain by a proteolytic α-secretase enzyme, with the release of two soluble nonamyloidogenic pieces. 10

 However, APP can also be cleaved at either end of the Aβ domain, leading to the release of intact and highly amyloidogenic Aβ that accumulates in senile plaques as amyloid fibrils.  There are at least three distinct forms of secretase enzymes (α-, β-, γ- secretase). Evidence suggests that cleavage by the β- and γ- secretase leads to the generation of Aβ. 11

12

 The neurofibrillary tangles, found in the cytoplasm of abnormal neurons, consist of fibrous proteins that are wound around each other in a helical fashion. These tangles are resistant to chemical or enzymatic breakdown, and they persist in brain tissue long after the neuron in which they arose has died and disappeared.  A major component of the paired helical filaments is an abnormally hyperphosphorylated form of the protein tau, an axonal microtubule-associated protein that enhances microtubule assembly. 13

14  Some plaques and tangles can be found in the brains of older persons who do not show cognitive impairment. The number and distribution of the plaques and tangles appear to contribute to the intellectual deterioration that occurs with Alzheimer disease.  In persons with Alzheimer disease, the plaques and tangles and associated neuronal loss and glial reaction are evident earliest in the entorhinal cortex, then spread through the hippocampal formation and isocortex, and then extend to the neocortex.

15

16  It is likely that Alzheimer disease is caused by several factors that interact differently in different persons.  Progress on the genetics of inherited early-onset Alzheimer disease shows mutations in at least three genes, which can cause Alzheimer disease in certain families: 1.the APP gene on chromosome 21: a gene which is associated with an autosomal dominant form of early-onset Alzheimer disease, and can be tested clinically. 2. presenilin-1 (PS1), a gene on chromosome 14; 3. and presenilin-2 (PS2), a gene on chromosome

17  Persons with Down syndrome develop the pathologic changes of Alzheimer disease and a comparable decline in cognitive functioning at a relatively young age.  Virtually all persons with Down syndrome exihibit the pathologic features of Alzheimer disease as they age. PS1 and PS2, both intracellular proteins, are components of γ-secretase and possibly part of a multiprotein complex containing the proteolytic site for breakdown of Aβ.  A fourth gene, an allele (_4) of the apolipoprotein E (ApoE) gene found on chromosome 19, increases the risk of Alzheimer disease and lowers the age of onset.  ApoE can bind Aβ and is present in plaques, but how this allele increases the risk of Alzheimer disease has not been established.

18

19 Microscopy image of a neurofibrillary tangle, conformed by hyper- phosphorylated tau protein.

20  Alzheimer-type dementia follows an insidious and progressive course, with an average survival of 8 to 10 years after diagnosis.  The hallmark symptoms are loss of short-term memory and denial of such memory loss, with eventual disorientation, impaired abstract thinking, apraxias, and changes in personality and affect.  Various stages of the disease have been recognized, ranging from four to the more nuanced seven stages identified by the Alzheimer Association.  All are characterized by progressive degenerative changes.  The initial change is subtle, characterized by short-term memory loss that often is difficult to differentiate from the normal forgetfulness that occurs in the elderly, and usually is reported by caregivers and denied by the patient.

21  Although most elderly persons have trouble retrieving from memory incidental information and proper names,  Persons with Alzheimer disease randomly forget important and unimportant details. They forget where things are placed, get lost easily, and have trouble remembering appointments and performing novel tasks.  Mild changes in personality, such as lack of spontaneity, social withdrawal, and loss of a previous sense of humor, occur during this stage.

22  As the disease progresses, the person with Alzheimer disease enters the moderate stage. This stage may last several years and is marked by a more global impairment of cognitive functioning.  During this stage, there are changes in higher cortical functioning needed for language, spatial relationships, and problem solving.  Depression may occur in persons who are aware of their deficits.

23  There is extreme confusion, disorientation, lack of insight, and inability to carry out the activities of daily living.  Personal hygiene is neglected, and language becomes impaired because of difficulty in remembering and retrieving words.  Behavioral changes can include agitation, sleep problems, restlessness and wandering, aggression, and suspiciousness.  Some persons may become hostile and abusive toward family members. Persons who enter this stage become unable to live alone and should be assisted in making decisions about supervised placement with family members or friends or in a community-based facility. Severe Alzheimer disease is the last stage of the disease.

24  It is characterized by a loss of ability to respond to the environment. Individuals in this stage require total care, and spend most of their time bedridden. Death can occur as a result of complications related to chronic debilitation. There is extreme confusion, disorientation, lack of insight, and inability to carry out the activities of daily living.  Personal hygiene is neglected, and language becomes impaired because of difficulty in remembering and retrieving words.  Behavioral changes can include agitation, sleep problems, restlessness and wandering, aggression, and suspiciousness.

25  Some persons may become hostile and abusive toward family members. Persons who enter this stage become unable to live alone and should be assisted in making decisions about supervised placement with family members or friends or in a community-based facility. Severe Alzheimer disease is the last stage of the disease.  It is characterized by a loss of ability to respond to the environment. Individuals in this stage require total care, and spend most of their time bedridden. Death can occur as a result of complications related to chronic debilitation.