The sign wasn’t placed there        By the Big Printer in the sky WHEN TO START, SWITCH ORADD IN ALZHEIMER’S DISEASE –    ...
2
DEMENTIA - Types• Two Types:  – Reversible  – Irreversible• Individuals must have intensive medical  physical to rule out ...
DEMENTIA• Reversible:  – D=    Drugs, Delirium  – E=    Emotions (such as depression) &          Endocrine Disorders  – M=...
DEMENTIA• Irreversible:  – Alzheimer’s  – Lewy Body Dementia  – Pick’s Disease (Frontotemperal Dementia)  – Parkinson’s  –...
DEMENTIA• Irreversible:  – Alzheimers most common type of irreversible    dementia  – Multi-Infarct dementia (VaD) second ...
DEMENTIA - Symptoms– Marked by progressive, irreversible declines in   • Memory.   • Visual-spatial relationships   • Perf...
DSM IV definitionA. The development of multiple cognitive   deficits manifested by both:  – Memory impairment.  – At least...
Dementia - types               9
Progression of dementia                                       Alzheimers         30                              DiseaseMM...
Dementia - Possible treatment outcomes                                    Disease                                    arres...
Alzheimer’s DiseaseDEFINITION:  – Progressive Neurodegenerative illness  –Behavioural disturbances  –Cognitive deficit  –D...
Alzheimer’s disease• Alzheimers disease is the most common form of  dementia, affecting about 4.5 million men and women  i...
Alzheimer’s disease• Alzheimers disease affects at least 15 million persons  throughout the world• As Alzheimers disease a...
Alzheimer’s disease• In people with Alzheimers disease, changes  in the brain may begin 10 to 20 years before  any visible...
Prevalence of Alzheimer’s diseaseincreases sharply with increasing age                         50                         ...
Estimated Number of New AD Cases              1200              1000               800  Thousands               600       ...
18
Clinical features of AD                     Insidious onset        Cognitive decline  Functional                          ...
Factors that increase the risk for  Alzheimers disease include:Age The risk of developing Alzheimers  disease increases w...
Factors that increase the risk for   Alzheimers disease include:• Gender -- Alzheimers disease affects women  more frequen...
Symptoms of Alzheimer’s Disease Alzheimers disease is a brain disorder in which  nerve cells in the brain die, making it ...
Symptoms cont’d…Impaired memory and thinking -- The person has difficultyremembering things or learning new information.In...
Symptoms cont’d• Misplacing things -- The person forgets where he or she  put things used every day, such as glasses, a he...
Symptoms cont’d• Changes in personality and behavior -- The person  becomes unusually angry, irritable, restless, or quiet...
Symptoms cont’d• Problems with language and communication – The  person cant recall words, name objects (even ones that  t...
Stage I: Mild Alzheimers diseaseSigns and symptoms of mild AD can include:• Memory loss and changes in expressive speech• ...
Stage II: Moderate Alzheimers disease Signs and symptoms of moderate AD can include: • Increased memory loss • Shortened a...
• Restlessness, agitation, anxiety, tearfulness,  and wandering, especially in the late afternoon  or evening (sometimes c...
Stage III: Severe Alzheimers disease Signs of severe Alzheimers disease may include: •   Complete loss of language and mem...
Pattern of symptoms over time in patients        with Alzheimer’s disease                              31
Clinical features of AD      Mild stage of AD (MMSE 21-30)                    IMPAIRMENTCognition           Function      ...
Clinical features of AD  Moderate stage of AD (MMSE 10-20)                    IMPAIRMENTCognition                Function ...
Clinical features of AD     Severe stage of AD (MMSE <10)                    IMPAIRMENTCognition            Function      ...
35
Alzheimer’s Disease: Impact on PatientCognitive impairments              Activities of daily living; Behavioural and      ...
Impact of Alzheimer’s Disease on the Caregiver                                 37
Alzheimer’s versus normal brainAlzheimer’s versus normal brain                                  38
39
Normal versus degenerating neuron                        40
Diagnosing AD - neuroimaging,  computed (axial) tomography (CT)               Various CT scan reports in AD               ...
Diagnosing AD laboratory tests All patients               Most patients * Complete blood count     * ECG * Thyroid functio...
Anatomical findings Alzheimer’s1. Plaques: clusters of abnormal cells2. Tangles of neurofilaments inside   neurons3. Deter...
Anatomical findings6. Amydgala 26% decrease in volume7. Cell density reduced by 75% (increase in  ventricular size)8.Those...
Preventative measures• Estrogen and ginkgo biloba: possibly due to anti-  inflammatory or circulatory properties• Anti-inf...
Steps to Getting a Diagnosis• Unfortunately, there is no one diagnostic  test that can detect Alzheimer’s Disease.  Have t...
Theories Regarding Causes of          Alzheimers• Changes in Neurotransmitters    • Acetycholine is decreased--necessary f...
Theories Regarding Causes of          Alzheimers• Genetic Theories     • Chromosome 21 --Responsible for early-onset      ...
Theories Regarding Causes of          Alzheimers• Environmental     • Aluminum--Traces of metal found in brain.     • Zinc...
Theories Regarding Causes of          Alzheimers• Head Trauma  – Head trauma increase the concentration of B-    amyloid p...
Causes of AD                                          H a llm a r k s o f A D                                           T ...
AD -Pathogenesis               52
Cholinergic Hypothesis• Atrophy of the nucleus basalis of  Meynert, the source of choline  acetyltransferase, causes defic...
Loss of cholinergic neurons• To preserve existing acetylcholine -  cholinesterase inhibitors are used• Cholinesterase enzy...
Amyloid plaque                 55
56
57
58
59
Dysfunction of glutamate       neurotransmission• In all neuro degenerative disorders , there  is excess of glutamate in s...
Why excess of glutamate                             B e t a a m y lo id    D y s fu n c t io n o f              D y s fu n...
Glutamate Excitoxicity     hypothesis           Glutamate    Stimulation of NMDA receptors           Influx of Ca++    Gen...
Excitotoxicity                 63
Mechanism of actionMemantine is• Uncompetitive• voltage dependent• moderate affinityNMDA receptor antagonist              ...
Mechanism of actionUncompetitive means it does not compete with glutamate for binding site.Memantine binding site is locat...
Mechanism of actionVoltage dependent means , Memantine blocks NMDA receptors only whenmembrane is hyperpolarised due to ex...
Mechanism of action                                   Glutamate                                                           ...
Mechanism of actionBenefits of uncompetitive, moderate  affinity & voltage dependent• It allows normal glutamate  neurotra...
Mechanism of action –        A useful analogy• NMDA receptor is a switch. Finger is  glutamate. Door is ion channel• By pr...
• When the switch is pressed continously with  finger, the door will be always remain open &  unwanted people can enter. T...
Mechanism of action –        A useful analogy• Memantine is voltage dependent NMDA  receptor antagonist. That means  Meman...
Pharamcokinetics - SummaryBioavailability                  100%Tmax                       3-8 hrsCmax (single 20 mg dose) ...
Memantine - Clinical EfficacyMemantine montherapy has been evaluated  in adult patients• With moderate to severe AD• Sever...
Clinical Efficacy - Moderate to           severe AD• Memantine in Moderate to Severe  Alzheimer’s Disease• Reisberg B., Do...
Moderate to severe AD –       Study Design• No. of patients - N = 252 (outpatients)• Diagnosis -Probable Alzheimer’s  dise...
• Dose; duration 20 mg memantine/day; 28  weeks• Primary efficacy parameters - Global:  CIBIC-plus Function: ADCS-ADLsev• ...
Entrance Criteria –      Moderate to severe AD• Male or female outpatients = 50 years• DSM-IV Dementia of the Alzheimer’s ...
Results - Moderate to severe AD• Patients• 252 patients randomized (126 memantine;  126 placebo)• 181 completers [97 (77%)...
Summary- Moderate to Severe AD• Statistically significant benefit of  memantine compared to placebo on three  independent ...
Beneficial across the entire spectrum                           80
Memantine          FDA – October 2003• Uncompetitive NMDA receptor antagonist• A low-moderate affinity• Allow normal physi...
Memantine Study• ADCS – ADL revealed at end points,  favoured Memantine over Placebo• Abilities in grooming• Being left al...
Short and Long-term Dementia –       Memantine is safe• Five double blind Placebo controlled trials• Four open label exten...
Memamtine - Role Beyond         dementia• NMDA receptors is involved in no. of  neurological & psychiachiatric  disorders•...
MEMANTINE IN THE TREATMENT OF DIABETICS WITH PAINFUL PERIPHERAL NEUROPATHY: A PLACEBO-CONTROLLED PHASE IIB TRIAL. Pain Med...
Results• Significant difference in mean nocturnal VAS at  week 8 in patients taking 40 mg/day Memantine  as compared to pl...
Dextromethorphan andmemantine in painful diabeticneuropathy and postherpeticneuralgia: efficacy and dose-      response tr...
Results• Memantine reduced pain intensity by 17%• 47% of patients achieved greater than  moderate pain relief• There was n...
Memantine in Parkinson’s disease• Parkinsons disease is a chronic, progressive,  neurodegenerative disease  • In Parkinson...
Memantine in Parkinson’s disease• The beneficial effect of memantine has been related to its  novel properties as an NMDA ...
91
92
Dedicated to my family formaking everything worthwhile                      93
READ not to contradict or confuteNor to Believe and Take for Grantedbut TO WEIGH AND CONSIDERTHANK YOU         My sincere ...
Upcoming SlideShare
Loading in …5
×

When to start, switch or add in alzheimers disease memantine

3,954 views

Published on

Published in: Health & Medicine
0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
3,954
On SlideShare
0
From Embeds
0
Number of Embeds
5
Actions
Shares
0
Downloads
236
Comments
0
Likes
2
Embeds 0
No embeds

No notes for slide
  • AD is one of the most distinctive of the dementing illnesses, with an insidious onset and progressive decline. Although the clinical features are characteristic in most sufferers, there is, however, great heterogeneity in age of onset and the rate of disease progression. Many areas of cognition are compromised by AD in the early stages of the disease. Problems include memory loss, aphasia, apraxia, agnosia and difficulties in executive function and visuospatial abilities. Functional disability is intrinsically linked to cognitive decline and a deterioration in social and occupational activities is characteristically observed. Problems may arise in the Instrumental Activities of Daily Living (IADL) such as driving the car, paying bills, or functioning at work. Later in the disease, the basic Activities of Daily Living (ADL), such as dressing and bathing, are affected. Changes in behavior are also common and may include mood swings, agitation and wandering.   The stage and course of AD can be monitored by evaluating the cognitive, functional and behavioural changes exhibited by individual patients.   International Psychogeriatric Association, Alzheimer&apos;s Disease ­ Applied Diagnosis and Assessment Conference, Geneva 1996.
  • Talk about the story with Great Grandpop and the condo on the beach story
  • Cognition: In the early stages of AD, the first symptom experienced is memory loss. Individuals experience forgetfulness that occurs much more frequently and persistently than that associated with normal aging. Common complaints include difficulty remembering appointments, conversation details or aspects of television programs. In this initial phase of the illness there are learning difficulties and delayed recall followed by language problems, such as difficulty finding specific words. In addition, elements of executive function can be affected, such as problem solving, judgement and calculation.   Function: Impaired Instrumental Activities of Daily Living (IADLs), associated with the cognitive deficits, develop early in the course of AD. Activities particularly dependent on memory are affected. These include functioning at work, shopping, managing finances, participating in hobbies, reading, writing, and household tasks (cooking, etc). Remembering appointments and plans is difficult. Basic Activities of Daily Living (ADLs) are usually unaffected.   Behavior: There is a relationship between the manifestation of behavioral symptoms and the progression of AD. It is, however, not possible to predict accurately who will develop these symptoms and when. Initial behavioral changes are subtle and include apathy, withdrawal and depressive symptoms (e.g. flat mood, reduced initiative, decreased activity). Often the patient becomes irritable in response to the frustration of dealing with the symptoms of AD. Important decisions regarding driving and personal finances should be considered at this stage of AD.   Galasko D. Correlating cognition, behavior and function. Presented at an official satellite symposium, &apos;Managing the Burden of Alzheimer&apos;s Disease: Beyond Cognition&apos;, at the European Federation of Neurological Societies Meeting, 4­7 June 1997, Prague, Czech Republic.
  • Cognition: As AD progresses, recent memory becomes severely restricted, although remote memory remains unaffected. Generating new memories becomes difficult and patients will tend to dwell on past events. Details of television programs cannot be retained and it becomes difficult to participate in conversation as patients increasingly find it difficult to remember people&apos;s names and to select the correct words. Sentence structure becomes less complex. In addition, insight, orientation and visuospatial ability become impaired.   Function: In the moderate stages of AD IADLs become severely restricted, so much so that the patient requires assistance from the caregiver or loses the ability to perform IADLs altogether. Misplacing objects such as spectacles or keys becomes increasingly more frequent and the patient often gets lost, even in familiar surroundings. Supervision is needed in dressing because it becomes difficult for the patient to select items of clothing and put them on in the right order. At this stage basic ADLs generally remain intact.   Behavior: Delusions and depression are common (experienced by 20­50% of patients). Common delusions include paranoia (people are stealing things) and misidentification (for example, their spouse is an impostor, the house is not their own, or TV images are real). In addition, motor dysfunction (e.g. wandering) and insomnia occur. Social graces remain intact.   Galasko D. Correlating cognition, behavior and function. Presented at an official satellite symposium, &apos;Managing the Burden of Alzheimer&apos;s Disease: Beyond Cognition&apos;, at the European Federation of Neurological Societies Meeting, 4­7 June 1997, Prague, Czech Republic.
  • Cognition: It becomes more difficult to differentiate meaningful changes in cognition in the late stage of AD. Attention becomes severely impaired and patients find it difficult to perform familiar activities (apraxis), and follow commands. It becomes impossible to recall the names of familiar objects and family members. Language becomes restricted to a few simple phrases or words, and eventually the patient becomes mute.   Function: A hierarchical loss of basic ADLs is observed; first dressing, then grooming, bathing, eating, and finally, continence, walking and motor slowing. The loss of each ADL is gradual. The patient becomes bed-bound and becomes completely dependent on the caregiver.   Behavior: Agitation, both verbal (screaming) and physical, and insomnia, are characteristic in the later stages of AD.   Galasko D. Correlating cognition, behavior and function. Presented at an official satellite symposium, &apos;Managing the Burden of Alzheimer&apos;s Disease: Beyond Cognition&apos;, at the European Federation of Neurological Societies Meeting, 4­7 June 1997, Prague, Czech Republic.
  • A CT scan without contrast is often recommended as part of the AD assessment. It is considered adequate in most cases to discount space-occupying lesions and is probably as effective as MRI for this purpose. CT can identify moderate to large areas of infarction and can detect significant subdural hematoma.   A standard axial CT angle may reveal: *Extent of cortical atrophy *Presence of focal atrophy *Extent of white-matter change *Brain infarction *Tumors *Subdural hemorrhage   Although a CT scan is used primarily to exclude other conditions, linear measurements of ventricular width, particularly the temporal horns of the lateral and third ventricles, can help support a diagnosis of AD. Generally the CT scan is interpreted by a specialist. This slide details a variety of common interpretations that appear on a CT scan report.
  • A number of laboratory tests should be requested to rule out concomitant illness and other causes of dementia. HIV testing may be indicated in high-risk groups.
  • Unfortunately, there is no one diagnostic test that can detect Alzheimer’s Disease.
  • Among the biochemical changes in the brains of patients with AD, the deficiency of acetylcholine has been found to be the most consistent and the most profound. This deficiency has been traced to cellular dysfunction in the nucleus basalis of Meynert, the source nucleus of choline acetyltransferase. The nucleus basalis is positioned between the limbic system and the neocortex; it has therefore been hypothesized that in AD the pathologic alterations of the nucleus basalis disrupt the limbic-neocortical connections underlying the cognitive and emotional processes. Although other neurochemical and neurohistologic abnormalities contribute to the psychopathology of AD, a substantial portion of memory and cognitive impairments has been attributed to cholinergic deficiency. In addition, cholinomimetic therapies have been developed that—uniquely among psychotropic medications—exhibit disease-specific and broad-spectrum effects. Although these agents were the first to be approved specifically for the treatment of AD, this class partially ameliorates behavioral symptoms with no effect on the underlying disease process.   Source Cummings JL, Back C. The cholinergic hypothesis of neuropsychiatric symptoms in AD. Am J Geriatr Psychiatry . 1998;6:S64–S78.
  • When to start, switch or add in alzheimers disease memantine

    1. 1. The sign wasn’t placed there By the Big Printer in the sky WHEN TO START, SWITCH ORADD IN ALZHEIMER’S DISEASE – MEMANTINE Prof. A.V. SRINIVASAN Institute of Neurology 1 Chennai
    2. 2. 2
    3. 3. DEMENTIA - Types• Two Types: – Reversible – Irreversible• Individuals must have intensive medical physical to rule out reversible types of dementia. 3
    4. 4. DEMENTIA• Reversible: – D= Drugs, Delirium – E= Emotions (such as depression) & Endocrine Disorders – M= Metabolic Disturbances – E= Eye and Ear Impairments – N= Nutritional Disorders – T= Tumors, Toxicity, Trauma to Head – I= Infectious Disorders –A= Alcohol, Arteriosclerosis 4
    5. 5. DEMENTIA• Irreversible: – Alzheimer’s – Lewy Body Dementia – Pick’s Disease (Frontotemperal Dementia) – Parkinson’s – Heady Injury – Huntington’s Disease – Jacob-Cruzefeldt Disease 5
    6. 6. DEMENTIA• Irreversible: – Alzheimers most common type of irreversible dementia – Multi-Infarct dementia (VaD) second most common type of irreversible dementia • Death of cerebral cells • Blockages of larger cerebral vessels, arteries • More abrupt in onset • Associated with previous strokes, hypertension • Can be traced through diagnostic procedures 6
    7. 7. DEMENTIA - Symptoms– Marked by progressive, irreversible declines in • Memory. • Visual-spatial relationships • Performance of routine tasks • Language and communication skills • Abstract thinking • Ability to learn and carry out mathematical calculations. 7
    8. 8. DSM IV definitionA. The development of multiple cognitive deficits manifested by both: – Memory impairment. – At least one of: aphasia, apraxia, agnosia, disturbance in cognitive functioning.B. Significant decline in social or occupational functioningC. There is evidence of organic etiologyD. Does not occur exclusively during the course of a delirium. 8
    9. 9. Dementia - types 9
    10. 10. Progression of dementia Alzheimers 30 DiseaseMMSE 25scores 20 Vascular 15 Dementia 10 Dementia with Lewy Bodies 5 0 1999 2000 2001 2002 2003 2004 10
    11. 11. Dementia - Possible treatment outcomes Disease arrest Stabili Slowed Function zation Treatment progress ion Symptomatic benefit No effect Time 11
    12. 12. Alzheimer’s DiseaseDEFINITION: – Progressive Neurodegenerative illness –Behavioural disturbances –Cognitive deficit –Decline in Functional capacity 12
    13. 13. Alzheimer’s disease• Alzheimers disease is the most common form of dementia, affecting about 4.5 million men and women in the United States.• The incidence of Alzheimers disease increases with age, and is very rare among people younger than 60. It affects up to 50 percent of people older than 85, and the risk increases with age.• Although the first symptoms of Alzheimers disease are often confused with the changes that take place in normal aging, its important to remember that Alzheimers disease is not a normal part of aging.• In AD, both Short & Long term memory is affected 13
    14. 14. Alzheimer’s disease• Alzheimers disease affects at least 15 million persons throughout the world• As Alzheimers disease advances, patients become progressively impaired in both cognitive and functional capacities, and the burden on caregivers increases• Alzheimers disease is a progressive illness, which means the disease, and its symptoms, worsens over time.• After first being diagnosed, some people may live 10 years or an average life expectancy. The course of the disease varies from person to person, but symptoms develop over the same general stages. 14
    15. 15. Alzheimer’s disease• In people with Alzheimers disease, changes in the brain may begin 10 to 20 years before any visible signs or symptoms appear.• Some regions of the brain may begin to shrink, resulting in memory loss, the first visible sign of Alzheimers disease.• Over time, Alzheimers disease progresses through three main stages: mild, moderate, and severe. 15
    16. 16. Prevalence of Alzheimer’s diseaseincreases sharply with increasing age 50 40 Prevalence (%) of AD 30 20 10 0 65-74 75-84 >84 Age groups ( years ) 16
    17. 17. Estimated Number of New AD Cases 1200 1000 800 Thousands 600 400 200 0 1995 2000 2010 2020 2030 2040 2050 year 17
    18. 18. 18
    19. 19. Clinical features of AD Insidious onset Cognitive decline Functional * Memory loss impairment * Aphasia * IADL * Apraxia * ADL * Agnosia AD * Executive functionBehavioral signs difficulties* Mood swings* Agitation Age over 60 years* Wandering No gait difficulties IPA AD Conference, 1996 19
    20. 20. Factors that increase the risk for Alzheimers disease include:Age The risk of developing Alzheimers disease increases with age. According to the Alzheimers Association, 10% of all people over the age of 65 have Alzheimers disease.• ~50% of people over 85 have it. 20
    21. 21. Factors that increase the risk for Alzheimers disease include:• Gender -- Alzheimers disease affects women more frequently than men.• Family history -- A clear, inherited pattern of Alzheimers disease exists for less than 10% of all cases.• Down syndrome -- People with Down syndrome often develop Alzheimers disease in their 30s and 40s, although the exact reason is not known. 21
    22. 22. Symptoms of Alzheimer’s Disease Alzheimers disease is a brain disorder in which nerve cells in the brain die, making it difficult for the brains signals to be transmitted properly. A Person with Alzheimers disease has problems with memory, judgment, and thinking, which makes it hard for the person to work or take part in day-to- day life. Most patients symptoms progress slowly over a number of years. Symptoms may not be noticed early on. Sometimes, it is only when family members look back that they realize when the changes started to occur. 22
    23. 23. Symptoms cont’d…Impaired memory and thinking -- The person has difficultyremembering things or learning new information.In the laterstages of the disease, long-term memory loss occurs, whichmeans that the person cant remember personal information,such as his or her place of birth or occupation, or names ofclose family members.Disorientation and confusion -- People with Alzheimersdisease may get lost when out on their own and may notbeable to remember where they are or how they gotthere.They may not recognize previously familiar places andsituations. They also may not recognize familiar faces orknow what time of the day it is, or even what year it is. 23
    24. 24. Symptoms cont’d• Misplacing things -- The person forgets where he or she put things used every day, such as glasses, a hearing aid, keys, etc. They may also put things in strange places, such as leaving their glasses in the refrigerator.• Abstract thinking -- may find certain tasks -- such as balancing a checkbook -- more difficult than usual. For example, they might forget what the numbers mean and what needs to be done with them.• Trouble performing familiar tasks -- The person begins to have difficulty performing daily tasks, such as eating, dressing, and grooming. Planning for normal day-to-day tasks is also impaired. 24
    25. 25. Symptoms cont’d• Changes in personality and behavior -- The person becomes unusually angry, irritable, restless, or quiet. At times, people with Alzheimers disease can become confused, paranoid, or fearful.• Poor or decreased judgment -- People with Alzheimers disease may leave the house on a cold day without a coat or shoes, or could go to the store wearing their pajamas.• Inability to follow directions -- The person has difficulty understanding simple commands or directions. The person may get lost easily and begin to wander. 25
    26. 26. Symptoms cont’d• Problems with language and communication – The person cant recall words, name objects (even ones that that are very familiar to them -- like a pen) the meaning of common words.• Impaired visual and spatial skills -- The person loses spatial abilities (the ability to judge shapes and sizes, and the relationship of objects in space) and cant arrange items in a certain order or recognize shapes.• Loss of motivation or initiative -- The person may become very passive and require prompting to become involved and interact with others.• Loss of normal sleep patterns -- The person may sleep during the day and be wide-awake at night. 26
    27. 27. Stage I: Mild Alzheimers diseaseSigns and symptoms of mild AD can include:• Memory loss and changes in expressive speech• Confusion about the location of familiar places• Taking longer to finish routine, daily tasks• Difficulty with simple math problems and related issues like handling money, paying bills, or balancing a checkbook• Poor judgment which leads to bad decisions• Mood and personality changes• Increased anxiety 27
    28. 28. Stage II: Moderate Alzheimers disease Signs and symptoms of moderate AD can include: • Increased memory loss • Shortened attention span • Difficulty recognizing friends and family • Problems with language, including speech, reading, comprehension, and writing • Difficulty organizing thoughts • Inability to learn new things or cope with unexpected situations 28
    29. 29. • Restlessness, agitation, anxiety, tearfulness, and wandering, especially in the late afternoon or evening (sometimes called sundowning)• Repetitive statements or movements• Hallucinations, delusions, suspiciousness, or paranoia• Loss of impulse control (for example, sloppy table manners, undressing at inappropriate times or inappropriate places, vulgar language) 29
    30. 30. Stage III: Severe Alzheimers disease Signs of severe Alzheimers disease may include: • Complete loss of language and memory • Weight loss • Seizures, skin infections, and difficulty swallowing • Groaning, moaning, or grunting • Increased sleeping • Lack of bladder and bowel control • Loss of physical coordination 30
    31. 31. Pattern of symptoms over time in patients with Alzheimer’s disease 31
    32. 32. Clinical features of AD Mild stage of AD (MMSE 21-30) IMPAIRMENTCognition Function Behavior* Recall/learning * Work * Apathy* Word finding * Money/shopping * Withdrawal* Problem * Cooking * Depression solving * Housekeeping * Irritability* Judgement * Reading* Calculation * Writing * Hobbies Adapted from Galasko, 1997 32
    33. 33. Clinical features of AD Moderate stage of AD (MMSE 10-20) IMPAIRMENTCognition Function Behavior* Recent memory * IADL loss * Delusions (remote memory * Misplacing * Depression unaffected) objects * Wandering* Language (names, * Getting lost * Insomnia paraphasias) * Difficulty * Agitation* Insight dressing * Social skills* Orientation (sequence and unaffected* Visuospatial ability selection) Adapted from Galasko, 1997 33
    34. 34. Clinical features of AD Severe stage of AD (MMSE <10) IMPAIRMENTCognition Function Behavior* Attention * Basic ADLs * Agitation* Difficulty ­Dressing ­ Verbal performing ­Grooming ­ Physical familiar activities ­Bathing * Insomnia (apraxis) ­Eating* Language ­Continence (phrases, mutism) ­Walking ­Motor slowing Adapted from Galasko, 1997 34
    35. 35. 35
    36. 36. Alzheimer’s Disease: Impact on PatientCognitive impairments Activities of daily living; Behavioural and unable to: psychotic symptomsMemory loss Depression Maintain their own financesAttention deficits Drive ConfusionDisorientation in time and place Keep appointments AnxietyLanguage difficulties Go out alone ApathyExecutive dysfunction Answer the telephone RestlessnessImpaired perception Keep themselves clean Inappropriate behaviourPraxis Dress themselves Fear or panic Feed themselves Delusions Use the toilet Hallucinations 36 Aggression
    37. 37. Impact of Alzheimer’s Disease on the Caregiver 37
    38. 38. Alzheimer’s versus normal brainAlzheimer’s versus normal brain 38
    39. 39. 39
    40. 40. Normal versus degenerating neuron 40
    41. 41. Diagnosing AD - neuroimaging, computed (axial) tomography (CT) Various CT scan reports in AD * Normal examination for the patients age * Generalized cerebral atrophy * Small vessel changes, areas of leucoencephalopathy * No signs of subdural hematoma (if head trauma suspected) * Absence of specific areas of cerebral infarctions or evidence of strokeNeuroimaging 41
    42. 42. Diagnosing AD laboratory tests All patients Most patients * Complete blood count * ECG * Thyroid function * Chest X­ray * Vitamin B12 and folate * Syphilis serology * BUN and creatinine * Calcium * Glucose * Electrolytes * Urinalysis * Liver function tests 42
    43. 43. Anatomical findings Alzheimer’s1. Plaques: clusters of abnormal cells2. Tangles of neurofilaments inside neurons3. Deterioration of dendrites4. Loss of neurons5. Hippocampus is 47% reduced in size (in normals it shrinks 27%). 43
    44. 44. Anatomical findings6. Amydgala 26% decrease in volume7. Cell density reduced by 75% (increase in ventricular size)8.Those who died show marked loss of cells in the nucleus basilis (releases ACh and projects to hippocampus and cortex.9. Cortex has plaques and tangles. 44
    45. 45. Preventative measures• Estrogen and ginkgo biloba: possibly due to anti- inflammatory or circulatory properties• Anti-inflammatory drugs: limit the production of amyloid• Vitamen E• Statin drugs- (for high cholesterol), reduce Alzheimer’s risk.• Folate-lowers the amino acid homocysteine (that increases Alzheimer’s and heart disease risk).• Ampalex- boosts LTP, seems to help memory loss• Mental exercise- active- do better. Use it or lose it. Take: Estrogen (HRT), anti-inflamatory painkillers, and statins = people are 30-50% less likely to get Alzheimer’s. 45
    46. 46. Steps to Getting a Diagnosis• Unfortunately, there is no one diagnostic test that can detect Alzheimer’s Disease. Have to wait till death to be sure.• 80-90% certainty of “probable” Alzheimer’s Disease 46
    47. 47. Theories Regarding Causes of Alzheimers• Changes in Neurotransmitters • Acetycholine is decreased--necessary for cognitive functioning.• Changes in Protein Synthesis • Beta amyloid--may be responsible for forming plaques. • Tau--major component of neurofibrillary tangles.• Genetic Theories • ApoE4 on chromosone 19 linked to late-onset Alzheimer’s Disease. 47
    48. 48. Theories Regarding Causes of Alzheimers• Genetic Theories • Chromosome 21 --Responsible for early-onset Alzheimer’s Disease.• Metabolic Theories • Glucose metabolism declines dramatically in Alzheimer’s patients.• Calcium Theories/ Excitoxicity • Too much calcium can kill cells. Suspect that it may reason why neurons die in Alzheimers patients. 48
    49. 49. Theories Regarding Causes of Alzheimers• Environmental • Aluminum--Traces of metal found in brain. • Zinc--found in brains on autopsies. • Food borne poisons--amino acids found in legumes in Africa and India my cause neurological damage.• Viral • May be hidden in body and attack brain cells years later. (NIH-1995) 49
    50. 50. Theories Regarding Causes of Alzheimers• Head Trauma – Head trauma increase the concentration of B- amyloid protein• Low Level of Education – Individuals with low level of education less able to compensate for cognitive deficits• Estrogen Deficiency• Early Life Experience---have lost parent before age 16 50
    51. 51. Causes of AD H a llm a r k s o f A D T y p e t it le h e r e Loss of S e n ile P la q u e s & D y s fu n c t io n o f g lu t a m a t e C h o lin e r g ic n e u r o n s N e u r o fib illa r y t a n g le s N e u r o t r a n s m is s io n30% of symptoms 70% of symptoms 51
    52. 52. AD -Pathogenesis 52
    53. 53. Cholinergic Hypothesis• Atrophy of the nucleus basalis of Meynert, the source of choline acetyltransferase, causes deficit• Other neurochemical and neurohistologic abnormalities contribute to the psychopathology of AD• Cholinergic therapy may partially improve behavioral symptoms of AD• Cholinergic therapy does not interrupt the disease process 53
    54. 54. Loss of cholinergic neurons• To preserve existing acetylcholine - cholinesterase inhibitors are used• Cholinesterase enzymes acetylcholinesterase & butrylcholinesterase) are involved in breakdown of acetylcholine neurotransmitte• Currently available ChEIs - Rivastigmine & Donepezil• Not approved in advanced stages of dementia 54
    55. 55. Amyloid plaque 55
    56. 56. 56
    57. 57. 57
    58. 58. 58
    59. 59. 59
    60. 60. Dysfunction of glutamate neurotransmission• In all neuro degenerative disorders , there is excess of glutamate in synapse.• This excess of glutamate is because of dysfunction of glutamate reuptake protein, or glutamine synthetase enzyme.• The dysfunction of Glutamine synthetase enzyme is caused by beta amyloid• Dysfuntion of reuptake is also caused by beta amyloid 60
    61. 61. Why excess of glutamate B e t a a m y lo id D y s fu n c t io n o f D y s fu n c t io n o f g lu t a m a t eG lu t a m a t e r e u p t a k e s y n th e ta s e e n z y m e pum p Excess of glutamate in synapse 61
    62. 62. Glutamate Excitoxicity hypothesis Glutamate Stimulation of NMDA receptors Influx of Ca++ Generation of free radicals Oxidation of RNA, DNA in the neuron Cell death 62
    63. 63. Excitotoxicity 63
    64. 64. Mechanism of actionMemantine is• Uncompetitive• voltage dependent• moderate affinityNMDA receptor antagonist 64
    65. 65. Mechanism of actionUncompetitive means it does not compete with glutamate for binding site.Memantine binding site is located inside the ion channelModerate affinity means it can be easily displaced from NMDA receptor 65
    66. 66. Mechanism of actionVoltage dependent means , Memantine blocks NMDA receptors only whenmembrane is hyperpolarised due to excess of Glutamate. Hence it allowsnormal Glutamate neurotransmission 66
    67. 67. Mechanism of action Glutamate Allows the action of Memantine blocks NMDA receptor A­APP on B­amyloid NO Stimulation of NMDA receptors NO Influx of Ca++ NO Accumulation of B­ amyloid & formation ofDOES NOT plaques N Generation of free radicalsdestroy O NO Stimulates enzyme kainasessurrounding neuron Prevents Cell deathCholinergic neurons NO Hyperphospholation of tau proteins & formation of NFTs 67
    68. 68. Mechanism of actionBenefits of uncompetitive, moderate affinity & voltage dependent• It allows normal glutamate neurotransmissio• Blocks pathological activation of NMDA receptors but preserves physiological activation of NMDA receptors• Does not hinder normal learning & memory function 68
    69. 69. Mechanism of action – A useful analogy• NMDA receptor is a switch. Finger is glutamate. Door is ion channel• By pressing the switch with the finger the door opens. That means when glutamte binds to NMDA receptor Ca++ ion channels get opened & influx of Ca++ occurs 69
    70. 70. • When the switch is pressed continously with finger, the door will be always remain open & unwanted people can enter. That means when there is excess of glutamate, NMDA receptor is always stimulated & excess of influx of Ca++ will occur.• Memantine is uncompetive NMDA antagonist. That means it does not compete with glutamate for the binding site at NMDA receptor. Memantine goes and stands at gate & blocks the entry of unwanted people like watchman 70
    71. 71. Mechanism of action – A useful analogy• Memantine is voltage dependent NMDA receptor antagonist. That means Memantine will not always stand as watchman at the door & block the entry of people. Memantine blocks entry when unwanted people enter. 71
    72. 72. Pharamcokinetics - SummaryBioavailability 100%Tmax 3-8 hrsCmax (single 20 mg dose) 22-46 ng/mlTime to steady state 11 daysElimination half life 60-100 hrs 72
    73. 73. Memantine - Clinical EfficacyMemantine montherapy has been evaluated in adult patients• With moderate to severe AD• Severe dementia due to AD or VaD• VaD• Long term efficacy is also confirmed• Memantine + Donepezil has been evaluated in adult patients with moderate to severe ADClinical efficacy of Memantine is confirmed in no. of double blind placebo controlled trials 73
    74. 74. Clinical Efficacy - Moderate to severe AD• Memantine in Moderate to Severe Alzheimer’s Disease• Reisberg B., Doody R., Stöffler A., Schmitt F., Ferris S. H., and Möbius H. J.• New England Journal of Medicine 2003, 348: 1333-1341 74
    75. 75. Moderate to severe AD – Study Design• No. of patients - N = 252 (outpatients)• Diagnosis -Probable Alzheimer’s disease• Design - Double-blind, randomized, placebo-controlled, multicenter study• Age - ≥ 50 years (mean 76)• Severity -MMSE : 3 – 14 (mean 7.9), GDS : 5 – 6, FAST ≥ 6a 75
    76. 76. • Dose; duration 20 mg memantine/day; 28 weeks• Primary efficacy parameters - Global: CIBIC-plus Function: ADCS-ADLsev• Secondary efficacy - Cognition: SIB, Behavior: NPI parameters MMSE, FAST, GDS• Resource Utilisation in Dementia (RUD) 76
    77. 77. Entrance Criteria – Moderate to severe AD• Male or female outpatients = 50 years• DSM-IV Dementia of the Alzheimer’s type• NINCDS-ADRDA probable Alzheimer’s disease• Global Deterioration Scale >= 5 or 6• Mini Mental State Exam (MMSE)> = 3 and< = 14• Functional Assessment Staging (FAST) = 6a 77
    78. 78. Results - Moderate to severe AD• Patients• 252 patients randomized (126 memantine; 126 placebo)• 181 completers [97 (77%) memantine, 84 (67%) placebo]• Mean age 76 years• 31% male, 69% female• Median MMSE at baseline 7.9 78
    79. 79. Summary- Moderate to Severe AD• Statistically significant benefit of memantine compared to placebo on three independent levels: – clinical global impression – functional capacity in activities of daily living – cognition in moderate to severe Alzheimer‘s disease• Good safety and tolerability of memantine 79
    80. 80. Beneficial across the entire spectrum 80
    81. 81. Memantine FDA – October 2003• Uncompetitive NMDA receptor antagonist• A low-moderate affinity• Allow normal physiological activation of NMDA receptors• Blocks prolonged pathological activation of NMDA receptors – One factor implicated in pathology of Alzheimer’s Disease• Cummings – Studied in moderate-severe AD patients stabilized on Donepezil 81
    82. 82. Memantine Study• ADCS – ADL revealed at end points, favoured Memantine over Placebo• Abilities in grooming• Being left alone• Watching Television• Agitation, Aggression, Irritability/ Lability, Appetite and Eating 82
    83. 83. Short and Long-term Dementia – Memantine is safe• Five double blind Placebo controlled trials• Four open label extension studiesShort term safety• Headache - >5% (Twice that of Placebo)• Constipation - > 5% (Twice that of VaD)Long-term safety• Agitation, UTI, Fall, Injury, Dizziness - <7% (Similar to Placebo)• Vital signs and Lab values – No relevant differences 83
    84. 84. Memamtine - Role Beyond dementia• NMDA receptors is involved in no. of neurological & psychiachiatric disorders• Memantine being NMDA receptor antagonist is used in indications like Neuropathic pain, Parkinson’s disease, Neuroproctive agent etc 84
    85. 85. MEMANTINE IN THE TREATMENT OF DIABETICS WITH PAINFUL PERIPHERAL NEUROPATHY: A PLACEBO-CONTROLLED PHASE IIB TRIAL. Pain Med. 2002 Jun;3(2):182. 85
    86. 86. Results• Significant difference in mean nocturnal VAS at week 8 in patients taking 40 mg/day Memantine as compared to placebo• Significant improvement in nocturnal categerical pain intensity• Reduces sleep interference• Discontinuation rates due to adverse events comparable with placebo• Memantine 40 mg/day was effective and well tolerated for the treatment of diabetic peripheral neuropathy 86
    87. 87. Dextromethorphan andmemantine in painful diabeticneuropathy and postherpeticneuralgia: efficacy and dose- response trials. Sang CN, Booher S, Gilron I, Parada S, Max MB. 87
    88. 88. Results• Memantine reduced pain intensity by 17%• 47% of patients achieved greater than moderate pain relief• There was no effect of age, pain duration, duration, duration of diabetes, level of PHN, or characteristic of pain• Effective, safe & well tolerated in PHN 88
    89. 89. Memantine in Parkinson’s disease• Parkinsons disease is a chronic, progressive, neurodegenerative disease • In Parkinsons disease, the tonic inhibition by basal ganglia output structures may be exacerbated by the action of the subthalamic nucleus • Glutamate antagonists may therefore be able to retard the progression and to improve the symptomatology of Parkinsons disease • Memantine has recently been shown to be non- competitive NMDA antagonist and is widely used in Europe as anti-parkinsonian agent. 89
    90. 90. Memantine in Parkinson’s disease• The beneficial effect of memantine has been related to its novel properties as an NMDA receptor blocker which can neutralize the effect of glutamate at striatal and subthalamic levels.• Clinical observation has revealed that coadministration of L- dopa with either memantine or amantadine results in enhancement of their action is also reflected in an animal model of Parkinsons disease.• Such a combination therapy should allow the use of lower doses of both drugs which may reduce the occurrence of side effects and may also be predicted to have additional benefits related to the neuroprotective properties of memantine » J Neural Transm Gen Sect. 1994;98(1):57-67. 90
    91. 91. 91
    92. 92. 92
    93. 93. Dedicated to my family formaking everything worthwhile 93
    94. 94. READ not to contradict or confuteNor to Believe and Take for Grantedbut TO WEIGH AND CONSIDERTHANK YOU My sincere thanks to Mr. G. Kakuthan for his meticulous computer work 94

    ×