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Prof. A.V. SRINIVASANInstitute of Neurology

Chennai

Prof. A.V. SRINIVASANInstitute of Neurology

Chennai

WHEN TO START, SWITCH OR ADD IN ALZHEIMER’S DISEASE –

MEMANTINE

The sign wasn’t placed there

By the Big Printer in the sky

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DEMENTIA - Types

• Two Types:– Reversible– Irreversible

• Individuals must have intensive medical physical to rule out reversible types of dementia.

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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

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DEMENTIA

• Irreversible:

– Alzheimer’s– Lewy Body Dementia– Pick’s Disease (Frontotemperal Dementia)– Parkinson’s– Heady Injury– Huntington’s Disease– Jacob-Cruzefeldt Disease

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DEMENTIA

• Irreversible:– Alzheimer's 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

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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.

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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.

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Dementia - types

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Progression of dementia

Alzheimer's Disease

Dementia with Lewy Bodies

Vascular Dementia

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5

10

15

20

25

30

MMSE scores

1999 2000 2001 2002 2003 2004

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Dementia - Possible treatment outcomes

No effect

Symptomatic benefit

Slowed progression

Disease arrest

Stabilization

Time

Treatment

Fu

nct

ion

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Alzheimer’s Disease

DEFINITION:

– Progressive Neurodegenerative illness

–Behavioural disturbances

–Cognitive deficit

–Decline in Functional capacity

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Alzheimer’s disease• Alzheimer's disease is the most common form of dementia,

affecting about 4.5 million men and women in the United States.

• The incidence of Alzheimer's 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 Alzheimer's disease are often confused with the changes that take place in normal aging, it's important to remember that Alzheimer's disease is not a normal part of aging.

• In AD, both Short & Long term memory is affected

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Alzheimer’s disease• Alzheimer's disease affects at least 15 million persons

throughout the world

• As Alzheimer's disease advances, patients become progressively impaired in both cognitive and functional capacities, and the burden on caregivers increases

• Alzheimer's 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.

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Alzheimer’s disease

• In people with Alzheimer's 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 Alzheimer's disease.

• Over time, Alzheimer's disease progresses through three main stages: mild, moderate, and severe.

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Prevalence of Alzheimer’s disease increases sharply with increasing age

0

10

20

30

40

50

65-74 75-84 >84

Age groups ( years )

Pre

vale

nce

(%

) o

f A

D

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Estimated Number of New AD Cases

0

200

400

600

800

1000

1200

1995 2000 2010 2020 2030 2040 2050

year

Th

ou

san

ds

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IPA AD Conference, 1996

Functionalimpairment * IADL * ADL

Insidious onset Cognitive decline* Memory loss * Aphasia * Apraxia * Agnosia * Executive function difficultiesBehavioral signs

* Mood swings * Agitation* Wandering

Age over 60 years

No gait difficulties

AD

Clinical features of AD

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Factors that increase the risk for

Alzheimer's disease include:Age The risk of developing Alzheimer's

disease increases with age. According to the Alzheimer's Association,

10% of all people over the age of 65 have Alzheimer's disease.

• ~50% of people over 85 have it.

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Factors that increase the risk for

Alzheimer's disease include:• Gender -- Alzheimer's disease affects women

more frequently than men.

• Family history -- A clear, inherited pattern of Alzheimer's disease exists for less than 10% of all cases.

• Down syndrome -- People with Down syndrome often develop Alzheimer's disease in their 30s and 40s, although the exact reason is not known.

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Symptoms of Alzheimer’s Disease Alzheimer's disease is a brain disorder in which

nerve cells in the brain die, making it difficult for the brain's signals to be transmitted properly.

A Person with Alzheimer's 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.

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Symptoms cont’d…

Impaired memory and thinking -- The person has difficulty remembering things or learning new information.In the later stages of the disease, long-term memory loss occurs, which means that the person can't remember personal information, such as his or her place of birth or occupation, or names of close family members.

Disorientation and confusion -- People with Alzheimer's disease may get lost when out on their own and may notbe able to remember where they are or how they got there.They may not recognize previously familiar places and situations. They also may not recognize familiar faces or know what time of the day it is, or even what year it is.

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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.

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Symptoms cont’d

• Changes in personality and behavior -- The person becomes unusually angry, irritable, restless, or quiet. At times, people with Alzheimer's disease can become confused, paranoid, or fearful.

• Poor or decreased judgment -- People with Alzheimer's 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.

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Symptoms cont’d• Problems with language and communication – The person can't 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 can't 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.

•

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Stage I: Mild Alzheimer's disease

Signs 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

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Stage II: Moderate Alzheimer's diseaseSigns 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

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• 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)

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Stage III: Severe Alzheimer's disease

Signs of severe Alzheimer's 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

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Pattern of symptoms over time in patients with Alzheimer’s disease

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Cognition * Recall/learning* Word finding* Problem solving* Judgement* Calculation

Function* Work* Money/shopping* Cooking* Housekeeping* Reading* Writing* Hobbies

Behavior* Apathy* Withdrawal* Depression* Irritability

IMPAIRMENT

Adapted from Galasko, 1997

Clinical features of ADMild stage of AD (MMSE 21 30)

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Cognition * Recent memory (remote memory unaffected) * Language (names, paraphasias)* Insight* Orientation* Visuospatial ability

Function* IADL loss* Misplacing objects* Getting lost* Difficulty dressing (sequence and selection)

Behavior * Delusions* Depression* Wandering* Insomnia* Agitation* Social skills unaffected

IMPAIRMENT

Clinical features of ADModerate stage of AD (MMSE 10 20)

Adapted from Galasko, 1997

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Cognition * Attention* Difficulty performing familiar activities (apraxis)* Language (phrases, mutism)

Function* Basic ADLs Dressing Grooming Bathing Eating Continence Walking Motor slowing

Behavior* Agitation Verbal Physical* Insomnia

Clinical features of ADSevere stage of AD (MMSE <10)

Adapted from Galasko, 1997

IMPAIRMENT

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Alzheimer’s Disease: Impact on Patient

Aggression

HallucinationsUse the toilet

DelusionsFeed themselves

Fear or panicDress themselvesPraxis

Inappropriate behaviourKeep themselves cleanImpaired perception

RestlessnessAnswer the telephoneExecutive dysfunction

ApathyGo out aloneLanguage difficulties

AnxietyKeep appointmentsDisorientation in time and place

ConfusionDriveAttention deficits

DepressionMemory loss

Behavioural and psychotic symptoms

Activities of daily living; unable to:

Cognitive impairments

Maintain their own finances

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Impact of Alzheimer’s Disease on the Caregiver

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Alzheimer’s versus normal brain

Alzheimer’s versus normal brain

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Normal versus degenerating neuron

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Neuroimaging

Various CT scan reports in AD * Normal examination for the patient's 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 stroke

Diagnosing AD - neuroimaging, computed (axial) tomography (CT)

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All patients* Complete blood count* Thyroid function* Vitamin B12 and folate* Syphilis serology * BUN and creatinine * Calcium * Glucose * Electrolytes * Urinalysis * Liver function tests

Most patients   * ECG* Chest X-ray

Diagnosing AD laboratory tests

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Anatomical findings Alzheimer’s

1. Plaques: clusters of abnormal cells

2. Tangles of neurofilaments inside neurons

3. Deterioration of dendrites

4. Loss of neurons

5. Hippocampus is 47% reduced in size (in normals it shrinks 27%).

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Anatomical findings

6. Amydgala 26% decrease in volume

7. 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.

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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.

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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

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Theories Regarding Causes of Alzheimer's

• 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.

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Theories Regarding Causes of Alzheimer's

• 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 Alzheimer's patients.

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Theories Regarding Causes of Alzheimer's

• 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)

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Theories Regarding Causes of Alzheimer's

• 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

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Causes of AD

L oss o fC h o lin e rg ic n eu ron s

S en ile P laq u es &N eu ro fib illa ry tan g les

D ys fu n c tion o f g lu tam ateN eu ro tran sm iss ion

H a llm arks o f A DTyp e t it le h ere

30% of symptoms 70% of symptoms

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AD - Pathogenesis

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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

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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

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Amyloid plaque

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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

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Why excess of glutamate

D ys fu n c tion o fG lu tam ate reu p take

p u m p

D ys fu n c tion o f g lu tam atesyn th e tase en zym e

B eta am ylo id

Excess of glutamate in synapse

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Glutamate Excitoxicity hypothesis

Glutamate

Stimulation of NMDA receptors

Influx of Ca++

Generation of free radicals

Oxidation of RNA, DNA

in the neuron

Cell death

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Excitotoxicity

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Mechanism of action

Memantine is

• Uncompetitive

• voltage dependent

• moderate affinity

NMDA receptor antagonist

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Mechanism of actionUncompetitive means it does not compete with glutamate for binding site.

Memantine binding site is located inside the ion channel

Moderate affinity means it can be easily displaced from NMDA receptor

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Mechanism of actionVoltage dependent means , Memantine blocks NMDA receptors only when

membrane is hyperpolarised due to excess of Glutamate. Hence it allows

normal Glutamate neurotransmission

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Mechanism of action

Glutamate

Stimulation of NMDA receptors

Influx of Ca++

Generation of free radicals

Prevents Cell death

DOES NOT

destroy

surrounding neuron

Cholinergic neurons

Allows the action of

A-APP on B-amyloid

NO Accumulation of B- amyloid & formation of plaques

NO Stimulates enzyme kainases

NO Hyperphospholation of tau

proteins & formation of NFTs

Memantine blocks NMDA receptor

NO

NO

NO

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Mechanism of action

Benefits 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

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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

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• 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

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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.

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Pharamcokinetics - Summary

Bioavailability 100%

Tmax 3-8 hrs

Cmax (single 20 mg dose) 22-46 ng/ml

Time to steady state 11 days

Elimination half life 60-100 hrs

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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 AD

Clinical efficacy of Memantine is confirmed in no. of double blind placebo controlled trials

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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

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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

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• 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)

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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

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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

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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

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Beneficial across the entire spectrum

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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

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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

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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

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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

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MEMANTINE IN THE TREATMENT OF DIABETICS WITH PAINFUL PERIPHERAL NEUROPATHY: A PLACEBO-

CONTROLLED PHASE IIB TRIAL.

Pain Med. 2002 Jun;3(2):182.

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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

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Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-

response trials.

Sang CN, Booher S, Gilron I, Parada S, Max MB.

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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

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Memantine in Parkinson’s disease

• Parkinson's disease is a chronic, progressive, neurodegenerative disease

• In Parkinson's 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 Parkinson's disease

• Memantine has recently been shown to be non-competitive NMDA antagonist and is widely used in Europe as anti-parkinsonian agent.

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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 Parkinson's 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.

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Dedicated to my family for making everything worthwhile

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My sincere thanks to Mr. G. Kakuthan for his meticulous

computer work

My sincere thanks to Mr. G. Kakuthan for his meticulous

computer work

READ not to contradict or confute

Nor to Believe and Take for Granted

but TO WEIGH AND CONSIDER

THANK YOU