Artistic Regression

• Distortion – comic-grotesque representation Condensation – filling to overflowing

• Transformation (neomorphism) – anatomic changes and strange facial features (physiognomy)

• Stereotype – ornamental stereotype and repetition of particular motives

• Woodenness – geometrical and diagrammatic design and pictures enclosed with a frame, lack of depth (lack of shading) and lack of movement (wooden rigidity)

• Disintegration – neglect of spacial relationships between objects and loosening of physiognomy of human beings and animals.

• Regression – relapse into primitive or child-like drawings and lack of perspective– Maurer K, Frolich L, ALZHEIMER INSIGHTS Paintings of and Artist

With Alzheimer Disease

Clock Drawing

Life expectancy with Dementia

• 3.3 years, comparable to some malignancies

• In patients diagnosed with dementia

• Wolfson et al NEJM 2001;344:1111-1116

Alzheimer Brain Atrophy

From Whole Brain Atlas

Neurodegenerative Diseases and PrionsStanley B. Prusiner, M.D. Twenty-five years ago, little was known about the causes of neurodegenerative diseases.

Volume 344:1516-1526 May 17, 2001

Number 20

Stanley Prusiner Nobel 1997

Thesis:

• Degenerative Disease is caused by the accumulation of toxic substances

• Deranged metabolism over long pds of time.

• Primarily diseases of elderly

• As in cholesterol and homocysteine in atherosclerosis

Neurologic Diseases attributed to Protein deposition

• Alzheimer disease: Aβ42• Amyloid Angiopathy: Aβ42• Huntington Disease: Huntingtin• Prion Disease: PrP sc• “Tauopathies: Pick’s, FT dementia, PSP• Parkinson Disease, Lewy body Dementia (alpha synuclein)• Spino-cerebellar Degenerations: Ataxins• ALS: Neurofilament• Macular Degeneration: A2E

Macular Degeneration=“Age Related Maculopathy”

• 5% of 60 year olds, 20% of 80 year olds• Disorder of Phagocytosing cells in Retinal

Pigment epithelium• Accumulation of drusen or lipofuscin in

Retinal Pigment Epithelium• Genetic forms: may be “A2E” accumulation• Retinal Alzheimer’s Disease

Macular Degeneration

Pathogenesis of MacularDegeneration fromScientific American 10/2001

First Hints to Causation

• Genetics

• Familial Alzheimer Disease

• Trisomy 21

Alzheimer Genes: Chromosome #s

• 21: Abn APP Gene <5%*

• 14: Presenilin 1 18-50%*

• 1 : Presenilin 2 <1%*

• 19:APOE-epsilon 4: Incr risk in Caucasions

• 19:APOE-epsilon2 on Chr 19: decr risk

*of early-onset Disease

Apolipoprotein E4

• Variant alleles E2,E3

• Variants differ by only 1 amino acid

• E4 is present in 64% of late-onset Alz patients as 34% of unaffected controls

• 2 copies (homozygote) of E4 increases risk of Alz from 45% to 91%

All have in Common:

• Increased Accumulation of Amyloid– Abnormal Accumulation– Defective Degradation

Alzheimer Disease

• Cerebral Amyloidosis

The Amyloid Hypothesis

Pathogenesis

• Beta-Amyloid Accumulation• Decrease in Acetylcholine, AchE• Injury• Free-Radical Formation• Genetics

– Polygenic– ApoE4– FAD

Characteristic Changes

• Pathology– Tangles, plaques, Granulo-vacuolar degeneration,

Atrophy,neuronal loss

• Biochemistry– Decreased Ach, AchE

• Imaging– Atrophy

– Decreased metab activity in post’r cerebral association Cortices

Senile Plaque

• A hallmark pathologic lesion specific for AD is senile plaque. Plaques are composed of amyloid-beta (A-beta), which is found in soluble form in the body fluids of patients with AD. Initially, A-beta aggregates into diffuse plaques that lack definite borders. Later, it matures into compact plaques formed of A-beta fibrils that may be toxic to surrounding neurons.

Amyloid Plaques

• Between Cells (extra-cellular)

• Appear before Tangles do

• Associated with Microglia (inflammation)– (microglia are phagocytes of the brain)

Amyloid Precursor Protein

• 695-770 Amino Acids

• Transmembrane protein

• Beta-Amyloid is snipped out precursor protein

• Beta-Amyloid- transmembrane component

Cast of Characters

• Amyloid Precursor Protein (APP)

• Secretases – alpha, beta, Gamma– Enzymes that cut up Amyloid Precursor Protein

• Beta-Amyloid (or Aβ42)

• Beta-Amyloid is the villain

• Setting: The neuron cell membrane

Secretase Steps

• Alpha then Gamma – OK

• Beta then Gamma – yields Beta Amyloid

• 40 Amino Acid fragment is OK but minority cut into toxic 42 Amino acid fragment which constitutes plaque (Aβ42)

Presenilins

• Early Onset Alzheimer's

• Trans-membrane Protein Cleavers

• PreI: Chr 14, PreII:Chr 1

• Knockout for these proteins: No Beta Amyloid

• Forms of Gamma-Secretase??

Are “Pre-Senilins” forms of Secretase??

Amyloid Plaque

Pathogenesis of Senile Plaque

• Toxic Beta Amyloid fragments build up outside the cell

• E4 may be selectively removed from the extracellular space in place of beta-amyloid

• Beta-Amyloid is toxic and leads to other pathology

Cutting β-Amyloid Precursor Protein

• Alpha and Gamma Secretase give rise to harmless p3 protein

• Beta then Gamma secretase yield either:– Harmless 40 amino acid residue of Beta-

Amyloid OR– Toxic 42 Amino Acid residue of Beta Amyloid

Gamma Secretase: a trans-membrane protease

Beta Amyloid Mediated Damage

• Ca++ Deregulation

• Creation of Free Radicals

• Immune Aggregation

Beta Amyloid

• 4.2 kD fragment, 42-43• Abnormal cleavage of Beta Amyloid

precursor protein (APP)– APP part of family of 70kD transmembrane

proteins

• Beta-Secretase, APP cleaving Protein• Injury, ischemia incr APP • Amyloid is neurotoxic

Mechanism of Amyloid destruction

• Liberating Calcium in Cells

• Damaging Mitochondria

• Enhancing inflammatory (Microglial) Response

New Strategies

• Beta-Amyloid Vaccine

• Beta and Gamma Secretase Blockers

• Zinc and Copper Chelators

Strategies to Prevent and treat Alzheimer’s

• 1. Inhibition of the proteases (enzymes) that produce Aβ42 ;2. Inhibition of Aβ42 aggregation that precedes A deposition; 3. Inhibition of Aβ42 -induced neurotoxicity

• Vaccine or antibody to Aβ42

Dennis Selkoe & Howard Weiner

Mouse Trials of Vaccine

• Nasal Administration

• Genetically affected mice make excessive Beta Amyloid

• Mice show evidence of Dementia

• 50% reduction in plaque formation

• Improvement on tests

• Human phase II trials begin this year

Elan Pharmaceutical trial

• In PDAPP mouse (a genetically engineered mouse model with Alzheimer’s-like pathology)

• AN-1792, both reduces pre-existing deposits of amyloid and inhibits accumulation

Gene linkage

• Long arm of Chromosome 10 in late onset Alzheimer

• ?Connected with degradation of Beta Amyloid?

• Insulin processing protein

• Rudy Tanzi Dec22,2000 Science

Treatment Cornerstones

• Cholinesterase Inhibitors• Ancillary Symptoms

– Anxiety– Agitation– Disorientation and Wandering– Sleep Disturbance

• Placement• Caring for Caretaker

Other Pathology

CSF in Alzheimer’s Disease

• They found levels of CSF beta-amyloid protein were significantly lower, onaverage, in people with Alzheimer's disease than the comparison group (183pg/mL vs. 491 pg/mL). In addition, levels of CSF tau protein weresignificantly higher in Alzheimer's disease patients than in the others (587pg/mL vs. 244 pg/mL).

Diagnosis Criteria• Alzheimer's disease is characterized by progressive decline and ultimately

loss of multiple cognitive functions, including both:

* Memory impairment--impaired ability to learn new information or torecall previously learned information.

* And at least one of the following:Loss of word comprehension ability, for example, inability to respond to"Your daughter is on the phone." (aphasia);Loss of ability to perform complex tasks involving muscle coordination,for example, bathing or dressing (apraxia);Loss of ability to recognize and use familiar objects, for example,clothing (agnosia);Loss of ability to plan, organize, and execute normal activities, forexample, going shopping.

B. The problems in "A" represent a substantial decline from previous abilitiesand cause significant problems in everyday functioning.

C. The problems in "A" begin slowly and gradually become more severe.

D. The problems in "A" are not due to:

* Other conditions that cause progressive cognitive decline, among them:stroke, Parkinson's disease, Huntington's chorea, brain tumor, etc.* Other conditions that cause dementia, among them: hypothyroidism, HIVinfection, syphilis, and deficiencies in niacin, vitamin B12, and folic acid.

E. The problems in "A" are not caused by episodes of delirium.

F. The problems in "A" are not caused by another mental illness: depression,schizophrenia, etc.

Granulo-vacuolar Degeneration

Granulo-vacuolar degeneration

• 5 clear intracytoplasmic vacuole

• Argyrophillic core

• Pyramidal cell region of hippocampus

Neurofibrillary Tangles

Neurofibrillary Tangles

Neurofibrillary Tangle

Neurofibrillary Tangles

• Paired Helical Filaments associated with Tau which binds to microtubules

• Phosphorylation of Tau inhibits its ability to stabilize microtubules

• Leads to microtubule agglomeration as PHF

• Test for Tau in CSF

Neurofibrillary Tangle

• Tau protein –Ass’d with microtubules

• Correlates more with degree of dementia

• Appear after than Senile plaque

• Not Specific for Alzheimer Disease

Neurofibrillary Tangle

• Abnormal intracellular structure caused by phosphorylation of the tau protein in the cytoskeleton of the neuron.

• Microglial cell proliferation, especially in association with senile plaques, suggests inflammatory processes play a role in the disease process.

Fuel and Longevity

• Daf-2 gene in C. elegans– When not functioning lifespan increases from 10

to 30 days

• An insulin receptor gene in humans

• Rat experiments with caloric reduction

• Monkey and human receptors

• Gary Ruvkun, Harvard Med’l School

Causes of Dementia

• Alzheimer –55%• Vascular - 20%• Lewy Body –15%• Pick’s and lobar atrophy –5%• Other 5%

– Small,GW et al JAMA 1997,278:1363-71, APA, Am J Psychiatry 1997,154 (suppl)1-39;

– Morris JC Clin GeriatrMed. 1994,10:257-76

Multi-infarct dementia

Whole brain Atlas

Hachinski Score for Dx of Vascular Dementia

• Abrupt onset

• Stepwise deterioration  

• Fluctuating course: improvement between strokes  

• Relative preservation of personality  Nocturnal confusion   

   • Depression

   

Hachinski Score (cont’d)

• Somatic complaints

• Emotional incontinence• History of hypertension• Evidence of atherosclerosis

– Pvd, MI

• Focal Neurological symptoms (TIA)   Focal neurological signs

Vascular Dementia

• CT or MRI critical• Either large volume of brain affected, preferably

in both hemispheres or multi-infarcts in strategic locations

• Small Vessel– Lacunar State, deep strokes– Subcortical deficits

• Multiple Cortical Infarcts:aphasia, agnosia, apraxia

Behavior cont’d

Wandering: can be dangerous, medications not effective

provide a "sheltered freedom". Example: Cover door knob with shoe boxes.

Screaming: very disturbing, may be related to pain,

delusion or Neuroleptic induced akathisia. ? background music may be helpful. Sleep disruption & Sundowning: very common

Agitation and Dementia

• Structure and routine. • Follow regular, predictable routines. 

• Keep things simple. 

• Distract. 

Behavior

• Why is depression relatively uncommon??

• Anosognosia for dementia

Simple and Active

• Break down complex tasks into many small, simple steps that the person can handle Folding towels while one is doing the laundry.  Allow time for frequent rests.  Redirect.  Get the person to do something else as a substitute. A person who is restless and fidgety can be asked to sweep, dust, rake, fold clothes, or take a walk or a car ride with the caregiver. 

• Repetitive simple movement

Distract

• Offer a snack Put on a favorite videotape or some familiar music  Be flexible.  Know when to back away from a task- a bath or dressing and reapproach later Soothe.  When agitated, do simple, repetitive activities such as massage, hair brushing, or giving a manicure.  Reassure. Let the person know that you are there and will keep him or her safe. 

Sleep and Anxiety

• Nonpharmacologic: Daytime stimulation, adequate supervision, avoidance of napping.

• Neuroleptics: may be helpful for delusion and agitation. 20% may get worse.

Preventing Alzheimer Disease

Alzheimer’s Burden

• 4 Million Americans• 14 Million Projected by 2050• 1/10 over 65• 85+ one of three has AD• Life expect: 8 years• in U.S .$110 B. in yr 2000• Half of all NH patients• $12500-70000/person year, avg lifetime

cost=$174000

Alzheimer’s Burden (cont’d)

• Prevalence doubles every 5 years after 65

• 360,000 new cases/yr

• Higher in non-Caucasians whose numbers are growing in population

• 65+ now 13% but will reach 18% by 2025

• Sltly more than 50% receive care at home

Neurological Diseases

• Alzheimer’s 4 Million $110 Bn • Affective Disorders 17 Million $44Bn• Drug & etoh 15Million $240Bn• Intractable Pain $65 Bn• Parkinson’s 500,000 $5.6Bn• Schizophrenia 2 Million $30Bn• Stroke 700,000/yr $30Bn• MS 350,000

– Source:JAMA 285:594(2001)

Neurological Disease(Prevalence)

• Alzheimer Disease: 4 million

• Stroke: 3-4 Million

• Traumatic Brain Inj: 2.5-3.7 Million

• Epilepsy: 1.75 Million

• Parkinson’s: 1.5 Million

Future Burden

• 2011: first baby boomers turn 65

• 18% of population by 2025

• 85+ now 4 million, 8.5 million by 2030

• 50% of Alz pts are at home, 50% in care

Risks

• Advanced Age– Half of those >85; 1/10 of those >65

• Female Sex• “Mild Cognitive Impairment”• Head Injury• APOE4• Family History• Low Education• Down’s• ?Race• ?Homocysteine?

Estrogen

• 2/3 of Alzheimer Patients are women• Onset After Menopause• May increase cholinergic transmission• Neurotrophic effects• Anti-amyloidogenic properties • Association with Neurotrophins• Regulates synapse formation in

hippocampus

Estrogen

• 3 studies in Neurology 2000;54 show no effect in women already Diagnosed

• Baltimore Long. Study “After adjusting for education, the relative risk for AD in ERT users as compared with nonusers was 0.46”

• Tang MX et al. Effect of estrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet 1996;348:429-432

• Jury Still Out• Prospective treatment trials

Estrogen Reviews

• NEJM 344:1242-1244 April 19, 2001 Number 16 Richard Mayeux

• Neurology 2000;54:2035-2037 Marder and Sano

Women’s Health Initiative Memory Study (WHIMS)

• In May 2003, scientists taking part in the Women's Health Initiative Memory Study (WHIMS), part of the Women's Health Initiative, reported new health risks for women over age 65 using a type of combined estrogen plus progestin known as Prempro™.

• The WHIMS scientists found that the number of women over age 65 who began having symptoms of dementia while using this form of estrogen plus progestin was twice as high as those not taking any hormones.

Homocysteine

• Eight years• RR= 1.4 for each increase of 1 SD in the log-

transformed homocysteine value either at base line or eight years earlier

• RR of Alzheimer's disease was 1.8 per increase of 1 SD at base line

• RR=1.6 per increase of 1 SD eight years before base line. • Plasma homocysteine level greater than 14 µmol per

liter doubled the risk of Alzheimer's disease. – Seshadri et al. N Engl J Med 346:476-483 February 14, 2002

NSAIDs

• Prospective, population-based cohort study of 6989 subjects 55 years of age or older who were free of dementia at base line.

• Relative risk of Alzheimer's disease was 0.95 in subjects with short-term use of NSAIDs

• RR= 0.83 with intermediate-term use• RR= 0.20 wit long-term use.• Risk did not vary according to age• Use of NSAIDs was not associated with a reduction

in the risk of vascular dementia. – Bas A. in 't Veld, N Engl J Med 2001; 345:1515-1521, Nov 22, 2001

Baltimore Longitudinal Study of Aging

Relative risk of Alzheimer's disease of 0.50 among regular users of NSAIDs, as compared with nonusers

Stewart et al Neurology 1997;48:626-632

Alzheimer Genes

• 21: Abn APP Gene

• 14: Presenilin 1

• 1 : Presenilin 2

• 19:APOE-epsilon 4: Incr risk in Caucasions

• 19:APOE-epsilon2 on Chr 19: decr risk

Late Stage

• Mixes up past and present

• Expressive and receptive aphasia

• Misidentifies familiar persons and places

• Parkinsonism and falls risk

• More mood and behavioral disturbances

• Needs help with all ADL’s, Incontinent

Ongoing Studies From May 16, 2002 ELEENA DE LISSER, The Wall Street Journal

PATHWAYS TO PREVENTION?Ongoing clinical trials related to Alzheimer&apos;s disease and possible modes of prevention:

STUDY WHO'S ELIGIBLE CONTACT

ADAPT (Alzheimer&apos;s Disease Anti-inflammatory Prevention Trial)

People 70+ who have not been diagnosed with

Alzheimer's but have a relative who had the disease.

1-866-2-STOP-AD or www.2stopad.org

PREPARE (Preventing Postmeno-pausal Memory Loss and Alzheimer's with Replacement Estrogens)

Women 65+ 1-877-DELAY-AD or www.delay-ad.org

PREADVISE (Prevention of Alzheimer&apos;s Disease by Vitamin E and Selenium)

Men 60 to 90 years old 1-800-333-8874 or www.mc.uky.edu/coa

GEM (Ginkgo Evaluation of Memory)

People 75+, Closed to new participants without dementia.

www.alz.org/research/clintrials/#prevention Study sponsors: National Institute on Aging (ADAPT, PREPARE, PREADVISE) and National Center for Complementary & Alternative Medicine (GEM) at the National Institutes of Health.

ADAPT

• Alzheimer Disease Anti inflammatory Prevention Trial

• Use celecoxib or naproxen for years

• Evaluation at Center– 3 X first year– 2 X per year after that

• Phone follow up

Prevent AD with Estrogen

• National Institute on Aging

• Mary Sano, PhD

• 5 year study

Strategies

• Vitamin E and Selegeline or donepezil

• Estrogens

• NSAIDs

• B12,B6,Folate (homocysteine)

• Statins

• Valproate ?”Neuroprotective”

• IPA (Indole-3-Propionic Acid) anti-oxidant

Homocysteine

• Does this mean that lowering H. levels will prevent A’s Disease?

• No one knows

Homocysteine

• 50 Mg pyridoxine

• Up to 4 mg. of Folate

• 500 mcg of B12

NSAIDs

• Inflammation is part of Aβ Accumulation

• Longitudinal Studies show dose related effect of NSAID’s

• Nature Nov. 8, 2001 NSAID’s directly decrease deposition of Aβ42– ASA,Celebrex, Naprosyn – no effect– Others at very high doses decreased production

in cells up to 80%

Selegiline and Vitamin E

• 2000 Units of Vitamin E and 10 mg. Selegiline• S. -4 month delay in disease progression e.g. to

NH placement• E. 6 month delay in Disease progression• No difference on cognitive scores• Combined treatment did slightly worse than either

treatment alone

– Sano et al. N Engl J Med 1997;336:1216-1222

Gingko Biloba

• 1 year

• 120 mg.

• 2.4% decrease in Alzheimer’s disease Assessment scale Cognitive subscale

• Very little other evidenceLe Bars PL et al.JAMA 1997;278:1327-1332

Alzheimer Disease

• Dissolution of the Personality

• Inexorable Progression

Keys of Therapy

• Early Recognition of Disease

• Cholinesterase Blockers

• Treatment of Ancillary Symptoms

• Maintaining Patient in own Environment

• Family Support

Diagnosis

• Index of Suspicion

• Age!

• Sensitivity to Patients and Family

Vigilance

• Now Important because there are now early treatments that help.

10 Warning Signs:

• Dysfunction on Job

• Problem with Language function

• Difficulty performing Familiar Tasks

• Disorientation

• Poor Judgment

• Altered Abstract thinking

More Signs

• Misplacing Objects

• Personality Change

• Altered Mood and Behavior

• Loss of initiative

Diagnostic Criteria for Dementia

• Multiple Cognitive Deficits with Both– Memory Impairment plus one or more of foll’g:– Aphasia, Apraxia, Agnosia, Executive function– Impaired abstraction, judgement

• Impaired Social or Occupational Function– DSM IV (1994), 133-35

Diagnostic Criteria (cont)

• Cognitive Deficits are not due to other processes incl– Substances– Systemic processes– Delirium and acute conditions– Not better accounted for by another Axis I

disorder

Diagnosis: Keys

• Not patient, but Persons Other than patient complain of decreased cognitive function.

• Backing away from or ceasing to participate in previous hobbies and activities

• Take spouse, signif other, employer reports seriously!!

Alzheimer Dementia

• Often “anosognosia” unawareness of problem on part of sufferer

• Also denial

Pseudo-Dementia

• Often patient will themselves complain of memory loss

• Younger patient

• Memory problem complained of

• Spouse and co-worker find no problem

• Pre-occupation

• Anxiety is the enemy of recall

Pseudo-Dementia

• Some sharp or compulsive persons notice a normal slipping with age– Ready recall– Word-finding

• Again, no complaints from others

• Difficult distinction

• May require psychometrics to distinguish

Pseudo-Dementia

• Associated with severe depression

• Lack of reactivity “psychomotor retardation”

• More abrupt onset

• Some old folks have combined organic dementia and severe depression

MCI

• 6-25% progress to Alzheimer’s disease per year.

Stages: Mild

• Routine loss of recent memory

• Mild aphasia or word-finding difficulty

• Seeks familiar and avoids unfamiliar places

• Some difficulty writing and using objects

• Apathy and depression

• Needs reminders for some ADL’s

Stages: Moderate

• Chronic loss of recent memory

• Moderate Aphasia

• Gets lost at times even inside home

• Repetitive actions, apraxia

• Possible mood and behavioral disturbances

• Needs reminders and help with most ADL’s

Evaluation

• Thorough Hx/Pex• Mental Function Evaluation• CBC, Chems, RPR, LFT’s,Thyroid, B12• HIV testing in selected cases• Imaging (CT, MRI) in most cases• Neuropsych testing if dx is uncertain• LP in doubtful cases

– Tau and amyloid beta

• Apolipoprotein genotype??

Evaluation: compare betw visits

• Folstein Mini-Mental Status

• Clock-drawing

• Scale of level of Function as reported by family member

• Language function

Rule Out

• Alcohol

• Depression

• Drug s

• Metabolic Derangement

• Nutritional Deficiencies

• Infection

Causes of Dementia

• Alzheimer –55%• Vascular - 20%• Lewy Body –15%• Pick’s and lobar atrophy –5%• Other 5%

– Small,GW et al JAMA 1997,278:1363-71, APA, Am J Psychiatry 1997,154 (suppl)1-39;

– Morris JC Clin GeriatrMed. 1994,10:257-76

Hachinski Score for Dx of Vascular Dementia

• Abrupt onset

• Stepwise deterioration  

• Fluctuating course: improvement between strokes  

• Relative preservation of personality  Nocturnal confusion   

   • Depression

   

Hachinski Score (cont’d)

• Somatic complaints

• Emotional incontinence• History of hypertension• Evidence of atherosclerosis

– Pvd, MI

• Focal Neurological symptoms (TIA)   Focal neurological signs

Vascular Dementia

• CT or MRI critical• Either large volume of brain affected, preferably

in both hemispheres or multi-infarcts in strategic locations

• Small Vessel– Lacunar State, deep strokes– Subcortical deficits

• Multiple Cortical Infarcts:aphasia, agnosia, apraxia

Pick’s Lobar atrophy

• Behavioral disturbances precede dementia• Disinhibition

– Exaggeration of previous eccentricities

– Exhibitionism and overt sexuality

– Inappropriate humor, loss of social skills• Ethnic jokes

– Slovenly behavior, decr hygiene and cleanliness

– Distractibility and impersistence

• Language dysfxn rather than memory

Pick’s

• Fronto-temporal atrophy on imaging or SPECT or PET scans show decr metabolism

• “Tau –opathy”– Grouped with PSP etc

• May be familial

“Others”

• Creutzfeldt-Jakob

• Cortico-Basal Degen

• Progressive Supranuclear Palsy

• Frontal Lobe Dementia

Parkinson Related Dementia

• Late consequence of Parkinson Disease

• Hallucination prominent– Dopaminergic Meds, anticholinergics are

hallucinogenic– Parkinson and age related perceptual changes

Parkinson’s and Dementia

• Diffuse Lewy Body Disease

• Alzheimer changes in the aged

• Parkinson-dementia complex

• Parkinson related diseases

• Anti-esterases seem effective here too

Treatment Cornerstones

• Cholinesterase Inhibitors• Ancillary Symptoms

– Anxiety– Agitation– Disorientation and Wandering– Sleep Disturbance

• Placement• Caring for Caretaker

Cholinergic hypothesis

• Diffusely projecting area: Nucleus Basalis of Meynert

• Layers I and II major cholinergic cortical innervation

• Amygdala and hippocampus lgest innervation

AChE inhibitors

• Establish a diagnosis of probable AD.  • Determine the stage of the patient (AChE-I are

approved for mild to moderate AD). • Discontinue agents with anticholinergic

effects. • Reduce dosage or discontinue if side effects

are intolerable.• Monitor efficacy by caregiver report, quantified

mental status examination, effects on activities of daily living, or effects on behavior.

AChE’s Cont’d• Continue for 6-12 months if any of the efficacy

measures indicate benefit or there is stabilization in functional, cognitive, or behavioral deterioration.

• Continue AChE-I therapy until there is evidence of ongoing cognitive decline. If there is evidence of continuing cognitive decline, reduce the dosage and monitor to determine if there is an acceleration of deterioration.  If deterioration is accelerated, reintroduce AChE-I. 

Activity of Daily Living

Behavior Cognitive Dysfunction

Alzheimer Manifestations

All aided by Anti-esterases

Cholinesterase BlockersYr avail 1993 1996 2000 2001

Drug Tacrine Aricept Exelon

Reminyl

Rev reversabl

Revers Pseudo-irrev

reversibl

class Acridine Piper-idine

carbamate

Phenantrene alkaloid

AchE yes yes yes yes

BuChE yes minimal

yes minimal

Cholinesterase blockers

characteristic

Tacrine

Cognex

Donepzi

Aricept

Rivastigmine

Exelon

Galantamine

Reminyl

Dose/D 4 1 3 2

Max dose 160 mg 10 mg 12 mg 24 mg

Food? no no yes Yes

D:D interactions?

yes yes None known

Yes, some

Initial dose

40 mg 5 mg 3 mg 8 mg

Types of Cholinergic Receptors

• Muscarinic – excitatory– M1 most common in cortex– M2 presynaptic autorecptor governing release

in basal forebrain– Work via G proteins

• Nicotinic –Inhibitory– Ligand-gated ion channels

Acetylcholine

• Formation: ChAT and Acetyl-CoA

• Degradation: AchE and Butyryl-cholinesterase

Butyrylcholinesterase

• Role is minor in normal brain

• Proportionate activity increases in Alzheimer brain

AChE inhibitors: Progression?

• Patients on AChE inhibitors had a slower rate of progression than placebo treated patients

• Raises the issue of possible biological effect of these agents to slow progression of disease

Galantamine (Reminyl)

• Start at 4 mg BID (8 mg/day) for at least 4 weeks, then 8 mg bid Available in 4 mg, 8 mg, and 12 mg tablets Most frequent adverse events that occurred with placebo, REMINYL 16 mg/day, and REMINYL 24 mg/day, respectively, were nausea (5%, 13%, 17%), vomiting (1%, 6%, 10%), diarrhea (6%, 12%, 6%), anorexia (3%, 7%, 9%), and weight decrease (1%, 5%, 5%).

Reminyl

• Average approx. 4 pts on ADAS-Cog Scores

Galantamine

• Common snowdrop (Galanthus nivalis) • Binds AChE

• Modulator of Nicotinic Receptors

• ?Enhanced Sexual Fxn

• Mythology– Iliad, Circe, Atropine, Jimsonweed

Rivastigmine

• Exelon Approved in April 2000 for treatment of mild to moderate Alzheimer's

disease. • Benefits: Improved activities of daily

living, including eating, dressing, and household chores.  Reduce behavioral

symptoms, such as delusions and agitation. Improved cognitive function

Reduced use of psychotropic medications

Faster Progression yields Increased response

• Patients with moderate-stage AD (Mini-Mental State Examination [MMSE] scores = 10-17) have a naturally faster rate of disease progression when taking placebo and a larger magnitude of response to cholinesterase inhibitors; patients with mild-stage AD (MMSE scores = 18-26) have a lesser magnitude of response.[28] In addition, a subanalysis of a large rivastigmine trial found that a faster rate of progression before therapy initiation (regardless of disease stage at baseline) predicted a more robust response to treatment.[29]

Rivastigmine

• Shown to improve: Global function, behavior, and Cognition

Rivastigmine

• Temporarily inactivates Cholinesterase by forming a Covalent Bond

• 3 mg bid decreases AChE in CSF by 46%

• 6mg bid decreases AChE by 62%

• Duration of signif inhibition lasts up to 6 hours.

Alzheimer Scales

• CIBIC-Plus: 1-7– Clinician’s interview-based impression of change with

caregiver input

– 1=marked improvement, 4=nc, 7=marked worsening

• ADAS-Cog:0-70– Higher scores=greater cognitive impairment

– Mild to moderate=15-25

– 6-12 points/yr average deterioration

Rivastigmine: GI Effects

• 18% Men, 26% Women at Max dose

ADAS-Cog Effects

Rivastigmine

• Dose: titrate dosage to achieve optimal effect. Usual dose: 6 to 12 mg/day given

BID. Start 1.5 mg bid, increase by 3 mg every 2 weeks.  Available in capsule doses

of 1.5, 3, 4.5, 6 mg. • Half life: 2 hours Few interactions with

other drugs Side effects: No hepatotoxicity GI disturbances, occur

mainly during dose adjustment. 

Aricept (donepezil)

• Indicated for mild to moderate Alzheimer's dementia

• More selective for acetylcholinesterase, the cholinesterase common in the brain, believed to account for the low incidence of GI side effects

• 5 mg qd for 4 to 6 wk, if tolerate increase to 10 mg qd

Aricept

• Pharmacology:  Half life: 72-hour Steady states are achieved in 15 days. 94% protein-bound metabolized by the hepatic P450 enzyme system, but few drug interactions have been identified. Adverse effect:  nausea, vomiting, gastrointestinal cramping, diarrhea and muscle cramping. Does not have hepatoxicity.

Behavior Problems

Personality change: apathetic or more impulsive Anxiety:

apprehension over upcoming events

Aggression: physical or verbal

Behavior cont’d

Wandering: can be dangerous, medications not effective

provide a "sheltered freedom". Example: Cover door knob with shoe boxes.

Screaming: very disturbing, may be related to pain,

delusion or Neuroleptic induced akathisia. ? background music may be helpful. Sleep disruption & Sundowning: very common

Agitation and Dementia

• Structure and routine. • Follow regular, predictable routines. 

• Keep things simple. 

• Distract. 

Behavior

• Why is depression relatively uncommon??

• Anosognosia for dementia

Simple and Active

• Break down complex tasks into many small, simple steps that the person can handle Folding towels while one is doing the laundry.  Allow time for frequent rests.  Redirect.  Get the person to do something else as a substitute. A person who is restless and fidgety can be asked to sweep, dust, rake, fold clothes, or take a walk or a car ride with the caregiver. 

• Repetitive simple movement

Distract

• Offer a snack Put on a favorite videotape or some familiar music  Be flexible.  Know when to back away from a task- a bath or dressing and reapproach later Soothe.  When agitated, do simple, repetitive activities such as massage, hair brushing, or giving a manicure.  Reassure. Let the person know that you are there and will keep him or her safe. 

Sleep and Anxiety

• Nonpharmacologic: Daytime stimulation, adequate supervision, avoidance of napping.

• Neuroleptics: may be helpful for delusion and agitation. 20% may get worse.

For Sleep• Chloral hydrate, 500 to 1000 mg prn up to 2/d or

10/wk• Zolpidem (Ambien), 5 to 10 mg hs prn • Lorazepam (Ativan), 0.5 to 1 mg prn (up to 2/d or

10/wk) • Buspirone (Buspar), 5 to 10 mg tid for short-term

(few weeks) • Trazodone (Desyrel), 50 mg hs, may increase

gradually to 50 mg bid or tid • Melatonin, 1 to 2 mg hs prn (investigational)

Agitation

Olanzapine (Zyprexa): 2.5 mg qhs; Max: 10-20 mg/day given in bid.

*Quetiapine (Seroquel): 12.5 mg bid; Max: 75 mg bid. More sedating, may cause transient orthostasis. 

Risperidone (Risprdal) 0.25-1 mg qd to bid, EPS may occur at 2 mg.

Little use for older neuroleptics: Haldol etc

Agitation (cont)

Trazadone 25 mg hs, increase as tolerated,

Prozac 10-20 mg qam

*Sertraline 25-100 mg qam

Desipramine 25-100 mg qhs

Nortriptyline 10-100 mg qhs

*Celexa 20 mg: Citalopram

Agitation (Cont)

Anxiolytics: for short term use, long term use may worsen cognitive function Lorazepam 0.5 - 2 mg

Buspar: Takes long to act. Anticonvulsants: Use is common, but

questionable. May ameliorate mood fluctuations, impulsiveness Carbamazepine 100 mg bid, titrate Depakene 125 mg bid, titrate

Beta blockers: ?behavioral outbursts

Vit E + Selegiline

• Slow the progression of AD (Sano et al, 1997). • Rate of progression -25% less than the rate in

placebo Dose used in study:• Vitamin E 2000 I.U. Selegiline 5 mg am, 5 mg

noon. • Long-term effects unknown. Side effects:

Selegiline: insomnia, confusion, and psychosis. Vitamin E: Can potentially cause a prolonged prothrombin time for pateints on coumadin – Selegiline, Vit E treatment - NEJM 1997

Time course in deterioration

Pathogenesis

• Beta-Amyloid Accumuation• Decrease in Acetylcholine, AchE• Injury• Free-Radical Formation• Genetics

– Polygenic– ApoE4– FAD

Characteristic Changes

• Pathology– Tangles, plaques, Hirano bodies, Atrophy,neuronal loss

• Biochemistry– Decreased Ach, AchE

• Imaging– Atrophy

– Decreased metab activity in post’r cerebral associaation Corices

Senile Plaque

• A hallmark pathologic lesion specific for AD is senile plaque. Plaques are composed of amyloid-beta (A-beta), which is found in soluble form in the body fluids of patients with AD. Initially, A-beta aggregates into diffuse plaques that lack definite borders. Later, it matures into compact plaques formed of A-beta fibrils that may be toxic to surrounding neurons.

Amyloid

Amyloid Plaque

Neurofibrillary Tangle

• Abnormal intracellular structure caused by phosphorylation of the tau protein in the cytoskeleton of the neuron.

• Microglial cell proliferation, especially in association with senile plaques, suggests inflammatory processes play a role in the disease process.

Neurofibrillary Tangles

Beta Amyloid

• 4.2 kD fragment, 42-43• Abnormal cleavage of Beta Amyloid

precursor protein (APP)– APP part of family of 70kD transmembrane

proteins

• Beta-Secretase, APP cleaving Protein• Injury, ischemia incr APP • Amyloid is neurotoxic

New Strategies

• Beta-Amyloid Vaccine

• Beta and Gamma Secretase Blockers

• Zinc and Copper Chelators

Evolving Therapies

• Vaccine

• Secretin inhibitors

• Blocking Amyloid Accumulation