Download
1 / 175

Keys to Care - PowerPoint PPT Presentation


  • 147 Views
  • Uploaded on

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

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Keys to Care' - livvy


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Artistic regression
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



Life expectancy with dementia
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
Alzheimer Brain Atrophy

From Whole Brain Atlas


Neurodegenerative Diseases and Prions

Stanley B. Prusiner, M.D.

Twenty-five years ago, little was known about the causes ofneurodegenerative diseases.



Thesis
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

Neurologic Diseases attributed to Protein deposition


Macular degeneration a ge r elated m aculopathy
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



Pathogenesis of Macular

Degeneration from

Scientific American

10/2001


First hints to causation
First Hints to Causation

  • Genetics

  • Familial Alzheimer Disease

  • Trisomy 21


Alzheimer genes chromosome s
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
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
All have in Common:

  • Increased Accumulation of b Amyloid

    • Abnormal Accumulation

    • Defective Degradation


Alzheimer disease

Cerebral Amyloidosis

Alzheimer Disease



Pathogenesis
Pathogenesis

  • Beta-Amyloid Accumulation

  • Decrease in Acetylcholine, AchE

  • Injury

  • Free-Radical Formation

  • Genetics

    • Polygenic

    • ApoE4

    • FAD


Characteristic changes
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
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
Amyloid Plaques

  • Between Cells (extra-cellular)

  • Appear before Tangles do

  • Associated with Microglia (inflammation)

    • (microglia are phagocytes of the brain)


Amyloid precursor protein
Amyloid Precursor Protein

  • 695-770 Amino Acids

  • Transmembrane protein

  • Beta-Amyloid is snipped out precursor protein

  • Beta-Amyloid- transmembrane component


Cast of characters
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
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
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??




Pathogenesis of senile 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 amyloid precursor protein
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



Beta amyloid mediated damage
Beta Amyloid Mediated Damage

  • Ca++ Deregulation

  • Creation of Free Radicals

  • Immune Aggregation


Beta amyloid
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
Mechanism of Amyloid destruction

  • Liberating Calcium in Cells

  • Damaging Mitochondria

  • Enhancing inflammatory (Microglial) Response


New strategies
New Strategies

  • Beta-Amyloid Vaccine

  • Beta and Gamma Secretase Blockers

  • Zinc and Copper Chelators


Strategies to prevent and treat alzheimer s
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



Mouse trials of vaccine
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
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

Gene linkage


Treatment cornerstones
Treatment Cornerstones

  • Cholinesterase Inhibitors

  • Ancillary Symptoms

    • Anxiety

    • Agitation

    • Disorientation and Wandering

    • Sleep Disturbance

  • Placement

  • Caring for Caretaker



Csf in alzheimer s disease
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
Diagnosis Criteria

  • Alzheimer's disease is characterized by progressive decline and ultimatelyloss 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 degeneration1
Granulo-vacuolar degeneration

  • 5 m clear intracytoplasmic vacuole

  • Argyrophillic core

  • Pyramidal cell region of hippocampus





Neurofibrillary tangles2
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 tangle1
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 tangle2
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

Fuel and Longevity


Causes of dementia
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
Multi-infarct dementia

Whole brain Atlas


Hachinski score for dx of vascular dementia
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
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
    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
    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
    Agitation and Dementia

    • Structure and routine.

    • Follow regular, predictable routines. 

    • Keep things simple. 

    • Distract. 


    Behavior
    Behavior

    • Why is depression relatively uncommon??

    • Anosognosia for dementia


    Simple and active
    Simple and Active

    • Break down complex tasks into many small, simple steps that the person can handleFolding 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
    Distract

    • Offer a snackPut on a favorite videotape or some familiar music Be flexible. Know when to back away from a task- a bath or dressing and reapproach laterSoothe. 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
    Sleep and Anxiety

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

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



    Alzheimer s burden
    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
    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
    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
    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
    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
    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
    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


    Estrogen1
    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
    Estrogen Reviews

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

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


    Women s health initiative memory study whims
    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
    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 346:476-483February 14, 2002


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

    PATHWAYS TO PREVENTION?

    Ongoing clinical trials related to Alzheimer&apos;sdisease and possible modes of prevention:


    Adapt
    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
    Prevent AD with Estrogen

    • National Institute on Aging

    • Mary Sano, PhD

    • 5 year study


    Strategies
    Strategies

    • Vitamin E and Selegeline or donepezil

    • Estrogens

    • NSAIDs

    • B12,B6,Folate (homocysteine)

    • Statins

    • Valproate ?”Neuroprotective”

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


    Homocysteine1
    Homocysteine

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

    • No one knows


    Homocysteine2
    Homocysteine

    • 50 Mg pyridoxine

    • Up to 4 mg. of Folate

    • 500 mcg of B12


    Nsaids1
    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
    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
    Gingko Biloba

    • 1 year

    • 120 mg.

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

    • Very little other evidence

      Le Bars PL et al.JAMA 1997;278:1327-1332


    Alzheimer disease1
    Alzheimer Disease

    • Dissolution of the Personality

    • Inexorable Progression


    Keys of therapy
    Keys of Therapy

    • Early Recognition of Disease

    • Cholinesterase Blockers

    • Treatment of Ancillary Symptoms

    • Maintaining Patient in own Environment

    • Family Support


    Diagnosis
    Diagnosis

    • Index of Suspicion

    • Age!

    • Sensitivity to Patients and Family


    Vigilance
    Vigilance

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


    10 warning signs
    10 Warning Signs:

    • Dysfunction on Job

    • Problem with Language function

    • Difficulty performing Familiar Tasks

    • Disorientation

    • Poor Judgment

    • Altered Abstract thinking


    More signs
    More Signs

    • Misplacing Objects

    • Personality Change

    • Altered Mood and Behavior

    • Loss of initiative


    Diagnostic criteria for dementia
    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
    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
    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
    Alzheimer Dementia

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

    • Also denial


    Pseudo dementia
    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 dementia1
    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 dementia2
    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
    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
    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
    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
    Evaluation: compare betw visits

    • Folstein Mini-Mental Status

    • Clock-drawing

    • Scale of level of Function as reported by family member

    • Language function


    Rule out
    Rule Out

    • Alcohol

    • Depression

    • Drug s

    • Metabolic Derangement

    • Nutritional Deficiencies

    • Infection


    Causes of dementia1
    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 dementia1
    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 d1
    Hachinski Score (cont’d)

    • Somatic complaints

    • Emotional incontinence

    • History of hypertension

    • Evidence of atherosclerosis

      • Pvd, MI

  • Focal Neurological symptoms (TIA)   Focal neurological signs


  • Vascular dementia1
    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
    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
    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
    “Others”

    • Creutzfeldt-Jakob

    • Cortico-Basal Degen

    • Progressive Supranuclear Palsy

    • Frontal Lobe Dementia


    Parkinson related 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
    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 cornerstones1
    Treatment Cornerstones

    • Cholinesterase Inhibitors

    • Ancillary Symptoms

      • Anxiety

      • Agitation

      • Disorientation and Wandering

      • Sleep Disturbance

    • Placement

    • Caring for Caretaker


    Cholinergic hypothesis
    Cholinergic hypothesis

    • Diffusely projecting area: Nucleus Basalis of Meynert

    • Layers I and II major cholinergic cortical innervation

    • Amygdala and hippocampus lgest innervation


    Ache inhibitors
    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
    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. 


    Alzheimer Manifestations

    Activity of Daily Living

    Behavior

    Cognitive Dysfunction

    All aided by Anti-esterases




    Types of cholinergic receptors
    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
    Acetylcholine

    • Formation: ChAT and Acetyl-CoA

    • Degradation: AchE and Butyryl-cholinesterase


    Butyrylcholinesterase
    Butyrylcholinesterase

    • Role is minor in normal brain

    • Proportionate activity increases in Alzheimer brain


    Ache inhibitors progression
    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
    Galantamine (Reminyl)

    • Start at 4 mg BID (8 mg/day) for at least 4 weeks, then 8 mg bidAvailable in 4 mg, 8 mg, and 12 mg tabletsMost 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
    Reminyl

    • Average approx. 4 pts on ADAS-Cog Scores


    Galantamine
    Galantamine

    • Common snowdrop (Galanthus nivalis)

    • Binds AChE

    • Modulator of Nicotinic Receptors

    • ?Enhanced Sexual Fxn

    • Mythology

      • Iliad, Circe, Atropine, Jimsonweed


    Rivastigmine
    Rivastigmine

    • ExelonApproved 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 functionReduced use of psychotropic medications


    Faster progression yields increased response
    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]


    Rivastigmine1
    Rivastigmine

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


    Rivastigmine2
    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
    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
    Rivastigmine: GI Effects

    • 18% Men, 26% Women at Max dose



    Rivastigmine3
    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 hoursFew interactions with other drugsSide effects:No hepatotoxicityGI disturbances, occur mainly during dose adjustment. 


    Aricept donepezil
    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
    Aricept

    • Pharmacology: Half life: 72-hourSteady states are achieved in 15 days.94% protein-boundmetabolized 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
    Behavior Problems

    Personality change: apathetic or more impulsive

    Anxiety:

    apprehension over upcoming events

    Aggression:

    physical or verbal


    Behavior cont d1
    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 dementia1
    Agitation and Dementia

    • Structure and routine.

    • Follow regular, predictable routines. 

    • Keep things simple. 

    • Distract. 


    Behavior1
    Behavior

    • Why is depression relatively uncommon??

    • Anosognosia for dementia


    Simple and active1
    Simple and Active

    • Break down complex tasks into many small, simple steps that the person can handleFolding 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


    Distract1
    Distract

    • Offer a snackPut on a favorite videotape or some familiar music Be flexible. Know when to back away from a task- a bath or dressing and reapproach laterSoothe. 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 anxiety1
    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
    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
    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
    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 cont1
    Agitation (Cont)

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

    Buspar: Takes long to act.

    Anticonvulsants: Use is common, but questionable. May ameliorate mood fluctuations, impulsivenessCarbamazepine 100 mg bid, titrateDepakene 125 mg bid, titrate

    Beta blockers: ?behavioral outbursts


    Vit e selegiline
    Vit E + Selegiline

    • Slow the progression of AD (Sano et al, 1997).

    • Rate of progression -25% less than the rate in placeboDose 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



    Pathogenesis1
    Pathogenesis

    • Beta-Amyloid Accumuation

    • Decrease in Acetylcholine, AchE

    • Injury

    • Free-Radical Formation

    • Genetics

      • Polygenic

      • ApoE4

      • FAD


    Characteristic changes1
    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 plaque1
    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.




    Neurofibrillary tangle3
    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.



    Beta amyloid1
    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 strategies1
    New Strategies

    • Beta-Amyloid Vaccine

    • Beta and Gamma Secretase Blockers

    • Zinc and Copper Chelators


    Evolving therapies
    Evolving Therapies

    • Vaccine

    • Secretin inhibitors

    • Blocking Amyloid Accumulation


    ad