DEMENTIAS

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DEMENTIAS

• Angeles Garcia MD, PhD
• Phase II
• Oct 30, 2002

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Definition

• IRREVERSIBLE FAILURE OF THE BRAIN CAUSING
  COGNITIVE DAMAGE
• DSM IV
• NINCDS

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Cognition

• Brain functions including
• Attention Initiation
• Memory Language
• Calculation Praxis
• Executive functions
• Visuospatial capacity
• Time and space orientation

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DSM IV definition

• Irreversible and progressive cognitive impairment
  affecting memory and at least another area of
  cognition, not due to medical or affective
  disorders, affecting the daily functioning of the
  patient.

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Other definitions of dementia

• Chronic and usually progressive decline of
  intellect and / or comportment which causes a
  gradual restriction of daily living activities,
  unrelated to changes of alertness, mobility, or
  sensorium.

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Working definition of dementia

• Progressive and abnormal deterioration of at
  least two areas of cognitive function, affecting
  the daily life of the patient, not due to
  affective disorders or delirium.

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Scope of the problem

• lt 1 of people under the age of 65
• 10-15 of people over the age of 65
• 4-20 between 65 and 75
• 15-30 between 75 and 85
• gt35 over the age of 85

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Grades of cognitive decline

• Normal, age associated cognitive decline
• Mild cognitive impairment (MCI)
• Dementia
• Difficulties establishing what is normal

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Normal cognitive decline vs. Dementia

• Cognitive function declines with age
• Slower learning curve
• Slower reaction time
• Decreased/slower working memory and frontal
  functions
• Maintenance of vocabulary and grammatical
  structures
• When compared to younger adults

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MCI vs.Dementia

• MCI
• Isolated memory deficit not affecting
  instrumental activities of daily living.
• Absence of any other cognitive deficits
• Between 10 and 30 of persons with MCI develop
  dementia within 1-2 years
• 25 of subjects with MCI have NOT developed
  dementia at 10 years.

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Treatment of MCI

• No specific treatment known to be effective.
• Important to treat risk factors of cognitive
  decline including Hypertension, diabetes, other
  metabolic abnormalities, vitamin deficits,
  isolation, depression, alcohol abuse.
• Data on other preventive measures such as
  anti-inflammatories, Ginkgo Biloba or Vit E are
  still controversial.

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Diagnosis of cognitive impairment

• Medical history and physical exam
• Cognitive testing
• Rule out medical causes of cognitive deficit
• Complementary tests
• Blood work (renal, liver function, B12, RBC
  Folate, TSH, VDRL, calcium, electrolytes, CBC,
  medications levels if appropriate)
• Imaging (CT or MRI, SPECT scan)

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Medical history and Physical exam (I)

• Analysis of presenting symptom Relevant factors
• Time frame
• Evolution
• Depth and impact on daily life
• Corroborative history

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Medical history (II)

• Ask for activities involving other cognitive
  functions and possible personality changes
• Driving (visuospatial, judgment, attention)
• Social interaction (initiation, frontal
  functions)
• Orientation (time and space)
• Word finding difficulties (ask and observe word
  flow)
• Banking, shopping (calculation, executive
  function)
• Character change (irritability, suspiciousness)

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Medical history (III)

• Past medical history
• Head trauma
• Depression
• Diabetes
• Hypertension
• Stroke and other neurological diseases
• Alcohol, smoking, medications
• Cardiac, thyroid, respiratory, renal, metabolic.
  
• Family history of dementia

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Physical exam

• Complete neurological exam
• Motor, sensory deficits
• Parkinsons signs
• Masked facies, pill rolling resting tremor,
  rigidity, cogwheel, festinating gate,
  micrographia
• General exam
• Hypertension, cardiac disease
• Thyroid, metabolic disease

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Cognitive testing (I)

• Factors that influence cognitive performance
• AGE
• YEARS OF EDUCATION
• TESTING LANGUAGE

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Cognitive testing (II)

• Types of testing
• Informal, non-standardized
• Formal, standardized tests
• Diagnostic tests
• Ensure testing is appropriate

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Cognitive testing (III)

• Screening tests
• Mini-mental state exam (MMSE)
• Score 30/30. Normal scores vary with age and
  years of education.
• Clock test

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MMSE

• Orientation to time and space 5 points each
• Registration 3 points
• Calculation or spelling backwards 5 points
• Short term recall 3 points
• Language 5 points
• Praxis 3 points
• Visuospatial 1 point

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MMSE

• Does not test for frontal, executive function
• Poor testing for visuospatial capacity
• Standardized scoring for age and years of
  education
• Is the most widely used dementia screening test.
• Takes 15-20 minutes to administer

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Clock test

• Screening test for executive function
• Test of visuospatial capacity
• Difficult scoring
• Takes few minutes to administer

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(No Transcript)
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Cognitive testing (IV)

• Diagnostic tests
• Memory tests
• Global cognitive tests Memory, attention,
  visuospatial, praxis, language, abstract
  thinking, conceptualization, calculation
• Tests of executive function

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Types of dementia

• Alzheimers disease (AD)
• Dementia with Lewy Bodies (LBD)
• Vascular
• Mixed
• Fronto-temporal Lobar Dementias
• Others
• Generalized neurodegenerative and mixed dementias
  are the most common dementias

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Generalized Neurodegenerative dementias (I)

• Alzheimers disease
• Progressive loss of cognitive function
  Prominent memory deficits, usually the
  presenting symptom, along with deficits of
  initiation.
• Visuospatial deficits
• Language deficits Word finding difficulties,
  comprehension, paraphasias, empty speech.
• Judgment, abstract capacity, executive functions
  (cant assess risks, driving)

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Cumulative prevalence of AD
70 60 50 40 30 20 10 0
AD ()
65 70 75 80 85 90
Age (years)
Adapted from Evans et al., 1989 Hebert et al.,
1995
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Factors influencing the development of AD

• Causative factors in early age AD (lt65)
• chromosome mutations
• different loci on chromosomes 1, 14, 19, 21

Dartigues and Orgogozo, 2000 Lannfelt, 1996
Mullan, 2000 Geerlings et al., 1999
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Factors influencing the development of AD

• Well-established risk factors
• increasing age
• ApoE4 genotype
• Downs syndrome
• previous head injury
• Hypertension and other vascular risk factors
• low educational achievement

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Factors influencing the development of AD

• Speculative risk factors
• female gender
• smoking
• vascular disease

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Factors influencing the development of AD

• Possibly protective
• moderate wine consumption
• ApoE2 genotype
• high educational achievement
• Estrogen?
• Antioxidants?

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Clinical course of AD (I)

• Insidious onset and slow progression over years.
• Most common initial presentation is complaints of
  memory problems, noted by the patient or by
  family/friends.
• Word finding difficulties and other language
  abnormalities.
• Initiation, orientation, visuospatial,
  calculation, conceptualization and other
  executive functions deteriorate progressively.
  

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Clinical course of AD (II)

• Behavioral abnormalities might be an early sign
  or might appear later in the disease.
• Paranoid behavior
• Prosapognosia
• Agitation
• Wondering

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Clinical course of AD (III)

• Cognitive deterioration progresses and affects
  all areas of cognition.
• Instrumental activities of daily living (driving,
  telephone, banking) worsen progressively.
• In moderate to advanced AD, patients can not
  perform the basic ADL.
• In late stages, the disease affects all brain
  functions.

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Generalized Neurodegenerative dementias

• Initial hippocampal and entorrhinal cortex
  atrophy.
• Associated with ApoE4 genotype in elderly
  population
• Associated with presenilin 1 and 2 abnormalities
  in younger adults.

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Treatment

• Correct biochemical abnormalities (TSH, B12,
  Folate)
• Acethylcholinesterase inhibitors
• Provide higher availability of ACh in the
  synaptic space
• Disease modifying agents, no curative
• Donepezil. One daily dose
• Rivastigmine. BID
• Galantamine. BID

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Acethylcholinesterase inhibitors

• Indicated only in generalized degenerative or
  mixed dementias
• Mild GI side effects (nausea, abdominal
  discomfort).
• Contraindicated in patients with severe cardiac
  conduction abnormalities or respiratory
  compromise.
• Improvement of daily activities, initiation and
  general function, but there is no significant
  improvement in memory.
• May improve behavioral abnormalities.

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Effects of donepezil on cognition ADAS-Cog
change from baseline
3 2 1 0 1 2 3 4
Improvement






ADAS-Cog mean change from baseline
10 mg/day (n157) 5 mg/day (n154) Placebo (n162)
Decline
0 6 12 18 24 30
Placebowashout
Weeks on therapy
ITT-LOCF analysis plt0.0012 plt0.0007
plt0.0001 vs placebo
Rogers et al., 1998
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Other treatments for neurodegenerative dementias

• Vit E 2000 u/day Antioxidant. Risk of bleeds.
  No proven efficacy on cognition.
• Anti-inflammatories Negative clinical trials
  with prednisone. More data pending.
• Ginko No proven efficacy.