Dementia: Diagnosis and Treatment

1
Dementia Diagnosis and Treatment

• November 2003

2
Case

• Mr. Jones is a 72 y/o gentleman brought to you by
  his daughter for progressive memory loss. He
  denies any problems. She reports that he was an
  accountant, and is now unable to keep his own
  check book straight. He has also had difficulty
  with getting lost while driving to the store.
  His wife died 2 years ago, and he was diagnosed
  with depression at that time. In addition, he
  has HTN and DM. His father was diagnosed with
  alzheimers disease at the age of 85. On exam,
  his BP is 170/90 he is oriented, scores 26/30 on
  the MMSE (0/3 recall and difficulty with the
  intersecting pentagon) he is unable to do the
  clockface.
• A few months later, his MMSE is 24/30 on exam he
  has some mild cogwheel rigidity and a slight
  shuffling gate, but no tremor. His daughter
  reports that he has been having vivid visual
  hallucinations and paranoid thought

3
Questions

• 1. What are some limitations to the MMSE?
• 2. Is there any association between HTN and
  dementia in the elderly?
• 3. What are the risk factors for dementia?
• 4. Would apo E testing be of benefit in this
  case?
• 5. What type of dementia might Mr. Jones have?
• 6. What medications should be avoided with this
  type of dementia?

4
Outline

• 1. Risk factors and definition of dementia
• 2. Types of Dementias
• 3. MMSE and testing
• 4. Treatment options

5
Risk factors for dementia

• Age (risk of AD 1 age 70-74, 2 age 75-79, 8.4
  for those over age 85)
• Family hx (10-30 risk of AD in patients with
  first degree relative with dementia) also cross
  with parkinsons with dementia
• Head trauma
• Depression (?early marker for dementia)
• Low educational attainment?
• ?hyperlipidemia
• ?diabetes

6
Risk factors for AD

• Gender (confounding in literature women more
  likely to live longer, be older.)
• Downs syndrome
• ?estrogen (probably not)
• ?NSAIDS (probably not)

7
Cognitive decline with aging

• Mild changes in memory and rate of information
  processing
• Not progressive
• Does not interfere with daily function

8
DSM Criteria

• 1. Memory impairment
• 2. At least one of the following
• Aphasia
• Apraxia
• Agnosia
• Disturbance in executive functioning
• 3. Disturbance in 1 and 2 interferes with daily
  function
• 4. Does not occur exclusively during delirium

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Activities of Daily Living

• ADLs bathing, toileting, transfer, dressing,
  eating
• IADLs (executive functioning)
• Maintaining household
• Shopping
• Transportation
• Finances

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Diagnosis of Dementia

• Delirium acute, clouding of sensorium,
  fluctuations in level of consciousness,
  difficulty with attention and concentration
• Depression more likely to complain of memory
  loss than in those with dementia
• Delirium and depression both markers for future
  dementia
• 5 people over age 65 and 35-50 over 85 have
  dementia, pretest probability of dementia in
  older person with memory loss at least 60

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Alzheimers Disease

• 60-80 of cases of dementia in older patients
• Memory loss, personality changes, global
  cognitive dysfunction and functional impairments
• Visual spatial disturbances (early finding)
• Apraxia
• Language disturbances
• Personality changes
• Delusions/hallucinations (usually later in course)

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Alzheimers Disease

• Depression occurs in 1/3
• Delusions and hallucinations in 1/3
• Extracellular deposition of amyloid-beta protein,
  intracellular neurofibrillary tangles, and loss
  of neurons
• Diagnosis at autopsy

13
Alzheimers Disease

• Onset usually near age 65 older age, more likely
  diagnosis
• Absence of focal neurological signs (but
  significant overlap in the elderly with hx of
  CVAs)
• Aphasia, apraxia, agnosia
• Family hx
• Normal/nonspecific EEG
• Personality changes

14
Vascular dementia

• Onset of cognitive deficits associated with a
  stroke (but often no clear hx of CVA, more
  multiple small, undiagnosed CVAs)
• Abrupt onset of sxs with stepwise deterioration
• Findings on neurological examination
• Infarcts on cerebral imaging (do not over read ct
  and mri scans.)
• In reality, significant overlap between
  alzheimers and vascular dementias 90 y/o likely
  to have both based purely on demographics
  treatment likely targets both

15
Dementia with Parkinsons

• 30 with PD may develop dementia Risk Factors
• Age over 70
• Depression
• Confusion/psychosis on levodopa
• Facial masking upon presentation
• Hallucinations and delusions
• May be exacerbated by treatment

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Dementia with Lewy Bodies

• Cortical Lewy Bodies on path
• Overlap with AD and PD
• Fluctuations in mental status (may appear
  delirious)
• Early delusions and hallucinations
• Mild extrapyramidal signs
• Neuroleptic hypersensitivity!!!
• Unexplained falls or transient changes in
  consciousness

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Progressive Supranuclear Palsy

• Uncommon
• Vertical supranuclear palsy with downward gaze
  abnormalities
• Postural instability
• Falls (especially with stairs)
• surprised look
• Difficulty with spilling food/drink

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Frontal Lobe Dementia

• Impairment of executive function
• Initiation
• Goal setting
• planning
• Disinhibited behavior
• Cognitive testing may be normal/minimally
  abnormal memory loss not prominent early
  feature
• 5-10 cases of dementia
• Onset usually 45-65

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Frontal Lobe Dementia

• Focal atrophy of frontal and/or anterior temporal
  lobes
• Frontal lobe degeneration of the non-AD type
  (lack of distinctive histopath findings seen with
  AD or Picks)
• May be autosomal dominant (inherited form known
  as frontotemporal dementia)

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Picks Disease

• Subtype of frontal lobe dementia
• Pick bodies (silver staining intracytoplasmic
  inclusions in neocortex and hippocampus)
• Language abnormalities
• Logorrhea (abundant unfocused speech)
• Echolalia (spontaneous repetition of
  words/phrases)
• Palilalia (compulsive repetition of phrases)

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Primary Progressive Aphasia

• Patients slowly develop nonfluent, anomic aphasia
  with hesitant, effortful speech
• Repetition, reading, writing also impaired
  comprehension initially preserved
• Slow progression, initially memory preserved but
  75 eventually develop nonlanguage deficits most
  patients eventually become mute
• Average age of onset 60

22
Reversible Causes of Dementia

• ?10 of all patients with dementia in reality,
  only 2-3 at most will truly have a reversible
  cause of dementia

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Modifiable Causes of Dementia

• Medications
• Alcohol
• Metabolic (b12, thyroid, hyponatremia,
  hypercalcemia, hepatic and renal dysfunction)
• Depression? (likely marker though)
• CNS neoplasms, chronic subdural
• NPH

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Normal Pressure Hydrocephalus

• Triad
• Gait disturbance
• Urinary incontinence
• Cognitive dysfunction

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NPH

• Diagnosis initially on neuroimaging
• Miller Fisher test objective gait assessment
  before and after removal of 30 cc CSF
• Radioisotope diffusion studies of CSF

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Creutzfeldt-Jacob Disease

• Rapid onset and deterioration
• Motor deficits
• Seizures
• Slowing and periodic complexes on EEG
• Myotonic activity

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Other infections and dementia

• Syphilis
• HIV

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MMSE

• 24/30 suggestive of dementia (sens 87, spec 82)
• Not sensitive for MCI
• Spuriously low in people with low educational
  level, low SES, poor language skills, illiteracy,
  impaired vision
• Not sensitive in people with higher educational
  background

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Additional evaluation

• Clockface
• Short assessments with good validity 3 item
  recall and clockface
• Neurological exam (focality, frontal release
  signs such as grasp, jawjerk apraxia,
  cogwheeling, eye movements)
• Lab testing and neuroimaging
• Apolipoprotein E epsilon 4 allele probably not

30
Prognosis

• Previous estimate of median survival after onset
  of dementia have ranged from 5-10 years
• Length bias failing to consider people with
  rapidly progressive illness who died before they
  could be included in the study

31
Prognosis

• NEJM, april 2001
• Data from Canadian Study of Health and Aging,
  estimate adjusted for length bias, with random
  sample of 10,263 people over age 65 screened for
  cognitive impairment for those with dementia,
  ascertained date of onset and conducted followup
  for 5 years

32
Prognosis

• 821 subjects (396 with probably AD)
• Unadjusted median survival 3.3 years
• Median survival 3.1 years for those with probably
  AD

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Treatment of AD
34
Tacrine

• Cholinesterase inhibitor
• 1 systematic review with 5 RCTs, 1434 people,
  1-39 weeks
• No difference in overall clinical improvement
• Some clinically insignificant improvement in
  cognition
• Significant risk of LFT abnormalities NO ON USE

35
Donepezil

• Aricept
• Cholinesterse inhibitor
• Easy titration (start 5/day, then 10)
• Side effects GI (nausea, diarrhea)
• Associated with improved cognitive function main
  effect seems to be lessening of rate of decline,
  delayed time to needing nursing home/more
  intensive care

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Other agents

• Rivastigmine
• Galantamine
• Cholinesterase inhibitors
• ?more side effects, more titration required
• Future directions
• Prevention of delirium in at risk patients
  (cholinergic theory of delirium)
• Behavioral effects in those with severe dementia
• Treatment of Lewy Body dementia
• Treatment of mixed Vascular/AD dementia

37
Comments about cholinesterase inhibitor studies

• Highly selected patients (mild-mod dementia)
• ?QOL improvements
• Not known severe dementia and mild CI

38
Memantine

• NEJM april 2003
• Moderate to severe AD (MMSE 3-14)
• N-methyl D aspartate (NMDA) receptor antagonist
  theory that overstimulation of NMDA receptor be
  glutamate leads to progressive damage in
  neurodegenerative diseases
• 28 week, double blinded, placebo controlled
  study 126 in each group 67 female, mean age
  76, mean MMSE 7.9

39
Memantine

• Found less decline in ADL scores, less decline in
  MMSE (-.5 instead of 1.2)
• Problem significant drop outs (overall 28
  dropout rate) in both groups data analyzed did
  not account for drop outs, followed those at
  risk

40
Selegiline

• Unclear benefit
• Less than 10mg day, selective MAO B inhibitor
• Small studies, not very conclusive

41
Vitamin E (alpha tocopherol)

• NEJM 1997 selegiline, vit E, both , placebo for
  tx of AD
• Double blind, placebo controlled, RCT with mod
  AD 341 patients
• Primary outcome time to death,
  institutionalization, loss of ADLS, severe
  dementia
• Baseline MMSE higher in placebo group
• No difference in outcomes adjusted for MMSE
  differences at baseline and found delay in time
  to NH from 670 days with vit E to 440 days with
  placebo)

42
Ginkgo Biloba

• 1 systematic review of 9 double blind RCTs with
  AD, vascular, or mixed dementia
• Heterogeneity, short durations
• High withdrawal rates best studies have shown no
  sig change in clinicians global impression scores

43
Other treatments

• NO good evidence to support estrogens or NSAIDS

44
Other treatments

• Behavioural/agitation
• Nonpharm strategies
• Low dose newer antipsychotics (.5 risperidone,
  olanzepine) Olanzepine has higher
  anticholinergic profile, but may benefit/not
  worsen tremor/rigidity of Parkinsons
• Reasons for NH placement
• Agitation
• Incontinence
• Falls
• Caregiver stress

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MMSE tips

• No on serial sevens (months backwards, name
  backwards assessment of attention)
• Assess literacy prior
• Assess for dominant hand prior to handing paper
  over
• Do not over lead
• 3 item repetition, repeat all 3 then have
  patients repeat 3 stage command, repeat all 3
  parts of command and then have patient do