Dementia: Diagnosis and Treatment

1
Dementia Diagnosis and Treatment

• Debra L. Bynum, MD
• Division of Geriatric Medicine
• University of North Carolina

2
Case

• Mr. Jones is a 72 y/o gentleman brought to you by
  his daughter for progressive memory loss. He
  denies any problems. Previously an accountant,
  he is now unable to balance his check book. He
  has had difficulty with getting lost while
  driving to the store. He was diagnosed with
  depression two years ago after his wife died. 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. What type of dementia might Mr. Jones have?

4
Outline

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

5
Question

• What are some risk factors for the development of
  dementia?

6
Risk factors for dementia

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

7
Risk factors for AD

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

8
Question

• What is the definition of a dementia? What is
  the line between normal memory loss with age
  and dementia

9
Cognitive decline with aging

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

10
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 or independence
• 4. Does not occur exclusively during delirium

11
Activities of Daily Living

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

12
Diagnosis of Dementia

• Delirium acute, clouding of sensorium,
  fluctuations in level of consciousness,
  difficulty with attention and concentration
• Depression patient complains of memory loss
• Delirium and depression markers of dementia?
• 5 people over age 65 and 35-50 over 85 have
  dementia, therefore pretest probability of
  dementia in older person with memory loss at
  least 60

13
Question

• What are some classic features of an Alzheimer
  type dementia?

14
Alzheimers Disease

• 60-80 of cases of dementia in older patients
• Early personality changes
• Loss of short term memory
• Functional impairment
• Visual spatial disturbances (early finding)
• Apraxia
• Language disturbances
• Delusions/hallucinations (usually later in course)

15
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 at autopsy
• Clinical diagnosis 87 of diagnosed AD
  confirmed pathologically (but high pretest
  probability increases predictive value of
  clinical diagnosis!!!)

16
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 (especially for early types)
• Normal/nonspecific EEG
• MRI bilateral hippocampal atrophy (suggestive)

17
Question

• What features would make you think more about a
  vascular etiology to a dementia?

18
Vascular dementia

• Onset of cognitive deficits associated with a
  stroke (but often no clear hx of CVA but multiple
  small, undiagnosed CVAs)
• Abrupt onset of sxs with stepwise deterioration
• Findings on neurological examination
• Infarcts on cerebral imaging (but ct/mri findings
  often have no clear relationship)

19
Overlap

• Most patients previously categorized as either
  Alzheimer type or vascular type dementias
  probably have BOTH
• Likelihood of AD and vascular disease
  significantly increases with age, therefore
  likelihood of both does as well
• Vascular risk factors predispose to AD -- ?does
  it allow the symptoms of AD to be unmasked
  earlier??

20
Question

• What is the risk of dementia with Parkinsons
  disease?

21
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

22
Some other dementias
23
Dementia with Lewy Bodies

• Cortical Lewy Bodies on path
• Overlap with AD and PD
• Second most common type of dementia

24
Dementia with Lewy Bodies

• Visual hallucinations (early)
• Parkinsonism
• Cognitive fluctuations
• Dysautonomia
• Sleep disorders
• Neuroleptic sensitivity
• Memory changes later in course

25
Dementia with Lewy Bodies

• Visual hallucinations
• 2/3 of patients with DLB
• Rare in AD
• May precede other symptoms of DLB
• Psychosis, paranoia and other psychiatric
  manifestations early in course

26
Dementia with Lewy Bodies

• Cognitive Fluctuations
• 60-80
• Episodic
• Loss of consciousness, staring spells, more
  confused or delirious like behavior
• Days of long naps
• Significant impact on functional status

27
Dementia with Lewy Bodies

• Parkinsonism
• 70-90
• More bilateral and symmetric than with PD
• Tremor less common
• Bradykinesia, rigidity, gait changes

28
Dementia with Lewy Bodies

• Sleep disorders
• REM sleep behavior disorder/parasomnia
• Acting out of dreams REM dreams without usual
  muscle atonia
• 85 of patients with DLB
• May precede other symptoms by years

29
DLB Neuroleptic Hypersensitivity

• 30-50 of patients
• May induce parkinsonian symptoms or cognitive
  changes that are not reversible, leading to rapid
  decline in overall status
• NOT dose related
• Slightly less likely with newer atypical
  antipsychotics, but can STILL happen

30
DLB Treatment

• More progressive course than AD or Vascular
  dementia
• Possibly better response to cholinergic drugs
  than AD or vascular dementias
• ?response of psychiatric type symptoms to
  cholinergic agents/cholinesterase inhibitors

31
Progressive Supranuclear Palsy

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

32
Frontotemporal Dementia

• Impairment of executive function
• Initiation
• Goal setting
• planning
• Disinhibited/inappropriate behavior (90)
• Cognitive testing may be normal memory loss NOT
  prominent early feature
• 5-10 cases of dementia
• Onset usually 45-65 (rare after age 75)
• Familial 20-40

33
Picks Disease

• Subtype of frontal lobe dementia
• Pick bodies (silver staining intracytoplasmic
  inclusions in neocortex and hippocampus)
• ?Serotonergic deficit?
• Language abnormalities and Behavioral
  disturbances
• Logorrhea (abundant unfocused speech)
• Echolalia (spontaneous repetition of
  words/phrases)
• Palilalia (compulsive repetition of phrases)
• Fluent or nonfluent forms

34
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
• Subset of FTD

35
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

36
Modifiable Causes of Dementia

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

37
Question

• An elderly patient with ataxia, incontinence,
  memory loss and large ventricles scan should
  raise suspicion for ?

38
Normal Pressure Hydrocephalus

• Triad
• Gait disturbance
• Urinary incontinence
• Cognitive dysfunction

39
NPH Clinical Features

• Gait
• Early Feature
• Most responsive to shunting
• Magnetic/gait apraxia/frontal ataxia
• Cognitive
• Psychomotor slowing, apathy, decreased attention
• Urinary
• Urgency or incontinence

40
NPH

• Hydrocephalus in absence of papilledema, with
  normal CSF pressure
• Begins as transient/intermittent increased CSF
  pressure, leading to ventricular enlargement
  ventricular enlargement leads to normalization of
  CSF pressure
• Thought to be due to decreased CSF absorption at
  arachnoid villi
• Causes SAH, tumors, CVA

41
NPH

• Diagnosis initially on neuroimaging
• Ventricular enlargement our of proportion to
  sulcal atrophy
• Miller Fisher test objective gait assessment
  before and after removal of 30 cc CSF
• Radioisotope diffusion studies of CSF
• MRI turbulent flow in posterior third ventricle
  and within aqueduct of sylvius
• MRI flow imaging cine MRI flow void
• SPECT (Single Photon emission CT) decreased
  blood flow in frontal and periventricular areas

42
NPH ?Shunting?

• Limited data
• Gait may be most responsive
• Predictors of better outcome
• Lack of significant dementia
• Known etiology (prior SAH)
• New (lt 6 months) symptoms
• Prominence of gait abnormality

43
Creutzfeldt-Jacob Disease

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

44
Other infections and dementia

• Syphilis
• HIV

45
Question

• What are some tools available to assess for the
  presence and severity of cognitive impairment?

46
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

47
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

48
Other evaluation tools

• Trails B test
• Numbers 1-25 and letters scattered across page
  patient must connect, 1-A, 2-B, 3-C, etc
  normally able to do in lt10 minutes
• Good for patients with high function/education
• Verbal Fluency Test
• Name all within category in 30 seconds 1 minute
• Letters FAS, animals, vegetables
• Tests executive function and language, semantic
  memory
• Normally should name 20-30 in 60 sec
• Highly associated with educational level
• Insight with grouping, rhyming, categories

49
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

50
Treatment of AD
51
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 NOT USED

52
Donepezil

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

53
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

54
Comments about cholinesterase inhibitor studies

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

55
Memantine

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

56
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

57
Selegiline

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

58
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 Primary 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

59
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

60
Other treatments

• NO good evidence to support estrogens or NSAIDS

61
Other treatments

• Behavioral/agitation
• Nonpharmacologic strategies
• Reasons for NH placement
• Agitation
• Incontinence
• Falls
• Caregiver stress

62
?Antipsychotics

• NO data to support any significant benefit for
  treating behavioral symptoms of dementia with
  antipsychotic agents
• Small group of patients with active psychoses,
  disturbing hallucinations, or aggressive
  behaviors who may have some benefit

63
Antipsychotics

• Side Effects
• Sedation
• Anticholinergic effects
• Prolonged QT
• Edema
• Orthostasis
• Weight gain
• Confusion
• Warnings
• FDA black box warning for increased mortality (OR
  1.5- 1.7), and increased ?increased stroke risk

64
Prevention?

• HTN and DM linked to future development of ALL
  types of dementia (not just vascular)
• Large initial studies of treating systolic
  hypertension in the elderly (SHEPS and others)
  demonstrated decreased risk of development of
  cognitive impairment over time in those patients
  in the original treatment group!
• Decreased risk included vascular AND alzheimer
  type dementias
• Cholinesterase inhibitors seem to work as well
  (or as poorly) for both vascular and alzheimer
  type of dementias
• What is the link? Both common in elderly, may be
  that one unmasks the other

65
Future

• Treating vascular risk factors to decrease
  development/unmasking of dementia?
• Actively seeking to differentiate different types
  of dementia, while also
• Recognizing significant OVERLAP of dementia
  etiologies in older patients
• Move toward agents other than cholinesterase
  inhibitors?
• Move away from broad use of antipsychotic agents