1. Dementia: Diagnosis and Treatment
Debra L. Bynum, MD
Division of Geriatric Medicine
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 alzheimer’s 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 parkinson’s 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….)
Down’s 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

9. Activities of Daily Living
ADLs: bathing, toileting, transfer, dressing, eating
IADLs (executive functioning):
Maintaining household
Shopping
Transportation
Finances

10. 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 % over 85 have dementia, pretest probability of dementia in older person with memory loss at least 60%

11. Alzheimer’s 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)

12. Alzheimer’s 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. Alzheimer’s 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 alzheimer’s and vascular dementias; 90 y/o likely to have both based purely on demographics; treatment likely targets both…

15. Dementia with Parkinson’s
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

16. 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

17. Progressive Supranuclear Palsy
Uncommon
Vertical supranuclear palsy with downward gaze abnormalities
Postural instability
Falls (especially with stairs)
“surprised look”
Difficulty with spilling food/drink

18. 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

19. 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 Pick’s)
May be autosomal dominant (inherited form known as frontotemporal dementia)

20. Pick’s 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)

21. 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

23. “Modifiable” Causes of Dementia
Medications
Alcohol
Metabolic (b12, thyroid, hyponatremia, hypercalcemia, hepatic and renal dysfunction)
Depression? (likely marker though…)
CNS neoplasms, chronic subdural
NPH

24. Normal Pressure Hydrocephalus
Triad:
Gait disturbance
Urinary incontinence
Cognitive dysfunction

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

26. Creutzfeldt-Jacob Disease
Rapid onset and deterioration
Motor deficits
Seizures
Slowing and periodic complexes on EEG
Myotonic activity

27. Other infections and dementia
Syphilis
HIV

28. 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

29. 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 probable AD

33. 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

36. 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 clinician’s 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 Parkinson’s
Reasons for NH placement:
Agitation
Incontinence
Falls
Caregiver stress

45. 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…