Project 2: Neuropathology of Dementia in Centenarians

1
Project 2 Neuropathology of Dementia in
Centenarians

• Robert Green, M.D., M.P.H.,
• Marla Gearing, Ph.D., and
• Bill Markesbery, M.D.

2
Specific Aims

• To determine the concordance between dementia
  and neuropathology in centenarians.
• To determine whether the presence of cerebral
  infarcts is a major determinant of the clinical
  expression of dementia in centenarians,
  independent of AD pathology.
• 3. To determine the relationship between clinical
  expression of AD pathology and factors
  representing neurocognitive reserve.

3
Goals

• Recruit 20-30 of GCS subjects to participate in
  Project 2 (total of 62-70 brains)
• Complete CERAD battery and Clinical Dementia
  Rating Scale at enrollment and at 6 month
  intervals thereafter
• Obtain brain at time of death

4
Year 4 Progress - General

• Departure of original donor coordinator Kathy
  Shaw with smooth transition to new donor
  coordinator Molly Burgess over the summer of 2005
• Distribution of business cards containing the new
  beeper numbers of Project 2 staff to subjects
  enrolled in the project and their families

5
Year 4 Progress Monitoring Systems

• Continued maintenance of an electronic database
  to track subjects enrolled in Project 2 and
  ensure that consent forms have been obtained,
  follow-up visits are conducted on schedule, etc.
• Regular communication among PIs and donor
  coordinator to monitor progress and address
  issues as they arise

6
Year 4 Progress Enrollment

• Enrollment in Project 2 began mid-March 2004 and
  was completed in September 2005.
• Brain donation discussed with 212 participants
• 65 consented brain donors (31 enrollment among
  those approached 27 enrollment among GCS
  subjects overall)
• Goal Recruit 20-30 of GCS subjects to
  participate in Project 2 (total of 62-70 brains)

7
Epidemiologic Comparison
8
Year 4 Progress Brain Donation

• 31 deaths
• 28 brains obtained and shipped to Univ. Kentucky
• 90 autopsy rate
• Regular contact and follow-up is critical!
• Could race be an issue after all???

9
Year 4 Progress Neuropathology

• Evaluation completed on 19 brains
• 9 more brains in the pipeline brains must fix
  at least 6 weeks before MRI scanning, and
  scanning must be completed before neuropathology
  work-up can begin

10
Year 4 Progress Neuropathology
11
Year 4 Progress Neuropathology
12
Year 4 Progress Neuropathology

• 10 cases with various combinations of infarcts,
  microinfarcts and micro-hemorrhages (8 cases with
  no infarcts)
• 5 cases with Lewy bodies
• 14 cases with amyloid angiopathy (mild to severe)
• 5 cases with hippocampal sclerosis (3 bilateral,
  2 unilateral)
• 7 cases with argyrophilic grains

13
Year 4 Progress Neuropathology
14
Conclusions

• We have successfully enrolled our target of
  20-30 of GCS participants in Project 2.
• The number of brains actually obtained will
  depend on death rate during the period of the
  study. To date, 31 of the 65 subjects enrolled
  in Project 2 have died. We have obtained brains
  on 28 of the 31 deceased subjects, for an autopsy
  rate of 90.

15
Conclusions

• Epidemiologic data of Project 2 participants
  generally reflects that of GCS participants as a
  whole there is no obvious reluctance of African
  Americans to enroll in Project 2 as compared to
  Caucasians, although men are somewhat more
  reluctant than women.
• Interestingly, the 3 participants from whom
  brains were not obtained were all African
  American, possibly indicating some reluctance on
  the part of their families to follow through to
  autopsy.

16
Conclusions

• Neuropathologic data suggest that only about
  one-quarter to one-third of centenarians meet
  current neuropathologic criteria for the
  diagnosis of AD.
• Approximately one-quarter were neuropathologically
  normal.
• The remainder fell somewhere in between,
  suggesting that current diagnostic criteria may
  not be adequate or appropriate for use with this
  age group.

17
Project 2 - Challenges

• Cognitive testing many subjects have sensory
  impairments that render accurate testing
  difficult
• Getting families to call when the subject dies
  staying in regular contact seems to be the best
  way to make this happen, but even that doesnt
  always work
• AD neuropathology diagnostic criteria what
  should they be in someone who is 100 years old?!
• Distributing data and reaching a consensus when
  investigators are at multiple sites