The Framingham Brain Donation Program: Neuropathology Along the Cognitive Continuum
Rhoda Au, Sudha Seshadri, Kristen Knox, Alexa Beiser, Jayandra J. Himali, Howard J. Cabral, Sanford Auerbach, Robert C. Green, Philip A. Wolf and Ann C. McKee
Affiliation: Departments of Neurology and Pathology, Boston University School of Medicine, 715 Albany Street, Boston MA, 02118 & Geriatric Research Educational Clinical Center, Bedford Veterans Administration Hospital, 200 Springs Road, 182-B, Bedford MA 01730, USA.
Keywords: Brain, autopsy, epidemiology, alzheimer’s disease, brain ischemia, cerebrovascular risk fac, Immunohistochemistry, tau protein, atherosclerosis
The Framingham Heart Study has enrolled 3 generations of participants, the Original cohort (Gen 1) enrolled in
1948, the Offspring cohort (Gen 2) enrolled in 1971 and the Third Generation enrolled in 2002. Participants have been
undergoing prospective surveillance for incident stroke and dementia and embedded within this cohort is the voluntary
Framingham Brain Donation Program that was begun in 1997. Participants who register to become brain donors have had
one or more brain MR and cognitive test batteries administered. In addition, they undergo neurological evaluation as indicated,
record review and post-mortem next-of-kin interview to determine the presence, type and extent of antemortem,
clinical neurological diagnoses and to assign a retrospective Clinical Dementia Rating (CDR) Scale score. Between 1997
and 2009 there were 1806 deaths, 186 of which were among registered brain donors and of these 139 brains could be examined.
58% were deemed cognitively normal at death. We present results for 3 projects; the first was to examine the sensitivity
and specificity of our clinical diagnosis against the gold standard of pathological AD in 59 persons who underwent
detailed cognitive assessment in the two years prior to death; we observed a 77.3% sensitivity (2 persons with AD were
diagnosed clinically as Lewy body dementia) and a 91.9% specificity. The second examined the correlation of regional
Alzheimer-type pathology to cognitive status at death among 34 persons who were over the age of 75 and without any
significant vascular or alternative neurodegenerative pathology and found that neurofibrillary tangle counts distinguished
between persons who were controls, had mild cognitive impairment, mild or moderate dementia; tangles in dorsolateral
frontal cortex best distinguished MCI and controls. The third project examined the extent and severity of vascular pathology,
again in a larger sample of varying cognitive abilities and in a subsample of persons with either amnestic or nonamnestic
MCI. We observed that an aggregate ischemic injury score was significantly higher in persons with a CDR score
of 0.5 than in normal controls.
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