Developing Topics e33

P4-346 TANGLES ARE DISTRIBUTED ACROSS TWO

TEMPORALLYAND SPATIALLY DISTINCT

POPULATIONS

Donald Royall1, Raymond Palmer1, Lon White2, 1University of Texas

Health Science Center San Antonio, San Antonio, Texas, United States;2Kuakini Medical Center, Honolulu, Hawaii, United States.

Background:We have applied latent growth curve (LGC) techniques to the

spatial distribution of Alzheimer’s disease (AD) pathology using autopsy

data from 435 participants in the Honolulu-Asia Aging Study (HAAS). Neu-

rofibrillary tangles (NFT) and neuritic plaques (NP) were distributed across

differently ordered sets of anatomical regions. When these were referenced

to pre-morbid temporal changes in cognitive performance, it appeared that

two populations of NFT might better fit the data. The current analysis ex-

plicitly tests the hypothesis that there are two distinct tangle forming pro-

cesses with different spatial origins and interregional vulnerability

gradients.Methods: Age at death adjusted regional NFT counts were mod-

eled as corticotropic and corticofugal growth processes, and regressed onto

a corticofugal NP growth process in a structural equation model (SEM)

framework, using AMOS. Raw pathology counts were provided by

HAAS. Analyses were limited to decedents with "normal" baseline cogni-

tion (circa 1991). Results: The final model showed excellent fit (CMIN/

DF¼ 3.6; RMSEA¼ 0.029; CFI¼ 0.967), and fit better than models of ei-

ther NFT growth process alone. The Corticotropic Intercept (CTi) in the hip-

pocampus significantly predicted only the Corticotropic Gradient (CTg)

into the neocortex. The CTg in the neocortex was significantly associated

with the Corticofugal Intercept (CFi) in the same regions and both the

"Early" NP intercept in the neocortex (Early NP), and the "Late" NP gradi-

ent (Late NP) extending into the hippocampus. The CFi in the neocortex was

significantly associated with "Early" NP in the same regions but not "Late"

NP in the hippocampus. "Late" NP in the hippocampus were significantly

associated only with CFg in the same structures, in a feedback loop.

Conclusions: These data suggest that there are two distinct tangle forming

processes that sum to produce observed ADpathology at autopsy. Corticofu-

gal tangle formation is associated with corticofugal NP formation, and may

precede it. Both corticofugal processesmaybe preceded by corticotropic tan-

gle formation that is not co-localized in space (and presumably time) with

cofticofugalNP formation. The corticofugal processesmost likely drive cog-

nitive decline (i.e., via beta amyloid neuro-toxicity) and can be dated relative

to cognitive changes in HAAS and /or NP formation, which is imagable.

P4-347 ISBRAAKSTAGESYMMETRICAL?APILOTSTUDY

FROMTHE HONOLULUASIA AGING STUDY

Jane Uyehara-Lock1, Helen Petrovitch2, G. Webster Ross3,

Kamal Masaki4, Lon White5, 1University of Hawaii, John A. Burns School of

Medicine, Department of Pathology, Kuakini Medical Center, Kaiser

Moanalua Medical Center, Tripler Army Medical Center, Honolulu, Hawaii,

United States; 2Pacific Health Research and Education Institute, Kuakini

Medical Center, Honolulu, Hawaii, United States; 3Honolulu Department of

Veterans Affairs, Pacific Health Research and Education Institute, Honolulu,

Hawaii, United States; 4University of Hawaii, John A. Burns School of

Medicine, Department of Geriatrics, Kuakini Medical Center, Honolulu,

Hawaii, United States; 5Kuakini Medical Center, Pacific Health Research and

Education Institute, Chaminade University, Honolulu, Hawaii, United States.

Background: Braak staging is utilized in the histologic analysis of Alz-

heimer’s disease and isusually assessedusing sections fromthe left of the brain

to evaluate neurofibrillary tangles. This reflects an expectation that lesions in

the dominant hemispherewill be better correlatedwith clinicalmanifestations.

The aim of this study is to estimate the frequency of contralateral stage non-

concordance and to consider the diagnostic and clinical implications of such

non-concordance. Methods: Nineteen Japanese American men who under-

went autopsy evaluation were included in this pilot series. Modified Biel-

schowsky and Gallyas stains of isocortical, hippocampal, and entorhinal

sections fromboth sides were independently assessed by a single neuropathol-

ogist. Left and right staging was done separately with the reader blinded to

contralateral observations, age, clinical history, handedness and neuropsy-

chology test scores. Results: Left and right stages were identical for 9

(47%), differed by one for 6 (32%), and varied by more than 1 point for 4

(21%). The Braak stage from the right was more often lower, consistent

with the expectationmentioned. The numbers in this pilot survey do not allow

definitive comment on correlations with handedness, severity of cognitive im-

pairment or age. Conclusions: A substantial frequency of non-concordant

left-right Braak staging raises questions about the utility of unilateral Braak

staging for the unbiased assessment of global Alzheimer pathology. In this pi-

lot series, non-concordancewasmore discerniblewith higher scores, and con-

sistent with an expectation that greater pathology on the left side would be

linked to greater cognitive impairment. Results for an expanded series will al-

low examination of correlations with clinical features, handedness, and age. It

seems likely that left-right differences in lesion densities are relevant to under-

standing relationships of brain pathology, neuroimaging findings and other

biomarkers with clinical manifestations of the Alzheimer process.

P4-348 THE RELATIONSHIP OF WHITE MATTER

HYPERINTENSITIES WITH PERFUSION AND

COGNITION IN MIDDLE-AGED ADULTS AT RISK

FOR ALZHEIMER’S DISEASE

Benjamin Austin1, Erik Kastman2, Yin Huang1, Guofan Xu2,

Nayanjyoti Pathak2, Vikas Singh1, Sean Fain1, Sanjay Asthana2,

Carey Gleason2, Howard Rowley2, Barbara Bendlin2, 1University of

Wisconsin - Madison, Madison, Wisconsin, United States; 2Wisconsin

Alzheimer’s Disease Research Center, University of Wisconsin School of

Medicine and Public Health, Madison, Wisconsin, United States.

Background:Alzheimer’s disease (AD) ismarked by the prevalence ofwhite

matter hyperintensities (WMH) which are frequently observed on T2-

weighted fluid-attenuated inversion-recovery (FLAIR) MRI scans. These re-

gions have been characterized by disrupted blood flow and can be classified

as periventricular (PVWMH) or deepWMH (DWMH). The functional signif-

icance of WMH and its relationship with perfusion and cognition in the pre-

clinical stages of disease, however, remains unclear. Objective: To

characterize the relationship between WMH, relative cerebral blood flow

(rCBF), and cognition in asymptomatic middle-aged adults at increased risk

of AD. Methods: 3T-MRI scans and a cognitive battery were administered

to 38 non-demented, middle-aged adult children of persons with AD (mean

6 SD; age¼ 54.26 6.6yrs; n¼ 28 [74%] women; n¼ 15 [39%] apolipopro-

tein E e4 allele carriers [APOE4þ]). For each participant, white matter maps

were segmented from T2-weighted FLAIR scans acquired in 3D with

0.530.532.0mmvoxel resolution andWMHprobabilitymapswere identified

using a random-walker segmentation algorithm.Measures of rCBFwere esti-

mated using DSC perfusion-weightedMRI scans, and contralateral regions of

normal-appearing white matter (NAWM) were targeted for comparison of

WMH tissue perfusion. Results: For all subjects, rCBF of all WMH was

less than that of NAWM, and DWMH was characterized by lower rCBF

than contralateral NAWM and PVWMH. The APOE4þ group demonstrated

greater volume of PVWMH and lower rCBF in PVWMH, NAWM, and