LACUNAR INFARCTS: A KEY NEUROPATHOLOGICAL FEATURE IN MILD COGNITIVE IMPAIRMENT

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Podium Presentations: Thursday, July 20, 2017

and had mean education¼4.763.7 years, while those 80 years and older (mean age: 85.764.7) were 39% male, 70% White, and had education¼3.363.4 years (Table 1). Compared to those <80, the oldest old had higher odds of neurofibrillary tangles (NFT) (OR¼5.02, 95%CI¼3.85-6.57), neuritic plaques (OR¼4.30, 95% CI¼3.33-5.56), hyaline arteriolosclerosis (OR¼1.99, 95% CI¼1.40-2.82), hippocampal sclerosis (OR¼4.40, 95%CI¼1.9010.16), cerebral amyloid angiopathy (OR¼1.94, 95%CI¼1.063.54), LBD (OR¼2.48, 95%CI¼1.65-3.74), and argyrophilic grain disease (OR¼2.05, 95%CI¼1.47-2.86) (Table 2). The oldest old had more than five times the odds of having 2 neuropathological diagnoses when compared to those <80yo (OR¼5.40, 95% CI¼3.30-8.83). NFT, lacunar infarcts, and hyaline arteriolosclerosis were associated with cognitive impairment in the two age groups in multivariate analyses, although these associations were attenuated in the oldest old (Table 3). Siderocalcinosis was associated with cognitive impairment in the oldest old only, while LBD was associated with cognitive impairment only in the youngest old (Table 3). Conclusions: The neuropathological profile and its relation to cognitive impairment differed in the oldest old when compared to younger subjects in a large sample from a LMIC. O5-07-04

COGNITIVE PERFORMANCE AND ALZHEIMER-ASSOCIATED PATHOLOGY IN THE CONTEXT OF EXTREME AGING

Nina Beker1,2, Andrea Ganz1,2, Annemieke Rozemuller1,2, Philip Scheltens1,2, Sietske A. M. Sikkes1,2, Jeroen J. M. Hoozemans1,2, Henne Holstege1,3, 1VU University Medical Center, Amsterdam, Netherlands; 2Amsterdam Neuroscience, Amsterdam, Netherlands; 3Neuroscience Campus Amsterdam, Amsterdam, Netherlands. Contact e-mail: n.beker@ vumc.nl Background: Presence of Ab deposits, neurofibrillary tangles

(NFTs), and neuritic plaques (NPs) are neuropathological hallmarks of Alzheimer’s disease (AD). However, these hallmarks are also observed in elderly without cognitive decline. To what extent these changes correlate with cognitive functioning during extreme aging remains elusive. As part of the 100-plus Study we aim to explore the relationship between AD-associated pathology and the cognitive task-performance of centenarians. So far, we included 270 participants, with age 100 years and self-reported cognitive health, of whom 77 agreed to brain donation. Methods: We administered neuropsychological tests aimed at measuring global cognition (Mini-Mental State Examination; MMSE), memory, language, attention, visuo-spatial and executive functioning (EF). These were repeated during follow-up visits after one year, until frailty or death no longer allowed assessment. Ab deposits were studied using immunohistochemistry, NFTs and NPs using Gallyas silver staining. Here we report preliminary data of the first 13 centenarians (8 females and 5 males, age range: 100-111) that came to autopsy. Results: According to NIA-Reagan criteria classification based on Ab, NFTs and NPs, 7 centenarians had “intermediate” AD pathology, 5 had a “low” level of AD pathology, and one had no AD pathology. The centenarian with the highest MMSE score (30) had intermediate Ab (Thal 3) and NFTs (Braak 3), but low NPs (CERAD 0). Relative to the performance of the 100plus cohort, one centenarian (MMSE 27) performed average on all cognitive tests, despite high amounts of Ab (Thal 5), NFTs (Braak 4), and few NPs (CERAD 1). A centenarian who scored 15 on the MMSE, and who performed poorly on visual memory, had high Ab (Thal 5), NFTs (Braak 4), and NPs (CERAD 2). More-

over, the centenarian with the lowest MMSE score (10), had Thal stage 3, Braak stage 4, and CERAD score 2. Conclusions: Our preliminary results suggest that there is no relationship between Ab, NFTs and cognitive functioning, whereas the occurrence of NPs might be associated with poor cognitive task-performance. Our unique collection of centenarian brain tissues, thoroughly tested for cognitive functioning, will allow us to further investigate the association between brain functioning and neuropathological features in context of extreme aging.

O5-07-05

LACUNAR INFARCTS: A KEY NEUROPATHOLOGICAL FEATURE IN MILD COGNITIVE IMPAIRMENT

Renata Elaine Paraizo Leite1,2, Mariana Molina1, Roberta Diehl Rodriguez1,2, Lea T. Grinberg1,3, Claudia K. Suemoto1,2, Renata Eloah de Lucena FerrettiRebustini2,4, Jose M. Farfel1, Carlos Augusto Pasqualucci1,2, Wilson Jacob-Filho1,2, Ricardo Nitrini1,2, 1University of S~ao Paulo Medical School, S~ao Paulo, Brazil; 2Brazilian Brain Bank of the Aging Brain Study Group; University of S~ao Paulo, S~ao Paulo, Brazil; 3University of California, San Francisco, San Francisco, CA, USA; 4University of S~ao Paulo, School of Nursing, S~ao Paulo, Brazil. Contact e-mail: [email protected] Background: The underlying neuropathological lesions associ-

ated with mild cognitive impairment (MCI) are not yet completely understood. Differences in individual characteristics between MCI and cognitively normal individuals could help to explain the cognitive impairment on that group. Methods: A post-mortem study evaluating individuals included in the Brain Bank of the Brazilian Aging Brain Study Group, Brazil. The clinical diagnosis was established through a postmortem interview with an informant using the Cognitive Dementia Rating (CDR). Individuals with a CDR score of 0 (n¼204) and 0.5 (n¼51) were included. Individuals who were alcoholics, bedridden or showed severe visual and/or auditory deficits were excluded from the study. Neuropathological examinations were carried out based on accepted criteria, using immunohistochemistry. We compared the frequency of neurofibrillary tangles, neuritic plaques, lacunar infarct, hyaline arteriolosclerosis, cerebral amyloid angiopathy, hippocampal sclerosis, synucleinopathy, and siderocalcinosis between groups, using logistic regression models, Table 1 Characteristics of the sample (n¼255) in very mild dementia (CDR¼0.5) and no dementia (CDR¼0) gruop

Age (years), mean (SD)* Male, %y Race, %y  White  Black  Mixed  Asian Education (years), mean (SD)* IQCODE, mean (SD)*

CDR 0 n¼204

CDR 0.5 n¼51

67.7 (10.5) 53.9

72.7 (10.6) 47.1

70.1 10.3 16.7 2.9 5.4 (4.1)

54.9 19.6 25.5 0.0 3.8 (2.9)

0.002

3.0 (0.0)

3.3 (0.2)

<0.0001

p 0.004 0.38 0.06

CDR¼Clinical Dementia Rating, IQCODE¼Informant Questionnaire on Cognitive Decline in the Elderly. *unpaired t -test, ychi-square test.

Podium Presentations: Thursday, July 20, 2017 Table 2 Odds ratio of very mild dementia (CDR¼0.5) compared to no dementia (CDR¼0), according to different neuropathological lesions (n¼255) OR (95% CI) Braak 0-II III-IV V-VI CERAD 0-A B-C Lacunar infarct Hyaline arteriolosclerosis Cerebral amyloid angiopathy Hippocampal sclerosis Synucleinopathy Siderocalcinosis

p* 0.19

1 (reference) 2.19 (0.94-5.11) 1.30 (0.29-5.90)

0.02 0.56 0.68 0.74 0.93 0.11

Table 3 Frequency of lacunar infarct in very mild dementia (CDR¼0.5) and no dementia (CDR¼0) gruop CDR 0

CDR 0.5

9 (4.5) 193 (95.5)

8 (16.0) 42 (84.0)

Table 4 Neuropathological classification of participants according to dementia status: Clinical Dementia Rating (CDR) Scale ¼0: no dementia; (B) CDR¼0.5: very mild dementia

AD, n(%) VaD, n(%) AD + LBD, n(%) AD + VaD, n(%) LBD, n(%) PART DEFINITIVE, n(%) PART POSSIBLE, n(%) Others, n(%) Normal, n(%)

for a neuropathological diagnoses, with PART definitive as the most common one (n¼59; 29%) (Table 4). Conclusions: This study corroborates findings of series with predominantly Caucasians of high educational level, pointing the role of lacunar infarct in impairing the cognition. As vascular risk factors associated with lacunar infarct are preventable , aggressive measures to reduce these factors may impact the prevalence of cognition associated dysfunction.

0.30 1 (reference) 0.62 (0.25-1.53) 3.39 (1.19-9.62) 1.33 (0.51-3.48) 1.34 (0.34-5.17) 1.52 (0.13-17.5) 1.05 (0.31-3.52) 1.86 (0.87-3.99)

* logistic regression model, adjusted for age, sex, and education.

presence lacunar infarct, n (%) ausence lacunar infarct, n (%)

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CDR 0 (n¼204)

CDR 0.5 (n¼51)

16 (7.84) 4 (1.96) 2 (0.98) 1 (0.49) 9 (4.41) 59 (28.92) 10 (4.9) 4 (1.96) 99 (48.53)

7 (13.73) 16 (31.37) 1 (1.96) 0 (0) 3 (5.88) 12 (23.53) 4 (7.84) 0 (0) 8 (15.69)

adjusted for age, sex, and education. We also described the frequency of neuropathological diagnoses in each group. Results: CDR 0.5 participants (mean age: 72.7610.6) were 47% male, 55% White, and had mean education of 3.862.9 years, while those cognitively normal (mean age: 67.7610.5) were 54% male, 70% White, and had education of 5.464.1 years (Table 1). Compared to cognitively normal, the CDR 0.5 individuals had higher odds of lacunar infarct (OR¼3.39, 95%CI¼1.199.62) (Table 2). The difference between the groups remained after adjusting for age, sex and educational level. The presence of lacunar infarcts was registered in 16% of the CDR 0.5 group, against 4.5% of cognitively normal individuals (Table 3). Among the 51 participants with CDR¼0.5, 84% met criteria for a neuropathological diagnosis, with vascular dementia as the most common diagnosis (n¼16; 31%). Among 204 cognitively normal participants (CDR¼0), 105 (51%) met criteria

O5-07-06

PULSE PRESSURE IN LATE-LIFE AND ALZHEIMER’S AND CEREBROVASCULAR NEUROPATHOLOGY

Lilah M. Besser1, Daniel A. Nation2, Timothy M. Hughes3, Nicole Barlow1, Walter A. Kukull1, 1University of Washington, Seattle, WA, USA; 2University of Southern California, Los Angeles, CA, USA; 3Wake Forest School of Medicine, Winston-Salem, NC, USA. Contact e-mail: lmbesser@u. washington.edu Background: Pulse pressure (PP), the difference between sys-

tolic (SBP) and diastolic blood pressure (DBP), is a marker of vascular aging previously associated with brain atrophy, Alzheimer’s disease (AD) dementia, and cerebrovascular neuropathology (CVNP) in older adults. Increased PP may be associated with CVNP, in turn lowering the threshold for those with AD neuropathology (ADNP) to be diagnosed with AD dementia. Initial studies suggest that increased PP may be associated with AD pathogenesis. Additional studies are needed to investigate the association of PP with ADNP and CVNP. Methods: We used data on non-demented and demented 60 year olds in the National Alzheimer’s Coordinating Center’s Uniform Data Set. Brachial PP was calculated by subtracting DBP from SBP. ADNP was defined as having moderate/frequent neuritic plaques and Braak stage III-VI, and a CVNP index was based on the presence/absence of five cerebrovascular neuropathologies (low CVNP: score3; high CVNP: score>3). Multivariable logistic regression was used to examine if baseline PP or annual PP change was associated with ADNP or CVNP. Covariates included demographics, time between baseline and death, apolipoprotein E genotype, and antihypertensive medication use. Interaction terms between baseline PP and APOE e4 genotype were tested in models focused on associations with baseline PP. Results: The 696 nondemented (ADNP: 39%; CVNP: 46%) and 1,481 demented participants (ADNP: 72%; CVNP: 39%) were a mean age of 79 years, 54% were male, 45% were APOE e4 carriers, and 58% took antihypertensives. High PP (>63mmHg) was present in 45% of non-demented and 34% of demented participants, respectively, and 76% of those with high PP had high SBP (140mmHg). Baseline PP and annual PP change were not associated with ADNP or CVNP, nor was APOE e4 genotype an effect modifier of the associations with baseline PP. Antihypertensive use was associated with lower odds of ADNP in non-demented participants (OR: 0.91, 95% CI: 0.83-1.00), and a higher odds of CVNP in non-demented (OR: 1.06, 95% CI: 1.00-1.12) and demented participants (OR: 1.08, 95% CI: 1.02-1.14). Conclusions: Baseline PP and annual change in PP were not associated with ADNP or CVNP; however, antihypertensive use was associated with both.