The cognitive reserve hypothesis in a population with low education

P108

O2-03-04

Oral O2-03: Diagnosis-Molecular Pathology/Histopathological

MAMMILLARY BODY ATROPHY IN THE DIFFERENTIAL DIAGNOSIS OF HIPPOCAMPAL ATROPHY

Melissa E. Murray1, Clifford R. Jack2, Dennis W. Dickson1, 1Mayo Clinic College of Medicine, Jacksonville, FL, USA; 2Mayo Clinic Rochester, Rochester, MN, USA. Contact e-mail: [email protected] Background: Hippocampal atrophy, which has been used to diagnose and follow progression of Alzheimer disease (AD) with neuroimaging, is seen in disorders other than AD, including hippocampal sclerosis (HpScl). HpScl is characterized by selective neuronal loss and gliosis of the hippocampal outflow pathway (CA1 and subiculum) that projects to the mammillary body (MB). Since the MB undergoes transsynaptic atrophy in HpScl, we hypothesized that MB atrophy could be used in differential diagnosis of HpScl from AD. Methods: Cases with HpScl were identified from the Mayo Clinic Jacksonville brain bank database, and postmortem photographs were analyzed. HpScl cases were limited to those with a Braak NFT stage (BS) Hp), ‘‘typical’’ (n¼26, ctx¼Hp) and limbic predominant (n¼19, Hp>ctx). Results: The MB was smaller in HpScl (5.460.6 mm) than controls (5.960.9 mm) (p¼0.020), however, when FTLD-U cases were removed, the significance was lost (p¼0.073). In a regression model of MB size, FTLD-U was the strongest variable (p<0.014) and not AD (p¼0.099) or HpScl (p¼0.514). Hp-sparing and typical AD showed no difference in MB size and were grouped for analytical purposes. Limbic predominant AD (5.260.7 mm) had a significantly smaller MB than other AD subtypes (6.060.6 mm). Conclusions: Our hypothesis that MB atrophy could be used to differentiate HpScl from AD was disproved. Significant MB atrophy was detected in FTLD-U and in limbic predominant AD. The results suggest that assessing MB atrophy has a limited value in macroscopic differential diagnosis of hippocampal atrophy. Volumetric analysis of MB size as one parameter in a multivariate analysis with hippocampal volume and cerebral atrophy may provide a more useful neuroimaging means to differentiate AD from HpScl and FTLD-U.

O2-03-05

TDP-43 DEPOSITION IN PRESENILIN MUTATION-ASSOCIATED ALZHEIMER’S, SPORADIC ALZHEIMER’S, AND NON-DEMENTED ELDERLY

James B. Leverenz1,2, Thomas J. Montine2, Ellen J. Steinbart1, Thomas D. Bird1,2, 1VA-PSHCS, Seattle, WA, USA; 2University of Washington, Seattle, WA, USA. Contact e-mail: [email protected]. edu Background: Abnormal deposition of TAR DNA binding protein-43 (TDP43) is associated with amyotrophic lateral sclerosis and certain frontotemporal dementias. However, recent studies have found that TDP-43 immunopositive inclusions and neurites can also be observed in a number of other neurodegenerative diseases including Alzheimer’s disease (AD). We explored the frequency and distribution of TDP-43 pathology in sporadic and presenilin mutation-associated AD and in non-demented elderly controls. Methods: Seventeen normal controls, 25 sporadic AD cases, and 26 familial AD cases with presenilin 1 or 2 mutations were evaluated for TDP-43 pathology (mean age at death 83.2, 81.9, 50.5, 69.5 years respectively). The regions examined included the amygdala, hippocampus including dentate gyrus, parahippocampal gyrus, cingulate gyrus, and frontal cortex. Detection of TDP-43 used an antibody to TDP-43 (ProteinTech, 1:2000) and included autoclave pretreatment and nickel enhancement (0.2%). Sections were assessed blinded to case category. Results: TDP-43 pathologic change was remarkably frequent in the hippocampal-amygdala transition area (HATA) of the both the sporadic AD cases (75%) and the elderly controls (58%), but significantly less frequent in the familial AD cases (31%, p<0.05, Fisher’s Exact). However, no control case had TDP-43 pathology in any other region examined. In contrast, hippocampal and parahippocampal TDP-43 pathologic change was observed in the sporadic AD

(63%) and familial AD (17%) cases. When all AD cases were combined frontal cortical TDP-43 pathology was uncommon (2 of 51, 4%). Conclusions: Consistent with previous reports, we observed a temporal lobe predominance of TDP-43 pathologic change in both the sporadic and familial AD cases. Our findings differ from previously reported studies in that the number of sporadic AD cases with any TDP-43 pathology was fairly high. We suspect this is a methodological issue due to the staining protocol and our focus on the examination of the HATA region for TDP-43 pathology. While we also found a remarkably high frequency of TDP-43 pathology in controls, this was restricted exclusively to the amygdala/HATA region in all cases. We suspect age may be important factor explaining the relatively low frequency of TDP-43 pathology in the presenilin mutation cases. O2-03-06

A MICROANATOMICAL CORRELATE OF COGNITIVE DECLINE IN MILD COGNITIVE IMPAIRMENT AND ALZHEIMER’S DISEASE

Steven A. Chance, Linda Clover, Leila Currah, Margaret M. Esiri, University of Oxford, Oxford, United Kingdom. Contact e-mail: steven.chance@ clneuro.ox.ac.uk Background: Age is the greatest risk factor for Alzheimer’s disease and early detection requires greater understanding of how normal age-associated neuroplasticity leads to the accumulation of disease-associated pathology such as plaques and tangles. Mild cognitive impairment (MCI) offers a window on this transitional stage but MCI and its possible division into a stable or progressive form has not yet been characterized at a cytoarchitectural level. Few microanatomical measures have been reliably correlated with cognitive measures in ageing and Alzheimer’s disease. Methods: Minicolumn spacing and organization of cells was measured in the Planum Temporale of the posterior superior temporal cortex (BA22), an area for which we have previously reported normal age-associated minicolumn thinning. Post-mortem brain tissue was sampled from 10 normal controls, 18 subjects with MCI (10 with stable MCI, 8 with progressing MCI), and 10 subjects with confirmed Alzheimer’s disease. Plaque density was also measured. Neuroanatomical measures were analysed with cognitive assessments (MMSE scores and semantic fluency) taken from the subjects a few months before they died as part of longitudinal neuropsychological testing within the OPTIMA project. Results: In group comparisons, minicolumn width was significantly* lower in Alzheimer’s disease and plaque density was significantly higher. Across all 38 subjects, minicolumn width was significantly* positively correlated with MMSE scores and semantic fluency. Plaque density was significantly* negatively correlated with MMSE scores and semantic fluency. Although minicolumn width in the MCI group as a whole was not significantly different from controls, the stable MCI group had wider minicolumns than progressing MCIs. In stable MCI low minicolumn width was significantly* associated with low semantic fluency, however progressing MCIs did not retain this relationship. (*p<0.05). Conclusions: Disruption of minicolumnar organization of neurons has been correlated with increased cognitive impairment in primates, however minicolumn correlations with cognitive function have not been shown before in humans. In particular, MCI has not been investigated in this manner. The results support the concept that MCI is intermediate between healthy ageing and Alzheimer’s disease but also that there is a separation between stable and progressing MCI with progressing MCI appearing to lose the quantitative relationship between minicolumn width and semantic fluency. O2-03-07

THE COGNITIVE RESERVE HYPOTHESIS IN A POPULATION WITH LOW EDUCATION

Jose M. Farfel, Lea T. Grinberg, Renata E. L. Ferretti, Renata E. P. Leite, Ana T. Alho, Katia C. Oliveira, Maria C. Lima, Antonio Caetano Junior, Carlos A. Pasqualucci, Paulo H. N. Saldiva, Ricardo Nitrini, Wilson Jacob Filho, University of Sao Paulo Medical School, Sao Paulo, Brazil. Contact e-mail: [email protected]

Oral O2-04: Disease Mechanisms: APOE Background: Education can modify the relationship between Alzheimer´s disease neuropathologic findings and cognitive fuunction. The objectives of this study are to evaluate the burden of AD-type pathology on a very-old, cognitively intact sample from a developing country and to investigate the role of few years of education over the constitution of a cognitive reserve on preclinical AD cases. Methods: A post-mortem study evaluating 57 individuals with normal cognition, aged 80 years or older, randomly selected from the Brazilian Aging Brain Study. Cognitive evaluation was performed with a knowledgeable informant using the CDR and the IQCODE combined. All the cases had a CDR¼0 and an IQCODE<3.20. Neuropathological examinations were performed using immunohistochemistry. The cases were classified according to the Braak and Braak staging, the CERAD and the NIA-RI criteria. A case was considered as ‘‘preclinical AD’’ if having Braak  IV or CERAD was B or C or NIA-RI criteria as intermediate or high likelihood. Age, gender, education, depression and cardiovascular risk factors were compared between the groups. Results: A considerable percentage of subjects fulfilled one or more neuropathologic criteria for ‘‘preclinical AD’’. (29.8%, 31.6% and 19.3%, according to Braak and Braak, CERAD and NIA-RI criteria, respectively). A higher educational level was found significant on the preclinical AD group, according to Braak and Braak staging (2.83 years for Braak III and 4.94 years for Braak IV, P¼0.026). Conclusions: A minimum neuropathologic threshold for clinical AD cannot be determined based on current diagnostic criteria. Cognitively normal elderly can frequently harbor disseminate pathology of AD. These individuals probably have a higher cognitive reserve in which educational level may play an important role.

O2-03-08

CLINICOPATHOLOGIC CORRELATIONS FROM THE NUN STUDY

Karen S. SantaCruz1, Michael Kuskowski1, Laura Hemmy1, Kelvin Lim1, Suzanne L. Tyas2, 1University of Minnesota, Minneapolis, MN, USA; 2 University of Waterloo, Waterloo, ON, Canada. Contact e-mail: [email protected] Background: The Nun Study is a longitudinal study of aging conducted on 678 U.S. School Sisters of Notre Dame, recruited in 1991, at age 75. Methods: Detailed neuropathological data has been collected for 523 of these participants who have come to autopsy in the past two decades. We compared neuritic plaque burden and neurofibrillary tangle distribution in participants with and without clinical dementia using Braak and Braak, CERAD and NIA-Reagan Institute criteria. Results: The most definitive diagnostic categories for each of these grading schemes showed good predictive values for dementia status. However, when all 498 cases with adequate pathological information were analyzed, 71 demented subjects fell into Braak and Braak categories 0-II and 31 non-demented subjects fit Braak and Braak categories V-VI. When participants with additional clinico-neuropathological findings which might complicate a dementia diagnosis were removed from analysis, only 13 subjects with antemortem clinical dementia had low stage neurofibrillary tangle pathology and 15 participants without dementia showed high stage tangle pathology. Conclusions: The absence of histopathological markers for a specific central nervous disease process in a demented person raises the possibility of systemic or neuropsychiatric disease. Participants with significant histopathological evidence of Alzheimer’s disease, but without clinical dementia have been characterized as showing pathological or presymptomatic aging or asymptomatic Alzheimer’s disease. These cases are rare and it is important to make comparisons of cognitive status with specific pathological features in order to determine whether this lack of correlation is truly reflective of factors which are protective against cognitive impairment in the face of Alzheimer’s disease pathogenesis or simply a reflection of difficulties in categorizing clinical and pathological features which may not fit neatly into pre-defined categories and stages.

P109 MONDAY, JULY 13, 2009 ORAL O2-04 DISEASE MECHANISMS: APOE

O2-04-01

STRESSED ASTROCYTES: A NEW PLAYER IN APOE4-ASSOCIATED ALZHEIMER’S DISEASE

Karl H. Weisgraber, Gladstone Institute for Neurological Disease, San Francisco, CA, USA. Contact e-mail: [email protected] Background: Domain interaction, a structural property of apolipoprotein (apo) E4 that distinguishes it from apoE3 and apoE2, is predicted to contribute to the association of apoE4 with Alzheimer’s disease (AD). Arg-61 apoE mice, a gene-targeted model specific for domain interaction, have lower brain levels of apoE than wildtype (WT), resulting from decreased secretion from astrocytes. These mice display synaptic, functional, and cognitive deficits that establish domain interaction as the causative factor. Arg-61 apoE does not accumulate in astrocytes, indicating it is abnormally folded and targeted for degradation. Thus, we sought to determine if domain interaction caused endoplasmic (ER) stress and an unfolded protein response (UPR) in astrocytes, compromising their function. Methods: We examined the three UPR pathway markers in astrocytes (IRE1, PERK, and astrocyte-specific OASIS) by real-time RT-PCR, measured glucose uptake, and determined the ability of astrocyte-conditioned media to support neurite outgrowth. Results: All three UPR pathways were activated in Arg-61 apoE astrocytes (mRNA levels 30 to 50% greater than in WT), full-length OASIS was cleaved into its 55-kDA transcriptionally active fragment, and several downstream UPR effecter genes were similarly elevated, establishing a chronic UPR in Arg-61 apoE astrocytes. We determined that glucose uptake in cultured Arg-61 apoE astrocytes was compromised (35% of WT). This finding correlates with astrocyte glucose hypometabolism observed in non-demented and demented apoE4 carriers by positron emission tomography. Conditioned medium from cultured Arg-61 apoE astrocytes was less effective in promoting neurite outgrowth in N2a cells (70% of WT). To determine if reduced apoE or cholesterol secretion in Arg-61 astrocytes was a factor, Apoeþ/- astrocytes were used in glucose uptake and neurite outgrowth studies. We found that that neither had the same effect as Arg-61 apoE. The lower levels of the astrocyte-specific glutamate transporter, GLT1, in Arg-61 apoE mice, further support astrocyte dysfunction. Conclusions: ApoE4 domain interaction causes a chronic ER stress and UPR in Arg-61 apoE astrocytes that compromises key functional pathways. These results implicate astrocytes as a new player in the association of apoE4 with neurodegeneration and AD and suggest targeting ER stress in astrocytes is a potential therapeutic target.

O2-04-02

ASTROCYTES PREFERENTIALLY DEGRADE APOE4: IMPACT ON Ab LEVELS AND NEURONAL PLASTICITY IN APOE TARGETED REPLACEMENT MICE

David Riddell, H. Zhou, K. Atchison, H. Warwick, P. Atkinson, W. Stewart, J. Jefferson, L. Xu, S. Aschmies, Y. Kirksey, Y. Hu, E. Wagner, A. Parratt, J. Xu, Z. Li, M. M. Zaleska, S. J. Jacobsen, M. Pangalos, P. Reinhart, Wyeth research, Princeton, NJ, USA. Contact e-mail: riddeld@ wyeth.com Background: Inheritance of the apoE4 allele (e4) increases the risk of developing Alzheimer’s disease, however, the mechanisms underlying this association remain elusive. Recent data suggest that inheritance of e4 may lead to reduced apoE protein levels in the CNS. Methods: We therefore examined apoE protein levels in the brains, CSF and plasma of e2/2, e3/3, and e4/4 targeted replacement mice. Results: These apoE mice showed a genotype dependant decrease in apoE levels; e2/2 > e3/3 > e4/4. Next, we sought to examine the relative contributions of apoE4