Kathryn P. Riley

Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: Findings from the Nun Study

The development of interventions designed to delay the onset of dementia highlights the need to determine the neuropathologic characteristics of individuals whose cognitive function ranges from intact to demented, including those with mild cognitive impairments. We used the Braak method of staging Alzheimers disease pathology in 130 women ages 76–102 years who were participants in the Nun Study, a longitudinal study of aging and Alzheimers disease. All participants had complete autopsy data and were free from neuropathologic conditions other than Alzheimers disease lesions that could affect cognitive function. Findings showed a strong relationship between Braak stage and cognitive state. The presence of memory impairment was associated with more severe Alzheimers disease pathology and higher incidence of conversion to dementia in the groups classified as having mild or global cognitive impairments. In addition to Braak stage, atrophy of the neocortex was significantly related to the presence of dementia. Our data indicate that Alzheimers neurofibrillary pathology is one of the neuropathologic substrates of mild cognitive impairments. Additional studies are needed to help explain the variability in neuropathologic findings seen in individuals whose cognitive performance falls between intact function and dementia.

Early life linguistic ability, late life cognitive function, and neuropathology: findings from the Nun Study

The relationships between early life variables, cognitive function, and neuropathology were examined in participants in the Nun Study who were between the ages of 75 and 95. Our early life variable was idea density, which is a measure of linguistic ability, derived from autobiographies written at a mean age of 22 years. Six discrete categories of cognitive function, including mild cognitive impairments, were evaluated, using the Consortium to Establish a Registry for Alzheimers Disease (CERAD) battery of cognitive tests. Neuropathologic data included Braak staging, neurofibrillary tangle and senile plaque counts, brain weight, degree of cerebral atrophy, severity of atherosclerosis, and the presence of brain infarcts. Early-life idea density was significantly related to the categories of late-life cognitive function, including mild cognitive impairments: low idea density was associated with greater impairment. Low idea density also was significantly associated with lower brain weight, higher degree of cerebral atrophy, more severe neurofibrillary pathology, and the likelihood of meeting neuropathologic criteria for Alzheimers disease.

Delayed recall, hippocampal volume and Alzheimer neuropathology: Findings from the Nun Study

Objective: To examine the associations of hippocampal volume and the severity of neurofibrillary lesions determined at autopsy with delayed verbal recall performance evaluated an average of 1 year prior to death. Methods: Hippocampal volumes were computed using postmortem brain MRI from the first 56 scanned participants of the Nun Study. Quantitative neuropathologic studies included lesion counts, Braak staging, and determination of whether neuropathologic criteria for Alzheimer disease (AD) were met. Multiple regression was used to assess the association of hippocampal volume and neuropathologic lesions with the number of words (out of 10) recalled on the Consortium to Establish a Registry for Alzheimer’s Disease Delayed Word Recall Test administered an average of 1 year prior to death. Results: When entered separately, hippocampal volume, Braak stage, and the mean neurofibrillary tangle counts in the CA-1 region of the hippocampus and the subiculum were strongly associated with the number of words recalled after a delay, adjusting for age and education. When hippocampal volume was entered together with each neuropathologic index, only hippocampal volume retained a significant association with the delayed recall measure. The association between hippocampal volume and the number of words recalled was present in both demented and nondemented individuals as well as in those with and without substantial AD neurofibrillary pathology. Conclusions: The association of neurofibrillary tangles with delayed verbal recall may reflect associated hippocampal atrophy.

Prediction of Preclinical Alzheimer's Disease: Longitudinal Rates of Change in Cognition

Preclinical Alzheimers disease (pAD) reflects neuropathological findings of AD in cognitively normal subjects. The present study represents an effort to determine if differences could be identified in the longitudinal patterns of cognitive performance in persons classified as pAD compared to those who did not meet criteria for AD at autopsy. We included 121 subjects who were cognitively normal from baseline through their last assessment before death and who underwent autopsy. Participants were classified into two groups: pathologically normal (PN; NIA-Reagan low or no-likelihood of AD, n = 89) and preclinical AD (pAD; NIA-Reagan criteria of intermediate or high-likelihood of AD in the absence of clinical dementia symptoms, n = 32) followed for a mean 7.5 years prior to death. Longitudinal rates and patterns of change in scores on a standard cognitive battery were compared between these two groups. While cognitive results at baseline and last evaluations revealed no clear cross sectional group differences after adjustment for age, ApoE status, education, and gender, statistically significant differences between the pAD and PN groups in slope of decline were seen on a composite score of cognitive function. Further analyses showed three components of this score reached significance: constructional praxis, delayed recall of a word list, and category verbal fluency. Despite being clinically viewed as normal at enrollment and at the final exam, there are significant differences in rates of cognitive decline in participants classified as pAD compared to those without this pathology. Longitudinal changes in slope of decline in specific cognitive test measures can serve as non-invasive methods for the detection of pAD.

Early-life linguistic ability, late-life pathology and asymptomatic Alzheimer's disease: Findings from the Nun Study

(4.1.0). VBM (SPM5 and DARTEL) and Freesurfer were used to assess effects within grey matter at each voxel and vertex respectively (FDR corrected, q<0.05). Linear regression was used to assess the individual and independent effects of gender, age and TIV. Results: Age, gender, and TIV were individually associated with all ROI volumes (see table) except age and caudate, age and amygdala and gender and hippocampus. Age and TIV had independent associations with all ROIs. Gender had an independent effect only on whole brain (p<0.001). The 95% CIs of the slope of TIV and ROIs never contained 1 indicating that dividing by TIV is not appropriate head-size adjustment. Age had a widespread negative association with thickness and volume throughout the cortex which survived gender and TIV adjustment (see figure). TIV was associated with increased thickness in the right-sided occipital lobe but not after age and gender adjustment. TIV had a large positive association with grey matter volume, which remained following age and gender adjustment. Gender had some effect on thickness in the left hemisphere (women>men) and a large effect on volume (men>women) but these were lost following TIV and age adjustment. Conclusions: Age has a large effect on results generated by all analysis techniques. Head-size adjustment is unnecessary for thickness analysis should gender and age be used, but is required for volume analyses. Gender-adjustment may be necessary for thickness studies and some ROI analysis but not for VBM should TIV and age be used.

Academic achievement in High school English courses and risk of Alzheimer's disease and dementia: Findings from the Nun Study

.17), working memory (r 1⁄4 .22), speed and flexibility (r 1⁄4 .39), CES-D (r 1⁄4 -.29), HDL (r 1⁄4 .26), and SPI2 (r 1⁄4 .59). Conclusions: Preliminary results across sleep measures link higher sleep ratings to better cognitive scores and healthier values on metabolic biomarkers. Longitudinal follow-up is needed to elucidate whether sleep plays a moderating or mediating role in the relationship between metabolic health, depression and cognitive decline.

P4-054: Cerebral cortical atrophy, brain infarcts, and clinical expression of Alzheimer pathology: Findings from The Nun Study

Background: The observation that not all who meet neuropathologic criteria for Alzheimer’s disease (AD) are demented has stimulated interest in the concept of cognitive reserve. Loss of cerebral cortical tissue is hypothesized to contribute to the loss of cognitive reserve. Vascular factors may also be important in cognitive reserve. Among those who meet neuropathologic criteria for AD, atrophy and brain infarcts may distinguish between those who resist clinical expression of AD (asymptomatic AD) and those who become demented (symptomatic AD). Methods: The Nun Study is a longitudinal study of aging in 678 participants 75 years; 237 met CERAD neuropathologic criteria for AD. Cerebral cortical atrophy, brain infarcts, and neuropathologic diagnosis of AD were determined by gross and microscopic postmortem examinations. Results: Cerebral cortical atrophy was strongly associated with symptomatic AD. This association persisted after adjustment for age at death, education, and APOE-e4 in logistic regression models of the presence of any atrophy (odds ratio [OR] 6.58, 95% CI 2.9215.95), and showed an increasing impact of atrophy from mild (OR 4.82; 95% CI 2.08-12.08) to moderate levels (OR 9.75; CI 2.00-37.19). Severe levels of atrophy showed a strong, significant association (OR 111.83; 95% CI 15.07-1000 ), but confidence limits could not be accurately calculated due to the paucity of subjects with severe atrophy and asymptomatic AD (1/22 or 4.5%). Frontal (OR 3.08; 95% CI 1.71-5.62), temporal (OR 5.29; 95% CI 2.7110.98) and parietal atrophy (OR 6.33; 95% CI 2.10-27.46) were all significantly associated with symptomatic AD; occipital atrophy was not a significant predictor, but few individuals (n 6) showed atrophy in this region. Large or lacunar brain infarcts were also significantly associated with symptomatic AD (OR 2.56; 95% CI 1.33-5.08) and remained significant in the presence of atrophy except for higher (moderate or severe) levels of atrophy. Conclusions: The presence of atrophy and brain infarcts significantly reduced the ability to resist clinical expression of AD pathology. Although the impacts of these pathologies are largely independent, brain infarcts may have a reduced contribution to symptomatic AD at more severe levels of atrophy. Studies of the association and interactions of brain pathologies on clinical expression of AD pathology may provide insight into mechanisms and predictors of cognitive reserve.