Jennifer S. Rabin

Global White Matter Diffusion Characteristics Predict Longitudinal Cognitive Change Independently of Amyloid Status in Clinically Normal Older Adults

&NA; White matter degradation has been proposed as one possible explanation for age‐related cognitive decline. In the present study, we examined 2 main questions: 1) Do diffusion characteristics predict longitudinal change in cognition independently or synergistically with amyloid status? 2) Are the effects of diffusion characteristics on longitudinal cognitive change tract‐specific or global in nature? Cognitive domains of executive function, episodic memory, and processing speed were measured annually (mean follow‐up = 3.93 ± 1.25 years). Diffusion tensor imaging and Pittsburgh Compound‐B positron emission tomography were performed at baseline in 265 clinically normal older adults (aged 63‐90). Tract‐specific diffusion was measured as the mean fractional anisotropy (FA) for 9 major white matter tracts. Global diffusion was measured as the mean FA across the 9 white matter tracts. Linear mixed models demonstrated independent, rather than synergistic, effects of global FA and amyloid status on cognitive decline. After controlling for amyloid status, lower global FA was associated with worse longitudinal performance in episodic memory and processing speed, but not executive function. After accounting for global FA, none of the individual tracts predicted a significant change in cognitive performance. These findings suggest that global, rather than tract‐specific, diffusion characteristics predict longitudinal cognitive decline independently of amyloid status.

Interactive Associations of Vascular Risk and β-Amyloid Burden With Cognitive Decline in Clinically Normal Elderly Individuals: Findings From the Harvard Aging Brain Study

Importance Identifying asymptomatic individuals at high risk of impending cognitive decline because of Alzheimer disease is crucial for successful prevention of dementia. Vascular risk and &bgr;-amyloid (A&bgr;) pathology commonly co-occur in older adults and are significant causes of cognitive impairment. Objective To determine whether vascular risk and A&bgr; burden act additively or synergistically to promote cognitive decline in clinically normal older adults; and, secondarily, to evaluate the unique influence of vascular risk on prospective cognitive decline beyond that of commonly used imaging biomarkers, including A&bgr; burden, hippocampal volume, fludeoxyglucose F18–labeled (FDG) positron emission tomography (PET), and white matter hyperintensities, a marker of cerebrovascular disease. Design, Setting, and Participants In this longitudinal observational study, we examined clinically normal older adults from the Harvard Aging Brain Study. Participants were required to have baseline imaging data (FDG-PET, A&bgr;-PET, and magnetic resonance imaging), baseline medical data to quantify vascular risk, and at least 1 follow-up neuropsychological visit. Data collection began in 2010 and is ongoing. Data analysis was performed on data collected between 2010 and 2017. Main Outcomes and Measures Vascular risk was quantified using the Framingham Heart Study general cardiovascular disease (FHS-CVD) risk score. We measured A&bgr; burden with Pittsburgh Compound-B PET. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite. Models were corrected for baseline age, sex, years of education, and apolipoprotein E &egr;4 status. Results Of the 223 participants, 130 (58.3%) were women. The mean (SD) age was 73.7 (6.0) years, and the mean (SD) follow-up time was 3.7 (1.2) years. Faster cognitive decline was associated with both a higher FHS-CVD risk score (&bgr;u2009=u2009−0.064; 95% CI, −0.094 to −0.033; Pu2009<u2009.001) and higher A&bgr; burden (&bgr;u2009=u2009−0.058; 95% CI, −0.079 to −0.037; Pu2009<u2009.001). The interaction of the FHS-CVD risk score and A&bgr; burden with time was significant (&bgr;u2009=u2009−0.040, 95% CI, −0.062 to −0.018; Pu2009<u2009.001), suggesting a synergistic effect. The FHS-CVD risk score remained robustly associated with prospective cognitive decline (&bgr;u2009=u2009−0.055; 95% CI, −0.086 to −0.024; Pu2009<u2009.001), even after adjustment for A&bgr; burden, hippocampal volume, FDG-PET uptake, and white matter hyperintensities. Conclusions and Relevance In this study, vascular risk was associated with prospective cognitive decline in clinically normal older adults, both alone and synergistically with A&bgr; burden. Vascular risk may complement imaging biomarkers in assessing risk of prospective cognitive decline in preclinical Alzheimer disease.

Sex, amyloid, and APOE ε4 and risk of cognitive decline in preclinical Alzheimer's disease: Findings from three well-characterized cohorts

Our objective was to investigate the effect of sex on cognitive decline within the context of amyloid β (Aβ) burden and apolipoprotein E genotype.

Connectome-derived diffusion characteristics of the fornix in Alzheimer's disease

The fornix bundle is a major white matter pathway of the hippocampus. While volume of the hippocampus has been a primary imaging biomarker of Alzheimers disease progression, recent research has suggested that the volume and microstructural characteristics of the fornix bundle connecting the hippocampus could add relevant information for diagnosing and staging Alzheimers disease. Using a robust fornix bundle isolation technique in native diffusion space, this study investigated whether diffusion measurements of the fornix differed between normal older adults and Alzheimers disease patients when controlling for volume measurements. Data were collected using high gradient multi-shell diffusion-weighted MRI from a Siemens CONNECTOM scanner in 23 Alzheimers disease and 23 age- and sex-matched control older adults (age rangeu202f=u202f53–92). These data were used to reconstruct a continuous fornix bundle in every participants native diffusion space, from which tract-derived volumetric and diffusion metrics were extracted and compared between groups. Diffusion metrics included those from a tensor model and from a generalized q-sampling imaging model. Results showed no significant differences in tract-derived fornix volumes but did show altered diffusion metrics within tissue classified as the fornix in the Alzheimers disease group. Comparisons to a manual tracing method indicated the same pattern of results and high correlations between the methods. These results suggest that in Alzheimers disease, diffusion characteristics may provide more sensitive measures of fornix degeneration than do volume measures and may be a potential early marker for loss of medial temporal lobe connectivity.

LONGITUDINAL DEPRESSIVE SYMPTOMS AND CORTICAL AMYLOID ARE ASSOCIATED WITH COGNITIVE DECLINE IN OLDER ADULTS

Figure 1. Higher GDS predicts worsening PACC, holding time and all other predictors constant, in thosewith elevated amyloid levels (greater than 1.10) Figure 1. PACC predicted by longitudinal GDS, holding time and all other predictors constant. Amyloid (Pittsburgh Compound B PET) levels represent one standard deviation below the mean of the sample (1.0), mean of the sample (1.2), one standard deviation above the mean (1.4), and the 95 percentile (1.6, given the positive skew). Time, GDS, age, and education are set at means; sex1⁄4female. PACC1⁄4 preclinical Alzheimer’s Disease Cognitive Composite; GDS1⁄4 Geriatric Depression Scale. Poster Presentations: Saturday, July 21, 2018 P116

The relationship between recall of recently versus remotely encoded famous faces and amyloidosis in clinically normal older adults.

Alzheimers disease (AD) patients exhibit temporally graded memory loss with remote memories remaining more intact than recent memories. It is unclear whether this temporal pattern is observable in clinically normal adults with amyloid pathology (i.e. preclinical AD).

QRISK2 AND FRAMINGHAM CARDIOVASCULAR RISK SCORES SIGNIFICANTLY CORRELATE WITH IMAGING BIOMARKERS OF PRECLINICAL AD: FINDINGS FROM THE HARVARD AGING BRAIN STUDY

were cross-sectionally related to worse memory functioning (p<0.05). Lower small-world coefficient values were related to a steeper decline in MMSE, memory, attention and executive functioning (p<0.05). Lower gamma values were associated with a faster decline in memory, attention and executive functioning and lower BC values correlated with a steeper decline in MMSE and memory functioning (p<0.05). At a regional level, lower BC values were most strongly associated with a steeper decline in MMSE and memory in the precuneus, medial frontal and temporal cortex (pFDR<0.05). Conclusions:Aberrant grey matter connectivity measures, indicating a more random network topology as often found in AD, were associated with a steeper decline in memory, attention, executive and general cognitive functioning. These results show that network measures might be useful to identify subjects who will show fast cognitive decline.

COGNITIVE RESERVE RELATES TO GREATER FUNCTIONAL CONNECTIVITY AND STRONGER INTERCONNECTIVITY WITHIN AND BETWEEN NODES, INDEPENDENT OF β-AMYLOID: FINDINGS FROM THE HARVARD AGING BRAIN STUDY

reserve (CR) and an individual with low CR. The individual with high CR has a higher premorbid level of cognitive functioning, and is able to maintain this premorbid level at more advanced levels of neuropathology. However, once both individuals have reached their inflection point (i.e. the onset of cognitive decline), clinical progression from a certain level of cognition function will be faster for the individual with high CR. The blue area reflects the estimated interval in which baseline and follow up measurements were obtained from the pre-dementia subjects in our sample. Modified version of figure 1 from The Lancet Neurology, 11(11), by Y. Stern, “Cognitive reserve in ageing and Alzheimer’s disease” (2012), 1006-1012, with permission from Elsevier. Podium Presentations: Monday, July 17, 2017 P582

BASELINE CARDIOVASCULAR RISK AND AMYLOID BURDEN SYNERGISTICALLY PREDICT LONGITUDINAL COGNITIVE DECLINE IN CLINICALLY NORMAL ELDERLY: FINDINGS FROM THE HARVARD AGING BRAIN STUDY

P1-256 BASELINE CARDIOVASCULAR RISK AND AMYLOID BURDEN SYNERGISTICALLY PREDICT LONGITUDINAL COGNITIVE DECLINE IN CLINICALLY NORMAL ELDERLY: FINDINGS FROM THE HARVARD AGING BRAIN STUDY Jennifer S. Rabin, Emily P. Kilpatrick, Rachel F. Buckley, Gad A. Marshall, Michael Properzi, Hannah Klein, Aaron P. Schultz, Vaishnavi Rao, Dorene M. Rentz, Trey Hedden, Keith Johnson, Reisa A. Sperling, Jasmeer P. Chhatwal, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; University of Melbourne, Melbourne, Australia; The Florey Institutes of Neurosciences and Mental Health, Melbourne, Australia; Brigham and Women’s Hospital, Boston, MA, USA; Massachusetts General Hospital, Charlestown, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA; Massachusetts Institute of Technology, Cambridge, MA, USA; Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Radiology, Division of Molecular Imaging and Nuclear Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. Contact e-mail: jrabin@mgh. harvard.edu