Michael Properzi

Region-Specific Association of Subjective Cognitive Decline With Tauopathy Independent of Global β-Amyloid Burden

Importance The ability to explore associations between reports of subjective cognitive decline (SCD) and biomarkers of early Alzheimer disease (AD) pathophysiologic processes (accumulation of neocortical &bgr;-amyloid [A&bgr;] and tau) provides an important opportunity to understand the basis of SCD and AD risk. Objective To examine associations between SCD and global A&bgr; and tau burdens in regions of interest in clinically healthy older adults. Design, Setting, and Participants This imaging substudy of the Harvard Aging Brain Study included 133 clinically healthy older participants (Clinical Dementia Rating Scale global scores of 0) participating in the Harvard Aging Brain Study who underwent cross-sectional flortaucipir F 18 (previously known as AV 1451, T807) positron emission tomography (FTP-PET) imaging for tau and Pittsburgh compound B carbon 11–labeled PET (PiB-PET) imaging for A&bgr;. The following 2 regions for tau burden were identified: the entorhinal cortex, which exhibits early signs of tauopathy, and the inferior temporal region, which is more closely associated with AD-related pathologic mechanisms. Data were collected from June 11, 2012, through April 7, 2016. Main Outcomes and Measures Subjective cognitive decline was measured using a previously published method of z-transforming subscales from the Memory Functioning Questionnaire, the Everyday Cognition battery, and a 7-item questionnaire. The A&bgr; level was measured according to a summary distribution volume ratio of frontal, lateral temporal and parietal, and retrosplenial PiB-PET tracer uptake. The FTP-PET measures were computed as standardized uptake value ratios. Linear regression models focused on main and interactive effects of A&bgr;, entorhinal cortical, and inferior temporal tau on SCD, controlling for age, sex, educational attainment, and Geriatric Depression Scale score. Results Of the 133 participants, 75 (56.3%) were women and 58 (43.6%) were men; mean (SD) age was 76 (6.9) years (range, 55-90 years). Thirty-nine participants (29.3%) exhibited a high A&bgr; burden. Greater SCD was associated with increasing entorhinal cortical tau burden (&bgr;u2009=u20090.35; 95% CI, 0.19-.52; Pu2009<u2009.001) and A&bgr; burden (&bgr;u2009=u20090.24; 95% CI, 0.08-.40; Pu2009=u2009.005), but not inferior temporal tau burden (&bgr;u2009=u20090.10; 95% CI, −0.08 to 0.28; Pu2009=u2009.27). This association between entorhinal cortical tau burden and SCD was largely unchanged after accounting for A&bgr; burden (&bgr;u2009=u20090.36; 95% CI, 0.15-.58; Pu2009=u2009.001), and no interaction influenced SCD (&bgr;u2009=u2009−0.36; 95% CI, −0.34 to 0.09; Pu2009=u2009.25). An exploratory post hoc whole-brain analysis also indicated that SCD was predominantly associated with greater tau burden in the entorhinal cortex. Conclusions and Relevance Subjective cognitive decline is indicative of accumulation of early tauopathy in the medial temporal lobe, specifically in the entorhinal cortex, and to a lesser extent, elevated global levels of A&bgr;. Our findings suggest multiple underlying pathways that motivate SCD that do not necessarily interact to influence SCD endorsement. As such, multiple biological factors must be considered when assessing SCD in clinically healthy older adults.

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.

Interactive versus additive relationships between regional cortical thinning and amyloid burden in predicting clinical decline in mild AD and MCI individuals

The biological mechanisms that link Beta-amyloid (Aβ) plaque deposition, neurodegeneration, and clinical decline in Alzheimers disease (AD) dementia, have not been completely elucidated. Here we studied whether amyloid accumulation and neurodegeneration, independently or interactively, predict clinical decline over time in a group of memory impaired older individuals [diagnosed with either amnestic mild cognitive impairment (MCI), or mild AD dementia]. We found that baseline Aβ-associated cortical thinning across clusters encompassing lateral and medial temporal and parietal cortices was related to higher baseline Clinical Dementia Rating Sum-of-Boxes (CDR-SB). Baseline Aβ-associated cortical thinning also predicted CDR-SB over time. Notably, the association between CDR-SB change and cortical thickness values from the right lateral temporo-parietal cortex and right precuneus was driven by individuals with high Aβ burden. In contrast, the association between cortical thickness in the medial temporal lobe (MTL) and clinical decline was similar for individuals with high or low Aβ burden. Furthermore, amyloid pathology was a stronger predictor for clinical decline than MTL thickness. While this study validates previous findings relating AD biomarkers of neurodegeneration to clinical impairment, here we show that regions outside the MTL may be more vulnerable and specific to AD dementia. Additionally, excluding mild AD individuals revealed that these relationships remained, suggesting that lower cortical thickness values in specific regions, vulnerable to amyloid pathology, predict clinical decline already at the prodromal stage.

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.

THE HEALTHY BRAIN PROJECT: STUDY METHODOLOGY AND BASELINE CHARACTERISTICS OF AN ONLINE STUDY OF 3,400 MIDDLE-AGED ADULTS

open field test (OFT) were assessed at 4 and 12-mo. Results:2xTg-AD mice exhibited earlier onset of age-associated increase in aortic stiffness vs. WT mice (Fig. 1). SBP increased with age in both genotypes, and 2xTg-AD mice had higher SBP at 12-mo compared to WT mice (Fig. 2). No differences in cardiac dimensions or functionwere evident between 2xTg-AD mice and WT mice at 4-mo. But at 12-mo there was an increase in left ventricle (LV) posterior wall thickness (LVPW), and narrowed LV internal diameter (LVID) in 2xTg-AD vs.WTmice. LV hypertrophy in 12-mo 2xTg-ADmicewas accompanied by lower LV volumes (LV-Vol), greater ejection fraction (EF) and fraction shortening (FS) vs. age-matched WTmice (Table). 2xTg-AD mice exhibited impaired spatial learning and memory in the MWM at both 4 and 12-mo vs. age-matched WT (Fig. 3, 4). 12-mo 2xTg-AD mice had a trend for lower scores in NBT and lower vertical activity in the OFT (Fig. 5) vs. 12-mo WT mice. Conclusions: 2xTg-AD mice, unlike age-matched non-transgenic counterparts, exhibit early onset of cardiovascular abnormalities that are evident only after the onset of amyloid accumulation and cognitive impairment. If and how amyloid accumulation in neurons adversely affects the cardiovascular system remain to be determined. Supported by the NIH/NIA Intramural Research Program.

AN APOEε4 DERIVED STATISTICAL METHOD FOR OPTIMIZING TARGET AND REFERENCE REGIONS FOR AMYLOID-PET IMAGING

between healthy and preclinical subjects was made by biomarkers of brain Ab using increased amyloid tracer retention on PET imaging. Results:BHAI was able to significantly distinguish normal aging and preclinical subjects (P<0.01). Moreover, preclinical and AD subjects showed similar values of BHAI (Figure 1). Conclusions:The major finding from this preliminary study was that individuals in the elevated group (preclinical AD) demonstrated lower CVR compared to the healthy group, and that this lower CVR was detected using our BHAI index. This noninvasive, inexpensive and easy to use index has the potential to be an ideal screening mothed for large populations.

CERTAIN PLASMA N-TERMINAL TAU FRAGMENTS ARE ELEVATED IN AD AND AD-MCI COMPARED TO CONTROLS

Gender (femal Age (years) MMSE CSF Ab42 (pg CSF Tau (pg/m CSF Tau/Ab42 FRAGMENTS ARE ELEVATED IN AD AND AD-MCI COMPARED TO CONTROLS Ashvini Keshavan, David Mengel, Zhicheng Chen, Purvish P. Patel, Andy Billinton, Michael Perkinton, Jennifer L. Percival-Alwyn, Henrik Zetterberg, Keith A. Johnson, Michael Properzi, Aaron P. Schultz, Reisa A. Sperling, Robert A. Rissman, Doug R. Galasko, Jonathan M. Schott, Dominic M. Walsh, Dementia Research Centre, Institute of Neurology, University College London, London, United Kingdom; Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Boston, MA, USA; Centre for Neurologic Diseases, Brigham and Women’s Hospital, Boston, MA, USA; Quanterix Corporation, Cambridge, MA, USA; AstraZeneca, Cambridge, United Kingdom; MedImmune, Cambridge, United Kingdom; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, M€olndal, Sweden; UCL Institute of Neurology, Department of Molecular Neuroscience, University College London, Queen Square, London, United Kingdom; Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, Boston, MA, USA; University of California San Diego, La Jolla, CA, USA; Ann Romney Centre for Neurologic Diseases, Brigham and Women’s Hospital, Boston, MA, USA. Contact e-mail: a.keshavan@ucl.ac.uk

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