CSF ANALYSIS DETECTS CEREBRAL B-AMYLOID ACCUMULATION EARLIER THAN AMYLOID PET

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Podium Presentations: Monday, July 25, 2016

However, centres prescribing complete, intermediate and incomplete work-ups were differently represented for the two diagnoses. No statistically significant change emerged in diagnosis, diagnostic confidence or clinical management between complete, intermediate or incomplete assessments (Table). Stratifying patients for etiopathology (AD-FTD) or clinical severity (MCI-dementia) led to the same results. Conclusions: Collection of additional core bio-markers does not seem to affect the incremental value of amyloid-PET in naturalistic clinical setting. The clinicians combinations and use of instrumental examination needs to be better understood and elucidated in view of the definition of an evidence-based diagnostic algorithm. O2-08-05

NEURONAL INJURY AND DEGENERATION EVALUATED WITH IMAGING AND CSF BIOMARKERS IN AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE: RESULTS FROM THE DIAN STUDY

Nelly Joseph-Mathurin1, Andrei G. Vlassenko1, Anne M. Fagan1, Yi Su1, Karl A. Friedrichsen1, Christopher J. Owen1, Brian A. Gordon1, Russ C. Hornbeck1, Robert A. Koeppe2, Chengjie Xiong1, John C. Morris1, Randall Bateman1, Tammie LS. Benzinger1, Dominantly Inherited Alzheimer Network (DIAN), 1Washington University School of Medicine, St. Louis, MO, USA; 2University of Michigan, Ann Arbor, MI, USA. Contact e-mail: [email protected] Background: Changes in Alzheimer’s disease (AD) biomarkers can be detected before cognitive decline using neuroimaging and CSF measures. In autosomal dominant AD (ADAD), PET imaging biomarkers of amyloidosis and hypometabolism (measured with Pittsburgh compound B [PiB] and fluorodeoxyglucose [FDG], respectively) are detectable 15 and 10 years before any symptoms develop. A new marker of neurodegeneration, increased CSF visinin-like protein 1 (VILIP-1), may predict cognitive decline and has been shown to be increased in carriers of an ADAD mutation. We wanted to further characterize in ADAD this new marker of neurodegeneration by evaluating its relationship with well-known AD biomarkers, in particular FDG hypometabolism, which is believed to reflect neuronal dysfunction and injury. Methods: Participants from the Dominantly Inherited Alzheimer Network (DIAN) study (n¼202, including 124 mutation carriers [MC], 43 of whom were symptomatic) underwent MRI, PiB and FDG PET scans and CSF VILIP-1 measurement. Dementia severity was defined by the Clinical Dementia Rating (CDR). The cohort was divided by mutation status (non-carriers [NC] vs. MC) and b-amyloid status (PiB-negative vs. PiB-positive) for group comparisons. The standardized uptake value ratio (SUVR) of PiB and FDG, obtained from an MRIbased PET processing method, were corrected and normalized to the brainstem. Partial correlations between PET SUVR data and CSF-VILIP-1 levels controlling for age and family history were performed. Results: This study confirmed increased CSF VILIP-1 levels and decreased FDG SUVR values in MC compared to NC. Among carriers, PiB-positive participants had higher VILIP-1 levels compared to PiB-negative (p<0.005). VILIP-1 trended higher in PiB-positive asymptomatic participants compared to PiB-negative (p¼0.07). A positive correlation between mean cortical PiB SUVR and VILIP-1 (r¼0.36, p<0.0001) and a negative correlation between FDG PET in the precuneus and VILIP-1 in all participants (r¼-0.33, p<0.0001) were observed. The negative correlation between CSF-VILIP-1 and FDG PET was driven by the PiB-positve MC participants. Conclusions: These preliminary results show that increased CSF VILIP-1, a marker of neuronal

injury, is associated with both abnormal amyloid deposition and cerebral glucose hypometabolism in the DIAN population. Longitudinal investigation and evaluation of other AD features are still needed. Support: NIH/NIA U01AG032438. O2-08-06

CSF ANALYSIS DETECTS CEREBRAL B-AMYLOID ACCUMULATION EARLIER THAN AMYLOID PET

Sebastian Palmqvist1, Niklas Mattsson2, Oskar Hansson2, Alzheimer’s Disease Neuroimaging Initiative, 1Lund University, Malm€o, Sweden; 2 Clinical Memory Research Unit, Lund University, Lund, Sweden. Contact e-mail: [email protected] Background: Cerebral accumulation of b-amyloid (Ab) is thought to be the starting mechanism in Alzheimer’s disease (AD).

Podium Presentations: Monday, July 25, 2016

Interventions against pathological Ab metabolism should be initiated early to halt the disease progression. Ab can be detected by analysis of cerebrospinal fluid (CSF) Ab42 or amyloid positron emission tomography (PET), but it is unknown if any of the methods can identify an abnormal Ab load prior to the other. Our aim was to determine whether CSF Ab42 change before amyloid PET during preclinical stages of AD. Methods: We included 437 non-demented subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). All underwent 18F-florbetapir PET and CSF Ab42 analysis at baseline and at least 1 additional PET at follow-up (mean duration 2.1 years, range 1.1–4.4 years). Group classifications were based on normal () and abnormal (+) CSF and PET baseline results. Ab accumulation during follow-up was measured in yearly change of standardized uptake value ratio (SUVR) of florbetapir. Results: Cases that were isolated CSF Ab positive (CSF+/ PET) accumulated Ab with a mean rate of 1.2%/year (0.0083 SUVR/year), which was similar to the rate in CSF+/PET+ cases (1.2%/year, p¼0.86; 0.011 SUVR/year, p¼0.28). The mean accumulation rates of CSF+/PET cases were more than three times that of CSF/PET cases (0.35%/year, p¼0.018; 0.0024 SUVR/ year, p¼0.015). By extrapolating from these rates, CSF+/PET subjects were predicted to convert to CSF+/PET+ after a mean of 9.4 years. CSF+/PET+ cases deteriorated more in memory and hippocampal volume than CSF+/PET subjects (p<0.001), indicating that they are closer to AD dementia. The results were replicated after adjustments of different factors and when using different CSF/ PET cutoffs including a PET classification based on the SUVR in regions where the initial Ab accumulation occurs in AD. Conclusions: This is the first study to show that individuals who are CSF Ab positive but PET Ab negative have an abnormal cortical Ab accumulating rate similar to CSF+/PET+ individuals and higher than CSF/PET individuals. The results indicate that CSF Ab42 becomes abnormal in the earliest stages of AD, before amyloid PET and before neurodegeneration starts. MONDAY, JULY 25, 2016 ORAL SESSIONS O2-09 EPIDEMIOLOGY: VASCULAR PATHOLOGY AND COGNITIVE IMPAIRMENT O2-09-01

AORTIC STIFFNESS AND THE RISK OF INCIDENT MILD COGNITIVE IMPAIRMENT AND DEMENTIA

Matthew P. Pase1,2,3, Alexa S. Beiser1,4,5, Jayandra J. Himali1, Connie Tsao6, Claudia L. Satizabal1,7, Ramachandran S. Vasan1, Sudha Seshadri8, Gary F. Mitchell9, 1Boston University School of Medicine, Boston, MA, USA; 2Swinburne University of Technology, Hawthorn, Australia; 3Framingham Heart Study, Framingham, MA, USA; 4Boston University School of Public Health, Boston, MA, USA; 5The Framingham Study, Framingham, MA, USA; 6Beth Israel Deaconess Medical Centre, Boston, MA, USA; 7The Framingham Heart Study, Framingham, MA, USA; 8 The National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA, USA; 9Cardiovascular Engineering, Norwood, MA, USA. Contact e-mail: [email protected] Background: Aortic stiffening increases the transfers of high pressure and flow pulsatility to small cerebral vessels potentially causing the accumulation of vascular brain injury and cognitive decline. However, the assocaition of aortic stiffness with incident dementia and clinical cognitive impairment remains unclear. Our aim was to investigate the prospective association of aortic stiffness with the risks of incident mild cognitive impairment and dementia.

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Methods: We studied 1,101 dementia-free Framingham Offspring study participants (mean age 6966 years; 54% women). Aortic stiffness was measured as carotid-femoral pulse wave velocity using applanation tonometry, and modelled as a linear variable and the top two quintiles (>11.4 m/s). Outcomes were the 10-year risk of incident mild cognitive impairment and dementia, including clinically characterized Alzheimer’s disease. We observed 106, 77 and 59 events of mild cognitive impairment, all-cause dementia and clinical Alzheimer’s disease respectively. Results: After adjustment for age and sex, higher continuous aortic stiffness predicted an increased risk of mild cognitive impairment (Hazard Ratio [HR], 1.40 [95% CI: 1.13-1.73]), all-cause dementia (HR, 1.45 [95% CI: 1.13-1.87]) and Alzheimer’s disease (HR, 1.41 [95% CI: 1.06-1.87]). In a risk factor-adjusted statistical model, aortic stiffness remained a significant predictor of mild cognitive impairment, whereas the association with dementia was attenuated. In non-diabetics, the top two quintiles of aortic stiffness were associated with a higher risk of incident all-cause dementia across all statistical models. Conclusions: Aortic stiffness was an independent predictor of incident mild cognitive impairment in the whole sample and with incident dementia in non-diabetics. Our findings suggest aortic stiffness as a potentially modifiable risk factor for clinical cognitive impairment and dementia. O2-09-02

MIDLIFE AND LATE LIFE VASCULAR RISK FACTORS AND MICROSTRUCTURAL INTEGRITY ASSESSED USING DIFFUSION TENSOR IMAGING: THE ARIC-NCS STUDY

Melinda C. Power1, Jonathan V. Tingle2, Robert I. Reid3, Juebin Huang2, A Richey Sharrett4, Josef Coresh4, Michael Griswold2, Clifford R. Jack, Jr3, David S. Knopman3, Tom Mosley5, Rebecca F. Gottesman4, 1George Washington University, Washington, DC, USA; 2University of Mississippi Medical Center, Jackson, MS, USA; 3Mayo Clinic, Rochester, MN, USA; 4 Johns Hopkins University, Baltimore, MD, USA; 5University Mississippi Medical Center, Jackson, MS, USA. Contact e-mail: [email protected] Background: The presence of vascular risk factors, particularly in midlife, appears to increase risk of subsequent cognitive decline and dementia. Differences in microstructural integrity on diffusion MRI also appear related to differences in cognitive performance and may partially mediate the adverse consequences of vascular risk factors on cognition. However, current studies on microstructural integrity and vascular risk factors are exclusively-cross sectional, and none have evaluated relations of midlife risk factors to late life microstructural integrity. Methods: Our study sample included 1851 participants of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) who completed 3T MRI, including a diffusion tensor imaging pulse sequence. We assessed the association between midlife (measured at the baseline ARIC visit in 1987-1989, when participants were, on average 53 years old) and late life (concurrent with the MRI, on average 24 years later, in 2011-2013) measures of blood pressure, blood lipids, and blood glucose with total or regional mean white matter mean diffusivity (MD) and fractional anisotropy (FA). We also considered whether additionally adjusting for white matter hyperintensity (WMH) volumes in our regression models impacted these associations. Results: Elevated systolic and diastolic blood pressure (BP), at both midlife and late life, was generally associated with worse total and regional FA and MD in late life. Elevated blood glucose at midlife, but not late life, was also associated with worse total and regional MD, although there was little evidence linking midlife