Pittsburgh Compound B Retention Research Articles

Association of platelet aggregation to amyloid and tau PET in the Framingham Heart Study

AbstractBackgroundPlatelets are key mediators of inflammation and vascular dysfunction. Prior work highlighted a role of platelet function in Ab and tau dynamics, and dementia risk. We hypothesized that platelet aggregation may associate with amyloid and tau brain levels in middled age people at risk of cardiovascular disease.MethodWe examined cross sectional associations of platelet aggregation with brain amyloid and tau PET levels (11C‐labeled Pittsburgh Compound‐B (PiB) and tau (18F‐Flortaucipir (FTP)) in middle aged cognitively normal participants at the Framingham Heart Study (FHS) Gen3 Cohort. Platelet aggregation was measured by light transmission aggregometry. The response to 0.98uM ADP stimulation was primarily evaluated followed by additional agonists and stimulation doses for sensitivity analysis. The associations were explored in multivariate regression models adjusted for age, age squared, sex, the time from blood to PET examination, and PET camera used.ResultThe final study sample included 356 participants (median [Q1,Q3] age, 55 [49, 61]; 51% women) of which 82 (23%) were on preventive platelet modifying treatments (PPT) (Table 1). We found significant interaction between PPT and platelet aggregation in their association with amyloid and tau PET levels, motivating a stratified analysis by the use or not of PPT. The platelet aggregation response was not associated with PiB or FTP retention in non‐PPT users (n = 274) (Table 2). In PPT users, the platelet aggregation response was positively associated with amyloid levels in the precuneus (β±SE: 0.36±0.14, P<0.05), and tau levels in the rhinal (β±SE: 0.49±0.15, P<0.01) and temporal regions (β±SE: 0.39±0.17, P<0.05).ConclusionOur results indicate that platelet aggregation is not associated with amyloid and tau PET levels in the general population. In people who are on PPT for primary prevention of CVD, platelet aggregation associates with amyloid and tau PET in Alzheimer’s disease (AD) relevant brain regions. This result reinforces the need for further examining the mediator role of platelet aggregation in the association of cardiovascular risk and AD.

Lower serum vitamin D aggravates hippocampal neurodegeneration related with amyloid pathology

AbstractBackgroundPrevious studies reported the associations between vitamin D deficiency and increased risk of Alzheimer’s disease (AD) dementia in older adults, but little is known how vitamin D is involved in the pathophysiology of AD. Thus, we aimed to examine the association and interaction of serum vitamin D level with in vivo AD pathologies including beta‐amyloid (Aβ) and neurodegeneration in nondemented older adults.MethodNondemented older adults consisting of cognitively normal and mild cognitive impairment groups were recruited from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease, an ongoing prospective cohort that began in 2014. All participants underwent comprehensive clinical assessments, measurement of serum 25(OH)D, and multimodal brain imaging including Pittsburgh compound‐B (PiB) positron emission tomography and magnetic resonance imaging at baseline. Global PiB retention was measured for Aβ biomarker, and hippocampal volume adjusted for intracranial volume (HVa) was used for neurodegeneration biomarker. Age, sex, apolipoprotein E (APOE) e4 positivity was controlled as covariates in all analyses.ResultA total 428 participants (mean age [SD]: 70.54 [7.97], female [N, %]: 182 [43%]) were included for analysis. Serum 25(OH)D levels were directly associated neither Aβ deposition nor HVa. However, serum 25(OH)D level had significant moderation effect on the association between Aβ and hippocampal neurodegeneration, in that lower serum 25(OH)D level significantly exacerbate the negative association between global Aβ retention and HVa (β = 34.612, p = 0.008) (Figure).ConclusionThe present findings suggest that lower serum vitamin D level may increase AD dementia risk by aggravating Aβ‐related neurodegeneration.

Abstract 10806: Ten Year Atherosclerotic Cardiovascular Disease Risk in Mid Life Predicts Late-Life Amyloid and Tau Deposition on Brain Imaging

Introduction: Risk factors of ASCVD have been associated with Alzheimer’s disease (AD) dementia. This association may be mediated by arteriosclerosis (ART), which have been implicated in incident dementia. However, the relationships among ASCVD risk factors, ART, and AD brain biomarkers (amyloid and tau) remains elusive. We investigated the association of the mid-life 10y ASCVD risk and subclinical ASCVD with late-life AD pathology. Methods: Participants >65y enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study between 2003-2005 (mid-life) underwent brain PET scans in 2018-2020 (late-life) to detect and quantify AD-specific amyloid [Pittsburgh Compound B (PiB)] and tau deposition. Mid-life 10-year ASCVD risk was categorized as borderline (5%-7.4%), intermediate (7.5%-14.9%), or high (≥15%). Logistic regression was used to calculate OR (95% CI) for association of late-life cortical amyloid and tau with mid-life ASCVD risk and marker of ART (vascular stiffness). Results: In 135 participants (mean age ~79y), global tau uptake had a graded association with increasing mid-life ASCVD risk categories (OR ASCVD high vs low risk% 11.00 [2.82-47.49]; p<0.05 ) while no significant association was found with PiB uptake on PET (Table) after mean 16y follow up. In fully adjusted models, Tau uptake was mainly driven by Black race ( OR 10.07 [3.25-36.39] ) and age ( OR 1.24 [1.10-1.41] ); all p<0.05. Midlife vascular stiffness showed a trend of association with late-life PiB retention (OR 1.76 [0.71-4.30]; p 0.05) but not with Tau . Conclusions: In an asymptomatic middle-aged biracial cohort, 10y ASCVD risk was predictive of late-life tau deposition but not amyloid. Vascular stiffness did not independently predict AD pathology. A simple mid-life ASCVD risk calculation may predict late-life AD risk. Further mechanistic studies are warranted to elucidate the race-related differences in the links between ASCVD risk and Alzheimer’s disease.

Abstract 14336: Association of Mid-Life Cardiovascular Disease and Late-Life Alzheimer's Disease Pathology: Insights From Heart Score Study

Introduction: Data show an association of CVD risk factors in mid-life with older age dementia. Atherosclerosis (ATH) and arteriosclerosis (ART) are both implicated in incident dementia however their relationship with incident Alzheimer’s disease (AD) remains elusive. We investigated the association of mid-life cardiovascular risk factors and mid-life subclinical CVD (ATH and ART) with late-life AD pathology. Methods: Non-demented participants over the age of 65 from the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study underwent brain PET acquisition (2018-2020) for AD specific amyloid deposition [by Pittsburgh Compound B (PiB)]. Pearson’s correlation and OR (95% CI) using Cox regression for association of cortical PiB retention with mid-life (2003-2005) markers of ATH (coronary artery calcium [CAC] score and carotid intima thickness [CIMT]) and ART (vascular stiffness) were calculated. Results: Among 121 participants in late-life (mean age ~79y), age was significantly correlated to lower cognition ( r =0.19, p=0.03) but gender, race and diabetes were not. Late-life AD pathology was not significantly associated with mid-life CAC (>150) [OR=0.12 (0.01, 2.36); p=0.16] or CIMT [OR=1.80 (0.84, 3.86); p=0.40]. Presence of increased vascular stiffness in mid-life showed a significant association with late-life PiB retention (Table ). Conclusions: In a small number of biracial middle-aged adults, subclinical markers of atherosclerosis did not independently predict increased biomarkers of AD pathology. However, vascular stiffness in mid-life was significantly associated with late-life brain biomarkers of Alzheimer’s disease pathology. Further research can elucidate the role of mid-life athero- and arteriosclerosis in Alzheimer's disease dementia.

Amyloid imaging of dutch‐type hereditary cerebral amyloid angiopathy carriers

To determine whether amyloid imaging with the positron emission tomography (PET) agent Pittsburgh compound B (PiB) can detect vascular β-amyloid (Aβ) in the essentially pure form of cerebral amyloid angiopathy associated with the Dutch-type hereditary cerebral amyloid angiopathy (D-CAA) mutation. PiB retention in a cortical composite of frontal, lateral, and retrosplenial regions (FLR) was measured by PiB-PET in 19 D-CAA mutation carriers (M+ ; 13 without neurologic symptoms, 6 with prior lobar intracerebral hemorrhage) and 17 mutation noncarriers (M- ). Progression of PiB retention was analyzed in a subset of 18 serially imaged individuals (10 asymptomatic M+ , 8 M- ). We also analyzed associations between PiB retention and cerebrospinal fluid (CSF) Aβ concentrations in 17 M+ and 11 M- participants who underwent lumbar puncture and compared the findings to PiB-PET and CSF Aβ in 37 autosomal dominant Alzheimer disease (ADAD) mutation carriers. D-CAA M+ showed greater age-dependent FLR PiB retention (p < 0.001) than M- , and serially imaged asymptomatic M+ demonstrated greater longitudinal increases (p = 0.004). Among M+ , greater FLR PiB retention associated with reduced CSF concentrations of Aβ40 (r = -0.55, p = 0.021) but not Aβ42 (r = 0.01, p = 0.991). Despite comparably low CSF Aβ40 and Aβ42, PiB retention was substantially less in D-CAA than ADAD (p < 0.001). Increased PiB retention in D-CAA and correlation with reduced CSF Aβ40 suggest this compound labels vascular amyloid, although to a lesser degree than amyloid deposits in ADAD. Progression in PiB signal over time suggests amyloid PET as a potential biomarker in trials of candidate agents for this untreatable cause of hemorrhagic stroke. ANN NEUROL 2019;86:616-625.

Neuropathologic correlates of amyloid and dopamine transporter imaging in Lewy body disease.

To develop imaging biomarkers of diseases in the Lewy body spectrum and to validate these markers against postmortem neuropathologic findings. Four cognitively normal participants with Parkinson disease (PD), 4 with PD with cognitive impairments, and 10 with dementia with Lewy bodies underwent amyloid imaging with [11C]Pittsburgh compound B (PiB) and dopamine transporter (DAT) imaging with [11C]Altropane. All 18 had annual neurologic examinations. All cognitively normal participants with PD developed cognitive impairment before death. Neuropathologic examinations assessed and scored Braak Lewy bodies, Thal distribution of amyloid, Consortium to Establish a Registry for Alzheimer's Disease neuritic amyloid plaques, Braak neurofibrillary tangles, and cerebral amyloid angiopathy, as well as total amyloid plaque burden in the superior frontal, superior parietal, occipital, and inferior temporal cortical regions. PET data were expressed as the standardized uptake value ratio with cerebellar reference. Analyses accounted for the interval between imaging and autopsy. All 18 patients met neuropathologic criteria for Lewy body disease; the DAT concentration was low in each case. All patients with elevated [11C]PiB retention measured in a neocortical aggregate had β-amyloid deposits at autopsy. [11C]PiB retention significantly correlated with neuritic plaque burden and with total plaque burden. [11C]PiB retention also significantly correlated with the severity of both Braak stages of neurofibrillary tangle and Lewy body scores. Neuritic plaque burden was significantly associated with neurofibrillary tangle pathology. Antemortem [11C]Altropane PET is a sensitive measure of substantia nigra degeneration. [11C]PiB scans accurately reflect cortical amyloid deposits seen at autopsy. These findings support the use of molecular imaging in the evaluation of patients with Lewy body diseases.

The Relationship of Current Cognitive Activity to Brain Amyloid Burden and Glucose Metabolism

Several studies have investigated how lifetime cognitive engagement affects levels of amyloid-beta (Aβ) deposition in the brain. However, there has been some disagreement, leaving the relationship of cognitive activity (CA) to Aβ a largely open question. The present study investigated the relationship between CA, Aβ deposition, and glucose metabolism. One hundred nine cognitively normal participants underwent Pittsburgh Compound-B (PiB) and [18F]fluorodeoxyglucose-positron emission tomography and completed a questionnaire designed to measure current CA. Statistical analyses revealed significant differences in PiB retention between those in the high and low CA groups. Linear regression models revealed a significant negative relationship between PiB retention and CA and a significant positive relationship between glucose metabolism and CA. These data suggest that CA may have a direct beneficial effect on the pathophysiology of AD or reflect another underlying process that results in both higher CA and lower AD pathophysiology.

ASSOCIATION OF HYPERTENSION WITH IN VIVO ALZHEIMER’S DISEASE PATHOLOGIES IN COGNITIVELY NORMAL, MCI AND DEMENTIA INDIVIDUALS

Hypertension increases the risk of Alzheimer's disease (AD) dementia. However, the relationship between hypertension and AD pathologies is still poorly understood. This study aimed to investigate the association of hypertension with in vivo AD pathologies including cerebral Aβ burden and neuronal injury in cognitively normal (CN), mild cognitive impairment (MCI) and AD dementia (ADD) individuals. Twenty-hundred sixty CN, 71 MCI, and 59 ADD elderly subjects from the Korean Brain Aging Study for Early Diagnosis & Prediction of Alzheimer's Disease (KBASE) were included. All participants underwent comprehensive clinical assessment, 11C-labelled Pittsburgh Compound B (PiB) positron emission tomography and magnetic resonance imaging. Comorbid hypertension was identified through systematic interview with subjects and their informants by trained nurses, when subjects were diagnosed with hypertension or treated for hypertension. As an Aβ biomarker of AD, global cerebral Aβ deposition was calculated as mean cortical PiB retention value (standardized uptake value ratio, SUVR) of the region-of-interests (ROIs) including the frontal, lateral temporal, lateral parietal and precuneus/posterior cingulate cortices. Subjects were defined to be Aβ positive if they have one or more ROIs with SUVR > 1.4. As a neuronal injury biomarker of AD, AD-signature region (ADsig) cortical thickness was defined as a mean cortical thickness of the regions including the bilateral inferior and middle temporal, entorhinal cortices and fusiform gyrus. In CN and MCI, hypertension was not associated with global cerebral Aβ deposition and Aβ positivity rate. However, the presence of hypertension was significantly associated with lower global Aβ retention value and Aβ positivity rate in ADD. In terms of neuronal injury biomarkers, hypertension was significantly associated with reduced ADsig cortical thickness only in CN, but not in MCI or ADD. Hypertension appears to contribute to the occurrence of clinical ADD by increasing neural injury or lowering brain reserve rather than by increasing cerebral Aβ burden.

Associations between cerebral amyloid and changes in cognitive function and falls risk in subcortical ischemic vascular cognitive impairment

BackgroundTo determine the association between amyloid-beta (Aβ) plaque deposition and changes in global cognition, executive functions, information processing speed, and falls risk over a 12-month period in older adults with a primary clinical diagnosis of subcortical ischemic vascular cognitive impairment (SIVCI).MethodsThis is a secondary analysis of data acquired from a subset of participants (N = 22) who were enrolled in a randomized controlled trial of aerobic exercise (NCT01027858). The subset of individuals completed an 11C Pittsburgh compound B (PIB) scan. Cognitive function and falls risk were assessed at baseline, 6-months, and 12-months. Global cognition, executive functions, and information processing speed were measured using: 1) ADAS-Cog; 2) Trail Making Test; 3) Digit Span Test; 4) Stroop Test, and 5) Digit Symbol Substitution Test. Falls risk was measured using the Physiological Profile Assessment. Hierarchical multiple linear regression analyses determined the unique contribution of Aβ on changes in cognitive function and falls risk at 12-months after controlling for experimental group (i.e. aerobic exercise training or usual care control) and baseline performance. To correct for multiple comparisons, we applied the Benjamini-Hochberg procedure to obtain a false discovery rate corrected threshold using alpha = 0.05.ResultsHigher PIB retention was significantly associated with greater decrements in set shifting (Trail Making Test, adjusted R2 = 35.3%, p = 0.002), attention and conflict resolution (Stroop Test, adjusted R2 = 33.4%, p = 0.01), and information processing speed (Digit Symbol Substitution Test, adjusted R2 = 24.4%, p = 0.001) over a 12-month period. Additionally, higher PIB retention was significantly associated with increased falls risk (Physiological Profile Assessment, adjusted R2 = 49.1%, p = 0.04). PIB retention was not significantly associated with change in ADAS-Cog and Verbal Digit Span Test (p > 0.05).ConclusionsSymptoms associated with SIVCI may be amplified by secondary Aβ pathology.Trial registrationClinicalTrials.gov, NCT01027858, December 7, 2009.

Cognitive decline and brain amyloid-β accumulation across 3 years in adults with Down syndrome

Adults with Down syndrome (DS) have a high incidence of Alzheimer's disease (AD), providing a unique opportunity to explore the early, preclinical stages of AD neuropathology. We examined change in brain amyloid-β accumulation via the positron emission tomography tracer [11C] Pittsburgh compound B (PiB) across 2 data collection cycles, spaced 3 years apart, and decline in cognitive functioning in 58 adults with DS without clinical AD. PiB retention increased in the anterior cingulate gyrus, precuneus cortex, parietal cortex, and anterior ventral striatum. Across the 2 cycles, 14 (27.5%) participants were consistently PiB+, 31 (60.8%) were consistently PiB−, and 6 (11.7%) converted from PiB− at cycle 1 to PiB+ at cycle 2. Increased global amyloid-β was related to decline in verbal episodic memory, visual episodic memory, executive functioning, and fine motor processing speed. Participants who were consistently PiB+ demonstrated worsening of episodic memory, whereas participants who were consistently PiB− evidenced stable or improved performance. Amyloid-β accumulation may be a contributor to or biomarker of declining cognitive functioning in preclinical AD in DS.

Association of Brain Amyloid-β With Slow Gait in Elderly Individuals Without Dementia

Motor slowing appears in preclinical Alzheimer disease (AD), progresses with AD progression, and is associated with AD pathologic findings at autopsy. Whether amyloid-β (Aβ) is associated with gait speed in elderly individuals without dementia and whether cognition and apolipoprotein E ε4 (APOE ε4) influence this association remain unknown. To examine the association between Aβ and gait speed in elderly individuals without dementia and to study the influence of cognition and APOE ε4 status on this association. This cross-sectional analysis included 183 elderly individuals without dementia, including a cognitively normal (CN) subsample of 144 adults, enrolled in the Ginkgo Evaluation of Memory study at a university center from January 1, 2000, through December 31, 2009, and enrolled in a follow-up substudy a mean (SD) of 10 (3) months after the initial study closeout. Data analysis was performed from October 1, 2015, to June 1, 2016. We assessed cerebral Aβ on Pittsburgh Compound B (PiB) positron emission tomography, gait speed over 4.57 m (15 ft), and cognition on the Mini-Mental State Examination and Trail Making Test Parts A and B. We grouped participants into high Aβ (PiB+) and low Aβ (PiB-) groups on standardized global PiB cutoffs and examined group differences. We studied the influence of cognition and APOE ε4 on the global and regional associations between gait speed and Aβ in the whole sample and the CN subsample. Among the 183 study participants, mean (SD) age was 85.5 (3) years, 76 were women (41.5%), and 177 were white (96.7%). The PiB+ individuals were comparable to the PiB- individuals on demographics, comorbidities, cognition, hippocampal volume, and small-vessel disease but not on gait speed (0.85 vs 0.92 m/s, P = .01) or proportion of APOE ε4 carriers (29 [29.0%] vs 5 [6.0%], P < .001). In the whole sample and the CN subsample, the association between global PiB retention and slower gait withstood adjustment for covariates (β = -0.068, P = .03 and β = -0.074, P = .04, respectively); however, this association was attenuated by Mini-Mental State Examination and Trail Making Test Parts A and B and was rendered statistically nonsignificant by APOE ε4 in both samples (β = -0.055 and β = -0.058, respectively; both P ≥ .10). Several regional associations between gait speed and PiB uptake withstood relevant adjustments; however, APOE ε4 rendered only the medial (β = -0.22, P = .03) and lateral (β = -0.08, P = .03) temporal regions, subcortical white matter (β = -0.13, P = .02), and occipital regions (β = -0.15, P = .03) in the whole sample and the occipital regions (β = -0.21, P = .01) in the CN subsample statistically significant. Cerebral Aβ deposition is associated with slower gait speed in elderly individuals without dementia; however, this association is weaker in those who are CN. Cognition and APOE ε4 carrier status influence the association between Aβ and gait speed in elderly individuals without dementia.

The Role of Cerebrovascular Disease inAmyloid Deposition.

Some patients clinically diagnosed with subcortical vascular cognitive impairment (SVCI) have co-morbidity with AD pathology. We investigated topographical differences in amyloid burden between SVCI and Alzheimer's disease type cognitive impairment (ADCI) using [11C] Pittsburgh compound B (PiB) positron emission tomography (PET). The purpose of this study was to investigate the role of cerebrovascular disease (CVD) in amyloid deposition. We recruited 44 patients with SVCI and 44 patients with ADCI (amnestic mild cognitive impairment or Alzheimer's disease) with absent or minimal white matter hyperintensities, all with PiB-positive PET scans [PiB+]. As controls, we included 13 participants with normal cognition and PiB-negative scans. We divided the SVCI and ADCI patients into three groups according to global PiB retention ratio of SVCI, and then compared the tertiles in terms of the distribution of PiB retention using statistical parametric mapping analyses. Lobar to global PiB retention ratio and asymmetry indices were also compared between SVCI and ADCI groupsResults: Compared to PiB+ ADCI patients, PiB+ SVCI patients exhibited: 1) increased left-right asymmetry, and increased anterior-posterior difference; and 2) increased PiB retention in the parietal cortex, the occipital cortex and the precuneus-posterior cingulate cortex. In contrast, ADCI patients showed increased PiB retention in the striatum. When stratified by level of PiB retention, each group showed different characteristics. Our results showed that the distribution of amyloid deposition differed between patients with PiB+ SVCI and ADCI. These suggest that CVD contribute to and alter the known progression pattern in amyloid deposition in Alzheimer's disease.

Synergistic effects of longitudinal amyloid and vascular changes on lobar microbleeds

To determine whether amyloid and hypertensive cerebral small vessel disease (hCSVD) changes synergistically affect the progression of lobar microbleeds in patients with subcortical vascular mild cognitive impairment (svMCI). Among 72 patients with svMCI who underwent brain MRI and [11C] Pittsburgh compound B (PiB)-PET, 52 (72.2%) completed the third year of follow-up. These patients were evaluated by annual neuropsychological testing, brain MRI, and follow-up PiB-PET. Over 3 years, 31 of 52 patients (59.6%) had incident cerebral microbleeds (CMBs) in the lobar and deep regions. Both baseline and longitudinal changes in lacune numbers were associated with increased numbers of lobar and deep microbleeds, while baseline and longitudinal changes in PiB uptake ratio were associated only with the progression of lobar microbleeds, especially in the temporal, parietal, and occipital areas. Regional white matter hyperintensity severity was also associated with regional lobar CMBs in the parietal and occipital regions. There were interactive effects between baseline and longitudinal lacune number and PiB retention on lobar microbleed progression. Increased lobar, but not deep, CMBs were associated with decreased scores in the digit span backward task and Rey-Osterrieth Complex Figure Test. Our findings suggest that amyloid-related pathology and hCSVD have synergistic effects on the progression of lobar microbleeds, providing new clinical insight into the interaction between amyloid burden and hCSVD on CMB progression and cognitive decline with implications for developing effective prevention strategies.

Florbetapir-PET to diagnose cerebral amyloid angiopathy: A prospective study.

We hypothesized that florbetapir, a Food and Drug Administration-approved PET tracer, could distinguish cerebral amyloid angiopathy (CAA)-related intracerebral hemorrhage (ICH) from hypertensive ICH (HTN-ICH). We prospectively enrolled survivors of primary ICH related to probable CAA (per Boston Criteria, n = 10) and HTN-ICH (n = 9) without dementia. All patients underwent florbetapir-PET and multimodal MRI, and patients with CAA had additional Pittsburgh compound B (PiB) PET. Amyloid burden was assessed quantitatively (standard uptake value ratio [SUVR]) and visually classified as positive or negative. The CAA and HTN-ICH groups had similar age (66.9 vs 67.1), sex, and leukoaraiosis volumes (31 vs 30 mL, all p > 0.8). Florbetapir uptake and PiB retention strongly correlated in patients with CAA both globally within cerebral cortex (r = 0.96, p < 0.001) and regionally in lobar cortices (all r > 0.8, all p ≤ 0.01). Mean global cortical florbetapir uptake was substantially higher in CAA than HTN-ICH (SUVR: 1.41 ± 0.17 vs 1.15 ± 0.08, p = 0.001), as was mean occipital SUVR (1.44 ± 0.12 vs 1.17 ± 0.08, p < 0.001), even after correcting for global SUVR (p = 0.03). Visual rating for positive/negative florbetapir demonstrated perfect interrater agreement (k = 1) and was positive for all 10 patients with CAA vs 1 of 9 HTN-ICH patients (sensitivity 100%, specificity 89%). Florbetapir appears to label vascular amyloid in patients with CAA-related ICH. The approved florbetapir binary visual reading method can have diagnostic value in appropriate clinical settings. This study provides Class II evidence that florbetapir-PET provides a sensitivity of 100% (95% confidence interval [CI] 66%-100%) and specificity of 89% (95% CI 51%-99%) for determination of probable CAA among cognitively normal patients.

Differential patterns of regional cerebral hypometabolism according to the level of cerebral amyloid deposition in patients with amnestic mild cognitive impairment

Although amnestic mild cognitive impairment (aMCI) with high cerebral deposition of amyloid-beta proteins (Aβ) could be classified as a prodromal state of Alzheimer’s disease (AD) dementia, aMCI with the absence of or very little cerebral Aβ deposition is likely related to other pathophysiological processes. Thus, the present study aimed to investigate the differential patterns of regional cerebral glucose metabolism (rCMglu) according to the level of Aβ burden in the brains of patients with aMCI. This study included 25 patients with aMCI and 33 cognitively normal (CN) elderly individuals who underwent a comprehensive clinical examination, 11C-labelled Pittsburgh Compound B (PiB) positron emission tomography (PET) scans, and 18F-fluorodeoxyglucose (FDG) PET scans. Based on cerebral PiB retention, the aMCI subjects were divided into low Aβ (aMCI−, n=10) and high Aβ (aMCI+, n=15) subgroups, and differences in rCMglu among the CN group and aMCI subgroups were estimated on a voxel-by-voxel basis. Compared with the CN group, rCMglu was decreased in the bilateral medial temporal regions of the aMCI− subgroup and in the medial temporal cortices as well as the right precuneus of the aMCI+ subgroup. Additionally, rCMglu was lower in the right precuneus of the aMCI+ subgroup compared with the aMCI− subgroup. The present findings indicate that, even though both aMCI subgroups were phenomenologically very similar, the patients with aMCI− exhibited a markedly different regional pattern of functional neurodegeneration compared with the aMCI+ patients.

Lower Late-Life Body-Mass Index is Associated with Higher Cortical Amyloid Burden in Clinically Normal Elderly.

Lower body-mass index (BMI) in late life has been associated with an increased risk of dementia, and weight loss has been associated with more rapid decline in Alzheimer's disease (AD) dementia. To explore the association between BMI and cortical amyloid burden in clinically normal (CN) elderly at risk for AD dementia. Cross-sectional analyses were completed using baseline data from the Harvard Aging Brain Study, consisting of 280 community-dwelling CN older adults aged 62-90. Assessments included medical histories and physical exam, Pittsburgh compound B (PiB) positron emission tomography (PET) amyloid imaging, and apolipoprotein E ɛ4 (APOE4) genotyping. For the primary analysis, a general linear regression model was used to evaluate the association of BMI with PiB retention. Covariates included age, sex, years of education, and APOE4 carrier status. Secondary analyses were performed for BMI subdivisions (normal, overweight, obese), APOE4 carriers, and BMI×APOE4 interaction. In the primary analysis, greater PiB retention was associated with lower BMI (β = -0.14, p = 0.02). In the secondary analyses, APOE4 carrier status (β= -0.27, p = 0.02) and normal BMI (β= -0.25, p = 0.01), as opposed to overweight or obese BMI, were associated with greater PiB retention. The BMI×APOE4 interaction was also significant (β= -0.14, p = 0.04). This finding offers new insight into the role of BMI at the preclinical stage of AD, wherein lower BMI late in life is associated with greater cortical amyloid burden. Future studies are needed to elucidate the mechanism behind this association, especially in those with lower BMI who are APOE4 carriers.

Gray and white matter changes linking cerebral small vessel disease to gait disturbances

To investigate the topographic changes of white matter (WM) integrity and cortical thickness related to gait disturbances and determine whether these neural correlates mediate the association between cerebral small vessel disease (CSVD) and gait disturbances. A total of 129 patients with subcortical vascular cognitive impairment were included. CSVD severity was quantified as global and regional WM hyperintensities (WMH) volume and lacune and microbleed numbers. Amyloid burdens were assessed using Pittsburgh compound B (PiB)-PET scanning. Gait score was measured using a standardized scale. WM integrity was assessed by applying tract-based spatial statistics. Cortical thickness was measured using surface-based methods. Path analysis for gait score was performed using regional CSVD markers as predictors and fractional anisotropy (FA) and cortical thickness as mediators. Periventricular WMH (PWMH) volume was associated with gait score, regardless of other CSVD. PiB retention ratio was not associated with gait score. Gait score was correlated with FA in the frontal and parietal WM and bilateral corpus callosum and with cortical thinning in the bilateral frontal and lateral temporo-parieto-occipital regions. Path analysis for gait score showed that PWMH contributed to gait disturbances with the mediation of mean FA or cortical thickness. Our findings suggest that WMH-related cortical thinning as well as disrupted integrity of periventricular WM is linked to gait disturbances.

Abstract WMP90: Florbetapir PET to Diagnose Cerebral Amyloid Angiopathy

Introduction: Previous studies showed that Pittsburgh Compound B (PiB) labels vascular amyloid characteristic of cerebral amyloid angiopathy (CAA) on PET scans; PiB is not approved for clinical use, however. Hypothesis: We hypothesized that Florbetapir, an FDA-approved PET tracer, can detect amyloid in CAA and help distinguish CAA-related intracerebral hemorrhage (ICH) from hypertensive ICH (HTN-ICH). Methods: We prospectively enrolled non-demented survivors of primary ICH related to probable CAA (per Boston Criteria, n=10) and HTN-ICH (n=9). All patients underwent Florbetapir-PET, multimodal MRI, and additional PiB-PET for the CAA patients. Amyloid burden was assessed quantitatively using parametric maps and also visually, classified as positive or negative. Spatial correlations between Florbetapir and PiB retention were used to test vascular amyloid binding in CAA. We have tested the diagnostic value of Florbetapir by comparing global and occipital mean Florbetapir retention (standard uptake value ratio, SUVR) as well as Florbetapir positive/negative status between CAA and HTN-ICH groups. Results: The CAA and HTN-ICH groups had similar age (66.9 vs 67.1), sex and white matter hyperintensity volumes (31ml vs 30ml, all p&gt;0.8). Florbetapir uptake and PiB retention strongly correlated in CAA patients both globally within cerebral cortex (r=0.96, p&lt;0.001) and regionally in occipital, frontal, temporal, parietal cortices (all r&gt;0.8, all p &lt; 0.01). Mean global cortical Florbetapir uptake was significantly higher in CAA than HTN-ICH (SUVR: 1.41±0.16 vs 1.16±0.08, p=0.001) as was mean occipital SUVR (1.44±0.12 vs 1.17±0.08, p&lt;0.001), remaining independent after correcting for global SUVR (p=0.02). Visual rating for Florbetapir positive/negative demonstrated perfect interrater agreement (k=1) between two trained neurologists blinded to all other information and was positive for all 10 CAA patients vs 1 of 9 HTN-ICH patients (sensitivity 100%, specificity 89%). Conclusions: Florbetapir, like PiB, appears to label vascular amyloid in patients with CAA-related ICH. Data using the approved Florbetapir binary visual reading method suggest sufficient sensitivity and specificity for diagnostic use in appropriate clinical settings.

Exploring the effects of coexisting amyloid in subcortical vascular cognitive impairment.

BackgroundMixed pathology, particularly Alzheimer’s disease with cerebrovascular lesions, is reported as the second most common cause of dementia. Research on mixed dementia typically includes people with a primary AD diagnosis and hence, little is known about the effects of co-existing amyloid pathology in people with vascular cognitive impairment (VCI). The purpose of this study was to understand whether individual differences in amyloid pathology might explain variations in cognitive impairment among individuals with clinical subcortical VCI (SVCI).MethodsTwenty-two participants with SVCI completed an 11C Pittsburgh compound B (PIB) position emission tomography (PET) scan to quantify global amyloid deposition. Cognitive function was measured using: 1) MOCA; 2) ADAS-Cog; 3) EXIT-25; and 4) specific executive processes including a) Digits Forward and Backwards Test, b) Stroop-Colour Word Test, and c) Trail Making Test. To assess the effect of amyloid deposition on cognitive function we conducted Pearson bivariate correlations to determine which cognitive measures to include in our regression models. Cognitive variables that were significantly correlated with PIB retention values were entered in a hierarchical multiple linear regression analysis to determine the unique effect of amyloid on cognitive function. We controlled for age, education, and ApoE ε4 status.ResultsBivariate correlation results showed that PIB binding was significantly correlated with ADAS-Cog (p < 0.01) and MOCA (p < 0.01); increased PIB binding was associated with worse cognitive function on both cognitive measures. PIB binding was not significantly correlated with the EXIT-25 or with specific executive processes (p > 0.05).Regression analyses controlling for age, education, and ApoE ε4 status indicated an independent association between PIB retention and the ADAS-Cog (adjusted R-square change of 15.0 %, Sig F Change = 0.03). PIB retention was also independently associated with MOCA scores (adjusted R-Square Change of 27.0 %, Sig F Change = 0.02).ConclusionWe found that increased global amyloid deposition was significantly associated with greater memory and executive dysfunctions as measured by the ADAS-Cog and MOCA. Our findings point to the important role of co-existing amyloid deposition for cognitive function in those with a primary SVCI diagnosis. As such, therapeutic approaches targeting SVCI must consider the potential role of amyloid for the optimal care of those with mixed dementia.Trial registrationNCT01027858

Amyloid-β Imaging in Older Adults Presenting to a Memory Clinic with Subjective Cognitive Decline: A Pilot Study.

Subjective cognitive decline (SCD) in otherwise normal aging may be identified via symptom inventories in a research setting ('questionnaire-discovered complaints') or via patients seeking evaluation/services in a clinical setting ('presenting complainers'). Most studies of SCD and amyloid-β (Aβ) imaging to date have used the former approach, with inconsistent results. To test whether 'presenting SCD' participants in an academic memory clinic setting show increased brain Aβ deposition on imaging. Fourteen patients (mean age 68.1, SD 4.0 years) diagnosed with subjective cognitive complaints with normal neuropsychological testing were recruited into a Pittsburgh compound B (PiB)-PET study. Detailed self-report inventories and additional cognitive tests were administered. Results were compared to a reference cohort of cognitively normal volunteers (NC) from an independent neuroimaging study (mean age 73.6, SD 5.8 years). 57% (8/14) of SCD participants were PiB-positive by a sensitive, regionally-based definition, compared to 31% (26/84) of the NC cohort. SCD participants had significantly higher PiB retention (SUVR) than NC in three of six regions of interest: frontal cortex (p = 0.02), lateral temporal cortex (p = 0.02), and parietal cortex (p = 0.04). SCD participants showed measurable deviations on questionnaires reflecting high negative affect (i.e., depressive symptoms and neuroticism). Findings were suggestive that deficits on verbal associative binding may be specific to Aβ-positive versus Aβ-negative SCD. Older participants with SCD presenting to a memory clinic in this pilot study sample have higher brain Aβ deposition compared to normal aging study volunteers unselected on complaints. Further study of presenting SCD are warranted to determine the prognostic significance of Aβ deposition in this context.