Dawn C. Matthews

The influence of biological and technical factors on quantitative analysis of amyloid PET: Points to consider and recommendations for controlling variability in longitudinal data

In vivo imaging of amyloid burden with positron emission tomography (PET) provides a means for studying the pathophysiology of Alzheimers and related diseases. Measurement of subtle changes in amyloid burden requires quantitative analysis of image data. Reliable quantitative analysis of amyloid PET scans acquired at multiple sites and over time requires rigorous standardization of acquisition protocols, subject management, tracer administration, image quality control, and image processing and analysis methods. We review critical points in the acquisition and analysis of amyloid PET, identify ways in which technical factors can contribute to measurement variability, and suggest methods for mitigating these sources of noise. Improved quantitative accuracy could reduce the sample size necessary to detect intervention effects when amyloid PET is used as a treatment end point and allow more reliable interpretation of change in amyloid burden and its relationship to clinical course.

Physical Activity, Mediterranean Diet and Biomarkers-Assessed Risk of Alzheimer's: A Multi-Modality Brain Imaging Study

Increased physical activity and higher adherence to a Mediterranean-type diet (MeDi) have been independently associated with reduced risk of Alzheimer’s disease (AD). Their association has not been investigated with the use of biomarkers. This study examines whether, among cognitively normal (NL) individuals, those who are less physically active and show lower MeDi adherence have brain biomarker abnormalities consistent with AD. Methods Forty-five NL individuals (age 54 ± 11, 71% women) with complete leisure time physical activity (LTA), dietary information, and cross-sectional 3D T1-weigthed MRI, 11C-Pittsburgh Compound B (PiB) and 18F-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) scans were examined. Voxel-wise multivariate partial least square (PLS) regression was used to examine the effects of LTA, MeDi and their interaction on brain biomarkers. Age, gender, ethnicity, education, caloric intake, BMI, family history of AD, Apolipoprotein E (APOE) genotype, presence of hypertension and insulin resistance were examined as confounds. Subjects were dichotomized into more and less physically active (LTA+ vs. LTA−; n = 21 vs. 24), and into higher vs. lower MeDi adherence groups (n = 18 vs. 27) using published scoring methods. Spatial patterns of brain biomarkers that represented the optimal association between the images and the groups were generated for all modalities using voxel-wise multivariate Partial Least Squares (PLS) regression. Results Groups were comparable for clinical and neuropsychological measures. Independent effects of LTA and MeDi factors were observed in AD-vulnerable brain regions for all modalities (p < 0.001). Increased AD-burden (in particular higher Aβ load and lower glucose metabolism) were observed in LTA− compared to LTA+ subjects, and in MeDi− as compared to MeDi+ subjects. A gradient effect was observed for all modalities so that LTA−/MeDi− subjects had the highest and LTA+/MeDi+ subjects had the lowest AD-burden (p < 0.001), although the LTA × MeDi interaction was significant only for FDG measures (p < 0.03). Adjusting for covariates did not attenuate these relationships. Conclusion Lower physical activity and MeDi adherence were associated with increased brain AD-burden among NL individuals, indicating that lifestyle factors may modulate AD risk. Studies with larger samples and longitudinal evaluations are needed to determine the predictive power of the observed associations

Comparing Brain Amyloid Deposition, Glucose Metabolism, and Atrophy in Mild Cognitive Impairment with and without a Family History of Dementia

This study compares the degree of brain amyloid-β (Aβ) deposition, glucose metabolism, and grey matter volume (GMV) reductions in mild cognitive impairment (MCI) patients overall and as a function of their parental history of dementia. Ten MCI with maternal history (MH), 8 with paternal history (PH), and 24 with negative family history (NH) received 11C-PiB and 18F-FDG PET and T1-MRI as part of the Alzheimers Disease Neuroimaging Initiative. Statistical parametric mapping, voxel based morphometry, and Z-score mapping were used to compare biomarkers across MCI groups, and relative to 12 normal controls. MCI had higher PiB retention, hypometabolism, and GMV reductions in Alzheimer-vulnerable regions compared to controls. Biomarker abnormalities were more pronounced in MCI with MH than those with PH and NH. After partial volume correction of PET, Aβ load exceeded hypometabolism and atrophy with regard to the number of regions affected and magnitude of impairment in those regions. Hypometabolism exceeded atrophy in all MCI groups and exceeded Aβ load in medial temporal and posterior cingulate regions of MCI MH. While all three biomarkers were abnormal in MCI compared to controls, Aβ deposition was the most prominent abnormality, with MCI MH having the greatest degree of co-occurring hypometabolism.

An Evaluation of MSDC-0160, A Prototype mTOT Modulating Insulin Sensitizer, in Patients with Mild Alzheimer’s Disease

Alzheimer’s disease (AD) is associated with insulin resistance and specific regional declines in cerebral metabolism. The effects of a novel mTOT modulating insulin sensitizer (MSDC-0160) were explored in non-diabetic patients with mild AD to determine whether treatment would impact glucose metabolism measured by FDG-PET in regions that decline in AD. MSDC-0160 (150 mg once daily; N=16) compared to placebo (N=13) for 12 weeks did not result in a significant difference in glucose metabolism in pre-defined regions when referenced to the pons or whole brain. However, glucose metabolism referenced to cerebellum was maintained in MSDC-0160 treated participants while it significantly declined for placebo patients in anterior and posterior cingulate, and parietal, lateral temporal, medial temporal cortices. Voxel-based analyses showed additional differences in FDG-PET related to MSDC-0160 treatment. These exploratory results suggest central effects of MSDC-0160 and provide a basis for further investigation of mTOT modulating insulin sensitizers in AD patients.

Dissociation of Down syndrome and Alzheimer's disease effects with imaging.

Down Syndrome (DS) adults experience accumulation of Alzheimers disease (AD)–like amyloid plaques and tangles and a high incidence of dementia and could provide an enriched population to study AD‐targeted treatments. However, to evaluate effects of therapeutic intervention, it is necessary to dissociate the contributions of DS and AD from overall phenotype. Imaging biomarkers offer the potential to characterize and stratify patients who will worsen clinically but have yielded mixed findings in DS subjects.

PET Imaging of Tau Pathology and Relationship to Amyloid, Longitudinal MRI, and Cognitive Change in Down Syndrome: Results from the Down Syndrome Biomarker Initiative (DSBI)

BACKGROUND Adults with Down syndrome (DS) represent an enriched population for the development of Alzheimers disease (AD), which could aid the study of therapeutic interventions, and in turn, could benefit from discoveries made in other AD populations. OBJECTIVES 1) Understand the relationship between tau pathology and age, amyloid deposition, neurodegeneration (MRI and FDG PET), and cognitive and functional performance; 2) detect and differentiate AD-specific changes from DS-specific brain changes in longitudinal MRI. METHODS Twelve non-demented adults, ages 30 to 60, with DS were enrolled in the Down Syndrome Biomarker Initiative (DSBI), a 3-year, observational, cohort study to demonstrate the feasibility of conducting AD intervention/prevention trials in adults with DS. We collected imaging data with 18F-AV-1451 tau PET, AV-45 amyloid PET, FDG PET, and volumetric MRI, as well as cognitive and functional measures and additional laboratory measures. RESULTS All amyloid negative subjects imaged were tau-negative. Among the amyloid positive subjects, three had tau in regions associated with Braak stage VI, two at stage V, and one at stage II. Amyloid and tau burden correlated with age. The MRI analysis produced two distinct volumetric patterns. The first differentiated DS from normal (NL) and AD, did not correlate with age or amyloid, and was longitudinally stable. The second pattern reflected AD-like atrophy and differentiated NL from AD. Tau PET and MRI atrophy correlated with several cognitive and functional measures. CONCLUSIONS Tau accumulation is associated with amyloid positivity and age, as well as with progressive neurodegeneration measurable using FDG and MRI. Tau correlates with cognitive decline, as do AD-specific hypometabolism and atrophy.

Mediterranean diet and 3-year Alzheimer brain biomarker changes in middle-aged adults.

Objective To examine in a 3-year brain imaging study the effects of higher vs lower adherence to a Mediterranean-style diet (MeDi) on Alzheimer disease (AD) biomarker changes (brain β-amyloid load via 11C-Pittsburgh compound B [PiB] PET and neurodegeneration via 18F-fluorodeoxyglucose [FDG] PET and structural MRI) in midlife. Methods Seventy 30- to 60-year-old cognitively normal participants with clinical, neuropsychological, and dietary examinations and imaging biomarkers at least 2 years apart were examined. These included 34 participants with higher (MeDi+) and 36 with lower (MeDi−) MeDi adherence. Statistical parametric mapping and volumes of interest were used to compare AD biomarkers between groups at cross section and longitudinally. Results MeDi groups were comparable for clinical and neuropsychological measures. At baseline, compared to the MeDi+ group, the MeDi− group showed reduced FDG-PET glucose metabolism (CMRglc) and higher PiB-PET deposition in AD-affected regions (p < 0.001). Longitudinally, the MeDi−-group showed CMRglc declines and PiB increases in these regions, which were greater than those in the MeDi+ group (pinteraction < 0.001). No effects were observed on MRI. Higher MeDi adherence was estimated to provide 1.5 to 3.5 years of protection against AD. Conclusion Lower MeDi adherence was associated with progressive AD biomarker abnormalities in middle-aged adults. These data support further investigation of dietary interventions for protection against brain aging and AD.

Lifestyle and vascular risk effects on MRI-based biomarkers of Alzheimer’s disease: a cross-sectional study of middle-aged adults from the broader New York City area

Objective To investigate the effects of lifestyle and vascular-related risk factors for Alzheimer’s disease (AD) on in vivo MRI-based brain atrophy in asymptomatic young to middle-aged adults. Design Cross-sectional, observational. Setting Broader New York City area. Two research centres affiliated with the Alzheimer’s disease Core Center at New York University School of Medicine. Participants We studied 116 cognitively normal healthy research participants aged 30–60 years, who completed a three-dimensional T1-weighted volumetric MRI and had lifestyle (diet, physical activity and intellectual enrichment), vascular risk (overweight, hypertension, insulin resistance, elevated cholesterol and homocysteine) and cognition (memory, executive function, language) data. Estimates of cortical thickness for entorhinal (EC), posterior cingulate, orbitofrontal, inferior and middle temporal cortex were obtained by use of automated segmentation tools. We applied confirmatory factor analysis and structural equation modelling to evaluate the associations between lifestyle, vascular risk, brain and cognition. Results Adherence to a Mediterranean-style diet (MeDi) and insulin sensitivity were both positively associated with MRI-based cortical thickness (diet: βs≥0.26, insulin sensitivity βs≥0.58, P≤0.008). After accounting for vascular risk, EC in turn explained variance in memory (P≤0.001). None of the other lifestyle and vascular risk variables were associated with brain thickness. In addition, the path associations between intellectual enrichment and better cognition were significant (βs≥0.25 P≤0.001), as were those between overweight and lower cognition (βs≥-0.22, P≤0.01). Conclusions In cognitively normal middle-aged adults, MeDi and insulin sensitivity explained cortical thickness in key brain regions for AD, and EC thickness predicted memory performance in turn. Intellectual activity and overweight were associated with cognitive performance through different pathways. Our findings support further investigation of lifestyle and vascular risk factor modification against brain ageing and AD. More studies with larger samples are needed to replicate these research findings in more diverse, community-based settings.

When an amyloid PET threshold of 1.5 becomes 1.4 and longitudinal accumulation is not what it appears: Interpreting and reconciling values amidst scanner variability

Background: Measurement of amyloid burden using 11C-PiB has been incorporated as an endpoint in Alzheimer’s Disease clinical research and therapeutic trials. Studies of Normal, MCI, and AD populations have been used to establish thresholds for amyloid positivity, impacting subject inclusion in trials and contributing to diagnosis. Yet, these values are highly dependent upon several factors including the scanner. Methods: One hundred eightyseven PiB scans from 94 ADNI subjects were evaluated from five scanner models: HR+ (76 scans), HRRT (42), GE Advance (32), GE Discovery (15), and Biograph HiRez (22). Using 50-70 minute summed images, values were sampled at 27 individual slices of gray matter cerebellum, 27 slices of subcortical white matter, 5 regions of interest (anterior cingulate, posterior cingulate/precuneus, frontal cortex, lateral temporal cortex, parietal cortex), and 8 additional reference regions including combinations of gray and white matter cerebellum and pons. Standardized Uptake Value Ratio (SUVR) values were compared across scanner models using PIBand PIB+ scans together and separated into subgroups, and across sites within scanner model. A subgroup of subjects each having scans from both a GEAdvance and HR+ scanner was evaluated. Differences between scanners were mathematically modeled and tested to predict cross-scanner equivalent values. Results: Significant SUVR differences were found across scanner models. Using PiBand PiBscans combined, averagewhite matter referenced to graymatter cerebellum SUVRs ranked: HR+ >GE Advance 1⁄4GE Discovery >BiographHiRez >HRRT(site-specific). Differences between HR+ and all other scanner models were significant (p<0.03 vs. Discovery to p<0.00001 vs. HRRT-site 1) and 20% in some cases. Significant differences were found between HRRT sites and between HR+ sites. Differences between 3 scanner types were reduced when pons was used as reference. Modeling showed potential to compensate for inter-scanner differences. Conclusions: Amyloid values measured using 11C-PiB must be evaluated in the context of the scanner used to collect data, particularly when the SUVR value is close to a positivity threshold. In longitudinal studies, within-subject data must be reconciled to account for variability in SUVR values that arise from change in the scanner, changes in acquisition on the same camera, and impact of different corrections applied to the emission data.

FDG PET Parkinson’s disease-related pattern as a biomarker for clinical trials in early stage disease

Background The development of therapeutic interventions for Parkinson disease (PD) is challenged by disease complexity and subjectivity of symptom evaluation. A Parkinsons Disease Related Pattern (PDRP) of glucose metabolism via fluorodeoxyglucose positron emission tomography (FDG-PET) has been reported to correlate with motor symptom scores and may aid the detection of disease-modifying therapeutic effects. Objectives We sought to independently evaluate the potential utility of the PDRP as a biomarker for clinical trials of early-stage PD. Methods Two machine learning approaches (Scaled Subprofile Model (SSM) and NPAIRS with Canonical Variates Analysis) were performed on FDG-PET scans from 17 healthy controls (HC) and 23 PD patients. The approaches were compared regarding discrimination of HC from PD and relationship to motor symptoms. Results Both classifiers discriminated HC from PD (p < 0.01, p < 0.03), and classifier scores for age- and gender- matched HC and PD correlated with Hoehn & Yahr stage (R2 = 0.24, p < 0.015) and UPDRS (R2 = 0.23, p < 0.018). Metabolic patterns were highly similar, with hypometabolism in parieto-occipital and prefrontal regions and hypermetabolism in cerebellum, pons, thalamus, paracentral gyrus, and lentiform nucleus relative to whole brain, consistent with the PDRP. An additional classifier was developed using only PD subjects, resulting in scores that correlated with UPDRS (R2 = 0.25, p < 0.02) and Hoehn & Yahr stage (R2 = 0.16, p < 0.06). Conclusions Two independent analyses performed in a cohort of mild PD patients replicated key features of the PDRP, confirming that FDG-PET and multivariate classification can provide an objective, sensitive biomarker of disease stage with the potential to detect treatment effects on PD progression.