Russ C. Hornbeck

Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease

Significance Beta-amyloid plaque accumulation, glucose hypometabolism, and neuronal atrophy are hallmarks of Alzheimer’s disease. However, the regional ordering of these biomarkers prior to dementia remains untested. In a cohort with Alzheimer’s disease mutations, we performed an integrated whole-brain analysis of three major imaging techniques: amyloid PET, [18F]fluro-deoxyglucose PET, and structural MRI. We found that most gray-matter structures with amyloid plaques later have hypometabolism followed by atrophy. Critically, however, not all regions lose metabolic function, and not all regions atrophy, even when there is significant amyloid deposition. These regional disparities have important implications for clinical trials of disease-modifying therapies. Major imaging biomarkers of Alzheimer’s disease include amyloid deposition [imaged with [11C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [18F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer’s disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer’s disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.

Retinal Pigment Epithelial Debridement as a Model for the Pathogenesis and Treatment of Macular Degeneration

PURPOSE To determine the effects of the absence of the retinal pigment epithelium on the choriocapillaris and outer retina by performing retinal pigment epithelial cell debridement with mitomycin C to inhibit cell proliferation pharmacologically in the porcine eye. METHODS A pars plana vitrectomy was performed in 12 eyes, and two neurosensory retinal detachments per eye were created by injecting 10(-3) mg/ml mitomycin C and 0.25% edetic acid into the subretinal space. Twenty minutes later, the retinal pigment epithelium was debrided, and the retina was reattached with a fluid-gas exchange. RESULTS Bruchs membrane was devoid of native retinal pigment epithelium, and the choriocapillaris was patent immediately after debridement. No proliferation of the retinal pigment epithelium occurred 1 week after debridement, and choriocapillaris atrophy was present beneath areas of Bruchs membrane that were devoid of retinal pigment epithelium. Four weeks postsurgery, choriocapillaris atrophy persisted in all debrided blebs, although unpigmented retinal pigment epithelium repopulated portions of Bruchs membrane in one of three blebs. Outer retinal atrophy was present in areas of Bruchs membrane with no retinal pigment epithelium and no choriocapillaris 4 weeks postsurgery. The choriocapillaris was patent in areas of mitomycin C injection without debridement. CONCLUSION Absence of the retinal pigment epithelium leads to atrophy of the choriocapillaris within 1 week after surgery. This finding provides an animal model to study transplantation of retinal pigment epithelium onto bare patches of Bruchs membrane in age-related macular degeneration and other diseases and provides insight into the pathogenesis of nonexudative age-related macular degeneration.

Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trial

The Dominantly Inherited Alzheimers Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimers disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimers disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.

Partial volume correction in quantitative amyloid imaging.

Amyloid imaging is a valuable tool for research and diagnosis in dementing disorders. As positron emission tomography (PET) scanners have limited spatial resolution, measured signals are distorted by partial volume effects. Various techniques have been proposed for correcting partial volume effects, but there is no consensus as to whether these techniques are necessary in amyloid imaging, and, if so, how they should be implemented. We evaluated a two-component partial volume correction technique and a regional spread function technique using both simulated and human Pittsburgh compound B (PiB) PET imaging data. Both correction techniques compensated for partial volume effects and yielded improved detection of subtle changes in PiB retention. However, the regional spread function technique was more accurate in application to simulated data. Because PiB retention estimates depend on the correction technique, standardization is necessary to compare results across groups. Partial volume correction has sometimes been avoided because it increases the sensitivity to inaccuracy in image registration and segmentation. However, our results indicate that appropriate PVC may enhance our ability to detect changes in amyloid deposition.

Functional connectivity in autosomal dominant and late-onset Alzheimer disease.

IMPORTANCE Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in 3 specific genes in contrast to late-onset Alzheimer disease (LOAD), which has a more polygenetic risk profile. OBJECTIVE To assess the similarities and differences in functional connectivity changes owing to ADAD and LOAD. DESIGN, SETTING, AND PARTICIPANTS We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of participants with ADAD (n = 79) and LOAD (n = 444), using resting-state functional connectivity magnetic resonance imaging at multiple international academic sites. MAIN OUTCOMES AND MEASURES For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity measured by the Clinical Dementia Rating Scale. In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within 5 RSNs. RESULTS A decrease in functional connectivity with increasing Clinical Dementia Rating scores were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in one type of Alzheimer disease accurately predicted clinical dementia rating scores in the other, further demonstrating the similarity of functional connectivity loss in each disease type. Among participants with ADAD, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared with asymptomatic mutation noncarriers. CONCLUSIONS AND RELEVANCE Resting-state functional connectivity magnetic resonance imaging changes with progressing AD severity are similar between ADAD and LOAD. Resting-state functional connectivity magnetic resonance imaging may be a useful end point for LOAD and ADAD therapy trials. Moreover, the disease process of ADAD may be an effective model for the LOAD disease process.

Experimental and Surgical Aspects of Retinal Pigment Epithelial Cell Transplantation

Abstract OBJECTIVES: To discuss the current status of experimental studies on transplantation of the retinal pigment epithelium (RPE), and surgical results on the excision of subfoveal choroidal new vessel membranes in age-related macular degeneration (AMD) and presumed ocular histoplasmosis (POHS). STUDY DESIGN: Experimental study on transplantation of the RPE in organ culture and in vivo, and results of a prospective series on surgical excision of choroidal neovascularization. SETTING: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine. PATIENTS: Patients with subfoveal neovascular membranes secondary to AMD and POHS. MAIN OUTCOME MEASURES: Histological results on transplantation of the RPE onto Bruchs membrane in experimental animal models, and visual results on surgical excision of subfoveal choroidal neovascularization in patients with AMD and POHS. RESULTS: We have demonstrated that the RPE monolayer can heal after surgical debridement in the experimental animal, and retinal recovery occurs after healing of the RPE monolayer. We have demonstrated that RPE can reattach to healthy Bruchs membrane in vitro, and have performed RPE transplantation into the subretinal space in vivo. CONCLUSIONS: We are currently involved in a multifaceted approach aimed at RPE transplantation and surgical reconstruction of the photoreceptor-RPE-Bruchs membrane interface. We are hopeful that our approach will be applicable to the clinical problem of subfoveal choroidal new vessel membranes in AMD and POHS, in addition to the broad applicability of RPE transplantation to patients with diseases arising from primary RPE dysfunction.

AV-1451 PET imaging of tau pathology in preclinical Alzheimer disease: Defining a summary measure

Abstract Utilizing [18F]‐AV‐1451 tau positron emission tomography (PET) as an Alzheimer disease (AD) biomarker will require identification of brain regions that are most important in detecting elevated tau pathology in preclinical AD. Here, we utilized an unsupervised learning, data‐driven approach to identify brain regions whose tau PET is most informative in discriminating low and high levels of [18F]‐AV‐1451 binding. 84 cognitively normal participants who had undergone AV‐1451 PET imaging were used in a sparse k‐means clustering with resampling analysis to identify the regions most informative in dividing a cognitively normal population into high tau and low tau groups. The highest‐weighted FreeSurfer regions of interest (ROIs) separating these groups were the entorhinal cortex, amygdala, lateral occipital cortex, and inferior temporal cortex, and an average SUVR in these four ROIs was used as a summary metric for AV‐1451 uptake. We propose an AV‐1451 SUVR cut‐off of 1.25 to define high tau as described by imaging. This spatial distribution of tau PET is a more widespread pattern than that predicted by pathological staging schemes. Our data‐derived metric was validated first in this cognitively normal cohort by correlating with early measures of cognitive dysfunction, and with disease progression as measured by &bgr;‐amyloid PET imaging. We additionally validated this summary metric in a cohort of 13 Alzheimer disease patients, and showed that this measure correlates with cognitive dysfunction and &bgr;‐amyloid PET imaging in a diseased population. HighlightsAV‐1451 binding in four key regions identifies tau‐positive individuals with preclinical AD.The SUVR cutoff for high and low tau PET is 1.25.Increased tau PET correlates with early cognitive impairment, and relates to &bgr;‐amyloid burden in preclinical AD individuals.The spatial pattern of AV‐1451 uptake in preclinical AD is more widespread than predicted by pathological staging.

Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study

Background Models of Alzheimer disease propose a sequence of amyloid-β (Aβ) accumulation, hypometabolism, and structural declines that precede the onset of clinical dementia. These pathological features evolve both temporally and spatially in the brain. This study aimed to characterize where in the brain and when in the course of the disease neuroimaging biomarkers become abnormal. Methods We analyzed data from mutation non-carriers, asymptomatic carriers, and symptomatic carriers collected between January 1st 2009 and December 31st 2015 from families carrying PSEN1, PSEN2, or APP mutations enrolled in the Dominantly Inherited Alzheimer’s Network. We analyzed [11C]Pittsburgh Compound B positron emission tomography (PiB PET), [18F]Fluorodeoxyglucose (FDG PET), and structural magnetic resonance imaging (MRI) data using regions of interest to assess change throughout the brain. We estimated rates of biomarker change as a function of estimated years from symptom onset at baseline using linear mixed-effects models and determined the earliest point at which biomarker trajectories differed between mutation carriers and non-carriers. Findings PiB PET was available for 346 individuals, with 162 having longitudinal imaging; FDG PET was available for 352 (175 longitudinal); and MRI data was available for 377 (201 longitudinal). We found a sequence to pathological changes, with rates of Aβ deposition in mutation carriers being significantly different from non-carriers first (on average across regions that showed a significant difference at −18·9 (sd 3·3) years before expected onset), followed by hypometabolism (−14·1 years, sd 5·1) and lastly structural declines (−4·7 years, sd 4·2). This biomarker ordering was preserved in most, but not all, regions. The temporal emergence within a biomarker varied across the brain, with the precuneus being the first cortical region in each modality to show divergence between groups (−22·2 years before expected onset for Aβ accumulation, −18·8 years for hypometabolism, and −13·0 years for cortical thinning). Interpretation Mutation carriers had elevations in Aβ deposition, reduced glucose metabolism, and cortical thinning which preceded the expected onset of dementia. Accrual of these pathologies varied throughout the brain, suggesting differential regional and temporal vulnerabilities to Aβ, metabolic decline, and structural atrophy, which should be taken into account when using biomarkers in a clinical setting as well as designing and evaluating clinical trials.

Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer's Disease: Results from the DIAN Study Group

Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer’s Network (DIAN), an autosomal dominant Alzheimer’s disease population. Cross-sectional and longitudinal [11C]-Pittsburgh Compound B (PiB) PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time. White matter referencing improved statistical power in the detecting longitudinal changes in relative tracer retention; however, the reason for this improvement is unclear and requires further investigation. Full dynamic acquisition and kinetic modeling improved statistical power although it may add cost and time. Several technical variations to amyloid burden quantification were examined in this study. Partial volume correction emerged as the strategy that most consistently improved statistical power for the detection of both longitudinal changes and across-group differences. For the autosomal dominant Alzheimer’s disease population with PiB imaging, utilizing brainstem as a reference region with partial volume correction may be optimal for current interventional trials. Further investigation of technical issues in quantitative amyloid imaging in different study populations using different amyloid imaging tracers is warranted.

Quantitative amyloid imaging using image-derived arterial input function.

Amyloid PET imaging is an indispensable tool widely used in the investigation, diagnosis and monitoring of Alzheimer’s disease (AD). Currently, a reference region based approach is used as the mainstream quantification technique for amyloid imaging. This approach assumes the reference region is amyloid free and has the same tracer influx and washout kinetics as the regions of interest. However, this assumption may not always be valid. The goal of this work is to evaluate an amyloid imaging quantification technique that uses arterial region of interest as the reference to avoid potential bias caused by specific binding in the reference region. 21 participants, age 58 and up, underwent Pittsburgh compound B (PiB) PET imaging and MR imaging including a time-of-flight (TOF) MR angiography (MRA) scan and a structural scan. FreeSurfer based regional analysis was performed to quantify PiB PET data. Arterial input function was estimated based on coregistered TOF MRA using a modeling based technique. Regional distribution volume (VT) was calculated using Logan graphical analysis with estimated arterial input function. Kinetic modeling was also performed using the estimated arterial input function as a way to evaluate PiB binding (DVRkinetic) without a reference region. As a comparison, Logan graphical analysis was also performed with cerebellar cortex as reference to obtain DVRREF. Excellent agreement was observed between the two distribution volume ratio measurements (r>0.89, ICC>0.80). The estimated cerebellum VT was in line with literature reported values and the variability of cerebellum VT in the control group was comparable to reported variability using arterial sampling data. This study suggests that image-based arterial input function is a viable approach to quantify amyloid imaging data, without the need of arterial sampling or a reference region. This technique can be a valuable tool for amyloid imaging, particularly in population where reference normalization may not be accurate.