How good are medical and death records for identifying dementia?

INTRODUCTION: Retrospective studies using administrative data may be an efficient way to assess risk factors for dementia if diagnostic accuracy is known. METHODS: Within-individual clinical diagnoses of Alzheimer's disease (AD) and all-cause dementia in ambulatory (outpatient) surgery, inpatient, Medicare administrative records and death certificates were compared with research diagnoses among participants of Cache County Study on Memory, Health, and Aging (CCSMHA) (1995-2008, N = 5092). RESULTS: Combining all sources of clinical health data increased sensitivity for identifying all-cause dementia (71%) and AD (48%), while maintaining relatively high specificity (81% and 93%, respectively). Medicare claims had the highest sensitivity for case identification (57% and 40%, respectively). DISCUSSION: Administrative health data may provide a less accurate method than a research evaluation for identifying individuals with dementing disease, but accuracy is improved by combining health data sources. Assessing all-cause dementia versus a specific cause of dementia such as AD will result in increased sensitivity, but at a cost to specificity.

Perceptions of tissue storage in a dementia population among spouses and offspring.

Cognitively impaired patients with dementia often rely on health advocates or guardians, such as spouses or adult offspring, to consent for medical procedures. These family members may also decide whether an autopsy is performed after death or whether their family member donates tissues. However, spouses are not genetically related to the patient and may have different perspectives than genetically related family members when making medical decisions with genetic implications, such as participation in a tissue repository (biobank). Interviews were conducted with spouses and adult offspring of individuals with a progressive dementing disease. Both spouses and offspring were supportive of the patient with dementia to participate in tissue storage. The top perceived benefits of tissue storage in both offspring and spouses were future value for family members and advancement of medical knowledge. Concerns included misuse of the tissue and insurance discrimination. Although the personal genetic implications differ between spouses and offspring, they share similar attitudes about the importance of tissue banking for the individual with a dementing disease.

The Alzheimer's Disease Neuroimaging Initiative 2 PET Core: 2015.

INTRODUCTION: This article reviews the work done in the Alzheimer's Disease Neuroimaging Initiative positron emission tomography (ADNI PET) core over the past 5 years, largely concerning techniques, methods, and results related to amyloid imaging in ADNI. METHODS: The PET Core has used [(18)F]florbetapir routinely on ADNI participants, with over 1600 scans available for download. Four different laboratories are involved in data analysis, and have examined factors such as longitudinal florbetapir analysis, use of [(18)F]fluorodeoxyglucose (FDG)-PET in clinical trials, and relationships between different biomarkers and cognition. RESULTS: Converging evidence from the PET Core has indicated that cross-sectional and longitudinal florbetapir analyses require different reference regions. Studies have also examined the relationship between florbetapir data obtained immediately after injection, which reflects perfusion, and FDG-PET results. Finally, standardization has included the translation of florbetapir PET data to a centiloid scale. CONCLUSION: The PET Core has demonstrated a variety of methods for the standardization of biomarkers such as florbetapir PET in a multicenter setting.

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 Alzheimer's 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.

Practice effects and amyloid deposition: preliminary data on a method for enriching samples in clinical trials.

Clinical trials in Alzheimer disease are moving toward prevention studies in prodromal individuals with amyloid burden. However, methods are needed to identify individuals expected to be amyloid positive for these studies to be feasible and cost-effective. The current study sought to determine whether short-term practice effects on cognitive tests can identify those with notable uptake on amyloid imaging. Twenty-five, nondemented older adults (15 cognitively intact, 10 with mild cognitive impairment) underwent amyloid imaging through F-flutemetamol and 2 cognitive testing sessions across 1 week to determine practice effects on a visual memory test. Results indicated that, whereas F-flutemetamol uptake showed little association with baseline performance on a visual memory test (r=-0.04, P=0.85), it was significantly correlated with practice effects across 1 week on that same memory measure (r=-0.45, P=0.02), with greater uptake being associated with lower practice effects. The odds ratio of notable F-flutemetamol uptake was 5 times higher in individuals with low practice effects compared with high practice effects. Although these preliminary results need to be replicated in larger samples, short-term practice effects on cognitive tests may provide an affordable screening method to identify individuals who are amyloid positive, which could enrich samples for preventative clinical trials in Alzheimer disease.

Justifying reimbursement for Alzheimer's diagnostics and treatments: Seeking alignment on evidence.

The increasing cost of health care combined with expensive new drugs and diagnostics is leading to more frequent gaps between regulatory and subsequent reimbursement approval decisions. As a result, persons with Alzheimer's disease may have difficulty accessing the benefit of medical advances. In contrast to the long history and established structure for drug approval, payer decision making is dispersed, not standardized, and perspectives on necessary evidence and the evaluation of this evidence differ and are often poorly defined. Particularly challenging is how to demonstrate the value of drugs and diagnostics for patients who do not yet have significant functional decline. Although discussions to develop consensus continue, clinical trials should begin to incorporate health system and patient-oriented outcomes. In some situations, additional studies designed to demonstrate value and comparative effectiveness will be needed. Such studies should examine outcomes of representative populations in community settings. To assure scientific advances in diagnosis and treatment benefit in patients, developing evidence to support reimbursement will become as important as obtaining regulatory approval.

Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association.

Positron emission tomography (PET) of brain amyloid b is a technology that is becoming more available, but its clinical utility in medical practice requires careful definition. To provide guidance to dementia care practitioners, patients, and caregivers, the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened the Amyloid Imaging Taskforce (AIT). The AIT considered a broad range of specific clinical scenarios in which amyloid PET could potentially be used appropriately. Peer-reviewed, published literature was searched to ascertain available evidence relevant to these scenarios, and the AIT developed a consensus of expert opinion. Although empirical evidence of impact on clinical outcomes is not yet available, a set of specific appropriate use criteria (AUC) were agreed on that define the types of patients and clinical circumstances in which amyloid PET could be used. Both appropriate and inappropriate uses were considered and formulated,and are reported and discussed here. Because both dementia care and amyloid PET technology are in active development, these AUC will require periodic reassessment. Future research directions are also outlined, including diagnostic utility and patient-centered outcomes.

Update on appropriate use criteria for amyloid PET imaging: dementia experts, mild cognitive impairment, and education. Amyloid Imaging Task Force of the Alzheimer's Association and Society for Nuclear Medicine and Molecular Imaging.

Amyloid PET imaging is a novel diagnostic test that can detect in living humans one of the two defining pathologic lesions of Alzheimer disease, amyloid-ß deposition in the brain. The Amyloid Imaging Task Force of the Alzheimer's Association and Society for Nuclear Medicine and Molecular Imaging previously published appropriate use criteria for amyloid PET as an important tool for increasing the certainty of a diagnosis of Alzheimer disease in specific patient populations. Here, the task force further clarifies and expands 3 topics discussed in the original paper: first, defining dementia experts and their use of proper documentation to demonstrate the medical necessity of an amyloid PET scan; second, identifying a specific subset of individuals with mild cognitive impairment for whom an amyloid PET scan is appropriate; and finally, developing educational programs to increase awareness of the amyloid PET appropriate use criteria and providing instructions on how this test should be used in the clinical decision-making process.

The RSNA QIBA Profile for Amyloid PET as an Imaging Biomarker for Cerebral Amyloid Quantification.

A standardized approach to acquiring amyloid PET images increases their value as disease and drug response biomarkers. Most 18F PET amyloid brain scans often are assessed only visually (per regulatory labels), with a binary decision indicating the presence or absence of Alzheimer disease amyloid pathology. Minimizing technical variance allows precise, quantitative SUV ratios (SUVRs) for early detection of ß-amyloid plaques and allows the effectiveness of antiamyloid treatments to be assessed with serial studies. Methods: The Quantitative Imaging Biomarkers Alliance amyloid PET biomarker committee developed and validated a profile to characterize and reduce the variability of SUVRs, increasing statistical power for these assessments. Results: On achieving conformance, sites can justify a claim that brain amyloid burden reflected by the SUVR is measurable to a within-subject coefficient of variation of no more than 1.94% when the same radiopharmaceutical, scanner, acquisition, and analysis protocols are used. Conclusion: This overview explains the claim, requirements, barriers, and potential future developments of the profile to achieve precision in clinical and research amyloid PET imaging.

Hypertensive disorders of pregnancy and subsequent risk of Alzheimer's disease and other dementias.

Introduction: Women with hypertensive disorders of pregnancy (HDP) have an increased risk of cardiovascular disease. Whether HDP is also associated with later-life dementia has not been fully explored. Methods: Using the Utah Population Database, we performed an 80-year retrospective cohort study of 59,668 parous women. Results: Women with, versus without, HDP, had a 1.37 higher risk of all-cause dementia (95% confidence interval [CI]: 1.26, 1.50) after adjustment for maternal age at index birth, birth year, and parity. HDP was associated with a 1.64 higher risk of vascular dementia (95% CI: 1.19, 2.26) and 1.49 higher risk of other dementia (95% CI: 1.34, 1.65) but not Alzheimer's disease dementia (adjusted hazard ratio = 1.04; 95% CI: 0.87, 1.24). Gestational hypertension and preeclampsia/eclampsia showed similar increased dementia risk. Nine mid-life cardiometabolic and mental health conditions explained 61% of HDP's effect on subsequent dementia risk. Discussion: Improved HDP and mid-life care could reduce the risk of dementia.

Incidence of dementia and cognitive impairment, not dementia in the United States.

OBJECTIVE: Estimates of incident dementia, and cognitive impairment, not dementia (CIND) (or the related mild cognitive impairment) are important for public health and clinical care policy. In this paper, we report US national incidence rates for dementia and CIND. METHODS: Participants in the Aging, Demographic, and Memory Study (ADAMS) were evaluated for cognitive impairment using a comprehensive in-home assessment. A total of 456 individuals aged 72 years and older, who were not demented at baseline, were followed longitudinally from August 2001 to December 2009. An expert consensus panel assigned a diagnosis of normal cognition, CIND, or dementia and its subtypes. Using a population-weighted sample, we estimated the incidence of dementia, Alzheimer disease (AD), vascular dementia (VaD), and CIND by age. We also estimated the incidence of progression from CIND to dementia. RESULTS: The incidence of dementia was 33.3 (standard error [SE], 4.2) per 1,000 person-years and 22.9 (SE, 2.9) per 1,000 person-years for AD. The incidence of CIND was 60.4 (SE, 7.2) cases per 1,000 person-years. An estimated 120.3 (SE, 16.9) individuals per 1,000 person-years progressed from CIND to dementia. Over a 5.9-year period, about 3.4 million individuals aged 72 and older in the United States developed incident dementia, of whom approximately 2.3 million developed AD, and about 637,000 developed VaD. Over this same period, almost 4.8 million individuals developed incident CIND. INTERPRETATION: The incidence of CIND is greater than the incidence of dementia, and those with CIND are at high risk of progressing to dementia, making CIND a potentially valuable target for treatments aimed at slowing cognitive decline.

18F-FDG PET Imaging in Neurodegenerative Dementing Disorders: Insights into Subtype Classification, Emerging Disease Categories, and Mixed Dementia with Copathologies.

Since the invention of 18F-FDG as a neurochemical tracer in the 1970s, 18F-FDG PET has been used extensively for dementia research and clinical applications. FDG, a glucose analog, is transported into the brain via glucose transporters and metabolized in a concerted process involving astrocytes and neurons. Although the exact cellular mechanisms of glucose consumption are still under investigation, 18F-FDG PET can sensitively detect altered neuronal activity due to neurodegeneration. Various neurodegenerative disorders affect different areas of the brain, which can be depicted as altered 18F-FDG uptake by PET. The spatial patterns and severity of such changes can be reproducibly visualized by statistical mapping technology, which has become widely available in the clinic. The differentiation of 3 major neurodegenerative disorders by 18F-FDG PET, Alzheimer disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB), has become standard practice. As the nosology of FTD evolves, frontotemporal lobar degeneration, the umbrella term for pathology affecting the frontal and temporal lobes, has been subclassified clinically into behavioral variant FTD; primary progressive aphasia with 3 subtypes, semantic, nonfluent, and logopenic variants; and movement disorders including progressive supranuclear palsy and corticobasal degeneration. Each of these subtypes is associated with differential 18F-FDG PET findings. The discovery of new pathologic markers and clinicopathologic correlations via larger autopsy series have led to newly recognized or redefined disease categories, such as limbic-predominant age-related TDP-43 encephalopathy, hippocampus sclerosis, primary age-related tauopathy, and argyrophilic grain disease, which have become a focus of investigations by molecular imaging. These findings need to be integrated into the modern interpretation of 18F-FDG PET. Recent pathologic investigations also have revealed a high prevalence, particularly in the elderly, of mixed dementia with overlapping and coexisting pathologies. The interpretation of 18F-FDG PET is evolving from a traditional dichotomous diagnosis of AD versus FTD (or DLB) to a determination of the most predominant underlying pathology that would best explain the patient's symptoms, for the purpose of care guidance. 18F-FDG PET is a relatively low cost and widely available imaging modality that can help assess various neurodegenerative disorders in a single test and remains the workhorse in clinical dementia evaluation.

Evaluating the Impact of Cochlear Implantation on Cognitive Function in Older Adults.

OBJECTIVES/HYPOTHESIS: We hypothesize that treating hearing loss through cochlear implantation in older adults will improve cognitive function. STUDY DESIGN: Prospective, interventional study. METHODS: Thirty-seven participants aged 65 years and older who met criteria for cochlear implantation were enrolled. Subjects underwent preoperative cognitive testing with a novel arrangement of standard neuropsychological tests, including tests of general cognition and mood (Mini-Mental Status Exam [MMSE]), tests of verbally based stimuli and responses (Digit Span, Stroop, Hopkins Verbal Learning Test-Revised [HVLT-R], Hayling Sentence Completion), and comparable visually based tests (Spatial Span, d2 Test of Attention, Brief Visuospatial Memory Test [BVMT], Trails A and B). Testing was repeated 12 months postoperatively. RESULTS: One year postoperatively, subjects showed a statistically significant improvement in hearing and on the following tests of cognitive function: concentration performance of the d2 Test of Attention, Hayling Sentence Completion Test, HVLT-R (total and delayed recall), Spatial Span (backward), and Stroop Color Word Test. A subgroup analysis was performed comparing 13 participants with preoperative cognitive impairment (MMSE ≤ 24) to 24 participants with normal cognition (MMSE ≥ 25). In this subgroup analysis, a greater magnitude of improvement was seen in those with impaired cognition, with statistically significant improvement in Digit Span (scaled score), Stroop Word (T-score), Stroop Color-Word (residual and T-score), HVLT-R, and Hayling (overall). All verbally based test scores improved, and 75% of the visually based test scores improved. CONCLUSIONS: This study demonstrates the cognitive benefits of cochlear implantation in older adults 1 year after surgery. For older adults with cognitive impairment prior to cochlear implantation, the cognitive benefits were even greater than in subjects with normal cognition. LEVEL OF EVIDENCE: 3, nonrandomized controlled cohort Laryngoscope, 132:S1-S15, 2022.

Overall and sex-specific risk factors for subjective cognitive decline: findings from the 2015-2018 Behavioral Risk Factor Surveillance System Survey.

BACKGROUND: Prior research indicates that at least 35% of Alzheimer's disease and related dementia risk may be amenable to prevention. Subjective cognitive decline is often the first indication of preclinical dementia, with the risk of subsequent Alzheimer's disease in such individuals being greater in women than men. We wished to understand how modifiable factors are associated with subjective cognitive decline, and whether differences exist by sex. METHODS: Data were collected from men and women (45 years and older) who completed the U.S. Behavioral Risk Factor Surveillance System Cognitive Decline Module (2015-2018), n = 216,838. We calculated population-attributable fractions for subjective cognitive decline, stratified by sex, of the following factors: limited education, deafness, social isolation, depression, smoking, physical inactivity, obesity, hypertension, and diabetes. Our models were adjusted for age, race, income, employment, marital and Veteran status, and accounted for communality among risk factors. RESULTS: The final study sample included more women (53.7%) than men, but both had a similar prevalence of subjective cognitive decline (10.6% of women versus 11.2% of men). Women and men had nearly equivalent overall population-attributable fractions to explain subjective cognitive decline (39.7% for women versus 41.3% for men). The top three contributing risk factors were social isolation, depression, and hypertension, which explained three-quarters of the overall population-attributable fraction. CONCLUSIONS: While we did not identify any differences in modifiable factors between men and women contributing to subjective cognitive decline, other factors including reproductive or endocrinological health history or biological factors that interact with sex to modify risk warrant further research.

Characterizing Alzheimer's disease using a hypometabolic convergence index.

This article introduces a hypometabolic convergence index (HCI) for the assessment of Alzheimer's disease (AD); compares it to other biological, cognitive and clinical measures; and demonstrates its promise to predict clinical decline in mild cognitive impairment (MCI) patients using data from the AD Neuroimaging Initiative (ADNI). The HCI is intended to reflect in a single measurement the extent to which the pattern and magnitude of cerebral hypometabolism in an individual's fluorodeoxyglucose positron emission tomography (FDG-PET) image correspond to that in probable AD patients, and is generated using a fully automated voxel-based image-analysis algorithm. HCIs, magnetic resonance imaging (MRI) hippocampal volume measurements, cerebrospinal fluid (CSF) assays, memory test scores, and clinical ratings were compared in 47 probable AD patients, 21 MCI patients who converted to probable AD within the next 18months, 76 MCI patients who did not, and 47 normal controls (NCs) in terms of their ability to characterize clinical disease severity and predict conversion rates from MCI to probable AD. HCIs were significantly different in the probable AD, MCI converter, MCI stable and NC groups (p=9e-17) and correlated with clinical disease severity. Using retrospectively characterized threshold criteria, MCI patients with either higher HCIs or smaller hippocampal volumes had the highest hazard ratios (HRs) for 18-month progression to probable AD (7.38 and 6.34, respectively), and those with both had an even higher HR (36.72). In conclusion, the HCI, alone or in combination with certain other biomarker measurements, has the potential to help characterize AD and predict subsequent rates of clinical decline. More generally, our conversion index strategy could be applied to a range of imaging modalities and voxel-based image-analysis algorithms.

Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease.

BACKGROUND: The promise of Alzheimer's disease biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging measure in Alzheimer's disease and thus represents the most rational target for an initial effort at standardization. METHODS AND RESULTS: The authors of this position paper propose a path toward this goal. The steps include the following: (1) Establish and empower an oversight board to manage and assess the effort, (2) adopt the standardized definition of anatomic hippocampal boundaries on magnetic resonance imaging arising from the European Alzheimer's Disease Centers-Alzheimer's Disease Neuroimaging Initiative hippocampal harmonization effort as a reference standard, (3) establish a scientifically appropriate, publicly available reference standard data set based on manual delineation of the hippocampus in an appropriate sample of subjects (Alzheimer's Disease Neuroimaging Initiative), and (4) define minimum technical and prognostic performance metrics for validation of new measurement techniques using the reference standard data set as a benchmark. CONCLUSIONS: Although manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent was to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry was envisioned as a template that could be applied to other imaging biomarkers.

Does Frailty or Age Increase the Risk of Postoperative Complications Following Cochlear Implantation?

OBJECTIVE: To evaluate whether frailty or age increases the risk of postoperative complications following cochlear implant (CI) surgery. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary academic center. METHODS: An evaluation of all adult patients undergoing cochlear implantation between 2006 and 2020 was performed. The 5-item Modified Frailty Index (mFI-5, comprising preoperative history of pulmonary disease, heart failure, hypertension, diabetes, and partially/totally dependent functional status) was calculated for all patients included in analysis in addition to demographic characteristics. The primary outcome was postoperative complications following CI within a 3-month period. Major complications included myocardial infarction, bleeding, and cerebrospinal fluid leak, among others. Predictors of postoperative complications were examined using multivariable logistic regression reporting odds ratios (ORs) and 95% CIs. RESULTS: There were 520 patients included for review with a median age of 68 (range, 18-94) years and a slight male predominance (n = 283, 54.4%). There were 340 patients (65.4%) who were robust (nonfrail) with an mFI of 0, while 180 (34.6%) had an mFI of ≥1. There were 20 patients who experienced a postoperative complication (3.85%). There was no statistically significant association between postoperative complications as a result of preoperative frailty (OR, 1.56; 95% CI, 0.98-2.48, P = .06) or age as a continuous variable (OR, 0.99; 95% CI, 0.97-1.02, P = .51). CONCLUSIONS: CI is safe for elderly and frail patients and carries no additional risk of complications when compared to younger, healthier patients. While medical comorbidities should always be considered perioperatively, this study supports the notion that implantation is low risk in older, frail patients.

Left Ear Hearing Predicts Functional Activity in the Brains of Patients with Alzheimer's Disease Dementia.

OBJECTIVES: To determine whether central speech processing ability, as measured by hearing in noise, differs between right and left ears in adults with Alzheimer's disease related dementia (AD) as well as whether differences in central speech processing ability correlate with an fMRI-based measurement of global functional brain connectivity. METHODS: This prospective study was carried out at a tertiary referral center. Patients with an AD diagnosis and pure tone averages 40 dB HL or better were included. They were examined using resting-state fMRI and underwent central audiometric testing using the Dichotic Sentence Identification Test (DSI), the Dichotic Digits Test (DD), and the Synthetic Sentence Identification Test (SS), which test hearing in noise. DSI scores were correlated with resting-state fMRI connectivity between 361 distinct gray matter brain regions of interest (ROIs). Average global connectivity was calculated as mean functional connectivity between an ROI and the other 360 regions, a quantitative marker representing overall functional connectivity in the brain. RESULTS: Sixteen subjects had adequate fMRI and hearing data. The average age was 71.5 years old (±6.0). The average DSI score for the left ear was 40% (±34%) compared to 90% (±10%) in the right ear (P < .001). No difference between ears was noted on the DD. SS does not differentiate between ears, but worsening scores were noted with increasing background noise. Of the fMRI ROIs, 269 of the 361 had multiple comparison corrected significant correlations between global connectivity and DSI of the left ear (P = .004, r = .673), and all 269 showed higher functional connectivity for individuals with higher left DSI score. No correlations between DSI of the right ear and functional connectivity were found. CONCLUSIONS: Correlation was noted between left sided DSI and functional connectivity in patients with AD. Auditory input from the left ear was more susceptible to impairment, suggesting that side-specific auditory input may influence central auditory processing.

Twelve-month metabolic declines in probable Alzheimer's disease and amnestic mild cognitive impairment assessed using an empirically pre-defined statistical region-of-interest: findings from the Alzheimer's Disease Neuroimaging Initiative.

Alzheimer's disease (AD) is characterized by specific and progressive reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose (CMRgl), some of which may precede the onset of symptoms. In this report, we describe twelve-month CMRgl declines in 69 probable AD patients, 154 amnestic mild cognitive impairment (MCI) patients, and 79 cognitively normal controls (NCs) from the AD Neuroimaging Initiative (ADNI) using statistical parametric mapping (SPM). We introduce the use of an empirically pre-defined statistical region-of-interest (sROI) to characterize CMRgl declines with optimal power and freedom from multiple comparisons, and we estimate the number of patients needed to characterize AD-slowing treatment effects in multi-center randomized clinical trials (RCTs). The AD and MCI groups each had significant twelve-month CMRgl declines bilaterally in posterior cingulate, medial and lateral parietal, medial and lateral temporal, frontal and occipital cortex, which were significantly greater than those in the NC group and correlated with measures of clinical decline. Using sROIs defined based on training sets of baseline and follow-up images to assess CMRgl declines in independent test sets from each patient group, we estimate the need for 66 AD patients or 217 MCI patients per treatment group to detect a 25% AD-slowing treatment effect in a twelve-month, multi-center RCT with 80% power and two-tailed alpha=0.05, roughly one-tenth the number of the patients needed to study MCI patients using clinical endpoints. Our findings support the use of FDG PET, brain-mapping algorithms and empirically pre-defined sROIs in RCTs of AD-slowing treatments.

The Alzheimer's Disease Neuroimaging Initiative positron emission tomography core.

BACKGROUND: This is a progress report of the Alzheimer's Disease Neuroimaging Initiative (ADNI) positron emission tomography (PET) Core. METHODS: The Core has supervised the acquisition, quality control, and analysis of longitudinal [(18)F]fluorodeoxyglucose PET (FDG-PET) data in approximately half of the ADNI cohort. In an "add on" study, approximately 100 subjects also underwent scanning with [(11)C] Pittsburgh compound B PET for amyloid imaging. The Core developed quality control procedures and standardized image acquisition by developing an imaging protocol that has been widely adopted in academic and pharmaceutical industry studies. Data processing provides users with scans that have identical orientation and resolution characteristics despite acquisition on multiple scanner models. The Core labs have used many different approaches to characterize differences between subject groups (Alzheimer's disease, mild cognitive impairment, controls), to examine longitudinal change over time in glucose metabolism and amyloid deposition, and to assess the use of FDG-PET as a potential outcome measure in clinical trials. RESULTS: ADNI data indicate that FDG-PET increases statistical power over traditional cognitive measures, might aid subject selection, and could substantially reduce the sample size in a clinical trial. Pittsburgh compound B PET data showed expected group differences, and identified subjects with significant annual increases in amyloid load across the subject groups. The next activities of the PET core in ADNI will entail developing standardized protocols for amyloid imaging using the [(18)F]-labeled amyloid imaging agent AV45, which can be delivered to virtually all ADNI sites. CONCLUSIONS: ADNI has demonstrated the feasibility and utility of multicenter PET studies and is helping to clarify the role of biomarkers in the study of aging and dementia.