Added value and limitations of amyloid-PET imaging: review and analysis of selected cases of mild cognitive impairment and dementia.

Amyloid-positron emission tomography (PET) imaging of the brain detects elevated amyloid-beta (amyloid-ß) neuritic plaques in vivo, which can be helpful in appropriately selected cases of mild cognitive impairment (MCI) and dementia, when Alzheimer's disease remains a possible etiology, after a comprehensive clinical evaluation. We reviewed cases of cognitively impaired patients who underwent amyloid-PET imaging because of diagnostic uncertainty. Pre- and post-PET elements of diagnosis and management were first compared, to assess impact of scan results on clinical decision-making, and then an analysis of those decisions was undertaken in appropriate clinical situations, to delineate the added value and limitations of amyloid-PET imaging. The potential benefits and limitations of this diagnostic tool are important to understand in an era when the utility of such scans in clinical practice is evolving.

Florbetapir PET, FDG PET, and MRI in Down syndrome individuals with and without Alzheimer's dementia.

INTRODUCTION: Down syndrome (DS) is associated with amyloid b (Ab) deposition. METHODS: We characterized imaging measurements of regional fibrillar Ab burden, cerebral metabolic rate for glucose (rCMRgl), gray matter volumes (rGMVs), and age associations in 5 DS with dementia (DS/AD1), 12 DS without dementia (DS/AD2), and 9 normal controls (NCs). RESULTS: There were significant group differences in mean standard uptake value ratios (SUVRs) for florbetapir with DS/AD1 having the highest, followed by DS/AD2, followed by NC. For [18F]-fluorodeoxyglucose positron emission tomography, posterior cingulate rCMRgl in DS/AD1 was significantly reduced compared with DS/AD2 and NC. For volumetric magnetic resonance imaging (vMRI), hippocampal volumes were significantly reduced for the DS/AD1 compared with DS/AD2 and NC. Age-related SUVR increases and rCMRgl reductions were greater in DS participants than in NCs. DISCUSSION: DS is associated with fibrillar Ab, rCMRgl, and rGMV alterations in the dementia stage and before the presence of clinical decline. This study provides a foundation for the studies needed to inform treatment and prevention in DS.

Subjective cognitive decline: self and informant comparisons.

BACKGROUND: It is unclear whether self- or informant-based subjective cognition better distinguishes emotional factors from early-stage Alzheimer's disease (AD). METHODS: Healthy members (n = 447) of the Arizona apolipoprotein E (APOE) cohort and their informants completed the self and informant paired Multidimensional Assessment of Neurodegenerative Symptoms questionnaire (MANS). RESULTS: Decline on the MANS was endorsed by 30.6% of members and 26.2% of informants. Self- and informant-based decliners had higher scores of psychological distress and slightly lower cognitive scores than nondecliners. Over the next 6.7 years, 20 developed mild cognitive impairment (MCI). Converters were older at entry than nonconverters (63.8 [7.0] vs 58.8 [7.3] years, P = .003), 85% were APOE ε4 carriers (P < .0001), and they self-endorsed decline earlier than informants (58.9 [39.2] vs 28.0 [40.4] months before MCI; P = .002). CONCLUSIONS: Self- and informant-based subjective decline correlated with greater psychological distress and slightly lower cognitive performance. Those with incident MCI generally self-endorsed decline earlier than informants.

Fibrillar amyloid correlates of preclinical cognitive decline.

BACKGROUND: It is not known whether preclinical cognitive decline is associated with fibrillar ß-amyloid (Aß) deposition irrespective of apolipoprotein E (APOE) ε4 status. METHODS: From a prospective observational study of 623 cognitively normal individuals, we identified all subjects who showed preclinical decline of at least 2 standard deviations beyond the decline of the entire group in memory or executive function. Fourteen decliners were matched by APOE ε4 gene dose, age, sex, and education with 14 nondecliners. Dynamic Pittsburgh compound B (PiB) positron emission tomography (PET) scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest were used to characterize and compare cerebral-to-cerebellar PiB distribution volume ratios (DVRs), reflecting fibrillar Aß burden. RESULTS: At P < .005 (uncorrected), decliners had significantly greater DVRs in comparison to nondecliners. CONCLUSIONS: Asymptomatic longitudinal neuropsychological decline is associated with subsequent increased fibrillar amyloid deposition, even when controlling for APOE ε4 genotype.

Improved power for characterizing longitudinal amyloid-ß PET changes and evaluating amyloid-modifying treatments with a cerebral white matter reference region.

UNLABELLED: In this article, we describe an image analysis strategy with improved power for tracking longitudinal amyloid-ß (Aß) PET changes and evaluating Aß-modifying treatments. METHODS: Our aims were to compare the power of template-based cerebellar, pontine, and cerebral white matter reference regions to track 24-mo florbetapir standardized uptake value (SUV) ratio (SUVR) changes; to relate those changes to 24-mo clinical declines; and to evaluate Aß-modifying treatments in Aß-positive (Aß+) and Aß-negative (Aß-) patients with probable Alzheimer dementia (pAD), in patients with mild cognitive impairment (MCI), in cognitively normal controls (NCs), and in cognitively normal apolipoprotein E4 (APOE4) carriers and noncarriers. We used baseline and follow-up (∼24 mo) florbetapir PET scans from 332 Aß+ and Aß- subjects participating in the multicenter Alzheimer's Disease Neuroimaging Initiative. Each of the proposed analyses included 31 pAD patients, 187 MCI patients, and 114 NCs. Cerebral-to-white matter, cerebellar, and pontine SUVRs were characterized in terms of their longitudinal variability; their power to track longitudinal fibrillar Aß increases in Aß+ and Aß- subgroups and cognitively normal APOE4 carriers and noncarriers; the sample sizes needed to detect attenuated accumulation of or clearance of fibrillar Aß accumulation in randomized clinical trials; and their ability to relate 24-mo fibrillar Aß increases to clinical declines. RESULTS: As predicted, cerebral-to-white matter SUVR changes were significantly less variable and had significantly greater power to detect 24-mo fibrillar Aß increases and evaluate Aß-modifying treatment effects in Aß+ pAD, MCI, and NC subjects and cognitively normal APOE4 carriers. They were also distinguished by the ability to detect significant associations between 24-mo Aß increases and clinical declines. CONCLUSION: A cerebral white matter reference region may improve the power to track longitudinal fibrillar Aß increases, to characterize their relationship to longitudinal clinical declines, and to evaluate Aß-modifying treatments in randomized clinical trials.

Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study.

IMPORTANCE: Age-associated changes in brain imaging and fluid biomarkers are characterized and compared in presenilin 1 (PSEN1)E280A mutation carriers and noncarriers from the world's largest known autosomal dominant Alzheimer disease (AD) kindred. OBJECTIVE: To characterize and compare age-associated changes in brain imaging and fluid biomarkers in PSEN1 E280A mutation carriers and noncarriers. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional measures of 18F-florbetapir positron emission tomography, 18F-fludeoxyglucose positron emission tomography, structural magnetic resonance imaging, cerebrospinal fluid (CSF), and plasma biomarkers of AD were assessed from 54 PSEN1 E280A kindred members (age range, 20-59 years). MAIN OUTCOMES AND MEASURES: We used brain mapping algorithms to compare regional cerebral metabolic rates for glucose and gray matter volumes in cognitively unimpaired mutation carriers and noncarriers. We used regression analyses to characterize associations between age and the mean cortical to pontine 18F-florbetapir standard uptake value ratios, precuneus cerebral metabolic rates for glucose, hippocampal gray matter volume, CSF Aß1-42, total tau and phosphorylated tau181, and plasma Aß measurements. Age at onset of progressive biomarker changes that distinguish carriers from noncarriers was estimated using best-fitting regression models. RESULTS: Compared with noncarriers, cognitively unimpaired mutation carriers had significantly lower precuneus cerebral metabolic rates for glucose, smaller hippocampal volume, lower CSF Aß1-42, higher CSF total tau and phosphorylated tau181, and higher plasma Aß1-42 measurements. Sequential changes in biomarkers were seen at age 20 years (95% CI, 14-24 years) for CSF Aß1-42, age 16 years (95% CI, 11-24 years) for the mean cortical 18F-florbetapir standard uptake value ratio, age 15 years (95% CI, 10-24 years) for precuneus cerebral metabolic rate for glucose, age 15 years (95% CI, 7-20 years) for CSF total tau, age 13 years (95% CI, 8-19 years) for phosphorylated tau181, and age 6 years (95% CI, 1-10 years) for hippocampal volume, with cognitive decline up to 6 years before the kindred's estimated median age of 44 years (95% CI, 43-45 years) at mild cognitive impairment diagnosis. No age-associated findings were seen in plasma Aß1-42 or Aß1-40. CONCLUSIONS AND RELEVANCE: This cross-sectional study provides additional information about the course of different AD biomarkers in the preclinical and clinical stages of autosomal dominant AD.

Brain glucose and acetoacetate metabolism: a comparison of young and older adults.

The extent to which the age-related decline in regional brain glucose uptake also applies to other important brain fuels is presently unknown. Ketones are the brain's major alternative fuel to glucose, so we developed a dual tracer positron emission tomography protocol to quantify and compare regional cerebral metabolic rates for glucose and the ketone, acetoacetate. Twenty healthy young adults (mean age, 26 years) and 24 healthy older adults (mean age, 74 years) were studied. In comparison with younger adults, older adults had 8 ± 6% (mean ± SD) lower cerebral metabolic rates for glucose in gray matter as a whole (p = 0.035), specifically in several frontal, temporal, and subcortical regions, as well as in the cingulate and insula (p ≤ 0.01, false discovery rate correction). The effect of age on cerebral metabolic rates for acetoacetate in gray matter did not reach significance (p = 0.11). Rate constants (min(-1)) of glucose (Kg) and acetoacetate (Ka) were significantly lower (-11 ± 6%; [p = 0.005], and -19 ± 5%; [p = 0.006], respectively) in older adults compared with younger adults. There were differential effects of age on Kg and Ka as seen by significant interaction effects in the caudate (p = 0.030) and post-central gyrus (p = 0.023). The acetoacetate index, which expresses the scaled residuals of the voxel-wise linear regression of glucose on ketone uptake, identifies regions taking up higher or lower amounts of acetoacetate relative to glucose. The acetoacetate index was higher in the caudate of young adults when compared with older adults (p ≤ 0.05 false discovery rate correction). This study provides new information about glucose and ketone metabolism in the human brain and a comparison of the extent to which their regional use changes during normal aging.

Clinical and multimodal biomarker correlates of ADNI neuropathological findings.

BACKGROUND: Autopsy series commonly report a high percentage of coincident pathologies in demented patients, including patients with a clinical diagnosis of dementia of the Alzheimer type (DAT). However many clinical and biomarker studies report cases with a single neurodegenerative disease. We examined multimodal biomarker correlates of the consecutive series of the first 22 Alzheimer's Disease Neuroimaging Initiative autopsies. Clinical data, neuropsychological measures, cerebrospinal fluid Aß, total and phosphorylated tau and α-synuclein and MRI and FDG-PET scans. RESULTS: Clinical diagnosis was either probable DAT or Alzheimer's disease (AD)-type mild cognitive impairment (MCI) at last evaluation prior to death. All patients had a pathological diagnosis of AD, but only four had pure AD. A coincident pathological diagnosis of dementia with Lewy bodies (DLB), medial temporal lobe pathology (TDP-43 proteinopathy, argyrophilic grain disease and hippocampal sclerosis), referred to collectively here as MTL, and vascular pathology were present in 45.5%, 40.0% and 22.7% of these patients, respectively. Hallucinations were a strong predictor of coincident DLB (100% specificity) and a more severe dysexecutive profile was also a useful predictor of coincident DLB (80.0% sensitivity and 83.3% specificity). Occipital FDG-PET hypometabolism accurately classified coincident DLB (80% sensitivity and 100% specificity). Subjects with coincident MTL showed lower hippocampal volume. CONCLUSIONS: Biomarkers can be used to independently predict coincident AD and DLB pathology, a common finding in amnestic MCI and DAT patients. Cohorts with comprehensive neuropathological assessments and multimodal biomarkers are needed to characterize independent predictors for the different neuropathological substrates of cognitive impairment.

Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease.

OBJECTIVES: Investigate apolipoprotein E ε4 (APOE4) gene and aging effects on florbetapir F18 positron emission tomography (PET) in normal aging and Alzheimer's disease (AD). METHODS: Florbetapir F18 PET images were analyzed from 245 participants, 18-92 years of age, from Avid Radiopharmaceutical's multicenter registered trials, including 86 younger healthy control volunteers (yHC), 61 older healthy control volunteers (oHC), 53 mild cognitive impairment (MCI) patients, and 45 AD dementia patients (DAT). Mean florbetapir standard uptake value ratios (SUVRs) were used to evaluate the effects of APOE4 carrier status, older age, and their interaction in each of these groups. RESULTS: In comparison with non-carriers, the APOE4 carriers in each of the oHC, MCI, and DAT groups had higher mean cortical-to-cerebellar florbetapir SUVRs, patterns of florbetapir PET elevations characteristic of DAT, and a higher proportion meeting florbetapir PET positivity criteria. Only the oHC group had a significant association between mean cortical florbetapir SUVRs and age. In cognitively normal adults, without regards to APOE4 genotype, amyloid began to increase at age 58 (95% confidence interval [CI]: 52.3-63.7), with a predicted typical age of florbetapir positivity occurring around age 71 years. Presence of the APOE4 gene reduced the age of predicted florbetapir positivity in normal aging to around age 56 years, approximately 20 years younger than non-carriers. INTERPRETATION: Cerebral amyloid deposition is associated with APOE4 carrier status in older healthy control subjects and symptomatic AD patients, and increases with age in older cognitively normal individuals. Amyloid imaging positivity appears to begin near age 56 years in cognitively intact APOE4 carriers and age 76 years in APOE4 non-carriers.

Genetic susceptibility for Alzheimer disease neuritic plaque pathology.

IMPORTANCE: While numerous genetic susceptibility loci have been identified for clinical Alzheimer disease (AD), it is important to establish whether these variants are risk factors for the underlying disease pathology, including neuritic plaques. OBJECTIVES: To investigate whether AD susceptibility loci from genome-wide association studies affect neuritic plaque pathology and to additionally identify novel risk loci for this trait. DESIGN, SETTING, AND PARTICIPANTS: Candidate analysis of single-nucleotide polymorphisms and genome-wide association study in a joint clinicopathologic cohort, including 725 deceased subjects from the Religious Orders Study and the Rush Memory and Aging Project (2 prospective, community-based studies), followed by targeted validation in an independent neuroimaging cohort, including 114 subjects from multiple clinical and research centers. MAIN OUTCOMES AND MEASURES: A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on ß-amyloid load by immunocytochemistry, and replication with fibrillar ß-amyloid positron emission tomographic imaging with Pittsburgh Compound B or florbetapir. RESULTS: Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P = .02) and CD2AP (rs9349407; P = .03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our genome-wide association study, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P = 3.3 × 10-6). This polymorphism was associated with postmortem ß-amyloid load as well as fibrillar ß-amyloid in 2 independent cohorts of adults with normal cognition. CONCLUSIONS AND RELEVANCE: These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, presymptomatic stages of AD.

Florbetapir PET analysis of amyloid-ß deposition in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional study.

BACKGROUND: Fibrillar amyloid-ß (Aß) is thought to begin accumulating in the brain many years before the onset of clinical impairment in patients with Alzheimer's disease. By assessing the accumulation of Aß in people at risk of genetic forms of Alzheimer's disease, we can identify how early preclinical changes start in individuals certain to develop dementia later in life. We sought to characterise the age-related accumulation of Aß deposition in presenilin 1 (PSEN1) E280A mutation carriers across the spectrum of preclinical disease. METHODS: Between Aug 1 and Dec 6, 2011, members of the familial Alzheimer's disease Colombian kindred aged 18-60 years were recruited from the Alzheimer's Prevention Initiative's registry at the University of Antioquia, Medellín, Colombia. Cross-sectional assessment using florbetapir PET was done in symptomatic mutation carriers with mild cognitive impairment or mild dementia, asymptomatic carriers, and asymptomatic non-carriers. These assessments were done at the Banner Alzheimer's Institute in Phoenix, AZ, USA. A cortical grey matter mask consisting of six predefined regions.was used to measure mean cortical florbetapir PET binding. Cortical-to-pontine standard-uptake value ratios were used to characterise the cross-sectional accumulation of fibrillar Aß deposition in carriers and non-carriers with regression analysis and to estimate the trajectories of fibrillar Aß deposition. FINDINGS: We enrolled a cohort of 11 symptomatic individuals, 19 presymptomatic mutation carriers, and 20 asymptomatic non-carriers, ranging in age from 20 to 56 years. There was greater florbetapir binding in asymptomatic PSEN1 E280A mutation carriers than in age matched non-carriers. Fibrillar Aß began to accumulate in PSEN 1E280A mutation carriers at a mean age of 28·2 years (95% CI 27·3-33·4), about 16 years and 21 years before the predicted median ages at mild cognitive impairment and dementia onset, respectively. (18)F florbetapir binding rose steeply over the next 9·4 years and plateaued at a mean age of 37·6 years (95% CI 35·3-40·2), about 6 and 11 years before the expected respective median ages at mild cognitive impairment and dementia onset. Prominent florbetapir binding was seen in the anterior and posterior cingulate, precuneus, and parietotemporal and frontal grey matter, as well as in the basal ganglia. Binding in the basal ganglia was not seen earlier or more prominently than in other regions. INTERPRETATION: These findings contribute to the understanding of preclinical familial Alzheimer's disease and help set the stage for assessment of amyloid-modifying treatments in the prevention of familial Alzheimer's disease. FUNDING: Avid Radiopharmaceuticals, Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Colciencias, National Institute on Aging, and the State of Arizona.

Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease.

OBJECTIVES: To characterize quantitative florbetapir F 18 (hereafter referred to as simply florbetapir) positron emission tomographic (PET) measurements of fibrillar ß-amyloid (Aß) burden in a large clinical cohort of participants with probable Alzheimer disease (AD) or mild cognitive impairment (MCI) and older healthy controls (OHCs). DESIGN: Cerebral-to-whole-cerebellar florbetapir standard uptake value ratios (SUVRs) were computed. Mean cortical SUVRs were compared. A threshold of SUVRs greater than or equal to 1.17 was used to reflect pathological levels of amyloid associated with AD based on separate antemortem PET and postmortem neuropathology data from 19 end-of-life patients. Similarly, a threshold of SUVRs greater than 1.08 was used to signify the presence of any identifiable Aß because this was the upper limit from a separate set of 46 individuals 18 to 40 years of age who did not carry apolipoprotein E (APOE) ε4. SETTING: Multiple research imaging centers. PARTICIPANTS: A total of 68 participants with probable AD, 60 participants with MCI, and 82 OHCs who were 55 years of age or older. Main Outcome Measure Florbetapir-PET activity. RESULTS: All of the participants (ie, those with probable AD or MCI and those who were OHCs) differed significantly in mean (SD) cortical florbetapir SUVRs (1.39 [0.24], 1.17 [0.27], and 1.05 [0.16], respectively; P < 1.0 × 10⁻7), in percentage meeting levels of amyloid associated with AD by SUVR criteria (80.9%, 40.0%, and 20.7%, respectively; P < 1.0 × 10⁻7), and in percentage meeting SUVR criteria for the presence of any identifiable Aß (85.3%, 46.6%, and 28.1%, respectively; P < 1.0 × 10⁻7). Among OHCs, the percentage of florbetapir positivity increased linearly by age decile (P = .05). For the 54 OHCs with available APOE genotypes, APOE ε4 carriers had a higher mean (SD) cortical SUVR than did noncarriers (1.14 [0.2] vs 1.03 [0.16]; P = .048). CONCLUSIONS: The findings of our analysis confirm the ability of florbetapir-PET SUVRs to characterize amyloid levels in clinically probable AD, MCI, and OHC groups using continuous and binary measures of fibrillar Aß burden. It introduces criteria to determine whether an image is associated with an intermediate-to-high likelihood of pathologic AD or with having any identifiable cortical amyloid level above that seen in low-risk young controls.