Correlation of Alzheimer Disease Neuropathologic Staging with Amyloid and Tau Scintigraphic Imaging Biomarkers.
Koychev Ivan,Hofer Monika,Friedman Nicholas
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
PET neuroimaging of amyloid-β (Aβ) provides an in vivo biomarker for pathologic changes associated with Alzheimer disease (AD). Aβ-targeted agents have been approved by the Food and Drug Administration, with additional agents, most notably targeting tau, currently under clinical investigation and one approved in May 2020. These agents, along with nonscintigraphic biomarkers from blood and cerebrospinal fluid, have provided an opportunity to investigate the pathogenesis, prodromal changes, and time course of the disease in living individuals. The current understanding is that the neuropathologic changes of the AD continuum begin up to 25 y before the onset of clinical symptomatology. The opportunities afforded by in vivo biomarkers of AD, whether by serum, cerebrospinal fluid examination or PET, have transformed the design of AD therapeutic trials by shifting focus to the preclinical stages of disease. Future disease-modifying therapies, should they be forthcoming, will rely heavily on the use of approved biomarkers or biomarkers currently under investigation to confirm the presence of target pathology. Understanding the progressive neuropathologic changes that occur in AD-and how scintigraphic findings relate to these changes-will help the interpreting physician to fully appreciate the implications of the scintigraphic findings and provide a basis to interpret the examinations. The recently adopted National Institute on Aging-Alzheimer Association guidelines define postmortem AD neuropathologic changes as a composite score based on 3 elements. These elements are the extent of involvement (spread) by cerebral Aβ based on the progression model defined by the Thal Aβ phases, the extent of involvement (spread) by neurofibrillary tangles (composed of hyperphosphorylated tau proteins) based on the progression model defined by Braak, and the Consortium to Establish a Registry for Alzheimer's Disease score, which describes the density of neuritic plaques based on certain key locations in the neocortex. This paper will review the 3 elements that define the National Institute on Aging-Alzheimer's Association scoring system and discusses current evidence on how these elements relate to findings based on Aβ and tau PET scintigraphy.
10.2967/jnumed.119.230458
Asymmetric Amyloid Deposition as an Early Sign of Progression in Mild Cognitive Impairment Due to Alzheimer Disease.
Clinical nuclear medicine
PURPOSE:In typical Alzheimer disease with dementia (ADD), amyloid pathologies affect both cerebral hemispheres symmetrically. However, the spatial distribution of amyloid-β (Aβ) in the early stage of ADD or over the course of disease has not been investigated. Therefore, we explored asymmetric pattern of Aβ deposition in both hemispheres according to the ADD continuum using 18F-florbetaben PET. METHODS:Sixty-eight subjects, including 15 Aβ-negative normal controls, 28 Aβ-positive mild cognitive impairment (Aβ+ MCI), and 25 Aβ-positive ADD (Aβ+ ADD) subjects, were enrolled. Differences in the asymmetry index and SUV ratio in each of the 6 target regions (4 cortical lobes, cingulate, precuneus) plus composite region between groups were explored. RESULTS:The composite and target regional asymmetry indices were significantly different between groups and was highest in Aβ+ MCI (composite, occipital, and temporal, P < 0.001; frontal, P = 0.004). The composite and target regional SUV ratios were significantly different according to 3 groups with gradual increase and were highest in Aβ+ ADD (composite and all target regions, P < 0.001). CONCLUSIONS:The asymmetric pattern of amyloid deposition was distinct between Aβ-negative normal controls and Aβ+ MCI. This pattern disappeared as the disease progressed. These data indicate that asymmetric amyloid deposition may be an early sign of MCI over the course of ADD.
10.1097/RLU.0000000000003662
Repetition Priming in Individuals with Amnestic Mild Cognitive Impairment and Alzheimer's Dementia: a Systematic Review and Meta-Analysis.
Neuropsychology review
The literature on repetition priming in Alzheimer's disease (AD) is inconsistent, with some findings supporting spared priming while others do not. Several factors may explain these inconsistencies, including AD severity (e.g., dementia vs. Mild Cognitive Impairment; MCI) and priming paradigm-related characteristics. This systematic review and meta-analysis provides a quantitative summary of repetition priming in AD. We examined the between-group standard mean difference comparing repetition priming in AD dementia or amnestic MCI (aMCI; presumably due to AD) to controls. Thirty-two studies were selected, including 590 individuals with AD dementia, 267 individuals with amnestic MCI, and 703 controls. Our results indicated that both individuals with aMCI and AD dementia perform worse on repetition priming tasks than cognitively older adults. Paradigm-related moderators suggested that the effect size between studies comparing the combined aMCI or AD dementia group to cognitively healthy older adults was the highest for paradigms that required participants to produce, rather than identify, primes during the test phase. Our results further suggested that priming in AD is impaired for both conceptual and perceptual priming tasks. Lastly, while our results suggested that priming in AD is impaired for priming tasks that require deep processing, we were unable to draw firm conclusions about whether priming is less impaired in aMCI or AD dementia for paradigms that require shallow processing.
10.1007/s11065-021-09504-5
Sex Differences in Alzheimer's Disease: Insights From the Multiomics Landscape.
Biological psychiatry
Alzheimer's disease (AD) has complex etiologies, and the impact of sex on AD varies over the course of disease development. The literature provides some evidence of sex-specific contributions to AD. However, molecular mechanisms of sex-biased differences in AD remain elusive. Multiomics data in tandem with systems biology approaches offer a new avenue to dissect sex-stratified molecular mechanisms of AD and to develop sex-specific diagnostic and therapeutic strategies for AD. Single-cell transcriptomic datasets and cell deconvolution of bulk tissue transcriptomic data provide additional insights into brain cell type-specific impact on sex-biased differences in AD. In this review, we summarize the impact of sex chromosomes and sex hormones on AD, the impact of sex-biased differences during AD development, and the interplay between sex and a major AD genetic risk factor, the APOE ε4 genotype, through the multiomics landscape. Several sex-biased molecular pathways such as neuroinflammation and bioenergetic metabolism have been identified. The importance of sex chromosome and sex hormones, as well as the associated pathways in AD pathogenesis, is further strengthened by findings from omics studies. Future research efforts should integrate the multiomics data from different brain regions and different cell types using systems biology approaches, and leverage the knowledge into a holistic examination of sex differences in AD. Advances in systems biology technologies and increasingly available large-scale multiomics datasets will facilitate future studies dissecting such complex signaling mechanisms to better understand AD pathogenesis in both sexes, with the ultimate goals of developing efficacious sex- and APOE-stratified preventive and therapeutic interventions for AD.
10.1016/j.biopsych.2021.02.968
Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy.
Nature
Alzheimer's disease (AD) is the most prevalent cause of dementia. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.
10.1038/s41586-021-03489-0
The propagation mechanisms of extracellular tau in Alzheimer's disease.
Wei Yun,Liu Meixia,Wang Dongxin
Journal of neurology
Tubulin-associated unit (tau) is an important microtubule-associated protein. The abnormal intracellular aggregation of tau has been strongly associated with Alzheimer's disease (AD). Accumulating evidence has conclusively demonstrated that tau is present in the cytoplasm of neurons and is also actively released into the extracellular space. However, the types of tau species that are released are unclear, as is the mechanism of their release by donor neurons and subsequent uptake by recipient neurons in AD. Understanding the underlying mechanisms of abnormal tau cell-to-cell transmission can provide novel insights into the etiology and pathogenesis of AD and can help identify new targets for the development of AD therapies focused on counteracting neurodegeneration or even preventing it. From this perspective, the present review focuses on recent advances in understanding the mechanisms regulating the levels of extracellular tau and discusses the role of such mechanisms in the propagation of tau-associated pathology.
10.1007/s00415-021-10573-y
Four distinct trajectories of tau deposition identified in Alzheimer's disease.
Nature medicine
Alzheimer's disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These 'subtypes' were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of 'typical AD' and a revisiting of tau pathological staging.
10.1038/s41591-021-01309-6
Distinct fiber-specific white matter reductions pattern in early- and late-onset Alzheimer's disease.
Luo Xiao,Wang Shuyue,Jiaerken Yeerfan,Li Kaicheng,Zeng Qingze,Zhang Ruiting,Wang Chao,Xu Xiaopei,Wu Dan,Huang Peiyu,Zhang Minming,
Aging
BACKGROUND:The underlying white matter impairment in patients with early and late-onset Alzheimer's disease (EOAD and LOAD) is still unclear, and this might due to the complex AD pathology. METHODS:We included 31 EOAD, 45 LOAD, and 64 younger, 46 elder controls in our study to undergo MRI examinations. Fiber density (FD) and fiber bundle cross-section (FC) were measured using fixel-based analysis based on diffusion weighted images. On whole brain and tract-based level, we compared these parameters among different groups (p<0.05, FWE corrected). Moreover, we verified our results in another independent dataset using the same analyses. RESULTS:Compared to young healthy controls, EOAD had significantly lower FD in the splenium of corpus callosum, limbic tracts, cingulum bundles, and posterior thalamic radiation, and higher FC in the splenium of corpus callosum, dorsal cingulum and posterior thalamic radiation. On the other hand, LOAD had lower FD and FC as well. Importantly, a similar pattern was found in the independent validation dataset. Among all groups, both the FD and FC were associated with cognitive function. Furthermore, FD of fornix column and body, and FC of ventral cingulum were associated with composite amyloid and tau level (r=-0.34 and -0.53, p<0.001) respectively. CONCLUSIONS:EOAD and LOAD were characterized by distinct white matter impairment patterns, which may be attributable to their different neuropathologies.
10.18632/aging.202702
Temporal Correlation of CSF and Neuroimaging in the Amyloid-Tau-Neurodegeneration Model of Alzheimer Disease.
Neurology
OBJECTIVE:To evaluate temporal correlations between CSF and neuroimaging (PET and MRI) measures of amyloid, tau, and neurodegeneration in relation to Alzheimer disease (AD) progression. METHODS:A total of 371 cognitively unimpaired and impaired participants enrolled in longitudinal studies of AD had both CSF (β-amyloid [Aβ], phosphorylated tau, total tau, and neurofilament light chain) and neuroimaging (Pittsburgh compound B [PiB] PET, flortaucipir PET, and structural MRI) measures. The pairwise time interval between CSF and neuroimaging measures was binned into 2-year periods. Spearman correlations identified the time bin when CSF and neuroimaging measures most strongly correlated. CSF and neuroimaging measures were then binarized as biomarker-positive or biomarker-negative using Gaussian mixture modeling. Cohen kappa coefficient identified the time bin when CSF measures best agreed with corresponding neuroimaging measures when determining amyloid, tau, and neurodegeneration biomarker positivity. RESULTS:CSF Aβ and PiB PET showed maximal correlation when collected within 6 years of each other ( ≈ -0.5). CSF phosphorylated tau and flortaucipir PET showed maximal correlation when CSF was collected 4 to 8 years prior to PET ( ≈ 0.4). CSF neurofilament light chain and cortical thickness showed low correlation, regardless of time interval ( ≈ -0.3). Similarly, CSF total tau and cortical thickness had low correlation, regardless of time interval ( < -0.2). CONCLUSIONS:CSF Aβ and PiB PET best agree when acquired in close temporal proximity, whereas CSF phosphorylated tau precedes flortaucipir PET by 4 to 8 years. CSF and neuroimaging measures of neurodegeneration have low correspondence and are not interchangeable at any time interval.
10.1212/WNL.0000000000012123
Haploinsufficiency of microglial MyD88 ameliorates Alzheimer's pathology and vascular disorders in APP/PS1-transgenic mice.
Glia
Growing evidence indicates that innate immune molecules regulate microglial activation in Alzheimer's disease (AD); however, their effects on amyloid pathology and neurodegeneration remain inconclusive. Here, we conditionally deleted one allele of myd88 gene specifically in microglia in APP/PS1-transgenic mice by 6 months and analyzed AD-associated pathologies by 9 months. We observed that heterozygous deletion of myd88 gene in microglia decreased cerebral amyloid β (Aβ) load and improved cognitive function of AD mice, which was correlated with reduced number of microglia in the brain and inhibited transcription of inflammatory genes, for example, tnf-α and il-1β, in both brain tissues and individual microglia. To investigate mechanisms underlying the pathological improvement, we observed that haploinsufficiency of MyD88 increased microglial recruitment toward Aβ deposits, which might facilitate Aβ clearance. Microglia with haploinsufficient expression of MyD88 also increased vasculature in the brain of APP/PS1-transgenic mice, which was associated with up-regulated transcription of osteopontin and insulin-like growth factor genes in microglia. Moreover, MyD88-haploinsufficient microglia elevated protein levels of LRP1 in cerebral capillaries of APP/PS1-transgenic mice. Cell culture experiments further showed that treatments with interleukin-1β decreased LRP1 expression in pericytes. In summary, haploinsufficiency of MyD88 in microglia at a late disease stage attenuates pro-inflammatory activation and amyloid pathology, prevents the impairment of microvasculature and perhaps also protects LRP1-mediated Aβ clearance in the brain of APP/PS1-transgenic mice, all of which improves neuronal function of AD mice.
10.1002/glia.24007
Small-World Networks and Their Relationship With Hippocampal Glutamine/Glutamate Concentration in Healthy Adults With Varying Genetic Risk for Alzheimer's Disease.
Zhang Hui,Chiu Pui W,Ip Isaac,Liu Tianyin,Wong Gloria H Y,Song You-Qiang,Wong Savio W H,Herrup Karl,Mak Henry K F
Journal of magnetic resonance imaging : JMRI
BACKGROUND:Apolipoprotein E ɛ4 allele (ApoE4) is the most common gene polymorphism related to Alzheimer's disease (AD). Impaired synaptic dysfunction occurs in ApoE4 carriers before any clinical symptoms. It remains unknown whether ApoE4 status affects the hippocampal neuromodulation, which further influences brain network topology. PURPOSE:To study the relationship of regional and global network properties by using graph theory analysis and glutamatergic (Glx) neuromodulation in the ApoE isoforms. STUDY TYPE:Prospective. SUBJECTS:Eighty-four cognitively normal adults (26 ApoE4 and 58 non-ApoE4 carriers). FIELD STRENGTH/SEQUENCE:Gradient-echo echo-planar and point resolved spectroscopy sequence at 3 T. ASSESSMENT:Glx concentration in bilateral hippocampi were processed with jMRUI (4.0), and graph theory metrics (global: γ, λ, small-worldness in whole brain; regional: nodal clustering coefficient (C ) and nodal characteristic path length (L )) in top 20% highly connected hubs of subgroups (low-risk: non-ApoE4; high-risk: APOE4) were calculated and compared. STATISTICAL TESTS:Two-sample t test was used to compare metrics between subgroups. Correlations between regional properties and Glx by Pearson's partial correlation with false discovery rate correction. RESULTS:Significant differences (P < 0.05) in C between subgroups were found in hubs of left inferior frontal, bilateral inferior temporal, and bilateral precentral gyri, right parahippocampus, and bilateral precuneus. In addition, there was a significant correlation between Glx in the left hippocampus and C in inferior frontal gyrus (r = -0.537, P = 0.024), right inferior temporal (r = -0.478, P = 0.043), right parahippocampus (r = -0.629, P = 0.016), left precentral (r = -0.581, P = 0.022), right precentral (r = -0.651, P = 0.003), left precuneus (r = -0.545, P = 0.024), and right precuneus (r = -0.567, P = 0.022); and L in left precuneus (r = 0.575, P = 0.032) and right precuneus (r = 0.586, P = 0.032) in the high-risk group, but not in the low-risk group. DATA CONCLUSION:Our results suggested that healthy ApoE4 carriers exhibit poorer local interconnectivity. Moreover, the close relationship between glutamate and small-world network properties in ApoE4 carriers might reflect a compensatory response to the impaired network efficiency. EVIDENCE LEVEL:2 TECHNICAL EFFICACY: Stage 3.
10.1002/jmri.27632
Bioenergetic and inflammatory systemic phenotypes in Alzheimer's disease APOE ε4-carriers.
Aging cell
We examined the impact of an APOE ε4 genotype on Alzheimer's disease (AD) subject platelet and lymphocyte metabolism. Mean platelet mitochondrial cytochrome oxidase Vmax activity was lower in APOE ε4 carriers and lymphocyte Annexin V, a marker of apoptosis, was significantly higher. Proteins that mediate mitophagy and energy sensing were higher in APOE ε4 lymphocytes which could represent compensatory changes and recapitulate phenomena observed in post-mortem AD brains. Analysis of the lipid synthesis pathway found higher AceCSI, ATP CL, and phosphorylated ACC levels in APOE ε4 lymphocytes. Lymphocyte ACC changes were also observed in post-mortem brain tissue. Lymphocyte RNAseq showed lower APOE ε4 carrier sphingolipid Transporter 3 (SPNS3) and integrin Subunit Alpha 1 (ITGA1) expression. RNAseq pathway analysis revealed APOE ε4 alleles activated inflammatory pathways and modulated bioenergetic signaling. These findings support a relationship between APOE genotype and bioenergetic pathways and indicate platelets and lymphocytes from APOE ε4 carriers exist in a state of bioenergetic stress. Neither medication use nor brain-localized AD histopathology can account for these findings, which define an APOE ε4-determined molecular and systemic phenotype that informs AD etiology.
10.1111/acel.13356
Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau.
EMBO molecular medicine
Alzheimer's disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer's disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N = 88), both plaque and tangle density contributed independently to higher P-tau217, but P-tau217 was not elevated in patients with non-Alzheimer's disease tauopathies (N = 9). Several findings were replicated in a cohort with PET imaging ("BioFINDER-2", N = 426), where β-amyloid and tau PET were independently associated with P-tau217. P-tau217 concentrations correlated with β-amyloid PET (but not tau PET) in early disease stages and with both β-amyloid and (more strongly) tau PET in late disease stages. Finally, P-tau217 mediated the association between β-amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P-tau217 concentration is increased by both β-amyloid plaques and tau tangles and is congruent with the hypothesis that P-tau is involved in β-amyloid-dependent formation of neocortical tau tangles.
10.15252/emmm.202114022
Astrocyte Biomarkers in Alzheimer Disease: A Systematic Review and Meta-analysis.
Neurology
OBJECTIVE:To perform a systematic review and meta-analysis to determine whether fluid and imaging astrocyte biomarkers are altered in Alzheimer disease (AD). METHODS:PubMed and Web of Science databases were searched for articles reporting fluid or imaging astrocyte biomarkers in AD. Pooled effect sizes were determined with standardized mean differences (SMDs) using the Hedge G method with random effects to determine biomarker performance. Adapted questions from the Quality Assessment of Diagnostic Accuracy Studies were applied for quality assessment. A protocol for this study has been previously registered in PROSPERO (registration number: CRD42020192304). RESULTS:The initial search identified 1,425 articles. After exclusion criteria were applied, 33 articles (a total of 3,204 individuals) measuring levels of glial fibrillary acidic protein (GFAP), S100B, chitinase-3-like protein 1 (YKL-40), and aquaporin 4 in the blood and CSF, as well as monoamine oxidase-B indexed by PET C-deuterium-l-deprenyl, were included. GFAP (SMD 0.94, 95% confidence interval [CI] 0.71-1.18) and YKL-40 (SMD 0.76, 95% CI 0.63-0.89) levels in the CSF and S100B levels in the blood (SMD 2.91, 95% CI 1.01-4.8) were found to be significantly increased in patients with AD. CONCLUSIONS:Despite significant progress, applications of astrocyte biomarkers in AD remain in their early days. This meta-analysis demonstrated that astrocyte biomarkers are consistently altered in AD and supports further investigation for their inclusion in the AD clinical research framework for observational and interventional studies.
10.1212/WNL.0000000000012109
Network interdigitations of Tau and amyloid-beta deposits define cognitive levels in aging.
Kim Chan-Mi,Montal Victor,Diez Ibai,Orwig William, ,Sepulcre Jorge
Human brain mapping
Amyloid-beta (Aβ) plaques and tau neurofibrillary tangles are pathological hallmarks of Alzheimer's disease (AD); their contribution to neurodegeneration and clinical manifestations are critical in understanding preclinical AD. At present, the mechanisms related to Aβ and tau pathogenesis leading to cognitive decline in older adults remain largely unknown. Here, we examined graph theory-based positron emission tomography (PET) analytical approaches, within and between tau and Aβ PET modalities, and tested the effects on cognitive changes in cognitively normal older adults (CN). Particularly, we focused on the network interdigitations of Aβ and tau deposits, along with cognitive test scores in CN at both baseline and 2-year follow-up (FU). We found highly significant Aβ-tau network integrations in AD vulnerable areas, as well as significant associations between those Aβ-tau interdigitations and general cognitive impairment in CN at baseline and FU. Our findings suggest a distinctive contribution of interlinking network relationships between Aβ and tau deposits in heteromodal areas of the human brain. They support a network-based interaction between Aβ and tau accumulations as a key factor for cognitive deterioration in CN prior to dementia.
10.1002/hbm.25350
Comparing PET and MRI Biomarkers Predicting Cognitive Decline in Preclinical Alzheimer Disease.
Neurology
OBJECTIVE:To compare how structural MRI, fluorodeoxyglucose (FDG), and flortaucipir (FTP) PET signals predict cognitive decline in high-amyloid vs low-amyloid participants with the goal of determining which biomarker combination would result in the highest increase of statistical power for prevention trials. METHODS:In this prospective cohort study, we analyzed data from clinically normal adults from the Harvard Aging Brain Study with MRI, FDG, FTP, and Pittsburgh compound B (PiB)-PET acquired within a year and prospective cognitive evaluations over a mean 3-year follow-up. We focused analyses on predefined regions of interest: inferior temporal, isthmus cingulate, hippocampus, and entorhinal cortex. Cognition was assessed with the Preclinical Alzheimer's Cognitive Composite. We evaluated the association between biomarkers and cognitive decline using linear mixed-effect models with random intercepts and slopes, adjusting for demographics. We generated power curves simulating prevention trials. RESULTS:Data from 131 participants (52 women, age 73.98 ± 8.29 years) were analyzed in the study. In separate models, most biomarkers had a closer association with cognitive decline in the high-PiB compared to the low-PiB participants. A backward stepwise regression including all biomarkers demonstrated that only neocortical PiB, entorhinal FTP, and entorhinal FDG were independent predictors of subsequent cognitive decline. Power analyses revealed that using both high PiB and low entorhinal FDG as inclusion criteria reduced 3-fold the number of participants needed in a hypothetical trial compared to using only high PiB. DISCUSSION:In preclinical Alzheimer disease, entorhinal hypometabolism is a strong and independent predictor of subsequent cognitive decline, making FDG a potentially useful biomarker to increase power in clinical trials. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that in people with preclinical Alzheimer disease, entorhinal hypometabolism identified by FDG-PET is predictive of subsequent cognitive decline.
10.1212/WNL.0000000000012108