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Evolution of neurodegeneration-imaging biomarkers from clinically normal to dementia in the Alzheimer disease spectrum.

ABSTRACT: The availability of antemortem biomarkers for Alzheimer's disease (AD) enables monitoring the evolution of neurodegenerative processes in real time. Pittsburgh compound B (PIB) positron emission tomography (PET) was used to select participants in the Mayo Clinic Study of Aging and the Mayo Alzheimer's Disease Research Center with elevated ?-amyloid, designated as "A+," and hippocampal volume and (18)fluorodeoxyglucose (FDG) positron emission tomography were used to characterize participants as having evidence of neurodegeneration ("N+") at the baseline evaluation. There were 145 clinically normal (CN) A+ individuals, 62 persons with mild cognitive impairment (MCI) who were A+ and 20 with A+ AD dementia. Over a period of 1-6 years, MCI A+N+ individuals showed declines in medial temporal, lateral temporal, lateral parietal, and to a lesser extent, medial parietal regions for both FDG standardized uptake value ratio and gray matter volume that exceeded declines seen in the CN A+N+ group. The AD dementia group showed declines in the same regions on FDG standardized uptake value ratio and gray matter volume with rates that exceeded that in MCI A+N+. Expansion of regional involvement and faster rate of neurodegeneration characterizes progression in the AD pathway.

SUBMITTER: Knopman DS

PROVIDER: S-EPMC5018437 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Evolution of neurodegeneration-imaging biomarkers from clinically normal to dementia in the Alzheimer disease spectrum.

Knopman David S DS Jack Clifford R CR Lundt Emily S ES Weigand Stephen D SD Vemuri Prashanthi P Lowe Val J VJ Kantarci Kejal K Gunter Jeffrey L JL Senjem Matthew L ML Mielke Michelle M MM Machulda Mary M MM Roberts Rosebud O RO Boeve Bradley F BF Jones David T DT Petersen Ronald C RC

Neurobiology of aging 20160616

The availability of antemortem biomarkers for Alzheimer's disease (AD) enables monitoring the evolution of neurodegenerative processes in real time. Pittsburgh compound B (PIB) positron emission tomography (PET) was used to select participants in the Mayo Clinic Study of Aging and the Mayo Alzheimer's Disease Research Center with elevated β-amyloid, designated as "A+," and hippocampal volume and (18)fluorodeoxyglucose (FDG) positron emission tomography were used to characterize participants as h ...[more]

PMID: 27460147

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Project description:ImportanceA substantial proportion of clinically normal (CN) older individuals are classified as having suspected non-Alzheimer disease pathophysiology (SNAP), defined as biomarker negative for β-amyloid (Aβ-) but positive for neurodegeneration (ND+). The etiology of SNAP in this population remains unclear.ObjectiveTo determine whether CN individuals with SNAP show evidence of early Alzheimer disease (AD) processes (ie, elevated tau levels and/or increased risk for cognitive decline).Design, setting, and participantsThis longitudinal observational study performed in an academic medical center included 247 CN participants from the Harvard Aging Brain Study. Participants were classified into preclinical AD stages using measures of Aβ (Pittsburgh Compound B [PIB]-labeled positron emission tomography) and ND (hippocampal volume or cortical glucose metabolism from AD-vulnerable regions). Classifications included stages 0 (Aβ-/ND-), 1 (Aβ+/ND-), and 2 (Aβ+/ND+) and SNAP (Aβ-/ND+). Continuous levels of PiB and ND, tau levels in the medial and inferior temporal lobes, and longitudinal cognition were examined. Data collection began in 2010 and is ongoing. Data were analyzed from 2015 to 2016.Main outcomes and measuresEvidence of amyloid-independent tau deposition and/or cognitive decline.ResultsOf the 247 participants (142 women [57.5%]; 105 men [42.5%]; mean age, 74 [range, 63-90] years), 64 (25.9%) were classified as having SNAP. Compared with the stage 0 group, the SNAP group was not more likely to have subthreshold PiB values (higher values within the Aβ- range), suggesting that misclassification due to the PiB cutoff was not a prominent contributor to this group (mean [SD] distribution volume ratio, 1.08 [0.05] for the SNAP group; 1.09 [0.05] for the stage 1 group). Tau levels in the medial and inferior temporal lobes were indistinguishable between the SNAP and stage 0 groups (entorhinal cortex, β = -0.005 [SE, 0.036]; parahippocampal gyrus, β = -0.001 [SE, 0.027]; and inferior temporal lobe, β = -0.004 [SE, 0.027]; P ≥ .88) and were lower in the SNAP group compared with the stage 2 group (entorhinal cortex, β = -0.125 [SE, 0.041]; parahippocampal gyrus, β = -0.074 [SE, 0.030]; and inferior temporal lobe, β = -0.083 [SE, 0.031]; P ≤ .02). The stage 2 group demonstrated greater cognitive decline compared with all other groups (stage 0, β = -0.239 [SE, 0.042]; stage 1, β = -0.242 [SE, 0.051]; and SNAP, β = -0.157 [SE, 0.044]; P ≤ .001), whereas the SNAP group showed a diminished practice effect over time compared with the stage 0 group (β = -0.082 [SE, 0.037]; P = .03).Conclusions and relevanceIn this study, clinically normal adults with SNAP did not exhibit evidence of elevated tau levels, which suggests that this biomarker construct does not represent amyloid-independent tauopathy. At the group level, individuals with SNAP did not show cognitive decline but did show a diminished practice effect. SNAP is likely heterogeneous, with a subset of this group at elevated risk for short-term decline. Future refinement of biomarkers will be necessary to subclassify this group and determine the biological correlates of ND markers among Aβ- CN individuals.

Project description:Study designProspective cohort study.ObjectiveApply a machine learning clustering algorithm to baseline imaging data to identify clinically relevant cervical spondylotic myelopathy (CSM) patient phenotypes.Summary of background dataA major shortcoming in improving care for CSM patients is the lack of robust quantitative imaging tools to guide surgical decision-making. Advanced diffusion-weighted magnetic resonance imaging (MRI) techniques, such as diffusion basis spectrum imaging (DBSI), may help address this limitation by providing detailed evaluations of white matter injury in CSM.MethodsFifty CSM patients underwent comprehensive clinical assessments and diffusion-weighted MRI, followed by DBSI modeling. DBSI metrics included fractional anisotropy, axial and radial diffusivity, fiber fraction, extra-axonal fraction, restricted fraction, and nonrestricted fraction. Neurofunctional status was assessed by the modified Japanese Orthopedic Association, myelopathic disability index, and disabilities of the arm, shoulder, and hand. Quality-of-life was measured by the 36-Item Short Form Survey physical component summary and mental component summary. The neck disability index was used to measure self-reported neck pain. K-means clustering was applied to baseline DBSI measures to identify 3 clinically relevant CSM disease phenotypes. Baseline demographic, clinical, radiographic, and patient-reported outcome measures were compared among clusters using one-way analysis of variance (ANOVA).ResultsTwenty-three (55%) mild, 9 (21%) moderate, and 10 (24%) severe myelopathy patients were enrolled. Eight patients were excluded due to MRI data of insufficient quality. Of the remaining 42 patients, 3 groups were generated by k-means clustering. When compared with clusters 1 and 2, cluster 3 performed significantly worse on the modified Japanese Orthopedic Association and all patient-reported outcome measures (P<0.001), except the 36-Item Short Form Survey mental component summary (P>0.05). Cluster 3 also possessed the highest proportion of non-Caucasian patients (43%, P=0.04), the worst hand dynamometer measurements (P<0.05), and significantly higher intra-axonal axial diffusivity and extra-axonal fraction values (P<0.001).ConclusionsUsing baseline imaging data, we delineated a clinically meaningful CSM disease phenotype, characterized by worse neurofunctional status, quality-of-life, and pain, and more severe imaging markers of vasogenic edema.Level of evidenceII.

Dataset Information

Evolution of neurodegeneration-imaging biomarkers from clinically normal to dementia in the Alzheimer disease spectrum.

Publications

Evolution of neurodegeneration-imaging biomarkers from clinically normal to dementia in the Alzheimer disease spectrum.

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