Dataset Information

Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer's Disease.

ABSTRACT: The relationships between ?-amyloid (A?), tau and neurodegeneration within Alzheimer's Disease pathogenesis are not fully understood. To explore these associations in vivo, we evaluated 30 A? PET-positive patients (mean ± sd age 62.4 ± 8.3) with mild probable AD and 12 A? PET-negative healthy controls (HC) (mean ± sd age 77.3 ± 6.9) as comparison. All participants underwent 3 T MRI, ¹¹C-PiB (A?) PET and ¹⁸F-AV1451 (tau) PET. Multimodal correlation analyses were run at both voxel- and region-of-interest levels. ¹¹C-PiB retention in AD showed the most diffuse uptake pattern throughout association neocortex, whereas ¹⁸F-AV1451 and gray matter volume reduction (GMR) showed a progressive predilection for posterior cortices (p<0.05 Family-Wise Error-[FWE]-corrected). Voxel-level analysis identified negative correlations between ¹⁸F-AV1451 and gray matter peaking in medial and infero-occipital regions (p<0.01 False Discovery Rate-[FDR]-corrected). ¹⁸F-AV1451 and ¹¹C-PiB were positively correlated in right parietal and medial/inferior occipital regions (p<0.001 uncorrected). ¹¹C-PiB did not correlate with GMR at the voxel-level. Regionally, ¹⁸F-AV1451 was largely associated with local/adjacent GMR whereas frontal ¹¹C-PiB correlated with GMR in posterior regions. These findings suggest that, in mild AD, tau aggregation drives local neurodegeneration, whereas the relationships between A? and neurodegeneration are not region specific and may be mediated by the interaction between A? and tau.

SUBMITTER: Iaccarino L

PROVIDER: S-EPMC5684433 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer's Disease.

Iaccarino Leonardo L Tammewar Gautam G Ayakta Nagehan N Baker Suzanne L SL Bejanin Alexandre A Boxer Adam L AL Gorno-Tempini Maria Luisa ML Janabi Mustafa M Kramer Joel H JH Lazaris Andreas A Lockhart Samuel N SN Miller Bruce L BL Miller Zachary A ZA O'Neil James P JP Ossenkoppele Rik R Rosen Howard J HJ Schonhaut Daniel R DR Jagust William J WJ Rabinovici Gil D GD

NeuroImage. Clinical 20170925

The relationships between β-amyloid (Aβ), tau and neurodegeneration within Alzheimer's Disease pathogenesis are not fully understood. To explore these associations in vivo, we evaluated 30 Aβ PET-positive patients (mean ± sd age 62.4 ± 8.3) with mild probable AD and 12 Aβ PET-negative healthy controls (HC) (mean ± sd age 77.3 ± 6.9) as comparison. All participants underwent 3 T MRI, 11C-PiB (Aβ) PET and 18F-AV1451 (tau) PET. Multimodal correlation analyses were run a ...[more]

PMID: 29159058

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Project description:BACKGROUND:The aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated ?-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease. METHODS:Forty-three subjects with mild cognitive impairment (MCI) had serial 11C-PK11195 PET over 2 years to measure inflammation changes, and 11C-PiB PET to determine ?-amyloid fibril load; 22 also had serial 18F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years. RESULTS:Those MCI subjects with high 11C-PiB uptake at baseline (classified as prodromal Alzheimer's disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their ?-amyloid levels continued to rise. Those MCI cases who had low/normal 11C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising ?-amyloid load. Those MCI cases with baseline low 11C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11C-PiB and 18F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation. CONCLUSIONS:Our baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer's disease: MCI cases with low baseline but subsequently rising ?-amyloid load show correlated levels of microglial activation which then later decline when the ?-amyloid load approaches AD levels. Later, as tau tangles form in ?-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.

Project description:ObjectiveThe primary study objective of this retrospective academic memory clinic-based observational longitudinal study was to investigate the prognostic value of a cerebrospinal fluid (CSF)-based ATN classification for subsequent cognitive decline during the 3 years following lumbar puncture in a clinical, real-life setting. The secondary objective was to investigate the prognostic value of CSF biomarkers as continuous variables.MethodsData from 228 patients (median age 67 (47-85) years), who presented at the Neurology Memory Clinic UZ/KU Leuven between September 2011 and December 2016, were included with a follow-up period of up to 36 months. Patients underwent a CSF AD biomarker test for amyloid-beta 1-42 (Aβ42), hyperphosphorylated tau (p181-tau) and total tau (t-tau) in the clinical work-up for diagnostic reasons. Patients were divided into ATN classes based on CSF biomarkers: Aβ42 for amyloid (A), p181-tau for tau (T), and t-tau as a measure for neurodegeneration (N). Based on retrospective data analysis, cognitive performance was evaluated by Mini Mental State Examination (MMSE) scores every 6 months over a period up to 36 months following the lumbar puncture. The statistical analysis was based on linear mixed-effects modeling (LME).ResultsThe distribution in the current clinical sample was as follows: A-/T-/N- 32.02%, A+/T-/N- 33.33%, A+/T+/N+ 17.11%, A+/T-/N+ 11.84%, A-/T-/N+ 4.39%, A-/T+/N+ 1.32% (3 cases), with no cases in the A-/T+/N- and A+/T+/N- class. Hence, the latter 3 classes were excluded from further analyses. The change of MMSE relative to A-/T-/N- over a 36-month period was significant in all four ATN classes: A+/T+/N+ = - 4.78 points on the MMSE; A-/T-/N+ = - 4.76; A+/T-/N+ = - 2.83; A+/T-/N- = - 1.96. The earliest significant difference was seen in the A+/T+/N+ class at 12 months after baseline. The effect of ATN class on future cognitive decline was confirmed for a different set of CSF thresholds. All individual baseline CSF biomarkers including the Aβ42/t-tau ratio showed a significant correlation with subsequent cognitive decline, with the highest correlation seen for Aβ42/t-tau.ConclusionATN classification based on CSF biomarkers has a statistically significant and clinically relevant prognostic value for the course of cognitive decline in a 3-year period in a clinical practice setting.

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Dataset Information

Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer's Disease.

Publications

Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer's Disease.

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