Clinical and multimodal biomarker correlates of ADNI neuropathological findings

Abstract

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 Aβ, 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.

Figure 1

Heatmaps summarizing the semiquantitative neuropathological grading (from left to right: diffuse amyloid plaques, neurofibrillary tangles (NFT), Lewy bodies (LB) and neuronal citoplasmatic TDP-immunoreactive inclusions (NCI)) for the different neuropathologic diagnostic groups (from top to bottom: AD, AD + MTL pathology, AD + DLB, AD + DLB + MTL pathology and DLB + MTL pathology).

Figure 2

Clinical correlates. a) Memory and b) Executive summary composites in subjects stratified by Braak stage and presence of coincident DLB and SVD-I. c) Last and d) Baseline visit executive-memory mismatch based on the absence or presence of coincident DLB and/or SVD-I. e) NPI-Q total score based on neuropatholgically defined groups.

Figure 3

CSF biomarker correlates. a) Aβ_1-42 levels based on a) NIA-AA criteria A score and Braak score. b)T-tau and c) P-tau₁₈₁ levels based on Braak stage. d) α-Synuclein-p-tau₁₈₁ mismatch and e) α-Synuclein based on presence or absence of coincident DLB and SVD-I.

Figure 4

Neuroimaging correlates. a) Right and b) Left occipital lobe FDG PET CMRgI stratified by presence or absence of coincident DLB and their relationship to ADAS-Cog measure, c) FDG-PET HCI stratified by presence or absence of coincident DLB and its relationship to ADAS-Cog measure. d) Left and e) Right occipital GM volume stratified by presence or absence of coincident DLB. f) Left and g) Right hippocampal volume stratified by neuropathologically defined groups. h) Occipital lobe GM volume and FDG PET CMRgI. i) Left hippocampal volume stratified by Braak stage and coincident MTL pathology.

Figure 5

Statistical cortical surface map for voxel-wise group comparison between subjects with and without DLB covarying out the effects of ADAS-Cog. Brain areas of significant hypometabolism in DLB were shown with an uncorrected threshold of p ≤ 0.005.