Abstract
BackgroundAutopsy 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.ResultsClinical 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.ConclusionsBiomarkers 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.
Highlights
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)
Brain donation status in ADNI and ADNI autopsy rates Information about the participation in the brain donation program is available on a total of 1119 ADNI subjects: 653 subjects have made a decision to donate their brains at death, 5 are reviewing the information and 461 have not made a decision
Up to the data download time on 17 August, 2013 there were 61 known deceased ADNI subjects, deaths that occurred in subjects lost to follow-up is not always known
Summary
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). We instead tried to assess how different combinations of biomarkers can detect different coincident pathologies and predict the different combinations of neuropathological substrates of the cognitive impairment in the studied subjects to help identify homogeneous cohorts of patients for clinical studies and clinical trials. This is especially true of clinical trials for DAT in which one pathology is targeted for study such as therapies that target Aβ or tau mediated mechanisms of neurodegeneration. We examined the first 22 patients in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who were longitudinally followed to death and underwent postmortem examination
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