Neuropathologic assessment of participants in two multi‐center longitudinal observational studies: The Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN)

Abstract

It has been hypothesized that the relatively rare autosomal dominant Alzheimer disease (ADAD) may be a useful model of the more frequent, sporadic, late-onset AD (LOAD). Individuals with ADAD have a predictable age at onset and the biomarker profile of ADAD participants in the preclinical stage may be used to predict disease progression and clinical onset. However, the extent to which the pathogenesis and neuropathology of ADAD overlaps with that of LOAD is equivocal. To address this uncertainty, two multicenter longitudinal observational studies, the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN), leveraged the expertise and resources of the existing Knight Alzheimer Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, Missouri, USA, to establish a Neuropathology Core (NPC). The ADNI/DIAN-NPC is systematically examining the brains of all participants who come to autopsy at the 59 ADNI sites in the USA and Canada and the 14 DIAN sites in the USA (8), Australia (3), UK (1), and Germany (2). By 2014, 41 ADNI and 24 DIAN autopsies (involving 9 participants and 15 family members) had been performed. The autopsy rate in the ADNI cohort in the most recent year was 93% (total since NPC inception: 70%). In summary, the ADNI/DIAN NPC has implemented a standard protocol for all sites to solicit permission for brain autopsy and to send brain tissue to the NPC for a standardized, uniform, and state-of-the-art neuropathologic assessment. The benefit to ADNI and DIAN of the implementation of the NPC is very clear. The NPC provides final ‘gold standard’ neuropathological diagnoses and data against which the antecedent observations and measurements of ADNI and DIAN can be compared.

Amyloid negativity in patients with clinically diagnosed Alzheimer disease and MCI

“…Of ADNI AD cases that have come to autopsy, there have been few non-AD primary diagnoses, but comorbidities have been observed in a majority of individuals. 10,37 Although the pattern of results in MCI was broadly consistent with AD, there were several important differences. First, patients with Ab2 MCI had less cognitive and functional impairment at baseline than patients with Ab1 MCI, whereas patients with AD did not differ.…”

“…8,9 Older adults with an amnestic profile that is suggestive of AD comprise a diverse group with heterogeneous pathology. Hippocampal sclerosis, argyrophilic grain disease, vascular dementia, Lewy body disease, and frontotemporal dementia have been observed at autopsy in addition to AD pathology 10 and in Ab2 cases with an antemortem AD diagnosis.…”

Differentiating cognitive impairment due to corticobasal degeneration and Alzheimer disease

“…Routinely, the right hemibrain was snap-frozen and preserved for biochemical studies with the use of established protocols. 26 The left hemibrain was fixed in buffered saline for neuropathologic examination. Briefly, formalin-fixed tissue samples were embedded in paraffin wax, and 7-mm sections were cut.…”

P1‐206: Clinical features of Alzheimer disease with and without lewy bodies

“…2 Lewy bodies are frequent in the setting of moderate-tosevere levels of AD neuropathologic change. [2][3][4] Neuroanatomical studies indicate that Lewy body accumulation follows a stereotypic pattern starting in the brainstem nuclei/olfactory regions and progressing to limbic areas and, in the most advanced stages, to the neocortex. 5,6 In contrast to this stereotypical pattern, Lewy bodies in AD may also be found concentrated in the amygdala without significant involvement of the brainstem or neocortical regions, 2,3 a distribution that has been called AD with amygdala Lewy bodies.…”