Abstract
The aging brain is characterized by the simultaneous presence of multiple pathologies, and the prevalence of cerebral multi-morbidity increases with age. To understand the impact of each subtype of pathology and the combined effects of cerebral multi-morbidity on clinical signs and symptoms, large clinico-pathological correlative studies have been performed. However, such studies are often based on semi-quantitative assessment of neuropathological hallmark lesions. Here, we discuss some of the new methods for high-throughput quantitative neuropathological assessment. These methods combine increased quantitative rigor with the added technical capacity of computers and networked analyses. There are abundant new opportunities - with specific techniques that include slide scanners, automated microscopes, and tissue microarrays - and also potential pitfalls. We conclude that quantitative and digital neuropathologic approaches will be key resources to further elucidate cerebral multi-morbidity in the aged brain and also hold the potential for changing routine neuropathologic diagnoses.
Highlights
The aging brain is characterized by the simultaneous presence of multiple pathologies, and the prevalence of cerebral multi-morbidity increases with age
Alzheimer’s disease (AD) in particular often presents with comorbid processes, including cerebrovascular disease, Lewy body (LB) pathology, argyrophilic grain disease, transactivation response DNA binding protein 43 kDa (TDP-43) pathology, and hippocampal sclerosis, and about two-thirds of aged human brains contain substantial non-AD pathology [9,10,11]
These semi-quantitative data are usually provided on standardized four-tiered ordinal scales: absent, mild, moderate, and severe. Such semi-quantitative data are very useful for providing the neuropathological diagnosis, they often inaccurately reflect the actual amount of pathology present and this has major implications when data from large clinico-pathological correlative studies are entered into databases, since cases that might differ quite considerably regarding the amount of pathology fall into the same category
Summary
The aging brain is characterized by the simultaneous presence of multiple pathologies, and the prevalence of cerebral multi-morbidity increases with age. Quantitative neuropathological assessment Clinico-pathological correlative studies are frequently based on semi-quantitative data and ordinal-type parameters to define the amount of pathology present in a given postmortem brain These semi-quantitative data are usually provided on standardized four-tiered ordinal scales: absent, mild, moderate, and severe (for example, for tau [20] and α-synuclein [21]). In quantitatively assessing entorhinal and hippocampal tau pathology in a large cohort (n = 889) of both clinically and neuropathologically diagnosed AD cases, Murray and colleagues [22] identified typical AD as well as hippocampal sparing and limbic predominant subtypes of AD When comparing their quantitative neuropathological data with clinical findings, the authors found that these subtypes of AD differed in clinical presentation, age at onset, disease duration, and rate of cognitive decline from typical AD [22]. The density of neuritic plaques and NFTs rose significantly as a function of severity of dementia in subjects who were 60 to 80 years old, but no such association was found when subjects were over 90 years old [28], suggesting that additional factors contribute to the development of dementia in the oldest old
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