Pathology's new role: defining disease process and protective responses.

摘要: Since inception, pathology has served as the indispensable link between basic science and clinical disease, encompassing defining of disease processes mechanisms through observation structural alterations, well hypothesis-driven experimentation. The careful study delivered an understanding sufficient to guide effective treatment, recognize ineffective so consequential man's enhanced life expectancy in past century. This paradigm been particularly successful providing insights for treatment acute diseases; however, setting chronic where relationship (typically end-stage) pathophysiology is often misinterpreted, progress towards therapy slow, at best [1]. Here we consider slow made effectively healing Alzheimer (AD) by some most talented scientists our time. At root issue role pathologist, who may, diseases such AD, assign too literal a meaning pathology. pathologists' fascination with lesions, particular, lesions that can be visualized – case senile plaque neurofibrillary tangle proven powerful distracting priori bias his assessment [1, 2]. Why this distinction important? medicine-pathology partnership headway (e.g., coronary artery thrombosis myocardial infarction), body responds quickly directly process if not addressed rapidly leads major morbidity mortality. changes are linked disequilibrium. In contrast, pathological AD develop over years, it remains open question whether mark movement toward health, i.e. adaptive response process, or death. Yet, studies addressing pathogenesis dominated latter construct, something more akin infection than age-related neurodegeneration, suggesting removal microscopic lesion (infectious agent analogy) will restore health [3, 4]. Such concrete thinking, believe, represents fundamental misconception one propagated decades perseverate on latest technologies rather clinico-pathological entities themselves. As such, re-organization thought surrounding paramount, open-minded view pathologists themselves, necessary fulfill ultimate goal useful information would efforts. Last year marked centennial discovery dementia characterized two [5]. Throughout time, up present, technology day continues attempt understand (Table 1). With each successive wave technology, precision increased, but target their surrogates remained essentially unchanged those 100 years. Table 1 Technological advance scientific AD Even hope unbiased analysis molecular genetics disclosed genes have all related focus surprising, since avenues therapeutics centuries. Unfortunately, focusing narrow prism “lesion = disease,” lead significant therapeutic advances [6]. Indeed, direct test hypothesis, vaccine therapy, led reversal cost increased mortality no cognitive benefits [4]. contradicted prediction based experimental models, amyloid-β (Aβ) tau accumulation from genetically engineered animals treats impairment neuronal However, distinct these models conditions produced using gene disturb normal metabolism; therefore, might surprising use agents remove/reverse abnormal brings system normal. sense much like infections, genetic linkage mechanism direct. Simple removal/reversal pathogen reverses disease. AD fails definition “pathology” mechanism. Considering primary may highly analogous same inflammation infection. Aspirin steroids modulate inflammation, reverse which requires eradication infectious agent. many other diseases, live decades. Even important, found similar extent aged [7]. Rather viewing traditional mechanism, they should instead viewed responses maintaining brain function face earlier changes, e.g., oxidative stress, cell cycle reentry, mitochondrial abnormalities [8–11]. light, could exacerbate progression protecting primary, yet unknown cellular transgenic mice, Aβ exogenous intervention physiological response, and, does model host required any considered relevant. Genetic used support [12]. Numerous mutations protein precursor (AβPP) presenilin metabolism leading Aβ1-42. Not emphasized absolute levels decrease [13, 14]. Further, critical unidentified cause alteration responsible alter responses. Instead arguing entering post-pathology era, complexity broader products on-going develop. Without understanding, pathologist continue search alternations reflexively them maladaptive, without fully considering body's potential On hand, thoughtful maintains priorities unique position interface contribute both strengths limitations basis disease.