Etiologic Framework for the Study of Neurodegenerative Disorders as Well as Vascular and Metabolic Comorbidities on the Grounds of Shared Epidemiologic and Biologic Features

Abstract

Background: During the last two decades, protein aggregation at all organismal levels, from viruses to humans, has emerged from a neglected area of protein science to become a central issue in biology and biomedicine. This article constitutes a risk-based review aimed at supporting an etiologic scenario of selected, sporadic, protein-associated, i.e., conformational, neurodegenerative disorders (NDDs), and their vascular- and metabolic-associated ailments.

Methods: A rationale is adopted, to incorporate selected clinical data and results from animal-model research, complementing epidemiologic evidences reported in two prior articles.

Findings: Theory is formulated assuming an underlying conformational transmission mechanism, mediated either by horizontal transfer of mammalian genes coding for specific aggregation-prone proteins, or by xeno-templating between bacterial and host proteins. We build a few population-based and experimentally-testable hypotheses focusing on: (1) non-disposable surgical instruments for sporadic Creutzfeldt-Jakob disease (sCJD) and other rapid progressive neurodegenerative dementia (sRPNDd), multiple system atrophy (MSA), and motor neuron disease (MND); and (2) specific bacterial infections such as B. pertussis and E. coli for all forms, but particularly for late-life sporadic conformational, NDDs, type 2 diabetes mellitus (T2DM), and atherosclerosis where natural protein fibrils present in such organisms as a result of adaptation to the human host induce prion-like mechanisms.

Conclusion: Implications for cohort alignment and experimental animal research are discussed and research lines proposed.

Keywords: disease induction vs. transmission in amyloid; epidemiological patterns; etiology of conformational protein deposits; multidisciplinary research overlaps; templating underlying risk/progression.

Figure 1

Normalized age-specific incidence, incidence per million and survival for selected neurodegenerative disorders (NDDs). Modified from de Pedro-Cuesta et al. (2015). Normalized age-specific incidence, age-adjusted incidence, and median clinical disease duration of different sporadic protein-associated neurodegenerative disorders (sCNDDs), obtained either from reported data [amyotrophic lateral sclerosis (ALS), personally modified by Fang F, sporadic Creutzfeldt-Jakob disease (sCJD)] or from registries [sporadic rapid progressive neurodegenerative dementia (sRPNDd) notified as suspected sCJD in Spain for 1995–2011, obtained from the Spanish CJD surveillance registry] and obtained from authors for multiple system atrophy (MSA). References for Figure 1 (Granieri et al., ; Gao et al., ; Baldereschi et al., ; Will et al., ; Benito-León et al., ; Pocchiari et al., ; de Lau et al., ; Fang et al., ; Chen and Lai, ; Steenland et al., ; Owen et al., ; Bjornsdottir et al., 2013). (a) 85–89 years is equivalent to 85 years and older for sCJD, ALS, Lewy body disease (LBD), Parkinson’s disease (PD), and sRPNDd; (b) 90–94 years is equivalent to 90 years and older for age-related macular degeneration (AMD) and frontotemporal dementia (FTD).

Figure 2

Outline of a proposed Public Health Prevention Model I for a single neurodegenerative disorder (Norton et al., 2014), e.g., Alzheimer’s disease (AD). Overlaps indicate risk-factor associations. Arrows indicate assumed direct causality.

Figure 3

Outline of an expanded Public Health Prevention Model I to Model II, assuming an age-at-onset related continuum for various late-age NDDs, and that the unfolded protein response explains—at least in part—the reported associations for diverse conformational neurodegenerative, vascular degenerative and metabolic disorders (type 2 diabetes mellitus, T2DM). Modified from de Pedro-Cuesta et al. (2016).

Figure 4

Outline of an expanded Public Health Prevention Model II to Model III for various conformational neurodegenerative, vascular degenerative disorders and metabolic disorders (type 2 diabetes mellitus), assuming unfolded protein response acts as a consequence of at least two environmental causal mechanisms/agents, namely, infection/inflammation by human-adapted microbiome (examples for Bordetella pertussis (BP) and Escherichia coli) and invasive medical procedures.