Abstract
BackgroundPreviously, we collected age-stratified incidence data of 404 epidemiological datasets of 10 neurodegenerative diseases (NDs), namely Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Fronto Temporal Dementia (FTD), Dementia with Lewy Bodies (DLB), Parkinsonism (PDM), Parkinson’s disease with Dementia (PDD), Creutzfeldt–Jakob disease (CJD), and Multiple Sclerosis (MS). We tested whether each ND follows a multistep model, found the number of steps necessary for the onset of each ND, found the number of common steps with other NDs and the number of specific steps of each ND, and built a parsimony tree of the genealogy of the NDs. The tree disclosed three groups of NDs: the stem NDs with less than 3 steps; the trunk NDs with 5–7 steps; and the crown NDs with more than 7 steps.MethodsWe made a multidimensional reduction of the previously collected age-stratified incidence epidemiological data of the 10 NDs. We studied the general range of incidence of the 10 NDs using the age- and sex-stratified incidence data. First, we calculated the log of the incidence versus the log of the age for each ND. Next, we calculated the age intervals of the spread of the incidence of each ND. We calculated the regression of the steps obtained with the multistep model versus the age of incidence of the NDs.ResultsWe found that the number of steps of the NDs is inversely correlated with the age of incidence of the NDs, and calculated the number of years required for a single step for each ND. Based on these results, we extended the genealogy tree model of the NDs to account for the time needed for a ND step to occur.ConclusionThe extended genealogy tree disclosed three groups of NDs according to the estimated time needed for a step to occur: the stem ND, HD, with 32.5 years/step, the trunk NDs ALS, FTD, PD and CJD, with 6.7–13.7 years/step; and the crown NDs PDM, PDD, AD and DLB, with 2.3–3.8 years/step. Thus, the NDs cluster into three groups according to both the number of steps and the number of years for a step to occur.
Highlights
Neurodegenerative diseases (NDs) are characterized with progressive loss of cognitive and/or motor function
We view the general multistep model of the neurode‐ generative diseases (NDs) in context of the number of years required for a single step for each ND to occur, and present a new revised genealogy tree of the NDs based on incidence-age epidemiological data taking into account these years per step
Epidemiological data Previously we collected 404 datasets on age-stratified incidence of the major NDs: Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), Fronto Temporal Dementia (FTD), as well as Dementia with Lewy Bodies (DLB), PDM, Parkinson’s disease with Dementia (PDD) and Creutzfeldt–Jakob disease (CJD), and under the assumption that they share pathogenic mechanisms, we studied whether such mechanisms have left a fingerprint on the dynamics of their incidence patterns with age and whether such fingerprints can provide insights about the ND triggering mechanisms
Summary
Neurodegenerative diseases (NDs) are characterized with progressive loss of cognitive and/or motor function. Intricate genotype–phenotype relationships and common cellular pathways emerged from recent genetic and mechanistic studies [1, 2]. Accumulation of misfolded proteins is shared among NDs [3,4,5]. Both malignant transformation and neurodegeneration are complex and lengthy multistep processes characterized by abnormal expression, post-translational modification, and processing of certain proteins. To maintain and allow the accumulation of these dysregulated processes, and to facilitate the step-wise evolution of the disease phenotype, cells co-opt a compensatory regulatory mechanism, with this role attributed to Hsp in cancer and proposed to have a similar role in neurodegeneration [6]. The tree disclosed three groups of NDs: the stem NDs with less than 3 steps; the trunk NDs with 5–7 steps; and the crown NDs with more than 7 steps
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