Comparative Incidence of Conformational, Neurodegenerative Disorders

Abstract

Background: The purpose of this study was to identify incidence and survival patterns in conformational neurodegenerative disorders (CNDDs).

Methods: We identified 2563 reports on the incidence of eight conditions representing sporadic, acquired and genetic, protein-associated, i.e., conformational, NDD groups and age-related macular degeneration (AMD). We selected 245 papers for full-text examination and application of quality criteria. Additionally, data-collection was completed with detailed information from British, Swedish, and Spanish registries on Creutzfeldt-Jakob disease (CJD) forms, amyotrophic lateral sclerosis (ALS), and sporadic rapidly progressing neurodegenerative dementia (sRPNDd). For each condition, age-specific incidence curves, age-adjusted figures, and reported or calculated median survival were plotted and examined.

Findings: Based on 51 valid reported and seven new incidence data sets, nine out of eleven conditions shared specific features. Age-adjusted incidence per million person-years increased from ≤1.5 for sRPNDd, different CJD forms and Huntington's disease (HD), to 1589 and 2589 for AMD and Alzheimer's disease (AD) respectively. Age-specific profiles varied from (a) symmetrical, inverted V-shaped curves for low incidences to (b) those increasing with age for late-life sporadic CNDDs and for sRPNDd, with (c) a suggested, intermediate, non-symmetrical inverted V-shape for fronto-temporal dementia and Parkinson's disease. Frequently, peak age-specific incidences from 20-24 to ≥90 years increased with age at onset and survival. Distinct patterns were seen: for HD, with a low incidence, levelling off at middle age, and long median survival, 20 years; and for sRPNDd which displayed the lowest incidence, increasing with age, and a short median disease duration.

Interpretation: These results call for a unified population view of NDDs, with an age-at-onset-related pattern for acquired and sporadic CNDDs. The pattern linking age at onset to incidence magnitude and survival might be explained by differential pathophysiological mechanisms associated with specific misfolded protein deposits.

Fig 1. Flow chart showing search and selection of reports on incidence studies of eight conformational neurodegenerative disorders (including AMD).

(^a) A report on HD, which did not fulfil the quality criteria, was subsequently included.

Fig 2. Flow chart showing selection of comparable incidence studies of conformational neurodegenerative disorders identified from the records reviewed.

Fig 3. Normalised age-specific incidence, age-adjusted incidence and median clinical disease duration of Huntington's disease and genetic CJD as well as different sCNDDs, obtained either from reported data (ALS personally modified by Fang F) or from registries (the latter for atCJD mainly from treatments with human growth hormone), vCJD in the UK for 1993–2007 provided by RG Will, and registered gCJD in Spain for 1995–2011 obtained from J. de Pedro-Cuesta (not-reported).

Other labelled data were obtained from reports [,–,,,–31]. Survival data sources: vCJD [27]; atCJD [28]; HD [30]; ALS, FTD, PD, AD and LBD [29]; AMD [24]. (a) 80–84 years is equivalent to 80 years and over for HD. (b) 85–89 years is equivalent to 85 years and over for sCJD, ALS, LBD, PD and sRPNDd. (c) 90–94 years is equivalent to 90 years and over for AMD and FTD. (d) 95–99 years is equivalent to 95 years and over for AD. Abbreviations: Creutzfeldt-Jakob disease (CJD); accidentally transmitted CJD (atCJD), genetic CJD (gCJD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), motor neurone disease (MND), fronto-temporal dementia (FTD), Parkinson's disease (PD), Lewy body disease (LBD), age-related macular degeneration (AMD), Alzheimer's disease (AD), sporadic rapid-progressive neurodegenerative dementia (sRPNDd), sporadic conformational neurodegenerative disorders (sCNDDs).

Fig 4. Reported and hypothesised (symmetrically replicated, dotted line) normalised incidence of sCJD, ALS, PD, LBD, AD, sRPNDd and AMD, assuming protracted population survival until 125 years for a substantial proportion of elderly.

(a) 80–84 years is equivalent to 80 years and over for HD. (b) 85–89 years is equivalent to 85 years and over for sCJD, ALS. Abbreviations: Creutzfeldt-Jakob disease (CJD); accidentally transmitted CJD (atCJD), amyotrophic lateral sclerosis (ALS), motor neurone disease (MND), fronto-temporal dementia (FTD), Parkinson's disease (PD), Lewy body disease (LBD), age-related macular degeneration (AMD), Alzheimer's disease (AD), sporadic rapid-progressive neurodegenerative dementia (sRPNDd).