Can neurodegenerative disease be defined by four ‘primary determinants’: anatomy, cells, molecules, and morphology?

Armstrong, Richard A.

doi:10.5114/fn.2016.60438

Cited by 5 publications

(8 citation statements)

References 150 publications

(229 reference statements)

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“…Several types of multivariate methods have been described [63] but their relative merits and limitations have yet to be studied with reference to neurodegenerative disease. Whichever methods ultimately emerge as the most useful, a major problem is the current lack of quantitative data of sufficient scope, quality, and consistency across categories of variables and disorders to define the individual cases appropriately [9].…”

Section: Discussionmentioning

confidence: 99%

“…First, it may provide a more realistic description of neurodegenerative disease as a whole by emphasising its continuous nature and by incorporating disease heterogeneity and overlap to their true extent. In addition, it would not be necessary to assign new cases to a classification but instead they would be located within an existing continuum of cases [9]. Second, it would emphasise that common pathological mechanisms may be involved within larger groups of cases thus increasing the chance that a single 'unifying' theory could be proposed which could account for all phenotypic variants of disease [41].…”

Section: Discussionmentioning

confidence: 99%

“…An important consideration, however, is the descriptive variables used to define each case and how they should be measured. Recently, a system based on multiple neuropathological features was described that could be used to provide such a framework, viz., the anatomical pathways affected by the disease ('anatomy'), the cell populations affected ('cells'), the molecular pathology of 'signature' pathological lesions ('molecules'), and the morphological types of neurodegeneration ('morphology'), each of which can be subdivided into several further variables as required [9]. Two examples of the application of PCA are illustrated: (1) a comparison of β-amyloid (Aβ) deposition in control patients, AD and DLB [8] and 2to examine the occurrence of multiple pathologies in FTLD [17].…”

Section: Systems Based On Multivariate Geometrymentioning

confidence: 99%

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The quantitative analysis of neurodegenerative disease: classification, noda, constellations, and multivariate geometry

Armstrong¹

2018

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A variety of methods are available for the quantitative description and analysis of neurodegenerative disease. If neurodegenerative disease exists as a series of distinct disorders, then classificatory methods such as hierarchical cluster analysis (HCA) and decision tree analysis (DTA) can be used to classify cases into groups more objectively. If neurodegenerative disease consists of overlapping phenotypes, then the Braun-Blanquet 'nodal' system and 'constellation diagrams' implicitly recognise intermediate cases and reveal their relationships to the main groupings. By contrast, if cases are more continuously distributed without easily distinguishable disease entities, then methods based on spatial geometry, such as a triangular system or principal components analysis (PCA), may be more appropriate as they display cases spatially according to their similarities and differences. This review compares the different methods and concludes that as a result of the heterogeneity and overlap commonly present plus the multiplicity of possible descriptive variables, methods such as PCA are likely to be particularly useful in the quantitative analysis of neurodegenerative disease. A more general application of such methods, however, has implications for studies of disease risk factors and pathogenesis and in clinical trials.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Systems Based On Multivariate Geometrymentioning

confidence: 99%

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The quantitative analysis of neurodegenerative disease: classification, noda, constellations, and multivariate geometry

Armstrong¹

2018

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“…33 Hence, the selective disruption of anatomical pathways observed in different neurodegenerative disorders could result from the differential effects of ageing. 34 Relative use or disuse during a lifetime could determine this selective disruption. Therefore, in individuals that suffer early blindness, there is significant reduction in white matter volume in the optic tracts, and radiation and significant loss of grey matter in the visual cortex.…”

Section: Ageing May Differentially Affect Anatomical Pathwaysmentioning

confidence: 99%

A Possible Explanation For Neurodegenerative Disease

Armstrong

2019

EMJ Neurol

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This review proposes an explanation for the pathogenesis of those neurodegenerative diseases which result in dementia and the resulting diversity of their disease phenotypes. The explanation is based on five principal observations, specifically: 1) neurodegenerative disease may be the direct consequence of neural ageing; 2) ageing may cause differential degeneration of neuroanatomical pathways; 3) breakdown of anatomical pathways may result in the formation of ‘reactive’ proteins; 4) these proteins may exhibit ‘prion-like’ behaviour and spread along anatomical pathways; and 5) neurodegenerative disease may be characterised by heterogeneity, overlapping phenotypes, and multiple pathology. The explanation proposes that genetic and environmental risk factors act cumulatively over a lifetime to increase an individual’s ‘allostatic load’, which determines the overall rate of neural ageing. This process results in the differential breakdown of neuro-anatomical pathways, influenced by their relative use or disuse during life, the consequence being the formation of one or more reactive proteins. Many of these proteins may spread through the brain from initial sites of ageing along neuro-anatomical pathways to affect specific neural networks. Variation in the proteins formed and in pathways of their spread result in the observed clinical and pathological diversity of disease phenotypes. Hence, minimising the factors that contribute to the allostatic load, together with cognitive and physical exercise to counter disuse of specific anatomical pathways over a lifetime, may be necessary to reduce the incidence of neurodegenerative disease.

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“…The present study investigates the four key features mentioned below, proposed by Armstrong [4] as the 'primary determinants' of a neurodegenerative disease, to provide a descriptive framework of NVSD. These features are the anatomical pathways affected by the disease, the target cell populations, the molecular pathology and the morphological degeneration, which are used to reveal the similarities and differences between NVSD and WARBM.…”

Section: Introductionmentioning

confidence: 99%

Neuronal vacuolation and spinocerebellar degeneration associated with altered neurotransmission

Giannakopoulou¹

2017

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Inherited neurodegenerative disorders are debilitating diseases that occur across different species, such as the domestic dog (Canis lupus familiaris), and many are caused by mutations in the same genes as corresponding human conditions. In the present study, we report an inherited neurodegenerative condition, termed 'neuronal vacuolation and spinocerebellar degeneration' (NVSD) which affects neonatal or young dogs, mainly Rottweilers, which recently has been linked with the homozygosity for the RAB3GAP1:c.743delC allele. Mutations in human RAB3GAP1 cause Warburg micro syndrome (WARBM), a severe developmental disorder characterized predominantly by abnormalities of the nervous system including axonal peripheral neuropathy. RAB3GAP1 encodes the catalytic subunit of a GTPase activator protein and guanine exchange factor for Rab3 and Rab18 proteins, respectively. Rab proteins are involved in membrane trafficking in the endoplasmic reticulum, autophagy, axonal transport and synaptic transmission. The present study attempts to carry out a detailed histopathological examination of NVSD disease, extending from peripheral nerves to lower brain structures focusing on the neurotransmitter alterations noted in the cerebellum, the major structure affected. NVSD dogs presented with progressive cerebellar ataxia and some clinical manifestations that recapitulate the WARBM phenotype. Neuropathological examination revealed dystrophic axons, neurodegeneration and intracellular vacuolization in specific nuclei. In the cerebellum, severe vacuolation of cerebellar nuclei neurons, atrophy of Purkinje cells, and diminishing of GABAergic and glutamatergic fibres constitute the most striking lesions. The balance of evidence suggests that the neuropathological lesions are a reaction to the altered neurotransmission. The canine phenotype could serve as a model to delineate the disease-causing pathological mechanisms in RAB3GAP1 mutation. .

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Can neurodegenerative disease be defined by four ‘primary determinants’: anatomy, cells, molecules, and morphology?

Cited by 5 publications

References 150 publications

The quantitative analysis of neurodegenerative disease: classification, noda, constellations, and multivariate geometry

The quantitative analysis of neurodegenerative disease: classification, noda, constellations, and multivariate geometry

A Possible Explanation For Neurodegenerative Disease

Neuronal vacuolation and spinocerebellar degeneration associated with altered neurotransmission

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