Molecular Pathological Classification of Neurodegenerative Diseases: Turning towards Precision Medicine

Abstract

Neurodegenerative diseases (NDDs) are characterized by selective dysfunction and loss of neurons associated with pathologically altered proteins that deposit in the human brain but also in peripheral organs. These proteins and their biochemical modifications can be potentially targeted for therapy or used as biomarkers. Despite a plethora of modifications demonstrated for different neurodegeneration-related proteins, such as amyloid-β, prion protein, tau, α-synuclein, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma protein (FUS), molecular classification of NDDs relies on detailed morphological evaluation of protein deposits, their distribution in the brain, and their correlation to clinical symptoms together with specific genetic alterations. A further facet of the neuropathology-based classification is the fact that many protein deposits show a hierarchical involvement of brain regions. This has been shown for Alzheimer and Parkinson disease and some forms of tauopathies and TDP-43 proteinopathies. The present paper aims to summarize current molecular classification of NDDs, focusing on the most relevant biochemical and morphological aspects. Since the combination of proteinopathies is frequent, definition of novel clusters of patients with NDDs needs to be considered in the era of precision medicine. Optimally, neuropathological categorizing of NDDs should be translated into in vivo detectable biomarkers to support better prediction of prognosis and stratification of patients for therapy trials.

Keywords: biomarker; classification; molecular pathology; neurodegenerative disease; proteinopathy.

Figure 1

Summary of the concept of vulnerability patterns in neurodegenerative diseases. Coloured boxes represent different vulnerability patterns.

Figure 2

Overview of cellular vulnerability in the most frequent neurodegenerative proteinopathies. N: nucleus. Asterisk (*) for PrP indicates periaxonal or perineuronal. Since the drawing of the full extent of an axon would be out of the image the lines (---) in the axons indicate discontinuation (at the middle segment of the axon) of the drawing. Synapses are indicated by short black and bold lines (-).

Figure 3

Cellular vulnerability patterns in rare hereditary forms of neurodegenerative diseases. N: nucleus. Since the drawing of the full extent of an axon would be out of the image the lines (---) in the axons indicate discontinuation (at the middle segment of the axon) of the drawing. Synapses are indicated by short black and bold lines (-).

Figure 4

Algorithm for the classification of neurodegenerative proteinopathies, Abbreviations: Abri and ADan: amyloidoses related to familial British dementia and familial Danish dementia; ACys: amyloidosis related to Cystatin C amyloid; AD: Alzheimer disease; AGD: Argyrophilic grain disease; AGel: amyloidosis related to Gelsolin amyloid; ATTR: amyloidosis associated with transthyretin amyloid; ALS: amyotrophic lateral sclerosis; BIBD: Basophilic inclusion body disease; CAA: sporadic cerebral amyloid angiopathy; CBD: Corticobasal degeneration; CJD: Creutzfeldt-Jakob disease; DLB: Dementia with Lewy bodies; FFI: fatal familial insomnia; FOLMA: familial oculoleptomeningeal amyloidosis; FTLD: frontotemporal lobar degeneration; aFTLD-U: atypical FTLD with ubiquitinated inclusions; FTLD-UPS: FTLD with inclusions immunoreactive only for the components of the ubiquitine proteasome system; FTDP-17T: Frontotemporal dementia and parkinsonism linked to chromosome 17 caused by mutations in the MAPT (tau) gene; GGT: globular glial tauopathies; GSS: Gerstmann-Sträussler-Scheinker disease; INIBD: intranuclear inclusion body diseases; MND: Motor neuron disease; MSA: multiple system atrophy (C: cerebellar, P: Parkinsonism, aMSA: atypical MSA); NFerr: neuroferritinopathy; NIFID: Neurofilament intermediate filament inclusion disease; NSerp: neuroserpinopathy; PART: primary age-related tauopathy; PD: Parkinson disease; PDD: PD with dementia; PiD: Pick disease; PSP: Progressive supranuclear palsy; TRD: trinucleotide repeat expansion disorder: refers to genetic disorder and associated with different proteins; VPSP: variably proteinase sensitive prionopathy. For CJD, v: indicates variant, s: sporadic, i: iatrogenic, and g: genetic CJD. Kuru is not indicated in this figure. Note that overlap between FTLD-TDP and ALS/MND indicates combined phenotypes (FTLD-ALS/MND). * indicates that PrP-CAA is very rare; for Aβ, CAA is frequent, for other amyloidoses, CAA is more frequent than parenchymal deposits. Note that FTLD-ni is not indicated here, since no proteinopathy is associated with it. ± indicates with or without. Green and blue coloured box indicates intra-, or extracellular proteins; gray box indicates clinical and/or pathological subtypes; arrows point to subtyping based on pathological aspects.