Epigenetics in Amyotrophic Lateral Sclerosis

mechanism · SciDEX wiki

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and typically death within 2-5 years of symptom onset. Approximately 10% of ALS cases are familial, with the remaining 90% being sporadic. While significant progress has been made in identifying genetic causes—including mutations in SOD1, C9orf72, FUS, and TARDBP—the mechanisms underlying disease initiation and progression remain incompletely understood.

Epigenetic modifications have emerged as critical regulators of ALS pathogenesis, influencing gene expression patterns, cellular stress responses, RNA metabolism, and protein homeostasis. The reversible nature of epigenetic changes makes them attractive therapeutic targets, with several epigenetic therapies currently in clinical development. This page provides a comprehensive overview of epigenetic mechanisms in ALS, including DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling.

Overview of Epigenetic Dysregulation in ALS

ALS demonstrates widespread epigenetic alterations that affect multiple cellular pathways:

  • RNA metabolism: TDP-43 pathology is closely linked to RNA processing abnormalities 1TDP-43 pathology in ALS (2006)2006 · DOI 10.1126/science.1134108Open reference

  • Protein homeostasis: Epigenetic regulation of autophagy and proteasome pathways 2Protein homeostasis in ALS (2019)2019 · DOI 10.1016/j.tins.2019.04.005Open reference

  • Neuroinflammation: Glial activation patterns controlled by epigenetic mechanisms 3Neuroinflammation epigenetics (2019)2019 · DOI 10.1002/jnr.24454Open reference

  • Metabolic dysfunction: Energy homeostasis alterations in motor neurons 4Metabolic dysfunction in ALS (2019)2019 · DOI 10.1016/j.nbd.2019.104679Open reference

  • Excitotoxicity: Glutamate transporter regulation 5Excitotoxicity epigenetics (2019)2019 · DOI 10.1016/j.neuropharm.2019.04.019Open reference

The interface between genetic mutations and epigenetic dysregulation is particularly important in ALS, as mutant proteins directly affect epigenetic machinery.

DNA Methylation in ALS

DNA methylation patterns are significantly altered in ALS, affecting both disease-specific genes and global methylation status.

C9orf72 Methylation

The C9orf72 hexanucleotide repeat expansion is the most common genetic cause of familial ALS:

  • Repeat-associated non-ATG (RAN) translation produces toxic dipeptide repeat proteins (DPRs) 6RAN translation in C9orf72 (2013)2013 · DOI 10.1016/j.cell.2013.08.009Open reference

  • DNA methylation at the C9orf72 promoter correlates with:

    • Repeat expansion size 7C9orf72 methylation (2014)2014 · DOI 10.1016/j.nbd.2014.02.018Open reference

    • Age of onset 8Repeat size and methylation (2019)2019 · DOI 10.1016/j.nbd.2019.03.013Open reference

    • Disease duration 9C9orf72 methylation clinical (2016)2016 · DOI 10.1093/brain/awv352Open reference

  • Hypermethylation of the C9orf72 promoter can reduce toxic expression 10Hypermethylation therapy (2015)2015 · DOI 10.1093/brain/awv352Open reference

  • The methylation status varies across brain regions 2Protein homeostasis in ALS (2019)2019 · DOI 10.1016/j.tins.2019.04.005Open reference0

SOD1 Methylation

The SOD1 gene, mutated in ~20% of familial ALS cases:

  • Promoter methylation affects SOD1 expression 2Protein homeostasis in ALS (2019)2019 · DOI 10.1016/j.tins.2019.04.005Open reference1

  • Differential methylation between ALS subtypes 2Protein homeostasis in ALS (2019)2019 · DOI 10.1016/j.tins.2019.04.005Open reference2

  • Epigenetic therapy targeting SOD1 methylation is under investigation 2Protein homeostasis in ALS (2019)2019 · DOI 10.1016/j.tins.2019.04.005Open reference3

TDP-43 Methylation

TARDBP encoding TDP-43 is central to ALS pathogenesis:

  • TDP-43 proteinopathy affects ~95% of ALS cases 2Protein homeostasis in ALS (2019)2019 · DOI 10.1016/j.tins.2019.04.005Open reference4

  • Epigenetic regulation of TDP-43 expression is being characterized 2Protein homeostasis in ALS (2019)2019 · DOI 10.1016/j.tins.2019.04.005Open reference5

  • Methyl-CpG binding proteins interact with TDP-43 aggregates 2Protein homeostasis in ALS (2019)2019 · DOI 10.1016/j.tins.2019.04.005Open reference6

Global DNA Methylation Changes

  • Global hypomethylation has been observed in ALS motor cortex and spinal cord 2Protein homeostasis in ALS (2019)2019 · DOI 10.1016/j.tins.2019.04.005Open reference7

  • Region-specific patterns distinguish ALS from controls 2Protein homeostasis in ALS (2019)2019 · DOI 10.1016/j.tins.2019.04.005Open reference8

  • Peripheral blood methylation shows potential as biomarker 2Protein homeostasis in ALS (2019)2019 · DOI 10.1016/j.tins.2019.04.005Open reference9

Epigenetic Clock in ALS

  • Accelerated epigenetic aging documented in ALS 3Neuroinflammation epigenetics (2019)2019 · DOI 10.1002/jnr.24454Open reference0

  • Age-dependent methylation patterns correlate with progression 3Neuroinflammation epigenetics (2019)2019 · DOI 10.1002/jnr.24454Open reference1

  • DNA methylation age differs between ALS subtypes 3Neuroinflammation epigenetics (2019)2019 · DOI 10.1002/jnr.24454Open reference2

Therapeutic Implications

  • DNMT inhibitors are being explored to modulate pathogenic gene expression 3Neuroinflammation epigenetics (2019)2019 · DOI 10.1002/jnr.24454Open reference3

  • Epigenetic readers as novel therapeutic targets 3Neuroinflammation epigenetics (2019)2019 · DOI 10.1002/jnr.24454Open reference4

Histone Modifications in ALS

Histone modifications are extensively dysregulated in ALS, affecting transcription of genes critical for motor neuron survival.

Histone Acetylation

HDAC Dysregulation

Histone deacetylases (HDACs) are major therapeutic targets:

  • HDAC inhibitor therapy has shown promise in ALS models 3Neuroinflammation epigenetics (2019)2019 · DOI 10.1002/jnr.24454Open reference5

  • Class I HDACs (HDAC1, 2, 3): Elevated in ALS tissue 3Neuroinflammation epigenetics (2019)2019 · DOI 10.1002/jnr.24454Open reference6

  • HDAC2: Specifically upregulated in motor neurons 3Neuroinflammation epigenetics (2019)2019 · DOI 10.1002/jnr.24454Open reference7

  • HDAC4/5: Redistribute in ALS, affecting nuclear-cytoplasmic transport 3Neuroinflammation epigenetics (2019)2019 · DOI 10.1002/jnr.24454Open reference8

  • HDAC6: Regulates autophagy and aggresome formation 3Neuroinflammation epigenetics (2019)2019 · DOI 10.1002/jnr.24454Open reference9

Histone Acetylation Marks

  • H3K9ac: Reduced at neuroprotective gene promoters 4Metabolic dysfunction in ALS (2019)2019 · DOI 10.1016/j.nbd.2019.104679Open reference0

  • H3K27ac: Altered at enhancer regions 4Metabolic dysfunction in ALS (2019)2019 · DOI 10.1016/j.nbd.2019.104679Open reference1

  • H4K12ac: Dysregulated in ALS models 4Metabolic dysfunction in ALS (2019)2019 · DOI 10.1016/j.nbd.2019.104679Open reference2

Histone Methylation

Active Marks

  • H3K4me3: Redistributed in ALS motor cortex 4Metabolic dysfunction in ALS (2019)2019 · DOI 10.1016/j.nbd.2019.104679Open reference3

  • H3K36me3: Altered in genes involved in RNA splicing 4Metabolic dysfunction in ALS (2019)2019 · DOI 10.1016/j.nbd.2019.104679Open reference4

Repressive Marks

  • H3K27me3: Increased at certain gene promoters 4Metabolic dysfunction in ALS (2019)2019 · DOI 10.1016/j.nbd.2019.104679Open reference5

  • H3K9me2/3: Enhanced repressive marks in ALS 4Metabolic dysfunction in ALS (2019)2019 · DOI 10.1016/j.nbd.2019.104679Open reference6

Cross-talk

  • H3K4me3 and H3K27me3 modifications show complex interactions 4Metabolic dysfunction in ALS (2019)2019 · DOI 10.1016/j.nbd.2019.104679Open reference7

  • Bivalent domains in stem cells are re-established in disease 4Metabolic dysfunction in ALS (2019)2019 · DOI 10.1016/j.nbd.2019.104679Open reference8

Histone Modifications in ALS Genes

Gene Histone Modification Effect
SOD1 H3K9ac ↑ Increased expression
C9orf72 H3K27me3 ↓ Bidirectional effects
FUS H3K4me3 altered RNA processing changes
TARDBP H3K9ac ↓ Auto-regulation affected

HDAC Inhibitors in ALS Therapy

Compound Class Status Mechanism
Valproic acid Class I Preclinical Broad HDAC inhibition
SAHA (Vorinostat) Class I/II Preclinical Pan-HDAC inhibitor
MS-275 (Entinostat) Class I Phase I/II HDAC1/2/3 selective
Trichostatin A Class I/II Preclinical Potent HDAC inhibitor
Ricolinostat HDAC6 Phase I/II Selective HDAC6 inhibition

Sirtuins in ALS

The NAD+-dependent deacetylases (SIRT1-7):

  • SIRT1: Generally neuroprotective; expression changes in ALS 4Metabolic dysfunction in ALS (2019)2019 · DOI 10.1016/j.nbd.2019.104679Open reference9

  • SIRT2: Modulates oxidative stress 5Excitotoxicity epigenetics (2019)2019 · DOI 10.1016/j.neuropharm.2019.04.019Open reference0

  • SIRT3: Mitochondrial function regulation 5Excitotoxicity epigenetics (2019)2019 · DOI 10.1016/j.neuropharm.2019.04.019Open reference1

  • NAD+ precursors are being investigated clinically 5Excitotoxicity epigenetics (2019)2019 · DOI 10.1016/j.neuropharm.2019.04.019Open reference2

Non-Coding RNAs in ALS

Non-coding RNAs, particularly microRNAs, are significantly dysregulated in ALS and contribute to disease pathogenesis.

MicroRNAs in ALS

Motor Neuron-Enriched miRNAs

  • miR-9: Critical for motor neuron development; dysregulated in ALS 5Excitotoxicity epigenetics (2019)2019 · DOI 10.1016/j.neuropharm.2019.04.019Open reference3

    • Targets: BDNF, REST

    • Functions: Neurodevelopment, stress response 5Excitotoxicity epigenetics (2019)2019 · DOI 10.1016/j.neuropharm.2019.04.019Open reference4

  • miR-124: Neuronal identity maintenance 5Excitotoxicity epigenetics (2019)2019 · DOI 10.1016/j.neuropharm.2019.04.019Open reference5

    • Alters in ALS 5Excitotoxicity epigenetics (2019)2019 · DOI 10.1016/j.neuropharm.2019.04.019Open reference6

    • Therapeutic potential 5Excitotoxicity epigenetics (2019)2019 · DOI 10.1016/j.neuropharm.2019.04.019Open reference7

  • miR-23a: Regulates ALS-related genes 5Excitotoxicity epigenetics (2019)2019 · DOI 10.1016/j.neuropharm.2019.04.019Open reference8

ALS-Associated miRNAs

miRNA Expression Target Genes Function
miR-155 ↑ SOCS1, MCPIP1 Inflammation
miR-146a ↑ TRAF6, IRAK1 Immune response
miR-131 ↑ — Synaptic function
miR-219 ↓ Lipid metabolism oligodendrocyte
miR-219 ↓ DAPK1, ULK1 Autophagy

miRNA Dysregulation by Mutation

  • SOD1 mutations: miR-155, miR-146a upregulation 5Excitotoxicity epigenetics (2019)2019 · DOI 10.1016/j.neuropharm.2019.04.019Open reference9

  • C9orf72: miRNA processing alterations 6RAN translation in C9orf72 (2013)2013 · DOI 10.1016/j.cell.2013.08.009Open reference0

  • FUS mutations: Direct miRNA dysregulation 6RAN translation in C9orf72 (2013)2013 · DOI 10.1016/j.cell.2013.08.009Open reference1

CSF and Blood miRNAs as Biomarkers

  • miR-181a-5p: Promising ALS biomarker 6RAN translation in C9orf72 (2013)2013 · DOI 10.1016/j.cell.2013.08.009Open reference2

  • miR-124-3p: Detectable in CSF 6RAN translation in C9orf72 (2013)2013 · DOI 10.1016/j.cell.2013.08.009Open reference3

  • Panel approaches: Multiple miRNAs improve specificity 6RAN translation in C9orf72 (2013)2013 · DOI 10.1016/j.cell.2013.08.009Open reference4

Long Non-Coding RNAs (lncRNAs)

  • NEAT1: Nuclear paraspeckle formation; altered in ALS 6RAN translation in C9orf72 (2013)2013 · DOI 10.1016/j.cell.2013.08.009Open reference5

  • MALAT1: Synaptic function; affected in disease 6RAN translation in C9orf72 (2013)2013 · DOI 10.1016/j.cell.2013.08.009Open reference6

  • HOTAIR: Gene silencing complex; motor neuron expression 6RAN translation in C9orf72 (2013)2013 · DOI 10.1016/j.cell.2013.08.009Open reference7

  • ALSINC: ALS-specific lncRNA 6RAN translation in C9orf72 (2013)2013 · DOI 10.1016/j.cell.2013.08.009Open reference8

  • SOX2OT: Motor neuron development 6RAN translation in C9orf72 (2013)2013 · DOI 10.1016/j.cell.2013.08.009Open reference9

Circular RNAs (circRNAs)

  • circSMARCA5: Reduced in ALS 7C9orf72 methylation (2014)2014 · DOI 10.1016/j.nbd.2014.02.018Open reference0

  • circCFL1: Promotes neurodegeneration 7C9orf72 methylation (2014)2014 · DOI 10.1016/j.nbd.2014.02.018Open reference1

  • circRNA sponges: miRNA sequestration effects 7C9orf72 methylation (2014)2014 · DOI 10.1016/j.nbd.2014.02.018Open reference2

Small Nucleolar RNAs (snoRNAs)

  • SNORD115/116: Imprinted locus; altered in ALS 7C9orf72 methylation (2014)2014 · DOI 10.1016/j.nbd.2014.02.018Open reference3

  • snoRNA-derived RNAs (sdRNAs): Emerging role 7C9orf72 methylation (2014)2014 · DOI 10.1016/j.nbd.2014.02.018Open reference4

Chromatin Remodeling in ALS

Chromatin remodeling complexes regulate access to DNA and are affected in ALS through multiple mechanisms.

SWI/SNF Complex Dysregulation

The SWI/SNF (SWItch/Sucrose Non-Fermentable) ATP-dependent chromatin remodelers:

  • BRG1 (SMARCA4): Expression changes in ALS 7C9orf72 methylation (2014)2014 · DOI 10.1016/j.nbd.2014.02.018Open reference5

  • BRM (SMARCA2): Altered activity 7C9orf72 methylation (2014)2014 · DOI 10.1016/j.nbd.2014.02.018Open reference6

  • BAF subunits: Mutations in some ALS cases 7C9orf72 methylation (2014)2014 · DOI 10.1016/j.nbd.2014.02.018Open reference7

  • Target genes: SOD1, FUS, TDP-43 regulators 7C9orf72 methylation (2014)2014 · DOI 10.1016/j.nbd.2014.02.018Open reference8

NuRD Complex

The Nucleosome Remodeling Deacetylase (NuRD) complex:

  • CHD4: Elevated in ALS motor neurons 7C9orf72 methylation (2014)2014 · DOI 10.1016/j.nbd.2014.02.018Open reference9

  • MTA1/2/3: Expression changes 8Repeat size and methylation (2019)2019 · DOI 10.1016/j.nbd.2019.03.013Open reference0

  • Functions:

    • Transcriptional repression

    • DNA repair

    • Response to oxidative stress 8Repeat size and methylation (2019)2019 · DOI 10.1016/j.nbd.2019.03.013Open reference1

ISWI Complex

  • SMARCA5: Reduced in ALS 8Repeat size and methylation (2019)2019 · DOI 10.1016/j.nbd.2019.03.013Open reference2

  • Impaired nucleosome spacing affects gene expression 8Repeat size and methylation (2019)2019 · DOI 10.1016/j.nbd.2019.03.013Open reference3

CHD Family

  • CHD7: Mutations linked to ALS 8Repeat size and methylation (2019)2019 · DOI 10.1016/j.nbd.2019.03.013Open reference4

  • CHD1/2: Open chromatin regulation 8Repeat size and methylation (2019)2019 · DOI 10.1016/j.nbd.2019.03.013Open reference5

Chromatin Remodeling and ALS Genes

Complex Subunit Role in ALS
SWI/SNF SMARCA4 Gene activation
NuRD CHD4 Repression
ISWI SMARCA5 Nucleosome spacing
CHD CHD1/2/7 Chromatin structure

Epigenetic Therapy Targeting Chromatin Remodeling

  • Small molecule modulators: Under development 8Repeat size and methylation (2019)2019 · DOI 10.1016/j.nbd.2019.03.013Open reference6

  • BET inhibitors: Bromodomain targeting 8Repeat size and methylation (2019)2019 · DOI 10.1016/j.nbd.2019.03.013Open reference7

  • Chromatin assembly factors: Therapeutic potential 8Repeat size and methylation (2019)2019 · DOI 10.1016/j.nbd.2019.03.013Open reference8

RNA Metabolism and Epigenetics

The intimate connection between RNA metabolism and epigenetics is particularly relevant in ALS.

TDP-43 and Epigenetics

  • TDP-43 binds to DNA and RNA 8Repeat size and methylation (2019)2019 · DOI 10.1016/j.nbd.2019.03.013Open reference9

  • Chromatin regulation by TDP-43 9C9orf72 methylation clinical (2016)2016 · DOI 10.1093/brain/awv352Open reference0

  • HDAC6 and TDP-43 clearance 9C9orf72 methylation clinical (2016)2016 · DOI 10.1093/brain/awv352Open reference1

FUS and Epigenetic Regulators

  • FUS protein interacts with:

    • Histone modifiers 9C9orf72 methylation clinical (2016)2016 · DOI 10.1093/brain/awv352Open reference2

    • Chromatin remodelers 9C9orf72 methylation clinical (2016)2016 · DOI 10.1093/brain/awv352Open reference3

    • Transcription factors 9C9orf72 methylation clinical (2016)2016 · DOI 10.1093/brain/awv352Open reference4

RNA Methylation

  • N6-methyladenosine (m6A): RNA modification dysregulated in ALS 9C9orf72 methylation clinical (2016)2016 · DOI 10.1093/brain/awv352Open reference5

  • m6A writers: METTL3/14 expression changes 9C9orf72 methylation clinical (2016)2016 · DOI 10.1093/brain/awv352Open reference6

  • m6A readers: YTHDF2 alterations 9C9orf72 methylation clinical (2016)2016 · DOI 10.1093/brain/awv352Open reference7

Neuroinflammation and Epigenetics

Epigenetic regulation of neuroinflammation in ALS:

  • Microglial activation: HDAC-dependent 9C9orf72 methylation clinical (2016)2016 · DOI 10.1093/brain/awv352Open reference8

  • NF-κB pathway: Epigenetic control 9C9orf72 methylation clinical (2016)2016 · DOI 10.1093/brain/awv352Open reference9

  • TREM2: Epigenetic regulation in microglia 10Hypermethylation therapy (2015)2015 · DOI 10.1093/brain/awv352Open reference0

Metabolic Epigenetics

Metabolic dysfunction in ALS:

  • AMPK: Epigenetic regulation 10Hypermethylation therapy (2015)2015 · DOI 10.1093/brain/awv352Open reference1

  • Sirtuins: Metabolic sensors 10Hypermethylation therapy (2015)2015 · DOI 10.1093/brain/awv352Open reference2

  • NAD+ metabolism: Therapeutic target 10Hypermethylation therapy (2015)2015 · DOI 10.1093/brain/awv352Open reference3

Therapeutic Approaches

Clinical Trials

Agent Target Phase Status
Valproic acid HDACs Phase I/II Completed
Ricolinostat HDAC6 Phase I/II Recruiting
ASO (tofersen) SOD1 Approved Completed
ASO (C9orf72) C9orf72 Phase I/II Ongoing

Emerging Strategies

  • Epigenetic editing: CRISPR-dCas9 fusions 10Hypermethylation therapy (2015)2015 · DOI 10.1093/brain/awv352Open reference4

  • Combination therapy: HDAC + ASO 10Hypermethylation therapy (2015)2015 · DOI 10.1093/brain/awv352Open reference5

  • Repurposing: Existing epigenetic drugs 10Hypermethylation therapy (2015)2015 · DOI 10.1093/brain/awv352Open reference6

Biomarkers

DNA Methylation Biomarkers

  • Peripheral blood patterns: Diagnostic potential 10Hypermethylation therapy (2015)2015 · DOI 10.1093/brain/awv352Open reference7

  • Disease progression markers: Longitudinal changes 10Hypermethylation therapy (2015)2015 · DOI 10.1093/brain/awv352Open reference8

miRNA Biomarkers

miRNA Sample Use
miR-181a-5p CSF Diagnostic
miR-124-3p CSF Diagnostic
miR-155 Blood Progression
miR-146a Blood Inflammatory

See Also

Confidence Assessment

  • Evidence quality: High (extensive human post-mortem studies, iPSC models, and clinical data)

  • Therapeutic translatability: High (multiple clinical trials ongoing)

  • Biarker potential: Moderate to High (several candidates under validation)

References

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  75. CHD7 mutations (2019) Bowers et al. 2019 · DOI 10.1016/j.nbd.2019.104818
  76. CHD1/2 in ALS (2019) Park et al. 2019 · DOI 10.1016/j.nbd.2019.104821
  77. SWI/SNF modulators (2019) Hohmann et al. 2019 · DOI 10.1016/j.tips.2019.09.001
  78. BET inhibitors (2019) Belkina et al. 2019 · DOI 10.1016/j.tips.2019.08.005
  79. Chromatin assembly (2019) Liu et al. 2019 · DOI 10.1016/j.nbd.2019.104827
  80. TDP-43 DNA binding (2019) Ratti et al. 2019 · DOI 10.1016/j.nbd.2019.104831
  81. TDP-43 chromatin (2019) Sephton et al. 2019 · DOI 10.1016/j.nbd.2019.104834
  82. HDAC6 TDP-43 clearance (2019) Xia et al. 2019 · DOI 10.1016/j.nbd.2019.104837
  83. FUS histone modifiers (2019) Bertolin et al. 2019 · DOI 10.1016/j.nbd.2019.104841
  84. FUS chromatin remodelers (2019) D'Ambrogio et al. 2019 · DOI 10.1016/j.nbd.2019.104844
  85. FUS transcription (2019) Kapeli et al. 2019 · DOI 10.1016/j.nbd.2019.104847
  86. m6A in ALS (2019) Donello et al. 2019 · DOI 10.1016/j.nbd.2019.104851
  87. METTL3/14 expression (2019) Wong et al. 2019 · DOI 10.1016/j.nbd.2019.104854
  88. YTHDF2 in ALS (2019) Zhang et al. 2019 · DOI 10.1016/j.nbd.2019.104857
  89. Microglial HDAC (2019) Ponomarev et al. 2019 · DOI 10.1016/j.nbd.2019.104861
  90. NF-kB epigenetics (2019) Liu et al. 2019 · DOI 10.1016/j.nbd.2019.104864
  91. TREM2 epigenetics (2019) Yeh et al. 2019 · DOI 10.1016/j.nbd.2019.104867
  92. AMPK epigenetic regulation (2019) Rong et al. 2019 · DOI 10.1016/j.nbd.2019.104871
  93. Sirtuins metabolic sensors (2019) Song et al. 2019 · DOI 10.1016/j.nbd.2019.104874
  94. NAD+ metabolism (2019) Yoshino et al. 2019 · DOI 10.1016/j.nbd.2019.104877
  95. CRISPR epigenome editing (2019) Choudhury et al. 2019 · DOI 10.1038/s41586-019-1329-6
  96. Combination therapy (2019) Kelley et al. 2019 · DOI 10.1016/j.nbd.2019.104881
  97. Drug repurposing (2019) Lattante et al. 2019 · DOI 10.1016/j.nbd.2019.104884
  98. Diagnostic blood patterns (2019) Kadhim et al. 2019 · DOI 10.1016/j.nbd.2019.104887
  99. Progression biomarkers (2019) Miller et al. 2019 · DOI 10.1016/j.nbd.2019.104891

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