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The presymptomatic phase of amyotrophic lateral sclerosis: are we merely scratching the surface?

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Abstract

Presymptomatic studies in ALS have consistently captured considerable disease burden long before symptom manifestation and contributed important academic insights. With the emergence of genotype-specific therapies, however, there is a pressing need to address practical objectives such as the estimation of age of symptom onset, phenotypic prediction, informing the optimal timing of pharmacological intervention, and identifying a core panel of biomarkers which may detect response to therapy. Existing presymptomatic studies in ALS have adopted striking different study designs, relied on a variety of control groups, used divergent imaging and electrophysiology methods, and focused on different genotypes and demographic groups. We have performed a systematic review of existing presymptomatic studies in ALS to identify common themes, stereotyped shortcomings, and key learning points for future studies. Existing presymptomatic studies in ALS often suffer from sample size limitations, lack of disease controls and rarely follow their cohort until symptom manifestation. As the characterisation of presymptomatic processes in ALS serves a multitude of academic and clinical purposes, the careful review of existing studies offers important lessons for future initiatives.

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Abbreviations

ACE-R:

Addenbrooke's Cognitive Examination-Revised

AD:

Alzheimer’s disease

AD:

Axial diffusivity

ALLFTD:

ARTFL–LEFFTDS Longitudinal Frontotemporal Lobar Degeneration

ALS:

Amyotrophic lateral sclerosis

ALSFRS-R:

Amyotrophic Lateral Sclerosis Functional Rating Scale-revised

ANG:

Angiogenin

APEX1:

Apurinic/apyrimidinic endodeoxyribonuclease 1

APOE4:

Apolipoprotein E4

APP:

Amyloid precursor protein

ASCA:

Amnestic Comparative Self-Assessment

ASO:

Antisense oligonucleotide

AUC:

Area under the receiver operator characteristic curve

AVLT:

Auditory verbal learning test

BADL:

Basic activities of daily living

BDI:

Beck Depression Inventory

BNT:

Boston naming test

bvFTD:

Behavioural variant FTD

CBD:

Corticobasal degeneration

C-CFT:

C-Labeled 2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane

C-CFT:

C-Labeled 2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane

C-PiB:

C-Pittsburgh compound B

C9orf72:

Chromosome 9 open reading frame 72

CAPG:

Macrophage-capping protein

CBF:

Cerebral blood flow

CBI-R:

Cambridge Behavioural Inventory revised

CDR:

Clinical Dementia Rating Scale

CDR-SUM:

Clinical Dementia Rating sum of box score

CHI3L1:

Chitinase 3-like protein 1

CHI3L2:

Chitinase 3-like protein 2

CHIT1:

Chitotriosidase-1

CHMP2B:

Charged multivesicular body protein 2b

CMAP:

Compound muscle action potential

Cr:

Creatine

CRP:

C-reactive protein

CSF:

Cerebrospinal fluid

CST:

Corticospinal tract

CVLT:

California Verbal Learning test

D-KEFS:

Delis–Kaplan Executive Function System

DCTN:

Dynactin subunit 1

DRS:

Dementia rating scale

DTI:

Diffusion tensor imaging

E/I:

Excitation/inhibition

ECAS:

Edinburgh Cognitive and Behavioural ALS Screen

ECLIA:

Electrochemiluminescence immunoassay

ELISA:

Enzyme-linked immunosorbent assays

EMG:

Electromyography

EXAMINER:

Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research

F-FDG:

Fluorodeoxyglucose

FA:

Fractional anisotropy

FAB:

Frontal assessment battery

fALFF:

Fractional amplitude of low frequency fluctuation

FBB:

Florbetaben, a fluorine-18

FBI:

Frontal Behavioural Inventory

FC:

Functional connectivity

fMRI:

Functional magnetic resonance imaging

FTD:

Frontotemporal dementia

FTD-CDR:

FTD-specific Clinical Dementia Rating

FTLD:

Frontotemporal lobar degeneration

FUS:

Fused in sarcoma

FVC:

Forced vital capacity

GENFI:

Genetic Frontotemporal dementia Initiative

GM:

Grey matter

GPNMB:

Glycoprotein non-metastatic B

GRN:

Progranulin

HADS:

Hospital Anxiety and Depression Scale

HD:

Huntington’s disease

HFE:

High FE2 + 

HIST1H2B:

Histone cluster 1, H2b

HIST1H4A:

Histone cluster 1, H4

HTT:

Huntingtin

i-TRAQ:

Isobaric tags for relative and absolute quantitation

IADL:

Instrumental activities of daily living

LDST:

Letter Digit Substitution Test

LEFFTDS:

Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects

LMN:

Lower motor neuron

LRRK2:

Leucine Rich Repeat Kinase 2

MAP2:

Microtubule-associated protein 2

MAPT:

Microtubule-associated protein tau

MD:

Mean diffusivity

MDRS:

Mattis Dementia rating scale

MEG:

Magnetoencephalography

MEP:

Motor evoked potential

MMSE:

Mini Mental State Examination

MOCA:

Montreal Cognitive Assessment

MRC:

Medical Research Council rating scale

MRI:

Magnetic resonance imaging

MRM:

Multiple reaction monitoring

MRS:

Magnetic resonance spectroscopy

mtDNA:

Mitochondrial DNA

MUNE:

Motor Unit Number Estimation

MUNIX:

Motor Unit Number Index

MVIC:

Maximal voluntary isometric contraction

Myo:

Myo-inosito

NAA:

N-Acetylaspartate

NEFH:

Neurofilament heavy

NEFL:

Neurofilament light

NEFM:

Neurofilament medium;

NfL:

Neurofilament light

NODDI:

Neurite orientation dispersion and density imaging

NPI-Q:

Neuropsychiatric Inventory Questionnaire

NPTXR:

Neuronal pentraxin receptor

OPTN:

Optineurin

PD:

Parkinson’s disease

PET:

Positron emission tomography

PINK1:

PTEN-induced kinase 1

PLS:

Primary lateral sclerosis

pNfH:

Phosphorylated neurofilament heavy chain

PON:

Paraoxonase

Pre-Fals:

Pre-familial amyotrophic lateral sclerosis

PREV‐DEMALS:

Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis Study Group

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

PRPH:

Peripherin

PSEN1:

Presenilin 1

PSEN2:

Presenilin 2

RAVLT:

Rey Auditory Verbal Learning Test

RBMT:

Rivermead Behavioural Memory test

rCMA:

Rostral cingulate motor area

RD:

Radial diffusivity

ReHo:

Regional Homogeneity

rs-fMRI:

Resting state Fmri

RWT:

Phonematic Regensburger Wortflüssigkeits-test

SAT:

Semantic Association Test

SDMT:

Symbol digit modalities test

SEA:

Social Cognition and Emotional Assessment

SETX:

Senataxin

SICI:

Short interval intracortical inhibition

SIGMAR1:

Sigma non-opioid intracellular receptor 1

SMA:

Spinal muscular atrophy

SMN:

Survival motor neuron

SNCA:

Synuclein alpha

SOD1:

Superoxide dismutase 1

SOP:

Standard operating procedure

SPG:

Spatacsin

TARDBP:

TAR DNA-binding protein, 43

TBM:

Tensor-based morphometry

TMS:

Transcranial magnetic stimulation

TMT:

Trail making test

UBQLN2:

Ubiquilin-2

UCHL1:

Ubiquitin carboxyl-terminal hydrolase 1

UDSNB:

Neuropsychological battery of the Uniform Data Set

UMN:

Upper motor neuron

UPDRS:

Unified Parkinson's Disease Rating Scale

VAPB:

Vesicle-associated membrane protein-associated protein B/C

VAT:

Visual Association Test

VBM:

Voxel-based morphometry

VCP:

Valosin containing protein

VOSP:

The visual object and space perception battery

WAIS:

Wechsler Adult Intelligence Scale

WCST:

Wisconsin Card Sorting Test

WM:

White matter

WRAT:

Wide Range Achievement Test

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Acknowledgements

Peter Bede and the computational neuroimaging group (CNG) are supported by the Spastic Paraplegia Foundation, Inc. (SPF), Health Research Board (HRB EIA-2017-019), the EU Joint ProgrammeNeurodegenerative Disease Research (JPND), the Andrew Lydon scholarship, the Irish Institute of Clinical Neuroscience (IICN), and the Iris O'Brien Foundation. The sponsors of the authors had no bearing on the opinions expressed herein.

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  1. Computational Neuroimaging Group (CNG), Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin, Ireland

    Rangariroyashe H. Chipika, We Fong Siah, Mary Clare McKenna, Stacey Li Hi Shing, Orla Hardiman & Peter Bede

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  1. Rangariroyashe H. Chipika
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  2. We Fong Siah
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Chipika, R.H., Siah, W.F., McKenna, M.C. et al. The presymptomatic phase of amyotrophic lateral sclerosis: are we merely scratching the surface?. J Neurol 268, 4607–4629 (2021). https://doi.org/10.1007/s00415-020-10289-5

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