Elsevier

The Lancet Neurology

Volume 13, Issue 12, December 2014, Pages 1228-1240
The Lancet Neurology

Review
Neuroimaging in amyotrophic lateral sclerosis: insights into structural and functional changes

https://doi.org/10.1016/S1474-4422(14)70167-XGet rights and content

Summary

In the past two decades, structural and functional neuroimaging findings have greatly modified longstanding notions regarding the pathophysiology of amyotrophic lateral sclerosis (ALS). Neuroimaging studies have shown that anatomical and functional lesions spread beyond precentral cortices and corticospinal tracts, to include the corpus callosum; frontal, sensory, and premotor cortices; thalamus; and midbrain. Both MRI and PET studies have shown early and diffuse loss of inhibitory cortical interneurons in the motor cortex (increased levels of functional connectivity and loss of GABAergic neurons, respectively) and diffuse gliosis in white-matter tracts. In ALS endophenotypes, neuroimaging has also shown a diverse spreading of lesions and a dissimilar impairment of functional and structural connections. A possible role of PET in the diagnosis of ALS has recently been proposed. However, most neuroimaging studies have pitfalls, such as a small number and poor clinical characterisation of patients, absence of adequate controls, and scarcity of longitudinal assessments. Studies involving international collaborations, standardised assessments, and large patient cohorts will overcome these shortcomings and provide further insight into the pathogenesis of ALS.

Introduction

Amyotrophic lateral sclerosis (ALS) is a disorder of adult life characterised by progressive degeneration of upper and lower motor neurons and the frontal cortex. The cause of ALS is still unknown and no disease-modifying treatments are available, apart from the anti-glutamatergic drug riluzole, which increases survival by about 2–3 months without affecting muscle strength.1 Up to 10% of patients with ALS inherit a genetic mutation, whereas the other 90% of cases occur sporadically in the population.2 The most common ALS-related genes in white populations are C9orf72, SOD1, TARDBP, and FUS, which account for about two-thirds of cases of familial ALS.2 Diagnosis of ALS is largely based on its clinical presentation, progression of symptoms, and exclusion of other diseases, supported by neurophysiological and neuroimaging examinations.3, 4

There is an increasing awareness that ALS is a clinically and pathogenically heterogeneous disease.5 Several different phenotypes of ALS exist, ranging from pure upper motor neuron disease (primary lateral sclerosis) to pure lower motor neuron disease (progressive muscular atrophy), with several demographically (age and sex) and prognostically different intermediate forms (flail arm, flail leg, prevalent upper motor neuron, and bulbar ALS).6 Moreover, up to 50% of patients with ALS have cognitive deficits, again with a range of different clinical presentations, ranging from overt frontotemporal dementia (FTD) to cognitive impairment below the diagnostic threshold for FTD (pure executive, pure non-executive, or pure behavioural impairment).7, 8 MRI, PET, and SPECT have been used variously in about 200 ALS studies (appendix). The contribution of imaging to the understanding of ALS cannot be overlooked, since it has enabled study of the brains of patients with ALS in vivo and, to a lesser extent, longitudinally. There are three main areas of neuroimaging research. First, anatomical and functional changes in ALS have been identified on structural (MRI) and functional (functional MRI [fMRI], PET, and SPECT) neuroimaging, including the spread of cortical and subcortical lesions. The extensive application of structural magnetic-resonance-based techniques (panel) has improved our understanding of ALS pathophysiology and the mechanisms underlying the progressive degenerative process. These findings have also given some insight into the dysfunction of local and distant neural circuits in the various phases of the disease. Second, MRI and radiotracers have been used to identify CNS alterations that could be used to improve ALS diagnostic accuracy with clinically useful sensitivity and specificity. Third, these techniques are being used to assess promising biomarkers of progression of motor and non-motor lesions, which will be used in both clinical (as markers of prognosis in a patient) and research settings (as biological markers for assessing the efficacy of experimental treatments).

Section snippets

Structural T1-weighted imaging

Structural T1-weighted MRI enables detailed analysis of focal brain atrophy, which is a key feature of patients with ALS. Cross-sectional voxel-based morphometry studies have yielded inconsistent results regarding the presence of atrophy in the primary motor cortex or premotor cortex in ALS and the extent of extra-motor atrophy, largely because of differences in sample sizes, image preprocessing, and statistical analysis, but also because of the clinical, cognitive, and genetic characteristics

Resting-state fMRI

Several resting-state fMRI studies of ALS reported significantly decreased functional connectivity within the sensorimotor network21, 22, 23, 24, 25 and in brain networks related to cognition and behaviour,21, 22, 24, 26, 27 in keeping with the altered motor and extramotor structural connectivity. Other studies have identified regions of increased functional connectivity, including somatosensory and extra-motor areas (figure 2; appendix).9, 24, 25, 26, 27, 28, 29, 30 Two scenarios have been

Neuroimaging as a diagnostic marker of ALS

In patients with ALS, conventional MRI is frequently not informative and its diagnostic use is restricted to exclusion of other mimic disorders.3, 4 Although the detection of corticospinal tract hyperintensities on conventional MRI and the presence of a T2-hypointense rim in the primary motor cortex can support a pre-existing suspicion of ALS, they are neither sensitive nor specific for ALS and are not recommended for a firm diagnosis.88

Findings from some studies suggested cortical thinning of

Pitfalls of MRI and radiotracer imaging studies

Despite great achievements, most published studies have several pitfalls (table). Some of the differences in reported results might be because of clinical and demographic characteristics of patients, particularly the variable duration of the disease at the time of MRI and PET or SPECT (ranging from 6 months to 180 months)—ie, patients are at different stages of the disease. Neurobiological evidence that the different involvement of cortical bulbar and spinal motor neurons from an early stage in

Conclusions and future directions

MRI and radiotracer imaging are powerful and rapidly evolving imaging techniques that allow the assessment of the involvement of brain structures and functions in ALS in vivo. Although conceptually and methodologically different, their findings tend be concordant (figure 6). There is substantial anatomical and functional damage of the primary motor cortex, associated with damage to the corpus callosum (in particular, the middle and posterior parts). The degeneration of corticospinal tracts and

Search strategy and selection criteria

We searched PubMed (1966, to March 31, 2014), Embase (1980, to March 31, 2014), and the Cochrane Library (April, 1996, to March 31, 2014) for the search terms “amyotrophic lateral sclerosis” or “motor neuron disease” or “primary lateral sclerosis” in combination with “imaging”, “neuroimaging”, “magnetic resonance imaging”, “positron emission tomography”, “single photon emission computed tomography”, “diffusion tensor imaging”, “voxel based morphometry”, and “spectroscopy”. Further

References (146)

  • M Tanaka et al.

    Cerebral blood flow and oxygen metabolism in progressive dementia associated with amyotrophic lateral sclerosis

    J Neurol Sci

    (1993)
  • K Abe et al.

    Cognitive function in amyotrophic lateral sclerosis

    J Neurol Sci

    (1997)
  • G Waldemar et al.

    Focal reductions of cerebral blood flow in amyotrophic lateral sclerosis: a [99mTc]-d,l-HMPAO SPECT study

    J Neurol Sci

    (1992)
  • LH Barbeito et al.

    A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis

    Brain Res Brain Res Rev

    (2004)
  • T Philips et al.

    Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease

    Lancet Neurol

    (2011)
  • MR Turner et al.

    Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study

    Neurobiol Dis

    (2004)
  • A Johansson et al.

    Evidence for astrocytosis in ALS demonstrated by [11C](L)-deprenyl-D2 PET

    J Neurol Sci

    (2007)
  • N Le Forestier et al.

    Primary lateral sclerosis: further clarification

    J Neurol Sci

    (2001)
  • I Yabe et al.

    Writing errors in ALS related to loss of neuronal integrity in the anterior cingulate gyrus

    J Neurol Sci

    (2012)
  • H Takahashi et al.

    Evidence for a dopaminergic deficit in sporadic amyotrophic lateral sclerosis on positron emission scanning

    Lancet

    (1993)
  • HK Park et al.

    Nigrostriatal dysfunction in patients with amyotrophic lateral sclerosis and parkinsonism

    J Neurol Sci

    (2011)
  • BR Foerster et al.

    Diagnostic accuracy of diffusion tensor imaging in amyotrophic lateral sclerosis: a systematic review and individual patient data meta-analysis

    Acad Radiol

    (2013)
  • C Pohl et al.

    Proton magnetic resonance spectroscopy and transcranial magnetic stimulation for the detection of upper motor neuron degeneration in ALS patients

    J Neurol Sci

    (2001)
  • RG Miller et al.

    Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)

    Cochrane Database Syst Rev

    (2012)
  • AE Renton et al.

    State of play in amyotrophic lateral sclerosis genetics

    Nat Neurosci

    (2014)
  • PM Andersen et al.

    EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)—revised report of an EFNS task force

    Eur J Neurol

    (2012)
  • BR Brooks et al.

    El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis

    Amyotroph Lateral Scler Other Motor Neuron Disord

    (2000)
  • A Chio et al.

    Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study

    J Neurol Neurosurg Psychiatry

    (2011)
  • J Phukan et al.

    The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study

    J Neurol Neurosurg Psychiatry

    (2012)
  • MJ Strong et al.

    Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis

    Amyotroph Lateral Scler

    (2009)
  • E Verstraete et al.

    Motor network degeneration in amyotrophic lateral sclerosis: a structural and functional connectivity study

    PLoS One

    (2010)
  • F Agosta et al.

    The cortical signature of amyotrophic lateral sclerosis

    PLoS One

    (2012)
  • DM Mezzapesa et al.

    Cortical thinning and clinical heterogeneity in amyotrophic lateral sclerosis

    PLoS One

    (2013)
  • E Mioshi et al.

    Cortical atrophy in ALS is critically associated with neuropsychiatric and cognitive changes

    Neurology

    (2013)
  • F Agosta et al.

    Intrahemispheric and interhemispheric structural network abnormalities in PLS and ALS

    Hum Brain Mapp

    (2014)
  • EP Pioro et al.

    1H-MRS evidence of neurodegeneration and excess glutamate + glutamine in ALS medulla

    Neurology

    (1999)
  • J Han et al.

    Study of the features of proton MR spectroscopy ((1)H-MRS) on amyotrophic lateral sclerosis

    J Magn Reson Imaging

    (2010)
  • BR Foerster et al.

    An imbalance between excitatory and inhibitory neurotransmitters in amyotrophic lateral sclerosis revealed by use of 3-T proton magnetic resonance spectroscopy

    JAMA Neurol

    (2013)
  • BR Foerster et al.

    Decreased motor cortex gamma-aminobutyric acid in amyotrophic lateral sclerosis

    Neurology

    (2012)
  • G Nair et al.

    Diffusion tensor imaging reveals regional differences in the cervical spinal cord in amyotrophic lateral sclerosis

    Neuroimage

    (2011)
  • LM Jelsone-Swain et al.

    Reduced interhemispheric functional connectivity in the motor cortex during rest in limb-onset amyotrophic lateral sclerosis

    Front Syst Neurosci

    (2011)
  • F Zhou et al.

    Altered motor network functional connectivity in amyotrophic lateral sclerosis: a resting-state functional magnetic resonance imaging study

    Neuroreport

    (2013)
  • T Fekete et al.

    Multiple kernel learning captures a systems-level functional connectivity biomarker signature in amyotrophic lateral sclerosis

    PLoS One

    (2013)
  • C Luo et al.

    Patterns of spontaneous brain activity in amyotrophic lateral sclerosis: a resting-state fMRI study

    PLoS One

    (2012)
  • G Douaud et al.

    Integration of structural and functional magnetic resonance imaging in amyotrophic lateral sclerosis

    Brain

    (2011)
  • F Agosta et al.

    Sensorimotor functional connectivity changes in amyotrophic lateral sclerosis

    Cereb Cortex

    (2011)
  • MR Turner et al.

    Does interneuronal dysfunction contribute to neurodegeneration in amyotrophic lateral sclerosis?

    Amyotroph Lateral Scler

    (2012)
  • CM Lloyd et al.

    Extramotor involvement in ALS: PET studies with the GABA(A) ligand [(11)C]flumazenil

    Brain

    (2000)
  • C Konrad et al.

    Pattern of cortical reorganization in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study

    Exp Brain Res

    (2002)
  • MA Schoenfeld et al.

    Functional motor compensation in amyotrophic lateral sclerosis

    J Neurol

    (2005)
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