Neuroimaging in hereditary spastic paraplegias: from qualitative cues to precision biomarkers

ABSTRACT

Introduction

Hereditary spastic paraplegias (HSP) include a clinically and genetically heterogeneous group of conditions. Novel imaging modalities have been increasingly applied to HSP cohorts, which help to develop monitoring markers for both clinical care and future clinical trials.

Areas covered

Advances in HSP imaging are systematically reviewed with a focus on cohort sizes, imaging modalities, study design, clinical correlates, methodological approaches, and key findings.

Expert opinion

A wide range of imaging techniques have been recently applied to HSP cohorts. Common shortcomings of existing studies include the evaluation of genetically admixed cohorts, limited sample sizes, lack of postmortem validation, and a limited clinical battery. A number of innovative methodological approaches have also been identified, such as robust longitudinal study designs, the implementation of multimodal imaging protocols, complementary cognitive assessments, and the comparison of HSP cohorts to MND cohorts. Collaborative multicenter initiatives may overcome sample limitations, and comprehensive clinical profiling with motor, extrapyramidal, cerebellar, and neuropsychological assessments would permit systematic clinico-radiological correlations. Academic achievements in HSP imaging have the potential to be developed into viable clinical applications to expedite the diagnosis and monitor disease progression.

KEYWORDS:

• Hereditary spastic paraplegia
• HSP
• MRI
• PET
• biomarker
• cognition

Article highlights

• Hereditary spastic Paraplegias (HSP) include a clinically and genetically heterogeneous group of conditions with diverse disability profiles.

• Radiological cues, such as the ‘ear of the lynx’ sign, thinning of the corpus callosum, cerebellar atrophy, high signal along the corticospinal tracts, and optic nerve hypoplasia have limited specificity to HSP genotypes.

• The practical relevance of robust, prospective computational imaging studies stems from their ability to ascertain HSP-specific imaging signatures, the prospect of expediting the diagnosis, and the development of viable monitoring markers for both clinical care and future pharmaceutical trials.

• A wide range of quantitative gray and white matter techniques have been recently applied to HSP cohorts including cortical thickness measurements, morphometric approaches, cortical and subcortical volumetry, spinal cord protocols, tractography, spectroscopy, PET, and SPECT.

• Stereotyped shortcomings of existing imaging studies include the evaluation of genetically unconfirmed or genetically admixed cohorts, limited sample sizes, unimodal imaging approaches, and a limited clinical battery often exclusively focusing on the motor aspects of the condition.

• Collaborative initiatives with harmonized protocols may overcome sample limitations; comprehensive clinical profiling with motor, extrapyramidal, cerebellar, cognitive, and behavioral assessments would permit systematic clinico-radiological correlations, and multi-timepoint longitudinal study designs will allow the nuanced characterization of anatomical propagation patterns.

Declaration of Interest

Professor Bede is sponsored by the Spastic Paraplegia Foundation (SPF). The authors are also supported by the Health Research Board (HRB EIA-2017-019 & JPND-Cofund-2-2019-1), the Irish Institute of Clinical Neuroscience (IICN), the EU Joint Programme – Neurodegenerative Disease Research (JPND), the Andrew Lydon scholarship, and the Iris O’Brien Foundation.

The sponsors had no bearing on the opinions expressed herein. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

The writing of this review was sponsored by the Spastic Paraplegia Foundation (SPF). The authors are also supported by the Health Research Board (HRB EIA-2017-019 & JPND-Cofund-2-2019-1), the Irish Institute of Clinical Neuroscience (IICN), the Spastic Paraplegia Foundation (SPF), the EU Joint Programme – Neurodegenerative Disease Research (JPND), the Andrew Lydon scholarship, and the Iris O’Brien Foundation.