Highlights
- •Neurodegeneration in Huntington disease may be traced before symptom manifestation.
- •A multimodal protocol for phenotypic study of premanifest carriers is proposed.
- •Striatal atrophy and occipital thinning is confirmed in close-to-onset carriers.
- •Posturography shows stance control deficits in close-to-onset carriers.
- •Calculation subtraction test shows defective combinatorial rule application.
Abstract
Background
Huntington disease (HD) is an inherited neurodegenerative disorder most commonly manifesting
in adulthood. Identification of biomarkers tracking neurodegeneration before the onset
of motor symptoms is important for future interventional studies. Our study aimed
to contribute in the phenotypic characterization of the premanifest HD phase.
Methods
28 premanifest subjects (preHD), 25 age-matched controls, and 12 manifest HD patients
were enrolled for the study. The participants underwent a multimodal protocol including
cognitive evaluations, arithmetic ability test, posturography, composite cerebellar
functional test (CCFS), and brain 3T-MRI. PreHD were divided at the group median for
predicted years to expected onset into “far-from-onset” (>15 years, PreHD-far), and
“close-to-onset” (≤15 years, preHD-close). Basal ganglia volumes and cortical thickness
were computed using FreeSurfer.
Results
PreHD-close showed significantly lower scores than controls in Symbol Digit Modalities
Test (p = 0.017), Arithmetic subtraction task (p = 0.04), and MMSE (p < 0.006). At
posturography, preHD-close showed increased sway velocity (<0.04) and distance (p < 0.02)
compared to controls. PreHD-close had reduced striatum and globus pallidus volumes
and left occipital cortical thinning compared to controls. Compared to PreHD far-from-onset,
PreHD-close showed bilateral cortical thinning in occipital and parahippocampal regions,
inversely correlating with burden score and prognostic index for HD. CCFS only differed
between controls and manifest HD. PreHD far-from-onset did not show significant differences
in comparison with controls.
Conclusions
We confirmed that quantitative brain MRI represents a valid biomarker of neurodegeneration
in preHD. Posturography and Arithmentic tests seem promising tools for detecting early
changes in premanifest HD, but need to be further confirmed in large cohorts.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Parkinsonism & Related DisordersAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Clinical and biomarker changes in premanifest Huntington disease show trial feasibility: a decade of the PREDICT-HD study.Front. Aging Neurosci. 2014; 6: 78
- Visuospatial processing deficits linked to posterior brain regions in premanifest and early stage Huntington's disease.J. Int. Neuropsychol. Soc. 2016; 22: 595-608
- Impaired postural stability as a marker of premanifest Huntington's disease.Mov. Disord. 2010; 25: 2428-2433
- Neurocognitive signs in prodromal Huntington disease.Neuropsychology. 2011; 25: 1-14
- Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data.Lancet Neurol. 2012; 11: 42-53
- The role of the striatum in rule application: the model of Huntington's disease at early stage.Brain. 2005; 128: 1155-1167
- Composite cerebellar functional severity score: validation of a quantitative score of cerebellar impairment.Brain. 2008; 131: 1352-1361
- A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length.Clin. Genet. 2004; 65: 267-277
- Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data.Lancet Neurol. 2009; 8: 791-801
- Validation of a prognostic index for Huntington's disease.Mov. Disord. 2017; 32: 256-263
- Huntington's disease: objective assessment of posture–a link between motor and functional deficits.Mov. Disord. 2012; 27: 555-559
- Neuroanatomical correlates of cognitive functioning in prodromal Huntington disease.Brain Behav. 2014; 4: 29-40
- Postural stability in patients with Huntington's disease.Neurology. 1992; 42: 1232-1238
- Postural stability limits in manifest and premanifest Huntington's disease under different sensory conditions.Neuroscience. 2014; 279: 102-112
- Cortical control of postural responses.J. Neural. Transm. 2007; 114: 1339-1348
- Role of the basal ganglia in balance control.Neural Plast. 2005; 12 (discussion 263–172): 161-174
- Cerebellar abnormalities in Huntington's disease: a role in motor and psychiatric impairment?.Mov. Disord. 2014; 29: 1648-1654
- Longitudinal change in regional brain volumes in prodromal Huntington disease.J. Neurol. Neurosurg. Psychiatry. 2011; 82: 405-410
- Early atrophy of pallidum and accumbens nucleus in Huntington's disease.J. Neurol. 2011; 258: 412-420
- Striatal and white matter predictors of estimated diagnosis for Huntington disease.Brain Res. Bull. 2010; 82: 201-207
- Detection of Huntington's disease decades before diagnosis: the Predict-HD study.J. Neurol. Neurosurg. Psychiatry. 2008; 79: 874-880
- Onset and rate of striatal atrophy in preclinical Huntington disease.Neurology. 2004; 63: 66-72
- Consistent neurodegeneration and its association with clinical progression in Huntington's disease: a coordinate-based meta-analysis.Neurodegener. Dis. 2013; 12: 23-35
- Cerebral cortex structure in prodromal Huntington disease.Neurobiol. Dis. 2010; 40: 544-554
- The impact of occipital lobe cortical thickness on cognitive task performance: an investigation in Huntington's disease.Neuropsychologia. 2015; 79: 138-146
- Regional cortical thinning in preclinical Huntington disease and its relationship to cognition.Neurology. 2005; 65: 745-747
- Morphology of the cerebral cortex in preclinical Huntington's disease.Am J Psychiatry. 2007; 164: 1428-1434
Article info
Publication history
Published online: February 22, 2018
Accepted:
February 19,
2018
Received in revised form:
February 12,
2018
Received:
September 4,
2017
Identification
Copyright
© 2018 Elsevier Ltd. All rights reserved.
