Key role of nuclear medicine in seeking biomarkers of Huntington’s disease
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- Squitieri, F. & Ciarmiello, A. Eur J Nucl Med Mol Imaging (2010) 37: 1124. doi:10.1007/s00259-010-1439-8
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Biomarkers are biological, easy to collect changes reflecting the main pathological processes responsible for HD. Biomarkers basically belong in two main fields: brain markers, namely “dry” biomarkers, investigated by non-invasive imaging procedures and peripheral markers, and “wet” biomarkers, investigated by biochemical, genetic and metabolic analyses. In detecting new biomarkers for HD, possible relationships must be sought between “dry markers” and “wet” markers and between these two groups and clinical changes in individuals with HD (Fig. 1c). According to the Huntington Study Group, standardized scales such as the Unified Huntington’s Disease Rating Scale (UHDRS) can help to measure qualitatively and quantitatively whether a given at-risk individual is becoming affected with specific signs and symptoms . These scales nevertheless have the disadvantage of providing a subjective evaluation susceptible to numerous human errors. Seeking to overcome these drawbacks, Tabrizi et al., within the TRACK-HD network, suggested some clinical automated procedures and tried to correlate them with global brain atrophy measured with voxel-based morphometry (VBM) using a highly sensitive 3-T magnetic resonance imaging (MRI) scanner . Using a different approach, MRI relaxometry  and a 1.5-T scanner, we have described the cross-sectional and longitudinal changes in cerebrospinal fluid (CSF) since the premanifest stage as potential markers of global brain atrophy and HD progression . Other approaches by diffusion tensor MRI have focused on white matter abnormalities in some connectivity brain structures including the corpus callosum [15, 16], starting from documented evidence showing a premanifest white matter volume loss . Although these and many other imaging studies helped to advance research and current knowledge, none of them proved able to highlight phenoconversion in the single at-risk individual. Especially useful help in elucidating potential biomarkers in neurodegenerative diseases has come from nuclear medicine . Among nuclear medicine techniques, positron emission tomography (PET) scan is highlighting many abnormalities in brain metabolism and in receptor functions. For example, using fluoro-D-glucose (PET) procedures Feigin et al. reported a possible correlation between progressive hypometabolism and clinical phenoconversion in premanifest HD . Interestingly, the investigators highlight a dual glucose uptake behaviour in thalamus, regulating connections with brain cortex and cell death in HD, first increasing, probably to compensate for the early and progressive striatal hypometabolism as previously widely documented , then, in followed up premanifest subjects who during their life started to show signs and symptoms suggesting HD phenoconversion, rapidly decreasing towards subnormal levels . If confirmed, this strategy by glucose uptake measurement would warrant analysing thalamic glucose metabolism as a key event in the search for HD biomarkers, as well as highlighting new potential candidate brain structures. Collectively, these combined structural-functional approaches will help to detect various dry biomarkers for use in the different HD life stages. Research using the structural-functional approach includes studies conducted with MRI, PET scan and brain scintigraphy (SPECT).
Another ideal, worthwhile direction for future research would entail integrating dry biomarkers with other markers analysed in the periphery, thus considering HD as a systemic disease rather than an exclusively brain pathology. This wider view accords with evidence that the mutated protein is widely expressed in all body tissues and exerts its toxic effects even out of brain [20, 21]. Indeed, emerging evidence highlights a growing number of potential biomarkers from peripheral tissues or wet biomarkers . Identifying a peripheral and measurable pathological change from an easy to get tissue such as blood and relating this change to a validated brain marker would unequivocally strengthen the meaning of a still unrecognizable subtle clinical presentation coming within the zone of onset (Fig. 1c). The only approaches so far used for predicting age at onset in premanifest people are mathematical mutation-sized models . Despite contributing worthwhile information that advances HD research, these models suffer from major bias owing to the wide confidence intervals for predicted onset ages. Future biomarkers should aim to narrow these confidence limits especially those for low-penetrance mutations. The search for new mechanisms and biomarkers owes much to the many in vivo (i.e. animal) and in vitro (i.e. animal and human cell lines) models that have detected abnormalities in brain structures (i.e. amygdala or hippocampus)  or peripheral organs (i.e. muscles, blood cells and gene pathway deregulations) [25, 26], heretofore considered unsuspected HD targets before manifest HD. These novel contributing mechanisms to HD pathology such as inflammation and glial reactivity [27, 28] or neurotrophin dysregulation [29, 30] extended the search for new potential peripheral biomarkers able to detect early abnormal levels of proinflammatory factors  and reduced levels of serum brain-derived neurotrophic factor (BDNF) [5, 32], or more recently, transforming growth factor (TGF)-beta 1 . Interestingly, BDNF is produced in the brain cortex and blood BDNF concentrations are low from the presymptomatic life stage onwards in accordance with the documented early degeneration and glucose hypometabolism of the brain cortex at this life stage [5, 17, 34]. Similarly, reduced blood TGF-beta 1 levels correlate with mutation length and with reduced caudate glucose uptake as measured by PET scan in premanifest HD subjects . Once extended and confirmed, these data obtained by relating wet and dry biomarkers might theoretically provide the starting point for studies validating novel premanifest biomarkers (Fig. 1c). For example, early dysfunction in striatum as highlighted by fMRI has been related to increasing chorea , whilst regional cortical atrophy and hypometabolism importantly contribute to the complexity of HD presentation [5, 34, 36]. Coherently to these studies, the increase of A2A receptor density (which are particularly expressed in striatum and downregulated in HD) in blood platelets (but not in other blood cells) linearly and positively depends on expanded CAG repeat size only in patients showing chorea, the typically caudate-related symptom, predominant on other clinical manifestations . Thus, different patterns of symptoms and stages of the disease may require different proper biomarkers to monitor HD development and therapeutic effects. The fine quantification of abnormalities in the brain metabolism by PET scan procedures may contribute to detect early, potentially therapeutically revertible malfunctions, before severe cell death occurs. Once validated, such procedures could be transferred to many other centres. Therefore, the relationships between brain and peripheral biological changes clarified by multimodal approaches will provide new insights into the search for valid biomarkers for application in clinical practice (Fig. 1b, c) and nuclear medicine is promising a key role in research advances in this field .
We thank the European Huntington’s Disease (EURO-HD) Network, all patients and their families (Associazione Italiana Corea di Huntington-Neuromed) and the Italian Society of Hospital Neurologists (SNO, ‘lascito Gobessi’) for their support to FS.