Magnetic resonance imaging and spectroscopy in Huntington’s disease

Introduction Huntington’s disease (HD) is a hereditary neurodegenerative disorder that manifests with motor control, cognitive, and psychiatric symptoms. HD is caused by an expansion of CAG repeats in the huntingtin gene, leading to an abnormally long polyglutamine stretch in the N-terminal tail of the protein that interferes with its normal function, and causes the accumulation of the mutated protein [1–3]. Normal huntingtin is a large protein (350 kDa) whose structure favors protein–protein interaction, and is more specifically involved with shuttling stress-induced signal proteins from the endoplasmic reticulum in and out of the nucleus [4], and with microtubule-associated axonal vesicular and mitochondrial trafficking, thereby facilitating neurotransmission [5–10]. Both loss of its normal function and the accumulation of the abnormal protein affect neuronal function by altering cell signaling, axonal transport, mitochondrial metabolism, and neurotransmission. Histologically, the GABAergic medium spiny neurons of the striatum, projecting to the globus pallidus and the substantia nigra, are largely affected in HD. This is manifested in the brain of patients by striatal (caudate and putamenal) atrophy and consequent malfunctioning of the long loop feedback pathways involving this region. More subtle, widespread cortical defects have also recently been identified in patients at an early stage, which increase over time [11]. Reactive microglia along with activated astrocytes and oligodendrocytes are also associated with HD pathology in the striatum and cortex [3, 12–14]. Altered energy production and utilization, identified in the muscles of patients, also affect the striatal neurons, which are more sensitive to mitochondrial defects [10, 15, 16]. Because HD is an autosomal dominant transmitted disorder for which the culprit gene is identified, diagnosis is often made by genetic testing. As such, magnetic resonance (MR) techniques rarely have a significant role in clinical diagnosis. However, because MR provides a non-invasive approach, the processes involved in HD pathogenesis (structural changes of the brain, neuronal death, gliosis, energy production and utilization deficits), it is an attractive and promising tool for clinical and fundamental research. In this chapter, we will focus on the main findings and advances brought by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to the understanding of prodromal and early-stage patients. We will also review new approaches used in animal models that will hopefully be translated in clinical studies in the near future.