LHON is a hereditary neurological disease caused by mitochondrial DNA (mtDNA) mutations characterized by painless progressive decline or loss of vision in young males(Chinnery et al., 2000; Poincenot, Pearson, & Karanjia, 2020). The main features of LHON anterior visual pathway lesions are loss of retinal ganglion cells (RGC), progressive thinning of retinal nerve fiber layer (RNFL), dilation of the radial papillary capillary (RPC) around the optic disk, and loss of optic nerve axons, and so on(Asanad et al., 2019; Balducci et al., 2016; Cui et al., 2020; Matsuzaki, Hirami, Uyama, & Kurimoto, 2018; Rizzo et al., 2012; L. Wang et al., 2017).
In addition to the progressive decline in vision, members of the LHON family may have other neurological abnormalities, including peripheral neuropathy (Finsterer & Zarrouk-Mahjoub, 2018), dystonia (Saracchi et al., 2013), hearing impairment (Rance et al., 2012), and cerebellar ataxia (Funakawa et al., 1995), etc. Besides, it suggests that LHON may damage brain tissue directly or indirectly. In recent years, some sporadic case reports have reported that LHON can cause brain gray matter (GM) and white matter abnormalities. For example, neuroimaging studies based on magnetic resonance imaging (MRI) have reported structural and functional abnormalities along the visual pathways, such as optic radiation (Barcella et al., 2010; Manners et al., 2015; Milesi et al., 2012), optic chiasm (Barcella et al., 2010), optic nerve(Grochowski, Symms, et al., 2020; L. Wang et al., 2017), lateral geniculate nuclei(LGN)(Jonak et al., 2020; Rizzo et al., 2012; Vaphiades, 2011), medial geniculate nuclei (MGN)(Jonak et al., 2020), primary visual cortex(Barcella et al., 2010) and extrastriate cortex(d'Almeida, Mateus, Reis, Grazina, & Castelo-Branco, 2013; Jonak, 2020; Mateus, d'Almeida, Reis, Silva, & Castelo-Branco, 2016). Moreover, brain abnormalities outside the visual pathway were also reported in the LHON, including abnormal microstructural integrity of acoustic radiation and other white matter structures (Long et al., 2019; Manners et al., 2015; L. Wang et al., 2021; J. Zhang et al., 2021), disrupted functional and structural connectivities (Rocca et al., 2011; Vacchiano et al., 2019), and higher hippocampus volume (Grochowski, Jonak, Maciejewski, Stepniewski, & Rahnama-Hezavah, 2020), and so on.
Most LHON mutations are located in genes encoding mitochondrial complex I, also called nicotinamide adenine dinucleotide dehydrogenase subunit (ND1). Mutations in ND1 change the amino acids of ND1(Yen, Wang, & Wei, 2006) and disrupt ATP function, leading to reduction in ATP production and cell respiration rate. A rapid reduction in ATP concentration was reported in all three types of LHON mutation-carrying cell cultures (ND1, ND4 and ND6)(Zanna et al., 2003). Thus, ND1 dysfunction in patients with LHON can limit ATP production, triggering brain cell metabolism changes and leading to abnormal brain activity. Thus, it is expected that LHON mutation would blunt the energy metabolism of the patients’ brain tissues and cause central never system (CNS) symptoms. Magnetic resonance spectroscopy (MRS) and arterial spin labeling (ASL) are two frequently used non-invasive MRI techniques to evaluate the brain's energy metabolism. For example, phosphorus MRS (31P-MRS) showed defective occipital lobe energy metabolism in LHON carriers of m.11778G > A(Barbiroli et al., 1995). A proton MRS (1H-MRS) study reported decreased absolute creatine followed by decreased absolute N-acetylaspartate concentration in the normal-appearing white matter of LHON carriers (Ostojic et al., 2009). These studies implied that LHON could cause abnormal brain metabolism, even during the pre-symptomatic period. ASL measures the rate of arterial blood transport to the capillary bed (termed cerebral blood flow (CBF)) by saturating (or labelling) the endogenous arterial blood, which is closely related to brain neural activity and metabolism (Alsop et al., 2015). Changed CBF has been detected in blind, high myopia people (De Volder et al., 1997; Ptito, Moesgaard, Gjedde, & Kupers, 2005; H. Wang et al., 2020) and neuropsychiatric diseases(Hays, Zlatar, & Wierenga, 2016; Jann et al., 2015; Xu et al., 2017). To our knowledge, there is no study reporting the brain CBF changes in LHON patients or pre-symptomatic carriers. Thus, detecting the potential CBF changes in LHON patients can help us further understand the patho-metabolic mechanism of LHON.
Based on the metabolic(Barbiroli et al., 1995; Ostojic et al., 2009), functional (Rocca et al., 2011; Vacchiano et al., 2019) and structural abnormalities(Long et al., 2019; L. Wang et al., 2021; J. Zhang et al., 2021) reported in LHON patients and carriers, we hypothesized that abnormal CBF would also be identified in both the visual and non-visual pathways; furthermore, we hypothesized that the disease process would influence the CBF changes in the LHON. To address these hypotheses, we collected ASL data from 55 LHON patients and 37 healthy controls. We first applied voxel-based data-driven statistics to explore which cerebral regions have abnormal CBF in the LHON patients. Then several curve fitting models were used to investigate the potential relationships among CBF abnormalities, disease duration, and neuro-ophthalmological metrics in these brain regions.