INTRODUCTION
Neurodegeneration with brain iron accumulation (NBIA) is a clinical--radiological syndrome with multiple genetic causes [1▪▪]. The prevalence of NBIA is about 0.5/100 000 [1▪▪]. Age of onset varies from early childhood to midlife. The clinical picture is one of a variable combination of movement disorders (dystonia--parkinsonism, cerebellar ataxia) with a prominent orofacial involvement, pyramidal dysfunction, intellectual disability or cognitive deterioration, and psychiatric disorders. Other clinical features may include epilepsy, pigmentary retinopathy, optic atrophy, axonal neuropathy or diabetes. Death usually occurs early. These clinical manifestations are typically associated with marked bilateral hypointensities in the globus pallidus on iron-sensitive magnetic resonance (MR) images, reflecting the alteration of iron homeostasis in this area [1▪▪,2▪▪]. By the time, neurologic features are obvious, brain MRI almost always shows characteristic changes, although these changes may occasionally appear only later over the disease course. Conversely, rare patients are asymptomatic despite typical bipallidal T2 and T2∗ hypointensity. Additional clinical or neuroimaging abnormalities can be seen depending on the underlying cause and the disease duration. The culprit genes, inheritance pattern, distinctive clinical features and biological markers are summarized in Table 1.
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Table 1: Overview of the main neurodegeneration with brain iron accumulation subtypes
NBIA may be broken into two groups: primary disorders of iron metabolism constituting neuroferritinopathy and aceruloplasminemia and disorders in which alteration of iron homeostasis results from a neuronal dysfunction of another origin. These secondary causes of disturbed iron homeostasis within the brain constitute panthotenate kinase-associated neurodegeneration (PKAN), phospholipase A2 group VI-associated neurodegeneration (PLAN), fatty acid 2 hydroxylase-associated neurodegeneration (FAHN), mitochondrial membrane protein-associated neurodegeneration (MPAN), beta-propeller protein-associated neurodegeneration (BPAN), coenzyme A synthase protein-associated neurodegeneration (CoPAN), Woodhouse--Sakati syndrome and Kufor--Rakeb syndrome [2▪▪]. A brief overview of the metabolic pathways supposed to be involved is presented in Supplementary box 1, https://links.lww.com/CONR/A51. Other diseases may present a NBIA-like pattern including GM1 gangliosidosis, AP4-deficiency syndrome and pathogenic variants in GTPBP2, DDHD1, or SCP2. Typically, primary disorders of iron metabolism have an onset later in life and are characterized by more diffuse MRI abnormalities.
The suspicion of a NBIA should not only be based upon brain MRI showing bilateral hypointensities in the globus pallidus on iron-sensitive MR images. The clinical symptoms are critical to guide diagnosis (Table 1), which shall be confirmed by molecular analysis of the various causative genes. Indeed, alteration of iron homeostasis is not confined to NBIA, and ferroptosis may participate in neurodegeneration in a wide range of disorders [3▪▪]. In clinical practice, physicians can occasionally encounter patients with neurodegenerative diseases and MRI abnormalities reminiscent of that observed in NBIA. This has been reported in various diseases, including multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, Huntington disease, and dentatorubral-pallidolyusian atrophy [4].
Neuroferritinopathy causes an alteration of iron storage by ferritin polymers with a subsequent release of free iron and subsequent iron-mediated oxidation. Aceruloplasminemia causes a major decrease of ferroxidase activity preventing iron exportation by astrocytes and their binding of extracellular transferrin. Iron thus accumulates in astrocytes, and neurons suffer from iron starvation at early stages, and eventually from iron-mediated oxidation at later stages. Interestingly, secondary alterations of iron homeostasis are mostly linked to disorders of synthesis or remodelling of complex lipids [2▪▪].
The treatment of NBIA is primarily symptomatic and may include deep brain stimulation and botulinum toxin for dystonia [5]. Physiotherapy, occupational therapy speech therapy and swallowing rehabilitation are critical for these patients. There are no registered drug for preventing gradual deterioration over the course of the disease. However, a recent double blind placebo-controlled trial testing iron chelation with deferiprone in patients with PKAN showed a trend towards slowing disease progression [6▪]. More promising, a recent preclinical study recently demonstrated that 4’-phosphopantetheine corrects coenzyme A, iron and dopamine metabolic defects in a mouse model of PKAN [7]. Survival of the severely disabled patients depends mostly on swallowing function and overall management.
Box 1: no caption available
MRI ACQUISITION PROTOCOL TO BE USED IN ROUTINE CARE FOR NEURODEGENERATION WITH BRAIN IRON ACCUMULATION PATIENTS
Brain iron accumulation may be visualized with MRI using sequences that are sensitive to metallic content, such as gradient echo T2∗-weighted imaging, susceptibility-weighted imaging (SWI) and may be quantified using T2∗ mapping and quantitative susceptibility mapping (QSM). T2∗ relaxation times is measured using a number of T2∗-weighted images with increasing echo time. T2∗ relaxation time (and hence the relaxation rate R2∗ = 1/T2∗) is calculated by measuring the exponential signal decay with increasing echo time. Iron accumulation in tissues results in a decrease T2∗ and an increase R2∗. SWI combines the magnitude and the phase images to enhance the contrast of structures containing molecules with high susceptibility such as iron. The magnetic susceptibility is a measure of how much a material will become magnetized in an applied magnetic field. QSM is calculated using the T2∗ magnitude and phase images and provides a measurement of local magnetic susceptibility variations. Because T2∗ and SWI images are more sensitive to microscopic inhomogeneities of the magnetic field reflecting iron deposition than spin echo T2-weighted images, these sequences should be added to the MRI acquisition protocol used for NBIA diagnosis. This effect increases with the magnetic field and is therefore greater at 3T, and even more at 7T, than at 1.5T. In contrast, T2 and FLAIR images better evaluate white matter changes, gliosis, and cavitation but are much less sensitive to iron deposition. Cavitation is seen as an area of high signal intensity on T2-weighted images and might provide additional diagnosis clues to the genetic diagnosis. Three-dimensional T1-weighted images are added to evaluate brain morphology changes and atrophy. T1-weighted images may also provide interesting information on metallic deposit. For instance, iron or copper bound to molecules such as neuromelanin form paramagnetic complexes that appear hyperintense on T1-weighted images [8]. This effect may explain the high signal intensity observed in the basal ganglia in some NBIA subtypes [9,10]. Studies have used R2∗ mapping, mostly in deferiprone trials [6▪,11–13], or QSM [14,15▪] to quantify iron deposition. Importantly, a CT scan shall be performed to look for brain calcifications, which MRI aspect is variable and can be difficult to distinguish from iron deposition in routine practice.
IRON DEPOSITION IN THE NORMAL BRAIN
Iron gradually deposits in specific regions of the normal brain and particularly the basal ganglia. Histologically, the structures richest in iron are the globus pallidus and substantia nigra, followed by the red nucleus, putamen, caudate nucleus, dentate nucleus and the subthalamic nucleus [16]. Weaker iron deposition is also observed in the cerebral and cerebellar cortex, nuclei of the thalamus, the mamillary body, and the tectum [16]. MRI shows early age-related increase in globus pallidus and substantia nigra iron levels, which reaches a plateau in early adulthood [17,18]. Using T2-weighted images at 1.5T, iron deposition is first seen in the globus pallidus, followed by the red nucleus and substantia nigra, and then the dentate nucleus. Decreased signal intensity was not seen in these regions in patients less than 10 years old [18]. Using SWI at 1.5T, iron deposition was detected in the globus pallidus in all children and young adults older than 3 years [19]. In the putamen, iron deposited from the posterolateral to the anteromedial areas of the putamen [19]. Iron deposition in the putamen was not seen in normal subjects during the first decade of life whereas all normal subjects older than 20 years of age exhibited a rim of low SWI signal around the putamen called putaminal pencil lining [20]. In the cortex, iron may be detected at 3T using SWI as a fine band of low signal intensity following the contour of the cortex called the cortical pencil lining. At 1.5T, this sign is observed in all subjects older than 50 years [20].
IMAGING ASPECTS IN THE MOST COMMON NEURODEGENERATION WITH BRAIN IRON ACCUMULATION SUBTYPES
A general summary of the different MRI anomalies observed in the different types of NBIA is presented in Table 2.
Table 2: MRI features in neurodegeneration with brain iron accumulation
Panthotenate kinase-associated neurodegeneration
The typical brain MRI aspect of PKAN is characterized by an abnormal central T2/T2∗ hyperintensity secondary to gliosis and spongiosis of the anteromedial part of the globus pallidus that is surrounded by a low signal intensity caused by iron accumulation. This pattern is referred to as the ‘eye of the tiger’ sign and is observed in almost all PKAN patients (Fig. 1a--d). The central hyperintensity can predate the surrounding hypointensity in some patients [21,22▪]. In addition, the hyperintense center may vary in shape over the disease course from small round to streak, and rare patient can eventually have a more homogeneous hypointensity of the globus pallidus [22▪,23]. This is likely because of further accumulation of iron eventually obscuring the central hyperintensity. Associated hypointensity can be observed frequently in the substantia nigra and more rarely in the subthalamic nucleus and the dentate nuclei [22▪,24]. Finally, it is important to keep in mind that bipallidal calcifications can be observed in PKAN [25], and can even be the first neuradiological abnormality [26].
FIGURE 1: Panthotenate kinase-associated neurodegeneration and phospholipase A2 group VI-associated neurodegeneration. (a--d) A 43-year-old male patient with PKAN. Coronal FLAIR (a), axial FLAIR (b), (c) T1-weighted (T1-w), and (d) T2-weighted (T2-w) images. The FLAIR and T2-w images show abnormal signal intensity in bilateral globus pallidus with central hyperintensiy (probably because of gliosis) and peripheral rim of hypointensity (because of iron deposition) corresponding to the eye of the tiger sign (arrows). The T1-w image shows central hypointenisy surrounded by a rim of high signal intensity probably because of the presence of paramagnetic material (arrows). (e--h) A 30-year-old female patient with PLAN. Axial T1-weighted (T1-w, e and f) and T2∗-weighted images (T2∗-w, g and h). Images show cerebellar atrophy (arrow in e), brain atrophy with ventricular enlargement (f) and signal hypointensity indicating iron deposition (arrows) in bilateral substantia nigra (g) and globus pallidus (h). PKAN, panthotenate kinase-associated neurodegeneration, PLAN, phospholipase A2 group VI-associated neurodegeneration.
Phospholipase A2 group VI-associated neurodegeneration
PLAN constitutes two forms of infantile neuroaxonal dystrophy (INAD) and atypical neuroaxonal dystrophy (ANAD). Brain MRI shows iron deposits in the globus pallidus, the substantia nigra and the dentate nucleus [24,27,28] but not in all patients [29▪] (Fig. 1e--h). Cerebellar atrophy is constant, affecting both the vermis and hemispheres, and T2/FLAIR hyperintensity of the cerebellar cortex and dentate nuclei are often present [29▪]. The dentate nucleus may be hypointense on T2∗-weighted images [24,27] or hyperintense on T2-weighted images [29▪]. Cerebellar atrophy is greater when disease onset is earlier [29▪]. Cerebral atrophy and white matter changes may also be observed [29▪,30,31]. Occasionally, the substantia nigra may be more affected than the globus pallidus in some patients [31].
Beta-propeller protein-associated neurodegeneration
Patients with BPAN displays iron deposition in the globus pallidus and substantia nigra on brain MRI [30,32–34] (Fig. 2). In contrast to normal individuals, the putaminal pencil lining was observed early during the first decade of life in BPAN patients [20]. A hyperintense halo has also been reported around the substantia nigra using T1-weighted images [30,32,35,36] but this sign seems inconstant [33]. Brain and hippocampal atrophy as well as cortical thinning have been reported in patients with epileptic encephalopathies [34,36–38]. During early childhood, BPAN patients can present transient hyperintensity and swelling in the globus pallidus and substantia nigra because of infections, followed by elevated iron measured by QSM [39].
FIGURE 2: Beta-propeller protein-associated neurodegeneration. A 37-year-old male patient. Axial T1-weighted (T1-w, a and d), T2∗-weighted (T2∗-w, b and e) and FLAIR images (c and f). The SN (arrows) is hypointense on T2∗-w (b) and FLAIR (c) images (b), and present a central area of hyposignal surrounded by a rim of high signal intensity on T1-w images (a). The globus pallidus (arrows) is hypointense in all images (d--f).
Mitochondrial membrane protein-associated neurodegeneration
Brain MRI in MPAN shows iron deposition in the globus pallidus and the substantia nigra (Fig. 3) [40]. Visibility of the internal medullary lamina as a band of high signal intensity in the globus pallidus has been reported [9,15▪,41,42]. Whether this aspect is specific to MPAN remains to be determined. Additional T1 hyperintensity [9], SWI hypointensity [43,44] and susceptibility increase [15▪] was reported in the caudate nucleus and putamen. Cortical or cerebellar atrophy was observed after long disease duration [15▪,40]. Autosomal dominant forms of MPAN also exist because of a likely gain of function of certain pathogenic variants in C19orf12[45▪▪]. Independent of inheritance pattern, most MPAN cases are phenotypically similar, including the neuroimaging aspects.
FIGURE 3: Mitochondrial membrane protein-associated neurodegeneration. A 26-year-old female patient. Axial images passing at the level of the cerebellum (a), the substantia nigra (b-d), coronal (e) and axial images passing at the level of lenticular nucleus (f--h). Images are T1-weighted (a, b, e, f), T2∗-weighted (c and g) and ADC maps (d and h). Boxes show enlargement of the substantia nigra (b--d) and the lenticular nucleus (f--h). Images show cerebellar atrophy (arrow in a). The SN (b--d) and the globus pallidus (f--h) are hypointense on T2∗-w images, present a central area of hyposignal surrounded by a rim of high signal intensity on T1-w images and show areas of increased apparent diffusion coefficient (ADC) probably because of gliosis (arrows). The internal medullary laminae is clearly visible in g (arrows).
IMAGING ASPECTS IN IRON HOMEOSTASIS-ASSOCIATED NEURODEGENERATION WITH BRAIN IRON ACCUMULATION
Aceruloplasminemia
Brain MRI in patients with aceruloplasminemia showed diffuse iron deposits involving all basal ganglia (globus pallidus, striatum, substantia nigra), the red nucleus, the dentate nucleus and the thalamus, the mammillary bodies, the lateral habenula, the hippocampus and the cortex [11,14,27,46–48] (Fig. 4a--d). It should be noted that patients with hypoceruloplasminemia, that is, bearing one heterozygous pathogenic CP variant, may be symptomatic and present with pallidal hypointensity, cerebral white matter hyperintensity, and cerebellar atrophy [49].
FIGURE 4: Aceruloplasminemia and neuroferritinopathy. (a--d) A 60-year-old female patient with aceruloplasminemia after 7 years of disease duration. Axial T2∗-weighted images showing widespread areas of hyposignal because of iron deposition in (a) the dentate nuclei (arrow), (b) the hippocampus (arrowhead), red nucleus (asterisk) and substantia nigra (arrow), (c) the caudate nucleus (arrow) and putamen (double arrows), the thalamus (double arrowheads), and the cortex (arrowhead), (d) the caudate nucleus (arrow) and the cortex (Image courtesy T. Tourdias). (e--h) A 62-year-old male patient with neuroferritinopathy after 12 years of disease duration. (e) Sagittal T1-weighted images showing cerebellar and midbrain atrophy (arrows), (f--h) Axial T2-weighted images showing (f) widespread areas of hyposignal because of iron deposition in the midbrain and substantia nigra (arrow), (g) the globus pallidus, caudate nucleus, thalamus and putamen (arrow) with areas of high signal intensity in the putamen corresponding to cavitation (arrowhead), (h) white matter hyperintensities (arrowhead).
Neuroferritinopathy
Brain MRI shows diffuse variable iron deposition in the globus pallidus, putamen, dentate nuclei, and in some patients in caudate nuclei and thalami (Fig. 4e--h). An eye of the tiger sign may be observed [24]. In about half of the subjects, cavitations or cystic degeneration are seen as confluent areas of T2/FLAIR hyperintensity involving the globus pallidus and putamen [24,50–52]. Iron deposition is also observed in the cortex, a sign described as ‘cortical pencil lining’ [53]. This sign is also observed in aceruloplasminemia [20]. However, it is also observed in subjects over 50 years of age so that its usefulness from this age is questionable [20].
IMAGING ASPECTS IN ULTRA RARE NEURODEGENERATION WITH BRAIN IRON ACCUMULATION DISORDERS
Fatty acid 2 hydroxylase-associated neurodegeneration
FAHN is remarkable because of the association of T2 hypointensity in the globus pallidus with marked brainstem (pons and medulla oblongata, not observed in PLAN) and cerebellar atrophy, T2/FLAIR white matter hyperintensities, thinning of the corpus callosum, and mild generalized cortical atrophy [54] (Fig. 5a--d). Recently, the acronym WHAT was proposed to highlight this combination of white matter changes, hypointensity of the globus pallidus, pontocerebellar atrophy, and thin corpus callosum [55▪▪].
FIGURE 5: FAHN and Woodhouse--Sakati syndrome. (a--d) A 29-year-old male patient with FAHN. (a) Sagittal T1-weighted image showing cerebellar (asterisk) and brainstem atrophy and thinning of the corpus callosum (arrow). (b and c) Axial SWI images showing hyposignal indicating iron deposition (arrows) in the substantia nigra (b), and the globus pallidus (c). (d) Axial T2-weighted image showing hypersignal in the white matter (double arrows). (e--h) Patient with Woodhouse--Sakati syndrome. (e) Axial T2-weighted and (f--h) T2∗-weighted images showing (e) enlarged perivascular spaces in the area of the substantia nigra (arrow) and hyposignal indicating iron deposition (arrows) in the substantia nigra (f), and the globus pallidus (g and h).
Woodhouse--Sakati syndrome
Some patients with this syndrome show iron deposition in the globus pallidus on brain MRI and, as disease progresses, in the substantia nigra and red nucleus [56,57▪] (Fig. 5e--h). Other findings are iron deposition in a small pituitary gland, leukodystrophy and more rarely prominent perivascular spaces and restricted diffusion in the splenium of the corpus callosum [57▪,58].
Kufor--Rakeb disease
In Kufor--Rakeb disease, brain MRI can show iron deposition in the basal ganglia (caudate and lenticular nucleus) and brain atrophy [59–61] (Supplementary Fig. 1, https://links.lww.com/CONR/A52), although this abnormality is inconstant [62].
Coenzyme A synthase protein-associated neurodegeneration
Brain MRI in CoPAN typically shows swollen striatum and thalamus, hyperintense in T2-weighted images in early childhood that may regress over time and later iron deposition in the globus pallidus and substantia nigra [63,64] (Supplementary Fig. 1, https://links.lww.com/CONR/A52). The early striatal and thalamic changes might thus occur before the increase of pallidal iron content that was observed between 7 and 9 years [63,64]. Pallidal changes can mimic the ‘eye-of-the-tiger’ sign seen in PKAN because of pallidal calcifications [64].
OTHER ENTITIES THAT MAY PRESENT WITH A NEURODEGENERATION WITH BRAIN IRON ACCUMULATION PATTERN
Other rare genetic diseases occur in young patients with slowly progressive generalized dystonia-parkinsonism and an accumulation of iron in the basal ganglia visible on MRI. Whether they belong to NBIA or are NBIA-like diseases is debated, however.
SCPx syndrome
Brain MRI in a 51-year-old man and a 44-year-old man with SCP2 pathogenic variants showed bilateral T2/FLAIR hyperintense signals in the thalamus, the pons, and the occipital region [65,66] and reduced SWI signal in the globus pallidus, substantia nigra, red nuclei, and dentate nuclei [66] (Supplementary Fig. 1, https://links.lww.com/CONR/A52).
GM1 type3 gangliosidosis
Reduced SWI signal because of iron deposition was observed in the globus pallidus with progression to the substantia nigra, the red nucleus and the subthalamic nucleus [67,68] (Supplementary Fig. 1, https://links.lww.com/CONR/A52). The aspect of the globus pallidus was particular with a marked drop in signal intensity of the external and internal parts of the pallidum separated by the hypersignal of the internal medullary lamina reminiscent of that of a wishbone [67]. T2 and FLAIR hyperintensity was present in the posterior putamen and posterior white matter [67]. The combination of the wishbone sign and the posterior putaminal hyperintensity is highly suggestive of this disorder.
AP4 deficiency
In three patients aged 16 to 23 years with biallelic AP4M1 pathogenic variants brain MRI showed global brain atrophy, white matter loss, ventricular enlargement, thinning of the splenium of the corpus callosum and SWI hypointensity in the globus pallidus [69] (Supplementary Fig. 1, https://links.lww.com/CONR/A52). Likewise, a 13-year-old girl with a homozygous pathogenic variant in AP4S1 had hypointensity in the globus pallidus and thinning of the splenium of the corpus callosum [70].
DDHD1 pathogenic variants
Brain MRI in a 55-year-old man showed T2 hyposignal in the globus pallidus, T2 hypersignal of the supratentorial white matter and thinning of the corpus callosum [71].
GTPBP2 pathogenic variants
Brain MRI in three patients aged 29–34 years (two males, one female) showed reduced signal on SWI in the globus pallidus and substantia nigra and vermian atrophy [72].
CONCLUSION
Brain MRI using iron-sensitive MRI sequences is crucial for the diagnosis of NBIA by showing iron deposits in the basal ganglia, mostly the globus pallidus and substantia nigra. Some subtypes also show characteristic or additional MRI changes: the ‘eye of the tiger ‘sign in PKAN and a similar pattern reported in some patients with CoPAN and neuroferritinopathies, widespread iron deposition in the basal ganglia, thalamus, dentate nucleus and red nucleus in aceruloplasminemia and neuroferritinopathy, cavitation in neuroferritinopathy, white matter abnormalities in FAHN, Woodhouse--Sakati and SCPx syndromes, cerebellar atrophy in PLAN, thinning of corpus callosum and pontocerebellar atrophy in FAHN, swollen striatum with T2 hyperintensity in CoPAN.
An important limitation of imaging to date is that examinations were carried out with different magnetic fields, different sequences not always comparable on small series of patients. Few quantitative studies of iron deposition have been published. This makes it difficult to study the specificity of the signal anomalies observed (such as the T1 hypersignal rim, the wishbone sign), the relative importance of iron load between the diseases and the involvement of the different regions (external and internal globus pallidus, internal medullary laminae, substantia nigra, dentate nucleus, subthalamic nucleus). Future studies using quantitative MRI, high resolution at 3T may help to better detect and quantify iron deposition in NBIA and to determine whether iron content correlates with clinical signs and disease prognosis and evolution.
Acknowledgements
We thank Drs. François Chalard, Denis Lacroix, Delphine Leclercq and Thomas Tourdias, who contributed to image acquisition and Patricia Maurin for molecular analyses of several patients whose images are presented in the figures.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
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