Genetic and degenerative disorders primarily causing other movement disorders

Handbook of Clinical Neurology, Vol. 135 (3rd series) Neuroimaging, Part I J.C. Masdeu and R.G. Gonza´lez, Editors © 2016 Elsevier B.V. All rights reserved

Chapter 25

Genetic and degenerative disorders primarily causing other movement disorders NICOLA PAVESE1,2* AND YEN F. TAI1 Division of Brain Sciences, Imperial College London, UK

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Aarhus University, Denmark

Abstract In this chapter, we will discuss the contributions of structural and functional imaging to the diagnosis and management of genetic and degenerative diseases that lead to the occurrence of movement disorders. We will mainly focus on Huntington’s disease, Wilson’s disease, dystonia, and neurodegeneration with brain iron accumulation, as they are the more commonly encountered clinical conditions within this group.

HUNTINGTON’S DISEASE Huntington’s disease (HD) is an autosomal-dominantly inherited neurodegenerative disease caused by a CAGrepeat expansion in the IT15 gene of chromosome 4 (The Huntington’s Disease Collaborative Research Group, 1993). This is translated into a mutant huntingtin protein with an elongated N-terminal polyglutamine chain, which in turn leads to the formation of abnormal intraneuronal inclusions (DiFiglia et al., 1997). The pathologic hallmark of HD is progressive and severe atrophy of the striatum (caudate nucleus and putamen). Medium spiny neurons of the striatum, which correspond to 90–95% of the striatal neuronal population, are preferentially lost in HD. The cerebral cortex is affected later on in the disease and the areas involved are widespread (Vonsattel et al., 1985). Clinically, HD manifests as a clinical triad of movement disorders, particularly chorea, cognitive impairment, and psychiatric disturbances.

Structural magnetic resonance imaging Magnetic resonance imaging (MRI) brain findings in HD patients reflect the underlying pathology, namely striatal and, to a lesser extent, cortical atrophy (Fig. 25.1A). Striatal atrophy is predominantly caused

by the loss of medium spiny neurons in the striatum (Guo et al., 2012). Striatal atrophy in premanifest HD gene carriers (pre-HD) can be detected using volumetric MRI up to 20 years before predicted disease onset (Paulsen et al., 2008). At the time of diagnosis, the striatal volume loss may be as much as 50% (Aylward et al., 1994). Compared to aged matched healthy controls, the annual whole-brain atrophy rates were 0.20% higher in pre-HD and 0.60% higher in early HD; whereas the caudate atrophy rates were 1.37% higher in pre-HD and 2.86% higher in early HD (Tabrizi et al., 2011). Striatal atrophy in HD correlated with the disease burden as estimated with age and length of the CAG repeat (Tabrizi et al., 2011) and the degree of motor and cognitive, but not psychiatric, impairment (Aylward et al., 2013). Two large-scale prospective multicenter studies, PREDICT-HD and TRACK-HD, have both shown that striatal volume strongly correlated with the likelihood of disease onset in pre-HD (Tabrizi et al., 2012; Paulsen et al., 2014). An MRI-based morphometric study found widespread degeneration in early to mid-HD involving virtually all brain structures, including basal ganglia, cerebral cortex, total white matter, amygdala, brainstem, and cerebellum (Rosas et al., 2003). Using cortical MRI

*Correspondence to: Dr. Nicola Pavese, MD, PhD, FRCP, Clinical Senior Lecturer and Consultant in Neurology, Division of Brain Sciences, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. Tel: +44-20-3313-3766, Fax: +44-20-3313-4320, E-mail: [email protected]

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Fig. 25.1. (A) T1-weighted volumetric magnetic resonance imaging (MRI) of a Huntington’s disease patient with disease duration of 3 years showing marked caudate atrophy with relative preservation of cortical volume. (B) [11C]-raclopride positron emission tomography binding potential map of a Huntington’s disease patients (left) and a normal subject (right) superimposed on their respective MRI. The color bar indicates binding potential values for [11C]-raclopride PET. The Huntington’s disease patient showed significantly reduced striatal [11C]-raclopride binding potential compared to the normal subject.

morphometry, the same group showed that cortical thinning in patients with early HD was heterogeneous and topographically selective, with greater volume loss seen in the sensorimotor and primary visual cortices, while anterior frontal and temporal regions were relatively spared. They also demonstrated that distinct motor phenotypes and cognitive impairments in HD are associated with discrete patterns of cortical thinning. For example, HD subjects with prominent parkinsonian motor phenotype demonstrated greater atrophy over the anterior frontal cortical regions compared with those with prominent chorea phenotype, but there was no difference in the striatal volume between the two groups (Rosas et al., 2008). These findings were corroborated in another study which demonstrated cortical atrophy in the superior and posterior regions of the cerebrum in preHD, with the subjects closest to predicted disease onset demonstrating greater volume loss (Nopoulos et al., 2010). A longitudinal study showed that the rate of atrophy was faster in the frontal and parietal regions, and earlier disease onset appeared to be associated with a greater rate of cortical atrophy (Rosas et al., 2011). Gray-matter volume was also shown to be strongly associated with the likelihood of disease onset in pre-HD in the TRACK-HD study (Tabrizi et al., 2013). Diffusion tensor imaging (DTI) studies also identified early and progressive involvement of pyramidal and extrapyramidal tracts (Rosas et al., 2006; Weaver et al., 2009) and white-matter microstructure in the corpus callosum (Rosas et al., 2010). A longitudinal MRI study in pre-HD showed that measures of volume change in striatum and white matter, particularly in the frontal lobe, are particularly sensitive markers of

disease progression (Aylward et al., 2011). In a multimodal MRI study investigating longitudinal macrostructural (regional and voxel-wide volumetric changes) and microstructural (diffusivity) changes in HD, the authors concluded that the former are more sensitive than the latter in detecting longitudinal group changes between pre-HD, early HD, and controls. In particular, caudate atrophy was the most sensitive marker of early neurodegeneration and could detect changes in pre-HD over 15 years prior to predicted disease onset (Dominguez et al., 2013).

FUNCTIONAL MRI Numerous activation studies using functional MRI (fMRI) have been performed in HD (Paulsen, 2009). Many of them have confirmed/corroborated the findings of impaired frontostriatal circuitry, as shown in previous H215O positron emission tomography (PET) activation studies (discussed further in the section on PET, below), but further insights were gained regarding longitudinal fMRI changes and default mode network (DMN) abnormalities, especially in pre-HD. It is hypothesized that striatal neuronal dysfunction may precede cell death in pre-HD, and hence functional imaging, including fMRI and PET, may be more sensitive than structural imaging in detecting earliest subclinical changes in pre-HD. One study investigated fMRI changes while performing a verbal working-memory task in pre-HD. The working-memory scores were similar between pre-HD and healthy controls, but the former demonstrated reduced activation in the left dorsolateral prefrontal cortex, even though morphometric study

GENETIC AND DEGENERATIVE DISORDERS showed that the area had not been affected by cortical atrophy. Pre-HD closer to predicted onset of motor symptoms had increased activation in the left inferior parietal lobule and right superior frontal gyrus compared with pre-HD further away from predicted disease onset and healthy controls, suggesting compensatory neural response in these pre-HD individuals (Wolf et al., 2007). However, a follow-up study 2 years later did not show progressive loss of activity in the left dorsolateral prefrontal cortex (Wolf et al., 2011). Using resting-state fMRI to study the integrity of DMN, one group showed that pre-HD exhibited reduced connectivity in the anterior medial prefrontal cortex, left inferior parietal, and posterior cingulate cortex, but there was increased connectivity between the anterior and posterior DMN subsystems (Wolf et al., 2012). This disturbed connectivity became more widespread in symptomatic HD, which correlated with the degree of cognitive impairment (Quarantelli et al., 2013).

MAGNETIC RESONANCE SPECTROSCOPY (MRS) A number of MRS studies have been carried out in HD, though sometimes with contradictory findings. An MRS study of pre-HD and early HD patients showed that most subjects demonstrated various combinations of reduced N-acetylaspartate (marker of neuronal integrity), enhanced glutamate/glutamine and lactate (a reflection of bioenergetics) activities, and reduced creatine levels (measure of metabolism) (Reynolds et al., 2005). However, there was significant heterogeneity in the findings between HD patients. For example, low creatine level was found in pre-HD but not in symptomatic patients. Another group found that there was no difference in the putamen metabolite levels of N-acetylaspartate, choline (an indicator of membrane synthesis), and creatine between pre-HD and controls (van Oostrom et al., 2007). A more recent MRS study has shown that the level of total N-acetylaspartate in the putamen was 8% lower in pre-HD and 17% lower in early HD compared to healthy controls, whereas the myo-inositol level, a glial cell marker, was 50% higher in early HD compared to pre-HD (Sturrock et al., 2010). At 24 months, these metabolite levels were stable (Sturrock et al., 2015), which suggests that MRS might not be sensitive enough to be employed as a marker of disease progression in HD.

Positron emission tomography The striatal medium spiny neurons, which bear the brunt of HD pathology, express dopamine, opioid, and cannabinoid receptors on their cell surface so their functions can be imaged with a variety of PET tracers.

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F-fluorodeoxyglucose (FDG) PET, which reflects cellular and synaptic glucose utilization, showed severely decreased striatal glucose metabolism in early symptomatic HD. The cortical uptake was normal initially, but as the disease progressed, impairment of frontal metabolism became apparent (Kuhl et al., 1982; Kuwert et al., 1990). A significant proportion of asymptomatic adult relatives at risk for HD also showed reduced striatal hypometabolism, though, as many of these studies were performed prior to the identification of HD gene, they were likely to have included some nonHD gene carriers (Hayden et al., 1987; Grafton et al., 1990; Kuwert et al., 1993). Network analysis of FDG PET showed a discrete pattern of metabolic abnormality in pre-HD compared to controls, with hypometabolism in the caudate, putamen, and mediotemporal regions and hypermetabolism in the occipital region (Feigin et al., 2001). [11C]-SCH23390 and [11C]-raclopride PET have been used to image striatal dopamine D1 and D2 binding respectively. Contrary to the classical basal ganglia circuit model which predicts preferential involvement of D2 receptor-expressing striatal neurons of the indirect pathway in choreic HD (Albin et al., 1989), PET studies have shown a parallel reduction in striatal D1 and D2 receptor binding in HD patients and many pre-HD (Turjanski et al., 1995; Weeks et al., 1996). Striatal [11C]-raclopride binding correlated cross-sectionally with motor and functional scores on the Unified Huntington’s Disease Rating Scale (Andrews et al., 1999). Striatal D2 binding also correlated with cognitive dysfunction, including frontal executive domain, in both manifest HD patients and pre-HD (Backman et al., 1997; Lawrence et al., 1998). [11C]-raclopride PET has also detected progressive frontal, temporal, and hypothalamic loss of D2 binding in HD (Pavese et al., 2003; Politis et al., 2008). However, using a different D2 tracer [11C]-FLB457, another group did not detect reduced extrastriatal D2 binding in early to mid-stage HD (Esmaeilzadeh et al., 2011). FDG and [11C]-raclopride PET have been evaluated as markers of disease progression in HD. One [11C]raclopride PET study reported that early to mid-stage HD showed a linear progression over 5 years, with striatal D2 receptor binding falling by approximately 5% of the baseline value per annum (Pavese et al., 2003) (Fig. 25.1B). A second group reported an annual reduction of 6.3% (Antonini et al., 1996) and suggested that the progression in striatal [11C]-raclopride binding is nonlinear over the whole course of the disease, later striatal degeneration being preceded by a period of relatively preserved neuronal function in pre-HD (Antonini et al., 1998). Studies of pre-HD have shown on average an annual decline in striatal [11C]-raclopride binding of

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2.7–6.5% and FDG metabolism of 2.3–7.6% (Antonini et al., 1996; Andrews et al., 1999; Ciarmiello et al., 2006; Feigin et al., 2007). Comparing the three imaging modalities, one group reported that [11C]-raclopride PET, which reflects striatal neuronal dysfunction in addition to striatal cell loss, was more sensitive than either FDG PET or volumetric MRI in detecting subclinical abnormalities in pre-HD (van Oostrom et al., 2005). However, a longitudinal study of pre-HD showed that the FDG network abnormalities, which increased linearly over 7 years, were more sensitive than regional glucose metabolism in detecting HD progression. Its rate of increase was greater than the rates of decline of caudate [11C]-raclopride binding or caudate volume, indicating that FDG network analysis could be a sensitive marker of disease progression in HD (Tang et al., 2013). Several studies investigating the efficacy of fetal striatal transplantation in HD have been carried out, with mixed outcomes. In two of the studies, where a proportion of implanted patients had demonstrated clinical improvement/stabilization, there was an accompanying improvement in their FDG uptake and [11C]-raclopride binding at the implantation sites, indicating graft survival and functional differentiation (Bachoud-Levi et al., 2006; Reuter et al., 2008). [11C]-dihydrotetrabenazine binds to vesicular monoamine transporter type-2 (VMAT2) and reflects the functional integrity of monoaminergic terminals in brain. One group reported reduced striatal 11Cdihydrotetrabenazine binding in HD, particularly in patients with akinetic-rigid rather than choreic phenotype. The reduction was most marked in the posterior putamen, a pattern similar to that seen in Parkinson’s disease. This suggests that nigrostriatal pathology is a feature of HD, particularly in those with akinetic-rigid phenotype (Bohnen et al., 2000). [11C]-diprenorphine PET is a marker of mu, kappa, and delta opioid receptors and is influenced by synaptic levels of endorphins. One study has reported reduced opioid receptor binding in the striatum and cingulate in HD while prefrontal and thalamic signals were increased (Weeks et al., 1997b). The increased opioid receptor availability in frontal and thalamic areas could reflect reduced endorphin levels. More recently, using a novel type 1 cannabinoid receptor (CB1) PET tracer, one study reported marked early and widespread reduction of CB1 binding in HD (Van Laere et al., 2010). This is felt to be due to the repression of CB1 transcription by mutant huntingtin. How this relates to neuronal injury in HD is yet to be fully elucidated, but it may represent a new avenue for therapeutic intervention. Preclinical studies have suggested that microglial activation may play an important role in the pathogenesis of HD (Sapp et al., 2001). Using [11C]-(R)-PK11195 (PK)

PET to image activated microglia, we have shown that HD patients demonstrated increased microglial activation in the striatum, which correlated with the degree of striatal neuronal dysfunction as measured with [11C]-raclopride PET (Pavese et al., 2006). Similar findings were also documented in pre-HD, where the degree of striatal microglial activation also correlated with a higher likelihood of developing HD in 5 years (Tai et al., 2007). The findings suggested that microglial activation is an early process in HD pathogenesis. The close spatial and temporal relationships between microglial activation and neuronal dysfunction in HD lend further support to the pathogenic link between the two processes (Tai et al., 2007). Cerebral activation studies using H215O PET to measure regional cerebral blood flow will be briefly reviewed here. Motor tasks such as paced sequential finger opposition movements or paced joystick movements in freely chosen directions in HD patients have revealed impaired activation of the striatum and its frontal motor projection areas, with compensatory hyperactivity of insular and parietal areas (Bartenstein et al., 1997; Weeks et al., 1997a). When vibrotactile stimulation was applied to the index fingers to investigate integrity of sensory processing in HD, one study demonstrated reduced activation of contralateral sensory cortex, parietal areas 39 and 40, basal ganglia and bilateral prefrontal cortex, with enhanced activation of ipsilateral sensory cortical areas. This suggests that central gating of sensory impulses is altered with compensatory recruitment of associative sensory areas in the presence of basal ganglia dysfunction (Boecker et al., 1999). Motor sequence learning is also impaired in pre-HD individuals, who showed abnormally increased activation responses in the left mediodorsal thalamus and orbitofrontal cortex during motor tasks, possibly to compensate for caudate degeneration (Feigin et al., 2006).

NEUROACANTHOCYTOSIS Neuroacanthocytosis syndromes refer to a group of rare genetically defined neurodegenerative disorders where underlying erythrocyte membrane abnormalities result in acanthocytosis. Within this group of disorders, they are subdivided into the “core” disorders, which include autosomal-recessive chorea-acanthocytosis (due to VPS13A mutation which encodes Chorein), X-linked McLeod syndrome (XK gene mutation), Huntington’s disease-like 2 (HDL2), and pantothenate kinaseassociated neurodegeneration (or PKAN, which will be discussed in the section on neurodegeneration with brain iron accumulation (NBIA), below). Acanthocytosis is only occasionally seen in the latter two conditions. The second group of neuroacanthocytosis disorders are

GENETIC AND DEGENERATIVE DISORDERS characterized by lipoprotein abnormalities and they include abetalipoproteinemia and hypobetalipoproteinemia (Walker et al., 2011). The “core” group of disorders often manifest clinically with choreic movement disorders, cognitive and psychiatric impairments, hence representing phenocopies of HD. There are further clinical features that help to distinguish these conditions. For example, patients with choreoacanthocytosis tend to develop marked orofaciolingual dystonia which can lead to involuntary tongue/lip biting, but this is an unusual finding in patients with McLeod syndrome. Patients with choreoacanthocytosis and McLeod syndrome both showed marked striatal atrophy on MRI and striatal hypometabolism on FDG PET (Jung et al., 2001), though, unlike HD, the cortical volume is usually preserved (Henkel et al., 2006). Significant periventricular and corpus callosum white-matter signal abnormalities have also been reported in cases of McLeod syndrome (Nicholl et al., 2004). The MRI findings of HDL-2 showed striatal and cortical atrophy and are indistinguishable from HD (Margolis, 1993).

WILSON’S DISEASE Wilson’s disease (WD) is an autosomal-recessive disorder of copper metabolism, caused by mutations in the copper-transporting ATPase ATP7B (Bull et al., 1993). The impaired biliary copper excretion leads to the accumulation of copper in a number of organs, particularly brain, liver, and cornea. Neurologic manifestations of WD include dysarthria, dystonia, ataxia, chorea, parkinsonism, and myoclonus (Lorincz, 2010).

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There are a number of characteristic MRI changes in WD. In an MRI study of 100 WD patients, signal abnormalities in the putamen, caudate, thalamus, and midbrain were found in 49–72% of patients (Fig. 25.2A). Most patients also exhibited widespread atrophy involving the cerebrum, cerebellum, and brainstem (Sinha et al., 2006). Globus pallidus hypointensity on T2-weighted MRI brain was seen in 34% of patients. The midbrain “face of the giant panda” sign on T2-weighted MRI (Fig. 25.2B) is caused by hyperintensity in the tegmentum and hypointensity in the superior colliculi, while sparing the red nuclei and lateral portion of the pars reticulata of substantia nigra (Shivakumar and Thomas, 2009). It is present in 12–16% of WD patients and is considered pathognomonic for the condition. Another characteristic T2-weighted MRI finding in the pontine tegmentum of WD patients, often termed “face of the panda cub” sign (Fig. 25.2C), is caused by relative hypointensity of the medial longitudinal fasciculi and central tegmental tract, and hyperintensity of the aqueductal opening to fourth ventricle (Jacobs et al., 2003). In a study comparing the MRI findings of 56 WD cases versus 44 other early-onset extrapyramidal disorders, tectal-plate hyperintensity (76%), central pontine myelinolysis-like abnormalities (62.5%), concurrent signal changes in basal ganglia, brainstem, and thalamus (55.3%) and “face of the giant panda” sign (14.3%) were seen only in WD but not in other movement disorders (Prashanth et al., 2010), hence are helpful to establish radiologic diagnosis of WD. FDG PET has shown severe reduction in regional glucose metabolism in the striatum and cortex of WD

Fig. 25.2. Magnetic resonance imaging (MRI) findings in Wilson’s disease. T2-weighted MRI findings of a patient’s with Wilson’s disease, showing (A) symmetric hyperintensity of the putamen and thalami; (B) the midbrain “face of the giant panda” sign is caused by hyperintensity in the tegmentum and hypointensity in the superior colliculi, while sparing the red nuclei and lateral portion of the pars reticulata of substantia nigra. (C) The pontine tegmentum “face of the panda cub” sign is caused by relative hypointensity of the medial longitudinal fasciculi and central tegmental tract, and hyperintensity of the aqueductal opening to fourth ventricle. (Reproduced from Shivakumar and Thomas, 2009.) With permission from Wolters Kluwer Publishers.

512 N. PAVESE AND Y.F. TAI patients with neurologic symptoms, with the striatum two components of the etiologic axis are, in fact, considbeing particularly affected. WD patients without neuroered separately. Idiopathic and acquired forms of dystologic symptoms had normal FDG PET (Hermann, 2014). nia include all forms of dystonia due to unknown or 123 I-b-CIT, which binds to presynaptic dopamine transknown specific causes, respectively, whereas inherited porters, and 123I-IBZM (benzamide), which binds to dopadystonia includes all dystonia forms of proven genetic mine D2 receptors on single-photon emission computed origin. The DYT classification is still used for designattomography (SPECT), have detected both pre- and posting subtypes of inherited dystonia but not as a classificasynaptic disruption of the nigrostriatal dopaminergic tion system. There are currently 25 locus symbols with a pathways in WD patients with neurologic symptoms. Simnumeric DYT designation; some of them, however, still ilar to their FDG PET findings, the pre- and postsynaptic need independent confirmation (recently reviewed by dopaminergic SPECT binding in WD patients without Klein (2014)). neurologic symptoms was normal (Barthel et al., 2003). Conventional structural MRI sequences can be used to The reduced striatal D2 binding and glucose metaboinvestigate anatomic causes of dystonia. A wide range of lism and abnormal MRI signals in Wilson’s disease have degenerative and destructive disorders of the nervous sysbeen shown to improve after successful treatment with tem, including tumors, arteriovenous malformations, copper chelation therapy (Roh et al., 1994; Schlaug head trauma, cerebral anoxia, infarction, and hemoret al., 1994; Schwarz et al., 1994) and liver transplantation rhage, can lead to the development of dystonia. Acquired (Wu et al., 2000). brain lesions that cause dystonia typically affect the putamen, thalamus, and/or globus pallidus, resulting in hemidystonia in the contralateral side of the body (Marsden DYSTONIA et al., 1985; Munchau et al., 2000). The development of The term dystonia refers to a group of movement disordystonia after basal ganglia lesions, however, is not preders that vary in symptoms, causes, and progression but dictable, as most individuals with such lesions do not are characterized by the presence of dystonic movedevelop dystonia. In a large neuroimaging study, dystonia ments. The definition of dystonia has recently been was observed in only about a third of patients with basal revised by an international panel of dystonia experts. ganglia lesions (Bhatia and Marsden, 1994). Consensus was reached that dystonia is a movement In patients with combined dystonia, conventional disorder characterized by sustained or intermittent musstructural MRI can often show abnormalities related cle contractions causing abnormal, often repetitive, to the coexisting neurologic or systemic condition. movements, postures, or both. Dystonic movements WD, a disorder where dystonia is combined with other are typically patterned, twisting, and may be tremulous. neurologic and psychiatric symptoms and liver disease, Dystonia is often initiated or worsened by voluntary and dystonia with NBIA are described elsewhere in this action and associated with overflow muscle activation chapter. (Albanese et al., 2013). In patients with idiopathic or inherited isolated The consensus committee also updated the classificadystonia (“primary dystonia” in previous classifications), tion system for dystonia, basing it upon clinical characterconventional MRI sequences, in line with postmortem istics (axis I) and etiology (axis II). The clinical studies, have shown no obvious degenerative changes characteristics (axis I) include age at onset, body distribuor structural abnormalities. However, recent neuroimagtion, temporal pattern, associated features, and coexising studies in these patients using more advanced MRI tence of other neurologic or systemic manifestations. In techniques, including voxel-based morphometry (VBM) axis I, the term isolated or combined refers to the clinical for gray-matter assessment, DTI for white-matter assessphenomenology, with no implications about the underlyment and structural connectivity (tractography), have ing etiology. “Isolated dystonia” encompasses all condiconsistently revealed subtle abnormalities in several brain tions where dystonia is the only motor feature, with the regions, including the basal ganglia, thalamus, brainstem, exception of tremor, whereas “combined dystonia” is cerebellum, and cerebral cortex. However, it remains to be used to classify forms of dystonia occurring in combinaestablished whether the reported brain structural changes tion with other movement disorders, previously classified are primary or secondary to “primary” focal dystonia. under “dystonia plus” or “heredodegenerative.” More longitudinal studies in larger cohorts with homogeThe etiologic characteristics (axis II) are the presence neous participants are required. or absence of identifiable anatomic changes and pattern VBM has been used to assess structural changes in of inheritance. It is suggested that the term “primary” gray matter in patients with several forms of focal dysshould no longer be used to indicate genetic or idiopathic tonia, including cervical dystonia, blepharospasm, and cases where dystonia is isolated and there is no consistent focal hand dystonia. Patients with generalized dystonia pathologic change. In the proposed classification, the have been less investigated.

GENETIC AND DEGENERATIVE DISORDERS 513 In general, VBM abnormalities have been found in reduced cell number and decreased number of axons the basal ganglia, particularly in the putamen, the thalaconnecting cortical regions of the two hemispheres mus, the sensorimotor cortex, and the cerebellum (Zoons (Colosimo et al., 2005; Fabbrini et al., 2008). et al., 2011). However, there is a large variability in the Disrupted thalamic-prefrontal pathways and altered different studies, which may be due to differences in connection between pallidal output and brainstem have the imaging sequences and/or population studied. also been reported in patients with cervical dystonia A large meta-analysis has recently been performed to (Bonilha et al., 2009; Blood et al., 2012). Patients with assess consistency of gray-matter changes in patients blepharospasm had similar FA and MD values as the with “primary” focal dystonia (Zheng et al., 2012). healthy volunteers (Fabbrini et al., 2008; Horovitz The final analysis included 11 comparisons between et al., 2012). However, corticobulbar tract volume and “primary” focal dystonia patients and healthy subjects peak tract connectivity appeared to be decreased in (199 patients and 247 healthy subjects in total). Graypatients compared with controls (Horovitz et al., matter volume was found to be greater in the caudate 2012). Patients with writer’s cramp had shown increased and in sensorimotor areas including postcentral area FA values bilaterally in the white matter of the posterior (BA2, 3, 40) and primary motor cortex, and smaller in limb of the internal capsule and adjacent structure, the thalamus and putamen. These findings provide eviinvolving fiber tracts connecting the primary sensorimodence that structures in the sensorimotor network are tor areas with subcortical structures (Delmaire abnormal in patients with “primary” focal dystonia. It et al., 2009). should be noticed that the authors report that each signifInterestingly, botulinum toxin treatment seems to icant cluster in the analysis was only contributed by two normalize some of the white-matter abnormalities seen to four studies, suggesting that the results had high senin dystonic patients. Blood and colleagues (2006) found sitivity but low robustness. that 4 patients with cervical dystonia and 2 with hand dysOne study has assessed VBM changes in 9 patients tonia exhibited an abnormal hemispheric asymmetry in a with “primary” generalized dystonia, 11 patients with focal region between the pallidum and the thalamus. This “primary” cervical dystonia, 11 patients with “primary” asymmetry disappeared after botulinum toxin treatfocal hand dystonia, and 31 age- and gender-matched ment, suggesting that it could have been an expression controls. Interestingly, all three dystonia subtypes of activity-dependent white-matter plasticity in these showed similar, although not identical, pattern of patients. gray-matter changes compared to healthy controls, sugFA abnormalities in the subgyral white matter of the gesting that different subtypes of “primary” dystonia sensorimotor cortex have been reported in both manimay share common pathophysiologic features (Egger festing and nonmanifesting DYT1 carriers compared et al., 2007). to controls (Carbon et al., 2004) (Fig. 25.3). Additional White matter in patients with “primary” dystonia also FA reductions were found in the dorsal brainstem in shows some abnormalities. DTI studies have shown a the vicinity of the pedunculopontine nucleus and cerenumber of abnormalities in the fiber tracks connecting bellar outflow pathways as a characteristic of manifestbasal ganglia, cortex, and cerebellum. Compared to coning subjects (Carbon et al., 2008). A more recent DTI trols, patients with cervical dystonia have been reported study with diffusion tractography has revealed reduced to have higher fractional anisotropy (FA) values in both integrity of cerebellothalamocortical fiber tracts, likely putaminal nuclei and lower FA values in the genu and in developmental in origin, in both manifesting (7 DYT1 the body of the corpus callosum. The same patients also and 5 DYT6) and clinically nonmanifesting (4 DYT1 had lower mean diffusivity (MD) values in the left paland 4 DYT6) dystonia mutation carriers (Argyelan lidum, left putamen, and caudate, bilaterally (Colosimo et al., 2009). In these subjects, reductions in cerebellothaet al., 2005). Another study found that FA in patients lamic connectivity correlated with increased motor actiwith cervical dystonia was significantly reduced in corvation responses, consistent with loss of inhibition at the pus callosum (body) and bilateral putamen, whereas cortical level. Nonmanifesting mutation carriers, howMD was reduced in the right caudate, left putamen, ever, were characterized by an additional area of fiber bilateral prefrontal cortex, and left supplementary area tract disruption situated distally along the thalamocorti(Fabbrini et al., 2008). The authors suggest that increased cal segment of the pathway, in tandem with the proximal FA and decreased MD values in these patients could cerebellar outflow abnormality. In individual gene carreflect increased cellularity, increased fiber coherence, riers, clinical penetrance was determined by the differand more ordered tissue containing a large number of ence in connectivity measured at these two sites. The similarly aligned neurons in the basal ganglia, whereas authors proposed this tandem-lesion model as a possible decreased FA in the prefrontal cortical areas, suppleexplanation for the differences in clinical expression in mentary motor area, and corpus callosum could reflect carriers of dystonia mutation (Argyelan et al., 2009).

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Fig. 25.3. Left: Statistical parametric map analysis showing declines in fractional anisotropy (FA) in DYT1 gene carriers compared to age-matched controls superimposed on the mean group FA map. The color scale represents T-scores at a threshold of 2.9, p less than 0.005. Right: Bar chart showing significant reduction in FA values in the subgyral white matter of the primary sensorimotor cortex (SMC) of DYT1 gene carriers (filled symbols) relative to controls (open symbols). Bars indicate standard errors. (Reproduced from Carbon et al., 2004.) With permission from John Wiley and Sons.

Briefly, reduced connectivity in the proximal segment of cerebellothalamocortical fiber tracts, present in all carriers, would result in symptom manifestation due to reduced cortical inhibition, unless this transmission was disrupted by a second lesion in the distal segment of the tract, as seen in nonmanifesting carriers. This model could also explain the variability in phenotype and clinical severity in acquired dystonias. However, this has not been investigated yet. Studies of regional cerebral glucose metabolism with FDG PET and cerebral blood flow with H215O PET, and, more recently, fMRI have revealed widespread changes in cortical and subcortical activity in patients with different types of dystonia both at rest and on action (van Eimeren and Siebner, 2006; Neychev et al., 2011). Using FDG PET and network analysis, Eidelberg and colleagues (1995) reported that idiopathic torsion dystonia was characterized by relative metabolic overactivity of the lentiform nucleus and premotor cortices (Fig. 25.4), suggesting that dystonia may arise through excessive activity of the direct putaminopallidal inhibitory pathway. An abnormal pattern of regional glucose utilization, characterized by hypermetabolism of the basal ganglia, cerebellum, and supplementary motor area, has been reported in affected and unaffected DYT1 carriers (Eidelberg et al., 1998). This distinct metabolic topography has also been identified in affected and unaffected DYT6 carriers (Trost et al., 2002), suggesting that the reported metabolic changes are not genotype-specific and overactivity of these regions is an important trait feature of dystonia. Activation studies with H215O PET and fMRI in both idiopathic and acquired dystonia have demonstrated abnormal activation patterns during motor tasks and on exposure to tactile stimuli (van Eimeren and

Siebner, 2006; Neychev et al., 2011; Zoons et al., 2011). The most common activation finding reported in these studies is the overactivity of premotor and parietal cortices during performances of motor tasks, particularly those inducing dystonia, which has been interpreted as evidence of cortical disinhibition. Abnormalities in movement imagination have also been reported. Compared with healthy controls, patients with writer’s cramp showed deficient activation of the left primary sensorimotor cortex, mesial and left dorsal premotor cortex, bilateral putamen, and bilateral thalamus during motor imagery (Castrop et al., 2012). Several lines of evidence suggest that abnormalities of dopaminergic pathways contribute to the pathophysiology of dystonia. A cohort of patients with idiopathic dystonia showed reduced dopamine D2 binding in the striatum, compatible with underfunctioning of the indirect basal ganglia pathway (Carbon et al., 2009). It has recently been suggested that a defect in D3, rather than D2, receptor expression may be associated with primary focal dystonia (Karimi et al., 2011). Disturbances in taskinduced endogenous dopamine release as measured by changes in [11C]-raclopride binding have been reported in patients with writer’s cramp, suggesting abnormal dopaminergic neurotransmission in these patients (Berman et al., 2013). Several studies have assessed striatal function in patients with dopa-responsive dystonia, which is linked to a mutation in the DYT5 gene coding for GTP cyclohydrolase 1 (Calne et al., 1997; van Eimeren and Siebner, 2006). [18F]-dopa uptake, a marker of dopamine synthesis and storage, in the striatum is generally normal in these patients, while striatal [11C]-dihydrotetrabenazine binding can be mildly increased, possibly reflecting upregulation of VMAT2 expression. Increased dopamine D2

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Fig. 25.4. Topographic profile of [18F]-fluorodeoxyglucose changes associated with asymmetric idiopathic torsion dystonia overlaid on a normal magnetic resonance imaging scan. Relative hypermetabolism of the contralateral lentiform nucleus (coronal) is associated with covariate metabolic increases in the lateral frontal cortex (transverse) and paracentral regions (sagittal), corresponding respectively to the lateral premotor cortex and supplementary motor areas. (Reproduced from Eidelberg et al., 1995.) With permission from Oxford University Press.

receptor availability has also been reported in these patients (Rinne et al., 2004). Finally, FDG PET has shown a specific pattern of regional metabolic covariation consisting of increases in the dorsal midbrain, cerebellum, and supplementary motor area and reductions in the motor and lateral premotor cortex and basal ganglia (Asanuma et al., 2005). Gamma-aminobutyric acid (GABA) transmission also appears to be impaired in primary dystonia, as indicated by reduced cortical [11C]flumazenil in carriers of DYT1 mutation and sporadic cases (Garibotto et al., 2011). Taken together, these studies support the view that dystonia is associated with reduced inhibitory basal ganglia output and abnormalities in cortical processing. Failure of cortical inhibition, abnormal sensorimotor integration, and maladaptive plasticity seem to be the key contributors to the pathogenesis of this movement disorder.

NEURODEGENERATION WITH BRAIN IRON ACCUMULATION NBIA is a group of disorders characterized by accumulation of iron in several brain regions, but more

consistently in the basal ganglia. Other pathologic findings include widespread alpha-synuclein-positive Lewy pathology, accumulation of hyperphosphorylated tau protein in neuronal cell bodies and cellular projections, axonal swelling, and cerebral and cerebellar atrophy, depending on NBIA subtype (Schneider et al., 2012). Clinically, these conditions manifest with a combination of movement disorders, including dystonia, parkinsonism, choreoathetosis, and spasticity. Oculomotor abnormalities and a spectrum of visual problems, including progressive blindness, due to retinal degeneration and optic atrophy, can also occur. Cognitive decline may occur in some types of NBIA. Onset of NBIA ranges from infancy to adulthood. Progression can be rapid or slow with long periods of stability. The factors that influence disease severity and the rate of progression are still unknown. Most NBIA types are genetically determined. To date, mutations in nine genes have been associated with NBIA (Arber et al., 2015). These include pantothenate kinase 2 (PANK2), phospholipase A2 group 6 (PLA2G6), fatty acid hydroxylase 2 (FA2H), coenzyme a synthase (COASY), ceruloplasmin (Cp), ferritin light chain

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(FTL), C19orf12, WDR45, and DCAF17 (C2orf37). Some patients, however, particularly those with onset of neurologic symptoms in mid to late life, have sporadic disorders of uncertain origin. Structural imaging with conventional MRI sequences and with more recently developed iron-sensitive MRI sequences, such as gradient recall echo (GRE) and susceptibility-weighted imaging (SWI), have a valuable role in diagnosing NBIA (McNeill et al., 2008; Amaral et al., 2015). In fact, excessive iron deposition in the brain is clearly detectable on MRI images, appearing as isointense areas on T1-weighted sequences and hypointense areas on GRE, SWI, and T2-weighted sequences. Additionally, in combination with clinical findings, specific MRI findings can help to distinguish the different subtypes of NBIA, although the presence of the specific mutation is required for the final diagnosis. The imaging findings in the most common NBIA subtypes will be summarized below.

Pantothenic kinase-associated neurodegeneration PKAN, previously known as Hallervorden–Spatz disease – terminology now abandoned as both physicians were involved in the Nazi euthanasia program – is an autosomal-recessive disease caused by mutations in the PANK2 gene on chromosome 20p13. PKAN is the most common form of NBIA, making up 35–50% of the NBIA population. The PANK2 gene encodes

pantothenate kinase, a key enzyme in the biosynthesis of coenzyme A from vitamin B5. PKAN can manifest itself in the classic form, characterized by early onset and more rapid progression of symptoms; or in the atypical form with late onset and slow disease over several years, and sometimes decades. Some people, however, have characteristics that place them between these two categories. Children with PKAN typically manifest with gait or postural problems around age 3 and later develop progressive dystonia, dysarthria, rigidity, and pyramidal symptoms. Visual symptoms and retinal degeneration are common in these patients. Individuals with later-onset PKAN generally present with speech difficulty and neurocognitive symptoms and less severe motor symptoms. The most common MRI finding in PKAN patients is bilateral area of hypointensity localized in the globi pallidi containing a central area of hyperintensity on GRE, SWI, and T2-weighted images. While the marked low signal intensity of the globi pallidi is due to the paramagnetic effects of excessive iron accumulation, the central high signal is attributed to neuronal loss, gliosis, and cavitation of the neuropil (Guillerman, 2000). These symmetric pallidal hypointensities with the central area of increased MRI signal create a peculiar visual effect on axial and coronal MRI images that recalls the appearance of a pair of eyes. This is known as “the eye of the tiger” sign (Sethi et al., 1988) and has been reported to have a sensitivity for PKAN close to 100% (Hayflick et al., 2003) (Figs 25.5 and 25.6A). However, this

Fig. 25.5. T2-weighted magnetic resonance imaging image (top) and 123ioflupane single-photon emission computed tomography images (bottom) of a 50-year-old woman with PANK2 mutation showing the “the eye of the tiger” sign and reduced striatal 123ioflupane binding, respectively. Clinically, the patient presented with oromandibular dystonia and mild parkinsonism.

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Fig. 25.6. (A) T2* magnetic resonance imaging (MRI) scan from a 17-year-old boy with pantothenate kinase-associated neurodegeneration. Note bilateral “eye of the tiger” sign in globus pallidus. (B) T2* MRI scan from a 9-year-old girl with infantile neuroaxonal dystrophy. Note bilateral hypointensity of globus pallidus. (C) T2* MRI scan from a 69-year-old woman with neuroferritinopathy. Note hypointensity of globus pallidus, putamen, caudate, and thalamus. (D) T2* MRI scan from a 55-year-old man with aceruloplasminemia. Note hypointensity of globus pallidus, putamen, caudate, and thalamus. (Reproduced from McNeill et al., 2008.) With permission from Wolters Kluwer Publishers.

characteristic MRI finding does not seem to be pathognomonic of PANK2 mutation and it has been described in patients with other NBIA (neuroferritinopathy) (McNeill et al., 2008), as well as in patients with multiple system atrophy (Strecker et al., 2007) and cortical basal degeneration (Molinuevo et al., 1999). Recently, the “eye of the tiger” sign has also been reported as an incidental finding in a healthy research control subject and negative genetic testing for PKAN2 and FTL gene mutation (van den Bogaard et al., 2014). The “eye of the tiger” sign can be found in premanifest gene carriers, suggesting that significant brain iron may accumulate before clinical symptoms appear (Hayflick et al., 2001). On the other hand, the sign may be not fully visible in later stages of the disease, but without necessarily indicating a devastating course.

Delgado and colleagues (2012) have recently reported 6 patients with a genetically proven PANK2 mutation with absence of the complete “eye of the tiger” on MRI images. This might be explained, at least in some cases, by an excessive accumulation of iron deposits obscuring the central hyperintensity. Another abnormality commonly observed on iron-sensitive sequences in these patients is T2 hypointensity in the substantia nigra (McNeill et al., 2008). There is also variable atrophy in the affected structures. Recent MRI studies have assessed gray- and whitematter changes in PKAN patients. VBM has shown that, compared to controls, children with PKAN have increased gray-matter density in the putamen and caudate nucleus, whereas affected adults have increased gray-matter density in the ventral part

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of the anterior cingulate cortex. Multiple regression analyses with dystonia score and age as predictors showed gray-matter reduction in several cortical and subcortical regions. The authors suggest that gray-matter increases represent secondary phenomena compensating the increased activity of the motor system due to a reduced inhibitory output of the globus pallidus. Gray-matter reduction of cortical midline structures combined with increasing age, on the other hand, might contribute to the progression of dystonic symptoms due to loss of compensatory control (Rodriguez-Raecke et al., 2014). A recent study in patients with dystonia due to PKAN has shown reductions of FA values in the periventricular substance surrounding the third ventricle, the medial part of putamen bilaterally, the frontal white matter, including the anterior limbs of the internal capsules, the corpus callosum, the cerebellar white matter and dorsal parts of pons and medulla, suggesting the occurrence of both gray-matter changes and microstructural white-matter alterations in these patients (Stoeter et al., 2015). At variance with this, Delgado and colleagues (2012) found that, with the exception of the frontobasal tracts, white matter was well preserved. Dopaminergic function of the basal ganglia, including dopamine D2 receptor, as measured with PET and SPECT, is generally reported to be normal (Hermann et al., 2000). However, a case of a patient with confirmed single mutation in the PANK2 gene, MRI evidence of “eye of the tiger” sign and reduced striatal 123ioflupane uptake has been reported (Kang and Minoshima, 2014) (Fig. 25.5), suggesting heterogeneity in these patients. Interestingly, in one study, PET measurement of cerebral blood flow using [15O]-labeled water found significant hypoperfusion of the head of the right caudate nucleus, pons, and cerebellar vermis but no pallidal abnormalities (Castelnau et al., 2001).

PLA2G6-associated neurodegeneration PLA2G6-associated neurodegeneration (PLAN) is an autosomal-recessive disease named after the responsible gene, PLA2G6, located on chromosome 22q13. This gene encodes the calcium-independent phospholipase A2 (iPLA2) beta, which contributes to membrane homeostasis and energy metabolism (Murakami et al., 2011). The clinical presentation of PLAN is age-dependent and three different subtypes have been identified: (1) infantile neuroaxonal dystrophy (INAD) with typical onset between 6 months and 3 years of age and rapid progression; (2) atypical neuroaxonal dystrophy (ANAD), which starts a few years later; and (3) an adult form of dystonia-parkinsonism in which onset occurs in the second to third decade.

The first sign in children with classic INAD is developmental delay, followed by progressive occurrence of hypotonia, ataxia, pyramidal symptoms, optic atrophy, sensorimotor axonal neuropathy, and seizures. ANAD typically starts during early childhood or, less frequently, during the second decade. It has a slower progression and a different variety of symptoms than INAD, including dystonia-parkinsonism, pyramidal signs, and cognitive and psychiatric features. Ataxia and sensory abnormalities are absent in ANAD. Patients with PLA2G6-related dystonia-parkinsonism usually present with dystonia, parkinsonism, abnormal eye movements, pyramidal signs, and marked neuropsychiatric changes. On iron-sensitive MRI sequences, excessive iron deposition in the globi pallidi is seen in up 50% of PLAN cases but the central T2 hyperintensity observed in PKAN is absent in these patients (Fig. 25.6B) (Gregory et al., 2008; McNeill et al., 2008). Iron deposition in the substantia nigra and the subthalamic nucleus can also been seen in INAD patients but is not common in ANAD patients (Schneider et al., 2012). However, the most common MRI finding in PLAN patients is the severe cerebellar atrophy affecting both cerebellar hemispheres and the vermis (Gregory et al., 2008). This is an early finding in INAD patients and may precede iron deposition, but occurs in later stages in ANAD patients. The presence of severe cerebellar atrophy in combination with the clinical phenotype described above is strongly suggestive of PLA2G6 mutation. Other characteristic MRI findings of PLAN patients include optic atrophy and reduced optic chiasm volume, thinning of the posterior part of the corpus callosum with a vertical orientation, and the occurrence of T2 hyperintensities in cerebellum and putamen (Gregory et al., 2008; Kurian et al., 2008). Kim and colleagues (2015) have recently reported MRI and PET findings in siblings of a Korean PLAN family showing intrafamilial phenotypic variability. Two brothers, one with adult-onset dystoniaparkinsonism and one with childhood-onset ANAD, were assessed with MRI and [18F]-FP-CIT PET, a dopamine transporter marker. The patient with adult-onset dystonia-parkinsonism showed markedly reduced [18F]FP-CIT uptake in the whole putamen, but fluidattenuated inversion recovery and GRE MRI studies revealed mild hypointensities in the substantia nigra and putamen and severe hypointensities in the globus pallidus. Conversely, the patient with childhood-onset ANAD had severe hypointensities in the substantia nigra and the pallidum, but the [18F]-FP-CIT PET was normal. These findings suggest that dopaminergic neuronal degeneration in PLAN may occur independently from iron accumulation.

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Other NBIA subtypes Less common NBIA subtypes include aceruloplasminemia (CP), neuroferritinopathy (FTL), beta-propeller protein-associated neurodegeneration (WDR45), Woodhouse–Sakati syndrome (DCAF17), CoA synthase protein-associated neurodegeneration (COASY), fatty acid hydroxylase-associated neurodegeneration (FA2H), and mitochondrial membrane protein-associated neurodegeneration (C19orf12). In most patients with these less common NBIA subtypes, the globus pallidus is uniformly hypointense on iron-sensitive MRI sequences without the central T2 hyperintensity characteristic of the “eye of the tiger” sign. Iron deposition in the substantia nigra, red nucleus, and dentate nucleus with cerebellar atrophy is also common in patients with these conditions. Additionally, specific MRI findings have been reported in these subtypes of NBIA (McNeill et al., 2008; Amaral et al., 2015). McNeill and colleagues (2008) reported a consistent involvement of the dentate nuclei, globus pallidus, and putamen in neuroferritinopathy (Fig. 25.6C). Fifty-two percent of patients had confluent areas of hyperintensity, probably due to cavitation, involving globus pallidus and putamen, and a subset of patients had similar lesions in caudate nuclei and thalami. Conversely, patients with aceruloplasminemia have a more uniform involvement of all basal ganglia and the thalami but without cavitation (Fig. 25.6D). Patients with beta-propeller protein-associated neurodegeneration show a characteristic bilateral and symmetric T1 hyperintensity in the substantia nigra, probably due to neuromelanin, with a band of central T1 hypointensity. In these patients, the earliest and most prominent iron accumulation occurs in the substantia nigra rather than globus pallidus. Patients with fatty acid hydroxylaseassociated neurodegeneration show moderate to severe white-matter abnormalities, prominent cerebellum and brainstem atrophy, and thinning of the corpus callosum (Kruer et al., 2010; Tonelli et al., 2012). Finally, patients with mitochondrial membrane protein-associated neurodegeneration have a characteristic T2 hyperintensity involving the medial medullary lamina between globus pallidus interna and externa and mild diffuse brain atrophy. In conclusion, different NBIA subtypes have specific MRI findings that, along with the clinical phenotype, can help in the differential diagnosis of these conditions and facilitate molecular diagnosis.

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